Transdermal therapeutic system containing asenapine

Abstract

The present invention relates to transdermal therapeutic systems (TTS) for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, such asenapine TTS for use in a method of treatment, processes of manufacture of such TTS as well as asenapine and transdermal therapeutic systems containing asenapine for use in a method of treatment and to a method of treating a human patient by transdermal administration of asenapine.

1 . (canceled) 
     
     
         2 . Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine,
 wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 48 hours of administration.   
     
     
         3 . Transdermal therapeutic system according to  claim 2 ,
 wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 72 hours, or over 84 hours of administration, and/or wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 48 hours of administration.   
     
     
         4 . Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine,
 wherein the transdermal therapeutic system provides by transdermal delivery one or more pharmacokinetic parameter(s) selected from the group consisting of   an asenapine AUC 0-48  from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h,   an asenapine AUC 0-72  from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h,   an asenapine AUC 0-84  from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h,   an asenapine C max  to C 48  ratio of less than 2.0,   an asenapine C max , to C 72  ratio of less than 3.0,   an asenapine C max  to C 84  ratio of less than 3.5, and   an asenapine C max  value of from 0.5 to 10 ng/ml.   
     
     
         5 . Transdermal therapeutic system according to  claim 2 , comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising:
 a) a backing layer;   b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising:
 i) asenapine; and 
 ii) a polymer. 
   
     
     
         6 . Transdermal therapeutic system according to  claim 4 , comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising:
 a) a backing layer;   b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising:
 i) asenapine; and 
   ii) a polymer.   
     
     
         7 . Transdermal therapeutic system according to  claim 2 , wherein the transdermal therapeutic system contains at least 0.70 mg/cm 2 , at least 0.80 mg/cm 2 , at least 0.82 mg/cm 2  or at least 0.83 mg/cm 2  asenapine, and/or
 wherein the transdermal therapeutic system contains from 0.70 mg/cm 2  to 4.0 mg/cm 2 , from 0.80 mg/cm 2  to 3.0 mg/cm 2 , from 0.82 mg/cm 2  to 2.0 mg/cm 2  or from 0.83 mg/cm 2  to 1.7 mg/cm 2  asenapine.   
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . Transdermal therapeutic system according to  claim 5 , wherein the asenapine in the asenapine-containing matrix layer composition is included in the form of the free base, or
 wherein the asenapine-containing matrix layer composition is obtainable by incorporating asenapine free base, and/or   wherein at least 90 mol %, preferably at least 95 mol %, more preferably at least 98 mol % and most preferably at least 99 mol % of the asenapine in the asenapine-containing matrix layer is present in the form of the free base, and/or   wherein the amount of asenapine in the asenapine-containing matrix layer composition ranges from 2 to 20%, from 3 to 15% or from 4 to 12% of the asenapine-containing matrix layer composition.   
     
     
         11 . (canceled) 
     
     
         12 . Transdermal therapeutic system according to  claim 5 , wherein the polymer is selected from acrylic polymers, or from a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate, a copolymer based on methyl acrylate, 2-ethylhexyl acrylate and t-octyl acrylamide, or a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate. 
     
     
         13 . Transdermal therapeutic system according to  claim 5 , wherein the amount of polymer ranges from 60 to 97%, from 70 to 96% from 75 to 88% or from 91 to 96% of the asenapine-containing matrix layer composition, or wherein the total polymer content in the asenapine-containing matrix layer composition ranges from 75 to 97%, from 80 to 96% or from 85 to 95% of the asenapine-containing matrix layer composition. 
     
     
         14 . Transdermal therapeutic system according to  claim 5 , wherein the asenapine-containing matrix layer composition comprises further excipients or additives selected from the group consisting of cross-linking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, pH regulators, and preservatives, and
 wherein the tackifier is selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone,   wherein the stabilizer is selected from sodium metabisulfite, ascorbic acid and ester derivatives thereof, butylated hydroxytoluene, tocopherol and ester derivatives thereof such as tocopheryl acetate and tocopheryl linoleate, as well as a combination of tocopherol and ascorbyl palmitate, preferably from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof, and is more preferably selected from ascorbyl esters of fatty acids and tocopherol, and most preferably is ascorbyl palmitate or α-tocopherol or a combination thereof, or   wherein the permeation enhancer is selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea and a mixture of propylene glycol monoesters and diesters of fatty acids.   
     
