U.S. patent application number 10/412555 was filed with the patent office on 2003-11-13 for methods, compositions, and kits for enhancing female sexual desire and responsiveness.
Invention is credited to Neal, Gary W..
Application Number | 20030212139 10/412555 |
Document ID | / |
Family ID | 27013489 |
Filed Date | 2003-11-13 |
United States Patent
Application |
20030212139 |
Kind Code |
A1 |
Neal, Gary W. |
November 13, 2003 |
Methods, compositions, and kits for enhancing female sexual desire
and responsiveness
Abstract
Topical application of a prostaglandin directly to the clitoris
is effective for enhancing female sexual desire and
responsiveness.
Inventors: |
Neal, Gary W.; (Knoxville,
TN) |
Correspondence
Address: |
REED & EBERLE LLP
800 MENLO AVENUE, SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
27013489 |
Appl. No.: |
10/412555 |
Filed: |
April 11, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10412555 |
Apr 11, 2003 |
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09880188 |
Jun 12, 2001 |
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6593369 |
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09880188 |
Jun 12, 2001 |
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09391412 |
Sep 8, 1999 |
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09391412 |
Sep 8, 1999 |
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08954122 |
Oct 20, 1997 |
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Current U.S.
Class: |
514/573 ;
514/530 |
Current CPC
Class: |
A61K 31/557 20130101;
A61K 9/0034 20130101; Y10S 514/874 20130101 |
Class at
Publication: |
514/573 ;
514/530 |
International
Class: |
A61K 031/557 |
Claims
We claim:
1. A pharmaceutical composition for topical administering to the
clitoris, comprising: (a) an effective amount of a prostaglandin;
and (b) a pharmaceutically acceptable carrier; wherein said carrier
provides release of the prostaglandin from the composition within
about 1 minute to about 60 minutes following administration.
2. The pharmaceutical composition of claim 1, wherein said
prostaglandin is selected from the group consisting of
prostaglandin E-1; prostaglandin E-2; prostaglandin F-2.alpha.;
prostaglandin A-1; prostaglandin B-1; prostaglandin D-2;
prostaglandin E-M; prostaglandin F-M; prostaglandin H-2;
prostaglandin 1-2; 19-hydroxy-prostaglandin A-1;
19-hydroxy-prostaglandin B-1; prostaglandin A-2; prostaglandin B-2;
19-hydroxy-prostaglandin A-2; 19-hydroxy-prostaglandin B-2;
prostaglandin B-3; prostaglandin F-1.alpha.;
15-methyl-prostaglandin F-2.alpha.;
16,16-dimethyl-.DELTA..sup.2-prostaglandin E-1 methyl ester;
15-deoxy-16-hydroxy-16-methyl-prostaglandin E-1 methyl ester;
16,16-dimethyl-prostaglandin E-2; 11-deoxy-15-methyl-prostaglandin
E-1; 16-methyl-18,18,19,19-tetrahydrocarbacyclin;
(16RS)-15-deoxy-16-hydroxy-1- -6-methyl-prostaglandin E-1 methyl
ester; (+)-4,5-didehydro-16-phenoxy-.al-
pha.-tetranor-prostaglandin E-2 methyl ester; 11-deoxy-11a,
16,16-trimethyl-prostaglandin E-2; (+)-11a,
16a,b-dihydroxy-1,9-dioxo-1-(-
hydroxymethyl)-16-methyl-trans-prostene;
9-chloro-16,16-dimethyl-prostagla- ndin E-2; and arboprostil.
3. The pharmaceutical composition of claim 1, wherein said
prostaglandin is selected from the group consisting of
prostaglandin E-1, prostaglandin E-2, prostaglandin F-2.alpha.,
prostaglandin D-2, prostaglandin F-1.alpha.,
15-methyl-prostaglandin F-2.alpha., prostaglandin E-3,
prostaglandin D-1, and misoprostol.
4. The pharmaceutical composition of claim 1, wherein said
prostaglandin is present in an amount of 0.1 nanograms to 2,000
.mu.g/ml.
5. The pharmaceutical composition of claim 1, wherein said
prostaglandin is PGE-1.
6. The pharmaceutical composition of claim 1, wherein said
prostaglandin is PGE-2.
7. The pharmaceutical composition of claim 1, which further
comprises at least one coagent selected from the group consisting
of agents which inhibit 15-hydroxyprostaglandindehydrogenase, ACE
inhibitors, nitro vasodilators, alpha blockers, yohimbine,
labetalol, carvedilol, bucindolol, phosphodiesterase inhibitors,
muscarinic agents, dopaminergic agonists, ergot alkaloids, opiate
antagonists, and polypeptide neurotransmitters.
8. The pharmaceutical composition of claim 7, wherein the at least
one coagent is an agent which inhibits
15-hydroxyprostaglandindehydrogenase.
9. The pharmaceutical composition of claim 1, wherein the
prostaglandin is a unit dose.
10. The pharmaceutical composition of claim 9, wherein the unit
dose is in the range of about 20 nanograms to about 2000 .mu.g.
11. The pharmaceutical composition of claim 10, wherein the unit
dose is in the range of about 200 nanograms to about 500 .mu.g.
12. The pharmaceutical composition of claim 1, wherein the carrier
provides release of the prostaglandin from the composition within
about 5 minutes to about 30 minutes following administration.
13. The pharmaceutical composition of claim 1, which is in the form
of a gel, solution, ointment, cream, liposomes or suppository.
14. The pharmaceutical composition of claim 1, comprising a
controlled-release dosage form.
15. A packaged kit for use in enhancing female sexual desire and
response, comprising: (a) means for containing a prostaglandin or a
pharmaceutical composition comprising a prostaglandin; and (b)
means for administering a prostaglandin or a pharmaceutical
composition comprising a prostaglandin to the clitoris, wherein
said means for containing contains a prostaglandin or a
pharmaceutical composition comprising a prostaglandin; and (c)
instructions for carrying out drug administration to enhance sexual
desire and responsiveness, on an as-needed basis.
16. The packaged kit of claim 15, wherein said prostaglandin is
selected from the group consisting of prostaglandin E-1;
prostaglandin E-2; prostaglandin F-2.alpha.; prostaglandin A-1;
prostaglandin B-1; prostaglandin D-2; prostaglandin E-M;
prostaglandin F-M; prostaglandin H-2; prostaglandin 1-2;
19-hydroxy-prostaglandin A-1; 19-hydroxy-prostaglandin B-1;
prostaglandin A-2; prostaglandin B-2; 19-hydroxy-prostaglandin A-2;
19-hydroxy-prostaglandin B-2; prostaglandin B-3; prostaglandin
F-1.alpha.; 15-methyl-prostaglandin F-2.alpha.;
16,16-dimethyl-.alpha.-.DELTA.-prostaglandin E-1 methyl ester;
15-deoxy-16-hydroxy-16-methyl-prostaglandin E-1 methyl ester;
16,16-dimethyl-prostaglandin E-2; 11-deoxy-15-methyl-prostaglandin
E-1; 16-methyl-18,18,19,19-tetrahydrocarbacyclin;
(16RS)-15-deoxy-16-hydroxy-1- 6-methyl-prostaglandin E-1 methyl
ester; (+)-4,5-didehydro-16-phenoxy-.alp-
ha.-tetranor-prostaglandin E-2 methyl ester; 11-deoxy-11a,
16,16-trimethyl-prostaglandin E-2; (+)-11a,
16a,b-dihydroxy-1,9-dioxo-1-(-
hydroxymethyl)-16-methyl-trans-prostene;
9-chloro-16,16-dimethyl-prostagla- ndin E-2; and arboprostil.
17. The packaged kit of claim 15, wherein said prostaglandin is
selected from the group consisting of prostaglandin E-1,
prostaglandin E-2, prostaglandin F-2.alpha., prostaglandin D-2,
prostaglandin F-1.alpha., and 15-methyl-prostaglandin
F-2.alpha..
18. The packaged kit of claim 15, wherein said prostaglandin is
PGE-1.
19. The packaged kit of claim 15, wherein said prostaglandin is
PGE-2.
20. The packaged kit of claim 15, wherein said means for
administering a prostaglandin or a pharmaceutical composition
comprising a prostaglandin to the clitoris is capable of delivering
said prostaglandin to said clitoris in an amount of 0.1 nanograms
to 2,000 .mu.g.
21. The packaged kit of claim 15, wherein the prostaglandin is a
unit dose.
22. The packaged kit of claim 21, wherein the unit dose is in the
range of about 20 nanograms to about 2000 .mu.g.
23. The packaged kit of claim 22, wherein the unit dose is in the
range of about 200 nanograms to about 500 .mu.g.
24. The packaged kit of claim 15, wherein the pharmaceutical
composition comprises a carrier that provides release of the
prostaglandin from the composition within about 1 minute to about
60 minutes following application.
25. The packaged kit of claim 15, which further comprises at least
one coagent selected from the group consisting of agents which
inhibit 15-hydroxyprostaglandindehydrogenase, ACE inhibitors, nitro
vasodilators, alpha blockers, yohimbine, labetalol, carvedilol,
bucindolol, phosphodiesterase inhibitors, muscarinic agents,
dopaminergic agonists, ergot alkaloids, opiate antagonists, and
polypeptide neurotransmitters.
