Topical pharmaceutical composition comprising a cholinergic agent or a calcium channel blocker

Abstract

A method and composition are provided for the treatment of an anorectal disorder and for controlling the pain associated therewith. The method comprises administering to a subject in need of such treatment therapeutically effective amounts of a calcium channel blocker either alone or together with a nitric oxide donor. Amlodipine, anipamil, barnidipine, benidipine, bepridil, darodipine, diltiazem, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine, nicardipine, nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil and pharmaceutically acceptable salts thereof, are suitable calcium channel blockers.

What is claimed is:  
     
         1 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a calcium channel blocker either alone or together with a nitric oxide donor.  
     
     
         2 . A method in accordance with  claim 1 , wherein both the calcium channel blocker and nitric oxide donor are administered.  
     
     
         3 . A method in accordance with  claim 2 , wherein said nitric oxide donor and said calcium channel blocker are administered in combination.  
     
     
         4 . A method in accordance with  claim 1 , wherein said anorectal disorder is an anal fissure.  
     
     
         5 . A method in accordance with any one of claims  1 ,  2 ,  3  or  4 , wherein said administration is topical.  
     
     
         6 . A method in accordance with  claim 5 , wherein said administration is in the form of a gel, ointment, cream, emollient, lotion, powder, solution, suspension, spray, paste, oil, foam, suppository or enema.  
     
     
         7 . A method in accordance with  claim 6 , wherein said calcium channel blocker is administered in an amount within the range of from 0.5% to 5% w/w.  
     
     
         8 . A method of treating a benign anal disorder, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a calcium channel blocker either alone or together with a nitric oxide donor.  
     
     
         9 . A method in accordance with  claim 8 , wherein both the calcium channel blocker and nitric oxide donor are administered.  
     
     
         10 . A method in accordance with  claim 9 , wherein said nitric oxide donor and calcium channel blocker are administered in combination.  
     
     
         11 . A method in accordance with  claim 8 , wherein said anorectal disorder is an anal fissure.  
     
     
         12 . A method in accordance with any one of claims  8 ,  9 ,  10  or  11 , wherein said administration is topical.  
     
     
         13 . A method in accordance with  claim 12 , wherein said administration is in the form of a gel, ointment, cream, emollient, lotion, powder, solution, suspension, spray, paste, oil, foam, suppository or enema.  
     
     
         14 . A method in accordance with  claim 13 , wherein said calcium channel blocker is administered in an amount within the range of from 0.5% to 5% w/w.  
     
     
         15 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of an agent selected from the group consisting of diltiazem, nifedipine and pharmaceutically acceptable salts thereof either alone or together with a nitric oxide donor.  
     
     
         16 . A method in accordance with  claim 15 , wherein both said agent and the nitric oxide donor are administered.  
     
     
         17 . A method in accordance with  claim 16 , wherein said agent and said nitric oxide donor are administered in combination.  
     
     
         18 . A method in accordance with  claim 15 , wherein said anorectal disorder is an anal fissure.  
     
     
         19 . A method in accordance with any one of claims  15 ,  16 ,  17  or  18 , wherein said administration is topical.  
     
     
         20 . A method in accordance with  claim 19 , wherein said administration is in the form of a gel, ointment, cream, emollient, lotion, powder, solution, suspension, spray, paste, oil, foam, suppository or enema.  
     
     
         21 . A method in accordance with  claim 20 , wherein said calcium channel blocker is administered in an amount within the range of from 0.5% to 5% w/w.  
     
     
         22 . A method of treating a benign anal disorder, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of an agent selected from the group consisting of diltiazem, nifedipine and pharmaceutically acceptable salts thereof either alone or together with a nitric oxide donor.  
     
     
         23 . A method in accordance with  claim 22 , wherein both said agent and said nitric oxide donor are administered.  
     
     
         24 . A method in accordance with  claim 23 , wherein said agent and said nitric oxide donor are administered in combination.  
     
     
         25 . A method in accordance with  claim 22 , wherein said anorectal disorder is an anal fissure.  
     
     
         26 . A method in accordance with any one of claims  22 ,  23 ,  24  or  25 , wherein said administration is topical.  
     
     
         27 . A method in accordance with  claim 26 , wherein said administration is in the form of a gel, ointment, cream, emollient, lotion, powder, solution, suspension, spray, paste, oil, foam, suppository or enema.  
     
     
         28 . A method in accordance with  claim 27 , wherein said calcium channel blocker is administered in an amount within the range of from 0.5% to 5% w/w.  
     
     
         29 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier and an agent which increases a level of cyclic guanidine monophosphate or cyclic adenosine monophosphate in a tissue of an anal sphincter muscle of the subject, thereby decreasing hypertonicity of the anal sphincter muscle of the subject, which composition comprises a calcium channel blocker either alone or together with a nitric oxide donor.  
     
