`TJ-J.E jDUHt J;\L Df DELJYEHY 1-\1 JfJ·T;\HGE"fJfJG%
`
`Volume 11 • Number 2 • March-April 2004
`
`itors-in-Chief
`Alfred Stracher • Tony L. Whateley
`
`04 0? 04
`
`•
`sc1ences
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`THE JOURNAL OF DELIVERY AND TARGETING OF THERAPEUTIC AGENTS
`
`EDITORS-IN-CHIEF
`Alfred Stracher
`Department of Biochemistry, The State University of
`New York, Health Science Center at Brooklyn, 450
`Clarkson Avenue, Brooklyn, NY 11023, (718) 270-
`1256 phone; (718) 270-3316 fax;
`strachea@ hscbklyn.edu
`
`Tony Whateley
`Department of Pharmaceutical Sciences, University of
`Strathclyde, SIBS, 27 Taylor Street, Glasgow G4 ONR,
`Scotland, +44-141-5524400 phone; +44-141-
`5526443 fax; t.l.whateley@strath.ac.uk
`ADVISORY EDITORS
`Carl Alving Walter Reed Army Institute of Research
`W. French Anderson
`USC Norris Cancer Center
`Robert S. Langer Massachusetts Institute of Technology
`Richard A. Lerner Scripps Clinic Research Institute
`George Poste SmithKline Beecham Pharmaceutical
`Glynn Wilson Tacora Corporation
`
`EDITORS
`Theresa M. Allen University of Alberta; David R. Bard
`Strangeways Research Laboratory; John H. Collett
`University of Manchester; Elazer R. Edelman Massa(cid:173)
`chusetts Institute of Technology; Robert F. Furchgott
`State University of New York, Brooklyn; Colin R.
`Gardner Merck Sharp and Dohme Research Laboratory;
`Yoshita Ikada Kyoto University; Rakesh K. Jain
`Harvard Medical School; Ian W. Kellaway University
`of London; Leo Kesner State University of New York,
`Brooklyn; Jindrich Kopecek University of Utah;
`Rimona Margalit Tel Aviv University; Gary P. Martin
`Kings College; Claude F. Meares University of
`California, Davis; Dirk K.F. Meijer University of
`Groningen; Michel Monsigny University of Orleans;
`Marc Ostro The Liposome Company; William M.
`Pardridge University of California School of Medicine,
`Los Angeles; Murray Saffran Medical College of Ohio;
`Peter Senter Bristol-Myers Squibb Pharmaceutical
`Research Institute; David Shepro Boston University;
`Songe Svenson The Dow Chemical Company; -John W.
`Weinstein National Institutes of Health; Richard J.
`Youle National Institutes of Health
`
`Abstracted/indexed in: Biochemistry & Biophysics Citation Index, Chemical Abstracts, EMBASE, Index Medicus, and MEDLINE,
`Research Alert, and SciSearch.
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`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2007 - 2/10
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`DRUG
`DELIVERY
`
`THE JOURNAl OF DELIVERY AND TARGETING OF THERAPEUTIC AGENTS
`
`Volume 11, Number 2, 2004
`
`CONTENTS
`
`83
`
`Liposomes Containing Distamycins: Preparation, Characterization and Antiproliferative Activity
`R. Cortesi, R. Romagno'li, E. Menegatti, E. Esposito, F. Cervellati, and C. Nastruzzi
`
`89 Development of Mucoadhesive Dosage Forms of Buprenorphine for Sublingual Drug Delivery
`Nandita G. Das and Sudip K. Das
`
`97
`
`Lipid N ano/Submicron Emulsions as Vehicles for Topical Flurbiprofen Delivery
`Jia-You Fang, Yann-Lii Leu, Chia-Chun Chang, Chia-Hsuan Lin, and Yi-Hung Tsai
`
`107 Chitosan Nanoparticles for Plasmid DNA Delivery: Effect of Chitosan Molecular Structure on Formulation
`and Release Characteristics
`Asuman Bozkir and Ongun Mehmet Saka
`
`113 Development and Characterization of Mucoadhesive Microspheres Bearing Salbutamol for Nasal Delivery
`S. K. Jain, M. K. Chourasia, A. K. Jain, R. K. Jain, and A. K. Shrivastava
`
`123
`
`129
`
`Stability of Liposomal Formulations in Physiological Conditions for Oral Drug Delivery
`M. C. Taira, N. S. Chiaramoni, K. M. Pecuch, and S. Alonso-Romanowski
`
`Polysaccharides for Colon Targeted Drug Delivery
`M. K. Chourasia and S. K. Jain
`
`149
`
`Patent Briefing
`
`153
`
`Literature Alerts
`
`159 Calendar
`
`1111111111111111111111111111111111111111111111111111111111
`10717544(2004)11(2)
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`Taylor &Francis
`health sciences
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`Teva Pharm. v. Indivior, IPR2016-00280
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`Drug Delivery, II :89-95, 2004
`Copyright© Taylor & Francis Inc.
