Transdermal delivery system

Abstract

The invention relates to transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, c) a viscosity-increasing substance in an amount of about 0.1% to about 8% of said buprenorphine-containing pressure-sensitive adhesive layer, and d) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture including said viscosity-increasing substance, and wherein the carboxylic acid-, buprenorphine- and viscosity-increasing substance-containing mixture forms dispersed deposits in the said pressure-sensitive adhesive, and wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

1 .- 63 . (canceled) 
     
     
         64 . A transdermal therapeutic system for transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising
 A) a buprenorphine-impermeable backing layer, and   B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, said adhesive layer comprising
 a) at least one polymer-based pressure-sensitive adhesive, 
 b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, 
 c) a viscosity-increasing substance in an amount of about 0.1% to about 8% of said buprenorphine-containing pressure-sensitive adhesive layer, and 
 d) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture including said viscosity-increasing substance, and wherein said carboxylic acid-, buprenorphine- and viscosity-increasing substance-containing mixture forms dispersed deposits in said pressure-sensitive adhesive, and 
   
       wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer. 
     
     
         65 . A transdermal therapeutic system for transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising
 A) a buprenorphine-impermeable backing layer, and   B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, said adhesive layer comprising
 a) at least one polymer-based pressure-sensitive adhesive, 
 b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, 
 c) soluble polyvinylpyrrolidone, and 
 d) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture including said polyvinylpyrrolidone, and wherein said carboxylic acid-, buprenorphine- and polyvinylpyrrolidone-containing mixture forms dispersed deposits in said pressure-sensitive adhesive, and 
   
       wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer. 
     
     
         66 . The transdermal therapeutic system of  claim 65 , wherein said polyvinylpyrrolidone has a K-Value of at least about 5, or of at least about 10, or of at least about 15, or of at least about 20, or of at least about 50, or of at least about 80. 
     
     
         67 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine is present in the form of buprenorphine base and/or wherein said carboxylic acid is levulinic acid. 
     
     
         68 . The transdermal therapeutic system of  claim 64 , wherein said polymer-based pressure-sensitive adhesive is based on polysiloxanes or polyisobutylenes. 
     
     
         69 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid and said polymer-based pressure-sensitive adhesive is based on polysiloxanes. 
     
     
         70 . The transdermal therapeutic system of  claim 64 , wherein said viscosity-increasing substance is present in an amount of about 0.1% to about 7%, or of about 0.5% to about 5%, or of about 1% to about 4%, or of about 2% to about 3% of said buprenorphine-containing pressure-sensitive adhesive layer. 
     
     
         71 . The transdermal therapeutic system of  claim 64 , wherein said viscosity-increasing substance comprises one or more cellulose derivatives selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose or microcrystalline cellulose. 
     
     
         72 . The transdermal therapeutic system of  claim 64 , wherein said viscosity-increasing substance comprises one or more high molecular mass polyacrylic acids, salts thereof or derivatives thereof. 
     
     
         73 . The transdermal therapeutic system of  claim 64 , wherein said viscosity-increasing substance comprises one or more of polyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate, tragacanth, xanthan gum, bentonite, carageenan or guar gum. 
     
     
         74 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid, said polymer-based pressure-sensitive adhesive is based on polysiloxanes and said viscosity-increasing substance is soluble polyvinylpyrrolidone in an amount of about 1% to about 4%. 
     
     
         75 . The transdermal therapeutic system of  claim 64 , wherein said amount of said buprenorphine contained in the transdermal therapeutic system ranges from
 about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or   about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or   about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or   about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or   about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.   
     
     
         76 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from
 about 1 cm 2  to about 4.8 cm 2 , or   about 3 cm 2  to about 9.5 cm 2 , or   about 6 cm 2  to about 19 cm 2 , or   about 12 cm 2  to about 28.5 cm 2 , or   about 16 cm 2  to about 38 cm 2 .   
     
     
         77 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 1 cm 2  to about 4.8 cm 2  and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof,
 wherein said transdermal therapeutic system provides a nominal mean release rate of about 5 μg/hr over about 168 hours of administration.   
     
     
         78 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 3 cm 2  to about 9.5 cm 2 , and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof,
 wherein said transdermal therapeutic system provides a nominal mean release rate of about 10 μg/hr over about 168 hours of administration.   
     
     
         79 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 6 cm 2  to about 19 cm 2  and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof,
 wherein said transdermal therapeutic system provides a nominal mean release rate of about 20 μg/hr over about 168 hours of administration.   
     
     
         80 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 12 cm 2  to about 28.5 cm 2 , and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof,
 wherein said transdermal therapeutic system provides a nominal mean release rate of about 30 μg/hr over about 168 hours of administration.   
     
     
         81 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 16 cm 2  to about 38 cm 2 , and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof,
 wherein said transdermal therapeutic system provides a nominal mean release rate of about 40 μg/hr over about 168 hours of administration.   
     
     
         82 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine is present in the form of buprenorphine base and said system provides a mean cumulative skin permeation rate measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 μg/cm 2 -hr over a 168 hours test and/or provides a cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 220 μg/cm 2  to 640 μg/cm 2  over a time period of 168 hours. 
     
