TWI354551B - Effervescent oral opiate dosage forms and uses the - Google Patents

Description

1354551 IX. Description of the Invention: [Technical Field] The present invention relates to a dosage form of an anesthetic material which can be defoamed by oral administration, and which is used to form an anesthetic material using the dosage form. /0 The method of treating pain and its use for making music. [Prior Art]

Fentanyl (CAS registration number: 437 38_7) ν Stupyl H (2-phenyl-ethyl)-4-cyanosyl] propylamine and its salts (especially its bar-like acid sleep (CAS) Registration number: 99〇_73_8)) is an anesthetic drug, a controlled substance and an extremely effective narcotic analgesic. Currently, fentanyl and its citrate are sold by a variety of companies in a variety of delivery formats. For example, fentanyl citrate is available as an injection and a stick-like buccal, the latter being sold under the trade name ACTIQ. Fda publishes the approved drug list (Appr〇ved Drug Pr〇ducts)

Therapeutic Equivalence Evaluations, hereinafter referred to as "Orange Book", identified three patents relating to ACTIQ: U.S. Patent Nos. 4,671,953, 4,863,737 and 5,785,989. The Physician's Desk Reference, 57th Edition, 2003, page 1184, available from Cephalon, Inc., 145 Brandy Wine Parkway West, Chester, PA 19380. The review of the packaging insert information for ACTIQ is caused by the patient. A direct review of the severity of the pain. According to its label, ACTIQ" is indicated only for the management of break-through cancer pain in patients with malignancies who are already receiving and who are tolerant to 〇pjjate therapy for their underlying persistent 100177.doc 1354551 cancer pain" Emphasized). The contents of the ACTIQ label are incorporated herein by reference. Providing relief from such sudden pain is related to the patient's immediate quality of life, and for such patients, providing pain to relieve sudden pain may be the only medicine that can be done.

Fentanyl is just one of a family of drugs called anesthetics. Legal anesthetics are prescription drugs, and include alfentanil, alphaprodine, anilide; anileridine, benzylmorphine, and schmidt (bezitramide), buprenorphine, butorphanol, clonitazene, codeine, codeine phosphate, dihydrodeoxy hydrazide Desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, hydrocodone ketol acetate Dihydrocodeinone enol acetate, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, whiffin diphenyl Dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine Love Tony Etonitazene, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, schizophrenia Ketobemidone, levophanol, lofentanil, meperidine, 100177.doc 8 1354551 meptazinol, metazocine, mesa Methadone, met〇p〇n, morphine, morphine hydrochloride, morphine sulfate, myrophine, nalbuphine, Narceien, nicomorphine, norlevorphanol, norniethadone, normorphine, norpipanone, opium (〇piurn) ), oxycodone, oxymorphone, papveretum, panta. Pentazocine, phenadoxone, phenazocine, phenotypic > phenoperidine, piminodine, piritramide ), pr〇heptazine, promedol, propirm, pr〇p〇xyphene, remifentanil, Sufentanii and tilidine. In general, the class of compounds known as anesthetics also includes illicit drugs such as heroin and cocaine. Anesthetic agents according to the present invention include those identified above and any of the controlled substances listed as 21 c.FR § 13 08.12. Anesthetic drugs are administered to patients for a number of reasons, most often to slow down one or another type of pain, although the side effects profile is not always the same as fentanyl, but the species is characterized by very strong drugs, two All are addictive and may have fatal side effects depending on the dose of the subject.

L. To date, the only fentanyl anesthetic has been formulated into an orally disintegrable dosage form. U.S. Patent No. 6,200,604 (" '604 Patent "), issued March 13, 2001 to CIMA LABS INC 100177.doc 8 10000 Valley View Road, Eden Prairie, MN 55344, exemplifies that each contains 36% A foaming agent and a fentanyl formulation of 1.57 mg of fentanyl citrate. See fact 1, column 5, line 60 to block 6, line 30. The 404 patent describes the use of foaming as a penetration enhancer in the absorption of oral drugs in other drugs. See also U.S. Patent Nos. 6,759,059 and 6,680,071. See also 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. With many incidents in medicine, there has been room for improvement. Narcotic drugs are expensive drugs, for example, fentanyl costs manufacturers up to $1/kg or more. Although fees are by no means the most important issue, drug costs are still a concern. Discretionary reductions in narcotic drug content can reduce the overall cost of patient care. More importantly, while the beneficial treatment of sudden pain can still be achieved in, for example, cancer patients or patients with chronic back pain, reducing the dose of such effective anesthetic drugs has a very urgent need and need for overall patient care. result. Anesthetic mu-receptor antagonists, including fentanyl, produce dose-dependent respiratory depression. Even at the recommended dose, severe or fatal respiratory depression can occur in susceptible individuals. Like other potent anesthetics, fentanyl is associated with severe cases of non-tolerogenic individuals in anesthesia and cases of respiratory depression caused by 100177.doc 1354551 ,, and side effects (even if they are not life threatening) It is remarkable.磾 In addition, mu-anaesthetic antagonists produce drug dependence and tolerance! Its own dependence on its own drug dependence is not necessarily a problem for certain types of cancer patients. However, anesthetic drugs can also be used in the treatment of other types of pain. 4 Dependence and tolerance may be significant problems. In addition, since cancer patients are usually subjected to a large number of medical treatments, it is possible to provide lower doses in a longer-term manner. Preferably. If a low dose is given but an anesthetic that relieves similar pain is still provided, the patient will be able to obtain a lower cost of the lesser drug and reduce the risk of side effects. Therefore, the improvement of the administration of anesthetic drugs is still urgently needed.

The present invention relates to a disintegrable/dissolvable foaming anesthetic for oral administration, a dosage form, a method for treating the same using the dosage form, and use thereof for the manufacture of a medicament. In a preferred embodiment, the 'anaesthetic drug or one or more of its pharmaceutically acceptable salts are contained in a form other than the other forms of transmission (including examples of U.S. Patent Nos. 6, 2, 6, 4) Oral administration is required at a lower dose of anesthetic drug to provide a phase-disintegratable disintegrable and/or soluble film and the like. A specific location in a cavity, as it is. Formulations of the Invention The "oral" dosage forms in the context of the present invention include degumming agents, capsules, caplets, gels, ointments, and, in general, such dosage forms are applied or placed in the mouth as they disintegrate and / or dissolved/disintegrated at the time of dissolution (this is preferably designed for buccal, gingival and/or sublingual administration 100177.doc 1354551 also referred to herein as residence time) on average about 5 and about ―, even better for 12·30 minutes. Please note; it: tube = different from the dissolution system, the concept of the tube solution stops and continues to exist as m~ "used as a key agent to identify the time spent transmitting the early delivery medium . In another embodiment of the present invention, an oral disintegrable/dissolvable foaming agent comprising a foaming combination, a pH adjusting substance and a specific disintegration is provided for the design of a sputum type system. The anesthetic and/or its pharmaceutically acceptable salt is administered via a mouth-of-mouth, Til sublingual path. Without wishing to be bound by a particular implementation theory, it is believed that the foaming action can penetrate the enhancer. Preferably, the pH adjusting substance is not used to produce a foaming action, and is preferably in contact with the surface of the dosage form when compared to a comparable dosage form having no pH adjusting substance. The microenvironment of the zone or any portion thereof provides a pH difference or change of at least about 〇5 pH units. One such embodiment of the invention comprises between about 2 Torr and about 2 Torr, an anesthetic between 〇〇〇 micrograms, based on the weight of the dosage form ("W/W") between about 〇5 and about 25 a pH adjusting substance suitable for the anesthetic, between about 5 and about 8 5 /〇w/w, a foaming combination or material, a glycolic acid starch and preferably a filler such as mannitol, The dosage form is designed to administer the anesthetic drug through the oral mucosa via a buccal 'gingival or sublingual route of administration. In another particularly preferred embodiment of the invention, an anesthetic is provided that is substantially an effective dose (to the a free-formulation of an anesthetic drug, or a salt thereof, a glycolic acid starch, at least one pH-adjusting substance, and a combination of at least a foaming agent. The materials are well formed, orally disintegrable or An effective amount of the dissolved dosage form is provided and, in an even better embodiment, it is possible to administer less illusion of drunkenness to achieve "comparable"cma. Average lysis time or residence time will Between 10 and 30 minutes: these The average residence time is based on multiple doses of patients with 10 or more H). The dosage forms are transmitted, and the size, shape and design are used for buccal, sputum or sublingual administration. It is envisioned that the present invention is another method of administering an anesthetic drug to a patient suffering from pain such as y, which generally includes (but is not limited to J, painful lower back, P pain, joint pain). , any form of arthritis pain, night from trauma or accident, deer», pain, neuralgia, surgery or postoperative pain,

Pain from a disease or condition other than cancer, cancer pain, and especially cancer

Sudden pain caused by the disease.铋#士, + A The preferred method includes the steps of a patient who needs any of the orally disintegrating dosage forms disclosed herein for buccal, gum or sublingual sputum, and is only right. An anesthetic drug that is 有效m effective agent 及 and the dosage form is sedated in the patient enough to cause the agent (or its treatment to have a S part, for example, to reduce the pain of the patient) to be delivered from the oral cavity through the oral mucosa to the bloodstream Preferably, the patient is patrolled, trained, or monitored to ensure that the agent is not swallowed' and, as an alternative, the anesthetic drug enters the body via the surface of the oral cavity or surfaces. Preferably, the method further comprises the step of retaining the sputum dosage form in the mouth while substantially not moving it in the oral cavity. In a further preferred embodiment, the dose dissolves on average by about 30 minutes or less, preferably about 20 minutes or less, and is generally H) minutes or longer. In another preferred embodiment, the dosage form to be administered is generally administered in response to a desired therapeutic response (degree of pain relief) based on a dosage form that does not include the foaming combination 'pH adjusting substance of the present invention and transglycosidic powder. Anesthetic 100177.doc 1354551 i Do not use the same anesthetic less. In one embodiment, the dosage form is comparable when compared to other identical formulations that do not have the pH adjusting substance and foaming combination in at least about 20% by weight of the anesthetic agent.

