U.S. patent application number 09/929818 was filed with the patent office on 2002-07-25 for treatment of female sexual dysfunction with vasoactive agents, particularly vasoactive intestinal polypeptide and agonists thereof.
Invention is credited to Place, Virgil A., Wilson, Leland F..
Application Number | 20020099003 09/929818 |
Document ID | / |
Family ID | 27497445 |
Filed Date | 2002-07-25 |
United States Patent
Application |
20020099003 |
Kind Code |
A1 |
Wilson, Leland F. ; et
al. |
July 25, 2002 |
Treatment of female sexual dysfunction with vasoactive agents,
particularly vasoactive intestinal polypeptide and agonists
thereof
Abstract
Methods for treating female sexual dysfunction are provided. A
pharmaceutical composition containing a vasoactive agent selected
from vasoactive intestinal polypeptide (VIP) and VIP agonists is
administered to the vagina and/or vulvar region of the individual
undergoing treatment. The formulations are also useful for
improving vaginal muscle tone and tissue health, enhancing vaginal
lubrication, and minimizing excess collagen deposition.
Pharmaceutical formulations and kits are also provided.
Inventors: |
Wilson, Leland F.; (Menlo
Park, CA) ; Place, Virgil A.; (Kawaihae, HI) |
Correspondence
Address: |
REED & ASSOCIATES
800 MENLO AVENUE
SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
27497445 |
Appl. No.: |
09/929818 |
Filed: |
August 13, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09929818 |
Aug 13, 2001 |
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09498522 |
Feb 4, 2000 |
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09498522 |
Feb 4, 2000 |
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09181316 |
Oct 27, 1998 |
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09181316 |
Oct 27, 1998 |
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08959064 |
Oct 28, 1997 |
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08959064 |
Oct 28, 1997 |
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08959057 |
Oct 28, 1997 |
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Current U.S.
Class: |
514/573 ;
514/13.1; 514/171; 514/182 |
Current CPC
Class: |
A61K 31/00 20130101;
A61K 31/5575 20130101; A61K 31/295 20130101; A61K 9/0034 20130101;
B82Y 5/00 20130101; A61K 31/5377 20130101; A61K 31/48 20130101;
A61K 31/5585 20130101; A61K 31/56 20130101; A61K 38/2278 20130101;
A61K 45/06 20130101; A61K 31/21 20130101; Y10S 930/17 20130101;
A61K 31/557 20130101; A61K 31/15 20130101; A61K 31/557 20130101;
A61K 2300/00 20130101; A61K 31/56 20130101; A61K 2300/00 20130101;
A61K 38/2278 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/2 ; 514/171;
514/182 |
International
Class: |
A61K 038/17; A61K
031/56 |
Claims
1. A method for treating sexual dysfunction in a female individual,
comprising administering to the vagina and/or vulvar region of the
individual a pharmaceutical formulation that comprises a
therapeutically effective amount of a vasoactive agent selected
from the group consisting vasoactive intestinal polypeptide and
agonists thereof.
2. The method of claim 1, wherein the pharmaceutical formulation
further includes a pharmaceutically acceptable carrier suited to
vaginal and/or vulvar drug administration.
3. The method of claim 1, flurther including administering a
steroid to the vagina and/or vulvar region of the individual.
4. The method of claim 3, wherein the steroid is selected from the
group consisting of progestins, estrogens, androgens, and
combinations thereof.
5. The method of claim 1, wherein the pharmaceutical formulation
further includes a compound selected from the group consisting of
steroid agonists, partial agonists and antagonists.
6. The method of claim 1, wherein the pharmaceutical formulation is
contained within a delivery system selected to provide a
predetermined agent release profile.
7. The method of claim 6, wherein the agent release profile is
pulsatile.
8. The method of claim 6, wherein the agent release profile is
continuous.
9. The method of claim 6, wherein the agent release profile is
cyclical.
10. The method of claim 6, wherein the agent release profile is
diurnal.
11. The method of claim 1, wherein the pharmaceutical formulation
is administered vaginally.
12. The method of claim 11, wherein the pharmaceutical formulation
is in the form of an ointment, cream, gel, solid, solution,
suspension, foam or liposomal composition.
13. The method of claim 11, wherein the pharmaceutical formulation
is contained within a vaginal ring, tampon, suppository, sponge,
pillow, puff, or osmotic pump system.
14. The method of claim 1, wherein the pharmaceutical formulation
is administered to the vulvar region.
15. The method of claim 1, wherein the vasoactive agent is
vasoactive intestinal polypeptide.
16. The method of claim 1, wherein the vasoactive agent is a
vasoactive intestinal polypeptide agonist.
17. The method of claim 16, wherein the vasoactive intestinal
polypeptide agonist comprises a polypeptide sequence comprising a
human vasoactive intestinal polypeptide sequence having amino acid
substitutions at one or more positions.
18. The method of claim 17, wherein the vasoactive intestinal
polypeptide agonist is terminally modified.
19. The method of claim 16, wherein the vasoactive intestinal
peptide agonist comprises at least one agonist selected from the
group consisting of SEQ. ID. NOS.:2-205 inclusive.
20. The method of claim 4, wherein the steroid is an androgenic
agent.
21. The method of claim 20, wherein the androgenic agent is
selected from the group consisting of androsterone, androsterone
acetate, androsterone propionate, androsterone benzoate,
androstenediol, androstenediol-3-acetate,
androstenediol-17-acetate, androstenediol-3,17-diacetate,
androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate,
androstenedione, dehydroepiandrosterone, sodium
dehydroepiandrosterone sulfate, 4-dihydrotestosterone,
dromostanolone, dromostanolone propionate, ethylestrenol,
fluoxymesterone, methyltestosterone, nandrolone phenpropionate,
nandrolone decanoate, nandrolone furylpropionate, nandrolone
cyclohexane-propionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol,
testolactone, testosterone, and pharmaceutically acceptable esters
of testosterone and 4-dihydrotestosterone.
22. The method of claim 21, wherein the androgenic agent is
selected from the group consisting of testosterone, C-17 esters of
testosterone, 4-dihydrotestosterone, C-17 esters of
4-dihydrotestosterone, dehydroepiandrosterone, and
methyltestosterone.
23. A method for enhancing sexual desire and responsiveness in a
female individual, comprising administering to the individual,
approximately 0.25 to 72 hours prior to sexual activity, a
therapeutically effective amount of a vasoactive agent selected
from the group consisting of vasoactive intestinal polypeptide,
agonists thereof, and combinations thereof.
24. A method for maintaining improving the tissue health of the
female genitalia, comprising administering to a female individual,
on an as-needed basis, a therapeutically effective amount of a
vasoactive agent selected from the group consisting of vasoactive
intestinal polypeptide, agonists thereof, and combinations
thereof.
25. A method for preventing vaginal atrophy, comprising
administering to a female individual, on an as-needed basis, a
therapeutically effective amount of a vasoactive agent selected
from the group consisting of vasoactive intestinal polypeptide,
agonists thereof, and combinations thereof.
26. A method for preventing vaginal pain during sexual intercourse,
comprising administering to a female individual suffering from
dyspareunia a therapeutically effective amount of a vasoactive
agent selected from the group consisting of vasoactive intestinal
polypeptide, agonists thereof, and combinations thereof.
27. A method for alleviating vaginal itching and dryness,
comprising administering to a female individual in need of such
treatment a therapeutically effective amount of a vasoactive agent
selected from the group consisting of vasoactive intestinal
polypeptide, agonists thereof, and combinations thereof, on an
as-needed basis.
28. A method for enhancing sexual desire and responsiveness in a
female individual, comprising administering a vasoactive agent
selected from the group consisting of vasoactive intestinal
polypeptide, agonists thereof, and combinations thereof to the
individual in an amount effective to provide a blood level of the
agent or a metabolite thereof that approximates the blood level of
the agent or a metabolite thereof during ovulation.
29. A pharmaceutical formulation for enhancing female sexual desire
and responsiveness, comprising (a) approximately 1.0 .mu.g to 1.0 g
of a vasoactive agent selected from the group consisting of
vasoactive intestinal polypeptide, agonists thereof, and
combinations thereof, per gram of formulation, (b) a
pharmaceutically acceptable carrier suitable for vaginal and/or
vulvar administration.
30. The formulation of claim 29, wherein the formulation comprises
approximately 50 .mu.g to about 500 mg of the vasoactive agent per
gram of formulation.
31. The formulation of claim 30, wherein the formulation comprises
approximately 1.0 mg to about 250 mg of the vasoactive agent per
gram of formulation.
32. The formulation of claim 29, wherein the carrier is selected to
provide immediate release of the vasoactive agent from the
formulation following application to the individual's vagina and/or
vulvar area, such that the formulation may be effectively
administered on an on-demand basis.
33. The formulation of claim 29, comprising a gel, cream, ointment,
solution or lotion.
34. The formulation of claim 29, comprising a suppository.
35. The formulation of claim 29, wherein the vasoactive agent is
vasoactive intestinal polypeptide.
