Transdermal estrogen device and delivery

Abstract

Described are transdermal drug delivery systems for the transdermal administration of estrogen, comprising a polymer matrix and estrogen. Methods of making and using such systems also are described.

1 - 20 . (canceled) 
     
     
         21 . A monolithic transdermal drug delivery system for estradiol, comprising a single polymer matrix layer defining an active surface area, wherein the single polymer matrix layer comprises a polymer matrix comprising about 2-25% by weight acrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25% by weight soluble PVP, about 5-15% penetration enhancer, and about 0.1-10% by weight estradiol as the only drug, all based on the total dry weight of the polymer matrix, wherein the polymer matrix layer includes greater than 0.156 mg/cm 2  estradiol and achieves an estradiol flux that is greater than 0.01 mg/cm 2 /day, based on the active surface area. 
     
     
         22 . The transdermal drug delivery system of  claim 21 , wherein the polymer matrix layer achieves an estradiol flux that is greater than 0.01 mg/cm 2 /day, based on the active surface area, when measured by a skin permeation study using stratum corneum obtained from split thickness, cryopreserved cadaver skin assayed on modified Franz diffusion cells using a receptor fluid of 0.9% NaCl and 0.01% NaN 3  in deionized water maintained at a constant 32° C. and magnetically stirred at approximately 300 rpm. 
     
     
         23 . The transdermal drug delivery system of  claim 21 , wherein the penetration enhancer comprises oleyl alcohol. 
     
     
         24 . The transdermal drug delivery system of  claim 21 , wherein the penetration enhancer comprises dipropylene glycol. 
     
     
         25 . The transdermal drug delivery system of  claim 21 , wherein the penetration enhancer comprises oleyl alcohol and dipropylene glycol. 
     
     
         26 . The transdermal drug delivery system of  claim 21 , wherein the acrylic adhesive and silicone adhesive are present in a ratio of from about 1:2 to about 1:6, based on the total weight of the acrylic and silicone adhesives. 
     
     
         27 . The transdermal drug delivery system of  claim 21 , wherein the polymer matrix comprises an amount of estradiol effective to deliver a therapeutically effective amount of estradiol over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. 
     
     
         28 . The transdermal drug delivery system of  claim 21 , wherein the polymer matrix comprises an amount of estradiol effective to deliver an amount of estradiol selected from the group consisting of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day. 
     
     
         29 . The transdermal drug delivery system of  claim 21 , wherein the system has an active surface area that is about 60% of a size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm 2  and is effective to deliver an amount of estradiol per day of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively. 
     
     
         30 . A method for administering estradiol, comprising applying to the skin or mucosa of a subject in need thereof a monolithic transdermal drug delivery system according to  claim 21 . 
     
     
         31 . The method of  claim 30 , wherein the system has an active surface area that is about 60% of a size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm 2  and is effective to deliver an amount of estradiol per day of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively. 
     
     
         32 . A method of making a monolithic transdermal drug delivery system for estradiol, comprising forming a polymer matrix comprising estradiol as the only drug and a polymer blend comprising an acrylic adhesive, a silicone adhesive, and soluble PVP, and applying the polymer matrix to a support layer to form a single polymer matrix layer such that the polymer matrix layer comprises about 2-25% by weight acrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25% by weight soluble PVP, about 5-15% penetration enhancer, and about 0.1-10% by weight estradiol as the only drug, all based on the total dry weight of the polymer matrix, and includes greater than 0.156 mg/cm 2  estradiol. 
     
     
         33 . The method of  claim 32 , wherein the system has an active surface area that is about 60% of a size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm 2 . 
     
     
         34 . A monolithic transdermal drug delivery system for estradiol, consisting of (i) a backing layer, (ii) a single adhesive polymer matrix layer defining an active surface area and, optionally, (iii) a release liner, wherein the single adhesive polymer matrix layer comprises an adhesive polymer matrix comprising about 2-25% by weight acrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25% by weight soluble PVP, about 5-15% penetration enhancer, and about 0.1-10% by weight estradiol as the only drug, wherein the adhesive polymer matrix layer includes greater than 0.156 mg/cm 2  estradiol and achieves an estradiol flux that is greater than 0.01 mg/cm 2 /day, based on the active surface area. 
     
     
         35 . The transdermal drug delivery system of  claim 34 , wherein the polymer matrix layer achieves an estradiol flux that is greater than 0.01 mg/cm 2 /day, based on the active surface area, when measured by a skin permeation study using stratum corneum obtained from split thickness, cryopreserved cadaver skin assayed on modified Franz diffusion cells using a receptor fluid of 0.9% NaCl and 0.01% NaN 3  in deionized water maintained at a constant 32° C. and magnetically stirred at approximately 300 rpm. 
     
     
         36 . The transdermal drug delivery system of  claim 34 , wherein the penetration enhancer comprises oleyl alcohol. 
     
     
         37 . The transdermal drug delivery system of  claim 34 , wherein the penetration enhancer comprises dipropylene glycol. 
     
     
         38 . The transdermal drug delivery system of  claim 34 , wherein the penetration enhancer comprises oleyl alcohol and dipropylene glycol. 
     
     
         39 . The transdermal drug delivery system of  claim 34 , wherein the acrylic adhesive and silicone adhesive are present in a ratio of from about 1:2 to about 1:6, based on the total weight of the acrylic and silicone adhesives. 
     
     
         40 . The transdermal drug delivery system of  claim 34 , wherein the polymer matrix comprises an amount of estradiol effective to deliver a therapeutically effective amount of estradiol over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. 
     
     
         41 . The transdermal drug delivery system of  claim 34 , wherein the polymer matrix comprises an amount of estradiol effective to deliver an amount of estradiol selected from the group consisting of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day. 
     
     
         42 . The transdermal drug delivery system of  claim 34 , wherein the system has an active surface area that is about 60% of a size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm 2  and is effective to deliver an amount of estradiol per day of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively. 
     
     
         43 . A method for administering estradiol, comprising applying to the skin or mucosa of a subject in need thereof a monolithic transdermal drug delivery system according to  claim 34 . 
     
     
         44 . The method of  claim 43 , wherein the system has an active surface area that is about 60% of a size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm 2  and is effective to deliver an amount of estradiol per day of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.