ADHESIVE MATRIX WITH HYDROPHILIC AND HYDROPHOBIC DOMAINS AND A THERAPEUTIC AGENT

Abstract

An adhesive matrix and adhesive formulation are described. The adhesive matrix is comprised of a hydrophilic domain and a hydrophobic domain, and a therapeutically active agent contained in the matrix in a supersaturated, stable, condition. The hydrophilic domain and the hydrophobic domain are co-soluble in a solvent system, to provide a homogeneous blend in which the active agent is solubilized. The proportion of the hydrophilic domain and hydrophobic domain is selected to optimize, or maximize, solubility of active agent in the matrix.

Claims

1. An adhesive matrix, comprising: a hydrophilic domain comprising a polyvinylpyrrolidone-vinyl acetate copolymer; a hydrophobic domain comprising one or both of a polyisobutylene and an acrylic acid/vinyl acetate copolymer; and an active agent is characterized by (a) a melting point of less than about 250° C. or (b) a solubility in water of less than about 500 mg/L or (c) an oil/water partition coefficient of between about 2.1 and about 5; wherein the hydrophilic domain and the hydrophobic domain are co-soluble in a solvent system and present in the adhesive matrix in a proportion to one another to solubilize an amount of active agent greater than the amount of active agent soluble in either domain alone.

2. The adhesive matrix of claim 1, wherein the hydrophobic domain comprises a combination of polyisobutylene and polybutene.

3. The adhesive matrix of claim 2, wherein the hydrophobic domain comprises an acrylic acid/vinyl acetate copolymer.

4. The adhesive matrix of claim 1, comprising between 10-25 wt % hydrophilic domain.

5. The adhesive matrix of claim 1, comprising between about 35-80 wt % hydrophobic domain.

6. The adhesive matrix of claim 1, comprising about 15-25 wt % active agent, about 50-60 wt % acrylate adhesive, about 7-15 wt % polyisobutylene and polybutene mixture, and about 10-20 wt % polyvinylpyrrolidone-vinyl acetate copolymer.

7. The adhesive matrix of claim 1, wherein the active agent is selected from the group of drugs consisting of donepezil, ropinrole, lidocaine, and oxybutynin.

8. A device for transdermal administration of an active agent, the device comprising an adhesive matrix layer according to claim 1.

9. A formulation for preparation of an adhesive matrix, comprising: about 10-25 wt % polyvinylpyrrolidone-vinyl acetate copolymer, about 35-75 wt % of polyisobutylene and polybutene, about 40-64 wt % of an acrylate adhesive, and about 5-50 wt % of an active agent in a solvent system comprised of an organic solvent in which the polyvinylpyrrolidone-vinyl acetate copolymer, the polyisobutylene and polybutene and soluble, wherein the active agent is characterized by (a) a melting point of less than about 250° C. or (b) a solubility in water of less than about 500 mg/L or (c) an oil/water partition coefficient of between about 2.1 and about 5.

10. A method for the manufacture of an adhesive matrix, comprising: (i) solubilizing a polyvinylpyrrolidone-vinyl acetate copolymer in a first solvent; (ii) solubilizing polyisobutylene and polybutene in a second solvent; (iii) mixing (i) and (ii) to form a homogeneous solution; (iv) adding to the homogeneous solution an acrylate adhesive solubilized in a third solvent to form an adhesive solution; (v) adding to the adhesive solution an active agent characterized by (a) a melting point of less than about 250° C. or (b) a solubility in water of less than about 500 mg/L or (c) an oil/water partition coefficient of between about 2.1 and about 5; and (v) forming an adhesive matrix from the adhesive solution with the active agent that comprises between about 35-80 wt % acrylate, between about 0.01-30 wt % polyisobutylene and polybutene mixture, between about 10-25 wt % polyvinylpyrrolidone-vinyl acetate copolymer, and between about 5-50 wt % active agent.

11. The method of claim 10, wherein the acrylate adhesive is not a methacrylate copolymer.

12. The method of claim 10, wherein the polyvinylpyrrolidone-vinyl acetate copolymer is a copolymer of n-vinyl-2-pyrrolidone and a vinyl acetate that is not ethylhexyl acrylate.