     
         30 . A method according to  claim 29 , wherein both said calcium channel blocker and said nitric oxide donor are administered.  
     
     
         31 . A method for the treatment or prophylaxis of benign anal disorders comprising local application to the anus of a patient a therapeutically effective amount of a calcium channel blocker either alone or in combination with a nitric oxide donor.  
     
     
         32 . A method in accordance with  claim 31 , wherein both said calcium oxide blocker and said nitric oxide donor are administered.  
     
     
         33 . A method in accordance with  claim 32 , wherein said calcium oxide blocker and said nitric oxide donor are administered in combination.  
     
     
         34 . A method in accordance with  claim 31 , wherein said administration is in the form of a gel, ointment, cream, emollient, lotion, powder, solution, suspension, spray, paste, oil, foam, suppository or enema.  
     
     
         35 . A method in accordance with  claim 34 , wherein said calcium channel blocker is administered in an amount within the range of from 0.5% to 5% w/w.  
     
     
         36 . A method for the treatment or prophylaxis of benign anal disorders associated with high anal pressure or anal sphincter spasm, comprising local application to the anus of a patient a therapeutically effective amount of a calcium channel blocker either alone or in combination with a nitric oxide donor.  
     
     
         37 . A method in accordance with  claim 36 , wherein both said calcium oxide blocker and said nitric oxide donor are administered.  
     
     
         38 . A method in accordance with  claim 37 , wherein said calcium oxide blocker and said nitric oxide donor are administered in combination.  
     
     
         39 . A method in accordance with  claim 36 , wherein said administration is in the form of a gel, ointment, cream, emollient, lotion, powder, solution, suspension, spray, paste, oil, foam, suppository or enema.  
     
     
         40 . A method in accordance with  claim 39 , wherein said calcium channel blocker is administered in an amount within the range of from 0.5% to 5% w/w.  
     
     
         41 . A method for the treatment or prophylaxis of benign anal disorders associated with high anal pressure or anal sphincter spasm, and the relief of symptoms associated therewith, comprising local application to the internal anal sphincter of a patient a therapeutically effective amount of a calcium channel blocker either alone or together with a nitric oxide donor.  
     
     
         42 . A method in accordance with  claim 41 , wherein both said calcium oxide blocker and said nitric oxide donor are administered.  
     
     
         43 . A method in accordance with  claim 42 , wherein said calcium oxide blocker and said nitric oxide donor are administered in combination.  
     
     
         44 . A method according to any one of claims  1 ,  8 , 15 ,  29 ,  31 ,  36  or  41 , wherein the calcium channel blocker is selected from the group consisting of amlodipine, anipamil, barnidipine, benidipine, bepridil, darodipine, diltiazem, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine, nicardipine, nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil, and pharmaceutically acceptable salts thereof.  
     
     
         45 . A method according to any one of claims  1 ,  8 ,  15 ,  22 ,  29 ,  31 ,  36  or  41 , wherein the nitric oxide donor is trinitroglycerine.  
     
     
         46 . A method according to any one of claims  1 ,  8 ,  15 ,  22 ,  29 ,  31 ,  36  or  41 , wherein the anal disorder is hemorrhoids.  
     
     
         47 . A method in accordance with  claim 41 , wherein said administration is in the form of a gel, ointment, cream, emollient, lotion, powder, solution, suspension, spray, paste, oil, foam, suppository or enema.  
     
     
         48 . A method in accordance with  claim 47 , wherein said calcium channel blocker is administered in an amount within the range of from 0.5% to 5% w/w.  
     
     
         49 . A composition adapted for topical application in and around the anal canal comprising a calcium channel blocker and a nitric oxide donor together with a pharmaceutically acceptable carrier.  
     
     
         50 . A composition according to  claim 49 , wherein the calcium channel blocker is selected from the group consisting of amlodipine, anipamil, barnidipine, benidipine, bepridil, darodipine, diltiazem, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine, nicardipine, nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil, and pharmaceutically acceptable salts thereof.  
     
     
         51 . A composition according to  claim 50 , wherein the calcium channel blocker is selected from the group consisting of diltiazem, nifedipine and pharmaceutically acceptable salts thereof.  
     
     
         52 . A composition according to  claim 49 , wherein the nitric oxide donor is trinitroglycerine or a pharmaceutically acceptable salt thereof.  
     
     
         53 . A composition according to  claim 51 , wherein said calcium channel blocker is diltiazem.  
     
     
         54 . A method in accordance with  claim 49 , wherein said composition is in the form of a gel, ointment, cream, emollient, lotion, powder, solution, suspension, spray, paste, oil, foam, suppository or enema.  
     
     
         55 . A method in accordance with  claim 49 , wherein said calcium channel blocker is present in an amount within the range of from 0.5% to 5% w/w.