ES2360114T3 - EFFERVESCENT ORAL OPERATIC PHARMACEUTICAL FORMS AND METHODS OF ADMINISTRATION OF OXICODONE. - Google Patents

Abstract

A pharmaceutical form comprising 20 to 200,000 micrograms of an opioid, 0.5 to 25% w / w of a pH regulating substance suitable for said opioid, 5 to 85% w / w of an effervescent material, mannitol and a starch glycolate; wherein said pharmaceutical form is designed for the administration of said opioid through the oral mucosa through a route of oral, gingival or sublingual administration; where said opioid is oxycodone.

Description

TECHNICAL FIELD

Fentanyl (CAS Registry No. 437-38-7) N-phenyl-N- [1- (2-phenylethyl) 4-piperidinyl] propanamide and its salts, in particular its citrate salt (CAS Registry No. 990-73-8) are opiates, controlled substances and extremely potent narcotic analgesics. Fentanyl and its citrate salt are currently marketed by several companies in different delivery formats. Fentanyl citrate, for example, is available in injectable and oral dragee with stick, the latter is sold under the trade name of ACTIQ®. In the publication Approved Pharmaceutical Products with Therapeutic Equivalence Assessments (hereinafter “FDA's Orange Book”), the FDA identifies three ACTIQ® related patents: US patents. UU. Nos. 4,671,953, 4,863,737 and 5,785,989.

A review of the information contained in the ACTIQ® package marketed by Cephalon, Inc., 145 Brandy Wine Parkway West, Chester, PA 19380, available from the Physician’s Desk Reference, 57th ed. 2003 on page 1184, immediately puts into perspective the severity of the afflictions of the patients who take it. According to its label, ACTIQ® "is indicated only for the treatment of breakthrough pain caused by cancer in patients with malignant tumors that are already receiving and are tolerant to opioid therapy to treat underlying persistent pain due to cancer." (Idem, emphasis on the original).

Getting pain relief in patients with such breakthrough pain is inexorably related to the patient's immediate quality of life. For such patients, getting relief from breakthrough pain may be the only thing that medical science can offer.

Fentanyl is a member of the family of drugs known as opiates. Legal opiates are prescription drugs and include alfentanil, alfaprodin, anileridine, benzylmorphine, becitramide, buprenorphine, butorphanol, clonitacene, codeine, codeine phosphate, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydroxromine diol enol, dynodinol diol enol acetate dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine hydrochloride, morphine, morphine sulfate, mirofin, nalbuphine, narcein, nicomorphine, norlevorphanol, normetadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papveretum, pentazocine, fenadoxone, phenazocine, phenoperidine, piminodine, proprcinamide, piritramidene, propyridine, pyrramidene, propyridine, pyrramidene, propyl pyrramidene, piritramidene, propyridine, pyrramidene, propyl pyrramidene, propyl pyrramidene, piritramidene, proprincinate remifentanil, sufentanil and tilidine. The type of compounds generally known as opiates also includes illicit drugs such as heroin and cocaine. The opioid according to the present invention is oxycodone. Opioids are given to patients for several reasons, the most frequent of which is the mitigation of any type of pain. Although the profile of side effects is not always the same as that of fentanyl, this type of compound is characterized by very strong drugs, which are addictive and can have lethal side effects, depending on the dose.

Until now, fentanyl is unique among opiates in the fact that it has been formulated as an orally disintegrable pharmaceutical form.

U.S. Patent UU. No. 6,200,604 ("the '604" patent), which was granted on March 13, 2001 to CIMA LABS INC., 10000 Valley View Road, Eden Prairie, MN 55344, exemplifies two fentanyl formulations each with a Effervescence of 36% and each containing 1.57 milligrams of fentanyl citrate. Refer to example I of this, from line 60 of column 5 to line 30 of column 6. The '604 patent describes the use of, among other things, effervescence as a penetration enhancer to influence absorption Oral drug. Refer also to US patents. UU. Nos. 6,759,059 and 6,680,071. Also refer to Brendenberg, S., 2003 New Concepts in Administration of Drugs in Tablet Form: Formulation and Evaluation of a Sublingual Tablet for Rapid Absorption, and Presentation of an Individualized Dose Administration System, Acta Universitiatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 287, p. 83. Uppsala ISBN 91-554-5600-6.

As often happens in medicine, it can always be improved. Opioids are expensive drugs. Fentanyl, for example, costs manufacturers up to $ 100 per gram or more. Although cost is by no means a primary factor, the cost of medication is a factor to consider. A formulation that allows a reduction in the amount of opioid could reduce the overall cost of caring for a patient.

Even more importantly, a reduction in the dose of an opioid so potent that it can still achieve a beneficial treatment of breakthrough pain, for example, in cancer patients or in patients with chronic back pain, would have desirable and far-reaching consequences. as for the general care of the patient. Opioid mu receptor agonists, including fentanyl, produce dose-dependent respiratory depression. Vulnerable individuals can develop severe or lethal respiratory depression, even at the recommended doses. Like other potent opiates, fentanyl has been associated with cases of severe and lethal respiratory depression in individuals who do not tolerate opiates. Such side effects, even those that do not endanger the patient's life, can be significant.

In addition, mu opioid agonists can produce dependence and tolerance to the drug. Drug dependence in itself is not necessarily a problem in certain types of cancer patients. But opiates can also be used in the treatment of other types of pain. In such treatment protocols, dependence and tolerance can be significant factors. In addition, cancer patients are generally under strong medication. The longer a lower dose of medication can be provided, the better.

If lower doses of opiates could be achieved that would nevertheless provide similar pain relief, patients could obtain comparable benefits with a lower amount of drug at a lower cost and with a reduced risk of side effects. Thus, the improvement of opioid administration remains desirable.

SUMMARY OF THE INVENTION

The present invention relates to orally disintegrable / soluble effervescent pharmaceutical forms containing opiates, methods for using such pharmaceutical forms to treat pain and their uses for the manufacture of a drug. In a preferred embodiment, the opioid or one or more of its pharmaceutically acceptable salts are administered orally in doses containing less amount of opioid than would be necessary in other forms of delivery, including the examples in US Pat. UU. No. 6,200,604, to provide a comparable Cmax. The pharmaceutical form according to the present invention comprises from 20 to 200,000 micrograms of an opioid, from 0.5 to 25% w / w of a pH regulating substance suitable for said opioid, from 5 to 85% w / w of a Effervescent material, mannitol and a starch glycolate, where said pharmaceutical form is designed to administer said opioid through the oral mucosa through a route of oral, gingival or sublingual administration, and where said opioid is oxycodone.

In the context of the invention, "oral" pharmaceutical form includes orally disintegrable and / or soluble tablets, capsules, pills, gels, creams, films and the like. Generally, these dosage forms are applied.

or they are located in a specific place in the oral cavity and remain unchanged in it until they disintegrate and / or dissolve. The pharmaceutical forms of the present invention are preferably designed for oral, gingival and / or sublingual administration. The dissolution / disintegration, also referred to herein as residence time, is on average between 5 and 30 minutes, more preferably 10-30 minutes, even more preferably 12-30 minutes. It should be noted that although disintegration and dissolution are different concepts, they are generally used interchangeably here as the time it takes for the tablet to cease to exist as an identifiable unit that acts as a supply vehicle.

In another preferred aspect of the present invention, an orally disintegrable / soluble effervescent pharmaceutical form is provided, comprising an effervescent additive, a pH regulating substance and specific disintegrants, designed for the administration of an opioid and / or pharmaceutically acceptable salts thereof. through the oral cavity, such as through oral, gingival or sublingual administration routes. Without wishing to be bound by any particular theory of operation, it is believed that effervescence acts as a penetration enhancer. Preferably, the pH regulating substance is different from one of the molecules used to generate effervescence and preferably provides a difference or a change in the pH of the microenvironment in the surface contact area of the oral mucosa and of the pharmaceutical form or any part of It is at least about 0.5 pH units when compared to a comparable pharmaceutical form without pH regulating substances. Such an embodiment of the invention comprises between 20 and 200,000 micrograms of an opioid, between 0.5 and 25% by weight of the pharmaceutical form ("w / w") of a pH regulating substance suitable for said opioid, between 5 and 85% w / w of an effervescent additive material, a starch glycolate and the mannitol filler; Said pharmaceutical form is designed for the administration of the opioid through the oral mucosa through a route of oral, gingival or sublingual administration.

In another particularly preferred embodiment of the present invention, a pharmaceutical form is provided consisting essentially of an effective amount of an opioid, calculated as the opioid in the form of a free base, or a proportional amount of a salt thereof, a starch glycolate , at least one pH regulating substance and at least one effervescent additive. All of them are provided in amounts effective to form a well-formed orally disintegrable or soluble pharmaceutical form and, in an even more preferred embodiment, which allows the administration of a smaller amount of the opioid to achieve a "comparable" Cmax. Preferably, the decay time

or average residence time will be between 10 and 30 minutes. These average residence times are based on multiple doses of 10 patients or more. These pharmaceutical forms have a size, shape and design suitable for oral, sublingual or gingival administration.

Also contemplated as another aspect of the invention are methods of administering an opioid to patients who experience pain in general including, but not limited to: back pain, low back pain, joint pain, any form of arthritic pain, pain caused by trauma or accidents. , neuropathic pain, surgical or postoperative pain, pain caused by a disease or condition other than cancer, pain caused by cancer and in particular, breakthrough pain caused by cancer. A preferred method includes the steps of administering to a patient requiring an orally disintegrable dosage form described herein for oral, gingival or sublingual administration, which includes an effective amount of an opioid, and maintaining the pharmaceutical form in the mouth. of the patient for a time sufficient to allow the transport of said dose (or a therapeutically significant portion thereof, for example, sufficient to reduce the pain of a patient) from the oral cavity to the blood flow through the oral mucosa. Preferably, the patient is taught, trained or observed to ensure that the dose is not swallowed and instead, as far as possible, the opioid enters the body through one or more of the surfaces inside the mouth and The oral cavity The method also preferably includes the step of keeping the pharmaceutical form in the mouth, substantially without moving it into the oral cavity. In another preferred aspect, the dose dissolves in an average of about 30 minutes or less, preferably in about 20 minutes or less and generally in 10 minutes or more. In yet another preferred embodiment, the administered pharmaceutical form contains a smaller amount of the same opioid than would normally be provided to achieve the intended therapeutic response (the level of pain relief that is intended) in relation to a pharmaceutical form that does not include the effervescent additive, the pH regulating substance or the starch glycolate of the invention. In one embodiment, the pharmaceutical form reaches a comparable Cmax value (80-120%) compared to an identical formulation but does not contain said pH regulating substance or the effervescent additive with an opioid dose that is at least about 20 % lower in p / p.

