Bioadhesive drug formulations for oral transmucosal delivery

Description of equivalent WO 2007081948 A2

BIOADHESIVE DRUG FORMULATIONS FOR ORAL TRANSMUCOSAL DELIVERY

Cross Reference To Other Applications

[0001] This application claims the priority benefit of U.S. Provisional Application No. 60/860,569, filed Nov. 22, 2006, which claims the priority benefit of U.S. Provisional Application No. 60/818,730, filed JuI. 6, 2006, which.claims the priority benefit of U.S. Provisional Application No. 60/756,937, filed Jan. 6, 2006, the disclosures of which are incorporated herein by reference in their entirety.

Field of the Invention

[0002] The present invention relates to formulations for oral transmucosal drug delivery and methods for delivery of medications across the oral mucosa using drug dosage forms comprising such formulations. Exemplary hydrogel and eroding formulations are provided.

Background Of The Technology

[0003] Oral dosage forms account for approximately eighty percent of all the drug dosage forms on the market. Oral dosage forms are non-invasive, easily administered and have high patient compliance.

[0004] Orally administered therapeutic agents are rapidly transported to the stomach and small intestine for absorption across the gastrointestinal (Gl) mucosal membranes into the blood. The efficiency of absorption of a drug following oral administration can be low because of metabolism within the GI tract and first-pass metabolism within the liver resulting in relatively lengthy onset times or erratic absorption characteristics that are not well suited to control acute disorders. The majority of oral dosage forms on the market are designed for GI delivery. Relatively few oral dosage forms are designed for delivery through the oral mucosa.

[0005] However, oral transmucosal delivery offers a number of advantages in that it can provide a shorter onset time and more consistent time (T_maχ) to maximal plasma concentration (C_max) than oral delivery, in particular for lipophilic drugs. This is because the drug rapidly passes directly and efficiently through the relatively permeable epithelium of the highly vascularized mucosal tissue to the plasma, thus rapidly reaching the circulation while avoiding the slower, often inefficient and variable GI uptake. In addition, due to the . avoidance of the first-pass metabolism and avoidance of inefficient drug absorption though the gut, sublingual drug uptake also improves drug bioavailability. It is therefore advantageous for a drug to be delivered through the mucus membranes of the oral cavity, (e.g., via the sublingual route), when rapid onset, consistent T_max and C_max are advantageous.

[0006] In carrying out oral transmucosal drug delivery, the drug is absorbed through the epithelial membranes of the oral cavity. However, frequently the key risk associated with oral transmucosal delivery is the enhanced potential for swallowing the medication owing to the continuous generation, backward flow and swallowing of the saliva. This becomes a particular risk when the used dosage forms are large, thereby producing increased saliva response, which, in turn, leads to increased swallowing and removal of the dosage form from the oral mucosa. The present invention provides the advantage that the formulations have bioadhesive properties which facilitate adherence to the oral mucosa during administration, thus minimizing the risk of ingestion and inefficient delivery potential.

[0007] Various solid dosage forms, such as sublingual tablets, troches, lozenges, lozenges- on-a-stick, chewing gums, and buccal patches, have been used to deliver drugs via the oral mucosal tissue. Solid dosage forms such as lozenges and tablets are commonly used for oral transmucosal delivery of drugs, e.g., nitroglycerin sublingual tablets.

[0008] Relevant formulations and delivery systems for oral or buccal administration of pain medication have been previously disclosed, for example, in: U.S. Patent Nos. 2,698,822; 3,972,995; 3,870,790; 3,444,858; 3,632,743; 4,020,558; 4,229,447; 4,671,953; 4,836,737; and 5,785,989.

[0009] Relevant non-patent publications that discuss buccal and sublingual administration of drugs include: Culling et al., in the Br. J. Clin. Pharm. 17, 125-131, 1984, disclosing the sublingual administration of the glyceryl trinitrate; Osborne et al., published in the Clin. Pharmac. Ther. 47, 12-19, 1990, on buccal administration of morphine; Rosen et al., published in the Am. J. Drug Alcohol Abuse, 19, 451-464, 1993, on the sublingual administration of buprenorphine.

[0010] U.S. Patent Publication No. 20020160043 discloses compositions and methods of manufacture for dissolvable and non-dissolvable drug-containing dosage-forms for noninvasive administration of medications through mucosal tissues of the mouth, pharynx, and esophagus of a patient.

[0011] U.S. Pat. Nos. 4,671,953 and 5,785,989 (Stanley, et al.) disclose a lozenge-on-a- stick dosage form for transmucosal drug delivery. Once the appropriate amount of drug is delivered, the patient or caregiver can remove the lozenge, thus, stopping the drug delivery to prevent overdose.

[0012] U.S. Pat. No. 5,296,234 (Hadaway, et al.) discloses a stick-like holder and packaging, including a tamper resistant foil pouch, for a hardened, sucrose based matrix containing a dosage of fentanyl citrate affixed to one end of the holder and a flange to prevent swallowing of the holder when placed in a patient's mouth to medicate or pre-medicate the patient.

[0013] U.S. Patent Nos. 6,974,590, 6,764,696, 6,641,838, 6,585,997, 6,509,036, 6,391,335, 6,350,470, 6,200,604 and US Patent Publication Nos. 20050176790, 20050142197 and 20050142198 describe pharmaceutical combinations of active compounds such as fentanyl and congeners thereof in combination with an effervescent agent used as penetration enhancer to influence the permeability of the active compound across the buccal, sublingual, and gingival mucosa.

[0014] U.S. Patent No. 6,761,910 and U.S. Patent Publication No. 20040213855 disclose pharmaceutical compositions for the treatment of acute disorders by sublingual administration of an essentially water-free, ordered mixture of microparticles with at least one pharmaceutically active agent adhered to the surfaces of the carrier particles by way of a bioadhesion and/or mucoadhesion promoting agent.

[0015] U.S. Patent No. 6,759,059 discloses compositions and methods for the treatment of acute pain by sublingual administration of compositions which contain from 0.05 to 20 mg fentanyl or a pharmaceutically acceptable salt thereof in the form of microparticles which are adhered to the surface of carrier particles by way of a bioadhesion and/or mucoadhesion promoting agent, wherein each tablet is approximately 100 mg in size.

[0016] U.S. Patent Nos. 5,800,832 and U.S. Pat. No. 6,159,498 (Tapolsky, et al.), and U.S. Patent Publication Nos. 20030194420 and 20050013845 disclose a water soluble, biodegradable drug delivery device, e.g., a bi layer film disk having an adhesive layer and a backing layer, both water-soluble, which adheres to mucosal surfaces.

[0017J U.S. Patent Nos. 6, 682,716; 6,855,310; 7,070,762 and 7,070,764 and (Rabinowitz, et al.), disclose delivery of an analgesic via the inhalation route using a method which comprises: a) heating a thin layer of analgesic drug on a solid support to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles.

[0018] U.S. Patent No. 6,252,981 (Zhang et al.) discloses oral mucosal drug delivery as an alternative method of systemic drug delivery formulation and method for oral transmucosal delivery of a pharmaceutical. The invention provides a drug formulation comprising a solid pharmaceutical agent in solid solution with a dissolution agent in solid form, yielding a solid solution. The solid solution formulation may be further combined with buffers and other excipients as needed in order to facilitate the drug's manufacturing, storage, administration and delivery through oral mucosal tissue. The formulation can be used with a variety of oral transmucosal delivery dosage forms, such as a tablet, lozenge, lozenge on a stick, chewing gum, and buccal or mucosal patch. See, also Zhang et al, CHn Pharmacokinet. 2002;41(9):661-80.

[0019] Although various oral mucosal drug delivery systems have been described, there remains a need for improved formulations for use in an oral transmucosal dosage form that allows for controlled drug delivery of the dosage form, ability to manipulate and control the drug dissolution kinetics and thereby enable a number of pharmacokinetic profiles. The present invention addresses this problem.

BRIEF SUMMARY OF THE INVENTION

[0020] The present invention provides compositions and methods comprising dissolvable drug dosage forms comprising a formulation of the invention, as described in detail herein below.

[0021] The dissolvable drug dosage forms of the invention have bioadhesive characteristics and can adhere to the oral mucosa, e.g., a sublingual or buccal membrane. The formulations of the invention can be of the hydrogel-forming or eroding type. [0022] A formulation of the invention finds utility in administration of any drug with particular application to drugs that can be absorbed via the transmucosal route.

[0023] In one aspect, a dissolvable drug dosage form made using a formulation of the invention comprises from about 0.25μg to 99.9mg, from about lμg to 50mg, or from about 1 μg to lOmg of the drug.

[0024] In another aspect, the invention provides a formulation wherein the drug is an opioid selected from the group consisting of sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, and mirfentanil.

[0025] More specifically, the invention provides a formulation which comprises an opioid drug in an amount selected from the group consisting of from about 0.25 micrograms (μg) to 200 μg, from about 2.5 μg to 100 μg of sufentanil, from about 0.02 μg to 5 micrograms per kilogram (μg/kg) of sufentanil, e.g., about 10 micrograms of sufentanil, from about 10 μg to 10 mg of alfentanil, from about 2 μg to 1500 μg of fentanyl, from about 50 μg to 1500 μg of fentanyl, 200 μg to 1500 μg of fentanyl, from about 0.25 μg to 99.9 mg of lofentanil, from about 0.25 μg to 99.9 mg of carfentanil, from about 0.25 μg to 99.9 mg of carfentanil, from about 0.25 μg to 99.9 mg of remifentanil, from about 0.25 μg to 99.9 mg of trefentanil, from about 0.25 μg to 99.9 mg of mirfentanil.

[0026] A dissolvable drug dosage form comprising a formulation of the invention may be characterized by an erosion time of from 30 seconds up to a 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or longer.

[0027] The bioavailability of a drug following a single or following repeated oral transmucosal administration of a dissolvable drug dosage form comprising a formulation of the invention to a subject is greater than 70%, greater than 75%, greater than 85%, greater than 90% or greater than 94% and has a coefficient of variation of less than 30% or less than 40%.

[0028] A dissolvable drug dosage form comprising a formulation of the invention is further characterized by a C_max with a coefficient of variation of less than 30% or 40%; a T_max to about 4 hours; and a therapeutic time ratio of greater than 0.05 or from about 0.05 to about 2.0 following a single oral transmucosal administration to a subject.

[0029] The amount of drug in a dissolvable drug dosage form comprising a formulation of the invention that is absorbed via the oral transmucosal route is at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% of the total amount of drug in the dosage form.

[0030] The invention further provides dissolvable drug dosage forms comprising a formulation of the invention which have a disintegration time of from about 30 seconds to about 30 minutes.

[0031] Oral transmucosal administration of such drug dosage forms result in a time of onset (T_oπset) of from about 3 minutes to about 23, 30, 45 or 60 minutes. Oral transmucosal administration of such drug dosage forms wherein the formulation comprises sufentanil results in a time of onset (T_onset) of from about 3 minutes to about 15, 20, 25 or 30 minutes. Oral transmucosal administration of such drug dosage forms wherein the formulation comprises alfentanil results in. a time of onset (T_onse0 of from about 10 minutes to about 15, 20, 25 or 30 minutes.

[0032] Oral transmucosal administration of such drug dosage forms result in a plasma half-life of from about 20 minutes and about 180 or 240 minutes. Oral transmucosal administration of such drug dosage forms wherein the formulation comprises sufentanil results in a plasma half-life of from about 25 minutes and about 70 minutes or from about 20 to about 80, 90 or 120 minutes.

[0033] Oral transmucosal administration of such drug dosage forms wherein the formulation comprises alfentanil results in a plasma half-life of from about 30 minutes to about 50 minutes or from about^'25 to about 100, 120 or 180 minutes.

[0034] Oral transmucosal administration of such drug dosage forms results in a therapeutic time ratio of from about 0.08 to about 0.48 or from about 0.05 to about 2.0. Oral transmucosal administration of such drug dosage forms wherein the formulation comprises sufentanil results in a therapeutic time ratio of from about 0.08 to about 0.45 or from about 0.05 to about 0.5, 0.8 or 1.0. Oral transmucosal administration of such drug dosage forms wherein the formulation comprises alfentanil results in a therapeutic time ratio of from about 0.25 to about 0.4 or from about 0.1 to about 0.5, 0.8 or 1.0.

[0035] The invention further provides dissolvable drug dosage forms comprising a formulation of the invention which have a disintegration time of from about 15 minutes to about 8 hours or greater.

[00361 Oral transmucosal administration of such drug dosage forms results in a time of onset (T_onset) of from about 14 minutes to about 82 minutes or from about 10 minutes to about 100 or 120 minutes. Oral transmucosal administration of such drug dosage forms wherein the formulation comprises sufentanil results in a time of onset (T_onSeι) of from about 14 minutes to about 82 minutes or from about 10 minutes to about 100 or 120 minutes.

[0037] Oral transmucosal administration of such drug dosage forms results in a plasma half-life of from about 100 minutes to about 300, 360 or 420 minutes. Oral transmucosal administration of such drug dosage forms wherein the formulation comprises sufentanil results in a plasma half-life of from about 1 12 minutes and about 298 minutes or from about 100 to about 300, 360 or 420 minutes.

[0038] Oral transmucosal administration of such drug dosage forms results in a therapeutic time ratio time ratio of from about 0.42 to about 1.82 or from about 0.4 to about 2.0, 2.5 or 4.0. Oral transmucosal administration of such drug dosage forms wherein the formulation comprises sufentanil results in a therapeutic time ratio time ratio of from about 0.42 to about 1.82 or from about 0.4 to about 2.0, 2.5 or 4.0.

[0039] The invention further provides a method of treating a subject exhibiting a symptomatic medical condition, by administering a dissolvable drug dosage form comprising a formulation of the invention as described herein such that the drug is effective to treat the symptomatic medical condition.

BRIEF DESCRIPTION OF THE FIGURES

[0040] Figure 1 is a graphic depiction of the design of a thin-film coated hydrogel bioadhesive tablet.

[0041] Figure 2 is a graphic depiction of the in vitro dissolution kinetics of a NanoTab^® comprising formulations #46-#48. [0042] Figure 3 is a graphic depiction of the pharmacokinetics of sufentanil following sublingual administration (n=3) of a NanoTab^® comprising formulation #44, as compared to intravenous administration (n=3) in a healthy, conscious Beagle dog model. Error bars represents standard errors around the mean (SEM).

[0043] Figure 4 is a graphic depiction of the pharmacokinetics of sufentanil following sublingual instillation (n=6) of a sufentanil solution and following oral ingestion of NanoTab^® comprising formulation #44 (n=6) as compared to intravenous administration of sufentanil (n=3) in a healthy, conscious Beagle dog model. Error bars represent standard errors around the mean.

[0044] Figure 5 is a graphic depiction of the pharmacokinetics of sufentanil following sublingual administration of fast-disintegrating NanoTab^® formulation #55 (n=3) and intermediate-disintegrating NanoTab^® formulation #54 (n=3), as compared to intravenous administration (n=3) in a healthy, conscious Beagle dog model. Error bars represent standard errors around the mean.

[0045] Figure 6 is a graphic depiction of the pharmacokinetics of sufentanil following sublingual administration of slowly-disintegrating NanoTab^® formulation #58 (n=3), as compared to intravenous administration of sufentanil (n=3) in a healthy, conscious Beagle dog model. Error bars represent standard errors around the mean.

[0046] Figure 7 is a graphic depiction of the pharmacokinetics of fentanyl following sublingual administration from medium-disintegrating NanoTab^® formulations #59 (n=2) and formulation #60 (n=3), as compared to fentanyl intravenous administration (n=3) in a healthy, conscious Beagle dog model. Error bars represent standard errors around the mean.

[0047] Figure 8 is a graphic depiction of the pharmacokinetics of fentanyi following sublingual administration from slow-disintegrating NanoTab^® formulation #62 (n=3) as compared to intravenous fentanyl administration (n=3) in a healthy, conscious Beagle dog model. Error bars represent standard errors around the mean.

[0048] Figure 9 is a graphic depiction of the pharmacokinetics of alfentanil following sublingual administration from NanoTab^® formulation #63 (n=2), as compared to intravenous alfentanil administration (n=3) in a healthy, conscious Beagle dog model. Error bars represent standard errors around the mean. [0049] Figure 10 is a graphic depiction of the pharmacokinetics of sufentanil following single sublingual administration (n=12) from NanoTab^® formulations #46-48 as compared to intravenous administration (n=12) in healthy human volunteers.

