Generally linear effervescent oral fentanyl dosage form and methods of administering

SUMMARY OF THE INVENTION

The present invention relates to a dosage form that is orally disintegrating, methods of producing such dosage forms, and methods of using them in the treatment of pain and the use in the manufacture of a medicament in which fentanyl, or one or more pharmaceutically acceptable salts thereof (where the term "fentanyl" in the text of this document should be understood to include all pharmaceutically acceptable salts, unless the context otherwise requires), administered orally at doses containing at least about 45% less fentanyl compared to currently available preparations in the form of non-effervescent lollipops (both lozenges and tablets). Despite the lower dose, the orally disintegrating dosage forms of the invention should have a Cmax value that is comparable to that in other dosage forms containing significantly more, e.g., about twice as much medicine. The term "comparable" means in this context that Cmax, the dosage form of the present invention is at least about 75% of that value for ACTIQ^® containing about twice as much fentanyl. Thus, if 400 μg tablet according to the present invention were compared to 400 μg ACTIQ® lollipop and both of them in turn to 800 μg ACTIQ® lollipop, the tablet according to the invention would have a C value_max equal to at least 75-125% C_max 800 μg ACTIQ®. 400 μg ACTIQ® will have a much lower C value_max. This is true for doses of around 800 μg based on the weight of fentanyl free base. It should be noted that "about" in this context means (doses) ± 10%. Thus, doses in the order of approximately 100-800 μg in practice mean doses in the order of 90-880 μg. More preferably "comparable" in the context of this invention may also mean that the Cmax of the dosage form of this invention is between 80-120% by weight of ACTIQ^® about twice as much fentanyl. You can also use the term "highly comparable". Even more preferably "comparable" in the context of the invention may also mean that the Cmax of the dosage form of this invention is 85-115% by weight of the same value for ACTIQ^®, containing approximately twice as much fentanyl. The term 'very comparable' can also be used here.

Preferably, the "oral dosage form" in the context of the invention omits lozenges in the form of lollipops, such as ACTIQ^®instead, it includes orodispersible / dissolving tablets, capsules, caplets, gels, creams, tablets in the form of thin, transparent flakes and the like. Preferably these dosage forms are effervescent tablets.

In addition, they may contain a pH regulating substance and a disintegrant. Typically, these dosage forms are applied to or placed in a particular place in the mouth where they remain for the time of disintegration and / or dissolution, generally about 10-30 minutes.

The dosage form of the present invention consists of 90-880 mg fentanyl, calculated as fentanyl as the free base, or equivalent amount of its salt,

- 4 effervescent pairs in an amount of 5-85% by weight of the dosage form, a substance that regulates the pH level, in the amount of 0.5-25% by weight of the dosage form, starch glycolate in an amount of 0.25-20% by weight of the dosage form, and mannitol, with as above the dosage form is appropriate for the abovementioned administration. fentanyl through the buccal, gingival or sublingual oral mucosa.

The dosage form of the present invention used for the treatment of pain contains 90880 micrograms fentanyl based on the weight of fentanyl free base, or equivalent amount of salt, effervescent vapor, a pH regulating substance that must be selected and provided in an amount that can cause a change in the pH in a specific at least 0.5 units, mannitol and starch glycolate, the dosage form is suitable for the administration of this fentanyl through the buccal, gingival or sublingual oral mucosa, and to provide a Cmax to dose ratio between 2.0-4.0 picograms / ml / micrograms, the dosage form is to be kept in close contact with such an oral mucosa for a time appropriate to administer the therapeutic amount of the abovementioned fentanyl through the oral mucosa.

The method of making the buccal, gingival or sublingual fentanyl administration tablet of this invention consists of the following steps: providing fentanyl or its salt in an amount of 90-880 micrograms per dose based on the weight of fentanyl base, or equivalent amounts of its salt, providing effervescent steam in an amount of 5-85% by weight of the dosage form, a pH regulating substance in an amount of 0.5- 25% by weight of the dosage form, starch glycolate in an amount of 0.25-20% by weight of the dosage form and filler in an amount of 10-80% by weight of the dosage form, the filler consisting of mannitol, a mixture of the abovementioned fentanyl, effervescent steam, pH regulating substance, starch glycolate and the abovementioned mix filler, and compress the resulting mixture into at least one tablet.

In another preferred embodiment of this invention, an effervescent and orally disintegrating dosage form is provided for the administration of fentanyl and / or pharmaceutically acceptable salts of fentanyl through the oral cavity by routes such as buccal, gingival or sublingual rather than swallowing. Preferably, this formulation has no stick or other such means that the patient can easily hold it in his hand or remove it from the mouth when the moisture dosage form is moistened in the mouth. In addition, the dosage form will contain at least 45% less fentanyl (based on the weight of the free base), and preferably, 45% -55% less fentanyl compared to the corresponding ACTIQ product^®. However, they will be comparable and even more preferably highly comparable in the Cmax range as well as usually equally effective.

Therefore, if 1600 micrograms of fentanyl is given in the ACTIQ preparation^®the corresponding dosage form according to the present invention would contain approximately 880 or less micrograms of fentanyl. More preferably, it would contain about 800 micrograms fentanyl. However, despite such a significant reduction in the amount of drug, at least one of the typical pharmacokinetic properties measured for various drugs, such as Cmax, would be similar, if not better. For example, according to this invention, preparations

- 5 may have a shorter Tmax, i.e. the time at which the maximum concentration is reached, and / or a comparable Cmax, if not a higher, highest observed blood concentration of the patient after administration, compared with the corresponding ACTIQ product^®, containing at least 80% by weight more fentanyl. The AUC or area under the curve will usually be linear for dosage forms with increasing fentanyl content within the considered dose ranges.

In a particularly preferred embodiment of the present invention, it has been found that preparations having a linear ratio of approximately between the dose of fentanyl (based on the weight of the free base) and Cmax can be produced, in particular for dose ranges in the range of about 100-800 micrograms per dose. The term "linear" should be understood here as the lack of a significant difference in dose normalized Cmax at a dose of 90-880 micrograms (more preferably, 100-810 μg) using ANOVA analysis of variance at p = 0.15 (p <0.15) when takes the form of part of a series containing at least 3 dosage forms with varying doses, ranging from 90 to 880 micrograms fentanyl. This is the preferred method of determining linearity according to the invention. In other words, the slope of ln (Cmax) in contrast to ln (dose) should be 1 ± 15% (0.85-1.15). As reported in the studies discussed herein, the 200, 500 and 810 μg doses were "linear" according to this invention. Doses of 1080 μg, a type far superior to those known in the art, were not "linear" according to the definition adopted in this text in terms of the ratio of Cmax to dose compared to other doses.

The Cmax dose ratio in this dosage range is 2.0-4.0 picograms / ml / micrograms. This means picograms of fentanyl base per ml of serum, or a proportional amount, if determined in blood or other fluid, normalized per microgram of dose. The term "between" the case of the invention includes endpoints. More preferably, the ratio is from 2.5 to 3.5, and most preferably 2.7-3.5 picograms / ml / micrograms. These ranges are based on average data calculated for at least 10 patients during the relevant clinical trial. In contrast, the tests showed that ACTIQ^® provides a ratio of approximately 1.4 picograms / ml / micrograms. Hence, for dosage forms containing the same amount of fentanyl, the present invention can provide about at least twice as high Cmax for doses up to 880 micrograms, e.g. about 800 micrograms, using the present invention. In another embodiment of the invention, these dosage forms would also have a linear relationship between dose and Cmax if the range was about 100-800 micrograms fentanyl (free base) or proportional amount of salt. Of course, with respect to the strength of a single dose, this means that the dose ratio and Cmax for this dose will show a linear relationship to the series, made only by changing this formulation to contain more or less fentanyl in the range described.

Also one of the preferred forms of this invention are the effervescent dosage forms of fentanyl for buccal, gingival or sublingual administration, containing approximately 880 or less micrograms of fentanyl (by weight based on the weight of the free base), and having a Tmax of less than 1.5

- 6 hours, and most preferably, less than 1 hour However, these dosage forms will have the desired Cmax as discussed above in the range of 2.0-4.0 picograms / ml / micrograms. Methods of administering these dosage forms for the treatment of pain are also being considered.

According to this invention, these formulations include effervescence as a means of improving penetration using an additional pH adjusting substance. In the most preferred embodiment of the invention / most preferably, the pH adjusting substance is a factor other than the components, compounds or molecules mentioned above used to generate effervescence. Particularly preferred dosage forms also include a disintegrant that allows the dose, linearity and / or ratio of Cmax and dose described herein to be reduced. A particularly preferred example of a disintegrant is starch glycolate. Dosage forms containing a filler that facilitate the same action as the above disintegrants are also preferred. Most preferably the filler is mannitol.

In a particularly preferred embodiment of this invention, there is provided an oral dosage form suitable for buccal, gingival or sublingual administration, containing up to 1 milligram, and more preferably, 100, 200, 300, 400, 600 or 800 micrograms of fentanyl (on a free weight basis) bases), and further comprising at least 1 effervescent pair, at least 1 pH adjusting substance, and appropriate excipients. Preferably such a formulation will be able to provide a Tmax of 1.5 hours. or less, and / or a Cmax of 2.0-4.0 picograms / ml / micrograms. In other words, the Cmax of the dosage forms of the present invention are comparable to the Cmax of ACTIO^® containing at least about 80% by weight more fentanyl. In another preferred embodiment, these dosage forms will have a Cmax in the range of about 25% of the ACTIO value^® containing at least 80% by weight more free fentanyl base; preferably in the range of about 20% by weight, and most preferably even in the range of about 15% by weight.

In yet another particularly preferred embodiment of the present invention is provided a disintegrating tablet suitable for buccal, gingival or sublingual administration, containing about 100, 200, 300, 400, 600 or 800 micrograms of fentanyl based on the free base, at least one effervescent steam, and at least one substance regulating the pH level, and appropriate excipients, this dosage form will be able to provide a Tmax of approx. 1.5 hours. or less, and / or Cmax in the range of 2.7-3.5 picograms / ml / micrograms.

In yet another embodiment of the present invention, any of the formulations previously mentioned in this text may essentially consist of fentanyl, preferably in an amount of about

800 or less micrograms (i.e. up to 880 μg), effervescent steam, at least 1 substance that regulates the pH level, and suitable excipients that can provide Cmax in the range of 2.0-4.0 picograms / ml / micrograms, more preferably in the range of 2.5- 3.5 picograms / ml / micrograms and most preferably in the range of 2.7-3.5 picograms / ml / micrograms, and containing at least 45% less fentanyl than the ACTIO dosage form^® providing comparable Cmax. In the context of the present invention, the phrase "consisting essentially of" should be understood to exclude any excipients or combinations of excipients, or if

- use, any amount of any excipient or combination of excipients, as well as any pH adjusting substance or any amount of pH adjusting substance that could change the basic and new features of the invention. Hence, a specific excipient or excipient mixture that would increase the Tmax to 2.5 hours. or longer, it would be excluded. Similarly, for the purpose of illustrating the example, a combination of excipients provided in a specific amount that would change the Cmax level to inappropriate would be excluded. A small amount of cross-linked polyvinylpyrrolidone and / or lactose monohydrate, being generally undesirable, would not significantly change the Tmax or Cmax of the dosage form of the invention, but could be used. However, if they were used together and at 5 and 20% levels respectively, they could change properties in an unfavorable way. Thus combinations of these amounts of earnings would be excluded.

In a particularly preferred embodiment of the present invention, dosage forms are provided comprising essentially: 90-880 micrograms fentanyl, calculated as the free base of fentanyl, or a salt thereof, sodium starch glycolate, mannitol, at least 1 pH adjusting substance, and at least 1 effervescent pair. Preferably these dosage forms provide a Tmax of 1.5 hours. or less, a Cmax to dose ratio in the range of 2.0-4.0 picograms / ml / micrograms, a linear Cmax for the dose, and / or Cmax which is comparable as defined herein at a dosage form suitable for buccal, gingival or oral administration. ęzykowo. More preferably the amount of fentanyl based on the weight of the free base is 100800 micrograms.

As another embodiment of the invention, methods of administering fentanyl to patients experiencing pain only including, but not limited to: back pain, lower back pain, joint pain, any form of arthritic pain, post-traumatic or accident pain, neuropathic, surgical or postoperative pain are contemplated. pain resulting from a disease or condition other than cancer, cancer-related pain, and in particular breakthrough pain caused by cancer. The preferred method includes steps such as administering to a patient in need of such assistance any orodispersible effervescent tablet disclosed herein for buccal, gingival or sublingual administration that contains a dose of fentanyl in the range of about 100-800 micrograms (based on the weight of the free base) . and maintaining this dosage form in the patient's mouth for a time sufficient to allow that dose (or therapeutically relevant and / or effective portion) from the oral cavity to enter the bloodstream. Preferably, the patient is instructed, trained or observed to ensure that the dose is not swallowed, and instead fentanyl enters the body within the desired range through one or more surfaces in the mouth and mouth. Preferably, this method comprises the step of retaining the dosage form in the mouth, substantially without moving it in the mouth. In another preferred embodiment, the dose dissolves / disintegrates within 5-30 min. or the average residence time is 5 - 30 min.