`ISSN: I 071-7 544 print I 1521-0464 online
`DOl: 10.1080/10717540490280688
`
`~P_" Taylor&Francis
`• health sciences
`
`Development of Mucoadhesive Dosage Forms
`of Buprenorphine for Sublingual Drug Delivery
`
`N andita G. Das and Sudip K. Das
`Idaho State University, College of Pharmacy, Pocatello, Idaho, USA
`
`The development of mucoadhesive formulations of buprenor(cid:173)
`phine for intended sublingual usage in the treatment of drug ad(cid:173)
`diction is described. The formulations include mucoadhesive poly(cid:173)
`mer films, with or without plasticizers, and mucoadhesive polymer
`tablets, with or without excipients that enhance drug release and/or
`improve tablet compaction properties. The mucoadhesive polymers
`studied include carbomers such as Carbopoi934P, Carbopol 974P,
`and the polycarbophil Noveon AA-1, with excipients chosen from
`pregelatinized starch, lactose, glycerol, propylene glycol, and var(cid:173)
`ious molecular weights of polyethylene glycol. The development
`of plasticizer-containing mucoadhesive polymer films was feasible;
`however, these films failed to release their entire drug content within
`a reasonable period. Thus, they were not determined suitable for
`sublingual usage because of possible loss by ingestion during rou(cid:173)
`tine meal intakes. The mucoadhesive strength of tablet formula(cid:173)
`tions containing Noveon AA-1 appears to be slightly superior to the
`Carbopol-containing tablets. However, the Carbopol 974P formu(cid:173)
`lations exhibited superior drug dissolution profiles while provid(cid:173)
`ing adequate mucoadhesive strength. The tablet formulations con(cid:173)
`taining Carbopol 974P as mucoadhesive polymer, lactose as drug
`release enhancer, and PEG 3350 as compaction enhancer exhib(cid:173)
`ited the best results. Overall, the mucoadhesive tablet formulations
`exhibited superior results compared with the mucoadhesive film
`formulations.
`
`Keywords Buprenorphine, Compressed Tablet, Drug Abuse, Film,
`Mucoadhesion, Sublingual
`
`Therapies to prevent and/or treat drug abuse need careful
`consideration of the biopharmaceutical aspects of the treatment
`drugs and suitable delivery systems that can provide an ideal
`therapeutic profile and improve patient compliance. Ideally,
`drugs for the treatment of abuse must possess sufficiently long
`
`Received 2 July 2003; accepted 12 August 2003.
`The authors acknowledge Peter Willeitner for his teclmical assis(cid:173)
`tance during the preliminary fommlation phase of the dosage forms.
`Address correspondence to Sudip K. Das, Idaho State University,
`College of Pharmacy, 970 South 5th Avenue, Pocatello, ID 83209-8334,
`USA. E-mail: das@pharrnacy.isu.edu
`
`half-lives that allow reduction in frequency of administration,
`slow metabolism to inactive metabolites, thus requiring less drug
`to be administered, and lack of addiction potential of their own.