DETAILED DESCRIPTION

[0050] The invention is based on formulations for oral transmucosal drug delivery that can adhere to the oral mucosa during the period of delivery such that the majority of drug is delivered across the oral mucosa.

[0051] The present invention provides novel formulations, including drug formulations which may be used to make dosage forms that are self-administered, provide a therapeutic effect and a predictable and safe pharmacokinetic profile.

[0052] Examples include formulations comprising a drug for treatment of acute, intermittent or breakthrough pain.

[0053] In one exemplary application, the present invention finds utility both in the hospital setting for use in place of intravenous (IV) opioids for treatment of acute pain and also in the outpatient setting for treatment of acute and breakthrough pain.

[0054] The following disclosure describes the formulations which constitute the invention. The invention is not limited to the specific formulations and methodology or medical conditions described herein, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.

[0055] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a drug formulation" includes a plurality of such formulations and reference to "a drug delivery device" includes systems comprising drug formulations and devices for containment, storage and delivery of such formulations.

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described.

[0057] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such a disclosure by virtue of prior invention.

Definitions

[0058] The term "formulation" or "drug formulation" or "dosage form" as used herein refers to a composition containing at least one therapeutic agent or medication for delivery to a subject. The dosage form comprises a given "formulation" or "drug formulation" and may be administered to a patient in the form of a lozenge, pill, tablet, capsule, membrane, strip, liquid, patch, film, gel, spray or other form.

[0059] The terms "drug", "medication", "pharmacologically active agent" and the like are used interchangeably herein and generally refer to any substance that alters the physiology of an animal. A dosage from comprising a formulation of the invention may be used to deliver any drug that may be administered by the oral transmucosal route. The term "drug" as used herein with reference to a formulation of the invention means any "drug", "active agent", "active", "medication" or "therapeutically active agent" that can be effectively administered by the oral transmucosal route.

[0060] The term "drug" as applied to analgesia includes sufentanil or a sufentanil congener, such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanϋ, trefentanil, or mirfentanil, as well as formulations comprising one or more therapeutic compounds. Use of "drug" or the phrase "sufentanil or a congener" is not meant to be limiting to use of, or formulations comprising, only one of these selected opioid compounds. Furthermore, reference to sufentanil alone or to a selected sufentanil congener alone, e.g., reference to "fentanyl", is understood to be only exemplary of the drugs suitable for delivery according to the methods of the invention, and is not meant to be limiting in any way.

[0061] The term "drug" may be used interchangeably herein with the term "therapeutic agent" or "medication". It will be understood that a "drug" formulation of the invention may include more than one therapeutic agent, wherein exemplary combinations of therapeutic agents include a combination of two or more opioid analogues, such as sufentanil plus an opioid such as fentanyl, alfentanil, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil, or any other drug that might be administered in combination.

[0062] The term "congener" as used herein refers to one of many variants or configurations of a common chemical structure.

[0063] The term "subject" includes any subject, generally a mammal (e.g., human, canine, feline, equine, bovine, ungulate etc.), in which treatment for a disorder, such as management of pain or anesthetization, is desired.

[0064] The term "mucosal membrane" refers generally to any of the mucus-coated biological membranes in the body. Absorption through the mucosal membranes of the oral cavity is of particular interest. Thus, buccal, sublingual, gingival and palatal absorption are specifically contemplated by the present invention. In a preferred embodiment, the penetration enhancers of the present invention are used to improve absorption through those oral tissues which most resemble the skin in their cellular structure, i.e. the gingiva and palate.

[0065] The term "transmucosal" delivery of a drug and the like is meant to encompass all forms of delivery across or through a mucosal membrane. In particular, "oral transmucosal" delivery of a drug includes delivery across any tissue of the mouth, pharynx, larynx, trachea, or upper gastrointestinal tract, particularly including the sublingual, gingival and palatal mucosal tissues.

[0066] The terms "oral dosage form", "oral transmucosal dosage form" and "dissolvable dosage form" may be used interchangeably herein and refer to a dosage form for use in practicing the present invention, which comprises a drug formulation as described herein. The oral dosage form is typically a "subungual dosage form", but in some cases other oral transmucosal routes may be employed. The invention relies upon such oral dosage forms to provide controlled delivery of drugs across the oral mucosa; by controlling the formulation design immediate, intermediate and sustained release of drugs can be achieved, as described below. The dosage form is a substantially homogeneous composition which comprises active ingredients and one or more of mucoadhesives (also referred to herein as "bioadhesives") that provide for adherence to the mucosa of the mouth of a patient, binders for binding the excipients in a single tablet, one or more hydrogel-forming excipients, one or more bulking agents, one or more lubricants, as well as other excipients and factors that affect dissolution time or drug stability. The dissolvable drug formulations of the invention are neither effervescent nor do they comprise an essentially water-free, ordered mixture of microparticles of drug adhered to the surface of carrier particles, where the carrier particles are substantially larger than the microparticles of drug. In one aspect, the present invention provides small- volume oral transmucosal drug delivery dosage forms.

[0067] The term "oral transmucosal drug delivery" as used herein refers to a dosage form wherein drug delivery occurs substantially via the transmucosal route and not via swallowing followed by GI absorption. The formulations of the current invention are designed to provide for a drug dissolution rate that allows for maximal delivery via the oral mucosa, and also provide controlled delivery rates across the oral mucosa typically via placement of the dosage form within the sublingual cavity.

[0068] As used herein, "sublingual", means literally "under the tongue" and refers to a method of administering substances via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract. Among the various transmucosal sites, the mucosa of the sublingual cavity is found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as controlled release dosage forms because it of its abundant vascularization and the near absence of Langerhans cells. Direct access to the systemic circulation through the internal jugular vein bypasses the hepatic first pass metabolism leading to high bioavailability. Further, owing to the highly vascularized nature of the sublingual mucosal membrane and the reduced number of epithelial cell layers compared to other mucosal membranes, absorption of therapeutic substances occurs rapidly, thus allowing for direct access to the systemic circulation and thus enable quick onset of action while avoiding complications of oral administration.

[0069] As used herein, the term "hydrogel-forming preparation", means a solid formulation largely devoid of water which upon contact with bodily fluids, and in particular those in the oral mucosa, is capable of absorbing water in such a way that it swells to at least 110% of the original mass or volume, while maintaining a structural matrix and forms a hydrated gel in situ. The formation of the gel follows unique disintegration (or erosion) kinetics while allowing for control of the therapeutic drug release over time, which occurs primarily by diffusion. [0070] The term "disintegration" as used herein means the physical process by which a tablet breaks down and pertains to the physical integrity of the tablet alone. This can occur in a number of different ways including breaking into smaller pieces and ultimately, fine and large particulates or, alternatively, eroding from the outside in until the tablet has disappeared.

[0071] The term "dissolution" as used herein means the process by which the active ingredient is dissolved from the tablet in the presence of a solvent, in vitro, or physiological fluids in vivo, e.g., saliva, irrespective of the mechanism of release, diffusion, erosion or combined erosion and diffusion.

[0072] The term "swelling ratio" or SR, as used herein means the mass ratio of the dosage form after full exposure to water as compared to its mass in the dry state prior to exposure. Swelling ratio (SR) can be defined based on a specified time of exposure to water and expressed as a ratio or a percentage, e.g., SR expressed as a percentage = (Mass After Exposure to Water-Initial Dry Mass)/(Initial Dry Mass) x 100.

[0073] Alternatively, such a 'swelling ratio' may be defined as the ratio of the volume of a dosage form of the invention following contact with water as compared to the volume of the same dosage form prior contact with water. Swelling ratio (SR) can be defined based on a specified time of exposure to water and expressed as a ratio or a percentage, e.g., SR expressed as a percentage = (Tablet Volume After Exposure - Tablet Volume Before Exposure)/(Tablet Volume Before Exposure) x 100. When the radial dimensions of such an experiment are well-controlled, the same swelling ratio can be defined in terms of the variable dimension, e.g. thickness, as: SR expressed as a percentage = (Tablet Thickness After Exposure - Tablet Thickness Before Exposure)/(Tablet Thickness Before Exposure) x 100.

[0074] The term "bioadhesion" as used herein refers to the process of adhesion of the dosage forms to a biological surface more in general, including mucosal membranes.

[0075] The expression "mucoadhesion" is used herein to refer to adhesion to mucosal membranes which are covered by mucus, such as those in the oral cavity and is used interchangeably herein with the term "bioadhesion" which refers to adhesion to any biological surface. [0076] The term "therapeutically effective amount" means an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect, such as pain relief. The precise desired therapeutic effect (e.g., the degree of pain relief, and source of the pain relieved, etc.) will vary according to the condition to be treated, the tolerance of the subject, the drug and/or drug formulation to be administered (e.g., the potency of the therapeutic agent (drug), the concentration of drug in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art.

[0077] "Controlled drug delivery" refers to release or administration of a drug from a given dosage form in a controlled fashion in order to achieve the desired pharmacokinetic profile in vivo. An aspect of "controlled" drug delivery is the ability to manipulate the formulation and/or dosage form in order to establish the desired kinetics of drug release.

[0078] "Sustained drug delivery" refers to release or administration of a drug from a source (e.g., a drug formulation) in a sustained fashion over a protracted yet specific period of time, which may extend from several minutes to a few hours, days, weeks or months. Specifically in this application the term "sustained" will be used to refer to delivery of consistent levels of drug over a time period ranging from a few minutes to a day, with a profile characterized by the absence of an immediate release phase, such as the one obtained from intravenous administration.

[0079] The term "T_max" as used herein means the time point of maximum observed plasma concentration.

[0080] The term "C_max" as used herein means the maximum observed plasma concentration.

[0081] The term "AUC" as used herein means "area under the curve" in a plot of concentration of drug in plasma versus time. AUC is usually given for the time interval zero to infinity, however, clearly plasma drug concentrations cannot be measured 'to infinity¹ for a patient so mathematical approaches are used to estimate the AUC from a limited number of concentration measurements. In a practical sense, the AUC (from zero to infinity) represents the total amount of drug absorbed by the body, irrespective of the rate of absorption. This is useful when trying to determine whether two formulations of the same dose release the same dose of drug to the body. The AUC of a transmucosal dosage form compared to that of the same dosage administered intravenously serves as the basis for a measurement of bioavailability.

[0082] The term "F" as used herein means "percent bioavailability" and represents the fraction of drug absorbed from the test article as compared to the same drug when administered intravenously. It is calculated from the AUC_∞ of the test article following delivery from the intended route versus the AUC₀₀ for the same drug after intravenous administration. It is calculated from the equation: F (%) = AUC₀₀ (test article)/ AUC₀₀ (intravenous route/article). This is an important term that establishes the relative fraction of the drug absorbed via the test route (or article) versus the maximum possible amount absorbed via the intravenous route.

[0083] The term "plasma W as used herein means the observed "plasma half-life" and represents the time required for the drug plasma concentration to reach the 50% of its maximal value (Cmax). This is a very useful term that allows determination of the mean duration of pharmacological effects. In addition, it allows direct and meaningful comparisons of the duration of different test articles after delivery via the same or different routes.

[0084] The term "T_onset" as used herein means the observed "time of onset" and represents the time required for the plasma drug concentration to reach 50% of the maximum observed plasma concentration, C_max.

[0085] The term "Therapeutic Time Ratio" or "TTR" represents the average time that the drug is present at therapeutic levels, defined as time within which the drug plasma concentration is maintained above 50% of C_max normalized by the drug's elimination half-life and it is calculated by the formula: TTR= (Time above 50% of C_max) / (Terminal intravenous elimination half-life of the drug). The last term is obtained from literature data for the drug of interest in the appropriate species.

[0086] As used herein, when a drug formulation is said to "adhere" to a surface, such as a mucosal membrane, it is meant that the formulation is in contact with said surface and is retained on the surface without the application of an external force. Adhesion is not meant to imply any particular degree of sticking or bonding, nor is it meant to imply any degree of permanency. [0087] The term "active agent" or "active" may be used interchangeably herein with the term "drug" and is used herein to refer to any therapeutically active agent.

[0088] The term "non-occlusive" is used herein in its broadest sense to refer to not trapping or closing the skin to the atmosphere by means of a patch device, fixed reservoir, application chamber, tape, bandage, sticking plaster, or the like which remains on the skin at the site of application for a prolonged length of time.

II. Oral Transmucosal Drug Delivery Dosage Forms

[0089] The present invention provides oral transmucosal drug delivery dosage forms, that produce a reduced saliva response when compared with other oral dosage forms, thus providing high absorption and controlled absorption rates of the pharmaceutically active substance across the oral mucosa, and reduced delivery to the gastrointestinal tract in addition to offering a more reproducible means of delivery.

[0090] The oral dosage form is typically a "sublingual dosage form", but in some cases other oral transmucosal routes may be employed. The invention relies upon such oral dosage forms for sustained delivery of drugs across the oral mucosa. The dosage form is a substantially homogeneous composition which comprises active ingredients and one or more mucoadhesives (also referred to herein as "bioadhesives") that provide for adhesion to the mucosa of the mouth of a patient, one or more binders that provide binding of the excipients in a single tablet, one or more hydrogel-forming excipients, one or more bulking agents, one or more lubricants, as well as other excipients and factors that modify and control the drug's dissolution time and kinetics or protect the active from degradation.

[0091] The dosage forms of the invention are adapted for oral transmucosal (for example sublingual) delivery of a drug and typically have an erosion time of from 30 seconds up to a time selected from 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours and 8 hours or longer.

[0092] In general, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% of the drug in a dosage form comprising a formulation of the invention is absorbed via the oral mucosa. in. Formulations of the Invention

[0093] A formulation of the invention is a substantially homogeneous composition which comprises 0.01-99% weight/weight (w/w), 0.05% to 99%, 0.01% to 50% and 0.1% to 10% w/w of the active ingredient(s) (drug, medication, etc.) and one or more of mucoadhesives (also referred to herein as "bioadhesives") that provide for adhesion to the mucosa of the mouth of a patient and may or may not further comprise one or more of the following: one or more binders that provide binding of the excipients in a single tablet; one or more hydrogel- forming excipients; one or more bulking agents; one or more lubricants; one or more glidants; one or more solubilizers; one or more surfactants; one or more flavors; one or more disintegrants; one or more buffering excipients; one or more coatings; one or more controlled release modifiers; and one or more other excipients and factors that modify and control the drug's dissolution or disintegration time and kinetics or protect the active drug from degradation.

[0094] A pharmaceutical dosage form of the invention for oral transmucosal delivery may be solid or non-solid. In one preferred embodiment, the dosage from is a solid that transforms into a hydrogel following contact with saliva.

[0095] Excipients include substances added to the formulations of the invention which are required to produce a quality product, include, but are not limited to: bulking agents, binders, surfactants, bioadhesives, lubricants, disintegrants, stabilizers, solubilizers, glidants, and additives or factors that affect dissolution or disintegration time.

[0096] Excipients are not limited to those above. Other suitable nontoxic pharmaceutically acceptable carriers for use in oral formulations can be found in Remington's Pharmaceutical Sciences, 17th Edition, 1985.

[0097] The formulations of the invention for oral transmucosal drug delivery include at least one bioadhesive (mucoadhesive) agent or a mixture of bioadhesives to promote ^• adhesion to the oral mucosa during drug delivery. In addition, the bioadhesive agents may also be effective in controlling the dosage form erosion time and/or, the drug dissolution kinetics over time when the dosage form is wetted by saliva. In addition, some of the mucoadhesives named in this invention may also serve as binders in the formulation to provide necessary bonding to the dosage form. Such mucoadhesive drug delivery systems are very beneficial, since they can prolong the residence time of the drug at the site of absorption and increase drug bioavailability. The mucoadhesive hydrogel-forming polymers are hydrophilic and swellable, containing numerous hydrogen bond-forming groups, like hydroxyl, thiol, carboxyl or amine, which favor adhesion. Upon contact with the mucosal surface they may interact with moieties on the biological interface that result in polymer/mucus interaction (adhesion) via hydrogen bonding, electrostatic, hydrophobic or van der Waals interaction. In addition, when used in a dry form, they can absorb water from the mucosal surface and swell.

