DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 21(17), 2013-2019 (1995)
`
`COMMUNICATIONS
`
`BIOADHESIVE POLYMER BUCCAL PATCHES FOR
`BUPRENORPHINE CONTROLLED DELIVERY: SOLUBILITY
`CONSIDERATION
`
`Jian-Hwa Guo and K. M. Cooklock
`3M Pharmaceuticals, 3M Center, 270-43-02, St. Paul, MN 55144-1000
`
`ABSTRACT
`
`By using a two-roll milling method, a new bioadhesive polymer patch
`for buprenorphine controlled delivery and consisting of
`formulation
`polyisobutylene, polyisoprene, and Carbopol@ 934P was prepared. Since
`solubility of drug in the polymer patches is the first factor which should be
`considered before to modify the feasibility of delivering drug through the
`buccal mucosa,
`the effects of a-cyclodextrin, P-cyclodextrin, sodium
`taurocholate,
`and
`sodium glycodeoxycholate on
`the
`solubility
`of
`buprenorphine were investigated, and P-cyclodextrin was found the strongest
`solubility enhancer of them. The drug release profiles were significantly
`affected by the drug loading and the existence of P-cyclodextrin. Increasing
`the drug loading and solubility enhancer would increase the drug release from
`the buccal polymer patches. The pH value change in the microenviroment of
`polymer patches during the hydration of Carbopol@ 934P could even release
`20% of drug from the polymer patches which didn’t contain any solubility
`enhancer.
`
`Copyright 0 1995 by Marcel Dekker, Inc.
`
`2013
`
`Drug Dev Ind Pharm Downloaded from informahealthcare.com by Doris Yen on 02/27/15
`
`For personal use only.
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`RBP_TEVA05017846
`
`DRL - EXHIBIT 1033
`DRL001
`
`

`
`2014
`
`GUOANDCOOKLOCK
`
`INTRODUCTION
`
`Recently the buccal mucosa has been studied as a potential site for
`
`delivery of drug, because of its accessibility and low enzymatic activity. The
`
`buccal mucosa may offer alternate route of delivery for drugs including those
`
`that are metabolically unstable (I). The buccal mucosa was investigated as a
`
`potential site for drug delivery several decades ago and interest in this area for
`
`transniucosal drug administration is still growing (1-3).
`Buprenorphine is a partial p agonist opioid analgesic that is well
`absorbed by both the intramuscular and sublingual routes and is 25-50 times
`more potent than morphine (4). The drug's onset of action occurs rapidly,
`with maximum blood drug levels attained within five minutes of intramuscular
`injection. The duration of action of buprenorphine can be extended from the
`4-5 hours obtained with a single intramuscular dose to 5-6 hours with the use
`of sublingual administration. The latter route is already being developed as an
`alternative to the injectable formulation (5).
`The in-vitro characterization of a newly developed bioadhesive patch for
`controlled drug delivery via the buccal mucosa was investigated by Guo (6-7)
`and Scherrer, et a1 (8). The effects of different ratios of Carbopol@ 934P,
`polyisobutylene, and polyisoprene on the surface properties, adhesion, and
`swelling of buccal patches were investigated. They had developed patches
`composed of Carbopol@ 934P, polyisobutylene, and polyisoprene having
`physical properties that are required for the buccal controlled drug delivery.
`Solubility of drug in the polymer patches is the first factor which
`should be considered before to modify the feasibility of delivering drug
`through the buccal mucosa. This paper describes the factors which would
`affect the solubility of buprenorphine, a partial p agonist opioid analgesic, via
`the buccal mucosa, in the polymer patches, and the effects on the release of
`buprenorphine from those patches would be discussed as well.
`
`Drug Dev Ind Pharm Downloaded from informahealthcare.com by Doris Yen on 02/27/15
`
`For personal use only.
`
`RBP_TEVA05017847
`
`DRL - EXHIBIT 1033
`DRL002
`
`