Cmax(80_120%) 〇[Embodiment] Throughout the specification, including the scope of the patent, the words "including" and having |including" and its variants mean the specified steps, components or materials It is essential that other steps, elements or materials may be added and still form the concept of a patented application or disclosure. When describing the invention and the patent Φ 士 Μ 四 四 四 四 四 四 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 These terms (especially when applied to the scope of the patent) are included in the formula, and do not exclude additional, unquoted elements or method steps "comparable to" in the present invention The dosage form of the invention is 80-120% of the same dosage form without foaming combination, pH adjusting substance and glycolic acid starch. For the purpose of the present invention, in terms of characteristics, characteristics or variables, unless two: Bu Yiyi Otherwise, the term "substantially" when applied to any standard, such as a characteristic, characteristic, or any of the criteria, is intended to satisfy a standard that is known to those skilled in the art to be aware of the benefits achieved by the #achievement, or the desired condition or characteristic value.

The method of administering an anesthetic to a patient suffering from pain is one aspect of the present invention. The method can include any conventional mode in which the oral cavity of the patient in need thereof can be grasped with H 100177.doc 1354551. Examples of appropriate research are as follows: Clinical study design and implementation. Informe (j Consent Forms) (ICF) is approved by the Institutional Review Board (IRB). All subjects read and signed the ICF approved by the IRB. The signed and notarized ICF. ▲ For the first two periods, the study used a single-dose 'random, open-labeled brother, two-way design and design designation The test and control products were tested and subjects were randomized to receive three additional test formulations during Phase 3. All subjects were random and were in a fasted state after 10 hours overnight fasting. There was a 7-day washout interval between doses of the drug. The subjects were limited to 36 hours after the administration of fentanyl. The subjects were screened within 21 days prior to the study registration. The screening program included medical history, physical examination (height , body weight, skeleton size, vital signs, and coffee), and clinical laboratory tests (Qianxue, serum chemistry, urine test', Qing antibody screening, hepatitis B surface antigen screening, hepatitis C antibody screening Screening for serum testing (only for women) and for cannabinoids and opioids All subjects enrolled in the study were satisfied with the inclusion/exclusion criteria listed in the protocol. Subjects (17 males and 25 females) were enrolled in the study, and 39 subjects (17 males and 22 females) completed the study. Subjects reported to the clinic in the morning before each dose. The lunch was eaten 19 hours before the administration, and the dinner was taken 14 hours before the administration, and the subjects were fasted overnight after 1 hour before the administration of the meal. The first 14 I00177.doc 8 1354551 days 'After 4.5 hours after administration, the main diet schedule is 'hours', and ^ standard diet schedule' dinner is provided after the hour-hours: two hours after the administration. (2) 33 hours after the administration. · 5 hours, and the dinner is in the essay:: Do not consume any wine during the hour and period before each restriction period

"," test, or yellow f slave food money. Tested away from tobacco and tobacco at least 6 months before the test. In addition, for the 7 days of the Lebe and the trial period, the non-Tiger period door is not allowed to be prescribed for 14 days before the administration of the “Zhu Le” and between the trials (the female hormone contraceptives are excluded during the test period) After Tenny, the subjects remained sit for 4 hours. Drinking water was restricted from 0 hours to 4 hours after dosing. The time was limited before the administration until 4 hours after the administration. The subjects were not allowed to engage in any intense during the test period. The subjects who received naltrexone (naItrexone) at each time were as follows. ReVia® 50 mg (Naltrexone hydrochloride lozenge)

Batch number manufactured by Bristol-Myers Squibb: 5C269A Effective semester: April 2004 Lot number: TB1798 Effective sputum: Subjects assigned to A, B, C, and D treatment regimens in March 2005 were administered to fentanyl An oral dose of -5 naltrexone tablet was administered 15 hours and 3 hours and 12 hours later and 240 mL of water was consumed. Subjects assigned to the E regimen received an oral dose of 5 mg of naltrexone tablet and consumed 240 mL of water 15 hours prior to fentanyl administration and 3 100177.doc 15 1354551 hours. Subjects received one of the following fentanyl treatments in each of three periods: A · OraVescent® fentanyl citrate 1 〇 80 (fentanyl base) manufactured by CIMA LABS INC Lot number: 930502 Randomly returned Subjects enrolled in the A treatment regimen received a single oral dose of a 1080 pg fentanyl lozenge placed between the teeth above the molars, the palate and the cheeks and φ allowed to disintegrate for 10 minutes. Note: "OraVescent" indicates a formulation and dosage form according to the present invention. B: Actiq® (oral transmucosal fentanyl citrate), equivalent to 16 screams manufactured by Cephalon, Inc. or Anesta Lot number: 02 689 W3 Subjects randomized to the B treatment regimen were placed on the cheeks A single oral dose between the lower gums;!: a 16 〇〇gg Actiq® unit. Use the handle to move the unit from side to side and allow it to dissolve for 5 minutes. ® C : OraVescent® fentanyl sulphate 13 ton (fentanyl base) Lot number manufactured by CIMA LABS INC · 930503 Subjects randomized to the C treatment regimen received the upper gingival above the molars A 13-fentanyl lozenge with a single oral dose between the buccal and buccal and allowed to disintegrate for 10 minutes. D ·· OraVescent fentanyl lozennate 8] squeak (fentanil) manufactured by CIMA LABS INC 100177.doc • 16 - 1354551 Lot number: 930501 Subjects randomized to the D treatment regimen Above the molars, a 8 10 pg fentanyl-depleted agent of a single oral dose between the teeth and the buccal was brewed and allowed to disintegrate for 10 minutes. E: OraVescent® fentanyl citrate, 27〇 (fentanyl base) manufactured by CIMA LABS INC Lot number: 930500 Subjects randomized to the E treatment regimen were placed between the gums and the cheeks above the molars One of the 270 single oral agents was called fentanyl lozenge and allowed to disintegrate for 10 minutes. The components of each of the fentanyl citrate tablets are described in Example 丨4. Before the administration (0th hour) and after the administration, 〇25, 〇5, 〇乃, 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, 1 (), 24, 36 hours to assess the posture of life signs (blood pressure, pulse and breathing). A continuous pulsating oxygen measurement method was performed 8 hours after administration. At the completion of the study, a 12-lead ECG, clinical laboratory evaluation (blood, serum chemistry, and urine test), and all vital signs were examined. Oral irritancy assessment was performed 4 hours after administration. Instruct the subject to report. Study any adverse events that occur during the study period by the physician and/or nurse. . Know the following time to collect the distribution to the A_D treatment plan, and the blood release (7 mL): before administration (the third hour) and 1〇, 2〇, 必必筚徭1 4 4 < and 45 Minutes; and after the mouth, 1, 2, 4, 6, 8, H), 12, 16, 2q „ . . U 24 , 28 , 32 , and 36 hours. Collected to (4) blood samples collected at the following times (7 mL): before administration (the third hour) and again "20' 30, and 45 minutes I00177.doc 1354551 clocks; and 1, 2, 4, 6, 8, 9, 10, 11' 12 after administration, 14, 16, 20, and 24 hours. A total of 54 blood samples (378 mL) were taken during the study for drug analysis. Samples were collected and processed at room temperature under fluorescent lighting. The blood sample is condensed into pieces 'by centrifugation, and it is cold at _2, and kept cold until the test is performed. Analytical method LC-MS/MS (liquid chromatography-mass spectrometry/mass error) of fentanyl in human serum. Pharmacokinetics and Statistical Methods Pharmacokinetics and Statutes are based on the Food and Drug Administration's Center for Drug Evaluation and Research (CDER). Named "statistical Approaches to Establishing" in January 2001

Bi〇eqUivalence" review guidelines and published in March 2003 and named Bioavailabihty and Bioequivalence Studies for Orally

Administered Drug Products-General Considerations."Guideance for Industry. The following non-ventricular pharmacokinetic parameters were calculated using WinN〇nlin Standard Version 2.1 from the fentanyl concentration-time data for each treatment regimen. A continuous (rather than nominal) sampling time is used in the analysis. AUC(O-t) AUC (0-infinity) Use linear trapezoidal area summation from time to time 〖 Calculated area under fentanyl concentration-time curve, where t is the last measurable concentration (Ct). From time 0 to infinity fentanyl concentration _ time curve below product ' AUC (0 - infinity) = AUC (0 - t) + Ct / Kd, where Kel is the terminal elimination rate constant. 100177.doc -18 - 1354551 AUC(O-t)/ AUC(0-infinity) =:tmAUc(〇_infinity)&. Also known as AUC (O-tmax), the local area of the value Tmax from time 0 to the control formulation is calculated using a linear trapezoidal area summation method.

Kel calculates the terminal elimination rate constant by linear regression of the terminal linear portion of the logarithmic curve of concentration versus time, where Kel = - slope. The linear portion of the terminal is determined by visual inspection. T1/2 eliminates half-life and is calculated as ln(2)/Kel.

Cmax maximum observed fentanyl concentration.