[0098] Exemplary mucoadhesive or bioadhesive materials, are selected from the group consisting of natural, synthetic or biological polymers, lipids, phospholipids, and the like. Examples of natural and/or synthetic polymers include cellulosic derivatives (such as methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, etc) , natural gums (such as guar gum, xanthan gum, locust bean gum, karaya gum, veegum etc), polyacrylates (such as Carbopol, polycarbophil, etc), alginates, thiol-containing polymers, polyoxyethylenes, polyethylene glycols (PEG) of all molecular weights (preferably between 1000 and 40,000 Da, of any chemistry, linear or branched), dextrans of all molecular weights (preferably between 1000 and 40,000 Da of any source), block copolymers, such as those prepared by combinations of lactic & glycolic acid (PLA, PGA, PLGA of various viscosities, molecular weights and lactic-to-glycolic acid ratios) polyethylene glycol- polypropylene glycol block copolymers of any number and combination of repeating units (such as Pluronics, Tektronix or Genapol block copolymers), combination of the above copolymers either physically or chemically linked units (for example PEG-PLA or PEG- PLGA copolymers) mixtures. Preferably the bioadhesive material is selected from the group of polyethylene glycols, polyoxyethylenes, polyacrylic acid polymers, such as Carbopols (such as Carbopol 71G, 934P, 971P 974P) and polycarbophils (such as Noveon AA-I, Noveon CA-I, Noveon CA-2), cellulose and its derivatives and most preferably it is polyethylene glycol, Carbopol, and/or a cellulosic derivative or a combination thereof.

[0099] The mucoadhesive/bioadhesive excipient is typically present at 1-50% w/w, preferably 1-40% w/w or most preferably between 5-30% w/w. A formulation of the invention may contain one or more different bioadhesives in any combination.

[00100] The formulations of the invention for oral transmucosal drug delivery also include a binder or mixture of two or more binders which facilitate binding of the excipients into a single dosage form. Exemplary binders are selected from the group consisting of cellulosic derivatives (such as methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, etc), polyacrylates (such as Carbopol, polycarbophil, etc), Povidone (all grades), Polyox of any molecular weight or grade, irradiated or not, starch, polyvinylpyrrolidone (PVP), Avicel, and the like.

[0100] The binder is typically present at 0.5-60% w/w, preferably 1-30% w/w and most preferably 1.5-15% w/w.

[0101] In one embodiment, the formulations of the invention for oral transmucosal drug delivery also include at least one hydrogel-forming excipient. Exemplary hydrogel-forming excipients are selected from the group consisting of polyethylene glycols and other polymers having an ethylene glycol backbone, whether homopolymers or cross-linked heteropolymers, block copolymers of ethylene glycol units, such as polyoxyethylene homopolymers (such as Polyox Nl 0/MW=100,0001 Polyox-80/MW=200,000; Polyox 1105/MW=900,000; Polyox- 301/MW=4,000,000; Polyox-303/MW=7,000,000, Polyox WSR-N-60K, all of which are tradenames of Union Carbide), hydroxypropylmethylcellylose (HPMC) of all molecular weights and grades, Poloxamers (such as Lutrol F-68, Lutrol F-127, F-105 etc, all tradenames of BASF Chemicals), Genapol, polyethylene glycols (PEG, such as PEG-1500, PEG-3500, PEG-4000, PEG-6000, PEG-8000, PEG-12000, PEG-20,000, etc.), natural gums (Xanthan gum, Locust bean gum, etc) and cellulose derivatives (HC, HMC, HMPC, HPC, CP, CMC), polyacrylic acid-based polymers either as free or cross-linked and combinations thereof, biodegradable polymers such as poly lactic acids, polyglycolic acids and any combination thereof, whether a physical blend or cross-linked. In an embodiment, the hydrogel components may be cross-linked. The hydrogel-forming excipient(s) are typically present at 0.1-70% w/w, preferably 1-50% w/w or most preferably 1-30% w/w.

[0102] The formulations of the invention fbr oral transmucosal drug delivery may also include at least one controlled release modifier which is a substance that upon hydration of the dosage form will preferentially interact with the drug in a physical or molecular level and thus reduce the rate of its diffusion from the transmucosal dosage form. Such excipients may also reduce the rate of water uptake by the formulation and thus enable a more prolonged drug dissolution and release from the tablet. In one embodiment, such controlled release modifiers are capable of binding molecularly to the active via physical (and therefore reversible) interactions, thus increasing the effective molecular weight of the active and thus further modifying their permeation (diffusion) characteristics through the epithelial and basal membranes of the sublingual mucosa. Such binding is reversible in nature and does not involve any chemical modifications of the active, thus it does not affect in any way its pharmacological action. In another preferred embodiment, such controlled release modifiers upon hydration may form discrete structures that may spontaneously entrap the drug and thus further prolong its action. Exemplary controlled release modifiers are selected from the group consisting of lipids, phospholipids, sterols, surfactants, polymers and salts. In general, the selected excipient(s) are lipophilic and capable of naturally form complexes with hydrophobic or lipophilic drugs. The degree of association of the release modifier(s) and the drug can be varied by altering the modifier-to-drug ratio in the formulation. In addition, such interaction may be appropriately enhanced by the appropriate combination of the release modifier with the active drug in the manufacturing process. Alternatively, the controlled release modifier may be a charged polymer either synthetic or biopolymer bearing a net charge, either positive or negative, and which is capable of binding to the active via electrostatic interactions thus modifying both its diffusion through the tablet and/or the kinetics of its permeation through the mucosal surface. Similarly to the other compounds mentioned above, such interaction is reversible and does not involve permanent chemical bonds with the active.

[0103] A controlled release modifier may typically be present at 0-80% w/w, preferably 1- 20% w/w, most preferably 1-10% w/w.

[0104] Such controlled release modifiers may further create pockets or microdomains dispersed throughout the swollen network of the hydrogel. These pockets can serve as reservoirs for drug compounds, as they will tend to decrease the driving force for diffusion by reducing the concentration of the drug solute in the bulk of the hydrogel. The hydrogel matrix along with the controlled release modifiers may be selected and designed such that drug reiease from the microdomains occurs slowly enough to enable the sustained dissolution of the drug from the dosage form.

[0105] The formulations of the invention for oral transmucosal drug delivery also include at least one filler (bulking agent). Exemplary bulking agents are selected from the group consisting of lactose USP, Starch 1500, mannitol, sorbitol, malitol or other non-reducing sugars; microcrystalline cellulose (e.g., Avicel), dibasic calcium phosphate dehydrate, sucrose, and mixtures thereof. The filler/bulking agent is typically present at 20-95% w/w, preferably 40-80% w/w. [0106] The formulations of the invention for oral transmucosal drug delivery may also include at least one solubilizing agent(s). Such agents are beneficial to improve the solubility of the active drug and enhance its absorption characteristics, but also facilitate handling and manufacturing. Appropriate solubilizers may include cyclodextrins, pH adjusters, salts and buffers, surfactants, fatty acids, phospholipids, metals of fatty acids etc. Exemplary surfactants are selected from the group consisting of ionic (sodium lauryl sulfate, etc), non- ionic such as polysorbates (Tween and Span surfactant series, Poloxamers, etc.), bile salts (such as sodium taurocholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium glycocholate, etc), various alkyl glycosides, fatty acids, phosphatidylcholines, triglycerides, sphingolipids, glycosylated lipids, PEGylated lipids and mixtures thereof and may be present at 0.01-5% w/w. Exemplary metal salts and buffers may include at least of either organic (acetate, citrate, tartrate, etc) or inorganic (phosphate, carbonate, bicarbonate, borate, sulfate, sulfite, bisulfite, metabisulfite, chloride, etc.) salts of metals such as sodium, potassium, calcium, magnesium, etc), Further, combinations of one or more of such salts may be used to ensure adequate stabilization of the drug in the dosage form and may be present in the formulation at 0.1-20% w/w, preferably between 1-10% w/w. Exemplary pH adjusters include hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, ammonium hydroxide and the like and may be present in the formulation between 0.1-5% w/w.

[0107] The formulations of the invention for oral transmucosal drug delivery also include at least one lubricant. Lubricants have several functions including preventing the adhesion of the tablets to the compression equipment and in some cases improving the flow of the granulation prior to compression or encapsulation. Lubricants are in most cases hydrophobic materials. Exemplary lubricants are selected from the group consisting of stearic acid and divalent cations of, such as magnesium stearate, calcium stearate, etc., talc, glycerol monostearate and the like. The lubricant is typically present at 0.01-10% w/w. preferably between 0.1-3% w/w.

[0108] The formulations of the invention for oral transmucosal drug delivery may also include at least one glidant. Glidants are substances that improve the flow characteristics of the blended or granulated material from the hopper into the feeding mechanism and ultimately, in the tablet die. Exemplary glidants are selected from the group comprising colloidal silicon dioxide, precipitated silicon dioxide, fumed silica (CAB-O-SIL M-5P, trademark of Cabot Corporation), stearowet and sterotex, silicas (such as SILOID and SILOX silicas - trademarks of Grace Davison Products, Aerosil — trademark of Degussa Pharma), higher fatty acids, the metal salts thereof, hydrogenated vegetable oils and the like. The glidant is typically present at 0.01-20% w/w, preferably between 0.1-5% w/w.

[0109] The formulation may also contain flavors or sweeteners and colorants such as aspartame, mannitol, lactose, sucrose, other artificial sweeteners; ferric oxides and FD&C lakes.

[0110] The formulation may also contain additives to help stabilize the drug substance from chemical of physical degradation. Such degradation reactions may include oxidation, hydrolysis, aggregation, deamidation, etc. Appropriate excipients that can stabilize the drug substance may include anti-oxidants, anti-hydrolytic agents, aggregation-blockers etc. Antioxidants may include BHT, BHA, vitamins, citric acid, EDTA, sodium bisulfate, sodium metabisulfate, thiourea, methionine, etc. Aggregation blockers may include surfactants, amino-acids, such as arginine, glycine, histidine, methionine etc. Additional excipients that may help protect the active against degradation are salts, pH adjusters, chelating agents and buffers in the dry or solution form. A number of salts may include all those known in the art and may be found in Remington's Pharmaceutical Sciences, 17th Edition, 1985. Exemplary pH adjusters include hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, ammonium hydroxide and the like. Examples of such chelating agents include polylysine of different molecular weights, disodium edetate, sodium citrate, condensed sodium phosphate and the like. Examples of salts and buffers may include at least of either organic (acetate, citrate, tartrate, etc) or inorganic (phosphate, carbonate, bicarbonate, borate, sulfate, sulfite, bisulfite, metabisulfite, chloride, etc.) salts of metals such as sodium, potassium, calcium, magnesium, etc), Further, combinations of one or more of such salts may be used to ensure adequate stabilization of the drug in the dosage form. Stabilizing excipients may be present at 0.01-15% w/w in the formulation, preferably between 0.1-5% w/w.

[0111] The formulation may also contain surfactants to increase wetting of the tablet, especially if faster release kinetics are desired, which can result in faster initiation of mucoadhesion. Such surfactants are generally present from 0.01 to 3% weight percent of the composition. Exemplary surfactants are selected from the group consisting of ionic (sodium lauryl sulfate, etc), non-ionic such as polysorbates (Tween and Span surfactant series), bile salts (such as sodium taurocholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium glycocholate, etc), various alkyl glycosides, fatty acids, phosphatidylcholines, triglycerides, sphingolipids, glycosylated lipids, PEGylated lipids and mixtures thereof.

[0112] A dosage form of the invention may additionally comprise one or more excipients that may affect both tablet disintegration kinetics and drug release from the tablet, and thus pharmacokinetics. Such disintegrants are known to those skilled in the art and may be selected from a group consisting of starch, carboxy-methycellulose type or crosslinked Polyvinyl Pyrrolidone (such as cross-povidone, PVP-XL), alginates, cellulose-based disintegrants (such as purified cellulose, methylcellulose, crosslinked sodium carboxy methylcellulose (Ac-Di-SoI) and carboxy methyl cellulose), low substituted hydroxypropyl ethers of cellulose, microcrystalline cellulose (such as Avicel), ion exchange resins (such as Ambrelite ΪPR 88), gums (such as agar, locust bean, karaya, Pectin and tragacanth), guar gums, gum Karaya, chitin and chitosan, Smecta, gellan gum, Isapghula Husk, Polacrillin Potassium (Tulsion ³³⁹), gas-evolving disintegrants (such as citric acid and tartaric acid along with the sodium bicarbonate, sodium carbonate, potassium bicarbonate or calcium carbonate), sodium starch glycolate (such as Explotab and Primogel), starch DC and the likes. Addition of such additives facilitates the fast breakup or disintegration of the tablet into smaller pieces that erode more rapidly. An additional benefit of inclusion of such disintegrants in the formulations of the present invention, is that the smaller, drug-containing particles formed upon disintegration have, by virtue of the highly increased surface area of contact with the oral mucosa, superior bioadhesive properties. In addition, the increased surface area may further facilitate the fast release of the active substance and thus further accelerate drug absorption and attainment of the required therapeutic levels systemically. However, as described above, such disintegrants are used at a low % w/w level in the solid dosage form, typically 1 - 30 % w/w relative to the total weight of the dosage unit, preferably 5-25%w/w.

[0113J In one aspect of the invention, the dosage forms may comprise one or more biodegradable polymers of any type useful for extended drug release. Exemplary polymer compositions include polyanhydrides and co-polymers of lactic acid and glycolic acid, poly(dl-lactide-co-glycolide) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyorthoesters, proteins, and polysaccharides.

[0114] Methods of making a formulation for oral transmucosal delivery are also provided by the invention. One method includes the steps of weighing the drug and one or more of bioadhesives, binders, hydrogel forming excipients, bulking agents, lubricants or glidants and factors that affect dissolution time, possibly powder grinding, dry powder mixing and tableting via direct compression. Alternatively, a wet granulation process may be used. Such a method (such as high shear granulation process) involves mixing the active drug and possibly some excipients in a mixer. The binder may be added in the mix dry or dissolved in the fluid used for granulation. The granulating solution or suspension is added to the dry powders in the mixer and mixed until the desired characteristics are achieved. This usually produces granules of suitable characteristics for producing dosage forms with adequate dissolution time, content uniformity, and other physical characteristics. After the wet granulation step, the product is most often dried and/or then milled after drying to get a major percentage of the product within a desired size range. Sometimes, the product is dried after being wet-sized using a suitable device, such as an oscillating granulator or a mill. The dry granulation mix may then processed to get an acceptable size range by first screening with a sieving device, and then milling the oversized particles. In some instances, an appropriate glidant is added to improve the flow properties of the granules; suitable glidants, as described above.

[01151 Additionally, the formulation may be manufactured by alternative granulation processes, all known to those skilled in the art, such as spray fluid bed granulation, extrusion and spheronization or fluid bed rotor granulation.

[0116] Additionally, the bioadhesive tablet of the invention may be prepared by coating the primary tablet manufactured as described above with suitable coatings known in the art. Such coatings are meant to protect the active cores against damage (abrasion, breakage, dust formation) against influences to which the cores are exposed during transport and storage (atmospheric humidity, temperature fluctuations), and naturally these film coatings can also be colored. The sealing effect of film coats against water vapor is expressed by the water vapor permeability. Coating may be performed by one of the well known processes such as Wϋrster coating, dry coating, film coating, fluid bed coating, pan coating, etc. Typical coating materials include polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone vinyl acetate copolymer (PVPVA), polyvinyl alcohol (PVA), polyvinyl alcohol/polyethylene glycol copolymer (PV A/PEG), cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, methacrylates, methyl cellulose, hydroxyl propyl methyl cellulose (HPMC of all grades and molecular weiehts"). carraeeenan and the like. [0117] In a special embodiment, the tablet core of the present invention may be coated with a bioadhesive material, such as those defined above, to improve bioadhesion of the tablet in the sublingual cavity. In such design, an eroding or hydrogel core is designed and coated with the appropriate bioadhesive material, thus creating a design such as that shown in Figure 1. A hydrogel-type core is preferred in such applications where fast disintegration of the tablet is required. Upon contact with saliva, water penetrates the thin bioadhesive film of the coat causing swelling of the tablet's hydrogel core. As the hydrogel continues to swell, it exerts significant forces on the thin coating film resulting in its breakdown and fast erosion of the tablet. To further facilitate the process, appropriate disintegrants may be included in the core, as described above. The thickness of the outer shell will generally be 0.05-1 mg/cm².