BEST METHOD FOR CARRYING OUT THE INVENTION

Throughout the specification, including the claims, the term "understand" and variations thereof, such as "comprising" and "comprising", as well as "having", "having", "includes", "include "And" which includes ", and variations thereof, means that the named steps, elements or materials referred to are essential, but that other steps, elements or materials may be added and still form a construction within the scope of the claim or description. When named in describing the invention and in a claim, it means that the invention and what is claimed are considered for what follows and potentially more. These terms, particularly when applied to the claims, are inclusive or open and do not exclude elements or steps of the additional non-mentioned methods. The term "between" includes the values of the ends of the interval, unless otherwise specified. In the present invention, the term "comparable" means that Cmax of a pharmaceutical form according to the invention will be 80-120% of that in an identical pharmaceutical form without an effervescent additive, a pH regulating substance or a glycolate of starch.

Unless otherwise defined with respect to a specific property, characteristic or variable, for the purposes of the present invention the term "substantially" when applied to any criterion, such as a property, characteristic or variable, means that it is achieved The criterion mentioned to such an extent that one skilled in the art would understand that the benefit to be achieved or the condition or value of the desired property are achieved.

An aspect of the invention is a method of administering an opioid to a patient experiencing pain. This method may comprise the steps of contacting the oral mucosa of a patient in need with an orally disintegrable dosage form. The pharmaceutical form includes a single dose of an effective amount of an opioid, generally between 20 and 200,000 micrograms (measured as the free base), and in another embodiment, between 50 and 160,000 micrograms and, more preferably, between 50 and 100,000 micrograms or a proportional amount of a salt from this. Although preferably the dose is delivered in a single pharmaceutical form, it can be divided or divided between two or more pharmaceutical forms administered more or less at the same time (for example, in an interval of one hour between them). These doses can be repeated up to several times a day, as directed by the doctor prescribing the treatment.

In one embodiment, the pharmaceutical form is kept in contact with the patient's oral mucosa for the time necessary to allow the transport of a therapeutically significant portion of the opioid, preferably more than 50%, more preferably more than 60% and even more preferably the 75% or more of the dose, from the oral cavity to the blood flow through the oral mucosa. In another embodiment, the pharmaceutical forms of the invention will have a residence time in the mouth of between 5 and 30, preferably between 10 and 30, more preferably between 12 and 30 minutes. This is based on repetitive trials with at least 10 patients.

It has now been discovered that, in certain embodiments, the use of effervescence and a pH regulating substance, together with specific disintegrants, can provide, in certain embodiments, significant advantages, particularly in terms of the amount of opioid that is required for the dose when compared to similar formulations that use different substituents. It has also been discovered that certain excipients in combination with effervescent additives and pH regulating substances can provide very unexpected results. Particularly preferred are effervescent formulations that include a pH regulating substance, mannitol as filler and, in addition, starch glycolate.

To determine whether or not a particular formulation is capable of obtaining the results described herein, only a routine human clinical study of said formulation needs to be carried out. The appropriate clinical study would use any of the traditional models. Examples of suitable studies are shown below:

Design and conduct of the comparative clinical study

This study and the informed consent forms (ICF) have been approved by the Institutional Review Committee (IRB). All subjects read and signed the ICF forms approved by the IRB before starting the study. The signed and attested ICF forms are archived.

During the first two periods, the study used a single, randomized, open-label, cross-dose design of two variables of the designated reference and test products, and the subjects randomly received one of the three additional test formulations during the Period 3. All subjects were randomly distributed in a fasting state, having spent 10 hours fasting overnight. A 7-day rest interval was left between the three doses administered. The subjects stayed in the clinic for 36 hours after the administration of fentanyl.

Subjects underwent a medical review within 21 days prior to the start of the study. The medical review included medical history, physical examination (height, weight, physical constitution, vital signs and ECG), clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody test, surface antigen test). hepatitis B, hepatitis C antibody test, serum pregnancy (women only)) and a test to detect cannabinoids and opioids.

All subjects enrolled in the study met the inclusion / exclusion criteria detailed in the protocol. A total of 42 subjects, 17 men and 25 women, enrolled in the study, and 39 subjects, 17 men and 22 women, completed the study.

The subjects showed up at the clinic the morning before each dose and received food 19 hours before the dose, dinner 14 hours before the dose and a snack 11 hours before the dose. The subjects then kept 10 hours of fasting overnight. On day 1, a standardized meal program was started, with food at 4.5 hours after the dose, dinner at 9.5 hours after the dose and a snack at 13 hours after the dose . On day 2, breakfast was served at 24.5 hours after the dose, lunch at 28.5 hours after the dose and dinner at 33 hours after the dose.

Subjects should not consume food or drinks that contain alcohol, broccoli, citrus, caffeine or xanthine during the 48 hours prior to each confinement period or during such periods. Subjects should not use tobacco or nicotine for at least 6 months before starting the study. In addition, non-prescription medicines were banned 7 days before the dose and during the study. Prescription medications were not allowed 14 days before the dose or during the study (except hormonal contraceptives for women).

During the study, subjects had to remain seated for 4 hours after administration of fentanyl citrate. Water was restricted from hour 0 to 4 hours after the dose. The food was restricted 10 hours before the dose and up to 4 hours after the dose. During the study, subjects were not allowed to participate in strenuous activities.

Subjects received naltrexone in each period, as detailed below:

Adm 1: ReVia® 50 mg (naltrexone hydrochloride tablets)

Manufactured by Bristol-Myers Squibb Company

Lot number: 5C269A

Expiry Date: April 2004

Lot number: TB1798

Expiry Date: March 2005

The subjects to whom treatments A, B, C and D were assigned received an oral dose of a 50 mg naltrexone tablet, taken with 240 ml of water 15 hours and 3 hours before and 12 hours after the fentanyl dose .

The subjects to whom treatment E was assigned received an oral dose of a 50 mg naltrexone tablet, taken with 240 ml of water 15 hours and 3 hours before the fentanyl dose.

Subjects received one of the following fentanyl treatments in each of the 3 periods:

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

Manufactured by CIMA LABS INC

Lot number: 930502

The subjects randomized to treatment A received a single oral dose of a tablet of 1080 µg of fentanyl, which was placed between the upper gum and the cheek on a tooth and allowed to disintegrate for 10 minutes. It should be noted that "OraVescent®" indicates a formulation and pharmaceutical form according to the present invention.

B: Actiq® (transmucosal oral fentanyl citrate) equivalent to 1600 µg

Manufactured by Cephalon, Inc. or Anesta

Lot number: 02 689 W3

Subjects randomized to treatment B received a single oral dose of a 1600 µg unit of Actiq®, which was placed between the cheek and lower gum. The unit had to move from side to side using the applicator and allowing its dissolution in 15 minutes.

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

Manufactured by CIMA LABS INC

Lot number: 930503

Subjects randomized to treatment C received a single oral dose of a 1300 µg tablet of fentanyl, which was placed between the upper gum and cheek on a tooth and allowed to disintegrate for 10 minutes.

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

Manufactured by CIMA LABS INC

Lot number: 930501

Subjects randomized to treatment D received a single oral dose of an 810 µg tablet of fentanyl, which was placed between the upper gum and cheek on a tooth and allowed to disintegrate for 10 minutes.

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

Manufactured by CIMA LABS INC

Lot number: 930500

Subjects randomized to treatment E received a single oral dose of a 270 µg tablet of fentanyl, which was placed between the upper gum and cheek on a tooth and allowed to disintegrate for 10 minutes.

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

Vital signs (blood pressure, pulse and breathing) were evaluated at rest every morning before the dose (hour 0) and at 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 the dose. Pulse oximetry was performed continuously during the first 8 hours after the dose. At the end of the study, a 12-lead electrocardiogram was performed, a clinical laboratory evaluation (hematology, serum chemistry and urinalysis) and a physical examination of all vital signs. Oral irritation evaluations were performed 4 hours after the dose. Subjects were instructed to inform the doctor and / or nurses of the study of any adverse events that occurred during the study.

In the subjects to whom the A-D treatments were assigned, blood samples (7 ml) were taken at the following times: before the dose (hour 0) and at 10, 20, 30 and 45 minutes; and at 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32 and 36 hours after the dose. In the subjects to whom treatment E was assigned, blood samples (7 ml) were taken at the following times: before the dose (hour 0) and at 10, 20, 30 and 45 minutes; and at 1, 2, 4, 6, 8, 9, 10, 11, 12, 14, 16, 20 and 24 hours after the dose. A total of 54 blood samples (378 ml) were taken during the study for drug analysis. Samples were taken and processed at room temperature under fluorescent light. Serum samples were allowed to clot, separated by centrifugation, frozen at -20 ° C and kept frozen until assay.

Analysis methods

An LC-MS / MS (liquid chromatography-mass spectrometry / mass spectrometry: liquid chromatography-mass spectroscopy / mass spectroscopy) of human serum fentanyl.

Pharmacokinetic and statistical methods

The pharmacokinetic and statistical analysis was based on the industry guide entitled “Statistical Approaches to Establishing Bioequivalence” published in January 2001 by the Center for Drug Evaluation and Research (CDER), Center for Drug Evaluation and Research ) of the Food and Drug Administration, and in the industry guide entitled "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations" published in March 2003.

