Transdermal hormone delivery system: compositions and methods

Abstract

A transdermal hormone delivery system (THDS) is disclosed. The THDS is useful for control of fertility and as therapy for a variety of diseases and conditions treatable by robust delivery of progestin and estrogen hormones, particularly the progestin, levonorgestrel. The THDS comprises a backing layer, an adjoining adhesive polymer matrix comprising an effective amount of at least a progestin hormone, delivery of which is enhanced by one or more skin permeation enhancing agents present in pre-determined amounts. The THDS is capable of providing effective daily doses of progestin and estrogen hormones from a small surface area in contact with the skin, e.g., less than 20 square centimeters. Methods of fertility control and various types of hormone replacement therapy utilizing the THDS are also disclosed.

1 - 162 . (canceled)  
   
   
       163 . A transdermal delivery system comprising a backing layer and an adhesive polymer matrix affixed to the backing layer, wherein the adhesive polymer matrix comprises: 
 (a) an adhesive polymer;    (b) a humectant;    (c) a combination of skin permeation enhancing agents comprising, on a final percentage by weight of the adhesive polymer matrix after fabrication of the system, from about 4% to about 12% pharmaceutically acceptable organic solvent; from about 4.2% to about 12.6% a fatty (C 8 -C 20 ) alcohol ester of a hydroxy acid; from about 0.7% to about 2.3% lower (C 1 -C 4 ) alkyl ester of a hydroxy acid; and from about 3% to about 9% C 6 -C 18  fatty acid;    (d) a progestin; and    (e) an estrogen.    
   
   
       164 . The transdermal delivery system of  claim 163 , comprising, on a final percentage by weight of the adhesive polymer matrix, from about 12% to about 36% of the combination of skin permeation enhancing agents.  
   
   
       165 . The transdermal delivery system of  claim 163 , wherein the adhesive polymer is a polyacrylate copolymer, a polyisobutylene or a silicone adhesive.  
   
   
       166 . The transdermal delivery system of  claim 165 , wherein the polyacrylate copolymer comprises a 2-ethylhexyl acrylate monomer.  
   
   
       167 . The transdermal delivery system of  claim 166 , wherein the polyacrylate copolymer further comprises about 3 to 60% w/w vinyl acetate.  
   
   
       168 . The transdermal delivery system of  claim 163 , wherein the humectant comprises polyvinylpyrrolidone.  
   
   
       169 . The transdermal delivery system of  claim 168 , wherein the humectant comprises a polyvinylpyrrolidone copolymer.  
   
   
       170 . The transdermal delivery system of  claim 169 , wherein the humectant is a polyvinylpyrrolidone/vinyl acetate copolymer.  
   
   
       171 . The transdermal delivery system of  claim 170 , wherein the polyvinylpyrrolidone is formulated in an amount of about 60% w/w and the vinyl acetate is formulated in an amount of about 40% w/w in the polyvinylpyrrolidone/vinyl acetate copolymer.  
   
   
       172 . The transdermal delivery system of  claim 163 , wherein the pharmaceutically acceptable organic solvent is dimethyl sulfoxide.  
   
   
       173 . The transdermal delivery system of  claim 163 , wherein the fatty alcohol ester of a hydroxy acid is a fatty alcohol ester of lactic acid.  
   
   
       174 . The transdermal delivery system of  claim 163 , wherein the lower alkyl ester of a hydroxy acid is a lower alkyl ester of lactic acid.  
   
   
       175 . The transdermal delivery system of  claim 163 , wherein the C 6 -C 18  fatty acid is capric acid.  
   
   
       176 . The transdermal delivery system of  claim 163 , wherein the progestin is levonorgestrel.  
   
   
       177 . The transdermal delivery system of  claim 163 , wherein the estrogen is ethinyl estradiol or 17 β-estradiol.  
   
   
       178 . The transdermal delivery system of  claim 163 , comprising dimethyl sulfoxide, a fatty alcohol ester of lactic acid, a lower alkyl ester of lactic acid, and capric acid.  
   
   
       179 . The transdermal delivery system of  claim 178 , wherein the fatty alcohol ester of lactic acid is lauryl lactate.  
   
   
       180 . The transdermal delivery system of  claim 178 , wherein the lower alkyl ester of lactic acid is ethyl lactate.  
   
   
       181 . The transdermal delivery system of  claim 178 , wherein the skin permeation enhancing agents are present in a weight ratio of about 4-8 parts dimethyl sulfoxide, about 4-8 parts fatty alcohol ester of lactic acid, about 1 part lower alkyl ester of lactic acid and about 3-6 parts capric acid.  
   
   
       182 . The transdermal delivery system of  claim 181 , wherein the fatty alcohol ester of lactic acid is lauryl lactate and the lower alkyl ester of lactic acid is ethyl lactate.  
   
   
       183 . The transdermal delivery system of  claim 163 , formulated for delivery of ethinyl estradiol and levonorgestrel, wherein the ethinyl estradiol is transdermally delivered at a rate of between about 10 μg and 50 μg per day for a term of about one day to about seven days, and the levonorgestrel is transdermally delivered at a rate of at least 20 μg per day for a term of about one day to about seven days.  
   
   
       184 . The transdermal delivery system of  claim 183 , wherein the levonorgestrel is transdermally delivered in an amount sufficient to produce a serum concentration of at least 1,000 μg/ml.  
   
   
       185 . The transdermal delivery system of  claim 163 , wherein the adhesive polymer matrix has a thickness of about 10 to about 300 μm.  
   
   
       186 . The transdermal delivery system of  claim 163 , wherein the adhesive polymer matrix has a surface area of about 20 cm 2  or less.  
   
   
       187 . The transdermal delivery system of  claim 163 , which further comprises an overlay layer, wherein the overlay layer is coated with an adhesive and extends beyond the perimeter of part or all of the backing layer and adhesive polymer matrix.  
   
   
       188 . The transdermal delivery system of  claim 187 , wherein the overlay layer is fabricated with the system, so as to be affixed to the non-dermal side of the backing layer.  
   
   
       189 . The transdermal delivery system of  claim 187 , wherein the overlay layer is fabricated separately from the system.  
   
   
       190 . The transdermal delivery system of  claim 187 , wherein a non-adhesive polymer is substituted for the adhesive polymer, and wherein skin adhesion is effected through the adhesive-coated overlay layer.