`
`BIOADHESIVE POLYMER BUCCAL PATCHES
`
`2015
`
`-
`
`Q, $ 50 -
`a,
`a, L
`
`40 -
`
`-
`
`L
`0
`a,
`$ 30
`P
`a,
`a, L
`* 20
`-
`a,
`E=
`2
`
`c
`a,
`h a
`
`R
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`:lo% BP, BP/B-CD=I/I
`
`v :lo% BP-HCI. BP-HCI/B-CD=I/l
`0 : l o % BP
`: l o % BP-HCI
`
`I
`
`I
`
`I
`
`FIGURE 1
`The effect of kcyclodextrin on the buprenorphine release from the
`CP/PIB/PIP = 60/35/5 buccal patches.
`
`MATERIALS AND METHODS
`
`ratio of
`Preparation of polymer patches was as follows: a desired
`bioadhesive polymer Carbopol@ (934P grade, BF Goodrich, Cleveland, OH)
`(CP), polyisobutylene (LMMH grade, EXXON Chemical Co., Houston, TX)
`(PIB), and polyisoprene (GoodYear Chemical Co., Akron, OH) (PIP) were
`mixed homogeneously with buprenorphine (Diosyngy , NJ) and additive (a-
`cyclodextrin,
`P-cyclodextrin,
`sodium
`taurocholate,
`or
`sodium
`glycodeoxycholate) (Sigma, MO) by a two-roll mill. The elastomer polymer
`
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`
`For personal use only.
`
`RBP_TEVA05017848
`
`DRL - EXHIBIT 1033
`DRL003
`
`

`
`2016
`
`GUOANDCOOKLOCK
`
`(3 10% BP. BP/@-CD=I/I
`10% BP. BP/@-CD=2/1
`6% BP, BP/@-CD=Z/l
`0 6% BP. BP/@-CD=4/1
`2% BP, BP/p-CD=2/1
`
`0
`
`0
`
`5
`
`15
`10
`Time (hr)
`
`20
`
`25
`
`30
`
`FIGURE 2
`The effect of -cyclodextrin and drug loading on the burprenorphine release
`from the CP/PIB/PIP = 50/43.75/6.25 buccal patches.
`
`mixture was compressed in a predetermined thickness, and appropriate sizes
`were punched out for in-vitro testing (6-7).
`the hydrated polyvinyl
`The
`in-vitro drug
`release
`through
`pyrrolidone/cellulose acetate hydrogel film was conducted by using diffusion
`cells and were performed in phosphate buffer (pH=7) at 37OC. Aliquots were
`taken at various times up to 24 hours and assayed for buprenorphine free base
`or HCI salt by high-pressure liquid chromatography. The gradient system
`used
`in
`this study consisted of mobile phase, CH3CN/16.6 mM
`CH3(CH2),S03Na aqueos solution/CH3COOH, 70%/30%/1%, (v/v/v) at
`flow rate 1.5 ml/min.
`
`Drug Dev Ind Pharm Downloaded from informahealthcare.com by Doris Yen on 02/27/15
`
`For personal use only.
`
`RBP_TEVA05017849
`
`DRL - EXHIBIT 1033
`DRL004
`
`

`
`BIOADHESIVE POLYMER BUCCAL PATCHES
`
`2017
`
`,
`
`I
`
`I
`
`I
`
`I
`
`1
`
`1
`
`v . CP-974P
`. c p - 9 3 4 ~
`
`0.6
`0.8
`0.2
`1.2
`0.4
`0.0
`1.0
`Carbopol concentration (g/ml of buffer solution)
`
`FIGURE 3
`The pH values of different CP-934P or CP-974P concentrations
`(at pH 7 Phosphate Buffer).
`
`RESULTS AND DISCUSSION
`
`The effects of a-cyclodextrin, pcyclodextrin, sodium taurocholate, and
`sodium glycodeoxycholate on the solubility of buprenorphine free base or HCI
`salt were investigated.
`j3-cyclodextrin was found the strongest solubility
`enhancer of buprenorphine free base and HCl salt (pcyclodextrin > ct-
`cyclodextrin > sodium taurocholate > sodium glycodeoxycholate). The
`effects of P-cyclodextrin and drug loading on the buprenorphine free base or
`HCI salt release profiles from CP/PIB/PIP = 60/35/5 and CP/PIB/PIP =
`50/43.75/6.25 formulations are demonstrated in Figures 1 and 2, respectively.
`
`Drug Dev Ind Pharm Downloaded from informahealthcare.com by Doris Yen on 02/27/15
`
`For personal use only.
`
`RBP_TEVA05017850
`
`DRL - EXHIBIT 1033
`DRL005
`
`