36. The formulation of claim 29, wherein the vasoactive agent is a
vasoactive intestinal polypeptide agonist.
37. The formulation of claim 36, wherein the vasoactive intestinal
polypeptide agonist comprises a polypeptide sequence comprising a
human vasoactive intestinal polypeptide sequence having amino acid
substitutions at one or more positions.
38. The formulation of claim 37, wherein the vasoactive intestinal
polypeptide agonist is terminally modified.
39. The formulation of claim 36, wherein the vasoactive intestinal
peptide agonist comprises at least one agonist selected from the
group consisting of SEQ. ID. NOS.:2-205 inclusive.
40. A packaged kit for a female individual to use in enhancing
sexual desire and responsiveness, comprising: a pharmaceutical
formulation of a vasoactive agent selected from the group
consisting of vasoactive intestinal polypeptide and agonists
thereof; a container housing the pharmaceutical formulation during
storage and prior to administration; and instructions for carrying
out drug administration to enhance sexual desire and
responsiveness.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/498,522, filed Feb. 4, 2000, which is a
divisional of U.S. patent application Ser. No. 09/181,316, filed
Oct. 27, 1998, abandoned, which was a continuation-in-part of U.S.
patent application Ser. No. 08/959,064, filed Oct. 28, 1997, which
issued on Mar. 2, 1999 as U.S. Pat. No. 5,877,216, and which was
also a continuation-in-part of U.S. patent application Ser. No.
08/959,057, also filed Oct. 28, 1997, now abandoned, the
disclosures of which are hereby incorporated by reference.
TECHNICAL FIELD
[0002] This invention relates generally to methods and
pharmaceutical formulations for treating female sexual dysfunction,
and more particularly relates to vaginal and/or vulvar
administration of a vasoactive agent, such as a prostaglandin or a
vasoactive intestinal polypeptide, in such treatment. The invention
further relates to additional methods of using the present
pharmaceutical formulations, including, but not limited to, the
prevention of yeast infections and the improvement of vaginal
muscle tone.
BACKGROUND
[0003] Sexual response in women is generally classified into four
stages: excitement, plateau, orgasm, and resolution. Masters and
Johnson, Human Sexual Response (Boston, Mass.: Little, Brown &
Co., 1966). With sexual arousal and excitement, vasocongestion and
muscular tension increase progressively, primarily in the genitals,
and is manifested by increased blood flow, elevated luminal oxygen
tension, and vaginal surface lubrication as a result of plasma
transudation that saturates the fluid reabsorptive capacity of the
vaginal epithelium. Vasoactive intestinal polypeptide ("VIP")
release may induce the physiological changes of sexual arousal and
excitement, and may be the major neurotransmitter effecting
neurologically controlled increase of the vaginal blood supply upon
arousal. The peptide histidine methionine has been co-located with
VIP within nerve fibers that innervate small blood vessels, smooth
muscle and epithelial cells in the vaginal tract.
[0004] VIP is a neurotransmitter known to effect small vessel
dilation in the mesenteric blood supply in response to mechanical
sensation of food in the gut to promote digestion. VIP is therefore
found in the cholinergic, parasympathetic ganglia of the intestinal
peripheral nervous system. Kandel, Schwartz and Jessel, Principles
of Neural Science, 4.sup.th Ed. (McGraw-Hill 2000). VIP was
initially discovered, isolated and purified from porcine intestine,
and the twenty-eight (28) amino acid VIP has extensive homology to
secretin and glucagon (Carlquist et al. (1982) Horm. Metab. Res.
14:28-29). VIP is known to exhibit a wide range of biological
activities in the gastrointestinal tract and circulatory system.
VIP has been shown to stimulate pancreatic and biliary secretion,
hepatic glycogenolysis, glucagon and insulin secretion and to
activate pancreatic bicarbonate release (Kerrins t al. (1972) Proc.
Soc. Exp. Biol. Med. 142:1014-1017; Domschke et al. (1977)
Gastroenterology 73:78-480).
[0005] The physiologic effects of VIP extend outside the digestive
system. For example, neurons containing VIP have been localized by
immunoassay in cells of the endocrine and exocrine systems,
intestine and smooth muscle (Polak et al. (1974) Gut 15:720-724),
and has been found to be a neuroeffector of the release of hormones
including prolactin (Frawley et al. (1981) Neuroendocrinology
33:79-83), thyroxine (Ahren et al. (1980) Nature 287:343-345), and
the aforementioned insulin and glucagon (Schebalin, et al. (1977)
Am. J. Physiology E. 232:197-200. VIP is present in neurons and
neural junctions in the airways of animal species including man
(Dey et al. (1980) Fed. Proc. 39:1062; Said et al. (1974) Ann. N.Y.
Acad. Sciences 221:103-114). VIP has also been found to stimulate
renin release from the kidney in vivo and in vitro (Porter et al.
(1983) Neuroendocrinology 36:404-408), and the presence of VIP in
other parts of the genito-urinary system has been shown. The widely
appreciated direct vasoactive effect of VIP is to increase blood
flow into capillary bed by dilation of the afferent blood vessel.
Various analogs of VIP, both agonistic and antagonistic are known
to exist (see for example U.S. Pat. Nos. 5,235,907, 5,141,924,
4,734,400 and 4,605,641 to Bolin; and U.S. Pat. Nos. 4,939,224 and
4,835,252 to Musso et al.).
[0006] Sexual excitement is initiated by any of a number of
psychogenic or somatogenic stimuli and must be reinforced to result
in orgasm. With continued stimulation, excitement progresses in
intensity into a plateau stage, from which the individual can shift
into orgasm. The orgasmic stage is characterized by a rapid release
from vasocongestion and muscular tension.
[0007] During the various stages of sexual response, characteristic
genital and extragenital responses occur. Estrogens magnify the
sexual responses; however, sexual responses may also occur in
estrogen-deficient individuals. Sexual dysfunction may be due to
organic or functional disturbances. For example, a variety of
diseases affecting neurologic function, including diabetes mellitus
and multiple sclerosis, may interrupt sexual arousal. More
commonly, local pelvic disorders, such as endometriosis and
vaginitis, both of which cause dyspareunia (difficult or painful
coitus) may also affect a woman's sexual response. In addition,
estrogen deficiency, causing vaginal atrophy and dyspareunia, is a
common cause of sexual dysfunction. For a discussion of other
causes of female sexual dysfunction, see, e.g., Kaplan, The
Evaluation of Sexual Disorders: Psychological and Medical Aspects
(New York, N.Y.: Brunner-Mazel, 1983), and Kolodny et al., Textbook
of Sexual Medicine (Boston, Mass.: Little, Brown & Co.,
1979).
[0008] Excitement stage dysfunction generally involves touch
sensation impairment, loss of clitoral sensation, vaginal dryness
and urinary incontinence. Such excitement phase dysfunction
generally results in dyspareunia. Dyspareunia is thought to affect
approximately 40% of women, due in large part to inadequate
lubrication. It has been estimated that over 40 million women will
suffer dyspareunia at some time in their lives. On the order of
twenty-five million women will experience dyspareunia in the peri-
and postmenopausal period (see Kelly, S. (1992) Clinical Practice
and Sexuality 8(8):2 and Sato et al. (1992) Clinical Practices in
Sexuality 8(5):1). Contemporary symptomatic treatments generally
involve the use of physiologically safe lubricants such as egg
white, K-Y surgical lubrication jelly (hydroxyethyl-cellulose),
Astroglide7, and Replens7. See, for example, Semmens (1974) Medical
Aspects of Human Sexuality 8:85-86, and Frishmen et al. (1992)
Fertility and Sterility 8(3):630. When symptomatic treatment fails,
pharmacological treatment may be indicated.
[0009] Estrogen therapy is commonly used in the pharmacological
treatment of sexual dysfunction in women. Estrogen-based therapies
are generally used to increase mucous production, provide
vasodilatory effects, or to increase the general health of the
vagina. Nadelson et al., eds., Treatment Interventions in Human
Sexuality (New York: Plenum Press, 1983). In such treatments,
estrogen is administered orally, parenterally (e.g., by injection),
or topically. With oral administration, the estrogen concentration
encountered by the liver is generally four- to five-fold greater
than estrogen levels in peripheral blood (the "first pass effect").
This effect may lead to an undesirable increase in the production
of certain coagulation factors and renin substrates by the liver.
Parenterally administered estrogen avoids the first pass effect in
the liver. However, all estrogen-based therapies are known to
increase the risk of endometrial hyperplasia, endometrial cancer
and breast cancer in treated individuals.
[0010] Because of the increased risk of endometrial hyperplasia and
endometrial cancer encountered with unopposed estrogen therapies,
estrogen/progestogen combinations have been employed. However,
progestogens are known to have some androgenic activity. Further,
common side effects from such therapies include uterine bleeding
and the continuation of menstrual periods. Accordingly, there
remains a need in the art to provide safer and more ways of
treating female sexual dysfunction.