[0118] In another special embodiment, the tablet core of the present invention may be coated with a moisture-resistant coating, such as a hydrophobic polymers, including celluloses, etc., to create a barrier for moisture ingress in the tablet core and thus further protect moisture-sensitive drugs. In addition, such water-resistant coat may improve the tablet behavior during manufacture by reducing its growth upon exposure to high %RH (relative humidity) environments, etc. A number of coating materials can be used to improve the moisture resistance of the tablet such as EUDRAGIT^® E PO, Opadry^® AMB₅ starch acetate and the like. Of particular interest in this application are coating materials that have very limited water uptake in <85% RH, yet rapidly absorb water at >85%RH. Such a function would facilitate wetting of the dosage form in the sublingual environment yet protect the dosage form under typical storage and moderate %RH conditions.

[0119] It will be understood that the formulation will be converted into a dosage form for delivery to a subject using procedures routinely employed by those of skill in the art. The process for preparation of the dosage form is optimized in order to achieve high dose content uniformity, which is particularly important for the potent compounds, which are generally present in mass ratios of 0.01-10% w/w. The formulations of the invention have a content uniformity with a % Relative Standard Deviation (%RSD) of less than 10%.

[0120] Many methods of making dosage forms for use in the invention are known in the art and may be employed in practicing the present invention, such as direct compression, wet granulation, etc. In preparing a small tablet, such as a NanoTab^®, it has been shown that erosion time and adhesion are independent of tableting force between 2-500K psi. [01211 The dosage forms of the invention are adapted to adhere to the oral mucosa during the period of drug delivery, and until most or all of the drug has been delivered from the dosage form via the oral mucosa.

[0122] The dosage form of the current invention is further designed to enable sustained and controlled disintegration of the dosage over an extended time period after application in an oral mucosal cavity in vivo. The dosage forms of this invention may be designed to erode within 30 seconds - 8 hours after administration. Further, they are designed to provide a range of disintegration rates, from linear to biphasic over the entire duration of the process.

[0123] In addition, the oral transmucosal dosage forms of this invention are designed to sustain and control the release (dissolution) of the drug from the dosage form after application in an oral mucosa in vivo or in vitro. The drug dissolution from these extended- release transmucosal dosage forms can follow first or second order dissolution kinetics which can be manipulated to achieve the optimal in vivo pharmacokinetic profile and pharmacological action.

[0124] In certain embodiments of the invention, the drug dosage form is adapted to deliver 30% or more of the total amount of drug contained in a single drug dosage form to an individual via the oral mucosa. In other embodiments the percentage of the total amount of drug contained in a single drug dosage delivered transmucosal Iy may be greater than 30-40%, 40-50%, 60-70%, 70-80%, 80-90% and preferably greater than 95%. In exemplary embodiments, at least 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%, of the total amount of drug contained in a single drug dosage form is delivered via the oral mucosa.

[0125] In certain embodiments of the invention, the drug dosage form is adapted to deliver no more than 60% of the total amount of drug contained in a single drug dosage form to an individual via the GI tract. In other embodiments the percentage delivered via the GI tract maybe lower, such that not more than 50%, 40%, 30%, 20%, 10%, 5% or 1% of the total amount of drug contained in the drug dosage form is delivered to the individual via the GI tract.

[0126] The delivery of a greater percentage (and amount) of drug via the oral mucosa and the corresponding lack of delivery via the GI tract provides a significant improvement over prior methods of drug delivery. [0127] The preferred site for drug delivery is the sublingual area, although in certain embodiments it may be advantageous for the dosage form to be placed inside the cheek, or to adhere to the roof of the mouth or the gum.

[0128] Minimizing the saliva response produces a delivery profile that is consistent and predictable from patient to patient, which is not the case with oral lozenge formulations that produce a significant saliva response. A reduced saliva response is particularly important for drugs with poor bioavailability through the GI tract.

[0129] Sublingual delivery is preferred as the sublingual mucosa is more readily permeable to medications than other mucosal areas, such as the buccal mucosa, resulting in more rapid uptake (Shojaei AH, et al.. Buccal mucosa as a route for systemic drug delivery: a review. Journal of Pharmacy and Pharmaceutical Sciences. 1:15-30, 1998).

[0130] The formulations of the invention also provide oral transmucosal dosage formulations with improved dissolution profiles over previous oral or oral transmucosal formulations, efficacious delivery of drug via the oral mucosa, and a consistent plasma level within the therapeutic window.

[0131] The decreased swallowing of drug and more consistent uptake of oral transmucosal medications made using the formulations of the present invention result in peak plasma levels that are more consistent between individual dosages as compared to those using commercially available formulations.

[0132] The dosage forms of the present invention are designed to work effectively in the unique environment of the oral cavity such that a limited amount of fluid, the relatively short period of time for drug delivery, and the pH levels within the oral cavity do not adversely affect absorption of the drug. The formulations are also designed to improve dissolution, solubility, and stability of the drug dosage form. The advantages of the present invention contribute to the ability of the drug formulation to provide higher levels of drug absorption via the oral transmucosal route and consistent dose-to-effect times, making the present formulation a significant improvement for the treatment of acute or break-through pain.

[0133] The oral transmucosal formulations of the present invention are designed to avoid the high peak plasma levels of immediate-release liquid formulations by independently controlling both tablet disintegration (or erosion) and drug dissolution and release from the tablet to enable more consistent delivery. The oral transmucosal formulations of the present invention provide individual, repetitive doses that include a defined amount of the active agent, thereby allowing the patient to accurately titrate the amount of drug delivered and to adjust the amount as appropriate in a safe and effective manner.

[0134] The advantage of the controlled-release oral transmucosal formulations described in this invention is that they can maintain the plasma drug concentration within a targeted therapeutic window for a longer duration than with immediate-release formulations, whether solid dosage forms or liquid-based dosage forms. The high peak plasma levels typically observed for such conventional immediate release formulations will be blunted by the controlled release of the drug. In addition, a rapid decline in plasma levels will be avoided since the drug will continually be crossing through the oral cavity into the systemic circulation during the entire process of tablet dissolution, thus providing plasma pharmacokinetics with a more stable plateau. In addition, the dosage forms described in this invention may improve treatment safety by minimizing the potentially deleterious side effects due to the reduction of the peaks and troughs in the plasma drug pharmacokinetics, which compromise treatment safety.

[0135] The oral transmucosal bioadhesive formulations of the present invention are typically designed to disintegrate (or totally erode) from 30 seconds up to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or longer dependent upon the patient and circumstances of drug administration as well as the intrinsic drug pharmacokinetics. It will be understood that the composition of the oral transmucosal formulations of the present invention may be adjusted to provide both a range of doses and a range of dissolution times to fit particular clinical situations.

[0136] Dissolution times for sublingual administration of the formulations of the invention will vary from 30 seconds up to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or longer.

[0137] The oral transmucosal dosage forms of invention are designed to fit comfortably under the tongue such that the drug form disintegrates sufficiently slowly to avoid the immediate peak plasma levels followed by significant drop off seen in prior art formulations such as described in US. Patent No. 6,759,059, wherein fentanyl was administered via tablets containing 400 μg of fentanyl which resulted in a peak plasma level of 2.5 ng/ml at 5 minutes post-administration, followed by an immediate drop in plasma level.

[0138] The formulations of the present invention will be provided in a number of dosage forms that vary according to the nature and amount of active ingredients while maintaining the features of the formulations of the invention for dissolution in the oral cavity such that a greater percentage of drug absorption takes place via the oral mucosal route and not the GI route.

[0139] In one aspect of the invention, when a homogeneous dosage form comprising a formulation according to the present invention is placed in the sublingual cavity, preferably under the tongue on either side of the frenulum linguae, it adheres upon contact. While not wishing to be bound by theory, it appears that when a dosage form comprising a formulation of the invention is exposed to the moisture of the sublingual space the dosage form absorbs water, resulting in the formation of a hydrogel network, comprising micro- and macro-pores (or channels). Hydration of the drug affects dissolution and subsequent diffusion through the porous network of the dosage form. However, since the process of dosage form hydration and gel formation appears to be relatively slow, drug release is also believed to be relatively slow during this early phase (phase I), thus avoiding an immediate drug 'burst' from the tablet. It is believed that when a critical hydration level is achieved, swelling resumes (phase 2) and the drug release process is accelerated. By appropriate combination of tablet excipients, the kinetics of the two phases can be modulated to achieve the suitable release profile for a particular drug candidate. Hydrogel dosage forms of the invention are characterized by swelling to at least 1 10% the initial volume upon contact with an aqueous solution.

[0140] Hydrogel formation in the dosage forms of the invention takes place in the presence of certain hydrogel-enabling excipients that have the capacity to absorb water and form gels. Such excipients include Polyox of all grades, polyethylene glycols (of all grades), PEG-based copolymers, whether homopolymers or heteropolymers (such as Poloxamer, etc), Dextran, HPMC, starch, etc, as detailed above. In addition, any combination of such excipients may favor hydrogel formation upon contact with bodily fluids. Further, combinations of such hydrogel forming excipients with excipients that do not favor gel formation (i.e., don't have such a capacity to swell), e.g., certain celluloses and the like will result in formation of hydrogel structures, albeit with modified properties. [0141] In another aspect of the invention, dosage forms referred to herein as "eroding- type" dosage forms are provided. Such "eroding-type" dosage forms, although they may absorb significant amounts of water (depending on their composition) they do not have the same capacity of swelling and consequently they do not form gels as described for the hydrogel type formulations defined above. These "eroding-type" formulations adhere to the sublingual cavity upon contact, similar to the hydrogel formulations. However, in contrast to hydrogels, they follow a surface-erosion mechanism without prior formation of a hydrated gel. As an "eroding-type" dosage form is exposed to the moisture of the sublingual space, the surface of the tablet hydrates and erodes thereby exposing the underlying layers; as the subsequent layers become hydrated they subsequently erode and so on, thus resulting in a continuous reduction in the size of the tablet.

[0142] Such eroding-type dosage forms are typically characterized by a lack of inclusion of hydrogel-forming excipients and in particular Polyox (of all grades) PEG-based copolymers, whether homopolymers or heteropolymers (such as Poloxamer, etc), HPMC, etc. However, it will be understood that the percentage w/w composition of the various components of the dosage form will impact the mechanism of erosion. For example, small amounts of particular hydrogel-enabling excipients may not induce formation of a hydrogel and as such, some hydrogel-enabling excipients may be included in eroding formulations without changing their erosion-based disintegration mechanism. It is both the combination of excipients and their percent weight composition that gives a hydrogel its capacity to swell and maintain a structural matrix upon contact with an aqueous solution. Therefore, inclusion of a hydrogel-forming excipient in a given formulation will not necessarily induce "swelling" as with the typical hydrogel formulations. Both hydrogel-forming and eroding-type formulations of the invention provide control of the drug dissolution and/or in vivo absorption kinetics to enable enhanced bioavailability and improved efficacy.

[0143] The formulations of the invention find particular utility in pediatric applications, since the comfortable and secure nature of the dosage form will allow small children to readily accept this mode of therapy and will reliably deliver drug transmucosally. Specific examples include, but are not limited to, treatment of pediatric acute pain when TV access is not available or inconvenient, treatment of pediatric asthma when the child is not able to use an inhaled route of administration effectively, treatment of nausea when a child can not or will not swallow a pill, pre-procedural sedation when a child is NPO (no oral intake allowed) or a more rapid onset is required.

[0144] The formulations of the invention find further utility in veterinary applications. Specific examples include, but are not limited to, any treatment of an acute condition for which IV administration is not readily available or inconvenient, such as pain relief, anxiety/stress relief, pre-procedural sedation, etc.

IV. Formulations Of The Invention For Suppression Or Mitigation Qf Pain.

[0145] In one exemplary application, the formulations of the invention find utility in a subject suffering from pain that may be associated with any of a variety of identifiable or unidentifiable etiologies. The formulations of the invention find utility in suppression or mitigation of pain. The term "treatment" or "management" of pain is used here to generally describe regression, suppression, or mitigation of pain so as to make the subject more comfortable, as determined for example by pain score.

[0146] The term "acute pain" is used herein with reference to pain that is typically present for less than one month, however, in some cases pain that is present for as long as three months may also be considered to be "acute".

[0147] The term "chronic pain" is used herein with reference to pain that is typically present for longer than one month.

[0148] In one exemplary aspect, the invention relates to oral transmucosal delivery of a formulation for pain-relief comprising a drug such as an opioid or opioid agonist, for the treatment of acute or break-through pain.

[0149] The active agent in such formulations may include sufentanil, or a sufentanil congener such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. One preferred embodiment utilizes sufentanil as the active agent. Another preferred embodiment utilizes fentanyl as the active agent. Other preferred embodiments utilize alfentanil, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil as the active agent. Yet another preferred embodiment utilizes a combination of sufentanil and at least one additional agent for treatment of analgesia as the active agent. [0150] In alternative embodiments, a formulation of the invention includes a combination of two or more opioid analogues, such as sufentanil plus an opioid such as fentanyl, alfentanil, trefentanil, mirfentanil or remifentanil. Various opioid drugs have different pharmacokinetic profiles and different interactions with mu opioid receptor splice variants and, therefore, may be used in combination to enhance the therapeutic effect. For example, sufentanil combined with fentanyl may have a rapid onset due to the sufentanil with a slower loss of analgesia due to the fentanyl.

[0151] In alternative embodiments, the drug dosage form of the invention may include at least one opioid drug and one or more other drugs wherein the other drug may be an opioid or non-opioid drug. The oral transmucosal drug delivery formulations are useful for delivery of any active drug compound and treatment of any condition wherein the active drug compound may be delivered via the oral mucosal route.

[0152] The formulation of the invention may contain a highly potent opioid, such as sufentanil, fentanyl or a sufentanil congener.

[0153] In one exemplary embodiment of the invention, each dosage form contains from about 0.25 to about 200 μg of sufentanil, in combination with one or more other therapeutic agents or drugs.

[0154] In yet another example of the invention, each dosage form contains from about 2 to about 1500 μg of fentanyl, in combination with one or more other therapeutic agents or drugs.

[0155] In some embodiments, the oral dosage formulations of the invention include an opioid antagonist, such as naloxone. In such embodiments, naloxone is provided in an appropriate concentration to inhibit activity of the opioid component of the formulation were it to be injected.

[0156] The invention finds utility in the treatment of both opioid naϊve patients and opioid tolerant patients.

[0157] The term "opioid naϊve patient" is used herein with reference to a patient who has not received repeated administration of an opioid substance over a period of weeks to months. [0158] The term "opioid tolerant patient" as used herein means a physiological state characterized by a decrease in the effects of an opioid substance (e.g., analgesia, nausea or sedation) with chronic administration. An opioid substance is a drug, hormone, or other chemical substance that has analgesic, sedative and/or narcotic effects similar to those containing opium or its derivatives. If analgesic tolerance develops, the dose of opioid substance is increased to result in the same level of analgesia. This tolerance may not extend to side effects and side effects may not be well tolerated as the dose is increased.

[0159] In certain embodiments, a dosage form comprising a formulation of the invention contains at least 0.001% percent by weight of the active ingredient. Preferably, the dosage form comprises from about at least 0.005% to as much as 99.9% by weight, 0.05% to 99%, 0.01% to 50%, 0.1% to 10% of the active ingredient. In certain other embodiments, a dosage form comprising a formulation of the invention contains as much as lOμg, 15μg, 25μg, 50μg, lOOμg, 500μg, lmg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or lOmg of the active ingredient or drug.

[0160] The percentage of active ingredient(s) will vary dependent upon the size of the dosage form and nature of the active ingredient(s), optimized to obtain maximal delivery via the oral mucosal route. In some aspects of the invention more than one active ingredient may be included in a single dosage form

[0161] In one exemplary embodiment, a dosage form for use in the treatment of pain may comprise from about 0.25 to about 200 μg of sufentanil, from about 2.5 to about 100 μg of sufentanil, from about 2.5 to about 40 μg of sufentanil, from about 2.5 to about 15.0 μg of sufentanil, from about 2.0 to about 1500 μg of fentanyl, from about 50 to about 1500 μg of fentanyl, or from about 200 to about 1500 μg of fentanyl.

