U.S. patent application number 09/888250 was filed with the patent office on 2002-03-28 for administration of phosphodiesterase inhibitors for the treatment of premature ejaculation.
Invention is credited to Abdel-Hamid Abdou Ali, Ibrahim AbouBakr, Doherty, Paul C. JR., Place, Virgil A., Smith, William L., Wilson, Leland F..
Application Number | 20020037828 09/888250 |
Document ID | / |
Family ID | 25392848 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020037828 |
Kind Code |
A1 |
Wilson, Leland F. ; et
al. |
March 28, 2002 |
Administration of phosphodiesterase inhibitors for the treatment of
premature ejaculation
Abstract
A method is provided for treatment of premature ejaculation by
administration of a phosphodiesterase inhibitor, e.g., an inhibitor
of a Type III, Type IV, or Type V phosphodiesterase. In a preferred
embodiment, administration is on as "as needed" basis, i.e., the
drug is administered immediately or several hours prior to sexual
activity. Pharmaceutical formulations and packaged kits are also
provided.
Inventors: |
Wilson, Leland F.; (Menlo
Park, CA) ; Doherty, Paul C. JR.; (Cupertino, CA)
; Place, Virgil A.; (Kawaihae, HI) ; Smith,
William L.; (Montclair, NJ) ; Abdel-Hamid Abdou Ali,
Ibrahim AbouBakr; (Mansoura, EG) |
Correspondence
Address: |
REED & ASSOCIATES
800 MENLO AVENUE
SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
25392848 |
Appl. No.: |
09/888250 |
Filed: |
June 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09888250 |
Jun 21, 2001 |
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09467094 |
Dec 10, 1999 |
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09467094 |
Dec 10, 1999 |
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09181070 |
Oct 27, 1998 |
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6037346 |
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09181070 |
Oct 27, 1998 |
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08958816 |
Oct 28, 1997 |
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Current U.S.
Class: |
514/1 |
Current CPC
Class: |
A61P 15/08 20180101;
A61K 31/4439 20130101; A61K 31/444 20130101; A61K 31/496 20130101;
A61K 31/5025 20130101; A61K 31/519 20130101; A61K 31/501 20130101;
A61K 31/52 20130101; A61K 31/4709 20130101; A61P 15/00 20180101;
A61K 31/00 20130101; A61K 31/437 20130101; A61K 31/549 20130101;
A61K 31/426 20130101; A61K 9/0031 20130101; A61K 31/4745 20130101;
A61K 31/381 20130101; A61K 31/4704 20130101; A61K 31/343 20130101;
A61K 31/50 20130101; A61K 9/0056 20130101; A61K 31/522 20130101;
A61K 31/4166 20130101; A61K 31/5513 20130101; A61K 31/4015
20130101; A61K 45/06 20130101; A61K 9/006 20130101; A61K 31/502
20130101; A61K 31/4164 20130101; A61K 31/40 20130101; A61P 43/00
20180101; A61K 31/505 20130101; A61K 31/538 20130101 |
Class at
Publication: |
514/1 |
International
Class: |
A61K 031/00 |
Claims
We claim:
1. A method for treating premature ejaculation, which comprises
administering to a male individual in need of such treatment a
therapeutically effective amount of an active agent selected from
the group consisting of phosphodiesterase inhibitors and
pharmaceutically acceptable salts, esters, amides, prodrugs, and
active metabolites thereof.
2. The method of claim 1, wherein the active agent is contained
within a pharmaceutical formulation.
3. The method of claim 2, wherein the pharmaceutical formulation is
a unit dosage form.
4. The method of claim 1, wherein the active agent is administered
on an as-needed basis.
5. The method of claim 4, wherein the active agent is administered
immediately prior to sexual activity.
6. The method of claim 4, wherein the active agent is administered
about 0.5 to about 24 hours prior to sexual activity.
7. The method of claim 6, wherein the active agent is administered
about 1 to about 12 hours prior to sexual activity.
8. The method of claim 7, wherein the active agent is administered
about 1 to about 4 hours prior to sexual activity.
9. The method of any one of claims 5, 6, 7, and 8, wherein the
sexual activity is sexual intercourse.
10. The method of claim 2, wherein the formulation is a controlled
release dosage form.
11. The method of claim 10, wherein the formulation is a delayed
release dosage form.
12. The method of claim 10, wherein the formulation is a sustained
release dosage form.
13. The method of claim 11, wherein the formulation is a sustained
release dosage form.
14. The method of claim 12, wherein the sustained release dosage
form provides drug release over a time period of about 4 to about
48 hours.
15. The method of claim 1, wherein the active agent is administered
orally.
16. The method of claim 2, wherein the active agent is administered
orally.
17. The method of claim 16, wherein the pharmaceutical formulation
is selected from the group consisting of tablets, capsules,
caplets, solutions, suspensions syrups granules, beads, powders and
pellets.
18. The method of claim 17, wherein the pharmaceutical formulation
comprises a tablet.
19. The method of claim 17, wherein the pharmaceutical formulation
comprises a capsule.
20. The method of claim 1, wherein the active agent is administered
transmucosally.
21. The method of claim 20, wherein the active agent is
administered sublingually.
22. The method of claim 20, wherein the active agent is
administered buccally.
23. The method of claim 20, wherein the active agent is
administered intranasally.
24. The method of claim 20, wherein the active agent is
administered transurethrally.
25. The method of claim 20, wherein the active agent is
administered rectally.
26. The method of claim 20, wherein the active agent is
administered by inhalation.
27. The method of claim 1, wherein the active agent is administered
topically.
28. The method of claim 1, wherein the active agent is administered
transdermally.
29. The method of claim 1, wherein the active agent is administered
parenterally.
30. The method of claim 1, wherein the active agent is selected
from the group consisting of Type III phosphodiesterase inhibitors,
Type IV phosphodiesterase inhibitors, Type V phosphodiesterase
inhibitors, and pharmaceutically acceptable salts, esters, amides,
prodrugs, active metabolites, and combinations thereof.
31. The method of claim 30, wherein the active agent is a Type III
phosphodiesterase inhibitor.
32. The method of claim 31, 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.
33. The method of claim 32, wherein the Type III phosphodiesterase
inhibitor is a bipyridine.
34. The method of claim 33, wherein the bipyridine is selected from
the group consisting of amrinone, milrinone and olprinone.
35. The method of claim 30, wherein the active agent is a Type IV
phosphodiesterase inhibitor.
36. The method of claim 35, 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.
37. The method of claim 36, wherein the Type IV phosphodiesterase
inhibitor is a pyrrolidinone.
38. The method of claim 37, wherein the pyrrolidinone is
rolipram.
39. The method of claim 30, wherein the active agent is a Type V
phosphodiesterase inhibitor.
40. The method of claim 39, wherein the Type V phosphodiesterase
inhibitor is selected from the group consisting of:
(S)-2-(2-hydroxymethyl-1-pyrrol-
idinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(2-pyrimidinylmethyl)carba-
moyl]pyrimidine;
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro--
4-methoxybenzylanmino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-
-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl] pyrimidine;
zaprinast; 1-(3-chloroanilino)-4-phenylphthalazine; dipyridamole;
vinpocetine; FR229934; 1-methyl-3-isobutyl-8-methylamino)xanthine;
IC-351, methyl
2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trime-
thoxyphenyl)-3-isoquinoline carboxylate dihydrochloride;
4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3(2H)pyridaz-
inone;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-
-piperidine-carboxylic acid;
(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluo-
romethyl)-phenylmethyl-5-methyl-cyclopent-4,5]midazo[2,1-]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-pro
poxyphenyl)-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-piper-
idine carboxylic acid; vardenafil; GF-196960; Sch-51866; sodium
1-[6-chloro-4-(3,
4-methylenedioxybenzyl)-aminoquinazolin-2-yl]piperidine-
-4-carboxylate sesquihydrate;
1,3-dimethyl-6(2-propoxy-5-methanesulfonamid-
ophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one; and
1-ethyl-3-methyl-6-(2-propoxy-5-(4-methylthiazol-2-yl)phenyl-1,5-dihydrop-
yrazolo[3,4-d]pyrimidin-4-one.
41. The method of claim 39, wherein the Type V phosphodiesterase
inhibitor is selected from the group consisting of griseolic acid
derivatives, 2-phenylpurinones, phenylpyridones, fused and
condensed pyrimidines, pyrimidopyrimidines, purine compounds,
quinazoline compounds, phenylpyrimidinones, and
imidazoquinoxalinones.
42. The method of claim 39, wherein the Type V phosphodiesterase
inhibitor is selected from the group consisting of sildenafil,
zaprinast, dipyridamole,
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methox-
y-benzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine,
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzyla-
mino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine, and
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-
-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine, and
pharmaceutically acceptable salts thereof.
43. The method of claim 42, wherein the Type V phosphodiesterase
inhibitor is sildenafil or a pharmaceutically acceptable salt
thereof.
44. The method of claim 43, wherein the Type V phosphodiesterase
inhibitor is sildenafil citrate.
45. The method of claim 1, wherein the active agent is a
nonspecific phosphodiesterase inhibitor selected from the group
consisting of theophylline, theobromine, IBMX, pentoxifylline and
papaverine.
46. The method of claim 2, wherein the pharmaceutical formulation
further comprises an additional active agent.
47. The method of claim 46, wherein the additional active agent is
selected from of antidepressant drugs, serotonin agonists,
serotonin antagonists, adrenergic agonists, adrenergic antagonists,
adrenergic neurone blockers, and derivatives and analogs
thereof.
48. The method of claim 47, wherein the agent is an antidepressant
drug.
49. The method of claim 48, wherein the antidepressant drug is
selected from the group consisting of amesergide, amineptine,
amitriptyline, amoxapine, benactyzine, brofaromine, bupropion,
butriptyline, cianoprarmine, citalopram, clomipramine, clorgyline,
clovoxamine, dapoxetine, demexiptiline, desipramine, dibenzepin,
dimetacrine, dothiepin, doxepin, duloxetine, etoperidone,
femoxetine, fezolamine, fluoxetine, fluvoxamine, ifoxetine,
imipramine, iprindole, isocarboxazid, levoprotiline, lofepramine,
maprotiline, medifoxamine, melitracen, metapramine,
methylphenidate, mianserin, milnacipran, minaprine, mirtazapine,
moclobemide, nefazodone, nialamide, nomifensine, nortriptyline,
opipramol, oxaflozane, oxaprotiline, oxitriptan, paroxetine,
phenelzine, pirlindole, propizepine, protriptyline, quinupramine,
rolipram, selegiline, sertraline, setiptiline, sibutranine,
teniloxazine, tianeptine, tofenacin, toloxatone, tranylcypromine,
trazodone, trimipramine, tryptophan, venlafaxine, viloxazine,
viqualine, zimeldine, and combinations thereof.
50. The method of claim 47, wherein the agent is a serotonin
agonist.
51. The method of claim 50, wherein the serotonin agonist is a
5-HT.sub.4 agonst.
52. The method of claim 51, wherein the 5-HT4 agonist is selected
from the group consisting of cisapride and norcisapride.
53. The method of claim 47, wherein the agent is a serotonin
antagonist.
54. The method of claim 53, wherein the serotonin agonist is a
5-HT.sub.3antagonist.
55. The method of claim 54, wherein the 5-HT.sub.3 antagonist is
selected from the group consisting of ondansetron, ergot alkaloids,
granisetron, trimethobenzamide, tropisetron, dolasetron,
batanopride and zacopride.
56. A pharmaceutical formulation for treating premature ejaculation
and adapted for transmucosal drug administration, comprising a
therapeutically effective amount of a phosphodiesterase inhibitor
and a carrier suitable for transmucosal drug delivery buccally,
sublingually, intranasally, rectally, or by inhalation.
57. The formulation of claim 56, comprising a solid dosage form for
application to the buccal mucosa, and wherein the carrier is
suitable for buccal drug delivery.
58. The formulation of claim 57, wherein the carrier is a
hydrolyzable polymer.
59. The formulation of claim 57, wherein the dosage form further
comprises an adhesive suitable for affixing the dosage form to the
buccal mucosa.
60. The formulation of claim 56, comprising a dosage form for
application to the sublingual mucosa, and wherein the carrier is
suitable for sublingual drug delivery.
61. The formulation of claim 56, comprising a dosage form for
application to the rectal mucosa, and the carrier is suitable for
rectal drug delivery.
62. The formulation of claim 61, comprising a rectal
suppository.
63. The formulation of claim 56, comprising a dosage form suitable
for inhalation.
64. The formulation of claim 63, comprising a liquid.
65. The formulation of claim 63, comprising a dry powder.
66. The formulation of claim 63, comprising an aerosol
composition.
67. The formulation of claim 1, wherein the active agent is
selected from the group consisting of Type III phosphodiesterase
inhibitors, Type IV phosphodiesterase inhibitors, Type V
phosphodiesterase inhibitors, and pharmaceutically acceptable
salts, esters, amides, prodrugs, active metabolites, and
combinations thereof.
68. The formulation of claim 67, wherein the active agent is a Type
III phosphodiesterase inhibitor.
69. The formulation of claim 68, 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.
70. The formulation of claim 69, wherein the Type III
phosphodiesterase inhibitor is a bipyridine.
71. The formulation of claim 70, wherein the bipyridine is selected
from the group consisting of amrinone, milrinone and olprinone.
72. The formulation of claim 67, wherein the active agent is a Type
IV phosphodiesterase inhibitor.
73. The formulation of claim 72, 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.
74. The formulation of claim 73, wherein the Type IV
phosphodiesterase inhibitor is a pyrrolidinone.
75. The formulation of claim 74, wherein the pyrrolidinone is
rolipram.