[0011] The present invention is directed to the aforementioned need
in the art, and provides a new, highly effective method of treating
sexual dysfunction in women. The method involves vaginal and/or
vulvar administration of a pharmaceutical formulation containing a
vasoactive agent, e.g., a prostaglandin, VIP or a VIP agonist or
the like.
[0012] Drug therapy for treating female sexual dysfunction has been
described. For example, U.S. Pat. No. 4,507,323 to Stern describes
the use of the anxiolytic
m-chloro-.alpha.-t-butylamino-propiophenone in the treatment of
sexual dysfunction in both male and female individuals.
Pharmaceutical compositions containing the agent are described,
which are presented in discrete units, e.g., cachets, tablets,
capsules, ampules and suppositories, for oral or rectal delivery of
the agent.
[0013] Additionally, U.S. Pat. No. 4,521,421 to Foreman describes
the treatment of sexual dysfunction in male and female individuals
using the stereoisomers of octahydropyrimido[4,5-g]quinolines,
centrally acting dopamine agonists.
[0014] U.S. Pat. No. 5,190,967 to Riley describes the treatment of
sexual disorders in male and female individuals using heterocyclic
benzodioxinopyrrole compounds, which, like the drugs described in
the aforementioned patents, are centrally acting agents.
[0015] U.S. Pat. Nos. 5,565,466 to Gioco et al., 5,731,339 to
Lowrey, and 5,773,457 to Nahoum pertain to methods for modulating
the human sexual response, with the Gioco et al. and Lowrey patents
emphasizing the utility of phentolarnine as an active agent.
[0016] A number of references describe various methods and devices
suitable for vaginal or uterine drug administration, and may
accordingly be of some interest with respect to the present
invention. The following are representative of such references:
[0017] U.S. Pat. No. 3,967,618 to Zaffaroni describes an
intrauterine device adapted for drug delivery. A number of drugs
are mentioned as being suitable for use in conjunction with the
device. However, the patent does not mention treatment of sexual
dysfunction, nor is application of a drug-containing composition to
the clitoris or vulvar region disclosed or suggested. U.S. Pat. No.
3,948,254 to Zaffaroni is a related patent that describes an
intrauterine device for continuous administration of a
contraceptive agent.
[0018] U.S. Pat. No. 4,014,987 to Heller et al. describes a
tampon-like device for delivery of a drug to the uterus or vagina.
Heller et al. mention that delivery of prostaglandins is a
preferred use of the invention; however, there is no disclosure
concerning treatment of sexual dysfunction or delivery to the
vulvar area or urethra.
[0019] U.S. Pat. No. 4,564,362 to Burnhill describes a vaginal
sponge for controlled release of a contraceptive agent.
[0020] U.S. Pat. No. 4,112,942 to Scaife generally describes
vaginal administration of medicinal foams.
[0021] There are, accordingly, a number of background references
relating to treatment of female sexual dysfunction, and cervical or
uterine administration of vasoactive agents. However, the present
method for treating female sexual dysfunction, by way of vaginal
and/or vulvar delivery of a vasoactive agent such as a
prostaglandin or VIP or a receptor agonist thereof, is completely
novel and unsuggested by the art.
SUMMARY OF THE INVENTION
[0022] Accordingly, it is a primary object of the invention to
provide a method for treating sexual dysfunction in a female
individual by administering a pharmaceutical formulation containing
a selected vasoactive agent to the vaginal and/or vulvar area of
the individual undergoing treatment.
[0023] It is still another object of the invention to provide
methods for improving vaginal muscle tone and tissue health,
enhancing vaginal lubrication, preventing vaginal atrophy,
preventing pain during intercourse as a result of dyspareunia,
alleviating vaginal itching and dryness associated with dyspareunia
and other conditions, and minimizing collagen misdeposition
resulting from hypoxia, each of such methods vaginal and/or vulvar
administration of a pharmaceutical formulation containing a
selected vasoactive agent, in combination with a pharmaceutically
acceptable vehicle.
[0024] It is an additional object of the invention to provide such
methods wherein the vasoactive agent is vasoactive intestinal
polypeptide or an agonist thereof.
[0025] It is still an additional object of the invention to provide
such methods wherein drug administration is carried out on an
as-needed basis.
[0026] It is a further object of the invention to provide
pharmaceutical formulations useful in conjunction with the
aforementioned methods.
[0027] Additional objects, advantages and novel features of the
invention will be set forth in part in the description that
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.
[0028] In one aspect of the invention, then, a method is provided
for treating sexual dysfunction in a female individual comprising
administering to the vagina and/or vulvar area a pharmaceutical
formulation containing a selected vasoactive agent. The vasoactive
agent is preferably a vasodilator, with preferred vasodilators
selected from the group consisting of VIP and vasoactive intestinal
polypeptide agonists, both natural and synthetic, and combinations
of any of the foregoing. Any number of drug delivery platforms may
be used, e.g., suppositories, ointments, creams, gels, solutions
and the like, which will be described in detail below. Also, one or
more additional types of drugs, i.e., pharmacologically active
agents other than vasoactive agents, may be incorporated into the
pharmaceutical formulations. In other aspects of the invention,
vaginal administration of a vasoactive agent as just described is
used to improve vaginal muscle tone and tissue health, to enhance
vaginal lubrication, or to minimize collagen misdeposition
resulting from hypoxia as well as the associated lack of elasticity
resulting from the collagen misdeposition.
[0029] In another aspect of the invention, pharmaceutical
compositions and dosage forms are provided for carrying out the
aforementioned methods. The compositions and dosage forms contain a
vasoactive agent as described above, a pharmaceutically acceptable
vehicle, and, optionally, one or more additional pharmacologically
active agents. The formulations contain a therapeutically effective
amount of the active agent, or a therapeutically effective
concentration of the active agent, i.e., a concentration that
provides a therapeutically effective amount of active agent upon
administration of a selected volume of composition.
[0030] In another embodiment, packaged kits are provided for
individuals to carry out the aforementioned methods. Packaged kits
include a pharmaceutical composition or dosage form containing the
active agent, a container housing the composition or dosage form
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 therapeutically effective manner. The
composition or dosage form may be any of those described
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Before describing the present invention in detail, it is to
be understood that this invention is not limited to delivery of
specific drugs, carriers or use of particular drug delivery
systems, 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.
[0032] 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 "a vasoactive agent" includes a
mixture of two or more vasoactive agents, reference to "a
pharmaceutically acceptable excipient" includes mixtures of such
excipients, and the like.
[0033] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0034] The terms "active agent," "pharmacologically active agent"
and "drug" are used interchangeably herein to refer to a chemical
compound that induces a desired pharmacological, physiological
effect, i.e., in this case, enhancement of female sexual desire and
responsiveness. The primary active agents herein are vasoactive
intestinal polypeptide and agonists thereof. The terms also
encompass pharmaceutically acceptable, pharmacologically active
derivatives of those active agents specifically mentioned herein,
including, but not limited to, salts, esters, amides, prodrugs,
active metabolites, and the like. When the terms "active agent,"
"pharmacologically active agent" and "drug" are used, then, it is
to be understood that applicants intend to include the active agent
per se as well as pharmaceutically acceptable, pharmacologically
active salts, esters, amides, prodrugs, metabolites, analogs,
etc.
[0035] The pharmacologically active agents herein are vasoactive
intestinal polypeptide and analogs thereof that serve as VIP
agonists.
[0036] 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 to enhance female sexual
desire and responsiveness.
[0037] "Carriers" or "vehicles" as used herein refer to
conventional pharmaceutically acceptable carrier materials suitable
for drug administration, and include any such materials known in
the art that are nontoxic and do not interact with other components
of a pharmaceutical composition or drug delivery system in a
deleterious manner.
[0038] 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., treatment of female sexual dysfunction. The
amount that is "effective" will vary from subject to subject,
depending on the age and general condition of the individual, the
particular active agent or agents, and the like. Thus, it is not
always possible to specify an exact "effective amount." However, an
appropriate "effective" amount in any individual case may be
determined by one of ordinary skill in the art using routine
experimentation.
[0039] The terms "treating" and "treatment" as used herein refer to
reduction in severity and/or frequency of symptoms, elimination of
symptoms and/or underlying cause, prevention of the occurrence of
symptoms and/or their underlying cause, and improvement or
remediation of damage. Thus, for example, "treating" sexual
dysfunction, as the term is used herein, encompasses both
prevention of sexual dysfunction in clinically asymptomatic
individuals and treatment of dysfunction in a clinically
symptomatic individual.
[0040] By "treating female sexual dysfunction" is meant enhancing
female sexual desire and responsiveness. Applicants intend to
include the treatment of disorders of female sexual desire and/or
response, meaning any disorder or dysfunction that causes a
decrease in or absence of female sexual responsiveness or female
sexual desire. This includes any persistent or recurrent deficiency
in the 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,
anti-hypertensives, tobacco, opiates, alcohol and any other drug
found to decrease or eliminate any part of the sexual response
cycle. Primary and secondary anorgasmia are included.
