Dermal Penetration enhancers and drug delivery systems involving same

Abstract

The invention relates to a method for treatment or prophylaxis of a disease or condition in an animal comprising administering to a mucosal membrane of said animal in need of such treatment a therapeutically effective amount of a drug delivery system comprising at least one physiologically active agent or prodrug thereof and at least one penetration enhancer selected from safe ester sunscreens.

1 - 35 . (canceled) 
     
     
         36 . An apparatus for applying a metered dose of a non-occlusive percutaneous or a non-occlusive transdermal hormone composition to the dermal surface of a person comprising:
 (a) a container,   (b) a metered dose applicator selected from the group consisting of a metered dose aerosol, a stored energy metered dose pump, and a metered dose pump,   wherein said container contains:   (c) a non-occlusive percutaneous or non-occlusive transdermal hormone composition comprising:
 (i) at least one hormone selected from the group consisting of oestrogen, progesterone and progestagens other than progesterone 
 (ii) at least one dermal penetration enhancer, and 
 (iii) at least one volatile liquid present in an amount to act as a vehicle for the hormone and penetration enhancer, wherein the dermal penetration enhancer is
 (1) adapted to transport the at least one hormone across a dermal surface of an animal, when the volatile liquid evaporates, to form a reservoir or depot of the at least one hormone within said surface and 
 (2) is of low toxicity to and is tolerated by the dermal surface of the animal. 
 
   
     
     
         37 . The apparatus of  claim 36 , wherein said non-occlusive percutaneous or non-occlusive transdermal hormone composition consists of:
 (i) at least one hormone selected from the group consisting of oestrogen, progesterone and progestagens other than progesterone,   (ii) at least one dermal penetration enhancer,   (iii) at least one volatile liquid present in an amount to act as a vehicle for the hormone and penetration enhancer, and   (iv) optionally, a propellant.   
     
     
         38 . The apparatus of  claim 36 , wherein after application of the non-occlusive percutaneous or non-occlusive transdermal hormone composition to an area of the dermal surface, the area becomes touch-dry within three minutes of application. 
     
     
         39 . The apparatus of  claim 37 , wherein the dermal penetration enhancer is a C 6 -C 18  alkyl para-aminobenzoate, C 6 -C 18  alkyl dimethyl-para-aminobenzoate, C 6 -C 18  alkyl cinnamate, C 6 -C 18  alkyl methoxycinnamate or C 6 -C 18  alkyl salicylate. 
     
     
         40 . The apparatus of  claim 39 , wherein the dermal penetration enhancer is octyl salicylate. 
     
     
         41 . The apparatus of  claim 37 , wherein the volatile liquid is ethanol or isopropanol. 
     
     
         42 . The apparatus of  claim 36 , wherein the apparatus provides one or more fixed metered doses of the non-occlusive percutaneous or non-occlusive transdermal hormone composition. 
     
     
         43 . The apparatus of  claim 36 , wherein said non-occlusive percutaneous or non-occlusive transdermal oestrogen composition comprises:
 (i) oestrogen,   (ii) at least one dermal penetration enhancer, and   (iii) at least one volatile liquid present in an amount to act as a vehicle for the oestrogen and penetration enhancer,   wherein the dermal penetration enhancer is
 (1) adapted to transport the oestrogen across a dermal surface of an animal, when the volatile liquid evaporates, to form a reservoir or depot of oestrogen within said surface and 
 (2) is of low toxicity to and is tolerated by the dermal surface of the animal. 
   
     
     
         44 . The apparatus of  claim 37 , wherein said non-occlusive percutaneous or non-occlusive transdermal oestrogen composition consists of:
 (i) oestrogen,   (ii) at least one dermal penetration enhancer,   (iii) at least one volatile liquid present in an amount to act as a vehicle for the oestrogen and penetration enhancer, and   (iv) optionally, a propellant.   
     
     
         45 . The apparatus of  claim 43 , wherein the oestrogen comprises oestradiol in an amount of about 2% (w/v) of the non-occlusive percutaneous or non-occlusive transdermal oestrogen composition. 
     
     
         46 . The apparatus of  claim 43 , wherein after application of the non-occlusive percutaneous or non-occlusive transdermal oestrogen composition to an area of the dermal surface, the area becomes touch-dry within three minutes of application. 
     
     
         47 . The apparatus of  claim 44 , wherein the dermal penetration enhancer is a C 6 -C 18  alkyl para-aminobenzoate, C 6 -C 18  alkyl dimethyl-para-aminobenzoate, C 6 -C 18  alkyl cinnamate, C 6 -C 18  alkyl methoxycinnamate or C 6 -C 18  alkyl salicylate. 
     
     
         48 . The apparatus of  claim 47 , wherein the dermal penetration enhancer is octyl salicylate. 
     
     
         49 . The apparatus of  claim 43 , wherein the non-occlusive percutaneous or non-occlusive transdermal oestrogen composition comprises:
 about 2% (w/v) oestradiol,   about 8% (v/v) penetration enhancer, and   about 90% (v/v) of one or more volatile liquid.   
     