[0162] In various embodiments, the formulation of the present invention generally provides appropriate pain relief in all types of patients including children, and adults of all ages who are opioid tolerant or naϊve. The invention finds utility in both the in-patient and out-patient setting.

[0163] The clinical use of sufentanil has predominantly been limited to IV administration in operating rooms or intensive care units. As further described herein, there have been a few studies on the use of liquid sufentanil preparations for low-dose intranasal administration and a case report of sublingual delivery of a liquid sufentanil preparation. In most of these studies, the smallest dosing of sufentanil in adults was 5 μg in opioid naϊve patients. Intranasal bioavailability was approximately 75% of that obtained by IV, however no pharmacokinetic data has been published on the sublingual use of sufentanil.

[0164] The bioadhesive transmucosal formulations of the invention contain from about 0.25 to about 200 μg of sufentanil per dosage form for oral transmucosal delivery. As will be understood by those of skill in the art, the dose will be on the low end of the range for children and the high end of the range for adults dependent upon body mass, in particular when administered long-term to opioid-tolerant adults. Small-volume oral transmucosal drug delivery dosage forms of sufentanil have not been described.

[0165] Exemplary formulations of the invention for administration to children (pediatric patients) contain from about 0.25 to about 120 μg of sufentanil per dosage form. For example, a formulation of the invention for administration to children may contain about 0.25, 0.5, 1, 2.5, 4, 5, 6, 8, 10, 15, 2O₅40, 60 or 120 μg of sufentanil for oral transmucosal delivery. It follows that for pediatric patients, an exemplary dose range is from at least about 0.02 μg/kg to about 0.5 μg/kg with a preferable range of from about 0.05 to about 0.1 μg/kg.

[0166] Exemplary formulations of the invention for administration to adults contain from about 2.5 to about 200 μg of sufentanil per dosage form. For example, a formulation of the invention for administration to adults may contain about 2.5, 3, 5, 7.5, 10, 15, 20, 40, 60, 80, 100, 120, 140, 180 or 200 μg or more of sufentanil for oral transmucosal delivery.

[0167] The dosage forms of the invention contain from about 2 to about 1500 μg of fentanyl per dosage form for oral transmucosal delivery. As will be understood by those of skill in the art, the dose will be on the low end of the range for children and the high end of the range for adults dependent upon body mass, in particular when administered long term to opioid-tolerant adults.

[016S] Exemplary dosage forms of the invention for administration to children (pediatric patients) contain from about 2 to about 900 μg of fentanyl per dosage form. For example, a dosage form of the invention for administration to children may contain about 2, 3.75, 7.5, 18.75, 30, 37.5, 45, 60, 75, 1 12.5, 150, 300, 450 or 900 μg of fentanyl for oral transmucosal delivery. [0169] Exemplary dosage forms of the invention for administration to adults contain from about 18.75 to about 1500 μg of fentanyl per dosage form. For example, a dosage form of the invention for administration to adults may contain about 18.75, 22.5, 37.5, 56, 75, 112.5, 150, 300, 450, 600, 750, 900, 1050, 1350 or 1500 μg or more of fentanyl for oral transmucosal delivery.

[0170J The dosage forms of the invention contain from about 10 to about 10000 μg of alfentanil per dosage form for oral transmucosal delivery. As will be understood by those of skill in the art, the dose will be on the low end of the range for children and the high end of the range for adults dependent upon body mass, in particular when administered long term to opioid-tolerant adults.

[0171] Exemplary dosage forms of the invention for administration of alfentanil contain from about lOμg to about 10 mg of alfentanil per dosage form. For example, a dosage form of the invention for administration may contain about 10, 25, 50, 150, 200, 300, 400, 600, 800, 1000, 2000, 3000, 5000, 7000, 9000 or 10000 μg of alfentanil for oral transmucosal delivery.

[0172] In a different exemplary embodiment, a dosage form for use in the treatment of pain may comprise from about 0.25 to about 200 μg of sufentanil in combination with from about 2 to about 1500 μg of fentanyl or from about 0.25 to about 200 μg of sufentanil or from about 2 to about 1500 μg of fentanyl in combination with one or more additional drugs.

[0173] Remifentanil, lofentanil, carfentanil, trefentanil and mirfentanil are potent fentanyl congeners which may be suitable for treatment of acute pain when delivered via a bioadhesive transmucosal formulation of this invention. The dose ranges for exemplary formulations of these congeners may include 0.25 μg to 99.9 mg for both adult and pediatric patients. These dosages may be repeated at appropriate time intervals, suitably defined for each molecule.

[0174] Alfentanil is also a potent fentanyl congener that is rapidly metabolized and may be suitable for use when delivered via a bioadhesive transmucosal formulation of this invention. Appropriate dosing of alfentanil may be in the range of 10 μg to 10 mg for both adult and pediatric patients. These dosages may be repeated at appropriate time intervals. [0175] Patients suffering from chronic painful conditions can also have intermittent exacerbations of their pain, requiring acute use of fast-acting breakthrough opioids in addition to their use of slow-onset time-release opioids for their baseline chronic pain.

[0176] Breakthrough pain or procedural pain can be intense for short periods of time, as short as 1 or 2 minutes or as long as 30 minutes or more, therefore there would be a significant advantage in providing an opioid formulation that produced more rapid clinically effective plasma levels with a more consistent and predictable period of effect.

[0177] Opioids remain the most powerful from of analgesics, however, improved forms are needed that have minimal side effects, and can be provided in a manner in which patient use can be easily tracked by the physician.

[0178] Using current treatment methods, pain control is attempted using a number of interventions, which generally include: intravenous patient-controlled analgesia (PCA), continuous epidural infusion (CEI), other types of acute pain control, palliative care pain control, and home health patient pain control. These methods meet with varying degrees of success with respect to duration of control, ease of treatment and safety versus side effects.

[0179] The need for rapid treatment of acute pain occurs in many different clinical situations, including post-operative recuperation, rheumatoid arthritis, failed back, end-stage cancer, etc. Ppst-operatively, for example, patients suffer from severe pain for the first few days followed by days of mild to moderate levels of pain.

[0180] The most common analgesic used to treat moderate to severe post-operative pain is IV morphine. This is either delivered on an "as needed" basis by a nurse to the patient by an IV injection or commonly a morphine syringe is placed in a PCA pump and the patient self- administers the opioid by pressing a button which has a lock-out feature. Other opioids, such as hydromorphone and fentanyl may also be used in this manner.

[0181] Treatment of acute pain is also necessary for patients in an outpatient setting. For example, many patients suffer from chronic pain and require the use of opioids on a weekly or daily basis to treat their pain. While they may have a long-acting oral or transdermal opioid preparations to treat their chronic underlying pain levels, they often need short-acting potent opioids to treat their severe breakthrough pain levels. [01821 Treatment of acute pain is also necessary "in the field" under highly sub-optimal conditions. Paramedics or military medics often are required to treat severe acute pain in un- sterile situations, where needles used for IV or IM administration can result in unintended needle sticks, risk of infection, etc. Oral opioid tablets often take 60 minutes to provide relief which is too long for someone in severe pain.

[0183] In a number of clinical settings, there is clearly a need for a formulation that produces effective pain relief in a manner that is titratable, may be used safely and conveniently, and provides pain relief for severe breakthrough or intermittent pain over an appropriate period of time.

V. Use of Formulations of the Invention.

[0184] Oral transmucosal drug delivery is simple, non-invasive, and can be administered by the caregiver or the patient with minimal discomfort. Generally, oral transmucosal delivery of pharmaceuticals is achieved using solid dosage forms such as lozenges or tablets, however, liquids, sprays, gels, gums, powders, and films may also be used.

[0185] For certain drugs, such as those with poor bioavailability via the GI tract, such as many lipophilic opioids, oral transmucosal (OT) delivery may provide a better delivery route than GI delivery. For drugs such as opioids, oral transmucosal delivery has shorter onset time (i.e., the time from administration to therapeutic effect) than does oral GI delivery and provides significantly improved bioavailability.

Pharmacokinetics (PK) and Formulation Attributes

[0186] The uptake of medications from the bioadhesive transmucosal formulations of the present invention results in a more consistent delivery between individual dosages and individual patients as compared to that of currently available oral transmucosal dosage forms for which a large fraction of drug uptake occurs via the Gl route.

[0187] The bioadhesive transmucosal formulations of the present invention are designed to work effectively in the unique environment of the oral cavity such that a limited amount of fluid, a relatively short period of time for drug dissolution, and pH levels within the oral cavity do not adversely affect absorption of the drug. The dosage forms are also designed to improve dissolution, solubility, and stability of the drug. The advantages of the present invention include the ability to provide higher levels of drug absorption via oral transmucosal delivery, and consistent dose-to-effect times, making the present formulation a significant improvement for the treatment of acute or break-through pain.

[0188] The oral transmucosal formulations of the present invention are designed to avoid the high peak plasma levels of intravenous dosage forms by utilizing the sublingual mucosa and by independently controlling both tablet disintegration (or erosion) and drug dissolution and release from the tablet over time to provide a safer delivery profile. The oral transmucosal formulations of the present invention provide individual, repetitive doses that include a defined amount of the active agent, thereby allowing the patient to accurately titrate the amount of drug delivered and to adjust the amount as appropriate in a safe and effective manner.

[0189] An advantage of the bioadhesive oral transmucosal formulations described in this invention is that they exhibit highly consistent bioavailability and can maintain the plasma drug concentration within a targeted therapeutic window with significantly lower variability for a longer duration than currently available dosage forms, whether solid dosage forms or IV dosage forms. The high peak plasma levels typically observed for IV dosage forms are blunted following administration of a formulation of the invention, which are characterized by controlled release of the drug. In addition, a rapid decline in plasma levels is avoided since the drug is continually crossing from the oral cavity into the bloodstream during the length of time of dissolution of the tablet or longer, thus providing plasma pharmacokinetics with an extended plateau phase as compared to the IV route of administration. Further, the dosage forms of this invention may improve treatment safety by minimizing the potentially deleterious side effects due to the relative reduction of the peaks and troughs in the plasma drug pharmacokinetics, which compromise treatment safety and is typical of currently available dosage forms.

[0190] Advantages of solid sublingual formulations of the present invention over various liquid forms for either sublingual or intranasal administration of opioids include the controlled local release of the solid dosage form and the avoidance of swallowing of drug from administration of liquid dosage forms either via the nasal or the oral route. Published pharmacokinetic data on intranasal sufentanil liquid administration (15 μg) in humans demonstrates a bioavailability of 78% (Helmers et al. Comparison of intravenous and intranasal sufentanil absorption and sedation. Canadian Journal of Anaesthesia 36:494-497, 1989). Sublingual liquid sufentanil administration (5 μg) in Beagle dogs (Example 8) resulted in a bioavailability of 40%. Both these bioavailabilities are less than the 91% average that was obtained in human volunteers using sufentanil administered sublingually in the form of a NanoTab^® formulation of the invention or greater than the 75% bioavailability obtained in the animal studies (Examples 7-12 below).

[0191] The oral transmucosal dosage forms of the invention are designed to fit comfortably under the tongue such that the drug-loaded dosage form disintegrates sufficiently slowly to avoid the immediate peak plasma levels followed by significant drop-off seen in prior art formulations such as described in US. Patent No. 6,759,059 (Rapinyl), wherein fentanyl was administered via tablets containing 400 μg of fentanyl which resulted in a peak plasma level of 2.5 ng/mL followed by an immediate drop in plasma levels. Fentora (fentanyl buccal tablets) also suffers from a lack of a plateau phase but rather has a steep incline up to the C_max followed by a significant drop-off in plasma levels (Fentora package insert).

[0192J The bioadhesive transmucosal formulations described in this invention are designed to form two specific kinds of delivery vehicles: hydrogels and eroding tablets. These follow two distinct disintegration and drug release mechanisms based on (i) diffusion from a hydrogel and (ii) erosion with diffusion from the eroding-type tablets. Using these fundamental designs the formulations of the invention can be designed to be fast-, intermediate- or slow-disintegrating. These system architectures are vastly different from effervescent-type tablets which are designed to break down rapidly by use of carbonate-type (or other) excipients. In addition, they are fundamentally different from dosage forms that are designed to disintegrate into large carrier particles that 'carry' the smaller (typically micron- sized) drug particles following 'ordered' mixing. The architecture of the transmucosal formulations of the present invention does not pose any requirements for specific particle sizes of drug or excipient particles, nor does require disintegration to the 'drug-coated' carrier particles to achieve the desired performance.

[0193] The bioadhesive transmucosal formulations of the present invention can be designed to manipulate and control the pharmacokinetic profile of the active drug. As such, the formulations can be adjusted to achieve fast disintegration and fast drug release and thus enable fast pharmacokinetic profiles that provide fast onset of action, while maintaining the other performance attributes of the tablet such as bioadhesion, reproducibility of action, blunted C_max, etc. Such fast-disintegrating tablets may be engineered to disintegrate from within 30 seconds up to 20 minutes and enable pharmacokinetic profiles that can vary accordingly with duration of action that can vary from 10 minutes to 1-2 hours. Alternatively, the formulations of the present invention can be adjusted to achieve 'intermediate' erosion times and drug release and thus enable 'intermediate' pharmacokinetic profiles that provide a more sustained action. Although such formulations may still provide a fast onset of action, they are mostly designed to enable the longer sustained effect while maintaining the other performance attributes of the tablet such as bioadhesion, reproducibility of action, blunted Cmax, etc. Such 'intermediate'-disintegrating tablets may be engineered to disintegrate from within 30 seconds up to 30 minutes and enable pharmacokinetic profiles that can vary accordingly. Finally, the formulations of the present invention can be adjusted to achieve 'slow' disintegration times (and erosion kinetic profiles) and slow drug release and thus enable very prolonged PK that provides sustained drug action. Although such formulations may be designed to still provide a fast onset, they are mostly intended to enable the sustained drug PK and effect while maintaining the other performance attributes of the tablet such as bioadhesion, reproducibility of action, blunted C_maχ, etc. Such slowly-disintegrating tablets may be engineered to disintegrate from within 15 minutes to up to 8 hours and enable pharmacokinetic profiles that can vary accordingly.

[0194] Further, the bioadhesive transmucosal dosage formulations of this invention can exhibit the aforementioned performance with a number of active drugs that may span a wide range of physicochemical properties, such as water solubility, partition coefficient, etc.

[0195] Finally, the performance and attributes of the bioadhesive transmucosal formulations of this invention are independent of the manufacturing process. A number of conventional, well-established and known in the art processes can be used to manufacture the formulations of the present invention (such as wet and dry granulation, direct compression, etc), without impacting the dosage form physicochemical properties or in vivo performance.

In vivo Pharmacokinetics - Animal studies

[0196] Selected dosage forms representing both eroding and hydrogel-type formulations were tested in a suitable animal model to evaluate the in vivo drug pharmacokinetics following sublingual administration and thus elucidate the properties of the formulations of the present invention. Comparisons of oral transmucosal drug delivery using formulations of the invention relative to liquid sublingual administration as well as swallowed NanoTabs^® were made to evaluate their performance. The results support our claim that the bioadhesive formulations of the invention are well tolerated sυblingually in dogs, result in higher bioavailability and more consistent pharmacokinetic profiles than other oral transmucosal dosage forms, including instilled liquids. Further, they demonstrate the ability of the transmucosal formulations of this invention to blunt the absorption C_max and modify the drug absorption profile to achieve fast, intermediate or prolonged absorption.

[0197] In order to demonstrate the broad applicability of the bioadhesive transmucosal dosage forms of this invention, formulations were prepared with three different opioids: sufentanil citrate, fentanyl citrate and alfentanil hydrochloride. These molecules, albeit members of the same opioid family of analgesics, span a wide range of physicochemical properties, as shown in Table 1. The ability of the formulations of the current invention to similarly manipulate the in vivo pharmacokinetics of these distinct molecules in vivo demonstrates the broad applicability of the formulations of the present invention to a wide range of molecules with distinct physicochemical characteristics.

Table 1. Phvsicochemical Properties of Selected Opioids.