13. The method of claim 10, wherein the polyvinylpyrrolidone-vinyl acetate copolymer is a linear random copolymer of n-vinyl-2-pyrrolidone and vinyl acetate.

14. The method of claim 13, wherein the copolymer is a 60:40 copolymer of n-vinyl pyrrolidone and vinyl acetate.

15. The method of claim 10, wherein the acrylate adhesive is an acrylic acid/vinyl acetate copolymer, excluding methacrylic acid/vinyl acetate copolymers.

16. The method of claim 15, wherein the acrylic acid/vinyl acetate copolymer is one without a cross-linker agent and has a viscosity between about 2000-8000 mPa-s when measured at 25° C.

17. The method of claim 10, wherein the first solvent is one in which polyvinylpyrrolidone homopolymer is insoluble.

18. The method of claim 10, wherein the first solvent comprises toluene.

19. The method of claim 10, wherein the first solvent comprises a mixture of toluene and iso-propyl alcohol.

20. The method of claim 19, wherein the mixture comprises 9 parts toluene and 1 part iso-propyl alcohol.

21. The method of claim 10, wherein the second solvent is the same as the first solvent.

22. The method of claim 10, wherein the first solvent is a mixture comprising toluene and the second solvent is toluene.

23. The method of claim 10, wherein the third solvent is ethyl acetate.

24. The method of claim 10, wherein forming an adhesive matrix comprises applying the adhesive solution with the active agent onto a substrate and drying at a temperature of between 50-100° C.

25. The method of claim 24, wherein the adhesive matrix comprises 15-25 wt % active agent, 50-60 wt % acrylate adhesive, 7-15 wt % polyisobutylene and polybutene mixture and 10-20 wt % polyvinylpyrrolidone-vinyl acetate copolymer.

26. The method of claim 10, wherein the active agent is selected from the group of drugs consisting of donepezil, ropinrole, lidocaine, and oxybutynin.

Description

DETAILED DESCRIPTION

I. Definitions

[0028] Various aspects now will be described more fully hereinafter. Such aspects may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0029] Where a range of values is provided, it is intended that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 μm to 8 μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also explicitly disclosed, as well as the range of values greater than or equal to 1 μm and the range of values less than or equal to 8 μm.

[0030] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a “polymer” includes a single polymer as well as two or more of the same or different polymers, reference to an “excipient” includes a single excipient as well as two or more of the same or different excipients, and the like.

II. ADHESIVE FORMULATION AND ADHESIVE MATRIX

[0031] The adhesive matrix described herein is comprised of a hydrophilic domain and a hydrophobic domain, and a therapeutically active agent contained in the matrix in a supersaturated, stable, condition. The hydrophilic domain and the hydrophobic domain are co-soluble in a solvent system, to provide a homogeneous blend in which the active agent is solubilized. The proportion of the hydrophilic domain and hydrophobic domain is selected to optimize, or maximize, solubility of active agent in the matrix. For example, and in one embodiment, the matrix comprises an amount of active agent greater than the amount of active agent soluble in the hydrophobic domain alone or, in another embodiment, the hydrophilic domain alone, or, in yet another embodiment, in both domains alone. In one embodiment, the amount of active agent in the matrix is about the saturation concentration of the active agent in the hydrophobic domain alone or, in another embodiment, the hydrophilic domain alone, or, in yet another embodiment, in both domains alone.

[0032] The hydrophilic domain is comprised of a polyvinylpyrrolidone-vinyl acetate copolymer and the hydrophobic domain comprises one or both of a polyisobutylene and an acrylic acid/vinyl acetate copolymer.

[0033] Polyvinylpyrrolidone-vinyl acetate copolymers are linear, random copolymers produced by the free-radical polymerization of the monomers N-vinyl-2-pyrrolidone (NVP) and vinyl acetate (VA). The amount of each monomer can be varied to product copolymers with ratios varying from 70/30 to 30/70 vinyl acetate to vinylpyrrolidone. In one embodiment, the copolymer comprises 30% vinylpyrrolidone; in another embodiment, the copolymer comprises 50% vinylpyrrolidone content; in another embodiment, the copolymer comprises 60% vinylpyrrolidone content; and in another embodiment, the copolymer comprises 70% vinylpyrrolidone content. In one embodiment, the polyvinylpyrrolidone-vinyl acetate copolymer results from polymerization of an n-vinyl-2-pyrrolidone monomer and a vinyl acetate monomer that is not ethylhexyl acrylate.

