Non-sedating dexmedetomidine treatment regimens

NON-SEDATING DEXMEDETOMIDINE TREATMENT REGIMENS

CROSS REFERENCE TO RELATED APPLICATIONS:

[01] This application claims the benefit of priority under 35 U.S.C. 119 (e) to U.S. Provisional Patent Application No. 62/876,371 on July 19, 2019; U.S. Provisional Patent Application No. 62/877,056 on July 22, 2019; U.S. Provisional Patent Application No, 62/963,769 on January 21, 2020; U.S. Provisional Patent Application No. 62/970,411 on February 5, 2020; U.S. Provisional Patent Application No 62/977,554 on February 17, 2020; U.S. Provisional Patent Application No 63/037,759 on June 11, 2020. U.S. Provisional Patent Application No. 62/943,022 on December 3, 2019; the disclosures of each of which are incorporated herein by reference in their entireties.

FIELD:

[02] Disclosed herein are methods of treating a human subject having a condition (e.g. agitation) which can be improved using an alpha-2 adrenergic receptor agonist. The methods comprise administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a suitable dose, and via an appropriate route of administration, to achieve a plasma concentration profile that provides a rapid improvement to the subject’s condition without also inducing significant sedation. The administration regimens are also selected to provide maximum therapeutic benefit to the subject, without incurring any significant side effects, such as undesirable cardiovascular events. Suitable routes of administration include sublingual, buccal, oral, mtranasal and parenteral. The disclosed methods are particularly suitable for the treatment of agitation or signs of agitation, especially when associated with neurodegenerative and/or neuropsychiatric diseases such as schizophrenia, a bipolar illness such as bipolar disorder or mania, dementia, depression and delirium.

BACKGROUND:

[03] On December 17, 1999, the U.S. Food and Drug Administration approved a dexmedetomidine product, PRECEDEX®, formulated as an intravenous solution for continuous infusion, and indicated as a sedative agent for initially intubated and mechanically ventilated patients during treatment in an intensive care setting. PRECEDEX® was later approved as a sedative agent for non-intubated patients prior to and/or during surgical and other procedures.

[04] Dexmedetomidine has also been administered intravenously and via other routes to treat a range of conditions, often peri- or post-surgery, including the treatment of pain, anxiety, delirium, withdrawal symptoms, sleep disorders and agitation. However, administration of dexmedetomidine in an appropriate dosage form to provide effective, rapid, relief for the subject without also causing significant sedation is a challenging task. The utilization of dexmedetomidine has also been limited in clinical practice due to its common side effects, such as hypotension and bradycardia. For example, significant cardiovascular side-effects have occurred at therapeutic doses following administration of dexmedetomidine hydrochloride via a sublingual spray or tablets, or intravenously. Thus, a continuing, unmet need exists for an effective dexmedetomidine product which does not cause significant sedation, and desirably is effective without also producing significant adverse effects, such as cardiovascular events. The unmet need is particularly acute for non-addictive medicines that can effectively treat agitation or signs of agitation without also producing the aforementioned adverse effects and sedation.

[05] The inventors of the present application have surprisingly found that relatively high doses of dexmedetomidine hydrochloride can be well-tolerated by human subjects without inducing accompanying significant sedation, when administered via particular treatment regimens. For example, a dose of at least 180 pg of dexmedetomidine hydrochloride, administered sublingually, is shown herein, according to the present disclosure, to be effective to treat agitation without inducing significant sedation, while being safe and well tolerated. Surprisingly, doses of 120pgand 180 pg of dexmedetomidine hydrochloride, administered sublingually, such as via a film, have also been found to produce pharmacokinetic profiles that are superior to PRECEDEX®, leading to fewer cardiovascular adverse events. Further, the inventors have found that subjects respond well when dexmedetomidine hydrochloride is administered at doses of at least 180 pg, and show a significant improvement in agitation as early as 45 minutes following administration, with the calming effect maintained for a prolonged period of time, e.g. up to at least 24 hours.

SUMMARY:

[06] In some embodiments, the present disclosure provides methods of treating agitation or signs of agitation m a human subject with schizophrenia or bipolar disorder (e.g. bipolar I disorder), without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, of about 3800 ng*h/L.

[07] In some embodiments, the present disclosure provides methods of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, of about 1800 ng*h L.

[08] In some embodiments, the present disclosure provides methods of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Teo, from about 600 ng*h/L to about 12600 ng*h/L.

[09] In some embodiments, the present disclosure provides methods of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 590 ng*h/L to about 8750 ng*h/L.

[010] The present disclosure also provides methods of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In another embodiment, an additional dose of 90 gg or 60 gg may be taken after 2 hours of first dose.

[0Γ1] The present disclosure further provides methods of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In another embodiment, an additional dose of 90 gg or 60 gg may be taken after 2 hours of first dose.

[012] In some embodiments, the present disclosure provides administering about 180 gg of dexmedetomidine hydrochloride sublingually as a single dose to a human subject, wherein said administration results in substantially lower systemic exposure levels of dexmedetomidine than administration of PRECEDEX® at its highest approved dose, as measured by comparative Cmax and AUC values.

[013] In some embodiments, the present disclosure provides administering about 120 pg of dexmedetomidine hydrochloride sublingually as a single dose to a human subject, wherein said administration results in substantially lower systemic exposure levels of dexmedetomidine than administration of PRECEDEX® at its highest approved dose, as measured by comparative Cmax and AUC values.

[014] The lower systemic exposure reduces the risk of reduced blood pressure and/or respiratory depression commonly encountered when administrating effective amounts of PRECEDEX®.

[015] In some embodiments, the administration of about 180 pg of dexmedetomidine hydrochloride sublingually as a single dose provides about a three-fold reduction in the Cmax value compared to administration of PRECEDEX®. In some embodiments, the aforementioned sublingual administration provides about a 7.5-fold reduction in the AUC value compared to administration of PRECEDEX®. In one particular embodiment, administering a sublingual film to a human subject comprising about 180 pg of dexmedetomidine hydrochloride provides about a three-fold reduction in the Cmax value and about a 7.5-fold reduction in the AUC value compared to administration of PRECEDEX®.

[016] In some embodiments, the present disclosure provides the administration of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally to a human subject, wherein said administration results in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of about 400 ng/L and AUC from TO to Teo of about 2900 ng*h/L.

[017] In some embodiments, the present disclosure provides the administration of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally to a human subject, wherein said administration results in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of about 220 ng 'L and AU C from TO to Too of about 1420 ng*h/L.

[018] In some embodiments, the present disclosure provides the administration of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally to a human subject, wherein said administration results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/'L and AUC from TO to Too of about 600 hr*ng/L about 9500 hr*ng/L.

[019] In some embodiments, the present disclosure provides the administration of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally to a human subject, wherein said administration results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/L and AUC from TO to Too of about 590 hr*ng/L about 4400 hr *ng/L.

[020] The present disclosure also provides methods of treating agitation or signs of agitation in a human subject with dementia, without also inducing significant sedation, comprising administering about 30 pg to about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides methods of treating agitation or signs of agitation m a human subject with dementia, without also inducing significant sedation, comprising administering 30 pg, 60 pg or 90 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose in a day. In some embodiments, the disclosure provides methods of treating agitation or signs of agitation in a human subject with dementia, without also inducing significant sedation, comprising oromucosally administering an unit dose containing about 30 pg to about 90 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to six times a day at an interval of at least 2 hours (e.g. 2, 4, 6, 8, or 12 hours) in the event of persistent or recurrent agitation. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride) is administered oromucosally (e,g. sublingually or buccally) as a film.

[021] The present disclosure provides a method of reducing a period of opioid withdrawal in a human subject in need thereof, comprising administering to said subject dexmedetomidine or a pharmaceutically acceptable salt thereof twice daily, wherein the period of withdrawal is up to 14 days. In some embodiments, the period of withdrawal may be 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days. In another embodiment, the human subject is an adult (at least 18 years old). In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered oromucosally (i.e. sublingually, buccally), orally, intranasal ly or parenterally. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt (e.g. hydrochloride) is administered sublingually as a film. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered at a dose range of about 30 gg to about 200 gg. In specific embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered at a unit dose containing about 30 gg, about 60 gg, about 90 gg, 120 gg or 180 gg twice daily. In some embodiments, the opioid may be selected from the group consisting of, but are not limited to fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil or pentazocine.

[022] The present disclosure also provides methods of managing or treating agitation in delirium in subjects, without also inducing significant sedation, comprising administering about 20 gg to about 240 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is hospitalized. In some embodiments, the subject is hospitalized in the intensive care unit. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered at a unit dose containing about 20 gg or 60 gg as a single dose. In some embodiments, each dosage unit may be administered one to four times at an appropriate dosing interval (for e.g. of at least 0.5 hours) to produce a desired effect; for example, 20 gg unit is administered four times at a dosing interval of 0.5 hours within 6 hours of first dose to produce the effect of a 80 gg dose or 60 gg unit is administered four times at a dosing interval of 0.5 hours within 6 hours of first dose to produce the effect of 240 gg dose. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e,g. sublingually or buccally) as a film.

[023] The present disclosure also provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 120 gg of dexmedetomidine (e.g. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof to a human patient. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (E.g. bipolar I disorder, and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g. bipolar I disorder).

[024] In some embodiments, the present disclosure provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 180 gg of dexmedetomidine (e.g. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof to a human patient. For example, in some embodiments, the patient has schizophrenia, m some embodiments, the patient has bipolar disorder (E.g. bipolar I disorder, and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g. bipolar I disorder).

[025] The present disclosure also provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 120 to about 180 pg of dexmedetomidine (e.g. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof to a human patient. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (E.g. bipolar I disorder, and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g. bipolar I disorder).

[026] The present disclosure also provides methods of treating or ameliorating opioid withdrawal symptoms, comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride) to a human patient in need thereof, wherein the patient is at least 18 years and wherein the period of withdrawal is up to 14 days. “Opioid withdrawal” refers to a variety of signs and complaints appearing with the abrupt removal of, or a rapid decrease in the regular dosage of opioids. Physical manifestations may include sweating, nausea, yawning, chills, diarrhea, papillary dilation, piloerection, tachycardia, increased blood pressure, hypersensitivity to pain, stomach cramps, and muscle cramps. Psychological manifestations of opioid withdrawal observed may include agitation, dysphoria, restlessness, irritability, anxiety, and depression. In some embodiments, the opioid withdrawal symptom is agitation. Onset often begins within 6-24 hours from last opioid use. In some embodiments, treating or ameliorating opioid withdrawal refers to the treatment or lessening of one or more of the aforementioned symptoms. The treating or ameliorating may be measured by a variety of well-known means m the art, including but not limited to, the Clinical Opiate Withdrawal Scale (COWS) and/or Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) score.

[027] The present disclosure also provides a pharmaceutical composition comprising from about 20 pg to about 240 pg dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride). In some embodiments, the dose of dexmedetomidine is about 120 pg. In some embodiments, the dose of dexmedetomidine is about 180 pg.

[028] The present disclosure also provides methods of achieving a >40 % reduction in agitation, within 2 hours of administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the PEC scale. In some embodiments, the agitation is reduced within about 20 minutes to about 1 hour; for example, within about 20 minutes, about 30 minutes, or about 40 minutes. In some embodiments, the reduction in agitation >40%, >50%, >60%, >70%, >80%, >90%, or >100%. In some embodiments, the reduction in agitation is maintained for greater than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 pg of dexmedetomidine. In some embodiments, the composition comprises about 180 pg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

[029] The present disclosure also provides a method of achieving a PEC score reduction in agitation for a sustained period of time in a subject with bipolar disorder or schizophrenia comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg wherein the PEC score reduction is about -8 to about -10 and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the PEC score reduction is about -8, about -9, or about -10.

[030] The present disclosure also provides a method of achieving an .ACES score improvement for a sustained period of time in a subject with bipolar disorder or schizophrenia comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg wherein the ACES score is improved to about 3 to about 4 and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the ACES score is about 4.

[031] The present disclosure also provides a method of achieving an CGI-I score improvement for a sustained period of time in a subject with bipolar disorder or schizophrenia comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg wherein the CGI-I score is improved to about 1 (very much improved) or about a 2 (much improved) and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the CGI-I score is about 1.

BRIEF DESCRIPTION OF THE DRAWINGS

[032] FIG. 1: depicts the mean change from baseline in PEC total score in schizophrenic patients (Intent to treat Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 pg, 80 pg, 120 pg and 180 pg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 pg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 pg, 120 pg and 180 pg) are exemplified in Example 2.

[033] FIG. 2: depicts the percent of responders in PEC total score over time in schizophrenic patients (Intent to treat Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 pg, 80 pg, 120 pg and 180 pg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 pg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 pg, 120 pg and 180 pg) are exemplified in Example 2.

[034] FIG. 3: depicts resolution of agitation as measured by achieving an ACES Score of at least 4 over time in schizophrenic patients (Intent to treat Population ) treated with a sublingual film containing dexmedetomidine hydrochloride (60 pg, 80 pg, 120 pg and 180 pg) versus a placebo group. The error bars in the figure represent “standard error”. The preparation of dexmedetomidine hydrochloride sublingual films (60 pg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 pg, 120 pg and 180 pg) are exemplified in Example 2.

[035] FIG 4: depicts percent of responders in CGI-I Score over time in schizophrenic patients (Intent to treat Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 pg, 80 pg, 120 pg and 180 pg) versus a placebo group. The error bars in the figure represent “standard error”. The preparation of dexmedetomidine hydrochloride sublingual film (60 pg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 pg, 120 pg and 180 pg) are exemplified in Example 2.

[036] FIG. 5A: depicts mean dexmedetomidine plasma concentration vs. nominal time sorted by dose and redose (Semilog Scale) in schizophrenic patients (Pharmacokinetic Population) treated with a sublingual film containing dexmedetomidine hydrochloride (20 pg, 20 pg (redose), 60 pg, 80 pg, 120 pg and 180 pg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (20 pg and 60 pg) are exemplified in Example I and dexmedetomidine hydrochloride sublingual films (80 gg, 120 gg and 180 gg) are exemplified in Example 2.

[037] FIG. 5B: depicts mean dexmedetomidine plasma concentration vs. nominal time sorted by dose and redose (Linear Scale) in schizophrenic patients (Pharmacokinetic Population) treated with a sublingual film containing dexmedetomidine hydrochloride (20 gg, 20 gg (redose), 60 gg, 80 gg, 120 gg and 180 gg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (20 gg and 60 gg) are exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 gg, 120 gg and 180 gg) are exemplified in Example 2.

[038] FIG. 6A: depicts mean values for resting systolic blood pressure (SBP) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 gg, 80 gg, 120 gg and 180 gg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 gg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 gg, 120 gg and 180 gg) are exemplified in Example 2.

[039] FIG. 6B: depicts mean values for resting diastolic blood pressure (DBP) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 gg, 80 gg, 120 gg and 180 gg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 gg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 gg, 120 gg and 180 gg) are exemplified in Example 2.

[040] FIG. 6C: depicts mean values for resting heart rate (HR) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 gg, 80 gg, 120 gg and 180 gg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 gg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 gg, 120 gg and 180 gg) are exemplified in Example 2.

[041] FIG. 7A: depicts mean change from baseline for resting systolic blood pressure (SBP) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 gg, 80 gg, 120 gg and 180 gg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 gg) is exemplified in Example

I and dexmedetomidine hydrochloride sublingual films (80 pg, 120 pg and 180 gg) are exemplified in Example 2.

[042] FIG. 7B: depicts mean change from baseline for resting diastolic blood pressure (DBP) over time m schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 pg, 80 pg, 120 pg and 180 pg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 pg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 pg, 120 pg and 180 pg) are exemplified in Example 2.

[043] FIG. 7C: depicts mean change from baseline for resting heart rate (HR) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 pg, 80 pg, 120 pg and 180 pg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 pg) is exemplified m Example 1 and dexmedetomidine hydrochloride sublingual films (80 pg, 120 pg and 180 pg) are exemplified in Example 2.

[044] FIG 8: shows the mean dexmedetomidine plasma log concentration vs. time for dose levels 10 pg, 20 pg and 40 pg of dexmedetomidine sublingual film (Semi-log scale). Error bars represent 1 standard deviation.

[045] FIG. 9A: depicts individual dexmedetomidine concentration-time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (10 pg) Semi-log Scale. Dexmedetomidine sublingual film is exemplified in Example 1.

[046] FIG, 9B: depicts individual dexmedetomidine concentration-time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (20 pg) Semi-log Scale. Dexmedetomidine sublingual film is exemplified in Example 1.

[047] FIG. 9C: depicts individual dexmedetomidine concentration-time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (40 pg) Semi-log Scale. The preparation of Dexmedetomidine sublingual film is exemplified in Example 1.

[048] FIG. 10: depicts mean VAS/S score vs. nominal time after administration of dexmedetomidine sublingual film (10 pg, 20 pg, 40 pg) and placebo. Dexmedetomidine sublingual film (10 pg and 20 pg) and the preparation of dexmedetomidine sublingual film (40 pg) are exemplified in Example I.

[049] FIG. 11: depicts standing systolic BP vs nominal time after administration of dexmedetomidine sublingual film (10 pg, 20 pg, 40 pg) and placebo. Dexmedetomidine sublingual film (10 pg and 20 pg) and the preparation of dexmedetomidine sublingual film (40 pg) are exemplified in Example 1.

[050] FIG. 12: depicts supine systolic BP. vs nominal time after administration of dexmedetomidine sublingual film 10 pg, 20 pg and 40 pg and placebo. Dexmedetomidine sublingual film (10 pg and 20 pg) and the preparation of dexmedetomidine sublingual film (40 pg) are exemplified in Example 1.

[051] FIG. 13: depicts standing diastolic BP vs nominal time after administration of dexmedetomidine sublingual film 10 pg, 20 pg and 40 pg and placebo. Dexmedetomidine sublingual film (10 pg and 20 pg) and the preparation of dexmedetomidine sublingual film (40 pg) are exemplified in Example 1.

[052] FIG. 14: depicts supine diastolic BP vs nominal time after administration of dexmedetomidine sublingual film 10 pg, 20 pg and 40 pg and placebo. Dexmedetomidine sublingual film (10 pg and 20 pg) and the preparation of dexmedetomidine sublingual film (40 pg) are exemplified in Example 1.

[053] FIG. 15: depicts pulse rate vs nominal time after administration of dexmedetomidine sublingual film 10 pg, 20 pg and 40 pg and placebo. Dexmedetomidine sublingual film (10 pg and 20 pg) and the preparation of dexmedetomidine sublingual film (40 pg) are exemplified in Example 1.

[054] FIG, 16: depicts the percentage of schizophrenic patients achieving RASS -1 in the treatment arm (IV dexmedetomidine hydrochloride treated group) versus placebo group,

[055] FIG, 17: depicts the mean drop in PEC score with time in schizophrenic patients in the treatment arm (IV dexmedetomidine hydrochloride treated group) versus placebo group.

[056] FIG. 18: depicts the maximum doses of IV dexmedetomidine hydrochloride received by schizophrenic patients for the treatment of agitation.

[057] FIG. 19: depicts the total intravenous dose of dexmedetomidine hydrochloride received by schizophrenic patients for the treatment of agitation.

[058] FIG. 20: depicts the mean plasma concentration (pg/ml) vs actual time in schizophrenic patients treated with dexmedetomidine hydrochloride.

[059] FIG. 21A: depicts change in PEC score from baseline in schizophrenia patients until 2 hours post-dose of 120 pg and 180 pg dexmedetomidine sublingual thin film (as exemplified in example 2) compared to placebo.

[060] FIG. 21B: depicts change in PEC score from baseline in schizophrenia patients until 6 hours post-dose of 120 pg and 180 pg dexmedetomidine sublingual film (as exemplified in example 2) compared to placebo.

[061] FIG. 22: depicts calming improvement in schizophrenia patients at 2 hours and 4 hours following administration of 120 pg (middle bar) and 180 pg dexmedetomidine (right bar) sublingual film (as exemplified in example 2) compared to placebo (left bar), as measured by Agitation and Calmness Evaluation Scale (ACES).

[062] FIG. 23: depicts percent response in schizophrenia patients at 30 minutes, 60 minutes, 120 minutes and 240 minutes following administration of 120 pg (middle bar) and 180 pg dexmedetomidine (right bar) sublingual film (as exemplified in example 2) compared to placebo (left bar), as measured by Clinical Global Impression-Improvement (CGI).

[063] FIG. 24A: depicts change in PEC score from baseline in bipolar patients until 2 hours post-dose of 120 pg and 180 pg dexmedetomidine sublingual film (as exemplified in example 2) compared to placebo.

[064] FIG. 24B: depicts change in PEC score from baseline in bipolar patients until 6 hours post-dose of 120 pg and 180 pg dexmedetomidine sublingual film (as exemplified in example 2) compared to placebo.

[065] FIG, 25 depicts calming improvement in bipolar patients at 2 hours and 4 hours following administration of 120 pg (middle bar) and 180 pg dexmedetomidine (right bar) sublingual film (as exemplified in example 2) compared to placebo (left bar), as measured by Agitation and Calmness Evaluation Scale (ACES).

[066] FIG. 26 depicts percent response in bipolar patients at 30 minutes, 60 minutes, 120 minutes and 240 minutes following administration of 120 pg (middle bar) and 180 pg dexmedetomidine (right bar) sublingual film (as exemplified in example 2) compared to placebo (left bar), as measured by Clinical Global Impression-Improvement (CGI).

DETAILED DESCRIPTION:

ABBREVIATIONS:

[067] .ACES: Agitation-Calmness Evaluation Scale;

[068] AD: Alzheimer disease;

[069] AE: Adverse event;

[070] AUC: Area under the curve;

[071] AUClast: area under the curve, calculated to the last observable time point;

[072] AUC0־Inf: Area under the plasma concentration-time curve from time of administration to infinity

[073] BID: twice a day;

[074] BMI: Body mass index;

[075] CGI-I: Clinical Global Impression-Improvement

[076] CGI-S: Clinical Global Impression-Severity

[077] Cmax: maximum plasma concentration;

[078] COWS: Clinical Opiate Withdrawal Scale;

[079] CMAI: Cohen Mansfield Agitation Inventory

[080] CMC: Carboxy methylcellulose

[081] C-SSRS: Columbia Suicide Severity Rating Scale

[082] CT: Computed tomography;

[083] CTCAE: Common Terminology Criteria for Adverse Events;

[084] DBP: Diastolic Blood Pressure

[085] Dex or DEX: Dexmedetomidine

[086] DLB: Dementia with Lewy bodies;

[087] DLT: Dose Limiting Toxicity;

[088] DSM: Diagnostic and Statistical Manual of Mental Disorders;

[089] DT: Disintegration time;

[090] ECG: Electrocardiogram;

[091] FTD: Fronto temporal disease;

[092] HPC: Hydroxypropyl cellulose;

[093] HPMC: Hydroxyl propyl methyl cellulose

[094] HR: Heart rate

[095] ICH: International Conference on Harmonisation;

[096] ICU- Intensive care unit;

[097] IUD: intrauterine device

[098] IPD: In-patient Departments;

[099] ITT: Intent to treat Population

[0100] LAR : Legally authorized representative;

[0101] LSM: Least square mean

[0102] LS: Least square;

[0103] MedDRA: Medical Dictionary for Regulatory Activities;

[0104] MMRM: Mixed model repeated measures:

[0105] MMSE: Mini-Mental State Examination;

[0106] MRI: Magnetic resonance imaging;

[0107] MW: Molecular weight;

[0108] mm: Millimeter;

[0109] mcg: microgram;

[0110] mg: Milligrams;

[0111] qg: microgram;

[0112] ml: milliliter;

[0113] mmHG: millimeters of mercury;

[0114] msec: millisecond;

[0115] ng: nanogram;

[0116] OPD: Out-Patient Department;

[0117] PANSS: Positive and Negative Syndrome Scale;

[0118] IMS: Pittsburgh Agitation Scale;

[0119] PCRS: Placebo-Control Reminder Script;

[0120] PEC: PANSS Excitement Component;

[0121] PEO: Polyethylene oxide;

[0122] PD: Pharmacodynamic;

[0123] PK: Pharmacokinetics

[0124] PVA: Polyvinyl alcohol;

[0125] QTcF: QT interval corrected for heart rate using Fridericia’s formula;

[0126] QID: Quater in die

[0127] RASS: Richmond Agitation Sedation Scale;

[0128] SAE: Serious adverse event;SOWS-Gossop : Short Opiate Withdrawal Scale of Gossop;

[0129] SAP: Statistical Analysis Plan;

[0130] SBP: Systolic Blood Pressure

[0131] SD = standard deviation;

[0132] SE = standard error

[0133] SL: Sublingual;

[0134] T1/2: Elimination half-life;

[0135] TEAE: treatment emergent adverse event;

[0136] Tmax: Time of maximum plasma concentration;

[0137] Wt%: Weight percentage

[0138] ULN: upper limit of normal

[0139] VAS: Visual Analog Scale;

[0140] YMRS: Young Mania Rating Scale

DEFINITIONS:

[0141] As used herein, “about” means plus or minus 10% of the indicated numeri cal value.

[0142] The terms “formulation” and “composition” are used interchangeably, except where otherwise clearly intended to have different meanings.

[0143] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

[0144] The term “a” or “an” refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein. In addition, reference to w,g, “an agent” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the agents are present, unless the context clearly requires that there is one and only one of the agents.

[0145] As used herein, the verb “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably “comprise”, “consist of’, or “consist essentially of’, the steps, elements, and/or reagents described in the claims.

[0146] The term pharmaceutically acceptable carrier” refers to a pharmacologically inert substance to be used as a carrier. As used herein, the phrase “carrier” and “excipients” are used interchangeably, except where otherwise clearly intended to have different meanings.

[0147] The term agitation, as used herein, means irritability, emotional outburst impaired thinking, or excess motor and verbal activity’ that may occur due to either dysfunction of specific brain regions such as frontal lobes or due to dysfunction of neurotransmitter systems such as dopamine and nor-epinephrine. In the present invention, agitation also includes aggression and hyper-arousal in post-traumatic stress disorder. The agitation may be acute or chronic.

[0148] The term the signs of agitation includes excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms), verbal aggression (e g. yelling, speaking in an excessively loud voice, using profanity’, screaming, shouting, threatening other people), physical aggression (e.g. grabbing, shoving, pushing, clenching hands into fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things), and destroying property.

[0149] The term “without significant sedation” and the like means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. Level 3 means sedated but responds to commands. In some embodiments, the dexmedetomidine may be dosed to achieve a Richmond Agitation Sedation Scale (RASS) of-1 (“light sedation”).

[0150] The term “dissolvable” means the films herein are readily disintegrated, e.g. at least within about 20 minutes, following administration to the oral mucosa. Disintegration is achieved by saliva and/or other aqueous materials on the mucosal surface.

[0151] The term neuropsychiatric conditions includes, but is not limited to, schizophrenia, bipolar illness (bipolar disorder, bipolar mania), depression, delirium or other related neuropsychiatric conditions.

[0152] The term an effective amount” is interchangeable with therapeutically effective dose, or ”therapeutically effective amount, and refers to an amount sufficient to produce the desired effect. An effective amount is sufficient to cause an improvement in a condition (e g. agitation) of the subject.

[0153] The terms treating, and treatment, as used herein refer to curative therapy, prophylactic therapy, and/or preventative therapy and can be used interchangeably.

[0154] The term “significantly reduced” refers to a reduction level by at least 10% or higher, preferably 20% or higher, more preferably 40% or higher, even more preferably 60% or higher, still more preferably 80% or higher, and 90% or higher, as compared to a control. For example, in the context of agitation, the a skilled artisan will readily understand that the reduction can be measured in terms of well-known agitation scales, such as PEC score and CGI-I (described in more detail in the examples). As an example, when agitation is significantly reduced in a patient, the reduction may be interpreted as as those who achieve at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or greater reduction in PEC total score from baseline (e.g. measured at 2 hours post-dose). In some embodiments, significantly reduced agitation refers to at least a 40% reduction in PEC total score from baseline. Similarly, a significant reduction in agitation may be measured on the CGI-I scale and may refer to a patient that has a score of 1 or 2 on the CGI-I scale (e.g. measured at 1, 2, or 4 hours post-dose) or the Agitation-Calmness Evaluation Scale (ACES) scale and may refer to a patient that has a score of e g. 3 or higher.

[0155] The term “pharmaceutically acceptable salt refers to a salt known to be non-toxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salt include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. A preferred salt is the hydrochloride salt. [0156] The term “film” herein includes thin films, sheets and wafers, in any shape, including rectangular, square, or other desired shape. The film may be of any desired thickness and size, such that it can be conveniently placed sub-lingually in the patient. For example, the film may be a relatively thin film having a thickness of from about 20 micrometers to about 200 micrometers or may be a somewhat thicker film having a thickness of from about 20 micrometers to about 1000 micrometers. In certain embodiments, the film may be even thicker, e.g., having a thickness greater than about 30 millimeters.

[0157] As used herein, the phrase “water-soluble polymer” refers to (i) a polymer that is at least partially soluble in water, and desirably fully or predominantly soluble in water, and/or (ii) a polymer that absorbs water. Polymers that absorb water are referred to herein as water-swellable polymers.

[0158] The term “self-supporting” means the films herein maintain structural integrity upon handling without the need for a backing layer. Some flexibility in the film is contemplated and may be desirable.

[0159] As used herein, the phrase “disposed within a polymer matrix” means that dexmedetomidine or a pharmaceutically acceptable salt thereof is incorporated directly into the polymer solution prior to the formation of the solid polymer matrix film composition.

[0160] As used herein, the phrase “deposited on the surface of a polymer matrix” means that dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as liquid composition separate from the preparation of the solid polymer matrix, and deposited onto the solid polymer, e.g. as one or more micro-deposits, where it dries. The dried product is sometimes referred to herein as the “micro-deposited matrix film”. The drug liquid formulation may be in any form, including as a solution, emulsion, suspension, or dispersion.

[0161] The term “intranasal administration” means administration by the nasal route, whereby a drug is insufflated through the nose. The administration can be either topical or systemic, meaning the locally delivered drug can go on to exhibit either purely local or systemic effects.

[0162] The term “parenteral” refers to administration of a drug by injection under one or more layer of skin or mucous membrane, and can include, for example, subcutaneous, intravenous, intraperitoneal or intramuscular injection.

[0163] The term “proportion of treatment responders” is defined as those subjects exhibiting about a 40 % drop in PEC score at 2 hours.

[0164] The term” clinically significant cardiovascular effects” means herein a lowering in blood pressure (hypotension) and/or heart rate (bradycardia) to the extent that medical intervention is required to address the cardiovascular side effects, where the term “medical intervention” means an intervention that more serious than administering fluids, such as an energy drink.

I. Active agent

[0165] Dexmedetomidine has the IUPAC name (+) 4-(S)-[l-(2,3-dimethylphenyl)ethyl]-lHimidazole. As the monohydrochloride salt, it is predominantly used as a medication for the 20 sedation of patients during treatment in an intensive care setting or to sedate patients prior to and/or during surgical and other procedures. Such medication is currently sold under the registered trade name PRECEDEX.

[0166] Pharmaceutically acceptable salts of dexmedetomidine that may be used herein include generally any suitable salt that has been or may be approved by the US FDA or other appropriate foreign or domestic agency for administration to a human. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbomc, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, hydrogen sulfuric, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, ptoluenesulfonic, citric, tartaric, and methanesulfonic acids, or combinations of these acid salts.

Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate.

dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate or the like. In other embodiments, deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included.

II. Dosage

[0167] In some embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of between about 0.5 pg to about 1200 pg, depending on the route of administration etc. Examples of sui table dosages include: about 0.5 pg to about 1200 pg, about 0.5 pg to about 500 pg, about 0.5 pg to about 450 pg, about 0.5 pg to about 405 pg, about 0.5 pg to about 360 pg, about 0.5 pg to about 270 pg, about 0.5 pg to about 180 pg, and about 0.5 pg to about 120 pg. The dose may be administered one or more times a day including twice, three times, four times, five times or six times per day.

[0168] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered at a dose of about 10 pg to about 300 pg, e.g. about 10 pg to 270 pg, about 20 pg to about 240 pg, about 30 pg to about 180 pg, about 40 pg to about 140 pg, about 60 pg to about 120 pg, about 70 pg to about 100 pg, about 80 pg to about 100 pg of unit dose total 21 weight of pharmaceutical composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (m pg): about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245 and about 250.

[0169] In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered oromucosally (e.g. sublingually or buccally) at a dose of about 10 pg to about 300 pg, e.g. about 10 pg to 270 pg, about 20 pg to about 240 pg, about 30 pg to about 180 pg, about 40 pg to about 140 pg, about 50 pg to about 120 pg , about 60 pg to about 120 pg, about 70 pg to about 100 pg, about 80 pg to about 100 pg of unit dose total weight of sublingual film composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (in pg): about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245 and about 250. [0170] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered at a dose of about 120 pg to about 405 pg, e.g, about 120 pg to about 270 pg, including about 120 pg and about 180 pg of unit dose total weight of pharmaceutical composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (in pg): about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400 and about 405.

[0171] In another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered oromucosally (e.g. sublingually or buccally) at a dose of about 120 gg to about 405 gg, e.g. about 120 gg to about 270 gg, including about 120 gg and about 180 gg of unit dose total weight of sublingual film composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (in gg): about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400 and about 405.

[0172] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 500 gg to about 1500 gg, e.g. about 900 gg to about 1200 gg, based on total weight of oral composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (in gg): about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 600, about 610, about 620, about 630, about 640, about 650, about 660, about 670, about 680, about 690, about 700, about 710, about 720, about 730, about 740, about 750, about 760, about 770, about 780, about 790, about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, about 900, about 910, about 920, about 930, about 940, about 950, about 960, about 970, about 980, about 990, about 1000, about 1010, about 1020, about 1030, about 1040, about 1050, about 1060, about 1070, about 1080, about 1090, about

1100, about 1110, about 1120, about 1130, about 1140, about 1150, about 1160, about1170, about 1180, about 1190, about 1200, about 1210, about 1220, about 1230, about 1240,about

1250, about 1260, about 1270, about 1280, about 1290, about 1300, about 1310, about1320, about 1330, about 1340, about 1350, about 1360, about 1370, about 1380, about 1390,about

1400, about 1410, about 1410, about 1420, about 1430, about 1440, about 1450, about1460, about 1470, about 1480, about 1490 and about 1500.

[0173] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered intramuscularly at a dose of about 100 gg to about 200 gg, e.g. about 120 gg to about 190 gg, based on total weight of intramuscular injection. Examples of suitable doses include (in gg): about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195 and about 200.

[0174] The exemplary’ dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof to be administered to a particular patient, will depend on the type and extent of the condition, the overall health status of the particular patient, the particular form of dexmedetomidine or a pharmaceutically acceptable salt thereof being administered, and the particular formulation used to treat the patient.

III. Pharmaceutical compositions

[0175] According to the present disclosure, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered to the human subject through various routes, including oromucosal (e.g. sublingual, buccal), oral, parenteral and the like. Formulations suitable for use according to the present disclosure are outlined below. Additional formulations suitable for use according to the present disclosure are described in US 2020/0000717, which is hereby incorporated by reference in its entirety for all purposes.

[0176] Oromucosal formulations (Sublingual and/or buccal formulations)

[0177] Dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated, according to the present disclosure, into dosage forms suitable for sublingual or buccal administration. Such dosage forms include tablets, powders, pills, films, capsules, liquids, gels, syrups, slurries, suspensions, and the like. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a film product,

[0178] Gamers suitable for inclusion in sublingual or buccal formulations include, but are not limited to, sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic salme, pyrogen - free water and combinations thereof. Carriers which readily dissolve in saliva may be preferred.

[0179] Sublingual or buccal formulations may also include other pharmaceutically acceptable carriers and/or excipients such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, colouring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilising agents, suspending agents and mixtures thereof. Particular excipients, which may be used according to this disclosure, are known in the art, for example as described in Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., Mcgraw Hill.

[0180] Films

[0181] Suitable films for sublingual or buccal administration (i.e. oromucosal administration) according to the present disclosure comprise dexmedetomidine or a pharmaceutically acceptable salt thereof either (i) disposed within a polymer matrix or (ii) deposited on the surface of a polymer matrix, e g., on the surface of a “placebo” film.

Polymer component of film

[0182] The polymer component consists of one or more water-soluble polymers within the film matrix and/or as part of the drug-containing deposit (e g. one or more droplets) on the surface of the polymer. In some embodiments of the disclosure, the polymer component consists of a single water-soluble polymer. In some embodiments, the polymer component consists of two or more water-soluble polymers, including two or more of the same water-soluble polymers having different molecular weights.

[0183] The polymer component in the film matrix is of a suitable composition and present in a sufficient amount to ensure rapid disintegration of the film matrix in the oral mucosa. For example, the presence of the polymer component may allow the film matrix to disintegrate completely oromucosally in about 15 seconds to about 180 seconds, for example, about 30 seconds to about 180 seconds, including about 120 seconds. The polymer component in the film matrix also provides the film with sufficient strength (i.e. the film is self-supporting).

[0184] When present in one or more droplets of the dexmedetomidine composition deposited onto the surface of the polymer matrix-substrate, the polymer component may, for example, consist of the water-soluble polymer hydroxypropyl cellulose, although different water-soluble polymers are also contemplated as described hereinafter under the definition “first water-soluble polymer” and “second water soluble polymer”. For example, the polymer component may consist of one, two or three hydroxypropyl celluloses having different molecular weights. The molecular weights of the different hydroxypropyl celluloses may conveniently range from (1) less than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000 daltons) (ii) about 90,000 daltons to about 200,000 daltons and (iii) about 200,000 daltons to about 500,000 daltons. The two or more hydroxypropyl celluloses may be mixed in any suitable ratio to achieve the desired droplet viscosity. The viscosity of the dexmedetomidine composition solution or suspension can be measured using a Brookfield viscometer with a small sample adapter at a temperature of 25’C and may range from about 5 cps to about 3700 cps. For example, it may range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6 cps to about 100 cps or about 6 cps to about 50 cps. In some embodiments of the present disclosure, the viscosity of the dexmedetomidine composition solution or suspension is from about 6 cps to about 20 cps at 25 °C and a shear rate of about Ί (1 /s).

[0185] When present in a monolithic (i.e. placebo or drug-containing) film, the polymer component may, for example, consist of one water soluble polymer or two different water-soluble polymers. When two different water-soluble polymers are present, one of the water-soluble polymers may include the same polymer but present in the polymer component as a combination of different molecular weights. For example, the polymer component may consist of one, two or three hydroxypropyl celluloses having different molecular weights, although different watersoluble polymers are also contemplated as described hereinafter under the definition “first watersoluble polymer” and “second water soluble polymer” such as polyethylene oxide. The molecular weights of the different hydroxypropyl celluloses may conveniently range from (1) less than about 60,000 daltons (e.g. about 5000 daltons to about 49000 daltons) (ii) about 90000 daltons to about 200000 daltons and (iii) about 200,000 daltons to about 500,000 daltons (e.g, about 300000 daltons to about 450000 daltons). The two or more hydroxypropyl celluloses (e.g. low and high molecular weight hydroxypropyl celluloses) may be mixed in any suitable ratio to achieve the desired film properties. When present in a monolithic (i.e. placebo or drug-containing) film or micro-deposited film matrix composition, the polymer component may conveniently consist of one or more water-soluble polymers having a molecular weight less than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000 daltons), and/or from about 90000 daltons to about 200,000 daltons and/or about 200,000 daltons to about 500,000 daltons (e.g. about 300000 daltons to about 450000 daltons). When a structurally different water-soluble polymer is also present, it may conveniently have a higher molecular weight, for example a molecular weight greater than about 500,000 daltons.

[0186] In some embodiments, the disclosure provides pharmaceutical film compositions, comprising: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component consisting of a first water-soluble polymer having a molecular weight less than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000 daltons), and one or more second-water soluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

[0187] In some embodiments, the disclosure provides pharmaceutical film compositions consisting essentially of: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component consisting of a first water-soluble polymer having a molecular weight less than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000 daltons), and one or more second-water soluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

[0188] In some embodiments, the disclosure provides pharmaceutical film compositions consisting of: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component consisting of a first water-soluble polymer having a molecular weight less than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000 daltons), and one or more second watersoluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

[0189] Examples of one or more first water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose and mixtures thereof, including mixtures of the same polymer having different molecular weights.

[0190] Examples of one or more second water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose and mixtures thereof, including mixtures of the same polymer having different molecular weights. Polyethylene oxide (PEO) may also be present herein as a second water-soluble polymer or may be described separately hereinafter in the pharmaceutical film compositions as an example of a pharmaceutically acceptable carrier, or more particularly, as a mucoadhesive agent.

[0191] In one embodiment, the weight ratio of said first water-soluble polymer to said second water-soluble polymer(s) (including PEO when present in the film) in the entire film composition is from about 2:1 to about 1:50, for example about 1:1 to about 1:40, including about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about

1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about

1:19, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26, about

1:27, about 1:28, about 1:29, about 1:30, about 1:31, about 1:32, about 1:33, about 1:34, about

1:35, about 1:36, about 1:37, about 1:38, about 1:39, about 1:40.

[0192] In a further embodiment, the weight ratio of said first water-soluble polymer to said second water-soluble polymer(s) (including PEO when present in the film) in the entire film composition is from about 1:10 to about 1:30, about 1:15 to about 1:25 or about 1:15 to about 1:20. In some embodiments, a ratio of about 1:15 to about 1:20 provides beneficial functional effects.

[0193] Examples of other water-soluble polymers which may be included in the film with the first water-soluble polymer/second water-soluble polymer or replace such polymer(s) include povidone (polyvinylpyrrolidone), copovidone (copolymers of N-vinyl pyrrolidone and vinyl acetate), polyvinyl alcohol, polyethylene glycol, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, polydextrose, pullulan, carboxymethyl cellulose, sodium alginate, chitosan, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, starch, carrageenan, gelatin and mixtures thereof. The water-soluble polymer component, including water-soluble polymer carriers when present, may conveniently comprise about 40% to about 99.8%, about 50% to about 99.7%, about 60% to about 99.6% of the film composition, based on the weight of the film on a dry weight basis.

[0194] In some embodiments, the polymer component for the film composition comprises a first water-soluble polymer present in an amount of from about 2% to about 15% on a dry weight basis of the polymer component (e.g. at about 3% to about 8% w/w of the total film weight). This watersoluble polymer may conveniently have a molecular weight from about 5,000 daltons to about 49,000 daltons. Examples of suitable such water-soluble polymers include those selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof.

[0195] In some embodiments, low molecular weight hydroxypropyl cellulose may be present in the film at about 3% to about 8% w/w of the total film weight.

[0196] In some embodiments, the one or more second water-soluble polymers (including watersoluble polymer carriers such as polyethylene oxide) may, for example, be present in an amount of from about 50 to about 98 weight percent on dry weight basis of the polymer component. The one or more second water-soluble polymers each has a molecular weight greater than 60,000 daltons; for example, from about 90,000 daltons to about 1,500,000 daltons, especially when the polymer is selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, and mixtures thereof.

[0197] In some embodiments, the one or more second water-soluble polymers may together be present in the film at about 25% to about 40% w/w of the total film weight when the one or more second water-soluble polymers each has a molecular weight from about 90,000 daltons to about 200,000 daltons and/or from about 200,000 daltons to about 500,000 daltons, and the polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, and mixtures thereof.

[0198] In some embodiments, a polyethylene oxide may be present in the film at about 50% to about 60% w/w of the total film weight.

[0199] In one embodiment, the polymer component for the film composition consists of a low molecular weight, water-soluble polymer (e.g., having a molecular weight less than about 60,000 daltons) and one or more high molecular weight polymers (e.g., having a molecular weight greater about 60,000, up to about 1,500,000 daltons when a polyethylene oxide is included in the polymer mixture or up to about 500,000 daltons when a polyethylene oxide is not included in the polymer mixture). This polymer combination, especially when the polymers are a combination of hydroxypropyl cellulose and polyethylene oxide, lends certain advantages to the tensile strength and pharmacokinetics of the film composition.

[0200] In some embodiments, the present disclosure provides a film composition comprising (e.g. consisting essentially of):

(1) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymer component consisting of one or more water-soluble polymers: and (in) one or more pharmaceutically acceptable carriers.

[0201] In one embodiment, the present disclosure provides a film composition comprising (e.g. consisting essentially of):

(i) therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymer component consisting of: (a) one or more first water-soluble polymer (e.g. hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, and mixtures thereof) having a molecular weight from about 5,000 daltons to about 49,000 daltons, for example, in about 2 to about 15 weight percent on dry weight basis of the total polymer component; and (b) one or more second water-soluble polymers (e.g. polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, and mixtures thereof) having a molecular weight greater than 60,000 daltons, such as greater than 100000 daltons, for example in about 50 to about 98 weight percent on dry weight basis of the total polymer component; and (iii) one or more pharmaceutically acceptable carriers.