76. The formulation of claim 67, wherein the active agent is a Type
V phosphodiesterase inhibitor.
77. The formulation of claim 76, wherein the Type V
phosphodiesterase inhibitor is selected from the group consisting
of:
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-
-5-[N-(2-pyrimidinylmethyl)-carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydro-1,-
7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoe-
thyl)carbamoyl]-pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-ch-
loro-4-methoxy-benzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]
pyrimidine; zaprinast; 1-(3-chloroanilino)-4-phenylphthalazine;
dipyridamole; vinpocetine; FR229934;
1-methyl-3-isobutyl-8-(methylamino)x- anthine; IC-351; methyl
2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinyl-
methoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate
dihydrochloride;
4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)prop-
oxy]-3(2H)pyridazinone;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-- 2-quinazolinyl]
-4-piperidine-carboxylic acid; (+)-cis-5,6a,7,9,9,9a-hexah-
ydro-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--
octahydrocyclo-pent[4,5]imidazo[2,1-b]purin-4-one;
3-acetyl-1-(2-chloroben- zyl)-2-propylindole-6-carboxylate;
4-bromo-5-(3-pyridylmethylamino)-6-(3-(- 4-chlorophenyl)
propoxy)-3-(2H)pyridazinone; 1-methyl-5-(5-morpholinoacety-
l-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-p-
iperidine carboxylic acid; vardenafil; GF-196960; Sch-51866; sodium
1-[6-chloro-4-(3,
4-methylenedioxybenzyl)-aminoquinazolin-2-yl]piperidine-
-4-carboxylate sesquihydrate;
1,3-dimethyl-6(2-propoxy-5-methanesulfonamid-
ophenyl)-1,5-dihydropyrazolo [3,4-d]pyrinidin-4-one; and
1-ethyl-3-methyl-6-(2-propoxy-5-(4-methylthiazol-2-yl)phenyl-1,5-dihydrop-
yrazolo[3,4-d]pyrimidin-4-one.
78. The formulation of claim 76, wherein the Type V
phosphodiesterase inhibitor is selected from the group consisting
of griseolic acid derivatives, 2-phenylpurinones, phenylpyridones,
fused and condensed pyrimidines, pyrimidopyrimidines, purine
compounds, quinazoline compounds, phenylpyrimidinones, and
imidazoquinoxalinones.
79. The formulation of claim 76, wherein the Type V
phosphodiesterase inhibitor is selected from the group consisting
of sildenafil, zaprinast, dipyridamole,
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methox-
y-benzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine,
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)
-4-(3-chloro-4-methoxybenzyl-
amino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine, and
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-
-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine, and
pharmaceutically acceptable salts thereof.
80. The formulation of claim 79, wherein the Type V
phosphodiesterase inhibitor is sildenafil or a pharmaceutically
acceptable salt thereof.
81. The formulation of claim 80, wherein the Type V
phosphodiesterase inhibitor is sildenafil citrate.
82. The formulation of claim 67, wherein the active agent is a
nonspecific phosphodiesterase inhibitor selected from the group
consisting of theophylline, theobromine, IBMX, pentoxifylline and
papaverine.
83. The formulation of claim 67, wherein the pharmaceutical
formulation further comprises an additional active agent.
84. The formulation of claim 83, wherein the additional active
agent is selected from of antidepressant drugs, serotonin agonists,
serotonin antagonists, adrenergic agonists, adrenergic antagonists,
adrenergic neurone blockers, and derivatives and analogs
thereof.
85. The formulation of claim 84, wherein the agent is an
antidepressant drug.
86. The formulation of claim 85, wherein the antidepressant drug is
selected from the group consisting of amesergide, amineptine,
amitriptyline, amoxapine, benactyzine, brofaromine, bupropion,
butriptyline, cianopramine, citalopram, clomipramine, clorgyline,
clovoxamine, dapoxetine, demexiptiline, desipramine, dibenzepin,
dimetacrine, dothiepin, doxepin, duloxetine, etoperidone,
femoxetine, fezolamine, fluoxetine, fluvoxamine, ifoxetine,
imipramine, iprindole, isocarboxazid, levoprotiline, lofepramine,
maprotiline, medifoxamine, melitracen, metapramine,
methylphenidate, mianserin, milnacipran, minaprine, mirtazapine,
moclobemide, nefazodone, nialamide, nomifensine, nortriptyline,
opipramol, oxaflozane, oxaprotiline, oxitriptan, paroxetine,
phenelzine, pirlindole, propizepine, protriptyline, quinupramine,
rolipram, selegiline, sertraline, setiptiline, sibutramine,
teniloxazine, tianeptine, tofenacin, toloxatone, tranylcypromine,
trazodone, trimipramine, tryptophan, venlafaxine, viloxazine,
viqualine, zimeldine, and combinations thereof.
87. The formulation of claim 84, wherein the agent is a serotonin
agonist.
88. The formulation of claim 87, wherein the serotonin agonist is a
5-HT.sub.4 agonist.
89. the formulation of claim 88, wherein the 5-HT.sub.4 agonist is
selected from the group consisting of cisapride and
norcisapride.
90. The formulation of claim 84, wherein the agent is a serotonin
antagonist.
91. The formulation of claim 90, wherein the serotonin agonist is a
5-HT.sub.3 antagonist.
92. The formulation of claim 91, wherein the 5-HT.sub.3 antagonist
is selected from the group consisting of ondansetron, ergot
alkaloids, granisetron, trimethobenzamide, tropisetron, dolasetron,
batanopride and zacopride.
93. A packaged kit for a patient to use in the treatment of
premature ejaculation, comprising: a pharmaceutical formulation of
a phosphodiesterase inhibitor; a container housing the
pharmaceutical formulation during storage and prior to
administration; and instructions for carrying out drug
administration in a manner effective to treat premature
ejaculation.
94. The packaged kit of claim 93, wherein the pharmaceutical
formulation is an oral dosage form containing a unit dosage of the
phosphodiesterase inhibitor, the unit dosage being a
therapeutically effective dosage for treatment of premature
ejaculation.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of U.S. patent application
Ser. No. 09/467,094, filed Dec. 10, 1999, which is a
continuation-in-part of U.S. Ser. No. 09/181,070, filed Oct. 27,
1998 and issued on Mar. 14, 2000 as U.S. Pat. No. 6,037,346, which
was a continuation-in-part of U.S. Ser. No. 08/958,816, filed Oct.
28, 1997, abandoned. The disclosures of each of the aforementioned
applications are incorporated by reference in their entireties.
TECHNICAL FIELD
[0002] This invention relates generally to methods and
pharmaceutical compositions for the treatment of premature
ejaculation. More particularly, the invention relates to the use of
phosphodiesterase inhibitors in such methods and compositions.
BACKGROUND
[0003] Premature ejaculation is a debilitating yet common sexual
dysfunction, and has been estimated to affect at least 30 to 40
percent of men at some point in their lives (Derogatis (1980) Med.
Aspects Hum. Sexuality 14:1168-76; Frank et al. (1978) New Engl. J.
Med. 299:111-115; Scheinetal. (1988) Fam. Pract. Res. J.
7(3):122-134). The condition can lead to an inability to enter into
or sustain relationships, can cause psychological damage to
sufferers, and can also impair reproductive success.
[0004] The Diagnostics and Statistical Manual of Mental Disorders
(DSM-IV) (Washington, D.C.: American Psychiatric Association, 1994)
delineates three criteria for a diagnosis of premature ejaculation:
(1) "persistent or recurrent ejaculation with minimal sexual
stimulation before, on or shortly after penetration and before the
person wishes it," which is (2) associated with "marked distress or
interpersonal difficulty," and (3) not due exclusively to the
"direct" effects of a "substance" (with withdrawal from opioids
cited as an example). The disorder is usually primary, but can also
be secondary. "Primary" premature ejaculation refers to a lifelong,
typically congenital condition, while "secondary" premature
ejaculation refers to a late onset condition, acquired after a
period of normal functioning. Sexual dysfunctions such as premature
ejaculation may also be further characterized as being generalized
or limited to certain situations, and with respect to degree or
frequency of the disturbance.
[0005] Premature ejaculation has historically been treated by
psychosexual counseling in combination with "behavioral" therapies
such as the so-called "pause" and "pause-squeeze" techniques. See
St. Lawrence et al. (1992), "Evaluation and Treatment of Premature
Ejaculation: A Critical Review," Int. J. Psychiatry in Medicine
22(1):77-97; Semans, "Premature Ejaculation: A New Approach,"
Southern Medical Journal 49:353-357, regarding the "pause"
technique; and Masters and Johnson, Human Sexual Inadequacy,
Little, Brown & Company, Boston, Mass., 1970, regarding the
"pause-squeeze" technique. Any improvement resulting from the
aforementioned techniques is short-lived, however, and the
cooperation of a man's sexual partner is required. Typically,
psychosexual counseling also requires the cooperation of the
partner. Furthermore, many men may demand a quicker solution to the
problem or are unwilling to attend counseling sessions. In
addition, psychosexual counseling requires specialized therapists
who may not be available to all patients, particularly in remote
locations. Finally, counseling benefits only a subset of patients,
i.e., those for whom the condition is psychogenic. Psychological
therapies cannot alleviate premature ejaculation resulting from
non-psychological causes.
[0006] Topical anesthetic agents and intracavemosal injection of
medicaments have also been employed to treat patients suffering
from premature ejaculation. However, anesthetic agents are
problematic insofar as they necessarily decrease tissue sensitivity
and thereby diminish sexual pleasure. Also, topical anesthetics can
be transferred to sexual partners and thereby decrease their
sensitivity and pleasure as well. Intracavernosal injection is
associated with pain and discomfort, and is not a preferred mode of
drug administration. Various devices have also been proposed to
delay ejaculation; however, such devices can be awkward,
inconvenient and embarrassing to use.
[0007] Methods for treating premature ejaculation by systemic
administration of several different antidepressant compounds have
been described (U.S. Pat. Nos. 4,507,323,4,940,731, 5,151,448, and
5,276,042; PCT Publication No. WO95/13072). However, these drugs
may not be effective for all patients, and the side effects of
these drugs can halt treatment or impair patient compliance.
Disease states or adverse interactions with other drugs may
contraindicate the use of these compounds or require lower dosages
that may not be effective to delay the onset of ejaculation.
[0008] For example, administration of the antidepressant fluoxetine
has been claimed to treat premature ejaculation; see U.S. Pat. No.
5,151,448. However, the administration of fluoxetine has many
undesired aspects. Patients with hepatic or renal impairments may
not be able to use fluoxetine due to its metabolism in the liver
and excretion via the kidney. Systemic events during fluoxetine
treatment involving the lungs, kidneys or liver have occurred, and
death has occurred from overdoses. In addition, numerous side
effects are associated with oral fluoxetine administration include
hair loss, nausea, vomiting, dyspepsia, diarrhea, anorexia,
anxiety, nervousness, insomnia, drowsiness, fatigue, headache,
tremor, dizziness, convulsions, sweating, pruritis, and skin
rashes. Fluoxetine interacts with a range of drugs, often by
impairing their metabolism by the liver.
[0009] U.S. Pat. No. 4,940,731 describes the oral or parenteral
administration of sertraline for treating premature ejaculation. It
has been recognized that sertraline shares many of the same
problems as fluoxetine; see Martindale, The Extra Pharmacopoeia,
31st edition, at p. 333 (London: The Royal Pharmaceutical Society,
1996). Sertraline is metabolized in the liver, and is excreted in
the urine and feces. Thus, patients with cirrhosis must take lower
doses, and caution must be exercised when administering sertraline
to patients with renal impairment. Individuals taking monoamine
oxidase inhibitors cannot take sertraline due to the risk of
toxicity. Side effects resulting from oral sertraline
administration include nausea, diarrhea, dyspepsia, insomnia,
somnolence, sweating, dry mouth, tremor and mania. Rare instances
of coma, convulsions, fecal incontinence and gynecomastia have
occurred in patients undergoing sertraline therapy.
[0010] U.S. Pat. No. 5,276,042 describes the administration of
paroxetine for the treatment of premature ejaculation. Paroxetine
is predominantly excreted in the urine, and decreased doses are
recommended in patients with hepatic and renal impairments. Like
sertraline, paroxetine cannot be given to patients undergoing
treatment with a monoamine oxidase inhibitor. Side effects from
oral administration of paroxetine include hyponatremia, asthenia,
sweating, nausea, decreased appetite, oropharynx disorder,
somnolence, dizziness, insomia, tremor, anxiety, impaired
micturition, weakness and paresthesia.
[0011] All of the known methods to treat premature ejaculation are
thus problematic in one or more respects. An ideal method would not
require ongoing ("chronic") drug therapy or use of active agents
with numerous and/or serious side effects. An ideal method would be
useful in the treatment of individuals with secondary, acquired
premature ejaculation as well as those suffering from a primary,
lifelong condition. The method would not involve application of
anesthetic agents, intracavemosal drug administration, or use of
devices, and would not require ongoing counseling sessions.
[0012] It has now been discovered by the present inventors that
phosphodiesterase (PDE) inhibitors, as a class, are unexpectedly
useful in treating premature ejaculation, and meet all of the
aforementioned requirements. The discovery is indeed surprising
insofar as PDE inhibitors--of which sildenafil citrate,
commercially available as Viagra.RTM., is a representative
compound--are used to treat impotence and thus enhance sexual
function, i.e., as opposed to modulating sexual function in a
manner that allows delay of ejaculation.
