Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction

• US 20020004498A1
• Filed: 08/23/2001
• Published: 01/10/2002
• Est. Priority Date: 10/28/1997
• Status: Abandoned Application

• Current Assignee: Paul C. Doherty Jr, Virgil A. Place, William L. Smith
• Original Assignee: Paul C. Doherty Jr, Virgil A. Place, William L. Smith
• Inventors: Smith, William L., Place, Virgil A., Doherty, Paul C. Jr.
• Application Number:
  US09/938,417
• Publication Number:
  US 20020004498A1
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/519 : ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 : Purines, e.g. adenine
• CPC Class Codes: A61K 31/522 : having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/538 : ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/549 : having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• CPC Class Codes: A61K 31/5513 : 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0031 : Rectum, anus
• CPC Class Codes: A61K 9/0034 : Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0056 : Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 : Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61P 15/10 : for impotence
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

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

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.