[0202] The molecular weight of hydroxypropyl cellulose, when present in the film of the present disclosure, may be varied, and may be present as both a low molecular weight, water-soluble polymer and as one or more high molecular weight, water-soluble polymers. In some embodiments, the molecular weight may be less than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000 daltons). In other embodiments the molecular weight may be in the range from about 90,000 daltons to about 200,000 daltons. In yet other embodiments, the molecular weight may be in the range from about 200,000 daltons to about 500,000 daltons.

[0203] Hydroxypropyl cellulose, when part of the film composition including polyethylene oxide, may conveniently be present in the range from about 10% to about 90% by weight on a dry weight basis of the polymer component, e.g. about 20% to about 80% by weight on dry weight basis of the polymer component, e.g. about 20% to about 50% by weight on dry weight basis of the polymer component, e.g. about 25% to about 45% by weight on dry weight basis of the polymer component.

[0204] The molecular weight of polyethylene oxide, when present m the film of the present disclosure, may also be varied. In some embodiments, a water-soluble, high molecular weight polyethylene oxide may be used, for example, to increase muco-adhesivity of the film. In certain embodiments, the molecular weight may range from about 100,000 daltons to about 1,500,000 daltons, including about 100,000, 200,000, 300,000, 600,000, 900,000 or 1,000,000 daltons. In some embodiments, it may be desirable to use a combination of polyethylene oxide having a molecular weight of about 600,000 daltons to about 900,000 daltons with polyethylene oxide having a molecular weight of about 100,000 daltons to about 300,000 daltons in the polymer component.

[0205] Polyethylene oxide, when part of the film composition, may conveniently be present range from about 30% to about 90% by weight on a dry weight basis of the total polymer component, e.g. about 40% to about 85% by weight on a dry weight basis of the polymer component, e.g. about 55% to about 80% by weight on a dry weight basis of the polymer component.

[0206] Such film compositions may contain the drug dispersed within the film, or microdeposited onto a surface of the film. When micro-deposited on the surface of a “placebo” film, the drug may conveniently be added as part of a dexmedetomidine composition as one or more droplets in a liquid carrier, such as a solvent (e g. an alcohol such as ethanol), optionally together with one or more (e.g. two) water-soluble polymers and/or pharmaceutically acceptable carriers. Suitable water-soluble polymers include (1) a low molecular weight, water-soluble polymer, for example a low molecular weight, water-soluble polymer having a molecular weight of less than about 60,000 daltons (e.g. a molecular weight of about 5,000 daltons to about 49,000 daltons and optionally (2) one or more (e.g. one or two) high molecular weight, water-soluble polymers, for example a high molecular weight, water-soluble polymer having a molecular weight of greater than about 60,000 daltons (e g. a molecular weight of from about 60,000 daltons to about 150,000 daltons such as hydroxypropyl cellulose (77,000MW), hydroxypropyl cellulose (80,000MW), hydroxypropyl cellulose (90,000MW), or hydroxypropyl cellulose (140,000MW)) and/or a high molecular weight, water-soluble polymer having a molecular weight of greater than about 60,000 daltons (e.g. a molecular weight of from about 200,000 daltons to about 900,000 daltons such as hydroxypropyl cellulose (340,000MW), hydroxypropyl cellulose (370,000MW), polyethylene oxide (200,000MW) or polyethylene oxide (600,000MW)). Each water-soluble polymer may independently be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene oxide and methyl cellulose, e.g. hydroxypropyl cellulose and/or polyethylene oxide.

[θ207] In some embodiments, the dexmedetomidine composition comprises dexmedetomidine hydrochloride, a low molecular weight polymer which is hydroxypropyl cellulose and one or two high molecular weight polymers which are each hydroxypropyl cellulose in an ethanol solvent.

[0208] In one embodiment, the dexmedetomidine composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride), hydroxypropyl cellulose (40,000MW) and one or both of hydroxypropyl cellulose (140,000MW) and hydroxypropyl cellulose (370,000MW).

[0209] In another embodiment, the dexmedetomidine composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride), and only two hydroxypropyl celluloses, namely hydroxypropyl cellulose (40,000MW) and hydroxypropyl cellulose (140,000MW).

[0210] In some embodiments, the deposition composition may be in any form, including as a solution, emulsion, suspension or dispersion. For example, the dexmedetomidine composition may be added as one or more droplets in an ethanol-based solution, optionally containing a pHneutralizing agent such as sodium hydroxide. In some embodiments, the film substrate surface contains two or more micro-deposited spots of dexmedetomidine hydrochloride (e.g. two microdeposited spots) in a polymer matrix. The viscosity of deposition solution/suspension may range from about 6 cps to about 3700 cps as measured at 25 C using a Brookfield viscometer with a small sample adapter. As an example, it may range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6 cps to about 100 cps or about 6 cps to about 50 cps.

[0211] In some embodiments of the present disclosure, the viscosity of the dexmedetomidine composition is from about 6 cps to about 20 cps at 25 °C and a shear rate of about 7 (1/s).

[0212] Following drying to remove the solvent, the film comprises a film substrate (e.g. a placebo) with the dexmedetomidine composition as previously described but absent the solvent deposited (e.g. micro-deposited) on the surface of the film substrate. The dried composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride) may cover the whole of the film substrate surface or only part of the film substrate surface.

[0213] In some embodiments, the dried dexmedetomidine composition appears as one or more discrete drug-containing droplets on the film substrate surface. Alternatively, stenciling may be used to achieve a one or more defined and discrete regions of drug-containing composition on the surface of the film substrate.

[0214] In some embodiments, the disclosure provides a dry film product comprising a film substrate with one or more discrete drug-containing droplets on the film substrate surface, wherein each such drug-containing droplet comprises dexmedetomidine or a pharmaceutically acceptable salt thereof , and hydroxypropyl cellulose of two molecular weights: hydroxypropyl cellulose (40,000MW) available as HPC-SSL, and hydroxypropyl cellulose (140,000MW) marketed under the tradename of KlucelTM Type JF NF, and wherein the film substrate comprises hydroxypropyl cellulose of three molecular weights: hydroxypropyl cellulose (40,000MW), hydroxypropyl cellulose (140,000MW), and hydroxypropyl cellulose (370,000MW) marketed under the tradename of KlucelTM Type GF NF. In some embodiments , the film substrate also comprises polyethylene oxide (600,000MW) available under the name of Sentry Polyox WSR 205 LEO NF. [0215] In some embodiments, the dry film product comprises a deposition composition (also referred to herein as a “dexmedetomidine composition”) comprising: (1) dexmedetomidine hydrochloride, present at about 9% to about 50% w/w of the deposition composition, e.g. about 15% to about 25% w/w of the deposition composition; (ii) hydroxypropyl cellulose (40,000MW), present at about 5% to about 85% w/w of the deposition composition; (lii) hydroxypropyl cellulose (140,000MW) present at about 5% to 85% w/w of the deposition composition; and (iv) hydroxypropyl cellulose (370,000MW) present at about 0% to about 65% w/w of the deposition composition. The film also comprises a polymer matrix, wherein the polymer matrix comprises: (i) hydroxypropyl cellulose (40,000MW) present at about 3% to about 40% w/w of the polymer matrix; (ii) hydroxypropyl cellulose (140,000MW) present at about 3% to about 40% w/w of the polymer matrix; (111) hydroxypropyl cellulose (370,000MW) present at about 0% to about 30% w/w of the polymer matrix, and (iv) polyethylene oxide (600,000MW) present at about 55% to about 75% w/w of the polymer matrix.

[0216] In some embodiments, the dry film product (e g. a micro-deposited film product) comprises(!) dexmedetomidine hydrochloride, present at about I % to about 50% w/w of the total film weight; (ii) hydroxypropyl cellulose (40,000MW), present at about 2% to about 30% w/w of the total film weight; (iii) hydroxypropyl cellulose (140,000MW) present at about 2% to about 30% w/w of the total film weight; (iv) hydroxypropyl cellulose (370,000MW) present at about 10% to about 50% w/w of the total film weight, (v) polyethylene oxide (600,000MW) present at about 40% to about 75% w/w of the total film weight and (vi) optionally other pharmaceutically acceptable carriers.

[0217] In some embodiments, the films disclosed herein combine several types of hydroxypropyl cellulose (HPC) to provide a film with advantageous properties. For example, the film composition may contain two or three of hydroxypropyl cellulose (40,000MW), hydroxypropyl cellulose (140.000MW) and hydroxypropyl cellulose (370.000MW) in combination. In certain embodiments, polyethylene oxide (600,000MW) is included with these types of HPC when part of a monolithic film.

[0218] In certain film compositions of the present disclosure, a low molecular weight hydroxypropyl cellulose (e.g. 40.000MW) is present at about 3% to about 8% (e.g. about 5%) w/w of the total film weight, a high molecular weight hydroxypropyl cellulose (e.g. 140.000MW) is present at about 3% to about 8% (e.g. about 5%) w/w of the total film weight, a high molecular weight hydroxypropyl cellulose (e.g. 370,000MW) is present at about 20% to about 40% w/w of the total film weight, and a polyethylene oxide (e.g. 600,000MW) is present at about 40% to about 70%, (e.g. about 50% to about 60%) w/w of the total film weight. In some embodiments, the two high molecular weight, water-soluble polymers are together present at about 25% to about 40% w/w of the total film weight.

[0219] The selection and ratio of water-soluble polymers can be made to effect complete dissolution of the film composition in oral mucosal fluids within seconds to minutes, e.g. in about 0.25 minutes to about 15 minutes, thus ensuring delivery of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa. For example, the film compositions may reside in the sublingual or buccal region of the mouth up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes, including for a period of from about 30 seconds to about 15 minutes, about 1 minute to about 10 minutes, or about 1 minute to about 5 minutes.

[0220] The standard basket or paddle apparatus described in any pharmacopoeia can be used for in vitro dissolution testing. The selection of dissolution medium will essentially depend as per the sink conditions and highest dose of drug. The temperature of dissolution medium should be maintained at 37 ± 0.5°C and rpm at 50 (see Bala et al., in Int J Pharm Investigation, vol. 3(2), pages 67-76).

[0221] Films disclosed herein have several functional advantages to promote rapid onset of drug effect. In some embodiments, thin films compositions of the disclosure have a disintegration time (DT) of about 15 seconds to about 180 seconds, about 15 seconds to about 160 seconds, about 25 seconds to about 150 seconds, about 15 seconds to about 140 seconds, about 15 seconds to about 120 seconds, about 40 seconds to about 120 seconds, about 50 seconds to about 120 seconds, for example about 120 seconds, when applied sublingually or buccally. A disintegration time in this time-frame provides optimal onset of drug effects.

[0222] In some embodiments, thin film compositions of the invention have mucoadhesion properties that provide practical benefits of localizing the film to the sublingual location and reducing, or preventing, effective removal prior to dissolution. This quality is particularly advantageous in a clinical setting with an agitated subject. Thus, in some embodiments, thin film compositions have a mucoadhesion force (the mucoadhesion strength or shear strength) of about 50g or above, about 100g or above, about 200g or above, about 300g or above, about 400g or above, about 500g or above, about 600g or above, about 700g or above, about 800g or above, about 900g or above, about 1000g or above. In some embodiments, the mucoadhesion force is in a range of about 300g to about 4000g, about 500g to about 3000g, or about 1000g to about 2000g. [0223] Burst strength of the film also contributes to drug delivery. Certain thin film compositions of the invention have a burst strength at or above 50g, 100g, 200g, 300g, 400g, 500g, 600g, 700g, 800g, 900g, 1000g, 1100g, 1200g, 1300g, 1400g, 1500g, 1600g, 1700g, 1800g, 1900g, 2,000 g, 2,500g, 3,000g, 3,500g, 4,000g, 4,500g, 5,000g, 5,500g, 6,000g, 6,500g, 7,000g, 7,500g, 8,000g, 8,500g, 9,000g, 9,500g, 10,000g or 15,000g. For example, the burst strength may be in a range of about 200g to about 15000 g, about 300 g to about 10,000 g, or 400 g to about 5,000 g.

[0224] Pharmaceutically acceptable earners

[0225] The film compositions may further comprise one or more pharmaceutically acceptable carriers that includes, but is not limited to, liquid carriers, flavours, sweeteners, refreshing agents, antioxidants, pH adjusting agents, permeation enhancers, mucoadhesive agents, plasticizers, bulking agents, surfactants/non-ionic solubilizers, stabilizers, anti-foam agents, colors or the like. In certain embodiments, the film compositions are substantially free of acidic buffer or other acidic agents.

[0226] Liquid carriers

[0227] According to some embodiments, the pharmaceutically acceptable carrier includes a liquid carrier. The liquid carrier comprises one or more solvents useful in the preparation of the polymer matrix (drug containing or placebo) and deposition composition on the polymer matrix. In some embodiments, the solvent may be water. In some embodiments, the solvent may a polar organic solvent including, but are not limited to, ethanol, isopropanol, acetone, butanol, benzyl alcohol and mixtures thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride, toluene, ethyl acetate and mixtures thereof. Certain solvents are alcohols, especially ethanol, water and mixtures thereof. Desirably, the solvent content in the wet polymer matrix is at least about 30% by weight of the total wet weight of the total film composition prior to drying. The subsequent dried film composition will desirably contain less than about 10% by weight of solvent, more desirably less than about 8% by weight of solvent, even more desirably less than about 6% by weight of solvent and most desirably less than about 2% by weight of solvent.

[0228] Flavors/sweeteners/refreshing agents

[0229] It may be beneficial to add a sweetener, flavoring agent, refreshing agent, taste-masking agent or a combination thereof to the film compositions to improve the film composition taste. Flavors may be chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. Non-limiting flavor oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. In one embodiment, the flavor is a peppermint oil flavour available as peppermint oil, NF.

[0230] The amount may be varied in order to obtain the result desired m the final product. Such variations are within the capabilities of those skilled in the art without the need for undue experimentation. In general, amounts of about 0.1 % to about 30 wt % may be used m the films to supply flavoring. Suitable sweeteners include both natural and artificial sweeteners. Nonlimiting examples of suitable sweeteners include, e.g.: water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, and dihydrochalcones; water-soluble artificial sweeteners such as the soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts and water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivatives of ordinary sugar (sucrose), known, for example, as sucralose. In one embodiment, the sweetener is sucralose.

[0231] Flavoring agents, sweeteners and refreshing agents can be added in conventional quantities, generally up to a total amount of about 0.01% to about 10% of the weight of the film on a dry weight basis, e.g. from about 0.1% to about 7% of the weight of the film on a dry weight basis, e.g. about 0.1% to about 5% based on the weight of the film on a dry weight basis.

[0232] Other taste-masking agents include, for example polymers, oils, or waxes. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is coated with a taste-masking agent prior to formulation of the film compositions. In some embodiments, if a taste-masking agent is used to coat the active ingredient, it may be present in an amount of from about 5% to about 80% by weight of the particle or granule containing the active ingredient. In another embodiment, the taste-masking agent is present in an amount from about 25% to about 35% by weight of the particle or granule containing the active ingredient.

[0233] Antioxidants

[0234] Examples of oxygen scavengers or antioxidants that substantially improve long-term stability of the film composition against oxidative degradation include sulfite salts, such as sodium sulfite, sodium bisulfite, sodium metabisulfite and analogous salts of potassium and calcium. A suitable amount of the sulfite salt (e g., sodium sulfite) is up to about 5%, e.g. about 0.001% to about 2% based on the weight of the film composition on a dry weight basis.

[0235] pH-adj usting agents/pH-neutralizing agents

[0236] The absorption of dexmedetomidine or a pharmaceutical acceptable salt thereof through the oral mucosa may increase m an alkaline microenvironment. As an example, this may be achieved when the film compositions are maintained at a pH of above 6, from about 6 to about 9, or about 6.5 to about 8. In some embodiments, the film may include an alkaline substance that increases the pH of the film product. Non-limiting examples of pH-adjustmg/pH-neutralizmg agents include bicarbonates (e.g., sodium bicarbonate), citrates (e.g., potassium citrate), carbonates (e.g., calcium carbonate), lactates (e.g., sodium lactate), acetates (e.g., calcium acetate), alkaline buffer (e.g. glycine), sodium hydroxide, sodium chloride or the like. An alkaline buffer, such as glycine, is one example of a pH-neutralizing agent. A suitable amount of pH adjusting/pH-neutrahzing agent present in the film composition includes, for example, up to about 10%, e.g. about 1% to about 5% based on the weight of the film composition on a dry weight basis

[0237] Permeation enhancer agents

[0238] Certain effective penetration enhancers that promote absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof across the oral mucosa include alcohols. An alcohol penetration enhancer, such as butanol, can conveniently be added to the film composition in an amount of up to about 10%, e.g. about 0.1% to about 5%, e.g. about 1% to about 3% based on the weight of the film composition on a dry weight basis.

[0239] Mucoadhesive agents

[0240] Examples of mucoadhesive agents that can be added to the film composition include, but are not limited to, sodium alginate, sodium carboxymethyl cellulose, guar gum, polyethylene oxide, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, karaya gum, methylcellulose, retene, tragacanth and the like. One mucoadhesive agent is polyethylene oxide, which may conveniently be added to the film composition in an amount of from about 20% to about 90%, e g. about 40% to about 70% based on the total weight of the film composition on a dry weight basis.

[0241] Plasticizers

[0242] Plasticizers that can be effectively employed herein include polyethylene glycol, propylene glycol, tributyl citrate, triethyl citrate and glycerol. Depending on the selected filmforming polymer(s) and other components of the film formulation, a suitable amount of plasticizer included in the film composition may typically be up to about 10%, e g. about 0.1% to about 5%, e.g. about 0.5% to about 5% based on the weight of the film on a dry weight basis. For certain applications, higher molecular weight polyethylene glycols may be utilized, including polyethylene oxide

[0243] Fillers:

[0244] Suitable fillers that can be added to a film composition of include starch, calcium salts, such as calcium carbonate, and sugars, such as lactose, glucose, sucrose, mannose, sorbitol, mannitol, galactitol, sucralose, trehalose and combinations thereof. The amount of filler that can conveniently be added to the film formulation is typically up to about 25%, e.g. about 0.5% to about 20%, e.g. about 1% to about 15%, e.g. about 2% to about 10%, based on the weight of the film composition on a dry weight basis.

[0245] Surfactants/Non-ionic solubilizers

[0246] The film typically incorporates at least one surfactant/non-iomc solubilizer including, for example, but are not limited to, a poloxamer, polyoxyl hydrogenated castor oil, glyceryl polyethylene glycol oxystearates, fatty acid glyceryl polyglyceryl esters, polyglyceryl esters, and combinations thereof. The amount of surfactant(s) that can be added to the film composition is typically up to about 5%, e.g. about 0.5% to about 3%, e.g. about 1% to about 3% based on the weight of the film composition on a dry weight basis.

[0247] Anti-foaming components

[0248] Simethicone is an example of a useful anti-foaming and/or de-foaming agent, although other anti-foaming and/or de־foaming agents may suitable be used. An anti-foaming and/or defoaming agent such as simethicone may be added to the film composition m an amount from about 0.01 % to about 5.0%, more desirably from about 0.05% to about 2.5%, and most desirably from about 0.1% to about 1.0% based on the weight of the film composition on a dry weight basis. [0249] Colorants

[0250] Color additives that may be included in a film composition include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants. Certain examples of color additives are inorganic pigments, such as oxides of iron or titanium, added in concentrations ranging from about 0.001% to about 10%, e.g. about 0.01% to about 3%, based on the weight of the film composition on a dry weigh basis. In one embodiment, the color used for the dexmedetomidine composition (i.e. the deposit composition) is different from the color used for the film substrate (e.g. the placebo film). One color of the monolithic film and the film substrate of the micro-deposited film is emerald green, and available as Fast Emerald Green Shade (06507). One color of the dexmedetomidine composition (i.e. the deposit composition) is a different color from the color of the film substrate, e.g. blue (available as FD&C Blue No. 1). In some embodiments of the film embodiments of the present invention, for example, as described in aspects and embodiments hereinabove, is a film comprising about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof containing two blue color microdeposited spots of dexmedetomidine hydrochloride on the green color film substrate .

[0251] In some embodiments of the film embodiments of the present invention, for example, as described in aspects and embodiments hereinabove, is a film comprising about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0252] In one embodiment (A), there is provided a self-supporting, dissolvable, film, comprising:

(1) about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. the hydrochloride salt);

(11) one or more water-soluble polymers;

(iii) a polyethylene oxide and, optionally, (iv) one or more pharmaceutically acceptable carriers.

[0253] In another embodiment (B), there is provided a self-supporting, dissolvable, film, comprising:

(1) about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. the hydrochloride salt);

(11) one or more water-soluble polymers;

(iii) a polyethylene oxide and, optionally, (iv) one or more pharmaceutically acceptable earners.

[0254] In a particular embodiment, the just-mentioned one or more water-soluble polymers (ii) of embodiment (A) or (B) above comprises a low molecular weight, water-soluble polymer and two high molecular weight, water-soluble polymers, for example wherein the low molecular weight, water-soluble polymer has a molecular weight from about 5,000 daltons to about 49,000 daltons (e.g. about 40,000 daltons), and each high molecular weight, water-soluble polymer has a molecular weight of greater than about 60,000 daltons (e.g. where one of the two high molecular weight, water-soluble polymers has a molecular weight of about 140,000 daltons, and the other high molecular weight, water-soluble polymer has a molecular weight of about 370,000 daltons). Each water-soluble polymer is, in some embodiments, hydroxypropyl cellulose. The polyethylene oxide, in some embodiments, has a molecular weight of about 600,000 daltons.

[0255] In certain embodiments, there is provided a pharmaceutical film composition comprising or consisting essentially of therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof and one or more excipients selected from polyethylene oxide, hydroxypropyl cellulose, sucralose, peppermint oil, Emerald green colorant, and FD&C blue colorant.

[0256] In another embodiment (C), there is provided a self-supporting, dissolvable, film, comprising:

(1) about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. the hydrochloride salt);

(11) a low molecular weight, water-soluble polymer having a molecular weight of about 40,000 daltons;

(lii) a high molecular weight, water-soluble polymer having a molecular weight from about 140,000 daltons;

(iv) a high molecular weight, water-soluble polymer having a molecular weight from about 370,000 daltons; and (v) a water-soluble polyethylene oxide having a molecular weight of about 600,000 daltons.

[0257] In another embodiment (D), there is provided a self-supporting, dissolvable, film, comprising:

(i) about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. the hydrochloride salt);

(ii) a low molecular weight, water-soluble polymer having a molecular weight of about 40,000 daltons;

(in) a high molecular weight, water-soluble polymer having a molecular weight from about 140,000 daltons;

(iv) a high molecular weight, water-soluble polymer having a molecular weight from about 370,000 daltons; and (v) a water-soluble polyethylene oxide having a molecular weight of about 600,000 daltons.

[0258] In a particular embodiment of the just-mentioned films of embodiments (C) and (D), the film components excluding dexmedetomidine or a pharmaceutically acceptable salt thereof form a single layer film substrate, and dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate (e.g. within a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, a low molecular weight, watersoluble polymer having a molecular weight of about 40,000 daltons, and a high molecular weight, water-soluble polymer having a molecular weight of about 140,000 daltons). Each water-soluble polymer is, in some embodiments, hydroxypropyl cellulose.

[0259] In another embodiment (E), there is provided a self-supporting, dissolvable, film, comprising:

(a) a composition consisting essentially of:

(i) about 180 pg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b).

[0260] In another embodiment (F), there is provided a self-supporting, dissolvable, film, comprising:

(a) a composition consisting essentially of:

(i) about 120 pg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b).

[0261] In a particular embodiment of the just-mentioned films of embodiments (E) and (F), dexmedetomidine hydrochloride is present at about 0.1% to about 2% w/w of the total film weight, hydroxypropyl cellulose (40,000MW) is present at about 4% to about 8 % w/w of the total film weight, hydroxy propyl cellulose (I40,000MW) is present at about 4% to about 8 % w/w of the total film weight, hydroxypropyl cellulose (370,000MW) is present at about 25 % to about

30% w/w of the total film weight, and polyethylene oxide (600,000MW) is present at about 50% to about 60% w/w of the total film weight.

[0262] In some embodiments, the pharmaceutical composition of the present disclosure provides detectable Cmax of dexmedetomidine in human plasma concentration after single dose administration and multiple dose administrations of the pharmaceutical composition of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure provides a Tmax of dexmedetomidine in human plasma concentration after a single dose administration or multiple dose administrations of the pharmaceutical composition of the present disclosure. In some embodiments, pharmaceutical compositions of the present disclosure provides detectable Area Under the Curve (AUC) of dexmedetomidine and its metabolites in human plasma concentration after single dose administration or multiple dose administrations. In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 (the time of administration) to 12 hours from the time 0 and is expressed as AUC012h. In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 (the time of administration) to 24 hours from the time 0 and is expressed as AUC0-24h. In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 to the last measurable concentration and is expressed as AUCo-iast. In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 (the time of administration) to time extrapolated to infinity and is expressed as AUCo-inf. In some embodiments, the ranges and values for AUCo-iast and AUCo-inf for dexmedetomidine (or its metabolites) are similar to the ranges and values for AUC0-6hfor dexmedetomidine (or its metabolites). Thus, in some embodiments, the ranges and values for AUC0-6h disclosed herein can also serve as the ranges and values for AUColast and AUCo-inf.

[0263] In some embodiments, administration of film (E) oromucosally (e.g. sublingually or buccally) to subjects with schizophrenia at about 180 pg of dexmedetomidine hydrochloride resulted in pharmacokinetic parameters from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L, Tmax from about 1 hours to about 8 hours and AUGast from about 500 hr*ng/'L to about 8900 hr*ng/L. In some embodiments, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 525 ng/L, about 550 ng/L, about 575 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L. In some embodiment, the Tmax is about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 11, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 11, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, or about 10 h. In some embodiments, the AUCiast is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng,%, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng I . about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, about 5500 hr*ng/L, about 5750 hr*ng I . about 6000 hr*ng/L, about 6250 hr*ng/L, about 6500 hr*11g/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, or about 11875 hr*ng/L. In some embodiments, the film is administered sublingually.

[0264] In some embodiments, administration of film (F) oromucosally (e g. sublingually or buccallyjto subjects with schizophrenia at about 120 pg of dexmedetomidine hydrochloride resulted m pharmacokinetic parameters from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400ng/L, Tmax from about 1 hours to about 4 hours and AUCiast from about 500 hr*ng/L to about 4200 hr*ng/L. In some embodiments, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, or about 500 ng/L. In some embodiments, the Tmax is about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h. In some embodiments, the AUCiast is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ngZL, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ngZL, about 2000 hr*ngZL, about 2250 hr*ngZL, about 2500 hr*ng'L, about 2750 hr*ng/'L, about 3000 hr*ng/L, about 3250 hr*ngZL, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ngZL, about 4250 hr*ngZL, about 4500 hr*ngZL, about 4750 hr*ng'L, about 5000 hr*ng/L, about 5250 hr*ng/L, or about 5500 hr*ng/L. In specific embodiment, the film is administered sublingually.

[0265] In some embodiments, the present disclosure provides pharmaceutical buccal film compositions comprising or consisting essentially of therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof one or more mucoadhesive polymers and optional excipients selected from one or more of plasticizers, penetration enhancers, coloring agents, sweetening agents, flavoring agents, taste-making agents or salivary stimulants. Mucoadhesive polymers may be selected from hydrophilic polymers and hydrogels. Examples of hydrophilic polymers include polyvinyl alcohol [PVA], sodium carboxy methylcellulose [NaCMC], hydroxyl propyl methyl cellulose [HPMC], hydroxyl ethyl cellulose and hydroxypropyl cellulose [HPC], Examples of hydrogels include anionic polymers like carbopol, polyacrylates, cationic polymers like chitosan and non-ionic polymers like Eudragit analogues.

[0266] Sprays, drops or gels

[0267] In some embodiments, the present disclosure provides pharmaceutical spray compositions or drop compositions suitable for sublingual or buccal administration comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable liquids (from about 1% to about 99.995% by weight). Such liquids may be solvents, co-solvents, or non-solvents for dexmedetomidine or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerine, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.) or the like. The pharmaceutically acceptable liquid is selected either to dissolve dexmedetomidine or pharmaceutically acceptable salt thereof, to produce a stable, homogenous suspension of it, or to form any combination of a suspension or solution. In addition to these ingredients, spray or drop formulations of dexmedetomidine or pharmaceutically acceptable salt thereof may include one or more excipients such as viscosity modulating materials (e.g. polymers, sugars, sugar alcohols, gums, clays, silicas, and the like, such as polyvinylpyrrolidone (PVP)); preservatives (e.g., ethanol, benzyl alcohol, propylparaben and methylparaben); flavoring agents (e.g. peppermint oil), sweeteners (e.g., sugars such as sucrose, glucose, dextrose, maltose, fructose, etc.), artificial sweeteners (e.g. saccharin, aspartame, acesulfame, sucralose), or sugar alcohols (e.g. mannitol, xylitol, lactitol, maltitol syrup); buffers and pH-adjustmg agent (e.g., sodium hydroxide, citrate, and citric acid); coloring agents; fragrances, chelating agents (e.g., EDTA); UV absorbers and antifoam agents (e.g., low molecular weight alcohols, dimethicone). In addition to one or more of the aforementioned ingredients suitable for sublingual or buccal sprays or drops, gel formulations of dexmedetomidine or pharmaceutically acceptable salt thereof may include one or more excipients such as viscosity modulating materials (e.g. water soluble or water swellable polymers such as carbopol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose). [0268] Sprays, drops, and gels may be made by mixing appropriate quantities of the foregoing ingredients in accordance with standard good manufacturing practices. Such excipients may be included in the formulation to improve patient or subject acceptance or taste, to improve bioavailability, to increase shelf-life, to reduce manufacturing and packaging costs, to comply with requirements of governmental regulatory agencies, and for other purposes. The relative amounts of each ingredient should not interfere with the desirable pharmacological and pharmacokinetic properties of the resulting formulation.

[0269] In some embodiments, there is provided an oromucosal spray composition comprising or consisting essentially of therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier or excipients.

[0270] A patient may, in one embodiment, be treated by administering sublingually or buccally 1 to 2 actuations from a spray pump. An advantage of spray delivery is the ability to easily titrate patients by I or 2 doses as required by a single actuation.

[0271] Pump action sprays are characterized in requiring the application of external pressure for actuation, for example, external manual, mechanical or electrically initiated pressure. This is in contrast to pressurized systems, e.g., propellant-driven aerosol sprays, where actuation is typically achieved by controlled release of pressure e.g., by controlled opening of a valve.

[0272] Various sublingual spray formulations comprising dexmedetomidine hydrochloride at doses of 20 pg, 30 pg, 60 pg, 90 pg, 120 pg and 180 pg and excipients as described in table 1.

[0273] Table 1: Sublingual spray formulation embodiments according to the disclosure

<td rowspan="2"> Ingredients</td><td colspan="4"> Sublingual Spray Formulation Embodiment No.</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> N-methylpyrrolidone</td><td></td><td></td><td></td><td></td>

<td> Propylene Glycol</td><td></td><td> /ץ</td><td></td><td></td>

<td> Polyethylene Glycol</td><td></td><td></td><td> /י</td><td></td>

<td> Glycerine</td><td></td><td></td><td></td><td> /ץ</td>

<td> Ethanol</td><td></td><td></td><td> /ן</td><td> /י</td>

<td> Sucralose</td><td> z</td><td> /ץ</td><td> /ץ</td><td></td>

<td> Peppermint Oil</td><td> /י</td><td> /י</td><td> /י</td><td> ¾/</td>

<td> Purified water</td><td></td><td> /ו</td><td> /ו</td><td></td>

<td> Optionally other pharmaceuti cal ly acceptable excipients</td><td></td><td></td><td></td><td></td>

BXTl-039/01WO (332712-2151)

[0274] Various sublingual drop compositions comprising dexmedetomidine hydrochloride at doses of 20 pg, 30 pg, 60 pg, 90 pg, 120 pg and 180 pg and excipients as described in table 2.

[0275] Table 2. Sublingual drop formulations embodiments according to the disclosure

<td rowspan="2"> Ingredients</td><td colspan="6"> Sublingual Dro</td><td> 1 Formu</td><td colspan="7"> ation Embodiment No.</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td> 10</td><td> 11</td><td> 12</td><td> 13</td><td> 14</td>

<td> Povidone</td><td> Z</td><td></td><td> z</td><td></td><td> z</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> N-methylpyrrolidone</td><td></td><td></td><td></td><td></td><td></td><td> z</td><td></td><td></td><td></td><td> Z</td><td></td><td></td><td></td><td></td>

<td> Hydroxypropyl methylcellulose</td><td></td><td></td><td></td><td></td><td></td><td> z</td><td></td><td> Z</td><td> Z</td><td></td><td></td><td></td><td></td><td></td>

<td> Carbopol</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> z</td><td> z</td><td> z</td><td> Z</td><td> z</td>

<td> Polyethylene glycol</td><td></td><td></td><td> z</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> z</td><td></td><td></td>

<td> Propylene glycol</td><td></td><td> z</td><td></td><td></td><td></td><td></td><td> ✓</td><td></td><td></td><td></td><td> z</td><td></td><td></td><td></td>

<td> Glycerine</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> z</td><td></td><td></td><td></td><td> z</td><td></td>

<td> Ethanol</td><td></td><td></td><td></td><td></td><td> z</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> z</td>

<td> Sucralose</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td>

<td> Peppermint Oil</td><td></td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td>

<td> Purified water</td><td></td><td> ✓</td><td> z</td><td> ✓</td><td> z</td><td> ✓</td><td> z</td><td> ✓</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td>

<td> Optionally other pharmaceutically acceptable excipients</td><td> ✓</td><td> z</td><td> ✓</td><td> z</td><td> ✓</td><td> z</td><td> ✓</td><td> z</td><td> Z</td><td> z</td><td> z</td><td> z</td><td> z</td><td> z</td>

229408712 v3

BXTI-039/01WO (332712-2151)

[0276] Various sublingual gel compositions comprising dexmedetomidine hydrochloride at doses of 20 gg, 30 gg, 60 gg, 90 gg, 120 gg and 180 gg and excipients as described in table 3.

[0277] Table 3. Sublingual gel formulations embodiments according to the disclosure.

<td rowspan="2"> Ingredients</td><td colspan="5"> Sub</td><td colspan="10"> mgual Gel Formulation Embodiment Nos,</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td> 10</td><td> 11</td><td> 12</td><td> 13</td><td> 14</td><td> 15</td>

<td> Carbopol</td><td> /י</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> /י</td><td></td><td></td>

<td> Hydroxypropyl methyl cellulose</td><td></td><td> /ר</td><td></td><td></td><td> /י</td><td></td><td></td><td> /י</td><td></td><td></td><td> Ζ</td><td></td><td></td><td> V</td><td></td>

<td> Hydroxypropyl cellulose</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Carboxymethyl cellulose</td><td></td><td></td><td> /ר</td><td></td><td></td><td> z</td><td></td><td></td><td></td><td></td><td></td><td> V</td><td></td><td></td><td> 3/</td>

<td> AMdethy !pyrrolidone</td><td></td><td></td><td></td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Propylene glycol</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> /י</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Polyethylene glycol</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> /י</td><td></td><td> 3/</td><td> V</td><td></td><td></td><td></td>

<td> Glycerine</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> V</td><td> V</td>

<td> Ethanol</td><td> J</td><td> V</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Sucralose</td><td> /י</td><td> Z</td><td> /י</td><td></td><td></td><td> V</td><td> 3/^</td><td> γ</td><td></td><td> /ו</td><td> /י</td><td></td><td> /י</td><td> 3/^</td><td> /י</td>

<td> Peppermint oil</td><td></td><td> /י</td><td></td><td> /י</td><td></td><td> /ד</td><td> /י</td><td></td><td> γ</td><td></td><td></td><td></td><td> 3/^</td><td></td><td></td>

<td> Purified water</td><td> /י</td><td> V</td><td> /י</td><td></td><td></td><td></td><td> 3/^</td><td> γ</td><td></td><td> /ד</td><td> /י</td><td> 3/</td><td> /י</td><td></td><td> /י</td>

<td> Optionally other pharmaceutically acceptable excipients</td><td></td><td></td><td></td><td> /י</td><td></td><td> z</td><td> /י</td><td></td><td> 3/</td><td></td><td> 3/</td><td> V</td><td> 3/^</td><td> 3/</td><td> 3/</td>

229408712 v3

[0278] Tablets

[0279] In some embodiments, the present disclosure provides tablet formulations suitable for oromucosal administration(e,g. sublingual or buccal administration) comprising or consisting essentially of therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier (from about 1% to about 99.995% by weight). Such carriers may be taste masking agents, diluents, disintegrants, binders, lubricants, glidants, flavouring agents or liquid solvents. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerine, N&amp;#1470;methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.) or the like. Taste masking agents include, for example, amberlite, Opadry® AMB TAN, polymethacrylates (especially Eudragit® Li 00), sodium starch glycolate (Primojel), carbopol polymers, PEG-5M, sodium acetate, ethylcellulose, betacyclodextrin. Flavouring agents may be, for example, mint powder, menthol, vanillin, aspartame, acesulfame potassium, saccharin. Disintegrants include, for example, sodium starch glycolate, low-substituted hydroxy propyl cellulose, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxyniethylcellulose sodium, croscarmellose sodium, guar gum, methylcellulose, polacrilin potassium, poloxamer, sodium alginate. Diluents may be, for example, microcrystalline cellulose, dextrates, dextrose, fructose, mannitol, sucralose, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, maltitol. Binders may be, for example, alginic acid, carbomer, ethyl cellulose, gelatine, liquid glucose, guar gum, hydroxyethyl cellulose, methylcellulose, polydextrose, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate. At least one lubricant may conveniently be incorporated into the formulation to prevent the powder from adhering to tablet punches during the compression procedure. Lubricants may be, for example, talc, magnesium stearate, calcium stearate, glyceryl behenate, hydrogenated castor oil, stearic acid, sodium lauryl sulphate. Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction. Glidants, may be, for example, colloidal silicon dioxide, calcium silicate, calcium phosphate tribasic.

[0280] Various buccal tablet formulations comprising dexmedetomidine hydrochloride at doses of 20 pg, 30 pg, 60 pg, 90 pg, 120 pg and 180 pg and excipients as described in table 4.

[0281] Table 4: Buccal tablet formulation embodiments according to the disclosure.

<td rowspan="2"> Ingredients</td><td colspan="5"> Buccal Tablet Formulation Embodiment No,</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td> Lactose monohydrate</td><td></td><td> y</td><td></td><td> y</td><td></td>

<td> Polyethylene oxide</td><td> z</td><td></td><td></td><td></td><td></td>

<td> Hydroxypropyl cellulose</td><td></td><td></td><td></td><td></td><td></td>

<td> Hydroxypropyl methylcellulose</td><td></td><td></td><td></td><td></td><td> z</td>

<td> Sodium alginate</td><td></td><td></td><td></td><td></td><td></td>

<td> Xanthan gum</td><td></td><td></td><td></td><td></td><td></td>

<td> Sucralose</td><td> /י</td><td> /י</td><td></td><td> /י</td><td> /ד</td>

<td> Magnesium stearate</td><td></td><td></td><td> /ץ</td><td></td><td> z</td>

<td> Talc</td><td></td><td></td><td> /י</td><td></td><td> z</td>

<td> Optionally other pharmaceutically acceptable excipients</td><td></td><td></td><td></td><td></td><td> /י</td>

BXTL039/01WO (332712-2151)

[0282] Various sublingual tablet compositions comprising dexmedetomidine hydrochloride at doses of 20 pg, 30 pg, 60 pg, 90 pg, 120 pg and 180 pg and excipients as described in table 5.

[0283] Table 5: Sublingual tablet formulation embodiments according to the disclosure.

<td rowspan="2"> Ingredients</td><td colspan="6"> Sublingual Tablet Formulation Em</td><td colspan="4"> jodiment No.</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> ר</td><td> 8</td><td> 9</td><td> 10</td>

<td> Lactose Monohydrate</td><td> y</td><td></td><td></td><td> /ו</td><td> /ו</td><td> ν'</td><td> /י</td><td></td><td></td><td> /ו</td>

<td> Hydroxypropyl methylcellulose</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Hydroxypropyl cellulose</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Croscarmellose Sodium</td><td></td><td></td><td></td><td></td><td> z</td><td></td><td> ν'</td><td></td><td> /ץ</td><td></td>

<td> Sodium starch glycolate</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Polyethylene oxide</td><td></td><td></td><td></td><td></td><td></td><td> /י</td><td></td><td></td><td></td><td></td>

<td> Xanthan gum</td><td></td><td></td><td></td><td></td><td></td><td></td><td> /י</td><td></td><td></td><td></td>

<td> Sodium alginate</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> /י</td><td></td>

<td> Sucralose</td><td></td><td></td><td></td><td> /ו</td><td> /ו</td><td> ν'</td><td> /י</td><td></td><td></td><td> /י</td>

<td> Magnesium stearate</td><td></td><td> y/</td><td> y/</td><td> ν'</td><td> V</td><td></td><td> '/י</td><td></td><td></td><td> '/י</td>

<td> Optionally other pharmaceutically acceptable excipients</td><td></td><td></td><td></td><td> /י</td><td> V</td><td></td><td></td><td></td><td></td><td></td>

229408712 v3

[0284] It it ran a sol Formulations

[0285] The compositions of the disclosure may be administered to the nasal cavity in any suitable form. For example, the composition may be administered to the nasal cavity m the form of a spray emulsion, suspension or solution, as drops or as a powder.

[0286] A powder blend according to the present disclosure may be prepared by mixing dexmedetomidine or a pharmaceutically acceptable salt thereof with inert ingredients that are standard in the art. Such inert ingredients include, but are not limited to diluents such as calcium phosphate, lactose, sugars such as dextrose and sucrose, polyols such as mannitol and sorbitol, and microcrystahine cellulose, glidants such as colloidal silica and lubricants such as magnesium stearate and hydrogenated vegetable oil and surfactants such as polysorbates; and polyethylene glycol. For preparing a uniform powder blend on a small scale, a pestle and mortar and/or sieve may be appropriate whereas mechanical mixers are required for larger scale manufacture. There are numerous types of mixers available and these are widely described in the literature, for example Chapter 37, Remington: The Science and Practice of Pharmacy, 20 Edition, Lipincott, Williams and Wilkins, Baltimore, 2000.

[0287] If the powder composition of the disclosure comprises granules, these granules may be produced by techniques well known to those skilled in the art such as wet granulation, dry granulation (slugging), extrusion/spheronisation, fluid bed granulation and spray congealing. Further details on granulation processes may be found in the literature, for example Chapter 6, Pharmaceutical Principles of Solid Dosage Forms, J. T. Carstensen, Technomic, Lancaster, PA, 1993.

[0288] In addition to dexmedetomidine or a pharmaceutically acceptable salt thereof, other ingredients may be incorporated into the granules. Such other ingredients include, but are not limited to diluents such as calcium phosphate, lactose, dextrose, mannitol and microcrystalline cellulose, binders such as povidone (polyvinylpyrrolidone), methylcellulose, polyethylene glycol, gelatin and acacia, disintegrants such as starch, croscarmellose and crospovidone, glidants such as colloidal silica, and lubricants such as magnesium stearate and hydrogenated vegetable oil. Methods for preparation of microspheres are well known to those skilled in the art and include, but are not limited to, spray drying, interfacial polymerisation, coarcervation/phase separation and solvent evaporation. Methods for producing microspheres are described in, for example, Physicochemical Principles of Pharmacy, 3rd Edition, pages 357 to 360, A T Florence and D

Attwood, Macmillan, London, 1998 and Physical Pharmacy, 4th Edition, pages 516 to 519, A Martin, Wilkins and Wilkins, Baltimore, 1993. The microspheres may alternatively be produced using the methods described in W098/30207 and the documents cited therein.

[0289] The powder compositions of the present disclosure may be administered to the subject in aerosolised form whereby energy from patient inhalation (sniffing) is used to aerosolise the powder into the nasal cavity or where the device itself provides the aerosolisation energy, such as via compressed air. An example of the former device is manufactured by Pfeiffer and an example of the latter is the Monopowder” manufactured by Valois. The present invention also provides a nasal drug delivery device or a dose cartridge for use in a nasal delivery device loaded with a composition as defined above.

[0290] In one embodiment, the compositions of the disclosure also disclose the process for preparing the solutions of the disclosure comprises mixing the components in a suitable solvent such as water, ethanol, propylene glycol, polyethylene glycol, glycofurol, benzyl benzoate and polyoxyethylene castor oil derivatives. The compositions may be prepared using methods known in the art.

[0291] The solutions of the present disclosure may also contain other pharmaceutically acceptable ingredients well known in the art. Such ingredients include, but are not limited to, thickening, adhesive or gelling agents, such as, but are not limited to, celluloses (e.g. hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose and microcrystalline cellulose), carbomers, polyethylene oxide, poloxamers or polyethylene glycols, antioxidants (for example sodium metabisulphite), chelating agents (such as edetic acid or one of its salts), preservatives (such as potassium sorbate, parabens, phenylethyl alcohol or benzalkonium chloride), flavours, sweeteners, thickening, adhesive or gelling agents, including, but are not limited to, celluloses such as hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, sodium carboxyl cellulose and microcrystalline cellulose, poloxamers, polyethylene glycols, carbomers or polyethylene oxide.