[0013] Phosphodiesterases are a class of intracellular enzymes
involved in the metabolism of the second messenger nucleotides,
cyclic adenosine monophosphate (cAMP), and cyclic guanosine
monophosphate (cGMP) (see, e.g., Doherty, "Oral, Transdermal and
Transurethral Therapies for Erectile Dysfunction" in Male
Infertility and Dysfunction, Hellstrom, ed., Chapter 34 (New York,
N.Y.: Springer-Verlag, 1997)). Numerous phosphodiesterase
inhibitors have previously been described in the literature for a
variety of therapeutic uses, including treatment of obstructive
lung disease, allergies, hypertension, angina, congestive heart
failure and depression (see, e.g., Goodman and Gilman's The
Pharmacological Basis of Therapeutic Ninth Edition, Chapter 34).
Oral and parenteral administration of phosphodiesterase inhibitors,
as alluded to above, has also been suggested for the treatment of
erectile dysfunction (Doherty, supra; see also PCT Publication Nos.
WO 96/16644 and WO 94/28902).
[0014] As explained by Komas et al. in Phosphodiesterase
Inhibitors, Schudt et al., Eds., Ch. 6 (San Diego, Calif.: Academic
Press, 1996), those initially working in the field partially
purified what was believed to be a single enzyme responsible for
specifically hydrolyzing the 3'-bond of cyclic nucleotides.
However, it later became clear that multiple forms of
phosphodiesterase inhibitors were present in different tissues; the
enzymes were classified into three major groups, one of which
exhibited high affinity for cAMP and designated as the "low
K.sub.m" cAMP PDE. This "low K.sub.m" cAMP PDE was ultimately
discovered to consist of two distinct isoenzymes having entirely
different properties, including physical properties, kinetic
characteristics and inhibitor specificities. One isoenzyme was
found to be very sensitive to inhibition by cilostamide and cGMP,
and is now known as the cAMP-specific, cGMP-inhibited cyclic
nucleotide phosphodiesterase (cGI-PDE) or PDE III, while the second
isoenzyme was classified as PDE IV. Komas et al., supra.
[0015] The phosphodiesterases have now been classified into ten
major families, Types I-XI, based on amino acid or DNA sequences.
The members of the family vary in their tissue, cellular and
subcellular distribution, as well as their links to cAMP and cGMP
pathways. For example, the corpora cavemosa contains: Type III
phosphodiesterases, which as explained above are cAMP-specific cGMP
inhibitable; Type IV phosphodiesterases, the high affinity,
high-specificity cAMP-specific form; and Type V phosphodiesterases,
one of the cGMP-specific forms.
[0016] Accordingly, the present invention is addressed to the
limitations of the prior art, and provides a novel treatment for
individuals suffering from either primary or secondary premature
ejaculation, wherein drug administration may be on an "as-needed"
basis rather than necessarily involving chronic pharmacotherapy,
and does not involve use of anesthetic agents, intracavemosal drug
administration, or use of devices. To the best of applicants'
knowledge, the present method of treating premature ejaculation is
novel and completely unsuggested by the prior art.
SUMMARY OF THE INVENTION
[0017] It is a primary object of the invention to address the
above-described need in the art by providing a novel method for the
treatment of premature ejaculation by administering an effective
amount of a phosphodiesterase inhibitor to an individual in need of
such therapy, wherein the term "phosphodiesterase inhibitor"
includes phosphodiesterase inhibitors per se as well as
pharmaceutically acceptable (and pharmacologically active) salts,
esters, amides, prodrugs, active metabolites and other derivatives
thereof It is another object of the invention to provide such a
method wherein the phosphodiesterase inhibitor is administered
orally.
[0018] It is another object of the invention to provide such a
method wherein the phosphodiesterase inhibitor is administered
transmucosally, e.g., via the sublingual, buccal, nasal,
transurethral or rectal routes, or via inhalation.
[0019] It is another object of the invention to provide such a
method wherein the phosphodiesterase inhibitor is administered
topically, transdermally, parenterally, or by other routes.
[0020] It is still another object of the invention to provide such
a method wherein the phosphodiesterase inhibitor is a Type III
inhibitor, a Type IV inhibitor, a Type V inhibitor, or a
nonspecific phosphodiesterase inhibitor.
[0021] It is yet another object of the invention to provide such a
method wherein the phosphodiesterase inhibitor is a Type V
inhibitor.
[0022] It is a further object of the invention to provide such a
method wherein drug administration is on an as-needed basis.
[0023] It is still a further object of the invention to provide
such a method wherein the active agent is administered in a
controlled release formulation.
[0024] It is yet a further object of the invention to provide such
a method wherein the controlled release formulation is a sustained
release formulation and/or a delayed release formulation.
[0025] It is an additional object of the invention to provide such
a method wherein the controlled release formulation is a sustained
release formulation that provides drug release over a time period
in the range of about 4 to about 48 hours.
[0026] It is still an additional object of the invention to provide
a composition containing an amount of a phosphodiesterase inhibitor
effective for the treatment of premature ejaculation.
[0027] It is another object of the invention to provide a packaged
kit comprised of a container housing a phosphodiesterase inhibitor
formulation as provided herein and instructions for administering
the formulation in a manner effective to treat premature
ejaculation.
[0028] Additional objects, advantages and novel features of the
invention will be set forth in part in the description which
follows, and in part will become apparent to those skilled in the
art upon examination of the following, or may be learned by
practice of the invention.
[0029] In a first aspect of the invention, a method is provided for
the treatment of an individual prone to or suffering from premature
ejaculation, the method comprising administering to an individual
in need of such treatment a pharmaceutical formulation containing a
therapeutically effective amount of an active agent selected from
the group consisting of phosphodiesterase inhibitors and
pharmaceutically acceptable, pharmacologically active salts,
esters, amides, prodrugs, active metabolites, and other derivatives
thereof Administration of the pharmaceutical formulation may be on
an "as-needed" basis or within the context of an ongoing dosage
regimen. By "as-needed" dosing, also known as pro re nata dosing,
is meant the administration of a single dose of the active agent at
some time prior to anticipated sexual activity. Administration can
be immediately prior to sexual activity, or up to about 2 or 3
hours prior to anticipated sexual activity, although with sustained
release dosage forms, a single dose can provide therapeutic
efficacy over an extended time period in the range of about 4 to 48
hours, depending on the formulation. Drug delivery may be
accomplished through any mode of administration, including, but not
limited to, the oral and transmucosal routes.
[0030] In a further aspect of the invention, pharmaceutical
formulations are provided for carrying out the method of the
invention. The pharmaceutical formulations comprise a
therapeutically effective amount of an active agent as provided
herein, a pharmacologically acceptable carrier or vehicle,
generally a carrier or vehicle suitable for transmucosal drug
administration, and, optionally, an enhancer. Other types of
components may be incorporated into the formulation as well, e.g.,
excipients, surfactants, preservatives (e.g., antioxidants),
stabilizers, chelating agents, and the like, as will be appreciated
by those skilled in the art of pharmaceutical formulation
preparation and drug delivery.
[0031] In another aspect of the invention, a packaged kit is
provided for a patient to use in the treatment of premature
ejaculation. The kit includes a pharmaceutical formulation of a
phosphodiesterase inhibitor, a container housing the pharmaceutical
formulation during storage and prior to administration, and
instructions, e.g., written instructions on a package insert or
label, for carrying out drug administration in a manner effective
to treat premature ejaculation. The pharmaceutical formulation may
be any formulation described herein, e.g., an oral dosage form
containing a unit dosage of the phosphodiesterase inhibitor, the
unit dosage being a therapeutically effective dosage for treatment
of premature ejaculation.
BRIEF DESCRIPTION OF THE DRAWING
[0032] FIG. 1 is an exploded, perspective view of one embodiment of
a transurethral drug administration device that may be used in
conjunction with the present method.
DETAILED DESCRIPTION OF THE INVENTION
[0033] I. Definitions and Overview:
[0034] Before describing the present invention in detail, it is to
be understood that this invention is not limited to specific active
agents, dosage forms, dosing regimens, or the like, as such may
vary. It is also to be understood that the terminology used herein
is for the purpose of describing particular embodiments only, and
is not intended to be limiting.
[0035] It must be noted that as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "an active agent" or "a
pharmacologically active agent" includes a single active agent as
well a two or more different active agents in combination,
reference to "a carrier" includes mixtures of two or more carriers
as well as a single carrier, and the like.
[0036] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0037] The terms "active agent" and "pharmacologically active
agent" are used interchangeably herein to refer to a chemical
compound that induces a desired effect, i.e., in this case,
treatment of premature ejaculation. The primary active agents
herein are phosphodiesterase inhibitors, although combination
therapy wherein a phosphodiesterase inhibitor is administered with
one or more additional active agents is also within the scope of
the present invention. Such combination therapy may be carried out
by administration of the different active agents in a single
composition, by concurrent administration of the different active
agents in different compositions, or by sequential administration
of the different active agents. Included are derivatives and
analogs of those compounds or classes of compounds specifically
mentioned that also induce the desired effect.
[0038] The term "phosphodiesterase inhibitor" as used herein is
intended to mean an agent that is capable of inhibiting or
reducing--selectively or nonselectively--the activity of a
phosphodiesterase. Unless otherwise indicated, the term
"phosphodiesterase inhibitor" is intended to include
phosphodiesterase inhibitors per se as well as salts, esters,
amides, prodrugs, active metabolites and other derivatives thereof,
it being understood that any salts, esters, amides, prodrugs,
active metabolites or other derivatives are pharmaceutically
acceptable as well as pharmacologically active. Phosphodiesterase
inhibitors that may be used in conjunction with the present method
of treating premature ejaculation include, but are not limited to,
inhibitors of the type III phosphodiesterases (i.e., the
cAMP-specific-cGMP inhibitable phosphodiesterases), the type IV
phospodiesterases (i.e., the high affinity-high specificity cAMP
phosphodiesterases) and the Type V phosphodiesterases
(cGMP-specific phosphodiesterases). Additional inhibitors that may
be used in conjunction with the present invention are nonspecific
phosphodiesterase inhibitors, inhibitors of cGMP-specific
phosphodiesterases other than Type V phosphodiesterase, and
specific and nonspecific inhibitors of any other phosphodiesterase
inhibitors that are known or hereafter identified.
[0039] The terms "treating" and "treatment" as used herein refer to
the ability to increase an individual's ejaculatory latency (i.e.,
delay ejaculation) during sexual activity, particularly sexual
intercourse, relative to that individual's ejaculatory latency in
the absence of pharmacotherapy as provided herein. Preferably, upon
treatment according to the present invention, an individual's
ejaculatory latency is increased by at least a factor of tvo, more
preferably a factor of four and most preferably a factor of at
least ten.
[0040] By an "effective" amount or a "therapeutically effective
amount" of a drug or pharmacologically active agent is meant a
nontoxic but sufficient amount of the drug or agent to provide the
desired effect, i.e., an increase in ejaculatory latency as
explained above.
[0041] By "pharmaceutically acceptable," such as in the recitation
of a "pharmaceutically acceptable carrier," or a "pharmaceutically
acceptable acid addition salt," is meant a material that is not
biologically or otherwise undesirable, i.e., the material may be
incorporated into a pharmaceutical composition administered to a
patient without causing any undesirable biological effects or
interacting in a deleterious manner with any of the other
components of the composition in which it is contained.
"Pharmacologically active" (or simply "active") as in a
"pharmacologically active" derivative or metabolite, refers to a
derivative or metabolite having the same type of pharmacological
activity as the parent compound and approximately equivalent in
degree. When the term "pharmaceutically acceptable" is used to
refer to a derivative (e.g., a salt) of an active agent, it is to
be understood that the compound is pharmacologically active as
well, i.e., therapeutically effective for the treatment of
premature ejaculation.
[0042] By "as-needed" dosing, also referred to as "pro re nata"
dosing, "pm" dosing, and "on demand" dosing or administration, is
meant the administration of an active agent at some time prior to
anticipated sexual activity and within a time interval sufficient
to provide for the desired therapeutic effect, i.e., delay in
ejaculation latency during sexual activity. Preferably, "as-needed"
administration herein does not involve priming doses or chronic
administration. As-needed administration may involve administration
immediately prior to sexual activity, but will generally be in the
range of about 0.5 to 24 hours prior to anticipated sexual
activity, preferably in the range of about 1 to 12 hours prior to
anticipated sexual activity, most preferably in the range of about
1 to 4 hours prior to anticipated sexual activity. "As-needed"
administration will generally not involve dosing more than once a
day.
[0043] The term "controlled release" is intended to refer to any
drug-containing formulation in which release of the drug is not
immediate, i.e., with a "controlled release" formulation, oral
administration does not result in immediate release of the drug
into an absorption pool. The term is used interchangeably with
"nonimmediate release" as defined in Remington: The Science and
Practice ofPharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing
Company, 1995). As discussed therein, immediate and nonimmediate
release can be defined kinetically by reference to the following
equation: 1
[0044] The "absorption pool" represents a solution of the drug
administered at a particular absorption site, and k.sub.r, k.sub.a
and k.sub.e are first-order rate constants for (1) release of the
drug from the formulation, (2) absorption, and (3) elimination,
respectively. For immediate release dosage forms, the rate constant
for drug release k.sub.r is far greater than the absorption rate
constant k.sub.a. For controlled release formulations, the opposite
is true, i.e., k.sub.r<<k.sub.a, such that the rate of
release of drug from the dosage form is the rate-limiting step in
the delivery of the drug to the target area. The term "controlled
release" as used herein includes any nonimmediate release
formulation, including but not limited to sustained release,
delayed release and pulsatile release formulations.
[0045] The term "sustained release" is used in its conventional
sense to refer to a drug formulation that provides for gradual
release of a drug over an extended period of time, and that
preferably, although not necessarily, results in substantially
constant blood levels of a drug over an extended time period.