One such method involves treating episodes of breakthrough cancer-induced pain and consists of stages providing an initial dose of approximately 100 micrograms fentanyl calculated as the fentanyl free base, or equivalent amount of salt of pentanyl, in a dosage form consisting of effervescent steam 5-85% by weight of the dosage form, a pH adjusting substance in an amount of 0.5-25% by weight of the dosage form and starch glycolate in an amount of from 0.25% to about 20% by weight of the dosage form. The dosage form is suitable for the above-mentioned administration. fentanyl through the patient's oral mucosa. By "delivery" is meant the removal of the dosage form from the package or the administration of such a form by someone else, or the preparation of such a dosage form. The method also includes placing the dosage form in the patient's mouth, between the cheek and the upper or lower gum, for a time sufficient to administer a therapeutically effective amount of the above. fentanyl through the above oral mucosa. The same method can be used to treat other types of pain, including any type of back pain, surgical or postoperative and neuropathic pain.

In the past, it was not expected that it would be possible to produce an orodispersible tablet for oral fentanyl administration that could provide a Tmax of 1.5 hours. or less, containing 880 or less micrograms of fentanyl based on the weight of the free base, preferably having the desired Cmax. As far as some references in the literature regarding the ACTIQ lozenges^® suggest a Tmax of about 45 minutes, tests have shown that a period of 2 hours is more likely

It was not expected that it would be possible to produce an orodispersible dosage form for oral fentanyl by buccal, gingival or sublingual route containing at least about 45% less fentanyl than the ACTIQ dosage form.^®which provided similar C max values.

It was also not expected that it would be possible to produce a disintegrating dosage form and use it to treat pain, in particular breakthrough pain experienced by cancer patients, whose therapeutically effective amount (an amount that can provide some pain relief), which is usually over 75%, more preferably over 80%, most preferably 90% or more of a dose of fentanyl is absorbed into the bloodstream from the oral cavity through the oral mucosa.

It was also not expected that Cmax of a dosage form containing a much less active drug compared to currently available products on the market could be linear in the C range_max relative to the dose, e.g. ± 15% confidence interval in the range of approximately 100-800 μg (90-880 gg).

According to yet another embodiment of this invention, there is provided a method in which an effervescent buccal, gingival or sublingual fentanyl dosage form can provide one or more of the following: a linear ratio between dose and Cmax in the range of about 100-800 micrograms; comparable Cmax at a dose containing at least about 45% less fentanyl compared to a non-effervescent preparation such as ACTIQ^® at the same dose; and a Cmax to dose ratio in the range of 2.0-4.0 picograms / ml / micrograms. This is achieved by mixing fentanyl (based on the weight of the free base) in an amount of about 100-800 micrograms per dosage form with an effective amount of a substance regulating the pH level capable of causing a change in pH in the microenvironment in the area of ​​contact of the surface of the oral mucosa and the dosage form after placing it in the patient's mouth ("pH in a specific place"), measured as described in this text, at least on the order of 0.5 units compared to an identical formulation without a pH adjusting substance and a disintegrant that allows the dose, linearity and Cmax ratio to be reduced as described above. They are compressed into a tablet or receive a different dosage form using conventional techniques. Preferably, this method is achieved without granulation, although the individual materials used may be granulated prior to mixing. Thus, wet granulated sugar could also be used as a filler in another direct compression process, which is also a process carried out using dry granulation technology.

More preferably this method is used to produce a dosage form, preferably a tablet, which gives a linear relationship between dose and Cmax in the range of about 100-800 micrograms, a highly comparable Cmax at a dose containing at least about 50% less fentanyl compared to ACTIQ^® at the same dose and / or Cmax to dose ratio in the range of 2.7-3.5 picograms / ml / micrograms. This is achieved by mixing fentanyl or its salt in an amount appropriate to provide a predetermined number of dosage forms, each containing approximately 100-800 micrograms of fentanyl, 5-85% by weight of the effervescent finished dosage forms, pH adjusting substance in an amount of 0.5-25% by weight, starch glycolate in an amount of 0.25-20% by weight, mannitol, and dry pressing into tablet form. Preferably, the pH adjusting substance will cause the pH to change at a specific location of at least 1 pH unit, compared to an identical formulation without this component.

DETAILED DESCRIPTION

Throughout the description, including the claims, the words "assemble" and derivatives thereof, such as "consisting" and "assembled", as well as the words "have", "having", "includes "," Include "and" including "and their variants mean that the stages, elements or materials listed above which words are relevant, essential, but other stages, elements or materials may be added and continue to form sentences regarding disclaimer or disclosure. When they are mentioned in the context of the invention and in the claim, this means that the invention and subject matter of the claim further include what is described and potentially a wider scope. These terms, especially those used in the claims, are general and open, and do not exclude additional non-listed elements or method steps.

For the purposes of the present invention, unless a different definition is given for a particular characteristic, characteristic or variable, the term "to a significant extent" in the sense used for any criteria, such as a characteristic, characteristic or variable, means that the criteria are met in such a way that an expert in the field knew that the advantage to be achieved or the desired condition or value of the characteristic had been achieved.

In one aspect, the present invention includes a dosage form containing about 100-800 μg (micrograms) of fentanyl based on the weight of the fentanyl free base or salt thereof, which is suitable for buccal, gingival or sublingual dosing. The dosage form, if properly administered, i.e. having contact with the oral mucosa for a sufficiently long time, can reach a Tmax of 1.5 hours. or shorter. In addition or instead, a Cmax to dose ratio in the range 2.0-4.0, more preferably in the range 2.3-3.5 or most preferably in the range 2.7-3.5 picograms / ml / micrograms will be achieved. Most preferably, the dose to Cmax ratio is linear over a range of doses from about 100 to 800 micrograms, which is different from other doses that were otherwise formulated in an identical manner.

Preferably, the dosage form further comprises at least 1 pH adjusting substance and at least 1 effervescent pair. They are supplied in an amount that is adequate to achieve the desired Cmax and / or Tmax values. Preferably the dosage form comprises at least 1 excipient selected and provided in an amount which, in combination with at least 1 substance that regulates the pH level, and at least 1 effervescent pair, provides the desired Tmax and / or Cmax.

Another aspect of the invention is the method of administering fentanyl to a patient who is experiencing pain. This method may include the steps of contacting the oral mucosa of a patient in need of such assistance with an orodispersible dosage form. The dosage form contains a dose of fentanyl in the range of about 100-800 (90-880) micrograms (based on the weight of the free base) per dosage form or its salt. The dosage form can provide a Tmax of 1.5 hours. or shorter, and / or a Cmax to dose ratio in the range of 2.0-4.0, preferably in the range of 2.3-3.5 and most preferably in the range of 2.7-3.5 picograms / ml / micrograms and / or linear the relationship between Cmax and dose, preferably for a dosage form comprising at least 45% less fentanyl compared to those known on the market that would be recommended in this case. The dosage form is kept in contact with the patient's oral mucosa for a time appropriate to transfer a therapeutically significant or effective portion of fentanyl, preferably above 75% and, more preferably above 80% and most preferably 90% or more of the dose, from the mouth to the bloodstream through the mucosa. oral cavity.

Another aspect of the invention provides a dosage form consisting of: about 100-800 micrograms fentanyl per dosage form based on the weight of the fentanyl free base. The fentanyl salt, when used, is used in an amount to provide an equivalent amount of the fentanyl free base by weight. The dosage form is suitable for buccal, gingival or sublingual dosing. If the dosage form is appropriately administered through contact with the oral mucosa for a sufficient time, it can provide a Cmax that is at least 75-125%, preferably more preferably in the range of 80-120% and most preferably in the range of 85-115% of the value for the form ACTIQ dosage^®which contains at least 80% by weight of fentanyl. Preferably, this dosage form also includes at least 1 pH adjusting substance and at least 1 effervescent pair in an amount sufficient to provide the indicated Cmax. More preferably even the dosage form

Further contains at least 1 excipient in an amount that in combination with at least 1 pH adjusting substance, and / or at least 1 effervescent pair that is sufficient to achieve the desired Cmax.

A method of administering fentanyl to a patient experiencing pain is also being considered, consisting of the following stages: contact with the patient's oral mucosa in need of such assistance with a disintegrating oral dosage form that contains a dose of fentanyl in the range of about 100-800 micrograms (based on by mass of the free base) per dosage form, or equivalent amount of its salt. The dosage form has a Cmax of at least 75-125%, more preferably between 80-120% and most preferably between 85-115% of the characteristic value for ACTIQ^® containing at least 80% by weight fentanyl more. The dosage form is kept in contact with the patient's oral mucosa for a time sufficient to transfer a therapeutically or effective portion of fentanyl, preferably above 75%, more preferably above 80% and most preferably 90% or more of the dose, from the mouth to the bloodstream through the oral mucosa .

It has now been discovered that the use of effervescence and a pH regulating substance, especially in combination with starch glycolate, can bring significant benefits, especially regarding the amount of fentanyl needed for dosing. It has also been found that certain excipients in combination with effervescent vapors and pH regulating substances can provide even better and quite unforeseen results.

To determine if a particular form of medicine is able to achieve the results described here, all you need is to undergo a routine clinical trial of this form of medicine in at least 10 patients. An appropriate clinical trial would be based on any of the traditional study designs. Examples of relevant tests are given below:

Design and conduct of clinical trial

This study and ICF (Informed Consent Form) have been approved by the IRB (Institutional Review Board). Prior to the start of the study, all subjects subjected to the study had read and signed the Informed Consent Form approved by IRB. Signed and certified Informed Consent Forms have been attached to the documentation.

In the first two stages of clinical trials, a single-dose, randomized, open, cross-designation and reference product assay scheme was used, and subjects were randomly selected to receive 1 out of 3 additional test preparations in phase 3. All study subjects were selected by randomization, and used for all 10 hours overnight fast before testing. Between administration of each subsequent of the total number of three doses, a 7-day break period was used to wash the test substance out of the body. The study subjects were left in the clinic for 36 hours follow-up after administration of fentanyl.

During the 21 days prior to formal registration to participate in the study, the candidates underwent screening. The screening procedure involved history

- 12 medical, medical examination (height, mass, skeleton size, signs of life and ECG), and clinical laboratory tests (hematology (blood counts), tests performed on blood serum, urine analysis, screening for HIV antibodies, screening for antigens surface hepatitis B, test for hepatitis C antibodies, blood tests to confirm or exclude pregnancy (only for women) and screening tests for cannabinoids and opioids).

All subjects who enrolled in clinical trials met the admission / exclusion criteria given in the protocol. A total of 42 individuals expressed willingness to participate in the study, including 17 men and 25 women. In contrast, 39 individuals, including 17 men and 22 women, did not stop participating in these studies.

Subjects reported to the clinic in the morning the day before each dose was given and received lunch 19 hours prior to dose administration, lunch 14 hours prior to dose administration, and a light meal 11 hours prior to dose administration. Then the subjects followed 10-hour fasting at night. On day 1, standardized meal distribution began with the lunch delivered 4.5 hours after dosing, followed by dinner 9.5 hours after dosing and a light meal 13 hours after dosing. On day 2, breakfast was delivered 24.5 hours post-dose, lunch 28.5 hours post-dose, and dinner 33 hours post-dose.

Subjects were prohibited from consuming beverages and products containing alcohol, broccoli, citrus products, caffeine or xanthine for 48 hours before and during each period of stay in the clinic. Subjects should have not used drugs containing tobacco and nicotine for at least 6 months before participating in the study. In addition, over-the-counter medications were banned within 7 days of dosing and during the study. Prescription drugs were banned within 14 days of dosing and during the study (except for hormonal contraceptives for women).

During the study, subjects were to remain seated for 4 hours after administration of fentanyl citrate. Water consumption was limited from 0 o'clock to 4 o'clock after dosing. It is forbidden to eat food in the period from 10 hours before dosing to 4 hours after dosing. During the study, subjects could not perform any comprehensive activities.

Subjects received naltrexone in each phase in the following rhythm:

Application 1: ReVia^® 50 mg (naltrexone hydrochloride tablets).

Manufactured by Bristol-Myers Squibb Company

Lot number: 5C269A

Expiration date: April 2004

Lot number: TB1798

- 13 Expiry date: March 2005.

The test subjects assigned to treatment A, B, C and D were given an oral dose of 50 mg naltrexone tablet, which they washed down with 240 ml of water 15 hours and 3 hours before and 12 hours after the dose of fentanyl.