[0292] The solutions of the disclosure may contain a preservative and/or are sterile. If preservatives are omitted from the compositions, microorganisms may be removed using any suitable method known m the art, for example by making the compositions aseptically or by terminally sterilising them. In some embodiments, the compositions of the invention are nonpyrogenic.

[0293] In one embodiment, intranasal compositions of the present disclosure comprise aqueous suspension, solution, or emulsion containing materials in addition to the active ingredient, such as suitable dispersant and/or wetting agent, for example propylene glycol or polyethylene glycol, emulsifier, suspending agent, surfactant, solubilizer, vehicle etc.

[0294] The pharmaceutical composition may also be formulated as liposomes, microcapsules or centrosomes, with one or more suitable pharmaceutically acceptable carrier.

[0295] In addition to dexmedetomidine or a pharmaceutically acceptable salt thereof, microspheres used in the present disclosure may include ingredients that are known in the art to be suitable to be included in microspheres such as, but are not limited to, starches, dextrans, gelatin, albumin, collagen, hyaluronic acid, chitosan, lactose, sucrose, dextrose, mannitol, methacrylate copolymers such as the Eudragit® polymers (Degussa, Germany), celluloses such as methylcellulose, and polyesters such as poly(lactide-co-glycolide).

[0296] Any device that is suitable for intranasal administration can be used. In some embodiments, the device is a metered dose device. The metered dose device can deliver a specific dosage amount of the composition. The metered dose device can be a unit-dose, bi-dose, or a multi-dose device. The pharmaceutically effective amount that can be administered using a metered dose device can be a unit dose device. The metered dose can, in some embodiments, be a device that can deliver a pharmaceutical composition intranasally. Examples of metered dose devices include, but are not limited to, devices that are pump devices, mechanical devices, pressurized devices, and/or electromechanical devices. Examples of a metered dose device include, but are not limited to, a spray pump, a pre-compression nasal spray pump, a metered valve device, an actuated spray device, a side actuated spray device, a syringe nasal spray device (e.g. a syringe that has an atomizer to deliver a spray to the nasal cavity), a mucosal atomization device, an electromechanical pump device (with and without a counter), and the like. Examples of metered dose devices also include, but are not limited to, devices manufactured by Aptar Pharma (Congers, NY) and are commercially available. Examples of metered dose devices also include, but are not limited to, UDS (Aptar Pharma), BDS (Aptar Pharma), eDevices (Aptar Pharma), Equadel (Aptar Pharma), Latitude (Aptar Pharma), DF30 (Aptar Pharma), VP7 (Aptar Pharma), Classic Nasal Device (Aptar Pharma), MAD Nasal Drug Device (Wolf Tory Medical, Inc ), BD Accuspray SCF™ (Becton Dickinson), and the like. Another example includes, but is not limited to, an .Aptar Unitdose Intranasal System.

[0297] Parenteral formulations:

[0298] Liquid pharmaceutical compositions for parenteral administration may be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion can include, but are not limited to, intravenous, intraperitoneal, intramuscular, intrathecal, and subcutaneous. In some embodiments, parenteral formulations can include prefilled syringes, vials, powder for infusion for reconstitution, concentrate for infusion to be diluted before delivery (ready to dilute) or solutions (ready to use).

[0299] Injectable pharmaceutical compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.

[0300] The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.

[0301] In certain embodiments, the pharmaceutical compositions of the present disclosure include biodegradable subcutaneous implant, osmotically controlled device, subcutaneous implant, subcutaneous sustained release injection, lipid nanoparticles, liposomes, and the like. Liquid preparations can include, but are not limited to, solutions, suspensions and emulsions. Such preparations are exemplified by water or water/propylene glycol solutions for parenteral injection. Liquid preparations may also include solutions for intranasal administration.

[0302] For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active mgredient(s) are usually employed, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of the solute(s) should be controlled to render the preparation isotonic.

[0303] The liquid vehicle used for the preparation of the intramuscular injection may be, for example, water, a saline solution, another aqueous liquid (aqueous solvent) or non-aqueous liquid (non-aqueous solvent). Non-aqueous solvents may include organic solvents such as ethanol, isopropyl alcohol, diethylene glycol monoethyl ether or other alkyl derivative, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like) or oily vehicles such as castor oil, arachis oil, sesame oil, or other solvents such as carboxymethylcellulose, polysorbate and mixtures thereof. These aqueous and non-aqueous solvents can also act as a co-solvent to increase the solubility of drugs or to reduce the viscosity of oily vehicles.

[0304] The formulation may contain an excipient. Pharmaceutically acceptable excipients which may be included in the formulation are buffers such as citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer; amino acids; urea; alcohols; ascorbic acid; phospholipids; proteins, such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA, and sodium chloride; liposomes; polyvinylpyrrolidones; sugars, such as dextran, mannitol, sorbitol, and glycerol; propylene glycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol; glycine; lipids; preservatives; suspending agents; stabilizers; and dyes. As used herein, the term “stabilizer” refers to a compound optionally used in the pharmaceutical compositions of the present invention in order to avoid the need for sulphite salts and increase storage life. Non-limiting examples of stabilizers include antioxidants. Buffer systems for use with the formulations include citrate; acetate; bicarbonate; and phosphate buffers.

[0305] The formulation also may contain a non-ionic detergent. Examples of non-ionic detergents include but are not limited to Polysorbate 20, Polysorbate 80, Triton X-100, Triton X-l 14, Nonidet P-40, Octyl a&amp;#1470;glucoside, Octyl β-glucoside, Brij 35, Pluronic, and Tween 20.

[0306] The parenteral formulations of the present disclosure can be sterilized. Non-limiting examples of sterilization techniques include filtration through a bacterial-retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, and heating.

[0307] Administration of the above-described parenteral formulations may be by periodic injections of a bolus of the preparation, or may be administered by intravenous or intraperitoneal administration from a reservoir which is external (e.g., an intravenous bag) or internal (e.g., a bioerodable implant, a bioartificial or organ). See, e.g., U.S. Patent Nos. 4,407,957 and 5,798,113, each incorporated herein by reference in their entireties. Intrapulmonary delivery methods and apparatus are described, for example, in U.S. Patent Nos. 5,654,007, 5,780,014, and 5,814,607, each incorporated herein by reference in their entireties. Other useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, pump delivery, encapsulated cell delivery, liposomal delivery, needle-delivered injection, needleless injection, nebulizer, aerosolizer, electroporation, and transdermal patch. Needle-less injector devices are described in U.S. Patent Nos. 5,879,327; 5,520,639; 5,846,233 and 5,704,911, the specifications of which are herein incorporated herein by reference in their entireties. Any of the formulations described herein can be administered in these methods. Further injectable formulations of dexmedetomidine are disclosed in U.S. Patent No. 8,242,158, U.S. Patent No.

9,649,296, JP. Patent No. 5,921, 928, JP. Pat. Appl. No. 2016154598, CN Pat. Appl. No. 103284945, CN Pat. Appl. No. 104161760, CN Pat. Appl. No. 105168122, CN Pat. Appl. No. 105534891, CNPat. Appl. No. 106038538, U.S. Pat. Appl. No. 20170128421, CNPat. Appl. No. 107028880, CN Pat. Appl. No. 107412152, CN Pat. Appl. No. 108498469, EP Patent. No. 2252290, JP. Pat. Appl. No. 2019048091 and U.S. Pat. Appl. No. 20190183729.

[0308] In certain non-iimiting embodiments, the dexmedetomidine intramuscular composition of the present disclosure comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a concentration of between about 0.05 ug/mL and about 15 pg/mL, sodium chloride at a concentration of between about 0.01 and about 2.0 weight percent and pH in the range of about 1 to about 10.

[0309] Oral formulations:

[0310] The present disclosure includes oral formulations that can be used for delivering dexmedetomidine. Examples of oral formulations includes tablets, orally disintegrating tablets, mouth dissolving tablets, wafers, solution, suspension, emulsions, and capsules.

[0311] The disclosure encompasses oral disintegrating tablets comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one orally disintegrating carrier, wherein the oral disintegrating tablet disintegrates in about 0.5 to about 120 seconds and/or a therapeutically effective amount of the dexm edetomidine is absorbed into the bloodstream within about 1 to about 5 minutes. In some embodiments, a therapeutically effective amount of the dexmedetomidine is absorbed into the bloodstream within about 3 minutes,

[0312] In some embodiments, the at least one orally disintegrating carrier is selected from the group consisting of water-soluble sugars or sugar alcohol, crospovidone, (low-substituted) hydroxypropyl cellulose, croscarmellose sodium, microcrystalline cellulose, lactose, pregelatinized starch, sodium starch glycolate, sodium lauryl sulphate, crystalline cellulose and the combination thereof. The water-soluble sugars or sugar alcohol is selected from the group consisting of sucrose, sorbitol, mannitol, xylitol, erythritol, isomalt and fructose. In some embodiments, the orally disintegrating carriers together constitute at least 50 wt.%, for example at least 80 wt.% or at least 85 wt.% of the orally disintegrating carriers. The aforementioned carriers are in the form of particles typically have a volume weighted mean particle size of 50-300 micrometers, for example of 70-200 micrometers. F-Melt® (Fuji Chemical Industry Co.) is an example of a commercially available particulate material that contains a disintegrating agent dispersed in a matrix containing C4-C6 sugar alcohol (mannitol and xylitol). Ludiflash® (BASF) is another example of a commercially available particulate material that contains a disintegrating agent dispersed in a matrix of C4-C6 sugar alcohol (mannitol).

[0313] The orally disintegrating tablet as used herein may be prepared by mixing the dexmedetomidine with water-soluble diluents and compressed in a tablet. A suspension comprising dexmedetomidine may be prepared with appropriate excipients and the dexmedetomidine suspension may be dispensed into blister packs and freeze-dried. An exemplar}&amp;#1523; freeze-dried preparation platform that could be used for the dexmedetomidine ODT is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation. In particular, the excipients, including water, are blended and the dexmedetomidine is separately milled to size and mixed with the excipients. The suspension then undergoes lyophilization by flash freezing and freeze drying. Other methods of preparing ODTs may be used without limitation, and detailed description of general methods thereof have been disclosed, for example, in U.S. Pat. No 5,631,023; 5,837,287; 6,149,938; 6,212,791; 6,284,270; 6,316,029; 6,465,010; 6,471,992; 6,471,992; 6,509,040; 6,814,978; 6,908,626; 6,908,626; 6,982,251; 7,282,217; 7,425,341 ; 7,939,105; 7,993.674; 8,048,449; 8,127,516; 8,158,152; 8,221,480; 8,256,233; and 8,313,768, each of which is incorporated herein by reference in its entirety.

[0314] A liquid pharmaceutical suspension of the present disclosure for oral administration contains at least one particulate drug as active ingredient wherein active ingredient is dexmedetomidine or a pharmaceutically acceptable salt thereof. The particulate dexmedetomidine may be partially dissolved in the liquid phase, but preferably more than about 50 percent should be particulates. The suspension of the present disclosure contains at least one suspending polymer exhibiting plastic flow that imparts a yield value of about 0.2 to about 15 Pa, preferably from about 0.5 to about 10 Pa Polymers exhibiting Bingham plastic and shear-thinning plastic flow are preferred. Polymers exhibiting thixotropic plastic flow can be used only if the lag time to recover 50% of the yield value is fast, less than about an hour, preferably less than about five minutes, most preferably less than about a minute. The polymer exhibiting plastic flow may be selected from but are not limited to xanthan gum, carbomer, microcrystal line cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and combinations thereof. The final yield value of the suspension must be less than about 15 Pa, preferably less than about 10 Pa to ensure that the product is pourable without shaking.

[0315] In addition to a yield value, the rheology of the final suspension should have an apparent viscosity of at least about 50 cps, preferably at least about 100 cps, most preferably at least about 200 cps, at a shear rate of 100 sec1 &amp;#1470;&amp;#1470;&amp;#1470; to retard particle motion when the shear rate exceeds the yield value such as when shaking or pouring. For thixotropic plastic fluid, the high viscosity retards particle motion while the yield value is recovering after application of shear. When the suspending polymer(s) added to impart the yield value is not adequate to achieve the desired apparent viscosity of at least about 50 cps at a shear rate of 100 sec-1, viscosity-building agents with no yield value can be added. These viscosity-building agents may be selected from but are not limited to hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, guar gum, locust bean gum, and combinations thereof.

[0316] The liquid suspension of the present disclosure may contain additional ingredients used in the drug industry, herein referred to as additives. Additives include well-known components, but are not limited to sweetening agents, flavors, colorants, antioxidants, chelating agents, surfactants, wetting agents, antifoaming agents, pH modifiers, acidifiers, preservatives, cosolvents, and mixtures thereof.

[0317] The present disclosure concerns also a homogeneous and stable pharmaceutical solution of dexmedetomidine suitable for oral administration to a mammal.

[0318] The oral liquid pharmaceutical solution of this disclosure comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient which is selected from the group comprising co-solvents, solvents, antioxidants, microbial preservatives, buffering agents, aromatic agents, sweeteners and diluents.

[0319] Co-solvents and solvents may include but are not limited to glycerine, alcohols, propylene glycol, polyethylene glycol, benzyl alcohol, water, ethanol, isopropyl alcohol or their mixtures thereof.

[0320] Suitable antioxidants may include but are not limited to butylated hydroxyanisole (BHA), butylated hydroxy toluene (BUT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycero, cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate (sodium/acid), bisulfite sodium, cystein/cysteinate HC1, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol (thioglycerol), propyl gallate, sulfite sodium, tocopherol alpha, thioglycolate sodium, EDTA in calcium and sodium compounds or the mixtures thereof.

[0321] Buffering agents may include but are not limited to ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, trisodium citrate dehydrate, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, carbonated calcium phosphate, magnesium hydroxide, hydrochloric acid, sodium hydroxide or their mixtures thereof.

[0322] Diluents may include but are not limited to maltitol solution, glucose syrup, glycerin, sorbitol and mannitol solutions, sucrose, sorbitol, xylitol, dextrose, fructose, sugar potassium, aspartame, saccharine, saccharine sodium, spray dried or anhydrase lactose, mannitol, starch or their mixtures thereof.

[0323] Sweeteners may include but are not limited to sucralose, aspartame, acesulfame-K, thaumatin, mogroside, saccharin and salts thereof sodium cyclamate, glucose, sucrose, lactose, fructose, mannitol, sorbitol, lactitol, xylitol, erythritol, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate, isomalt, glycerine, dextrose or their mixtures thereof.

[0324] Aromatic agents may include but are not limited to fruit aromas such as orange, banana, strawberry&amp;#1523;, cherry, wild cherry-, lemon and the like, and other aromas such as cardamom, anis, mint, menthol, vanillin or their mixtures thereof.

[0325] Microbial preservatives may include but are not limited to sodium benzoate, benzoic acid, boric acid, sorbic acid and their salts thereof, benzyl alcohol, benzalkonium chloride, parahydroxybenzoic acids and their alkyl esters, methyl and propyl parabens or their mixtures thereof.

[0326] In one embodiment, the present disclosure relates to an oral solid pharmaceutical composition, e.g. in form of a tablet, comprising pharmacologically effective amounts of dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The compositions of the disclosure comprise additives conventional in the dosage form in question. Tabletting aids, commonly used in tablet formulation can be used and reference is made to the extensive literature on the subject, see in particular Fiedler's “Lexikon der Hilfsstoffe”, 4th Edition, ECV Aulendorf, 1996, which is incorporated herein by reference. These include but are not limited to disintegrants, binders, lubricants, glidants, stabilising agents, fillers or diluents, surfactants and the like.

[0327] As disintegrants suitable for compositions of this disclosure, one can particularly mention crosslinked PVP, crospovidone, guar gum, alginic acid, sodium alginate, crosslinked CMC and Ac-Di-Sol®. In some embodiments, the disintegrant is crospovidone.

[0328] As binders suitable for compositions of this disclosure, one can particularly mention starches, e.g. potato starch, wheat starch, corn starch, celluloses such as microcrystalline cellulose, e.g. products known under the registered trademarks Avicel®, Filtrak®, Heweten® or Pharmacel®, hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropylmethyl cellulose, e.g. hydroxypropyl cellulose having a hydroxypropyl content of 5 to 16% by weight and a molecular weight of from 80 000 to 1 150 000, more particularly 140 000 to 850 000.

[0329] As glidants suitable for compositions of this disclosure, one can mention in particular colloidal silica, e.g. Aerosil®, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0330] As fillers or diluents suitable for compositions of this invention, one can mention confectioner’s sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, sucrose, microcrystalline cellulose, in particular having a density of about 0.45 g/cm3, e.g. Avicel®, or powdered cellulose, and talc.

[0331] A preferred filler may be Avicel®.

[0332] As lubricants suitable for compositions of this disclosure, one can mention in particular magnesium-, aluminium-, or calcium-stearate, polyethylene glycol (PEG) having a molecular weight of 4,000 to 8,000, and talc,

[0333] One or more of these additives may be selected and used by the skilled artisan having regard to the particular desired properties of the solid oral dosage form by routine experimentation and without any undue burden. The amount of each type of additive employed, e.g. ghdant, binder, disintegrant, filler or diluent and lubricant may vary within ranges conventional in the art. For example, the amount of glidant may vary within a range of from 0.1 to 10% by weight, in particular 0.1 to 5% by weight, e.g. 0.1 to 0.5% by weight; the amount of binder may vary within a range of from about 10 to 65.3% by weight, e.g. 10 to 45%, e.g. 20 to 30% by weight; the amount of disintegrant may vary within a range of 5 to 60% by weight, e.g. 13 to 50%, e.g. 15 to 40%, e.g. 20 to 30%, e.g. 25%; the amount of filler or diluent may vary within a range of from 15 to 65% by w&amp;#1523;eight e.g. 20 to 50%, e.g. 25 to 40%, e.g. 30%, whereas the amount of lubricant may vary within a range of from 0.1 to 5.0% by weight.

IV. Methods and administration

[0334] In some embodiments (A), the present disclosure provides a method of treating a condition (e.g. agitation) m a human subject, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose of at least about 120 pg to said subject. In some embodiments, the treatment is effective without causing significant sedation. In some embodiments, the condition is agitation or signs of agitation. In some embodiments, the agitation or signs of agitation are associated with schizophrenia. In some embodiments, the agitation or signs of agitation are associated with a bipolar illness such as bipolar I disorder. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects.

[0335] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 pg to about 405 pg, such as about 120 pg to about 270 pg, or at a dose of about 180 pg to about 405 pg, such as about 180 pg to about 270 pg, including administering doses of about 120 pg or about 180 pg.

[0336] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 pg to about 405 pg, such as about 120 pg to about 270 pg, or at a dose of about 180 pg to about 405 pg, such as about 180 pg to about 270 pg, including administering doses of about 120 pg or about 180 pg, to treat agitation or signs of agitation m a human subject.

[0337] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 pg to about 405 pg, such as about 120 pg to about 270 pg, or at a dose of about 180 pg to about 405 pg, such as about 180 pg to about 270 pg, including administering doses of about 120 pg or about 180 pg, to treat agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation. [0338] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 pg to about 405 pg, such as about 120 pg to about 270 pg, or at a dose of about 180 pg to about 405 pg, such as about 180 pg to about 270 pg, including administering doses of about 120 pg or about 180 pg, to treat agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation or causing clinically significant cardiovascular effects.

[0339] In some embodiments (B), the present disclosure provides a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. the hydrochloride salt) as a single dose of about 120 gg or about 180 gg. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects.

[0340] In some embodiments, the present disclosure provides a method of treating acute agitation associated with schizophrenia and bipolar disorder (e.g. bipolar I disorder )ma human subject, comprising oromucosally administering a film composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride salt) as a single dose of 120 gg or 180 gg. In some embodiments, an additional dose (e g. 90 gg or 60 gg) may be taken after a suitable period of time (e.g. 2-hours) in the event of persistent or recurrent agitation (e.g. by cutting a 180 gg or 120 gg film in half).

[0341] In some embodiments, the present disclosure provides a method of treating acute agitation associated with schizophrenia and bipolar disorder (e.g. bipolar I disorder ) in a human subject, comprising oromucosally administering a film composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e g. hydrochloride salt), wherein the subject is co-treated with an anti-psychotic agent. Suitable anti-psychotic agents contemplated within the scope of the present disclosure include but are not limited to aripiprazole, benperidol, flupentixol, amisulpride, chlorpromazine, asenapine, risperidone, ziprasidone, lurasidone, clozapine, cariprazine, olanzapine and quetiapine. In some embodiments, the anti-psychotic agent is aripiprazole.

[0342] In a particular embodiment (C), the present disclosure provides methods of treating agitation or signs of agitation in a human subject with dementia, without also inducing significant sedation, comprising administering from about 30 gg to about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, 30 gg, 60 gg or 90 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof are administered as a single dose in a day. In some embodiments, an additional dose (e.g. 30 gg) may be taken after a suitable period of time (e.g. 2, 4, 6, 8, or 12 hours) in the event of persistent or recurrent agitation. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered as a unit dose containing about 30 gg to about 90 gg between 1 and 6 times in a day. For example, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered I, 2, 3, 4, 5, or 6 times every 2 hours, every 4 hours, every 6 hours, every 8 hours, every 10 hours, or every 12 hours. In some embodiments, each unit dose containing about 30 gg to 60 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof may be taken one to six times in a day at an interval of 2 hours with the provision of maximum of three doses within 12 hours of first dose. In some embodiments, each unit dose containing about 90 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof may be taken one to four times in a day at an interval of 2 hours with the provision of maximum of two doses within 12 hours of first dose. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosaliy (e.g. sublingually or buccaliy) as a film. In some embodiments, the dosing may be achieved by cutting a film in half to deliver a half-dose (e.g. a 60 pg dose may be administered with a half of a second 60 pg dose (30 pg) to make a 90pg dose.).

[0343] In a particular embodiment (D), the present disclosure also provides methods of managing or treating agitation in delirium in subjects, without also inducing significant sedation, comprising administering about 20 pg to about 240 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is hospitalized. In some embodiments, the subject is hospitalized m the intensive care unit. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. the hydrochloride salt) is oromucosaliy administered at a unit dose containing about 20 pg or about 60 pg as a single dose. In some embodiments, each unit dose may be administered one to four times at an appropriate dosing interval (e.g. every 0.5 hour, 1 hour, 2 hours, or 3 hours) within 6 hours of first dose to produce a desired effect; for example, 20 pg unit is administered four times at a dosing interval of 0.5 hours within 6 hours of first dose to produce the effect of a 80 pg dose or 60 pg unit is administered four times at a dosing interval of 0.5 hours within 6 hours of first dose to produce the effect of 240 pg dose. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosaliy (e.g. sublingually or buccaliy) as a film described herein.

[0344] In a particular embodiment (E), the present disclosure provides a method of reducing a period of opioid withdrawal in a human subject in need thereof, comprising administering to said subject dexmedetomidine or a pharmaceutically acceptable salt thereof twice daily, wherein the period of withdrawal is up to 14 days. In some embodiments, the period of withdrawal may be 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days. In some embodiments, the human subject is an adult (i.e. at least 18 years old) and suffering with opioid use disorder who is physically dependent on opioids. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered sublingually, buccally, orally, intranasally or parenterally. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt (e.g. hydrochloride) is administered sublingually as a film. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered at a dose range of about 30 qg to about 200 qg as a single dose. In some embodiments, dexmedetomidine is administered as a dose of about 30 qg, about 60qg, or about 90 qg, about 120 qg or about 180 qg, twice daily approximately 12 hours apart for a period of at least 3 days ( e.g. 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days or 13 days). In further embodiments, each unit may be administered at an appropriate dosing interval (e.g. about 12 hours between doses) or can be administered concurrently, for example two units of 30 qg can be administered concurrently to produce the effect of a 60 qg dose or three units of 60 qg can be administered concurrently to produce the effect of a 180 qg dose. In an embodiment, the withdrawal symptoms following the treatment are assessed using the Clinical Opiate Withdrawal Scale and/or the Short Opiate Withdrawal Scale of Gossop (e.g. over a 10-day period). In some embodiments, the opioid may be selected from the group consisting of, but are not limited to fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil or pentazocine. In some embodiments, the opioid had been administered for the amount of time longer than neonate treatment prior to withdrawal. It was unexpectedly discovered that dexmedetomidine is effective at reducing the period of opioid withdrawal in an adult subject. This is surprising because opioids (e.g. fentanyl) become localized in body fat over time and are released intermittently and have unpredictable effects on patients during the withdrawal process. Due to the high degree of variability and intermittent release of opioids, a clinician would not expect repeated administration of dexmedetomidine to be an effective therapy.

[0345] In some embodiments, the present disclosure provides a method of promoting non-rapid eye movement (non-REM) stage 3 sleep in a human subject, comprising administering sublingually an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In some embodiments, the human subject is hospitalized m ICU with hyperactive delirium.

[0346] In some embodiments, the present disclosure provides a method of treating cocaine toxicity and/or symptoms associated with cocaine toxicity comprising administering oromucosally an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as an oromucosal film at a dose range of about 30 pg to about 200 pg as a single dose or as a multi-dose therapy.

[0347] In another embodiment (F), the present disclosure provides a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. the hydrochloride salt) resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUG from TO to Teo, of about 3800 ng*h/L. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, the dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by plasma AUG from TO to Teo, is from about 80% to about 125% of 3800 ng*h/L. For example, the AUG is about 3024 ng*h/L, about 3100 ng*h/L, about 3200 ng*h/L, about 3300 ng*h/L, about 3400 ng*h/L, about 3500 ng*h/L, about 3600 ng*h/L, about 3700 ng*h/L, about 3800 ng*h/L, about 3900 ng*h/L, about 4000 ng*h/L, about 4100 ng*h F. about 4200 ng*h/L, about 4300 ng*h/L, about 4400 ng*h/L, about 4500 ng*h/L, about 4600 ng*h/L, or about 4725 ng*h/L.

[0348] In another embodiment (G), the present disclosure provides a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. the hydrochloride salt) resulting m a mean total exposure of dexmedetomidine, as measured by plasma AUG from TO to Too, of about 1800ng*h/L. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, the dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by plasma AUG from To to Teo, is from about 80% to about 125% of 1800 ng*h/L. For example, the AUG is about 1440 ng*h/L, 1500 ng*h/L, about 1600 ng*h/L, about 1700 ng*h/L, about 1800 ng*h/L, about 1900 ng*h/L, about 2000 ng*h/L, about 2100 ng*h/L, about 2200 ng*h/L, or about 2250 ng*h/L.

[0349] In a further embodiment (H), the present disclosure provides a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUG from TO to Too, from about 600 to about 9500 ng*h/L. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, the dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, is from about 80% to about 125% of about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ngZL, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hUngT, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ngZL, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hUngT, about 5000 hr*ngZL, about 5250 hr*ng/L, to about 5500 hUngT, about 5750 hr*ng/L, about 6000 hr*ngZL, about 6250 hr*ng/L, to about 6500 hr*ng%, about 6750 hr*ng/L, about 7000 hUngT, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ngZL, to about 8500 hr*ng/L, about 8750 hr*ng L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng L, about 11250 hr*ng/U, about 11500 hr*ngZL, or about 11875 hr*ng/L.

[0350] In a further embodiment (I), the present disclosure provides a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting m a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Ta:&amp;#1523;, from about 590. to about 4400ng*h/L. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, the dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, is from about 80% to about 125% of about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hwng'L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ngZL, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ngZL, about 3750 hr*ng/L, about 4000 hr*ngZL, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, or about 5500 hr*ng/L.

[0351] In some embodiments of each of embodiments (A) to (I), dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered orally, oromucosally (e.g. sublingually, buccally), intravenously, intramuscularly, subcutaneously, topically, transdermally, intratracheally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, mtraventricularly or intranasally.

[0352] In some embodiments of each of embodiments (A) to (I), dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject by the sublingual, buccal, oral, intranasal or parenteral route. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by the sublingual or buccal route. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops, particularly a film. In some embodiments, the film is placed under the tongue, close to the base of the tongue, on the left or right side. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet, particularly a film. In some embodiments, the film is placed against the inner lip or check, close to the jaw line. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally to the subject in the form of an intramuscular injection. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject by oral route. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets, orally disintegrating tablets (GDI's), effervescent tablets, capsules, pellets, pills, lozenges or troches, powders, dispersible granules, catchets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions and the like. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally to the subject in the form of an orally disintegrating tablet.

[0353] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually to the subject as a single dose containing about 180 gg dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein agitation or signs of agitation are treated without also inducing clinically significant cardiovascular effects. In some embodiments, agitation or signs of agitation is treated without diastolic blood pressure falling below about 60 mmHg and/or without heart rate falling below about 50 beats per minute.

[0354] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually to the subject as a single dose containing about 120 pg dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein agitation or signs of agitation is treated without also inducing clinically significant cardiovascular effects. In some embodiments, agitation or signs of agitation is treated without systolic blood pressure falling below about 80 mmHg and or/ without diastolic blood pressure falling below about 60 mmHg and/or without heart rate falling below about 50 beats per minute.

[0355] In certain embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting m a total exposure of dexmedetomidine, as measured by plasma AUG from TO to Teo, from about 600 to about 9500 ng*h/L, wherein the plasma Tmax is about 1 to about 8 hours. In some embodiments, the dexmedetomidine is administered as a single dose. In some embodiments, the total exposure of dexmedetomidine, as measured by plasma AUG from TO to Too, is from about 80% to about 125% of about 600 to about 9500 ng*h/L. For example, about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/&amp;#1523;L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hrongL, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, or about 11875 hr*ng/L. In some embodiments, the plasma Tmax from TO to Too, is from about

80% to about 125% of about 1 to about 8 hours. For example, about 0.8 h, about 0.9h, about I h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 11, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 11, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 11, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, or about 10 h.

[0356] In certain embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 590 to about 4400 ng*h/L, wherein the plasma Tmax is about 1 to about 4 hours. In some embodiments, the dexmedetomidine is administered as a single dose. In some embodiments, the total exposure of dexmedetomidine, as measured by plasma AUC from To to Too, is from about 80% to about 125% of about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng,%, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng,%, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, or about 5500 hr*ng/L. In some embodiments, the plasma Tmax from To to Too, is from about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, or about 5.0 h.

[0357] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 300 ng/L to about 500 ng/L (e.g. about 400 ng/L) and AUC from TO to Ta:&amp;#1523; of from about 2300 ng*π I. to about 3600 ng*h/L (e.g. about 2900 ng*h/L). For example, the Cmax is about 240 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L, or about 625 ng/L and the AUCO-inf is about 1840 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, or about 4500 hr* ng/L.

[0358] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 150 ng/L to about 350.ng/L (e.g. about 220 ng/L) and AUC from TO to Too of from about 1100. ng*h/L to about 1800 ng*h/L (e.g. about 1410 ng*h/L). For example, the Cmax is about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, and the AUCO-inf is about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, or about 2250 hr*ng/L.

[0359] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too of about 3800 ng*h/L, wherein the mean plasma Cmax is about 400 ng/L. In some embodiments, the plasma AUC from TO to Teo is from 80% to about 125% of about 3800 ng*h/L, wherein the mean plasma Cmax is from about 80% to about 125% of about 400 ng/L.

[0360] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too of about 1800 ng*h/L, wherein the mean plasma Cmax is about 200 ng/L. In some embodiments, the plasma AUC from TO to Teo is from 80% to about 125% of about 1800 ng*h/L, wherein the mean plasma Cmax is from about 80% to about 125% of about 200 ng/L.

[0361] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too of about 3800 ng*h/L, wherein the median plasma Tmax is about 2 hours. In some embodiments, the plasma AUC from TO to Too is from 80% to about 125% of about 3800 ng*h/L, wherein the median plasma Tmax is from about 80% to about 125% of about 2 hours.

[0362] In some embodiments, there is provided a method of treating agitation or signs of agitation m a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too of about 1800ng*h/L, wherein the median plasma Tmax is about 2 hours. In some embodiments, the plasma AUC from TO to Teo is from 80% to about 125% of about 1800 ng*h/L, wherein the median plasma Tmax is from about 80% to about 125% of about 2 hours.

[0363] In some embodiments, there is provided a method of treati ng agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too of about 3800 ng*h/L, wherein the mean plasma Cmax is about 400 ng/L and the median plasma Tmax is about 2 hours. In some embodiments, the plasma AUC from TO to Too is from 80% to about 125% of about 3800 ng*h/L, the mean plasma Cmax is from about 80% to about 125% of about 400 ng/L, and the median plasma Tmax is from about 80% to about 125% of about 2 hours.

[0364] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Ta:&amp;#1523; of about 1800 ng*h/L, wherein the mean plasma Cmax is about 200 ng/L and the median plasma Tmax is about 2 hours. In some embodiments, the plasma AUC from TO to Teo is from 80% to about 125% of about 1800 ng*h/L, the mean plasma Cmax is from about 80% to about 125% of about 200 ng/L, and the median plasma Tmax is from about 80% to about 125% of about 2 hours.

[0365] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Teo, from about 600 to about 9500 ng*h/L, wherein the plasma Cmax is about 100 ng/L to about 800 ng/L. In some embodiments, the plasma AUC from TO to Too is from 80% to about 125% of about 600 ng*h/L to about 9500 ng*h&amp;#1523;'L and the mean plasma Cmax is from about 80% to about 125% of about 100 ng/L to about 800 ng/L.

[0366] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Teo, from about 590 to about 4400 ng*h/L, wherein the plasma Cmax is about 110 ng/L to about 400 ng/L. In some embodiments, the plasma AUC from TO to Too is from 80% to about 125% of about 590 ng*h/L to about 4400 ng*h/L and the mean plasma Cmax is from about 80% to about 125% of about 110 ng/L to about 400 ng/L.

[0367] In certain embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Teo, from about 600 to about 9500 ng*h/L, wherein the plasma Tmax is about 1 to about 8 hours. In some embodiments, the plasma AUC from TO to Too is from 80% to about 125% of about 600 ng*h/L to about 9500 ng*h/L and the plasma Tmax is from about 80% to about 125% of about 1 to about 8 hours.

[0368] In certain embodiments, there is provided a method of treating agitation or signs of agitation m a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising sublingually administering a dose of 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUG from TO to Ta:&amp;#1523;, from about 590 to about 4400ng*h/L, wherein the plasma Tmax is about 1 to about 4. hours. In some embodiments, the plasma AUC from TO to Too is from 80% to about 125% of about 5900 ng*h/L to about 4400 ng*h/L and the plasma Tmax is from about 80% to about 125% of about 1 to about 4 hours.

[0369] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from TO to Too of about 600 hr*ng I. to about 9500 hr*ng/L.

[0370] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/L and AUC from TO to Too of about 590 hr*ng/L to about 44OO.hr*ng/'L.

[0371] In certain embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject in need thereof, without also inducing significant sedation, comprising administering an unit dose of 1 80 gg or 120 gg dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in rapid absorption with maximum concentration achieved on average within about 2.5 hours after administration.

[0372] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from TO to Ta:&amp;#1523; of about 600 hr*ng/L to about 9500 hr*ng/L. In some embodiments, the plasma Tmax is about 1 hour to about 8 hours.

[0373] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values:

Cmax from about 110 ng/L to about 400 ng/L and AUG from TO to Too of about 590hr*ng L to about 4400hr*ng/L. In some embodiments, the plasma Tmax is about! hour to about 4 hours.

[0374] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of from about 300 ng/L to about 500 ng/L (e.g. about 400 ng/L) and ALTC from TO to Too of from about 2300 ng*h/L. to about 3600 ng*h/L (e.g. about 2900 ng*h/L), In some embodiments, the plasma Tmax is about 2 hours.

[0375] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of from about 150 ng/L to about 300 ng/L (e.g. about 220 ng/L) and AUC from TO to Too of from about 1100 ng*h/L to about 1800 ng*h/L (e.g. about 1400ng*h/L). In some embodiments, the plasma Tmax is about 2 hours.

[0376] In certain embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccally administering a dose of 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 9500 ng*h/L, wherein the plasma Tmax is about 1 to about 8 hours.

[0377] In certain embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccally administering a dose of 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 590 to about 4400 ng*h&amp;#1523;'L, wherein the plasma Tmax is about 1 to about 4 hours.

[0378] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 300 ng/L to about 500 ng/L (e.g. about 400 ng/L) and AUC from TO to Too of from about 2300 ng*h/L to about 3600 ng*h/L (e.g. about 2900 ng*h/L).

[0379] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 150ng/L to about 300 ng/L (e.g. about 22O.ng/L) and AUC from TO to Too of from about 1100 ng*h/L to about 1800 ng*h/L (e.g. about 1400 ng*h/L).

[0380] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccally administering a dose of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting m a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too of about 3800 ng*h/L, wherein the mean plasma Cmax is about 400 ng/L.

[0381] In some embodiments, there is provided a method of treating agitation or signs of agitation m a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccally administering a dose of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too of about 1800 ng*h/L, wherein the mean plasma Cmax is about 200ng/L.

[0382] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccally administering a dose of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too of about 3780 ng*h/L, wherein the median plasma Tmax is about 2 hours.

[0383] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccally administering a dose of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUG from TO to Ta:&amp;#1523; of about 1800 ng*h/L, wherein the median plasma Tmax is about 2 hours.

[0384] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccaily administering a dose of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUG from TO to Too of about 3800 ng*h/L, wherein the mean plasma Cmax is about 400 ng/L and the median plasma Tmax is about 2 hours.

[0385] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccaily administering a dose of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUG from TO to Too of about 1800 ng*h/L, wherein the mean plasma Cmax is about 200ng/L and the median plasma Tmax is about 2 hours.

[0386] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccaily administering a dose of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 9500 ng*h/L, wherein the plasma Cmax is about 100 ng/L to about 800 ng/L.

[0387] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccaily administering a dose of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 590 to about 4400 ng*h/L, wherein the plasma Cmax is about 110 ng/L to about 400 ng/L.

[0388] In certain embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccaily administering a dose of about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Teo, from about 600 to about 9500 ng*h L. wherein the plasma Tmax is about 1 to about 8 hours.

[0389] In certain embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising buccally administering a dose of about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 590 to about 4400 ng*h/L, wherein the plasma Tmax is about 1 to about 4 hours.

[0390] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally to said subject, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from. TO to Teo of about 600 hr*ng,D to about 9500 hr*ng/L.

[0391] In some embodiments, there is provided a method of treating a condition in a human subject, comprising administering to said subject about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally to said subject, resulting m plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/L and AUC from TO to Teo of about 590 hr*ng/L to about 4400 hr*ng/L.

[0392] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally to said subject, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from TO to Teo of about 600 hr*ng/L to about 9500 hr*ng/, wherein the plasma Tmax is about 1 hour to about 8 hours.

[0393] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally to said subject, resulting m plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about IIO ng/L to about 400ng/L and AUG from TO to Ta:&amp;#1523; of about 590 hr*ng/L to about 4400hr*ng/L, wherein the plasma Tmax is about I hour to about 4 hours.

[0394] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 180 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of from about 300 ng/L to about 500 ng/L (e.g. about 400 ng/L) and AUC from TO to Too of from about 2300 ng*hL to about 3600 ng*h/L (e.g. about 2900 ng*h/L), wherein the median plasma Tmax is about 2 hours.

[0395] In some embodiments, there is provided a method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of from about 150ng/L to about 300 ng/L (e.g. about 200 ng/L) and AUC from TO to Teo of from about 1100 ng*h/L to about 1800 ng*h/L (e.g. about 1400 ng*h/L), wherein the median plasma Tmax is about 2 hours.

[0396] In certain embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally to the subject in the form of an intramuscular injection, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 140 gg to about 190 gg.

[0397] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising intramuscularly administering a dose of about 120 gg to about 190 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 9500 ng*h/L, wherein the plasma Tmax is about 5 minutes to about 4 hours.

[0398] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising intramuscularly administering a dose of about 120 gg to about 190 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 12600 ng*h/L, wherein the plasma Tmax is about 5 minutes to about 4 hours.

[0399] In some embodiments, there is provided a method of treating agitation or signs of agitation m a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising intramuscularly administering a dose of about 120 pg to about 190 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 12600 ng*h/L, wherein the plasma Cmax is about 200 to about 800 ng/L.

[0400] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising intramuscularly administering a dose of about 120 pg to about 190 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 12600 ng*h/L, wherein the median Tmax is about 2 hours.

[0401] In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising intravenously administering a dose of about 120 pg to about 190 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 12600 ng*h/L, wherein the plasma Tmax is about 5 minutes to about 15 minutes.

[0402] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally to the subject, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 900 pg to about 1200 pg.

[0403] In certain embodiments, there is provided a method of treating agitation or signs of agitation m a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising orally administering a dose of about 900 pg to about 1200 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 12600 ng*h/L, wherein the plasma Tmax is about I hour to about 8 hours.

[0404] In certain embodiments, there is provided a method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising orally administering a dose of about 900 qg to about 1200 qg of dexmedetomidine or a pharmaceutically acceptable salt thereof resulting in a total exposure of dexmedetomidine, as measured by plasma AUG from TO to Too, from about 600 to about 12600 ng*h L. wherein the median Tmax is about 2 hours.

[0405] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose (e.g. as a single unit dose or multiple unit doses administered simultaneously).

[0406] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising about 180 qg of dexmedetomidine hydrochloride, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from TO to Too of about 600 hr*ng/L to about 9500 hr*ng/L. [0407] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising about 120 qg of dexmedetomidine hydrochloride, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/L and AUC from TO to Too of about 590 hr*ng/L to about 4400 hr*ng/L. [0408] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising about 180 qg of dexmedetomidine hydrochloride, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 300 ng/L to about 500 ng/L (e g. about 400 ng/L) and AUC from TO to Teo of about 2300 ng*h/L to about 3600 ng*h/L (e.g, about 2900 ng*h/L), wherein the median plasma Tmax is about 2 hours. [0409] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising about 120 qg of dexmedetomidine hydrochloride, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 150 ng/L to about 300. ng/L (e.g. about 200ng/L) and AUC from TO to Ta:&amp;#1523; of about 1100 ng*h L. to about 1800ng*h/L (e.g. about 1400 ng*h IA wherein the median plasma Tmax is about 2 hours. [0410] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising about 180 qg to about 240 qg of dexmedetomidine hydrochloride, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 12600 ng*h/L, wherein the plasma Tmax is about 1 to about 8 hours.

[0411] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising:

(a) a composition consisting essentially of:

(i) about 180 gg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (ill) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyi cellulose (370.000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from To to Too of about 600 hr*ng/L to about 9500 hr*ng/L. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 525 ng/L, about 550 ng/L, about 575 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, to about 1000 ng/L, and the AUCo-inf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hUngL, about 1000 hr*ng/L, about 1250 hr*ng%, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng%, about 3750 hr*ng/L, about

4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ngZL, about 5500 hr*ng/L, about 5750 hr*ngZL, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ngZL, about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about 11875 hr*ng/L. In some embodiments, the Tmax is from about 1 to about 8 hours. For example, the Tmax is about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 11, about 1.75 h, about 2.0 h, about 2.25 11, about 2.5 h, about 2.75 h, about 3.0 11, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 11, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 11, about 5.75 h, about 6.0 h, about 6.25 11, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 11, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 11, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 11, about 9.5 h, about 9.75 11, to about 10 11.

[0412] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising:

(a) a composition consisting essentially of:

(i) about 120 gg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/T. and AUC from To to Too of about 590 hr*ng/L to about 4400 hr*ng/L. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, to about 500 ng/L, and the AUCo-mf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr^ng/L, about 900 hr*11g/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*11g/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ngL, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*11g/L. In some embodiments, the Tmax is from about 1 to about 4 hours. For example, the Tmax is about 0.8 h, about 0.9h, about 1 h, about 1.25 11, about 1.5 11, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, to about 5.0 h.

[0413] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising:

(a) a composition consisting essentially of:

(i) about 180 pg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng,T. to about 800 ng/L and AUC from To to Too of about 600 hr*ng/L to about 9500 hr*ng/U, wherein the plasma Tmax is about 1 hour to about 8 hours. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about

200 ng/L, about 225 ng/L, about 250 ng 'L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about

350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about

725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about

875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, to about 1000 ng/L, and the AUCo-mf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr* ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 250011r*ng/L, about 2750 hr*ng/L, about 3000 hr*ng'L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about 11875 hr*ng/L, and the Tmax is about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, to about 10 h.

[0414] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising:

(a) a composition consisting essentially of:

(1) about 120 pg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(1) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/L and AUC from To to Too of about 590 hr*ng/L to about 4400 hr*n/L, wherein the plasma Tmax is about 1 hour to about 4 hours. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, to about 500 ng/L, and the AUCo-inf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, and the Tmax is about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, to about 5.0 h.