     
         15 . (canceled) 
     
     
         16 . Transdermal therapeutic system according to  claim 2 , providing a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of
 0 μg/(cm 2  h) to 10 μg/(cm 2  h) in the first 8 hours,   2 μg/(cm 2  h) to 20 μg/(cm 2  h) from hour 8 to hour 24,   3 μg/(cm 2  h) to 20 μg/(cm 2  h) from hour 24 to hour 32,   3 μg/(cm 2  h) to 20 μg/(cm 2  h) from hour 32 to hour 48,   2 μg/(cm 2  h) to 15 μg/(cm 2  h) from hour 48 to hour 72, or   
       providing a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0.05 mg/cm 2  to 1.0 mg/cm 2 , or of 0.1 mg/cm 2  to 0.7 mg/cm 2  over a time period of 48 hours, or 
       providing a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0.1 mg/cm 2  to 2.0 mg/cm 2 , or of 0.2 mg/cm 2  to 1.0 mg/cm 2  over a time period of 72 hours. 
     
     
         17 . Transdermal therapeutic system according to  claim 2  for use in a method of treatment, for use in a method of treating psychosis, for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder, for use in a method of treating schizophrenia and/or bipolar disorder or for use in a method of treating bipolar disorder, in particular acute manic or mixed episodes of bipolar disorder. 
     
     
         18 . Transdermal therapeutic system according to  claim 17  for use in a method of treating a patient, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. 
     
     
         19 . Transdermal therapeutic system according to  claim 18  for use in a method of treating a patient, wherein the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof, or
 the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or 
 the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 
 the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or 
 the at least one asenapine-related side effect is dizziness, and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. 
 
     
     
         20 - 42 . (canceled) 
     
     
         43 . A method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days. 
     
     
         44 . The method of treating a human patient by transdermal administration of asenapine according to  claim 43 , for a dosing interval of at least 72 hours or 3 days, up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days, or
 wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days, and/or   providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 48 hours of administration, or   providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 72 hours of administration, or   providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 84 hours of administration, or   providing by transdermal delivery an AUC 0-48  from 20 to 300 (ng/ml) h, from more than 300 to 450 (ng/ml) h or from 30 to 200 (ng/ml) h, or   providing by transdermal delivery an AUC 0-72  from 30 to 400 (ng/ml) h, from more than 400 to 600 (ng/ml) h or from 50 to 300 (ng/ml) h, or   providing by transdermal delivery an AUC 0-84  from 35 to 450 (ng/ml) h, from more than 450 to 700 (ng/ml) h or from 60 to 350 (ng/ml) h, or   providing by transdermal delivery a C max  to C 48  ratio of less than 2.0, less than 1.5 or less than 1.3, or   providing by transdermal delivery a C max  to C 72  ratio of less than 3.0, less than 2.5 or less than 2.0, or   providing by transdermal delivery a C max  to C 84  ratio of less than 3.5, less than 3.0, less than 2.5 or less than 2.0, or   providing by transdermal delivery a C max  value of from 0.5 to 10 ng/ml or from 1 to 8 ng/ml.   
     
     
         45 . The method of treating a human patient according to  claim 43 , wherein the transdermal administration of asenapine provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. 
     
     
         46 . The method of treating a human patient according to  claim 45 , wherein the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, or
 the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or   the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or wherein the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or   the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or   the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%.   
     
     
         47 - 59 . (canceled) 
     
     
         60 . Transdermal therapeutic system according to  claim 5  wherein the matrix layer composition comprises:
 i) 7 to 13% by weight of asenapine free base; 
 ii) 75 to 85% by weight of a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate, and glycidyl-methacrylate; 
 iii) 0.1 to 2% by weight of tocopherol; and 
 iv) 5 to 15% by weight of polyvinylpyrrolidone. 
 
     
     
         61 - 114 . (canceled) 
     
     
         115 . Transdermal therapeutic system according to  claim 5 , wherein the asenapine-containing matrix layer has an area weight that ranges from 90 to 230 g/m 2 , from 110 to 210 g/m 2 , or from 120 to 170 g/m 2 .