The following non-compartmental pharmacokinetic parameters were calculated from the data of fentanyl concentration versus time for each treatment using the standard edition of WinNonlin version

2.1. The actual sample collection times (instead of the nominal ones) were used in the analysis.

AUC (0-t) Area under the fentanyl concentration curve versus the calculated time

using the linear trapezoidal sum from time zero to time t, where

t is the time of the last quantifiable concentration (Ct).

AUC (0-inf) Area under the concentration curve of fentanyl versus time from time zero to infinity, AUC (0-inf) = AUC (0-t) + Ct / kel, where kel is the velocity constant terminal removal.

AUC (0-t) / AUC (0-inf) Ratio of AUC (0-t) to AUC (0-inf). It can also be called AUCR.

AUC (0-tmax) The partial area from time 0 to the average Tmax of the reference formulation, calculated using the linear trapezoidal sum.

Kel Terminal elimination rate constant calculated by regression of the linear terminal portion of the concentration log curve versus time, where kel = -dependent. The linear terminal portion was determined by visual inspection.

T1 / 2 Elimination half-life calculated as ln (2) / kel.

Cmax Maximum concentration of fentanyl observed.

Tmax Time in which the maximum concentration of fentanyl is obtained (obtained without interpolation).

This study was a single, randomized, open-label, two-dose cross-section of the designated reference and test products (treatment A and treatment B, periods 1 and 2) with randomized subjects to receive one of the three formulations of Additional test (treatment C, treatment D or treatment E) during period 3. Due to the large number of subjects, the study was conducted in two groups. The main comparison in this study was treatment A versus treatment B. For the analysis of variance when comparing these two treatments, only two sequences (AB, BA), two periods (1, 2) and two treatments (A, B).

A general linear (normal theory) parametric model was applied to the logarithmic transformation of AUC (0-inf), AUC (0-t) and Cmax of treatments A and B.5-7 The complete analysis model of variance ( ANOVA) considered the group in the model and included the following factors: group, period within the group, treatment, sequence, sequence by group, subject within the sequence by group and treatment by group. Because the interaction of the treatment by group was not significant, the model was reduced to sequence, subject within the sequence, period and treatment. The effect of the sequence was evaluated using the square of the subject's mean within the sequence and all other main effects were evaluated using the residual error (the square of the error mean). The two unilateral hypotheses were evaluated at the 5% level for AUC (0-t), AUC (0-inf) and Cmax, constructing 90% confidence intervals for the ratio of the reference and test means (A versus treatment). to treatment B).

The differences in Tmax in treatment A and treatment B were evaluated using the Wilcoxon test of the indicated ranges (α = 0.05).

Serum fentanyl concentrations and pharmacokinetic parameters were also determined following treatment C, treatment D and treatment E (OraVescent® fentanyl citrate tablet of 1300 µg, 810 µg and 270 µg, respectively). To assess the dose proportionality of the OraVescent® fentanyl citrate formulation, a mixed linear model was applied to the Cmax normalized by the dose and to the AUC parameters of treatments A, C, D and E.5-7 All The model considered the group and included the following terms: group, period within the group, treatment, sequence, sequence by group, subject within the sequence by group and treatment by group. The interaction of the treatment per group was not significant for 2 of the 3 parameters [Cmax and AUC (0-t)] and the model was reduced to a unilateral ANOVA with the treatment factor. In cases where an effect of the overall treatment was found, paired comparisons were made using treatment A as a reference.

5

10

fifteen

twenty

25

30

35

The residence time values (period of time that the formulation remained in the oral cavity) were calculated by subtracting the administration time of the treatment from the perceived and documented time of disappearance of the formulation. These values were tabulated and statistics summaries were presented.

RESULTS

Demography and arrangement of subjects

A total of 42 subjects, 17 men and 25 women, enrolled in the study, and 39 subjects, 17 men and 22 women, completed the study.

Three subjects interrupted / were withdrawn from the study. A subject dropped out of the study before period 2 because the subject did not want to continue in the study. A second subject dropped out of the study before period 3 because the subject did not want to continue in the study. A third subject dropped out of the study before period 2 because the subject took an antibiotic.

The average age of the subjects was 27 years (ranging between 19-55 years), the average height of the subjects was 68 inches (1.73 m) (ranging between 62-74 inches; 1.57-1.88 m) and the average weight of the subjects was 152.1 pounds (69 kg) (ranging from 109.0-197.0 pounds; 49.4-89.4 kg).

Protocol deviations and adverse events

The following deviations from the protocol took place during the course of the study.

According to the protocol, subjects' breathing should be measured at the 3.5-hour evaluation point of vital signs. The breathing of a subject was not measured at the 3.5-hour evaluation point during period 2. The reassessment of vital signs was not carried out at the 3-hour evaluation point of period 2 in two subjects. The reassessment of vital signs was not carried out at the 2.25 hour evaluation point of period 3 in a subject. Blood samples from these two subjects were not properly labeled at the 0.33 hour evaluation point of period 1 (treatment A). These samples were not analyzed. According to the protocol, the pulse of the subjects should be taken at the 3.5-hour evaluation point of the vital signs. The pulse of a subject was not taken at the 3.5-hour evaluation point during period 1. None of the subjects were exposed to more than one of the deviations detailed above. No serious adverse events were reported.

To process the clinical samples of this study, a total of 15 batches were necessary. Of these 15 lots, 14 were acceptable. The standard retrocalculated concentrations for the 14 acceptable batches of human serum used in this study covered a range of 50.0 to 5000.0 pg / ml (picograms / ml) with a quantification limit of 50.0 pg / ml. The quality control samples analyzed in each acceptable lot had coefficients of variation less than or equal to 7.89%.

Residence time

The data of residence times are summarized in the following table.

Summary of the residence time of the tablet / dragee

 Treatment A

B treatment C treatment D treatment E treatment

Subject No.

Time (minutes) Time (minutes) Time (minutes) Time (minutes) Time (minutes)

Half

 twenty-one 3. 4 19 25 22

SD

12 fifteen eleven 14 17

CV

58 44 56 57 75

SEM

2 2 3 4 4

N

40 42 12 13 14

Minimum

 3 9 4 4 4

Maximum

 48 77 33 fifty 62

Treatment A = 1 x 1080 mcg OntaVescent® fentanyl citrate tablet: test Treatment B = 1 x 1600 mcg of transmucosal oral fentanyl citrate (Actiq®): reference

5

10

fifteen

twenty

25

30

Treatment C = 1 x tablet of 1300 mcg OntaVescent® fentanyl citrate: test Treatment D = 1 x 810 mcg OntaVescent® citrate tablet: test Treatment E = 1 x 270 mcg OntaVescent® citrate tablet: SD test = standard deviation; CV = coefficient of variance; SEM = standard error of the mean; N = number (of

observations). One subject reported a mild oral irritation (2 on a scale of 1 to 10) that occurred after treatment C. The irritation appeared on the right side of the mouth after administration of the test product during period 3. There was a notification of redness after a visual inspection of the area by the study staff, which occurred after treatment E. The redness appeared on the upper part of the right cheek after administration of the test product during period 3. Of the 42 subjects enrolled, 40 subjects completed periods 1 and 2, and were included in the summary statistics, ANOVA analysis and mean figures for treatments A and B. Thirty-nine subjects completed periods 1, 2 and 3, and were included in the analysis dose proportionality statistic. The arithmetic averages and standard deviations of the pharmacokinetic parameters of serum fentanyl and the statistical comparisons of treatment A and treatment B are summarized in the following table. Summary of the pharmacokinetic parameters of serum fentanyl in treatments A and B ------------------ Serum Fentanyl -------------- --- Treatment A Treatment B

Parameters

Half Half 90% %relationship

pharmacokinetics

N arithmetic SD N arithmetic SD CI * half

Cmax (pg / ml)

0 2704.3 877.6 0 2191.6 693.5 . -. .

AUC (0-tmax) (pg * h / ml)

0 3840.1 1266.2 0 2566.2 911.82 . -. .

AUC (0-t) (pg * h / ml)

0 16537 5464.6 0 16701 6530.1 . -. .

AUC (0-inf) (pg * h / ml)

5 17736 5424.3 9 18319 7118.5 . -. .

T1 / 2 (h)

5 11.7 5.04 9 11.2 4.37 . -. .

Kel (1 / h)

5 0.0701 0.0310 9 0.0695 0.0227 . -. .

AUCR

5 0.918  0.0458 9 0.917  0.0335 . -. .

ln (Cmax)

 0 7,854 0.3132 0 7,640 0.3349  111.82-136.20 23.4

ln [AUC (0-1)]

0 9,662 0.3226 0 9,649  0.3945 94.42-108.86 01.4

ln [AUC (0-inf)]

5 9,739 0.3027 9 9,742  0.3941 93.60-109.23 01.1

Treatment A = 1 x tablet of 1080 mcg OraVescent® fentanyl citrate: test Treatment B = 1 x 1600 mcg transmucosal oral fentanyl citrate (Actiq®): reference The results of the Wilcoxon test of indicated ranges showed that Tmax The mean for treatment A (0.998 hours) was significantly lower (p <0.0001) compared to treatment B (1.999 hours). Individual and medium serum fentanyl pharmacokinetic parameters were calculated for treatments C, D and E. Kel could not be calculated for 5 subjects in treatment E. Similarly, AUC (0-inf could not be calculated in these cases) ), AUCR and T1 / 2. The arithmetic mean and standard deviations of the pharmacokinetic parameters of serum fentanyl from treatments C, D and E are summarized in the following table. Summary of the pharmacokinetic parameters of serum fentanyl in treatments C, D and E

 -------------------------------- Serum Fentanyl --------------- -------------

Treatment C Treatment D Treatment E  -------------------------- ------------------------ - -------------------------- Medium Media Parameters

pharmacokinetics N arithmetic SD N arithmetic SD

Cmax (pg / ml)

12 2791.4 874.3  13 2646.9 778.7

AUC (0-tmax) (pg * h / ml)

12 4008.3 1259.1 13 3694.8 971.89

AUC (0-t) (pg * h / ml)