[0046] By the term "transdermal" drug delivery is meant delivery by
passage of a drug through the skin or mucosal tissue and into the
bloodstream. "Transdermal" delivery is also intended to encompass
passage through scrotal skin.
[0047] The term "topical administration" is used in its
conventional sense to mean delivery of a topical drug or
pharmacologically active agent to the skin or mucosa.
[0048] By "transmucosal" drug delivery is meant administration of a
drug to the mucosal surface of an individual so that the drug
passes through the mucosal tissue and into the individual's blood
stream. Transmucosal drug delivery may be "buccal" or
"transbuccal," referring to delivery of a drug by passage through
an individual's buccal mucosa and into the bloodstream. Another
form of transmucosal drug delivery herein is "sublingual" drug
delivery, which refers to delivery of a drug by passage of a drug
through an individual's sublingual mucosa and into the bloodstream.
An additional form of transmucosal drug delivery herein is "rectal"
or "transrectal" drug delivery, referring to delivery of a drug by
passage of a drug through an individual's rectal mucosa and into
the bloodstream. Another form of transmucosal drug delivery is
"urethral" or "transurethral" delivery, referring to delivery of
the drug into the urethra such that the drug contacts and passes
through the wall of the urethra.
[0049] In order to carry out the method of the invention, a
selected phosphodiesterase inhibitor is administered to a male
individual suffering from or prone to premature ejaculation, either
chronic, lifelong ("primary") premature ejaculation or acquired
("secondary") premature ejaculation. The active agent may be
administered orally, transmucosally (including buccally,
sublingually, transurethrally, and rectally), topically,
transdermally, by inhalation, or using any other route of
administration. Oral administration, because of its convenience, is
preferred for those active agents that have sufficient oral
bioavailability.
[0050] II. Active Agents:
[0051] The active agent administered using the method of the
invention is a phosphodiesterase inhibitor. The agent may be an
inhibitor of a Type III phosphodiesterase, a Type IV
phosphodiesterase, Type V phosphodiesterase, and/or another
phosphodiesterase. Further, the agent may be a specific or a
nonspecific inhibitor.
[0052] Suitable Type III inhibitors include, but are not limited
to, those described in U.S. Pat. No. 6,156,753 to Doherty, Jr. et
al., assigned to VIVUS, Inc. (Mountain View, Calif.). Such
inhibitors include, by way of example: bipyridines such as
milrinone, amrinone and olprinone; imidazolones such as piroximone
and enoximone; imidazolines such as imazodan and 5-methyl-imazodan;
imidazoquinoxalines; dihydropyridazinones such as indolidan and LY
81512 (5-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-y-
l)-1,3-dihydro-indol-2-one); dihydroquinolinone compounds such as
cilostamide, cilostazol, vesnarinone, and OPC 3911
(N-cyclohexyl-N-hydroxymethyl-4-(2-oxo-1,2-dihydro-quinolin-6-yloxy)-buty-
ramide); other compounds such as anagrelide, bemoradan, ibudilast,
isomazole, lixazinone, motapizone, olprinone, phthalazinol,
pimobendan, quazinone, siguazodan and trequinsin; and mixed Type
III and Type IV inhibitors such as benafentrine,
cis-6-[p-acetamidophenyl]-1,2,3,4,4a,10b-
-hexahydro-8,9-dimethoxy-2-methylbenzo-[c][1,6]-naphthyridine, EMD
54622
(5-[1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-1,2,3,4-tetrahydrochinolin-6-yl-
]-6-methyl-3,6-dihydro-1,3,4-thiadiazin-2-one), Org 20241
(N-hydroxy-4-[3,4-dimethoxyphenyl]-thiazole-2-carboximidamide),
Org30029
(N-hydroxy-5,6-dimethoxybenzo-[b]-thiophene-2-carboximidamide),
saterinone, tolafentrine and zardaverine.
[0053] Suitable Type IV inhibitors include, but are not limited to,
those described in U.S. Pat. No. 6,127,363 to Doherty, Jr. et al.,
also assigned to VIVUS, Inc. Examples of Type IV inhibitors that
can be administered in conjunction with the present method include,
by way of example: pyrrolidinones such as rolipram
(4-(3-cyclopentyloxy-4'-methoxyp- henyl)-2-pyrrolidinone)) and
rolipram derivatives such as RO20-1724
(4-(3-butyloxy-4-methoxyphenyl)-imidazolidinone) and RS 33793
(8-(3-nitrophenyl)-6-(3-methyl-2-butenyl)pyrido-[2,3a]pyrazin-5-one);
quinazolinediones such as nitraquazone (3-[3'-nitrophenyl]
N-ethylquinazoline-2,6-dione), CP-77059
(1-(carbomethoxyphenyl)-3-benzyl-- pyrido[2,3d]
pyrimidine-2,4(1H,3H)dione), RS-25344(1-(3-nitrophenyl)-3-(4--
pyridylmethyl)-1,2,3,4-tetrahydro pyrido(2,3-d)
pyrimidine-2,4-dione)) and other nitraquazone analogs; xanthine
derivatives such as denbufylline (1,3-di-n-butyl-7-[2'-oxopropyl]
xanthine), XT-44 (1-n-butyl-3-n-propylxa- nthine), arofylline (LAS
31025; 1-propyl-3-(4-chlorophenyl)-xanthine) and BRL 61063; phenyl
ethyl pyridines such as CDP 840 (4-(1-(3-cyclopentyloxy-
-4-methoxyphenyl)-2-phenylethyl) pyridine) and compounds disclosed
in WO 97/22585 to Guay et al.; tetrahydropyrinidones such as
atizoram (CP 80633); diazepine derivatives such as CI 1018 and
compounds disclosed in WO 97/36905 to Pascal et al.; oxime
carbamates such as filaminast (PDA-641); naphthyridinones such as
RS 17597; benzofurans such as
2-butyl-7-methoxy-benzofuran-4-carboxylic acid
(3,5-dichloropyridin-4yl)-- amide,
2-benzyl-7-methoxy-benzofuran-4-carboxylic acid
(3,5-dichloropyridin-4-yl)-amide,
7-methoxy-2-phenethyl-benzofuran-4-carb- oxylic acid
(3,5-dichloropyridin-4-yl)-amide and 5-(2-butyl-7-methoxy-benz-
ofuran-4-yl)-tetrahydro-pyrimidin-2-one, phenanthridines, such as
those disclosed in U.S. Pat. No. 6,191,138 to Gutterer;
2-heteroaryl and 2-heterocyclic benzoxazoles, such as those
disclosed in U.S. Pat. No. 6,166,041 to Cavalla et al.;
phenyldihydro-benzofurane compounds such as those disclosed in U.S.
Pat. No. 5,902,824 to Ulrich; benzofuran carboxamides as disclosed
in U.S. Pat. No. 6,211,203 to Amschler et al.; 4-substituted
benzofurane compounds such as those disclosed in EP 819688A1;
substituted furans as disclosed in Perrier et al. (1999) Bioorg.
Med. Chem. Lett. 9:323-326 (1999); naphthalene derivatives such as
T 440; purine derivatives such as V 112294A and those compounds
disclosed in U.S. Pat. No. 6,228,859 to Cavalla et al.; cyclohexane
carboxylic acids such as ariflo (SB 207499,
c-4-cyano-4-[3'-cyclopentylox-
y-4'-methoxyphenyl]-r-1-cyclohexane-carboxylic acid); benzamides
such as piclamilast (RP73401;
N-(3,5-dichloro-4-pyridyl)-3-cyclopentoxy-4-methoxy- benzamide);
benzothiophenes such as tibenelast (LY 186655); pyridopyridazinones
such as 8-(3-nitrophenyl)-6-pyridin-4-ylmethyl-6H-pyr-
ido[2,3-d]pyridazin-5-one; imidazolidinones such as
5-[3-bicyclo[2.2.
1]hept-2-yloxy)-4-methoxyphenyl-1-methyl-imidazolidin-2-one;
substituted phenyl compounds, as disclosed in U.S. Pat. No.
5,891,896 to Warrellow et al.; substituted biphenyl compounds as
disclosed in U.S. Pat. No. 5,877,190 to Dhainaut et al.; etazolate;
and S-(+)-glaucine ((S)-(+)-1,2,9,10-tetramethoxy-aporphine).
[0054] Examples of type V phosphodiesterase inhibitors include, but
are not limited to, the pyrazolopyrimidinones such as those
disclosed in PCT Publication No. WO 94/28902, and the griseolic
acid derivatives, 2-phenylpurinone derivatives, phenylpyridone
derivatives, fused and condensed pyrimidines, pyrimidopyrimidine
derivatives, purine compounds, quinazoline compounds,
phenylpyrimidinone derivative, imidazoquinoxalinone derivatives,
and other compounds disclosed in WO 96/16644.
[0055] Suitable pyrazolopyrimidinones, as disclosed in WO 94/28902,
are
5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H--
pyrazolo[4,3-d]pyrimidin-7-one,
5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-
-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propy-
l-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-allyloxy-5-(4-methyl-
-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazol-
o[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl-
)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on-
e,
5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl)phenyl]-1-methy-
l-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl]-2-n-propoxyphenyl]-1-meth-
y 1,3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-
-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and
5-[2-ethoxy-5-(1-methyl-
-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]py-
rimidin-7-one.
[0056] The griseolic acid derivatives, 2-phenylpurinones, etc.
disclosed in WO 96/16644 include
1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-o- ne,
2-(2-propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)-
1,2-dihydro-2-oxypyridine-3-carboxamide,
2-(2-propoxyphenyl)-pyrido[2,3-d- ]pyrimid-4(3H)-one,
7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyr-
imido[4,5-d]pyrimidine,
6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxam- ide,
1-ethyl-3-methylirmidazo[1,5a]quinoxalin-4(5H)-one,
4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline,
5-ethyl-8-[3-(N-cyclohexyl-N-methylcarbamoyl)-propyloxy]-4,5-dihydro-4-ox-
o-pyrido[3,2-e]-pyrrolo[1,2-a]pyrazine,
5'-methyl-3'-(phenylmethyl)-spiro[-
cyclopentane-1,7'(8'H)-(3'H)-imidazo[2,1-b]purin]4'(5'H)-one,
1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine--
4-carboxylic acid,
(6R,9S)-2-(4-trifluoromethyl-phenyl)methyl-5-methyl-3,4-
,5,6a,7,8,9,9a-octa hydrocyclopent[4,5]-imidazo[2,1-b]-purin-4-one,
1-t-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-d]-pyrimid-4-one,
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro- H-pyrazolo
[3,4-d]pyrimid-4-one,
2-butyl-1-(2-chlorobenzyl)6-ethoxy-carbonylbenzimid- aole,
2-(4-carboxy-piperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-nitroq-
uinazoline and 2-phenyl-8-ethoxycycloheptimidazole.
[0057] Still other type V phosphodiesterase inhibitors useful in
conjunction with the method of the present invention include: those
compounds described in PCT Publication No. WO 01/19802 to Aoyama
(Tanabe Seiyaku Co., Ltd.), particularly
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-
-(3-chloro-4-methoxy-benzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyri-
midine,
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxy-
benzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine, and
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-
-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine; zaprinast
(1,4-dihydro-5-(2-propoxyphenyl)-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one)-
; 1-(3-chloroanilino)-4-phenylphthalazine (MY5445); dipyridamole,
vinpocetine; FR229934 (Fujisawa Pharmaceutical Co., Ltd.);
1-methyl-3-isobutyl-8-(methylamino)xanthine; IC-351 (Cialis);
4-aryl-1-isoquinolinone derivatives such as methyl
2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trime-
thoxyphenyl)-3-isoquinoline carboxylate dihydrochloride and the
sulfate salt thereof (T-1032);
4-bromo-5-(pyridylmethylamino)-6-[3-(4-chloropheny-
l)propoxy]-3(2H)pyridazinone;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-c-
hloro-2-quinazolinyl]-4-piperidine-carboxylic acid, monosodium
salt;
(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-met-
hyl-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-propoxyph-
enyl)-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-piper-
idine carboxylic acid, monosodium salt; Pharmaprojects No. 4516
(Glaxo Wellcome); vardenafil (Bayer); Pharmaprojects No. 5064
(Kyowa Hakko; see WO 96/26940); Pharmaproj ects No. 5069 (Schering
Plough); GF-196960 (Glaxo Wellcome); Sch-51866; sodium
1-[6-chloro-4-(3,
4-methylenedioxybenzyl)-aminoquinazolin-2-yl]piperidine-4-carboxylate
sesquihydrate (E4021); and 6-phenylpyrazolo[3,4-d] pyrimidinones
such as
1,3-dimethyl-6(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydropyrazolo[-
3,4-d]pyrimidin-4-one and
1-ethyl-3-methyl-6-(2-propoxy-5-(4-methylthiazol-
-2-yl)phenyl-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one.
[0058] Particularly preferred Type V phosphodiesterase inhibitors
for use in conjunction with the present invention are sildenafil
(5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-prop-
yl-1,6-dihydro-7H-pyrazolo[4,3-dipyrimidin-7-one]), zaprinast,
dipyridamole, and the compounds described in WO 01/19802 to Aoyama,
particularly
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-
-benzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine,
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzyla-
mino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine, and
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-
-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine, and
pharmaceutically acceptable salts thereof Sildenafil, preferably in
the form of an acid addition salt (e.g., sildenafil citrate), is
most preferred.
[0059] Other phosphodiesterase inhibitors include nonspecific
inhibitors such as theophylline, theobromine, IBMX, pentoxifylline
and papaverine.
