ADHESIVE MATRIX WITH HYDROPHILIC AND HYDROPHOBIC DOMAINS AND A THERAPEUTIC AGENT
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.
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.