     
         50 . The apparatus of  claim 44 , wherein the non-occlusive percutaneous or non-occlusive transdermal oestrogen composition consists of:
 about 2% (w/v) oestradiol,   about 8% (v/v) penetration enhancer, and   about 90% (v/v) of one or more volatile liquid.   
     
     
         51 . The apparatus of  claim 44 , wherein the volatile liquid is ethanol or isopropanol. 
     
     
         52 . The apparatus of  claim 43 , wherein the apparatus provides one or more fixed metered doses of the non-occlusive percutaneous or non-occlusive transdermal oestrogen composition. 
     
     
         53 . The apparatus of  claim 43 , wherein the metered dose applicator further comprises a shroud adapted to keep the nozzle of the apparatus at a pre-determined height above the site of application. 
     
     
         54 . A method of contraception in a woman comprising applying to the skin of a woman in need thereof an effective amount of a non-occlusive percutaneous or non-occlusive transdermal hormone composition comprising:
 (a) at least one hormone selected from the group consisting of oestrogen, progesterone and progestagens other than progesterone   (b) at least one dermal penetration enhancer, and   (c) at least one volatile liquid present in an amount to act as a vehicle for the hormone and penetration enhancer,   wherein the dermal penetration enhancer is
 (i) adapted to transport the at least one hormone across a dermal surface of an animal, when the volatile liquid evaporates, to form a reservoir or depot of the at least one hormone within said surface and 
 (ii) is of low toxicity to and is tolerated by the dermal surface of the animal; 
   wherein said composition is applied dermally using an apparatus comprising:   a container that contains said non-occlusive percutaneous or non-occlusive transdermal hormone composition, and   a metered dose applicator selected from the group consisting of a metered dose aerosol, a stored energy metered dose pump, and a metered dose pump.   
     
     
         55 . The method of  claim 54 , wherein the non-occlusive percutaneous or non-occlusive transdermal hormone composition is applied by an aerosol or spray comprising a shroud adapted to keep an actuator nozzle of the apparatus at a pre-determined height above the site of application. 
     
     
         56 . A method of supplementing hormone deficiency in a postmenopausal woman comprising applying to the skin of a woman in need thereof an effective amount of a non-occlusive percutaneous or non-occlusive transdermal oestrogen composition comprising:
 (a) oestrogen,   (b) at least one dermal penetration enhancer, and   (c) at least one volatile liquid present in an amount to act as a vehicle for the hormone and penetration enhancer,   
       wherein the dermal penetration enhancer is
 (i) adapted to transport the at least one hormone across a dermal surface of an animal, when the volatile liquid evaporates, to form a reservoir or depot of the at least one hormone within said surface and 
 (ii) is of low toxicity to and is tolerated by the dermal surface of the animal; 
 
       wherein said composition is applied dermally using an apparatus comprising:
 a container that contains said non-occlusive percutaneous or non-occlusive transdermal oestrogen composition, and 
 a metered dose applicator selected from the group consisting of a metered dose aerosol, a stored energy metered dose pump, and a metered dose pump. 
 
     
     
         57 . The method of  claim 56 , wherein the non-occlusive percutaneous or non-occlusive transdermal oestrogen composition is applied by an aerosol or spray comprising a shroud adapted to keep an actuator nozzle of the apparatus at a pre-determined height above the site of application. 
     
     
         58 . A composition for the transdermal delivery of oestrogen comprising
 (a) a therapeutically effective amount of oestrogen,   (b) at least one dermal penetration enhancer wherein the dermal penetration enhancer is at least one of a safe skin-tolerant ester sunscreen of formula (I):   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, lower alkyl, lower alkoxy, halide, hydroxyl, or NR 3 R 4 ; 
         R 2  is a C 8  to C 18  alkyl, 
         R 3  and R 4  are each independently hydrogen, lower alkyl, or R 3  and R 4  together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring; 
         n is 0 or 1, and 
         q is 1 or 2; and 
         (c) at least one volatile liquid present in an amount to act as a vehicle for the oestrogen and penetration enhancer, 
       
       wherein the composition is a non-occlusive percutaneous or non-occlusive transdermal composition that is administered to the skin in the form of a mist or spray. 
     
     
         59 . The composition of  claim 58  consisting of
 (a) a therapeutically effective amount of oestrogen,   (b) at least one dermal penetration enhancer wherein the dermal penetration enhancer is at least one of a safe skin-tolerant ester sunscreen of formula (I):   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, lower alkyl, lower alkoxy, halide, hydroxyl, or NR 3 R 4 ; 
         R 2  is a C 8  to C 18  alkyl, 
         R 3  and R 4  are each independently hydrogen, lower alkyl, or R 3  and R 4  together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring; 
         n is 0 or 1, and 
         q is 1 or 2; and 
         (c) at least one volatile liquid present in an amount to act as a vehicle for the oestrogen and penetration enhancer, 
       
       wherein the composition is a non-occlusive percutaneous or non-occlusive transdermal composition that is administered to the skin in the form of a mist or spray. 
     
     
         60 . The composition of  claim 58 , wherein the oestrogen comprises oestradiol in an amount of about 2% (w/v) of the composition.