[0060] One or more additional active agents can be administered
with the phosphodiesterase inhibitor, either simultaneously or
sequentially. The additional active agent will generally although
not necessarily be one that is effective in treating premature
ejaculation, and/or an agent that potentiates the effect of the
phosphodiesterase inhibitor. Suitable secondary agents include, for
example, those described in U.S. Pat. No. 6,228,864 to Smith et
al., assigned to VIVUS, Inc. (Mountain View, Calif.), i.e.:
[0061] antidepressant drugs such as amesergide, amineptine,
amitriptyline, amoxapine, benactyzine, brofaromine, bupropion,
butriptyline, cianopramine, citalopram, clomipramine, clorgyline,
clovoxamine, dapoxetine, demexiptiline, desipramine, dibenzepin,
dimetacrine, dothiepin, doxepin, duloxetine, etoperidone,
femoxetine, fezolamine, fluoxetine, fluvoxamine, ifoxetine,
imipramine, iprindole, isocarboxazid, levoprotiline, lofepramine,
maprotiline, medifoxamine, melitracen, metapramine,
methylphenidate, mianserin, milnacipran, minaprine, mirtazapine,
moclobemide, nefazodone, nialamide, nomifensine, nortriptyline,
opipramol, oxaflozane, oxaprotiline, oxitriptan, paroxetine,
phenelzine, pirlindole, propizepine, protriptyline, quinupramine,
rolipram, selegiline, sertraline, setiptiline, sibutramine,
teniloxazine, tianeptine, tofenacin, toloxatone, tranylcypromine,
trazodone, trimipramine, tryptophan, venlafaxine, viloxazine,
viqualine and zimeldine;
[0062] serotonin agonists such as 2-methyl serotonin, buspirone,
ipsaperone, tiaspirone, gepirone,
8-hydroxy-(2-N,N-dipropylamino)-tetrali- ne,
I-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride,
sumatriptan, m-chlorophenyl-piperazine, trazodone, zacopride and
mezacopride;
[0063] serotonin antagonists such as ondansetron, granisetron,
metoclopramide, tropisetron, dolasetron, palonosetron,
trimethobenzamide, methysergide, risperidone, ketanserin,
ritanserin, clozapine, amitriptyline, MDL 100,907, azatadine,
cyproheptadine, fenclonine, chlorpromazine, mianserin, zacopride
and mezacopride;
[0064] adrenergic agonists including methoxamine, methpentermine,
metaraminol, mitodrine, clonidine, apraclonidine, guanfacine,
guanabenz, methyldopa, amphetamine, methamphetamine, epinephrine,
norepinephrine, ethylnorepinephrine, phenylephrine, ephedrine,
pseudoephedrine, methylphenidate, pemoline, naphazoline,
tetrahydrozoline, oxymetazoline, xylometazoline,
phenylpropanolamine, phenylethylamine, dopamine, dobutamine,
colterol, isoproterenol, isotharine, metaproterenol, terbutaline,
metaraminol, tyramine, hydroxyamphetamine, ritodrine, prenalterol,
albuterol, isoetharine, pirbuterol, bitolterol, fenoterol,
formoterol, procaterol, salmeterol, mephenterine and
propylhexedrine;
[0065] adrenergic neurone blockers including bethanidine,
debrisoquine, guabenxan, guanadrel, guanazodine, guanethidine,
guanoclor and guanoxan; and
[0066] adrenergic antagonists including phenoxybenzamine,
phentolamine, tolazoline, prazosin, terazosin, doxazosin,
trimazosin, yohimbine, ergot alkaloids, labetalol, ketanserin,
urapidil, alfuzosin, bunazosin, tamsulosin, chlorpromazine,
haloperidol, phenothiazines, butyrophenones, propranolol, nadolol,
timolol, pindolol, metoprolol, atenolol, esmolol, acebutolol,
bopindolol, carteolol, oxprenolol, penbutolol, carvedilol,
medroxalol, naftopidil, bucindolol, levobunolol, metipranolol,
bisoprolol, nebivolol, betaxolol, carteolol, celiprolol, sotalol,
propafenone and indoramin.
[0067] Some of these additional active agents, as may be seen, are
encompassed by more than one of the above categories, e.g.,
serotonin antagonists and antidepressants, or serotonin agonists
and antagonists.
[0068] Preferred additional active agents are 5-HT.sub.3
antagonists and 5-HT.sub.4 agonists. 5-HT.sub.3 receptors can be
found, for example, on parasympathetic terminals in the
gastrointestinal tract and in the central nervous system, both of
which participate in the emetic response. 5-HT.sub.4 receptors are
found throughout the body, including on nerve terminals in the CNS,
the gastrointestinal tract, and on smooth muscle and secretory
cells. 5-HT.sub.4 receptors activate adenylyl cyclase, and are
involved in the regulation of secretion and peristalsis. Examples
of 5-HT.sub.3 antagonists include, without limitation, ondansetron,
ergot alkaloids, granisetron, metoclopramide, trimethobenzamide,
tropisetron, dolasetron, batanopride and zacopride. Exemplary
5HT.sub.4 agonists include, but are not limited to, the following:
N-(3-hydroxy-4-piperideny- l) benzamides such as cisapride
(cis-4-amino-5-chloro-N-[1-[3-(4-fluorophe-
noxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide) and
norcisapride (4-amino-5-chloro-N-(3-methoxy-4-piperidinyl)-2
methoxybenzamide), as racemates or in isomerically pure form;
indazolecarboxamides, as described in U.S. Pat. No. 5,817,676; and
1-phenylalkanones, as described in U.S. Pat. No. 5,763,458.
Cisapride and norcisapride, whether racemic or optically pure, are
preferred 5-HT.sub.4 agonists.
[0069] Other preferred additional active agents are antidepressant
drugs classified as selective serotonin reuptake inhibitors
(SSRIs). These include, by way of example, amitryptyline,
clomipramine, citalopram, dapoxetine, desipramine, doxepin,
duloxetine, fluoxetine, fluvoxamine, irmipranine, isocarboxazid,
mirtazapine, nortriptyline, paroxetine, phenelzine, protriptyline,
nefazodone, selegiline, sertraline, tranylcypromine, trazodone,
trimipramine and venlafaxine. By virtue of combining such agents
with phosphodiesterase inhibitors, the dosage of an SSRI that will
be effective in treating premature ejaculation may be substantially
reduced, in turn minimizing those side effects that commonly result
from SSRI administration.
[0070] Other additional active agents that may be co-administered
with the phosphodiesterase inhibitor, but are less preferred, are
disclosed in U.S. Pat. No. 6,228,864 to Smith et al., and include
vasoactive agents such as: nitrates and like compounds such as
nitroglycerin, isosorbide dinitrate, erythrityl tetranitrate, amyl
nitrate, sodium nitroprusside, molsidomine, linsidomine
chlorhydrate ("SIN-I"), S-nitroso-N-acetyl-d,l-p- enicillamine
("SNAP"), S-nitroso-N-cysteine and S-nitroso-N-glutathione
("SNO-GLU") and diazenium diolates ("NONOates"); long and short
acting .alpha.-blockers such as phenoxybenzamine, dibenamine,
doxazosin, terazosin, phentolamine, tolazoline, prazosin,
trimazosin, alfuzosin, tamsulosin and indoramin; ergot alkaloids
such as ergotamine and ergotamine analogs, e.g., acetergamine,
brazergoline, bromerguride, cianergoline, delorgotrile,
disulergine, ergonovine maleate, ergotamine tartrate, etisulergine,
lergotrile, lysergide, mesulergine, metergoline, metergotamine,
nicergoline, pergolide, propisergide, proterguride and terguride;
antihypertensive agents such as diazoxide, hydralazine and
minoxidil; vasodilators such as nimodepine, pinacidil,
cyclandelate, dipyridamole and isoxsuprine; chlorpromazine;
haloperidol; yohimbine; Rec15/2739; trazodone; naturally occurring
prostaglandins such as PGE.sub.0, PGE.sub.1, PGA.sub.1, PGB.sub.1,
PGF.sub.1.alpha., 19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1,
PGE.sub.2, PGA.sub.2, PGB.sub.2, 19-hydroxy-PGA.sub.2,
19-hydroxy-PGB.sub.2, PGE.sub.3, PGF.sub.3.alpha.; semisynthetic or
synthetic derivatives of natural prostaglandins, including
carboprost tromethamine, dinoprost tromethamine, dinoprostone,
lipoprost, gemeprost, metenoprost, sulprostone and tiaprost; and
vasoactive intestinal peptide.
[0071] Any of the active agents may be administered in the form of
a salt, ester, amide, prodrug, active metabolite, derivative, or
the like, provided that the salt, ester, amide, prodrug or
derivative is suitable pharmacologically, i.e., effective in the
present method. Salts, esters, amides, prodrugs and other
derivatives of the active agents may be prepared using standard
procedures known to those skilled in the art of synthetic organic
chemistry and described, for example, by J. March, Advanced Organic
Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York:
Wiley-Interscience, 1992). For example, acid addition salts are
prepared from the free base using conventional methodology, and
involves reaction with a suitable acid. Suitable acids for
preparing acid addition salts include both organic acids, e.g.,
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like, as well as
inorganic acids, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. An acid
addition salt may be reconverted to the free base by treatment with
a suitable base. Particularly preferred acid addition salts of the
active agents herein are salts prepared with organic acids.
Conversely, preparation of basic salts of acid moieties which may
be present on an active agent are prepared in a similar manner
using a pharmaceutically acceptable base such as sodium hydroxide,
potassium hydroxide, ammonium hydroxide, calcium hydroxide,
trimethylamine, or the like. Preparation of esters involves
functionalization of hydroxyl and/or carboxyl groups that may be
present within the molecular structure of the drug. The esters are
typically acyl-substituted derivatives of free alcohol groups,
i.e., moieties that are derived from carboxylic acids of the
formula RCOOH where R is alky, and preferably is lower alkyl.
Esters can be reconverted to the free acids, if desired, by using
conventional hydrogenolysis or hydrolysis procedures. Amides and
prodrugs may also be prepared using techniques known to those
skilled in the art or described in the pertinent literature. For
example, amides may be prepared from esters, using suitable amine
reactants, or they may be prepared from an anhydride or an acid
chloride by reaction with ammonia or a lower alkyl amine. Prodrugs
are typically prepared by covalent attachment of a moiety, which
results in a compound that is therapeutically inactive until
modified by an individual's metabolic system.
[0072] Other derivatives and analogs of the active agents may be
prepared using standard techniques known to those skilled in the
art of synthetic organic chemistry, or may be deduced by reference
to the pertinent literature. In addition, chiral active agents may
be in isomerically pure form, or they may be administered as a
racemic mixture of isomers.
[0073] III. Pharmaceutical Compositions and Dosage Forms:
[0074] Suitable compositions and dosage forms include tablets,
capsules, caplets, gel caps, troches, dispersions, suspensions,
solutions, syrups, transdermal patches, gels, powders, magmas,
lozenges, creams, pastes, plasters, lotions, discs, suppositories,
liquid sprays for nasal or oral administration, dry powder or
aerosolized formulations for inhalation, and the like.
[0075] A. Oral Dosage Forms:
[0076] Oral dosage forms are preferred for those therapeutic agents
that are orally active, and include tablets, capsules, caplets,
solutions, suspensions and/or syrups, and may also comprise a
plurality of granules, beads, powders or pellets that may or may
not be encapsulated. Such dosage forms are prepared using
conventional methods known to those in the field of pharmaceutical
formulation and described in the pertinent texts, e.g., in
Remington: The Science and Practice of Pharmacy, 20.sup.th Edition,
Gennaro, A. R., Ed. (Lippincott, Williams and Wilkins, 2000).
Tablets and capsules represent the most convenient oral dosage
forms, in which case solid pharmaceutical carriers are
employed.
[0077] Tablets may be manufactured using standard tablet processing
procedures and equipment. One method for forming tablets is by
direct compression of a powdered, crystalline or granular
composition containing the active agent(s), alone or in combination
with one or more carriers, additives, or the like. As an
alternative to direct compression, tablets can be prepared using
wet-granulation or dry-granulation processes. Tablets may also be
molded rather than compressed, starting with a moist or otherwise
tractable material; however, compression and granulation techniques
are preferred.
[0078] In addition to the active agent(s), then, tablets prepared
for oral administration using the method of the invention will
generally contain other materials such as binders, diluents,
lubricants, disintegrants, fillers, stabilizers, surfactants,
coloring agents, and the like. Binders are used to impart cohesive
qualities to a tablet, and thus ensure that the tablet remains
intact after compression. Suitable binder materials include, but
are not limited to, starch (including corn starch and
pregelatinized starch), gelatin, sugars (including sucrose,
glucose, dextrose and lactose), polyethylene glycol, waxes, and
natural and synthetic gums, e.g., acacia sodium alginate,
polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl
cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl
cellulose, hydroxyethyl cellulose, and the like), and Veegum.
Diluents are typically necessary to increase bulk so that a
practical size tablet is ultimately provided. Suitable diluents
include dicalcium phosphate, calcium sulfate, lactose, cellulose,
kaolin, mannitol, sodium chloride, dry starch and powdered sugar.
Lubricants are used to facilitate tablet manufacture; examples of
suitable lubricants include, for example, magnesium stearate,
calcium stearate, and stearic acid. Stearates, if present,
preferably represent at no more than approximately 2 wt. % of the
drug-containing core. Disintegrants are used to facilitate
disintegration of the tablet, and are generally starches, clays,
celluloses, algins, gums or crosslinked polymers. Fillers include,
for example, materials such as silicon dioxide, titanium dioxide,
alumina, talc, kaolin, powdered cellulose and microcrystalline
cellulose, as well as soluble materials such as mannitol, urea,
sucrose, lactose, dextrose, sodium chloride and sorbitol.