[0034] The molecular weight of polyvinylpyrrolidone-vinyl acetate copolymers may vary, and copolymers in a range of molecular weights are commercially available. In one embodiment, a polyvinylpyrrolidone-vinyl acetate copolymer with a molecular weight (weight average) is between 40,000-60,000 Daltons, and in another embodiment, is between about 25,000-200,000 Daltons.

[0035] In the working examples set forth hereinbelow, a polyvinylpyrrolidone-vinyl acetate copolymer comprised of 60% vinylpyrrolidone content and a weight average molecular weight of 47,000 Daltons was used.

[0036] The hydrophobic domain in the adhesive matrix comprises one or both of a polyisobutylene and an acrylic acid/vinyl acetate copolymer. In another embodiment, the hydrophobic domain in the adhesive matrix comprises an acrylic acid/vinyl acetate copolymer, and optionally, a polyisobutylene.

[0037] In one embodiment, a polyisobutylene is a blend or a mixture of a high molecular weight polyisobutylene and a medium molecular weight polyisobutylene. The term. “high molecular weight polyisobutylene” refers to a polyisobutylene having an average molecular weight in the range of about 450,000 to about 2,100,000 Daltons, and preferably from about 500,000 to about 1,500,000 Daltons. The term, “medium molecular weight polyisobutylene” refers to a polyisobutylene having an average molecular weight in the range of about 10,000 to about 450,000 Daltons, and preferably from about 25,000 to about 100,000 Daltons,

[0038] In the working examples set forth hereinbelow, a high molecular weight polyisobutylene of 1,000,000 Daltons and a medium molecular weight polyisobutylene of about 50,000 Daltons were blended in a ratio of 1:5. Stated alternatively, on a 100 weight basis, the matrix comprised a ratio of high molecular weight polyisobutylene to medium molecular weight polyisobutylene of 17:83. In other embodiments, the adhesive matrix contains a high molecular weight polyisobutylene to medium molecular weight polyisobutylene ratio of between about 5-40:95-60, or between about about 10-25:90-75 or between about 10-20:90-80.

[0039] In another embodiment, the polyisobutylene (also referred to as a polyisobutylenen blend) in the hydrophobic domain further comprises a polybutene. Polybutene is a viscous, non-drying, liquid polymer, prepared by the copolymerization of 1- and 2-butene with a small quantity of isobutylene. The polybutene in one embodiment has a molecular weight of between about 750-6000 Daltons, preferably between about 900-4000 Daltons, and preferably between about 900-3000 Daltons. In the working examples below, some embodiments of the hydrophobic domain comprised a polybutene of 2500 Dalton molecular weight, present in the polyisobutylene blend at 40 weight percent. More generally, the polybutene is present in the polyisobutylene blend of the hydrophobic domain in an amount between 20-50 weight percent, or between 25-45 weight percent.

[0040] The hydrophobic domain of the adhesive matrix comprises an acrylic polymer pressure sensitive adhesive. An acrylic polymer pressure sensitive adhesive intends a polyacrylate adhesive that is a polymer or a copolymer of a monomer or monomers selected from acrylic acid esters and methacrylic acid esters. Other monomers, such as acrylic acid and vinyl acetate, may be present. In one embodiment, the acrylate adhesive is not a methacrylate copolymer; that is, the polyacrylate adhesive excludes a methacrylic acid monomeric unit. Preferably the acrylic polymer pressure sensitive adhesive has pendent carboxyl (—COOH) or hydroxyl (—OH) functional groups attached to the polymer chain.

[0041] In one embodiment, the acrylic acid/vinyl acetate copolymer is one without a cross-linker agent. The exclusion of cross-linker agents containing metals, particularly transition metal cross-linking agents, which act as catalysts of several chemical reactions, such as esterification, transesterification, oxidation and addition, avoids the possibility of chemical interaction with the active agent in the matrix and a possible loss of potency, impurity formation and stability problems. Preferably the adhesive matrix layer contains no component acting as a cross-linking agent for the acrylic polymer.