[0415] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising:

(a) a composition consisting essentially of:

(i) about 180 pg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydiOxypropyl cellulose (140,000MW);

(lii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of about 300 ng/L to about 474ng/L (e.g. about 400 ng/L)and AUC from To to Too of about 2300 ng*h/L. to about 3600 ng*h/L (e.g, about 2900 ng*h/L), wherein the median plasma Tmax is about 2 hours. For example, the Cmax is about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, to about 475 ng/L, and the AUCo-inf is about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L. In some embodiments, the Tmax is from about 1 to about 4 hours. For example, the Tmax is about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, to about 5.0 h.

[0416] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising:

(a) a composition consisting essentially of:

(i) about 120 pg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of about 150 ng/L to about 300 ng/L (e.g. about 200 ng/L) and AUC from To to Too of about 1100 ng*h/L. to about 1800 ng*h/L (e.g. about 1400 ng*h/L), wherein the median plasma Tmax is about 2 hours. For example, the Cmax is about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, or about 300 ng/L, and the AUCoinf is about 1100 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, to about 1800 hr*ng/L. In some embodiments, the Tmax is from about 1 to about 4 hours. For example, the Tmax is about 0.8 11, about 0.9h, about 1 11, about 1.25 11, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 11, about 2.5 h, about 2.75 11, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 11, about 4.25 h, about 4.5 h, about 4.75 h, to about 5.0 11

[0417] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising:

(a) a composition consisting essentially of:

(i) about 180 gg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (hi) hydroxypropyl cellulose (I40,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(hi) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in a total exposure of dexmedetomidine, as measured by plasma AUC from To to Too, from about 600 to about 12600 ng*h/L, wherein the plasma Tmax is about 1 to about 8 hours. For example, the AUCo-inf is about 470 hr*ng/L, about 500 11r*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng,%, about 1500 hr*ng/L, about 1750 hi&amp;#1470;*ng/L, about 2000 hr*ngZL, about 2250 hr*ng/L, about 2500 hr*ngZL, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ngZL, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr* ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ngZL, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ngZL, about 11250 hr*ng/L, about 11500 hr*ng/L, about 11750 hr*ng/L, about 12000 hr*ng/L, about 12250 hr*ng/L, or about 12600 hr*ng/L, and the Tmax is about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, or about 8 11.

[0418] Another embodiment of the present disclosure provides a self-supporting, dissolvable, film comprising:

(a) a composition consisting essentially of:

(i) about 120 ug of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in a total exposure of dexmedetomidine, as measured by plasma AUC from To to Too, from about 590 to about 8750 ng*h/L, wherein the plasma Tmax is about 1 to about 4 hours. For example, the AUCo-mf is about 590 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ngZL, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, about 8500 hr*ng/L, or about 8750 hr*ng/L, and the Tmax is about 1 h, about 2 h, about 3 h, or about 4 h.

[0419] In some embodiments, agitation or signs of agitation are significantly reduced within 60 minutes in a patient with schizophrenia or bipolar disorder following administration of a single dose of 120 pg or 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride, as measured by the relative PEC scores just prior to and 60 minutes after administering dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, the relative PEC scores are different by at least six points. In another embodiment, the relative PEC scores are different by at least eight points. In yet another embodiment, the difference in relative PEC scores is maintained for at least six hours. In a particular embodiment, a difference of at least eight points is maintained for up to about 24 hours when administering a single dose of 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride).

[0421] In some embodiments, the decrease in PEC score at 2 hours, as measured by change from baseline total PEC score post-administration of 180 pg of dexmedetomidine hydrochloride is -10.8 compared to placebo (-4.5). In some embodiments, the decrease in PEC score at 2 hours postadministration of 180 pg of dexmedetomidine hydrochloride is greater (-10.8) as compared to administering 120 pg (-9.2) or 80 pg (-7.3) dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately prior to or immediately following the appearance of agitation or signs of agitation in the human subject.

[0422] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 10 minutes following the appearance of agitation or signs of agitation in the human subject. In some embodiments, an additional dose of 90 pg or 60 pg may be taken after a suitable period of time (e.g. two hours) of first dosing.

[0423] In some embodiments, following administering a unit dose of about 30 pg, about 60 pg, about 90 pg, about 120 pg, or about 180 pg of dexmedetomidine or a pharmaceutically acceptable thereof in a human subject experiencing opioid withdrawal symptoms (e.g. agitation or signs of agitation), the withdrawal symptoms are significantly reduced as measured by the relative COWS and/or the SOWS-Gossop scores just prior to and 2 hour post administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In a particular embodiment, each unit may be administered twice daily over an appropriate period of withdrawal (e.g. for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days).

[0424] In certain embodiments, following administering of about 20 gg to about 240 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride) to an agitated human subject with delirium hospitalized (e.g. in an ICC), the agitation or signs of agitation and delirium severity are significantly reduced as measured by the RASS and DRS-R-98 respectively. For example, the agitation or signs of agitation and delirium severity are significantly reduced as measured by the RASS and DRS-R-98 just prior to and after every 30 minutes, 1 hour, 2 hours, 3, hours, 4 hours, 5 hours, or 6 hours post-administration of dexmedetomidine. In some embodiments, dexmedetomidine is oromucosally (e.g. sublingually or buccally) administered one to four times a day at an appropriate dosing interval (e.g. after every 30 minutes) within 6 hours of first dose to produce a desired effect; for example, a 20 gg unit dose is administered four times at a dosing interval of 30 minutes within 6 hours of first dose to produce the effect of a 80 gg dose or a 60 gg unit dose is administered four times at a dosing interval of 30 minutes within 6 hours of first dose to produce the effect of a 240 gg.

[0425] In some embodiments, following administration of about 30 gg to about 90 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride) to an agitated human subject with dementia, the agitation or signs of agitation are significantly reduced as measured by the PAS and PEC. For example, the agitation or signs of agitation are significantly reduced as measured by the PAS and PEC just prior to and after every 2 hours up to at least 24 hours post administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In one embodiment, dexmedetomidine is oromucosally (e.g. sublingually or buccally) administered. In some embodiments, each unit dose comprises about 30 gg to 60 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, a dose of dexmedetomidine may be taken I, 2, 3, 4, 5, or 6 times in a day every 2 hours with the provision of maximum of three doses within 12 hours of first dose. In some embodiments, each unit dose containing about 90 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof may be taken 1, 2, 3, or 4 times in a day at every 2 hours with the provision of maximum of two doses within 12 hours of first dose.

[0426] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e.g. sublingually or buccaily) as a film. In some embodiments, the dosing may be achieved by cutting the film into half to deliver a half-dose (for e.g. 60 pg dose may be administered with a half of a 60 pg dose (30 pg) to make a 90pg dose.).

[0427] In some embodiments, the present disclosure provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine (e.g. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof to a human patient. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (E.g. bipolar I disorder, and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g. bipolar I disorder).

[0428] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, the composition may be administered a variety of means. For example, in some embodiments, the composition comprising dexmedetomidine (e.g. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt is administered sublingually, buccaily, orally, mtranasally or parenterally. In some embodiments, the composition is administered sublingually or buccaily. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel or drops. In some embodiments, the composition is administered buccaily in the form of a film, patch or tablet,

[0429] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, the method may further comprises administering a second dose of dexmedetomidine after a period of time ranging from about 30 minutes to about 12 hours. For example, the period of time may be about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, or about 23 hours. In some embodiments, the second dose is administered after a period of about 2 hours. In some embodiments, the second dose ranges from about 10 pg to about 180 gg. For example, the additional dose may be about 10 gg, about 20 gg, about 30 gg, about 40 gg, about 50 gg, about 60 gg, about 70 gg, about 80 gg, about 90 gg, about 100 gg,, about 110 gg, about 120 gg, about 130 gg, about 140 gg, about 150 gg, about 160 gg, about 170,or about 180 gg. In some embodiments, the additional dose is about 60gg or 90gg.

[0430] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 gg of dexmedetomidine, the unit dose composition may be administered to a patient in the fasted state. In some embodiments, the unit dose composition has been administered in the fed state.

[0431] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 gg of dexmedetomidine, agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline. In some embodiments, the agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, the agitation is significantly reduced in less than 45 minutes (e.g. about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient experiences >40% decrease from baseline in PEC score. For example, the patient may experience greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% from baseline. Treatment efficacy may also be compared by comparing PEC score to placebo. In some embodiments, the PEC score is >30% lower than placebo (e.g. the placebo group has mean change from baseline in PEC total score of3 and the dexmedetomidine-containing composition has a score of -3.9). For example, compared to placebo, the patient’s PEC score may be lower by greater than or equal to about 30,%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient experiences a mean change in PEC score of greater than about -4 (i.e. a decrease of 4 or more points) relative to baseline within hours of administering the composition. For example, at the 2 hour time point, the patient may experience a mean change in PEC score of greater than about -4, about -5, about -6, about -7, about -8, about 9&#1470;, about -10, about -11, or about 12&#1470;. In some embodiments, the decrease in PEC score (e.g. of greater than about -4) is maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline m PEC total score of e.g. -6 at 2 hours, then at 6 hours patient’s mean change in PEC score will be about -6 or lower (e.g. -7, -8, etc.). In some embodiments, the decrease in PEC score (e.g. of greater than about -4) is substantially maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline in PEC total score of e.g. -6 at 2 hours, then at 6 hours patient’s mean change in PEC score will be about -4, about -5, or about -6 or lower (e.g. -7, -8, etc ). In some embodiments, the mean change in PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 6 hours following administration of the composition.

[0432] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

[0433] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, administration of a single dose provides a mean Cmax within the range of about 80% to about 125% of about 110 ng/L to about 400 ng/L. For example, a single dose provides a mean Ct&amp;#1524;ax of about 88 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, or about 500 ng/L, including all integers and ranges therebetween. In some embodiments, the mean Cmax is between about 100 ng/L to about 500 ng/L, about 150 ng/L to about 450 ng,&amp;#1523;L, about 150 ng/L to about 400 ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L to about 300 ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L to about 240 ng/L. In some embodiments, the mean Cmax is withm the range of about 80% to about 125% of about 238 ng/L. the mean Cmax is within the range of about 80% to about 125% of about 238 ng/L. In some embodiments, the mean Cmax is about 238 ng/L.

[0434] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, administration of a single dose provides a mean AUCo-mf within the range of about 80% to about 125% of about 590 hr*ng/L to about 4400 hr*ng/L. For example, a single dose provides a mean AUCo-inf of about 475 hr*ng/L, about 500 hr*ng/L, about 1000 hr*ng/L, about 1500 hr*ng/L, about 2000 hr*ng/L, about 2500 hr*ng/L, about 3000 hr*ng/L, about 3500 hr*ng/L, about 4000 hr*ng/L, about 4500 hr* ng/L, about 5000 hr*ng/L, or about 5500 hr*ng/L, including all integers and ranges therebetween.In some embodiments, the mean AUCo-mf is between about 500 hr*ng/L to about 5000 hr*ng/L, about 500 hr*ng/'L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 2500 hr*ng/L, about 1000 hr*ng/L to about 2000 hr*ng/L, about 1000 hr*ng/L to about 1500 hr*ng/L, or about 1500 hr*ng/L to about 2000 hr*ng/L. In some embodiments, the mean AUCo-inf is within the range of about 80% to about 125% of about 1800 ng*h/L. In some embodiments, the mean AUCo-inf is about 1800 ng*h/L.

[0435] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, administration of a single dose provides a mean Tmax within the range of about 80% to about 125% of about 1 hour to about 4 hours. For example, a single dose provides a mean Tmax of about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, to about 5.0 h. In some embodiments, the Tmax is between about 1 h to about 4 h, about 1 h to about 3 h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h, about 1.75 h to about 2.25 h. In some embodiments, the Tmax is within the range of about 80% to about 125% of about 2 hours. In some embodiments, the Tmax is about 2 hours.

[0436] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, administration of a single dose provides a geometric mean Cmax within the range of about 80% to about 125% of about 110 ng/L to about 400 ng/L. For example, a single dose provides a geometric mean Cmax of about 88 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, or about 500 ng/L, including all integers and ranges therebetween. In some embodiments, the geometric mean Cmax is between about 100 ng/L to about 500 ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/L to about 400 ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L to about 300 ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L to about 240 ng/L. In some embodiments, the geometric mean Cmax is within the range of about 80% to about 125% of about 220 ng/L. In some embodiments, the geometric mean Cmax is about 220 ng/L. In some embodiments, the median Cmax is about 238 ng/L.

[0437] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, administration of a single dose provides a geometric mean AUCo-inf within the range of about 80% to about 125% of about 590 hr*ng/L to about 4400 hr*ng/L. For example, a single dose provides a geometric mean AUCo-inf of about 475 hr*ng/L, about 500 hr*ng/L, about 1000 hr*ng/L, about 1500 hr*ng/L, about 2000 hr*ng,%, about 2500 hr*ng/L, about 3000 hr*ng/L, about 3500 hr*ng/L, about 4000 hr*ng/L, about 4500 hr*ng/L, about 5000 hr*ng/L, or about 5500 hr*ng,%, including all integers and ranges therebetween.In some embodiments, the geometric mean AUCo-inf is between about 500 hr*ng/L to about 5000 hr*ng,%, about 500 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 2500 hr*ng/L, about 1000 hr*ng/L to about 2000 hr*ng/L, about 1000 hr*ng/L to about 1500 hr*ng/L, about 1500 hr*ng/L to about 2000 hr*ng/L, about 1200 hr*ng/L to about 1500 hr*ng/L, about 1300 hr*ng/L to about 1500 hr*ng/L, or about 1350 hr*ng/L to about 1450 hr*ng/L,. In some embodiments, the geometric mean AUCo-inf is within the range of about 80% to about 125% of about 1410 ng*h/L. In some embodiments, the geometric mean AUCo-inf is about 1410 ng*h/L.

[0438] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, administration of a single dose provides a geometric mean Tmax within the range of about 80% to about 125% of about I hour to about 4 hours. For example, a single dose provides a geometric mean Tmax of about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, to about 5.0 h. In some embodiments, the geometric mean Tmax is between about 1 h to about 4 h, about 1 h to about 3 h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h, about 1.75 h to about 2.25 h. In some embodiments, the Tmax is within the range of about 80% to about 125% of about 2 hours. In some embodiments, the 1 max is about 2 hours.

[0439] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 qg of dexmedetomidine, administration of a single dose provides a median Cmax within the range of about 80% to about 125% of about 110 ng/L to about 400 ng/L. For example, a single dose provides a median Cmax of about 88 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, or about 500 ng/L, including all integers and ranges therebetween. In some embodiments, the mean median Cmax is between about 100 ng/L to about 500 ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/L to about 400 ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L to about 300 ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L to about 240 ng/L. In some embodiments, the median Cmax is within the range of about 80% to about 125% of about 230 ng,/L. In some embodiments, the median Cmax is about 230 ng,/L.

[0440] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 qg of dexmedetomidine, administration of a single dose provides a median AUCo-inf withm the range of about 80% to about 125% of about 590 hr*ng/L to about 4400 hr*ng/L. For example, a single dose provides a median AUCo-inf of about 475 hr*ng/L, about 500 hr*ng/L, about 1000 hr*ng/L, about 1500 hr*ng/L, about 2000 hr*ng/L, about 2500 hr*ng/L, about 3000 hr*ng/L, about 3500 hr*ng/L, about 4000 hr*ng/L, about 4500 hr*ng/L, about 5000 hr*ng/L, or about 5500 hr*ng/L, including all integers and ranges therebetween.In some embodiments, the median AUCo-inf is between about 500 hr*ng/L to about 5000 hr*ng/L, about 500 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 2500 hr*ng/L, about 1000 hr*ng/'L to about 2000 hr*ng/L, about 1000 hr*ng/L to about 1500 hr*ng/L, about 1500 hr*ng/L to about 2000 hr*ng/L, about 1000 hr*ng/L to about 1250 hr*ng/L, about 1000 hr*ng/L to about 1200 hr*ng/L, about 1100 hr*ng/L to about 1200 hr*ng,L, or about 1150 hr*ng/L to about 1250 hr*ng/L. In some embodiments, the median AUCo-inf is within the range of about 80% to about 125% of about 1180 ng*h/L. In some embodiments, the median AUCo-mf is about 1180 ng*h/L.

[0441] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, administration of a single dose provides a median Tmax within the range of about 80% to about 125% of about 1 hour to about 4 hours. For example, a single dose provides a median Tmax of about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, to about 5.0 11. In some embodiments, the median Tmax is between about 1 h to about 4 h, about 1 h to about 3 h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h, about 1.75 h to about 2.25 h. In some embodiments, the median Tmax is within the range of about 80% to about 125% of about 2 hours. In some embodiments, the median Tmax is about 2 hours.

[0442] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady state.

[0443] In some embodiments, the present disclosure provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine (e.g. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof to a human patient. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (E g. bipolar I disorder, and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g. bipolar I disorder).

[0444] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine, the composition may be administered a variety of means. For example, in some embodiments, the composition comprising dexmedetomidine (eg. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt is administered sublingually, buccally, orally, mtranasally or parenterally. In some embodiments, the composition is administered sublingually or buccally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel or drops. In some embodiments, the composition is administered buccaily in the form of a film, patch or tablet.

[0445] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine, the method may further comprises administering a second dose of dexmedetomidine after a period of time ranging from about 30 minutes to about 12 hours. For example, the period of time may be about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, or about 23 hours. In some embodiments, the second dose is administered after a period of about 2 hours. In some embodiments, the second dose ranges from about 10 pg to about 180 pg. For example, the additional dose may be about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 60 pg, about 70 pg, about 80 pg, about 90 pg, about 100 pg&amp;#1524; about 110 pg, about 120 pg, about 130 pg, about 140 pg, about 150 pg, about 160 pg, about 170,or about 180 pg. In some embodiments, the additional dose is about 60pg or 90pg.

[0446] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine, the unit dose composition may be administered to a patient in the fasted state. In some embodiments, the unit dose composition has been administered in the fed state.

[0447] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine, agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline. In some embodiments, the agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, the agitation is significantly reduced in less than 45 minutes (e.g. about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient experiences >40% decrease from baseline in PEC score. For example, the patient may experience greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about

135%, about 140%, about 145%, or about 150% from baseline. Treatment efficacy may also be compared by comparing PEC score to placebo. In some embodiments, the PEC score is >30% lower than placebo (e g. the placebo group has mean change from baseline in PEC total score of 3 and the dexmedetomidine-containing composition has a score of -3.9). For example, compared to placebo, the patient’s PEC score may be lower by greater than or equal to about 30,%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient experiences a mean change in PEC score of greater than about 4&#1470; (i.e. a decrease of 4 or more points) relative to baseline within 2 hours of administering the composition. For example, at the 2 hour time point, the patient may experience a mean change in PEC score of greater than about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or about -12. In some embodiments, the decrease in PEC score (e.g. of greater than about -4) is maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline in PEC total score of e g. -6 at 2 hours, then at 6 hours patient’s mean change in PEC score will be about -6 or lower (e g. -7, -8, etc ). In some embodiments, the decrease m PEC score (e g. of greater than about -4) is substantially maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline in PEC total score of e.g. -6 at 2 hours, then at 6 hours patient’s mean change in PEC score will be about -4, about -5, or about -6 or lower (e g. -7, -8, etc.). In some embodiments, the mean change m PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 24 hours following administration of the composition.

[0448] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 gg of dexmedetomidine, the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

[0449] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 gg of dexmedetomidine, administration of a single dose provides a mean Cmax within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all integers and ranges therebetween. In some embodiments, the mean Cmax is between about 100 ng/L to about 1000 ng/L, about 100 ng/L to about 800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/L to about 600 ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L to about 500 ng/L, about 300 ng/L to about 450 ng/L, about 400 ng/L to about 500 ng/L, or about 400 ng/L to about 450 ng/L. In some embodiments, the mean Cmax is within the range of about 80% to about 125% of about 440 ng/L. In some embodiments, the mean Cmax is about 440 ng,4.,

[0450] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine, administration of a single dose provides a mean AUCo-inf within the range of about 80% to about 125% of about 600 hr*ng/L to about 9500 hr*ng/L. For example, the AUCo-inf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 h!*ng L. about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about 11875 hr*ng/L, including all integers and ranges therebetween. In some embodiments, the AUCo-inf is between about 500 hr*ng/L to about 10000 hr*ng/L, about 1000 hr*ng/L to about 7500 hr*ng/L, about 1000 hr*ng/L to about 6000 hr*ng/L, to about 1500 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about

5000 hr*ng/L, about 2000 hr*ngZL to about 4000 hr*ng/L, about 2000 hr*ng/L to about 3000 hr*ng/L, about 2500 hr*ng/L to about 4000 hr*ngZL, about 3000 hr*ng/L to about 4000 hr*ngZL, about 3500 hr*ng/L to about 4000 hr*ng/L, or about 2500 hr*ngZL to about 3000 hr*ng/L. In some embodiments, the mean AUCo-mf is within the range of about 80% to about 125% of about 3800 ng*h/L. In some embodiments, the mean AUCo-mf is about 3800 ng*hZL.

[0451] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 gg of dexmedetomidine, administration of a single dose provides a mean Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours. For example, a single dose provides a mean Tmax of About 0.8 11, about 0.911, about 1 11, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 11, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 11, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 11, about 4.25 h, about 4.5 h, about 4.75 11, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 11, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 11, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 11, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 11, about 9.5 h, about 9.75 11, to about 10 h. In some embodiments, the Tmax is between about Ih to about 8 h, about 1 11 to about 6 h, about 1 h to about 4 h, about 1 h to about 3 11, about 1.5 11 to about 3 11, about 1.75 11 to about 2.5 h, about 1.75 h to about 2.25 11. In some embodiments, the Tmax is within the range of about 80% to about 125% of about 2 hours. In some embodiments, the Tmax is about 2 hours.

[0452] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 gg of dexmedetomidine, administration of a single dose provides a geometric mean Cmax within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about

250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about

400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about

775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about

925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all integers and ranges therebetween. In some embodiments, the geometric mean Cmax is between about 100 ng/L to about 1000 ng/L, about 100 ng/L to about 800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/L to about 600 ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L to about 500 ng L.

about 300 ng/L to about 450 ng/L, about 400 ng/L to about 500 ng/L, about 400 ng/L to about 450 ng/L, about 350 ng/L to about 450 ng/L, or about 350 ng/L to about 400 ng/L. In some embodiments, the geometric mean Cmax is within the range of about 80% to about 125% of about 380 ng/L. In some embodiments, the geometric mean Cmax is about 380 ng/L.

[0453] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine, administration of a single dose provides a geometric mean AUCo-inf within the range of about 80% to about 125% of about 600 hr*ng/L to about 9500 hr*ng/L. For example, the AUCo-inf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng,%, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/&amp;#1523;L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng,%, about 7000 11r*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750 hUng/T, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hUngT, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about 11875 hr*ng/L, including all integers and ranges therebetween. In some embodiments, the AUCo-inf is between about 500 hr*ng/L to about 10000 hr*ng/L, about 1000 hr*ng/L to about 7500 hr*ng/L, about 1000 hr*ng/L to about 6000 hr*ng/L, to about 1 500 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about 4000 hr*ng/L, about 2000 hrmg L. to about 3000 hr*ng/L, about 2500 hr*ng/L to about 4000 hr*ng/L, about 3000 hr*ng/L to about 4000 hr*ng/L, about 3500 hr*ng/L to about 4000 hr*ng/L, or about 2500 hr*ng/L to about 3000 hr*ng/L. In some embodiments, the geometric mean AUCo-inf is within the range of about 80% to about 125% of about 2880 ng*h/L. In some embodiments, the geometric mean AUCo-inf is about 2880 ng*h/L.

[0454] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 gg of dexmedetomidine, administration of a single dose provides a geometric mean Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours. For example, a single dose provides a geometric mean Tmax of about 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 11, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 11, about 7.5 h, about 7.75 11, about 8.0 h, about 8.25 h, about 8.5 11, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 11, to about 10 11. In some embodiments, the Tmax is between about 111 to about 8 11, about 1 11 to about 6 11, about 1 11 to about 4 11, about 1 h to about 3 h, about 1.5 11 to about 3 11, about 1.75 h to about 2.5 h, about 1.75 11 to about 2.25 h. In some embodiments, the geometric mean Tmax is within the range of about 80% to about 125% of about 2 hours. In some embodiments, the geometric mean Tmax is about 2 hours.

[0455] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 gg of dexmedetomidine, administration of a single dose provides a median Cmax within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng I . about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all integers and ranges therebetween. In some embodiments, the median Cmax is between about 100 ng/L to about 1000 ng/L, about 100 ng/L to about 800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/L to about 600 ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L to about 500 ng L. about 300 ng/L to about 450 ng/L, about 400 ng/L to about 500 ng/L, about 400 ng/L to about 450 ng/L, about 450 ng/L to about 500 ng/L, about 470 ng/L to about 490 ng/L. In some embodiments, the median Cmax is within the range of about 80% to about 125% of about 485 ng/L. In some embodiments, the median Cmax is about 485 ng/L

[0456] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 gg of dexmedetomidine, administration of a single dose provides a median AUCo-inf within the range of about 80% to about

125% of about 600 hr*ng/L to about 9500 hr*ng/L. For example, the AUCo-mf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng/L, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about 8500 hrmg L. about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about 11875 hr*ng/L, including all integers and ranges therebetween. In some embodiments, the AUCo-mf is between about 500 hr*ng L to about 10000 hr*ng/L, about 1000 hr*ng/L to about 7500 hr*ng/L, about 1000 hr*ng/L to about 6000 hr*ng/L, to about 1500 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng L to about 4000 hr*ng/L, about 2000 hr*ng/L to about 3000 hr*ng/L, about 2500 hr*ng/L to about 4000 hr*ng/L, about 3000 hr*ng/L to about 4000 hr*ng/L, about 3500 hr*ng/L to about 4000 hr*ng/L, or about 2500 hr*ng/L to about 3000 hr*ng/L. In some embodiments, the median AUCo-iuf is within the range of about 80% to about 125% of about 2900 ng*hZL. In some embodiments, the median AUCo-inf is about 2900 ng*h/L.

[0457] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine, administration of a single dose provides a median Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours. For example, a single dose provides a median Tmax of About 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, to about 10 h. In some embodiments, the Tmax is between about Ih to about 8 h, about 1 h to about 6 h, about 1 h to about 4 h, about 1 h to about 3 h, about 1.5 h to about 3 h, about 1.75 h to about

2.5 h, about 1.75 h to about 2.25 h. In some embodiments, the Tuiax is within the range of about 80% to about 125% of about 2 hours. In some embodiments, the Tmax is about 2 hours.

[0458] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady state.

[0459] In some embodiments, the present disclosure provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 120 to about 180 pg of dexmedetomidine (e.g. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof to a human patient. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (E.g. bipolar I disorder, and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g. bipolar I disorder).

[0460] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, the composition may be administered a variety of means. For example, in some embodiments, the composition comprising dexmedetomidine (e.g. dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt is administered sublingually, buccally, orally, intranasally or parenterally. In some embodiments, the composition is administered sublingually or buccally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel or drops. In some embodiments, the composition is administered buccally in the form of a film, patch or tablet,

[0461] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, the method may further comprises administering a second dose of dexmedetomidine after a period of time ranging from about 30 minutes to about 12 hours. For example, the period of time may be about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, or about 23 hours. In some embodiments, the second dose is administered after a period of about 2 hours. In some embodiments, the second dose ranges from about 10 pg to about 180 pg.

For example, the additional dose may be about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 60 pg, about 70 pg, about 80 pg, about 90 pg, about 100 pg&amp;#1524; about 110 pg, about 120 pg, about 130 pg, about 140 pg, about 150 pg, about 160 pg, about 170,or about 180 pg. In some embodiments, the additional dose is about 60pg or 90pg.

[0462] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, the unit dose composition may be administered to a patient in the fasted state. In some embodiments, the unit dose composition has been administered in the fed state.

[0463] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline. In some embodiments, the agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, the agitation is significantly reduced in less than 45 minutes (e.g. about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient experiences >40% decrease from baseline in PEC score. For example, the patient may experience greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% from baseline. Treatment efficacy may also be compared by comparing PEC score to placebo. In some embodiments, the PEC score is >30% lower than placebo (e.g. the placebo group has mean change from baseline in PEC total score of -3 and the dexmedetomidine-containing composition has a score of -3.9). For example, compared to placebo, the patient’s PEC score may be lower by greater than or equal to about 30,%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient experiences a mean change in PEC score of greater than about 4&#1470; (i.e. a decrease of 4 or more points) relative to baseline within 2 hours of administering the composition.

For example, at the 2 hour time point, the patient may experience a mean change in PEC score of greater than about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -I I, or about -12. In some embodiments, the decrease in PEC score (e.g. of greater than about -4) is maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline in PEC total score of e.g. -6 at 2 hours, then at 6 hours patient’s mean change in PEC score will be about -6 or lower (e.g. 8- ,7&amp;#1524;, etc.). In some embodiments, the decrease in PEC score (e.g. of greater than about 4&amp;#1470;) is substantially maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline in PEC total score of e.g. -6 at 2 hours, then at 6 hours patient’s mean change in PEC score will be about -4, about -5, or about -6 or lower (e.g. -7, -8, etc.). In some embodiments, the mean change in PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 24 hours following administration of the composition.

[0464] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

[0465] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, administration of a single dose provides a mean Cmax within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all integers and ranges therebetween. In some embodiments, the mean Cmax is between about 100 ng/L to about 1000 ng/L, about 100 ng/L to about 800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/L to about 600 ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L to about 500 ng/L, about 300 ng/L to about 450 ng/L, about 400 ng/L to about 500 ng/L, or about 400 ng/L to about 450 ng/L, about 100 ng/L to about 500 ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/L to about 400 ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L to about 300 ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L to about 240 ng/L. In some embodiments, the mean Cmax is within the range of about 80% to about 125% of 200 ng/L to about 500 ng/L. In some embodiments, the mean Cmax is about 230 ng/L to about 440 ng/L.

[0466] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, administration of a single dose provides a mean AUCo-inf within the range of about 80% to about 125% of about 600 hr*ng/L to about 9500 hr*ng/L. For example, the AUCoinf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr%g/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng,/I., about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng/L, to about 8500 hr*ng/L, about 8750 hr*ng/L, about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hr*ng/L, about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about 11875 hr*ng/L, including all integers and ranges therebetween. In some embodiments, the AUCo-inf is between about 500 hr*ng/L to about 10000 hr*ng/L, about 1000 hr*ng/L to about 7500 hr*ng/L, about 1000 hr*ng/L to about 6000 hr*ng/L, to about 1500 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/'L to about 4000 hr*ng/L, about 2000 hr*ng/L to about 3000 hr*ng/L, about 2500 hr*ng/L to about 4000 hr*ng/L, about 3000 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 5000 hr*ng/L, about 500 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 2500 hr*ng/L, about 1000 hr*ng/L to about 2000 hr*ng/L, about 1000 hr*ng/L to about 1500 hr*ng/L, or about 1500 hr*ng/L to about 2000 hr*ng/L, about 3500 hr*ng/L to about 4000 hr*ng/L, or about 2500 hr*ng/L to about 3000 hr*ng/L. In some embodiments, the mean AUCo-inf is within the range of about 80% to about 125% of 1400 ng*h/L to about 4000 hr*ng/L. In some embodiments, the mean AUCo-inf is about 3800 ng*h/L. In some embodiments, the mean AUCo-inf is within the range of about 80% to about 125% of 1800 ng*h/L to about 3800 ng*h L.

[0467] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, administration of a single dose provides a mean Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours. For example, a single dose provides a mean Tmax of About 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 11, about 2.5 h, about 2.75 h, about 3.0 11, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 11, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 11, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 11, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 11, about 9.5 h, about 9.75 11, to about 10 h. In some embodiments, the Tmax is between about Ih to about 8 h, about 1 h to about 6 h, about 1 h to about 4 h, about 1 h to about 3 h, about 1.5 h to about 3 h, about 1.75 h to about 2.5 h, about 1.75 h to about 2.25 h. In some embodiments, the Tmax is within the range of about 80% to about 125% of about 2 hours. In some embodiments, the Tmax is about 2 hours.

[0468] In accordance with some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady state.

[0469] In some embodiments, the present disclosure provides methods of treating or ameliorating opioid withdrawal symptoms, comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride) to a human patient in need thereof, wherein the patient is at least 18 years and wherein the period of withdrawal is up to 14 days. “Opioid withdrawal” refers to a variety of signs and complaints appearing with the abrupt removal of, or a rapid decrease m the regular dosage of opioids. Physical manifestations may include sweating, nausea, yawning, chills, diarrhea, papillary dilation, piloerection, tachycardia, increased blood pressure, hypersensitivity to pain, stomach cramps, and muscle cramps. Psychological manifestations of opioid withdrawal observed may include agitation, dysphoria, restlessness, irritability, anxiety, and depression. In some embodiments, the opioid withdrawal symptom is agitation. Onset often begins within 6-24 hours from last opioid use. In some embodiments, treating or ameliorating opioid withdrawal refers to the treatment or lessening of one or more of the aforementioned symptoms. The treating or ameliorating may be measured by a variety of well-known means m the art, including but not limited to, the Clinical Opiate Withdrawal Scale (COWS) and/or Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) score.

[0470] Thus, in some embodiments, the present disclosure provides methods of treating or ameliorating agitation associated with opioid withdrawal symptoms. In some embodiments, the treatment or amelioration comprises reducing the period of opioid withdrawal. For example, a patient treated in accordance with the embodiments of the present disclosure, may experience an opioid withdrawal period of about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, or about 14 days, where a similar patient that was not treated in accordance with the embodiments of the present disclosure will have a longer opioid withdrawal treatment.

[0471] In some embodiments, the composition is administered twice daily. In some embodiments, the composition comprises a dose range of dexmedetomidine or a pharmaceutically acceptable salt thereof of between about 30 pg and about 200 pg. For example, the composition comprises a unit dose of about 30 pg, about 60 pg, about 90 pg, about 120 pg, or 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, a single dose of a composition comprising about 180 pg dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for up to at least about 24 hours. In some embodiments, the composition is administered twice daily for 7 days.

[0472] In some embodiments, the patient is suffering from opioid withdrawal, wherein the opioid is one or more of fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil and pentazocine. In some embodiments, the opioid is fentanyl. In some embodiments, the opioid had been administered for amount of time longer than neonate treatment prior to withdrawal.

[0473] In some embodiments, the composition is administered sublingually, buccally, orally, intranasally or parenterally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel or drops. In some embodiments, the composition is administered sublingually in the form of a film. In some embodiments, the composition is administered buccally in the form of a film, patch or tablet. In some embodiments, the composition is administered buccally in the form of a film. In some embodiments, the patient is treated without also inducing clinically significant cardiovascular effects.

[0474] In some embodiments, the present disclosure provides a pharmaceutical composition comprising from about 20 pg to about 240 pg dexmedetomidine or a pharmaceutically acceptable salt thereof (e g. dexmedetomidine hydrochloride). In some embodiments, the dose of dexmedetomidine is about 120 pg. In some embodiments, the dose of dexmedetomidine is about 180 pg.

[0475] In some embodiments, the composition is formulated for sublingual or buccal administration. In some embodiments, the composition is formulated for sublingual administration in the form of a tablet, film, spray, gel or drops. In some embodiments, the composition is formulated for buccal administration in the form of a film, patch or tablet.

[0476] In some embodiments, the pharmaceutical composition comprising from about 20 pg to about 240 pg dexmedetomidine is administered to a patient having agitation associated with schizophrenia or bipolar disorder, the agitation is significantly reduced within about 2 hours of administering the composition as measured by a mean change in Positive and Negati ve Syndrome Scale Excited Component (PEC) scores relative to baseline. For example, the agitation is significantly reduced with 30 minutes, 45 minutes, 1 hour, 90 minutes, or about 2 hours. In some embodiments, the patient experiences >40% decrease from baseline in PEC score. For example, the patient may experience greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% from baseline. Treatment efficacy may also be compared by comparing PEC score to placebo. In some embodiments, the PEC score is >30% lower than placebo (e g. the placebo group has mean change from baseline in PEC total score of 3 and the dexmedetomidine-containing composition has a score of -3.9). For example, compared to placebo, the patient’s PEC score may be lower by greater than or equal to about 30,%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient experiences a mean change in PEC score of greater than about -4 (i.e. a decrease of 4 or more points) relative to baseline within 2 hours of administering the composition. For example, at the 2 hour time point, the patient may experience a mean change in PEC score of greater than about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or about -12. In some embodiments, the decrease in PEC score (e.g. of greater than about -4) is maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline in PEC total score of e.g. -6 at 2 hours, then at 6 hours patient’s mean change in PEC score will be about -6 or lower (e.g. -7, -8, etc ). In some embodiments, the mean change in PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 24 hours following administration of the composition.

[0477] In accordance with some embodiments of the pharmaceutical composition comprising from about 20 pg to about 240 pg dexmedetomidine, the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

[0478] Administration of a single dose of the pharmaceutical composition comprising from about 20 pg to about 240 pg dexmedetomidine provides a mean Cmax within the range of about 80% to about 125% of about 100 ngZL to about 800 ng/L. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all integers and ranges therebetween. In some embodiments, the mean Cmax is between about 100 ng/L to about 1000 ng/L, about 100 ng/L to about 800 ng/L, about 200 ng/L to about 600 ng/L, about 300 ng/L to about 600 ng/L, about 300 ng/L to about 500 ng/L, about 350 ng/L to about 500 ng/L, about 300 ng/L to about 450 ng/L, about 400 ng/L to about 500 ng/L, or about 400 ng/L to about 450 ng/L, about 100 ng/L to about 500 ng/L, about 150 ng/L to about 450 ng/L, about 150 ng/L to about 400 ng/L, about 200 ng/L to about 350 ng/L, about 200 ng/L to about 300 ng/L, about 200 ng/L to about 250 mg/L, or about 210 ng/L to about 240 ng/L. In some embodiments, the mean Cmax is within the range of about 80% to about 125% of 200 ng/L to about 500 ng/L. In some embodiments, the mean Cmax is about 230 ng/L to about 440 ng/L.

[0479] Administration of a single dose of the pharmaceutical composition comprising from about 20 pg to about 240 pg dexmedetomidine provides a mean AUCo-inf within the range of about 80% to about 125% of about 600 hr*ng/L to about 9500 hr*ng/L. For example, the AUCo-inf is about 470 hr*ng/L, about 500 hr*ng/L, about 600 hr*ng/L, about 700 hr*ng/L, about 800 hr*ng/L, about 900 hr*ng/L, about 1000 hr*ng/L, about 1250 hr*ng/L, about 1500 hr*ng/L, about 1750 hr*ng/L, about 2000 hr*ng/L, about 2250 hr*ng/L, about 2500 hr*ng/L, about 2750 hr*ng/L, about 3000 hr*ng/L, about 3250 hr*ng/L, about 3500 hr*ng/L, about 3750 hr*ng/L, about 4000 hr*ng/L, about 4250 hr*ng/L, about 4500 hr*ng/L, about 4750 hr*ng/L, about 5000 hr*ng/L, about 5250 hr*ng/L, to about 5500 hr*ng/L, about 5750 hr*ng/L, about 6000 hr*ng/L, about 6250 hr*ng/L, to about 6500 hr*ng/L, about 6750 hr*ng,U, about 7000 hr*ng/L, about 7250 hr*ng/L, to about 7500 hr*ng/L, about 7750 hr*ng/L, about 8000 hr*ng/L, about 8250 hr*ng I . to about 8500 hr*ng/L, about 8750 hUng/T., about 9000 hr*ng/L, about 9250 hr*ng/L, about 9500 hUngT., about 9750 hr*ng/L, about 10000 hr*ng/L, about 10250 hr*ng/L, about 10500 hr*ng/L, about 10750 hr*ng/L, about 11000 hr*ng/L, about 11250 hr*ng/L, about 11500 hr*ng/L, to about 11875 hr*ng/L, including all integers and ranges therebetween. In some embodiments, the AUCo-inf is between about 500 hr*ng/L to about 10000 hr*ng/L, about 1000 hr*ng/L to about 7500 hr*ng/L, about 1000 hr*ng/L to about 6000 hr*ng/L, to about 1 500 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about 5000 hr*ng/L, about 2000 hr*ng/L to about 4000 hr*ng/L, about 2000 hrwg L. to about 3000 hr*ng/L, about 2500 hr*ng/L to about 4000 hr*ng/L, about 3000 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 5000 hr*ng/L, about 500 hr*ng/L to about 4000 hr*ng/L, about 500 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng/L to about 3000 hr*ng/L, about 1000 hr*ng&amp;#1523;L to about 2500 hr*ng/L, about 1000 hr*ng/L to about 2000 hr*ng/L, about 1000 hr*ng/L to about 1500 hr*ng/L, or about 1500 hr*ng/L to about 2000 hr*ng/L, about 3500 hr*ng/L to about 4000 hr*ng&amp;#1523;'L, or about 2500 hr*ng/L to about 3000 hr*ng/L. In some embodiments, the mean AUCo-inf is within the range of about 80% to about 125% of 1400 ng*h/L to about 4000 hr*ng/L. In some embodiments, the mean AUCo-inf is about 3800 ng*h/L. In some embodiments, the mean AUCo-inf is within the range of about 80% to about 125% of 1800 ng*h/L to about 3800 ng*h/L.

[0480] Administration of a single dose of the pharmaceutical composition comprising from about 20 qg to about 240 qg dexmedetomidine provides a mean Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours. For example, a single dose provides a mean Tmax of About 0.8 h, about 0.9h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 11, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 11, about 9.25 h, about 9.5 h, about 9.75 h, to about 10 11. In some embodiments, the Tmax is between about Ih to about 8 h, about 1 h to about 6 h, about 1 h to about 4 h, about 1 h to about 3 11, about 1.5 h to about 3 h, about 1.75 11 to about 2.5 h, about 1.75 h to about 2.25 h. In some embodiments, the Tmax is within the range of about 80% to about 125% of about 2 hours. In some embodiments, the Tmax is about 2 hours.

[0481] In some embodiments, the aforementioned pharmacokinetic parameters are non-steady state.

[0482] In some embodiments, the present disclosure provides methods of reducing agitation to a 1 (very much improved) or 2 (much improved) within 2 hours of administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride), as measured by the Clinical Global Impression - Improvement Scale. In some embodiments, the agitation is reduced withm about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation is maintained for greater than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23, or about 24 hours. In some embodiments, the composition comprises about 120 qg of dexmedetomidine. In some embodiments, the composition comprises about 180 qg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

[0483] In some embodiments, the present disclosure provides methods of reducing agitation to a 3 (mild agitation) or 4 (normal behavior) within 2 hours of administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the Agitation

Calmness Evaluation Scale (ACES). In some embodiments, the agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation is reduced to a 4 (normal behavior). In some embodiments, the reduction in agitation is maintained for greater than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 gg of dexmedetomidine. In some embodiments, the composition comprises about 180 gg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

[0484] In some embodiments, the present disclosure provides methods of achieving a >40% reduction in agitation, within 2 hours of administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the PEC scale. In some embodiments, the agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation >40%, >50%, >60%, >70%, >80%, >90%, or >100%. In some embodiments, the reduction m agitation is maintained for greater than about 2 hours. For example, the reduction m agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 gg of dexmedetomidine. In some embodiments, the composition comprises about 180 gg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

[0485] In some embodiments, the present disclosure provides a method of achieving a PEC score reduction in agitation for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 gg to about 180 gg wherein the PEC score reduction is about -8 to about 10&amp;#1470; and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 pg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 pg. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the PEC score reduction is about -8, about -9, or about -10.

[0486] In some embodiments, the present disclosure provides a method of achieving an ACES score improvement for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 pg to about 180 pg wherein the ACES score is improved to about 3 to about 4 and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the ACES score is about 4.

[0487] In some embodiments, the present disclosure provides a method of achieving an CGI-I score improvement for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 pg to about 180 pg wherein the CGI-I score is improved to about a 1 (very much improved) or about a 2 (much improved) and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 pg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 pg. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the CGI-I score is about 1.

[0488] SPECIFIC EMBODIMENTS:

[0489] Embodiment 1. A method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Teo, of about 3800 ng*h/L.

[0490] Embodiment 2. A method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 600 to about 12600 ng*h/L.

[0491] Embodiment 3. A methods of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a mean total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, of about 1800ng*h/L.

[0492] Embodiment 4. A method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a total exposure of dexmedetomidine, as measured by plasma AUC from TO to Too, from about 590 ng*h/L to about 8750 ng*h/L.

[0493] Embodiment 5. The method of embodiments 1 to 4, wherein said agitation or signs of agitation is associated with schizophrenia.

[0494] Embodiment 6 The method of embodiments I to 4, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, orally, intranasally or parenterally.

[0495] Embodiment 7. The method of embodiment 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally.

[0496] Embodiment 8. The method of embodiment 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually.

[0497] Embodiment 9. The method of embodiment 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0498] Embodiment 10. The method of embodiment 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a film.

[0499] Embodiment 11. The method of embodiment 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally.

[0500] Embodiment 12. The method of embodiment 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally m the form of a film, patch or tablet.

[0501] Embodiment 13. The method of embodiment 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally.

[0502] Embodiment 14. The method of embodiment 13, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally in the form of an intramuscular injection.

[0503] Embodiment 15. The method of embodiment 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally.