Stabilizers are used to inhibit or retard drug decomposition
reactions that include, by way of example, oxidative reactions.
Surfactants may be anionic, cationic, amphoteric or nonionic
surface active agents.
[0079] The dosage form may also be a capsule, in which case the
active agent-containing composition may be encapsulated in the form
of a liquid or solid (including particulates such as granules,
beads, powders or pellets). Suitable capsules may be either hard or
soft, and are generally made of gelatin, starch, or a cellulosic
material, with gelatin capsules preferred. Two-piece hard gelatin
capsules are preferably sealed, such as with gelatin bands or the
like. See, for example, Remington: The Science and Practice of
Pharmacy, cited supra, which describes materials and methods for
preparing encapsulated pharmaceuticals. If the active
agent-containing composition is present within the capsule in
liquid form, a liquid carrier is necessary to dissolve the active
agent(s). The carrier must be compatible with the capsule material
and all components of the pharmaceutical composition, and must be
suitable for ingestion.
[0080] Solid dosage forms, whether tablets, capsules, caplets, or
particulates, may, if desired, be coated so as to provide for
delayed release. Dosage forms with delayed release coatings may be
manufactured using standard coating procedures and equipment. Such
procedures are known to those skilled in the art and described in
the pertinent texts, e.g., in Remington, supra. Generally, after
preparation of the solid dosage form, a delayed release coating
composition is applied using a coating pan, an airless spray
technique, fluidized bed coating equipment, or the like. Delayed
release coating compositions comprise a polymeric material, e.g.,
cellulose butyrate phthalate, cellulose hydrogen phthalate,
cellulose proprionate phthalate, polyvinyl acetate phthalate,
cellulose acetate phthalate, cellulose acetate trimellitate,
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate, dioxypropyl methylcellulose succinate,
carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate
succinate, polymers and copolymers formed from acrylic acid,
methacrylic acid, and/or esters thereof.
[0081] Sustained release dosage forms provide for drug release over
an extended time period, and may or may not be delayed release.
Generally, as will be appreciated by those of ordinary skill in the
art, sustained release dosage forms are formulated by dispersing a
drug within a matrix of a gradually bioerodible (hydrolyzable)
material such as an insoluble plastic, a hydrophilic polymer, or a
fatty compound, or by coating a solid, drug-containing dosage form
with such a material. Insoluble plastic matrices may be comprised
of, for example, polyvinyl chloride or polyethylene. Hydrophilic
polymers useful for providing a sustained release coating or matrix
cellulosic polymers include, without limitation: cellulosic
polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose,
cellulose acetate, cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropylmethyl cellulose phthalate,
hydroxypropylcellulose phthalate, cellulose hexahydrophthalate,
cellulose acetate hexahydrophthalate, and carboxymethylcellulose
sodium; acrylic acid polymers and copolymers, preferably formed
from acrylic acid, methacrylic acid, acrylic acid alkyl esters,
methacrylic acid alkyl esters, and the like, e.g. copolymers of
acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate,
methyl methacrylate and/or ethyl methacrylate, with a terpolymer of
ethyl acrylate, methyl methacrylate and trimethylammonioethyl
methacrylate chloride (sold under the tradename Eudragit RS)
preferred; vinyl polymers and copolymers such as polyvinyl
pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate,
vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate
copolymers; zein; and shellac, ammoniated shellac, shellac-acetyl
alcohol, and shellac n-butyl stearate. Fatty compounds for use as a
sustained release matrix material include, but are not limited to,
waxes generally (e.g., camauba wax) and glyceryl tristearate.
[0082] B. Transmucosal Compositions and Dosage Forms:
[0083] Although the present compositions will generally be
administered orally, other modes of administration are suitable as
well. For example, transmucosal administration may be
advantageously employed. Transmucosal administration is carried out
using any type of formulation or dosage unit suitable for
application to mucosal tissue. For example, the selected active
agent may be administered to the buccal mucosa in an adhesive
tablet or patch, sublingually administered by placing a solid
dosage form under the tongue, administered nasally as droplets or a
nasal spray, administered by inhalation of an aerosol formulation,
a non-aerosol liquid formulation, or a dry powder, placed within or
near the rectum ("transrectal" formulations), or administered to
the urethra as a suppository, ointment, or the like.
[0084] Preferred buccal dosage forms will typically comprise a
therapeutically effective amount of the selected phosphodiesterase
inhibitor and a bioerodible (hydrolyzable) polymeric carrier that
may also serve to adhere the dosage form to the buccal mucosa. The
buccal dosage unit is fabricated so as to erode gradually over a
predetermined time period, wherein drug delivery is provided
essentially throughout. The time period is typically in the range
of approximately 0.5 hours to 24 hours. Buccal drug delivery, as
will be appreciated by those skilled in the art, avoids the
disadvantages encountered with oral drug administration, e.g., slow
absorption, degradation of the active agent by fluids present in
the gastrointestinal tract and/or first-pass inactivation in the
liver. The "therapeutically effective amount" of phosphodiesterase
inhibitor in the dosage unit will of course depend on the potency
of the agent and the intended dosage, which, in turn, is dependent
on the particular individual undergoing treatment, the specific
indication, and the like. The dosage unit will generally contain
from approximately 1.0 wt. % to about 60 wt. % active agent,
preferably on the order of 1 wt. % to about 30 wt. % active agent.
With regard to the bioerodible (hydrolyzable) polymeric carrier, it
will be appreciated that virtually any such carrier can be used, so
long as the desired drug release profile is not compromised, and
the carrier is compatible with the phosphodiesterase inhibitor to
be administered and any other components of the buccal dosage unit.
Generally, the polymeric carrier comprises a hydrophilic
(water-soluble and water-swellable) polymer that adheres to the wet
surface of the buccal mucosa. Examples of polymeric carriers useful
herein include acrylic acid polymers and co, e.g., those known as
"carbomers" (Carbopol.RTM., which may be obtained from B.F.
Goodrich, is one such polymer). Other suitable polymers include,
but are not limited to: hydrolyzed polyvinylalcohol; polyethylene
oxides (e.g., Sentry Polyox.RTM. water soluble resins, available
from Union Carbide); polyacrylates (e.g., Gantre.RTM., which may be
obtained from GAF); vinyl polymers and copolymers;
polyvinylpyrrolidone; dextran; guar gum; pectins; starches; and
cellulosic polymers such as hydroxypropyl methylcellulose, (e.g.,
Methocel.RTM., which may be obtained from the Dow Chemical
Company), hydroxypropyl cellulose (e.g., Klucel.RTM., which may
also be obtained from Dow), hydroxypropyl cellulose ethers (see,
e.g., U.S. Pat. No. 4,704,285 to Alderman), hydroxyethyl cellulose,
carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl
cellulose, ethyl cellulose, cellulose acetate phthalate, cellulose
acetate butyrate, and the like.
[0085] Other components may also be incorporated into the buccal
dosage forms described herein. The additional components include,
but are not limited to, disintegrants, diluents, binders,
lubricants, flavoring, colorants, preservatives, and the like.
Examples of disintegrants that may be used include, but are not
limited to, cross-linked polyvinylpyrrolidones, such as
crospovidone (e.g., Polyplasdone.RTM. XL, which may be obtained
from GAF), cross-linked carboxylic methylcelluloses, such as
croscarmelose (e.g., Ac-di-sol.RTM., which may be obtained from
FMC), alginic acid, and sodium carboxymethyl starches (e.g.,
Explotab.RTM., which may be obtained from Edward Medell Co., Inc.),
methylcellulose, agar bentonite and alginic acid. Suitable diluents
are those which are generally useful in pharmaceutical formulations
prepared using compression techniques, e.g., dicalcium phosphate
dihydrate (e.g., Di-Tab.RTM., which may be obtained from Stauffer),
sugars that have been processed by cocrystallization with dextrin
(e.g., co-crystallized sucrose and dextrin such as Di-Pa.RTM.,
which may be obtained from Amstar), calcium phosphate, cellulose,
kaolin, mannitol, sodium chloride, dry starch, powdered sugar and
the like. Binders, if used, are those that enhance adhesion.
Examples of such binders include, but are not limited to, starch,
gelatin and sugars such as sucrose, dextrose, molasses, and
lactose. Particularly preferred lubricants are stearates and
stearic acid, and an optimal lubricant is magnesium stearate.
[0086] Preferred sublingual dosage forms include sublingual
tablets, creams, ointments and pastes. The tablet, cream, ointment
or paste for sublingual delivery comprises a therapeutically
effective amount of the selected phosphodiesterase inhibitor and
one or more conventional nontoxic carriers suitable for sublingual
drug administration. The sublingual dosage forms of the present
invention can be manufactured using conventional processes. The
sublingual dosage unit is fabricated to disintegrate rapidly. The
time period for complete disintegration of the dosage unit is
typically in the range of from about 10 seconds to about 30
minutes, and optimally is less than 5 minutes.
[0087] Other components may also be incorporated into the
sublingual dosage forms described herein. The additional components
include, but are not limited to binders, disintegrants, wetting
agents, lubricants, and the like. Examples of binders that may be
used include water, ethanol, polyvinylpyrrolidone, starch solution
gelatin solution, and the like. Suitable disintegrants include dry
starch, calcium carbonate, polyoxyethylene sorbitan fatty acid
esters, sodium lauryl sulfate, stearic monoglyceride, lactose, and
the like. Wetting agents, if used, include glycerin, starches, and
the like. Particularly preferred lubricants are stearates and
polyethylene glycol. Additional components that may be incorporated
into sublingual dosage forms are known, or will be apparent, to
those skilled in this art; for example, see Remington: The Science
and Practice of Pharmacy, cited supra.
[0088] For transurethral administration, the formulation comprises
a urethral dosage form containing the active agent and one or more
selected carriers or excipients, such as water, silicone, waxes,
petroleum jelly, polyethylene glycol ("PEG"), propylene glycol
("PG"), liposomes, sugars such as mannitol and lactose, and/or a
variety of other materials, with polyethylene glycol and
derivatives thereof particularly preferred.
[0089] Depending on the particular phosphodiesterase inhibitor
administered, it may be desirable to incorporate a transurethral
permeation enhancer in the urethral dosage form. Examples of
suitable transurethral permeation enhancers include
dimethylsulfoxide ("DMSO"), dimethyl formamide ("DMF"),
N,N-dimethylacetamide ("DMA"), decylmethylsulfoxide
("C.sub.10MSO"), polyethylene glycol monolaurate ("PEGML"),
glycerol monolaurate, lecithin, the 1-substituted
azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Nelson Research & Development Co., Irvine,
Calif.), SEPA.RTM. (available from Macrochem Co., Lexington,
Mass.), surfactants as discussed above, including, for example,
Tergitol.RTM., Nonoxynol-9.RTM. and TWEEN-80.RTM., and lower
alkanols such as ethanol.
[0090] Transurethral drug administration, as explained in U.S. Pat.
Nos. 5,242,391, 5,474,535, 5,686,093 and 5,773,020 to Place et al.,
can be carried out in a number of different ways using a variety of
urethral dosage forms. For example, the drug can be introduced into
the urethra from a flexible tube, squeeze bottle, pump or aerosol
spray. The drug may also be contained in coatings, pellets or
suppositories that are absorbed, melted or bioeroded in the urethra
In certain embodiments, the drug is included in a coating on the
exterior surface of a penile insert. A preferred drug delivery
device for administering a drug transurethrally is shown in FIG. 1.
It is preferred, although not essential, that the drug be delivered
at least about 3 cm into the urethra, and preferably at least about
7 cm into the urethra. Generally, delivery at about 3 cm to about 8
cm into the urethra will provide effective results in conjunction
with the present method.
[0091] Urethral suppository formulations containing PEG or a PEG
derivative are particularly preferred urethral dosage forms herein,
and may be conveniently formulated using conventional techniques,
e.g., compression molding, heat molding or the like, as will be
appreciated by those skilled in the art and as described in the
pertinent literature and pharmaceutical texts. See, for example,
Remington: The Science and Practice of Pharmacy, cited supra, which
discloses typical methods of preparing pharmaceutical compositions
in the form of urethral suppositories. The PEG or PEG derivative
preferably has a molecular weight M.sub.w in the range of about 200
to 2500, more preferably in the range of about 1000 to 2000.
Suitable polyethylene glycol derivatives include polyethylene
glycol fatty acid esters, for example, polyethylene glycol
monostearate, polyethylene glycol sorbitan esters, e.g.,
polysorbates, and the like. Depending on the particular active
agent, it may also be preferred that urethral suppositories contain
one or more solubilizing agents effective to increase the
solubility of the active agent in the PEG or other transurethral
vehicle.
[0092] It may be desirable to deliver the active agent in a
urethral dosage form that provides for controlled or sustained
release of the agent. In such a case, the dosage form comprises a
biocompatible, biodegradable material, typically a biodegradable
polymer. Examples of such polymers include polyesters,
polyalkylcyanoacrylates, polyorthoesters, polyanhydrides, albumin,
gelatin and starch. As explained, for example, in PCT Publication
No. WO96/40054, these and other polymers can be used to provide
biodegradable microparticles that enable controlled and sustained
drug release, in turn minimizing the required dosing frequency.
[0093] The urethral dosage form will preferably comprise a
suppository that is on the order of 2 to 20 mm, preferably 5 to 10
mm, in length and less than about 5 mm, preferably less than about
2 mm in width. The weight of the suppository will typically be in
the range of approximately 1 mg to 100 mg, preferably in the range
of approximately 1 mg to 50 mg. However, it will be appreciated by
those skilled in the art that the size of the suppository can and
will vary, depending on the potency of the drug, the nature of the
formulation, and other factors.