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[0198] One study was carried out to compare a sublingual 5 μg sufentanil NanoTab^® formulation to IV sufentanil as described more fully in Example 7 (Table 12). A total of three Beagle dogs were studied and the results of the pharmacokinetic analysis are presented in Figure 3 and tabulated in Table 13. All tablets disintegrated in &lt;20 min following administration in dogs. The bioavailability sufentanil from the sublingual NanoTab^® formulation was 74.8±10.7 compared to IV, thus confirming the superior attributes of the formulation over other dosage forms or formulation types (effervescent, etc). The coefficient of variation for the bioavailability was low (CV=I 4.4%) compared to that of other commercial transmucosal dosage forms, indicating unexpectedly very reproducible and efficient delivery. Absorption from the sublingual NanoTab^® formulations is fast with an average T_max of approximately 12 minutes, while the onset of delivery occurs within 7 minutes from administration. However, in contrast to IV administration, the formulation blunts the absorption maximum by 2-3-fold compared to IV. In addition, the absorption half- life is extended significantly (3.3-fold over IV) indicating a more sustained absorption profile.

[0199] An important mathematical ratio that demonstrates the prolonged plateau phase of the measured blood plasma levels of sufentanil following administration of the transmucosal bioadhesive formulations is the Therapeutic Time Ratio, which is defined as the time spent above 50% of C_max normalized by the known IV terminal elimination half-life of the drug:

[0200] The Therapeutic Time Ratio of the sublingual sufentanil formulation of this example is 0.28 whereas the ratio for IV sufentanil is 0.05 (using the published IV elimination half-life of sufentanil in dogs of 139 minutes). Therefore, the transmucosal formulation (#44) resulted in a 5.6-fold increased therapeutic time ratio compared to IV sufentanil, indicating that after delivery from a sublingual bioadhesive formulation of this invention, sufentanil achieves and remains within efficacious therapeutic levels for longer time compared to IV. This example highlights some of the advantages of the sublingual sufentanil formulations of this invention, which include (i) efficient and reproducible delivery (ii) fast onset of action (iii) blunted C_max of absorption and (iv) prolonged absorption profile. These attributes suggest that the transmucosal formulations of the present invention can lead to improved drug therapeutic benefit while minimizing side effects and improving the safety of drug administration.

[0201] Another study in Beagle dogs was performed to evaluate the advantages of the sublingual formulations over liquid administration sublingually. This study is described in detail in Example 8 (Table 14). The results (presented in Table 15 and Figure 4) indicate that although sublingual delivery of sufentanil (5 μg) via instillation from a liquid dosage form results in rapid T_max, this method of drug administration results in very low absorption (F=40.0±32.5%) and very high variability of absorption (83.1% CV) compared to the sublingual sufentanil formulation of Example 7. This is probably due to partial oral absorption of the drug following partial swallowing of the instilled liquid. The C_max is also highly variable with this method of drug administration, exhibiting a high coefficient of variation of 72%. The Therapeutic Time Ratio for the instilled liquid sufentanil was calculated as 0.04±0.02, which is very similar to the IV sufentanil arm. Therefore, sublingual instillation from a liquid does not provide the advantageous therapeutic plateau observed with the sublingual formulation. These findings demonstrate that the high sublingual bioavailability observed from the bioadhesive formulations claimed in this application is not intrinsic to the molecule but rather it is a direct result of the unique design of the dosage form and its formulation. The transmucosal formulation's strong adhesion to the sublingual cavity minimizes the variability in the surface area available for absorption, as is the case of a liquid solution, thus improving delivery of the molecule to the systemic circulation. In addition, owing to its unique design and small dimensions, the NanoTab^® does not elicit significant saliva production, thus reducing the potential for ingestion of the released drug. Both factors contribute to the higher and more uniform drug absorption from the sublingual cavity.

[0202] In another part of the same study (presented in Example 9), the bioavailablity of sufentanil following swallowing of the NanoTab^® was determined in the same animal model. Since there is little to no literature data on the GI sufentanil bioavailability, it was important to evaluate the bioavailability of this route of administration to further support the observation that drug from the sublingual administration of formulations could not be swallowed and maintain a high bioavailability. As indicated by the PK analysis data in Table 15, oral absorption of sufentanil from the bioadhesive tablets results in very low drug bioavailability (F=12.2±16.3%). The low absorption leads to extremely high variability both in the amount of drug absorbed and the pharmacokinetics of absorption (C_mm T_max) as shown in Table 15 (134.2% CV). The data further demonstrate that absorption from the bioadhesive formulation of Example #7 occurred almost exclusively via sublingual rather than GI absorption in contrast to commercially available opioid transmucosal dosage forms, in which a considerable amount of the drug is delivered to the GI tract (Actiq^® — 75%; Fentora^® - 50% oral absorption). These findings support the conclusion that the bioadhesive sublingual formulations of the current invention strongly adhere in the sublingual cavity in such a manner that they don't dislodge, thus avoiding oral ingestion and avoiding the high variability of plasma levels which is typical when drug is absorbed via the GI route.

[0203] In certain embodiments, the bioadhesive transmucosal formulations of the present invention can be modified in order to manipulate and control the pharmacokinetic profile. As an example the formulations can be adjusted to achieve fast disintegration and drug release and thus enable fast pharmacokinetic profiles that enable fast onset of action, while maintaining the other performance attributes of the tablet such as bioadhesion, reproducibility of action, blunted Cn_13x, etc. Such fast-disintegrating tablets may be engineered to disintegrate from within 30 seconds up to 20 minutes and enable pharmacokinetic profiles that can vary accordingly with duration of action that can vary from 10 minutes to 1-2 hours. Alternatively, the formulations of the present invention can be adjusted to achieve 'intermediate' erosion times (and erosion kinetic profiles) and drug release and thus enable 'intermediate' pharmacokinetic profiles that provide a more sustained action. Although such formulations may still provide a fast onset of action, they are mostly designed to enable the longer sustained effect while maintaining the other performance attributes of the tablet such as bioadhesion, reproducibility of action, blunted C_max, etc. Such Mntermediate'-disintegrating tablets may be engineered to disintegrate from within 30 seconds up to 30 minutes and enable pharmacokinetic profiles that can vary accordingly. Finally, the formulations of the present invention can be adjusted to achieve 'slow' disintegration times (and erosion kinetic profiles) and slow drug release and thus enable very prolonged pharmacokinetic profiles that provide sustained drug action. Although such formulations may be designed to still provide a fast onset, they are mostly intended to enable the sustained drug PK and effect while maintaining the other performance attributes of the tablet such as bioadhesion, reproducibility of action, blunted C_max&gt; etc. Such slowly-disintegrating tablets may be engineered to disintegrate from within 15 minutes to up to 8 hours and enable pharmacokinetic profiles that can vary accordingly.

[0204] In addition, the pharmacokinetic profiles obtained from such bioadhesive sublingual formulations may vary depending on the dosage form design, geometry, compositions, etc. Examples of such PK profiles include ascending pharmacokinetics, which resemble bell-shaped curves, profiles that exhibit more than a single peak, prolonged seemingly flat PK profiles over the entire duration of action or intermediate profiles. Of particular interest are bi-phasic absorption profiles that exhibit a fast release component followed by a slow, extended release phase.

[0205] It should be noted that the bioadhesive transmucosal formulation described herein (whether the fast-, intermediate- or slow-disintegrating type) are neither effervescent nor do they disintegrate to the individual carrier particles comprising the dosage form. [0206] To demonstrate the ability of the bioadhesive transmucosal formulations of the present invention to enable such distinct pharmacokinetic profiles, a number of formulations (#54-#58) were prepared in Example 10 representing both hydrogel- and eroding-type formulations. They were prepared with sufentanil citrate and designed to provide fast, intermediate and slow release of the drug from the dosage form. The formulations, which are described in Table 16, were prepared by direct compression, as described in Example 1, except for formulation #56, which was prepared by wet granulation, as described in Example 3 and were evaluated in a healthy conscious Beagle dog model, as described in Example 10 and Table 17.

[0207] A. Sufentanil Administration from Fast- and Medium-Disintegrating Formulations (#55, 54). The analytical results are shown in Figure 5 and the results of the pharmacokinetic analysis are summarized in Table 18. Tablets of formulation #55 disintegrated in &lt;5 min following administration, while tablets of formulation #54 disintegrated in &lt;20 minutes. Formulation #54 exhibited a fast onset of action (T_onset⁼ 7.1±0.5 min) and a relatively fast T_max (as early as 10 minutes) following administration. In-spite of the fast onset of action, the formulation resulted in blunting of the C_max, albeit smaller than the longer-acting formulation of Example 7 and a somewhat prolonged action, as indicated by the longer plasma half-life (26.7±2.2 min) compared to IV. The performance of this formulation mirrors that of Example 7, in that it maintains high sufentanil bioavailability (F=90.4±25.3% compared to IV) and low coefficient of variation (CV=28%) compared to other commercial transmucosal dosage forms. Finally, the TTR was increased 3-fold compared to IV, thereby confirming the very reproducible and efficient delivery enabled by the formulations of the present invention over other dosage forms or formulation types.

[0208] Formulation #54 exhibits a similarly fast (albeit slower than Formulation #55) onset of action <img file="WO2007081948A2_D0002.tif" /> 9.2±4.3 min) and a relatively slower T_max (25.0±8.7 min), while it enables increased blunting of the C_max. In addition, it displays more prolonged action, as indicated by the longer plasma half-life (49.2±22 min) compared to IV. Still, the formulation exhibits high bioavailability (F=88.2±28.9%) of sufentanil and an enhanced therapeutic benefit as indicated by the almost 6-fold increase of the TTR (0.28±0.13) compared to IV.

[0209] B. Sufentanil Administration from Slow-Disintegrating Formulation (#58). The tablets of this formulation disintegrated slowly between 35 and 120 minutes following administration. This formulation exhibited a very slow onset of action <img file="WO2007081948A2_D0003.tif" /> 48.0±34.1 min) and sustained sufentanil pharmacokinetics even after 8 hours post-administration (plasma half-life of 205±93.1 min). The prolonged PK resulted in significant (almost 2.4-fold) blunting of the C_max compared to IV and a very pronounced increase (almost 22.6-fold) of the TTR (range of 8.8-36.4). These examples serve to illustrate the ability of the bioadhesive transmucosal formulations of the present invention to modify and control the drug release and pharmacokinetic action of the drug in vivo.

[0210] To further demonstrate the ability of the bioadhesive transmucosal formulations of the present invention to modify and control drug pharmacokinetics independent of the type of drug and its physicochemical properties, a number of formulations were prepared with two additional opioids, fentanyl and alfentanil.

[0211] As presented in Example 11, a number of formulations (#59-#62) were prepared (by direct compression) with fentanyl citrate representing both hydrogel- and eroding-type, designed to achieve intermediate and slow release of the drug. They were evaluated in a healthy conscious Beagle dog model, as described in Table 21. The results of the PK analysis are summarized in Table 22 and the analytical results are illustrated in Figures 7 and 8.

[0212] A. Fentanyl Administration from Medium-Disintegrating Formulations (#59, 60). Tablets of formulation #59 disintegrated between 20 and 50 min, similarly with those of formulation #60 which disintegrated within 20 min following administration. Both formulations exhibited a relatively fast onset of action (16.2±6.8 and 9.0±2.6 min, respectively) and blunted the blunted the C_max, albeit to a different extent each: 2.4-fold for formulation #59 and 6.7-fold for formulation #60. Further, they achieved high drug bioavailability (around 95% compared to IV) and low variability of absorption (8.4 and 10.5% for formulations #59 and #60, respectively) compared to other commercial transmucosal dosage forms. In addition, both preparations significantly prolonged the drag PK. Formulation #59 exhibited a more pronounced absorption peak and exhibited a plasma half-life of 75.5±32.5 minutes (7.5-fold prolongation over IV). In contrast, formulation #60 exhibited a more prolonged absorption profile, as shown by the 12.1-fold extension of its plasma half life (121.5±19.1 minutes). This prolongation of action was also reflected in the increased TTR which increased by 6-fold for formulation #59 to 11.5-fold for formulation #60. This data confirms that fentanyl absorption via the bioadhesive transmucosal formulations of this invention results in very reproducible and efficient delivery over other dosage forms or formulation types (effervescent, etc). [0213] B. Fentanyl Administration from Slow-Disintegrating Formulation (#62). Tablets of the slowly-disintegrating formulation #62 eroded slower that the medium- disintegrating ones; erosion was completed between 35 and 65 minutes. In contrast to the medium-disintegrating formulations, the slow formulation exhibited a delayed onset of action (43.6±20.7 min), albeit maintained a very high bioavailability (F==99.0±4.4%) and very low variability (CV=4.5%) compared to other commercial transmucosal dosage forms. This formulation provides an even more prolonged absorption of fentanyl compared to the intermediate-disintegrating formulations: the plasma half-life is extended to 154.4±52.6 minutes, representing a very prolonged drug absorption profile — a nearly 15.5-fold extension for the duration of action compared to IV. This is also reflected in the nearly 4-fold reduction of the C_max compared to IV. Finally, the Therapeutic Time Ratio is also increased compared to IV to 0.46=1=0.12, representing an 11.5-fold increase.

[0214] In addition, as shown in Example 12, a bioadhesive transmucosal formulation (#63) was prepared with alfentanil (Table 23) and was evaluated in a healthy conscious Beagle dog model, as described in Table 24. The results of the pharmacokinetic analysis are summarized in Table 25 and the PK analysis results are illustrated in Figure 9.

[0215] Disintegration of both tablets of formulation #63 occurred within 20 minutes from administration. Alfentanil administration from the bioadhesive formulation resulted in a high bioavailability of 94% compared to IV alfentanil and a coefficient of variation of 15% for the bioavailability, 7% for C_max and 28% for T_max. The onset of alfentanil absorption from this formulation was fast, occurring within 5 minutes from administration. The formulation blunted the absorption peak by almost 4-fold. Overall, the formulation enabled a sustained absorption profile of the drug, as indicated by the 8-to-10-fold increased plasma half-life (40.8 vs 4.4 minutes). The TTR was calculated to be 0.33, compared to 0.04 for the IV aifentanii arm of this study (calculated using a published IV elimination half-life of 104 min for alfentanil in dogs). Therefore, the alfentanil transmucosal formulation (as described in Example 12) produces an 8-fold improved TTR over the IV alfentanil arm. The high bioavailability of this formulation again supports the claim that minimal swallowing of drug occurs with use of a NanoTab^®.

[0216] These examples illustrate the highly efficacious delivery of a number of molecules from the bioadhesive transmucosal formulations, which enabled high drug bioavailability with low variability for all three drugs examined. The overall drug efficacy is also portrayed in the enhanced Therapeutic Time Ratio indicating that after delivery from a sublingual formulation of the present invention, the drug achieves and remains within efficacious therapeutic levels longer than intravenous administration. In addition, the above data support the claim of the transmucosal bioadhesive formulations of the present invention are capable of controlling the drug release and enable a number of modified pharmacokinetic profiles, ranging from fast, intermediate, to slow drug absorption.

In vivo Pharmacokinetics - Human Clinical Study

[0217] The pharmacokinetics of sufentanil following sublingual administration of selected bioadhesive formulations (#46, #47 and #48 described in Table 9) were evaluated in a crossover clinical study, which is described in detail in Example 13, involving healthy, naltrexone-blocked human volunteers.

[0218] The transmucosal formulations eroded over a period of 10-30 minutes in all subjects. In addition, there was only one incident of tablet dislodgment from the point of administration out of a total of 72 tablet administrations, indicating strong bioadhesion of the tablet to the sublingual cavity. Sublingual sufentanil administration from the bioadhesive formulations results in a remarkably consistent pharmacokinetic profile as illustrated in Figure 10 and summarized in Table 26. The bioavailability compared to IV (for single administration) of all three dosages averaged 91%, which is far superior to that measured for commercially available fentanyl transmucosal preparations, Actiq and Fentora (47% and 65%, respectively - Fentora package insert). Although the attainment of high bioavailability could be due to a number of factors, it can be largely attributed to the reduced (if any) swallowing of the drug owing to both (i) the strong tablet bioadhesion to the sublingual mucosa that did not allow its dislodgment and subsequent swallowing, but also (ii) the lack of increased saliva production due to the small size of the dosage form. In contrast to these findings, both commercial products of Fentora and Actiq (as stated in their package inserts) claim at least 50% and 75% of the drug dose, respectively, is swallowed via saliva ingestion, thus leading to lower bioavailability than the formulations of the present invention. This finding mirrors the results of the animal studies described in Examples 7-12, which indicate very high bioavailability for the transmucosal formulations of this invention. All studies presented in this invention support the conclusion that greater than 75% of the drug is absorbed transmucosally. Therefore, less than 25% of the drug is swallowed, which is a much lower to that reported by the aforementioned commercial products. [0219] Importantly, this high bioavailability is also linked to high reproducibility of delivery, as indicated by the low coefficients of variation for bioavailability of 24.7-34.1% for the three formulations evaluated compared to 20.1% for IV. This is much lower than that reported for Fentora (CV=45%) and Actiq (CV=41%) (Fentora package insert). Therefore the total dose delivered to the patient/subject is not only more bioavailable for the sufentanil formulations of this invention but it is more consistently the same from patient to patient. Although, as described above, this may be due to a number of factors, this is largely due to (i) the strong bioadhesion of the transmucosal dosage form in all patients, thereby reducing movement of the tablet and thereby decreasing variability of absorption and (ii) the reduced swallowing of the drug.