Tmax Maximum fentanyl concentration time (obtained without interpolation). This study is a single dose, randomized, open-label, two-way crossover test of the indicated test and control products. Subjects (A treatment regimen and B treatment regimen, Phases 1 and 2) and Phase 3 were randomized to receive one of three additional test formulations (C treatment regimen, D treatment regimen, or E treatment regimen). Due to the large number of subjects, the study was conducted in two groups. The primary comparison in this study was the A treatment regimen versus the B treatment regimen. To achieve an analysis of the variance of the two treatment regimens, only two phases (AB, BA) were considered (1, 2), and two treatment regimens (A, B). A parametric (normal theory) general linear model was applied to the log transformed AUC (0-infinity), AUC (O-t), and Cmax values from the A and B treatment regimens. 5.7 In this model, the entire analysis of variance (ANOVA) model is considered and includes the following factors: group, period within the group, treatment plan, order, order by group, subject in order of group And treatment options according to the group. Since the interactions in the order of the groups are not important, the model is reduced to subjects, periods, and treatments in order, order. The order effect is tested using subjects in the order of mean squares, and the other major effects are tested using residuals (error mean squares). For auc (〇_t), AUC (〇-infinity), and Cmax, the double unilateral hypothesis is based on the ratio of the test to the control method (A treatment plan versus B treatment plan). The interval was tested at 5%. The difference between the A treatment regimen and the treatment # was evaluated using the WilCoxon Signed Ranks Test (a = 〇〇 5). Serum fentanyl concentration and pharmacokinetic parameters were also measured after the D treatment regimen and the bench treatment regimen (i3 bark, 81〇μδ, and 270 tons of 〇raVescent® fentanyl citrate) To evaluate the dose ratio (4) of the (10)(10)8 fentanyl citrate formulation, a mixed linear model was applied to the dose-normalized Cmax and AUC parameters from the a, c'd, and e treatment regimens. The 5-7 grouping considered the entire model and included The following factors: 'groups, periods within the group, treatment plan, order, order by group, subjects in the order of the group, and treatment groups according to the group For two of the three parameters [. earn and take (0 · not heavy |, The (4) is reduced to a one-way ANOVA with treatment regimen factors. If the overall treatment regimen effect is found, the a treatment regimen is used as a control for pairwise comparison. The ancient week tears, t-stops, confirmed by the detection and recording The time of loss of the compound minus the time of treatment and the time of stay (the length of time the formulation is present in the mouth). The value of the equivalent is tabulated and the summary statistics are provided. Assigned I00I77.doc 8 •20·°° (17 males and 25 females) In the study, A 4 and 3-9 subjects (17 males and 22 females) completed the study. The subjects in the three subjects were out of the study because the subject did not wish to continue the study. The second subject = the third phase of the patient was stopped because the subject did not wish to continue the study. : The subject was stopped before the second period because the subject took == average age was 27 years old (in the range of ... age), and the subject was Pingdan, 68夬吋 (between 62_74 inches) Within the range), and the test is 152.1 broken (between 1〇9〇_197(4)) Case deviations and adverse events The following program deviations occurred during the study. The roots were taken. The subjects were measured at the time point of the 3 hour life sign. The time during the call-out period was not measured at the time of the 3.5-hour life sign. Test = Suction. The 2-hour time point of the second period was not checked again. Two. At the first time of the third period, one subject was not checked for signs of birth and sputum. Two subjects at the hourly time (A treatment) The blood samples of the party:) are not correctly labeled, and the samples are not analyzed. Root=door subjects should measure the pulse at the time of 3.5 hours of life sign. The second period of time is not measured by one subject pulse. . There is no above-mentioned deviation of ::U more than once. No serious adverse events occurred. For the clinical samples of this study, a total of postal tests were required. There are 14 batches acceptable for this batch. The back-calculated standard concentrations of 14 batches of acceptable I00177.doc 1354551 human serum used in this study ranged from 50.0 to 5000.0 pg/mL with a limit of 50.0 (picks/mL) pg/mL. . The quality control sample analyzed with each acceptable batch has a coefficient of variation lower than or equal to 7.89%. Residence time The residence time data is summarized in the table below. Lozenges / Bulk Retention Time Summary A Treatment Protocol B Treatment Protocol C Treatment Protocol D Treatment Protocol E Treatment Protocol Number of Subjects Time (minutes) Time (minutes) Time (minutes) Time (minutes) Time (minutes) Average Value 21 34 19 25 22 SD 12 15 11 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 50 62 A treatment plan = 1x1080 meg OraVescent fentanyl citrate:

Test B treatment regimen = 1 X 1600 meg Oral transmucosal fentanyl citrate (Actiq): Control C treatment regimen = 1 x 1300 meg OraVescent citrate citrate: test sputum treatment regimen = 1 parent 81 〇! 110§ 0 ^\^806111; fentanyl citrate: test E treatment regimen = 1 x 270 meg OraVescent citrate citrate: agent: test SD = standard deviation; CV = coefficient of variation; SEM = standard error of the mean; = (observation) number 100177.doc -22- 8 1354551 - Subject report (3) treatment plan (level 2 on the 1-10 level) spurs... (6) oral stimulation reaction) Stimulation response during the third period 1 # After administration, it is located on the right side of the mouth. After the E treatment plan, the study 1 = the drug is located at the right upper cheek, and the red (4) is in the 3rd__ test product, 42 registered subjects, and the 4G subjects complete the first and second phases. And included in the general statistics, detailed analysis and average table of A and B treatment plans.

Thirty-nine subjects completed Phases 2 and 3 and were included in the proportional statistical analysis of doses. The arithmetic mean of serum fentanyl pharmacokinetic parameters and statistical comparisons after the 丨』1 king, nine-T A treatment regimen and treatment regimen are summarized in the following table. Deuterated kinetic parameters of serum fentanyl in treatment regimens of sputum and sputum............"*;;...........λ &... ......................

Shang-sheng-............ϋϋFenfenidine treatment regimen = lxi〇8〇mcg 〇raVescent citrate citrate tablets: test B treatment regimen=1 X 1600 meg oral Acetyl citrate citrate (Actiq): The results of the Welchson symbol rank test show that the median value of A treatment regimen is 100i77.doc • 23·

Tmax (0.998 hours) was significantly earlier than the B treatment regimen (1·999 hours) (ρ < 0·0001). We calculated the individual and mean serum fentanyl pharmacokinetic parameters of the C, D, and sputum treatment regimens. Five subjects in the sputum treatment regimen were unable to calculate Kel. Therefore, AUC (0-infinity), AUCR, and T1/2 cannot be calculated in these cases. The arithmetic mean and standard deviation of serum fentanyl pharmacokinetic parameters following the C, D, and E treatment regimens are summarized in the following table. A brief summary of the pharmacokinetic parameters of serum fentanyl after the C, D, and E treatment regimens.............. serum fentanyl........-. ....C treatment regimen D treatment regimen E treatment regimen pharmacokinetic parameters N arithmetic mean SD N arithmetic mean SD Cmax (pg/mL) 12 2791.4 874.3 13 2646.9 778.7 AUC(0-tmax)(pg* Hr/mL) 12 4008.3 1259.1 13 3694.8 971.89 AUC(0-t)(pg*hr/mL) 12 18921 6470.2 13 15339 4260.4 AUC (0-infinity) (pg*hr/mL) 12 21033 7346.3 13 16831 4449.8 Tl/ 2(Hr) 12 13.2 7.67 13 11.7 4.66 Kel(l/hr) 12 0.0687 0.0354 13 0.0703 0.0352 AUCR 12 0.907 0.0683 13 0.909 0.0376 C treatment regimen = 1x1300 meg OraVescent citrate fentanyl bond D treatment regimen = 1 x 8 1 0 meg OraVescent fentanyl citrate E treatment regimen = 1 x 270 meg OraVescent citrate fentanyl bond AUCR is AUC 〇 _ t / AUC 〇 - no s ratio. The dose proportionality assessment of the A, C, D, and E treatment regimens, including the P-value, is summarized in the following table. Summary of dose standardization parameters for serum fentanyl in the treatment regimens of A, C, D, and E----------------------------- ------....................-..........------ A treatment plan C treatment Acid regimen D treatment regimen E treatment regimen 100177.doc • 24· 1354551 Pharmacokinetic parameters P-value arithmetic SD arithmetic SD arithmetic SD arithmetic SD mean mean mean value 0 „„/dose 2.5 0.8 2.1 0.7 3.3 1.0 3.0 1.2 (pg/mL/mcg) AUC (0-tV dose - 15.4743 5.01901 14.555 4.9771 18.937 5.2597 16.050 5.9180 (pg*hr/mL/mcg) AUC (0-infinity) / dose - 16.5851 5.00318 16.179 5.6510 20.779 5.4935 15.637 6.4732 (pg*hr/mL/mcg) ln(Cmax/dose) 0.0127 0.8788 0.3115 0.7190 0.3151 1.137 0.3356 1.011 0.3974 Ln(AUC(0-t)/dose) 0.1727 2.690 0.3170 2.625 0.3409 2.901 0.3032 2.706 0.4002 ln[AUC(0- Infinity) / Dose] 0.0783 2.765 0.3003 2.725 0.3633 2.998 0.2894 2.691 0.3892 A treatment plan = 1x1 080 meg OraVescent fentanyl bond