26. A pharmaceutical composition for topical administration to the
clitoris, comprising: (a) a prostaglandin; (b) a
15-hydroxyprostaglandind- ehydrogenase inhibitor; and (c) a
pharmaceutically acceptable carrier; wherein said carrier provides
release of the prostaglandin from the composition within about 1
minute to about 60 minutes following administration.
27. The pharmaceutical composition of claim 26, wherein said
prostaglandin is selected from the group consisting of
prostaglandin E-1; prostaglandin E-2; prostaglandin F-2.alpha.;
prostaglandin A-1; prostaglandin B-1; prostaglandin D-2;
prostaglandin E-M; prostaglandin F-M; prostaglandin H-2;
prostaglandin I-2; 19-hydroxy-prostaglandin A-1;
19-hydroxy-prostaglandin B-1; prostaglandin A-2; prostaglandin B-2;
19-hydroxy-prostaglandin A-2; 19-hydroxy-prostaglandin B-2;
prostaglandin B-3; prostaglandin F-1.alpha.;
15-methyl-prostaglandin F-2.alpha.;
16,16-dimethyl-.DELTA..sup.2-prostaglandin E-1 methyl ester;
15-deoxy-16-hydroxy-16-methyl-prostaglandin E-1 methyl ester;
16,16-dimethyl-prostaglandin E-2; 11-deoxy-15-methyl-prostaglandin
E-1; 16-methyl-18,18,19,19-tetrahydrocarbacyclin;
(16RS)-15-deoxy-16-hydroxy-1- -6-methyl-prostaglandin E-1 methyl
ester; (+)-4,5-didehydro-16-phenoxy-.al-
pha.-tetranor-prostaglandin E-2 methyl ester; 11-deoxy-11.alpha.,
16,16-trim-ethyl-prostaglandin E-2; (+)-11a,
16a,b-dihydroxy-1,9-dioxo-1--
(hydroxymethyl)-16-methyl-trans-prostene;
9-chloro-16,16-dimethyl-prostagl- andin E-2; and arboprostil.
28. The pharmaceutical composition of claim 26, wherein said
prostaglandin is selected from the group consisting of
prostaglandin E-1, prostaglandin E-2, prostaglandin F-2.alpha.,
prostaglandin D-2, prostaglandin F-1.alpha.,
15-methyl-prostaglandin F-2.alpha., prostaglandin E-3,
prostaglandin D-1, and misoprostol.
29. The pharmaceutical composition of claim 26, wherein said
prostaglandin is present in an amount of 0.1 nanograms to 2,000
.mu.g/ml.
30. The pharmaceutical composition of claim 26, wherein said
prostaglandin is PGE-1.
31. The pharmaceutical composition of claim 26, wherein said
prostaglandin is PGE-2.
32. The pharmaceutical composition of claim 26, which further
comprises at least one coagent selected from the group consisting
of agents which inhibit ACE inhibitors, nitro vasodilators, alpha
blockers, yohimbine, labetalol, carvedilol, bucindolol,
phosphodiesterase inhibitors, muscarinic agents, dopaminergic
agonists, ergot alkaloids, opiate antagonists, and polypeptide
neurotransmitters.
33. The pharmaceutical composition of claim 26, wherein the
prostaglandin is a unit dose.
34. The pharmaceutical composition of claim 33, wherein the unit
dose is in the range of about 20 nanograms to about 2000 .mu.g.
35. The pharmaceutical composition of claim 34, wherein the unit
dose is in the range of about 200 nanograms to about 500 .mu.g.
36. The pharmaceutical composition of claim 26, wherein the carrier
provides release of the prostaglandin from the composition within
about 5 minutes to about 30 minutes following application to the
clitoris.
37. The pharmaceutical composition of claim 26, which is in the
form of a gel, solution, ointment, cream, liposomes or suppository.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Ser. No.
09/880,188, filed on Jun. 12, 2001, which is a continuation of U.S.
Ser. No. 09/391,412, filed Sep. 8, 1999, which is a
continuation-in-part of U.S. Ser. No. 08/954,122, filed on Oct. 20,
1997, now abandoned.
FIELD OF THE INVENTION
[0002] The present invention relates to methods for enhancing
female sexual desire and responsiveness. The present method also
relates to compositions and kits useful for enhancing female sexual
desire and responsiveness.
DISCUSSION OF THE BACKGROUND
[0003] The female sexual response cycle can be divided into the
four following phases (as adapted from Diagnostic and Statistical
Manual IV, "Sexual and Gender Identity Disorder," American
Psychiatric Association, Washington, D.C., pp. 493-494 and 735-751,
1994:
[0004] 1. Desire, which includes fantasies about sexual activity
and the desire to have sexual activity;
[0005] 2. Excitement, which consists of subjective senses of sexual
pleasure and accompanying physiological changes including
vasocongestion in the pelvis, vaginal lubrication, and expansion
and swelling of the external genitalia;
[0006] 3. Orgasm, which consists of peaking of sexual pleasure with
release of sexual tension; and
[0007] 4. Resolution, which consists of a sense of muscular
relaxation and general well-being.
[0008] Disorders of female sexual desire or response are estimated
to affect from 30 to 50 percent of the adult population in various
studies (see, e.g., Nathon (1986) J. of Sex and Marital Therapy
12(4 :267-281; Diagnostic and Statistical Manual IV, "Sexual and
Gender Identity Disorder," American Psychiatric Association,
Washington, D.C., pp.493-539, 1994; Osborn et al, (1988) British
Medical Journal 296:959-962; Frank et al. (1978) New England
Journal of Medicine 299:111-115; and Garde et al. (1980) Maturitas
2:225-240). These very common disorders may have a variety of
causes including psychogenic etiologies, anatomical disorders,
drug-induced disorders, diabetes mellitus, post-surgical disorders,
atherosclerosis, post-traumatic disorders, as well as endocrine
etiologies.
[0009] The search for effective pharmacologic treatments to
influence sexual behavior has been a preoccupation of all societies
throughout history (see, e.g., E. L. Abel, Psychoactive Drugs and
Sex, Plenum Press, New York, 1985; and Buffum (1988) J Psychoact.
Drugs 20:165-168). In one of the few scientific review articles on
this topic (Rosen et al. (1993) Archives of Sexual Behavior
22(6):521-543), Rosen states: "In particular, the search for the
perfect aphrodisiac--a drug that will heighten sexual desire,
pleasure and performance has been a continuing cultural quest from
ancient to modern times. Natural substances such as datura,
belladonna and henbane were key ingredients in the sexual orgies of
ancient fertility cults. Yohimbine has long been used by the
natives of Africa to enhance their sexual prowess, as was the
mandrake plant in medieval Europe (E. L. Abel, Psychoactive Drugs
and Sex, Plenum Press, New York, 1985). Oysters, ginseng and
Vitamin E have similarly been recommended at various times as
possessing aphrodisiacal qualities (R. C. Rosen et al., Sexuality,
Random House, New York, 1984). Given the perennial search for an
effective aphrodisiac, it is surprising that relatively few drugs
have been demonstrated to have specific prosexual properties."
[0010] L-dopa has been reported to stimulate sexual responsiveness
in male and female patients. However, subsequent studies have
yielded inconsistent or contradictory results regarding the effect
of L-dopa on sexual behavior (Hyppa et al., "Is L-dopa an
aphrodisiac in patients with Parkinson's disease?," in Sexual
Behavior Pharmacology and Biochemistry, M. Sandler et al, Eds.,
Plenum Press, New York, 1975; and Benkert et al. (1972)
Psychopharmacologia 23:91-95). Most of these studies deal
exclusively with men and extremely few studies have even mentioned
women. Apomorphine has been investigated for erectile dysfunction
in men, but there have been no positive reports in women.
Nomifensine and bupropion which are a typical anti-depressants
acting on dopamine have been reported to have stimulatory effects
on females with decreased sexual desire (Lal et al. (1987) Prog.
Neurol. Psychopharmacol. Biol. Psychiat. 11:235-242. Subsequent
studies by Klein et al did not replicate these effects (Klein et
al., "Drug treatment of patients with inhibited sexual desire: A
controlled clinical trial," presented at the SSTAR annual meeting,
New Orleans, 1987).
[0011] Prostaglandins may have a possible role in human ovulation
(Craig (1975) PMJ 51:74-84). Prostaglandin El (PGE-1),
prostaglandin E.sub.2 (PGE-2), and prostaglandin F.sub.2,
(PGF-2.alpha.) cause uterine contraction in women. Indeed, PGE-2 is
presently used in the United States for inducing labor and cervical
ripening.
[0012] Present therapies for disorders of sexual response and
desire include various types of psychotherapeutic counseling
(LoPiccolo et al. (1986) J. of Counseling and Clinical Psychology
54(2):158-167). There is also a report of using electrical
stimulators placed inside the vagina to induce orgasms (see:
Boutos, U.S. Pat. No. 5,571,118). Neither of these methods are
particularly desirable or effective in treating these
disorders.
[0013] Thus, there remains a need for a method for enhancing female
sexual desire and responsiveness. There also remains a need for
pharmaceutical compositions and kits useful for enhancing female
desire and responsiveness
SUMMARY OF THE INVENTION
[0014] Accordingly, it is one object of the present invention to
provide novel methods for enhancing female sexual desire and
responsiveness.