The test subjects assigned to treatment E were orally dosed in the form of a 50 mg naltrexone tablet, which they washed down with 240 ml water 15 hours and 3 hours before the dose of fentanyl.

Subjects were treated with fentanyl in the following form in each of 3 phases:

A: OraVescent® 1080 μg fentanyl citrate tablets (as fentanyl base)

Manufactured by CIMA LABS INC

Lot number: 930502

Individuals selected by randomization for treatment A were given a single dose of 1 tablet containing 1080 μg of fentanyl orally, which they placed between the upper gum and cheek, above the molar and kept in their mouths for 10 minutes until it breaks down. It should be noted that the name "OraVescent^®"Indicates the formulation and dosage form of the invention.

B: Actiq® (oral mucosal fentanyl citrate), equivalent to 1600 μg Manufactured by Cephalon, Inc. or Anesta Lot number: 02 689 W3

Test subjects selected by randomization for treatment B were orally administered a single dose of 1,1600 μg Actiq® unit, which they placed between the cheek and lower gum. It had to be moved from side to side with a stick and allowed to dissolve for 15 minutes.

C: OraVescent® fentanyl citrate tablets 1300 μg (as fentanyl base)

Manufactured by CIMA LABS INC

Lot number: 930503

Test subjects selected by randomization for treatment C were given a single dose of 1 tablet containing 1300 μg of fentanyl orally, which they placed between the upper gum and cheek above the molar and kept in the wake for 10 minutes until its decay.

D: OraVescent® 810 μg fentanyl citrate tablets (as fentanyl base)

Manufactured by CIMA LABS INC

Lot number: 930501

Test subjects selected by randomization for treatment D were orally administered a single dose of 1 tablet containing 810 μg fentanyl, which they placed between the upper gum and cheek, above the molar and kept on awakening for 10 minutes until it decays.

E: OraVescent® 270 μg fentanyl citrate tablets (as fentanyl base)

Manufactured by CIMA LABS INC

Lot number: 930500

Test subjects selected by randomization for treatment E were orally administered a single dose of 1 tablet containing 270 μg of fentanyl, which they placed between the upper gum and cheek, above the molar, and held it in their mouths for 10 minutes until it decays.

The composition of each of these fentanyl citrate tablets is described in Examples 1-4.

Signs of living in a sitting position (blood pressure, pulse and breathing) were assessed each morning before dosing (0 o'clock) and 0.25; 0.50; 0.75; 1; 1.25; 1.50; 1.75; 2; 2.25; 2.50; 2.75; 3; 3.25; 3.50; 3.75; 4; 5; 6; 8; 10; 24 and 36 hours after dosing. Pulse oximetry was continuously measured during the first 8 hours after the test. At the end of clinical trials, tests were performed using a 12-lead electrocardiogram, clinical evaluation tests (morphology, blood tests, urine analysis) and medical examination including full examination of signs of life. Assessment of oral dose irritation was made 4 hours after dosing. Subjects were instructed to inform the attending physician and / or nurse about any negative symptoms that occurred during the study.

Blood samples (7 ml) were taken from test subjects selected for AD treatment at the following hours: pre-dose (0 o'clock), and 10; twenty; 30 and 45 minutes, as well as 1; 2; 4; 6; 8; 10; 12; 16; twenty; 24; 28; 32 and 36 hours after dosing. Blood samples (7 ml) were taken from test subjects selected for treatment E at the following hours: pre-dose (hour 0), and 10; twenty; 30 and 45 minutes, as well as 1; 2; 4; 6; 8; 9; 10; 11; 12; 14; 16; 20 and 24 hours after dosing. In total, 54 blood samples (378 ml) were collected during the study for drug analysis. Samples were taken and tested at room temperature under fluorescent lighting. Serum samples were allowed to clot, after which they were separated by centrifugation, frozen at -20 ° C, and left frozen until examined.

Analytical methods

LC-MS / MS (liquid chromatography-mass spectrometry / mass spectrometry) was used to analyze fentanyl in human blood serum.

Pharmacokinetic and statistical methods

Pharmacokinetic and statistical analysis was based on industry guidelines developed by the Food and Drug Administration, Center for Drug Evaluation and Research (CDER) issued in January 2001 under the title "Statistical Approaches to Estabilishing Bioequivalence" approaches to determining bioequivalence) and industry guidelines issued in March 2003. and entitled "Bioavibility and Bioequivalence Studiem for Orally Administered Drug Products - General

Considerations "(Studies on bioavailability and bioequivalence in the field of orally administered medical products - general considerations)

The following noncompartmental pharmacokinetic parameters were calculated from the concentration-time data of fentanyl for each treatment using version 2.1 of the WinNonlin Standard Edition software. Real (rather than nominal) sampling times were used in the analysis.

AUC (0-t) area under the time-concentration curve of fentanyl calculated by the linear method of summing the trapezoid fields from time 0 to time t, where t is the time of the last measurable concentration (Ct).

AUC (0-inf) area under the time-concentration curve of fentanyl from time 0 to infinity, AUC (0-inf) = AUC (0-t) + Ct / Kel, where Kel is the drug elimination rate constant.

AUC (0-t) / AUC (0-inf) ratio of AUC (0-t) to AUC (0-inf). Also known as AUCR.

AUC (0-tmax) partial area from time 0 to the median Tmax of the standard drug formulation, calculated using the linear method of adding trapezoidal fields.

Kel constant of drug elimination calculated by linear regression method of elimination of the log portion of concentration versus time curve, where Kel = - slope of the descending arm of the curve. The final linear portion was visually determined.

T1 / 2 drug half-life calculated as In (2) / Kel.

Cmax maximum observed concentration of fentanyl.

Tmax time of maximum fentanyl concentration (obtained without interpolation)

It was a single-dose, randomized, open-label study, based on the crossed designation test and reference products test (treatment A and treatment B, phase 1 and 2), and subjects who were to be given 3 additional study preparations (treatment C, treatment D or treatment E) in phase 3, selected on a random basis basis. Due to the greater number of subjects tested, the study was conducted in two groups. The main goal of clinical trials was to compare treatment A to treatment B. For analysis of variance comparing the two types of treatment, only two sequences (AB and BA), two phases (1, 2) and two treatments (A, B) were considered.

The general linear parametric model (standard theory) was used for log-transformed AUC (0-inf), AUC (0-t) and Cmax values ​​for treatment A and B^5-7. The Full Analysis of Variance (ANOVA) model included the group and included the following factors: group, period within the group, treatment, sequence, sequence by group, individual within sequence by group, and treatment by group. Because treatment with group interaction was not significant, the model was reduced to sequence, object within the sequence, phase and

- 16 treatments. The sequence effect was checked using an object within the mean square sequence, and all other major effects were checked using the residual error (mean square error). Two unilateral hypotheses were tested at 5% for

AUC (0-t), AUC (0-inf), and Cmax by creating a 90% confidence interval for the test mean and reference index (treatment A depending on treatment B).

Differences in Tmax for treatment A and B were estimated by conducting Wilcoxon test for observation pairs (α = 0.05).

Serum fentanyl and pharmacokinetic parameters were also determined after C, D and E treatment (consisting of 1300 gg, 810 gg and 270 gg OraVescent citrate tablets respectively)^®). To estimate dose proportionality in the form of OraVescent fentanyl citrate^® a mixed linear model was used to dose-normalized Cmax and AUC for treatment A, C, D and E.^5-7 The complete model included the group and included the following terms: group, period within the group, treatment, sequence, sequence by group, individual within sequence by group and treatment by group. Group interaction treatment was not significant for 2 out of 3 parameters [Cmax and AUC (0-t)], and the model was reduced to a one-way ANOVA with treatment factor in mind. If the overall effect of the treatment was found, then pairwise comparisons were made using treatment A.

The residence time values ​​(the period of time that the drug form was present in the mouth) were calculated by reducing the observed and documented disappearance of the preparation by the value of the time of administration. These values ​​were compiled and presented in the summary statistical table.

RESULTS

Demographic data and disposition of subjects

A total of 42 candidates, including 17 men and 25 women, were qualified to participate in the study, of which 39 subjects, including 17 men and 22 women, did not stop participating in the study.

Three tested individuals discontinued the study / their participation was abandoned. In one case it occurred before the start of phase 2, because the subject did not want to continue participation in the further phases of the clinical trial. Another individual refused to continue clinical trials prior to phase 3. However, a third person was discontinued prior to the start of phase 2 due to the individual taking the antibiotic.

The average age of subjects was 27 years (age range: 19-55 years), average height 1.73 cm (range 1.57 cm-1.88 cm), and the average weight of the subjects was 69 kg (range 49.44- 89.36 kg).

Deviations from the study protocol and adverse events

During the clinical trial, the following deviations from the protocol occurred.

- 17 According to the protocol, subjects were to be subjected to breath tests at a time point of 3.5 hours. from studying the signs of life. At a time point of 3.5 hours 1 subject was not subjected to the phase 2 breath test. 2 subjects were not re-screened for signs of life at a time point of 3 hours. in phase 2. Re-screening of signs of life did not include 1 test subject at a time point of 2.25 hours. in phase 3. Blood samples from 2 test subjects were incorrectly marked1) at a time point of 33 hours. in phase 1 (treatment A). These samples were not analyzed. According to the protocol, the pulse tests of the individuals had to be carried out at a time point of 3.5 hours. from studying the signs of life. This test at a time point of 3.5 hours. one individual was not included in phase 1. None of the subjects tested experienced more than one of the above deviations. No significant adverse events were reported.

The management of clinical samples in this study required a total of 15 batches, 14 of which met the admission requirements. The back calculations of the standard concentrations of the 14 acceptable human blood samples used in this study covered the range from 50.0 to 5000.0 pg / ml (picogram / milliliter) with a detection limit of 50 pg / ml. Quality control samples analyzed with each acceptable batch had coefficients of variation less than or equal to 7.89%.

Residence time

Data regarding residence time are summarized in the table below.

Summary of residence time of tablets / lozenges

<td></td><td>Treatment A.</td><td>Treatment B</td><td>Treatment C.</td><td>Treatment of D</td><td>Treatment E</td>

<td>Test subject number</td><td>Time (min.)</td><td>Time (min.)</td><td>Time (min.)</td><td>Time (min.)</td><td>Time (min.)</td>

<td>average</td><td> 21</td><td> 34</td><td> 19</td><td> 25</td><td> 22</td>

<td>SD</td><td> 12</td><td> 15</td><td> 11</td><td> 14</td><td> 17</td>

<td>CV</td><td> 58</td><td> 44</td><td> 56</td><td> 57</td><td> 75</td>

<td>SEM</td><td> 2</td><td> 2</td><td> 3</td><td> 4</td><td> 4</td>

<td>L</td><td> 40</td><td> 42</td><td> 12</td><td> 13</td><td> 14</td>

<td>min.</td><td> 3</td><td> 9</td><td> 4</td><td> 4</td><td> 4</td>

<td>max.</td><td> 48</td><td> 77</td><td> 33</td><td> 50</td><td> 62</td>

Treatment A = 1 x 1080 mcg OraVescent® fentanyl citrate tablet - test preparation

Treatment B = 1 x 1600 mcg fentanyl citrate administered orally, transmucosally (Actiq®) - reference preparation

Treatment C = 1 x 1300 mcg OraVescent fentanyl citrate tablet^® - test preparation

Treatment D = 1 x 810 mcg OraVescent fentanyl citrate tablet^® - test preparation

Treatment E = 1 x 270 mcg OraVescent fentanyl citrate tablet^® - test preparation

SD - standard deviation; CV - coefficient of variation; SEM - standard error of the mean; N - number of (observations)

One of the test subjects reported slight oral irritation (on a scale of 1-10 this irritation was set at level 2) which occurred after treatment C. Irritation occurred on the right side of the mouth after administration of the test preparation in phase 3. In one case

- 18 employees participating in the study noticed redness after applying E.

Place redness occurred in the upper right cheek after administration of the test preparation in phase 3.

Of the 42 registered volunteers, 40 underwent Phase 1 and 2 of the clinical trial and were included in the summary statistical table, ANOVA analysis and mean numerical values ​​for treatment A and B. 39 subjects completed Phase 1, 2 and 3 of the clinical trial and were included proportional dose proportionality in statistical analysis.

The arithmetic means and standard deviations of the pharmacokinetic parameters of serum fentanyl concentration and statistical comparisons performed after treatment A and B are summarized in the table below.