12 18921 6470.2 13  15339  4260.4

AUC (0-inf) (pg * h / ml)

12 21033 7346.3 13  16831  4449.8

T1 / 2 (h)

12 13.2 7.67 13 11.7 4.66

Kel (1 / h)

12 0.0687 0.0354 13  0.0703  0.0352

AUCR

12 0.907 0.0683 13  0.909  0.0376

5 Treatment C = 1 x 1300 mcg OntaVescent® fentanyl citrate tablet Treatment D = 1 x 810 mcg OntaVescent® fentanyl citrate tablet Treatment E = 1 x tablet of 270 mcg fentanyl citrate OraVescent® citrate

AUCR is the ratio AUC0-t / AUC0-∞ The calculation of the dose proportionality that includes the p-values for treatments A, C, D and E is summarized in the following table. Summary of the parameters normalized by the dose of serum fentanyl in treatments A, C, D and E ---------------------------- - Serum Fentanyl ---------------------------- Treatment A Treatment C Treatment D Treatment E ---------- --------- ------------------------------------ ----- -------------- Parameters Mean Average Average Pharmacokinetic mean P arithmetic value SD arithmetic SD arithmetic SD arithmetic SD

Cmax / dose (pg / ml / mcg). 2.5 0.8 2.1 0.7 3.3 1.0 3.0 1.2 AUC (0-t) / dose (pg * h / ml / mcg). 15,4743 5,01901 14,555 4,9771 18,937 5,2597 16,050 5.9180 AUC (0-inf) / dose (pg * h / ml / mcg). 16.5851 5.00318 16.179 5.6510 20.779 5.4935 15.637 6.4732 ln (Cmax / dose) 0.0127, 8788, 3115, 7190, 3151, 137, 3356, 011, 3974 ln [AUC (0-t ) / dose] 0.1727, 690, 3170, 625, 3409, 901, 3032, 706, 4002 Ln [AUC (0-inf) / dose] 0.0783, 765, 3003, 725, 3633, 998, 2894, 691, 3892

Treatment A = 1 x 1080 mcg OntaVescent® fentanyl citrate tablet Treatment C = 1 x tablet of fentanyl citrate OraVescent® of 1300 mcg

Treatment D = 1 x 810 mcg OntaVescent® fentanyl citrate tablet

Treatment E = 1 x tablet of 270 mcg fentanyl citrate OraVescent® citrate

Time intervals were determined against kel values.

The main objective of this study was to evaluate the bioequivalence of a dose of 1080 µg of an OraVescent® fentanyl citrate tablet from CIMA LABS INC (treatment A, test) compared to 1600 µg of transmucosal oral commercial fentanyl citrate, Actiq® (treatment B, reference) under fasting conditions. The study was a single-dose randomized, open-label, cross-label two-variable design for periods 1 and 2. All subjects also returned in period 3 to be administered one of the three test formulations of fentanyl citrate OraVescent®: 1300 µg (treatment C), 810 µg (treatment D) or 270 µg (treatment E). The dose proportionality of the OraVescent® fentanyl citrate tablet formulation (treatments A, C, D and E) was evaluated.

A total of 42 healthy subjects were initially enrolled in the study, 39 subjects completed all three study periods and 40 subjects completed treatments A and B (periods 1 and 2). Data from the 40 subjects who completed treatments A and B were included in the pharmacokinetic and statistical analysis.

The geometric mean ratios of the least squares (test / reference) for the Fentanyl Cmax, AUC (0-t) and AUC (0-inf) were 123.4%, 101.4% and 101.1%, respectively, for treatment A versus treatment B. These data indicate that the average exposure of fentanyl was similar, but the maximum exposure was higher in treatment A compared to treatment B. The Tmax in treatment A (0.998 hours) It occurred one hour earlier than in treatment B (2.00 hours) and Cmax was 23% higher, which indicates that the absorption rate of fentanyl was significantly faster in treatment A compared to treatment B.

The 90% confidence intervals for Cmax of 111.82% -136.20%, AUC (0-t) of 94.42% -108.86% and AUC (0inf) of 93.60% -109.23 % indicated that treatment A and treatment B met the bioequivalence requirements with respect to AUC but not with respect to Cmax. In fact, the Cmax of treatment A indicates that a dose of approximately 30-35% less fentanyl by weight supplied using the OraVescent® formulation exemplified in Example 1 provided a statistically and significantly higher Cmax compared to an Actiq® formulation of 1600 micrograms To obtain bioequivalent results in terms of Cmax, it is more to obtain comparable results, an OraVescent® fentanyl formulation would have to be used that included at least about 45%, more preferably about 47.5% and even more preferably about 50% less fentanyl (calculated as fentanyl in free form by weight) than that found in the Actiq® tablet used in the comparison. In this case, approximately 800-880 micrograms were compared with an Actiq® 1600 microgram tablet.

Thus it was discovered that, using the present invention and for pharmaceutical forms of 1 milligram or less, a Cmax comparable to even less fentanyl than initially thought could be obtained. A fast Tmax was also obtained. This allowed a further reduction in the doses contemplated with the advantages described above herein that come from a dose reduction that is not associated with a reduction in efficacy.

The AUC of fentanyl increased proportionally to the dose in the range of 270 to 1300 µg, following the administration of the formulation of the OraVescent® fentanyl citrate tablet. There were no significant differences in AUC (0-t) or AUC (0-inf) normalized by the dose in the 4 doses of OraVescent®. A significant effect of overall treatment was found in the comparison of Cmax normalized by dose. Paired comparisons were made using treatment A as a reference because all subjects received treatment A. No pattern was observed in the paired comparisons. A significant difference was found between treatment D (810 µg) and treatment A (1080 µg).

The average residence time of the 1080 µg OraVescent® fentanyl citrate tablet (21 minutes) was 13 minutes shorter than that of Actiq® (34 minutes). The average residence times of the other three doses of the OraVescent® fentanyl citrate tablet formulation (19, 25 and 22 minutes) were similar to those of the 1080 µg OraVescent® formulation.

One subject reported mild irritation of the oral mucosa and one subject experienced redness after administration of the OraVescent® fentanyl citrate tablet. No irritation or redness was reported following the administration of Actiq®.

When comparing the pharmacokinetics of serum fentanyl after administration of the 1080 µg OraVescent® fentanyl citrate tablet and 1600 µg transmucosal oral fentanyl citrate (Actiq®), it was observed that the average exposure of fentanyl was similar but that the Absorption rate was different between the two products. The average geometric ratios of the least squares (“LS”) for AUC (0-t) and AUC (0-inf) were close to 100%, and the 90% confidence intervals were between 80% and 125%. The geometric mean LS of Cmax was 23% higher for the OraVescent® fentanyl citrate of 1080 µg, and the upper limit of the 90% confidence interval for the treatment / reference ratio was greater than 125%, indicating that the Bioequivalence criteria were not met for this parameter. In this way, an additional dose reduction could still be obtained. The Tmax was significantly lower (1 hour before) for the OraVescent® fentanyl citrate tablet.

The fentanyl AUC increased proportionally to the dose in the range of 270 to 1300 µg for the formulation of OraVescent® fentanyl citrate.

The average residence time of the 1080 µg OraVescent® fentanyl citrate tablet (21 minutes) was 13 minutes shorter than the average Actiq® residence time (34 minutes).

During the study, no serious or unexpected adverse events occurred. Both formulations were well tolerated by the oral mucosa.

REFERENCES

Physician’s Desk Reference. 56th ed. Montvale, NJ: Medical Economics Company, Inc .; 2002. Actiq®; P. 405-409.

Fentanyl Micromedex [online] Vol. 107: Health Series Integrated Index; 2002 [Date of access: June 371, 2003]. http://www.tomescps.com

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

Naltrexone Micromedex [online] Vol. 107: Health Series Integrated Index; 2002 [Date of access: June 16, 2003]. http://www.tomescps.com

SAS® Institute, Inc., SAS® / STAT User’s guide, Ver. 6. 4th ed. Vol. 1 Cary, NC: SAS Institute; 1989

SAS® Institute, Inc., SAS® / STAT User’s guide, Ver. 6. 4th ed. Vol. 2 Cary, NC: SAS Institute; 1989

SAS® Institute, Inc., SAS® Procedures guide, Ver. 6. 3rd ed. Cary, NC: SAS Institute; 1990.

A second study was also performed.

This comparative study was carried out to assess the extent to which the dose proportionality (AUC and Cmax) for fentanyl citrate formulated in tablets according to the invention existed (referred to herein as OraVescent® tablets. ) in a range that can be used therapeutically, and to confirm the observations of Cmax of the study just discussed.

An Institutional Review Committee (IRB) approved the protocol and the informed consent form. All subjects read and signed an ICF (Informed Consent Form: Informed Consent Form) approved by the IRB before beginning the study. This study had a single-dose, randomized, open-label, 4-treatment, 4-period, cross-dose design.

Subjects underwent a medical review within 21 days prior to enrollment in the study. The medical review included medical history, physical examination (height, weight, physical constitution, vital signs and electrocardiogram [ECG]), clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody test, antibody test of hepatitis A, hepatitis B surface antigen test, hepatitis C antibody test and serum pregnancy [women only]) and a test to detect cannabinoids and opiates.

All subjects enrolled in the study met the inclusion / exclusion criteria detailed in the protocol and the principal investigator reviewed the medical records and laboratory clinical evaluations, and performed physical exams on the subjects before being enrolled in the study. A total of 28 subjects, 16 men and 12 women, enrolled in the study, and 25 subjects, 14 men and 11 women, completed the study.

The subjects showed up at the clinic the afternoon before the dose and received lunch at 2:00 pm, dinner at 7:00 pm and a snack at 10:00 pm. The subjects then kept 10 hours of fasting overnight. On day 1, a standardized meal program began, with lunch at 1:30 p.m., dinner at 6:30 p.m. and a snack at 10 p.m. On day 2 a standardized meal program (including breakfast) was started.

