Transdermal Therapeutic System for 5-Aminolevulinic Acid Hydrochloride

Abstract

The invention relates to a transdermal therapeutic system that includes a back layer that is impermeable to an active ingredient; a polymer matrix containing the active ingredient and a protective layer that can be pulled off. The active ingredient is 5-aminolevulinic acid hydrochloride and the basic polymer of the polymer matrix is an adhesive polyacrylate. The inventive transdermal therapeutic systems are suitable for diagnosing and treating preliminary stages of skin cancer, such as actinic keratosis, and oncological skin diseases.

That which is claimed: 
     
         1 . A transdermal therapeutic system comprising a back layer that is impermeable to an active ingredient, an active ingredient-containing polymer matrix and a protective layer that can be pulled off,
 wherein the transdermal therapeutic system is a monolithic active ingredient-in-adhesive system;   the active ingredient is 5-aminolevulinic acid hydrochloride, which is present in an amount of 10 to 30% by weight based on the polymer matrix;   the polymer matrix contains more than 60% by weight of an adhesive polyacrylate having a viscosity of 500 to 25,000 mPa-s at 25° C.;   the adhesive polyacrylate is based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate or based on acrylic acid, 2-ethylhexyl acrylate and methyl acrylate, and   the adhesive polyacrylate does not comprise a cross-linking agent.   
     
     
         2 . The transdermal therapeutic system according to  claim 1 , wherein the 5-aminolevulinic acid hydrochloride is a crystalline 5-aminolevulinic acid hydrochloride. 
     
     
         3 . The transdermal therapeutic system according to  claim 2 , wherein 50% of the crystals in the crystalline 5-aminolevulinic acid hydrochloride are larger than the polymer matrix layer thickness. 
     
     
         4 . The transdermal therapeutic system according to  claim 2 , wherein more than 99.9% of the crystals of the crystalline 5-aminolevulinic acid hydrochloride are smaller than about 250 μm. 
     
     
         5 . The transdermal therapeutic system according to  claim 4 , wherein more than 99.9% of the crystals of the crystalline 5-aminolevulinic acid hydrochloride have a particle size of 90 to 160 μm. 
     
     
         6 . The transdermal therapeutic system according to  claim 1 , wherein the polymer matrix contains less than 30% by weight plasticizer, based on the adhesive polyacrylate. 
     
     
         7 . The transdermal therapeutic system according to  claim 6 , wherein the polymer matrix contains less than 20% by weight plasticizer, based on the adhesive polyacrylate. 
     
     
         8 . The transdermal therapeutic system according to  claim 6 , wherein the polymer matrix contains less than 5% by weight plasticizer, based on the adhesive polyacrylate. 
     
     
         9 . The transdermal therapeutic system according  claim 1 , wherein the polyacrylate has acid functionalities. 
     
     
         10 . The transdermal therapeutic system according to  claim 1 , wherein the polymer matrix contains more than 65% by weight polyacrylate. 
     
     
         11 . The transdermal therapeutic system according to  claim 10 , wherein the polymer matrix contains more than 70% by weight polyacrylate. 
     
     
         12 . The transdermal therapeutic system according  claim 1 , wherein the viscosity of the adhesive polyacrylate is in the range from 1,500 to 12,000 mPa·s at 25° C. 
     
     
         13 . The transdermal therapeutic system according to  claim 1 , wherein the adhesive polyacrylate is based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate. 
     
     
         14 . The transdermal therapeutic system according to  claim 13 , wherein the adhesive polyacrylate is produced from a monomer mixture containing 1 to 10% by weight acrylic acid, 5 to 25% by weight butyl acrylate, 60 to 80% by weight 2-ethylhexyl acrylate and 1 to 10% by weight vinyl acetate. 
     
     
         15 . The transdermal therapeutic system according to  claim 13 , wherein the monomer mixture contains 3 to 7% by weight acrylic acid, 10 to 20% by weight by weight butyl acrylate, 70 to 78% by weight 2-ethylhexyl acrylate and 2 to 8% by weight vinyl acetate. 
     
     
         16 . The transdermal therapeutic system according to  claim 13 , wherein the monomer mixture contains about 5% by weight acrylic acid, about 15% by weight butyl acrylate, about 75% by weight 2-ethylhexyl acrylate and about 5% by weight vinyl acetate. 
     
     
         17 . The transdermal therapeutic system according to  claim 1 , wherein the adhesive polyacrylate is based on acrylic acid, 2-ethylhexyl acrylate and methyl acrylate. 
     
     
         18 . The transdermal therapeutic system according to  claim 17 , wherein the adhesive polyacrylate is produced from a monomer mixture which contains 1 to 10% by weight acrylic acid, 50 to 70% by weight 2-ethylhexyl acrylate and 20 to 40% by weight methyl acrylate. 
     
     
         19 . The transdermal therapeutic system according to  claim 17 , wherein the adhesive polyacrylate is produced from a monomer mixture which contains 2 to 8% by weight acrylic acid, 55 to 65% by weight 2-ethylhexyl acrylate and 30 to 35% by weight methyl acrylate. 
     
     
         20 . The transdermal therapeutic system according to  claim 17 , wherein the adhesive polyacrylate is produced from a monomer mixture which contains about 5.7% by weight acrylic acid, about 62.2% by weight 2-ethylhexyl acrylate and about 32% by weight methyl acrylate. 
     
     
         21 . The transdermal therapeutic system according to  claim 1 , wherein the polymer matrix contains about 28% by weight crystalline 5-aminolevulinic acid hydrochloride and about 72% by weight of adhesive polyacrylate based on acrylic acid, 2-ethylhexyl acrylate and methyl acrylate. 
     
     
         22 . A cancer treatment comprising the transdermal therapeutic system according to  claim 1 . 
     
     
         23 . A method of diagnosing and treating skin cancer stages comprising applying the transdermal therapeutic system according to  claim 1 . 
     
     
         24 . The method as claimed in  claim 23 , wherein the skin cancer stages are actinic keratosis and oncological skin diseases. 
     
     
         25 . A method for treating skin cancer, said method comprising:
 adhering a transdermal therapeutic system containing 5-aminolevulinic acid hydrochloride in the form of particles less than 250 μm to skin at a place affected by cancer or precancerous lesions,   allowing said 5-aminolevulinic acid hydrochloride to dissolve via sweat from the place on the skin where the transdermal therapeutic system is applied,   transdermally absorbing the dissolved 5-aminolevulinic acid hydrochloride and enriching the concentration of 5-aminolevulinic acid hydrochloride in proximity of said cancer or precancerous lesions,   allowing said 5-aminolevulinic acid hydrochloride to convert into protoporphyrin IX,   irradiating said cancer or precancerous lesions enriched with protoporphyrin IX with light of a wavelength selected from the group consisting of 408 nm, 506 nm, 532 nm, 580 nm and 635 nm, thereby producing reactive oxygen compounds, and   allowing said reactive oxygen compounds to induce necrosis in said cancer or precancerous lesions.