`Buprenorphine has gained much interest in recent years in the
`treatment of opioid-type drug addiction. It has strong analgesic
`and narcotic antagonist activity and is 25-50 times more po(cid:173)
`tent than morphine (Gutstein and Akil 2001). Pharmacologi(cid:173)
`cally, buprenorphine, a highly lipophilic semisynthetic deriva(cid:173)
`tive of the opioid alkaloid thebaine, is a partial opiate agonist.
`It has agonistic effect on the mu and antagonistic effect on the
`kappa receptors, with the agonist properties predominating at
`low doses and antagonist properties predominating at higher
`doses (Cowan, Lewis, and Macfarlane 1977). A partial agonist
`is less likely to cause respiratory depression, which is the major
`toxic effect of opiate drugs, compared with full agonists such as
`heroin and methadone. Buprenorphine hydrochloride, the water(cid:173)
`soluble salt form of buprenorphine, has a mean plasma half-life
`of 3.21 hr (Kuhlman et al. 1996) and is highly metabolized in
`the intestinal wall and liver to norbuprenorphine, which is a
`weakly active metabolite with half-life of 57 hr (Kuhlman et al.
`1998). Both buprenorphine and norbuprenorphine form inactive
`glucuronides (Iribame et al. 1997).
`Compared with the potential of buprenorphine as a first- or
`second-line agent in the treatment of opiate addiction, studies on
`buprenorphine drug delivery systems are relatively few. A sub(cid:173)
`cutaneously implanted system utilizing a cholesterol-glyceryl
`tristearate matrix produced sustained analgesic effect in rats for
`12 weeks or more (Pontani and Misra 1983). In an early study
`on noncrystalline prodrugs of buprenorphine, synthesized for
`transdermal delivery, success was limited because the lipophilic
`form was sequestered in the lipid-rich skin layers (Stinchcomb
`et al. 1996). A matrix-type tra~sdermal patch of buprenorphine
`(Transtec®, Napp Pharmaceuticals) was recently introduced in
`the European market for the management of stable cancer and
`noncancer pain, and early clinical efficacy reports are fairly
`promising (Radbruch 2003). Eriksen et al. (1989) reported that
`the systemic bioavailability of buprenorphine administered by
`nasal spray is greater than 40%, which is comparable to the
`
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`N. G. DAS AND S. K. DAS
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`30-40% bioavailability via the intramuscular and subcutaneous
`routes. Addition of 30% polyethylene glycol (PEG) 300 as a
`co-solvent to a nasal fmmulation of buprenorphine does not en(cid:173)
`hance bioavailability of the drug any further (Lindhardt et al.
`2001). Buprenorphine has been studied in a microcapsule sys(cid:173)
`tem intended for parenteral use and produced a steady in vitro
`release for 45 days (Mandai 1999). Concerns over residual or(cid:173)
`ganic solvents used in most microparticle preparations have re(cid:173)
`stricted FDA approval of parenteral microparticulate systems, in
`general, and further studies are needed to evaluate their efficacy
`and safety in vivo.
`Intravenous buprenorphine has been used in pain manage(cid:173)
`ment for many years. The oral route of administration produces
`poor bioavailability of approximately 15% (McQuay, Moore,
`and Bullingham 1986) and lacks commercial potential. Systemic
`bioavailability following sublingual administration, which by(cid:173)
`passes first pass metabolism, is much superior and has been re(cid:173)
`ported to be up to 58% (Bullingham et al. 1982). The sublingual
`region offers a nonkeratinized epithelium with high petmeability
`and a smooth and relatively immobile surface with easy acces(cid:173)
`sibility. For the treatment of drug abuse, an immediate release
`sublingual tablet of buprenorphine, Subutex TM (manufactured
`by Reckitt Benckiser), was recently introduced in the U.S. mar(cid:173)
`ket. This delivery system for buprenorphine has been available
`in Europe for nearly a decade and is widely used as an alterna(cid:173)
`tive to methadone in the treatment of opiate addiction (Gasquet,
`Lancon, and Parquet 1999). Literature on bioavailability of sub(cid:173)
`lingual buprenorphine presents variable numbers ranging from
`19-58% of the administered dose. Although sublingual delivery
`of buprenorphine has been proven effective, bioavailability by
`this route can be enatic because of salivary washout and invol(cid:173)
`untary swallowing.