[0220] The sufentanil sublingual formulations are also superior in terms of consistent drug plasma levels early after administration. The C_maχ obtained with formulation #48 was 27.5 ± 7.7 pg/ml with a CV of only 28%. In contrast, the Fentora and Actiq C_max suffers from increased variability with CVs of 41-56% and 33%, respectively (Fentora package insert).

[0221] In addition to superior bioavailability and consistency in plasma concentrations, the T_max, is a very important parameter due to the requirement for quick and consistent onset of pain relief is important in the treatment of acute pain. The T_maχ for the transmucosal formulation #48 was 40.8 + 13.2 minutes (range 19.8 — 60 minutes) which is superior to the reported average T_maχ for Fentora (46.8 min with a range of 20 — 240 min) and Actiq (90.8 min, range 35 - 240 min) (Fentora package insert). Therefore the bioadhesive transmucosal formulations of this invention offer markedly improved onset and consistency in the onset of analgesia over Fentora and Actiq, with a 400% decrease in the slowest onset of T_max.

[0222] Important in the treatment of acute pain, especially acute breakthrough pain, is a consistent and relatively short half-life of the drug. The plasma elimination half-life of the 10 μg sufentanil NanoTab^® was 1.71 + 0.4 hours, which allows the drug to be titratable for various levels of pain. If the breakthrough pain event lasts longer than 1.5 hours then the patient can dose with another NanoTab^®. The half-life of Actiq and Fentora are 3.2 hours and 2.63 hours, respectively, for the lowest doses. The half-lives for the higher doses increase substantially for these drugs, thereby limiting the titratability of these drugs.

[0223] Another aspect of the PK curves generated by sublingual sufentanil formulations tested in the human studies is the plateau phase, which allows for a period of consistent plasma levels, which is important for both safety and efficacy. Compared to either IV bolus administration (see Animal Studies Examples 7-12) or the 10 minute IV infusion in the human study (Example 13), the PK profile for the sufentanil formulations is clearly safer, as they result in blunting of the C_max plasma levels. Given the ability of opioids to produce respiratory depression, avoiding these high peaks in the PK profile is advantageous.

(0224] The time spent above 50% of C_max on average for the 12 volunteers for the 2.5, 5 and 10 μg dosage strengths was 110, 111 and 106 minutes, respectively, resulting in TTRs (for all the sufentanil formulations evaluated in the clinical study) that ranged from 0.72 — 0.75. These values are well in agreement with those obtained in the animal studies with sufentanil formulations (0.14-1.13). As the transmucosal formulation is modified to enable shorter or longer disintegration times, the Therapeutic Time Ratio may be modified from approximately 0.2 — 2.0 for sufentanil in humans.

[0225] In addition, the Therapeutic Time Ratio is a measure of how successfully short- acting drugs are formulated to produce an increase in therapeutic time and increase safety by avoiding high peak plasma C_max concentrations. For example, as a comparison, the sufentanil IV arm of the human study demonstrated a Therapeutic Time Ratio of 0.067. This low ratio value for the IV arm, therefore, is a measure of the high peak produced by IV infusion of sufentanil and demonstrates that this formulation does not produce a significant plateau phase. In contrast, the bioadhesive transmucosal formulations evaluated in the clinical study demonstrated 10-fold higher Therapeutic Time Ratios versus IV, thereby supporting a prolonged therapeutic plateau profile for these formulations.

[0226] In summary, the data from both the clinical and animal studies clearly demonstrate the advantages of the bioadhesive transmucosal formulations of the present invention over intravenous delivery and delivery from commercially available product based on conventional technologies. The examples provided herein provide compelling data that demonstrate (i) efficient and reproducible delivery (ii) fast onset of action (iii) blunted C_max of absorption and (iv) prolonged absorption profile. These attributes suggest that the bioadhesive formulations of the present invention can lead to improved drug therapeutic benefit while minimizing side effects and improving the safety of drug administration. In vitro Formulation Characterization In vitro Bioadhesion Force

[0227] As illustrated in Example 5, the transmucosal formulations of the present invention can be engineered to demonstrate varying degrees of bioadhesion. In the exemplary formulations of that example, the transmucosal formulations exhibited attachment forces to the porcine mucosa substrate that varied between 0.03 to 0.18 N/cm². The determined forces of attachment correlate directly to the magnitude of the force of adhesion in vivo. It is important to note that the specific experimental conditions (such as contact time, rinsing, etc) are expected to significantly influence the recorded detachment force; for example increased contact time will lead to increased interaction and thereby increased force of adhesion. For the determinations the 2 minutes of contact time were selected to reflect the contact time of a fast-disintegrating formulation.

[0228] The results summarized in Table 11 indicate that the strength of adhesion of the selected transmucosal formulations of Example 5 varied over a 6-fold range. However, the formulations of this invention are expected to exhibit strengths of adhesion that can extend well beyond this experimentally determined range. It is anticipated that the strength of bioadhesion of the formulations presented in this invention can be modified over the range of 0.005-1.0 N/cm² (500-10⁵ dyn/cm²).

In Vitro Drug Dissolution Kinetics

[0229] Sufentanil citrate dissolution from formulations #46-#48 (Figure 2) follows diffusion-type kinetics according to Higuchi's law. This type of release is the signature of hydrogel-type systems. In addition, the data is described well by the Korsmeyer &amp; Peppas equation (Korsmeyer, R. W., Gurney, R., Doecker, E., Buri, P., Peppas, N.A., Mechanisms of solute release from hydrophilic polymers, J. Pharm. Sci. 15: 25-35, 1983), with R² values between 0.96-0.98. Fitting of the dissolution curve indicated that drug release from all three systems was independent of the amount of drug loaded and that the exponent n returned fitted values of 0.566±0.109 (0.068% w/w sufentanil citrate tablet), 0.673±0.123 (0.163% w/w sufentanil citrate tablet) and 0.446±0.116 (0.273% w/w sufentanil citrate tablet). It is noted that all values of n approach 0.5, which indicates Fickian diffusion-controlled release which is somewhat influenced by the swelling of the tablet, further corroborating the hydrogel-type release from these formulations. [0230] As also demonstrated in vivo (Examples 7-12), it is expected that the formulations of this invention can exhibit a range of dissolution profiles that may extend from a few minutes (2-4 min) to over several hours (6-8). In addition, depending on the drug physicochemical properties, the formulation composition and tablet design (such as physical dimensions, presence of coatings, number of coating layers, etc), the obtained in vitro drug dissolution profiles may exhibit a number of dissolution kinetics, such as first or second order, diffusion or erosion-controlled or following a mixed erosion-diffusion mechanism.

Swelling Ratio

[0231] The term "swelling ratio" as used herein means the mass ratio of the dosage form after full exposure to water as compared to its mass in the dry state prior to exposure. Swelling ratio (SR) can be defined based on a specified time of exposure to water and expressed as a ratio or a percentage, e.g., SR expressed as a percentage = (Mass After Exposure to Water-Initial Dry Mass)/(Initial Dry Mass) x 100.

[0232] Alternatively, such a 'swelling ratio' may be defined as the ratio of the volume of a dosage form of the invention following contact with water as compared to the same dosage form prior contact with water. Swelling ratio (SR) can be defined based on a specified time of exposure to water or water vapor and expressed as a ratio or a percentage, e.g., SR expressed as a percentage = (Tablet volume after exposure - Tablet volume before exposure)/(tablet volume before exposure) X 100. When the radial dimensions of such an experiment are well-controlled, the same swelling ratio can be defined in terms of the variable dimension, e.g. thickness, as: SR expressed as a percentage = (Tablet Thickness After Exposure - Tablet Thickness Before Exposure)/(Tablet Thickness Before Exposure) X 100.

[0233] The bioadhesive transmucosal formulations of this invention can be used to determine their swelling ratio by exposure to elevated relative humidity (such as 100% RH) over a specified period of time (such as 2 hours or longer). The tablet dimensions and weight can be determined before and after exposure to humidity to calculate the swelling ratios as described above. Dosage Form Disintegration

[0234] Dosage form erosion can be monitored by observing the disappearance over time of the sublingual dosage form by visual examination. Complete dosage form erosion may be evident by visual examination in about 30 seconds up to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours or as long as 8 hours or longer.. The oral transmucosal formulations of the present invention are typically designed to disintegrate (or totally erode) in 1 minute up to about 60 minutes, i.e., in an amount of time to achieve efficacious levels that are maintained for as long as 5, 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60 minutes 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours or longer, dependent upon the patient and circumstances of drug administration as well as the intrinsic drug pharmacokinetics. It will be understood that the composition of the oral transmucosal formulations of the present invention may be adjusted to provide for both a range of doses and a range of dissolution times to fit particular clinical situations.

EXAMPLES

[0235] The following examples are offered to illustrate, but not to limit the claimed invention. Unless noted, the total mass of all tablets made below is 5.5 mg. Further, all tablets prepared with active drug substances whether by direct compression or by wet granulation exhibited high content uniformity, as defined by the USP Pharmacopoeia with %RSD&lt;10%.

Example 1: Exemplary Eroding formulations prepared by Direct Compression

[0236] For purposes of illustration a number of exemplary eroding placebo formulations prepared by the method of direct compression are provided below in Tables 1 - 4. For each of the formulations, all excipients were weighed, ground with a mortar and pestle for 1-2 minutes manually mixed; the formulation included a small amount of a colorant (aluminum blue lake) as a surrogate for the active drug substance. 5.5-8.0 mg aliquots of the dry blend were weighed, loaded in a specially constructed load cell and were compressed in a Carver press at 5-20K psi. to form a dosage form. Exemplary formulations prepared using this methodology are provided in Tables 2-5 below as % w/w compositions of the excipients, wherein Tables 6 and 7 provide exemplary hydrogel formulations.

Table 2. Exemplary Eroding Formulations prepared by Direct Compression <img file="WO2007081948A2_D0004.tif" />

Table 3. Exemplary Eroding Formulations prepared by Direct Compression

<img file="WO2007081948A2_D0005.tif" />

Table 4. Exemplary Eroding Formulations prepared by Direct Compression

<img file="WO2007081948A2_D0006.tif" />

Table 5. Exemplary Eroding Formulations prepared by Direct Compression

<img file="WO2007081948A2_D0007.tif" />

Example 2: Exemplary Hydrogel formulations prepared by Direct Compression

[0237] For purposes of illustration a number of exemplary hydrogel placebo formulations prepared by the method of direct compression are provided below in Tables 6-7. For each of the formulations, all excipients were weighed, ground with a mortar and pestle for 1-2 minutes and manually mixed; the formulations included a small amount of a colorant (aluminum blue lake) as a surrogate for the active drug substance. 5.5-8.0 mg aliquots of the dry blend were weighed, loaded in a specially constructed load cell and were compressed in a Carver press at 5-20K psi. to form a dosage form. Exemplary formulations prepared by this methodology are provided in Tables 6-7 below as % w/w compositions of the excipients.

Table 6. Exemplary Hydrogel Formulations Prepared by Direct Compression

<img file="WO2007081948A2_D0008.tif" />

Example 3: Exemplary Eroding &amp; Hydrogel formulations prepared by Wet Granulation

[0238] For purposes of illustration a number of exemplary eroding placebo formulations prepared by the method of wet granulation are provided in Table 8. In a typical preparation, a full wet granulation was employed. In such a process, the aluminum lake dye (acting as he drug surrogate) was dissolved in the appropriate diluent (water, EtOH or hydroaicohoiic mixtures of a number of ratios) and was added either via direct pouring or by spraying onto the dry blend of the remaining excipients. The wet mix was then mixed in a high-shear mixer and processed to form granules of the desired size, in a high shear granulator (such as the KG-5). The formed granules were then dried in a tray oven and mixed. The final mix was fed to a Piccola rotary press (or a beta press) equipped with the specially designed load cell to enable the preparation of dosage forms. To achieve that approximately 5.5-8.0 mg of the dried granules were compressed at 1-20 KN. For some of the examples below additional excipients, such as the binder or the bioadhesive, were included in the solution that was poured over the dry blend of excipients.

[0239] Further, a number of different grades and particle sizes of mannitol can be employed to help optimize the granulation process. In the examples provided below, the mannitol grades were varied (Pearlitol 100SD₅ Pearlitol 200SD or Pearlitol 160C) obtain different quality granules (size, distribution, etc.)

[0240] As well-known to those skilled in the art, there is a number of process alterations that could be used in this process. In one such alteration, a partial wet granulation was employed to prepare dosage forms. In this process only a portion of the excipients was used in the formation of the granules (intra-granular mix). In such process, the remaining excipients were added extra-granularly to the granules and the mix would be blended for a few minutes in order to create a homogeneous matrix. The formulation examples given below (Table 8) also reflect partial granulation process.

Table 7. Exemplary Eroding &amp; Hydrogel Formulations Prepared By Full Wet

Granulation

<img file="WO2007081948A2_D0009.tif" /> Table 8. Exemplary Hydrogel Formulations Prepared By Partial Wet Granulation

<img file="WO2007081948A2_D0010.tif" />

Example 4: Exemplary Hydrogel Formulations Prepared With Active Substance: Sufentanil Citrate

[0241] For purposes of illustration, a number of formulations were prepared with active drug substance. The drug substance used in these examples is sufentanil citrate. The formulations, which are described in Table 9, were prepared for the sake of illustration using the same partial wet granulation methodology as described above and as detailed in the Table.

Table 9. Exemplary Hydrogel Formulations Prepared With Sufentanil Citrate

<img file="WO2007081948A2_D0011.tif" />

In vitro Evaluations of Transmucosal Formulations

[0242] A number of placebo formulations of both eroding and hydrogel-type were prepared using direct compression and/or wet granulation and their properties were evaluated in vitro for bioadhesion and in vitro drug dissolution kinetics using the procedures outlined above.

Table 10. Exemplary Placebo Formulations for Evaluations In Vitro .

<img file="WO2007081948A2_D0012.tif" /> Example 5: In Vitro Evaluation Of Bioadhesion

[0243] The mucoadhesive strength was determined by attaching the tablets to the bottom of a hanging platform and determining the force required to detach the formulations from a porcine buccal mucosa substrate. The mucoadhesive testing system is consisting of a precision load cell (GS-500 Tranducer techniques, Temecula, CA) and a hook attachment. The load cell generates analogue signals, which are converted into digital signals through a data acquisition system equipped with an A/D converter and a computer; data are analyzed using EasyLx software (Keithley Metrabyte). A hanging platform comprising a glass slide attached with plastic plunger (8 cm) on the top and a circular-steel projection (0.5cm) with flat surface on the bottom is attached to the load cell. A flat-surfaced tablet die serves as a lower static-platform. The mucosal tissue is mounted onto the lower platform using a screw- clamp. The hanging platform with the film is brought down and placed over the surface of the mucosa with a known applied force for a specified time. The detachment force in N/cm² is determined and compared. Between each measurement, the mucosal surface is rinsed with 4 mL of purified water. The excess water is wiped with a soft tissue paper and the mucosa is wetted with a known volume of phosphate buffer pH 6.8. Studies are performed in triplicate at room temperature (23-25 ⁰C). Adhesion and peak detachment force can be used to evaluate the bioadhesive strength of dosage forms comprising various formulations of the invention. A dosage form of the invention expresses bioadhesion forces greater than 100 dynes/cm², eg 500 dynes/cm².

[0244] The bioadhesive strength of the placebo formulations was evaluated and the results are given in Table 11.