Subjects should not consume food or drinks that contain alcohol, broccoli, caffeine or xanthine during the 48 hours prior to each confinement period or during such periods. Grapefruit was restricted 10 days before the dose and throughout the study. Subjects should not use tobacco or nicotine for at least 6 months before starting the study and until completing it. In addition, over-the-counter medicines (including herbal supplements) were banned 7 days before the dose and during the study. Prescription drugs (including MAO inhibitors) were not allowed from 14 days before the dose or during the study.

During the study, subjects were to remain upright, sitting, for 4 hours after administration of fentanyl citrate. Water was restricted from the moment of receiving the dose until 4 hours after the dose. The food was restricted 10 hours before the dose and up to 4 hours after the dose. During the study, subjects were not allowed to participate in strenuous activities.

The subjects were randomized to receive the following treatments:

Adm 1: ReVia® (naltrexone hydrochloride tablets) 50 mg

Manufactured by Duramed Pharmaceuticals, Inc.

Lot number: 402753001T

Expiry Date: June 2006

The subjects received an oral dose of a 50 mg ReVia® tablet, taken with 240 ml of water 15 hours and 3 hours before the treatment dose A.

Subjects received an oral dose of a 50 mg ReVia® tablet, taken with 240 ml of water 15 hours and 3 hours before the dose and 12.17 hours after the dose of treatment B, C and D.

A: 200 µg OraVescent® fentanyl citrate tablets

Manufactured by CIMA LABS INC

Lot number: 930859

Subjects randomized to treatment A received a single oral dose of a 200 µg OraVescent® fentanyl citrate tablet, which was placed between the upper gum and cheek, on a tooth and allowed to disintegrate for 10 minutes.

B: 500 µg OraVescent® fentanyl citrate tablets

Manufactured by CIMA LABS INC

Lot number: 930860

Subjects randomized to treatment B received a single oral dose of a 500 µg OraVescent® fentanyl citrate tablet, which was placed between the upper gum and cheek, on a tooth and allowed to disintegrate for 10 minutes.

C: 810 µg OraVescent® fentanyl citrate tablets

Manufactured by CIMA LABS INC

Lot number: 930501

Subjects randomized to treatment C received a single oral dose of an 810 µg OraVescent® fentanyl citrate tablet, which was placed between the upper gum and cheek, on a tooth and allowed to disintegrate for 10 minutes.

D: 1080 µg OraVescent® fentanyl citrate tablets

Manufactured by CIMA LABS INC

Lot number: 930502

Subjects randomized to treatment D received a single oral dose of an OraVescent® 1080 µg fentanyl citrate tablet, which was placed between the upper gum and cheek, on a tooth and allowed to disintegrate for 10 minutes.

Vital signs (blood pressure, heart rate and respiratory rate) were assessed at rest every morning before the dose and at 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 the dose. Pulse oximetry was performed continuously during the first 8 hours after the dose and, in the case that the subject tried to sleep, during the first 12 hours after the dose. At the end of the study, a 12-lead ECG was performed, a clinical laboratory evaluation (hematology, serum chemistry and urinalysis) and a brief physical examination of all vital signs. Oral irritation evaluations were performed 4 hours after the dose. At each check-up, the oral cavity was examined to ensure that the subjects did not have sores in the area of application of the drug. Subjects were instructed to inform the doctor and / or nurses of the study of any adverse events that occurred during the study.

In the subjects to whom treatment A was assigned, blood samples (7 ml) were taken at the following times: before the dose (hour 0) and at 10, 20, 30 and 45 minutes; and at 1, 2, 4, 6, 8, 10, 11, 12, 16, 20, and 24 hours after the dose. In the subjects to whom treatments B, C and D were assigned, blood samples (7 ml) were taken at the following times: before the dose (hour 0) and at 10, 20, 30 and 45 minutes; and at 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32 and 36 hours after the dose.

Human serum samples were analyzed for fentanyl concentrations using a specific and sensitive LC-MS / MS procedure.

The following non-compartmental pharmacokinetic parameters were calculated from the data of fentanyl concentration versus time for each treatment, using the standard edition of WinNonlin version

2.1. The actual sample collection times (instead of the nominal ones) were used in the analysis.

AUC (0-t) Area under the concentration curve of fentanyl versus time calculated using the linear trapezoidal sum from time zero to time t, where t is the time of the last quantifiable concentration (Ct).

AUC (0-inf) Area under the concentration curve of fentanyl versus time from time zero to infinity, AUC (0-inf) = AUC (0-t) + Ct / kel, where kel is the velocity constant terminal removal.

AUC (0-t) / AUC (0-inf) Ratio of AUC (0-t) to AUC (0-inf). It can also be called AUCR.

Kel Terminal elimination rate constant calculated by regression of the linear terminal portion of the concentration log curve versus time, where kel = -dependent. The linear terminal portion was determined by visual inspection.

T1 / 2 Elimination half-life calculated as ln (2) / kel.

Cmax Maximum concentration of fentanyl observed.

Tmax Time in which the maximum concentration of fentanyl is obtained (obtained without interpolation).

Plasma fentanyl concentration values were listed and summarized by treatment and evaluation point with descriptive statistics (mean, standard deviation [SD], 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 assigned as zero. Graphs of average and individual concentrations were presented versus time. The pharmacokinetic parameters of fentanyl and the pharmacokinetic parameters normalized by the dose were tabulated by treatment and statistical summaries were calculated.

The proportionality of the dose from 200 µg to 1080 µg was evaluated using the methodology described by Smith et al.8 First, the logarithmic transformations of the parameters were analyzed using a mixed effects model that includes the log transformation of the dose as well. as fixed and random effects for interception. This model was adjusted using SAS® Proc Mixed. 9-11

A confidence interval (CI) of 90% on the fixed effect for the slope (β1) was calculated and compared with the range (0.8677, 1.1323), which is the appropriate critical range given the range of doses investigated in this study.

The conclusions were based on the following:

If the 90% CI for β1 was completely contained in the range (0.8677, 1.1323), dose proportionality should be concluded.

If the 90% CI for β1 was completely outside this range, a lack of dose proportionality should be concluded.

If the 90% CI for β1 was partially within and partially outside this range, the results should be considered "inconclusive." In this case, the value of β1 should be considered as the best estimate of the deviation from the ideal proportionality and the upper and lower limits of the IC of 90% in the context of data on safety, efficacy or pharmacological effects of the drug.8

In cases where inconclusive results were observed, the maximum dose ratio was calculated so that the IQ of 90% for β1 was completely in the critical range and the dose ratio so that the IQ of 90% for β1 It will be totally outside the critical range. These dose ratios are called ρ1 and ρ2, respectively, according to Smith et al.

ρ1 = θH ^ [1 / max (1-L, U-1)], where θH = 1.25,

L = lower limit of the CI of 90%,

U = upper limit of the IC of 90%.

ρ2 = θH ^ [1 / max (L-1,1-U)], with θH, L and U as defined above.

A secondary analysis was conducted to examine the difference in Cmax normalized by the dose between the 3 lowest dose levels (200 µg, 500 µg and 810 µg). A parametric GLM (normal theory) was applied to the values of the Cmax normalized by the dose in treatments A, B and C after the logarithmic transformation. The variance analysis model (ANOVA) included the following factors: treatment, sequence, subject within the sequence and period. A p value of less than 0.05 was considered statistically significant.

5

10

fifteen

twenty

25

30

35

The residence time values (period of time that the formulation remained in the oral cavity) were calculated by subtracting the administration time of the medication from the perceived and documented time of disappearance of the formulation. These values were tabulated and statistics summaries were presented.

Three subjects interrupted / were withdrawn from the study. Two subjects dropped out of the study before period 3 because they did not want to continue in the study. One subject dropped out after the period 2 dose due to adverse events. The average age of the subjects was 33 years (ranging between 19-55 years), the average height of the subjects was 68.6 inches (1.74 m) (ranging between 60-76 inches; 1.52-1 , 93 m) and the average weight of the subjects was 160.9 pounds (73 kg) (ranging from 110-215 pounds; 50.9-97.5 kg).

The following deviations from the protocol took place during the course of the study. The reassessment of vital signs was not performed at 0.5 hour of period 2 in a subject. The reassessment of vital signs was not carried out at time 2.5 of period 3 in a subject. One subject did not have the result of their available serum pregnancy test before the naltrexone dose of -15 in period 3. The result was available before the naltrexone dose of hour -3. The ECG of hour 36 of period 4 of a subject was lost. One subject did not complete the early termination procedures. This subject was considered lost for follow-up. Finally, an oral irritation evaluation should have been performed at 3.83 hours after the dose for all subjects during period 3. The nurse responsible for the event recalled carrying out the evaluations but mentioned that the evaluation forms of Oral irritation was not completed at the time of the event. Therefore, the evaluation information cannot be verified and should be considered not carried out.

The data of residence times are summarized in the following table.

Treatment A

B treatment C treatment D treatment

Subject No.

Time (minutes) Time (minutes) Time (minutes) Time (minutes)

Half

 14 14 17 fifteen

SD

8 6 10 eleven

CV

59 Four. Five 57 72

SEM

2 one 2 2

N

25 26 27 27

Minimum

 4 6 5 4

Maximum

 37 33 41 60

Treatment A = 200 µg

Treatment B = 500 µg

Treatment C = 810 µg

Treatment D = 1080 µg

During the check of the oral cavity evaluations, it was perceived that a subject had a sore in the lower right inner part of the cheek at the beginning of period 4, however, administration of the test product during period 3 took place in the right cheek. The principal investigator did not identify this sore as an aphthous ulcer and approved the administration of the dose to the subject during period 4.

Two subjects reported mild oral irritation (2 and 3 on a scale of 1 to 10), which occurred during treatment A. The irritation occurred on the left side of the mouth after administration of the test product during period 2 to both subjects; One of these subjects also showed redness when performing the visual inspection of the area by the study staff. An additional subject reported pain in the upper left side of the buccal area on the gum line 11 minutes after treatment C. No serious or unexpected adverse events were reported.