Summary of pharmacokinetic parameters of serum fentanyl in treatment A and B

<td colspan="9">serum concentration of fentanyl</td>

<td></td><td colspan="3">Treatment A.</td><td colspan="3">Treatment B</td><td></td><td></td>

<td>parameters Pharmacokinetic</td><td>N</td><td>Average arithmetical</td><td>SD</td><td>N</td><td>Average arithmetical</td><td>SD</td><td>90% CI *</td><td>% ratio value average</td>

<td>Cmax (pg / ml)</td><td> 40</td><td> 2704,3</td><td> 877,6</td><td> 40</td><td> 2191,6</td><td> 693,5</td><td> -</td><td> -</td>

<td>AUC (0-tmax) (pg10h / ml)</td><td> 40</td><td> 3840,1</td><td> 1266,2</td><td> 40</td><td> 2566,2</td><td> 911,82</td><td> -</td><td> -</td>

<td>AUC (0-t) (pg4h / ml)</td><td> 40</td><td> 16537</td><td> 5464,6</td><td> 40</td><td> 16701</td><td> 6530,1</td><td> -</td><td> -</td>

<td>AUC (0-inf) (pg * h / ml)</td><td> 35</td><td> 17736</td><td> 5424,3</td><td> 39</td><td> 18319</td><td> 7118,5</td><td> -</td><td> -</td>

<td>T1 / 2 (hours)</td><td> 35</td><td> 11,7</td><td> 5,04</td><td> 39</td><td> 11,2</td><td> 4,37</td><td> -</td><td> -</td>

<td>Kel (1 / hour)</td><td> 35</td><td> 0,0701</td><td> 0,0310</td><td> 39</td><td> 0,0695</td><td> 0,0227</td><td> -</td><td> -</td>

<td>AUCR</td><td> 35</td><td> 0,918</td><td> 0,0458</td><td> 39</td><td> 0,917</td><td> 0,0335</td><td> -</td><td> -</td>

<td>ln (Cmax)</td><td> 40</td><td> 7,854</td><td> 0,3132</td><td> 40</td><td> 7,640</td><td> 0,3349</td><td> 111,82136,20</td><td> 123,4</td>

<td>ln (AUC (0-t))</td><td> 40</td><td> 9,662</td><td> 0,3226</td><td> 40</td><td> 9,649</td><td> 0,3945</td><td> 94,42108,86</td><td> 101,4</td>

<td>ln (AUC (0-inf))</td><td> 35</td><td> 9,739</td><td> 0,3027</td><td> 39</td><td> 9,742</td><td> 0,3941</td><td> 93,60109,23</td><td> 101,1</td>

* based on the average LS value in Table 13

Treatment A = 1 x 1080 mcg OraVescent fentanyl citrate tablet - test preparation treatment B = 1 x 1600 mcg fentanyl citrate (Actiq^®) administered orally, transmucosally - reference preparation

Based on the Wilcoxon test results for paired observations, it was found that the median Tmax for treatment A (0.998 hours) was reached much earlier (p &lt;0.0001) compared to treatment B (1.999 hours).

- 19 Single and mean pharmacokinetic parameters of serum fentanyl concentration were calculated for treatment C, D and E. In treatment E, it was not possible to calculate Kel for the 5 subjects tested. Therefore, in these cases, AUC (0-inf), AUCR and T1 / 2 could not be calculated.

The arithmetic mean and standard deviations of the pharmacokinetic parameters of serum fentanyl concentration after treatment C, D and E are summarized in the table below.

Summary of pharmacokinetic parameters of serum fentanyl for treatment C, D and E

<td colspan="10">serum concentration of fentanyl</td>

<td></td><td colspan="3">Treatment C.</td><td colspan="3">Treatment of D</td><td colspan="3">Treatment E</td>

<td>parameters Pharmacokinetic</td><td>N</td><td>Average arithmetical</td><td>DS</td><td>N</td><td>Average arithmetical</td><td>DS</td><td>N</td><td>Average arithmetical</td><td>DS</td>

<td>^Cmax / (pg / ml)</td><td> 12</td><td> 2791,4</td><td> 874,3</td><td> 13</td><td> 2646,9</td><td> 778,7</td><td> 14</td><td> 797,9</td><td> 312,9</td>

<td>AUC (0^tmax⁾(Pg * hr. / M l)</td><td> 12</td><td> 4008,3</td><td> 1259,1</td><td> 13</td><td> 3694,8</td><td> 971,89</td><td> 14</td><td> 1095,6</td><td> 433,92</td>

<td>AUC (0-t) (Pg * hr. / M l)</td><td> 12</td><td> 18921</td><td> 6470,2</td><td> 13</td><td> 15339</td><td> 4260,4</td><td> 14</td><td> 4333,5</td><td> 1597,9</td>

<td>AUC (0-inf) (Pg * hr. / M l)</td><td> 12</td><td> 21033</td><td> 7346,3</td><td> 13</td><td> 16831</td><td> 4449,8</td><td> 9</td><td> 4221,9</td><td> 1747,8</td>

<td>T1 / 2 (hours)</td><td> 12</td><td> 13,2</td><td> 7,67</td><td> 13</td><td> 11,7</td><td> 4,66</td><td> 9</td><td> 6,62</td><td> 3,17</td>

<td>kel (1 / hr).</td><td> 12</td><td> 0,0687</td><td> 0,0354</td><td> 13</td><td> 0,0703</td><td> 0,0352</td><td> 9</td><td> 0,126</td><td> 0,0538</td>

<td>AUCR</td><td> 12</td><td> 0,907</td><td> 0,0683</td><td> 13</td><td> 0,909</td><td> 0,0376</td><td> 9</td><td> 0,865</td><td> 0,0381</td>

treatment C = 1 x 1300 mcg OraVescent fentanyl citrate tablets^® treatment D = 1 x 810 mcg OraVescent fentanyl citrate tablet ^®treatment E = 1 x 270 mcg OraVescent fentanyl citrate tablet ^®AUCR is the ratio AUC (0-t) / AUC (0-inf)

Dose proportionality assessments with p-values ​​for treatment A, C, D and E are summarized in the table below.

Summary of dose normalized serum parameters of fentanyl in the treatment of A, C, D and E

<td colspan="10">serum concentration of fentanyl</td>

<td colspan="2"></td><td colspan="2">Treatment A.</td><td colspan="2">Treatment C.</td><td colspan="2">Treatment of D</td><td colspan="2">Treatment E</td>

<td>parameters Pharmacokinetic</td><td>P value</td><td>Average arytmet.</td><td>AXIS</td><td>Average arytmet.</td><td>AXIS</td><td>Average arytmet.</td><td>AXIS</td><td>Average arytmet.</td><td>AXIS</td>

<td>C_max/dose (Pg / mL / mcg)</td><td> -</td><td> 2,5</td><td> 0,8</td><td> 2,1</td><td> 0,7</td><td> 3,3</td><td> 1,0</td><td> 3,0</td><td> 1,2</td>

<td>AUC (0-t) / dose (pg * h / ml / mcg)</td><td> -</td><td> 15,4743</td><td> 5,01901</td><td> 14,555</td><td> 4,9771</td><td> 18,937</td><td> 5,2597</td><td> 16,050</td><td> 5,9180</td>

<td>AUC (0-inf) / dose (pg * h / ml / mcg)</td><td> -</td><td> 16,5851</td><td> 5,00318</td><td> 16,179</td><td> 5,6520</td><td> 20,779</td><td> 5,4935</td><td> 15,637</td><td> 6,4732</td>

<td>ln (C_max)/dose</td><td> 0,0127</td><td> 0,8788</td><td> 0,3115</td><td> 0,7190</td><td> 0,3151</td><td> 1,137</td><td> 0,3356</td><td> 1,011</td><td> 0,3974</td>

<td>ln (AUC (0-t) / dose)</td><td> 0,1727</td><td> 2,690</td><td> 0,3170</td><td> 2,625</td><td> 0,3409</td><td> 2,901</td><td> 0,3032</td><td> 2,706</td><td> 0,4002</td>

<td>ln (AUC (0-inf) / dose)</td><td> 0,0783</td><td> 2,765</td><td> 0,3003</td><td> 2,725</td><td> 0,3633</td><td> 2,998</td><td> 0,2894</td><td> 2,691</td><td> 0,3892</td>

treatment A = 1 x 1080 mcg OraVescent® fentanyl citrate tablet

- 20 treatment C = 1 x 1300 mcg OraVescent® fentanyl citrate tablets treatment D = 1 x 810 mcg OraVescent® fentanyl citrate tablets treatment E = 1 x 270 mcg OraVescent® fentanyl citrate tablets

Time intervals were determined in relation to Kel values.

The basic premise of this study was to assess the bioequivalence of a 1080 μg dose of the OraVescent® fentanyl citrate tablet manufactured by CIMA LABS INC (treatment A, test formulation) compared to the commercially available 1600 μg fentanyl citrate Actiq^®, which is administered orally, transmucosally to individuals observing fasting, treatment B, reference preparation). In phase 1 and 2 clinical trials, a single-dose, randomized, open, cross-over scheme was used. In phase 3, all subjects were treated with one of the three OraVescent fentanyl citrate preparations tested^®: 1300 μg (treatment C), 810 μg (treatment D) or 270 μg (treatment E). The dose proportionality of the OraVescent fentanyl citrate tablet was evaluated^® (treatment A, C, D and E).

Initially, a total of 42 healthy participants were qualified for the study. 39 of them underwent all 3 phases of the clinical trial, and 40 subjects completed both A and B treatment (Phases 1 and 2). Data on 40 subjects who completed treatment A and B were included in the pharmacokinetic and statistical analysis.

Geometric mean least squares ratios (test / reference) for Cmax, AUC (0-t), and AUC (0-inf) of fentanyl were 123.4%, 101.4% and 101.1% for treatment A in relative to treatment B. These data indicate that the average exposure to fentanyl was similar, but the peak exposure was higher for treatment A compared to treatment B. Treatment A achieved a Tmax (0.998 hours) one hour earlier than treatment B (2 , 00 h), and Cmax was 23% higher. This indicated that the absorption rate of fentanyl was significantly higher in treatment A than in treatment B.

90% confidence intervals for Cmax in the range of 111.82% -136.20%, AUC (0-t) in the range of 94.42% -108.86% and AUC (0-inf) in the range of 93.60% -109 , 23% indicated that treatment A and treatment B met the bioequivalence requirements for AUC, but not for Cmax. In fact, the Cmax for treatment A indicates that the dose containing 30-35% less fentanyl by weight given in OraVescent^®, as set forth in Example 1, enabled a statistically significantly higher C value_max compared to 1600 μg of Actiq®. In order to achieve bioequivalence effects with respect to Cmax, in fact, in order to obtain comparable results, the formula should use the OraVescent fentanyl preparation^® containing at least about 45%, more preferably about 47.5%, and most preferably about 50% less fentanyl (based on the weight of fentanyl free base) than found in the compared Actiq tablet^®. In this case, an estimated 800-880 micrograms were compared to 1600 micrograms ACTIQ^®.

Thus, it has been found that comparable Cmax values ​​can be achieved even with less fentanyl than initially thought using the invention and for dosage forms of 1 milligram or less. Immediate Tmax was reached. This allowed further reduction of the doses considered along with the benefits described herein due to dose reduction that is not associated with a reduction in efficacy.

Fentanyl AUC increased proportionally (linearly as defined herein) to a dose in the range of 2701300 μg after administration of the OraVescent® fentanyl citrate tablet. No significant differences were observed in the AUC (0-t) or AUC (0-inf) normalized dose among the 4 OraVescent doses^®. A significant overall effect of the treatment was noted when comparing the Cmax of the normalized dose. Pairwise comparison was performed using treatment A as the reference treatment because all subjects were treated with treatment A. No relationship was observed in pairwise comparison. A significant difference was found between treatment D (810 μg) and treatment A (1080 μg).

The average residence time of 1080 μg OraVescent® fentanyl citrate tablet (21 minutes) was 13 minutes shorter than for Actiq^®(34 minutes). Average residence times for the 3 remaining doses of the drug in the form of the OraVescent fentanyl citrate tablet^® (19, 25 and 22 minutes) were similar to the values ​​for 1800 μg of OraVescent®.

One test subject reported slight irritation to the oral mucosa, while another experienced redness after administration of the OraVescent fentanyl citrate tablet^®. No redness or irritation was reported after administration of Actiq^®.

Comparison of pharmacokinetic parameters of serum fentanyl after 1800 μg OraVesc fentanyl citrate tablet and 1600 μg fentanyl citrate preparation (Actiq^®), orally, transmucosally showed that the average exposure to fentanyl was similar, but the absorption rate of the two preparations was different. The geometric mean least squares (LS) ratio for AUC (0-t) and AUC (0-inf) was almost 100%, and 90% confidence intervals were in the range 80-125%. Geometric average C_max was 23% higher for 1080 μg OraVescent® fentanyl citrate and the upper limit of the 90% confidence interval relative to the treatment / reference treatment ratio was greater than 125% indicating that bioequivalence criteria were not met for this parameter. From here, you could even further reduce the dose. Tmax was significantly reached much earlier (by 1 hour) than with the OraVescent fentanyl citrate tablet^®.

