Transdermal Therapeutic System for Administering an Active Substance

Abstract

The present invention relates to a transdermal therapeutic system for administering an active substance through the skin, said system being suitable for an application period of at least three days, comprising the layers arranged in the following order with respect to each other: a) a cover layer, b) an active substance layer comprising a polymer matrix containing the active substance, c) an adhesive layer comprising a contact adhesive, which consists of a mixture of one or more polyisobutylenes and one or more polybutenes, and d) a pull-off layer.

1 . A transdermal therapeutic system for administering an active substance through the skin, comprising the layers arranged in the following order with respect to each other:
 a) a cover layer,   b) an active substance layer comprising a polymer matrix containing the active substance,   c) an adhesive layer comprising (1) a polyisobutylene or a mixture of several polyisobutylenes and (2) a polybutene or a mixture of several polybutenes; and   d) a pull-off layer,   
       characterized in that the active substance layer does not contain any free hydroxyl groups and free carboxyl groups and the transdermal therapeutic system is configured to provide a substantially linear permeation profile of the active substance over a period of at least 48 hours. 
     
     
         2 . The transdermal therapeutic system according to  claim 1 , characterized in that the adhesive layer comprises at least two polyisobutylenes with different average molecular weights and at least two polybutenes with different average molecular weights. 
     
     
         3 . The transdermal therapeutic system according to  claim 2 , characterized in that the first polyisobutylene polymer has an average molecular weight M v  of about 40,000 g/mol and the second polyisobutylene polymer has an average molecular weight M v  of about 400,000 g/mol. 
     
     
         4 . The transdermal therapeutic system according to  claim 3 , characterized in that the first polybutene polymer has an average molecular weight M n  in the range of 700-2,800 g/mol and the second polybutene polymer has an average molecular weight M n  in the range of 2,200-6,500 g/mol. 
     
     
         5 . The transdermal therapeutic system according to  claim 1 , wherein the active substance layer contains 30-50% by weight of the active substance and 50-70% by weight of the polymer matrix, based on the total weight of the active substance layer. 
     
     
         6 . The transdermal therapeutic system according to  claim 1 , characterized in that the polymer matrix of the active substance layer comprises at least one polymer and/or copolymer without free hydroxyl groups and without free carboxyl groups selected from the group consisting of polyacrylates, acrylate-vinyl acetate copolymers, polyisobutylene, styrene-butadiene copolymers, and mixtures thereof. 
     
     
         7 . The transdermal therapeutic system according to  claim 1 , characterized in that it does not contain tocopherols. 
     
     
         8 . The transdermal therapeutic system according to  claim 1 , characterized in that it does not contain any antioxidant selected from the group consisting of tocopherols, butylated hydroxyanisole, and butylated hydroxytoluene. 
     
     
         9 . The transdermal therapeutic system according to  claim 1 , characterized in that it does not contain any antioxidant. 
     
     
         10 . The transdermal therapeutic system according to  claim 1 , characterized in that it is suitable for the application over at least 2 days. 
     
     
         11 . The transdermal therapeutic system according to  claim 1 , characterized in that it shows a substantially linear skin permeation of the active substance over a period of at least 48 hours, as measured by an in vitro skin permeation test. 
     
     
         12 . A method for the preparation of a transdermal system according to  claim 1  comprising
 i) the preparation of a component containing the active substance layer that contains the cover layer and the active substance layer, which is on the side of the cover layer that is supposed to be the side facing the skin; 
 ii) the preparation of a component containing the adhesive layer that contains the pull-off layer and the adhesive layer on the pull-off layer; 
 iii) laminating onto each other the components of i) and ii) such that the cover and pull-off layer in the cross-section of the finished TTS represent the opposing outermost layers. 
 
     
     
         13 . The method according to  claim 12  comprising
 i) applying and optionally subsequent drying of a film of a composition forming the active substance layer, optionally in the form of a solution or dispersion in a suitable medium, onto the side of the cover layer supposed to be the side facing the skin; 
 ii) applying and optionally subsequent drying of a film of a composition forming the adhesive layer, optionally in the form of a solution or dispersion in a suitable medium, onto the pull-off layer; and 
 iii) laminating onto each other the components of i) and ii) such that the cover and pull-off layer in the cross-section of the finished TTS represent the opposing outermost layers; 
 
     
     
         14 . Method of treating Alzheimer's disease and Parkinson's dementia by administrating the transdermal therapeutic system according to  claim 1 . 
     
     
         15 . The method for treating Alzheimer's disease and Parkinson's dementia according to  claim 14 , characterized in that the transdermal therapeutic system administered over a period of at least 48 hours. 
     
     
         16 . A method for the stabilization of rivastigmine in a TTS, characterized in that rivastigmine, or a salt or solvate thereof, is (i) embedded in a polymer matrix having no free hydroxyl groups and no free carboxyl groups, or (ii) introduced into an active substance layer containing no free hydroxyl groups and no free carboxyl groups. 
     
     
         17 . A method for the reduction of the degradation of rivastigmine in a TTS, characterized in that rivastigmine, or a salt or solvate thereof, is (i) embedded in a polymer matrix having no free hydroxyl groups and no free carboxyl groups, or (ii) introduced into an active substance layer containing no free hydroxyl groups and no free carboxyl groups. 
     
     
         18 . The transdermal therapeutic system according to  claim 2 , characterized in that the first polybutene polymer has an average molecular weight M n  in the range of 700-2,800 g/mol and the second polybutene polymer has an average molecular weight M n  in the range of 2,200-6,500 g/mol.