Of the 28 enrolled subjects, 25 subjects completed treatment A, 26 subjects completed treatment B and 27 subjects completed treatments C and D. Statistical analyzes of the pharmacokinetic data were performed for all subjects. The elimination rate constant in a subject in treatment A could not be calculated because there was a limited number of data points in the terminal phase. Thus, AUC (0-inf), AUCR and T1 / 2 could not be calculated for this subject.

The arithmetic averages and standard deviations of the pharmacokinetic parameters of serum fentanyl for all treatments are summarized in the following table. Summary of the pharmacokinetic parameters of serum fentanyl -------------- Serum Fentanyl ------------- Treatment A Treatment B

Pharmacokinetic Parameters

 Arithmetic average SD  Arithmetic average SD

Cmax (pg / ml)

5 617.8 236.7  6 1546.2 621.4

* Tmax (h)

5 0.76 0.334.0 6 0.75 0.334.0

AUC (0-t) (pg * h / ml)

5 2876.3  1107.7 6 8501.2  3346.2

AUC (0-inf) (pg * h / ml)

4 3543.9  1304.5 6 9701.9  2651.5

T1 / 2 (h)

4 6.48 3.69 6 12.0 8.18

Kel (1 / h)

4 0.143 0.0802 6 0.0746 0.0377

AUCR

4 0.843 0.0604 6 0.875 0.0929

Cmax / dose (pg / ml / mcg)

5 3.09  1.18 6 3.09  1.24

AUC (0-t) (pg * h / ml / mcg)

5 14.4 5.54 6 17.0 6.69

AUC (0-inf) (pg * h / ml / mcg)

4 17.7 6.52 6 19.4 7.30

ln (Cmax / dose)

 5 1.06 0.383  6 1.05 0.426

ln [AUC (0-t) / dose]

5 2.59  0.424 6 2.75  0.441

ln [AUC (0-inf) / dose]

4 2.81 0,369 6 2.89 0.413

Treatment C Treatment D

Pharmacokinetic Parameters

Arithmetic average SD Arithmetic average SD

Cmax (pg / ml)

7 2280.1 968.9  7 2682.3 1106.0

* Tmax (h)

7 0.99 0.334.0 7 0.75 0.334.0

AUC (0-t) (pg * h / ml)

7 13301 4069.1 7 16813 5232.2

AUC (0-inf) (pg * h / ml)

7 14962 4709.1 7 18664 6266.0

T1 / 2 (h)

7 12.8 4.08 7 11.4 4.34

Kel (1 / h)

7 0.0592 0.0167 7 0.0679 0.0216

AUCR

7 0.893 0.0589 7 0.909 0.0602

Cmax / dose (pg / ml / mcg)

7 2.81  1.20 7 2.48  1.02

AUC (0-t) (pg * h / ml / mcg)

7 16.4 5.02 7 15.6 4.84

AUC (0-inf) (pg * h / ml / mcg)

7 18.5 5.81 7 17.3 5.80

ln (Cmax / dose)

 7 0.945 0.439  7 0.836 0.386

ln [AUC (0-t) / dose]

7 2.75  0.324 7 2.69  0.356

ln [AUC (0-inf) / dose]

7 2.87 0,329 7 2.79 0.372

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

* The median and min-max are shown 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 OntaVescent® fentanyl citrate tablet

Treatment D = 1 x 1080 mcg OntaVescent® fentanyl citrate tablet

The slopes of ln [AUC (0-t)] versus ln (dose) and ln [AUC (0-inf)] versus ln (dose), at 1,0574 and 0,9983, respectively, 1, and 90% CI for each parameter was completely contained within the critical range required for dose proportionality from 200 µg to 1080 µg. The slope of ln (Cmax) versus ln (dose), 0.8746, was less than 1 and the CI of 90% (0.8145-0.9347) was not completely contained within the critical range required to conclude the proportionality of the dose. The maximum dose ratio such that the 90% CI for β1 was fully contained in the critical range was 3.33. The maximum dose ratio such that the 90% CI for β1 was totally outside the critical range was 30.48. The ANOVA results of the Cmax normalized by the dose for treatments A, B and C indicate that there was no statistically significant difference in the Cmax normalized by the dose in the dose range of 200 µg to 810 µg (p = 0, 13).

The main objective of this comparative study was to assess the extent to which the dose proportionality for AUC of fentanyl and Cmax exists, after fentanyl doses of 200 µg (treatment A), 500 µg (treatment B), 810 µg (treatment C) and 1080 µg (treatment D) in the form of OraVescent® fentanyl citrate tablets. In addition, this study was carried out to confirm previous observations in relation to Cmax after administration of doses of 810 µg and 1080 µg of OraVescent® fentanyl citrate tablets. This study was a single, randomized, open-label, cross-dose 4-period design.

Of the 28 enrolled subjects, 25 subjects completed treatment A, 26 subjects completed treatment B and 27 subjects completed treatments C and D. Statistical analyzes of the pharmacokinetic data were performed for all subjects.

The slopes of ln [AUC (0-t)] against ln (dose) and ln [AUC (0-inf)] against ln (dose), at 1,0574 and 0,9983, respectively, were close to 1 , and the 90% CI for each parameter was completely contained within the critical range required for dose proportionality. These results indicate that fentanyl AUC increased proportionally with each dose increase level of OraVescent® fentanyl citrate tablets between the study doses of 200 µg to 1080 µg.

The slope of ln (Cmax) versus ln (dose), 0.8746, was less than 1, which indicates that Fentanyl Cmax presented a smaller than proportional increase with respect to the dose. The CI of 90% (0.8145-0.9347) was not completely contained within the critical range. The smaller than proportional increase was observed in the highest dose (1080 µg) and, to a lesser extent, in the second highest dose (810 µg). Cmax increased proportionally from 200 µg to 500 µg. The increase in Cmax with the dose was "linear" to approximately 800 µg of fentanyl, inclusive. The value of ρ1 (maximum dose ratio such that the 90% CI for β1 is completely within the critical range) was 3.33, while the ratio of 810 µg: 200 µg is 4.05. This indicates that the formulation almost meets the proportionality criteria in the range between 200 µg and 810 µg according to this method. A secondary analysis using ANOVA to compare the normalized Cmax by the dose dose of 200 µg, 500 µg and 810 µg indicated that there was no statistically significant difference (p = 0.13) between these dose levels. The least squares means (“LS”) for ln (Cmax / dose) were 1.06 (200 µg), 1.06 (500 µg) and 0.94 (810 µg), so that they did not show any difference between doses of 200 and 500 µg and presented a minimum difference (10%) in the dose of 810 µg compared to the lower doses. The lack of significant results regarding ANOVA, together with the small magnitude difference between the dose of 810 µg and the two lowest doses indicates that there is no clinically important deviation in the proportionality of the dose (linearity) in Cmax from 200 µg to 810 µg.

The average residence times for the OraVescent® fentanyl citrate tablets of 200 µg, 500 µg, 810 µg and 1080 µg were similar, 14 minutes, 14 minutes, 17 minutes and 15 minutes, respectively.

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

The AUC of fentanyl increased proportionally to the dose increase in the range of 200 µg to 1080 µg. Fentanyl Cmax presented a smaller than proportional increase with respect to the dose at the two higher dose levels. The mean ln (Cmax / dose) for the 810 µg dose was 10 to 11% lower than for the 200 µg and 500 µg doses. This is linear as defined herein. The mean ln (Cmax / dose) for the 1080 µg dose was 20 to 21% lower than for the 200 µg and 500 µg doses. There was no clinically important deviation in the proportionality of the dose in Cmax from 200 µg to 810 µg. The average residence times for the OraVescent® fentanyl citrate tablets of 200 µg, 500 µg, 810 µg and 1080 µg were similar, 14 minutes, 14 minutes, 17 minutes and 15 minutes, respectively.

During the study, no serious or unexpected adverse events occurred. Both formulations were well tolerated by the oral mucosa.

REFERENCES

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

SAS® Institute, Inc., SAS® / STAT User’s guide, Ver. 6. 4th ed. Vol. 1. Cary, NC: SAS Institute; 1989

SAS® Institute, Inc., SAS® / STAT User’s guide, Ver. 6. 4th ed. Vol. 2. Cary, NC: SAS Institute; 1989

SAS® Institute, Inc., SAS® Procedures guide, Ver. 6. 3rd ed. Cary, NC: SAS Institute; 1990.

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

It is believed that the '604 patent formulations that include lactose monohydrate in an amount of more than 20% and / or microcrystalline cellulose in an amount of at least about 20% and crosslinked PVP in an amount of 5% or more, they are not able to provide fentanyl formulations having the desired properties of the invention, despite the presence of a pH regulating substance and an effervescent additive. That is, a larger dose of the opioid would be necessary to provide a comparable Cmax. Moreover, a dose reduction of 20% or greater can be achieved using the present invention. For example, when fentanyl is formulated in the pharmaceutical forms of the present invention it will have a Cmax greater than a given dose compared to those described in the ‘604 patent. Therefore, to achieve a comparable Cmax, a smaller amount of opioid will be necessary. Other opiates should behave similarly. A pharmaceutical form consisting essentially of certain fillers in certain quantities will exclude the foregoing, since it will not be able to reach the desired comparable Cmax at the appropriate dose reduction.

The pharmaceutical forms according to the present invention will provide effective amounts of oxycodone which will vary according to the opioid and according to the indications. For oxycodone, the normal daily dose can range from about 5 to about 160 milligrams. For fentanyl, by comparison, an effective amount is an amount between 100 and 2000 µg per dose, depending on the form of the free base fentanyl. For demerol, the range can be up to 150 mg per dose. Proportional amounts of a salt, such as a citrate, can also be used. Daily doses of hydromorphone can range between 5 and 45 mg and, for morphine, they range between 10 and 120 mg.