[0094] In FIG. 1, a suitable transurethral drug delivery device is
shown generally at 10. The device comprises a transurethral
inserter 11 having an easily graspable segment 12 that has opposing
symmetrically concave surfaces 13 and 14 adapted to be held by two
fingers. Drug is contained within a urethral suppository (not
shown) within shaft 15, which is sized to fit within the urethra. A
longitudinal plunger, the tip of which is seen at 16, is slidably
insertable into the longitudinal bore contained within shaft 15. To
extrude drug into the urethra, shaft 15 is inserted into the
urethra, and plunger tip 16 is pushed into segment 12. The inserter
11 is then removed. Prior to use, and during storage, the device is
capped with elongate cap 17 which fits snugly over flange 18 at the
proximal end of shaft 15. The cap 17 is provided with a series of
parallel ridges 19 to facilitate gripping of the cap and removal
from inserter 11.
[0095] Although the transurethral drug delivery device shown in
FIG. 1 represents a preferred device for use herein, again, it
should be emphasized that a wide variety of device configurations
and urethral dosage forms can be used.
[0096] Transurethral drug delivery may involve an "active" delivery
mechanism such as iontophoresis, electroporation or phonophoresis.
Devices and methods for delivering drugs in this way are well known
in the art. Iontophoretically assisted drug delivery is, for
example, described in PCT Publication No. WO96/40054, cited above.
Briefly, the active agent is driven through the urethral wall by
means of an electric current passed from an external electrode to a
second electrode contained within or affixed to a urethral
probe.
[0097] Preferred transrectal dosage forms include rectal
suppositories, creams, ointments, and liquid formulations (enemas).
The suppository, cream, ointment or liquid formulation for
transrectal delivery comprises a therapeutically effective amount
of the selected phosphodiesterase inhibitor and one or more
conventional nontoxic carriers suitable for transrectal drug
administration. The transrectal dosage forms of the present
invention can be manufactured using conventional processes. The
transrectal dosage unit can be fabricated to disintegrate rapidly
or over a period of several hours. The time period for complete
disintegration is preferably in the range of from about 10 minutes
to about 6 hours, and optimally is less than 3 hours.
[0098] Other components may also be incorporated into the
transrectal dosage forms described herein. The additional
components include, but are not limited to, stiffening agents,
antioxidants, preservatives, and the like. Examples of stiffening
agents that may be used include, for example, paraffin, white wax
and yellow wax. Preferred antioxidants, if used, include sodium
bisulfite and sodium metabisulfite.
[0099] The active agents may also be administered intranasally or
by inhalation. Compositions for nasal administration are generally
liquid formulations for administration as a spray or in the form of
drops, although powder formulations for intranasal administration,
e.g., insufflations, are also known.
[0100] Formulations for inhalation may be prepared as an aerosol,
either a solution aerosol in which the active agent is solubilized
in a carrier (e.g., propellant) or a dispersion aerosol in which
the active agent is suspended or dispersed throughout a carrier and
an optional solvent. Non-aerosol formulations for inhalation may
take the form of a liquid, typically an aqueous suspension,
although aqueous solutions may be used as well. In such a case, the
carrier is typically a sodium chloride solution having a
concentration such that the formulation is isotonic relative to
normal body fluid. In addition to the carrier, the liquid
formulations may contain water and/or excipients including an
antimicrobial preservative (e.g., benzalkonium chloride,
benzethonium chloride, chlorobutanol, phenylethyl alcohol,
thimerosal and combinations thereof), a buffering agent (e.g.,
citric acid, potassium metaphosphate, potassium phosphate, sodium
acetate, sodium citrate, and combinations thereof), a surfactant
(e.g., polysorbate 80, sodium lauryl sulfate, sorbitan
monopalmitate and combinations thereof), and/or a suspending agent
(e.g., agar, bentonite, microcrystalline cellulose, sodium
carboxymethylcellulose, hydroxypropyl methylcellulose, tragacanth,
veegum and combinations thereof). Non-aerosol formulations for
inhalation may also comprise dry powder formulations, particularly
insufflations in which the powder has an average particle size of
about 0.1 .mu.m to 50 .mu.m, preferably 1 .mu.m to about 25
.mu.m.
[0101] C. Topical Formulations:
[0102] Topical formulations may be in any form suitable for
application to the body surface, and may comprise, for example, an
ointment, cream, gel, lotion, solution, paste or the like, and/or
may be prepared so as to contain liposomes, micelles, and/or
microspheres. Preferred topical formulations herein are ointments,
creams and gels.
[0103] Ointments, as is well known in the art of pharmaceutical
formulation, are semisolid preparations that are typically based on
petrolatum or other petroleum derivatives. The specific ointment
base to be used, as will be appreciated by those skilled in the
art, is one that will provide for optimum drug delivery, and,
preferably, will provide for other desired characteristics as well,
e.g., emolliency or the like. As with other carriers or vehicles,
an ointment base should be inert, stable, nonirritating and
nonsensitizing. As explained in Remington: The Science and Practice
of Pharmacy, supra, at pages 1399-1404, ointment bases may be
grouped in four classes: oleaginous bases; emulsifiable bases;
emulsion bases; and water-soluble bases. Oleaginous ointment bases
include, for example, vegetable oils, fats obtained from animals,
and semisolid hydrocarbons obtained from petroleum. Emulsifiable
ointment bases, also known as absorbent ointment bases, contain
little or no water and include, for example, hydroxystearin
sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion
ointment bases are either water-in-oil (W/O) emulsions or
oil-in-water (O/W) emulsions, and include, for example, cetyl
alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred
water-soluble ointment bases are prepared from polyethylene glycols
of varying molecular weight; again, see Remington: The Science and
Practice of Pharmacy for further information.
[0104] Creams, as also well known in the art, are viscous liquids
or semisolid emulsions, either oil-in-water or water-in-oil. Cream
bases are water-washable, and contain an oil phase, an emulsifier
and an aqueous phase. The oil phase, also called the "internal"
phase, is generally comprised of petrolatum and a fatty alcohol
such as cetyl or stearyl alcohol. The aqueous phase usually,
although not necessarily, exceeds the oil phase in volume, and
generally contains a humectant. The emulsifier in a cream
formulation is generally a nonionic, anionic, cationic or
amphoteric surfactant.
[0105] As will be appreciated by those working in the field of
pharmaceutical formulation, gels are semisolid, suspension-type
systems. Single-phase gels contain organic macromolecules
distributed substantially uniformly throughout the carrier liquid,
which is typically aqueous, but also, preferably, contain an
alcohol and, optionally, an oil. Preferred "organic
macromolecules," i.e., gelling agents, are crosslinked acrylic acid
polymers such as the "carbomer" family of polymers, e.g.,
carboxypolyalkylenes that may be obtained commercially under the
Carbopol.RTM. trademark. Also preferred are hydrophilic polymers
such as polyethylene oxides, polyoxyethylene-polyoxypropylene
copolymers and polyvinylalcohol; cellulosic polymers such as
hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl
methylcellulose, hydroxypropyl methylcellulose phthalate, and
methyl cellulose; gums such as tragacanth and xanthan gum; sodium
alginate; and gelatin. In order to prepare a uniform gel,
dispersing agents such as alcohol or glycerin can be added, or the
gelling agent can be dispersed by trituration, mechanical mixing,
and/or stirring.
[0106] Various additives, known to those skilled in the art, may be
included in the topical formulations. For example, solubilizers may
be used to solubilize certain active agents. For those drugs having
an unusually low rate of permeation through the skin or mucosal
tissue, it may be desirable to include a permeation enhancer in the
formulation; suitable enhancers are described in part (B) of this
section.
[0107] D. Transdermal Administration:
[0108] The compounds of the invention may also be administered
through the skin or mucosal tissue using conventional transdermal
drug delivery systems, wherein the agent is contained within a
laminated structure (typically referred to as a transdermal
"patch") that serves as a drug delivery device to be affixed to the
skin. Transdermal drug delivery may involve passive diffusion or it
may be facilitated using electrotransport, e.g., iontophoresis. In
a typical transdermal "patch," the drug composition is contained in
a layer, or "reservoir," underlying an upper backing layer. The
laminated structure may contain a single reservoir, or it may
contain multiple reservoirs. In one type of patch, referred to as a
"monolithic" system, the reservoir is comprised of a polymeric
matrix of a pharmaceutically acceptable contact adhesive material
that serves to affix the system to the skin during drug delivery.
Examples of suitable skin contact adhesive materials include, but
are not limited to, polyethylenes, polysiloxanes, polyisobutylenes,
polyacrylates, polyurethanes, and the like. Alternatively, the
drug-containing reservoir and skin contact adhesive are separate
and distinct layers, with the adhesive underlying the reservoir
which, in this case, may be either a polymeric matrix as described
above, or it may be a liquid or hydrogel reservoir, or may take
some other form.
[0109] The backing layer in these laminates, which serves as the
upper surface of the device, functions as the primary structural
element of the laminated structure and provides the device with
much of its flexibility. The material selected for the backing
material should be selected so that it is substantially impermeable
to the active agent and any other materials that are present; the
backing is preferably made of a sheet or film of a flexible
elastomeric material. Examples of polymers that are suitable for
the backing layer include polyethylene, polypropylene, polyesters,
and the like.
[0110] During storage and prior to use, the laminated structure
includes a release liner. Immediately prior to use, this layer is
removed from the device to expose the basal surface thereof, either
the drug reservoir or a separate contact adhesive layer, so that
the system may be affixed to the skin. The release liner should be
made from a drug/vehicle impermeable material.
[0111] Transdermal drug delivery systems may in addition contain a
skin permeation enhancer. That is, because the inherent
permeability of the skin to some drugs may be too low to allow
therapeutic levels of the drug to pass through a reasonably sized
area of unbroken skin, it is necessary to coadminister a skin
permeation enhancer with such drugs. Suitable enhancers are well
know in the art and include, for example, those enhancers listed
above in part (B) of this section.
[0112] E. Parenteral Administration:
[0113] Parenteral administration, if used, is generally
characterized by injection, including intramuscular,
intraperitoneal, intravenous (IV) and subcutaneous injection.
Injectable formulations can be prepared in conventional forms,
either as liquid solutions or suspensions, solid forms suitable for
solution or suspension in liquid prior to injection, or as
emulsions. Preferably, sterile injectable suspensions are
formulated according to techniques known in the art using suitable
dispersing or wetting agents and suspending agents. The sterile
injectable formulation may also be a sterile injectable solution or
a suspension in a nontoxic parenterally acceptable diluent or
solvent. Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. A more recently revised
approach for parenteral administration involves use of a slow
release or sustained release system; see, e.g., U.S. Pat. No.
3,710,795.
[0114] IV. Dosage and Administration:
[0115] The concentration of the active agent in any of the
aforementioned dosage forms and compositions can vary a great deal,
and will depend on a variety of factors, including the type of
composition or dosage form, the corresponding mode of
administration, the nature and activity of the specific active
agent, and the intended drug release profile.
[0116] Preferred dosage forms contain a unit dose of active agent,
i.e., a single therapeutically effective dose. For creams,
ointments, etc., a "unit dose" requires an active agent
concentration that provides a unit dose in a specified quantity of
the formulation to be applied. The unit dose of any particular
active agent will depend, of course, on the active agent and on the
mode of administration. For sildenafil citrate, the unit dose for
oral administration will be in the range of about 1 mg to about 250
mg, typically in the range of about 15 mg to about 100 mg; for
local administration, suitable unit doses may be lower. Those of
ordinary skill in the art of pharmaceutical formulation can readily
deduce suitable unit doses for other phosphodiesterase inhibitors,
as well as suitable unit doses for other types of active agents
that may be incorporated into a dosage form of the invention.
[0117] The amount of a particular active agent administered to a
given individual will, of course, be dependent on a number of
factors as well, including the specific active agent, composition
or dosage form, the selected mode of administration, the age and
general condition of the individual being treated, the severity of
the individual's condition, and other factors known to the
prescribing physician.
[0118] In a preferred embodiment, drug administration is on an
as-needed basis, and does not involve chronic drug administration.
With an immediate release dosage form, i.e., a composition or
dosage form that is not "controlled release" as defined
hereinabove, as-needed administration may involve drug
administration immediately prior to sexual activity, but will
generally be in the range of about 0.5 to 24 hours prior to
anticipated sexual activity, preferably in the range of about 1 to
12 hours prior to anticipated sexual activity, most preferably in
the range of about 1 to 4 hours prior to anticipated sexual
activity. With a sustained release dosage form, a single dose can
provide therapeutic efficacy over an extended time period in the
range of about 4 to 48 hours, typically in the range of about 4 to
24 hours, depending on the formulation. That is, the release period
may be varied by the selection and relative quantity of particular
sustained release polymers; see Section III, part (A). If
necessary, however, drug administration may be carried out within
the context of an ongoing dosage regimen, i.e., on a weekly basis,
twice weekly, daily, etc.
[0119] V. Packaged Kits:
[0120] In another embodiment, a packaged kit is provided that
contains the pharmaceutical formulation to be administered, i.e., a
pharmaceutical formulation containing a phosphodiesterase inhibitor
for the treatment of premature ejaculation, a container, preferably
sealed, for housing the formulation during storage and prior to
use, and instructions for carrying out drug administration in a
manner effective to treat premature ejaculation. The instructions
will typically be written instructions on a package insert and/or
on a label. Depending on the type of formulation and the intended
mode of administration, the kit may also include a device for
administering the formulation (e.g., a transurethral drug delivery
device such as shown in FIG. 1). The formulation may be any
suitable formulation as described herein. For example, the
formulation may be an oral dosage form containing a unit dosage of
the phosphodiesterase inhibitor. The kit may contain multiple
formulations of different dosages of the same agent. The kit may
also contain multiple formulations of different active agents.