Table 11. Bioadhesion force of lacebo Formulations.

<img file="WO2007081948A2_D0013.tif" /> Example 6: Evaluation Of Sufentanil Dissolution In Vitro from Formulations.

[0245] Sufentanil dissolution kinetics from formulations #46, #47 and #48 was determined in a Type II USP dissolution apparatus suitably modified to accommodate a small volume NanoTab^® containing a small amount of sufentanil. Drug release from the bioadhesive transrhucosal formulations were monitored by LC/MS. The dissolution medium was defined as phosphate buffer pH between 6.5-7.8. A dosage form of the invention has a dissolution time that typically occurs in up to about 60 minutes, however, in some cases dissolution is evident after up to about 120 minutes or 240 minutes. The results are shown in Figure 2.

Example 7: Bioavailability and Pharmacokinetics of Sufentanil following Sublingual Administration of Formulations in a Healthy Dog Model.

[0246] The bioavailability of sufentanil following sublingual administration from formulation #44 as compared to intravenous was evaluated in a healthy, conscious Beagle dog animal model, as described in Table 12. Intravenous administrations were performed by single administration (n=3) of Sufenta^® 50 μg/mL by bolus injection to the cephalic vein via a sterile needle and syringe of appropriate size at a dose of 5 μg of sufentanil base). For the sublingual administrations (Group 2) the test article (Formulation #44 strength of 5 μg of sufentanil base) was administered sublingually (n=3) by placement under the tongue, adjacent to the frenulum via forceps. Blood samples were collected from a jugular or other suitable vein prior to dosing and approximately 1, 3, 5, 10, 15, 30 min, I₃ 2, 4, 8 and 24 hours post- dose. Approximately 2 mL of blood were collected per timepoint into pre-chilled tubes containing K2 EDTA. The samples were centrifuged at 3,000g for approximately 10 minutes in a refrigerated centrifuge. Plasma was collected and frozen within 20 minutes of centrifugation at approximately -70⁰C and was maintained at that temperature until analysis. Sample analysis was performed using a validated LC/MS/MS method for analysis of sufentanil in dog plasma.

Table 12. Dosing Parameters for Administration of Sufentanil (i) by sublingual administration from Sublingual Bioadhesive Formulation #44 and (ii) by an intravenous solution.

<img file="WO2007081948A2_D0014.tif" /> a = Expressed as a free base. b = Same animals will be used for Groups 1 through 3 with a minimum 2-day washout period between dosing.

[0247] The plasma PK profiles are shown in Figure 3. PK analysis results are summarized in Table 13.

Table 13. PK Analysis of Sufentanil sublingual formulation (#44) compared to intravenous sufentanil.

<img file="WO2007081948A2_D0015.tif" />

Time to reach 50% of C_max

Represents the relative time that the drug achieves therapeutic levels (above 50% C_mβx), defined as time within which the drug plasma concentration is maintained above 50% of C_max normalized by the drug's elimination half-life intravenously and it is calculated by the formula: TTR= (Time above 50% of C_max) / (Terminal intravenous elimination half-life of the drug). The denominator is obtained from literature studies of sufentanil to be 139 min in beagle dogs.

Example 8: Bioavailability and Pharmacokinetics of Sufentanil following Sublingual Solution Instillation in a Healthy Dog Model

[0248] For purposes of comparison to the sufentanil dosage forms, the bioavailability and pharmacokinetics of sufentanil citrate after sublingual administration via instillation of a sufentanil solution (n=6) was evaluated and compared to IV (n=6). The bioavailability of sufentanil following sublingual administration from a solution as compared to that intravenously was evaluated in a healthy, conscious Beagle dog animal model, as described in Table 14. In both arms of the study the commercially available formulation of sufentanil citrate (Sufenta^® 50 μg/mL) was used and was dosed at the same total dose of 5 μg of sufentanil base. Intravenous administrations were performed by single administration (n=3) of Sufenta^® 50 μg/mL by bolus injection to the cephalic vein via a sterile needle and syringe of appropriate size. Doses were slowly applied under the tongue, adjacent to the frenulum via a sterile syringe. Blood sampling and storage mirrored the conditions described in Example #7; sample analysis was performed using a validated LC/MS/MS method for analysis of sufentanil in dog plasma.

Table 14. Dosing Parameters for Administration of Sufentanil (i) by sublingual administration via instillation of a sufentanil solution, (ii) by oral ingestion of a NanoTab^® formulation and (ii) by an intravenous solution.

<img file="WO2007081948A2_D0016.tif" /> a = Expressed as a free base. b = Group 2 &amp; 3 animals were dosed twice with a minimum 2-day washout period for a total of n=6 c = Normal saline was used to dilute the test article (Sufenta^® 50 μg/mL) to the desired concentration.

[0249] The analytical results are shown in Figure 4. PK analysis results are summarized in Table 15.

Table 15. PK Analysis of intravenously administered sufentanil compared to (i) a sublingually instilled solution and (ii) an ingested NanoTab®

<img file="WO2007081948A2_D0017.tif" />

Time to reach 50% of C_raα

² Represents the relative time that the drug achieves therapeutic levels (above 50% C_max), defined as time within which the drug plasma concentration is maintained above 50% of C_max normalized by the drug's elimination half-life intravenously and it is calculated by the formula: TTR= (Time above 50% of C_max) / (Terminal intravenous elimination half-life of the drug). The denominator is obtained from literature studies of sufentanil to be 139 min in beagle dogs.

Example 9: Evaluation of the Bioavailability and Pharmacokinetics of Sufentanil following Oral Ingestion of a Sufentanil Transmucosal Formulation.

[0250] The bioavailability of sufentanil following ingestion of a bioadhesive tablet described in this invention (formulation #44) as compared to that intravenously was evaluated in a healthy, conscious Beagle dog animal model, as described in the previous example. A single bioadhesive formulation prepared at a total strength of 5.0 μg of sufentanil (base units) was administered twice orally, with each dose separated by a minimum of a 2-day washout for a total of n=6 (Table 14). The bioadhesive tablets were placed manually as far back as possible in the throat and flushed with water to promote the swallow response in the animal.

Example 10: Exemplary Sufentanil Formulations to Control Drug Release and In Vivo Pharmacokinetics.

[0251] For purposes of illustration, a number of formulations were prepared with sufentanil citrate in order to evaluate the rate of drug release and in vivo pharmacokinetics of various dosage forms. Both eroding and hydrogel-based formulations, as described in Table 16, were prepared by direct compression, as described in Example 1, except for formulation #56, which was prepared by wet granulation, as described in Example 3.

<img file="WO2007081948A2_D0018.tif" /> [0252] The pharmacokinetics of sufentanil following sublingual administration of formulations #54-58 were evaluated in a healthy, conscious Beagle dog animal model, as described in Table 17. Intravenous administrations were performed by single administration (n=3) of Sufenta^® 50 μg/mL (total dose of 5 μg of sufentanil base) by bolus injection to the cephalic vein via a sterile needle and syringe of appropriate size. For the sublingual administrations the test articles (n=2 or 3) were placed under the tongue, adjacent to the frenulum via forceps. Blood sampling and storage mirrored the conditions described in Example #7; sample analysis was performed using a validated LC/MS/MS method for analysis of sufentanil in dog plasma.

Table 17. Dosing Parameters for Administration of Sufentanil (i) via sublingual administration of fast (#55), intermediate (#54) and slow (#58) formulations and (ii) by an intravenous solution.

<img file="WO2007081948A2_D0019.tif" />

Expressed as a free base.

[0253] The results are shown in Figures 5 and 6. PK results are summarized in Tables 18 and 19.

Table 18. PK Analysis sublingual fast- and intermediate-disintegrating Sufentanil formulations compared to intravenously administered Sufenta^®.

<img file="WO2007081948A2_D0020.tif" />

Time to reach 50% of C_mnx Represents the relative time that the drug achieves therapeutic levels (above 50% C_mBX), defined as time within which the drug plasma concentration is maintained above 50% of C_mnx normalized by the drug's elimination half-life intravenously and it is calculated by the formula: TTR= (Time above 50% of C_msx) / (Terminal intravenous elimination half-life of the drug). The denominator is obtained from literature studies of sufentanil to be 139 min in beagle dogs.

Table 19. PK Analysis sublingual slow-disintegrating Sufentanil formulations compared to intravenously administered Sufenta^®.

<img file="WO2007081948A2_D0021.tif" />

Time to reach 50% of C_max

² Represents the relative time that the drug achieves therapeutic levels (above 50% C_1110x), defined as time within which the drug plasma concentration is maintained above 50% of C_maϊc normalized by the drug's elimination half-life intravenously and it is calculated by the formula: TTR= (Time above 50% of C_mαx) / (Terminal intravenous elimination half-life of the drug). The denominator is obtained from literature studies of sufentanil to be 139 min in beagle dogs.

Example 11. In vivo Evaluation of Sublingual Fentanyl Formulations in a Dog Model.

[0254] For purposes of illustration, a number of transmucosal formulations were prepared with fentanyl citrate in order to evaluate the rate of drug release and in vivo pharmacokinetics of various dosage forms. Both eroding and hydrogel-based formulations, as described in Table 20, were evaluated; all dosage forms were prepared by direct compression, as described in Example 1.

Table 20. Exemplary Fentanyl Formulations for Evaluation Tn Vivo.

<img file="WO2007081948A2_D0022.tif" />

[0255] The pharmacokinetics of fentanyl following sublingual administration from a number of formulations intended to provide distinct PK profiles as compared to that intravenously was evaluated in a healthy, conscious Beagle dog animal model, as described in Table 21. The commercially available formulation of fentanyl citrate (Sublimaze^® 50 μg/mL) was used and was dosed at the same total dose of 70 μg of fentanyl base. Intravenous administrations were performed by single administration (n=3) of Sublimaze^® 50 μg/mL by bolus injection to the cephalic vein via a sterile needle and syringe of appropriate size. Both hydrogel and eroding formulations were developed to provide intermediate and slow release of the drug from the dosage form. For the sublingual administrations the test articles were administered sublingually (n=2 or 3) by placement under the tongue, adjacent to the frenulum via forceps. Blood sampling and storage mirrored the conditions described in Example 7; sample analysis was performed using a validated LC/MS/MS method for analysis of fentanyl in dog plasma.

Table 21. Dosing Parameters for Administration of Fentanyl (i) via sublingual administration of intermediate (#59, 60) and slow-acting (#62) formulations and (ii) by an intravenous solution.

<img file="WO2007081948A2_D0023.tif" />

[0256] The results are shown in Figures 7 and 8. Pharmacokinetic analysis results are summarized in Table 22.

Table 22. PK Analysis of sublingually administered Fentanyl formulations as compared to intravenous Sublimaze®.

<img file="WO2007081948A2_D0024.tif" />

Represents the relative time that the drug achieves therapeutic levels (above 50% C_max), defined as time within which the drug plasma concentration is maintained above 50% of C_WBX normalized by the drug's elimination half-life intravenously and it is calculated by the formula: TTR= (Time above 50% of C_mox) / (Terminal intravenous elimination half-life of the drug). The denominator is obtained from literature intravenous studies of fentanyl to be 244 min in beagle dogs. [0257] The pharmacokinetics of sublingual fentanyl from medium-disintegrating NanoTabs^® are illustrated in Figure 7. The pharmacokinetics of sublingual fentanyl from slow-disintegrating NanoTabs^® are illustrated in Figure 8.

Example 12: In vivo Evaluation of Sublingual Alfentanil HCl Formulations in a Dog Model.

[0258] For purposes of illustration, an eroding dosage form was prepared with alfentanil HCl in order to demonstrate the ability of the dosage forms described in this application to modulate and control the rate of drug release and ultimately in vivo pharmacokinetics. The formulation composition is described in Table 23; all tablets were prepared by direct compression, as described in Example 1.

Table 23. Exemplary Alfentanil Formulations for Evaluation of In Vivo Drug

Pharmacokinetics.

<img file="WO2007081948A2_D0025.tif" />

[0259] The bioavailability and pharmacokinetics of alfentanil foiiowing sublingual administration from a formulation as compared to that intravenously was evaluated in a healthy, conscious Beagle dog animal model, as described in Table 24. Intravenous administrations were performed by single administration (n=3) of Alfentanil HCl (Alfenta^® 500 μg/mL by bolus injection to the cephalic vein via a sterile needle and syringe of appropriate size at a dose of 253 μg of alfentanil base). For the sublingual administrations the test article (Formulation #63, strength of 239±16.2 μg of alfentanil base) was administered sublingually (n=2) by placement under the tongue, adjacent to the frenulum via forceps. Blood sampling and storage mirrored the conditions described in Example 7; sample analysis was performed using a validated LC/MS/MS method for analysis of alfentanil in dog plasma..

Table 24. Dosing Parameters for Administration of Alfentanil (i) sublingually from a formulation and (U) by an intravenous solution.

<img file="WO2007081948A2_D0026.tif" /> a = Expressed as a free base, b = Same animals will be used for Groups 1 through 3 with a minimum 2-day washout period between dosing.

[0260] The results are shown in Figure 9. PK analysis results are summarized in Table 25.

Table 25. PK Analysis of Alfentanil sublingual formulations compared to intravenous alfentanil

<img file="WO2007081948A2_D0027.tif" />

Represents the relative time that the drug achieves therapeutic levels (above 50% C_max), defined as time within which the drug plasma concentration is maintained above 50% of C_mm normalized by the drug's elimination half-life intravenously and it is calculated by the formula: TTR= (Time above 50% of C_raox) / (Terminal intravenous elimination half-life of the drug). The denominator is obtained from literature studies of alfentanil to be 104 min in beagle dogs. Example 13; Evaluation of the Pharmacokinetics of Sufentanil from Bioadhesive NanoTab^® Formulations in Human Volunteers.

[0261] The bioadhesive transmucosal formulations #46, #47 and #48 which are described in Table 9 (respective doses of 2.5, 5.0 and 10.0 μg of sufentanil base units, respectively) were evaluated in a crossover human clinical study in 12 human volunteers with wash-out periods between transitions from higher to lower doses. Subjects were blocked with naltrexone daily to avoid opioid-induced side-effects. The sufentanil NanoTab^® formulations were administered sublingually at the base of the frenulum using forceps. For comparison, intravenous sufentanil at a total dose of 5 μg was prepared by dilution of commercially available Sufenta^® (strength of 50 μg/mL) in 0.9% saline to a total volume of 20 mL and was administered through an TV catheter as a continuous infusion over 10 minutes. Plasma samples were drawn from all subjects and for all groups at -5.0 (before the start of infusion), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120, 160, 320, 480 and 640 minutes post- administration.

[0262] In addition, the pharmacokinetics of sufentanil were evaluated in the same 12 volunteers following repeated-dosing of four 5.0 mg formulation (#47) administered at 10 minute intervals. Administration was performed as described above. Plasma samples were drawn from all subjects at the following time points: -5.0 (before the first NanoTab^® administration), 5, 7.5 minutes, 10 (immediately prior to the second NanoTab^® administration), 15, 17.5 minutes, 20 (immediately prior to the third NanoTab^® administration), 25, 27.5 minutes, 30 (immediately prior to the fourth NanoTab^® administration), 35, 40, 45, 50, 55, 60, 90, 120, 150, 190, 350, 510 and 670 minutes. Sufentanil concentrations in plasma were determined using a fully validated LC-MS/MS sufentanil plasma assay.

[0263] The disintegration of the NanoTab^® formulations in humans was monitored in the study. All NanoTabs^® used in this study disintegrated over a period of 10-30 minutes in all subjects. After placement of each sufentanil sublingual NanoTab^® in the sublingual cavity of the 12 healthy volunteers, a remarkably consistent pharmacokinetic profile was obtained for the three dosages, as illustrated in Figure 10 and summarized in Table 26. Table 26. Pharmacokinetic Analysis of the sufentanil following sublingual administration of NanoTab^® formulations (#46 at 2.5 μg strength, #47 at S.O μg strength and #48 at 10 μg strength all at n=12) compared to IV (n=12) in human volunteers

<img file="WO2007081948A2_D0028.tif" />

Represents the relative time that the drug achieves therapeutic levels (above 50% of C_mnx) and it is calculated by the formula: TTR= (Time spent above 50% of C_100x) / (IV Terminal elimination half-life). The denominator is obtained from literature and is 148 min in humans for sufentanil.