[0504] Embodiment 16. The method of any one of embodiments 1 to 15, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose.

[0505] Embodiment 17. The method of any one of embodiments 1 to 15, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose containing about 180 pg dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0506] Embodiment 18. The method of any one of embodiments I to 15, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose containing about 120 pg dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0507] Embodiment 19. The method of embodiment 14, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 140 to 190 pg.

[0508] Embodiment 20 The method of embodiment 15, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 900 to 1200 pg.

[0509] Embodiment 21. The method of any one of embodiments 1 to 20, wherein agitation or signs of agitation is treated without also inducing clinically significant cardiovascular effects.

[0510] Embodiment 22. The method of any one of embodiments 1 to 21, wherein agitation or signs of agitation are significantly reduced within 60 minutes of administering dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0511] Embodiment 23. The method of any one of embodiments 1 to 21, wherein agitation or signs of agitation are significantly reduced within 60 minutes of administering dexmedetomidine or a pharmaceutically acceptable salt thereof as measured by a significant relative change in PEC scores just prior to and 60 minutes after administering dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0512] Embodiment 24. The method of embodiment 23, wherein the said relative PEC scores are different by at least six points.

[0513] Embodiment 25. The method of embodiment 23, wherein the said relative PEC scores are different by at least eight points.

[0514] Embodiment 26. The method of embodiment 24 or 25, wherein the difference in relative PEC scores is maintained for at least six hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0515] Embodiment 27. The method of embodiment 23, wherein the said relative PEC scores are different by at least eight points, and wherein this difference of at least eight points is maintained for up to at least about 24 hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0516] Embodiment 28. The method of any one of embodiments 1 to 27, wherein the mean plasma Cmax is about 400 ng/L.

[0517] Embodiment 29. The method of any one of embodiments 1 to 28, wherein the median piasma Tmax is about 2.0 hours.

[0518] Embodiment 30. The method of any one of embodiments 1 to 29, wherein the mean plasma Cmax is about 400 ng/L and the median plasma Tmax is about 2.0 hours.

[0519] Embodiment 31. The method of any one of embodiments 28 to 30, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually.

[0520] Embodiment 32. The method of any one of embodiments 28 to 30, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually m the form of a film.

[0521] Embodiment 33. The method of any one of embodiments 1 to 27, wherein the plasma Cmax is about 100 to about 1100 ng/L.

[0522] Embodiment 34. The method of any one of embodiments 1 to 27, wherein the plasma Cmax is about 200 to about 800ng/L.

[0523] Embodiment 35. The method of any one of embodiments 1 to 27, wherein the plasma Cmax is about 3000 to about 5000 ng/L.

[0524] Embodiment 36. The method of any one of embodiments 33 to 35, wherein the plasma Tmax is about 1 to about 8 hours.

[0525] Embodiment 37. The method of any one of embodiments 33 to 35, wherein the plasma Tmax is about 5 minutes to about 4 hours.

[0526] Embodiment 38. The method of any one of embodiments 33 to 35, wherein the plasma Tmax is about 5 to about 15 minutes.

[0527] Embodiment 39. A method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax of from about 300 ng/L to about 500.ng/L (e.g. about 400 ng/L) and AUC from TO to Too of from about 2300 ng*h/L to about 3600 ng*h/L (e.g. about 2900 ng*h/L).

[0528] Embodiment 40. A method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally to said subject, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from TO to Too of about 600 hr*ng/L to about 9500 hr*ng/L.

[0529] Embodiment 41. A method of treating a condition (e.g. agitation) in a human subject, comprising administering to said subject about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally to said subject, resulting in mean plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values Cmax from about 150ng/L to about 300 ng/L (e.g. about 22O.ng/L) and AUC from TO to Teo of from about 1100 ng*h/L to about 1800 ng*h/L (e.g. about 1420 ng*h/L).

[0530] Embodiment 42. A method of treating a condition (e g. agitation) in a human subject, comprising administering to said subject about 120 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally to said subject, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/L and AUC from TO to Too of about 590 hr*ng/L to about 4400 hrfog L

[0531] Embodiment 43. The method of embodiments 39 to 42, wherein the condition is agitation or signs of agitation.

[0532] Embodiment 44. The method of embodiment 39 to 43, wherein said agitation or signs of agitation is associated with schizophrenia or bipolar disorder.

[0533] Embodiment 45. The method of any one of embodiments 39 to 44 wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e.g. sublingually or buccally).

[0534] Embodiment 46. The method of embodiments 45, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0535] Embodiment 47. The method of embodiment 46, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film.

[0536] Embodiment 48. The method of embodiment 45, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally.

[0537] Embodiment 49. The method of embodiment 48, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet.

[0538] Embodiment 50. The method of embodiment 49, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film.

[0539] Embodiment 51. The method of any one of embodiments 39 to 50, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose.

[0540] Embodiment 52. The method of any one of embodiments 39 to 51, wherein the subject is treated without also inducing significant sedation.

[0541] Embodiment 53. The method of any one of embodiments 39 to 52, wherein the subject is treated without also inducing clinically significant cardiovascular effects.

[0542] Embodiment 54. The method of any one of embodiments 43 to 53, wherein agitation or signs of agitation are significantly reduced within 60 minutes of administering dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0543] Embodiment 55. The method of any one of embodiments 43 to 54, wherein agitation or signs of agitation are significantly reduced within 60 minutes of administering dexmedetomidine or a pharmaceutically acceptable salt thereof as measured by the relative PEC scores just prior to and 60 minutes after administering dexmedetomidine or a pharmaceuti cally acceptable salt thereof. [0544] Embodiment 56. The method of embodiment 55, wherein the said relative PEC scores are different by at least six points.

[0545] Embodiment 57. The method of embodiment 55, wherein the said relative PEC scores are different by at least eight points.

[0546] Embodiment 58. The method of embodiment 56 or 57 wherein the difference in relative PEC scores is maintained for at least six hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0547] Embodiment 59. The method of embodiment 55, wherein the said relative PEC scores are different by at least eight points, and wherein this difference of at least eight points is maintained for up to at least about 24 hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0548] Embodiment 60. The method of any one of embodiments 39 to 59, wherein the median plasma Tmax is about 2 hours.

[0549] Embodiment 61. The method of any one of embodiments39 to 59, wherein the plasma Tmax is about I to about 8 hours.

[0550] Embodiment 62. A method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering 180 gg dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose.

[0551] Embodiment 63. A method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering 120 gg dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose.

[0552] Embodiment 64. A method of mitigation or preventing the occurrence of a further agitation event in a human subject with schizophrenia or bipolar disorder within about 24 hours of an earlier agitation event, comprising administering about 180 gg dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose immediately following said earlier agitation event.

[0553] Embodiment 65. A m ethod of mitigation or preventing the occurrence of a further agitation event in a human subject with schizophrenia or bipolar disorder within about 24 hours of an earlier agitation event, comprising administering about 120 gg dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose immediately following said earlier agitation event.

[0554] Embodiment 66. The method of embodiment 62 or 63, wherein said agitation or signs of agitation is associated with schizophrenia.

[0555] Embodiment 67. A method of treating agitation or signs of agitation in a human subject with dementia, without also inducing significant sedation, comprising oromucosally administering about 30 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to six times a day at a dosing interval of at least 2 hours.

[0556] Embodiment 68. A method of treating agitation or signs of agitation in a human subject with dementia, without also inducing significant sedation, comprising oromucosally administering about 60 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to six times a day at a dosing interval of at least 2 hours.

[0557] Embodiment 69. A method of treating agitation or signs of agitation in a human subject with dementia, without also inducing significant sedation, comprising oromucosally administering about 90 gg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to four times a day at a dosing interval of at least 2 hours.

[0558] Embodiment 70. A method of treating agitation or signs of agitation in a human subject with delirium hospitalized in ICO, without also inducing significant sedation, comprising oromucosally administering about 20 qg of dexmedetomidine or a pharmaceutically acceptable salt one to four times within 6 hours of first dose at a dosing interval of at least 30 minutes thereof. [0559] Embodiment 71. A method of treating agitation or signs of agitation in a human subject with delirium hospitalized in ICU, without also inducing significant sedation, comprising oromucosally administering about 60 qg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to four times within 6 hours of first dose at a dosing interval of at least 30 minutes [0560] Embodiment 72. A method of reducing a period of opioid withdrawal by administering to a human subject of at least 18 years in need thereof dexmedetomidine twice daily for the period of withdrawal, wherein the period of withdrawal is up to 14 days.

[0561] Embodiment 73. The method of embodiment 72, wherein the dexmedetomidine is administered at a dose range between 30 qg to about 200 qg.

[0562] Embodiment 74. The method of embodiment 73, wherein the dexmedetomidine is administered at a unit dose of about 30 qg, 60 qg, 90 qg, 120 qg and 180 qg. Embodiment 75. The method of embodiment 72, wherein the period of withdrawal is up to: 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days.

[0563] Embodiment 76. The method of embodiment 72, wherein the opioid is selected from the group comprising of fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil or pentazocine.

[0564] Embodiment 77. The method of embodiment 72, wherein the opioid had been administered for amount of time longer than neonate treatment prior to withdrawal.

[0565] Embodiment 78. A method of treating agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder, without also inducing significant sedation, comprising administering an oromucosal film comprising about 120 qg or about 180 qg dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose.

[0566] Embodiment 79. The method of embodiment 78, wherein the subject has been previously administered a liquid formulation of dexmedetomidine or a pharmaceutically acceptable salt thereof via a parenteral route (intravenous, intramuscular, subcutaneous injection or intravenous infusion).

[0567] Embodiment 80. The method of any of embodiments 78 and 79, wherein the oromucosal administration is followed within 3 to 5 hours of previous administration of liquid formulation of dexmedetomidine via a parenteral route.

[0568] Embodiment 81. The method of embodiment 78, wherein the parenteral administration is followed within 3 to 5 hours of previous administration of oromucosal film.

[0569] Embodiment 82. The method of embodiment 79, wherein the liquid formulation is prefilled in disposable syringes for self-administration by patients with an auto-injector.

[0570] Embodiment 83. The method of embodiment 78, wherein the subject is currently is cotreated with an anti-psychotic.

[0571] Embodiment 84. The method of embodiments 83, wherein the anti-psychotic is selected from but are not limited to aripiprazole, benperidol. flupentixol, amisulpride, chlorpromazine, asenapme, risperidone, ziprasidone, lurasidone, clozapine, cariprazine, olanzapine and quetiapine. In a preferred embodiment, the anti-psychotic is aripiprazole.

[0572] Embodiments 85. The method of embodiment 72, wherein improvement in the subject is assessed using a Clinical Opiate Withdrawal Scale and/or the Short Opiate Withdrawal Scale of Gossop (e.g. over a 10-day period) after following the treatment.

[0573] Embodiment 86. The method of embodiment 70 or 71, wherein changes in severity of delirium are measured using DRS-R-98 scale.

[0574] Embodiment 87. The method of embodiment 70 or 71, wherein changes in agitation are monitored using RASS scale.

[0575] Embodiment 88. The method of any one of the embodiments 62, 63, 64, 65, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e.g. sublingually, buccally), orally, intranasally or parenterally.

[0576] Embodiment 89. The method of any one of the embodiments 67, 68, 69, 70, 71 and 72, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e.g. sublingually or buccally) in the form of a tablet, film, spray, gel or drops.

[0577] Embodiment 90. The method of embodiment 89, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0578] Embodiment 91. The method of embodiment 90, wherein dexmedetomidine or a pharmaceuticaily acceptable salt thereof is administered sublingually in the form of a film.

[0579] Embodiment 92. The method of embodiment 89, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccaliy in the form of a film, patch or tablet.

[0580] Embodiment 93. The method of embodiment 92, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccaliy in the form of a film.

[0581] Embodiment 94. The method of embodiments 62 to 65, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally in the form of an intravenous or intramuscular injection or an intravenous infusion.

[0582] Embodiment 95. The method of embodiments 62 to 65, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by intramuscular injection.

[0583] Embodiment 96. The method of embodiments 62 to 65, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once a day.

[0584] Embodiment 97. The method of claim 62 to 65, 67, 68, 69, 70, 71 and 72, wherein agitation or signs of agitation is treated without also inducing clinically significant cardiovascular effects.

[0585] Embodiment 98. The method of claim 62 or claim 64, wherein a single dose of about 180 pg dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for up to at least about 24 hours.

[0586] Embodiment 99. The method of embodiments 62 to 65, wherein agitation or signs of agitation are significantly reduced within 60 minutes of administering dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by a significant relative change in PEC scores just prior to and 60 minutes after administering dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0587] Embodiment 100. The method of embod!ment99, wherein the said relative PEC scores are different by at least six points or eight points.

[0588] Embodiment 101. The method of embodiment 99 or embodiment 100, wherein the difference in relative PEC scores is maintained for at least six hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0589] Embodiment 102. The method of embodiment 99 or embodiment 100, wherein the said relative PEC scores are different by at least eight points, and wherein this difference of at least eight points is maintained for up to at least about 24 hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0590] Embodiment 103. The method of any of relevant preceding embodiments, where dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a film, wherein said film is a self-supporting, dissolvable, film, comprising:

(1) dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) one or more water-soluble polymers; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

[0591] Embodiment 104. The method of embodiment 103, wherein (ii) comprises a low molecular weight, water-soluble polymer and two high molecular weight, water-soluble polymers.

[0592] Embodiment 105. The method of embodiment 104, wherein the low molecular weight, water-soluble polymer has a molecular weight from about 5,000 daltons to about 49,000 daltons, and each high molecular weight, water-soluble polymer has a molecular weight of greater than about 60,000 daltons.

[0593] Embodiment 106. The method of embodiment 104, wherein the low molecular weight, water-soluble polymer has a molecular weight of about 40,000 daltons, one of the two high molecular weight, water-soluble polymers has a molecular weight of about 140,000 daltons, and the other high molecular weight, water-soluble polymer has a molecular weight of about 370,000 daltons.

[0594] Embodiment 107. The method of any one of embodiments 103 to 106, wherein each watersoluble polymer is hydroxy propyl cellulose.

[0595] Embodiment 108. The method of any one of embodiments 103 to 106, wherein the film also comprises a polyethylene oxide.

[0596] Embodiment 109. The method of embodiment 108, wherein the polyethylene oxide has a molecular weight of about 600,000 daltons.

[0597] Embodiment! 10. The method of any of relevant preceding embodiments, where dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a film, wherein said film is a self-supporting, dissolvable, film, comprising:

(1) dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a low molecular weight, water-soluble polymer having a molecular weight of about 40,000 daltons;

(iii) a high molecular weight, water-soluble polymer having a molecular weight from about 140,000 daltons;

(iv) a high molecular weight, water-soluble polymer having a molecular weight from about 370,000 daltons; and (v) a water-soluble polyethylene oxide having a molecular weight of about 600,000 daltons.

[0598] Embodiment! 11. The method of embodiment 110, wherein the film components excluding dexmedetomidine or a pharmaceutically acceptable salt thereof form a single layer film substrate, and dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate.

[0599] Embodiment! 12. The method of embodiment 111, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate within a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, a low molecular weight, water-soluble polymer having a molecular weight of about 40,000 daltons, and a high molecular weight, water-soluble polymer having a molecular weight of about 140,000 daltons.

[0600] Embodiment 113. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 120 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human patient.

[0601] Embodiment 114. The method of embodiment 113, wherein the patient has schizophrenia. [0602] Embodiment 115. The method of embodiment 113 or embodiment 114, wherein the patient has bipolar I disorder.

[0603] Embodiment 116. The method of any one of embodiments 113-115, wherein the composition comprises dexmedetomidine hydrochloride.

[0604] Embodiment 117. The method of any one of embodiments 113-116, wherein the composition is administered sublingually or buccally.

[0605] Embodiment 118. The method of embodiment 117, wherein the composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0606] Embodiment 119. The method of embodiment 117, wherein the composition is administered buccally in the form of a film, patch or tablet.

[0607] Embodiment 120. The method of any one of embodiments 113-119, further comprising administering a second dose after a period of time ranging from about 30 minutes to about 12 hours.

[0608] Embodiment 121. The method of embodiment 120, wherein the additional dose is about 60pg or 90pg.

[0609] Embodiment 122. The method of embodiment 120 or embodiment 121, wherein the second dose is administered after a period of about 2 hours.

[0610] Embodiment 123.

in a fed state.

[0611] Embodiment 124.

in a fasted state.

[0612] Embodiment 125.

The method of any one of embodiments 113-122, wherein the patient is

The method of any one of embodiments 113-122, wherein the patient is

The method of any one of embodiments 113-124, wherein agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline.

[0613] Embodiment 126. The method of embodiment 125, wherein the agitation is significantly reduced within about 30 minutes to about 1 hour.

[0614] Embodiment 127. The method of embodiment 125 or embodiment 126, wherein the patient experiences >40% decrease from baseline in PEC score.

[0615] Embodiment 128. The method of embodiment 127, wherein the patient experiences >60% decrease from baseline in PEC score.

[0616] Embodiment 129. The method of any one of embodiments 125-128, wherein the PEC score is >30% lower than placebo.

[0617] Embodiment 130. The method of embodiment 129, wherein the PEC score is >60% lower than placebo.

[0618] Embodiment 131. The method of any one of embodiments 125-130, wherein the mean change in PEC score is greater than -4 (i.e. a decrease of 4 or more points) relative to baseline wathin 2 hours of administering the composition.

[0619] Embodiment 132. The method of embodiment 131, wherein mean change in PEC score is greater than -6 relative to baseline within 2 hours of administering the composition.

[0620] Embodiment 133. The method of embodiment 131, wherein mean change in PEC score is greater than 8&amp;#1524; relative to baseline within 2 hours of administering the composition.

[0621] Embodiment 134. The method of any one of embodiments 125-133, wherein the decrease in PEC score is maintained for at least six hours following administration of the composition.

[0622] Embodiment 135. The method of any one of embodiments 125-134, wherein the mean change in PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 6 hours following administration of the composition.

[0623] Embodiment 136. The method of any one of embodiments 113-135, wherein the subject is treated without experiencing significant sedation.

[0624] Embodiment 137. The method of any one of embodiments 113-136, wherein the subject is treated without experiencing clinically significant cardiovascular effects.

[0625] Embodiment 138. The method of any one of embodiments 113137&amp;#1470;, wherein administration of a single dose provides a mean Cmax within the range of about 80% to about 125% of about 110 ng/L to about 400 ng/L.

[0626] Embodiment 139. The method of embodiment 138, wherein the mean Cmax is within the range of about 80% to about 125% of about 238 ng/L.

[0627] Embodiment 140. The method of embodiment 138, wherein the mean Cmax is about 238 ng/L

[0628] Embodiment 141. The method of any one of embodiments 113-140, wherein administration of a single dose provides a mean AUCo-inf within the range of about 80% to about 125% of about 590 hr*ng/L to about 4400 hr*ng/L.

[0629] Embodiment 142. The method of embodiment 141, the mean AUCo-inf is within the range of about 80% to about 125% of about 1810 ng*h/L.

[0630] Embodiment 143. The method of embodiment 141, wherein the mean AUCo-inf is about 1810ng*h/L.

[0631] Embodiment 144. The method of any one of embodiments 113-143 wherein administration of a single dose provides a mean Tmax within the range of about 80% to about 125% of about 1 hour to about 4 hours.

[0632] Embodiment 145. The method of embodiment 144, wherein the mean Tmax is within the range of about 80% to about 125% of about 2 hours.

[0633] Embodiment 146. The method of embodiment 144, wherein the mean Tmax is about 2 hours.

[0634] Embodiment 147. The method of any one of embodiments 113-146, wherein administration of a single dose provides a geometric mean Cmax within the range of about 80% to about 125% of about 110 ng/L to about 400 ng/L.

[0635] Embodiment 148. The method of embodiment 147, wherein the geometric mean Cmax is within the range of about 80% to about 125% of about 220 ng/L.

[0636] Embodiment 149. The method of embodiment 147, wherein the geometric mean Cmax is about 220 ng/L

[0637] Embodiment 150. The method of any one of embodiments 113-149, wherein administration of a single dose provides a geometric mean AUCo-inf within the range of about 80% to about 125% of about 590 hr*ng/L to about 4400 hr*ng/L.

[0638] Embodiment 151. The method of embodiment 150, the geometric mean AUCo-inf is within the range of about 80% to about 125% of about 1410 ng*h/L.

[0639] Embodiment 152. The method of embodiment 150, wherein the geometric mean AUCo-inf is about 1410 ng*h/L.

[0640] Embodiment 153. The method of any one of embodiments 113152&amp;#1470; wherein administration of a single dose provides a geometric mean Tmax within the range of about 80% to about 125% of about 1 hour to about 4 hours.

[0641] Embodiment 154. The method of embodiment 153, wherein the geometric mean Tmax is wi thin the range of about 80% to about 125% of about 2 hours.

[0642] Embodiment 155. The method of embodiment 153, wherein the geometric mean Tmax is about 2 hours.

[0643] Embodiment 156. The method of any one of embodiments 113-155, wherein administration of a single dose provides a median Cmax within the range of about 80% to about 125% of about 110 ng/L to about 400 ng/L.

[0644] Embodiment 157. The method of embodiment 156, wherein the median Cmax is within the range of about 80% to about 125% of about 230 ng/L.

[0645] Embodiment 158. The method of embodiment 156, wherein the median Cmax is about 230 ng/L.

[0646] Embodiment 159. The method of any one of embodiments 113-158, wherein administration of a single dose provides a median AUCo-mf within the range of about 80% to about 125% of about 590 hr*ngZL to about 4400 hr*ngZL.

[0647] Embodiment 160. The method of embodiment 159, the median AUCo-inf is within the range of about 80% to about 125% of about 1180 ng*h/L.

[0648] Embodiment 161. The method of embodiment 141, wherein the median AUCo-inf is about 1810ng*h/L.

[0649] Embodiment 162. The method of any one of embodiments 113-161 wherein administration of a single dose provides a median Tmax within the range of about 80% to about 125% of about 1 hour to about 4 hours.

[0650] Embodiment 163. The method of embodiment 162, wherein the median Tmax is within the range of about 80% to about 125% of about 2 hours.

[0651] Embodiment 164. The method of embodiment 162, wherein the median Tmax is about 2 hours.

[0652] Embodiment 165. The method of any one of embodiments 138-164, wherein the pharmacokinetic parameters are non-steady state.

[0653] Embodiment 166. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human patient.

[0654] Embodiment 167. The method of embodiment 166, wherein the patient has schizophrenia. [0655] Embodiment 168. The method of embodiment 166 or embodiment 167, wherein the patient has bipolar I disorder.

[0656] Embodiment 169. The method of any one of embodiments 166-168, wherein the composition comprises dexmedetomidine hydrochloride.

[0657] Embodiment 170. The method of any one of embodiments 166-169, wherein the composition is administered sublingually or buccally.

[0658] Embodiment 171. The method of embodiment 170, wherein the composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0659] Embodiment 172. The method of embodiment 170, wherein the composition is administered buccally in the form of a film, patch or tablet.

[0660] Embodiment 173. The method of any one of embodiments 166-172, further comprising administering a second dose after a period of time ranging from about 30 minutes to about 12 hours.

[0661] Embodiment 174. The method of embodiment 173, wherein the additional dose is about

60pg or 90pg.

[0662] Embodiment 175. The method of embodiment 8 or embodiment 174, wherein the second dose is administered after a period of about 2 hours.

[0663] Embodiment 176.

in a fed state.

[0664] Embodiment 177.

in a fasted state.

[0665] Embodiment 178.

The method of any one of embodiments 166-1/5, wherein the patient is

The method of any one of embodiments 166-1/5, wherein the patient is

The method of any one of embodiments 166-17 /, wherein agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline.

[0666] Embodiment 179. The method of embodiment 178, wherein the agitation is significantly reduced within about 30 minutes to about 1 hour.

[0667] Embodiment 180. The method of embodiment 178 or embodiment 179, wherein the patient experiences >40% decrease from baseline in PEC score.

[0668] Embodiment 181. The method of embodiment 180, wherein the patient experiences >60% decrease from baseline in PEC score.

[0669] Embodiment 182. The method of any one of embodiments 178-181, wherein the PEC score is >30% lower than placebo.

[0670] Embodiment 183. The method of embodiment 182, wherein the PEC score is >60% lower than placebo.

[0671] Embodiment 184. The method of any one of embodiments Γ78-183, wherein the mean change in PEC score is greater than -4 (i.e. a decrease of 4 or more points) relative to baseline wfahin 2 hours of administering the composition.

[0672] Embodiment 185. The method of embodiment 184, wherein mean change in PEC score is greater than -6 relative to baseline within 2 hours of administering the composition.

[0673] Embodiment 186. The method of embodiment 184, wherein mean change in PEC score is greater than -8 relative to baseline within 2 hours of administering the composition.

[0674] Embodiment 187. The method of any one of embodiments 178-186, wherein the decrease in PEC score is maintained for at least six hours followang administration of the composition.

[0675] Embodiment 188. The method of any one of embodiments 178-187, wherein the mean change in PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 24 hours following administration of the composition.

[0676] Embodiment 189. The method of any one of embodiments 166-188, wherein the subject is treated without experiencing significant sedation.

[0677] Embodiment 190. The method of any one of embodiments 166-189, wherein the subject is treated without experiencing clinically significant cardiovascular effects.

[0678] Embodiment 191. The method of any one of embodiments 166190&amp;#1470;, wherein administration of a single dose provides a mean Cmax within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L.

[0679] Embodiment 192. The method of embodiment 191, wherein the mean Cmax is within the range of about 80% to about 125% of about 440 ng/L

[0680] Embodiment 193. The method of embodiment 191, wherein the mean Cmax is about 440 ng/L

[0681] Embodiment 194. The method of any one of embodiments 166-193, wherein administration of a single dose provides a mean AUCo-inf within the range of about 80% to about 125% of about 600 hr*ng/L to about 9500 hr*ng/L.

[0682] Embodiment 195. The method of embodiment 194, the mean AUCo-inf is within the range of about 80% to about 125% of about 3800 ng*h/L.

[0683] Embodiment 196. The method of embodiment 194, the mean AUCo-inf is about 3800 ng*n L.

[0684] Embodiment 197. The method of any one of embodiments 166196&amp;#1470;, herein administration of a single dose provides a mean Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours.

[0685] Embodiment 198. The method of embodiment 197, wherein the mean Tmax is within the range of about 80% to about 125% of about 2 hours.

[0686] Embodiment 199. The method of embodiment 197, wherein the mean Tmax is about 2 hours.

[0687] Embodiment 200. The method of any one of embodiments 166-199, wherein administration of a single dose provides a geometric mean Cmax within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L.

[0688] Embodiment 201. The method of embodiment 200, wherein the geometric mean Cmax is within the range of about 80% to about 125% of about 380 ng/L.

[0689] Embodiment 202. The method of embodiment 200, wherein the geometric mean Cmax is about 380 ng/L.

[0690] Embodiment 203. The method of any one of embodiments 166-202, wherein administration of a single dose provides a geometric mean AUCo-mf within the range of about 80% to about 125% of about 600 hr*ng/L to about 9500 hr*ng/L.

[0691] Embodiment 204. The method of embodiment 203, the geometric mean AUCo-inf is within the range of about 80% to about 125% of about 2880 ng*h/L.

[0692] Embodiment 205. The method of embodiment 203, wherein the geometric mean AUCo-inf is about 2880 ng*h/L.

[0693] Embodiment 206. The method of any one of embodim ents 166205&amp;#1470; wherein administration of a single dose provides a geometric mean Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours.

[0694] Embodiment 207. The method of embodiment 206, wherein the geometric mean Tmax is within the range of about 80% to about 125% of about 2 hours.

[0695] Embodiment 208. The method of embodiment 206, wherein the geometric mean Tmax is about 2 hours.

[0696] Embodiment 209. The method of any one of embodiments 166-208, wherein administration of a single dose provides a median Cn^x within the range of about 80% to about 125% of about 110 ng/L to about 800 ng/L.

[0697] Embodiment 210. The method of embodiment 209, wherein the median Cmax is within the range of about 80% to about 125% of about 485 ng/L.

[0698] Embodiment 211. The method of embodiment 209, wherein the median Cmax is about 485 ng/L.

[0699] Embodiment 212. The method of any one of embodiments 166-211, wherein administration of a single dose provides a median AUCo-mt within the range of about 80% to about 125% of about 600 hr*ng/E to about 9500 hr*ng/E.

[0700] Embodiment 213. The method of embodiment 212, the median AUCo-mf is within the range of about 80% to about 125% of about 2900 ng*h/L.

[0701] Embodiment 214. The method of embodiment 194, wherein the median AUCo-inf is about 2900 ng*h/L.

[0702] Embodiment 215. The method of any one of embodiments 166-214 wherein administration of a single dose provides a median Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours.

[0703] Embodiment 216. The method of embodiment 215, wherein the median Tmax is within the range of about 80% to about 125% of about 2 hours.

[0704] Embodiment 217. The method of embodiment 215, wherein the median Tmax is about 2 hours.

[0705] Embodiment 218. The method of any one of embodiments 191-217, wherein the pharmacokinetic parameters are non-steady state.

[0706] Embodiment 219. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising about 120 pg to about 180 pg of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human patient.

[0707] Embodiment 220. The method of embodiment 219, wherein the patient has schizophrenia. [0708] Embodiment 221. The method of embodiment 219 or embodiment 220, wherein the patient has bipolar I disorder.

[0709] Embodiment 222. The method of any one of embodiments 219-221, wherein the composition comprises dexmedetomidine hydrochloride.

[0710] Embodiment 223. The method of any one of embodiments 219-222, wherein the unit dose of dexmedetomidine is about 120 pg.

[0711] Embodiment 224. The method of any one of embodiments 219-222, wherein the unit dose of dexmedetomidine is about 180 pg.

[0712] Embodiment 225. The method of any one of embodiments 219-224, wherein the composition is administered sublingually or buccaily.

[0713] Embodiment 226. The method of embodiment 225, wherein the composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0714] Embodiment 227. The method of embodiment 225, wherein the composition is administered buccally in the form of a film, patch or tablet.

[0715] Embodiment 228. The method of any one of embodiments 219-227, further comprising administering a second dose after a period of time ranging from about 30 minutes to about 12 hours.

[0716] Embodiment 229. The method of embodiment 228, wherein the additional dose is about 60pg or 90pg.

[0717] Embodiment 230. The method of embodiment 228 or embodiment 229, wherein the second dose is administered after a period of about 2 hours.

[0718] Embodiment 231. The method of any one of embodiments 219-230, wherein agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline.

[0719] Embodiment 232. The method of embodiment 231, wherein the agitation is significantly reduced within about 30 minutes to about 1 hour.

[0720] Embodiment 23 3. The method of embodiment 231 or embodiment 232, wherein the patient experiences >40% decrease from baseline in PEC score.

[0721] 234. The method of embodiment 233, wherein the patient experiences >60% decrease from baseline in PEC score.

[0722] Embodiment 235. The method of any one of embodiments 231 -234, wherein the PEC score is >30% lower than placebo.

[0723] Embodiment 236. The method of embodiment 235, wherein the PEC score is >60% lower than placebo.

[0724] Embodiment 237. The method of any one of embodiments 231-236, wherein the mean change in PEC score is greater than -4 (i.e. a decrease of 4 01&amp;#1470; more points) relative to baseline within 2 hours of administering dexmedetomidine.

[0725] Embodiment 238. The method of embodiment 237, wherein mean change in PEC score is greater than -6 relative to baseline within 2 hours of administering the composition.

[0726] Embodiment 239. The method of embodiment 237, wherein mean change in PEC score is greater than 8&amp;#1524; relative to baseline withm 2 hours of administering the composition.

[0727] Embodiment 240. The method of any one of embodiments 231-239, wherein the decrease m PEC score is maintained for at least six hours followang administration of the composition.

[0728] Embodiment 241. The method of any one of embodiments 231-240, wherein the mean change in PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 24 hours following administration of the composition.

[0729] Embodiment 242. The method of any one of embodiments 219-241, wherein the subject is treated without experiencing significant sedation.

[0730] Embodiment 243. The method of any one of embodiments 219-242, wherein the subject is treated without experiencing clinically significant cardiovascular effects.

[0731] Embodiment 244. The method of any one of embodiments 219-243, wherein administration of a single dose provides a mean peak plasma concentration (Cmax) within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L.

[0732] Embodiment 245. The method of embodiment 244, wherein the mean Cmax is within the range of about 80% to about 125% of about 200 ng/L to about 500 ng/L.

[0733] Embodiment 246. The method of embodiment 244, wherein the mean Cmax is within the range of about 80% to about 125% of 230 ng/L to about 440 ng/L.

[0734] Embodiment 247. The method of any one of embodiments 219-246, wherein administration of a single dose provides a mean area under the curve (AUC)o-inf within the range of about 80% to about 125% of about 590 hr*ng/L to about 9500 hr*ng/L.

[0735] Embodiment 248. The method of embodiment 247, wherein the mean AUCo-inf is within the range of about 80% to about 125% of 1400 ng*h/L to about 4000 hr*ng/L.

[0736] Embodiment 249. The method of embodiment 247, wherein the mean AUCo-inf is wathin the range of about 80% to about 125% of 1800 ng*h/L to about 3800 ng*h/L.

[0737] Embodiment 250. The method of any one of embodiments 219-249 wherein administration of a single dose provides a mean time to peak plasma concentration (Tmax) within the range of about 80% to about 125% of about I hour to about 8 hours.

[0738] Embodiment 251. The method of embodiment 250, wherein the mean Tmax is within the range of about 80% to about 125% of about hours.

[0739] Embodiment 252. The method of embodiment 250, wherein the mean Tmax is about 2 hours.

[0740] Embodiment 253. The method of any one of embodiments 244-252, wherein the pharmacokinetic parameters are non-steady state.

[0741] Embodiment 254. The method of any one of embodiments 219-253, wherein the patient is in a fed state.

[0742] Embodiment 255. The method of any one of embodiments 219-253, wherein the patient is in a fasted state.

[0743] Embodiment 256. A method of treating or ameliorating opioid withdrawal symptoms, comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof to a human patient in need thereof, wherein the patient is at least 18 years and wherein the period of withdrawal is up to 14 days.

[0744] Embodiment 257. The method of embodiment 256, wherein the treatment comprises reducing the period of opioid withdrawal.

[0745] Embodiment 258. The method of embodiment 256 or embodiment 257, wherein the treating or ameliorating is measured by the Clinical Opiate Withdrawal Scale (COWS) and/or Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) score.

[0746] Embodiment 259. The method of any one of embodiments 256-258, wherein the composition is administered twice daily.

[0747] Embodiment 260. The method of any one of embodiments 256-259, wherein the composition comprises a dose range of dexmedetomidine or a pharmaceutically acceptable salt thereof of between about 30 qg and about 200 qg.

[0748] Embodiment 261. The method of any one of embodiments 256-260, wherein the composition comprises a unit dose of about 30 qg, about 60 qg, about 90 qg, about 120 qg, or 180 qg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0749] Embodiment 262. The method of any one of embodiments 256-261, wherein the period of withdrawal is up to 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days.

[0750] Embodiment 263. The method of any one of embodiments 256-262, wherein the opioid is selected from the group comprising of fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil and pentazocine.

[0751] Embodiment 264. The method of embodiment 263, wherein the opioid is selected from the group comprising of fentanyl.

[0752] Embodiment 265. The method of any one of embodiments 256-262, wherein the opioid had been administered for amount of time longer than neonate treatment prior to withdrawal.

[0753] Embodiment 266. The method of any one of embodiments 256-265, wherein the composition is administered sublingually, buccaliy, orally, mtranasally or parenterally.

[0754] Embodiment 267. The method of embodiments any one of embodiments 256-266, wherein the composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0755] Embodiment 268. The method of embodiment 267, wherein the composition is administered sublingually in the form of a film.

[0756] Embodiment 269. The method of any one of embodiments 256-266, wherein the composition is administered buccaliy in the form of a film, patch or tablet.

[0757] Embodiment 270. The method of embodiment 269, wherein the composition is administered buccaliy in the form of a film.

[0758] Embodiment 271. The method of any one of embodiments 256-270, wherein the patient is treated without also inducing clinically significant cardiovascular effects.

[0759] Embodiment 272. The method of any one of embodiments 256-271 wherein a single dose of a composition comprising about 180 pg dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for up to at least about 24 hours.

[0760] Embodiment 273. The method of any one of embodiments 256-272, wherein the composition comprises dexmedetomidine hydrochloride.

[0761] Embodiment 274. The method of any one of embodiments 256-273, wherein the opioid withdrawal symptom is agitation.

[0762] Embodiment 275. The method of any one of embodiments 256-274, wherein the composition is administered twice daily for 7 days.

[0763] Embodiment 276. A pharmaceutical composition comprising from about 20 pg to about 240 pg dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0764] Embodiment 277. The composition of embodiment 276, wherein dexmedetomidine is present as dexmedetomidine hydrochloride.

[0765] Embodiment 278. The composition of embodiment 276 or embodiment 277, wherein the dose of dexmedetomidine is about 120 pg.

[0766] Embodiment 279. The composition of any one of embodiments 276-278, wherein the dose of dexmedetomidine is about 180 pg.

[0767] Embodiment 280. The composition of any one of embodiments 276-279, wherein the composition is formulated for sublingual or buccal administration.

[0768] Embodiment 281. The composition of embodiment 280, wherein the composition is formulated for sublingual administration in the form of a tablet, film, spray, gel or drops.

[0769] Embodiment 282. The composition of embodiment 280, wherein the composition is formulated for buccal administration in the form of a film, patch or tablet.

[0770] Embodiment 283. The composition of any one of embodiments 276-282, wherein if administered to a patient having agitation associated with schizophrenia or bipolar disorder, the agitation is significantly reduced within about 2 hours of administering the composition as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline.

[0771] Embodiment 284. The composition of embodiment 283, wherein the agitation is significantly reduced within about 30 minutes to about 1 hour.

[0772] Embodiment 285. The composition of embodiment 283 or embodiment 284, wherein the patient experiences >40% decrease from baseline in PEC score.

[0773] Embodiment 286. The composition of embodiment 285, wherein the patient experiences >60% decrease from baseline in PEC score.

[0774] Embodiment 287. The composition of any one of embodiments 283-286, wherein the PEC score is >30% lower than placebo.

[0775] Embodiment 288. The composition of embodiment 287, wherein the PEC score is >60% lower than placebo.

[0776] Embodiment 289. The composition of any one of embodiments 283-288, wherein the mean change in PEC score is greater than -4 (i.e. a decrease of 4 or more points) relative to baseline within 2 hours of administering the composition.

[0777] Embodiment 290. The composition of embodiment 289, wherein mean change in PEC score is greater than -6 relative to baseline within 2 hours of administering the composition.

[0778] Embodiment 291. The composition of embodiment 289, wherein mean change in PEC score is greater than -8 relative to baseline within 2 hours of administering the composition.

[0779] Embodiment 292. The composition of any one of embodiments 283-291, wherein the decrease in PEC score is maintained for at least six hours following administration of the composition.

[0780] Embodiment 293. The composition of any one of embodiments 283-292, wherein the mean change m PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 24 hours following administration of the composition.

[0781] Embodiment 294. The composition of any one of embodiments 283-293, wherein the subject is treated without experiencing significant sedation.

[0782] Embodiment 295. The composition of any one of embodiments 283-294, wherein the subject is treated without experiencing clinically significant cardiovascular effects.

[0783] Embodiment 296. The composition of any one of embodiments 276-295, wherein if administered to a patient having schizophrenia or bipolar disorder, a single dose provides a mean Cmax within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L.

[0784] Embodiment 297. The composition of embodiment 296, wherein the geometric mean is from about 200 ng/L to about 400 ng/L.

[0785] Embodiment 298. The composition of embodiment 296, wherein the mean Cmax is within the range of about 80% to about 125% of 230 ng/L to about 440 ng/L.

[0786] Embodiment 299. The composition of any one of embodiments 276-298, wherein if administered to a patient having schizophrenia or bipolar disorder, a single dose provides a mean aAUCo-inf within the range of about 80% to about 125% of about 590 hr*ng/L to about 9500 hr*ng/L.

[0787] Embodiment 300. The composition of embodiment 299, wherein the mean AUCo-irf is within the range of about 80% to about 125% of 1400 ng*h/L to about 4000 hr*ng/L.

[0788] Embodiment 301. The composition of embodiment 299, wherein the mean AUCo-irf is within the range of about 80% to about 125% of 1800 ng*h/L to about 3800 ng*h/L.

[0789] Embodiment 302. The composition of any one of embodiments 276-301, wherein if administered to a patient having schizophrenia or bipolar disorder, a single dose provides a mean time to peak plasma concentration (Tmax) within the range of about 80% to about 125% of about 1 hour to about 8 hours.

[0790] Embodiment 303. The composition of embodiment 302, wherein the mean Tmax is wathin the range of about 80% to about 125% of about hours.

[0791] Embodiment 304. The composition of embodiment 302, wherein the mean Tmax is about 2 hours.

[0792] Embodiment 305. The composition of any pharmacokinetic parameters are non-steady state.

one of embodiments

296-304, wherein the

[0793] Embodiment 306. patient is in a fed state.

[0794] Embodiment 307. patient is in a fasted state. [0795] Embodiment 308.

The composition of any

The composition of any one one of embodiments of embodiments

283-305, wherein the

283-305, wherein the

A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof to a human patient, wherein the dose provides one or more of the following pharmacokinetic parameters:

[0796] (1) a mean Cmax within the range of about 80% to about 125% of about 110 ng/L to about

400 ng/L; and/or

[0797] (2) a mean AUCo-inf within the range of about 80% to about 125% of about 590 hr*ng/L to about 4400 hr*ng/L; and/or

[0798] (3) a mean Tmax within the range of about 80% to about 125% of about 1 hour to about 4 hours.

[0799] Embodiment 309. The method of embodiment 308, wherein the patient has schizophrenia. [0800] Embodiment 310. The method of embodiment 308 or embodiment 309, wherein the patient has bipolar I disorder.

[0801] Embodiment 311. The method of any one of embodiments 308-310, wherein the composition comprises dexmedetomidine hydrochloride.

[0802] Embodiment 312. The method of any one of embodiments 308-311, wherein the composition is administered sublingually or buccally.

[0803] Embodiment 313. The method of embodiment 312, wherein the composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0804] Embodiment 314. The method of embodiment 312, wherein the composition is administered buccally in the form of a film, patch or tablet.

[0805] Embodiment 315. The method of any one of embodiments 308-314, further comprising administering a second dose after a period of time ranging from about 30 minutes to about 12 hours.

[0806] Embodiment 316. The method of embodiment 315, wherein the additional dose is about

60pg or 90pg.

[0807] Embodiment 317. The method of embodiment 315 or embodiment 316, wherein the second dose is administered after a period of about 2 hours.

[0808] Embodiment 318.

in a fed state.

[0809] Embodiment 319.

in a fasted state.

[0810] Embodiment 320.

The method of any one of embodiments 308-317, wherein the patient is

The method of any one of embodiments 308-317, wherein the patient is

The method of any one of embodiments 308-319, wherein agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline.

[0811] Embodiment 321. The method of embodiment 320, wherein the agitation is significantly reduced within about 30 minutes to about 1 hour.

[0812] Embod iment 322. The method of embodiment 320 or embodiment 321, wherein the patient experiences >40% decrease from baseline in PEC score.

[0813] Embodiment 323. The method of embodiment 322, wherein the patient experiences >60% decrease from baseline in PEC score.

[0814] Embodiment 324. The method of any one of embodiments 320-323, wherein the PEC score is >30% lower than placebo.

[0815] Embodiment 325. The method of embodiment 324, wherein the PEC score is >60% lower than placebo.

[0816] Embodiment 326. The method of any one of embodiments 320-325, wlierein the mean change in PEC score is greater than -4 (i.e. a decrease of 4 or more points) relative to baseline wathin 2 hours of administering the composition.

[0817] Embodiment 327. The method of embodiment 326, wherein mean change in PEC score is greater than -6 relative to baseline within 2 hours of administering the composition.

[0818] Embodiment 328. The method of embodiment 326, wherein mean change in PEC score is greater than -8 relative to baseline within 2 hours of administering the composition.

[0819] Embodiment 329. The method of any one of embodiments 320-328, wherein the decrease in PEC score is maintained for at least six hours follow'ing administration of the composition.

[0820] Embodiment 330. The method of any one of embodiments 320-329, wherein the mean change in PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 6 hours following administration of the composition.

[0821] Embodiment 331. The method of any one of embodiments 308-330, wherein the subject is treated without experiencing significant sedation.

[0822] Embodiment 332. The method of any one of embodiments 308-331, wherein the subject is treated without experiencing clinically significant cardiovascular effects.

[0823] Embodiment 333. The method of any one of embodiments 308-332 wherein two or more of the pharmacokinetic parameters are present.

[0824] Embodiment 334. The method of any one of embodiments 308-333, wherein all three of the pharmacokinetic parameters are present.

[0825] Embodiment 335. The method of any one of embodiments 308-334, wherein the mean Cmax is within the range of about 80% to about 125% of about 238 ng/L.