[0041] 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 a time just prior to
the time at which drug efficacy is wanted, e.g., just prior to
anticipated sexual activity, and within a time interval sufficient
to provide for the desired therapeutic effect, i.e., enhancement in
sexual desire and in sexual responsiveness during sexual activity.
"As-needed" administration herein does not involve priming doses or
chronic administration, "chronic" meaning administration at regular
time intervals on an ongoing basis. As-needed administration may
involve administration immediately prior to sexual activity, but
will generally be about 0.25 to 72 hours, preferably about 0.5 to
48 hours, more preferably about 1 to 24 hours, most preferably
about 1 to 12 hours, and optimally about 1 to 4 hours prior to
anticipated sexual activity. "As-needed" administration may or may
not involve administration of a sustained release formulation in
advance of anticipated sexual activity, with drug release taking
place throughout an extended drug delivery period typically in the
range of about 4 to 72 hours.
[0042] 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 of Pharmacy, 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
[0043] 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.
[0044] 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. A
sustained release formulation may be administered once to provide a
single bolus dose of the active agent, which is then effective for
up to a day or even up to several days.
[0045] By the term "transdermal" drug delivery is meant delivery by
passage of a drug through the skin or mucosal tissue and into the
bloodstream.
[0046] 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. Topical
administration thus includes transmucosal administration.
[0047] Generally, "vaginal delivery" of a pharmaceutical
formulation involves administration to the distal several
centimeters of the vagina. The terms "vulvar delivery" and "vulvar
administration" are used herein to refer to application of a
pharmaceutical formulation to the vulvar area of an individual
undergoing treatment. The term is intended to encompass application
to the clitoris as well as the surrounding vulvar area. The terms
"vulvar delivery" and "clitoral delivery" are used interchangeably
herein and are both intended to refer to administration to the
vulvar area of the individual undergoing treatment.
[0048] In order to carry out the method of the invention, VIP or an
agonist thereof is administered to the vagina and/or vulvar region
of a female individual to enhance sexual desire and responsiveness;
the individual may or may not be suffering from a sexual disorder
or dysfunction. The active agent is administered locally and
transmucosally, i.e., vaginally and/or to the vulvar region.
[0049] As used herein, the term "C.sub.1-3 alkyl" refers to methyl,
ethyl, propyl, and isopropyl.
[0050] The nomenclature used to define the vasoactive intestinal
peptides of the invention is that typically used in the art,
wherein the amino group at the N-terminus appears to the left and
the carboxyl group at the C-terminus appears to the right. By
natural amino acids is meant one of the naturally occurring amino
acids found in proteins, i.e., Gly, Ala, Val, Leu, Ile, Ser, Thr,
Lys, Arg, Asp, Asn, Glu, Gln, Cys, Met, Phe, Tyr, Pro, Trp, and
His. By Nle is meant norleucine. By Orn is meant ornithine. By Ac
is meant acetyl (CH.sub.3CO.sub.2). Where the amino acid has
isomeric forms, it is the L form of the amino acid that is
represented unless otherwise expressly indicated.
[0051] Analogs of VIP, i.e., those analogs included herein as VIP
agonists, are indicated by setting forth the substituted amino acid
in brackets before "VIP." Derivatization of the N-terminal amino
group is indicated to the left of the bracketed substitutions.
Sequence numbers appearing in parentheses to the right of "VIP"
indicate amino acid deletions and additions to the native sequence
numbering. That is, for example,
Ac-[Lys.sup.12,Nle.sup.17,Gly.sup.29]-VIP(2-29) indicates a
polypeptide having an amino acid sequence corresponding to native
human VIP in which an acetyl group has been substituted for
hydrogen at the N-terminus, lysine has been substituted for
arginine at position 12 and norleucine has been substituted for
methionine at position 17, the histidine at position 1 has been
deleted and a glycine has been coupled onto the carboxyl side of
asparagine 28, termed position 29. The suffixes "--OH" and
"--NH.sub.2" following "VIP" refer to the free acid and amide forms
of the polypeptide, respectively. In the event neither suffix is
used, the expression is intended to encompass both forms.
[0052] The following abbreviations are also defined:
N--CH.sub.3-Ala is N-methyl-alanine, p-F-Phe is
fluoro-phenylalanine, 1-Nal is 3-(1'-naphthyl)-alanine, 2-Nal is
3-(2'-naphthyl)-alanine, p-NH.sub.2-Phe is p-amino-phenylalanine,
O--CH.sub.3-Tyr is O-methyl-tyrosine, Cys(Acm) is
S-acetoamidomethyl-cysteine, m-F-Tyr is m-fluoro-tyrosine.
[0053] In a first embodiment, the invention relates to a method for
treating sexual dysfunction in a female individual and involves
vaginal and/or vulvar administration of a pharmaceutical
formulation containing a vasoactive agent, preferably a
vasodilator. Preferred vasodilators are selected from the group
consisting of vasoactive intestinal polypeptide, VIP agonists,
pharmaceutically acceptable salts, esters, derivatives, prodrugs,
and inclusion complexes thereof, and combinations of any of the
foregoing, in combination with a pharmaceutically acceptable
vehicle.
[0054] VIP agonists are, as noted above, useful for practicing the
invention. The sequence of human VIP, which is the same as rat,
bovine and porcine VIP is known to be:
[0055]
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-
-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn.
[0056] In the conventional single letter amino acid code the VIP
amino acid sequence is:
H-S-D-A-V-F-T-D-N-Y-T-R-L-R-K-Q-M-A-V-K-K-Y-L-N-S-I-L-N (SEQ. ID.
NO.: 1). VIP sequences from other species are known to exhibit
homology to human VIP and therefore expected to exhibit VIP
agonistic and/or antagonistic activity. Partial agonists of VIP
that are also antagonists of VIP, for example agonists that are
less active than endogenously secreted VIP may be used in the
methods of the invention depending upon activity relative to
physiologic human VIP and local dosage. The usefulness of partial
VIP agonists for practicing the invention may be ascertained by
conventional trials and pharmacologic assays known in the art.
[0057] Representative vasoactive intestinal polypeptide analogs
include peptides having the following amino acid sequences:
[0058] [Lys.sup.12, Nle.sup.17]-VIP (SEQ. ID. NO.: 2);
[0059] Ac-[Lys.sup.12, Nle.sup.17]-VIP (SEQ. ID. NO.: 3);
[0060] [Orn.sup.12, Nle.sup.17]-VIP (SEQ. ID. NO.: 4);
[0061] Ac-[Orn.sup.12, Nle.sup.17]-VIP (SEQ. ID. NO.: 5);
[0062] [Ser.sup.11,Phe.sup.13,Nle.sup.17]-VIP (SEQ. ID. NO.:
6);
[0063] Ac-[Ser.sup.11,Phe.sup.13,Nle.sup.17]-VIP (SEQ. ID. NO.:
7);
[0064] [Nle.sup.17,Thr.sup.25]-VIP (SEQ. ID. NO.: 8);
[0065] [Nle.sup.17,Thr.sup.24]-VIP (SEQ. ID. NO.: 9);
[0066] [Ala.sup.9,Nle.sup.17]-VIP (SEQ. ID. NO.: 10);
[0067] Ac-[Ala.sup.9,Nle.sup.17]-VIP (SEQ. ID. NO.: 11);
[0068] [Lys.sup.14,Nle.sup.17]-VIP (SEQ. ID. NO.: 12);
[0069] [Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP (SEQ. ID. NO.:
13);
[0070] [Lys.sup.12,Lys.sup.14,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 14);
[0071] [Nle.sup.17,Thr.sup.28]-VIP (SEQ. ID. NO.: 15);
[0072] Ac-[Nle.sup.17,Thr.sup.28]-VIP (SEQ. ID. NO.: 16);
[0073] [Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP (SEQ. ID.
NO.: 17);
[0074] Ac-[Orn.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP (SEQ.
ID. NO.: 18);
[0075]
Ac-[Lys.sup.12,Lys.sup.14,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 19);
[0076]
Ac-[Lys.sup.12,Nle.sup.17,Thr.sup.25,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 20);
[0077] Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Ala.sup.28]-VIP;
[0078]
Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Ala.sup.27,Thr.sup.28]-VIP
(SEQ. ID. NO.: 21);
[0079] Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.26,Thr.sup.28]-VIP (SEQ.
ID. NO.: 22);
[0080]
Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.25,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 23);
[0081]
Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.24,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 24);
[0082]
Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.23,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 25);
[0083]
Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.22,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 26);
[0084]
Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.21,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 27);
[0085]
Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.20,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 28);
[0086]
Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.19,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 29);
[0087] Ac-[Lys.sup.12,Ala.sup.17,Val.sup.26,Thr.sup.28]-VIP (SEQ.
ID. NO.: 30);
[0088]
Ac-[Lys.sup.12,Ala.sup.16,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 31);
[0089]
Ac-[Lys.sup.12,Ala.sup.15,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 32);
[0090]
Ac-[Lys.sup.12,Ala.sup.14,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 33);
[0091]
Ac-[Lys.sup.12,Ala.sup.13,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 34);
[0092] Ac-[Ala.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP (SEQ.