[0015] It is another object of the present invention to provide
novel pharmaceutical compositions which are useful for enhancing
female sexual desire and responsiveness.
[0016] It is another object of the present invention to provide
novel kits useful for enhancing female sexual desire and
responsiveness.
[0017] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventor's discovery that application of a prostaglandin directly
to the clitoris of a female is effective for enhancing female
sexual desire and responsiveness.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0018] Thus, in a first embodiment, the present invention provides
novel methods for enhancing female sexual desire and
responsiveness. In the context of the present invention, the term
enhancing female sexual desire and responsiveness includes the
treatment of disorders of female sexual desire and/or response. The
term disorders of female sexual desire and/or response means any
disorder which causes a decrease in or absence of female sexual
responsiveness or female sexual desire. This includes any
persistent or recurrent deficiency or absence of sexual fantasies
and desire for sexual activity. It also includes decreases in the
physiological response to sexual stimulation such as slowed or
decreased erectile response of the female erectile tissues; slowed,
decreased or absent lubrication of the vagina; slowed, decreased,
or absent ability to have orgasms; decreased intensity of or
pleasure in orgasms; frigidity; sexual aversion; and disorders of
female sexual desire and response that are secondary to a general
medical condition such as the menopausal or post-menopausal state,
radiotherapy of the pelvis, atherosclerosis, pelvic trauma or
surgery, peripheral neuropathies, autonomic neuropathies, diabetes
mellitus, and disorders of the innervation of any of the sexual
organs. This term also includes substance-induced sexual
dysfunction including but not limited to decreases in desire and
responsiveness secondary to anti-depressants, neuroleptics,
antihypertensives, opiates, alcohol and any other drug found to
decrease or eliminate any part of the sexual response cycle.
Primary and secondary anorgasmia are included. Vaginismus (a
psychologically induced spasm of the vagina) may be resistant to
the present method and compositions.
[0019] Specifically, the present method involves application of a
prostaglandin directly to the clitoris. Examples of suitable
prostaglandins include PGE-1; PGE-2; PGF-2.alpha.; PGA-1; PGB-1;
PGD-2; PGE-M; PGF-M; PGH-2; PGI-2; 19-hydroxy-PGA-1;
19-hydroxy-PGB-1; PGA-2; PGB-2; 19-hydroxy-PGA-2; 19-hydroxy-PGB-2;
PGB-3; PGF-1.alpha.; 15-methyl-PGF-2.alpha.;
16,16-dimethyl-.DELTA..sup.2-PGE-1 methyl ester;
15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester;
16,16-dimethyl-PGE-2; 11-deoxy-15-methyl-PGE-1;
16-methyl-18,18,19,19-tetrahydrocarbacyclin;
(16RS)-15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester;
(+)-4,5-didehydro-16-phenoxy-.alpha.-tetranor-PGE-2 methyl ester;
11-deoxy-11a, 16,16-trimethyl-PGE-2; (+)-11a,
16a,b-dihydroxy-1,9-dioxo-1-
-.alpha.-(hydroxymethyl)-16-methyl-trans-prostene;
9-chloro-16,16-dimethyl- -PGE-2; arboprostil; and semisynthetic or
synthetic derivatives of these natural prostaglandins, or any
derivative or any prostaglandin analog capable of acting as a
vasodilator or neuromodulator. Cyclodextrin complexes are also
included as they may enhance the activity of the solution and
stabilize the prostaglandin. Racemic, optically enriched or
purified stereoisomers of any of these compounds are also included.
Physiologically acceptable salts are also included. Preferably, the
prostaglandin is PGE-1, PGE-2, PGF-2.alpha., PGD-2, PGF-1a, and
15-methyl-PGF-2.alpha.. Most preferably, the prostaglandin is PGE-2
or PGE-1.
[0020] Preferably, the prostaglandin is administered topically,
directly to the clitoris. Administration topically to the clitoris
may be accomplished by applying an amount of a liquid, gel, or
solid which contains an effective amount of the prostaglandin
directly onto the clitoris. In the case when the prostaglandin is
contained in a pharmaceutical composition which is a liquid, the
administration may be accomplished by means of a dropper or
syringe. The liquid solution may also be sprayed or delivered in an
aerosol onto the clitoris. When the composition containing the
prostaglandin is in the form of a gel, lotion, or cream the
administration may be carried out by means of a tube, brush, swab
or the finger tip. Pharmaceutical compositions which contain the
prostaglandin and which are in the form of a solid may be
administered by placing the appropriate amount of the solid
directly on the clitoris or by dusting or spraying a powder.
[0021] Although the exact amount of prostaglandin to be
administered will depend on the exact size and condition of the
patient, the prostaglandin is suitably administered in an amount of
0.1 nanograms to 2,000 .mu.g, preferably 1.0 nanogram to 500 .mu.g.
Specifically, when the prostaglandin is PGE-1, the PGE-l is
suitably administered in an amount of 20 nanograms to 2,000 .mu.g,
preferably 200 nanograms to 500 .mu.g, per unit dosage. When the
prostaglandin is PGE-2, the PGE-2 is suitably administered in an
amount of 0.1 nanograms to 2,000 .mu.g, preferably I nanogram to
500 .mu.g, per unit dosage. These broad ranges of suitable dosages
reflect clinical findings that various coagents and carriers can
either increase or decrease the drug activity exhibited by a given
mixture.
[0022] Typically, the prostaglandin will be administered 1 to 60
minutes, preferably 5 to 30 minutes, prior to the time when it is
desired to commence sexual intercourse.
[0023] PGE-1, prostaglandin E.sub.1, is also known as alprostadil
or PGE.sub.1. The formal chemical name of PGE-1 is
3-hydroxy-2-(3-hydroxy-1-- octenyl)-5-oxocyclopentaneheptanoic
acid, and the structure of PGE-1 is: 1
[0024] Prostaglandin El may be isolated from sheep seminal vesicle
tissue as described in Bergstrom et al. (1962) Acta. Chem. Scand.
16:501 and (1963) J. Biol. Chem. 238:3555. The synthesis of
prostaglandin El may be carried out as described in Corey et al.
(1969) J. Am. Chem. Soc. 91:535; Corey et al. (1970) J. Am. Chem.
Soc. 92:2586; Sih et al. (1972), J. Am. Chem. Soc. 94:3643; Sih et
al. (1973) J. Am. Chem. Soc. 95:1676; Schaaf et al. (1974) J. Org.
Chem. 37:292; and Slates et al. (1974) Tetrahedron 30:819.
[0025] PGE-2, prostaglandin E.sub.2, is also known as dinoprostone
or PGE.sub.2. The formal chemical name of PGE-2 is
7-[3-hydroxy-2-(3-hydroxy-
-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid, and the structure
of PGE-2 is: 2
[0026] Prostaglandin E.sub.2 may be isolated from sheep seminal
vesicle tissue as described in Bergstrom et al.(1962) Acta. Chem.
Scand. 16:501. Prostaglandin E.sub.2 may be synthesized as
described in Corey et al.(1970) J. Am. Chem. Soc. 92:397; Corey et
al. (1970) J. Am. Chem. Soc. 92:2586; and Heather et al. (1973)
Tetrahedron Letters, p. 2313. Both prostaglandin E.sub.1 and
E.sub.2 are commercially available from Sigma Chemical Company of
St. Louis, Mo.
[0027] PGE-2 is also commercially available as a Prostin E-2
suppository and as Prepidil Gel from Pharmacia & UpJohn
Company, Kalamazoo, Mich., and as Cervidil from Forrest
Pharmaceuticals, Inc., St. Louis, Mo. These preparations are
indicated for cervical ripening and contain between 0.5 and 20 mgs
of PGE-2. No reports in the medical literature, Physicians Desk
Reference, 51.sup.st Edition, Medical Economics, Montvale, N.J.,
1997; or Goodman and Gillman's The Pharmacologic Basis of
Therapeutics, gth Edition, McGraw-Hill, 1996 can be found with
respect to prostaglandins stimulating the female sexual response.
Indeed, in labor induction as much as 1000-10,000,000 times the
dose effective in the present method of PGE-2 is administered to
the cervix without sexual stimulation ever being reported as a side
effect.
[0028] PGF-2.alpha., prostaglandin E.sub.2.alpha., is also known as
dinoprost or PGF.sub.2.alpha.. The formal chemical name is
7-[3,5-dihydroxy-2-(3-hydroxy-1-octenyl)cyclopentyl]-5-heptenoic
acid. PGF-2.alpha. may be prepared as described in U.S. Pat. No.
3,657,327, which is incorporated herein by reference.
[0029] 15-Deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester is also
known as misoprostol and has the formal chemical name of
(.+-.)-methyl-(1R,2R,3R)--
3-hydroxy-2-[(E)-(4RS)-4-hydroxy-4-methyl-1-octenyl]-5-oxocyclopentanehept-
anoate. 15-Deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester may be
prepared as described in U.S. Pat. No. 3,965,143, which is
incorporated herein by reference
[0030] Enprostil has the formal chemical name of
[1.alpha.,2.beta.(1E,3R*)-
,3.alpha.]-7-[3-hydroxy-2-(3-hydroxy-4-phenoxy-1-butenyl)-5-oxocyclopentyl-
]-4,5-heptadienoic acid methyl ester. Enprostil may be prepared as
described in U.S. Pat. No. 4,178,457, which is incorporated herein
by reference.