[0826] Embodiment 336. The method of embodiment 335, wherein the mean Cmax is about 238 ng/L

[0827] Embodiment 337. The method of any one of embodiments 308-336, wherein administration of a single dose provides a mean AUCo-inf within the range of about 80% to about 125% of about 1810 ng*h/L.

[0828] Embodiment 338. The method of embodiment 337, wherein the mean about 1810 ng*h/L. [0829] Embodiment 339. The method of any one of embodiments 308-338 wherein administration of a single dose provides a mean Tmax within the range of about 80% to about 125% of about 2 hours.

[0830] Embodiment 340. The method of embodiment 339, wherein the mean Tmax is about 2 hours.

[0831] Embodiment 341. The method of any one of embodiments 308-340, wherein the pharmacokinetic parameters are non-steady state.

[0832] Embodiment 342. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering a unit dose composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof to a human patient, wherein the dose provides one or more of the following pharmacokinetic parameters:

[0833] (1) a mean Cmax within the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L; and/or

[0834] (2) a mean AUCo-inf within the range of about 80% to about 125% of about 600 hr*ng/L to about 9500 hr*ng/L; and/or

[0835] (3) a mean Tmax within the range of about 80% to about 125% of about 1 hour to about 8 hours.

[0836] Embodiment 343. The method of embodiment 342, wherein the patient has schizophrenia. [0837] Embodiment 344. The method of embodiment 342 or embodiment 343, wherein the patient has bipolar I disorder.

[0838] Embodiment 345. The method of any one of embodiments 342-344, wherein the composition comprises dexmedetomidine hydrochloride.

[0839] Embodiment 346. The method of any one of embodiments 342-345, wherein the composition is administered sublingually or buccally.

[0840] Embodiment 347. The method of embodiment 346, wherein the composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

[0841] Embodiment 348. The method of embodiment 346, wherein the composition is administered buccally in the form of a film, patch or tablet,

[0842] Embodiment 349. The method of any one of embodiments 342-348, further comprising administering a second dose after a period of time ranging from about 30 minutes to about 12 hours.

[0843] Embodiment 350. The method of embodiment 349, wherein the additional dose is about 60pg or 90gg.

[0844] Embodiment 351. The method of embodiment 349 or embodiment 350, wherein the second dose is administered after a period of about 2 hours.

[0845] Embodiment 352. The method of any one of embodiments 342-351, wherein the patient is in a fed state.

[0846] Embodiment 353. The method of any one of embodiments 342-351, wherein the patient is in a fasted state.

[0847] Embodiment 354. The method of any one of embodiments 342-353, wherein agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline.

[0848] Embodiment 355. The method of embodiment 354, wherein the agitation is significantly reduced within about 30 minutes to about 1 hour.

[0849] Embodiment 356. The method of embodiment 354 or embodiment 355, wherein the patient experiences >40% decrease from baseline in PEC score.

[0850] Embodiment 357. The method of embodiment 356, wherein the patient experiences >60% decrease from baseline in PEC score.

[0851] Embodiment 358. The method of any one of embodiments 354-357, wherein the PEC score is >30% lower than placebo.

[0852] Embodiment 359. The method of embodiment 358, wherein the PEC score is >60% lower than placebo.

[0853] Embodiment 360. The method of any one of embodiments 354359&amp;#1470;, wherein the mean change in PEC score is greater than -4 (i.e. a decrease of 4 or more points) relative to baseline within 2 hours of administering the composition.

[0854] Embodiment 361. The method of embodiment 360, wherein mean change in PEC score is greater than 6&amp;#1470; relative to baseline within 2 hours of administering the composition.

[0855] Embodiment 362, The method of embodiment 360, wherein mean change in PEC score is greater than 8&amp;#1470; relative to baseline within 2 hours of administering the composition.

[0856] Embodiment 363. The method of any one of embodiments 354-362, wherein the decrease m PEC score is maintained for at least six hours following administration of the composition.

[0857] Embodiment 364. The method of any one of embodiments 354-363, wherein the mean change in PEC score is greater than or equal to -8 and is maintained from 2 hours post administration up to at least about 6 hours following administration of the composition.

[0858] Embodiment 365. The method of any one of embodiments 342-364, wherein the subject is treated without experiencing significant sedation.

[0859] Embodiment 366. The method of any one of embodiments 342-365, wherein the subject is treated without experiencing clinically significant cardiovascular effects.

[0860] Embodiment 367. The method of any one of embodiments 342-366 wherein two or more of the pharmacokinetic parameters are present.

[0861] Embodiment 368. The method of any one of embodiments 342-367, wherein all three of the pharmacokinetic parameters are present.

[0862] Embodiment 369. The method of any one of embodiments 342-368, wherein the mean Cmax is within the range of about 80% to about 125% of about 440 ng/L.

[0863] Embodiment 370. The method of embodiment 369, wherein the mean Cmax is about 440 ng/L

[0864] Embodiment 371. The method of any one of embodiments 342-370, wherein administration of a single dose provides a mean AUCo-inf within the range of about 80% to about 125% of about 3800 ng*h/L.

[0865] Embodiment 372. The method of embodiment 371, wherein the mean about 3800 ng*h/L. [0866] Embodiment 373. The method of any one of embodiments 342372&amp;#1470; wherein administration of a single dose provides a mean Tmax within the range of about 80% to about 125% of about 2 hours.

[0867] Embodiment 374. The method of embodiment 373, wherein the mean Tmax is about 2 hours.

[0868] Embodiment 375. The method of any one of embodiments 342-374, wherein the pharmacokinetic parameters are non-steady state.

[0869] Embodiment 376. The method of any of the preceding embodiments, wherein agitation is reduced to a 1 (very much improved) or 2 (much improved) within 2 hours of administering the composition, as measured by the Clinical Global Impression -Improvement Scale.

[0870] Embodiment 377. The method of embodiment 376, wherein the agitation is reduced within about 30 minutes to about 1 hour.

[0871] Embodiment 378. The method of embodiment 377, wherein the agitation is reduced within about 30 minutes.

[0872] Embodiment 379. The method of any one of embodiments 376-378, wherein the reduction in agitation is reduced to a 1 (very much improved).

[0873] Embodiment 380. The method of embodiment any one of embodiments 376-379, wherein the reduction in agitation is maintained for greater than about 2 hours.

[0874] Embodiment 381. The method of any one of embodiments 376-380, wherein the reduction in agitation is maintained for greater than about 4 hours.

[0875] Embodiment 3 82. The method of any one of embodiments 376-381, wherein the reduction in agitation is maintained for greater than about 6 hours.

[0876] Embodiment 383. The method of any one of embodiments 376-382, wherein the reduction in agitation is maintained for greater than about 8 hours.

[0877] Embodiment 384. The method of any one of embodiments 376-383, wherein the composition comprises 120 pg of dexmedetomidine.

[0878] Embodiment 385. The method of any one of embodiments 376-383, wherein the composition comprises 180 pg of dexmedetomidine.

[0879] Embodiment 386. has schizophrenia.

[0880] Embodiment 387. has bipolar disorder.

[0881] Embodiment 388.

The method of any one of embodiments 376-385, wherein the patient

The method of any one of embodiments 376-386, wherein the patient

The method of any of the preceding embodiments, wherein agitation is reduced to a 3 (mild agitation) or 4 (normal behavior) within 2 hours of administering the composition, as measured by the Agitation-Calmness Evaluation Scale (ACES).

[0882] Embodiment 389. The method of embodiment 388, wherein the agitation is reduced within about 30 minutes to about 1 hour.

[0883] Embodiment 390. The method of embodiment 388 or embodiment 389, wherein the reduction in agitation is reduced to a 4 (normal behavior).

[0884] Embodiment 391. The method of any one of embodiments 388-390, wherein the reduction m agitation is maintained for greater than about 2 hours.

[0885] Embodiment 392. The method of any one of embodiments 388-391, wherein the reduction m agitation is maintained for greater than about 4 hours.

[0886] Embodiment 393. The method of any one of embodiments 388-392, wherein the reduction m agitation is maintained for greater than about 6 hours.

[0887] Embodiment 394. The method of any one of embodiments 388-393, wherein the reduction in agitation is maintained for greater than about 8 hours.

[0888] Embodiment 395. The method of any one composition comprises 120 gg of dexmedetomidine.

[0889] Embodiment 396. The method of any one composition comprises 180 gg of dexmedetomidine.

of embodiments of embodiments

388-394, wherein

388-394, wherein the the

[0890] Embodiment 397. has schizophrenia.

[0891] Embodiment 398. has bipolar disorder.

[0892] Embodiment 399.

The method of any one of embodiments 388-396, wherein the patient

The method of any one of embodiments 388-397, wherein the patient

The method of any of the preceding embodiments, wherein the patient experiences a >40 reduction in agitation, as measured by the PEC Scale.

[0893] Embodiment 400. The method of embodiment 399, wherein the agitation is reduced within about 30 minutes to about 1 hour.

[0894] Embodiment 401. The method of embodiment 399 or embodiment 400, wherein the patient experiences a >60 reduction in agitation.

[0895] Embodiment 402. The method any one of embodiments 399-401, wherein the patient experiences a >80 reduction in agitation.

[0896] Embodiment 403. The method of any one of embodiments 399-402, wherein the reduction in agitation is maintained for greater than about 2 hours.

[0897] Embodiment 404. The method of any one of embodiments 399-403, wherein the reduction in agitation is maintained for greater than about 4 hours.

[0898] Embodiment 405. The method of any one of embodiments 399-404, wherein the reduction in agitation is maintained for greater than about 6 hours.

[0899] Embodiment 406. The method of any one of embodiments 399-405, wherein the reduction in agitation is maintained for greater than about 8 hours.

[0900] Embodiment 407. The method of any one of embodiments 399-406, wherein the composition comprises 120 gg of dexmedetomidine.

[0901] Embodiment 408. The method of any one of embodiments 399-406, wherein the composition comprises 180 gg of dexmedetomidine.

[0902] Embodiment 409. The method of any one of embodiments 399-408, wherein the patient has schizophrenia.

[0903] Embodiment 410. The method of any one of embodiments 399-409, wherein the patient has bipolar disorder.

[0904] Embodiment 411. A method of achieving a PEC score reduction in agitation for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg wherein the PEC score reduction is about -8 to about -10 and wherein the sustained period is about 2 hours to about 6 hours.

[0905] Embodiment 412. The method of embodiment 411, wherein the composition comprises dexmedetomidine hydrochloride.

[0906] Embodiment 413. The method of embodiment 411 or 412, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg.

[0907] Embodiment 414. The method of embodiment 411 or 412, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 180 mcg.

[0908] Embodiment 415. The method according to any one of embodiments 411 to 414, wherein the sustained period is about 4 hours.

[0909] Embodiment 416. The method according to embodiment 415, wherein the sustained period is about 6 hours.

[0910] Embodiment 417. The method according to any one of embodiments 411-416, wherein the PEC score reduction is about -10.

[0911] Embodiment 418. A method of achieving an ACES score improvement for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg wherein the ACES score is improved to about 3 to about 4 and wherein the sustained period is about 2 hours to about 6 hours. [0912] Embodiment 419. The method of embodiment 418, wherein the composition comprises dexmedetomidine hydrochloride.

[0913] Embodiment 420. The method of embodiment 418 or 419, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg.

[0914] Embodiment 421. The method of embodiment 418 or 419, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 180 mcg.

10915^ Embodiment 422, The method according to any one of embodiments 418 to 421, wherein the sustained period is about 4 hours.

[0916] Embodiment 423. The method according to embodiment 422, wherein the sustained period is about 6 hours.

[0917] Embodiment 424. The method according to any one of embodiments 418-423, wherein the ACES score is about 4.

[0918] Embodiment 425. A method of achieving an CGI-I score improvement for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg wherein the CGI-I score is improved to about a 1 (very much improved) or about a 2 (much improved) and wherein the sustained period is about 2 hours to about 6 hours.

[0919] Embodiment 426. The method of embodiment 425, wherein the composition comprises dexmedetomidine hydrochloride.

[0920] Embodiment 427. The method of embodiment 425 or 426, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg.

[0921] Embodiment 428. The method of embodiment 425 or 426, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 180 mcg.

[0922] Embodiment 429. The method according to any one of embodiments 425 to 428, wherein the sustained period is about 4 hours,

[0923] Embodiment 430. The method according to embodiment 425, wherein the sustained period is about 6 hours.

[0924] Embodiment 431 The method according to any one of embodiments 425-430, wherein the CGI-I score is about 1.

[0925] Embodiment 432. The method of any one of embodiments 110 to 112, wherein each watersoluble polymer is hydroxypropyl cellulose.

[0926] Embodiment 433. The method of any one of embodiments 103 to 113, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0927] Embodiment 434. The method of any relevant preceding embodiments, wherein dexmedetomidine hydrochloride is administered as a film, wherein said film is a self-supporting, dissolvable, film, comprising:

(a) a composition comprising:

(1) dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate comprising:

(1) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b).

[0928] Embodiment 435. The method of any relevant preceding embodiment, wherein dexmedetomidine hydrochloride thereof is administered as a film, wherein said film is a selfsupporting, dissolvable, film, comprising:

(a) a composition consisting essentially of:

(i) dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (in) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(in) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b).

[0929] Embodiment 436. The method of embodiment 434 or embodiment 435, wherein dexmedetomidine hydrochloride is present at about 0.1% to about 0.2% w/w of the total film weight, hydroxypropyl cellulose (40,000MW) is present at about 4% to about 6% w/w of the total film weight, hydroxypropyl cellulose (140,000MW) is present at about 4% to about 6% w/w of the total film weight, hydroxypropyl cellulose (370,000MW) is present at about 27% to about 30% w/w of the total film weight, and polyethylene oxide (600,000MW) is present at about 55% to about 60% w/w of the total film weight.

[0930] Embodiment 437. A self-supporting, dissolvable, film, comprising:

(a) a composition consisting essentially of:

(i) about 180 pg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (iii) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b).

[0931] Embodiment 438. The film of embodiment 437 wherein dexmedetomidine hydrochloride is present at about 0.1% to about 0.2% w/w of the total film weight, hydroxypropyl cellulose (40.000MW) is present at about 4% to about 6% w/w of the total film weight, hydroxypropyl cellulose (140,000MW) is present at about 4% to about 6% w/w of the total film weight, hydroxypropyl cellulose (370,000MW) is present at about 27% to about 30% w/w of the total film weight, and polyethylene oxide (600,000MW) is present at about 55% to about 60% w/w of the total film weight.

[0932] Embodiment 439. A self-supporting, dissolvable, film, comprising:

(a) a composition consisting essentially of:

(i) about 120 pg of dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000MW); and (in) hydroxypropyl cellulose (140,000MW); and (b) a film substrate consisting essentially of:

(i) hydroxypropyl cellulose (40,000MW);

(ii) hydroxypropyl cellulose (140,000MW);

(iii) hydroxypropyl cellulose (370,000MW); and (iv) polyethylene oxide (600,000MW);

wherein the composition of part (a) is present on the surface of the film substrate (b).

[0933] Embodiment 440. The film of embodiment 439 wherein dexmedetomidine hydrochloride is present at about 0.1% to about 0.2% w/w of the total film weight, hydroxypropyl cellulose (40,000MW) is present at about 4% to about 6% w/w of the total film weight, hydroxypropyl cellulose (140.000MW) is present at about 4% to about 6% w/w of the total film weight, hydroxypropyl cellulose (370,000MW) is present at about 27% to about 30% w/w of the total film weight, and polyethylene oxide (600,000MW) is present at about 55% to about 60% w/w of the total film weight.

[0934] Embodiment 441. The method of any of relevant preceding embodiments, where dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a sublingual spray, sublingual drop, sublingual gel, buccal tablet or sublingual tablet as embodied 111 table 1, table 2, table 3, table 4 or table 5 respectively.

Example 1: Dexmedetomidine sublingual film formulation

[0935] Table 6: Dexmedetomidine deposited on the surface of a polymer matrix film composition

<td> Ingredients</td><td> Concentration g/lOOg (10 pg film)</td><td> Concentration g/lOOg (20 pg film)</td><td> Function</td>

<td colspan="4"> Drug-containing composition</td>

<td> Dexmedetomidine hydrochloride</td><td> 0.136</td><td> 0.267</td><td> Active agent</td>

<td> Hydroxypropyl cellulose, HPC-SSL (MW - 40,000)</td><td> 0.301</td><td> 0.593</td><td> Film former</td>

<td> Hydroxypropyl cellulose (MW === 140,000)</td><td> 0.301</td><td> 0.593</td><td> Film former</td>

<td> FD&amp;C Blue #1 Granular</td><td> 0.002</td><td> 0.004</td><td> Color</td>

<td> Ethyl Alcohol as a solvent</td><td> qs</td><td> qs</td><td> Solvent</td>

<td colspan="4"> Polymer matrix composition</td>

<td> Hydroxypropyl cellulose (MW = 140,000)</td><td> 4.803</td><td> 4.768</td><td> Film former</td>

<td> Hydroxypropyl cellulose, HPC-SSL ' (MW = 40,000)</td><td> 4.803</td><td> 4.768</td><td> Film former</td>

<td> Hydroxypropyl cellulose (MW = 370,000)</td><td> 28.809</td><td> 28.601</td><td> Film former</td>

<td> Fast Emerald Green Shade (NO. 06507)</td><td> 0.129</td><td> 0.128</td><td> Color</td>

<td> Sucralose, USP-NF Grade</td><td> 0.993</td><td> 0.985</td><td> Sweetener</td>

<td> Peppermint Oil, NF</td><td> 2.104</td><td> 2.089</td><td> Flavor</td>

<td> Polyethylene oxide (Sentry Polyox WSR 205 LEO NF) (MW - 600,000)</td><td> 57.618</td><td> 57.202</td><td> Film former &amp; Mucoadhesive</td>

<td> Water as a solvent</td><td> qs</td><td> qs</td><td> Solvent</td>

[0936] (A) Process for the preparation of polymer matrix:

[0937] Polymer mixture: Polyethylene oxide and fast emerald green shade were mixed m water for at least 180 minutes at about 1400 rpm to about 2000 rpm. Sucralose, hydroxypropyl cellulose (molecular weight 140K), hydroxypropyl cellulose, HPC-SSL (molecular weight 40K) and hydroxypropyl cellulose (molecular weight 370K) were added and mixed for at least 120 minutes at about 1600 rpm to 2000 rpm. Peppermint Oil was added to water and the resultant dispersion was then added to the polymer mixture and mixed for at least 30 minutes. The resultant mixture was further mixed under vacuum (248 torr) for at least for 30 minutes at a speed of 350 rpm and at temperature of 22.9°C.

[0938] Coating station: A roll was placed on an unwind stand and the leading edge was thread through guide bars and coating bars. The silicone-coated side of the liner was placed faced up. A gap of 40 millimeters was maintained between the coating bars. The oven set point was adjusted to 7O0C and the final drying temperature was adjusted to 85°C.

[0939] Coating/drymg process: The polymer mixture was poured onto the liner between the guide bars and the coating bars. The liner was pulled slowly through the coating bar at a constant speed by hand until no liquid was remained on the coating bars. The liner was cut to approximately 12meh length hand sheets using a safety knife. Each hand sheet was placed on a drying board and was tapped on the corners to prevent curl during drying. The hand sheets were dried in the oven until the moisture content was less than 5% (approximately 30 minutes) and then removed from the diving board. The coating weights were checked against the acceptance criteria, and if met, the hand sheets were then stacked and placed in a 34 inch x 40 inch foil bag that was lined with PET release liner.

[0940] (B) Process for the preparation of deposition solution:

[0941] FDC blue was dissolved in ethyl alcohol for at least 180 minutes. Dexmedetomidine hydrochloride was added to the ethyl alcohol solution with continuous stirring for 10 minutes at about 400 rpm to about 800 rpm. Hydroxypropyl cellulose (40K) and hydroxypropyl cellulose (140K) were added to the mixture, and stirred for at least 30 minutes until all the materials were dissolved.

[0942] (C) Process for the preparation of micro-deposited matrix:

[0943] The deposition solution obtained in Step (B) above was filled into a pipette to the required volume (determined according to the specific drug product strength of the final product). An appropriate amount (1.5 microliters = approximately 5 pg) of the deposition solution were deposited (e.g. as droplets) onto the polymer matrix obtained in Step (A), and repeated to a total of 10 times (i.e. 10 deposits/droplets) with space between each deposit to prevent merging of the deposits/droplets and allow subsequent cutting of the film into individual drug-containing units. The film was initially die cut m individual units with dimensions of 22 mm x 8.8 mm containing a single deposit of the drug-containing composition. The die cut micro-deposited matrixes were then dried in an oven for 70°C for 10 minutes and further die cut into 10 units with each unit containing a single deposit of the drug-containing composition.

[0944] (D) Packaging:

[0945] Each defect-free unit was sealed individually into a foil pouch, which was then heat sealed. If the heat seal was acceptable the package was considered as an acceptable unit for commercial use.

[0946] Other unit strengths (e.g. 40 pg and 60 pg films) were similarly prepared by varying the concentrations of drug, polymers and colorant within the drug-containing composition. For example, the 40 pg and 60 pg, films were prepared from drug-containing compositions containing, respectively, approximately 2x and3x, the amounts of drug, polymers and colorant that appear in the 20pg drug-containing composition described in table 6 above.

Example 2:

[0947] Table 7: Dexmedetomidine deposited on the surface of a polymer matrix film composition

<td> Ingredients</td><td> Concentration mg/unit (80 pg film)</td><td> Concentration mg/unit (120 pg film)</td><td> Concentration mg/unit (180 pg film)</td><td> Function</td>

<td colspan="5"> Drug-containing composition</td>

<td> Dexmedetomi dine hydrochloride</td><td> 0.0945</td><td> 0.142</td><td> 0.213</td><td> Active agent</td>

<td> Hydroxypropyl cellulose, HPC-SSL (MW == 40,000)</td><td> 0.0812</td><td> 0.122</td><td> 0.183</td><td> Film former</td>

<td> Hydroxypropyl cellulose (MW == 140,000)</td><td> 0.0812</td><td> 0.122</td><td> 0.183</td><td> Film former</td>

<td> FD&amp;C Blue #1 Granular</td><td> 0.0008</td><td> 0.001</td><td> 0.002</td><td> Color</td>

<td> Ethyl .Alcohol as a solvent</td><td> q.s</td><td> q.s.</td><td> q.s.</td><td> Solvent</td>

<td colspan="5"> Polymer matrix composition</td>

<td> Hydroxypropyl cellulose (MW === 140,000)</td><td> 0.627</td><td> 0.627</td><td> 0.627</td><td> Film former</td>

<td> Hydroxypropyl cellulose, HPC-SSL (NW === 40,000)</td><td> 0.627</td><td> 0.627</td><td> 0.627</td><td> Film former</td>

<td> Hydroxypropyl cellulose (MW === 370,000)</td><td> 3.763</td><td> 3.763</td><td> 3.763</td><td> Film former</td>

<td> Fast Emerald Green Shade (NO. 06507)</td><td> 0.017</td><td> 0.017</td><td> 0.017</td><td> Color</td>

<td> Sucralose, USP-NF Grade</td><td> 0.130</td><td> 0.130</td><td> 0.130</td><td> Sweetener</td>

<td> Peppermint Oil, NF</td><td> 0.275</td><td> 0.275</td><td> 0.275</td><td> Flavor</td>

<td> Polyethylene oxide (Sentry Polyox WSR 205 LEO NF) (MW = 600,000)</td><td> 7.526</td><td> 7.526</td><td> 7.526</td><td> Film former &amp; Mucoadhesive</td>

<td> Water as a solvent</td><td> qs</td><td> qs</td><td> qs</td><td> Solvent</td>

[0948] The formulations (80 pg, 120 pg and 180 pg) in table7 were prepared using the same manufacturing process as described above in Example 1.

Example 3: A Phase lb multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose study to determine efficacy, pharmacokinetics and safely' of dexmedetomidine hydrochloride sublingual film in treating agitation associated with schizophrenia.

[0949] Primary objective:

[0950] To determine the doses of dexmedetomidine hydrochloride sublingual film needed to effectively reduce symptoms of acute agitation associated with schizophrenia, schizoaffective disorder or schizophreniform disorder assessed using the Positive and Negative Syndrome Scale Excited Component (PEC) change from baseline after drug treatment.

[0951] Secondary obj ective:

[0952] Determine PK, safety and tolerability of the various film strengths of dexmedetomidine hydrochloride sublingual film in patients with acute agitation associated with schizophrenia, schizoaffective disorder or schizophreniform disorder.

1. Describe overall clinical improvement after drug administration by Clinical Global Impression - Improvement scale (CGI-I).

2. Describe the duration of calming effect as measured by PEC and ACES.

3. Determine the safety profile of dexmedetomidine hydrochloride sublingual film as measured by vital signs and reports of adverse events.

4. Describe the overall tolerability in terms of adverse event reports and local site (oral/sublingual) tolerability of the sublingual film.

5. Describe the pharmacokinetics of dexmedetomidine hydrochloride sublingual film in the patient population,

6. Visual Analog Scales (VAS) to capture subject’s opinion on taste and acceptability as well as questions regarding likability of study medication,

[0953] Methodology: This was a two-stage adaptive Phase lb trial design. It was a randomized, double-blind, placebo-controlled, multiple ascending dose study assessing efficacy, pharmacokinetics, safety and tolerability of dexmedetomidine hydrochloride sublingual film dosing in adult (18-65 years old) males and females with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder.

[0954] The first stage was designed to characterize a safe and tolerable dose range which produced a calming effect as measured using the PEC total score. The second stage was designed to enroll a total of 40 subjects per dose group m a three-arm placebo-controlled design to better characterize the broader range of safety and tolerability as well as better estimate variability (effect size).

[0955] Adaptive evaluation of escalating dose regimens of 20gg, 60 pg and 120 pg were performed for the first stage, with an option to test a different dose should a safety or tolerability signal be observed. Male and female adults with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder were enrolled in each cohort. Investigators were permitted to repeat dosing 1 hour after administration if there was a lack of significant efficacy (PEC change from baseline &lt; 40%) (maximum number of doses per subject was 2) and in the absence of safety concerns.

[0956] Blinded periodic safety data review's were undertaken after completion of dosing each cohort to review all safety data as it became available. Dose escalation was allowed unless a safety or tolerability issue became evident upon periodic regular safety reviews. Based upon blinded analyses of the safety and tolerability of all subject cohorts, additional doses were selected.

[0957] Eligible subjects (acutely agitated subjects with schizophrenia, schizoaffective, or schizophreniform disorder) were identified in outpatient clinics, mental health, psychiatric or medical emergency services including medical/psychiatric observation units, or as newly admitted to a hospital setting for acute agitation or already in hospital for chronic underlying conditions. Subjects were domiciled in a clinical research setting or hospitalized to remain under medical supervision while undergoing screening procedures to assess eligibility.

Upon confirmation of eligibility, subjects were randomized to dexmedetomidine hydrochloride sublingual film or placebo film. At the beginning of each study session, a single dose of dexmedetomidine hydrochloride sublingual film was self-administered sublingually, after training with a placebo film and under the supervision of an unblinded staff who did not participate in evaluation of safety or efficacy. The drug film was retained in the sublingual (SL) cavity until dissolved. Participants were also evaluated for local irritation around the area where the film was placed. Efficacy and safety assessments were conducted periodically before and after dosing. If reduction in PEC was less than or equal to 40% one hour after the first administration, the investigator could administer a second dose of dexmedetomidine hydrochloride sublingual film (of the same randomized dose) with an additional PEC assessment completed at 1.5 hr post-dose. All efforts were made to have the patient perform all assessments as per protocol. However, should the patient’s situation warrant it, standard of care treatment was initiated, preferably after the 4 hr assessments were completed. In Stage 1 each cohort included 27 subjects randomized 2:1 to dexmedetomidine hydrochloride sublingual film or placebo film (i.e. 18 received dexmedetomidine hydrochloride sublingual film and 9 received placebo film). Three doses were initially planned (total of 81 subjects). Per protocol, different or additional doses could be tested based on ongoing safety reviews, and two additional dose levels were tested: 80 gg and 180 gg (Table 8).

[0958] Efficacy assessments:

[0959] The efficacy of dexmedetomidine hydrochloride sublingual film on reducing acute agitation was assessed using the Positive and Negative Syndrome Scale - Excited Component (PEC) scale which was performed at screening, baseline (i.e. also referred to as pre-dose) and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6 and 24 hours post the first dose.

• Overall agitation and sedation were evaluated with the Agitation-Calmness Evaluation Scale (ACES), which was performed at baseline (pre-dose) and at 2 and 4 hours post-first dose.

• The change in agitation in response to treatment was also measured by the Clinical Global Impressions -- Improvement (CGI-I), performed at 1, 2 and 4 hours post the first dose.

[0960] Safety and tolerability assessments:

[0961] AEs, clinical laboratory tests, electrocardiogram (ECG) with rhythm strip, and vital signs were monitored for tolerability assessment. All observed and volunteered AEs were recorded. The relationship of AEs to the study drugs was graded as not related, unlikely/remotely related, possibly related, probably related or definitely related by the investigators.

10962] Resting vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate, as well as ECG were measured at prior to the PK assessments. Resting vital signs (SBP, DBP and HR) were taken at screening, baseline (pre-dose) and at 30 min, 1, 2, 4 and 8 hours post-first dose. Orthostatic measurements which included (SBP, DBP, HR, respiratory rate and temperature) were taken at screening, pre-dose, 2, 4 and 24 hours post-first dose. ECGs were conducted at screening, , baseline (pre-dose), 2 and 24 hours post-first dose. The application site of the SL preparation (buccal mucosa) were also inspected for any signs of local irritation.

[0963] Safety and tolerability assessments were continued until the morning of Day 3 (day of discharge) and were repeated on Day 7(+2). AEs evaluation were conducted at screening, baseline (pre-dose), 2 hours, Day 3 and Day 7(+2) post-the first dose. Safety Labs including chemistry, hematology, urinalysis, UDS, alcohol breathalyzer, and urine pregnancy were performed at screening, Day 3 and Day 7(+2).

[0964] Any abnormal vital sign measurement, clinical laboratory test, physical examination finding, or ECG parameter deemed clinically significant by the investigator was repeated, including test results obtained on the final study day or upon early termination. For any test abnormality deemed clinically significant, repeat analysis was performed during the follow-up period and until the value returned to baseline (or within normal limits) or the investigator deemed the abnormality to be stable and no longer of clinical concern.

[0965] Three analysis populations were defined for the study:

[0966] Safety Population: All subjects who receive study drug

[0967] Intent to treat (ITT) Population: All subjects in the Safety Population who have a PEC Score

[0968] Per Protocol (PP) Population: All subjects in the ITT Population with no major protocol deviations

[0969] Subjects were on a range of typically prescribed antipsychotics.

[0970] Table 8: Arms and Interventions

<td> Arms</td><td> intervention</td>

<td> Placebo Comparator: Placebo Sublingual Film with no active drag; single administration</td><td> Drug: Placebo film Placebo film for dexmedetomidine hydrochloride</td>

<td> Experimental; 20 pg Sublingual Film containing 20 pg dexmedetomidine; single administration with repeat dose after 1 hour</td><td> Drug: Sublingual film containing dexmedetomidine hydrochloride Administration: Sublingual film containing dexmedetomidine for the treatment of agitation associated with Schizophrenia</td>

<td> Experimental: 60 pg Sublingual Film containing 60 pg de xmedeto midine; single administration</td><td> Drug: Sublingual film containing dexmedetomidine hydrochloride. Administration: Sublingual film containing dexmedetomidine for the treatment of agitation associated with Schizophrenia</td>

<td> Experimental: 80 pg Sublingual Film containing 80 pg dexmedetomidine; single administration</td><td> Drug: Sublingual film containing dexmedetomidine hydrochloride. Administration: Sublingual film containing dexmedetomidine for the treatment of agitation associated with Schizophrenia</td>

<td> Experimental: 120 pg 2 Sublingual Films, each containing 60 pg dexmedeto midine; single administration of 2 films</td><td> Drug: Sublingual film containing dexmedetomidine hydrochloride. Administration: Sublingual film containing dexmedetomidine for the treatment of agitation associated with Schizophrenia</td>

<td> Experimental: 180 pg 3 Sublingual Films, each containing 60 pg dexmedetomidine; single administration of 3 films</td><td> Drag: Sublingual film containing dexmedetomidine hydrochloride. Administration: Sublingual film containing dexmedetomidine for the treatment of agitation associated with Schizophrenia</td>

[0971] Number of Subjects (Planned and Analyzed):

[0972] An estimated 81 subjects in Stage 1 were planned in 3 cohorts (27 per cohort), however including the 2 additional cohorts (80 pg and 180 pg dexmedetomidine hydrochloride sublingual films), a total of 135 subjects were enrolled in 5 cohorts and analyzed,.

[0973] Diagnosis and Main! Criteria for Eligibili ty:

[0974] Inclusion Criteria:

1. Male and female patients between the ages of 18 to 65 years, inclusive.

2. Patients who had met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia, schizoaffective, or schizophreniform disorder.

3. Patients who were judged to be clinically agitated at screening and baseline (pre-dose with a total score of > 14 on the 5 items (poor impulse control, tension, hostility, uncooperativeness, and excitement) comprising the PANSS Excited Component (PEC).

4. Patients who have a score of > 4 on at least 1 of the 5 items on the PEC at baseline (pre-dose).

5. Patients who read, understood and provide written informed consent.

6. Patients who were in good general health prior to study participation as determined by a detailed medical history, physical examination, 12&amp;#1470;lead ECG with rhythm strip, blood chemistry profile, hematology, urinalysis and in the opinion of the Principal Investigator.

7. Female participants, if of child-bearing potential and sexually active, and male participants, if sexually active with a partner of child-bearing potential, who agreed to use a medically acceptable and effective birth control method throughout the study and for one week following the end of the study. Medically acceptable methods of contraception that could be used by the participant and/or his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization and progestin implant or injection. Prohibited methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone.

[0975] Exclusion Criteria:

1. Patients with agitation caused by acute intoxication, including positive identification of alcohol by breathalyzer or drugs of abuse or non-prescription drugs (with the exception of tetrahydrocannabinol (THC)) during urine screening.

2. Patients treated within 4 hours prior to study drug administration with benzodiazepines, other hypnotics or oral or short-acting intramuscular antipsychotics.

3. Treatment with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, and alfuzosin, and prazocin) or other prohibited medications.

4. Patients with significant risk of suicide or homicide per the investigator’s assessment, or any suicidal behaviour in last 6 months prior to screening.

5. Female patients who had a positive pregnancy test at screening or were breastfeeding.

6. Patients who had hydrocephalus, seizure disorder, or history of significant head trauma, stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, meningitis, Parkinson’s disease or focal neurological findings.

7. History of syncope or other syncopal attacks, current evidence of hypovolemia, orthostatic hypotension, a screening heart rate of &lt; 55 beats per minutes (bpm) or systolic blood pressure (SBP) &lt;110 mmHg or diastolic blood pressure (DBP) &lt;70 mmHg.

8. Patients with laboratory or ECG abnormalities considered clinically significant by the investigator or qualified designee [Advanced heart block (second-degree or above atrioventricular block without pacemaker), diagnosis of Sick sinus syndrome] that would have clinical implications for the patient's participation in the study.

9. Patients with serious or unstable medical illnesses. These include current hepatic (moderate severe hepatic impairment), renal, gastroenterologic, respirator}&amp;#1523;, cardiovascular (including ischemic heart disease, congestive heart failure), endocrinologic, or hematologic disease.

10. Patients who had received an investigational drug within 30 days prior to the current agitation episode.

11. Patients who were unable to use the sublingual film or considered by the investigator, for any reason, to be an unsuitable candidate for receiving dexmedetomidine; e g. patients with a history of allergic reactions to dexmedetomidine.

[0976] Test Product, Dose and. Mode of Administration:

[0977] Dexmedetomidine sublingual film (formulation of Examples 1 and 2 above) was tested in a small, solid-dose film formulations with dimensions of approximately 193.6 mm2 in area and 0.7 mm thick designed to completely dissolve in the SL space within 2-3 minutes. Reference therapy,

[0978] Dose and Mode of Administration:

Matching placebo films to be taken sublingually as described above.

[0979] Duration of Treatment: 1 day

[0980] Criteria for Evaluation: The primary endpoints in this study pertamed to the efficacy, pharmacokinetics, safety, and tolerability of each dose level.

[0981] Efficacy: The efficacy of dexmedetomidine hydrochloride sublingual film on acute agitation was assessed using the Positive and Negative Syndrome Scale - Excited Component (PEC) scale. PEC comprised 5 items associated with agitation: poor impulse control, tension, 166 hostility, uncooperativeness, and excitement; each scored I (minimum) to 7 (maximum). The PEC, the sum of these 5 subscales, thus ranging from 5 to 35.

[0982] Overall agitation and sedation were evaluated with the Agitation-Calmness Evaluation Scale (ACES), where 1 indicates marked agitation; 2 - moderate agitation; 3 - mild agitation; 4 normal behavior; 5 - mild calmness; 6 - moderate calmness; 7 - marked calmness; 8 - deep sleep; and 9 - unarousabie.

[0983] The change in agitation in response to treatment was also measured by the Clinical Global Impressions - Improvement (CGI-I). CGI-I scores range from 1 to 7: 0 = not assessed (missing), 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse.

[0984] Pharmacokinetics:

[0985] Pharmacokinetic analysis was performed using dexmedetomidine plasma concentrations after administration of dexmedetomidine hydrochloride sublingual films. A dose proportionality analysis was conducted.

[0986] Safety and tolerability : AEs, clinical laboratory tests, ECG with rhythm strip, vital signs and signs of local irritation (buccal) were monitored for safety and tolerability.

[0987] Additional Assessments:

- Demographic Data

- Medical History

- Prior and Concomitant Medication

- Physical Examination and

- Pregnancy testing

[0988] Statistical Analysis:

[0989] Efficacy Analyses: The primary efficacy endpoint of the study was the absolute change from baseline in PEC score at 120 mins (2 hours). The intent to treat population (ITT) was analyzed and consisted of all patients who took any study medication and who had both baseline and at least 1 efficacy assessment after dosing. Analyses were conducted using a restricted maximum likelihood repeated measures mixed model on change from baseline values with baseline as a covariate and timepoint, and its interaction with treatment groups as repeated measures using an unstructured covariance structure. Responder comparisons were made via Fisher’s exact test.

[0990] Pharmacokinetic Analyses:

[0991] Pharmacokinetic analysis was conducted using a validated install of Phoenix® WinNonlin® version 8.1. Non-compartmental analysis was also conducted on the final audited data which consisted of a total of 135 participants in 5 cohorts receiving 20, 60, 80 (I x 20 pg films and I x 60 pg films), 120 (2 x 60 pg films) and 180 pg (3 x 60 pg films) of dexmedetomidine sublingual films. All areas under the concentration-time curve (AUCs) were calculated using the linear trapezoidal method. Dose proportionality was assessed using a power model for PK parameters. Mean and individual concentration (sorted by dose level) versus time plots were generated.

[0992] Safety and Tolerability analyses:

[0993] Safety data analysis was conducted on all subjects receiving at least 1 dose of study drug. The number and percentage of subjects experiencing 1 or more AEs were summarized by treatment, relationship to study drug, and severity. AEs were coded using Medical Dictionary for Regulatory Activities (Med DRA) terminology. Listings of subjects who experience withdrawal due to an AE, serious AEs and/or death were presented. Laboratory parameters were summarized by treatment using descriptive statistics and data listings of clinically significant abnormalities. Vital signs and ECG data were summarized by changes from baseline values at each dose level using descriptive statistics.

[0994] Sample Size Determination: The sample size is based on clinical experience and judgment relative to the study design and objectives in Stage 1. A sample size of at least 18 subjects on active drug in each dosing cohort should provide adequate clinical information to meet the objectives of the study.

[0995] All efficacy, safety, and tolerability measurements were conducted at regularly scheduled intervals as described in table 9.

BXTI-039/01WO (332712-2151)

[0996] Table 9: Schedule of Events

<td></td><td></td><td colspan="11"> Treatment Evaluation Day 1</td><td colspan="3"></td>

<td> Activity</td><td> Screening</td><td> PreDose¹</td><td colspan="10"> Post Dose Time¹</td><td> Day 2 Follow- Up(+1)</td><td> Day 3 Discharge</td><td> Day 7 (+2)</td>

<td> Time point</td><td> Pretreatment</td><td> hr to time 0</td><td> 10 min</td><td> 20 min</td><td> 30 min</td><td> 45 min</td><td> 1 hr</td><td> 1.5 hr</td><td> 2 hr</td><td> 4 hr</td><td> 6 hr</td><td> 8 hr</td><td> 24 hr (-9/+12 hr)</td><td></td><td> End of Study</td>

<td> Informed Consent</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Medical History</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Demographics</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Weight</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td></td><td></td>

<td> Height</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> BMI</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> MINI</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> PANSS¹⁰</td><td></td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td> X</td><td></td><td></td>

<td> Physical Exam</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td></td><td></td>

<td> Safety Labs’</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td> X</td>

<td> ECG with rhythm strip ⁹</td><td> X</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td></td><td></td><td></td><td> X</td><td></td><td></td>

<td> Resting vital signs²</td><td> X</td><td> X</td><td></td><td></td><td> X</td><td></td><td> X</td><td></td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td></td><td></td>

<td> Orthostatic vital signs²</td><td> X</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td> X</td><td></td><td> X</td><td> X</td><td></td><td></td>

<td> Admit to Unit</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Training/Review of study drug administration</td><td></td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Ind usi on/Excl us ion criteria</td><td> X</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Randomization</td><td></td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Study drug administration⁸</td><td></td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

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<td></td><td></td><td colspan="11"> Treatment Evaluation Day 1</td><td colspan="3"></td>

<td> Activity</td><td> Screening</td><td> PreDose¹</td><td colspan="10"> Post Dose Time¹</td><td> Day 2 FollowUp (+1)</td><td> Day 3 Discharge</td><td> Day 7 (+2)</td>

<td> Time point</td><td> Pretreatment</td><td> hr to time 0</td><td> 10 min</td><td> 20 min</td><td> 30 min</td><td> 45 min</td><td> 1 hr</td><td> 1.5 hr</td><td> 2 hr</td><td> 4 hr</td><td> 6 hr</td><td> 8 hr</td><td> 24 hr (-9/+12 hr)</td><td></td><td> End of Study</td>

<td> PCRS¹¹</td><td> X</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td></td><td></td><td></td><td> X</td><td></td><td></td>

<td> PEC³</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td></td><td> X</td><td></td><td></td>

<td> ACES</td><td></td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td> X</td><td></td><td></td><td></td><td></td><td></td>

<td> CGI-Severity⁴</td><td> X</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> CGl-lmprovement⁴</td><td></td><td></td><td></td><td></td><td> X</td><td></td><td> X</td><td> X</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> C-SSRS</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td></td><td></td>

<td> Buccal (SL) assessment for local irritation⁷</td><td></td><td></td><td></td><td></td><td> X</td><td></td><td></td><td></td><td> X</td><td> X</td><td></td><td></td><td> X</td><td></td><td></td>

<td> Visual Analog Scales</td><td></td><td></td><td></td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Likability Question</td><td></td><td></td><td></td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> PK Sampling</td><td></td><td> X</td><td></td><td></td><td></td><td></td><td> X</td><td> X</td><td> X*</td><td> X</td><td> X</td><td> X</td><td> X</td><td></td><td></td>

<td> Concomitant Medications</td><td> X</td><td> X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> X</td><td> X</td><td> X</td>

<td> Adverse Events</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td><td> X</td>

Abbreviations: ACES = Agitation-Calmness Evaluation Scale; BMI = body mass index; CLIA = Clinical Laboratory Improvement Amendments; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-Severity; C-SSRS - Columbia-Suicide Severity Rating Scale; DBP = diastolic blood pressure; ECG = electrocardiogram; MINI - Mini International Neuropsychiatric Interview; PANSS = Positive and Negative Syndrome Scale; PCRS = Placebo Control Reminder Script; PEC == Positive and Negative Syndrome Scale - Excited Component; PK = pharmacokinetic; SBP = systolic blood pressure; SI, = sublingual; UDS = urine drug screen

Notes to the Schedule of Events:

1 Pre-dose assessments had a window of 60 minutes prior to first dose. Timing of all subsequent assessments was relative to the first dose. All post-dose assessments had a window of ± 3 minutes until 2 hours and ± 10 minutes until 8 hours.

2 Resting vital signs (SB P, DBP and HR) will be taken at Screening, Pre-dose and at 30 min, 1,2, 4 and 8 hours post first dose. Triplicate measurements were performed in case of Systolic BP &lt;90 mmHg, Diastolic BP &lt;60 mmHg or Pulse &lt; 60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate and temperature) were taken at Screening, Pre-dose, 2, 4 and 24 hours post first dose. Vital signs were done prior to each PK sample.

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BXTI-039/01WO (332712-2151) 3 PEC was performed at Screening, Pre-dose and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6 and 24 hours post first dose.

4 CGI-Severity was performed at Screening and pre-dose. CGI-Improvement was performed at 1, 2 and 4 hours post first dose. The PEC (preceded by the Placebo Control Reminder Script [PCRS], when required) was done prior to any other assessments.