[0121] The kit may also include a venous flow control (VFC) device
such as that described in U.S. Pat. No. 5,855,548 to Place,
assigned to VIVUS, Inc., Mountain View, Calif. Such devices are
formed from a length of flexible tubing having an integral
fastening means, so as to provide for readily adjustable venous
flow control when applied to the penis. The device is applied to
the base of the penis prior to and during sexual intercourse, such
that it effectively enhances retention of blood within the penis
without substantially obstructing arterial inflow or becoming too
constrictive during the erectile process. Use of the VFC device
also enables enhanced effectiveness of local drug therapy, in that,
for example, a transurethrally administered active agent is
retained within the penis, allowing movement into the corpus
cavernosa.
[0122] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, that the foregoing description as well as the examples
which follow are intended to illustrate and not limit the scope of
the invention. Other aspects, advantages and modifications within
the scope of the invention will be apparent to those skilled in the
art to which the invention pertains.
[0123] All patents, patent applications, and publications mentioned
herein are hereby incorporated by reference in their
entireties.
EXAMPLE 1
[0124] Preparation of Transmucosal Paste:
[0125] A transmucosal formulation is prepared containing zaprinast,
a Type V phosphodiesterase inhibitor. 10 g of bulk zaprinast is
placed in a mortar and a pestle is used to grind the solid into a
fine powder. About 10 g of a previously weighed out quantity of 100
g of ORABASE.RTM. (Colgate-Hoyt Laboratories, Norwood, Mass.) is
combined with the zaprinast powder on an ointment tile. The
zaprinast powder and ORABASE.RTM. are levigated together using a
spatula. The remaining ORABASE.RTM. is added to the ointment tile
and levigated with the previously mixed components to produce a
smooth, consistent formulation. The resulting formulation is a 10%
zaprinast transmucosal formulation.
[0126] This procedure can be used with various phosphodiesterase
inhibitors, ointment bases and additional components, e.g.,
enhancers or the like.
EXAMPLE 2
[0127] Preparation of Transmucosal Paste:
[0128] A transmucosal formulation is prepared containing sildenafil
citrate, a Type V phosphodiesterase inhibitor. About 5 g of bulk
sildenafil citrate is placed in a mortar and a pestle is used to
grind the solid into a fine powder. About 5 g of a previously
weighed out quantity of 100 g of ORABASE.RTM. is combined with the
sildenafil citrate powder on an ointment tile. The sildenafil
citrate powder and ORABASE.RTM. are levigated together using a
spatula. The remaining ORABASE.RTM. is added to the ointment tile
and levigated with the previously mixed components to produce a
smooth, consistent formulation. The resulting formulation is a 5%
sildenafil citrate transmucosal formulation.
EXAMPLE 3
[0129] Preparation of Buccal Dosage Form:
[0130] 10 g of zaprinast and 90 g of gelatin are mixed and
pulverized in a mill. After the mixing is complete, 20 g of
concentrated glycerin, 10 g of lactose and 20 g of mannitol are
added and the components are mixed until uniform. 150 mg aliquot
portions of the mixture are compression-molded to provide a buccal
dosage unit. Each buccal unit contains 10 mg of zaprinast.
EXAMPLE 4
[0131] Preparation of a Buccal Dosage Form:
[0132] 10 g of sildenafil citrate and 90 g of gelatin are mixed and
pulverized in a mill. After the mixing is complete, 20 g of
concentrated glycerin, 10 g of lactose and 20 g of mannitol are
added and the components are mixed until uniform. 150 mg aliquot
portions of the mixture are compression-molded to provide a buccal
dosage unit. Each buccal unit contains 10 mg of sildenafil
citrate.
EXAMPLE 5
[0133] Preparation of a Buccal Dosage Form:
[0134] 10 g of milrinone (a Type III phosphodiesterase inhibitor)
and 90 g of gelatin are mixed and pulverized in a mill. After the
mixing is complete, 20 g of concentrated glycerin, 10 g of lactose
and 20 g of mannitol are added and the components are mixed until
uniform. 150 mg aliquot portions of the mixture are
compression-molded to provide a buccal dosage unit. Each buccal
unit contains 10 mg of milrinone.
EXAMPLE 6
[0135] Preparation of a Buccal Dosage Form:
[0136] 10 g of rolipram (a Type V phosphodiesterase inhibitor) and
90 g of gelatin are mixed and pulverized in a mill. After the
mixing is complete, 20 g of concentrated glycerin, 10 g of lactose
and 20 g of mannitol are added and the components are mixed until
uniform. 150 mg aliquot portions of the mixture are
compression-molded to provide a buccal dosage unit. Each buccal
unit contains 10 mg of rolipram.
EXAMPLE 7
[0137] Preparation of a Sublingual Tablet:
[0138] 1.0 g of zaprinast, 1.0 g of mannitol, 2.0 g of
microcrystalline cellulose, and 10 mg of magnesium stearate are
blended in a suitable mixer and then compressed into sublingual
tablets. Each sublingual tablet contains 10 mg of zaprinast.
EXAMPLE 8
[0139] Preparation of a Sublingual Tablet:
[0140] 1.0 g of sildenafil citrate, 1.0 g of mannitol, 2.0 g of
microcrystalline cellulose, and 10 mg of magnesium stearate are
blended in a suitable mixer and then compressed into sublingual
tablets. Each sublingual tablet contains 10 mg of sildenafil
citrate.
EXAMPLE 9
[0141] Preparation of a Rectal Suppository:
[0142] A pharmaceutical formulation containing a Type V
phosphodiesterase inhibitor for transrectal administration is
prepared by mixing 10 to 100 mg zaprinast with polyethylene glycol,
molecular weight approximately 4000, and heating the mixture to a
temperature just high enough to produce a zaprinast-polymer melt.
The zaprinast-polyethylene glycol mixture can then be poured into a
mold suitable to provide a zaprinast rectal suppository, and
allowed to cool. The suppository so provided is a unit dosage form
suitable for transrectal administration.
EXAMPLE 10
[0143] Preparation of a Rectal Suppository:
[0144] A pharmaceutical formulation containing an a Type V
phosphodiesterase inhibitor for transrectal administration is
prepared by mixing 10 to 100 mg sildenafil citrate with
polyethylene glycol, molecular weight approximately 4000, and
heating the mixture to a temperature just high enough to produce a
sildenafil citrate-polymer melt. The sildenafil
citrate-polyethylene glycol mixture can then be poured into a mold
suitable to provide a sildenafil citrate rectal suppository, and
allowed to cool. The suppository so provided is a unit dosage form
suitable for transrectal administration.
EXAMPLE 11
Evaluation of Orally Administered Active Agents in Treating
Premature Ejaculation
[0145] Methods:
[0146] A double-blind randomized crossover study was performed with
31 heterosexual men suffering from primary premature ejaculation,
defined for the purpose of the study as an intravaginal ejaculation
latency time (IVELT) of less than 2 minutes. Exclusion criteria
included the following: (a) history of a psychiatric disorder; (b)
current physical illness; (c) previous surgery or drug therapy with
an active agent known to affect sexual function; (d) current
substance abuse; (e) patients with secondary premature ejaculation
combined with erectile dysfunction. All patients were asked not to
use condoms or topical penile applications.
[0147] Treatment phases comprised five four-week consecutive
treatment periods, each separated by a two-week washout period.
Each patient was informed that he would be treated with five
different modalities of identical action to determine which of the
five was most effective. The patients were randomly assigned to
receive clomipramine hydrocloride (25 mg), sertraline hydrochloride
(50 mg), paroxetine hydrochloride (20 mg), or sildenafil citrate
(50 mg), or instructed to use the pause-squeeze technique developed
by Masters and Johnson (Masters and Johnson, Human Sexual
Inadequacy, Little, Brown & Company, Boston, Mass., 1970). The
drugs were administered as needed 3 to 5 hours before planned
intercourse and not more than twice a week. The pause-squeeze
technique was used during intercourse. Each patient was randomly
assigned to receive any of the available treatments as the first
treatment and a sequence of treatment regimens. The assignment was
unknown by the patient. Subjects were asked to complete a
questionnaire regarding intravaginal ejaculation latency time of
the last two consecutive experiences of intercourse, frequency of
intercourse and possible side effects. The first nine items of the
sexual satisfaction questionnaire designed by Althof et al. (Althof
et al.(1999), "EDITS: Development of Questionnaires for Evaluating
Satisfaction with Treatment for Erectile Dysfunction," Urology
53:793-399) was used to measure the degree of sexual satisfaction,
with higher scores indicating greater satisfaction. All
measurements were obtained before treatment, after each treatment
and after each washout period. Twenty healthy men who reported a
sexual history free of symptoms of premature ejaculation served as
a control group.
[0148] Statistical Analysis:
[0149] The variables in this study were statistically processed
using the SPSS program for MicroSoft Windows.RTM., standard
version, release 8.0. The data were subjected to the
Kolmogorov-Smimov one-sample test, to test for normal distribution.
This test showed that all the outcome variables were nonparametric.
Nonparametric statistical tests were used to assess differences in
the measurements. Friedman's two-way analysis of variance was used
for comparison between all the treatment periods. Wilcoxon signed
rank test was used for evaluation of measures between baseline and
after each treatment and also between every two treatment periods.
The relationship between parameters was quantified by using the
Spearman rank correlation coefficient. Chi-square and Fisher exact
tests were used for comparison of the incidence of side effects
among different treatments. Student's t-test and Chi-square test
were used for comparison between the study group and control group.
A two-tailed P-value <0.05 was considered significant.
[0150] Results:
[0151] After four-week treatments with clomipramine, sertraline,
paroxetine, sildenafil, and the pause-squeeze technique, the median
intravaginal ejaculation latency time was significantly increased
from the pretreatment median of 1 minutes to 4 minutes, 3 minutes,
4 minutes, 15 minutes and 3 minutes respectively (Wilcoxon z=-4.54,
-4.63, -4.71, -4.63 and -4.55, respectively, all P<0.0001).
[0152] According to Friedman's test, treatment with sildenafil
caused a significant increase in the median IVELT, median sexual
satisfaction score and median IVELT during the washout period
(Table 1). The most effective treatment in prolongation of IVELT
was sildenafil in 28 patients (90.3%), followed by paroxetine
(80.6%), sertraline (71.2%), clomipramine (71%) and the
pause-squeeze technique (54.8%). Clomipramine, sertraline and
paroxetine were more or less equivalent to each other in terms of
ejaculation latency time and sexual satisfaction score (all
P>0.05). Paroxetine was found to be superior to the
pause-squeeze technique in terms of ejaculatory latency and sexual
satisfaction score (Wilcoxon z=-2.05, P=0.04, z=-2.24, P=0.025,
respectively).
[0153] Sexual satisfaction scores showed statistically significant
positive correlation with VELT during all treatment periods (all
P=0.01). There was a significant positive correlation (r=0.666,
P=0.01) between anxiety score and IVELT during treatment with the
pause-squeeze technique. Moreover, we found significant negative
correlation between anxiety score and sexual satisfaction score
during treatment with the pause-squeeze technique (r=-0.547,
P=0.01), clomipramine (r=-0.381, P<0.05), sildenafil (r=-0.573,
P=0.01).
[0154] Table 2 displays overall incidence and types of the reported
side effects for each treatment. No adverse effects on sexual
function were noted, and most of the side effects were mild to
moderate in severity.
1 TABLE 1 Squeeze Friedman Baseline Clomipramine Sertraline
Paroxetine Sildenafil Technique .chi..sup.2 dF P Anxiety score
Median 12 11 11 9 8 12 55.15 5 0.0001 (Range) (5-25) (4-22) (5-22)
(5-23) (4-15) (5-21) IVELT (min) Median 1 4 3 4 15 3 92.53 5 0.0001
(Range) (0.5-1.5) (1-8) (1-10) (2-10) (5-30) (1-7) Sexual
satisfaction score Median 11 10 12 30 6 57.87 4 0.0001 (Range)
(0-25) (0-31) (0-29) (17-34) (0-22) IVELT during washout periods
(min) Median 1 1 1 1.75 1 32.52 5 0.0001 (Range) (0.5-1.5) (0.5-2)
(0.5-2) (0.5-8) (0.5-1.5)
[0155]
2 TABLE 2 SERTRALINE PAROXETINE SILDENAFIL CLOMIPRAMINE No.
patients 3 (10.3%) 5 (17.2%) 5 (17.9%) 7 (25%) with side effects
(%) P-value* 0.27 0.69 0.75 Side effects (no.): dry mouth 2 3
anorexia 1 nausea 1 1 1 headache 2 flushing 2 drowsiness 1 1
sleepiness 2 nasal 1 congestion yawning 2 *Compared to incidence of
side effects with clomipramine
[0156] As may be seen, then, treatment with clomipramine,
sertraline, paroxetine, sildenafil and the pause-squeeze technique
on an "as needed" basis resulted in a statistically significant and
clinically relevant delay of intravaginal ejaculation latency time
in patients suffering from premature ejaculation. Sildenafil, in
particular, was quite effective, insofar as over 90% of patients
experienced a prolongation of IVELT, and the IVELT was increased by
a factor of 15, on average. The results demonstrate that a
phosphodiesterase inhibitor such as sildenafil is highly effective
in the treatment of premature ejaculation.
* * * * *