ID. NO.: 35);
[0093]
Ac-[Ala.sup.11,Lys.sup.12,Nle.sup.17,Val.sup.26Thr.sup.28]-VIP
(SEQ. ID. NO.: 36);
[0094]
Ac-[Ala.sup.10,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 37);
[0095]
Ac-[Ala.sup.9,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 38);
[0096]
Ac-[Ala.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 39);
[0097]
Ac-[Ala.sup.7,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 40);
[0098]
Ac-[Ala.sup.6,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 41);
[0099]
Ac-[Ala.sup.5,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 42);
[0100]
Ac-[Ala.sup.3,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 43);
[0101]
Ac-[Ala.sup.2,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 44);
[0102]
Ac-[Ala.sup.1,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 45);
[0103]
Ac-[Gly.sup.1,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 46);
[0104]
Ac-[Leu.sup.5,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 47);
[0105]
Ac-[1-Nal.sup.6,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 48);
[0106] Ac-[p-F-Phe.sup.6,Lys.sup.12,Nle.sup.17,Val
26,Thr.sup.28]-VIP (SEQ. ID. NO.: 49);
[0107]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 50);
[0108] Ac-[2
-Nal.sup.10,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP (SEQ.
ID. NO.: 51);
[0109]
Ac-[p-NH.sub.2-Phe.sup.10,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.-
28]-VIP (SEQ. ID. NO.: 52);
[0110]
Ac-[O--CH.sub.3-Tyr.sup.10,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup-
.28]-VIP (SEQ. ID. NO.: 53);
[0111] Ac-[Lys.sup.12
Nle.sup.17,m-F-Tyr.sup.22,Val.sup.26,Thr.sup.28]-VIP (SEQ. ID. NO.:
54);
[0112]
Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.29,30,Met.s-
up.31]-VIP (SEQ. ID. NO.: 55)
[0113]
Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.29,30,Cys(A-
cm).sup.31]-VIP (SEQ. ID. NO.: 56);
[0114]
Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.29,30,Thr.s-
up.31]-VIP (SEQ. ID. NO.: 57);
[0115]
Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Ala.sup.29,30,Met.s-
up.31]-VIP (SEQ. ID. NO.: 58);
[0116]
Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Ala.sup.29-31]-VIP
(SEQ. ID. NO.: 59);
[0117]
Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.29,Lys.sup.-
30]-VIP (SEQ. ID. NO.: 60);
[0118] Ac-[Lys.sup.12,
14,Nle.sup.17,Ala.sup.19,Val.sup.26,Thr.sup.28]-VIP (SEQ. ID. NO.:
61);
[0119]
Ac-[2-Nal.sup.10,Lys.sup.12,Ala.sup.17,Val.sub.26,Thr.sup.28]-VIP
(SEQ. ID. NO.:62);
[0120]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Ala.sup.2-
9,30,Met.sup.31]-VIP (SEQ. ID. NO.: 63);
[0121]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Phe.sup.3-
1]-VIP (SEQ. ID. NO.:64);
[0122]
Ac-[p-F-Phe.sup.6,Glu.sup.8,Lys.sup.12,Nle.sup.17,Ala.sup.19,Val.su-
p.26,Thr.sup.28,Gly.sup.29,30,Cys(Acm).sup.31]-VIP (SEQ. ID. NO.:
65);
[0123]
Ac-[p-F-Phe.sup.6,p-NH.sub.2-Phe.sup.10,Lys.sup.12,Nle.sup.17,Val.s-
up.26,Thr.sup.28]-VIP (SEQ. ID. NO.: 66);
[0124]
Ac-[Lys.sup.12,Ala.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.29,30,Cys(A-
cm).sup.31]-VIP (SEQ. ID. NO.: 67);
[0125] Ac-[Glu.sup.8,Lys.sup.12,14,Nle.sup.17,Val.sup.26,
Thr.sup.28,Gly.sup.29,30,Met.sup.31]-VIP (SEQ. ID. NO.: 68);
[0126]
Ac-[p-NH.sub.2-Phe.sup.10,Lys.sup.12,Nle.sup.17,Ala.sup.19,Val.sup.-
26,Thr.sup.28]-VIP (SEQ. ID. NO.: 69);
[0127]
Ac-[p-F-Phe.sup.6,Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.su-
p.28,Gly.sup.29,30,Cys(Acm).sup.31]-VIP (SEQ. ID. NO.: 70);
[0128] Ac-[Glu.sup.8,Lys.sup.12
Ala.sup.17,19,Val.sup.26,Thr.sup.28,Gly.su- p.29,30,Met.sup.31]-VIP
(SEQ. ID. NO.: 71);
[0129] Ac-[Glu.sup.8Lys.sup.12,Nle.sup.17,Val.sup.26
Thr.sup.28,Gly.sup.29,30,Ala.sup.31]-VIP (SEQ. ID. NO.: 72);
[0130]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Ala.sup.19,Val.sup.26,Thr.sup.2-
8,Gly.sup.29,30,Met.sup.31]-VIP (SEQ. ID. NO.: 73);
[0131]
Ac-[p-F-Phe.sup.6,Lys.sup.12,Nle.sup.17,Ala.sup.19,Val.sup.26,Thr.s-
up.28,Gly.sup.29,30,Cys(Acm).sup.31]-VIP (SEQ. ID. NO.: 74);
[0132]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.2-
9,30,Ser.sup.31]-VIP (SEQ. ID. NO.: 75);
[0133]
Ac-[p-F-Phe.sup.6,Glu.sup.8,Lys.sup.12,Nle.sup.17,Ala.sup.19,Val.su-
p.26,Thr.sup.28]-VIP (SEQ. ID. NO.: 76);
[0134]
Ac-[Glu.sup.8,Orn.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 77);
[0135]
Ac-[Lys.sup.12Nle.sup.17,Ala.sup.25,Leu.sup.26Lys.sup.27,28,Gly.sup-
.29,30,Thr.sup.31]-VIP (SEQ. ID. NO.: 78);
[0136]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.7,Val.sup.26,Thr.sup.28,Ala.sup.29-
-31]-VIP (SEQ. ID. NO.: 79);
[0137] Ac [Lys.sup.12,Ala.sup.17,19,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 80);
[0138]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.2-
9,Lys.sup.30]-VIP (SEQ. ID. NO.: 81);
[0139]
Ac-[p-HN.sub.2-Phe.sup.10,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.-
28,Gly.sup.29,30,Cys(Acm).sup.31]-VIP (SEQ. ID. NO.: 82);
[0140]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.2-
9,30,Cys (Acm).sup.31]-VIP (SEQ. ID. NO.: 83);
[0141]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.2-
9,30,Met.sup.31]-VIP (SEQ. ID. NO.: 84);
[0142]
CH.sub.3S(CH.sub.2).sub.2CO-[Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.s-
up.28]-VIP(2-28) (SEQ. ID. NO.: 85);
[0143]
CH.sub.3SO(CH.sub.2).sub.2CO-[Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.-
sup.28]-VIP(2-28) (SEQ. ID. NO.: 86);
[0144]
Ac-[N--CH.sub.3-Ala.sub.1,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.-
28]-VIP (SEQ. ID. NO.: 87);
[0145]
Ac-[Leu.sup.5,Orn.sup.12,Ala.sup.17,19,Thr.sup.25,Val.sup.26,Thr.su-
p.28,Gly.sup.29,30,Cys(Acm).sup.31]-VIP (SEQ. ID. NO.: 88);
[0146] Ac-[p-F-Phe.sup.6,
2-Nal.sup.10,Lys.sup.12,Nle.sup.17,Val.sup.26,Th-
r.sup.28,Gly.sup.29,30,Met.sup.31]-VIP (SEQ. ID. NO.: 89);
[0147]
Ac-[p-F-Phe.sup.6,Glu.sup.8,Lys.sup.12,14,Nle.sup.17,Ala.sup.19,Val-
.sup.26,Thr.sup.28,Gly.sup.29,30,Cys(Acm).sup.31]-VIP (SEQ. ID.
NO.: 90).
