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.

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; 
 (d) isopropyl myristate; and 
 (e) 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 of the compound of formula (2), said composition having greater storage stability compared to a composition comprising an aqueous solvent or aqueous buffer, with the proviso that said ingredients are present in amounts such that the product of any transesterification is the same as the compound of formula (2), and/or with the proviso that said anhydrous ethanol is present in an amount sufficient to act as a non-aqueous solvent for the compound of formula (2). 
 
     
     
         2 . The composition of  claim 1 , comprising at least about 70% w/w anhydrous ethanol. 
     
     
         3 . The composition of  claim 1 , comprising from about 70% to about 99.99% w/w anhydrous ethanol. 
     
     
         4 . The composition of  claim 1 , comprising from about 70% to about 85% w/w anydrous ethanol. 
     
     
         5 . The composition of  claim 1 , comprising at least one gelling or viscosity-controlling ingredient. 
     
     
         6 . The composition of  claim 1 , comprising at least one additional carrier or excipient. 
     
     
         7 . The composition of  claim 1 , 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  claim 1 , wherein the compound of formula (2) is present 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 present at a concentration of from about 2% w/v or w/w to about 10% w/v or w/w. 
     
     
         10 . A package comprising a multiple dose container, wherein the multiple dose container meters a dose of from about 0.5 ml to about 1.0 ml of the composition of  claim 1  for each application. 
     
     
         11 . A package comprising a single or unit dose container, wherein the single or unit dose container delivers a single or unit dose of about 0.5 ml to about 1.0 ml of the composition of  claim 1  for each application. 
     
     
         12 . The composition of  claim 1 , 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  claim 5 , wherein the gelling or viscosity-controlling ingredient is hydroxypropyl cellulose. 
     
     
         14 . The composition of  claim 1 , further comprising citric acid. 
     
     
         15 . The composition of  claim 1 , further comprising hexylene glycol. 
     
     
         16 . The composition of  claim 1 , further comprising at least one member selected from the group consisting of dimethicone and cyclomethicone. 
     
     
         17 . The composition of  claim 1 , further comprising a 6% silicone gum blend in dimethicone. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A method of treating hyperhidrosis in a subject, said method comprising topically administering the composition of  claim 1  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 . A method of treating hyperhidrosis in a subject, said method comprising topically administering the composition of  claim 1  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 . The method of  claim 20 , wherein said composition is topically administered in a one to four times daily regimen to an affected skin area of the subject. 
     
     
         23 . The method of  claim 20 , wherein said composition is topically administered to an affected skin area of the subject, within 1-2 hours prior to the subject's sleep period. 
     
     
         24 . The method of  claim 21 , wherein said composition is topically administered in a one to four times daily regimen to an affected skin area of the subject.