Transdermal delivery rate control using amorphous pharmaceutical compositions

Abstract

A pharmaceutical composition for transdermal delivery comprising one or more physiologically active agents; one or more dermal penetration enhancers; and a volatile pharmaceutically acceptable carrier comprising a volatile solvent; and wherein the physiologically active agent and dermal penetration enhancer form an amorphous deposit upon evaporation of the volatile carrier, said amorphous deposit forming a reservoir within the stratum corneum; and (A) wherein the composition has a release rate profile of physiologically active agent so as to provide a ratio of the maximum concentration (C max ) to the average concentration (C avg ) for the physiologically active agent over the dosage interval within the range of 1 to 10.

1 .- 25 . (canceled) 
     
     
         26 . A pharmaceutical composition for transdermal delivery comprising
 from 0.1% to 10% by weight of testosterone;   from 0.1% to 10% by weight of one or more dermal penetration enhancers, wherein the dermal penetration enhancer is a non-volatile lipophilic liquid having a vapour pressure below 10 mm Hg at atmospheric pressure and at a temperature of 32° C., said dermal penetration enhancer having a molecular weight in the range of from 200 to 400 Daltons; and   from 85% to 99.8% by weight of a volatile solvent selected from the group consisting of ethanol, isopropanol or a mixture thereof;   
       wherein the combination of physiologically active agent and dermal penetration enhancer is such that, upon evaporation of the volatile solvent at physiological temperatures, the composition forms an amorphous deposit comprising an amorphous phase containing the dermal penetration enhancer. 
     
     
         27 . A pharmaceutical composition according to  claim 26 , wherein the penetration enhancer has an organic nature value of from 200 to 400 and an inorganic nature value of from 0 to 200. 
     
     
         28 . A composition according to  claim 26 , wherein the molar ratio of the testosterone and the dermal penetration enhancer is from 1:20 to 20:1. 
     
     
         29 . A composition according to  claim 26 , wherein the one or more penetration enhancers are selected from the group consisting of fatty acids, fatty acid esters, glycols, glycol esters, 1,3-dioxolanes, 1,3-dioxanes, macrocyclic ketones containing at least 12 carbon atoms, oxazolidinones, alkyl-2-(N,N-disubstituted amino)alkanol alkanoates and mixtures thereof. 
     
     
         30 . A composition according to  claim 26 , wherein the penetration enhancer is selected from the group consisting of isopropyl myristate, dodecyl 2-(N,N-dimethylamino)propionate 2-n-nonyl-1,3-dioxolane, laurocapram, myristic acid, octyl salicylate and Padimate O. 
     
     
         31 . A composition according to  claim 26 , wherein the penetration enhancer is selected from the group consisting of isopropyl myristate, octyl salicylate and Padimate O. 
     
     
         32 . The transdermal drug delivery system according to  claim 26 , wherein the composition provides a zero order release rate profile of the physiologically active agent so as to reduce the ratio of the maximum concentration (C max ) to the average concentration (C avg ) to a value less than 2 for the physiologically active agent over the dosage interval in order to reduce potential side effects associated with elevated C max  to C avg  ratios. 
     
     
         33 . The transdermal drug delivery system according to  claim 26 , wherein the composition provides a first order release rate profile of the physiologically active agent so as to increase the ratio of C max  to C avg  to a value greater than 1.5 and decrease the time for maximum systemic concentration (t max ) to less than 6 hours for the physiologically active agent over the dosage interval in order to decrease the time to onset of therapeutic response or increase the therapeutic response after a single dose interval. 
     
     
         34 . The transdermal drug delivery system according to  claim 26 , wherein the penetration enhancer is octyl salicylate which is present in an amount of 5% by weight of the composition. 
     
     
         35 . A pharmaceutical composition for transdermal delivery comprising
 from 0.1% to 10% by weight of testosterone;   from 0.1% to 10% by weight of one or more dermal penetration enhancers, wherein the dermal penetration enhancer is a non-volatile lipophilic liquid having a vapour pressure below 10 mm Hg at atmospheric pressure and at a temperature of 32° C., said dermal penetration enhancer having a molecular weight in the range of from 200 to 400 Daltons an organic nature value of from 200 to 400 and an inorganic nature value of from 0 to 200 and wherein the molar ratio of testosterone to penetration enhancer is from 1:20 to 20:1; and   from 85% to 99.8% by weight of a volatile solvent selected from the group consisting of ethanol, isopropanol or a mixture thereof;   
       wherein the combination of physiologically active agent and dermal penetration enhancer are such that, upon evaporation of the volatile solvent at physiologic, the composition forms an amorphous deposit comprising an amorphous phase containing the dermal penetration enhancer. 
     