The fentanyl AUC increased in proportion to the dose, but not completely linearly over the full dose range from 270 to 1300 μg for the OraVescent® fentanyl citrate formulation.

The average residence time of 1080 μg OraVescent® fentanyl citrate tablet (21 minutes) was 13 minutes shorter than the average residence time of Actiq^® (34 minutes). The "residence time" according to the invention is the amount of time from the start of using the dosage form (oral administration) to the disappearance of the entire dosage form that is visually identifiable.

No serious or unexpected adverse events were found during the study. Both preparations were well tolerated by the oral mucosa. SOURCES

- 22 1. Physician's Desk Reference. Edition 56. Montvale, NJ: Medical Economics Company, Inc .; 2002. Actiq^®; str.405-409.

2. Fentanyl. Micromedex [online] volume 107: Health Series Integrated Index; 2002 [Date Accessed: 2003 / Jun / 371.<a href="http://www.tomescps.com">http://www.tomescps.com</a>

3. Streisand YB, et. al., Dose Proportionality and Pharmacokinetics of Oral Transmucosal Fentanyl Citrate. Anesthesiology 88: 305-309, 1998.

4. Naltrexone. Micromedex [online] volume 107: Health Series Integrated Index; 2002 [Date Accessed: 2003 / Jun / 16.<a href="http://www.tomescps.com">http://www.tomescps.com</a>.

5. SAS^® Institute, Inc., SAS^®/ STAT User's guide, version 6, edition 4, volume 1. Cary, NC: SAS Institute; 1989.

6. SAS^® Institute, Inc., SAS^®/ STAT User's guide, version 6, edition 4, volume 2. Cary, NC: SAS Institute; 1989.

7. SAS^® Institute, Inc., SAS^® Procedures guide, version 6, 3rd edition. Cary, NC: SAS Institute; 1990.

A second study was also carried out. It showed a generally linear relationship between dose and Cmax for doses in the range 100-800 micrograms.

This study was conducted to assess the dose proportionality (AUC and Cmax) of fentanyl citrate tablets according to the invention (hereinafter referred to as OraVescent tablets)^®) in the range that can be used therapeutically and to confirm the observation for the Cmax of the previously discussed study.

The Institutional Review Board (IRB) approved the protocol and the Informed Consent Form. Prior to the start of the study, all subjects subjected to the study had read and signed the Informed Consent Form approved by IRB. In this study, a single-dose, randomized, open, cross-over scheme was used involving 4 forms of treatment and 4 phases.

During the 21 days prior to formal registration to participate in the study, the candidates underwent screening. The screening procedure included medical history, medical examination (height, weight, skeleton size, signs of life and ECG), and clinical laboratory tests (hematology (blood counts), blood tests, urine analysis, HIV antibody screening, test screening for hepatitis B surface antigens, test for hepatitis C antibodies, blood tests to confirm or exclude pregnancy (only for women) and screening tests for cannabinoids and opioids).

All individuals who enrolled in clinical trials met the admission / exclusion criteria given in the protocol, and the Chief Researcher reviewed the medical history, clinical laboratory examinations and conducted physical examinations prior to the formal registration of participants. A total of 28 individuals expressed willingness to participate in the study, in

- 23 including 16 men and 12 women. However, 25 individuals, including 14 men and 11 women, did not stop participating in these studies.

Subjects reported to the clinic in the afternoon the day before each dose was given and received lunch at 14, lunch at 19 and a light meal at 22. Then, the subjects followed 10-hour fasting at night. On day 1, the standardized meal schedule began with lunch delivered at 13:30, then there was dinner at 18:30 and a light meal at 22:00. On day 2, standardized meal schedule (including breakfast) began

Subjects were prohibited from consuming beverages and products containing alcohol, broccoli, citrus products, caffeine or xanthine for 48 hours before and during each period of stay in the clinic. Grapefruit intake should have been restricted 10 days prior to dosing and throughout the study period. Subjects should have not used drugs containing tobacco and nicotine for at least 6 months before participating in the study. In addition, over-the-counter medications (including herbal supplements) were banned within 7 days of dosing and during the study. Prescription drugs (including MAO inhibitors) were banned within 14 days of dosing and during the study.

During the study, subjects were to remain upright, sitting for 4 hours after administration of fentanyl citrate. Water intake was restricted from the time of dosing to 4 hours after dosing. It is forbidden to eat food in the period from 10 hours before dosing to 4 hours after dosing. During the study, subjects could not perform any comprehensive activities.

Individuals for the following forms of treatment were selected by randomization:

Application No. 1: ReVia^® (naltrexone hydrochloride tablets) 50 mg.

Manufactured by Duramed Pharmaceuticals, Inc.

Lot number: 402753001T

Expiry date: June 2006.

Test subjects were given an oral dose of one 50 mg naltrexone ReVia tablet^®that they drank with 240 ml water 15 hours and 3 hours before and 12 hours after dosing as part of treatment A.

Test subjects were given an oral dose of one 50 mg naltrexone ReVia tablet^®which they drank with 240 ml water 15 hours and 3 hours before and 12.17 hours after dosing as part of treatment B, C and D.

A: 200 μg Oravescent® fentanyl citrate tablet

- 24 Manufactured by CIMA LABS INC

Lot number: 930859

Individuals selected by randomization for treatment A were given a single oral dose of one tablet containing 200 gg of fentanyl Oravescent citrate^®, which they placed between the upper gum and cheek, above the molar, and kept it in their mouths for 10 minutes until it breaks down.

B: 500 gg Oravescent fentanyl citrate tablets^®

Manufactured by CIMA LABS INC

Lot number: 930860

Individuals selected by randomization for treatment B were orally given a single dose of one tablet containing 500 gg of fentanyl citrate Oravescent^®, which they placed between the upper gum and cheek, above the molar, and kept it in their mouths for 10 minutes until it breaks down.

C: 810 gg Oravescent fentanyl citrate tablets^®

Manufactured by CIMA LABS INC

Lot number: 930501

Individuals selected by randomization for treatment C were orally given a single dose of one tablet containing 810 gg fentanyl Oravescent citrate^®, which they placed between the upper gum and cheek, above the molar, and kept it in their mouths for 10 minutes until it breaks down.

D: 1080 gg OraVescent fentanyl citrate tablets^®

Manufactured by CIMA LABS INC

Lot number: 930502

Individuals selected by randomization for treatment D were given a single oral dose of one tablet containing 1080 gg of fentanyl citrate Oravescent^®, which they placed between the upper gum and cheek, above the molar, and kept it in their mouths for 10 minutes until it breaks down.

Signs of living in a sitting position (blood pressure, pulse and breathing) were assessed each morning before dosing over a period of 0.25; 0.5; 0.75; 1; 1.25; 1.5; 1.75; 2; 2.25; 2.5; 2.75; 3; 3.25; 3,5; 3.75; 4; 5; 6; 8; 10; 24 and 36 hours after dosing. Pulse oximetry was continuously measured during the first 8 hours after the test and when the test subject fell asleep during the first 12 hours after dosing. At the end of the clinical trials, tests were performed using a 12-lead electrocardiogram, clinical evaluation tests (morphology, blood tests, urine analysis) and a medical examination including a complete examination of signs of life. Assessment of oral dose irritation was made 4 hours after dosing. During each control, the oral cavity was examined to determine if the test subjects had a mouth ulcer after taking the medicine. respondents

- 25 subjects were instructed to inform the attending physician and / or nurse about any negative symptoms that occurred during the study.

Blood samples (7 ml) were taken from test subjects selected for treatment A at the following hours: before dose administration (0 o'clock), and 10; twenty; 30 and 45 minutes, as well as 1; 2; 4; 6; 8; 9; 10; 11; 12; 14; 16; 20 and 24 hours after dosing. Blood samples (7 ml) were taken from test subjects selected for treatment B, C and D at the following hours: before dose (0 o'clock), and 10; twenty; 30 and 45 minutes, as well as 1; 2; 4; 6; 8; 10; 12; 16; twenty; 24; 28; 32 and 36 hours after dosing.

Sensitive and specific LC-MS / MS (liquid chromatography mass spectrometry / mass spectrometry) methods were used to analyze the concentration of fentanyl in human blood serum.

The following noncompartmental pharmacokinetic parameters were calculated from the concentration-time data of fentanyl for each treatment using version 2.1 of the WinNonlin Standard Edition software. Real (rather than nominal) sampling times were used in the analysis.

AUC (0-t) area under the time-concentration curve of fentanyl calculated by the linear method of summing the trapezoid fields from time 0 to time t, where t is the time of the last measurable concentration (Ct).

AUC (0-inf) area under the fentanyl time-concentration curve from 0 to infinity, AUC (0-inf) = AUC (0-t) ± Ct / Kel, where Kel is the drug elimination rate constant.

AUC (0-t) / AUC (0-inf) ratio of AUC (0-t) to AUC (0-inf). Also known as AUCR. Kel is the drug elimination rate constant calculated by linear regression elimination of the log portion of concentration relative to the time curve, where Kel = - the slope of the descending arm of the curve. The final linear portion was visually determined.

T1 / 2 drug half-life calculated as In (2) / Kel.

Cmax maximum observed concentration of fentanyl.

Tmax is the time of maximum fentanyl concentration (obtained without interpolation).

Times of serum fentanyl concentration values ​​were listed and summarized by treatment and by point using descriptive statistics (mean, standard deviation (DS), coefficient of variation (CV), standard error of mean (SEM), sample size, minimum, maximum and median).^9-11 Values ​​below the lower limit of quantification (LOQ) were configured as a value of 0. Graphs of mean and single values ​​of concentration to time are presented. The pharmacokinetic parameters for fentanyl and the pharmacokinetic parameters of the normalized dose are included in the table and determined as calculated summary statistics.

Dose proportionality in the range from 200 μg to 1080 μg was evaluated using the methodology described by Smith et al.⁸ Initially, transformation was performed on an analysis of logarithmically transformed parameters using a mixed effects model, including a logarithmically transformed dose, as well as random and fixed effects at the intersection of the axes. It was the right model to use the SAS statistical package^®PROC MIXED.^9-11

The 90% confidence interval of the effect set for the slope (β1) was calculated and compared to the range (0.8677, 1.1323), which is the appropriate critical range considering the dose range of this study.

The conclusions are based on the following statements:

1) If the 90% confidence interval for β1 was entirely within the range (0.8677, 1.1323), dose proportionality should be stated.

2) If the 90% confidence interval for β1 was completely outside this range, dose proportionality should be stated,

3) If the 90% confidence interval for β1 was partly in this range and partly out of it, the results should be considered "not final". In this case, β1 as the best estimate of the deviation from ideal proportionality and the lower and upper limits of the 90% confidence interval can be considered in the context of data on drug safety, efficacy or pharmaceutical effect.

For non-final results, the maximum dose ratio was calculated such that the 90% confidence interval for β1 was completely within the critical range and the dose ratio such that the 90% confidence interval for β1 was completely outside the critical range. These dose ratios are determined by Smith et al. as p1 and p2 respectively.

p1 = O_h* [1 / max (1-L, U-1)], where 0_H- = 1,25

L = lower level 90% confidence interval

U = upper level of the 90% confidence interval p2 = O_h* [1 / max (L-1, 1-U)], where O_h*, L and U are as defined above.

A secondary analysis to examine the difference between the Cmax of the normalized dose for the 3 lowest dose levels (200 μg, 500 μg and 810 μg) was performed. The parametric GLM model (standard theory) was applied to the Cmax of the dose normalized from treatment A, B and C after log transformation. The Full Analysis of Variance model (ANOVA) included the following factors: treatment, sequence, subject within sequence, and phase. Because treatment with group interaction was not significant, the model was reduced to sequence, object within the sequence, phase and treatment. A p value less than 0.05 was considered statistically significant.

- 27 The residence time values ​​(the period of time the drug form was present in the mouth) were calculated by reducing the observed and documented disappearance of the preparation by the value of the time of administration. These values ​​were compiled and presented in the summary statistical table. These values ​​were compiled and presented in the summary statistical table.

Three subjects discontinued the participation in the study / gave up their participation in the study. In two cases, this occurred before the start of phase 3, because the subjects did not want to continue participating in further phases of the clinical trial. Another subject was excluded after phase 2 due to other factors.

The average age of subjects was 33 years (age range: 19-55 years), average height 1.74 cm (range 1.52 cm-1.93 cm), and the average weight of subjects was 73 kg (range 50.9- 97.5 kg).

During the clinical trial, the following deviations from the protocol occurred.