[0031] PGI-2 is also known as prostacyclin, epoprostenol,
prostaglandin 12, prostaglandin X, PGI.sub.2, and PGX. Prostacyclin
may be prepared as described in U.S. Pat. No. 4,539,333, which is
incorporated herein by reference.
[0032] The remaining prostaglandins are described in Alex Gringanz,
Introduction to Medicinal Chemistry, Wiley-VCH, Inc., New York, pp.
158-159 and 641-642, 1997, which is incorporated herein by
reference.
[0033] Cyclodextrin complexes of the prostaglandin may be used in
order to increase the stability and efficacy. Cyclodextrin
complexes may be prepared by adding the proper stoichiometric ratio
of the prostaglandin to .alpha., .beta., or .gamma. cyclodextrin in
an aqueous solvent and then either using as is or lyophilizing to
provide a solid clathrate for mixing. These complexes are described
in Yamamura et al. (1985) J. Chromatogr. 331:383-388; Hirayama et
al. (1984) Chem. Pharm. Bull. 32:4237-4240; Uekama et al. (1984) J.
Pharm. Sci. 73:382-384; and Yamamura et al. (1984) J. Chromatogr.
303:165-172, which are incorporated herein by reference.
[0034] The prostaglandin may be administered alone or it may be
advantageous to simultaneously administer or to pretreat the
patient with one or more co-agents to increase the efficacy of the
method. Examples of co-agents which may be coadministered
include:
[0035] Agents which inhibit 15-hydroxyprostaglandindehydrogenase
(PGDH);
[0036] ACE inhibitors, including but not limited to captopril,
enalapril, enalaprilat, quinapril, lisinopril, and ramipril, may
enhance the efficacy of the present method and decrease long term
complications, such as inflammatory and fibrotic responses;
[0037] Nitro vasodilators, including but not limited to
nitroglycerin, isosorbide dinitrate, amyl nitrate, isosorbide
mononitrate, erythrityl tetranitrate, and sodium nitoprusside, may
enhance the efficacy of the present method;
[0038] Alpha blockers, including but not limited to prazosin,
phentolamine, phenoxybenzamine, dibenzamine, doxazosin, terazosin,
trimazosin, tolazoline, corynthanine, rauwolscine, and piperoxan,
are especially desirable for increasing the efficacy and prolonging
the action of the present method;
[0039] Other adrenoreceptor agents, including but not limited to
yohimbine, labetalol, carvedilol, and bucindolol, may also enhance
the activity and prolong the action of the present method;
[0040] Phosphodiesterase (PDE) inhibitors, including but not
limited to caffeine, aminophylline, theophylline, amrinone,
milrinone, vesnarinone, vinpocetine, pemobendan, cilostamide,
enoximone, peroximone, rolipram, R020-1724, zaniprast,
dipyridamole, and sildenafil, may also be effective in enhancing
the efficacy of the present method and for prolonging the
effect;
[0041] Muscarinic agents such as pilocarpine, edrophonium, and
bethanacol;
[0042] Dopaminergic agonists such as apomorphine and
bromocriptine;
[0043] Ergot alkaloids such as ergotamine and ergotamine analogs,
including acetergamine, bravergoline, bromerguride, clanegollone,
ergonovine, ergotamine tartrate, and pergolide;
[0044] Opiate antagonists such as naloxone, naltrexone, nalmefene,
nalorphine, methyl naltrexone, CTOP, diprenorphine,
.beta.-funaltrexamine, naloxonazine, nor-binaltorphimine,
natrindole, BNTX, and other analogs, which exhibit opioid
antagonistic properties; and
[0045] Polypeptide neurotransmitters such as VIP, calcitonin,
calcitonin gene related product, VIP analogs, and cholecystokinin
and all its analogs such as CCK8.
[0046] Particularly desirable combinations are PGE and
alpha-blockers, PGE and PGDH inhibitors, and PGE and PDE
inhibitors. Any combinations of the single above-listed compounds
or multiple combinations of different compounds or different groups
may also be used. In some instances, it may be advantageous to
pretreat with one or more of the co-agents. For example,
pretreatment with a PGDH inhibitor followed by treatment with PGE
will enhance the efficacy of the present method.
[0047] By the term "15-hydroxyprostaglandindehydrogenase inhibitor"
it is meant any compound which exhibits a significant and selective
inhibition of prostaglandin degrading enzyme, or
15-hydroxyprostaglandindehydrogenas- e (PGDH). Two forms of
15-hydroxyprostaglandindehydrogenase (PGDH) are known: Type I,
which is NAD+dependent, and Type II, which is NAD.sup.+dependent.
Type I operates at a Km one order of magnitude lower than Type II
and is thus more significant physiologically. Type I PGDH is
described in Mak et al. (1990) Biochimica etBiophysica Acta
1035:190-196; Ensor et al. (1995) J. Lipid Mediators Cell
Signalling 12:313-319; and Berry et al. (1983) Biochemical
Pharmacology 32(19):2863-2871, which are incorporated herein by
reference. Partially purified bovine lung Type I PGDH is
commercially available from BDH, Limited (Poole, UK). Berry et al.,
Tai et al., Muramatsu et al., and Mak et al. describe assays for
determining enzymatic activity of Type I PGDH as well as methods
for determining the degree of inhibition of this enzyme.
[0048] Type II PGDH is described in Chang et al. (1981) Biochem.
Biophys. Res. Commun. 99:745-751; Jarabak et al. (1979)
Prostaglandins 18:241-246, and Lin et al. (1978) Biochem. Biophys.
Res. Commun. 81:1227-1234, all of which are incorporated herein by
reference.
[0049] Examples of suitable 15-hydroxyprostaglandindehydrogenase
inhibitors include but are not limited to glycyrrhizic acid,
licorice, glycyrrhetinic acid, various glycosides of glycrrhetinic
acid, carboxenolone, DHEA, spironolactone, sofalcone, indomethacin,
sulindac, etodolac, oleic acid, palmitic acid, and sulphasalazine
and analogues thereof. Antibodies which bind to and inhibit Type I
PGDH may also be used.
[0050] Glycyrrhizic acid is also known as glycyrrhizin,
glycyrrhizinic acid, and glycyrrhetinic acid glycoside. The formal
chemical name is
20.beta.-carboxy-11-oxo-30-norolean-12-en-3.beta.-yl-2-O-.beta.-D-glucopy-
ranuronosyl-.alpha.-D-glucopyranosiduronic acid, and the structure
is: 3
[0051] Glycyrrhizic acid is commercially available from Sigma
Chemical Company of St. Louis, Mo.
[0052] Glycyrrhetinic acid is unglycosylated glycyrrhizic acid, and
its structure is: 4
[0053] Glycyrrhetinic acid may be obtained from licorice
extract.
[0054] Carbenoxolone is also known as 3
.beta.-hydroxy-11-oxo-20.beta.-ole- an-12-en-29-oic acid hydrogen
butanedioate and has the following structure: 5
[0055] Carbenoxolone may be synthesized as described in U.S. Pat.
No. 3,070,623, which is incorporated herein by reference.
[0056] Licorice is also known as sweet root liquorice and
glycyrrhiza and is described in the Merck Index, 10.sup.th edition,
citation 4368 as "glycyrrhiza, Licorice, liquorice; sweet root.
Dried rhizome and root of Glycyrrhiza glabra L., var. typica Regel
& Herder (Spanish licorice), or of G. Glabra L., var.
glandulifera (Waldst. & Kit.) Regel & Herder (Russian
licorice), or of other varieties of G. g yielding a yellow and
sweet wood, Leguminosaw. Habt. Southern Europe to Central Asia.
Constit. 6-14% glycyrrhizin (the glucoside of glycyrrhetic acid),
asparagine, sugars, resin."
[0057] Licorice is a crude preparation prepared from dried rhizomes
or roots and as such contains large numbers of compounds many of
which are not identified. A simple aqueous extract of a
commercially available dried licorice root preparation may be
prepared as follows. Two grams of this dried licorice root was
mixed with 10 mls of distilled water, stirred until thoroughly
mixed at room temperature and filtered to remove particulate
matter. This simple aqueous extract of licorice is effective in
inhibiting PGDH and may be used as is in the present invention.
[0058] Spironolactone is also known as Aldactone A or Verospiron.
The formal chemical name of spironolactone is
17-hydroxy-7-mercapto-3-oxo-17.- alpha.-pregn-4-ene-21-carboxylic
and .gamma.-lactone, 7-acetate, and the structure is: 6
[0059] Spironolactone is commercially available from Sigma Chemical
Company of St. Louis, Mo.
[0060] Sofalcone is formally known as
[5-[(3-methyl-2-butenyl)oxy]-2-[3-[4-
-[(3-methyl-2-butenyl)oxy]phenyl]-1-oxo-2-propenyl]phenoxy]acetic
acid and has the formula: 7
[0061] Sofalcone may be prepared as described in U.S. Pat. No.
4,085,135, which is incorporated herein by reference.
