Transdermal delivery system comprising buprenorphine

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) e 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 and c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid and 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, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

1 - 79 . (canceled) 
     
     
         80 . A method of treating pain in a patient comprising applying a transdermal therapeutic system for the transdermal administration of buprenorphine to the skin of the patient, wherein the 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, the adhesive layer comprising
 i. at least one polymer-based pressure-sensitive adhesive based on polysiloxanes or polyisobutylenes, 
 ii. an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and 
 iii. 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, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the said pressure-sensitive adhesive, 
   wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer; and wherein the transdermal therapeutic system is applied on the skin of the patient for about 168 hours;   
       wherein the transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg·hr/ml-cm 2  over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
         81 . The method of  claim 80 , wherein said buprenorphine is present in the form of buprenorphine base and said carboxylic acid is levulinic acid. 
     
     
         82 . The method of  claim 80 , wherein said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid and the polymer-based pressure-sensitive adhesive is based on polysiloxanes. 
     
     
         83 . The method of  claim 80 , wherein the 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.   
     
     
         84 . The method of  claim 80 , wherein the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranges 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 .   
     
     
         85 . The method of  claim 80 , wherein said transdermal therapeutic system provides an arithmetic mean tmax of from about 60 hr to about 120 hr after a single-dose administration to a subject population. 
     
     
         86 . The method of  claim 85 , wherein said transdermal therapeutic system provides an arithmetic mean tmax of from about 66 hr to less than 108 hr after a single-dose administration to a subject population. 
     
     
         87 . The method of  claim 80 , wherein said buprenorphine-containing pressure-sensitive adhesive layer containing more than 0.55 mg/cm 2 , or more than 0.6 mg/cm 2  of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 
     
     
         88 . The method of  claim 80 , wherein the buprenorphine-containing pressure-sensitive adhesive layer being coated at a dry weight of more than 6 mg/cm 2 , or more than 8 mg/cm 2 . 
     
     
         89 . The method of  claim 80 , wherein the carboxylic acid is levulinic acid, said buprenorphine-containing pressure-sensitive adhesive layer containing the same % amounts of levulinic acid and buprenorphine, based on the % amount of buprenorphine base. 
     
     
         90 . The method of  claim 80 , wherein the carboxylic acid is levulinic acid, said buprenorphine-containing pressure-sensitive adhesive layer containing less % amounts of levulinic acid than % amounts of buprenorphine, based on the % amount of buprenorphine base. 
     
     
         91 . The method of  claim 80 , wherein said buprenorphine-containing self-adhesive layer structure being attached to a second larger active agent-free self-adhesive layer structure for enhancing the adhesive properties of the overall transdermal therapeutic system. 
     
     
         92 . The method of  claim 91 , wherein said second active-free self-adhesive layer structure comprises a backing layer and an active agent-free pressure-sensitive adhesive layer of pressure-sensitive adhesive based on polyacrylates or polysiloxane. 
     
     
         93 . The method of  claim 80 , wherein buprenorphine is present in the form of buprenorphine base and the transdermal therapeutic system provides a mean cumulative skin permeation rate measured in a Franz diffusion cell with dermatoned human skin of more than 1.3 μg/cm 2 -hr over a 168 hours test. 
     
     
         94 . The method of  claim 80 , wherein buprenorphine is present in the form of buprenorphine base and the transdermal therapeutic system provides a cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatoned human skin of 220 μg/cm 2  to 640 μg/cm 2  over a time period of 168 hours. 
     
     
         95 . The method of  claim 80 , wherein buprenorphine is present in the form of buprenorphine base and the transdermal therapeutic system provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatoned 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.   
     
     
         96 . The method of  claim 80 , wherein said transdermal therapeutic system is selected from
 a first transdermal therapeutic system that provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the 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, wherein the first transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 6.25 cm 2  and providing a nominal mean release rate of about 5 μg/hr over about 168 hours of administration;   a second transdermal therapeutic system that provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the 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, wherein the second transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 12.5 cm 2  and providing a nominal mean release rate of about 10 μg/hr over about 168 hours of administration;   a third transdermal therapeutic system that provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the 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, wherein the third transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 25 cm 2  and providing a nominal mean release rate of about 20 μg/hr over   
       about 168 hours of administration;
 a fourth transdermal therapeutic system that provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the 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, wherein the fourth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 37.5 cm 2  and providing a nominal mean release rate of 
 
       about 30 μg/hr over about 168 hours of administration; and
 a fifth transdermal therapeutic system that provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the 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, wherein the fifth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 50 cm 2  and providing a nominal mean release rate of about 40 μg/hr over 
 
       about 168 hours of administration; 
       wherein the reference product is prepared by the following steps:
 (1) homogenizing of 1,139 g of a 47.83% polyacrylate solution of a self-crosslinked acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid, 100 g of levulinic acid, 150 g of oleyl oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate, and 100 g of buprenorphine base to provide a mixture; 
 (2) stirring the mixture of step 1 for about 2 hours and controlling the dissolution of all solids visually whereas controlling the evaporation loss by re-weighing and replenishing the possible solvent loss by ethyl acetate; 
 (3) subsequently applying the mixture on a transparent polyester film in such a manner that the mass per unit area of the dry adhesive layer amounts to about 80 g/m 2  wherein the polyester film is rendered removable by means of siliconization and serves as protective layer; 
 (4) removing the solvents of the mixture applied on a transparent polyester film in step 3 by drying with heated air which is led over a moist lane resulting in evaporation of the solvents, but also in melting of the levulinic acid and covering the adhesive film with a polyester foil; and 
 (5) punching the area of release of 6.25 cm 2 , 12.5 cm 2 , 25 cm 2 , 37.5 cm 2  and 50 cm 2 , respectively, by means of suitable cutting tools and removing the edges left between the individual systems. 
 
     
     
         97 . The method of  claim 96 , wherein the polyacrylate solution comprises a solvent comprising ethyl acetate, heptanes, isopropanol, toluene and acetylacetonate in a ratio of 37:26:26:4:1. 
     
     
         98 . The method of  claim 80 , wherein the transdermal therapeutic system is manufactured by a method comprising the steps of
 (1) providing a buprenorphine-containing adhesive mixture or solution comprising
 a) buprenorphine base or a pharmaceutically acceptable salt thereof, 
 b) a carboxylic acid, 
 c) a polymer-based pressure-sensitive adhesive, and 
 d) solvent, 
   (2) coating said buprenorphine-containing adhesive mixture or solution on a film in an amount to provide the desired coating dry weight,   (3) drying said coated buprenorphine-containing adhesive mixture or solution to provide a buprenorphine-containing adhesive layer with the desired coating dry weight,   (4) laminating said buprenorphine-containing adhesive layer to a backing layer to provide an buprenorphine-containing self-adhesive layer structure,   (5) punching the individual systems from the buprenorphine-containing self-adhesive layer structure with the desired area of release, and   (6) optionally adhering to the individual systems an active-free self-adhesive layer structure comprising also 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.   
     
     
         99 . The method of  claim 98 , wherein in step (1) buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid and are suspended in ethanol and subsequently combined with a polymer-based pressure-sensitive adhesive based on polysiloxane in heptane to provide the buprenorphine-containing adhesive mixture or solution.