[0148] Particularly common vasoactive intestinal polypeptide
analogs known in the art include the following:
[0149]
Ac-[p-F-Phe.sup.6,Lys.sup.12,Nle.sup.17Ala.sup.19,Val.sup.26,Thr.su-
p.28Gly.sup.29,30Cys(Acm).sup.31]-VIP (SEQ. ID. NO.: 91);
[0150] Ac-[Leu.sup.5,Orn.sup.12,Ala.sup.17
Thr.sup.25,Val.sup.26,Thr.sup.2-
8,Gly.sup.29,30,Cys(Acm).sup.31]-VIP (SEQ. ID. NO.: 92);
[0151]
Ac-[p-F-Phe.sup.6,Glu.sup.8,Lys.sup.12,Nle.sup.17,Ala.sup.19,Val.su-
p.26,Thr.sup.28,Gly.sup.29,30,Cys(Acm).sup.31]-VIP (SEQ. ID. NO.:
93);
[0152]
Ac-[N-Me-Ala.sup.1,Lys.sup.12Nle.sup.17,Val.sup.26,Thr.sup.28]-VIP
(SEQ. ID. NO.: 94);
[0153]
Ac-[p-F-Phe.sup.6,p-NH.sub.2-Phe.sup.10,Lys.sup.12,Nle.sup.17,Val.s-
up.26,Thr.sup.28]-VIP (SEQ. ID. NO.: 95);
[0154] Ac-[Glu.sup.8
Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.2-
9,30,Met.sup.31]-VIP (SEQ. ID. NO.: 96);
[0155]
Ac-[p-NH.sub.2-Phe.sup.10,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.-
28]-VIP (SEQ. ID. NO.: 97);
[0156]
Ac-[Glu.sup.8,Lys.sup.12,Nle.sup.17,Val.sup.26,Thr.sup.28,Gly.sup.2-
9,30,Cys (Acm).sup.31]-VIP (SEQ. ID. NO.: 98).
[0157] Other VIP analogs known in the art include:
[0158] [Nle.sup..sup.17]-VIP (SEQ. ID. NO.: 99);
[0159] Ac-[Nle.sup..sup.17]-VIP (SEQ. ID. NO.: 100);
[0160] [Tyr.sup.6]-VIP (SEQ. ID. NO.: 101);
[0161] [Phe.sup.22]-VIP (SEQ. ID. NO.: 102);
[0162] [Ser.sup.7]-VIP (SEQ. ID. NO.: 103);
[0163] [Lys.sup.7]-VIP (SEQ. ID. NO.: 104);
[0164] [Gln.sup.7]-VIP (SEQ. ID. NO.: 105);
[0165] [Asn.sup.7]-VIP (SEQ. ID. NO.: 106);
[0166] [Arg.sup.7]-VIP (SEQ. ID. NO.: 107);
[0167] [Arg.sup.9]-VIP (SEQ. ID. NO.: 108);
[0168] [Gln.sup.9]-VIP (SEQ. ID. NO.: 109);
[0169] [Lys.sup.9]-VIP (SEQ. ID. NO.: 110);
[0170] [Leu.sup.9]-VIP (SEQ. ID. NO.: 111);
[0171] [Ser.sup.9] (SEQ. ID. NO.: 112);
[0172] [Thr.sup.9]-VIP (SEQ. ID. NO.: 113);
[0173] [Leu.sup.11]-VIP (SEQ. ID. NO.: 114);
[0174] [Lys.sup.11]-VIP (SEQ. ID. NO.: 115);
[0175] [Asn.sup.11]-VIP (SEQ. ID. NO.: 116);
[0176] [Gln.sup.11]-VIP (SEQ. ID. NO.: 117);
[0177] [Arg.sup.11]-VIP (SEQ. ID. NO.: 118);
[0178] [Thr.sup.16]-VIP (SEQ. ID. NO.: 119);
[0179] [Ser.sup.16]-VIP (SEQ. ID. NO.: 120);
[0180] [Leu.sup.16]-VIP (SEQ. ID. NO.: 121);
[0181] [Lys.sup.16]-VIP (SEQ. ID. NO.: 122);
[0182] [Asn.sup.16]-VIP (SEQ. ID. NO.: 123);
[0183] [Arg.sup.16]-VIP (SEQ. ID. NO.: 1243);
[0184] [Arg.sup.24]-VIP (SEQ. ID. NO.: 125);
[0185] [Gln.sup.24]-VIP (SEQ. ID. NO.: 126);
[0186] [Lys.sup.24]-VIP (SEQ. ID. NO.: 127);
[0187] [Leu.sup.24]-VIP (SEQ. ID. NO.: 128);
[0188] [Ser.sup.24]-VIP (SEQ. ID. NO.: 129);
[0189] [Ser.sup.12]-VIP (SEQ. ID. NO.: 130);
[0190] [Ser.sup.20]-VIP (SEQ. ID. NO.: 131);
[0191] [Orn.sup.20]-VIP (SEQ. ID. NO.: 132);
[0192] [Arg.sup.20]-VIP (SEQ. ID. NO.: 133);
[0193] [Phe.sup.23]-VIP (SEQ. ID. NO.: 134);
[0194] [Phe.sup.26]-VIP (SEQ. ID. NO.: 135);
[0195] [Tyr.sup.13]-VIP (SEQ. ID. NO.: 136);
[0196] [Tyr.sup.23]-VIP (SEQ. ID. NO.: 137);
[0197] [Tyr.sup.26]-VIP (SEQ. ID. NO.: 138);
[0198] [Leu.sup.26]-VIP](SEQ. ID. NO.: 139);
[0199] [Ile.sup.13]-VIP (SEQ. ID. NO.: 140);
[0200] [Ile.sup.23]-VIP (SEQ. ID. NO.: 141);
[0201] [Val.sup.13]-VIP (SEQ. ID. NO.: 142);
[0202] [Val.sup.23]-VIP (SEQ. ID. NO.: 143);
[0203] [Nle.sup.13]-VIP (SEQ. ID. NO.: 144);
[0204] [Nle.sup.23]-VIP (SEQ. ID. NO.: 145);
[0205] [Nle.sup.26]-VIP (SEQ. ID. NO.: 146);
[0206] [Arg.sup.21]-VIP (SEQ. ID. NO.: 147);
[0207] [Leu.sup.14]-VIP (SEQ. ID. NO.: 148);
[0208] [Leu.sup.21]-VIP (SEQ. ID. NO.: 149);
[0209] [Orn.sup.14]-VIP (SEQ. ID. NO.: 150);
[0210] [Orn.sup.21]-VIP (SEQ. ID. NO.: 151);
[0211] [Nle.sup.14]-VIP (SEQ. ID. NO.: 152);
[0212] [Nle.sup.21]-VIP (SEQ. ID. NO.: 153);
[0213] [Arg.sup.15]-VIP (SEQ. ID. NO.: 154);
[0214] [Ser.sup.15]-VIP (SEQ. ID. NO.: 155);
[0215] [Gln.sup.15]-VIP (SEQ. ID. NO.: 156);
[0216] [Orn.sup.15]-VIP (SEQ. ID. NO.: 157);
[0217] [Met.sup.19]-VIP (SEQ. ID. NO.: 158);
[0218] [Leu.sup.17]-VIP (SEQ. ID. NO.: 159);
[0219] [Leu.sup.19]-VIP (SEQ. ID. NO.: 160);
[0220] [Val.sup.17]-VIP (SEQ. ID. NO.: 161);
[0221] [Lys.sup.17]-VIP (SEQ. ID. NO.: 162);
[0222] [Lys.sup.19]-VIP (SEQ. ID. NO.: 163);
[0223] [Ile.sup.17]-VIP (SEQ. ID. NO.: 164);
[0224] [Ile.sup.19]-VIP (SEQ. ID. NO.: 165);
[0225] [Nle.sup.19]-VIP (SEQ. ID. NO.: 166);
[0226] [Leu.sup.18]-VIP (SEQ. ID. NO.: 167);
[0227] [Asn.sup.25]-VIP (SEQ. ID. NO.: 168);
[0228] [Leu.sup.25]-VIP (SEQ. ID. NO.: 169);
[0229] [Gln.sup.25]-VIP (SEQ. ID. NO.: 170);
[0230] [Val.sup.27]-VIP (SEQ. ID. NO.: 171);
[0231] [Phe.sup.3]-VIP (SEQ. ID. NO.: 172);
[0232] [Tyr.sup.3]-VIP (SEQ. ID. NO.: 173);
[0233] [Phe.sup.7]-VIP (SEQ. ID. NO.: 174);
[0234] [Tyr.sup.7]-VIP (SEQ. ID. NO.: 175);
[0235] [Phe.sup.19]-VIP (SEQ. ID. NO.: 176);
[0236] [Tyr.sup.19]-VIP (SEQ. ID. NO.: 177);
[0237] [Thr.sup.4]-VIP (SEQ. ID. NO.: 178);
[0238] [Ser.sup.4]-VIP (SEQ. ID. NO.: 179);
[0239] [Asn.sup.4]-VIP (SEQ. ID. NO.: 180);
[0240] [Gln.sup.4]-VIP (SEQ. ID. NO.: 181);
[0241] [Thr.sup.6]-VIP (SEQ. ID. NO.: 182);
[0242] [Ser.sup.6]-VIP (SEQ. ID. NO.: 183);
[0243] [Asn.sup.6]-VIP (SEQ. ID. NO.: 184);
[0244] [Gln.sup.6]-VIP (SEQ. ID. NO.: 185);
[0245] [Ala.sup.6]-VIP (SEQ. ID. NO.: 186);
[0246] [Thr.sup.8]-VIP (SEQ. ID. NO.: 187);
[0247] [Ser.sup.8]-VIP (SEQ. ID. NO.: 188);
[0248] [Asn.sup.8]-VIP (SEQ. ID. NO.: 189);
[0249] [Gln.sup.8]-VIP (SEQ. ID. NO.: 190);
[0250] [Ser.sup.28]-VIP (SEQ. ID. NO.: 191);
[0251] [Gln.sup.28]-VIP (SEQ. ID. NO.: 192);
[0252] [Gln.sup.12]-VIP (SEQ. ID. NO.: 193);
[0253] [Gln.sup.20]-VIP (SEQ. ID. NO.: 194);
[0254] [Ser.sup.21]-VIP (SEQ. ID. NO.: 195);
[0255] [Gln.sup.21]-VIP (SEQ. ID. NO.: 196);
[0256] [Met.sup.13]-VIP (SEQ. ID. NO.: 197);
[0257] [Ile.sup.17]-VIP (SEQ. ID. NO.: 198);
[0258] [Met.sup.23]-VIP (SEQ. ID. NO.: 199);
[0259] [Met.sup.26]-VIP (SEQ. ID. NO.: 200).