One subject was not re-monitored for signs of life at 0.5 after dosing in phase 2. One subject did not re-check for signs of life at 2.5 from the dose in phase 3. One of the subjects did not receive the results of a serum test confirming or excluding pregnancy for 15 hours. before the administration of naltrexone in phase 3. For one test subject ECG results were lost in 36 hours. in phase 4. One of the subjects did not undergo the entire procedure in the event of early termination of the study. The participation of this individual is not considered in the further phase of the study. In addition, oral stage irritation was expected to be assessed in 3.83 hours in all subjects tested in phase 3. after dosing. The nurse responsible for this activity remembers its performance, but said that the oral irritation assessment forms were not filled out at that time. Therefore, it is not possible to verify information from the assessment and it should be considered that no such assessment has been carried out. The residence time data is summarized in the table below.

<td></td><td>Treatment A.</td><td>Treatment B</td><td>Treatment C.</td><td>Treatment of D</td>

<td>Test subject number</td><td>Time (min.)</td><td>Time (min.)</td><td>Time (min.)</td><td>Time (min.)</td>

<td>average</td><td> 14</td><td> 14</td><td> 17</td><td> 15</td>

<td>SD</td><td> 8</td><td> 6</td><td> 10</td><td> 11</td>

<td>CV</td><td> 59</td><td> 45</td><td> 57</td><td> 72</td>

<td>SEM</td><td> 2</td><td> 1</td><td> 2</td><td> 2</td>

<td>N</td><td> 25</td><td> 26</td><td> 27</td><td> 27</td>

<td>min.</td><td> 4</td><td> 6</td><td> 5</td><td> 4</td>

<td>max.</td><td> 37</td><td> 33</td><td> 41</td><td> 60</td>

treatment A = 200 μg treatment B = 500 μg treatment C = 810 μg treatment D = 1080 μg

28 During the oral examination at the beginning of phase 4, one subject was found to have ulceration of the oral mucosa in the inner lower right cheek at the beginning. However, the test product in phase 3 was administered in the upper part of the right cheek. The Main Investigator did not recognize this ulcer as aphthae, and qualified this individual for phase 4 dose.

Two subjects reported mild oral irritation (on a scale of 1-10 this irritation was assessed at levels 2 and 3) that occurred after treatment A. Irritation in both subjects occurred on the left side of the mouth after administration of the test preparation in phase 2. Employees participating in the study also noticed redness in one of the examined individuals. In addition, one subject reported upper left cheek pain on the gum line 11 minutes after treatment C. No serious or unexpected adverse events were reported.

Of the 28 registered volunteers, 25 completed treatment A, 26 completed treatment B and 27 completed treatment C and D. Statistical analysis was performed for pharmacokinetic data for all subjects tested.

The drug elimination rate constant could not be calculated for one test subject for treatment A because limited data points occurred in the final phase. Therefore, AUC (0-inf), AUCR, and T1 / 2 could not be calculated for this test subject.

The arithmetic mean and standard deviations of the pharmacokinetic parameters of serum fentanyl concentration after applying all forms of treatment are summarized in the table below.

Comparison of pharmacokinetic parameters of serum fentanyl

Treatment A Treatment B

<td>parameters Pharmacokinetic</td><td>N</td><td>average arithmetical</td><td>SD</td><td>N</td><td>arithmetic average</td><td>SD</td>

<td>Cmax (pg / ml)</td><td> 25</td><td> 617,8</td><td> 236,7</td><td> 26</td><td> 1546,2</td><td> 621,4</td>

<td>* tmax (hours)</td><td> 25</td><td> 0,76</td><td> 0,33-4,0</td><td> 26</td><td> 0,75</td><td> 0,33-4,0</td>

<td>AUC (0-t) (pg * h / ml)</td><td> 25</td><td> 2876,3</td><td> 1107,7</td><td> 26</td><td> 8501,2</td><td> 3346,2</td>

<td>AUC (0-inf) (pg * h / ml)</td><td> 24</td><td> 3543,9</td><td> 1304,5</td><td> 26</td><td> 9701,9</td><td> 2651,5</td>

<td>T1 / 2 (hours)</td><td> 24</td><td> 6,48</td><td> 3,69</td><td> 26</td><td> 12,0</td><td> 8,18</td>

<td>Kel (1 / hour)</td><td> 24</td><td> 0,143</td><td> 0,0802</td><td> 26</td><td> 0,0746</td><td> 0,0377</td>

<td>AUCR</td><td> 24</td><td> 0,843</td><td> 0,0604</td><td> 26</td><td> 0,875</td><td> 0,0929</td>

<td>Cmax / dose (pg / ml / mcg)</td><td> 25</td><td> 3,09</td><td> 1,18</td><td> 26</td><td> 3,09</td><td> 1,24</td>

<td>AUC (Ot) (pg * h / ml / mcg)</td><td> 25</td><td> 14,4</td><td> 5,54</td><td> 26</td><td> 17,0</td><td> 6,69</td>

<td>AUC (O-inf) (Pg * hr. / ML / mcg)</td><td> 24</td><td> 17,7</td><td> 6,52</td><td> 26</td><td> 19,4</td><td> 7,30</td>

<td>ln (C_max /dose)</td><td> 25</td><td> 1,06</td><td> 0,383</td><td> 26</td><td> 1,05</td><td> 0,426</td>

<td>ln (AUC (0-t) / dose)</td><td> 25</td><td> 2,59</td><td> 0,424</td><td> 26</td><td> 2,75</td><td> 0,441</td>

<td>ln (AUC (O-inf) / dose)</td><td> 25</td><td> 2,81</td><td> 0,369</td><td> 26</td><td> 2,89</td><td> 0,413</td>

- 29 Treatment C Treatment D

<td>parameters Pharmacokinetic</td><td>N</td><td>average arithmetical</td><td>SD</td><td>N</td><td>arithmetic average</td><td>SD</td>

<td>C_{It has}x (pg / ml)</td><td> 27</td><td> 2280,1</td><td> 968,9</td><td> 27</td><td> 2682,3</td><td> 1106,0</td>

<td>* t_{It has}x (hours)</td><td> 27</td><td> 0,99</td><td> 0,33-4,0</td><td> 27</td><td> 0,75</td><td> 0,33-4,0</td>

<td>AUC (0-t) (pg * h / ml)</td><td> 27</td><td> 13301</td><td> 4069,1</td><td> 27</td><td> 16813</td><td> 5232,2</td>

<td>AUC (0-inf) (pg * h / ml)</td><td> 27</td><td> 14962</td><td> 4709,6</td><td> 27</td><td> 18664</td><td> 6266,0</td>

<td>T1 / 2 (hours)</td><td> 27</td><td> 12,8</td><td> 4,08</td><td> 27</td><td> 11,4</td><td> 4,34</td>

<td>Kel (1 / hour)</td><td> 27</td><td> 0,0592</td><td> 0,0167</td><td> 27</td><td> 0,0679</td><td> 0,0216</td>

<td>AUCR</td><td> 27</td><td> 0,893</td><td> 0,0589</td><td> 27</td><td> 0,909</td><td> 0,0602</td>

<td>Cmax / dose (pg / ml / mcg)</td><td> 27</td><td> 2,81</td><td> 1,20</td><td> 27</td><td> 2,48</td><td> 1,02</td>

<td>AUC (0-t) (pg * h / ml / mcg)</td><td> 27</td><td> 16,4</td><td> 5,02</td><td> 27</td><td> 15,6</td><td> 4,84</td>

<td>AUC (0-inf) (Pg * hr. / ML / mcg)</td><td> 27</td><td> 18,5</td><td> 5,81</td><td> 27</td><td> 17,3</td><td> 5,80</td>

<td>ln (C_max /dose)</td><td> 27</td><td> 0,945</td><td> 0,439</td><td> 27</td><td> 0,836</td><td> 0,386</td>

<td>ln (AUC (0-t) / dose)</td><td> 27</td><td> 2,75</td><td> 0,324</td><td> 27</td><td> 2,69</td><td> 0,356</td>

<td>ln (AUC (0-inf) / dose)</td><td> 27</td><td> 2,87</td><td> 0,329</td><td> 27</td><td> 2,79</td><td> 0,372</td>

* median and minimum-maximum values ​​given for Tmax treatment A = 1 x 200 mcg OraVescent fentanyl citrate tablet^® treatment B = 1 x 500 mcg OraVescent fentanyl citrate tablet^® treatment C = 1 x 810 mcg OraVescent fentanyl citrate tablet^® treatment D = 1 x 1080 mcg OraVescent fentanyl citrate tablet^®

Slope of ln [AUC (0-t)] relative to ln (dose) and ln [AUC (0-inf)] relative to ln (dose), with 1.0574 and 0.9983.1, respectively, and a 90% confidence interval for each parameter completely within the critical range necessary for dose proportionality in the 200-1080 μg range. Slope ln (C_max) relative to ln (dose), 0.8746, was less than 1, and the 90% confidence interval (0.8145-0.9347) was not entirely within the critical range required to determine dose proportionality. The maximum dose ratio such that the 90% confidence interval for β1 was entirely within the critical range was 3.33. The maximum dose index such that the 90% confidence interval for β1 was completely outside the critical range was 30.48. ANOVA results for the Cmax normalized dose for treatment A, B and C indicate that there was no statistically significant difference in the Cmax normalized dose in the 200-810 μg dose range (p = 0.13).

The basic assumption of this study was to assess the extent to which a normalized dose occurs for AUC and C_max fentanyl after administration of 200 μg doses of fentanyl (treatment A), 500 μg (treatment B), 810 μg (treatment C) or 1080 μg (treatment D) in the form of OraVescent fentanyl citrate tablets^®. In addition, this study was conducted to confirm previous observations relating to C_maxafter administration of 810 μg or

- 30 1080 μg doses of OraVescent® fentanyl citrate tablets. This study was based on a single-dose, open, cross-over, 4-phase scheme.

Of the 28 registered participants, 25 completed treatment A, 26 completed treatment B, and 27 completed treatment C and D. Statistical analysis was performed for pharmacokinetic data for all subjects tested.

Slopes of ln [AUC (0-t)] relative to ln (dose) and ln [AUC (0-inf)] relative to ln (dose), at 1.0574 and 0.9983, respectively, were close to 1 and the 90% range confidence for each parameter was entirely within the critical range required for dose proportionality. These results indicate that the AUC of fentanyl increased proportionally with each increased dose level of OraVescent fentanyl citrate tablets^® for tested doses in the range of 200-1080 μg.

The slope of ln [Cmax] relative to ln (dose), 0.8746, was less than 1, indicating that Cmax of fentanyl did not increase in proportion to dose. The 90% confidence interval (0.8145-0.9347) was not completely within the critical range. A smaller than proportional increase was observed at the highest dose (1080 μg) and in a smaller range (± 11% confidence interval) in the second largest dose (810 μg). C_max increased proportionally in the range from 200 μg to 500 μg. Value for p₁ (maximum dose index such that the 90% confidence interval for β1 was completely within the critical range) was 3.33, while the ratio of 810: 200 μg was 4.05. This indicates that the dosage form is linear according to the invention up to about 800 μg per dose.

Secondary analysis using ANOVA, which aimed to compare the Cmax dose normalized for 200 μg, 500 μg and 810 μg doses, showed no statistically significant differences (p = 0.13) between these dose levels. The mean LS for ln (Cmax / dose) were 1.06 (200 μg), 1.06 (500 μg) and 0.94 (810 μg) showing no difference between the 200 μg and 500 μg doses and showing a minimal (less than 15 %) the difference for the 810 μg dose compared to the lower doses. The lack of significant differences between ANOVA due to the small difference between the 810 μg dose and the two lower doses indicates that there is no clinically significant deviation in dose proportionality for Cmax in the range of 200 to 810 μg. Hence they are "linear" as defined here.

Average residence times of 200, 500, 810 and 1080 μg OraVescent fentanyl citrate tablets^® 2 were similar at 14, 14, 17 and 15 minutes, respectively.

Two subjects reported slight irritation of the oral mucosa, and one subject experienced redness after administration of the OraVescent fentanyl citrate tablet^®.

Fentanyl AUC increased proportionally with increasing dose over the range of 200-1080 μg. C_max fentanyl increased less than proportionally to the dose for the two highest dose levels. The increase, however, was linear as defined herein for all doses except for a dose greater than 1 milligram. The mean ln (Cmax / dose) for the 810 μg dose was 10 to 11% lower than for the 200 μg and 500 μg doses. Mean ln (C_max/ dose) for the 1080 μg dose was 20 to 21% lower than for the 200 μg and 500 μg doses.

- There was no clinically significant deviation in dose proportionality for Cmax in the range of

200 up to 810 gg. Average residence times of 200, 500, 810 and 1080 gg OraVescent fentanyl citrate tablets^® it was similar at 14, 14, 17 and 15 minutes, respectively.

No serious or unexpected adverse events were found during the study. Each Oravescent preparation^® was well tolerated by the oral mucosa.

