Stable transdermal amphetamine compositions and methods of manufacture

Abstract

Described are transdermal drug delivery compositions comprising amphetamine, methods of making transdermal drug delivery compositions comprising amphetamine, and therapeutic methods of using them. In specific embodiments, the compositions are free of components with moieties that are reactive with amphetamine. In specific embodiments, the compositions are manufactured using solvents free of components with moieties that are reactive with amphetamine. Therapeutic methods using the compositions also are described.

What is claimed is: 
     
         1 . A composition for the transdermal delivery of amphetamine in the form of a flexible finite system for topical application, comprising a polymer matrix comprising amphetamine or a pharmaceutically acceptable salt or prodrug thereof, wherein the polymer matrix comprises a polymer that is free of vinyl acetate moieties. 
     
     
         2 . The composition of  claim 1 , wherein the polymer is selected from the group consisting of acrylic polymers that are free of vinyl acetate moieties, rubber-based polymers, and mixtures thereof. 
     
     
         3 . The composition of  claim 2 , wherein the polymer comprises an acrylic polymer made from one or more monomers selected from the group consisting of butyl acrylate, methyl acrylate, methyl methacrylate, acrylic acid, ethyl hexyl acrylate, and hydroxy ethyl acrylate. 
     
     
         4 . The composition of  claim 2 , wherein the polymer comprises an acrylic polymer made from one or more monomers selected from the group consisting of ethyl hexyl acrylate, methyl acrylate, methyl methacrylate, butyl acrylate, and octyl acrylamide. 
     
     
         5 . The composition of  claim 2 , wherein the polymer is a rubber-based polymer selected from the group consisting of polyisobutylene polymers and styrene-isoprene-styrene block copolymers. 
     
     
         6 . The composition of  claim 1 , wherein the polymer matrix is free of components that include a reactive moiety selected from the group consisting of acetyl moieties, vinyl acetate moieties, acyl halide moieties, carbonate ester moieties, carboxyl moieties, and ester moieties. 
     
     
         7 . The composition of  claim 1 , wherein the polymer matrix further comprises an antioxidant. 
     
     
         8 . The composition of  claim 7 , wherein the antioxidant is free of reactive moieties selected from the group consisting of acetyl moieties, vinyl acetate moieties, acyl halide moieties, carbonate ester moieties, carboxyl moieties, and ester moieties 
     
     
         9 . The composition of  claim 7 , wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and mixtures thereof. 
     
     
         10 . The composition of  claim 1 , wherein the polymer matrix further comprises a component selected from the group consisting of silicone dioxide, hydrogenated hydrocarbon resins, and styrene-isobutylene-styrene block coplymers. 
     
     
         11 . The composition of  claim 1 , wherein the composition is stable against the formation of N-acetyl amphetamine. 
     
     
         12 . The composition of  claim 1 , wherein the composition is stable against the formation of d-amphetamine-related compound B. 
     
     
         13 . A transdermal drug delivery system comprising a composition as claimed in  claim 1  and a backing layer. 
     
     
         14 . The transdermal drug delivery system according to  claim 13 , further comprising a release liner. 
     
     
         15 . A method of manufacturing a composition as claimed in  claim 1 , comprising forming a blend comprising the polymer and amphetamine or pharmaceutically acceptable salt or prodrug thereof in a solvent that is free of reactive moieties selected from the group consisting of acetyl moieties, vinyl acetate moieties, acyl halide moieties, carbonate ester moieties, carboxyl moieties, and ester moieties. 
     
     
         16 . The method of  claim 15 , wherein the solvent is selected from the group consisting of cyclohexane, hexane, pentane, petroleum ether, diethyl ether, tert-butyl methyl ether, tert-butyl alcohol, isopropanol, acetonitrile, ethanol, methanol, isobutyl alcohol, 1-propanol, 2-butanol, isoamyl alcohol, isoamyl alcohol, 1-octanol, p-xylene, m-xylene, toluene, dimethoxyethane, benzene, 1-chlorobutane, tetrahydrofuran, o-xylene, 2-ethoxyethyl ether, n,n-dimethylacetamide, diethylene glycol dimethyl ether, n,n-dimethylformamide, 2-methoxyethanol, pyridine, and mixtures of two or more thereof. 
     
     
         17 . A method of manufacturing a composition for the transdermal delivery of amphetamine in the form of a flexible finite system for topical application, comprising forming a blend comprising a polymer and amphetamine or pharmaceutically acceptable salt or prodrug thereof in a solvent that is free of reactive moieties selected from the group consisting of acetyl moieties, vinyl acetate moieties, acyl halide moieties, carbonate ester moieties, carboxyl moieties, and ester moieties. 
     
     
         18 . The method of  claim 17 , wherein the solvent is selected from the group consisting of cyclohexane, hexane, pentane, petroleum ether, diethyl ether, tert-butyl methyl ether, tert-butyl alcohol, isopropanol, acetonitrile, ethanol, methanol, isobutyl alcohol, 1-propanol, 2-butanol, isoamyl alcohol, isoamyl alcohol, 1-octanol, p-xylene, m-xylene, toluene, dimethoxyethane, benzene, 1-chlorobutane, tetrahydrofuran, o-xylene, 2-ethoxyethyl ether, n,n-dimethylacetamide, diethylene glycol dimethyl ether, n,n-dimethylformamide, 2-methoxyethanol, pyridine, and mixtures of two or more thereof. 
     
     
         19 . A composition for the transdermal delivery of amphetamine made by a method according to  claim 17 . 
     
     
         20 . A method of transdermally administering amphetamine, comprising topically applying a composition according to  claim 1  to a subject in need thereof.