`
`2018
`
`GUOANDCOOKLOCK
`
`e -
`
`,
`
`FIGURE 4
`The solubilities of buprenorphine in the CP-934P solutions.
`
`I ne arug release proriies were signiricantiy arrectea ~y tne arug ioaaing
`and the existence of P-cyclodextrin.
`Increasing the drug loading and
`solubility enhancer would increase the drug release from the buccal polymer
`patches, since increasing the amount of P-cyclodextrin and drug loading
`would increase the driving force of drug in the polymer patches. However, as
`shown in Figure 1, even 20% of drug released from the polymer patches
`which didn't contain the P-cyclodextrin.
`This phenomenon could be
`explained by the pH value change in the microenviroment of polymer patches
`during the hydration of CP.
`The pH values of different concentrations of CP 934P and 974P solutions
`(dissolved in pH 7 buffer solution) were indicated in Figure 3. Increasing the
`
`Drug Dev Ind Pharm Downloaded from informahealthcare.com by Doris Yen on 02/27/15
`
`For personal use only.
`
`RBP_TEVA05017851
`
`DRL - EXHIBIT 1033
`DRL006
`
`

`
`BIOADHESIVE POLYMER BUCCAL PATCHES
`
`2019
`
`CP concentration would decrease the pH value of the CP solution. The
`decrease of pH value of CP solution was accompanied by the increase of
`buprenorphine solubility in this solution (Figure 4). Therefore, it can explain
`that even 20% of drug could release from the polymer patches which didn't
`include the P-cyclodextrin. However, the buprenorphine solubility decreased
`slightly at higher CP concentration solution, because the CP solution became
`some of
`more viscous at higher CP concentration and entrapped
`buprenorphine.
`
`REFERENCES
`
`1.
`2.
`
`3.
`4.
`
`5.
`6.
`7.
`8.
`
`D. Harris and J.R. Robinson. J. Pharm. Sci. 81, 1-10 (1992).
`A.H. Beckett and E.J. Triggs. J. Pharm. Pharmucol. 19(suppl), 31s
`-41s (1967).
`T. Nagai and R. Konishi. J. Contr. Rel. 6, 353-360 (1987).
`J.H. Jaffe and W.R. Martin. Opioid analgesics and antagonists. In
`A.G. Gilman, T.W. Rall, A.S. Nies, and P. Taylor (eds.), The
`Pharmacological Basis of Therapeutics, Pergamon Press, New Y ork,
`1990, pp. 485-521.
`D. Harris and J.R. Robinson. J. Pharm. Sci. 81:l-10 (1992).
`J-H. Guo. J. Pharm. Pharmucol. 46, 647-650 (1994).
`J-H. Guo. Drug Dev. Znd. Pharm. 20, 2809-2821 (1994).
`R.N. Scherrer, M.T. Scholz, R.L. McQuinn, J.K. Barkhaus and
`N.M. Marecki. Pharm. Res. 9, S252 (1992).
`
`Drug Dev Ind Pharm Downloaded from informahealthcare.com by Doris Yen on 02/27/15
`
`For personal use only.
`
`RBP_TEVA05017852
`
`DRL - EXHIBIT 1033
`DRL007