[0062] DHEA is formally known as 3-hydroxyandrost-5-en-17-one or
dehydroepiandrosterone or prasterone. The structure of DHEA is:
8
[0063] DHEA may be prepared as described in H. Hosoda et al. (1973)
J. Org. Chem. 38:4209, which is incorporated herein by
reference.
[0064] Sulfasalazine is also known as
2-hydroxy-5[[4-[(2-pyridinylamino)su- lfonyl]phenyl]azo]benzoic
acid and has the structure: 9
[0065] A number of sulfasalazine analogs have been shown to be
inhibitors of PGDH by Berry et al. (1983) Biochemical Pharmacology
32:2863-2871. Examples of sulfasalazine analogs which may be used
as the PGDH inhibitor in the present compositions include: 1011
[0066] Etodolac is also known as
1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4- -b]indole-1-acetic acid.
Etodolac may be prepared as described U.S. Pat. No. 3,843,681,
which is incorporated herein by reference.
[0067] Indomethacin is also known as
1-(4-chlorobenzoyl)-5-methoxy-2-methy- -1H-indole-3-acetic acid.
Indomethacin may be prepared as described in U.S. Pat. No.
3,161,654, which is incorporated herein by reference.
[0068] Sulindac is also known as
5-fluoro-2-methyl-1-[[4-methylsulfinyl)ph-
enyl]methylene]-1H-indene-3-acetic acid. Sulindac may be prepared
as described in U.S. Pat. Nos. 3,654,349 and 3,647,858, which are
incorporated herein by reference.
[0069] The 15-hydroxyprostaglandindehydrogenase inhibitor will
typically be present in an amount of 25 to 100, preferably 50 to
100, pig clitoral units of PGDH inhibition activity, per unit
dosage. The amount of inhibitor which corresponds to a unit of pig
clitoral PGDH inhibition activity is determined using either the
spectrophotometric or radio-chemical assay described in the
Examples. For inhibitors which exhibit a significant absorption at
340 nm, it is preferred to use the radio-chemical assay.
[0070] In a second embodiment, the present invention provides novel
pharmaceutical compositions which are useful for enhancing female
sexual desire and responsiveness. The present pharmaceutical
compositions are characterized as containing: (a) a prostaglandin;
(b) a pharmaceutically acceptable carrier; and having a pH of 3 to
7, preferably 4 to 6. In cases in which an aqueous component is
present, one may simply add a sufficient amount of a
pharmaceutically acceptable acid or base, e.g., HCl or NaOH to
adjust the pH to the desired value. For nonaqueous compositions,
one may add to each unit dose the residual powder from 0.5 ml of a
0.01 Molar aqueous solution of a pharmaceutically acceptable
citrate salt, e.g., sodium citrate, which has the desired pH. For
example, 0.5 ml of 0.01 Molar sodium citrate at pH 4.5 is
lyophilized, and the powdered residue is added to a unit dose of
PGE-2 in polyethylene glycol (PEG) MW 1450. Upon contact of this
dose with a mucosal membrane, the lyophilized citrate will dissolve
and buffer the pH of the mucosal fluid to about pH 4.5 and thereby
enhance the activity of the PGE-2 as the PEG pellet dissolves.
[0071] In a preferred embodiment, the present composition further
comprises: (c) an antioxidant selected from the group consisting of
citrate salts and tocopherol. It has been found that
prostaglandins, in particular PGE-2, are especially stabile when
formulated in a composition which contains a citrate salt, such as
sodium, potassium, or ammonium citrate, or tocopherol. Typically,
the present pharmaceutical composition will contain 1 to 2,000
.mu.g, preferably 50 to 1,000 .mu.g, of the citrate salt, or 20 to
2,000 .mu.g, preferably 50 to 1,000 .mu.g, of tocopherol.
Particularly good results have been achieved when the prostaglandin
is present in a 1 millimolar sodium citrate aqueous solution or in
liposomal solution which also contains 1 mg per ml of tocopherol as
an antioxidant.
[0072] The present compositions may also contain the same coagents
described above in the context of the present method. Thus, the
present compositions may contain one or more agents which block
prostaglandin degrading enzymes, one or more ACE inhibitors, one or
more muscarinic agents, one or more adrenoreceptor agents, one or
more dopamine agonists, one or more opiate antagonists, one or more
nitrates or nitroso compounds, one or more polypeptide
neurotransmitters, and/or one or more agents which inhibit
phosphodiesterase.
[0073] The present pharmaceutical composition can be in any
conventional form, such as a liquid, solid or gel. Examples of
suitable liquids include sterile solutions, suspensions, and
emulsions, including creams, ointments, and liposomes. For oil
based or lipophilic preparations, other suitable anti-oxidants
include BHT. For water based or hydrophilic preparations, other
suitable anti-oxidants include ascorbic acid and its sodium and
potassium salts. Preferred PEG suppositories contain a PEG which is
solid at ambient or room temperature but rapidly dissolves/melts
when placed on the clitoris. Good results have been achieved using
isotonic aqueous solutions which contain sodium citrate.
[0074] Examples of suitable solids include polyethylene glycol
(PEG), polyethylene oxide and other low melting point or
water-soluble polymers including fatty acid esters made into
suppositories or pellets. Examples of suitable gels include
triacetin, hydroxycellulose, gels composed of water, propylene
glycol, hydroxypropyl methylcellulose and any other gels which are
compatible with the prostaglandin. Liposomal mixtures are
particularly preferred as they tend to induce a stronger effect at
a given dose of prostaglandin and stabilize the prostaglandin. A
commercially available liposome to which the prostaglandin can be
added is Liposyn II.TM. 10% or 20% sold by Abbott Laboratories,
North Chicago Ill. The liposomes may be prepared as either anionic
or cationic liposomes depending upon the prostaglandin and any
co-agent present in order to maximize the desired effect. A
particularly preferred gel is lecithin organogel prepared according
to H. Willimann et al. (1992) J. Pharm. Sci. 81((9):871-874. This
particular preparation exhibits a dramatically enhanced
potency.
[0075] One may also use a gel in which one or more of the
prostaglandins or co-agents is released in a controlled-released
manner (i.e., released over time) to prolong the effect of the
composition. For example, PGE can be formulated into a cross-linked
polyethylene oxide/urethane polymer which is well tolerated by
living tissues and releases the prostaglandin in a controlled
release manner. Controlled release compositions are disclosed in D.
H. Lewis, Controlled Release of Pesticides and Pharmaceuticals,
Plenum Press, New York, 1981; and A. F. Kydonieus, Controlled
Release Technologies: Methods, Theory, and Applications, CRC Press,
Boca Raton, 1980, which are incorporated herein by reference.
[0076] In another preferred embodiment, the present composition is
in the form of a solution in which the prostaglandin with or
without a PGDH inhibitor or coagent is dissolved or suspended in
1,2,3-propanetriol triacetate, triacetin. Triacetin is a well known
solvent and is commercially available from Aldrich Chemical
Company, St. Louis, Mo. This composition enhances the drug potency
dramatically and chemically stabilizes the prostaglandin at room
temperature. Other similar short-chain triglycerides with alkyl
chains from C.sub.1-6 are expected to have similar beneficial
effects. These compounds are available from Sigma Chemical Company
(St. Louis, Mo.).
[0077] Typically, the present pharmaceutical composition will
contain the prostaglandin in a concentration such that an effective
amount of the prostaglandin is delivered to the clitoris with a
single application of the composition. For example, in the case of
a liquid, the composition will contain sufficient prostaglandin
such that an effective amount of the prostaglandin is delivered to
the clitoris by application of a drop (0.01 to 0.30 ml) of the
liquid. Thus, the present compositions, when in the form of a
liquid will suitably contain 10 nanograms/ml to 1,500 .mu.g/ml,
preferably 100 nanograms/ml to 1,000 .mu.g/ml, of the
prostaglandin. In the case of a suppository, the suppository will
preferably contain sufficient prostaglandin such that an effective
amount of the prostaglandin is delivered to the clitoris by
application of a single suppository to the clitoris. Suppositories
according to the present invention typically have volumes of 0.01
to 0.30 ml, preferably 0.1 to 0.2 ml. Thus, pharmaceutical
compositions according to the present invention which are in the
form of a suppository will suitably contain the prostaglandin in a
concentration of 10 nanograms/ml to 1,500 .mu.g/ml, preferably 100
nanograms to 1,000 .mu.g/ml. Similarly, when the composition is in
the form of a gel, the gel will typically contain sufficient
prostaglandin such that an effective amount of prostaglandin is
delivered to the clitoris upon application of a single dose (0.01
to 0.60 ml, preferably 0.05 to 0.40 ml) of the gel to the clitoris.
Thus, the gels of the present invention will suitably contain the
prostaglandin in a concentration of 10 nanograms/ml to 1,500
.mu.g/ml, preferably 100 nanograms to 1,000 .mu.g/ml. Since drug
dosages typically vary from person to person, repeated applications
may be used to achieve the desired effect.
[0078] When the prostaglandin is prostaglandin El, the
pharmaceutical composition will suitably contain the prostaglandin
El in an amount of 20 nanograms to 2,000 .mu.g, preferably 200
nanograms to 500 .mu.g, per unit dosage. When the prostaglandin is
prostaglandin E.sub.2, the pharmaceutical composition will suitably
contain the prostaglandin E.sub.2 in an amount of 0.1 nanograms to
2,000 .mu.g, preferably 1.0 nanograms to 500 .mu.g, per unit
dosage.