[0042] In one embodiment, the acrylic acid/vinyl acetate copolymer has a viscosity between about 2000-8000 mPa-s when measured at 25° C.

[0043] The adhesive matrix can include additives and excipients as is common in the art. By way of example, the matrix can include penetration enhancers such as fatty acids having a carbon number of 6-20, aliphatic alcohols, fatty acid esters or ethers or amides, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers (saturated or unsaturated, and either cyclic, straight chain or branched), furthermore, lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, Azone, Azone derivatives, glycerin fatty acid esters, sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene hardened castor oil (HCO), sucrose fatty acid esters and the like. Fatty acids having a carbon number of 8 or more (such as caprylic acid, capric acid, myristic acid, palmitic acid, oleic acid, stearic acid, etc.), and aliphatic alcohols (such as oleyl alcohol, isostearyl alcohol, lauryl alcohol, octyl alcohol, decyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, etc.) are contemplated. The amount of enhancer is, taking into consideration the sufficient permeability of active components into the skin and skin irritation as adhesive patches, between about 1-10 wt %, or about 2-8 wt %, and or about 3-6 wt % relative to the weight of the adhesive matrix.

[0044] Additives such as antioxidants, fillers, preservatives and ultraviolet absorbers may be blended in the adhesive matrix. As antioxidants, tocopherol and its ester derivatives, ascorbic acid, ascorbic acid-stearic acid ester, nordihydroguaretic acid, dibutyl hydroxy toluene (BHT), butyl hydroxy anisole and the like are preferred. As fillers, calcium carbonate, magnesium carbonate, silicates (such as aluminum silicate, magnesium silicate, etc.), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like are preferred. As preservatives, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate and the like are preferred. As ultraviolet absorbers, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino-acid compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like are preferred. These additives may be present in the adhesive matrix at an amount of preferably 10 wt % or less, more preferably 5 wt % or less, and especially preferably 2 wt % or less.

[0045] The adhesive matrix also comprises a therapeutically active agent. The active agent is characterized by (a) a melting point of less than about 250° C. or (b) a solubility in water of less than about 500 mg/L or (c) an oil/water partition coefficient of between about 2.1 and about 5. Examples of active agents are set forth in the table below, and include donepezil, ropinrole, lidocaine, and oxybutynin.

TABLE-US-00001 Active Agent Melting Point (base) Water solubility (° C/) LogP donepezil 2.931 mg/L 206.7 4.86 (pubchem.ncbi.nlm.nih.gov) ropinole   133 mg/mL 243-250 2.7 lidocaine 410 mg/L at 30 C. 68 2.26 oxybutynin 10 mg/L (drugbank.ca) 129-130 4.3

[0046] Adhesive formulations and matrices were prepared to illustrate the concepts described above. Examples 1-10 set forth exemplary formulations and resulting adhesive matrices using the active agent donezepil, in its base form, as a model drug.

[0047] In Example 1, an adhesive matrix comprising 66 wt % of a hydrophobic domain and 14% of a hydrophilic domain was prepared, with the active agent present at 20 wt % in the matrix. The active agent was present at a concentration above its saturation concentration in the hydrophobic domain alone, due to the presence of the hydrophilic domain, which lowered the solublity of the hydrophobic domain for the active agent. Accordingly, the active agent was present in the adhesive matrix at a supersaturated concentration, to thereby provide a thermodynamic activity greater than unity to provide a maximum driving force for permeation of the agent across the skin. The hydrophobic domain in the exemplary adhesive matrix of Example 1 was comprised of a homogeneous blend of an acrylic acid/vinyl acetate copolymer and a polyisobutylene mixture of a high molecular weight polyisobutylene, a medium molecular weight polyisobutylene, and a polybutene. The blend had 86 parts of the acrylic acid/vinyl acetate copolymer and 14 parts of polyisobutylene mixture.

