Transdermal Delivery System Containing Rotigotine

Abstract

The present invention relates to transdermal therapeutic systems for the transdermal administration of rotigotine containing a therapeutically effective amount of rotigotine base in a self-adhesive layer structure that includes a backing layer and a rotigotine-containing biphasic layer. The biphasic layer has an outer phase formed from a polymer or a polymer mixture along with an inner phase that includes rotigotine base and a polymer mixture including polyvinylpyrrolidone having a K-Value of at least 80 and at least one further hydrophilic polymer selected from the polymer groups: copolymers of vinyl caprolactam, vinylacetate and ethylene glycol, copolymers of vinylpyrrolidone and vinylacetate, copolymers of ethylene and vinylacetate, polyethylene glycols, polypropylene glycols, acrylic polymers, and modified celluloses. The inner phase forms dispersed deposits in the outer phase. The inventive transdermal therapeutic systems optionally include a skin contact layer.

That which is claimed: 
     
         1 . A transdermal therapeutic system for the transdermal administration of rotigotine containing an therapeutically effective amount of rotigotine base in a self-adhesive layer structure, 
       comprising
 A) a backing layer, and 
 B) a rotigotine-containing biphasic layer, the biphasic layer having
 a) an outer phase having a composition comprising 75% to 100% of a polymer or a polymer mixture, and 
 b) an inner phase having a composition comprising rotigotine base, 
 wherein the inner phase forms dispersed deposits in the outer phase, and wherein the inner phase comprises
 i. rotigotine base, and 
 ii. a polymer mixture comprising at least two hydrophilic polymers, including polyvinylpyrrolidone having a K-Value of at least 80 and at least one further hydrophilic polymer selected from the polymer groups:
 copolymers of vinyl caprolactam, vinylacetate and ethylene glycol, 
 copolymers of vinylpyrrolidone and vinylacetate, 
 copolymers of ethylene and vinylacetate, 
 polyethylene glycols, 
 polypropylene glycols, 
 acrylic polymers, and 
 modified celluloses, 
 wherein the polymer mixture in the inner phase is present in an amount sufficient so that said rotigotine base forms a solid solution with the polymer mixture in the inner phase, 
 
 
 
 
       and
 C) optionally an additional skin contact layer. 
 
     
     
         2 . The transdermal therapeutic system in accordance with  claim 1 , wherein said polymer or polymer mixture in the outer phase is a/are hydrophobic polymer(s). 
     
     
         3 . The transdermal therapeutic system in accordance with  claim 1 , wherein said polymer or polymer mixture in the outer phase is a/are pressure-sensitive adhesive polymer(s) selected from the group of polysiloxanes, polyisobutylenes, polyacrylates, copolymers of styrene and butadiene, copolymers of styrene and isoprene. 
     
     
         4 . The transdermal therapeutic system in accordance with  claim 1 , wherein said polymer or polymer mixture in the outer phase is a/are pressure-sensitive adhesive polysiloxane(s). 
     
     
         5 . The transdermal therapeutic system in accordance with  claim 1 , wherein the polyvinylpyrrolidone having a K-Value of at least 80 has a K-Value of from 80 to 200. 
     
     
         6 . The transdermal therapeutic system in accordance with  claim 1 , wherein the ratio of rotigotine base to polyvinylpyrrolidone having a K-Value of at least 80 is 1:0.1 to 1:0.5. 
     
     
         7 . The transdermal therapeutic system in accordance with  claim 1 , wherein the polymer mixture in the inner phase comprises two hydrophilic polymers in a ratio of 1:1 to about 1:10. 
     
     
         8 . The transdermal therapeutic system in accordance with  claim 7 , wherein the polymer mixture in the inner phase comprises two hydrophilic polymers in a ratio of 1:1 to about 1:4. 
     
     
         9 . The transdermal therapeutic system in accordance with  claim 8 , wherein the polymer mixture in the inner phase comprises two hydrophilic polymers in a ratio of 1:1 to about 1:2. 
     