C treatment regimen = 1x1300 meg OraVescent citrate fentanyl bond D treatment regimen = 1 x 8 1 0 meg OraVescent citrate fentanyl bond E treatment regimen = 1 x 2 70 meg Ora Ve scent fentanyl citrate tablets Etc. Determine the time interval on the Kel value. The primary objective of this study was to evaluate CIMA LABS INC OraVescent® citrate fentanol at a dose of 1080 pg under fasting conditions compared to commercially available 1600 pg oral transmucosal fentanyl citrate, Actiq® (B treatment regimen, control). Bioequivalence of bismuth tablets (A treatment regimen, test). The study was a single-dose randomized, open-label, two-way crossover design for Phases 1 and 2. All subjects also returned to the third period to administer three OraVescent® fentanyl citrate test formulations: 1300 pg (C treatment regimen), 810 pg (D treatment regimen), or 270 μ§ (Ε treatment regimen) One of them. We evaluated the dose proportionality of OraVescent® fentanyl citrate (A, C, D, and sputum treatment regimens). A total of 42 healthy subjects were initially enrolled in the study. Thirty-nine subjects completed all three periods of the study, and 40 subjects completed both A and B treatment regimens (stages 1 and 2). Data from 40 subjects who completed the A and B treatment regimens were included in pharmacokinetics and statistical analysis. 100177.doc -25·

1354551 The ratio of the geometric mean squared mean of fentanyl Cmax, AUC (〇_t), & AUC (〇·infinity) (test/control) is 123.4% ' 1〇1.4%, and 101.1 /〇, respectively / σ treatment plan than B treatment plan). These data indicate that the average fentanyl exposure is similar, but the peak exposure of the A regimen is higher compared to the B regimen. The Tmax (〇 998 hours) of the A treatment regimen occurred one hour earlier than the (1) regimen regimen (2.00 hours), and the Cmax was 23% higher, indicating that the fentanyl absorption rate of the A regimen was significantly faster than the regimen regimen. .

The 90% confidence interval for CmaX is 111.82%-136.20%, AUC(Ot) is 94.42%-108.86%' and AUC(0_ infinity) is 93 6〇%1〇9 23%, indicating that for AUC instead of Cmax, The A treatment regimen and the B treatment regimen meet the requirements for bioequivalence. In fact, the Cmax of the A treatment regimen indicates that the use of the OraVescent® formulation exemplified in the Example [IraVescent® formulation provides less than about 3〇35% by weight of fentanyl provided statistically when compared to the 1600 micrograms of Actiq® formulation. Significantly higher Cmax. To obtain comparable results for Cmax's bioequivalence results, we should only use the OraVescent® fentanyl formulation, which includes fentanyl (as free) than in the comparative Actiq8 lozenge. The fentanyl weight is at least about 45%, more preferably about 47.5% and even more preferably about 5% fentanyl. In this case, about 800-880 micrograms is comparable to 16 micrograms of ACTIQ. Thus, it has been found that a dosage form of 1 mg or less using the present invention can be obtained with comparable Cmax from even less than originally thought to be fentanyl. A rapid Tmax has also been achieved. This allows for further dose reductions that are expected to have the aforementioned advantages described herein. These advantages are derived from dose reductions that are not associated with reduced efficacy. I00177.doc ^26- 8 1354551 After the OraVescent® transgenic fentanyl bond formulation, the fentanyl AUC is proportionally increased corresponding to a dose in the range of 270 to 1300 。. Among the four OraVescent® doses, there was no significant difference in dose-normalized AUC (0-t) or AUC (0_ infinity). Contrast Dose Standardized Cmax found a significant overall therapeutic effect. Since all subjects received the A treatment regimen, a treatment regimen was used as a control for pairwise comparisons. The pairwise comparison did not follow any pattern. Significant differences between the sputum treatment regimen (810 pg) and the A treatment regimen (1 〇 8 〇 pg) were found. The average residence time (21 minutes) of 1080 〇raVescent(g) fentanyl citrate was 13 minutes shorter than ACtiq® (34 minutes). The average residence time of the remaining three doses of OraVescent® fentanyl citrate formulation (19, 25, and 22 minutes) was similar to the 1〇8 88 formulation.

After OraVescent® fentanyl citrate, one subject reported mild irritation to the oral mucosa and one subject experienced erythema. No irritation or erythema was reported after Actiq®. Pharmacokinetic comparison of serum fentanyl after administration of M 0raVescent9 fentanyl bond and oral viscous fentanyl citrate (Actiq8) showed an average fentanyl exposure rate between the two products. different. The ratio of the geometric least squares (LS) of AUC ((M) and AUC (〇. infinity) is close to _%, and the 9G% confidence interval is within the hidden ice. 1〇80 is called 〇^6 reading citric acid The fentanyl geometry ^ mean CmaX is 23% higher and the upper limit of the treatment/control ratio _ the interval is older than the ' indicates that the bioequivalence criterion is not met for this parameter. I00177.doc • 27· 1354551 Even further dose reductions can be achieved. The Omax of the OraVescent® fentanyl lozenge is significantly earlier (1 hour earlier). OraVescent® fentanyl citrate formulation corresponding to the range of 270 to 1300 pg The dose, fentanyl AUC increased proportionally. The average residence time of the 1 080 pg OraVescent® fentanyl citrate tablet (21 minutes) was 13 minutes shorter than Actiq® (34 minutes). There was no serious or unexpected during the study period. Adverse events. Both formulations are well tolerated by the oral mucosa. ® References

Physician's Desk Reference ‘ 56th edition, Montvale, NJ: Medical Economics Company, Inc.; 2002. Actiq®; pp. 405-409.

Fentanyl. Micromedex [online] Vol. 107: Health Series Integrated Index; 2002 [acquisition date: 2003/July /371. 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 Inde; 2002 [Getting the deadline: 2003/June 16 曰]. Http://www.tomescps.com SAS Institute, SAS®/STAT User Guide, Version 6, 4th Edition, Volume 1, Cary, NC: SAS Institute; 1989. SAS Institute, SAS®/STAT User Guide, Version 6, 4th 100I77.doc • 28·8 1354551 Edition 'Volume 2' Cary, NC: SAS Institute; 1989. SAS lnstitute & Division, SAS8/Program Guide, Version 6, 3rd Edition’

Cary, NC: SAS Institute; 1990. A second study was conducted in the same manner. We performed this study to assess the dose proportionality (auq(5) called the presence of fentanyl citrate (referred to herein as Omcen Blue) formulated in a tablet according to the present invention beyond the scope of pharmaceutically acceptable use. And confirm the Cmax observations of the study just discussed. The Human Body Test Committee (IRB) approved the party and the informed consent form (ICF). Before the study began, 'all subjects read and signed the (IV) approved ICF ^ This study has a single dose, randomized, publicly labeled, 4 treatments, 4 periods, and design. The screening test is performed within 21 days before the study registration. The examination program includes medical history and physical examination ( Height, weight, skeleton, gold, life image, and electrocardiogram [ECG], and clinical laboratory test hematology, serum chemistry, urine test, HIV antibody screening, hepatitis A antibody screening, hepatitis B Surface antigen test, hepatitis C antibody screening, sputum and serum pregnancy test [only for women], and screening for cannabinoids and crow-like moons. All subjects enrolled in the study were satisfied with the inclusion/exclusion criteria listed in the protocol and the subjects were reviewed by the deaf before the patient's medical examination. Laboratory evaluation, A« and medical examinations performed. A total of 28 testers (16 males and 12 females) were registered in the study nine, and 9 ^ · "M·, (M males and 】 Female) completed the study. Five subjects were reported to the clinic before the trial, and at 14:00, they entered 100l77.doc -29. D1: lunch'] 9·00 hours for dinner, and 22•(10) for one time Add meals. Both follow the call and the overnight fast. On the first day, the standard diet was started at 4, the dinner was at 18:3 (), and the meal was at 22 thorns. The next day, start the standard diet schedule (including breakfast). Subjects did not consume any alcohol, broccoli, coffee, or yellow for 48 hours before and during each restriction period. Ticket food or drink. Pre-dose mail = Limit grapefruit during the study period ((4) pefruh). Subjects were kept away from nicotine and tobacco for at least 6 months after the enrollment study and throughout the study. In addition, over-the-counter medications (including herbal supplements) are prohibited 7 days prior to dosing and during the study period. Prescription medication (including ma inhibitors) is not allowed for 4 days before and during the study period. During the study period, subjects were placed in a vertical position for 4 hours after administration of fentanyl citrate. Drinking water was restricted from the time of administration until 4 hours after administration. Limit food intake 10 hours before administration until 4 hours after administration. During the study period, the test subject is not allowed to engage in any intense activities. The following treatment regimens were randomly selected by the formula: Pharmacy: 1:1^\^3© (naltrexone hydrochloride tablets) 5〇111§ Manufactured by Duramed Pharmaceuticals, Inc. Batch number: 402753001T Valid period: June 2006 Subjects received an oral dose of a 50 mg naltrexone tablet at 15 hours and 3 hours prior to the administration of the A treatment regimen and drank 24 mL of water. Subjects received an oral dose of a 5 mg mg of naltrexone tablet at 1 hour and 3 hours prior to dosing of the B, C, and D regimens and 12.17 hours after dosing and drank I00177.doc • 30· 1354551 with 240 mL water. A : Oravescent® fentanyl citrate 200 pg agent manufactured by CIMA LABS INC Lot number: 930859 Subjects randomized to the A treatment regimen received a single oral dose between the silver and the mouth frequency above the molars. An Oravescent® fentanyl citrate 200 pg tablet was allowed to disintegrate for 10 minutes. B ·· Oravescent® fentanyl citrate 500 pg agent manufactured by CIMA LABS INC Lot number: 930860 Subjects randomized to the B treatment regimen received a single oral dose placed between the gums and the mouth frequency above the molars An Oravescent® fentanyl quinine 5 00 pg bond: and allowed to disintegrate for 10 minutes. C : Oravescent® fentanyl citrate 8 1 0 pg spinner manufactured by CIMA LABS INC Batch number: 930501