     
         83 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine is present in the form of buprenorphine base and said system provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of
 2 μg/cm 2  to 10 μg/cm 2  in the first 8 hours,   20 μg/cm 2  to 80 μg/cm 2  from hour 8 to hour 24,   20 μg/cm 2  to 80 μg/cm 2  from hour 24 to hour 32,   30 μg/cm 2  to 120 μg/cm 2  from hour 32 to hour 48,   40 μg/cm 2  to 150 μg/cm 2  from hour 48 to hour 72,   100 μg/cm 2  to 300 μg/cm 2  from hour 72 to hour 144, and   30 μg/cm 2  to 100 μg/cm 2  from hour 144 to hour 168.   
     
     
         84 . The transdermal therapeutic system of  claim 65 , wherein said buprenorphine is present in the form of buprenorphine base and said system provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of
 2 μg/cm 2  to 10 μg/cm 2  in the first 8 hours,   20 μg/cm 2  to 80 μg/cm 2  from hour 8 to hour 24,   20 μg/cm 2  to 80 μg/cm 2  from hour 24 to hour 32,   30 μg/cm 2  to 120 μg/cm 2  from hour 32 to hour 48,   40 μg/cm 2  to 150 μg/cm 2  from hour 48 to hour 72,   100 μg/cm 2  to 300 μg/cm 2  from hour 72 to hour 144, and   30 μg/cm 2  to 100 μg/cm 2  from hour 144 to hour 168.   
     
     
         85 . A set of two to five different transdermal therapeutic systems each in accordance with  claim 64 , wherein
 said first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 1 cm 2  to about 4.8 cm 2  and contains an amount of said buprenorphine from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof;   said second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 3 cm 2  to about 9.5 cm 2  and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof;   said third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 6 cm 2  to about 19 cm 2  and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof;   said fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 12 cm 2  to about 28.5 cm 2  and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and   said fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 16 cm 2  to about 38 cm 2  and contains an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.   
     
     
         86 . The transdermal therapeutic system of  claim 64 , wherein said buprenorphine base-containing pressure-sensitive adhesive layer comprises an anti-oxidant selected from the group consisting of ascorbyl palmitate, tocopherol and esters thereof, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, propyl gallate and mixtures thereof. 
     
     
         87 . The transdermal therapeutic system of  claim 86 , wherein said anti-oxidant is ascorbyl palmitate and is present in an amount of from about 0.01 to about 0.5% of said buprenorphine-containing pressure-sensitive adhesive layer. 
     
     
         88 . A method of treating pain in a patient comprising applying a transdermal therapeutic system for transdermal administration of buprenorphine to the skin of said patient, wherein said transdermal therapeutic system comprises a buprenorphine-containing self-adhesive layer structure comprising
 A) a buprenorphine-impermeable backing layer, and   B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, said adhesive layer comprising
 a) at least one polymer-based pressure-sensitive adhesive, 
 b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, 
 c) a viscosity-increasing substance in an amount of about 0.1% to about 8% of said buprenorphine-containing pressure-sensitive adhesive layer, and 
 d) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture including said viscosity-increasing substance, and wherein said carboxylic acid-, buprenorphine- and viscosity-increasing substance-containing mixture forms dispersed deposits in said pressure-sensitive adhesive, and 
   
       wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer. 
     
     
         89 . The method  claim 88 , wherein said transdermal therapeutic system is applied on the skin of the patient for more than 96 hours. 
     
     
         90 . The method  claim 88 , wherein said transdermal therapeutic system is applied on the skin of the patient for about 168 hours. 
     
     
         91 . A method of manufacturing said transdermal therapeutic system of  claim 64 , comprising the steps of
 1. providing a buprenorphine-containing adhesive mixture comprising
 a) buprenorphine base or a pharmaceutically acceptable salt thereof, 
 b) a carboxylic acid, 
 c) a viscosity-increasing substance, 
 d) a polymer-based pressure-sensitive adhesive, and 
 e) a solvent; 
   2. storing said mixture between 0 hours and 6 days;   3. homogenizing said buprenorphine-containing adhesive mixture;   4. storing said homogenized mixture between 0 hours and 6 days;   5. coating said buprenorphine-containing adhesive mixture on a film using a roller coater in an amount to provide the desired coating dry weight;   6. drying said coated buprenorphine-containing adhesive mixture to provide a buprenorphine-containing adhesive layer with the desired coating dry weight;   7. optionally laminating said buprenorphine-containing adhesive layer to a backing layer to provide a buprenorphine-containing adhesive layer structure;   8. optionally punching individual systems from the buprenorphine-containing self-adhesive layer structure with the desired area of release; and   9. optionally adhering to the individual systems an active-free self-adhesive layer structure comprising a backing layer and an active agent-free pressure-sensitive adhesive layer and which is larger than the individual systems of buprenorphine-containing self-adhesive layer structure.   
     
     
         92 . The method of  claim 91 , wherein said viscosity-increasing substance is polyvinylpyrrolidone, and wherein said polyvinylpyrrolidone is used to control said deposit size during the manufacture. 
     
     
         93 . The method of  claim 91 , wherein in step 1 said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid and said viscosity-increasing substance is polyvinylpyrrolidone, and are dissolved in ethanol and subsequently suspended in a polymer-based pressure-sensitive adhesive based on polysiloxane in heptane to provide the buprenorphine-containing adhesive mixture.