SOURCES

8. Smith BP, et. al. Confidence Interval Criteria for Assessment of Dose Proportionality. Pharmaceutical Research 17: 1278-1283, 2000.

9. SAS^® Institute, Inc., SAS^®/ STAT User's guide, version 6, edition 4, volume 1. Cary, NC: SAS Institute; 1989.

10. SAS^® Institute, Inc., SAS^®/ STAT User's guide, version 6, edition 4, volume 2. Cary, NC: SAS Institute; 1989.

11. SAS^® Institute, Inc., SAS^®/ STAT Procedures guide, version 6, 3rd edition. Cary, NC: SAS Institute; 1990.

12. Summary Basis of Approval NDA 20-747 (Actiq^®). Approval date: November 4, 1998 Clinical Pharmacology and Biopharmaceutics Review, p. 6.

Any form of drug that contains appropriate amounts of effervescent material and a pH adjusting substance may be used, preferably with a suitable disintegrant that can provide a dosage form of fentanyl that is beneficial for buccal, gingival or sublingual administration at the dose levels considered herein, and enabling a reduction of the dose and / or ratio of Cmax to the dose that is disclosed herein. Most preferably, for dosage forms containing about 100-800 micrograms fentanyl (based on the weight of fentanyl free base), any effervescent vapor and / or pH adjusting substance may be used that can be provided in an amount appropriate to provide a dosage form with a Tmax of 1 , 5 hours or less, and / or provides a Cmax dose in the range of 2.0-4.0 picograms / ml / micrograms, more preferably in the range 2.5-3.5; and most preferably in the range of 2.7-3.5 picograms / ml / micrograms. Preferably the dosage forms also have a linear Cmax dose ratio as described herein. This means that the ratio C_max to the dose index this will decrease along a line (p &lt;0.15) formed by a series of at least three different doses of fentanyl of this invention in the range of 100 800 micrograms having the same composition except for the amount of fentanyl.

Similarly, any amount of effervescent steam and pH regulating substance that provides a dosage form with comparable Cmax to ACTIQ is considered.^® containing at least 80% more fentanyl is considered. This means that this form has a Cmax of at least 75-125% Cmax of such ACTIQ preparation^®, more preferably in the range of 80% - 125% (p less than or equal to 0.15), and most preferably in the range of 85% - 115% of the value of the Cmax preparation, despite containing at least 45% less fentanyl (based on the weight of fentanyl free base) . In a particularly preferred form, these formulations will not contain a significant amount of any disintegrant or excipient or combination of excipients whose properties would interfere with such properties. Spray dried mannitol is the preferred filler. Another excipient is a disintegrant, which is starch glycolate, preferably sodium starch glycolate. Starch glycolate is usually described as a filler and sodium starch glycolate as a disintegrant. However, this characteristic is not critical.

Preparations in the '604 patent which included lactose monohydrate in an amount greater than 20% and / or microcrystalline cellulose in an amount of at least 20% and cross-linked PVP in an amount of 5% or more are considered incapable of providing preparations with the desired linear dose behavior and Cmax at the levels discussed here despite the presence of a pH regulating substance and effervescent vapor. The preparations in the '604 patent also contain more than 880 μg of fentanyl.

Preferably the effervescent, orally disintegrating dosage form of this invention is such a dosage form which, based on the weight of fentanyl free base, contains from about 100 to 800 micrograms of fentanyl (90-880), or a proportional weight of one of its pharmaceutically acceptable salts . In addition, these figures are intended to cover basic procedure variations such as composition uniformity, etc. Dosages of about 100, 200, 300, 400, 600 and 800 micrograms, respectively, are particularly preferred.

It is preferred that the average particle size of fentanyl, as determined by laser diffraction technique, used in the range of formulations ranging from 0.2 to 150 microns, preferably from 0.5 to 100 microns, and more preferably from 1 to 20 microns.

Any known combination can be used as the effervescent agent or effervescent pair. These are the combinations described in US Patent Nos. 5,178,878 and 5,503,846 to the extent that they relate to various sparkling pairs and the construction of their structures. Generally, effervescent vapors are materials activated by water or saliva, which are usually in anhydrous state with little or no moisture absorbed or in solid hydrated form. They usually contain at least one source of acidity, and at least one source of reactive base, usually carbonate or bicarbonate. Each of the components of the effervescent pair can be any ingredient that is safe for human consumption.

Generally, acids include food acids, acid anhydrides and acid salts. Food acids include citrate, tartaric, malic, fumaric, adipic, ascorbic and succinic acid. Acid anhydrides or salts of these acids may be used. Salts in this context may include any known salts, but in particular sodium, dihydrogen phosphate, dihydrogen phosphate dihydrate, citrate salts and sodium acid sulfate. Bases useful according to the invention typically include sodium bicarbonate, potassium bicarbonate and the like. Sodium carbonate, potassium carbonate, magnesium carbonate and the like can also be used to the extent that they are used as part of an effervescent pair. However, more preferably they are used as pH adjusting substances. Preferably, stoichiometrically equivalent amounts of acid, acid anhydride or are used

- 33 salts of acid and base. However, it is possible to use some excess acid or base. However, care should be taken when preparing such a preparation, especially in view of the overall effect of the substances controlling the pH level of the case for such ingredients. Excess can affect absorption.

The amount of useful effervescent material according to this invention is the amount determined based on properties other than those that would be necessary to achieve tablet disintegration in the mouth. Instead, effervescence is used as a basis to improve the transfer of fentanyl when buccal, gingival or sublingual administration across the oral mucosa. Accordingly, the amount of effervescent steam should be in the range of 5-85%, more preferably in the range of 15-60%, even more preferably in the range of 30-45%, preferably and most preferably in the range of 35-40%, based on the weight of the whole preparation. Of course, the relative acid-base ratios will depend on the particular ingredients (e.g., whether the acid is monobasic, dibasic or tribasic), relative molecular weights, etc. Preferably, however, a stoichiometric amount of each element is provided, although, of course, surpluses are allowed.

Preferably, the preparations according to the invention contain at least one pH adjusting substance. Without wishing to be bound by any theory, it can be assumed that a drug in an ionized state susceptible to changes can be administered providing appropriate conditions for its dissolution and transfer through one or more membranes or tissues within the oral cavity, such as mucus through the mucosa oral cavity. If the ideal conditions for transferring a particular medicine are alkaline, then it may not be advisable to add a sufficient surplus of sufficiently strong acid as part of the effervescent vapor or as a pH regulating substance. It would be preferable to choose another pH adjusting substance such as, for example, anhydrous sodium carbonate, which acts separately and independent of effervescent agents.

The pH regulating substance of the invention can be used to provide further improvement in permeation. The choice of the right substance to regulate the pH level will depend on the medicine to be administered, and in particular on the pH value for which the drug is in ionized or non-ionized form and the ionized or non-ionized form facilitates transmission across the oral mucosa. With respect to fentanyl and its salts, a basic substance is advantageous for providing fentanyl. The pH regulating substances of the present invention may include, but are not limited to, any substances that can adjust the pH level at a particular location so that it is beneficial for transport across the oral membranes in amounts that will result in an overall pH level of from 4 to about 9, in this case the "pH" in the patient's oral microenvironment in the area of ​​the surface contact of the oral mucosa and the dosage form or any part thereof (such as when it breaks down). For the purposes of the invention, the pH at a specific location can be determined as follows: in vitro pH measurement was used to characterize the dynamic pH changes exhibited by the subject tablets. This method involves using 0.5-10 ml of phosphate buffered saline in a suitable sized tube or similar vessel.

- 34 The amount of medium depends on the tablet size and dose. For example, for fentanyl tablets, a volume of 1 ml was used for tablets that weigh 100 mg. Immediately after contact of the tablet with the medium, the pH profile of the solution is monitored as a function of time, using a microelectrode for pH measurement. Preferably, the materials that can be used as pH adjusting substances of this invention include carbonates such as sodium, potassium or calcium carbonate, or phosphates such as calcium or sodium phosphate. Most preferably it is sodium carbonate. The amount of pH adjusting substance useful according to this invention may vary depending on the type of pH adjusting substance used, the amount of any excess acid or base from the effervescent pair, the type of other ingredients, and of course the medication in this case is fentanyl.

Most preferably the amount of pH adjusting substance is in the range of 0.5-25%, more preferably in the range of 2-20%, even more preferably in the range of 5-15% and most preferably in the range of 7-12% by weight of the whole preparation. Most preferably the pH adjusting substance is carbonate, bicarbonate or phosphate. Also preferred are those pH adjusting substances that, when provided in the right amount, can cause a change in the pH level at a specific location of at least 0.5 units, more preferably 1.0 pH units, and even more preferably about 2.0 pH units compared to an identical formulation without a pH adjusting substance. Any filler or any amount of filler can be used as long as the resulting dosage forms lead to the effects described herein. Sugar and sugar alcohols are the most preferred fillers as well as direct and indirect compression. Generally, direct compression fillers, at least at the time of their formulation, are characterized by flow and / or compression that render them impractical for use in a rapid tabletting process without increasing or adjusting them. For example, the flow of preparation may not be sufficient and therefore it may be necessary to add a glidant such as, for example, silicon dioxide.

Unlike direct compression fillers, they do not require such additives. Their compressibility and flowability allow their direct use. It was noted that depending on the method of production of the formulations, indirect compression fillers can be given the characteristics of direct compression fillers. The reverse also applies. Generally, indirect compression fillers typically have a relatively small particle size compared to fillers for which direct compression was used. However, certain specific fillers, such as spray dried mannitol with relatively small particle sizes, are often subjected to direct compression, depending on which further treatment they are subjected to. There are also relatively large fillers that are subjected to indirect compression.

Preferred fillers according to this invention include mannitol, lactose, sorbitol, dextrose, sucrose, xylitol and glucose, to the extent that their use can provide the results described herein. More preferably, according to this invention, the filler is not lactose monohydrate used in an amount of about 20% by weight or more of the formulation, and even more preferably lactose monohydrate is not used. Most preferably, according to this invention, spray dried mannitol is used. The amount of filler can range from 10 to about

80%, more preferably within 25-80%, and most preferably within 35-60% by weight of the formulation.

Disintegrants may also be used in accordance with this invention insofar as they enable or even facilitate dose reduction, linearity and / or Cmax and dose ratio as described herein. They may also include binders that have disintegrating properties. The disintegrants according to this invention may include microcrystalline cellulose, cross-linked polyvinyl pyrrolidone (PVP-XL), sodium starch glycolate, croscarmellose sodium, cross-linked hydroxypropyl cellulose. Of course, the choice of disintegrant depends on whether the results described herein can be achieved. More preferably, the formulation will not contain more than about 20% of microcrystalline cellulose and cross-linked polyvinyl pyrrolidone in an amount of 5% or more, especially a formulation that further includes 20% lactose monohydrate. Most preferably the disintegrant to be used is sodium starch glycolate. In fact, it has been found that the use of sodium starch glycolate in the formulations of this invention can provide a significant improvement in dose reduction while still providing comparable Cmax to effervescent formulations that include pH regulators and other disintegrants. GLYCOSYL is a particularly useful sodium starch glycolate^® (standard degree), available from Roquette of Lestrem, France. In fact, it is even more advantageous if the formulation does not contain microcrystalline cellulose or cross-linked PVP.

The amount of disintegrant depends on known factors such as the size of the dosage form, the type and amount of other ingredients used, etc. However, in general, the amount should be in the range of 0.25 to 20% by weight of the final formulation, more preferably in the range of 0.515% by weight, even more preferably in the range of 0.5 to 10% by weight, and more preferably in the range of 1 to 8% by weight. These amounts are again based on the weight of the final formulation.

A lubricant is also commonly useful according to this invention. Magnesium stearate is the most common lubricant and its use is preferred. Colloquially, according to traditional wisdom on lubricants, less is more. In most situations, it is preferable to use less than 1% of such substance. Typically, this amount should be 0.5% or less. However, magnesium stearate may be used in an amount exceeding 1.0%. In fact, it is preferred that the amount is greater than about 1.5%, most preferably in the range of 1.5-3%. It is most preferred to use about 2% magnesium stearate. Other conventional lubricants, such as, for example, stearic acid, calcium stearate and the like can also be used instead of all or part of the magnesium stearate.

The effervescent tablets of this invention may be relatively soft or hard. For example, they can be produced according to the methods described in US Patent No. 5,178,878, and their durability will typically be less than about 15 newtons. Unlike the preparations described in Patent No. 5,178,878, here the active ingredient will not necessarily be coated with a protective layer. In fact, active fentanyl will not be deliberately coated.