     
         36 . A method of transdermal delivery of testosterone to a subject comprising topically applying to the subject a pharmaceutical composition for transdermal delivery comprising:
 from 0.1% to 10% by weight testosterone;   from 0.1% to 10% by weight of one or more dermal penetration enhancers, wherein the dermal penetration enhancer is a non-volatile lipophilic liquid having a vapour pressure and at a temperature of 32° C., said dermal penetration enhancer having a molecular weight of from 200 Daltons to 400 Daltons; and from 85% to 95% by weight of a volatile solvent selected from the group consisting of ethanol, isopropanol and mixtures thereof;   to form an amorphous deposit of the active agent and penetration enhancer upon evaporation of the volatile solvent.   
     
     
         37 . A method according to  claim 36 , wherein the penetration enhancer has an organic nature value of from 200 to 400 and an inorganic nature value of from 0 to 200. 
     
     
         38 . A method according to  claim 36 , wherein the molar ratio of the physiologically active agent compound and the dermal penetration enhancer is from 1:20 to 20:1. 
     
     
         39 . A method according to  claim 36 , wherein the one or more penetration enhancers are selected from the group consisting of fatty acids, fatty acid esters, glycols, glycol esters, 1,3-dioxolanes, 1,3-dioxanes, macrocyclic ketones containing at least 12 carbon atoms, oxazolidinones, alkyl-2-(N,N-disubstituted amino)alkanoate esters, (N,N-disubstituted amino)alkanol alkanoates and mixtures thereof. 
     
     
         40 . A method according to  claim 36 , wherein the penetration enhancer is selected from the group consisting of isopropyl myristate, dodecyl 2-(N,N-dimethylamino)propionate 2-n-nonyl-1,3-dioxolane, laurocapram, myristic acid, octyl salicylate and Padimate O. 
     
     
         41 . A composition according to  claim 36 , wherein the penetration enhancer is selected from the group consisting of isopropyl myristate, octyl salicyclate and Padimate O. 
     
     
         42 . The method according to  claim 36 , wherein the composition provides a zero order release rate profile of the physiologically active agent so as to reduce the ratio of the maximum concentration (C max ) to the average concentration (C avg ) to a value less than 2 for the physiologically active agent over the dosage interval in order to reduce potential side effects associated with elevated C max  to C avg  ratios. 
     
     
         43 . The method according to  claim 36 , wherein the composition provides a first order release rate profile of the physiologically active agent so as to increase the ratio of C max  to C avg  to a value greater than 1.5 and decrease the time for maximum system concentration (t max ) to less than 6 hours for the physiologically active agent over the dosage interval in order to decrease the time to onset of therapeutic response or increase the therapeutic response after a single dose interval. 
     
     
         44 . The method according to  claim 36 , wherein the amount of testosterone is 5% by weight. 
     
     
         45 . The method of transdermal delivery of testosterone to a subject comprising topically applying to the subject a pharmaceutical composition for transdermal delivery comprising:
 from 0.1% to 10% by weight of testosterone;   from 0.1% to 10% by weight of one or more dermal penetration enhancers, wherein the dermal penetration enhancer is a non-volatile lipophilic liquid having a vapour pressure below 10 mm Hg at atmospheric pressure and at a temperature of 32° C., said dermal penetration enhancer having a molecular weight in the range of from 200 to 400 Daltons an organic nature value of from 200 to 400 and an inorganic nature value of from 0 to 200 and wherein the molar ratio of testosterone to penetration enhancer is from 1:20 to 20:1; and   from 85% to 99.8% by weight of a volatile solvent selected from the group consisting of ethanol, isopropanol or a mixture thereof;   
       wherein the combination of physiologically active agent and dermal penetration enhancer are such that, upon evaporation of the volatile solvent at physiologic, the composition forms an amorphous deposit comprising an amorphous phase containing the dermal penetration enhancer.