US2002004498A1PendingUtilityA1

Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction

49
Priority: Oct 28, 1997Filed: Aug 23, 2001Published: Jan 10, 2002
Est. expiryOct 28, 2017(expired)· nominal 20-yr term from priority
Inventors:Paul C. Doherty, Jr.Virgil A. PlaceWilliam L. Smith
A61P 43/00A61P 9/00A61P 25/02A61K 31/4709A61K 31/343A61K 31/444A61K 31/549A61K 9/0031A61K 31/538A61K 31/40A61K 9/0056A61K 31/5025A61K 31/52A61K 9/0034A61P 15/10A61K 31/4015A61K 31/496A61K 31/522A61K 31/00A61K 31/502A61K 31/426A61K 45/06A61K 31/4166A61K 31/50A61K 31/4745A61K 31/437A61K 31/501A61K 31/381A61K 31/4439A61K 31/519A61K 9/006A61K 31/4164A61K 31/5513A61K 31/4704A61K 31/505
49
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Claims

Abstract

A method is provided for treating erectile dysfunction in a mammalian male individual. The method involves the transmucosal administration of a phosphodiesterase inhibitor or a pharmaceutically acceptable salt, ester, amide or derivative thereof, within the context of an effective dosing regimen. Preferred modes of administration include transbuccal, sublingual and transrectal routes. Pharmaceutical formulations and kits are provided as well.

Claims

exact text as granted — not AI-modified
1 . A method for treating erectile dysfunction in a male individual, comprising transmucosally administering to the individual an effective amount of a phosphodiesterase inhibitor or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein the phosphodiesterase inhibitor is selected from the group consisting of Type III phosphodiesterase inhibitors, Type IV phosphodiesterase inhibitors, Type V phosphodiesterase inhibitors, and combinations thereof.  
     
     
         2 . The method of  claim 1 , wherein administration is transbuccal.  
     
     
         3 . The method of  claim 1 , wherein administration is sublingual.  
     
     
         4 . The method of  claim 1 , wherein administration is transrectal.  
     
     
         5 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is a Type III phosphodiesterase inhibitor.  
     
     
         6 . The method of  claim 5 , 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.  
     
     
         7 . The method of  claim 6 , wherein the Type III phosphodiesterase inhibitor is a bipyridine.  
     
     
         8 . The method of  claim 7 , wherein the bipyridine is selected from the group consisting of amrinone and milrinone.  
     
     
         9 . The method of  claim 5 , wherein the Type III phosphodiesterase inhibitor is an imidazolone.  
     
     
         10 . The method of  claim 9 , wherein the imidazolone is selected from the group consisting of piroximone and enoximone.  
     
     
         11 . The method of  claim 5 , wherein the Type III phosphodiesterase inhibitor is a dihydroquinolinone.  
     
     
         12 . The method of  claim 11 , wherein the dihydroquinolinone is selected from the group consisting of cilostamide, cilostazol, vesnarinone and OPC 3911.  
     
     
         13 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is a Type IV phosphodiesterase inhibitor.  
     
     
         14 . The method of  claim 13 , 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, pyridopyridazinones, benzothiophenes, etazolate, S-(+)-glaucine, substituted phenyl compounds and substituted biphenyl compounds.  
     
     
         15 . The method of  claim 14 , wherein the Type IV phosphodiesterase inhibitor is a pyrrolidinone.  
     
     
         16 . The method of  claim 15 , wherein the pyrrolidinone is selected from the group consisting of rolipram, RO20-1724 and RS 33793.  
     
     
         17 . The method of  claim 16 , wherein the pyrrolidinone is rolipram.  
     
     
         18 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor.  
     
     
         19 . The method of  claim 18 , wherein the Type V phosphodiesterase inhibitor is selected from the group consisting of zaprinast; dipyridamole; pyrazolopyrimidinones; griseolic acid derivatives; 2-phenylpurinones; phenylpyridone derivatives; pyrimidines; pyrimidopyrimidines; purines; quinazolines; phenylpyrimidinones; imidazoquinoxalinones or aza analogues thereof; phenylpyridones; 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]-1H-imidazol-2 -carboxamide; 4,9-diethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methylimidazo[5,1 -]pteridin-6(5H)-one; and 9-ethyl-2(2-ethyl-4-methyl- lH-imidazol-1-yl)-7-methyl-4 -(2-propyl)imidazo[5,1-h]pteridin-6(5H)-one.  
     
     
         20 . The method of  claim 19 , wherein the Type V phosphodiesterase inhibitor is zaprinast.  
     
     
         21 . The method of  claim 19 , wherein the Type V phosphodiesterase inhibitor is a pyrazolopyrimidinone.  
     
     
         22 . The method of  claim 21 , wherein the Type V phosphodiesterase inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.  
     
     
         23 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline, doxazosin, papaverine, prazosin, terazosin, trimazosin and hydralazine.  
     