[0079] In a third embodiment, the present invention provides kits
which are useful for enhancing female sexual desire and response.
The present kits are characterized as containing: (a) a means for
containing a prostaglandin or pharmaceutical composition containing
the prostaglandin; and (b) means for administering the
prostaglandin or pharmaceutical composition containing the
prostaglandin to the clitoris. The means for containing the
prostaglandin or pharmaceutical composition containing the
prostaglandin may be a vial, a bottle, a pouch, an envelope, a can,
a tube, an atomizer, an aerosol can, etc. The means for
administering the prostaglandin or pharmaceutical composition
containing the prostaglandin to the clitoris may be a dropper, a
swab, a stick, or the nozzle or outlet of an atomizer or aerosol
can. It is to be understood that the means for administering the
prostaglandin or pharmaceutical composition containing the
prostaglandin to the clitoris may be connected to or a part of the
means for containing the prostaglandin or pharmaceutical
composition containing the prostaglandin. For example, the
containing means may be an atomizer or an aerosol can, and the
administering means may be the nozzle or outlet of the atomizer or
the aerosol can.
[0080] Examples of preferred kits include:
[0081] A kit which includes a container which can hold 1 to 100
unit doses of the prostaglandin or the pharmaceutical composition
containing the prostaglandin and a dropper which can dispense
between 0.01 to 0.6 ml as a unit dose. The container is preferably
glass, metal, or a plastic known not to adsorb hydrophobic
compounds.
[0082] A kit which includes a container which can hold 1 to 100
unit doses of the prostaglandin or the pharmaceutical composition
containing the prostaglandin with a spray or aerosol applicator to
spray the prostaglandin or pharmaceutical composition onto the
clitoris. The container is preferably glass, metal, or a plastic
known not to adsorb hydrophobic compounds.
[0083] A kit which includes a tube which holds 1 to 100 unit doses
of a pharmaceutical composition containing the prostaglandin, which
is in the form of a cream or gel, and an applicator which can
dispense a unit dose of the composition.
[0084] A kit which includes 1 to 100 unit doses of pellets, film or
suppositories containing a pharmaceutical composition comprising
the prostaglandin and each individually wrapped in foil and sealed
to protect the prostaglandin from the air. The foil is preferably
opaque to eliminate the degrading effects of light on the
prostaglandin.
[0085] A kit which includes 1 to 100 unit doses of a pharmaceutical
composition which comprises the prostaglandin and which have been
lyophilized and sealed under inert gas in an ampoule or vial.
Lyophilized compositions typically exhibit a much longer shelf life
than other forms and may be reconstituted close to the time of use
so that degradation of the prostaglandin is minimized. The kit may
also include a suitable diluent, syringe and needle, and/or alcohol
swabs.
[0086] The present kits will also typically include means for
packaging the container means and the administering means. Such
packaging means may take the form of a cardboard or paper box, a
plastic or foil pouch, etc. The present kits will also usually
include written instructions which describe how to administer the
prostaglandin or pharmaceutical composition containing the
prostaglandin to the clitoris. It is to be understood that the
written instructions may be on any of the container means, the
administering means, or the packaging means, in addition to being
present on a separate piece of paper.
[0087] In another embodiment, the present invention provides novel
methods of diagnosing sexual dysfunction in a female. The present
method of diagnosing female sexual dysfunction involves monitoring
the baseline clitoral temperature of the clitoris in a female,
administering a prostaglandin agent, known to cause a sexual
response when applied to a clitoris, to the clitoris of said
female, measuring the clitoral temperature response of said female
to said administering, and comparing said clitoral temperature
response of said female to that found in females not suffering
sexual dysfunction.
[0088] Other features of the present invention will become apparent
in the course of the following descriptions of exemplary
embodiments which are given for illustration of the invention and
are not intended to be limiting thereof.
EXAMPLES
[0089] I. Formulations
[0090] General Instructions
[0091] The composition should be sterilely prepared and stored.
Prostaglandins are degraded by high temperatures. Therefore, the
compositions should be stored between 38-45.degree. F. Freezing a
liquid composition may degrade the prostaglandin, so storage of
frozen compositions for long periods of time should be avoided. The
composition should also be protected from light. The prostaglandin
may have an adverse effect on children and pregnant women. So the
present compositions should be kept away from children and not used
by pregnant women.
[0092] The clitoris is often retracted or hidden under the clitoral
hood. Thus, prior to administration of the present composition, the
clitoral hood should be retracted with the finger of one hand, and
the clitoral hood should be held back as the dose is applied.
[0093] A. Water-Soluble Prostaglandins, Prostaglandin Salts, And
Prostaglandin Complexes
[0094] 5 mg of PGE-2 is added to sterile cold water (10 ml, 1 mM in
sodium citrate), stirred until dissolved and the pH adjusted with
either NaOH or HCl, to a pH of about 5.4. The resulting composition
was dispensed using any of the kits. For kit E, the aqueous PGE-2
solution is rapidly frozen in the vial using dry ice or liquid
nitrogen and lyophilized using a hard vacuum (<0.001 Torr), then
covered with anhydrous nitrogen (other inert gases may be used),
and sealed with a septum. This procedure can be used for any
prostaglandin which is water soluble. Using the same procedure,
fresh aqueous solutions of prostaglandin can be prepared with
isotonic saline or any water-soluble compound desired. For example,
lactose may be used instead of saline. PGE-1 is soluble to the
extent of 80 .mu.g/ml in water and has been used in this method of
composition preparation. PGE-1 .alpha.-cyclodextrin complex and
PGE-2.beta.-cyclodextrin complex are more water-soluble and
chemically stable than either free prostaglandin, and may also be
used in this method.
[0095] B. Aqueous Solutions with a Coagent
[0096] To prepare aqueous solutions of a prostaglandin and a
coagent, one may combine aqueous solutions of the components in the
proportion necessary to give the final desired concentration or add
the desired aqueous diluent to the pure components and mix. For
example, 1 mg of PGE-2 was dissolved in 10 ml of an aqueous
solution of 1 mM sodium citrate, and then 300 mg of papaverine HCl
was added. The resulting mixture was stirred until all the
components dissolved. Then 15 mg phentolamine HCl were added, and
the mixture was stirred until all components were dissolved, and
the pH of the resulting solution was adjusted to about 5.4. This
solution, containing 100 .mu.g of PGE-2, 30 mg of papaverine, and
1.5 mg of phentolamine HCl per ml, may then be used in any of the
compatible kits above as is or lyophilized and used in Kit E.
Alternatively, 1 ml of aqueous PGE-2 (1.0 mg/ml), 5 ml of aqueous
60 mg/ml papaverine HCl, 1 ml of aqueous phentolamine HCI (1.5
mg/ml), and 3 ml water may be combined and mixed to produce the
same solution. As stated above in Procedure A, one may use aqueous
solutions of any compatible compound. For example, isotonic saline,
1 mM sodium citrate, or isotonic lactose may also be used.
[0097] C. Liposomal Solutions
[0098] Either an aqueous or oil-based solution of the prostaglandin
and a coagent can be added to a liposomal mixture of, for example;
10 gm of safflower oil, 10 gm of soybean oil, 1.2 gm of egg
phosphotides, and 2.5 gm of glycerin in a final volume of 100 ml
(the remainder being water). Addition of 1 mg/ml of tocopherol
stabilizes the prostaglandin. 2 mg of PGE-2, 10 mg of tocopherol,
and 2 mg of Naloxone HCl may be added to 10 ml of this prepared
liposomal solution, and the resulting mixture is stirred until all
the components are dissolved. The pH of the resulting solution is
then adjusted to about 5.4. This solution may then be used in any
of the kits listed above or lyophilized and used in Kit E.
Alternatively, liposomal mixtures of PGE-2 and coagents may be
prepared as outlined in MacDonald et al. (1991) Biochem. Biophys.
Acta. 1061:297, which is incorporated herein by reference.
[0099] Liposomal solutions are particularly favored for compounds
with limited solubility in water. They also increase stability of
the prostaglandin, decrease burning sensation, and lower the dose
of the prostaglandin needed.
[0100] D. Organogel Preparation
[0101] Organogels are excellent as a matrix for transdermal
transport of drugs (H. Willimann et al., J. of Pharmaceutical
Sciences, vol. (9), pp. 871-874 (1992). 3.0 mg of PGE-2 and 3.0 mg
of prazosin HCl were dissolved in 1.0 ml of isopropyl myristate and
100 mg of soybean lecithin (high purity from Sigma Chemical, St.
Louis). Then, 40 .mu.l of water were slowly added with agitation to
produce a thick viscous gel. This may be used in any appropriate
kit listed above. Utilization of a prostaglandin cyclodextrin
complex in an organogel is particularly preferred.
