Transmucosal phosphodiesterase inhibitors for the treatment of erectile dysfunction

Abstract

A pharmaceutical formulation is provided for treating erectile dysfunction in a mammalian male individual. The pharmaceutical formulation includes a phosphodiesterase inhibitor or a pharmaceutically acceptable salt, ester, amide or derivative thereof, that is administered transmucosally within the context of an effective dosing regimen. Preferred modes of administration include transbuccal, sublingual and transrectal routes. A kit for the administration of the pharmaceutical formulation is also provided.

What is claimed is:  
     
         1 . A pharmaceutical formulation for treating erectile dysfunction in an individual and suitable for transmucosal drug administration, comprising a therapeutically effective amount of a phosphodiesterase inhibitor, a carrier suitable for transmucosal drug administration, and, optionally, a permeation enhancer.  
     
     
         2 . The formulation of  claim 1 , wherein the formulation comprises a solid dosage form for application to buccal mucosa, and the carrier is suitable for transbuccal drug delivery.  
     
     
         3 . The formulation of  claim 2 , wherein the carrier is a hydrolyzable polymer.  
     
     
         4 . The formulation of  claim 3 , wherein the dosage form further comprises an adhesive suitable for affixing the dosage form to the buccal mucosa.  
     
     
         5 . The formulation of  claim 2 , wherein the phosphodiesterase inhibitor represents approximately 1 wt % to 30 wt % of the buccal solid dosage form.  
     
     
         6 . The formulation of  claim 2 , wherein the buccal solid dosage form contains at least one additional component selected from the group consisting of disintegrants, diluents, binders, lubricants, flavoring, colorants, and preservatives.  
     
     
         7 . The formulation of  claim 1 , wherein the formulation comprises a dosage form for application to sublingual mucosa, and the carrier is suitable for sublingual drug delivery.  
     
     
         8 . The formulation of  claim 7 , wherein the sublingual dosage form completely disintegrates in less than five minutes after administration.  
     
     
         9 . The formulation of  claim 7 , wherein the sublingual dosage form contains at least one additional component selected from the group consisting of binders, disintegrators, wetting agents, and lubricants.  
     
     
         10 . The formulation of  claim 1 , wherein the formulation comprises a dosage form for application to rectal mucosa, and the carrier is suitable for transrectal drug delivery.  
     
     
         11 . The formulation of  claim 10 , wherein the transrectal dosage form completely disintegrates within approximately 3 hours following administration.  
     
     
         12 . The formulation of claims  11 , wherein the transrectal dosage form is a rectal suppository.  
     
     
         13 . The formulation of  claim 12 , wherein the rectal suppository further includes at least one additional component selected from the group consisting of stiffening agents, antioxidants, and preservatives.  
     
     
         14 . The formulation of  claim 1 , wherein the phosphodiesterase inhibitor is a Type III phosphodiesterase inhibitor.  
     
     
         15 . The formulation of  claim 14 , wherein the Type III phosphodiesterase inhibitor is selected from the group consisting of bipyridines, imidazolones, imidazolines, dihydropyridazinones, dihydroquinolones, mixed Type III-Type IV inhibitors, anagrelide, bemoradan, ibudilast, isomazole, lixazinone, motapizone, olprinone, phthalazinol, pimobendan, quazinone, siguazodan and trequinsin.  
     
     
         16 . The formulation of  claim 15 , wherein the Type III phosphodiesterase inhibitor is a bipyridine.  
     
     
         17 . The formulation of  claim 16 , wherein the bipyridine is selected from the group consisting of amrinone and milrinone.  
     
     
         18 . The formulation of  claim 15 , wherein the Type III phosphodiesterase inhibitor is an imidazolone.  
     
     
         19 . The formulation of  claim 18 , wherein the imidazolone is selected from the group consisting of piroximone and enoximone.  
     
     
         20 . The formulation of  claim 15 , wherein the Type III phosphodiesterase inhibitor is a dihydroquinolinone.  
     
     
         21 . The formulation of  claim 20 , wherein the dihydroquinolinone is selected from the group consisting of cilostamide, cilostazol, vesnarinone and OPC 3911.  
     
     
         22 . The formulation of  claim 1 , wherein the phosphodiesterase inhibitor is a Type IV phosphodiesterase inhibitor.  
     