     
         10 . The transdermal therapeutic system in accordance with  claim 7 , wherein the polyvinylpyrrolidone having a K-Value of at least 80 is present in a same or smaller amount than the further hydrophilic polymer. 
     
     
         11 . The transdermal therapeutic system in accordance with  claim 1 , wherein the transdermal therapeutic system contains 1.5 mg/cm 2  to 5 mg/cm 2  of rotigotine base in said self-adhesive layer structure. 
     
     
         12 . The transdermal therapeutic system in accordance with  claim 1 , wherein the biphasic layer has an area weight of about 30 g/m 2  to about 200 g/m 2 . 
     
     
         13 . The transdermal therapeutic system in accordance with  claim 1 , wherein rotigotine base is present in an amount of 10% to 26% of said biphasic layer. 
     
     
         14 . The transdermal therapeutic system in accordance with  claim 1 , providing a permeation rate of rotigotine base as measured through an EVA membrane in a 4 hours time interval from hour 8 to hour 12 that is therapeutically effective. 
     
     
         15 . The transdermal therapeutic system in accordance with  claim 1 , providing a permeation rate of rotigotine base as measured through an EVA membrane in a 4 hours time interval from hour 8 to hour 12 of at least 11 μg/cm 2 /hr to about 15 μg/cm 2 /hr. 
     
     
         16 . The transdermal therapeutic system in accordance with  claim 15 , providing a permeation rate of rotigotine base as measured through an EVA membrane in 4 hour or 6 hour time intervals from 24 hours to 168 hours that is constant within 20% points from 24 hours to 168 hours. 
     
     
         17 . The transdermal therapeutic system in accordance with  claim 1 , wherein the skin contact layer is active agent-free. 
     
     
         18 . The transdermal therapeutic system in accordance with  claim 1 , wherein the skin contact layer comprises rotigotine base. 
     
     
         19 . The transdermal therapeutic system in accordance with  claim 18 , wherein the skin contact layer comprising rotigotine base has an area weight of about 10 g/m 2  to about 150 g/m 2 . 
     
     
         20 . The transdermal therapeutic system in accordance with  claim 18 , wherein the skin contact layer differs from the rotigotine-containing biphasic layer but is also in the form of the rotigotine-containing biphasic layer,
 the biphasic layer having
 a) an outer phase having a composition comprising 75% to 100% of a polymer or a polymer mixture, and 
 b) an inner phase having a composition comprising rotigotine base, 
 wherein the inner phase forms dispersed deposits in the outer phase, and wherein the inner phase comprises
 i. rotigotine base, and 
 ii. at least one hydrophilic polymer,
 wherein the at least one hydrophilic polymer in the inner phase is present in an amount sufficient so that said rotigotine base forms a solid solution with the at least one hydrophilic polymer. 
 
 
   
     
     
         21 . The transdermal therapeutic system in accordance with  claim 20 , wherein the skin-contact-layer inner phase comprises polyvinylpyrrolidone having a K-Value of at least 80. 
     
     
         22 . The transdermal therapeutic system in accordance with  claim 20 , wherein rotigotine base is present in the skin contact layer in an amount of 1% to 15% of said skin contact layer. 
     
     
         23 . The transdermal therapeutic system in accordance with  claim 20 , wherein rotigotine base is present in the skin contact layer in an amount of less than 9% of said skin contact layer. 
     
     
         24 . The transdermal therapeutic system in accordance with  claim 20 , wherein rotigotine base is present in the skin contact layer in a smaller amount than in said biphasic layer. 
     
     
         25 . The transdermal therapeutic system in accordance with  claim 20 , wherein therapeutically effective amounts of rotigotine base are provided for 1 to 7 days by said transdermal therapeutic system during an administration period to a patient's skin of 1 to 7 days. 
     
     
         26 . The transdermal therapeutic system in accordance with  claim 20 ,
 wherein the biphasic layer is a dried biphasic layer.   
     
     
         27 . A method of treating patients suffering from Parkinson's disease, Parkinson's plus syndrome, depression, anxiety, attention-deficit/hyperactivity syndrome (ADHS), fibromyalgia, restless-legs syndrome, dopaminergic neuron los, cognitive disorders, dementia or lewy body disease comprising applying a transdermal therapeutic system in accordance with  claim 1  for about 168 hours on the skin of a human patient. 
     