[0102] E. Pellets and Suppositories
[0103] Any suitable matrix material may be used such as
polyethylene glycol (PEG), PEG-ethers, polyethoxylene glycols, and
long chain fatty acid esters so that a dose is produced which
either melts at body temperature or dissolves in water. For
example, 2.0 mg of PGE-2 is melted in 20 mg of PEG-1450 and formed,
while molten, into cylindrical pellets or drops and allowed to
cool. Each 1 mg pellet contains 100 .mu.g of PGE-2. By changing the
weight of the pellet, one may easily produce a unit dose of
prostaglandin of any size. Coagents which are not soluble in PEG or
molten at 50-55.degree. C. may be suspended in the molten
PEG-prostaglandin mixture to give a solid suspension, which is
formed into as pellets or drops as described above. Buffered
lyophilized sodium citrate powder may be added to give an enhanced
effect on contact with a mucosal membrane. Ethyl stearate forms a
good solid matrix at room temperature which will melt at body
temperature.
[0104] F. Non-Aqueous Liquids and Gels
[0105] It has been found that short-chain triglycerides impart a
dramatic and unexpected increase in the potency of the
prostaglandin. The effects of triacetin as a carrier are described
in Section V where an increase in PGE potency of several orders of
magnitude are observed. Such triglycerides are expected to increase
the chemical stability of prostaglandins during storage, thus
imparting a room-temperature shelf life to these delicate
compounds. Any of the triglycerides may be effective in this
manner. Short-chain (C.sub.1-6 alkyl chains) triglycerides are
particularly desired for preparations that are liquid at room
temperature. Higher melting triglycerides can be selected to
produce a gel-like composition.
[0106] II. PGDH Activity
[0107] A. Pig Clitoral Preparation
[0108] Fresh sow external genitalia from sexually mature animals
are obtained from a local slaughter house. The excised external
genitalia are immediately washed in tap water and then in normal
saline. The clitoris is then exposed by retracting the clitoral
hood if necessary and the glans clitoridis which corresponds to the
free extremity of the clitoris is separated from the rest of the
genitalia by sharp dissection. The length in millimeters and the
weight in milligrams of the glans clitoridis are measured and
recorded. The entire glans clitoridis is homogenized with four
volumes of an ice-cold 100 mM potassium phosphate buffer (pH 7.5)
containing 1 mM EDTA. Following centrifugation at 15,000 g for 15
minutes, the resultant supernatant fraction is used as the enzyme
source of the clitoral mucosa.
[0109] B. 15-Hydroxyprostaglandindehydrogenase (PGDH) Activity
Determination
[0110] Spectrophotometric analysis: As a substrate, prostaglandin
El is incubated with the pig clitoral enzyme prepared above. The
reaction mixture is contained in a total volume of 2.0 ml of the
same buffer used above for the preparation of the pig clitoral
preparation.
[0111] Prostaglandin E.sub.1 (50 microM) and NAD (300 microM) are
used as substrates. The reaction is initiated by the addition of
the prostaglandin E.sub.1. Incubation is done at 37.degree. C. and
is terminated by the addition of 0.5 mL of 2NaOH. The oxidation of
the prostaglandin is assayed by monitoring the reduction of
NAD.sup.+at 340 nanometers in a spectrophotometer. Reaction times
are adjusted so that the initial quantity of prostaglandin is
oxidized by 50 to 80%.
[0112] Radiochemical determination: The same reactions conditions
listed for spectrophotometric analysis are used except that (5, 6,
8, 11, 12, 14, 15(n)-.sup.3H)-prostaglandin E.sub.2 (specific
activity, 171 Ci, mmol) from Dupont de Nemours is used as a typical
substrate. Any other tritiated prostaglandin substrate can be
utilized in this assay. To terminate the reaction, methanol
precipitation (75% volume/volume)) is performed; then, water is
added to dilute the methanol to 10 volume percent. Soluble phase
extractions are performed using octadecyl 18-C silica cartridges
(J. T. Baker, Deventer, Holland). Dried extracts are run on
20.times.20, 60 A silica plates using the organic phase of ethyl
acetate/acetic acid/isooctane/water (11:2:5:10). Authentic
prostaglandin E.sub.2, 15-keto-prostaglandin E.sub.2, and 13,
14-dihydro-15-keto-prosta- glandin E.sub.2 are comigrated on
separate lanes. After localization of the compounds using
phosphomolybdic spray, the silica is scraped, and the respective
amounts of prostaglandin E.sub.2 and 15-keto-prostaglandin E.sub.2
are determined by radioactive counting. A mU is defined as that
amount of enzyme which oxidizes 1 n mole of prostaglandin E.sub.2
per min at 37.degree. C., pH 7.5. The number of mU PGDH per mm of
pig clitoris is then calculated by dividing the total number of mU
by the mm of clitoris used to prepare the enzyme.
[0113] III. PGDH Inhibitor Activity Determination
[0114] In the context of the present invention, one pig clitoris
unit of PGDH inhibition activity is defined as the quantity of
inhibitor that prevents one percent of the quantity of
prostaglandin present from being oxidized, using the assay
described below on a pig clitoris of 5 mm.
[0115] Spectrophotometric: Using the above listed
spectrophotometric analytical system for PGDH activity, the
inhibitor in question is added to the reaction mixture prior to the
addition of the prostaglandin E.sub.1. At termination of the
reaction, the quantity of the prostaglandin E.sub.1 degraded is
calculated and compared to the reaction without the inhibitor.
Percent inhibition is defined as B/A.times.100 where:
[0116] A=nmoles of prostaglandin oxidized without inhibitor.
[0117] B=nmoles prostaglandin oxidized with inhibitor.
[0118] For example, if A=50 mmoles and B=25 nmoles with inhibitor
C, then inhibitor C gives 25/50.times.100 or 50% inhibition in this
assay.
[0119] Radiochemical Determination: The assay for inhibition is run
with and without inhibitor added as listed above in the
determination of PGDH activity radiochemically. A given inhibitor
is added to the reaction mixture just prior to the addition of the
prostaglandin E.sub.1 being analyzed and the analysis performed as
listed. The quantity of prostaglandin oxidized is calculated and
interpreted as listed above for spectrophotometric analysis of
inhibitor activity.
[0120] IV. Subjective Examples
Example 1
[0121] Two drops of an aqueous solution containing 20 .mu.g of
prostaglandin E.sub.2, 150 .mu.g of phentolamine hydrochloride, and
3 mg of papaverine hydrochloride in a liposomal solution was
applied directly to the clitoris of a 41 year old female with no
history of sexual dysfunction, using a dropper. Within one minute
the subject reported a pleasurable tingling in her genitals. In the
next two to three minutes, increasing sexual feelings were noted in
the clitoris and generally throughout the subject's body. In
addition, the clitoris became engorged and vaginal lubrication was
noted in the same time frame without any stimulation other than the
administration of the present composition. The subject reported
multiple orgasms upon coitus, which represented an unusual and
increased response for her.
[0122] The same 41 year old female had 2 drops of an aqueous
solution containing 125 .mu.g of PGE-2 and 125 .mu.g of
phentolamine applied to her clitoris with essentially the same
response as in part A.
[0123] The same female had 3 drops of an aqueous saline solution
containing 125 .mu.g of PGE-2 applied to her clitoris and had the
same response described in part A but with reduced intensity.
[0124] This Example illustrates the efficacy of using a
prostaglandin, the additive effect of coadministering a coagent,
and the increased activity associated with liposomal mixtures.
Example 2
[0125] Two drops of an aqueous solution containing 50 .mu.g of
prostaglandin E.sub.2 and 150 .mu.g of phentolamine hydrochloride
was applied directly to the clitoris of a 32 year old female with
no history of sexual dysfunction, using a dropper. The subject
reported warm tingling sexual feelings in her clitoris within one
minute. Clitoral engorgement ensued in the next several minutes
along with increasing feelings that the subject identified as most
similar to those that she normally experiences with sexual
stimulation. The stimulation peaked at around 15 minutes after
application of the composition. The subject rated the intensity of
her response at eight (8) on a scale of one (1) to ten (10), with
ten being the highest. Both the observable clitoral enlargement and
the feeling of sexual excitement were gone within one hour after
application of the composition. Repeat dosing at one and a half
hours after the first dose gave the same response as the first
dose.
Example 3
[0126] A pellet containing 70 .mu.g of prostaglandin E.sub.2 and 70
.mu.g of phentolamine hydrochloride distributed in 1.4 mg of MW
1450 polyethyleneglycol (PEG) was applied directly to the clitoris
of a 41 year female with no history of sexual dysfunction. The
result was similar to those observed in Example 1.
Example 4
[0127] A pellet containing 70 .mu.g of prostaglandin E.sub.2
distributed in 1.4 mg of MW 1450 PEG was applied directly to the
clitoris of a 41 year old female with no history of sexual
dysfunction. The results were similar to those observed in Example
1.
Example 5
[0128] Three drops of a liposomal solution containing 150 .mu.g of
PGE-2 were applied directly to the clitoris of a 37 year old female
with a history of decreased sexual responsiveness. The patient
reported warm sexual feelings in her genitalia and had increased
genital lubrication and sexual receptiveness. On intercourse, she
had an orgasm and reported that she felt that the drops had greatly
increased her sexual desire and responsiveness.
Example 6
[0129] A 41 year old female with a history of decreased sexual
responsiveness and anorgasmia secondary to paroxetine took 50 mg of
naltrexone HCI 2 hours before sex and then placed two (2) drops of
a liposomal mixture containing 300 .mu.g of PEG-2 on her clitoris.