[0048] In Example 2, an adhesive matrix comprising 62 wt % of a hydrophobic domain and 13% of a hydrophilic domain was prepared, with the active agent present at 20 wt % in the matrix. The active agent was present at a concentration above its saturation concentration in the hydrophobic domain alone, due to the presence of the hydrophilic domain, which lowered the solublity of the hydrophobic domain for the active agent. Accordingly, the active agent was present in the adhesive matrix at a supersaturated concentration, to thereby provide a thermodynamic activity greater than unity to provide a maximum driving force for permeation of the agent across the skin. The hydrophobic domain in the exemplary adhesive matrix of Example 2 was comprised of a homogeneous blend of an acrylic acid/vinyl acetate copolymer and a polyisobutylene mixture of a high molecular weight polyisobutylene, a medium molecular weight polyisobutylene, and a polybutene. The blend had 93 parts of the acrylic acid/vinyl acetate copolymer and 7 parts of polyisobutylene mixture. The adhesive matrix additionally included a penetration enhancer.

[0049] In Example 3, an adhesive matrix comprising 62 wt % of a hydrophobic domain and 13% of a hydrophilic domain was prepared, with the active agent present at 20 wt % in the matrix. The hydrophobic domain in the exemplary adhesive matrix of Example 3 was comprised of a homogeneous blend of an acrylic acid/vinyl acetate copolymer and a polyisobutylene mixture of a high molecular weight polyisobutylene, a medium molecular weight polyisobutylene, and a polybutene. The blend had 85 parts of the acrylic acid/vinyl acetate copolymer and 15 parts of polyisobutylene mixture. The adhesive matrix additionally included a penetration enhancer.

[0050] In Example 4, an adhesive matrix comprising 62 wt % of a hydrophobic domain and 5 wt % of a hydrophilic domain was prepared, with the active agent present at 20 wt % in the matrix. The hydrophobic domain in the exemplary adhesive matrix of Example 4 was comprised of a homogeneous blend of an acrylic acid/vinyl acetate copolymer and a polyisobutylene mixture of a high molecular weight polyisobutylene, a medium molecular weight polyisobutylene, and a polybutene. The blend had 79 parts of the acrylic acid/vinyl acetate copolymer and 21 parts of polyisobutylene mixture. The adhesive matrix additionally included a penetration enhancer.

[0051] In Example 5, an adhesive matrix comprising 57 wt % of a hydrophobic domain and 13 wt % of a hydrophilic domain was prepared, with the active agent present at 20 wt % in the matrix. The hydrophobic domain in the exemplary adhesive matrix of Example 5 was comprised of a homogeneous blend of an acrylic acid/vinyl acetate copolymer and a polyisobutylene mixture of a high molecular weight polyisobutylene, a medium molecular weight polyisobutylene, and a polybutene. The blend had 77 parts of the acrylic acid/vinyl acetate copolymer (44/57) and 22 parts (13/57) of polyisobutylene mixture. The adhesive matrix additionally included a penetration enhancer.

[0052] In Example 6, an adhesive matrix comprising 45 wt % of a hydrophobic domain and 15 wt % of a hydrophilic domain was prepared, with the active agent present at 40 wt % in the matrix. The hydrophobic domain in the exemplary adhesive matrix of Example 6 was comprised of an acrylic acid/vinyl acetate copolymer.

[0053] In Example 7, an adhesive matrix comprising 42 wt % of a hydrophobic domain and 14 wt % of a hydrophilic domain was prepared, with the active agent present at 40 wt % in the matrix. The hydrophobic domain in the exemplary adhesive matrix of Example 7 was comprised of an acrylic acid/vinyl acetate copolymer. The adhesive matrix additionally included a penetration enhancer.

[0054] In Examples 8-10, adhesive matrices comprised of a hydrophobic domain and a hydrophilic domain of a polyvinylpyrrolidone homopolymer are set forth.

[0055] The table below summarizes the weight ratios of the hydrophobic domain to hydrophilic domain in the exemplary adhesive matrices of Examples 1-10, and also shows the ratio of drug to hydrophobic domain.