Generally, the dose of active ingredient that is supplied in one or more pharmaceutical forms according to the invention (per dose, not necessarily per day) will range between 20 and 200,000 micrograms, preferably between 50 and 160,000 micrograms, more preferably between 50 and 100,000 micrograms

Any combination known as effervescent agent or effervescent additive can be used. This includes those described in US Pat. UU. No. 5,178,878 and in US Pat. UU. No. 5,503,846 as they describe various effervescent additives and constructions thereof. Effervescent additives are generally materials that are activated with water or saliva, normally maintained in an anhydrous state with little or no moisture absorbed or in a stable hydrated form. Normally these additives consist of a source of acid and a source of a reactive base, generally a carbonate or bicarbonate. Both can be any that are safe for human consumption.

Acids generally include food acids, acid anhydrides and acid salts. Food acids include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, ascorbic acid and succinic acid. Anhydrides or salts of these acids can be used. In this context, the salts may include any known salt but in particular sodium salts, dihydrogen phosphate, dihydrogen phosphate disodium, citrate salts of acids and sodium sulfate of acids. According to the invention, useful bases usually include sodium bicarbonate, potassium bicarbonate and the like. Sodium carbonate, potassium carbonate, magnesium carbonate and the like can also be used, provided they are used as part of an effervescent additive. However, they are more preferably used as pH regulating substances. Preferably, stoichiometric equivalent amounts of acid and base are used. However, it is possible to use some excess acid or base. However, care must be taken when formulating a formulation. An excess could affect absorption.

The amount of effervescent material or additive useful in accordance with the present invention is an effective amount and is determined based on properties other than those that would be necessary to achieve disintegration of the tablet in the mouth. In contrast, effervescence is used as a basis for increasing opioid transmission through mucous membranes through oral, gingival or sublingual administration in the oral cavity. This can be evaluated by comparing the opioid blood levels of a formulation of the invention with an identical formulation but without the effervescent additive. Consequently, the amount of effervescent additive should range between 5 and 85 percent, more preferably between 15 and 60 percent, even more preferably between 30 and 45 percent and more preferably between 35 and 40 percent, depending on the weight of the total formulation ("p / p"). Naturally, the relative proportion of base acid will depend on the specific ingredients (for example, whether the acid is monoprotic, diprotic or triprotic), relative molecular weights, etc. However, preferably, a stoichiometric amount of each is provided, although excesses can of course be accepted.

Formulations according to the present invention include a pH regulating substance. Without wishing to be bound by any particular theory of operation, this guarantees that a drug that is susceptible to changes in the ionization state can be administered, while ensuring adequate conditions for its dissolution as well as its transmission to one or more of the membranes or tissues within the oral cavity. If the ideal conditions for transmission are basic, the addition of a sufficient excess of a suitable strong acid as part of the manufacture of an effervescent additive or as a pH regulating substance may not be adequate. The selection of another pH regulating substance such as, for example, anhydrous sodium carbonate, which operates separately and apart from effervescent agents, is suitable and preferred.

In accordance with the present invention, pH regulating substances can be used to provide a further increase in permeation. The selection of the appropriate permeation promoter will depend on the drug being administered and, in particular, on the pH at which it is ionized or deionized. A basic substance is "suitable" for the release of fentanyl. Acids may be suitable for other opiates. In accordance with the present invention, pH regulating substances may include, without limitation, any substance capable of regulating the local pH to stimulate transport through the membranes in the oral cavity in amounts that will result in a pH that generally ranges from 3 and 10 and more preferably between 3 and 9 in the microenvironment in the surface contact area of the oral mucosa and in the pharmaceutical form or any portion thereof (also referred to herein as "local pH"). To characterize the dynamic pH changes manifested by the tablets in question, an in vitro pH measurement was used. The method consists of using 0.5-10 ml of a phosphate buffer saline solution in a test tube of suitable size or a similar container. The amount of the medium depends on the size and dose of the tablet. For example, for fentanyl tablets, a volume of 1 ml was used for tablets weighing 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 combined micro pH electrode. Depending on the molecule in question, the combination of the effervescence and the pH regulating substance may provide a local pH ranging from 3-10 and, more preferably, is selected and provided in an amount capable of providing a change in the pH. of at least 0.5 pH units.

Preferably, materials that can be used as pH regulating substances according to the present invention include carbonates such as sodium, potassium or calcium carbonate, or a phosphate such as calcium or sodium phosphate. Sodium carbonate is the most preferred. The amount of pH regulating substance useful in accordance with the present invention may vary according to the type of pH regulating substance used, the amount of any excess acid or base of the effervescent additive, the nature of the remaining ingredients and, of course , the drug, which in this case is oxycondone.

An effective amount of a pH regulating substance is an amount that is sufficient to change the pH in the local microenvironment (local pH) (increase the pH in the case of fentanyl), when dissolved in the mouth, to a pH in the which effervescence can enhance penetration through the mucous membrane in the oral cavity. The effective amount will be able to provide a pH between 3 and 10. Any pH regulating substance capable of providing these conditions is contemplated. Preferably, the pH regulating substance provides a local pH of 3-10 and, more preferably, is selected and provided in an amount capable of providing a change in the local pH of at least 0.5 pH units. More preferably, a suitable pH regulating substance will change the local pH of the microenvironment by 1 or more pH units and, more preferably, by 2 or more pH units.

More preferably, the amount of pH regulating substance will range between 0.5 and 25 percent, more preferably between 2 and 20 percent, even more preferably between 5 and 15 percent and more preferably between 7 and 12 percent by weight depending on the weight of the total formulation. The most preferred pH regulating substance is a carbonate, bicarbonate and the like.

Any filler or any quantity of a filler may be used as long as the resulting dosage forms achieve the results described herein. Among the most preferred fillings are sugars and sugar alcohols and these may include non-direct and direct compression fillings. Generally, non-direct compression fillings, at least when formulated, have a flow and / or compression characteristics that make them impractical for use in high-speed tablet formation processes without any increase or adjustment. For example, it may be that a formulation does not flow well enough and therefore the addition of a slip agent such as, for example, silicone dioxide is needed. Typically, these materials could also be granulated or sprayed dry to improve their properties.

Direct compression fillings, on the other hand, do not require similar complements. Generally, they have characteristics of compressibility and fluidity that allow them to be used directly. It should be noted that, depending on the method used to prepare the formulations, non-direct compression fillings can be conferred with the properties of direct compression fillings. The opposite also is true. In general, non-direct compression fillings usually have a relatively smaller particle size compared to direct compression fillings. However, certain fillers such as spray-dried mannitol have relatively smaller particle sizes and yet are often directly compressible, depending on how they are subsequently processed. There are also relatively large non-direct compression fillings. Mixtures of direct and non-direct compression fillings are also contemplated.

In accordance with the present invention, it is most preferred to use spray dried mannitol. Generally, the amount of filler may range between 10 and 80% w / w and more preferably between 25 and 80%. Even more preferably, the amount of filler will range between 35 and about 60% by weight of the pharmaceutical form or formulation.

In accordance with the present invention, disintegrants can also be used as long as they can provide the results described herein. These may also include binders that have disintegrating properties. The most preferred for use as a disintegrant is sodium starch glycolate. A sodium starch glycolate useful in accordance with the present invention is GLYCOLYS® (standard quality) from Roquette de Lestrem, France.

The amount of disintegrant will vary with known factors such as the size of the pharmaceutical form, the nature and amounts of the other ingredients used, the degree of dose reduction desired, etc. However, in general the amount should range between 0.25 and 20% by weight of the final formulation, more preferably between 0.5 and 15%, more preferably between 0.5 and about 10% p / p and even more preferably between one and eight percent by weight. Again, this is a function of the weight of the finished formulation (pharmaceutical form).

A compression or ejection lubricant is also generally useful in accordance with the present invention. The most common known lubricant is magnesium stearate and the use of magnesium stearate is preferred. In general, the commonly accepted opinion about compression lubricants is that less is more. In most circumstances it is preferred to use less than about one percent of a compression lubricant. Usually, the amount should be zero point five percent or less. However, the amount of magnesium stearate used may be more than 1.0%. Moreover, it is preferably greater than 1.5% and most preferably between 1.5 and 3%. The use of approximately 2% magnesium stearate is the most preferred. Other conventional compression lubricants such as, for example, stearic acid, calcium stearate and the like, can also be used instead of part or all of the magnesium stearate.

Effervescent tablets according to the present invention may be relatively soft or resistant. They can be manufactured, for example, in accordance with the methods described in US Pat. No.

5,178,878

and will generally have a hardness of less than 15 Newtons. Unlike the formulations described in the ‘878 patent, the active ingredient herein will not necessarily be coated with a protective material. Moreover, preferably, the active opioid principle will not be coated. When soft and malleable / fragile tablets such as these are produced, they can be advantageously packaged in a blister pack as described in US Pat. No. 6,155,423. They can also be resistant with a hardness of more than 15 Newtons and a friability of 2% or less, manufactured in accordance with the procedures set forth in US Pat. No.

6,024,981.

In a preferred embodiment, the pharmaceutical forms of the invention are provided in a childproof blister pack. Refer, for example, to US Pat. No. 6,155,423 to Katzner et al., Published on December 5, 2000 and granted to CIMA LABS INC. Most preferably, the package meets the standards set forth in 16 U.S.C. paragraphs 1700.15 and .20 (2003). Preferred packages also include those commonly referred to in the industry as the so-called "F1" and "F2" packages.

The tablets according to the present invention can be designed slightly differently for oral, gingival or sublingual administration. In each case, however, the disintegration time in the mouth (average residence time) reached by the formulations is preferably less than 30 minutes. Generally, these tablets will have an average residence time of between 5 and 30 minutes, more preferably between 10 and 30 minutes, even more preferably between 12 and 30 minutes.

In accordance with a particularly preferred embodiment of the present invention, an orally disintegrable effervescent tablet designed for oral, sublingual or gingival administration of an opioid, or a pharmaceutically acceptable salt thereof, which comprises or consists essentially of an opioid is provided (in weight depending on the weight of the free base), an effective amount of an effervescent additive and an effective amount of a pH regulating substance. The formulation will also include one or more excipients. In a preferred embodiment, the excipients include mannitol and sodium starch glycolate. In a particularly preferred embodiment, these formulations do not include amounts of lactose monohydrate or MCC and PVP XL in amounts that significantly reduce the advantages of the invention.