     
         28 . A method of manufacture of a transdermal therapeutic system for the transdermal administration of rotigotine in accordance with  claim 1 , comprising the steps of:
 (1) preparing a rotigotine-containing biphasic coating mixture having an inner phase dispersed in an outer phase,   (2) coating said rotigotine-containing biphasic coating mixture on a film in an amount to provide a layer with a coating weight,   (3) drying said coated layer to provide a dried layer with a coating weight to provide a rotigotine-containing dried biphasic layer with the desired area weight,   (4) optionally laminating two or more of said dried layers to provide a rotigotine-containing dried biphasic layer with the desired area weight,   (5) laminating said rotigotine-containing dried biphasic layer to a backing layer,   (6) optionally laminating said rotigotine-containing dried biphasic layer to an additional skin contact layer.   
     
     
         29 . A transdermal therapeutic system for the transdermal administration of rotigotine containing an therapeutically effective amount of rotigotine base in a self-adhesive layer structure, comprising
 A) a backing layer, and   B) a rotigotine-containing dried biphasic layer, the dried biphasic layer having
 a) an outer phase having a pressure-sensitive adhesive composition comprising 75% to 100% of pressure sensitive adhesive polysiloxanes, and 
 b) an inner phase having a composition comprising rotigotine base, 
 wherein the inner phase forms dispersed deposits in the outer phase, and wherein the inner phase comprises
 i. 16% to 26% of rotigotine base of said dried biphasic layer, and 
 iii. a polymer mixture comprising polyvinylpyrrolidone having a K-Value of at least 80 and at least one further hydrophilic polymer selected from the polymer groups:
 copolymers of vinyl caprolactam, vinylacetate and ethylene glycol, 
 copolymers of vinylpyrrolidone and vinylacetate, 
 copolymers of ethylene and vinylacetate, 
 polyethylene glycols, 
 polypropylene glycols, 
 acrylic polymers and 
 modified celluloses, 
 
 
 wherein the polymer mixture in the inner phase is present in an amount sufficient so that said rotigotine base forms a solid solution with the polymer mixture in the inner phase, 
 wherein the dried biphasic layer has an area weight of about 100 g/m 2  to about 200 g/m 2 , 
   
       and
 C) optionally an additional skin contact layer. 
 
     
     
         30 . A transdermal therapeutic system for the transdermal administration of rotigotine containing 2.0 mg/cm 2  to 3.0 mg/cm 2  of rotigotine base in a self-adhesive layer structure, comprising
 A) a backing layer, and   B) a rotigotine-containing biphasic layer, the biphasic layer having
 a) an outer phase having a pressure-sensitive adhesive composition comprising 75% to 100% of pressure sensitive adhesive polysiloxanes, and 
 b) an inner phase having a composition comprising rotigotine base, 
 wherein the inner phase forms dispersed deposits in the outer phase, and wherein the inner phase comprises
 i. rotigotine base, and 
 ii. a polymer mixture comprising polyvinylpyrrolidone having a K-Value of at least 80 and at least one further hydrophilic polymer selected from the polymer groups:
 copolymers of vinyl caprolactam, vinylacetate and ethylene glycol, 
 copolymers of vinylpyrrolidone and vinylacetate, 
 copolymers of ethylene and vinylacetate, 
 polyethylene glycols, 
 polypropylene glycols, 
 acrylic polymers and 
 modified celluloses, 
 
 wherein the polymer mixture in the inner phase is present in an amount sufficient so that said rotigotine base forms a solid solution with the polymer mixture in the inner phase, 
 wherein the biphasic layer has an area weight of about 100 g/m 2  to about 200 g/m 2 , 
 
   
       and
 C) an additional skin contact layer. 
 
     
     
         31 . The transdermal therapeutic system in accordance with  claim 30 , wherein therapeutically effective amounts of rotigotine base are provided for 7 days by said transdermal therapeutic system during an administration period to the skin of the patient of 7 days.