If such soft, flexible and crunchy tablets are produced, they may preferably be packaged in blister packs, such as those in US Patent No. 6,155,423. They can also be hard with a durability of more than 15 newtons, manufactured according to the procedures referred to in US Patent No. 6,024,981. In a preferred embodiment, the fentanyl dosage forms of this invention are provided in a blister pack that is child-resistant. See, for example, US Patent No. 6,155,423 to Katzner et. al., issued on December 5, 2000, and owned by CIMA LABS INC. The packaging most preferably meets the standards referred to in Act 16 USC §1700.15 and .20 (2003). Preferably, the packaging also includes those commonly referred to in the industry as "F1" and "F2" packaging. "F1" packaging is most preferred.

The tablets of this invention may be made in a slightly different manner for buccal, gingival or sublingual administration. In any case, however, the preferred disintegration / dissolution time (residence time) of the formulations is less than about 30 minutes, and most preferably about 20 minutes or even less. Usually it is over 5 minutes, usually 10 minutes or more. This is a subjective statement based on the patient's response.

According to a particularly preferred embodiment of this invention, an effervescent, orodispersible tablet is provided for adjusting the administration of fentanyl, or a pharmaceutically acceptable salt thereof, buccal, gingival or sublingual, which contains between about 100 to about 800 micrograms of fentanyl (based on the weight of its free base ), an effective amount of effervescent steam and an effective amount of pH regulating substance and starch glycolate. The formulation also contains mannitol.

In a particularly preferred aspect of this embodiment, the formulations described above contain lactose monohydrate and / or cross-linked PVP in amounts that do not render them unable to provide a dose reduction relative to ACTIQ^® at least 45% by weight fentanyl. In particular, it is preferred that no more than about 10% by weight of the formulation is lactose monohydrate or microcrystalline cellulose, and no more than about 4% is cross-linked PVP. More preferably, the formulation only contains random amounts of such excipients. Most preferably according to this invention sodium starch glycolate is used as a disintegrant and mannitol as a filler. Most preferably, the filler contains spray dried mannitol.

The formulations of this invention may include other conventional excipients in generally known amounts to the extent that they do not diminish the advantages of the benefits described herein. These may include binders, sweeteners, coloring, flavoring, glidants, preservatives and disintegrants.

Tablets, the preferred dosage form according to this invention, can be produced using any known tableting technique. However, mixing of the bulk materials used and direct compression technology is preferably used. Although granulation can be used to make tablets, this is not preferred. Of course, the individual excipients and materials used in the formulations of this invention can

- 37 be produced using dry or wet granulation technology. For example, granulated mannitol can be used as a filler. It may also be desirable for a portion of the formulation to be granulated or premixed before final mixing and compression. The materials discussed are previously selected to provide a suitable dose, uniform content, as well as dose reduction, Cmax / dose ratio and / or linearity described herein. From here, the appropriate amount of effervescent vapor, the appropriate and appropriate pH adjusting substance, and the appropriate disintegrant are selected, which are provided in predetermined amounts and formulated in dosage forms, preferably tablets.

Preferred pH regulating substances are carbonates, bicarbonates or phosphates, the preferred disintegrant is sodium starch glycolate. The amounts of each used are described elsewhere in this document. Preferably, however, the disintegrant is selected and provided in an amount sufficient to allow a further reduction of the dose in terms of fentanyl compared to an identical formulation containing effervescent vapor and a pH adjusting substance without the disintegrant. Preferably, the pH adjusting substance is selected and provided in an amount sufficient to change the pH level at a specific location by at least 0.5 units, more preferably by 1.0 unit and most preferably by 2.0 units or more. Insofar as the tablets can be compressed to any stability and / or fragility, the same must be achieved without adversely affecting the residence times, release of the drug and its transmission through the oral mucosa. Wherever possible, it is desirable to provide compressed tablets as a dosage form of fentanyl, with durability of 5 to 100 newtons, more preferably of 10 to 50 newtons.

The dosage forms of this invention can be used to treat any type of pain, in particular pain to treat which opioid therapy is usually recommended. As with all opiates, fentanyl products, and in particular those discussed in this invention, should always be taken after consulting a physician and under close medical supervision. General guidelines for the use of ACTIQ® are contained in the content of the previously mentioned label, which are in the development of the Physician Desk Reference, and the warnings and contraindications contained therein are widely used for the use of the dosage forms of this invention. This usually includes dose modifications administered to patients by reducing the dose before increasing the dose.

The dosage forms of this invention are administered by placing in the patient's mouth, preferably under the tongue or between the cheek and jaw, where they remain until they break up / dissolve and when they cease to be recognizable. Preferably, swallowing is minimized to assist maximum transmission of fentanyl across the oral mucosa.

Additional doses are taken as needed. As previously noted, a single dose such as, for example, 800 micrograms fentanyl may be taken as the single dosage form of this invention or as a series of several dosage forms such as, for example, two dosage forms of this invention, each containing 400 mg

Fentanyl, or four dosage forms of this invention, each containing approximately

200 mg fentanyl. Preferably, such multiple dosing includes all dosage forms that will be administered within 1 hour, preferably at approximately the same time, if not simultaneously.

In particular, one form of tablet production of this invention useful for buccal, gingival or sublingual administration includes providing fentanyl or a salt thereof in an amount of about 100 to about 800 micrograms per dose (based on the weight of fentanyl base), or an equivalent amount thereof. Effervescent steam is also provided in an amount of 5 to about 85% by weight of the dosage form, at least 1 substance adjusting the pH level in an amount of 5-25% by weight of the dosage form, and at least one disintegrant, which is starch glycolate supplied in an amount of 0.25-20 % by weight of the dosage form. They are mixed and compressed to form a tablet. Filler is also used. In particularly preferred embodiments, the portion of filler may be previously mixed with fentanyl or another excipient such as, for example, a coloring agent.

In addition, one of the excipients commonly used in this invention is a glidant such as magnesium stearate. It is usually added at the end of the mixing process. Mixing is often interrupted to add magnesium stearate, after which it resumes for a few extra minutes.

In a preferred embodiment, the blister pack containing the dosage form and according to this invention should be opened immediately before administration. The patient should place the dosage form in his mouth, preferably between the cheek and lower or upper gums. The dosage form should not be chewed or sucked. The amount of fentanyl, like many other opiates, is preferably adjusted starting from a relatively low initial dose. The initial dosage form of the fentanyl formulations of this invention, especially that used to treat episodes of breakthrough pain due to cancer, should be 100 micrograms. The patient should be given a limited initial supply of 100 mg dosage forms so as to limit the number of units used at home while gradually increasing the dose. Then the doses may be increased under medical supervision.

EXAMPLES

Production method

In each of Examples 1-7 and 9-11, the materials were checked before use, placed in a V-type mixer, they could also be mixed in any low-shear mixer and mixed for a sufficiently long time. After removal from the mixer, the materials were compressed on a typical rotary tablet machine to obtain a target durability of 13 newtons and a target mass of 100 or 200 mg as described in each example.

- EXAMPLE 1 - Form A

OraVescent® fentanyl, 1080 mcg, tablet size 7.94 mm *, red

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 1,688</td>

<td>mannitol, USP *</td><td> 95,312</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, USP / NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td>red iron oxide, NF</td><td> 1,000</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

* spray dried (Mannogem EX manufactured by SPI Pharma)

EXAMPLE 2 - Form C

OraVescent® fentanyl, 1300 mcg, 7.94 mm tablet *, red

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 2,042</td>

<td>mannitol, USP *</td><td> 94,958</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, USP / NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td>red iron oxide, NF</td><td> 1,000</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

spray dried

- 40 EXAMPLE 3 - Form D

OraVescent® fentanyl, 810 mcg, tablet size 7.94 mm * ,. yellow

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 1,266</td>

<td>mannitol, USP *</td><td> 95,734</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, USP / NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td>yellow iron oxide, NF</td><td> 1,000</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

spray dried

- 41 EXAMPLE 4 - Form E

OraVescent® fentanyl, 270 mcg, tablet size 7.94 mm *, white

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 0,422</td>

<td>mannitol, USP *</td><td> 97,578</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, USP / NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

spray dried

EXAMPLE 5

OraVescent® fentanyl, 500 mcg, tablet size 7.94 mm *,. Orange

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 0,786</td>

<td>mannitol, USP *</td><td> 96,214</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td>yellow iron oxide, NF</td><td> 0,600</td>

<td>red iron oxide, NF</td><td> 0,400</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

spray dried

- 42 EXAMPLE 6

OraVescent® fentanyl, 200 mcg, tablet size 7.94 mm *, white

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 0,315</td>

<td>mannitol, USP *</td><td> 97,685</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

spray dried

EXAMPLE 7

OraVescent® fentanyl, 100 mcg, 6.35 mm * tablet, white

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 0,157</td>

<td>mannitol, USP *</td><td> 48,843</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 21,000</td>

<td>citric acid, USP / EP / JP</td><td> 15,000</td>

<td>sodium carbonate, NF</td><td> 10,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 3,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 2,000</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 100,000</td>

spray dried

- 43 EXAMPLE 8

The materials can be checked before use, placed in a V-type mixer or any other low-shear mixer and mixed for a sufficiently long time. After removal from the mixer, the materials were compressed on a typical rotary tablet press to obtain a target stability of 13 newtons and a target weight of 200 mg / tablet.

OraVescent® fentanyl, 300 mcg, 7.94 mm tablet *, light yellow

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 0,472</td>

<td>mannitol, USP *</td><td> 97,328</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td>yellow iron oxide, NF</td><td> 0,200</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

* spray dried

EXAMPLE 9

OraVescent® fentanyl, 400 mcg, tablet size 7.94 mm *,. pink

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 0,629</td>

<td>mannitol, USP *</td><td> 97,171</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td>red iron oxide, NF</td><td> 0,200</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

spray dried

- 44 EXAMPLE 10

OraVescent® fentanyl, 600 mcg, tablet 7.94 mm *,. Orange

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 0,943</td>

<td>mannitol, USP *</td><td> 96,057</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td>yellow iron oxide, NF</td><td> 0,600</td>

<td>red iron oxide, NF</td><td> 0,400</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

spray dried

EXAMPLE 11

OraVescent® fentanyl, 800 mcg, tablet size 7.94 mm * ,. yellow

<td>INGREDIENT NAME</td><td>QUANTITY (mg / tablet)</td>

<td>Fentanyl Citrate, USP</td><td> 1,257</td>

<td>mannitol, USP *</td><td> 95,743</td>

<td>sodium bicarbonate, USP / EP / JP</td><td> 42,000</td>

<td>citric acid, USP / EP / JP</td><td> 30,000</td>

<td>sodium carbonate, NF</td><td> 20,000</td>

<td>sodium starch glycolate, NF / EP</td><td> 6,000</td>

<td>magnesium stearate, USP / EP / JP</td><td> 4,000</td>

<td>yellow iron oxide, NF</td><td> 1,000</td>

<td></td><td></td>

<td></td><td></td>

<td>TOGETHER</td><td> 200,000</td>

spray dried

- 45 EXAMPLE 12

The following materials are weighed and screened

<td> #</td><td>Description</td><td>quantity / tablet (% by weight)</td><td>quantity / batch (Kg)</td>

<td> 1.</td><td>fentanyl citrate</td><td> 0,6285</td><td>502.8 g *</td>

<td>2a.</td><td>EZ mannitol</td><td> 23,875</td><td> 19,1</td>

<td>2b.</td><td>EZ mannitol</td><td> 24,014</td><td> 19,2</td>

<td> 3.</td><td>sodium bicarbonate, No. 1</td><td> 21,0000</td><td> 16,8</td>

<td> 4.</td><td>citric acid, anhydrous, with small granular parts</td><td> 15,0000</td><td> 12,0</td>

<td> 5.</td><td>sodium carbonate, anhydrous</td><td> 10,0000</td><td> 8,000</td>

<td> 6.</td><td>sodium starch glycolate</td><td> 3,0000</td><td> 2,400</td>

<td> 7.</td><td>yellow iron oxide 10</td><td> 0,5000</td><td> 0,400</td>

<td> 8.</td><td>magnesium stearate, of non-calming origin</td><td> 2,0000</td><td> 1,600</td>

<td></td><td></td><td></td><td></td>

<td></td><td>Together</td><td> 100,0000</td><td> 80,0</td>

* spray dried

Transfer mannitol EZ (2a) and yellow iron oxide to a type V mixer and mix for 30 minutes. Remove and grind the premix. Add the whole amount of pre-mixed fentanyl citrate, sodium bicarbonate, citric acid, sodium carbonate, and sodium starch glycolate to the type V mixer and mix for 30 minutes. Add mannitol (2b) to the type V mixer and mix for 13 minutes. Add magnesium stearate to the V-type mixer and mix for 5 minutes. After final mixing, compress the tablets. These tablets have a 1/4 '' diameter, are flat, white and have a bevelled edge. They are compressed to obtain a fully equipped 36-position Fette tablet press^® to obtain an average lifetime of 13 newtons.