Subjects randomized to the C regimen received a single oral dose of Oravescent® fentanyl 8 10 pg dextran placed between the teeth above the white teeth and allowed to disintegrate 1 0 minutes. C : Oravescent® fentanyl citrate 1 080 pg rotatory agent manufactured by CIMA LABS INC Batch number: 930502 Subjects randomized to the C treatment regimen received a single oral dose placed between the gums and the cheeks above the molars An Oravescent® Citrate I00177.doc 8 1354551 Tony 1080 卯 tablet and make it disintegrate ίο min. In the morning before and after the administration, Horn 125, i.5, mouth 5, 2'2·25, 2.5, 2.75, 3, 3.25, 3.5, 3:75, 4, 5, 6, 8, 1 (), 24, and 36 hours to assess the position of life signs (blood =, pulse, and call rate, _ after call, time and before dosing ..., as long as the subject tries to sleep to obtain continuous pulsation Oxygen measurement method. 2 Conduction 12-lead ECG, clinical laboratory evaluation (blood, serum: learning 'and urine test), and simple physical examination of all vital signs. 4 hours after the mouth for mouth irritation Evaluation. Check the oral cavity at each registry to ensure that the subject does not have oral ulceration at the drug administration area. Instruct the subject to inform the study physician and 7 or nurse of any adverse events that occurred during the study. f Collect and distribute to Blood samples from subjects with eight treatment regimens ^ mL): before administration (0th hour) and 丨〇, 20, 30, and 45 minutes; and after music 1, 2, 4, 6, 8, 9 ' 10, 11, 12, 14, 16, 20, and 24 hours. The distribution is assigned to B at the following times. Blood samples (7 mL) from subjects in the treatment regimen: before dosing (days) and 10, 2, 30, and 45 minutes; and 28, 32, and 36 hours after dosing. The fentanyl concentration of human serum samples was analyzed by sensitive and specific LC-MS/MS procedures. The following non-ventricular pharmacokinetic parameters were calculated using WinNonlin Standard Version 2.1 from the fentanyl concentration and time data for each treatment regimen. The actual (rather than nominal) sampling time is used for analysis. I00177.doc 8 -32- AUC(Ot): Use linear chess to open j-shaped ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ For the last measurable concentration (Ct) » AUC (0-infinity): from time 0 to infinity fentanyl concentration-time curve area, AUC (Q·infinity) = whip (four) soil Ct/Ke b where Kel is The terminal eliminates the rate constant. Uc(0 t)/ AUC(0-infinity): ratio of AUC(〇 t) to Auc(3) infinity). Also known as A position. Kel: The terminal elimination speed (four) is calculated by the line (4) of the terminal linear portion of the logarithmic curve of concentration versus time, where Kel = _ slope. The linear portion of the terminal is determined by visual inspection. T1/2. Elimination of half-life, calculated as in(2)/Kel.

Cmax: Maximum observed fentanyl concentration.

Tmax: time of maximum fentanyl concentration (descriptive statistics obtained without interpolating (mean, standard deviation [SD] coefficient of variation [cv], standard error of mean [SEM], sample size, minimum Value, maximum and median) The plasma concentration values of fentanyl are listed and summarized according to the treatment schedule and time point. 9·11 sets the value below the lower limit of quantitation [L〇Q] to zero. Separate concentration-time point. The fentanyl pharmacokinetic parameters and dose-standardized pharmacokinetic parameters were tabulated and the generalized statistics were calculated according to the treatment protocol. The methodology was evaluated using the methodology described by Smith et al. Even proportional to the dose of 1〇8〇Kg. 8 First, the logarithmic transformation parameters, including the logarithmic conversion of the dose and the fixed and random effects on the wear distance, were analyzed using a mixed-effects model. This model is suitable for SAS Proc Mixed » 9· 11 ΚΪ0 丨77.doc -33- 551 - The calculation of the slope of the solid effect (βι) 9〇% confidence interval ((7) and compared with the range (0.8677, 1.1323), this range is the agreement studied in this study Appropriate critical range of dose range The conclusions are based on the following: Hungarian 1-9% CI is included in the range (0.8677, 1.1323), then the dose proportionality can be introduced. If β<90〇/〇CI is completely outside this range, it cannot be introduced. Dosage proportionality. If the 90〇/〇CI portion of β丨 is within this range and part is outside this range, the results should be considered as “non-conclusive, % in this case, β 1 The best estimate of the deviation as the ideal ratio and the lower bound and upper bound of C can be considered to be within the data of drug safety, efficacy, or pharmacological effects. 8 If non-conclusive results are observed, then β is calculated. The maximum dose ratio at which 9% CI is completely within the critical range and the dose ratio that causes 90% CI of β to completely exceed the critical range. These dose ratios are referred to by Smith et al., respectively, and p2. = θΗΛ [l/max(i_L,U-1)], where ΘΗ = 1.25, L = 90% CI lower limit, U = 90% CI upper limit. P2 = 9h Λ [l/max(Ll,1-U )], and ΘΗ, L, and U are as defined above.

We performed a secondary analysis between the three lowest dose levels (200 pg, 500 pg, and 81 〇 pg) to detect differences in dose normalized Cmax. The parameter (normal theory) GLM was applied to the dose normalized cmax values from the a, B and C 100177.doc -34· 1354551 treatment regimen after logarithmic transformation. The analysis of variance (AN〇VA) model includes the following factors: treatment plan, sequence, order, and time period of the subject. A p-value below 0.05 was considered to be statistically significant. The disappearance time of the formulation confirmed by the sensation and the record minus the time of the treatment administration time (the length of time in which the formulation is present in the oral cavity) is tabulated and provides a summary statistic. The person stopped 'exiting the study. The two stopped before the third period because he did not wish to continue the study. Due to adverse events - the subjects stopped after the second period of the music. The average age of the subjects was 33. The average height of the 6-year-old (between 19 and 55 years old) is 66.6 inches (between 60 and 76 inches), and the average weight of the subjects is (10) (in iiG2i5__). , Department: During the period of the study, 'the following program deviation occurred'. After the second period. The target was not detected at the 5th hour. The subject was not checked for one time. The type m A is called 2.5- Hours, naltrexone; re-checking the signs of life. The fruit of the third period is not available. 3. J 'A subject's serum pregnancy test is used. As a result, the subject was put down for the 36th hour of the fourth period. Cheng. It was determined that the subject could not continue during the third period for all the sputum 1 to be 3.83 hours after the administration. The oral irritancy assessment was evaluated but the incident was stated: the nurse responsible for the incident recalled Therefore, it is not possible to verify the self-into-oral irritancy assessment form. The door is at the time of stay and should not be considered. The following table: i〇〇177.doc -35*

Treatment regimen B = 500 treatment regimen C = 810 treatment regimen D = 1080 pg During the registration of the oral assessment, note that at the beginning of the 4th phase, one subject had an oral ulcer in the lower cheek of the right side, ._ layer, and 'the first The product of the test product during the 3rd period occurred on the upper part of the right cheek. , „ Λ 九 九 员 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认 确认In grades 2 and 3), for both subjects, the stimuli were based on the test product during the second phase of the test. 'Lee is on the right side of the mouth; among the subjects One person also studied only ·<*曰曰h domain showed no erythema. 11 minutes after the C treatment plan, another _ + called to go and another 4 reported pain in the left cheek upper mouth P area at the gingival line福郝主古.π去』* Nanhe reported serious or unexpected adverse events β 28 registered subjects I 25 subjects completed the AS treatment program '26 subjects completed 8 treatment options, Twenty-seven subjects completed the treatment regimen. All subjects were statistically based on pharmacokinetic data. Due to the presence of restricted data points at the end stage, the elimination rate constant could not be calculated for one subject in the A treatment regimen. Therefore, this subject cannot be calculated Ϊ 00J77.doc -36- 1354551

AUC (0-infinity), AUCR, and T1/2. The arithmetic mean and standard deviation of serum fentanyl pharmacokinetic parameters after all treatment regimens are summarized in the following table. 100177.doc •37- 8 1354551

A brief list of the pharmacokinetic parameters of serum fentanyl ..... serum fen A ------------------ A treatment regimen B treatment plan Pharmacokinetic parameters N arithmetic mean SD N arithmetic mean SD C〇iax (PR/mL) 25 617.8 236.7 26 1546.2 621.4 *Tmax(hr) 25 0.76 0.33-4.0 26 0.75 0.33-4.0 AUC(0-t) (pg*hr/mL) 25 2876.3 1107 .7 26 8501.2 3346.2 AUC (0-infinity) (pg*hr/mL) 24 3543.9 1304.5 26 9701.9 2651.5 Tl/2(hr) 24 6.48 3.69 26 12.0 8.18 Kel(l/ Hr) 24 0.143 0.0802 26 0.0746 0.0377 AUCR 24 0.843 0.0604 26 0.875 0.0929 Cmax/dose (pg/mL/mcg) 25 3.09 1.18 26 3.09 1.24 AUC(0-t)(pg*hr/mL/mcg) 25 14.4 5.54 26 17.0 6.69 AUC (0-infinity) (pg*hr/mL/mcg) 24 17.7 6.52 26 19.4 7.30 Ιη((:TMχ/dose) 25 1.06 0.383 26 1.05 0.426 ln[AUC(0-t)/dose] 25 2.59 0.424 26 2.75 0.441 ln[AUC(0-infinity)/dose] 24 2.81 0.369 26 2.89 0.413 C treatment regimen D treatment regimen pharmacokinetic parameters N arithmetic mean SD N arithmetic mean SD Cmax (PRZmL) 27 2280.1 968.9 27 2682.3 1106.0 *Tmax(hr) 27 0.99 0.33-4.0 27 0.75 0.33-4.0 AUC(0-t)(pg*hr/mL) 27 13301 4069.1 27 16813 5232.2 AUC (0-infinity) (pg*hr/mL) 27 14962 4709.6 27 18664 6266.0 Tl/2(hr) 27 12.8 4.08 27 11.4 4.34 Kel(l/hr) 27 0.0592 0.0167 27 0.0679 0.0216 AUCR 27 0.893 0.0589 27 0.909 0.0602 Cmax/dose (pg/mL/mcg) 27 2.81 1.20 27 2.48 1.02 AUC(0-t)(pg*hr/mL/mcg) 27 16.4 5.02 27 15.6 4.84 AUC (0-infinity) (pg*hr/mL/mcg) 27 18.5 5.81 27 17.3 5.80 ln(Cmax/dose) 27 0.945 0.439 27 0.836 0.386 In [AUC (0-t)/dose] 27 2.75 0.324 27 2.69 0.356 ln[AUC(0-infinity)/dose] 27 2.87 0.329 27 2.79 0.372 * Median and minimum-maximum reported for Tmax. A treatment regimen = 1 x 200 meg OraVescent fentanyl fentanyl bond B treatment regimen = 1 x 500 meg OraVescent citrate fentanyl bond C treatment regimen = 1 x81 0 meg Ora Ve scent citrate citrate D Treatment regimen = 1 x 1080 meg Ora Ve scent fentanyl citrate ln [AUC(0-t)] for In (dose) and In [AUC (0-infinity)] for In (dose) slope close to 1 , 1.05 74 and 0.99 83, respectively, and 90 ° / for each parameter. CI is fully contained in the critical range required for the proportionality of doses from 200 pg to 1 080 pg 100177.doc -38-8 1354551. The slope of n(Cmax) vs. n (dose) 0 8746 is less than 1, and 9〇% CI (0.8145-0.9347) is not fully included in the critical range required for the proportionality of the push dose. The maximum dose ratio for all CI bits within the critical range is 3.33. The maximum dose ratio outside the critical range of 90% CI of h is 30.48. Dosage of treatment regimens for A, B, and C The AN0VA results for standardized Cmax showed no statistically significant difference in dose-normalized Cmax between the 2 ton to 81 yoke dose ranges (}3 = 〇 13). The main purpose of this study is to evaluate 200 Kg (A treatment regimen), 500 μ§ (treatment regimen), 81 〇Mg (C treatment regimen), and 1080 卯 (1) as 〇raVescent8 citrate fentanol tablets. Treatment Protocol) The extent to which the fentanyl dose is proportional to the dose of fentanyl AUC and Cmax. In addition, we conducted this study to determine the observation of Cmax after the previous OraVescent® fentanyl citrate tablet for dose 81 bark and 1 bar bark. The study was designed for single dose, random, public labeling, and four periods. Of the 28 registered subjects, 25 completed the A treatment regimen, φ subjects completed the B treatment regimen, and 27 subjects completed (: and sputum treatment regimen. Based on the pharmacokinetic $ data pair All subjects were statistically analyzed. ln[AUC(0-t)] for in (dose) and & [AUC (〇 infinity)] Η (dose) slope is close to 1 ', respectively, and 9 of each parameter 〇% 王 王 王 I 3 is within the critical range required for the proportionality of the salience. These results show that fentanyl AUC will follow OraVescent® citric acid between 2 〇〇叩 and 1 〇 8 〇叩 study dose. The proportion of each dose of fentanyl lozenge increased. The slope of ln(CmaX) versus ΐη (dose) is lower than 丨, which is 〇8746, which shows that the increase in Cmax of rutinib is lower than the dose, 9〇% He - 100177.doc .39- 1354551 0.9347) Not all included in the critical range. This under-proportion increase was found at the last dose (1080 μβ), while the other was found at the next highest dose (810 μ8). From 2〇〇μg to 500, Cmax will increase proportionally, and Cmax will increase linearly with the dose, up to and including about 8〇〇Kg fentanyl. Port 1 value (making 9% of 01%) The maximum ratio of CI in the critical range is 3.33, and the ratio of 81〇48:20〇4£ is 4.〇5. This shows that the blending is in the range of 200 to 810 pg according to this method. The material approached the proportionality standard. A second analysis of dose-normalized Cmax using ANOVA to compare doses from 200, 500 pg' and 8 10 pg showed no statistically significant difference in the level of the agents (p = 〇13). The average squared ("LS" of ln(Cmax/dose) is 106 (200 μβ), 1〇6 (5 〇〇), and 0.94 (810 μ8), showing 200 and 5 〇〇 There was no difference between doses, and the 8 〇pg dose had the smallest (丨〇%) difference compared to the lower doses. Since there is no significant result for ANOVA and a small difference between the 8 剂量 dose and the two lower doses, there is no clinically significant deviation in the proportional (linear) dose of Cmax from 200 to 500. 200 μΕ, 500 μ§, 810 tons, and 1〇8〇?~ The average residence time of the 8 fentanyl citrate tablets was similar, 14 minutes, 14 minutes, 17 minutes, and 15 minutes, respectively. .

After OraVescent® fentanyl citrate, two subjects reported mild irritation to the oral mucosa and one subject experienced erythema.

Ik increased the dose from 200 pg to 1〇8〇, and fentanyl auc increased proportionally. At the two highest dose levels, the Cmax of fentanyl was lower than the dose. The average in (Cmax/dose) of the 810 pg dose is 10 to 11% lower than 2 〇〇 ton 100l77.doc 8 1354551 and 500 Kg. This is linear as defined herein. The average In (Cmax/dose) in 1〇8〇Mg agent is 2〇 to 2 1/〇〇叩 from 2 K to 2 1 /〇 from 200 Kg to 8 1 0 μβ, and the dose in Cmax is not proportional. Clinically significant deviations, 200, 500吒' 81 〇, and 1〇8〇叩

The average residence time of OraVescent® fentanyl citrate was similar, 14 minutes, 14 minutes, 17 minutes, and 15 minutes, respectively. There were no serious or unexpected adverse events during the study. Both formulations are 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, SAS®/STAT User Guide, Version 6, 4th Edition, Volume 1, Cary, NC: SAS Institute; 1989. SAS Institute, SAS®/STAT User Guide, Version 6, 4th Edition, Volume 2, Cary, NC: SAS Institute; 1989.

SAS Institute, SAS®/Program Guide, Version 6, 3rd Edition,

Cary, NC: SAS Institute; 1990. Approved Baseline Summary (Summary Basis of Approval NDA 20-747 (Actiq®). Approved Issued November 4, 1998, Clinical Pharmacology and Biopharmaceutics Review, page 6. Despite the presence of pH-adjusting substances and bubble combinations, it is believed to be ' Formulations comprising more than 20% of the amount of monohydrated lactose and/or at least about 20% of microcrystalline cellulose and 5% or more of crosslinked PVP in the 604 patent are not capable of 100177.doc 8 丄, θ ', a fentanyl formulation having the desired characteristics of the present invention. It is intended that a high-dose anesthetic is required to provide a comparable sputum. By using this hair, it is possible to achieve a 2G% dose reduction. Or more. By way of example, fentanyl formulated in a dosage form of the invention will have a higher c_ at the agreed dose when compared to those similar to those in the '6〇4 patent. For 达 = comparable (: _ χ 'less anesthetic drugs will be necessary. Other anesthetics should act in a similar manner. Because of their inability to achieve the appropriate dose reduction / reduction of the comparable Cmax , generally by some amount of certain fillers The dosage form of composition I will not include the aforementioned dosage forms. The dosage form according to the invention will provide an effective amount of an anesthetic that varies between different anesthetic drugs and different indications. For example, for fentanyl, a free base form of fen The effective dose of fentan is between about 1 〇〇 and about 2 〇〇〇pg per dose. For demer〇i, the range may be as much as 150 mg of the parent. A corresponding amount of salt, such as a sulphate, is used. The normal daily dose for the hydrocodone can be between about 5 and about 1 mg. The dose of dihydromorphone It may be in the range of between 4 and 45 mg, and the morphine is in the range of 1 to 12 mg. 1 and s 'the active agent to be delivered according to one or more of the dosage forms of the invention (per dose, Not necessarily daily) will be between about 2 〇 and about 2 〇〇, in the range between 〇〇〇 micrograms, preferably between about 5 〇 to about 16 〇, between 〇〇〇 micrograms, optimally between about 50 to about 1 inch, between 00 micrograms. Any known compound can be used as a foaming agent or a foaming combination. It is described in U.S. Patent No. 5,178,878 and U.S. Patent No. 5,5,3,846,100, filed on filed in The degree is as described for the various foaming combinations and their composition. In general, the foaming combination is a water or saliva-initiated material that is typically stored in anhydrous or non-absorbent form in anhydrous or stable hydrated form. Typically, the combination is acid. The source, and the reactive source (usually carbonate or bicarbonate). For both, human consumption may be safe. By the way, the acids include edible acids, anhydrides, and acid salts. Edible acid _ includes citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, ascorbic acid, and butyl acid. The acid anhydride or salt of the ## acid can be used. The salts herein may include any of the known salts, but are specifically sodium dihydrogen phosphate, disodium hydrogen phosphate, acid citrate, and sodium acid sulphate. Bases suitable for use in accordance with the present invention generally include rabbit hydrogen, hydrogen carbonate, and the like. It is also possible to use sodium carbonate, potassium carbonate, magnesium carbonate and the like to the extent that they are used as a partial foaming combination. However, it is more preferably used as a pH adjusting substance. Preferably, 'stoichiometrically equivalent amounts of acid and base are used. However, it is possible to use a partial excess of acid or -φ base. However, when formulating the formulation as such, care should be taken. Excess may affect absorption. The amount of the applicable foaming material or foaming combination according to the present invention is an effective dose and is not determined based on the characteristics of the tablet disintegration effect achieved in the mouth. Instead, the foaming action is used as an enhancement in the oral cavity. The basis for the transmission of anesthetic drugs through the mucosa by buccal, gum or sublingual administration. This can be measured by comparing the blood content of the anesthetic from the formulation of the present invention as compared to the same formulation without the foaming combination. Therefore, the amount of the foaming combination in the weight of the total formulation ("w/w") should be between about 5 and about 100 J77.doc • 43· 1354551: outside the range 'better between about ι5 To 6. Between %, even better: = 45% of the heart is best between about 35 to surgery. between. Of course, the acid = Γ will depend on the particular ingredient (for example, a single proton 'double proton or three scorpions. However, it is preferred to provide a stoichiometric amount of 1, of course, an excess is acceptable. " According to the invention Formulations include pH adjusting substances. It is not intended to be limited to any particular sinus sinus a y y non 疋 疋 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Appropriate conditions: drugs that are sensitive to changes in ion state. If the effect of the transfer is: :: Alkaline: add a sufficient excess of the appropriate strong acid as the foam, and the mouth-part or as a PH The conditioning material may be inappropriate. Other pH adjusting materials, such as sodium carbonate which performs separation and separation of the foaming agent, are suitable and preferred. The pH adjusting substance according to the present invention can be used to provide further penetration enhancement. The choice of appropriate penetration enhancer will depend on the drug to be administered and the ionization or rotorization of the sputum (4). The test substance is suitable for the delivery system of fentan^. Other anesthetic drugs may be suitable. The pH adjusting substance according to the present invention may include, without limitation, any that can be produced in a microenvironment that can be in the oral mucosa and the surface contact area of the dosage form or any portion thereof. A quantity of PH (also referred to herein as "local pH") between about 3 and 10 and more preferably between about 3 and about 9 to modulate the localist to promote transport through the oral lining In order to characterize the dynamic PH changes exhibited by the tablets in question, we use the in vitro positivity method. This method is used in test tubes or similar containers of appropriate size 5.5_一100177.doc -44 1354551 The amount of the medium is determined by the size and dosage of the tablet. For example, when measuring the pH curve of the fentanyl tablet, the volume of 1 mL is used for tablets weighing 100 mg. Immediately after contact with the medium, the micro-combined pH electrode is used to monitor the pH profile of the solution over time. Depending on the molecule in question, the combination of foaming and pH adjusting material provides a local pH in the range of 3_1 Å, and Better' Selecting an amount of at least 0.5 pH units of the pH change and provide it.

Preferably, materials suitable for the pH adjusting substance according to the present invention include carbonates (such as sodium, potassium or calcium carbonates) or phosphates (such as calcium or sodium phosphonium salts). . The amount of the modulating substance to be used in accordance with the present invention may vary depending on the type of pH adjusting substance used, the amount of any pericylic acid or alkali derived from the foaming combination, the nature of the remaining ingredients, and of course the drug (in this case, fen Tai Ni) and change. The effective dose of the P-modulating substance is sufficient to change the pH (local pH) in the local microenvironment (in the case of fentanyl, raising the pH) to foaming when dissolved in the mouth to enhance the administration into the oral cavity. The sputum of the mucosa penetrates. The effective dose will be capable of providing a pH between about 3 and about 〇. Any pH adjuster f that provides these conditions is encompassed. Preferably, it is capable of providing at least 匕. More preferably, the one or more pH single pH adjusting substances provide a local pH of 3.1 Å and, more preferably, the amount of local pH change of the 〇'5 pH unit is selected and provided when the pH adjusting substance will make the microenvironment The local pH is shifted to 'and more preferably 2 or more pH units. Preferably, the amount of pH adjusting material is between about 2 and about 2%, preferably between about 0.5 and about 25% by weight of the total formulation, 100177.doc • 45 Between 1354551, even more preferably between about 5 and about ι5% and optimally between about 7 and about 12%. The most preferred pH adjusting materials are carbonates, bicarbonates and the like. Any dosage of any filler or filler can be used as long as the resulting dosage form achieves the results described herein. The most preferred of the fillers are sugars and sugar alcohols, and these may include non-direct compression tablets and direct compression tablet fillers. At least when formulated, indirect tablet formulations generally have fluidity and/or compression characteristics that are not used in the idling process without some amplification or adjustment. For example, the formulation does not flow sufficiently well and, therefore, it may be desirable to add a flow aid such as cerium oxide. Generally, the materials may also be granulated or spray dried to improve their properties. In contrast, direct ingot fillers do not require similar considerations. In general, they have the characteristics of compressibility and flowability that allow them to be used directly. Note that depending on the method of making the formulation, the properties of the direct tablet filler can be imparted to the indirect tablet filler. vice versa. As a general matter, a non-direct ingot filler tends to have a relatively small particle size as compared to a direct tablet filler. However, depending on how it is further processed, certain fillers, such as spray dried mannitol, have a smaller particle size, but are generally directly compressible. There are also relatively large non-direct ingot fillers. Mixtures of direct and non-direct compression fillers are also included. The most preferred according to the invention is mannitol, and in particular is spray dried mannitol. Generally, the amount of filler can range from about 1 Torr to about 80% w/w, and more preferably from 25 to 8% by weight. Even more preferably, the amount of filler will range from 3 5 to about 6 % by weight of the formulation or the weight of the formulation 100l77.doc -46 - 1354551 as long as the results described herein are provided, according to A disintegrant can also be used in the invention. These may also include binders having disintegration properties. The most preferred as a disintegrant is transbasic starch, such as sodium starch glycolate. One suitable sodium starch glycolate according to the invention is GLYCOLYS® (standard grade) from R〇quette 〇f Lestrem, France. The amount of disintegrant will vary depending on factors such as the size of the dosage form, the nature and amount of other ingredients used, and the degree to which the dosage sought is reduced. However, the amount "generally based on the weight of the final formulation" should generally range from about 〇25 to about 20%. The range between / is more preferably between about 5 and about 5% by weight, more preferably from 0.5 to about 10% by weight, and even more preferably from about i to about 8% by weight. This is also based on the weight of the finished formulation (dosage form). Also suitable for use in accordance with the invention are ingot lubricants or mold release lubricants. The most commonly known lubricant is magnesium stearate and magnesium stearate is preferred. In general, the common knowledge about ingot lubricants is that the less the better. The use of less than 1% of the tableting lubricant is preferred in most cases. The pass*' should be 0.5% or less. However, the amount of stearic acid used may be more than 1.0%. In practice, it is preferably more than 丨 5% and most preferably between about 1.5% and about 3%. Most preferably, about 2% magnesium stearate is used. Other conventional key lubricants such as stearic acid, stearic acid and the like may also be used in place of some or all of the stearic acid locks. The foaming lozenge according to the present invention can be relatively soft or hard. For example, it can be made according to the method described in U.S. Patent No. 5,178,878 and will generally have a hardness of less than 15 Newtons. Unlike the formulation described in the 878 patent, 100177.doc • 47·1354551, it is not necessary to apply a protective material to the active ingredient. In fact, the preferentially active anesthetic drug will not be coated. When a soft and flexible/fragile tablet is produced, it can be conveniently packaged in a blister pack such as that found in U.S. Patent No. 6,155,423. The foaming lozenge may also be rigid, having a hardness of greater than 15 Newtons and a hardness of 2% friability or less, and is manufactured according to the procedure set forth in U.S. Patent No. 6, 〇24,981.

In a preferred embodiment, the dosage form of the present invention is provided in a blister pack that prevents child opening. See, for example, U.S. Patent No. 6,155,423.

Katzner et al., issued on December 5, 2000, and assigned to 0 on LABS, the contents of which are incorporated by reference. Preferably, the package meets the criteria set forth in 16 1;.8. (:.§ 1700.15 and .20 (2003). Also preferred packages include those that are commonly referred to in industry as the so-called "F丨" & &quot The F2"packer"F1" package is optimal. The tablet of the present invention can be designed to be used in a slightly different manner for buccal, toothed, or sublingual drugs. However, in each case The disintegration time (average residence time) achieved by the formulations is preferably less than 30 minutes. The cyclonic agents will generally exhibit an average residence time between 5 and 3 minutes, more Preferably, it is from 10 to 30 minutes, most preferably from 12 to 30 minutes. A particularly preferred embodiment of the invention provides a foamed oral disintegrable tablet designed for buccal, gingival or sublingual administration. Free: The pharmaceutically acceptable salt thereof comprises or consists of an anesthetic drug (by weight of the drug), an effective amount of a foaming combination, and an effective amount of the composition. The formulation will further comprise one or more excipients. In a preferred embodiment, the excipients include mannitol and transacetic acid condensate 77.doc & g t;48-1354551 Sodium powder. In a particularly preferred embodiment, the formulations do not include an amount of monohydrated lactose or both MCC and PVP XL in amounts that significantly impair the advantages of the present invention. Formulations may include other conventionally known amounts of conventionally known excipients that do not detract from the advantages achieved. Such excipients may include, without limitation, binders, sweeteners, coloring ingredients, flavoring agents, and so on. Flowing agents, lubricants, preservatives, disintegrating agents, and the like. Examples: Manufacturing methods: In each of Examples 1-7 and 9-11, the materials were screened prior to use and fed to a V-blend. , or may be blended in any other suitable low shear blender and blended for the appropriate time. After pouring out of the blender, compress the material to 1 on a standard rotary tablet press. The target hardness of 3 Newtons and the target weight as described in the examples.