5 Safety Labs included chemistry, hematology , urinalysis, UDS (local lab)(only conducted at screening), alcohol breathalyzer (only conducted at screening), and urine pregnancy (only conducted at scree ning). Screening/enrollment labs: local labs drawn within 7 days prior to screening may suffice with the exception of urine drag screen. If results not available on the same day, a ‘desktop’ or non-CLIA test might be performed; to confirmed, results from a CLIA-certified laboratory should be recorded once available.

6 PK blood samples were collected Predose (up to 15 min prior to first and, if applicable, second dose), 1, 1.5, 2, 4. 6, 8-10 hrs (collect one sample between 8 and 10 hours) and 24hr after first dose. A sample may not be collected if the Physician indicates in source documents that the patient is in a mental state that was not conducive to PK sample collection. Non-compliance or refusal of all or any PK draw were exclusionary nor result in ET. All PK collections had a window of ± 3 minutes with the exception of the 24 hour post-dose collection which had a window of ± 1 hour.

*For re-dosed subjects only: PK blood sample was collected at 2.5 hrs post first dose in addition to the other times.

7 Buccal exam (al 30 min ±15, and other times ±30min) for local irritation performed by blinded staff.

Day 2 follow up with I day window.

8 In the investigator’s clinical judgement the same randomized dose might be repeated at 1 11 r if there was no clinical effect (PEC change from baseline &lt;40%) and in rite absence of safety concerns.

9 ECG for pre-dose was not repeated if screening ECG was conducted on the day of dosing. ECGs collected following treatment were performed prior to PK assessments 19 PANSS had administered at any time on the day of dosing prior to dosing and post-dose. Full PANSS was to be conducted in addition to stand alone PEC.

i! PCRS was performed immediately prior to the PEC

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[0997] Results Summary:

[0998] 1. Data Sets Analyzed

[0999] The number of subjects in each dataset were the same for all 3 populations (ie, Safety7, ITT and PP) (Table 10). Additionally, the number of subjects in each dataset were the same for the pharmacokinetic population, as all subjects provided blood samples for analysis.

[01000] Table 10 Summary of Datasets .Analyzed

<td rowspan="2"> Dataset</td><td></td><td colspan="5"> Dexmedetomidine sublingual film</td><td rowspan="2"> Overall (N=135)</td>

<td> Placebo (N=45)</td><td> 2« Jig (N=18)</td><td> 60 gg (N=18)</td><td> 80 gg (N=18)</td><td> 120 gg (N=18)</td><td> 180 gg (N=18)</td>

<td> Safety־ Population</td><td> 45 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 135 (100.0)</td>

<td> Tntent-to-Treat Population</td><td> 45 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 135 (100.0)</td>

<td> Per-Proto co 1 Populatio n</td><td> 45 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 18 (100.0)</td><td> 135 (100.0)</td>

01001 ] Di sposition:

[01002] A total of 135 subjects were enrolled and received study drug and comprised the

Safety Population. Of the 135 subjects, all subjects completed the inpatient study drug treatment period; 127 subjects completed the end of the study period (i.e. study Day 7). Of the 8 subjects who did not complete the study, 7 subjects were lost to follow-up after discharge from the inpatient facility on study Day 3 and 1 subject withdrew from the study on study Day 3.

[01003] 2. Demographics and Baseline Characteristics:

[01004] For subjects in the Safety Population (N=135), mean age was 47.6 years, the majority of subjects were male (65.9% [89/135]), and mean BMI was 30.58 kg/m2. Subjects were predominantly Black or African American (74.8% [101/135]) and not Hispanic or Latino (90.4% [122/135]). The majority of subjects in all treatment groups had a diagnosis of schizophrenia (assessed by the Mini-International Neuropsychiatric Interview [MINI-Plus] instrument). The proportion of subjects with schizophrenia ranged from 72.2 % to 83.3% in the Dexmedetomidine sublingual film treatment groups. Based on MINI-Plus results, all subjects m the study met the inclusion criteria of having a diagnosis of schizophrenia, schizoaffective, or schizophreniform disorder (Table 11).

[01005] Table 11 Demographics and Baseline Characteristics

<td rowspan="2"> Variable</td><td rowspan="2"> Placebo (N-45)</td><td colspan="5"> Dexmedetomidine sublingual film</td><td rowspan="2"> Overall (N-135)</td>

<td> 20 pg (N=18)</td><td> 60 pg (N=18)</td><td> 80 pg (N=18)</td><td> 120 gg (N=18j</td><td> 180 gg (N=18j</td>

<td colspan="8"> Age (years)</td>

<td> Mean (SD)</td><td> 48.4 (10.88)</td><td> 50.1 (7.37)</td><td> 45.8 (10.87)</td><td> 50.2 (9.72)</td><td> 40.5 (8.40)</td><td> 49.1 (10.61)</td><td> 47.6 (10.26)</td>

<td> Median</td><td> 52.0</td><td> 50.0</td><td> 47.0</td><td> 52.0</td><td> 40.0</td><td> 48.0</td><td> 50.0</td>

<td> Min - Max</td><td> 21, 63</td><td> 29, 59</td><td> 26,63</td><td> 26,63</td><td> 25, 54</td><td> 26,64</td><td> 21, 64</td>

<td colspan="8"> Gender, !1%</td>

<td> Male</td><td> 27 (60.0)</td><td> 9 (50.0)</td><td> 15 (83.3)</td><td> 13 (72.2)</td><td> 13 (72.2)</td><td> 12 (66.7)</td><td> 89 (65.9)</td>

<td> Female</td><td> 18 (40.0)</td><td> 9 (50.0)</td><td> 3 (16.7)</td><td> 5 (27.8)</td><td> 5 (27.8)</td><td> 6 (33.3)</td><td> 46 (34.1)</td>

<td colspan="8"> Race, n%</td>

<td> Black or African American</td><td> 37 (82.2)</td><td> 13 (72.2)</td><td> 11 (61.1)</td><td> 12 (66.7)</td><td> 15 (83.3)</td><td> 13 (72.2)</td><td> 101 (74.8)</td>

<td> White</td><td> 7(15.6)</td><td> 5 (27.8)</td><td> Ί (38.9)</td><td> 6 (33.3)</td><td> 2(11.1)</td><td> 4 (22.2)</td><td> 31 (23.0)</td>

<td> Asian</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 1 (0.7)</td>

<td> Multiple</td><td> 1 (2.2)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (0.7)</td>

<td> Unknown</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 1 (0.7)</td>

<td colspan="8"> Ethnicity, n%</td>

<td> Not Hispanic or Latino</td><td> 44 (97.8)</td><td> 16 (88.9)</td><td> 15 (83.3)</td><td> 15 (83.3)</td><td> 16 (88.9)</td><td> 16 (88.9)</td><td> 122 (90.4)</td>

<td> Hispanic or Latino</td><td> 1 (2.2)</td><td> 2(11.1)</td><td> 3 (16.7)</td><td> 3 (16.7)</td><td> 2(11.1)</td><td> 2(11.1)</td><td> 13 (9.6)</td>

<td colspan="8"> Height (cm)</td>

<td> Mean (SD)</td><td> 171.15 (10.25)</td><td> 169.29 (10.63)</td><td> 174.08 (H.12)</td><td> 174.90 (10.66)</td><td> 175.33 (13.81)</td><td> 174.87 (8.95)</td><td> 172.85 (10.87)</td>

<td> Median</td><td> 169.00</td><td> 170.30</td><td> 174.05</td><td> 175.90</td><td> 175.70</td><td> 175.25</td><td> 173.00</td>

<td> Min - Max</td><td> 149.9, 198.1</td><td> 149.9, 188.0</td><td> 150.5, 195.0</td><td> 157.0, 198.1</td><td> 137.0, 205.0</td><td> 160.0, 188.4</td><td> 137.0, 205.0</td>

<td colspan="8"> Weight (kg)</td>

<td> Mean (SD)</td><td> 86.86 (16.62)</td><td> 86.92 (18.83)</td><td> 94.89 (15.53)</td><td> 92.84 (19.77)</td><td> 90.54 (18.04)</td><td> 100.53 (19.10)</td><td> 91.05 (18.06)</td>

<td> Median</td><td> 84.10</td><td> 82.50</td><td> 97.10</td><td> 91.95</td><td> 90.80</td><td> 100.45</td><td> 91.00</td>

<td> Min - Max</td><td> 56.8, 121.2</td><td> 58.9, 119.6</td><td> 64.9, 127.7</td><td> 65.3, 133.6</td><td> 57.2, 135.4</td><td> 68.4, 143.2</td><td> 56.8, 143.2</td>

<td colspan="8"> Body Mass Index (kg/m²)</td>

<td> Mean (SD)</td><td> 29.74 (5.61)</td><td> 30.23 (5.37)</td><td> 31.45 (5.47)</td><td> 30.56 (7.02)</td><td> 29.81 (6.96)</td><td> 32.97 (6.47)</td><td> 30.58 (6.06)</td>

<td> Median</td><td> 29.27</td><td> 29.58</td><td> 31.09</td><td> 30.03</td><td> 29.08</td><td> 32.56</td><td> 29.40</td>

<td> Min - Max</td><td> 17.9,41.5</td><td> 20.9, 40.3</td><td> 22.5,42.8</td><td> 20.9, 44.5</td><td> 18.3,45.4</td><td> 24.8,45.4</td><td> 17.9, 45.4</td>

Abbreviations: cm - centimeter; kg - kilogram; max - maximum; min - minimum; SD - standard deviation; Percentages are based on the number of Safety Population subjects in each treatment ami.

[01006] 3. Efficacy

[01007] Dexmedetomidine sublingual film significantly improved the severity of agitation from baseline as measured by PEC, ACES scales and CGI-I scores. Key efficacy findings at 2 hours post-dose are presented below.

[01008] (a) Primary Efficacy Endpoint (PEC reduction): a reduction in the PEC score (PANSS or the Positive and Negative Syndrome Scale, Excitatory' Component) for agitation was observed with rapid calming without excessive sedation at the clinical regulatory endpoint and at earlier time-points. The primary efficacy endpoint was the mean change from baseline in PEC total score at 2 hours (120 minutes) compared to placebo. There were 5 dose cohorts (20 gg, 60 gg, 80 gg, 120 gg and 180 gg) with 18 active patients (total of 90 patients) and 9 placebo patients (total of 45 patients) in each cohort. Active patients in each of the 5 dose cohorts were compared to placebo patients from all 5 cohorts (pooled placebo group). The change from baseline in PEC at 2 hours for patients treated with dexmedetomidine sublingual film was compared with placebo using a mixed model repeated measures (MMRM) analysis, with baseline PEC, treatment group, time, the interaction between treatment groups and time, and the interaction between baseline PEC and time as covariates.

[01009] The efficacy of dexmedetomidine hydrochloride sublingual film as measured by PEC reduction is dose-responsive and robust. The decrease from baseline in PEC score in the 180 gg dose group showed significant response with a -10.8 mean change from baseline (CFB) total PEC score at 2 hours post dosing compared to placebo (Table 12 and FIG. 1). Mean changes from baseline were -9.2 and -7.3 points, respectively for the 120 gg and 80 gg treatment groups, compared to placebo (-4.5 Mean change). LSM mean differences from placebo were -2.9 (P == 0.0210), -4.6 (P = 0.0003), and —6.3 (P &lt;0.0001) for the 80 gg, 120 gg, and 180 gg treatment groups (table 11) Mean changes from baseline at 2 hours post dosing in the 20 gg and 60 gg groups were not significantly different than placebo. Additionally, as early onset of action is an important attribute for therapy in reducing agitation, the 180 gg group showed a statistically significant separation from placebo as early as 45 minutes post dosing (LS mean difference of -3.5 [P&lt;0.0049]).

[01010] Table 12: Summary of Change from Baseline at all Timepoints in PANSS-PEC Total Score by Treatment Group (Intent to treat population)

<td rowspan="2"> Time Point Statistics</td><td rowspan="2"> Placebo (N=45)</td><td colspan="5"> Dexmedetomidine Sublingual film</td>

<td> 20 pg (N=18)</td><td> 60 pg (N=18)</td><td> 80 pg (N=18)</td><td> 120 pg (N=18)</td><td> 180 pg (N=18)</td>

<td colspan="7"> Basetine, n</td>

<td> Mean (SD)</td><td colspan="2"> (2,33) 117.5(2,37) 1 8 ־ i</td><td> 17.5 (2.07)</td><td> 17,4(1.42)</td><td> 18.3 (1.64)</td><td> 18,3 (2.95)</td>

<td colspan="7"> 10 minutes post-dose</td>

<td> Mean (SD)</td><td> 116.0 (4.33)</td><td> 16.2 (2.86)</td><td> 15.1 (3.92)</td><td> 15.2 (3.26)</td><td> 17,8 (3.19)</td><td> 16.8 (4.26)</td>

<td> Change from baseline, mean (SD)</td><td> (3.60) 2.1־ |</td><td> (1.67) 1.3־</td><td>.4 (3.45)</td><td>.2 (3.01)</td><td> (2.31) 0.6־</td><td> (2.68) 1.5־</td>

<td> Change from baseline, LS mean (SE)</td><td>.1 (0.5)</td><td>.4 (0.7)</td><td>.5(0.7)</td><td>.3 (0.7)</td><td>.5 (0.7)</td><td>.4 (0.7)</td>

<td colspan="2"> LSM difference (SE)’׳</td><td> 0.7 (0.9)</td><td>.4 (0.9)</td><td>.2 (0.9)</td><td> 1.6 (0.9)</td><td> 0.7 (0.9)</td>

<td colspan="7"> 20 minutes post-dose</td>

<td> Mean (SD)</td><td> j 15.2 (4.41)</td><td> 15.1 (2.88)</td><td> 14.1 (4 64}</td><td> 14.2 (3.81)</td><td> 15,8 (3.47)</td><td> 15.6 (4,12)</td>

<td> cnange trom oaseiine, mean (bU)</td><td> (3.60) 2.9־ 1</td><td>.4 (2.33)</td><td>.4 (4.29)</td><td> (3.89) 3.2־</td><td>.5 (3.03)</td><td>.7 (2.72)</td>

<td> Change from baseline, LS mean (SE)</td><td> 1 -2.9(0.5)</td><td>.5 (0.8)</td><td>.5 (08)</td><td>.3 (0.8)</td><td>.4 (0.8)</td><td> (0.8) 2.6־</td>

<td colspan="2"> LSM difference (SE)^a</td><td> 0.4 (1.0)</td><td>.6 (1.0)</td><td>.4 (1.0)</td><td> 0.5 (1.0)</td><td> 0.2 (1.0)</td>

<td colspan="7"> 30 minutes post-dose</td>

<td> Mean (SD)</td><td> i 14.8 (4.94)</td><td> 14.2 (2.79)</td><td> 13.1 (4.97)</td><td> 12.7 (3.82)</td><td> 15.0 (3.74)</td><td> 14.2 (4.48)</td>

<td> Change from baseline, mean (SD)</td><td> | -3,3 (4,46)</td><td>.3 (3.07)</td><td>.4 (4.67)</td><td>,7 (3.82)</td><td>.3 (3,56)</td><td> i (3.26)</td>

<td> cnange trom easeiine, Lb mean (bt)</td><td> I -3.2(0.6)</td><td> (0.9) 3.4־</td><td> 4 5 (0.9)</td><td>.8 (0.9)</td><td>.2(0.9)</td><td>.0(0.9)</td>

<td colspan="2"> LSM difference (SE)^a |</td><td>.2 (1.1)</td><td>.2 (1.1)</td><td>.5(1.1)</td><td> 0.0 (1.1)</td><td>.7(1.1)</td>

<td colspan="7"> 45 minutes post-dose</td>

<td> Mean (SD)</td><td> i 14.5 (4.88)</td><td> 13.8 (3.15)</td><td> 12.4 (5.41)</td><td> 11.3 (4.80)</td><td> 13.3 (4.66)</td><td> 11.1 (5.08)</td>

<td> Change from baseline, mean (SD)</td><td>.6 (4.14)</td><td> (2.83) 3.7־</td><td>.1 (5.11)</td><td>.1 (5.13)</td><td> (4.92) 5.1־</td><td>.2 (4.73)</td>

<td> Change from baseline, LS mean (SE)</td><td>.6(0.7)</td><td>.8(1.0)</td><td>.2 (1,0)</td><td> (1.0) 6.2־</td><td>.0 (1.0)</td><td> (1.0) 7.1־</td>

<td colspan="2"> LbM cirtterence (St)</td><td> (1.2) 0.2־</td><td>.6(1.2)</td><td>.6 (1.2)</td><td> (1.2) 1.4־</td><td> (1.2) 3.5״</td>

<td colspan="7"> 1 hour post-dose</td>

<td> Mean (SD)</td><td> 114.0 (4.65)</td><td> 13.0 (4.33)</td><td> 11.4 (5.40)</td><td> 10.9 (5.03)</td><td> 10.9 (5.29)</td><td> 9.2 (4.08)</td>

<td> Change from baseline, mean (SD)</td><td> (4.29) 4.1־</td><td> 4.5 (3.67)</td><td>.1 (5.49)</td><td>.5 (5.28)</td><td>.4 (5.48)</td><td>.1 (4.58)</td>

<td> Change from baseline, LS mean (SE)</td><td>.0,0.7</td><td>.6 (1.1)</td><td>.2(1.1)</td><td>.6 (1.1)</td><td>.3 (1.1)</td><td>.0 (1.1)</td>

<td colspan="2"> LSM difference (SE)^a</td><td>.6 (1.3)</td><td>.2 (1,3)</td><td> (1.3) 2.6־</td><td>.3 (1.3)</td><td> (1.3) 5.0־</td>

<td colspan="2"> P-value^b</td><td> 0.6647</td><td> 0,0968</td><td> 0.0488</td><td> 0.0130</td><td> 0.0002</td>

<td colspan="7"> 1.5 hours post-dose</td>

<td> Mean (SD)</td><td> 113.8 (4.62)</td><td> 12.1 (4.13)</td><td> 11.3 (5.26)</td><td> 10.8 (5.81)</td><td> 10.8 (5.52)</td><td> 7.8 (3.05)</td>

<td> Change from baseline, mean (SD)</td><td> (4.43) 4.3־ 1</td><td>.4 (3.96)</td><td>.2 (5.24)</td><td>.6 (6.05)</td><td>.5 (5.57)</td><td>.4 (4.38)</td>

<td> Change from baseline, LS mean (SE)</td><td>.3 (0.7)</td><td>.5 (1.1)</td><td>.3 (1.1)</td><td>.7(1.1)</td><td>.4 (1.1)</td><td>.4 (1.1)</td>

<td colspan="2"> LSM difference (SE)^a</td><td>.2(1.3)</td><td>.0 (1,3)</td><td> (1.3) 2.4־</td><td> i (1.3)</td><td>.1 (1.3)</td>

<td colspan="2"> P-vaiue^b</td><td> 0.3661</td><td> 0,1279</td><td> 0.0743</td><td> 0.0199</td><td> &lt;0.0001</td>

<td colspan="7"> 2 hours post-dose</td>

<td> Mean (SD)</td><td> 113.6 (4.56)</td><td> 11.0 (3.87)</td><td> 11.4 (5.07)</td><td> 10.1 (5.45)</td><td> 9.1 (4.20)</td><td> 7.4 (2.68)</td>

<td> Change from baseline, mean (SD)</td><td> (4.58) 4.5־ 1</td><td>.5 (3.91)</td><td>.1 (5.09)</td><td>.3 (5.70)</td><td>.2 (4.47)</td><td>.8 (3.15)</td>

<td> Change from baseline, LS mean (SE)</td><td>.5 (0.7)</td><td>.6 (1.0)</td><td>.1 (1.0)</td><td>.4 (1.0)</td><td>.1 (1.0)</td><td>.8 (1.0)</td>

<td colspan="2"> LSM difference (SE)^a</td><td>.1 (1.2)</td><td>.7(1.2)</td><td> (1.2) 2.9־</td><td>,6 (1.2)</td><td> (1.2) 6.3־</td>

<td colspan="2"> P-vaiue^b</td><td> 0.0933</td><td> 0,1850</td><td> 0.0210</td><td> 0.0003</td><td> &lt;0.0001</td>

<td colspan="7"> 4 hours post-dose</td>

<td> Mean (SD)</td><td> 113.7 (4.13)</td><td> 9.4 (3.90)</td><td> 11.2 (5.11)</td><td> 10.2 (5.12)</td><td> 9.1 (3.69)</td><td> 7.3 (2.54)</td>

<td> Change from baseline, mean (SD)</td><td> | -4.4 (4.44)</td><td>.1 (4.32)</td><td>.3 (5.22)</td><td>.2 (5.48)</td><td>.2 (4.02)</td><td>.9 (3.61)</td>

<td> Change from baseline, LS mean (SE)</td><td>.3 (0.7)</td><td>.1(1.0)</td><td>.4(1.0)</td><td>.3 (1.0)</td><td>.1 (1.0)</td><td>.9 (1.0)</td>

<td colspan="2"> LSM difference (SE)^a</td><td>.8 (1.2)</td><td>.1 (1,2)</td><td> (1.2) 2.9־</td><td>.8 (1.2)</td><td> (1.2) 6.5־</td>

<td colspan="2"> P-vaiue^b</td><td> 0.0022</td><td> 0,0895</td><td> 0.0172</td><td> 0.0001</td><td> &lt;0,0001</td>

<td rowspan="2"> Time Point Statistics</td><td rowspan="2"> Placebo (N=45)</td><td colspan="5"> Dexmedetomidine Sublingual film</td>

<td> 20 pg (N=18)</td><td> 60 pg (N=18)</td><td> 80 pg (N=18)</td><td> 120 pg (N=18)</td><td> 180 pg (N=18)</td>

<td colspan="7"> 6 hours post-dose</td>

<td> Mean (SD)</td><td> 113.1 (4.22)</td><td> 10.0 (4.00)</td><td> 11.9 (5.21)</td><td> 10.1(4.90)</td><td> 9.3 (4.23)</td><td> 7.2 (2.51)</td>

<td> Change from baseline, mean (SD)</td><td> i -5.0 (4.79)</td><td>.5 (4.03)</td><td>.6 (5.19)</td><td> (5.30) 7.3־</td><td>.1 (5.00)</td><td> (3.47) 11.1־</td>

<td> Change from baseline, LS mean (SE)</td><td>.9(0.7)</td><td>.6 (1.1)</td><td>.6 (1.1)</td><td>.4 (1.1)</td><td>.0 (1.1)</td><td>.0 (1.1)</td>

<td colspan="2"> LSM difference (SE)^a 1</td><td>.7 (1.3)</td><td>.7 (1.3)</td><td>.5 (1.3)</td><td> (1.3) 4.0־</td><td>.0 (1.3)</td>

<td colspan="2"> P-value^b</td><td> 0.0375</td><td> 0.5752</td><td> 0.0490</td><td> 0.0018</td><td> &lt;0.0001</td>

<td colspan="7"> 24 hours post-dose</td>

<td> Mean (SD)</td><td> i 13.5 (3.91)</td><td> 11.4 (3.58)</td><td> 13.6 (4.10)</td><td> 11.3 (4.18)</td><td> 12.8 (3.59)</td><td> 9.4 (4.82)</td>

<td> Change from baseline, mean (SD)</td><td> | -4.6 (4.03)</td><td>.1 (4.23)</td><td>.9 (4.34)</td><td>.1 (4.50)</td><td>.6 (3.29)</td><td> (3.53) 8.9־</td>

<td> Change from baseline, LS mean (SE)</td><td>.6(0.6)</td><td>.2 (0.9)</td><td>.0 (0.9)</td><td>.2 (0.9)</td><td>.5 (0.9)</td><td>.8 (0.9)</td>

<td colspan="2"> LSM difference (SE)^a</td><td> (1.1) 1.6־</td><td> 0.6 (1.1)</td><td>.6 (1.1)</td><td> (1.1) 0.9־</td><td>.2 (1.1)</td>

<td colspan="2"> P-value^b</td><td> 0.1464</td><td> 0.5697</td><td> 0.1407</td><td> 0.4310</td><td> 0.0002</td>

Note: subjects counts for all timepoints were 18 subjects for each dexmedetomidine sublingual film treatment group and 45 subjects for she placebo group a Treatment effect between dexmedetomidine sublingual film and placebo b - p value comparing dexmedetomidine sublingual film and placebo

[01011] PEC Responder Analyses: The proportion of treatment responders, defined as those with a 40 % decrease from baseline in PEC total score at 2 hours post dose, was greatest in the 180 pg group (94.4% [P &lt; 0.0001] for 180 pg, 68.8% [P == 0.0158] for 120 pg, 58.8% for 80 pg [P == 0.0759]) and significantly greater than placebo (31% responders) (Table 13 and FIG. 2). Response rates with 180 pg were significantly higher than placebo starting at 45 minutes post dose (44.4% versus 16.7%, respectively), continued to increase after 2 hours (to 94.4% at 4 and 6 hours) and sustained until at least 24 hours post-dose (83.3% versus 17.5%, respectively). Finally, the durability of calming effects of the 180 pg dose was remarkably prolonged with a sustained statistically significant reduction in PEC evident after 24 hrs. After a single dose in the 180 pg group, 83.3% of subjects maintained response after 24 hours with a mean PEC decrease of -8.9 (Mean CFB) compared to 37.5% m the 120 pg group (-5.6 Mean CFB) and 43.8% in the 80 pg group (-6.1 Mean CFB. Response rates over time for the 80 pg and 120 pg groups were high and similar between the 2 groups (Table 13 and FIG. 2).

[01012] Table 13: Percent of Responders in the PEC Score (Intent to treat Population)

<td rowspan="2"> Time Point Statistics</td><td rowspan="2"> Placebo (NM5)</td><td colspan="5"> Dexmedetomidine Sublingua! Film</td>

<td> 20 pg (N-18)</td><td> 6« Jig (N=18)</td><td> 80 Pg (N~18)</td><td> 120 pg (N=18)</td><td> 180 pg (N~18)</td>

<td colspan="7"> 10 minutes post-dose</td>

<td rowspan="2"> Time Point Statistics</td><td rowspan="2"> Placebo (N=45)</td><td colspan="5"> Dexmedetomidine Sublingual Film</td>

<td> 20 gg (N=18)</td><td> 60 ug (N=18)</td><td> 80 gg (N=18)</td><td> 120 gg (N=18)</td><td> 180 gg (N=18)</td>

<td> Percent responders</td><td> 11.9%</td><td> 0%</td><td> 12.5%</td><td> 5.9%</td><td> 6.3%</td><td> 5.6%</td>

<td colspan="7"> 20 minutes post-dose</td>

<td> Percent responders</td><td> 14.3%</td><td> 0%</td><td> 25.0%</td><td> 2.3.5%</td><td> 6.3%</td><td> 5.6%</td>

<td colspan="7"> 30 minutes post-dose</td>

<td> Percent responders</td><td> 21.4%</td><td> 11.8%</td><td> 37.5%</td><td> 23.5%</td><td> 12,5%</td><td> 11.1%</td>

<td colspan="7"> 45 minutes post-dose</td>

<td> Percent responders</td><td> 16.7%</td><td> 17.6%</td><td> 37.5%</td><td> 41.2%</td><td> 25.0%</td><td> 44.4%</td>

<td colspan="7"> 1 hour post-dose</td>

<td> Percent responders</td><td> 21.4%</td><td> 29.4%</td><td> 43.8%</td><td> 58.8%</td><td> 56.3%</td><td> 55.6%</td>

<td> P-value^a</td><td></td><td> 0.5178</td><td> 0.1091</td><td> 0.0120</td><td> 0.0236</td><td> 0.0150</td>

<td colspan="7"> 1.5 hours post-dose</td>

<td> Percent responders</td><td> 26.2%</td><td> 41.2%</td><td> 56.3%</td><td> 52.9%</td><td> 50.0%</td><td> 77.8%</td>

<td> P-value^a</td><td></td><td> 0.3505</td><td> 0.0612</td><td> 0.0699</td><td> 0.1190</td><td> 0.0004</td>

<td colspan="7"> 2 hours post-dose</td>

<td> Percent responders</td><td> 31.0%</td><td> 58.8%</td><td> 43.8%</td><td> 58.8%</td><td> 68.8%</td><td> 94.4%</td>

<td> P-xah:c</td><td></td><td> 0.0759</td><td> 0.3735</td><td> 0.0759</td><td> 0.0158</td><td> &lt;0.0001</td>

<td colspan="7"> 4 hours post-dose</td>

<td> Percent responders</td><td> 21.4%</td><td> 64.7%</td><td> 50.0%</td><td> 64.7%</td><td> 68.8%</td><td> 94.4%</td>

<td> P-xaiue</td><td></td><td> 0.0024</td><td> 0.0519</td><td> 0.0024</td><td> 0.0015</td><td> &lt;0.0001</td>

<td colspan="7"> 6 hours post-dose</td>

<td> Percent responders</td><td> 28.6%</td><td> 64,7%</td><td> 43.8%</td><td> 58.8%</td><td> 68.8%</td><td> 94.4%</td>

<td> P-value^a</td><td></td><td> 0.0173</td><td> 0.3510</td><td> 0.0399</td><td> 0.0075</td><td> &lt;0.0001</td>

<td colspan="7"> 24 hours post-dose</td>

<td> Percent responders</td><td> 17.5%</td><td> 43.8%</td><td> 26.7%</td><td> 43.8%</td><td> 37.5%</td><td> 83.3%</td>

<td> P־value^a</td><td></td><td> 0.0838</td><td> 0.4676</td><td> 0.0838</td><td> 0.1610</td><td> &lt;0.0001</td>

A responder is defined as a subject who achieved a >40% decrease from base tine in PEC score after dosing.

The number of subjects with non-missing data in the dexmedetomidine sublingual film treatment groups were: 18 (180 pg), 17 (20 ug and 80 pg), and 16 (60 pg and 120 pg); 42 subjects in the placebo group had non-missing data.

a P-value based on a comparison of dexmedetomidine sublingual film versus placebo via a Fisher’s exact test

[01013] PANSS-EC (5 Items Subscale Scores): The PEC 5 subscale scores associated with agitation (ie, poor impulse control, tension, hostility, uncooperativeness, and excitement) were summarized in table 14, at 2 hours post dosing, significant improvements (ie, decreases) from baseline in all 5 PEC subscale scores were observed in the 80 gg, 120 gg and 180 gg groups compared to placebo; with the exception of “excitement” in the 80 gg group.

[01014] Table 14: Change from Baseline in PANSS-EC subscale scores at 2 hours post dosing in schizophrenia patients (Intent to treat Population)

<td rowspan="2"> PANNS-EC Subscale Statistics</td><td rowspan="2"> Placebo (N=45)</td><td colspan="5"> Dexmedetomidine Sublingual Film</td>

<td> 20 ₍ug (N=18)</td><td> 60 jig (N=18)</td><td> 80 ug (N=18)</td><td> 120 pg (N=18)</td><td> 180 jig (N=18)</td>

<td colspan="7"> Poor Impulse Control</td>

<td> Baseline, Mean (SD)</td><td> 3.5 (0.63)</td><td> 3.5 (0.62)</td><td> 3.5 (0.62)</td><td> 3.3 (0.49)</td><td> 3.4 (0.50)</td><td> 3.4 (0.70)</td>

<td colspan="7"> 2 hours post-dose</td>

<td> Mean (SD)</td><td> 2.7 (0.87)</td><td> 2.1 (1.13)</td><td> 2.2 (1.11)</td><td> 1.9 (1 06)</td><td> 1.7 (0.75)</td><td> 1.4 (0.70)</td>

<td> Change from baseline, mean (SD)</td><td>.8 (0.89)</td><td>.4(1.14)</td><td>.3 (1.13)</td><td>.4 (1.04)</td><td>.7 (1.03)</td><td>.0 (0.91)</td>

<td> Change from baseline, LS mean (SE)</td><td>.8(0.1)</td><td>.4 (0.2)</td><td>.3 (0.2)</td><td>.4 (0.2)</td><td> (0.2) 7.!־</td><td>.0 (0.2)</td>

<td> LSM difference (SE)^a</td><td></td><td>.6 (0.3)</td><td>.5 (0.3)</td><td>.6 (0.3)</td><td>.9 (0.3)</td><td>.2 (0.3)</td>

<td> p value</td><td></td><td> 0.0307</td><td> 0.0810</td><td> 0.0178</td><td> 0.0009</td><td> &lt;0.0001</td>

<td colspan="7"> Tension</td>

<td> Baseline, Mean (SD)</td><td> 4.0 (0.64)</td><td> 3.8 (0.65)</td><td> 3.6 (0.92)</td><td> 3.8(0.71)</td><td> 4.1 (0.47)</td><td> 4.1 (0.87)</td>

<td colspan="7"> 2 hours post-dose</td>

<td> Mean (SD)</td><td> 3.0(1.13)</td><td> 2.4(1.15)</td><td> 2.3 (1.32)</td><td> 2.1 (1.23)</td><td> 1.9 (1.06)</td><td> 1.5 (0.71)</td>

<td> Change from baseline, mean (SD)</td><td>.0 (1.24)</td><td>.3 (1.14)</td><td>.3 (1.19)</td><td>.7(1.45)</td><td> (0.92) 2.2־</td><td>.6 (1.04)</td>

<td> Change from baseline, LS mean (SE)</td><td>.9 (0.2)</td><td>.5 (0.3)</td><td>.5 (0.3)</td><td>.8 (0.3)</td><td>.2 (0.3)</td><td>.6 (0.3)</td>

<td> LSM difference (SE)a</td><td></td><td>.5 (0.3)</td><td>.5 (0.3)</td><td>.8 (0.3)</td><td>.2 (0.3)</td><td>.6 (0.3)</td>

<td> p value</td><td></td><td> 0.1397</td><td> 0.0947</td><td> 0.0085</td><td> 0.0002</td><td> &lt;0.0001</td>

<td colspan="7"> Hostility</td>

<td colspan="2"> Baseline,Mean(SD) | 3.5(0.73)</td><td> 3.5 (0.62)</td><td> 3.6 (0.70)</td><td> 3.3 (0.77)</td><td> 3.6 (0.62)</td><td> 3.6 (0.61)</td>

<td colspan="7"> 2 hours post-dose</td>

<td> Mean (SD)</td><td> 2.6(1.12)</td><td> 2.2 (0.71)</td><td> 2.4 (1.04)</td><td> 1.9 (1.11)</td><td> 1.8 (0.79)</td><td> 1.4 (0.51)</td>

<td> Change from baseline, mean (SD)</td><td>.9(1.11)</td><td>.3 (0.84)</td><td>.2(1.15)</td><td> (1.14)1.4־</td><td>.7(1.18)</td><td>.2 (0.71)</td>

<td> Change from baseline, LS mean (SE)</td><td>.9 (0.1)</td><td>.3 (0.2)</td><td>.1 (0.2)</td><td>.5 (0.2)</td><td>.7(0.2)</td><td>.1 (0.2)</td>

<td> LSM difference (SE)a</td><td></td><td>.4 (0.3)</td><td>.2 (0.3)</td><td>.6 (0.3)</td><td>.8 (0.3)</td><td>.2(0.3)</td>

<td> p value</td><td></td><td> 0.0973</td><td> 0.3609</td><td> 0.0272</td><td> 0.0029</td><td> &lt;0.0001</td>

<td colspan="7"> Uncoopcrativencss</td>

<td> Baseline, Mean (SD)</td><td> 3.3 (0.72)</td><td> 3.2 (0.81)</td><td> 3.3 (0.83)</td><td> 3.4 (0.92)</td><td> 3.4 (0.70)</td><td> 3.2 (0.81)</td>

<td colspan="7"> 2 hours post-dose</td>

<td> Mean (SD)</td><td> 2.5 (0.97)</td><td> 2.0 (0.84)</td><td> 2.2 (0.94)</td><td> 2.0 (1.24)</td><td> 1.7 (0.91)</td><td> 1.4 (0.62)</td>

<td> Change from baseline, mean (SD)</td><td>.8 (0.98)</td><td>.2 (1.06)</td><td>.1 (1.11)</td><td>.4 (1.33)</td><td>.8(1.06)</td><td>.8 (0.81)</td>

<td> Change from baseline, LS mean (SE)</td><td>.8 (0.1)</td><td>.3 (0.2)</td><td>.1 (0.2)</td><td>.4 (0.2)</td><td>.7 (0.2)</td><td>.8 (0.2)</td>

<td> LSM difference (SE)a</td><td></td><td>.5 (0.3)</td><td>.3 (0.3)</td><td>.6 (0.3)</td><td>.0 (0.3)</td><td>.0 (0.3)</td>

<td> p value</td><td></td><td> 0.0669</td><td> 0.2607</td><td> 0.0268</td><td> 0.0004</td><td> 0.0001</td>

<td> Excitement</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Baseline, Mean (SD)</td><td> 3.8 (0.64)</td><td> 3.5 (0.62)</td><td> 3.6 (0.70)</td><td> 3.5 (0.62)</td><td> 3.8(0.71)</td><td> 3.9 (0.64)</td>

<td> 2 hours post- dose</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Mean (SD)</td><td> 2.7 (1.07)</td><td> 2.3 (0.83)</td><td> 2.3 (1.24)</td><td> 2.1 (1.37)</td><td> 1.9 (1.06)</td><td> 1.6 (0.70)</td>

<td> Change from baseline, mean (SD)</td><td>.1(1.11)</td><td>.2 (0.88)</td><td>.2(1.22)</td><td>.4 (1.46)</td><td>.9 (1.02)</td><td>.3 (0.77)</td>

<td> Change from baseline, LS mean (SE)</td><td>.1(0.2)</td><td>.3 (0.2)</td><td>.3 (0.2)</td><td>.5 (0.2)</td><td>.8(0.2)</td><td> (0.2) 2.2־</td>

<td> LSM difference (SE)a</td><td></td><td>.2 (0.3)</td><td>.2 (0.3)</td><td>.4 (0.3)</td><td>.8 (0.3)</td><td> (0.3)2.־־</td>

<td> p value</td><td></td><td> 0.3967</td><td> 0.4394</td><td> 0.1577</td><td> 0.0081</td><td> &lt;0.0001</td>

[01015] Secondary Efficacy Endpoints:

[01016] Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at 2 hours post-dose were consi stent with the results for PEC total scores and were indicative of improvement in symptoms of agitation after treatment with dexmedetomidine sublingual film.

[01017] ACES scores: A secondary objective for this study was to evaluate the duration of calming effect of dexmedetomidine sublingual thin film drug utilizing the Agitation-Calmness Evaluation Scale (ACES) collected at pre-dose, 2 hr, and 4 hr after first dose. The ACES assessment was consistent with the analysis of the primary endpoint, and met statistically significance for calming as measured by ACES at two hours compared to placebo in the three highest doses evaluated (80 pg; p=0.0150), (120 pg; p=0.0003) and (180 pg; p&lt;0.0001). At 2 hours after dosing, subjects in the 80 pg, 120 pg, and 180 pg treatment groups showed significantly greater improvements relative to placebo in ACES scores (+2.3 [P = 0.0150], +3.1 [P = 0.0003], and +4.2 [P = &lt;0.0001], respectively, compared to placebo of +1.2). The improvements at 4 hours post-dose were similar (+2.1 [P = 0.0252], +3.2 [P = &lt;0.0001], and +4.1 [P = &lt;0.0001], placebo was +1.1). (Table 15 and FIG. 3). In terms of calming effect (as measured by ACES scores), mean scores in 120 pg and 180 pg groups increased from a baseline of approximately 2 “moderate agitation” to 5.1 “mild calmness” and 6.2 “moderate calmness”, respectively at 2 hours post-dose, compared with a score of 3.4 “mild agitation” in the placebo group. The improvements in calmness in the groups were statistically significant with P values of 0.0003 and &lt;0.0001, respectively, compared with placebo (Table 15).

[01018] Time to resolution of agitation: The percentage of subjects achieving an ACES score of at least 4 (normal)) at 2 and 4 hours post dosing is displayed m FIG 3. At 2 and 4 hours after dosing, the percentage of subjects who achieved a ACES score of at least 4, which indicated resolution of agitation, was significantly greater in the 120 pg group (72.2% [P = 0.0045] and 77.8% [P = 0.0016], respectively) and the 180 pg group (88.9% [P &lt;0.0001] and 83.3% [P =0.0002], respectively) compared with the placebo group (31.1% at both 2 and 4 hours post-dose). In terms of sedation (as measured by ACES scores) the results indicated that a total of 9 subjects in the treatment groups had scores of 8 “deep sleep” at 2 hours and/or 4 hours post-dose, however, no subject m any of the treatment groups had a score of 9 “unarousable.” (Table 16). Calming effect was durable lasting at least 6 hours as evidenced by separation from placebo for 80 pg, 120 pg and 180 pg dose groups.

[01019] Table 15: Change from Baseline in ACES Score at 2 and 4 hours post dosing (Intent to treat population)

<td rowspan="2"> Time Post dose</td><td rowspan="2"> Placebo (N=45)</td><td colspan="4"> Dexmedetomidine Sublingual Film</td>

<td> 20 ug (N=18)</td><td> 60 pg (N=18)</td><td> 80 pg | 120 pg (N=18) I (N=18)</td><td> 180 pg (N=18)</td>

<td colspan="6"> Baseline, si</td>

<td> Mean (SD)</td><td colspan="2"> 2.1 (0.55) i 2.3 (0.49)</td><td> 2.2 (0.55)</td><td> 2.2 (0.55) i 2.0 (0.34)</td><td> 1.9 (0.54)</td>

<td colspan="6"> 2 hours post-dose</td>

<td> Mean (SD)</td><td> 3.4 (1.55)</td><td> 3.8 (1.11)</td><td> 4.2 (1.70)</td><td> 4.6 (2.25) i 5.1 (2.05)</td><td> 6.2 (1.58)</td>

<td> Change from baseline, mean (SD)^a</td><td> 1.2 (1.46)</td><td> 1.4 (1.29)</td><td> 2.0 (1.71)</td><td> 2.3 (2.43) 3.1 (2.03)</td><td> 4.2 (1.83)</td>

<td> Change from baseline, LS mean (SE)^b</td><td> 1.2 (0.3)</td><td> 1.6 (0.4)</td><td> 2.1 (0.4)</td><td> (0.4)3.0 ן (0.4)2.4</td><td> 4.1 (0.4)</td>

<td> LSM difference (SE)^C</td><td></td><td> 0.4 (0.5)</td><td> 0.8 (0.5)</td><td> 1.2(0.5) 1.8(0.5)</td><td> 2.9 (0.5)</td>

<td> P-value^d</td><td></td><td> 0.4371</td><td> 0.0795</td><td> 0.0150 0.0003</td><td> &lt;0.0001</td>

<td colspan="6"> 4 hours post-dose</td>

<td> Mean (SD)</td><td> 3.2 (1.42)</td><td> 4,4 (1.54)</td><td> 3.9 (1.76)</td><td> 4.3 (2.22) i 5.2 (L72)</td><td> 6.0 (1.75)</td>

<td> Change from baseline, mean (SD)^a</td><td> 1.1 (1.40)</td><td> 2.1 (1.53)</td><td> 1.7(1.81)</td><td> 2.1 (2.19) | 3.2 (1.69)</td><td> 4.1 (2.04)</td>

<td> Change from baseline, LS mean (SE)^b</td><td> 1.1(0.3)</td><td> 2.3 (0.4)</td><td> 1.8 (0.4)</td><td> (0.4)3.1 ן (0.4)2.2</td><td> 3.9 (0.4)</td>

<td> LSM difference (SE)^C</td><td></td><td> 1.2 (0.5)</td><td> 0.7 (0.5)</td><td> 1.1 (0.5) 2.0 (0.5)</td><td> 2.8 (0.5)</td>

<td> P־value^d</td><td></td><td> 0.0164</td><td> 0.1524</td><td> 0.0252 1 &lt;0.0001</td><td> &lt;0.0001</td>

a Change from baseline (pre-dose) ACES score, with positive values in favor of improvement.

b Least square mean and standard error per treatment group.

c Treatment Effect: Least square mean difference, standard error, and 95% confidence intervals between Dexmedetomidine sublingual film and

Placebo.

d p value comparing Dexmedetomidine sublingual film and Placebo

[01020] Table 16: Subjects Rates with an ACES Scores of 8 (Deep Sleep) or 9 (Unarousable

Sleep) for all dose groups

<td> ACES Scare</td><td> Bose Group</td><td> Number of Subjects at Baseline</td><td> Number of Subjects at 2 hr</td><td> Number of Subjects at 4 hr</td>

<td rowspan="6"> Deep Sleep ACES Score== 8</td><td> Placebo</td><td> 0</td><td> 0</td><td> 0</td>

<td> 20 pg</td><td> 0</td><td> 0</td><td> 1</td>

<td> 60 pg</td><td> 0</td><td> 0</td><td> 0</td>

<td> 80 pg</td><td> 0</td><td> 1</td><td> 1</td>

<td> 120 pg</td><td> 0</td><td> 2</td><td> 0</td>

<td> 180 pg</td><td> 0</td><td> 2</td><td> 3</td>

<td rowspan="6"> Ltnarousable Sleep ACES Score = 9</td><td> Placebo</td><td> 0</td><td> 0</td><td> 0</td>

<td> 20 pg</td><td> 0</td><td> 0</td><td> 0</td>

<td> 60 pg</td><td> 0</td><td> 0</td><td> 0</td>

<td> 80 pg</td><td> 0</td><td> 0</td><td> 0</td>

<td> 120 pg</td><td> 0</td><td> 0</td><td> 0</td>

<td> 180 pg</td><td> 0</td><td> 0</td><td> 0</td>

[01021] CGI-I scores: Mean baseline CGI-S scores were comparable across all treatment groups (range: 3.9 to 4.3). The CGI-S scores indicated that the subjects were clinically agitated (ie, moderately ill) prior to dosing (Table 17). Significant improvements in agitation (ie, lower CGI-I scores) from baseline were observed at 1 hour after dosing in the dexmedetomidine sublingual film 120 pg and 180 pg groups. Mean (SD) scores were 2.3 (1.13) and 2.1 (0.87), respectively, compared with 3.0 (0.98) in the placebo group (Table 18). LSM differences from placebo were

0.7 (P == 0.0167) and -0.9 (P === 0.0019) in the 120 pg and 180 pg groups, respectively. Significant improvements in agitation (i.e. lower mean CGI-I scores) from baseline were observed at 2 hours post-dose in the 120 pg group (1.9 [P === 0.0007]) and in the 180 pg group (1.4 [P&lt;0.0001]), compared with a mean score of 3 in the placebo group (Table 18). LSM differences from placebo were 1.1&amp;#1470; (P = 0.0007) and -1.6 (PO.OOOl). Significant improvements were also observed at 4 hours post-dose in the dexmedetomidine sublingual film 120 pg and 180 pg groups The percentage of subjects achieving CGI-I scores of 1 or 2 (very much improved' or 'much improved') at 2 hours post-dose was significantly higher in the 120 pg group (66.7% [P= 0.0125]) and in the 180 pg dose group (94.4% [P &lt; 0.0001]), compared with placebo (31.0%). Significant improvements were also observed at 1 hour and at 4 hours after dosing for both treatment groups (Table 19 and FIG. 4).