[0260] The preceding list of VIP agonists is by way of example
rather than limitation, and other known VIP agonists include
permutations of the preceding amino acid sequences and
lesser-included deviations from the VIP sequence. Permutations
include, for example sequences such as [Thr.sup.18]-VIP (SEQ. ID.
NO.: 201), which is not listed explicitly above but is a
lesser-included deviation from the naturally occurring human VIP
sequence that is described, for example, in
Ac-[Lys.sup.12,Nle.sup.17,Val.sup.26,Ala.sup.27,Thr.sup.28]-VIP
(SEQ. ID. NO.: 21) and
Ac-[Lys.sup.12,Nle.sup.17,Ala.sup.16,Thr.sup.28]-VIP (SEQ. ID. NO.:
22), as well as a number of other of the above listed VIP analog
sequences, for example, SEQ. ID. NO.: 46. Further a permutation of
SEQ. ID. NO. 21 and SEQ. ID. NO. 22, is exemplified by
Ac-[Lys.sup.12,Nle.sup.- 17,Ala.sup.26,Ala.sup.27,Thr.sup.28]-VIP
(SEQ. ID. NO.: 202), which substitutes the Ala.sup.26 of SEQ. ID.
NO.:22 for the Val.sup.26 of SEQ. ID. NO.: 21 and is otherwise
identical to SEQ. ID. NO.:21.
[0261] Analogs for use with the instant invention are intended that
are essentially equivalent to an explicitly disclosed analog, as
specified above. An analog is essentially equivalent to one
specified above if it has one or more of the biological activities
characteristic of human VIP, has the same number of amino acids as
the specified analog and, in comparison with the sequence of the
specified analog, has at most five amino acid substitutions, all of
which would be considered neutral in the art (i.e., acidic for
acidic, basic for basic, uncharged polar for uncharged polar,
hydrophobic for hydrophobic, and the like). As is widely known:
acidic amino acids are Asp, Glu and gamma-carboxyglutamic acid;
basic amino acids are Arg, Lys, His and Orn; hydrophobic amino
acids are Ala, Ile, Leu, Met, Nor, Phe, Trp, Tyr, Val,
t-butylglycine, norvaline, cyclohexylalanine, t-butylalanine,
amino-4-phenylbutyric acid, beta-2-thienylalanine,
p-bromophenylalanine, p-chlorophenylalanine, p-iodophenylalanine,
p-nitrophenylalanine, 3,5-diiodotyrosine, phenylglycine, and
naphthylalanine; uncharged polar amino acids are Asn, Gln, Ser, and
Thr. Gly can be substituted for an uncharged polar or a hydrophobic
amino acid, but substitutions with Gly are often avoided because
helical structures may be destabilized thereby. Substitutions with
Pro are generally avoided because of a significant effect on
secondary structure of inserting a Pro in place of another amino
acid. Substitutions with Cys are also generally avoided because of
the reactivity of the sulfhydryl group.
[0262] Various synthetic VIP analogs, including many of the above,
are explicitly listed in U.S. Pat. Nos. 5,235,907, 5,141,924,
4,734,400 and 4,605,641 to Bolin, and in U.S. Pat. Nos. 4,939,224
and 4,835,252 to Musso et al.
[0263] Other suitable VIP agonists include conjugates of VIP and
long chain fatty acids or fatty amines, such as
CH.sub.3(CH.sub.2).sub.6CO-VIP- , CH.sub.3(CH.sub.2).sub.16CO-VIP,
CH.sub.3(CH.sub.2).sub.16CO-VIP.sub.7-2- 8,
CH.sub.3(CH.sub.2).sub.16CO-VIP.sub.16-28,
VIP-CONH--CH.sub.2CH.sub.3, VIP-CONH--(CH.sub.2).sub.3CH.sub.3, and
VIP-CONH-(CH.sub.2).sub.7CH.sub.3- , the synthesis of which is
described in U.S. Pat. No. 5,147,855 to Gozes et al.
[0264] Still other suitable VIP agonists are nitrosylated VIP
analogs having the structure VIP-Gly-Cys-NO (SEQ. ID NO.: 203), and
the related analogs VIP-Gly-Cys-NH.sub.2 (SEQ. ID NO.: 204) and
VIP-Gly-Cys (SEQ. ID NO.: 205), preparation of which is described
in U.S. Pat. No. 5,612,314 to Stamler et al.
[0265] VIP analogs known in the art that are useful for practicing
the present invention include those compounds listed above and
others that exhibit agonistic VIP activity, preferably strong
agonistic activity. Also preferred are those analogs that exhibit
agonistic activity with a relatively long biological activity, e.g.
a relatively long pharmacologic half-life. Methods for determining
the agonistic VIP activity and half-life of a given VIP analog are
known to those ordinarily skilled in the art. One attribute of a
VIP analog that makes it useful for practicing the invention is a
resistance to hydrolysis, a property of synthetic VIP analogs that
are disclosed in U.S. Pat. No. 4,939,224 to Musso et al. for
bronchodilation.
[0266] As the practice of the instant invention will often if not
typically involve topical delivery of the vasoactive VIP agonists
to the female sex organs, absorption of the VIP analog through the
epithelium covering the organ or organs to which it is applied is
required for the desired pharmacologic effects. The ordinarily
skilled artisan in the therapeutic pharmaceutical art will be able
to ascertain whether the absorption of a particular VIP analog is
sufficient for the desired effects. VIP analogs are expected to be
capable of crossing such epithelial barriers, as the peptide is
small relative to proteins.
[0267] The ability of VIP peptides to cross such epithelial
barriers has been demonstrated in the context of administering VIP
by inhalation for bronchodilation. Although administration by
inhalation has been shown to be more tissue specific and to have
fewer side-effects than intravenous administration but appears to
be less effective than intravenous administration (Altiere et al.
(1983) Pharmacologist 25:123; Bundgaard et al. (1983) Eur. J.
Respir. Dis. 64(Suppl. 128):427-429; Altiere et al. (1984) Chest
86:153-154. This observed lower efficacy of VIP in bronchodilation
when administered by inhalation, compared with administration
intravenously, is thought to be caused by one or a combination of:
(1) rapid degradation of VIP by compounds, including proteolytic
enzymes, present in the respiratory tract both in the bronchial
airways and the passageways leading thereto (Barrowcliffe et al.
(1986) Thorax 41:88-93); or (2) limited absorption of VIP through
nasal and pulmonary mucosa, due in part to the size of VIP (about
3300 Daltons)(Effros and Mason (1982) Am. Rev. Resp. Dis.
127:S59-S65; Altiere et al. (1984) supra).
[0268] In the context of the present invention, the ability of
various VIP analogs that exhibit VIP agonist activity to cross the
pertinent epithelial barrier as a naked peptide is expected.
Further, those of skill in the art will appreciate that the ability
of VIP agonists to cross the epithelial barrier of the female
genitalia for use with the instant invention may be enhanced by
known techniques, such as packaging in liposomes or the like.
[0269] The above representative VIP analogs may be readily
synthesized by known conventional techniques for forming a peptide
linkage between amino acids. Such conventional procedures include,
for example, all solution phase techniques permitting a
condensation between the free alpha amino group of an amino acid or
residue thereof having its carboxyl group or other reactive groups
protected and the free primary carboxyl group of another amino acid
or residue thereof having its amino group or other reactive groups
protected.
[0270] The process for synthesizing the representative compounds
may be carried out by a procedure whereby each amino acid in the
desired sequence is added one at a time in succession to another
amino acid or residue thereof or by a procedure whereby peptide
fragments with the desired amino acid sequence are first
synthesized conventionally and then condensed to provide the
desired peptide.