     
         24 . The method of  claim 1 , wherein the individual is given a daily dose of phosphodiesterase inhibitor in the range of approximately 0.2 to 1.5 g/day.  
     
     
         25 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is administered one to four times in a twenty-four hour period.  
     
     
         26 . The method of  claim 1 , wherein the erectile dysfunction is vasculogenic impotence.  
     
     
         27 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is contained within a pharmaceutical formulation comprising an additional active agent.  
     
     
         28 . The method of  claim 27 , wherein the additional active agent is a vasoactive agent.  
     
     
         29 . The method of  claim 27 , wherein the additional active agent is a smooth muscle relaxant.  
     
     
         30 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is contained within a unit dosage pharmaceutical formulation.  
     
     
         31 . 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.  
     
     
         32 . The formulation of  claim 31 , wherein the formulation comprises a solid dosage form for application to the buccal mucosa, and the carrier is suitable for transbuccal drug delivery.  
     
     
         33 . The formulation of  claim 31 , wherein the carrier is a hydrolyzable polymer.  
     
     
         34 . The formulation of  claim 31 , wherein the dosage form further comprises an adhesive suitable for affixing the dosage form to the buccal mucosa.  
     
     
         35 . The formulation of  claim 31 , wherein the formulation comprises a dosage form for application to the sublingual mucosa, and the carrier is suitable for sublingual drug delivery.  
     
     
         36 . The formulation of  claim 31 , wherein the formulation comprises a dosage form for application to the rectal mucosa, and the carrier is suitable for transrectal drug cars delivery.  
     
     
         37 . The formulation of  claim 31 , wherein the phosphodiesterase inhibitor is a Type III phosphodiesterase inhibitor.  
     
     
         38 . The formulation of  claim 37 , 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.  
     
     
         39 . The formulation of  claim 38 , wherein the Type III phosphodiesterase inhibitor is a bipyridine.  
     
     
         40 . The formulation of  claim 39 , wherein the bipyridine is selected from the group consisting of amrinone and milrinone.  
     
     
         41 . The formulation of  claim 37 , wherein the Type III phosphodiesterase inhibitor is an imidazolone.  
     
     
         42 . The formulation of  claim 41 , wherein the imidazolone is selected from the group consisting of piroximone and enoximone.  
     
     
         43 . The formulation of  claim 37 , wherein the Type III phosphodiesterase inhibitor is a dihydroquinolinone.  
     
     
         44 . The formulation of  claim 43 , wherein the dihydroquinolinone is selected from the group consisting of cilostamide, cilostazol, vesnarinone and OPC 3911.  
     
     
         45 . The formulation of  claim 31 , wherein the phosphodiesterase inhibitor is a Type IV phosphodiesterase inhibitor.  
     
     
         46 . The formulation of  claim 45 , wherein the Type IV phosphodiesterase  2 - 0  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, pyridopyridazinones, benzothiophenes, etazolate, S-(+)-glaucine, substituted phenyl compounds and substituted biphenyl compounds.  
     
     
         47 . The formulation of  claim 46 , wherein the Type IV phosphodiesterase inhibitor is a pyrrolidinone.  
     
     
         48 . The formulation of  claim 47 , wherein the pyrrolidinone is selected from the group consisting of rolipram, RO20-1724 and RS 33793.  
     
     
         49 . The formulation of  claim 48 , wherein the pyrrolidinone is rolipram.  
     
     
         50 . The formulation of  claim 31 , wherein the phosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor.  
     
     
         51 . The formulation of  claim 50 , wherein the Type V phosphodiesterase inhibitor is selected from the group consisting of zaprinast; dipyridamole; pyrazolopyrimidinones; griseolic acid derivatives; 2-phenylpurinones; phenylpyridone derivatives; pyrimidines; pyrimidopyrimidines; purines; quinazolines; phenylpyrimidinones; imidazoquinoxalinones or aza analogues thereof; phenylpyridones; 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,7,8,9,9 a-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-ethyl4 -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]-1H-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-methyl4-(2-propyl)imidazo[5,1 -h]pteridin-6(5H)-one.  
     
     
         52 . The formulation of  claim 51 , wherein the Type V phosphodiesterase inhibitor is zaprinast.  
     
     
         53 . The formulation of  claim 51 , wherein the Type V phosphodiesterase inhibitor is a pyrazolopyrimidinone.  
     
     
         54 . The formulation of  claim 53 , wherein the Type V phosphodiesterase inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.  
     
     
         55 . The formulation of  claim 31 , wherein the phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline, doxazosin, papaverine, prazosin, terazosin, trimazosin and hydralazine.  
     
     
         56 . The formulation of  claim 31 , further comprising an additional active agent.  
     
     
         57 . The formulation of  claim 56 , wherein the additional active agent is a vasoactive agent.  
     
     
         58 . The formulation of  claim 57 , wherein the additional active agent is a smooth muscle relaxant.

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