[01022] Table 17: CGI-S Mean Scores at Baseline (Intent to treat Population)

<td rowspan="2"> Time Point Statistics</td><td rowspan="2"> Placebo (NM5)</td><td colspan="5"> Dexmedetomidine Sublingual Fiim</td>

<td> 20 Pg (V-W)</td><td> 60 pg (V-W)</td><td> 80 pg (V-W)</td><td> 120 pg (N=18)</td><td> 180 pg (N~18)</td>

<td> Number of subjects</td><td> 45</td><td> 18</td><td> 18</td><td> 18</td><td> 18</td><td> 18</td>

<td colspan="7"> Baseline (pre-dose)</td>

<td> Mean (SD)</td><td> 4.2 (0.44)</td><td> 3.9 (0.47)</td><td> 4.1 (0.68)</td><td> 4.1 (0.32)</td><td> 4.3 (0.57)</td><td> 4.3 (0.46)</td>

<td> Minimum - Maximum</td><td> 3.0 - 5.0</td><td> 3.0 - 5.0</td><td> 3.0-5.0</td><td> 4.0-5.0</td><td> 3.0 - 5.0</td><td> 4.0 - 5.0</td>

[01023] . Table 18: Summary of Change from Baseline for CGI-I Score (Intent to treat

Population)

<td rowspan="2"> Time Point Statistics</td><td rowspan="2"> Placebo (N=45)</td><td colspan="5"> Dexmedetomidine Sublingual Fiim</td>

<td> 20 pg (N=18)</td><td> 60 pg (N=18)</td><td> 80 pg (N=18)</td><td> 120 pg (N=18)</td><td> 180 pg (N=18)</td>

<td colspan="7"></td>

<td> Number of subjects</td><td> 45</td><td> 18</td><td> 18</td><td> 18</td><td> 18</td><td> 18</td>

<td colspan="7"> 30 minutes post-dose</td>

<td> Mean (SD)</td><td> 3.1 (1.04)</td><td> 3.1 (0.76)</td><td> 2.8 (1.15)</td><td> 3.2 (1.15)</td><td> 3.1 (0.76)</td><td> 3.1 (0.76)</td>

<td> LS mean (SE)^a</td><td> 3.2 (0.1)</td><td> 3.1 (0.2)</td><td> 2.8 (0.2)</td><td> 3.2 (0.2)</td><td> 3.1 (0.2)</td><td> 3.1 (0.2)</td>

<td> LSM difference (SE)^b</td><td rowspan="2"></td><td>.1 (0.3)</td><td>.4 (0.3)</td><td>.0 (0.3)</td><td>.1 (0.3)</td><td>.1 (0.3)</td>

<td> P-value^c</td><td> 0.7431</td><td> 0.1778</td><td> 0.9022</td><td> 0.7431</td><td> 0.7431</td>

<td colspan="7"> 1 hour post-dose</td>

<td> Mean (SD)</td><td> 3.0 (0.98)</td><td> 2.9 (0.83)</td><td> 2.4 (1.20)</td><td> 2.8 (1.42)</td><td> 2.3 (1.13)</td><td> 2.1 (0.87)</td>

<td> LS mean (SE)^a</td><td> 3.0 (0.2)</td><td> 2.9 (0.3)</td><td> 2.4 (0.3)</td><td> 2.8 (0.3)</td><td> 2.3 (0.3)</td><td> 2.1(0.3)</td>

<td> LSM difference (SE)^B</td><td rowspan="2"></td><td>.1 (0.3)</td><td>.6 (0.3)</td><td>.2 (0.3)</td><td>.7 (0.3)</td><td>.9 (0.3)</td>

<td> P-value^c</td><td> 0.7098</td><td> 0.0645</td><td> 0.5769</td><td> 0.0167</td><td> 0.0019</td>

<td colspan="7"> 2 hours post-dose</td>

<td> Mean (SD)</td><td> 3.0 (1.09)</td><td> 2.4 (0.98)</td><td> 2.3(1.13)</td><td> 2.6 (1.54)</td><td> 1.9 (LOO)</td><td> 1.4 (0.61)</td>

<td> LS mean (SE)^a</td><td> 3.0 (0.2)</td><td> 2.4 (0.3)</td><td> 2.3 (0.3)</td><td> 2.6 (0.3)</td><td> 1.9 (0.3)</td><td> 1.4 (0.3)</td>

<td> LSM: difference (SE)^b</td><td></td><td>.6 (0.3)</td><td>.7 (0.3)</td><td>.4 (0.3)</td><td>.1 (0.3)</td><td>.6 (0.3)</td>

<td rowspan="2"> Time Point Statistics</td><td rowspan="3"> Placebo (N=45)</td><td colspan="5"> Dexmedetomidine Sublingual Film</td>

<td> 20 pg (N=18)</td><td> 60 pg (N=18)</td><td> 80 pg (N=18)</td><td> 120 pg (N=18)</td><td> 180 pg (N=18)</td>

<td> P-value^c</td><td> 0.0701</td><td> 0.0190</td><td> 0.2034</td><td> 0.0007</td><td> &lt;0.0001</td>

<td colspan="7"> 4 hours post-dose</td>

<td> Mean (SD)</td><td> 3.0 (1.08)</td><td> 2.4 (0.92)</td><td> 2.8 (1.22)</td><td> 2.6 (1.60)</td><td> 1.8 (0.73)</td><td> 1.4 (0.62)</td>

<td> LS mean (SE)^a</td><td> 3.0 (0.2)</td><td> 2.4 (0.3)</td><td> 2.8 (0.3)</td><td> 2.7 (0.3)</td><td> 1.8 (0.3)</td><td> 1.4 (0.3)</td>

<td> LSM difference (SE)^b</td><td rowspan="2"></td><td>.6 (0.3)</td><td>.2 (0.3)</td><td>.3 (0.3)</td><td>.2 (0.3)</td><td>.5 (0.3)</td>

<td> P-value^c</td><td> 0.0516</td><td> 0.5071</td><td> 0.4139</td><td> 0.0001</td><td> &lt;0.0001</td>

Clinical Global Impression - Improvement scores range from 1 (Very much improved) to 7 (Very much worse).

Test statistics and estimates are from a restricted maximum likelihood repeated measures mixed model on observed values with timepoint and its interaction with treatment group as repeated measures using an unstructured covariance structure.

a Least square mean and standard error per treatment group. The corresponding estimates for the placebo group are not included as they vary with the dexmedetomidine sublingual film dosing group being compared.

b Treatment Effect: Least square mean difference, standard error, and 95% confidence intervals between dexmedetomidine sublingual film and Placebo c P value comparing dexmedetomidine sublingual film and Placebo

[01024] Table 19. Percent of Responders in the CGI-I Scale over Time (Intent-to-Treat

Population)

<td rowspan="2"> Time Point Statistics</td><td rowspan="2"> Placebo (N=45)</td><td colspan="5"> Dexmedetomidine sublingual film</td>

<td> 20 .ug (N=18)</td><td> 60 pg (N=18)</td><td> 80 pg (N=18)</td><td> 120 pg (N=18)</td><td> 180 pg (N=18)</td>

<td colspan="7"> 30 minutes post-dose</td>

<td> Percent responders</td><td> 22.2%</td><td> 22.2%</td><td> 38.9%</td><td> 27.8%</td><td> 22.2%</td><td> 22.2%</td>

<td> P-value^a</td><td></td><td> 1.000</td><td> 0.2158</td><td> 0.7457</td><td> 1.000</td><td> 1.000</td>

<td colspan="7"> 1 hour post-dose</td>

<td> Percent responders</td><td> 24.4%</td><td> 38.9%</td><td> 44.4%</td><td> 44.4%</td><td> 55.6%</td><td> 72.2%</td>

<td> P-value^a</td><td></td><td> 0.3549</td><td> 0.1383</td><td> 0.1383</td><td> 0.0361</td><td> 0.0011</td>

<td colspan="7"> 2 hours post-dose</td>

<td> Percent responders</td><td> 31.1%</td><td> 55.6%</td><td> 55.6%</td><td> 50.0%</td><td> 66.7%</td><td> 94.4%</td>

<td> P-vah1e^a</td><td></td><td> 0.0896</td><td> 0.0896</td><td> 0.2462</td><td> 0.0125</td><td> &lt;0.0001</td>

<td colspan="7"> 4 hours post-dose</td>

<td> Percent responders</td><td> 32.6%</td><td> 55.6%</td><td> 44.4%</td><td> 57.1%</td><td> 83.3%</td><td> 94.4%</td>

<td> P-value^a</td><td></td><td> 0.1499</td><td> 0.3968</td><td> 0.1231</td><td> 0.0005</td><td> &lt;0.0001</td>

a P-value based on a comparison of dexmedetomidine sublingual film versus placebo via a Fisher’s exact test

[01025] Pharmacokinetic Results:

[01026] Pharmacokinetic analysis was conducted using a validated install of Phoenix® WinNonlin® version 8.1. Non-compartmental analysis was also conducted on the final audited data which consisted of a total of 135 participants in 5 cohorts receiving 20, 60, 80 (1 x 20 pg films and 1 x 60 pg films), 120 (2 x 60 pg films) and 180 pg (3 x 60 pg films) of dexmedetomidine sublingual film. Measurable concentrations of dexmedetomidine were observed at the first collected post dose plasma sample (I hr) for all dose levels and tabulated in table 20. There were no measurable concentrations at pre-dose (0 hr) at any dose level. Measurable concentrations of dexmedetomidine were observable until 8 hr for all dose levels with measurable concentrations at 24 hr in some subjects at each dose level (Table 20; Error! Reference source not found.A and 5B). Dexmedetomidine sublingual film is absorbed rapidly with maximum concentration achieved on average within about 2.5 hours after administration. The median Tmax ranged from 1.50-2.31 hr while the median tl/2 ranged from 2.36-3.06 hr across the 5 dose levels. The exposure (Cmax and AUC) increased in an approximately dose proportional manner within the dose range (20 pg --180 pg) studied after single administration. The median Cmax ranged from about 40 ng/L to about 500 ng/L. After absorption, it was eliminated with about a 3-hour half-life which was consistent across dose groups. In 20 pg dose group, 8 of 18 subjects were given a second dose of dexmedetomidine sublingual film, the exposure (Cmax and AUC) was about 2-fold higher than in the group which was not redosed

[01027] Observed exposures following a single dose of 180 pg (Mean Cmax: 379 ng/L; Mean AUC 2881 ng/L) (Table 20) are significantly below the mean exposures (IV PRECEDEX® at approved dose is estimated): Cmax: 1339 ng/L; AUC: 31713 ng.h/L (PKPD18-1054) with the highest approved dose of dexmedetomidine.

[01028] Table 20: Individual and summary statistics of PK parameter estimates of dexmedetomidine in plasma after administration of dexmedetomidine sublingual film in schizophrenia patients.

<td> Cehort</td><td> Dose feg)</td><td> Redose</td><td> Subject ID</td><td> Cmax (ng/L)</td><td> Tmax (hr)</td><td> AUClast (hr* ng/L)</td><td> AUCinfobs (hr *ng/L)</td><td> tl/2 (hr)</td>

<td rowspan="10"> 1</td><td rowspan="10"> 20</td><td rowspan="10"> No</td><td> 01-001</td><td> 35.54</td><td> 1.50</td><td> 224.01</td><td> NC</td><td> NC</td>

<td> 01-002</td><td> 38.55</td><td> 1.50</td><td> 186.08</td><td> NC</td><td> 3.79</td>

<td> 01-010</td><td> 59.82</td><td> 1.00</td><td> 104.40</td><td> NC</td><td> 2.12</td>

<td> 01-026</td><td> 14.07</td><td> 4.02</td><td> 57.43</td><td> NC</td><td> NC</td>

<td> 07-015</td><td> 33.41</td><td> 1.53</td><td> 177.60</td><td> NC</td><td> 5.36</td>

<td> 07-030</td><td> 34.31</td><td> 2.00</td><td> 176.11</td><td> 203.81</td><td> 2.29</td>

<td> 10-027</td><td> 35.38</td><td> 2.00</td><td> 184.37</td><td> NC</td><td> 3.64</td>

<td> 23-016</td><td> 69.05</td><td> 1.48</td><td> 264.45</td><td> NC</td><td> 2.95</td>

<td> 23-018</td><td> 40.37</td><td> 1.97</td><td> 154.62</td><td> 186.40</td><td> 3.17</td>

<td> 23-020</td><td> 38.49</td><td> 1.95</td><td> 190.81</td><td> 226.26</td><td> 2.51</td>

<td rowspan="9"></td><td rowspan="9"></td><td rowspan="9"></td><td> N</td><td> 10</td><td> 10</td><td> 10</td><td> 3</td><td> 8</td>

<td> Mean</td><td> 39.90</td><td> 1.89</td><td> 171.99</td><td> 205.49</td><td> 3.23</td>

<td> SD</td><td> 15.02</td><td> 0.81</td><td> 57.74</td><td> 19.98</td><td> 1.05</td>

<td> cv%</td><td> 37.64</td><td> 42.89</td><td> 33.57</td><td> 9.72</td><td> 32.61</td>

<td> Min</td><td> 14.07</td><td> 1.00</td><td> 57.43</td><td> 186.40</td><td> 2.12</td>

<td> Median</td><td> 37.02</td><td> 1.74</td><td> 180.99</td><td> 203.81</td><td> 3.06</td>

<td> Max</td><td> 69.05</td><td> 4.02</td><td> 264.45</td><td> 226.26</td><td> 5.36</td>

<td> Geometric Mean</td><td> 37.16</td><td> 1.78</td><td> 160.36</td><td> 204.85</td><td> 3.0 9</td>

<td> Geometric CV%</td><td> 43.89</td><td> 36.99</td><td> 45.49</td><td> 9.72</td><td> 31.23</td>

<td rowspan="8"> 1</td><td rowspan="8"> 20</td><td rowspan="8"> Yes</td><td> 01-009</td><td> 130.44</td><td> 2.00</td><td> 662.46</td><td> NC</td><td> 3.94</td>

<td> 01-013</td><td> 122.23</td><td> 2.00</td><td> 486.82</td><td> 563.33</td><td> 2.73</td>

<td> 05-007</td><td> 49.87</td><td> 2.50</td><td> 230.06</td><td> NC</td><td> 4.02</td>

<td> 05-008</td><td> 66.64</td><td> 2.12</td><td> 272.47</td><td> 304.52</td><td> 2.00</td>

<td> 05-021</td><td> 86.86</td><td> 2.50</td><td> 410.74</td><td> NC</td><td> 3.10</td>

<td> 05-023</td><td> 52.29</td><td> 2.50</td><td> 236.04</td><td> NC</td><td> NC</td>

<td> 05-024*</td><td> 138.69</td><td> 8.03</td><td> 1912.52</td><td> NC</td><td> NC</td>

<td> 07-028</td><td> 125.70</td><td> 2.00</td><td> 476.62</td><td> 519.25</td><td> 1.81</td>

<td rowspan="9"></td><td rowspan="9"></td><td rowspan="9"></td><td> N</td><td> 8</td><td> 8</td><td> 8</td><td> 3</td><td> 6</td>

<td> Mean</td><td> 96.59</td><td> 2.96</td><td> 585.96</td><td> 462.37</td><td> 2.93</td>

<td> SD</td><td> 36.95</td><td> 2.06</td><td> 556.20</td><td> 138.47</td><td> 0.94</td>

<td> cv%</td><td> 38.26</td><td> 69.85</td><td> 94.92</td><td> 29. 95</td><td> 31.98</td>

<td> Min</td><td> 49.87</td><td> 2.00</td><td> 230.06</td><td> 304.52</td><td> 1.81</td>

<td> Median</td><td> 104.54</td><td> 2.31</td><td> 443.68</td><td> 519.25</td><td> 2.91</td>

<td> Max</td><td> 138.69</td><td> 8.03</td><td> 1912.52</td><td> 563.33</td><td> 4.02</td>

<td> Geometric Mean</td><td> 89.71</td><td> 2.61</td><td> 453.42</td><td> 446.60</td><td> 2.80</td>

<td> Geometric CV%</td><td> 44.50</td><td> 49.35</td><td> 78.77</td><td> 34.37</td><td> 34.49</td>

<td rowspan="7"> 2</td><td rowspan="7"> 60</td><td rowspan="7"> No</td><td> 01-044</td><td> 93.67</td><td> 1.00</td><td> 442.23</td><td> NC</td><td> 3.10</td>

<td> 01-047</td><td> 73.42</td><td> 1.00</td><td> 265.85</td><td> 293.67</td><td> 2.23</td>

<td> 01-055</td><td> 113.35</td><td> 1.50</td><td> 474.46</td><td> 562.60</td><td> 2.87</td>

<td> 01-056</td><td> 154.79</td><td> 1.50</td><td> 413.53</td><td> 428.64</td><td> 1.48</td>

<td> 03-036</td><td> 83.52</td><td> 1.55</td><td> 347.11</td><td> 369.07</td><td> 1.62</td>

<td> 05-050</td><td> 121.52</td><td> 1.00</td><td> 355.87</td><td> 381.27</td><td> 1.84</td>

<td> 05-052</td><td> 105.84</td><td> 1.50</td><td> 330.30</td><td> 369.14</td><td> 2.36</td>

<td rowspan="11"></td><td rowspan="11"></td><td rowspan="11"></td><td> 06-033</td><td> 253.14 i 1.45</td><td> 737.87</td><td> 834.44</td><td> 2.27</td>

<td> 06-034</td><td> 206.42 1.53</td><td> 887.27</td><td> 1007.71</td><td> 2.35</td>

<td> 06-041</td><td> 144.27 2.07</td><td> 1714.29</td><td> 1882.10</td><td> 6.98</td>

<td> 06-043</td><td> 186.40 1.02</td><td> 748.96</td><td> 877.63</td><td> 2.53</td>

<td> 07-048</td><td> 201.12 | 0.98</td><td> 874.85</td><td> 1030.25</td><td> 2.81</td>

<td> 08-046*</td><td> 93.22 1 2.00</td><td> 346.61</td><td> NC</td><td> NC</td>

<td> 09-042</td><td> 146.17 3.95</td><td> 2072.02</td><td> 2195.38</td><td> 5.43</td>

<td> 10-032</td><td> 136.25 | 1.50</td><td> 650,22</td><td> NC</td><td> NC</td>

<td> 10-035</td><td> 127.27 1.50</td><td> 519.54</td><td> 616.68</td><td> 2.78</td>

<td> 10-039</td><td> 144.93 1.00</td><td> 603.55</td><td> 691.00</td><td> 2.27</td>

<td> 10-045</td><td> 127.30 i 1.50</td><td> 495.69</td><td> 548.50</td><td> 2.30</td>

<td rowspan="9"></td><td rowspan="9"></td><td rowspan="9"></td><td> N</td><td> 18 18</td><td> 18</td><td> 15</td><td> 16</td>

<td> Mean</td><td> 139.59 1.53</td><td> 680.71</td><td> 805.85</td><td> 2.83</td>

<td> SD</td><td> 47.22 0.69</td><td> 481.66</td><td> 555.95</td><td> 1.42</td>

<td> cv%</td><td> 33.83 45.0</td><td> 70.76</td><td> 68.89</td><td> 50.15</td>

<td> Min</td><td> 73.42 0.98</td><td> 265.85</td><td> 293.67</td><td> 1.48</td>

<td> Median</td><td> 131.78 | 1.50</td><td> 507.61</td><td> 616.68</td><td> 2.36</td>

<td> Max</td><td> 253.14 1 3.95</td><td> 2072.02</td><td> 2195.38</td><td> 6.98</td>

<td> Geometric Mean</td><td> 132.56 1.43</td><td> 575.95</td><td> 674.14</td><td> 2.60</td>

<td> Geometric CV%</td><td> 33.88 36.02</td><td> 59.93</td><td> 65.01</td><td> 40.94</td>

<td rowspan="18"> 3</td><td rowspan="18"> 120</td><td rowspan="18"> No</td><td> 01-059</td><td> 128.89 2.00</td><td> 1143.72</td><td> 1192.51</td><td> 5.28</td>

<td> 01-062</td><td> 380.78 1 2.00</td><td> 2927.15</td><td> 2958.80</td><td> 3.64</td>

<td> 01-065</td><td> 393.58 4.00</td><td> 3935.47</td><td> 4063.95</td><td> 4.62</td>

<td> 01-080</td><td> 316.57 1.00</td><td> 1536.77</td><td> 1538,84</td><td> 2.60</td>

<td> 01-082</td><td> 315.51 4.00</td><td> 4156.65</td><td> 4371.55</td><td> 5.32</td>

<td> 01-086</td><td> 201.58 1.00</td><td> 915.85</td><td> 918.48</td><td> 2.56</td>

<td> 03-068</td><td> 308.19 | 1.02</td><td> 1039.39</td><td> 1039.79</td><td> 2.02</td>

<td> 06-077</td><td> 108.84 | 3.82</td><td> 585.94</td><td> 586.93</td><td> 2.59</td>

<td> 06-078</td><td> 228.53 1 1.47</td><td> NC</td><td> NC</td><td> NC</td>

<td> 06-083</td><td> 154.65 1.47</td><td> 592.96</td><td> 593.28</td><td> 2.01</td>

<td> 06-084</td><td> 160.33 | L47</td><td> 682.91</td><td> 683.47</td><td> 2.59</td>

<td> 07-066</td><td> 366.09 2.00</td><td> 3920.86</td><td> 4012.15</td><td> 4.35</td>

<td> 10-063</td><td> 184.22 2.00</td><td> NC</td><td> NC</td><td> 3.50</td>

<td> 10-076</td><td> 149.11 1 2.00</td><td> 990.19</td><td> 989.76</td><td> 2.81</td>

<td> 23-069</td><td> 286.88 2.00</td><td> 1230.19</td><td> 1230.90</td><td> 1.98</td>

<td> 23-070</td><td> 243.63 1.52</td><td> NC</td><td> NC</td><td> 3.21</td>

<td> 23-073*</td><td> 125.62 4.00</td><td> NC</td><td> NC</td><td> NC</td>

<td> 23-074</td><td> 233.12 1.55</td><td> 1162.59</td><td> 1166.09</td><td> 2.83</td>

<td rowspan="8"></td><td rowspan="8"></td><td rowspan="8"></td><td> N</td><td> 18 i 18</td><td> 18</td><td> 14</td><td> 16</td>

<td> Mean</td><td> 238.12 | 2.13</td><td> 1513.91</td><td> 1810.47</td><td> 3.25</td>

<td> SD</td><td> 92.98 1.06</td><td> 1264.13</td><td> 1395.65</td><td> 1.1</td>

<td> cv%</td><td> 39.05 50.03</td><td> 83.50</td><td> 77.09</td><td> 34.27</td>

<td> Mln</td><td> 108.84 | 1.00</td><td> 499.50</td><td> 586.93</td><td> 1.98</td>

<td> Median</td><td> 230.83 2.00</td><td> 970.38</td><td> 1179.30</td><td> 2.82</td>

<td> Max</td><td> 393.58 | 4.00</td><td> 4158.05</td><td> 4371.55</td><td> 5.32</td>

<td> Geemetric Mean</td><td> 220.53 1.91</td><td> 1169.33</td><td> 1411.79</td><td> 3.08</td>

<td></td><td></td><td></td><td> Geometric CV%</td><td> 42.89 49.10</td><td> 78.73</td><td> 81.15</td><td> 33.71</td>

<td rowspan="18"> 4</td><td rowspan="18"> 180</td><td rowspan="18"> No</td><td> 01-089</td><td> 490.60 1.00</td><td> 5498.99</td><td> 5592.92</td><td> 3.92</td>

<td> 01-097</td><td> 636.45 1 1.50</td><td> 2508.31</td><td> 2676.44</td><td> 1.76</td>

<td> 01-105</td><td> 685.45 1.00</td><td> 2628.09</td><td> 3126.77</td><td> 2.73</td>

<td> 01-111*</td><td> 88.10 8.00</td><td> 1311.33</td><td> NC</td><td> NC</td>

<td> 05-088</td><td> 127.77 1.02</td><td> 520.53</td><td> 569.19</td><td> 2,03</td>

<td> 05-098</td><td> 563.94 | 1.47</td><td> 2435.38</td><td> 2644.08</td><td> 1.86</td>

<td> 05-100</td><td> 487.88 1 1.47</td><td> 4630.43</td><td> 4705.04</td><td> 3.90</td>

<td> 06-091</td><td> 592.99 3.98</td><td> 6835.79</td><td> 7310.47</td><td> 5.92</td>

<td> 06-093</td><td> 406.57 | 2.07</td><td> 2173.00</td><td> NC</td><td> 3.22</td>

<td> 07-095*</td><td> 443.70 2.00</td><td> 1911,81</td><td> NC</td><td> NC</td>

<td> 10-090</td><td> 546.65 2.00</td><td> 3808.10</td><td> NC</td><td> 5.19</td>

<td> 10-123</td><td> 797.37 i 1.50</td><td> 8928.20</td><td> 9468.70</td><td> 5.80</td>

<td> 10-127</td><td> 640.01 | 2.00</td><td> 2444.45</td><td> 2746.20</td><td> 2.30</td>

<td> 10-129</td><td> 483.07 1 2.00</td><td> 3578.09</td><td> 4340.66</td><td> 9.65</td>

<td> 23-103</td><td> 225.12 1.98</td><td> 1034,07</td><td> 1140.28</td><td> 1.90</td>

<td> 23-104</td><td> 227.51 1.97</td><td> 1086.53</td><td> NC</td><td> 2.94</td>

<td> 23-125</td><td> 237.95 1.98</td><td> 943.23</td><td> 1049.33</td><td> 2.10</td>

<td> 23-126</td><td> 224.88 | 1.98</td><td> 1243.11</td><td> NC</td><td> 2.84</td>

<td rowspan="9"></td><td rowspan="9"></td><td rowspan="9"></td><td> N</td><td> 18 I 18</td><td> 18</td><td> 12</td><td> 16</td>

<td> Mean</td><td> 439.22 2.16</td><td> 2973.31</td><td> 3780.85</td><td> 3.63</td>

<td> SD</td><td> 206.41 | 1.60</td><td> 2255.10</td><td> 2663.22</td><td> 2.12</td>

<td> cv%</td><td> 46.99 73.99</td><td> 75.84</td><td> 70.44</td><td> 58.29</td>

<td> Min</td><td> 88.10 1.00</td><td> 520.53</td><td> 569.19</td><td> 1.76</td>

<td> Median</td><td> 485.48 i 1.98</td><td> 2439.91</td><td> 2936.49</td><td> 2.89</td>

<td> Max</td><td> 797.37 8.00</td><td> 8928.20</td><td> 9468.70</td><td> 9.65</td>

<td> Geometric Mean</td><td> 379.13 1.87</td><td> 2294.38</td><td> 2881.18</td><td> 3.20</td>

<td> Geemetrie CV%</td><td> 68.19 52.19</td><td> 87.67</td><td> 100.34</td><td> 53.08</td>

<td rowspan="18"> 5</td><td rowspan="18"> 80</td><td rowspan="18"> No</td><td> 01-144</td><td> 160.18 i 2.00</td><td> 784.24</td><td> 917.99</td><td> 2.49</td>

<td> 02-133</td><td> 142.99 | 2.03</td><td> 747.42</td><td> 886.35</td><td> 2.41</td>

<td> 02-142</td><td> 222.79 1 2.00</td><td> 2480.66</td><td> 2594.62</td><td> 5.37</td>

<td> 03-112</td><td> 68.41 1.55</td><td> 416.50</td><td> NC</td><td> NC</td>

<td> 03-114</td><td> 70.46 | 1.03</td><td> 244.38</td><td> NC</td><td> NC</td>

<td> 03-120</td><td> 107.00 1.53</td><td> 450.79</td><td> 531.82</td><td> 2,67</td>

<td> 03-134</td><td> 135.30 | 1,55</td><td> 759.89</td><td> 894.79</td><td> 2.57</td>

<td> 08-092</td><td> 167.57 i 1.88</td><td> 938.26</td><td> NC</td><td> NC</td>

<td> 08-094</td><td> 199.63 1.45</td><td> 684.60</td><td> 737.33</td><td> 1.88</td>

<td> 08-109</td><td> 102.29 1 1.50</td><td> 561.56</td><td> NC</td><td> 3.12</td>

<td> 09-137</td><td> 151.89 2.25</td><td> 635.19</td><td> 767.51</td><td> 3.07</td>

<td> 20-115</td><td> 224.70 1,22</td><td> 1114.91</td><td> 1366.03</td><td> 2.72</td>

<td> 20-138</td><td> 175.94 i 4.32</td><td> 2218.17</td><td> 2334.99</td><td> 5.33</td>

<td> 20-140</td><td> 182.32 | 1.58</td><td> 659.20</td><td> 702.28</td><td> 1.78</td>

<td> 20-141</td><td> 253.29 1 1.20</td><td> 888.38</td><td> NC</td><td> 4.75</td>

<td> 22-131</td><td> 184.62 2.12</td><td> 1020.28</td><td> NC</td><td> 2.96</td>

<td> 24-116</td><td> 315.11 | 1.53</td><td> 1145.23</td><td> 1305,66</td><td> 2.53</td>

<td> 24-130</td><td> !39.94 4.03</td><td> 1325.85</td><td> 1375.38</td><td> 4.93</td>

<td></td><td></td><td></td><td> N</td><td> 18 18</td><td> 18</td><td> 12</td><td> 15</td>

<td rowspan="8"></td><td rowspan="8"></td><td rowspan="8"></td><td> Mean</td><td> 166.91</td><td> 1.93</td><td> 948.64</td><td> 1201.23</td><td> 3.24</td>

<td> SD</td><td> 62.75</td><td> 0.88</td><td> 579.45</td><td> 651.50</td><td> 1.22</td>

<td> cv%</td><td> 37.59</td><td> 45.71</td><td> 61.08</td><td> 54.24</td><td> 37.76</td>

<td> Min</td><td> 68.41</td><td> 1.03</td><td> 244.38</td><td> 531.82</td><td> 1.78</td>

<td> Median</td><td> 163.88</td><td> 1.57</td><td> 772.07</td><td> 906.39</td><td> 2.72</td>

<td> Max</td><td> 315.11</td><td> 4.32</td><td> 2480.66</td><td> 2594.62</td><td> 5.37</td>

<td> Geometric Mean</td><td> 155.27</td><td> 1.79</td><td> 816.58</td><td> 1071.37</td><td> 3.05</td>

<td> Geometric CV%</td><td> 42.27</td><td> 38.50</td><td> 60.56</td><td> 51.21</td><td> 36.76</td>

[01029] 3.Safety and Tolerability:

[01030] Dexmedetomidine sublingual film (formulations of Example 1 and 2) was well tolerated and had a favourable safety profile in the treatment of subjects with agitation. An overview of subjects who experienced at least 1 treatment emergent adverse event (TEAE) by treatment group for the safely. population is given in Tables 21 and 22. Overall, a total of 55 subjects (40.7% [55/135]) experienced a least 1 TEAE. The proportion of subjects who experienced TEAEs was similar in the 80 pg, 120 pg, and 180 pg dose groups (55.6%, 66.7%, and 66.7%, respectively). In comparison, the proportion of subjects with TEAEs was lower in the 20 pg and 60 pg dose groups (27.8% and 33.3%, respectively) and the placebo group (22.2%). Most (81.1%) of the TEAEs in all treatment groups were mild in severity. Almost all (90.9%) of the TEAEs were considered to be related to study drug in all treatment groups. None of the subjects experienced a TEAE that was considered to be severe in intensity. There were no deaths, SAEs, or discontinuations due to an AE reported in this study (Tables 21 and 22).

[01031] The TE AEs reported in this study were consistent with known common side effects of dexmedetomidine, namely, dry mouth, bradycardia, hypotension, and somnolence (Table 21). [01032] The most frequently reported TEAE was somnolence with 26 subjects experiencing the event of which 20 events were mild in severity and 4 events were moderate in severity. Incidences for somnolence in the groups were 16.7% (20 pg and 60 pg), 22.2% (120 pg), 33.3% (80 pg), and 44.4% (180 pg); incidence in the placebo group was 4.4%. The second most frequently reported TEAE was dry mouth which was reported by 5.6%, 16.7%, 16.7%, and 11.1% of subjects in the 20 pg, 80 pg, 120 pg, and 180 pg groups, respectively, compared with 13.3% of subjects in the placebo group. No subject in the 60pg dose group reported an event of dry mouth. All cases of dry mouth were mild in severity.

[01033] In the dexmedetomidine hydrochloride treatment groups, TEAEs associated with vital signs were: hypotension m 6 subjects (n==2 [120 gg], n==4 [180 gg]), orthostatic hypotension (n=l [80 gg], n==I [I20gg], and n==I [180 gg), and bradycardia (n=l [20 gg]). All subjects recovered from the events.

[01034] Three laboratory related adverse events (3x upper limit of normal for T Bill, 3+ Glucose in urine, and 4+ Protein in urine) were being followed-up at each respective clinical site and remained unresolved at this time. Otherwise there were no clinically significant changes in laboratory parameters and ECG assessments. No physical examination finding was considered clinically significant by the investigators. None of the subjects had a negative reaction (i.e. local irritation) to study drug as determined by buccal examination.

[01035] Also, the dose dependent decreases in SBP and DBP were observed with maximum changes at 2 hours post-dose:

* SBP: -4.6 (9.63), -5.6 (10.85), -8.2 (11.50), -12.1 (20.50), and -14.7 (12.09) mmHg m the 20gg, 60gg, 80gg, 120 gg, and 180 gg groups, respectively, and +1.2 (9.23) mmHg in the placebo group.

* DBP: 0.3 (10.39), -5.3 (7.86), -6.4. (8.05), -7.8 (9.40), and -6.6 (6.41) mmHg in the 20 gg, 60gg, 80gg, 120gg, and 180 gg groups, respectively, and +0.2 (7.82) mmHg in the placebo group.

* HR: -0.1 (6.24), -3.9 (9.13), -0.8 (8.39), -2.2 (13.03), and -10.7 (12.97) bpm in the 20gg, 60gg, 80gg, 120gg, and 180gg groups, respectively, and -0.8 (8.29) bpm in the placebo group.

[01036] Further, the orthostatic measurements of SBP, DBP, and HR were performed after the subject had been standing for a total of 5 minutes.

[01037] Mean changes from baseline at hours 2 postdosmg for standing SBP, DBP, and HR are provided below (FIGs.7A, 7B and 7C). These changes are similar to the changes from baseline values for resting measurements for SBP, DP, and HR (FIGs. 6A, 6B and 6C). Total of 3 subjects (1 m each dose groups 80 gg, 120 gg, and 180 gg) experienced TEAEs of orthostatic hypotension. [01038] Mean (±SD) changes from baseline at 2 hours postdosing for standing SBP, DBP, and HR were:

* SBP: -3.1 (8.34), -4.6(9.04), -12.6(12.83), -11.9 (16.43) and-15.0 (11.3) mmHg in the 20 pg, 60 pg, 80 pg, 120 pg, and 180 pg dose groups, respectively, and +0.5 (8.35) mmHg in the placebo group.

® DBP: -1.4 (6.97), -4.2 (4.78), -6.7 (8.49), -6.9 (7.86), and -7.1 (8.51) mmHg in the 20 pg, 60 pg, 80 pg, 120 pg, and 180 pg dose groups, respectively, and -1.3 (7.36) mmHg in the placebo group.

* HR: 0.6(7.92), -4.3 (11.87),-1.1 (10.47), -1.7 (13.98), and-10.4 (10.08) bpm in the 20 pg, 60 pg, 80 pg, 120 pg, and 180 pg dose groups, respectively, and 9.88) 0.3&amp;#1470;) bpm in the placebo group.

BXTI-039/01WO (332712-2151)

Table 21: Treatment Emergent Adverse Events by System Organ Class and Preferred Term During the Treatment Period(Safety Population)

<td rowspan="2"> Jr pan Class Preferred Term</td><td rowspan="2"> Placebo (N=45)</td><td colspan="5"> Dexmedetomidine sublingual film</td>

<td> 20 pg (N=18)</td><td> 60 pg (N=18)</td><td> 80 pg (N=18)</td><td> 120 pg (N=18)</td><td> 180 pg (N=18)</td>

<td> Any Arts</td><td> 10 (22.2)</td><td> 5 (27.8)</td><td> 6 (33.3)</td><td> 10 (55.6)</td><td> 12 (66.7)</td><td> 12 (66.7)</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> \en ous system disorders</td><td> 6 (13.3)</td><td> 4 (22.2)</td><td> 4 (22.2)</td><td> 8 (44.4)</td><td> 9 (50.0)</td><td> 9 (50.0)</td>

<td> Somnolence</td><td> 2 (4.4)</td><td> 3 (16.7)</td><td> 3 (16.7)</td><td> 6 (33.3)</td><td> 4 (22.2)</td><td> 8 (44.4)</td>

<td> Headache</td><td> 2 (4.4)</td><td> 1 (5.6)</td><td> 0</td><td> 1 (5.6)</td><td> 3 (16.7)</td><td> 0</td>

<td> Dizziness</td><td> 2 (4.4)</td><td> 0</td><td> 2 (11.1)</td><td> 1 (5.6)</td><td> 1 (5.6)</td><td> 0</td>

<td> Paraesthesia</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 1 (5.6)</td><td> 0</td>

<td> Hypoaesthesia</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 0</td><td> 0</td>

<td> Sedation</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td>

<td> Gastrointestinal disorders</td><td> 7 (15.6)</td><td> 2 (11.1)</td><td> 1 (5.6)</td><td> 4 (22.2)</td><td> 4 (22.2)</td><td> 2 (11.1)</td>

<td> Dry mouth</td><td> 6 (13,3)</td><td> 1 (5,6)</td><td> 0</td><td> 3 (16.7)</td><td> 3 (16.7)</td><td> 2 (11.1)</td>

<td> Constipation</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 1 (5.6)</td><td> 0</td><td> 0</td>

<td> Diarrhoea</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> A</td>

<td> Dyspepsia</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 0</td><td> 0</td><td></td>

<td> Nausea</td><td> 1 (2.2)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td></td>

<td> Toothache</td><td> 1 (2.2)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td></td>

<td> Vascular disorders</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 3 (16.7)</td><td> 5(</td>

<td> Hypotension</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(11.1)</td><td> 4(</td>

<td> Orthostatic hypotension</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 1 (5.6)</td><td> 11</td>

<td> Investigations</td><td> 3 (6.7)</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 1 (5.6)</td><td> 11</td>

<td> Alanine aminotransferase increased</td><td> 1 (2.2)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td></td>

<td> Aspartate aminotransferase increased</td><td> 1 (2.2)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td></td>

<td> Blood bilirubin increased</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 0</td><td></td>

<td> Glucose urine present</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td></td>

<td> Heart rate increased</td><td> 1 (2.2)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td></td>

WO 2021/016112,—,—,—,——.—.—,-

229408712 v3

BXTI-039/01WO (332712-2151) unction test increased &amp;#970; urine present is and infestations tis

Nasopharyngitis

Urinasy tract infection

Cardiac disorders

Bradycardia

Musculoskeletal and connective tissue disorders

Pain in extremity

<td> 1 (2.2)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td>

<td> 1 (2.2)</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 1 (5.6)</td><td> 0</td>

<td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td>

<td> 1 (2.2)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 0</td><td> 0</td>

<td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td>

<td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td>

<td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 0</td>

<td> 0</td><td> 0</td><td> 0</td><td> 1 (5.6)</td><td> 0</td><td> 0</td>

WO 2021/016112;—,—,—,—,

229408712 v3

[01040] Table 22. Summary of Adverse Events (Safety Population)

<td rowspan="2"> Category', a (%)</td><td rowspan="2"> Placebo (N~45)</td><td colspan="5"> Dose groups</td>

<td> 20 pg (V-W)</td><td> 60 pg (N~18)</td><td> 80 pg (NM8)</td><td> 120 pg (N~18)</td><td> 180 pg (N~18)</td>

<td> Any TEAE</td><td> 10 (2.2.2)</td><td> 5 (27.8)</td><td> 6 (33.3)</td><td> 10 (55.6)</td><td> 12 (66.7)</td><td> 12 (66.7)</td>

<td> Any treatment related TEAE</td><td> 10 (22.2)</td><td> 4 (22.2)</td><td> 5 (27.8)</td><td> 10 (55.6)</td><td> 10 (55.6)</td><td> 11 (61.1)</td>

<td> TEAE severity Mild Moderate Severe</td><td> 8 (17.8) 2 (4.4) 0</td><td> 5 (27.8) 0 0</td><td> 5 (27.8) 1 (5.6) 0</td><td> 9 (50.0) 1 (5.6) 0</td><td> 11 (61.1) 1 (5.6) 0</td><td> 7 (38.9) 5 (27.8) 0</td>

<td> Any SAE</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td> Any AE: leading to discontinuation</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

Abbreviations: AE == adverse events; TEAE = treatment-emergent adverse event; SAE == serious adverse event Percentages are based on the number of Safety Population subjects in each treatment arm. If a subject experienced more than one adverse event in a category, the subject is counted only once in that category.

[01041] Conclusion: Dexmedetomidine sublingual film treatment significantly improved the severity&#1523; of agitation from baseline as measured by PEC, CGI-I, and ACES scales in schizophrenia patients. The primary efficacy endpoint was met in 80 pg, 120 pg, and 180 pg treatment groups as there was significant improvements in PEC total scores from baseline at 2 hours post-dose with mean changes of -7.3, -9.2, and -10.8 points, respectively, versus 4.5&#1470; for placebo. LSM differences from placebo were -2.9 (P = 0.0210), -4.6 (P = 0.0003), and -6.3 (P <0.0001) for the 80 pg, 120 pg, and 180 pg groups, compared with placebo The proportion of responders (ie, a >40% decrease in PEC total score) at 2 hours post-dose was significantly higher in the 120 pg and 180 pg dose groups (68.8% [P = 0.0158]) and 94.4% [P < 0.0001], respectively) compared with placebo (31.0%). Further, changes in secondary&#1470;&#1523; efficacy measures (ie, CGI-I and ACES scores) at 2 hours post-dose were consistent with the results for PEC total scores and were indicative of improvement in symptoms of agitation after treatment with Dexmedetomidine sublingual film.

Example 4: A Phase Ib/II, Multicenter, Randomized, Double Blind, Placebo Controlled, Ascending Dose Finding, Efficacy, Pharmacokinetic and Safety Study of dexmedetomidine hydrochloride sublingual film in Agitation Associated with Dementia

[01042] Primary objective:

[01043] Describe the safety and tolerability of single doses of dexmedetomidine hydrochloride that are efficacious in treatment of acute agitation associated with dementia.

[01044] Secondary objective:

I. Describe the onset and magnitude of calming effects of different doses of Dexmedetomidine hydrochloride on symptoms of acute agitation associated with dementia compared to placebo.

2. Describe the duration of calming as measured by PEC and ACES.

3. Describe the tolerability and safety profile of Dexmedetomidine hydrochloride, as determined by adverse events and vital signs versus placebo.

4. Describe clinical effects as measured by the Clinician Global Impression of Severity of agitation scale (CGI-S) and then Improvement (CGI-I) after drug administration.