TABLE-US-00002 Ratio Hydrophobic Ratio Example Domain/Hydrophilic Drug/Hydrophobic No. Domain Domain 1 4.67 3.29 2 4.68 3.09 3 4.77 3.1 4 12.4 3.1 5 4.38 2.85 6 3.0 1.12 7 3.0 1.05 8 6.37 1.28 9 6.4 2.59 10 6.39 4.90

Preparation of Adhesive Matrix and Transdermal Device

[0056] In another aspect, a formulation for preparation of an adhesive matrix is provided. The formulation comprises, in one embodiment, between about 10-25 wt % polyvinylpyrrolidone-vinyl acetate copolymer and about 40-64 wt % of an acrylate adhesive and about 5-50 wt % of an active agent in a solvent system. In one embodiment, the solvent system is comprised of an organic solvent in which the polyvinylpyrrolidone-vinyl acetate copolymer is soluble and a polyvinylpyrrolidone homopolymer is insoluble. In one embodiment, the solvent system is a binary mixture of organic solvents, and in another embodiment, is a ternary mixture.

[0057] A method for the manufacture of an adhesive matrix is also provided. With reference to Example 1, the method comprises (i) solubilizing a polyvinylpyrrolidone-vinyl acetate copolymer in a first solvent; (ii) solubilizing polyisobutylene and polybutene (when present in the formulation) in a second solvent; (iii) mixing (i) and (ii) to form a homogeneous solution; (iv) adding to the homogeneous solution an acrylate adhesive solubilized in a third solvent to form an adhesive solution; (v) adding to the adhesive solution an active agent as described herein, and (v) forming an adhesive matrix from the adhesive solution with the active agent that comprises between about 35-80 wt % acrylate, between about 0.01-30 wt % polyisobutylene and polybutene mixture, between about 10-25 wt % polyvinylpyrrolidone-vinyl acetate copolymer, and between about 5-50 wt % active agent.

[0058] In another embodiment, the method comprises (i) solubilizing a polyvinylpyrrolidone-vinyl acetate copolymer in a first solvent; (ii) solubilizing an acrylate adhesive in a second solvent; (iii) mixing (i) and (ii) to form a homogeneous solution; (iv) adding to the homogeneous solution an active agent as described herein, and (v) forming an adhesive matrix from the solution of (iv). In one embodiment, the adhesive matrix formed from the solution comprises between about 35-80 wt % acrylate, between about 10-25 wt % polyvinylpyrrolidone-vinyl acetate copolymer, and between about 5-50 wt % active agent.

[0059] In forming the adhesive matrix, the formulation is cast onto a suitable film, such as a release liner film, dried to eliminate all volatile compounds at temperature or temperatures in the range between 50° C. and 100° C.

[0060] To form a transdermal device, the adhesive matrix is then laminated to a suitable film, generally to a backing film. Backing films are known in the industry and any that provide support for the adhesive layer and are impermeable or substantially impermeable to the active agent can be used. It can be flexible or nonflexible. Suitable materials are well known to the art and include, without limitation, polyethylene terephthalate, various nylons. polypropylene, metalized polyester films, polyvinylidene chloride, and aluminum foil. In other embodiments, the transdermal device may comprise a fabric or tie layer in the adhesive matrix, and any stretch or nonstretch material may be used. For example, fabric and non-woven fabric material including polyesters such as polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylidene chloride and polyethylene, may be used.

III. EXAMPLES

[0061] The following examples are illustrative in nature and are in no way intended to be limiting.

Example 1

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0062] A formulation for a hydrophilic domain was prepared by dissolving a polyvinylpyrrolidone vinyl acetate copolymer (Plasdone S-630) in a 9:1 mixture of toluene and isopropyl alcohol to yield a solution with 35 wt % polyvinylpyrrolidone vinyl acetate copolymer. A formulation for a hydrophobic domain was prepared by dissolving a blend of a high molecular weight polyisobutylene homopolymer (Oppanol B-100; 1,000,000 Dalton molecular weight) and a medium moleculear weight polyisobutylene homopolymer (Oppanol B-12; 50,000 Dalton molecular weight) with polybutene (Indopol H-1900) in a ratio of 1:5:4 in toluene, where the polyisobutylene blend was at a concentration of 60 wt %.

[0063] An acrylate adhesive solution was prepared by dissolving an acrylic acid/vinyl acetate copolymer (DuroTak 87-2015) in ethyl acetate at a concentration of 51.5 wt %. An adhesive formulation was prepared as follows. 2.017 g of the hydrophilic domain formulation was mixed with 0.784 g of the hydrophobic domain formulation until a homogeneous solution was formed. An additional 2.49 g of toluene and 0.72 g of isopropyl alcohol were added and the solution was well mixed. Next, 5.483 g of the acrylate adhesive solution was added, mixing until homogeneous. Then, 1.00 g of donepezil base was added and dissolved with vortexing.