`We hypothesize that increasing the contact time with the sub(cid:173)
`lingual mucosa with a mucoadhesive delivery system could im(cid:173)
`prove sublingual bioavailability and result in more predictable
`plasma levels of the drug, leading to better therapeutic efficacy
`and reproducibility. No study has been published to date on mu(cid:173)
`coadhesive sublingual delivery of buprenorphine aimed at the
`treatment of drug addiction. These dosage fmms would adhere
`to the sublingual mucosa and withstand tongue movement for
`a significant period, potentially decreasing the chances of in(cid:173)
`voluntary swallowing of the dosage form. A sustained release
`effect also may be expected from the dosage form, which would
`make delivery of higher doses ofbuprenorphine for the prefened
`3-times/week dosing regimen feasible with minimal side effects.
`With easy accessibility to the sublingual area, the delivery sys(cid:173)
`tems can be self-administered by the patient with minimal or no
`supervision that in tum can reduce health care costs involved in
`the treatment of drug addiction.
`In this article, we discuss the development of mucoadhesive
`polymer films and tablets of buprenorphine and evaluation of
`their physical properties and drug release characteristics. The
`effect of plasticizers on the film properties was studied, as well
`as the effect of excipients on "tabletability" and drug release
`
`properties from the compressed tablets. The polymeric dosage
`fmms described are hydrogels that swell on coming in contact
`with water and do not allow prompt dissolution like an imme(cid:173)
`diate release tablet; therefore, we anticipate that potential for
`diversion of these dosage fmms as a street drug for intravenous
`use would be limited if applied in the clinical arena in the future.
`
`MATERIALS AND METHODS
`The carbomers Carbopol934P, 974P and Noveon AA-1 were
`obtained by the courtesy of Noveon Inc. (OH, USA). Starch
`1500 (pregelatinized maize starch) was obtained by the courtesy
`of Colorcon Inc. (PA, USA). Lactose monohydrate, glycerol,
`propylene glycol, PEG (MW 400, 1000,3350, and 8000), mucin,
`and buprenorphine were obtained from Sigma Chemical Co.
`(MO, USA).
`
`Preparation of Mucoadhesive Polymer Films
`Considering the comfort issue involved with a drug delivery
`system designed to adhere to a sensitive and mobile area, we
`adjudged that a thin, flexible polymer film would be ideal for
`sublingual use. A general protocol used in several literature ref(cid:173)
`erences describing polymer films was adopted. Double-filtered
`deionized water was degassed under vacuum before adding the
`polymers to minimize the formation of air bubbles within the
`gel. Each of the following polymers in 200-500 mg quanti(cid:173)
`ties, Carbopol 934P, Carbopol 974P, and Noveon AA-1, were
`solubilized in water or 95% ethanol using a paddle stiner at
`1000 rpm for 10 min to result in 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0,
`4.5, and 5.0% w/w gels. Homogeneous gel formation for the
`higher concentrations (4.5 and 5% w/w) proved difficult by stir(cid:173)
`ring and was achieved by placing the mixtures in plastic bags
`and kneading by hand to prevent formation of poorly wetted
`polymer agglomerates. Amounts higher than 5.0% w/w could
`not be homogeneously solubilized. All gels were kept overnight
`at 4°C to allow complete hydration, following which they were
`centrifuged at 5000 rpm for 30 min to remove air bubbles be(cid:173)
`fore film casting. Two techniques were used to cast the polymer
`films: (a) gels poured on Teflon® plates and placed in the oven
`at 40°C for 24 hr or until dry to the touch; and (b) gels placed
`between two Teflon® plates separated with 1 mm thick spacers
`at the edges and dried in a desiccator under vacuum for 48-72 hr.
`
`Preparation of Plasticizer Containing Mucoadhesive
`Polymer Films
`Plasticizers were added to the aqueous gel systems described
`above to reduce brittleness, improve flexibility, and improve sur(cid:173)
`face texture and smoothness of the films. PEG has been described
`in the literature to also improve mucoadhesion properties of cer(cid:173)
`tain polymers. Glycerol, propylene glycol, or PEG 400, 1000,
`3350, or 8000 were each added to the aqueous gel systems to
`result in final concentrations of0.5, 1.0, 5.0, or 10.0% w/w plas(cid:173)
`ticizer in the system and stored overnight under refrigeration.