The formulations according to the present invention may include other conventional excipients in generally known amounts as long as they do not detract from the mentioned advantages. These may include binders, sweeteners, coloring components, flavorings, gliding agents, lubricants, preservatives and disintegrants.

EXAMPLES

10 Manufacturing method

In each case of examples 1-7 and 9-11, the materials were analyzed before being used, introduced into a type V mixer, or mixed in any other suitable low speed mixer, and mixed for a time. suitable. After being removed from the mixer, the materials were compressed in a standard rotary tablet press until an objective hardness of 13 Newtons and an objective weight as described were obtained.

15 in each example.

COMPARATIVE EXAMPLE 1 - Formulation A of the first study

OraVescent®, fentanyl, 1080 mcg, 5/16 ”(7.94 mm) tablet, red

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

1,688

Mannitol, USP *

95,312

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium carbonate, USP / NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Red ferric oxide, NF

1,000

TOTAL

 200,000

*

 spray drying (Mannogem EZ from SPI Pharma) COMPARATIVE EXAMPLE 2 - Formulation C of the first OraVescent® study, fentanyl, 1300 mcg, 5/16 ”(7.94 mm) tablet, red

*

 spray drying COMPARATIVE EXAMPLE 3 - Formulation D of the first OraVescent® study, fentanyl, 810 mcg, 5/16 ”(7.94 mm) tablet, yellow

*

 spray drying COMPARATIVE EXAMPLE 4 - Formulation E of the first OraVescent® study, fentanyl, 270 mcg, 5/16 ”(7.94 mm) tablet, white

*

 spray drying COMPARATIVE EXAMPLE 5 OraVescent®, fentanyl, 500 mcg, 5/16 ”(7.94 mm) tablet, orange

*

 spray drying COMPARATIVE EXAMPLE 6 OraVescent®, fentanyl, 200 mcg, 5/16 ”(7.94 mm) tablet, white

*

 spray drying COMPARATIVE EXAMPLE 7 OraVescent®, fentanyl, 100 mcg, 1/4 ”(6.35 mm) tablet, white

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

2,042

Mannitol, USP *

94,958

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium carbonate, USP / NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Red ferric oxide, NF

1,000

TOTAL

 200,000

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

1,266

Mannitol, USP *

95,734

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium carbonate, USP / NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Red ferric oxide, NF

1,000

TOTAL

 200,000

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

0.422

Mannitol, USP *

97,578

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium carbonate, USP / NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

TOTAL

 200,000

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

0.786

Mannitol, USP *

96,214

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium Carbonate, NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Yellow Ferric Oxide, NF

0.600

Red ferric oxide, NF

0.400

TOTAL

 200,000

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

0.315

Mannitol, USP *

97,685

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium Carbonate, NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

TOTAL

 200,000

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

0.157

Mannitol, USP *

48,843

Sodium bicarbonate, USP / EP / JP

21,000

Citric Acid, USP / EP / JP

15,000

Sodium Carbonate, NF

10,000

Sodium starch glycolate, NF / EP

3,000

Magnesium Stearate, NF / EP / JP

2,000

TOTAL

 200,000

* spray drying

5 COMPARATIVE EXAMPLE 8

The materials can be analyzed before being used, introduced into a type V mixer or other suitable low speed mixer and mixed for a suitable time. After being removed from the mixer, the materials can be compressed in a standard rotary tablet press until an objective hardness of 13 Newtons and a target weight of 200 mg / tablet are obtained.

10 OraVescent®, fentanyl, 300 mcg, 5/16 ”(7.94 mm) tablet, pale yellow * spray dried

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

0.472

Mannitol, USP *

97,328

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium Carbonate, NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Yellow ferric oxide

0.200

TOTAL

 200,000

COMPARATIVE EXAMPLE 9 OraVescent®, fentanyl, 400 mcg, 5/16 ”(7.94 mm) tablet, pink

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

0.629

Mannitol, USP *

97,171

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium Carbonate, NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Red ferric oxide, NF

0.200

TOTAL

 200,000

*

 spray drying COMPARATIVE EXAMPLE 10 OraVescent®, fentanyl, 600 mcg, 5/16 ”(7.94 mm) tablet, orange

*

 spray drying COMPARATIVE EXAMPLE 11 OraVescent®, fentanyl, 800 mcg, 5/16 ”(7.94 mm) tablet, yellow

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

0.943

Mannitol, USP *

96,057

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium Carbonate, NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Yellow Ferric Oxide, NF

0.600

Red ferric oxide, NF

0.400

TOTAL

 200,000

COMPONENT NAME

QUANTITY (mg / tablet)

Fentanyl Citrate, USP

1,257

Mannitol, USP *

95,743

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium Carbonate, NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Yellow Ferric Oxide, NF

1,000

TOTAL

 200,000

* spray drying

COMPARATIVE EXAMPLE 12

The materials can be analyzed before being used, introduced into a type V mixer or other suitable low speed mixer and mixed for a suitable time. After being removed from the mixer, the materials can be compressed in a standard rotary tablet press until an objective hardness of 13 Newtons and a target weight of 200 mg / tablet are obtained.

OraVescent ® Oxycodone, 5 mg, 5/16 ”(7.94 mm) tablet, white

COMPONENT NAME

QUANTITY (mg / tablet)

Oxycodone hydrochloride, USP

5,000

Mannitol, USP *

93,000

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium Carbonate, NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

TOTAL

 200,000

* Spray drying

COMPARATIVE EXAMPLE 13

The materials can be analyzed before being used, introduced into a type V mixer or other suitable low speed mixer and mixed for a suitable time. After being removed from the mixer, the materials can be compressed in a standard rotary tablet press until an objective hardness of 13 Newtons and a target weight of 200 mg / tablet are obtained.

OraVescent ® Hydromorphone, 2 mg, 5/16 ”(7.94 mm) tablet, slightly yellow

COMPONENT NAME

QUANTITY (mg / tablet)

Hydromorphone Hydrochloride, USP

2,000

Mannitol, USP *

95.80

Sodium bicarbonate, USP / EP / JP

42,000

Citric Acid, USP / EP / JP

30,000

Sodium Carbonate, NF

20,000

Sodium starch glycolate, NF / EP

6,000

Magnesium Stearate, NF / EP / JP

4,000

Yellow Ferric Oxide, NF

0.200

TOTAL

 200,000

* Spray drying

COMPARATIVE EXAMPLE 14 The following materials are weighed and analyzed.

#

Description Amount / tablet (% w / w) Quantity / lot (Kg)

one

Fentanyl citrate 0.6285 502.8 g *

2nd.

 Mannitol EZ 23,875 19.1

2b

 Mannitol EZ 24,014 19.2

3.

Baking Soda, No. 1 21,0000 16.8

Four.

Citric acid, anhydrous, Fine granular 15,0000  12.0

5.

Sodium carbonate, anhydrous 10,0000 8,000

6.

Sodium Starch Glycolate 3,0000 2,400

7.

Yellow iron oxide 10 0.5000 0.400

8.

Magnesium stearate, non bovine 2,0000  1,600

 Total

100,0000 80.0

Transfer the EZ mannitol (2a.) And the yellow iron oxide 10 to a V-type mixer and mix for 30 minutes. Remove and grind the premix. Add the total amount of premix, fentanyl citrate, sodium bicarbonate,

5 Citric acid, sodium carbonate and sodium starch glycolate to a type V mixer and mix for 30 minutes. Introduce mannitol (2b) to the type V mixer and mix for 13 minutes. Introduce magnesium stearate to the type V mixer and mix for 5 minutes. Compress the tablets from this final mixture. These tablets have a diameter of 1/4 "(6.35 mm), are smooth-faced, white and have a beveled edge. They are compressed to an average hardness of 13 Newtons in a 36-station Fette® tablet press fully equipped

10

Claims (17)

one.

A pharmaceutical form comprising 20 to 200,000 micrograms of an opioid, 0.5 to 25% w / w of a pH regulating substance suitable for said opioid, 5 to 85% w / w of an effervescent material, mannitol and a starch glycolate; wherein said pharmaceutical form is designed for the administration of said opioid through the oral mucosa through a route of oral, gingival or sublingual administration; where said opioid is oxycodone.

2.

The pharmaceutical form of claim 1, wherein said pH regulating substance provides a local pH of 3 to 10.

3.

The pharmaceutical form of claim 2, wherein said pH regulating substance can change the local pH by at least 0.5 pH units.

Four.

The pharmaceutical form of claim 3, wherein said pH regulating substance can change the local pH by at least 1.0 pH unit.

5. The pharmaceutical form of claim 1, wherein said pH regulating substance is a carbonate or baking soda.

6.

The pharmaceutical form of claim 1, wherein said starch glycolate is provided in an amount of 0.25 to 20% w / w.

7.

The pharmaceutical form of claim 6, wherein said starch glycolate is provided in an amount of 0.5 to 15% w / w.

8.

The pharmaceutical form of claim 1, wherein said mannitol is provided in an amount of 10 to 80% w / w.

9.

The pharmaceutical form of claim 8, wherein said mannitol is provided in an amount of 25 to 80% w / w.

10.

The pharmaceutical form of claim 1, which has a residence time in the patient's mouth of between about 5 and about 30 minutes when administered orally, gingivally or sublingually, with minimal manipulation in the mouth.

eleven.

The pharmaceutical form of claim 1 further comprising a binder, a sweetener, a coloring component, a flavoring agent, a sliding agent, a lubricant, a preservative, a filler and / or a disintegrant.

12.

The pharmaceutical form of any of claims 1 to 11 for use as a medicament.

13.

The pharmaceutical form of claim 1 for use in the treatment of pain.

14. The pharmaceutical form of claim 13, wherein said pain is breakthrough pain caused by the cancer.

fifteen.

The pharmaceutical form of claim 13, wherein said pain is back pain.

16.

The pharmaceutical form of claim 13, wherein said pain is surgical or postoperative pain.

17.

 The pharmaceutical form of claim 13, wherein said pain is neuropathic pain.