     
         23 . The formulation of  claim 22 , wherein the Type IV phosphodiesterase inhibitor is selected from the group consisting of pyrrolidinones, quinazolinediones, xanthine derivatives, phenyl ethyl pyridines, tetrahydropyrimidones, diazepine derivatives, oxime carbamates, naphthyridinones, benzofurans, naphthalene derivatives, purine derivatives, imidazolidinones, cyclohexane carboxylic acids, benzamides, benzothiophenes, pyridopyridazinones, etazolate, S-(+)-glaucine, substituted phenyl compounds, and substituted biphenyl compounds.  
     
     
         24 . The formulation of  claim 23 , wherein the Type IV phosphodiesterase inhibitor is a pyrrolidinone.  
     
     
         25 . The formulation of  claim 24 , wherein the pyrrolidinone is selected from the group consisting of rolipram, R020-1724 and RS 33793.  
     
     
         26 . The formulation of  claim 25 , wherein the pyrrolidinone is rolipram.  
     
     
         27 . The formulation of  claim 1 , wherein the phosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor.  
     
     
         28 . The formulation of  claim 27 , wherein the Type V phosphodiesterase inhibitor is selected from the group consisting of zaprinast; MY 544; dipyridamole; sildenafil; pyrazolopyrimidinones; griseolic acid derivatives; 2-phenylpurinones; phenylpyridone derivatives; pyrimidines; pyrimidopyrimidines; purines; quinazolines; phenylpyrimidinones; imidazoquinoxalinones or aza analogues thereof; phenylpyridones; 1C-351 (ICOS); 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3 (2H)pyridazinone; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinazolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl) propoxy)-3-(2H)pyridazinone; 1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic acid, monosodium salt; pyrrolo[1,2-c]imidazolone derivatives; 1-phenylmethyl-N-[[4-ethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)]pyrimidin-5-yl]-1H-imidazol-2-carboxamide; 1-phenylmethyl-N-[4-ethyl-2-(1H-imidazol-1-yl)pyrimidin-5-yl-]H-imidazol-2-carboxamide; 4,9-diethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methylimidazo[5,1-h]pteridin-6(5H)-one; and 9-ethyl-2(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methyl-4-(2-propyl)imidazo[5,1-h]pteridin-6(5H)-one.  
     
     
         29 . The formulation of  claim 28 , wherein the Type V phosphodiesterase inhibitor is zaprinast.  
     
     
         30 . The formulation of  claim 28 , wherein the Type V phosphodiesterase inhibitor is a pyrazolopyrimidinone.  
     
     
         31 . The formulation of  claim 28 , wherein the Type V phosphodiesterase inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.  
     
     
         32 . The formulation of  claim 1 , wherein the phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline, papaverine, doxazosin, prazosin, terazosin, trimazosin and hydralazine.  
     
     
         33 . The formulation of  claim 1 , further comprising an additional active agent.  
     
     
         34 . The formulation of  claim 33 , wherein the additional active agent is a vasoactive agent.  
     
     
         35 . The formulation of  claim 33 , wherein the additional active agent is a smooth muscle relaxant.  
     
     
         36 . The formulation of  claim 1 , wherein the daily dose of the formulation is in the range of approximately 5 mg to 100 mg.  
     
     
         37 . The formulation of  claim 36 , wherein the phosphodiesterase inhibitor in the daily dose of the formulation is in a range of approximately 0.1 to 500 mg.  
     
     
         38 . A kit to assist an individual in administering a drug used for the treatment of erectile dysfunction comprising: 
 a pharmaceutical formulation comprising a selected phosphodiesterase inhibitor;    a container for housing the pharmaceutical formulation during storage and prior to use; and    instructions for carrying out drug administration in a manner effective to treat erectile dysfunction.    
     
     
         39 . The kit according to  claim 38 , wherein the pharmaceutical formulation is for buccal administration.  
     
     
         40 . The kit according to  claim 39 , wherein the phosphodiesterase inhibitor is housed in a buccal storage unit with a bioerodible polymeric carrier.  
     
     
         41 . The kit according to  claim 38 , further comprising a venous flow control device.  
     
     
         42 . The kit according to  claim 41 , wherein the venous flow control device comprises a flexible tubing having integral fastening means.