Formulation for soft anticholinergic analogs

Abstract

Topical formulations comprising soft glycopyrrolates are useful for treating excessive sweating conditions in subjects, such as humans suffering from hyperhidrosis. Preferably, at least one soft anticholinergic agent is provided in an effective amount or concentration in an anhydrous formulation that can inhibit excessive perspiration resulting from a condition such as hyperhidrosis.

What is claimed is: 
     
         1 . A topical composition for treating, inhibiting or ameliorating excessive sweating, said composition comprising the following ingredients:
 (a) a compound having the formula:   
       
         
           
           
               
               
           
         
       
       said compound having the R stereoisomeric configuration at the 2 position and the R, S or RS stereoisomeric configuration at the 1′ and 3′ positions, or being a mixture thereof;
 (b) anhydrous ethanol; 
 (c) optionally, at least one gelling or viscosity-controlling ingredient; and 
 (d) optionally, at least one additional carrier or excipient; 
 provided that said topical composition is anhydrous and comprises from about 1% to about 25% w/w or w/v of the compound of formula (2), said composition having greater storage stability compared to a composition comprising an aqueous solvent or aqueous buffer, said ingredients being present in amounts such that the product of any transesterification is the same as the compound of formula (2). 
 
     
     
         2 . The composition of  claim 1 , comprising at least about 70% w/w or w/v anhydrous ethanol. 
     
     
         3 . The composition of  claim 1  or  2 , comprising from about 70% to about 99.99% w/w or w/v anhydrous ethanol. 
     
     
         4 . The composition of  claim 1 ,  2  or  3 , comprising from about 70% to about 85% w/w or w/v anhydrous ethanol. 
     
     
         5 . The composition of any one of  claims 1 - 4 , wherein at least one gelling or viscosity-controlling ingredient is present. 
     
     
         6 . The composition of any one of  claims 1 - 5 , wherein at least one additional carrier or excipient is present. 
     
     
         7 . The composition of any one of  claims 1 - 6 , wherein the compound of formula (2) is selected from the group consisting of:
 (i) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;   (ii) (2R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;   (iii) (2R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;   (iv)(2R,3′S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;   (v) (2R,1′R,3′S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;   (vi)(2R,1′S,3′S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;   (vii) (2R,1′R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and   (viii) (2R,1′S,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide.   
     
     
         8 . The composition of any one of  claims 1 - 7 , wherein the compound of formula (2) is at a concentration of from about 1% w/v or w/w to about 20% w/v or w/w of the composition. 
     
     
         9 . The composition of  claim 8 , wherein the compound of formula (2) is at a concentration of from about 2% w/v or w/w to about 10% w/v or w/w. 
     
     
         10 . The composition of any one of the preceding claims, packaged into a multiple dose container that meters a dose of from about 0.5 ml to about 1.0 ml of the composition for each application. 
     
     
         11 . The composition of any one of the preceding claims, packaged into a single or unit dose container that delivers a single or unit dose of about 0.5 ml to about 1.0 ml of the composition for each application. 
     
     
         12 . The composition of any one of the preceding claims, wherein the compound of formula (2) is (2R, 3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide. 
     
     
         13 . The composition of any one of  claims 5 - 12 , wherein the gelling or viscosity-controlling ingredient is hydroxypropyl cellulose. 
     
     
         14 . The composition of any one of  claims 5 - 13 , further comprising citric acid. 
     
     
         15 . The composition of any one of  claims 5 - 14 , further comprising hexylene glycol. 
     
     
         16 . The composition of any one of  claims 5 - 15 , further comprising a 6% silicone gum blend in dimethicone. 
     
     
         17 . The composition of any one of  claims 5 - 15 , further comprising at least one member selected from the group consisting of dimethicone, cyclomethicone, myristyl propionate, isopropyl myristate and C 12 -C 15  alkyl lactate. 
     
     
         18 . The composition of  claim 17 , wherein the cyclomethicone is cyclomethicone 5-NF and/or where the dimethicone is dimethicone 350 c5t. 
     
     
         19 . The composition of any one of  claims 5 - 15 , further comprising isopropyl myristate. 
     
     
         20 . Use of a composition as claimed in any one of  claims 1 - 19  in treating hyperhidrosis in a subject by topically administering to skin of an area of a subject suffering from hyperhidrosis, before bedtime, such that, compared to untreated, baseline conditions, sweat production is reduced by at least 25% for at least six (6) hours; and such that sweat production is reduced by an amount substantially equivalent to an amount that sweat production is reduced as compared to untreated, baseline conditions, following administration of a composition comprising the same concentration of glycopyrrolate, and with an improved safety profile compared to topical glycopyrrolate. 
     
     
         21 . Use of a composition as claimed in any one of  claims 1 - 19  in treating hyperhidrosis in a subject by topically administering to skin of an area of a subject suffering from hyperhidrosis, such that, compared to untreated, baseline conditions, sweat production is reduced by at least 25% for at least six (6) hours;
 and such that sweat production is reduced by an amount substantially equivalent to an amount that sweat production is reduced as compared to untreated, baseline conditions, following administration of a composition comprising the same concentration of glycopyrrolate, and with an improved safety profile compared to topical glycopyrrolate. 
 
     
     
         22 . A method of treating hyperhidrosis in a subject, said method comprising topically administering a composition as claimed in any one of  claims 1 - 19  to skin of an area of a subject suffering from hyperhidrosis, before bedtime, such that, compared to untreated, baseline conditions, sweat production is reduced by at least 25% for at least six (6) hours; and such that sweat production is reduced by an amount substantially equivalent to an amount that sweat production is reduced as compared to untreated, baseline conditions, following administration of a composition comprising the same concentration of glycopyrrolate, and with an improved safety profile compared to topical glycopyrrolate. 
     
     
         23 . A method of treating hyperhidrosis in a subject, said method comprising topically administering a composition as claimed in any one of  claims 1 - 19  to skin of an area of a subject suffering from hyperhidrosis, such that, compared to untreated, baseline conditions, sweat production is reduced by at least 25% for at least six (6) hours; and such that sweat production is reduced by an amount substantially equivalent to an amount that sweat production is reduced as compared to untreated, baseline conditions, following administration of a composition comprising the same concentration of glycopyrrolate, and with an improved safety profile compared to topical glycopyrrolate. 
     
     
         24 . The composition of any one of  claims 1 - 19 , for use in the treatment of hyperhidrosis, wherein said composition is to be topically administered in a one to four times daily regimen to an affected skin area of a subject. 
     
     
         25 . The composition for use according to  claim 24 , wherein said composition is to be topically administered to an affected skin area of the subject, within 1-2 hours prior to the subject's sleep period.