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`BUPRENORPHINE SUBLINGUAL MUCOADHESIVE DOSAGES
`
`91
`
`Gels were centrifuged and films were cast on Teflon® plates
`using the method (a) described previously.
`
`Tablet
`
`Preparation of Mucoadhesive Tablets
`Flat-faced core tablets were prepared by direct compression
`of various combinations of the polymers Carbopol 934P, 941,
`971P, or 974P or Nov eon AA-1, with or without starch, lactose,
`PEG 3350 and 8000, using a hydraulic laboratory pellet press
`(Carver Inc., IN, USA). After testing for physical characteristics
`and petforming thermal analysis to study polymer-excipient in(cid:173)
`teractions, select formulations were chosen and 8 mg buprenor(cid:173)
`phine incorporated into each unit dose. The total weight of com(cid:173)
`ponents per compact was kept constant at 200 mg, and a constant
`force of 1 ton was applied for 60 sec. The diameter of the die
`used was 13 mm, providing a potential surface contact area of
`1.33 cm2 for the tablets. Formulations were designed so that the
`tablet thickness would not exceed 2 mm and preferably be close
`to 1.5 mm.
`
`Physical Characterization and In Vitro Disintegration
`and Dissolution Tests
`The physical characteristics of the compacts such as thickness
`and hardness were evaluated using a micrometer (Central Tool
`Co., RI, USA) and a manual hardness tester (Pfizer, NY, USA),
`respectively. Visual observations were noted for surface smooth(cid:173)
`ness. Thermal analysis was done using a differential scanning
`calorimeter (MDSC 2920, TA Instruments, DE, USA) by plac(cid:173)
`ing 2-4 mg samples in sealed aluminum pans and ramp heating
`from room temperature to 300°C at a scan rate of 10°C/min.
`All components were scanned in their pure state and compared
`with thermo grams of the compressed tablets to observe changes
`in peak position or any characteristics that would indicate inter(cid:173)
`actions between the drug and excipients. In vitro disintegration
`tests were done using a single-station USP disintegration appa(cid:173)
`ratus (Erweka, NJ, USA) and double-distilled deionized water
`(ddH20) as the medium. In vitro dissolution tests were done
`using a USP dissolution apparatus (Vankel, NJ, USA) with the
`basket rotating at 50 rpm in 500 mL ddH20 at 37°C. Then 5-mL
`samples were withdrawn at selected time intervals until the gel
`matrix completely dissolved.
`The amount of buprenorphine in the dissolution samples
`was estimated by UV spectroscopy (Lambda-Bio, Perkin-Elmer,
`MA, USA). The reference medium for UV spectroscopy was
`obtained by dissolving a drug-free tablet in 500 ml ddH20. Mu(cid:173)
`coadhesive strength was estimated by using a manually oper(cid:173)
`ated surface tension apparatus (DuNuoy Tensiometer, Cenco,
`IL, USA) modified for this purpose and similar to a design re(cid:173)
`ported by Robert, Buri, and Peppas (1988). A schematic sketch
`of the instrument is presented in Figure 1. We replaced the sus(cid:173)
`pension ring (meant for measuring surface/interfacial tension)
`with an A-shaped wire affixed to an aluminum plate (weight
`456 mg, thickness 0.5 mm, and diameter 2 em) at the open ends.
`One face of the mucoadhesive tablet was immobilized on the
`
`FIG. 1. Schematic of modified tensiometer used for mucoadhesion studies.
`
`aluminum plate using glue and the system was suspended. Next
`30% (w/w) mucin gel was placed on the metal station at the base
`of the tensiometer. The tablet was brought into contact with the
`mucin gel, manually, and held in place for 10 sec. The dial on
`the tensiometer was then gently twisted until separation occmTed
`and the reading at the point of separation was noted.