[0064] An adhesive matrix was prepared by coating the adhesive formulation onto a silicon-coated release liner at a wet thickness of 20 mils and then drying at 70° C. for 20 minutes. The adhesive matrix had a final composition as follows:

TABLE-US-00003 Adhesive Matrix No. 1 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 56.47 wt % 65.8 wt % polyisobutylene homopolymer  9.41 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone vinyl acetate 14.12 wt % 14.1 wt % copolymer Active Agent—20 wt % donepezil base   20 wt %

[0065] A backing layer (Scotchpak 9732) was then laminated onto the matrix and transdermal devices of 10 cm2 were die cut from the laminate.

Example 2

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0066] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00004 Adhesive Matrix No. 2 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 57.4 wt % 61.8 wt % polyisobutylene homopolymer 4.40 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone vinyl acetate 13.2 wt % 13.2 wt % copolymer Active Agent—20 wt % donepezil base 20.0 wt % Penetration Enhancer Lauryl lactate  5.0 wt %

Example 3

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0067] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00005 Adhesive Matrix No. 3 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 53.0 wt % 62.0 wt % polyisobutylene homopolymer  9.0 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone vinyl acetate 13.0 wt % 13.0 wt % copolymer Active Agent—20.0 wt % donepezil base 20.0 wt % Penetration Enhancer Lauryl lactate  5.0 wt %

Example 4

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0068] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00006 Adhesive Matrix No. 4 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 49.0 wt % 62.0 wt % polyisobutylene homopolymer 13.0 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone vinyl acetate  5.0 wt % 5.0 wt % copolymer Active Agent—20 wt % donepezil base 20.0 wt % Penetration Enhancer Lauryl lactate  5.0 wt %

Example 5

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0069] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00007 Adhesive Matrix No. 5 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 44.0 wt % 57.0 wt % polyisobutylene homopolymer 13.0 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone vinyl acetate 13.0 wt % 13.0 wt % copolymer Active Agent—wt % donepezil base 20.0 wt % Penetration Enhancer Lauryl lactate  5.0 wt %

Example 6

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0070] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00008 Adhesive Matrix No. 6 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 45.0 wt % 45.0 wt % polyisobutylene homopolymer  0.0 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone vinyl acetate 15.0 wt % 15.0 wt % copolymer Active Agent— donepezil base 40.0 wt % 40.0 wt %

Example 7

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0071] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00009 Adhesive Matrix No. 7 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 42.0 wt % 42.0 wt % polyisobutylene homopolymer  0.0 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone vinyl acetate 14.0 wt % 14.0 wt % copolymer Active Agent—40.0 wt % donepezil base 40.0 wt % Penetration Enhancer lauryl lactate  4.0 wt %

Example 8

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0072] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00010 Adhesive Matrix No. 8 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 51.61 wt % 51.6 wt% polyisobutylene homopolymer  0.0 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone  8.06 wt % 8.1 wt % (Kollidone 90K) Active Agent— donepezil base 40.32 wt % 40.32 wt %

Example 9

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0073] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00011 Adhesive Matrix No. 9 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer  64.8 wt % 64.8 wt % polyisobutylene homopolymer  0.0 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone 10.14 wt % 10.1 wt % (Kollidone 90K) Active Agent—25 wt % donepezil base  25.0 wt %

Example 10

Adhesive Formulation, Adhesive Matrix and Transdermal Devices Comprising Donepezil

[0074] An adhesive formulation was prepared as described in Example 1 to yield an adhesive matrix with the following composition:

TABLE-US-00012 Adhesive Matrix No. 10 Hydrophobic Domain— acrylic acid/vinyl acetate copolymer 73.51 wt % 73.5 wt % polyisobutylene homopolymer  0.0 wt % blend/polybutene Hydrophilic Domain— polyvinylpyrrolidone 11.49 wt % 11.5 wt % (Kollidone 90K) Active Agent—15 wt % donepezil base  15.0 wt %

[0075] While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope.