Multi-Day Patch for the Transdermal Administration of Rotigotine

Abstract

The present invention relates to a transdermal therapeutic system formed from (a) a backing layer, (b) a solvent-based self-adhesive matrix layer containing rotigotine as active ingredient, and (c) a release liner, in which the self-adhesive matrix layer has a coating weight of about 75-400 g/m 2 and comprises a reservoir layer containing about 9-25 wt.-% rotigotine based on the weight of the reservoir layer; a kit containing two transdermal therapeutic systems of the present invention; and methods for the preparation of the transdermal therapeutic system of the present invention. The present invention further relates to methods of treatment based upon the application of the inventive transdermal therapeutic systems once or twice weekly via systems adapted to allow for the transdermal administration of therapeutically effective amounts of rotigotine for at least 3 days.

That which is claimed: 
     
         1 . A method for dissolving rotigotine free base of crystalline form II comprising dissolving the rotigotine free base in a solvent system consisting of an aprotic polar solvent and a protic polar solvent, wherein the aprotic polar solvent and the protic polar solvent are present in a ratio of 2:1 to 9:1 (w/w). 
     
     
         2 . The method as claimed in  claim 1 , wherein the aprotic polar solvent and the protic polar solvent are present in a ratio of 2:1 to 6:1 (w/w). 
     
     
         3 . The method as claimed in  claim 1 , wherein the aprotic polar solvent is a carboxylic acid ester and the protic polar solvent is an aliphatic alcohol. 
     
     
         4 . The method as claimed in  claim 1 , wherein the aprotic polar solvent is ethyl acetate and the protic polar solvent is ethanol. 
     
     
         5 . The method as claimed in  claim 1 , wherein the method comprises dissolving the rotigotine free base in its entirety, with the dissolving step performed at 40° C. 
     
     
         6 . The method as claimed in  claim 1 , wherein the method comprises dissolving a first portion of the rotigotine free base while stirring and subsequently dissolving a second portion of the rotigotine free base while stirring with both the dissolving steps performed at room temperature. 
     
     
         7 . The method as claimed in  claim 1 , wherein the solvent system comprises one or more adhesive(s) in addition to the aprotic polar solvent and the protic polar solvent. 
     
     
         8 . The method as claimed in  claim 1 , wherein the method comprises adding a stabilizer to the solvent system. 
     
     
         9 . The method as claimed in  claim 1 , wherein the method comprises adding polyvinylpyrrolidone to the solvent system. 
     
     
         10 . A method of making a transdermal therapeutic system, comprising preparing a solvent-based self-adhesive matrix layer or layers containing rotigotine as active ingredient by
 (i) preparing a solution of adhesive(s) in a solvent system comprising an aprotic polar solvent and a protic polar solvent optionally containing further excipients;   (ii) forming a mixture by adding either all or a first portion of the rotigotine free base of crystalline form II to the solution of step (i);   (iii) adding a stabilizer to the mixture of step (ii);   (iv) optionally adding a second portion of the rotigotine free base of crystalline form II to the mixture of step (iii);   (v) coating the mixture of step (iii) or step (iv) onto a release liner;   (vi) drying the coated mixture to thereby forming the solvent-based self-adhesive matrix layer(s); and   (vii) laminating the dried self-adhesive matrix layer(s) to a backing foil.   
     
     
         11 . The method as claimed in  claim 10 , wherein the aprotic polar solvent is a carboxylic acid ester and the protic polar solvent is an aliphatic alcohol. 
     
     
         12 . The method as claimed in  claim 10 , wherein the aprotic polar solvent is ethyl acetate and the protic polar solvent is ethanol. 
     
     
         13 . The method as claimed in  claim 10 , wherein the aprotic polar solvent and protic polar solvent are present in a ratio of 2:1 to 9:1 (w/w). 
     
     
         14 . The method as claimed in  claim 10 , wherein the stabilizer is polyvinylpyrrolidone and the adhesives(s) is/are one or more silicone adhesive(s). 
     
     
         15 . The method as claimed in  claim 10 , wherein the method comprises adding the entirety of the rotigotine free base, with the adding step (ii) performed while heating. 
     
     
         16 . The method as claimed in  claim 10 , wherein the method comprises adding the entirety of the rotigotine free base, with the adding step (ii) performed while heating at 40° C. 
     
     
         17 . The method as claimed in  claim 10 , wherein the method comprises adding a first portion of the rotigotine free base while stirring in adding step (ii) and subsequently adding a second portion of the rotigotine free base while stirring in adding step (iv), with both steps (ii) and (iv) performed at room temperature. 
     
     
         18 . The method as claimed in  claim 10 , wherein the method has a total processing time to form the transdermal therapeutic system ranging from approximately 8.5 to 9 hours. 
     
     
         19 . A method of preparing a kit comprising two rotigotine-containing transdermal therapeutic systems, wherein the method comprises forming two transdermal therapeutic systems as claimed in  claim 10 , the two transdermal therapeutic systems having the same or a different rotigotine content. 
     
     
         20 . A method of preparing a kit as claimed in  claim 19 , wherein the two transdermal therapeutic systems have the same rotigotine content and each of them is adapted to allow for the transdermal administration of therapeutically effective amounts of rotigotine for at least 3 days. 
     
     
         21 . A method of preparing a kit as claimed in  claim 19 , wherein the two transdermal therapeutic systems have a different rotigotine content and one of them is adapted to allow for the transdermal administration of therapeutically effective amounts of rotigotine for at least 3 days and the other one is adapted to allow for the transdermal administration of therapeutically effective amounts of rotigotine for at least 4 days.