`
`RESULTS AND DISCUSSION
`Prolonging drug delivery is well recognized as an advantage
`as it increases the therapeutic value of many drugs. Nevertheless,
`for mucoadhesive sublingual delivery, even if the system were
`capable of staying in place for prolonged periods, it would still be
`impractical to design a delivery system that would be retained in
`place beyond 2-3 hr. If not disturbed by drinking fluids, it is diffi(cid:173)
`cult to imagine that a sublingual drug delivery system would not
`be lost while eating regular meals, which would invariably lead
`to loss of drug from first-pass metabolism. Therefore, our goal
`was to develop a formulation that would localize buprenorphine
`in the sublingual area and prolong the release better than the cur(cid:173)
`rently marketed immediate release dosage form, while releasing
`the entire drug content within approximately 120 min. Addition(cid:173)
`ally, the formulation must lack any burst release effects, must
`not exhibit drug-excipient interactions, must possess sufficient
`mucoadhesive strength, and possess suitable physical properties
`such as tablet hardness, thickness, and surface smoothness for
`proper adhesion.
`
`Mucoadhesive Polymer Film formulations
`Films with No Plasticizers
`The films prepared by method (a) were brittle, with variable
`thicknesses and uneven surfaces. The films prepared by method
`(b), which was hoped to improve on method (a) by controlling
`film thickness, were comparably brittle and difficult to remove
`from the sandwiched Teflon® casting surfaces without distort(cid:173)
`ing the structure of the film. The nature of solvent (water or
`ethanol) used to solubilize the polymers did not appear to cause
`a significant difference in the gel formation process or in the end
`products, except that ethanol dried faster and produced a more
`uneven surface in method (a). We concluded that these formu(cid:173)
`lations, produced using either of these methods, would not be
`suitable for industrial scale-up.
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`92
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`N. G. DAS AND S. K. DAS
`
`16
`
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`Films with Plasticizers
`In general, the plasticizer containing polymer films were eas(cid:173)
`ier to fabricate and handle. The films containing either glycerol
`or propylene glycol as plasticizers took 48 hr or longer to set
`and tended to stretch irreversibly during removal from the cast(cid:173)
`ing surface. We determined that these plasticizers are capable of
`yielding films with excellent flexibility, but for ease of handling
`they must be cast on an impervious flexible backing, with the
`latter incorporated as part of the formulation design as manip(cid:173)
`ulations to the film must be done in conjunction to the backing
`material to prevent distortion. Hence, these plasticizers may be
`more suitable for designing transdermal films compared with
`dosage forms that need to be placed in the oral cavity, which
`preferably must be devoid of nonedible material.
`In formulations containing PEG as plasticizer, the films with
`5.0 and 10.0% w/w plasticizer content did not set properly and
`were too stretchy to be removed intact from the casting surface.
`The 0.5 and 1.0% w/w PEG 400-containing films exhibited the
`best physical characteristics, as the surface was smooth and the
`films were flexible. Once the formulations were optimized, we
`added buprenorphine to the gel during the preparation process,
`filled the prepared gels in a hypodermic glass syringe, and placed
`0.2-2 ml quantities on wax paper such that each unit dose con(cid:173)
`tained 8 mg of buprenorphine. The drug-containing gels were
`allowed to spread and set into circular discs that were formed nat(cid:173)
`urally. As expected, an inverse relationship was noted between
`film diameter and thickness. Figures 2 and 3 illustrate the effect
`of drying conditions on film thickness and diameter produced by
`various quantities of 0.5% w/w PEG 400-containing gels. The
`vacuum dried films showed greater thickness and smaller diam(cid:173)
`eters compared with oven dried films. The 40°C temperature
`in the oven likely allows for the spread of the films more than
`occurs at room temperature in the desiccator. This phenomenon
`is more evident when the volume of gel to be dried is larger.
`
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`/_}{
`
`·- o-- Vacuum dried, room temp.
`-111- Oven dried, 40°C
`
`0.0
`
`0.5
`
`1.5
`1.0
`Volume of gel (mL)
`
`2.0
`
`FIG. 2. Dependence of the polymer film thickness on volume of gel cast
`and drying conditions. The drug-free formulation represented here contained
`2.5% w/w Carbopol 974P and 0.5% w/w PEG 400.