She described tingling sexual feelings in her pelvis and the
spreading of the feeling over her body within 1 minute. She noticed
a remarkable generalized feeling of sexual receptivity and, upon
subsequent coitus, had the best sexual experience of her life.
[0130] Conclusions from Subjective Examples: The above-listed
examples are given to illustrate a few of the possible applications
of the invention. A number of women have been treated and
evaluated. Overall, the results indicate a response rate of
approximately 70% utilizing various drug doses and combinations
similar to these examples. It is impossible to predict with
certainty whether any given patient will respond to a given
treatment for female sexual dysfunction. Some patients did not
respond to any treatment. In general, it appears that women with
diabetes mellitus that is poorly controlled and women on some
psychiatric drugs known to cause sexual dysfunction are less likely
to respond to the present method.
[0131] The following Examples illustrate methods for evaluating
female sexual dysfunction and determining the response to a given
treatment.
[0132] V. Blood Flow, Thermographic, and Subjective Examples
[0133] A. Methods
[0134] 1. Measurement of Clitoral Blood Flow By Ultrasound
[0135] Clitoral blood flow was estimated by utilizing the
Knoll-Midas ultrasonic Doppler velocitometer (Urometrics, Inc.).
The ultrasound probe was manually positioned over the middle of the
clitoral body as it courses superficially through the perineum
between the external vaginal opening and the end of the clitoris
(glans clitoris). Each measurement was taken when the arterial
pulse profile as displayed in real-time on the video screen was
optimized. This method is analogous to that used in measuring the
cavernosal artery velocity in the penis. The clitoral artery was
easily visualized. Measurements were made at baseline and at
various time intervals following the application of a drug to the
clitoris. Peak systolic blood flow at baseline was compared to peak
systolic blood flow following drug administration as a method of
comparing relative efficacy in inducing clitoral artery
vasodilatation in a manner analogous to studies of such drugs in
men. Ultrasonic blood flow data in a single patient (Patient #1
shown in table) demonstrates good correlation between increases in
clitoral artery peak systolic blood flow and increases in clitoral
skin temperature.
[0136] 2. Measurement of Clitoral Skin Temperature
[0137] A highly sensitive thermocouple capable of determining
changes in skin temperature of 0.002 degrees Fahrenheit was
connected to a computer-based recording device (F1000 by Focused
Technology, Inc.) and used to measure changes in clitoral skin
temperature. The patient changed from her clothes into a gown and
was placed in a semi-reclining position in a comfortable recliner.
Room temperature was controlled at 76.degree. F. (.+-.1) and no air
drafts were present. The thermocouple was coated with a small
amount of lubricating jelly and placed in a labial skin fold
adjacent to the clitoris. A period of equilibration (.about.15
minutes) allowed the measured temperature to stabilize. Next,
precise doses of various pharmaceuticals were applied as solutions
directly to the clitoris by a calibrated micropipette (Justor
h11100DG, Sigma; St. Louis, Mo.). Typical volumes used were 20-50
microliters. Clitoral temperatures were continually measured and
printed for analysis. Increases in skin temperature directly
correlate with changes in cutaneous blood flow. See Birnbaum (U.S.
Pat. No. 4,311,707) for an example of using this method to compare
the relative vasodilatory potency of topical prostaglandins.
Changes in skin temperature are reported as maximum recorded
temperature in an interval minus the temperature at the end of the
equilibration period. The magnitudes of these recorded temperature
changes may be used as a measurement of the change in clitoral
blood flow.
[0138] 3. Patient Subjective Reports
[0139] Patient reports of symptoms and effects of agents on sexual
arousal measures (such as warmth and tingling, vaginal lubrication
and excitation) were recorded. Blood pressure and pulse were also
recorded. Different drugs were given on different days. Some series
of drug titrations were recorded on several days.
[0140] B. Drug Solutions
[0141] Solutions of prostaglandin E-1 and E-2 were prepared by
dissolving weighed amounts of the prostaglandin in triacetin to
produce a concentrated stock solution. Serial dilutions of this
stock solution were made by a micropipette. Since triacetin can
partially hydrolyze on standing to produce traces of acetic acid,
the triacetin was treated with a small amount of a concentration
potassium bicarbonate solution to remove any acetic acid, then
dried with magnesium sulfate and filtered to give a triacetin free
of acid or water. Solutions were used the same day that they were
made. Concentrations of prostaglandin varied from 2.0-1,000
micrograms per milliliter of triacetin. Following equilibration of
clitoral temperature, a dose of triacetin was applied to the
clitoris prior to active drug solutions to determine the effect of
the carrier on the clitoris.
[0142] R-alphamethylhistamine hydrochloride is not soluble in
triacetin but is soluble in saline. Normal saline +2 millimolar
potassium phosphate at pH 7.4 was used to prepare solutions of
R-alphamethylhistamine hydrochloride with concentrations from
2.5-100 micrograms per milliliter of saline.
[0143] C. Patients
[0144] Patient No. 1 was a 23 year old white female without current
medical problems. She was on no medication and had no history of
sexual problems.
[0145] Patient No. 2 was a 41 year old pre-menopausal white female
without current medical problems. She was on no medication and had
no history of sexual problems.
[0146] D. Administration
[0147] Solutions were applied directly to the clitoris by means of
a calibrated micropipette (Justor 11000DG, Sigma; St. Louis,
Mo.).
[0148] E. Results
[0149] The results for Patient Nos. 1 and 2 are shown in the Tables
below.
1 PATIENT NO. 1 Temperature Change in Clitoral Change (.degree. F.)
Blood Flow (cm/sec) Subjective Response PGE-2 DOSE triacetin only
0.4 0 None 0.020 mcg 2.1 0 Rare tingle. 0.200 mcg 2.4 11 [+50%]
Very excited. 0.400 mcg 4.5 12 [+92%] Very excited, 9/10. 1.000 mcg
2.3 10 [+77%] Excited, 7/10. 10.0 mcg 4.8 10 [+100%] Very excited.
50.0 mcg 2.0 2 [+20%] Excited. 2/10 abdominal cramping. PGE-1 DOSE
Triacetin Only 0.2 None. 0.400 mcg -0.6 Felt cold. 1.000 mcg 0.3
Clitoral burning; 6/10; Abdominal eramping; 7/10; headache 20.0 mcg
0.3 4 [+46%] Clitoral burning; 4/10. Exciting. 50.0 mcg 0.1 3.5
[+32%] Exciting. Jaw pain. 100.0 mcg 2.7 6.5 [+33%] Exciting.
Flushing. Pain in jaw, headache. 200.0 mcg 0.4 11 [+80%] Diffuse
pain, flushing, cramping. R-alphamethyl histamine Potent H3 agonist
Saline Only -0.2 None. 1.0 mcg -0.1 None. 10.0 mcg -0.5 Numb
feeling in clitoris. 100.0 mcg 0.1 Clitoral burning; 2/10;
abdominal cramping, less excited than at start.
[0150]
2 PATIENT NO. 2 Temperature Change (.degree. F.) Subjective
Response PGE-2 Dose Triacetin Only 0.2 Felt drop go on. 0.050 mcg
1.8 Increased sensitivity in clitoris, 5/10 general sexual
stimulation. 1.000 mcg 2.4 Excited. 10.0 mcg 2.0 Very excited-8/10.
As good as best ever sexual excitement. PGE-1 Dose Triacetin Only
-0.25 Drop felt cold. 1.000 mcg -0.35 Felt drop go on. No
excitement. 10.0 mcg -0.10 Felt drop go on. No excitement. 100.0
mcg -0.10 Felt nothing.
[0151] F. Conclusions
[0152] Both patients showed increases in clitoral temperatures with
administration of PGE-2. The increase in Patient No. 1 resulting
from 0.200 mcg of PGE-2 was about equal to that produced by 100 mcg
of PGE-1, indicating that PGE-2 was about 500 times more potent
than PGE-1. Patient No. 2 did not have a temperature increase with
PGE-1.
[0153] Temperature increases correlated very well with patient
experiences of pleasurable sexual feelings.
[0154] The best dose of PGE-2 for Patient No. 1 was 0.400 mcg.
Patient No. 1 had pleasurable feelings from PGE-1 at doses of 20 or
more mcg. Patient No. 1 had adverse effects at all doses of PGE-1
and at doses of PGE-2 of 50 mcg.
[0155] Patient No. 2 had a sexual response from administration of
PGE-2 in an amount of 0.050 mcg or greater. Patient No. 2 had
neither positive nor negative effects from PGE-1.
[0156] R-alphamethylhistamine decreased temperature and decreased
sexual excitement in Patient No. 1.
[0157] Patient No. 1 was later treated with a triacetin solution
containing a PGDH inhibitor (palmitic acid) and PGE2 in a 10:1
weight ratio. The addition of palmitic acid further enhanced the
potency of the PGE2 resulting in an increase in clitoral blood flow
at a dose of 0.4 nanograms of PGE2 and subjective reports of a
sexual response at 2 nanograms of PGE2.
[0158] Obviously, numerous modifications and variations of the
present invention are possible in light of the above-given
teachings. It is therefore to be understood that, within the scope
of the appended claims, the invention may be practiced otherwise
than as specifically described herein.
* * * * *