Example 1 - Table A of the First Study

OraVescent® fentanyl, 1080 mcg, 5/16" key, red

Component name amount (mg/bond) 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 Hydroxyl Sodium starch acetate, NF/EP 6.000 Magnesium stearate, NF/EP/JP 4.000 Red iron oxide, NF 1.000 Total 200.000 * Spray dried (mannogem EZ supplied by SPI Pharma) 100177.doc -49- 1354551

Example 2 - Table of the first study C 0^'\^8. 61^@芬丁尼,130〇111〇§,5/16" Lozenges, red component name amount (mg/ingot) Citric acid fen Tony, 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 Hydroglycolate, NF/EP 6.000 Magnesium Stearate , NF/EP/JP 4.000 red iron oxide, NF 1.000 total 200.000

* Spray dried

Example 3 - Table D of the First Study

OraVescent® fentanyl, 810 mcg, 5/16"key, yellow component name (mg/ingot) 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 Yellow iron oxide, NF 1.000 Total 200.000 * Spray dried

Example 4 - Table E of the First Study

OraVescent® fentanyl, 270 meg, 5/16" keying agent, white component name amount (mg/ingot) fentanyl citrate, USP 0.422 mannitol, USP* 97.578 100177.doc -50- 1354551 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 * Spray dried example 5

OraVescent® fentanyl, 500 mcg, 5/16" keying agent, coloring component name (mg/bond) 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 iron oxide, NF 0.600 red iron oxide, NF 0.400 total 200.000

* Spray dried Example 6

OraVescent® fentanyl, 200 meg, 5/16" suspect, white component name (mg/poor) 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 100177.doc 1354551 * Spray dried example 7

OraVescent® fentanyl, 100 mcg, 1/4" lozenges, white component name (mg/ingot) fentanyl citrate, USP 0.157 mannitol, USP* 48.843 sodium bicarbonate, USP/EP/JP 21.000 Lemon 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 100.000

* Spray dried Example 8 The material was screened prior to use, fed into a V-blender or other suitable low shear blender and blended for the appropriate time. After decanting from the blender, the materials were compressed to a target hardness of 13 Newtons and a target weight of 200 mg/ingle on a standard rotary tablet press.

OraVescent® fentanyl, 300 meg, 5/16" Cyclone, light yellow component name (mg/bond) 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 iron oxide, NF 0.200 total 200.000 100177.doc -52- 8 1354551 * Spray dried example 9

OraVescent® fentanyl, 400 mcg, 5/16" lozenges, pink component name (mg/bond) fentanyl citrate, USP 0.629 mannitol, USP1 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 iron oxide, NF 0.200 total 200.000

* Spray dried Example 10

OraVescent® fentanyl, 600 meg, 5/16" keying agent, coloring component name (mg/ingot) fentanyl citrate, USP 0.943 mannitol, USP1 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 iron oxide, NF 0.600 red iron oxide, NF 0.400 total 200.000

100177.doc -53 - 8 1 by spray drying Example 11 1354551

OraVescent® fentanyl, 800 mcg, 5/16" sharp, yellow component name (mg/ingot) fentanyl citrate, USP 1.257 mannitol, USP1 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 iron oxide, NF 1.000 Total 200.000 * Spray dried Example 12 Material Screened prior to use, fed to a V-blender or other suitable low shear blender, and blended for the appropriate time. After decanting from the blender, the materials were compressed to a target hardness of 13 Newtons and a target weight of 200 mg/ingle on a standard rotary tablet press.

OraVescent ® dihydrocodeinone, 5 mg, 5/16": white component name (mg/bond) hydroxyhydrocodone ketone hydrochloride, USP 5.000 mannitol, USP1 93.000 Sodium hydride, 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, NP/EP/JP 4.000 Total 200.000

100177.doc -54- 1 Spray dried Example 13 1354551 The material was screened prior to use, fed into a v-type blender or other suitable low shear blender, and blended for the appropriate time. After decanting from the blender, the materials were compressed to a target hardness of 13 Newtons and a target weight of 200 mg/ingle on a standard rotary tablet press.

OraVescent ® Dihydro- ketone, 2 mg, 5/1 6" Bonding agent, amount of light yellow component name (mg/re:) Dihydrogen #ketone hydrochloride, USP 2.000 mannitol, USP*. 95.80 Carbonic acid Sodium hydride, 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 iron oxide, NF 0.200 200.000 * Spray dried Example 14 Weighed and screened for the following materials. # describing amount / lozenge (%w / w) amount / batch (kg) 1 fentanyl citrate 0.6285 502.8 g * 2a. mannitol EZ 23.875 19.1 2b. mannitol EZ 24.014 19.2 3. sodium bicarbonate, first No. 21.0000 16.8 4. Citric acid, anhydrous, fine particles 15.0000 12.0 5. Sodium carbonate, anhydrous 10.0000 8.000 6. Sodium starch glycolate 3.000 2.400 7. Iron oxide yellow 10 0.5000 0.400 8. Magnesium stearate, non-cows 2.000 1.600 Total 100.0000 80.0 100177.doc -55- Mannitol EZ (2a.) and iron oxide yellow 1〇 were transferred to a 推-type pusher and the y-knife was decanted and the pre-blend was ground. The total amount of the preblend, fentanyl citrate (4 acid hydrogen steel, citric acid, sodium carbonate and sodium methicillate) was added to the v-type blender and blended for 3 minutes. Mannitol was added. (2b) was fed into a V-type blender and blended for 13 minutes. Magnesium stearate was fed into the ▽ type blender and blended for 5 minutes. The final blend thus pressed the tablet. The tablet is 1/4 round, flat, white and has a beveled edge. It is compressed on a fully processed 36 die Fette sharp press to an average hardness of 13 Newtons. [Simple illustration] No image Formula 100177.doc " -5〇- 8

Claims (1)

1354551 Patent Application No. 094,107,151 • Chinese Patent Application Substitute Replacement γ Year 8 ff) X. Patent Application Announcement 1. A dosage form comprising between about 2 〇 and about 2 〇〇, between 〇〇〇 micrograms An anesthetic, between about 0.5 and about 25% by weight of a pH adjusting substance suitable for the anesthetic, between about 5 and about 85 angstroms. A foaming substance between weight ratios, and glycolic acid starch, which is designed to administer the anesthetic through the oral mucosa via a buccal, gingival or sublingual route of administration. 2. The dosage form of #1, when administered by the buccal, gingival or sublingual route of administration, has a cmax at a dose of 20% less anesthetic than can be obtained without the glycolic acid starch. The foaming combination and the other identical formulation of the pH adjusting substance. 3. A dosage form according to the formula or wherein the pH adjusting substance provides a local pH between 3 and 10. The dosage form of t h #项3, wherein the pH adjusting substance can be locally changed by at least pH5 pH units. A dosage form according to the invention of claim 4, wherein the pH adjusting substance changes the local pH by at least 1.0 pH unit. , the dosage form of item 1 or 2 wherein the pH adjusting substance is carbonate or carbon 8. 9. 10. For the dosage form of claim 1 or 2 in D month, JL is continued; < 7 private W i , A thioglycolic acid starch provides a medium, 〇 25 and about 2 〇% The content between the weight ratios. For example, the dosage form of Item 7 and the medium-poor 叛3 ruthenium acetate milling system provide a content of between 0.5 and about 15% by weight. The dosage form of claim 1 or 2, further comprising a filler. The dosage form of claim 9, wherein the filler is mannitol.约约约100177-960827.d〇, 11. 12. 13. 14. 15. 16. 17. 18. 19. The dosage form of claim 9 is the ratio between the weight ratios of the sails. The filler is provided in a dosage form of between about 10 and about claim 10, 80% by weight + A, and the mannose system is provided in an amount between about 25 and about rib. In the dosage form of claim 1 or 2, the buccal and field are orally administered in the mouth for a minimum of 30 minutes and 1 hour, with an average residence time of between about 5 and / in the patient's mouth. For example, the dosage form of the item 1 or 2, the coloring component, the coloring agent, the binder, the sweetener, and the disintegrating agent. θ _ slip agent, preservative, filler: the dosage form of claim (4), which is packaged in a blister package, such as the dosage form of claim 1, for the preparation of m*^ for the treatment of pain in need The use of the agent, and Φ close contact placement, and ... with the patient's oral mucosa _ keep the agent in close contact with the oral mucosa: to transport at least the therapeutically effective part of the anesthetic through the s Xu The time of the oral mask. The use of item 16, wherein at least substantially all of the anesthetic is delivered through the oral mucosa. The use of the item of claim 16, wherein the agent is in contact with the oral mask with minimal movement Maintaining a contact between about 5 and about 3 (minutes). ', as in the use of item 16, wherein the agent can reach and not have the base, the pH of the week, and the combination of the foam. The composition may have a phase max, but has less anesthetic than the formulation. 100I77-960827.doc 1354551 2 〇-Α-φ Κ月" Use of item 16, wherein the pain is sudden pain in cancer. Use of item 16, wherein the pain is back pain 22·士口言杳立 ts 1 / 永项16, where the pain is surgery or postoperative pain 0 23. For the use of claim 16 24. According to the dosage form of claim 1, mg. It is a neuralgia. Among them, there are less than 1 anesthetic drug in the dosage form. 100I77-960827.doc