`
`/I
`yi
`~ .---f
`
`---
`
`-
`
`P~l:f··l
`
`.-----
`
`-··O·· Vacuum dried, room temp.
`
`-
`
`/
`
`-•- Oven dried, 40°C
`
`0.0
`
`0.5
`
`1.0
`1.5
`Volume of gel (mL)
`
`2.0
`
`FIG. 3. Dependence of the film diameter on volume of gel cast and drying
`conditions. The drug-free formulation represented here contained 2.5% w/w
`Carbopol974P and 0.5% w/w PEG 400.
`
`Mucoadhesive Tablet formulations
`All tablets were observed to possess a smooth, shiny surface,
`regardless of the composition; therefore, the entire surface area
`would potentially be available for adhesion. Table 1 shows the
`dependence of tablet thickness and hardness on the composition
`of some representative formulations.
`
`Tablets Prepared with Mucoadhesive Polymer Only
`In vitro disintegration tests indicated that all pure polymer
`compacts, containing no other excipients, required over 8 hr to
`swell and erode. We incorporated buprenorphine in the polymer
`Carbopol 974P (8 mg buprenorphine +192 mg polymer) and
`studied the tablet for in vitro dissolution using a USP apparatus;
`the amount of buprenorphine released over 12 hr was very small
`when the absorbance was recorded in the UV spectrophotome(cid:173)
`ter. This observation corroborates the observations of McQuinn
`et al. (1995) who found that mucoadhesive polymer discs con(cid:173)
`taining Carbopol 934P and 2.9 mg buprenorphine free base,
`when placed on the gum of human volunteers, released 0.42 ±
`0.18 mg of the drug over 12 hr, which translates to approxi(cid:173)
`mately 14% drug release. This led us to conclude that the pure
`polymer compacts would not be capable of releasing therapeu(cid:173)
`tically effective quantities of buprenorphine in the sublingual
`environment in vivo within a reasonable usage period.
`
`Tablets Prepared with Mucoadhesive Polymer and PEG
`Addition of up to 10% w/w PEG 3350 improved the disso(cid:173)
`lution profile compared with the pure polymer compacts, but
`further increase in PEG content did not make additional im(cid:173)
`provements in the dissolution rate or extent. As shown in Table 1,
`the addition of PEG 3350 slightly increased the hardness of the
`tablets; however, it did not make any difference to the tablet
`thickness.
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2007 - 7/10
`
`
`
`BUPRENORPHINE SUBLINGUAL MUCOADHESIVE DOSAGES
`
`93
`
`TABLE 1
`Physical characteristics of mucoadhesive tablet formulations
`
`Composition(% w/w)
`
`Carbopol
`934P
`
`Carbopol Nov eon
`AA-1
`974P
`
`PEG 3350
`
`Lactose
`
`100
`95
`85
`80
`60
`40
`30
`
`5
`10
`5
`10
`10
`10
`
`5
`10
`5
`10
`10
`10
`
`5
`10
`5
`10
`10
`10
`
`5
`15
`30
`50
`60
`
`5
`15
`30
`50
`60
`
`5
`15
`30
`50
`60
`
`100
`95
`85
`80
`60
`40
`30
`
`100
`95
`85
`80
`60
`40
`30
`
`Thickness
`(mm);
`3
`n
`
`1.78 ± 0.06
`1.79 ± 0.04
`1.81 ± 0.05
`1.84 ± 0.10
`1.86 ± 0.10
`1.94 ± 0.12
`1.98 ± 0.14
`1.68 ± 0.04
`1.68 ± 0.04
`1.71 ± 0.05
`1.72 ± 0.08
`1.76 ± 0.10
`1.76 ± 0.10
`1.78 ± 0.12
`1.89 ± 0.02
`1.82 ± 0.04
`1.82 ± 0.02
`1.80 ± 0.04
`1.86 ± 0.04
`1.88 ± 0.12
`1.90 ± 0.14
`
`Hardness
`(kg);
`3
`n
`
`9.8 ± 0.6
`10.0 ± 0.8
`9.8 ± 0.6
`8.8 ± 0.6
`7.4 ± 0.6
`6.2 ± 0.8
`5.6 ± 1.0
`9.6 ± 0.6
`10.0 ± 0.8
`9.2 ± 0.6
`7.8 ± 0.4
`6.8 ± 0.4
`5.4 ± 0.8
`5.2 ± 1.0
`10.6 ± 0.6
`10.8 ± 0.8
`10.4 ± 0.8
`9.6 ± 0.6
`8.2 ± 0.8
`7.8 ± 1.0
`7.6 ± 1.2
`
`Disintegration
`time (lu:);
`3
`11
`
`Tensile strength
`(Newtons)
`n = 1
`
`9.0 ± 1.0
`9.0 ± 0.75
`8.5 ± 0.75
`7.0 ± 0.75
`5.0 ± 0.5
`3.0 ± 0.5
`2.0 ± 0.2
`8.5 ± 0.75
`8.0 ± 0.75
`7.5 ± 0.5
`6.0 ± 0.5
`4.0 ± 0.4
`2.5 ± 0.3
`2.0 ± 0.3
`10.0 ± 1.0
`10.0 ± 0.75
`9.5 ± 1.0
`8.0 ± 0.75
`6.0 ± 0.5
`4.0 ± 0.5
`3.0 ± 0.5
`
`13.7
`13.0
`13.1
`11
`8.3
`5.2
`3.9
`16.2
`16.8
`16.1
`14.0
`11.2
`8.8
`7.3
`15.0
`15.5
`14.8
`12.8
`10.1
`8.1
`6.8
`
`Tablets Prepared with Mucoadhesive Polymer and Starch
`We hypothesized that the addition of pregelatinized starch
`would improve the disintegration and dissolution profiles of the
`compacts and increase the porosity of the compressed poly(cid:173)
`mer matrix. Amounts of pregelatinized starch between 5 and
`70% w/w were added to the formulation. But contrary to our
`expectations, all concentrations of starch. increased the tablet
`hardness beyond 12 kg and increased disintegration time beyond
`12 hr. There was no improvement in the dissolution profiles of
`the starch-polymer compacts compared with the pure polymer
`compacts; hence, the results for this group of formulations are
`not discussed further.
`
`Tablets Prepared with Mucoadhesive Polymer and Lactose,
`with or Without PEG
`Lactose was the second excipient that we expected would
`increase porosity of the swelling polymer gel matrix. Various
`amounts of lactose, between 5-80% w /w, were added to the
`formulations. As shown in Table 1, an increase in lactose con(cid:173)
`tent was inversely related to tablet hardness and disintegration
`time for all polymers, and the tablet thickness was directly re(cid:173)
`lated to lactose content. At lactose content 70% w /w and above,
`the tablets become increasingly friable and chip easily during
`
`removal from the die. However, tablets with relatively high
`lactose content and low mucoadhesive polymer concentrations
`provided the most desirable disintegration and dissolution pro(cid:173)
`files, while providing adequate mucoadhesive force. We added
`various amounts of PEG 3350 to the high lactose-containing
`formulations to investigate whether it improves "tabletability."
`The addition of PEG 3350 indeed increased the hardness, re(cid:173)
`duced friability, and improved the surface smoothness of the
`tablets, while maintaining the desirable disintegration and dis(cid:173)
`solution profiles provided by the large amount of lactose in
`the formulations. All formulations were tested for their mu(cid:173)
`coadhesive (tensile) strength and the results are presented in
`Table 1. From our experiments and similar reports in literature,
`we concluded that formulations containing Carbopol 974P and
`Noveon AA-1 were comparable in their mucoadhesive capabil(cid:173)
`ity and were superior to the other polymers we tested in our
`formulations.
`Differential scanning calorimetry (DSC) revealed no inter(cid:173)
`actions between buprenorphine and the formulation excipients.
`Figure 4 shows the DSC thermograms for pure Carbopol 974P,
`lactose, PEG 3350