[0271] Such conventional procedures for synthesizing the active
agents of the present invention include for example any solid phase
peptide synthesis method. In such a method the synthesis of the
active agents can be carried out by sequentially incorporating the
desired amino acid residues one at a time into the growing peptide
chain according to the general principles of solid phase methods
(Merrifield (1963) J. Amer. Chem. Soc. 85:2149-2154; Barany et al,
The Peptides, Analysis, Synthesis and Biology, Vol. 2, 1-284 Gross,
E. and Meienhofer, J., Eds. (Academic Press 1980)).
[0272] The chemical syntheses of peptides is widely appreciated to
require the protection of reactive side chain groups of the various
amino acid moieties, in addition to .alpha.-amino or
.alpha.-carboxyl group of the reacted amino acids, with suitable
protecting groups which will prevent a chemical reaction from
occurring at that site until the protecting group is ultimately
removed. Groups requiring such protection include: .alpha.-amino,
side chain-amino, carboxyl, hydroxyl, side chain amide, guanidino
and imidazole. Methods for protecting both reactive side chain
groups and .alpha.-amino or .alpha.-carboxyl groups are known in
the art and enumerated in U.S. Pat. Nos. 5,235,907, 5,141,924,
4,734,400 and 4,605,641 to Bolin. Although the synthetic organic
methods described in the preceding publications may be employed to
synthesize VIP analogs described above, many may also be expressed
in eukaryotic or prokaryotic cells by use of the appropriate
expression vector.
[0273] Additional pharmacologically active agents may be
co-administered along with the primary active agent, i.e., with the
VIP or VIP agonist. Such additional active agents are also referred
to herein as "secondary" active agents. Preferred secondary agents
are vasoactive agents, particularly vasodilators, selected from the
group consisting of vasoactive prostaglandins, endothelin-derived
relaxation factors, smooth muscle relaxants, leukotriene
inhibitors, pharmaceutically acceptable salts, esters, analogs,
derivatives, prodrugs, active metabolites, and inclusion complexes
thereof, and combinations of any of the foregoing. Other suitable
secondary agents include rho kinase inhibitors, melanocortin
peptides, endothelin antagonists, growth factors and other peptidyl
drugs; selective androgen receptor modulators (SARMs),
neuropeptides, amino acids, serotonin agonists, serotonin
antagonists, calcium channel blockers, potassium channel openers,
potassium channel blockers, dopamine agonists, dopamine
antagonists, non-androgenic steroid hormones, and combinations
thereof.
[0274] Particularly preferred vasoactive agents are vasoactive
prostaglandins selected from the group consisting of naturally
occurring prostaglandins, semisynthetic prostaglandins, synthetic
prostaglandins, and pharmaceutically acceptable, pharmacologically
active salts, esters, amides, inclusion complexes prodrugs,
metabolites, and analogs thereof. Racemic, optically enriched or
purified stereoisomers of any of these compounds are also included.
A suitable unit dose of a prostaglandin herein is in the range of
approximately 1 to 5000 .mu.g, preferably in the range of
approximately 20 to 2000 .mu.g. Preferred prostaglandins include,
but are not limited to, the naturally occurring prostaglandins
prostaglandin E.sub.0 (PGE.sub.0, also referred to
13,14-dihydro-PGE.sub.1, hereinafter, the abbreviation "PG" is used
for "prostaglandin"), PGE.sub.1, 19-hydroxy-PGE.sub.1, PGE.sub.2,
19-hydroxy-PGE.sub.2,PGA.sub.1, 19-hydroxy-PGA.sub.1, PGA.sub.2,
19-hydroxy-PGA.sub.2, PGB.sub.1, 19-hydroxy-PGB.sub.1, PGB.sub.2,
19-hydroxy-PGB.sub.2, PGB.sub.3, PGD.sub.2, PGF.sub.1.alpha.,
PGF.sub.2.alpha.,(dinoprost), PGE.sub.3, PGF.sub.3.alpha.,
PGI.sub.2 (prostacyclin), and combinations thereof. PGE.sub.0,
PGE.sub.1, PGE.sub.2, and the hydrolyzable lower alkyl esters
thereof (e.g., the methyl, ethyl and isopropyl esters) are,
however, particularly preferred. Other suitable prostaglandins are
exemplified, without limitation, by arboprostil, carbaprostacyclin,
carboprost tromethamine, dinoprost tromethamine, dinoprostone,
enprostil, iloprost, lipoprost, gemeprost, metenoprost,
sulprostone, tiaprost, viprostil (CL 115,347), viprostil methyl
ester, 16,16-dimethyl-.DELTA..sup.2-PGE.sub.1, methyl ester,
15-deoxy-16-hydroxy-16-methyl-PGE.sub.1, methyl ester
(misoprostol), 16,16-dimethyl-PGE.sub.1,
11-deoxy-15-methyl-PGE.sub.1,
16-methyl-18,18,19,19-tetrahydrocarbacyclin,
16(RS)-15-deoxy-16-hydroxy-1- 6-methyl-PGE.sub.1, methyl ester,
(+)-4,5-didehydro-16-phenoxy-.alpha.-tet- ranor-PGE.sub.2 methyl
ester, 11-deoxy-11.alpha., 16,16-trimethyl-PGE.sub.- 2,
(+)-11.alpha., 16.alpha.,
16.beta.-dihydroxy-1,9-dioxo-1-(hydroxymethyl-
)-16-methyl-trans-prostene, 9-chloro-16,16-dimethyl-PGE.sub.2,
16,16-dimethyl-PGE.sub.2, 15(S)-15-methyl-PGE.sub.2,
9-deoxy-9-methylene-16,16-dimethyl-PGE.sub.2, potassium salt,
19(R)-hydroxy-PGE.sub.2, and 11-deoxy-16,16-dimethyl-PGE.sub.2.
[0275] Additional vasoactive agents useful as secondary active
agents herein include endothelin-derived relaxation factors
("EDRFs") such as nitric oxide releasing agents, e.g., sodium
nitroprusside and diazenium diolates, or "NONOates." NONOates
include, but are not limited to,
(Z)-1-{N-methyl-N-[6-(N-methyl-ammoniohexyl)amino]}diazen-1-ium-1,2-diola-
te ("MAHMA/NO"),
(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]-diazen-1-iu-
m-1,2-diolate ("PAPA/NO"), (Z)-1-
{N-[3-aminopropyl]-N-[4-(3-aminopropylam-
monio)butyl]amino}diazen-1-ium-1,2-diolate (spermine NONOate or
"SPER/NO") and sodium
(Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (diethylamine
NONOate or "DEA/NO") and derivatives thereof). Still other
vasoactive agents include vasoactive intestinal polypeptide analogs
and derivatives thereof (particularly derivatives in the form of
hydrolyzable lower alkyl esters), smooth muscle relaxants,
leukotriene inhibitors, calcium channel blockers,
.beta.2-adrenergic agonists, angiotensin-converting enzyme ("ACE")
inhibitors, angiotensin II receptor antagonists, and
phosphodiesterase inhibitors.
[0276] Still other suitable vasoactive agents include, but are not
limited to: nitrates and like compounds such as nitroglycerin,
isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate,
molsidomine, linsidomine chlorhydrate ("SIN-1"),
S-nitroso-N-acetyl-d,1-penicillamine ("SNAP") and
S-nitroso-N-glutathione ("SNO-GLU"); 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; nimodepine; pinacidil; cyclandelate; dipyridamole;
isoxsuprine; chlorpromazine; haloperidol; yohimbine; and
trazodone.
[0277] Other secondary active agents herein are inhibitors of rho
kinase, an enzyme belonging to the rhoA/rho associated kinase
pathway, which regulates the state of phosphorylation of myosin
phosphatase, in turn leading to the control of smooth muscle
contraction. One example of a suitable rho kinase inhibitor has the
structural formula 2
[0278] and is identified as Y-27632. Other suitable rho kinase
inhibitors are disclosed, for example, in U.S. Pat. No.
6,218,410.
[0279] Additional secondary agents useful herein are peptide
analogs of .alpha.-melanocyte-stimulating hormone (.alpha.-MSH),
also referred to as "melanocortin peptides." Such peptides include
the sequence His-Phe-Arg-Trp, His-D-Phe-Arg-Trp, or are homologs
thereof, and are preferably cyclic. A preferred melanocortin
peptide is Ac-Nle-cyclo-(-Asp-His-D-Phe-Arg-Trp-Lys)--OH. See U.S.
Pat. No. 6,051,555 to Hadley and International Patent Publication
No. WO 01/00224 to Blood et al., assigned to Palatin Technologies,
Inc. The aforementioned amino acid residues have their conventional
meaning as given in Chapter 2422 of the Manual of Patent Examining
Procedure (2000). Thus, "Arg" is arginine, "Nle" is norleucine,
"His" is histamine, "Phe" is phenylalanine, "D-Phe" is
D-phenylalanine, "Trp" is tryptophan, and "Ac" refers to an acetyl
moiety, i.e., an acetyl moiety present in a peptide or amino acid
sequence that is acetylated.
[0280] Suitable endothelin antagonists include antagonists of any
or all of the three isoforms of endothelin, i.e., ET-1, ET-2, and
ET-3, and are exemplified by: phenoxyphenylacetic acids and
derivatives thereof, such as
N-(4-isopropylbenzene-sulbonyl)-.alpha.-(4-carboxy-2-n-propylphenoxy)--
3,4-methylenedioxyphenyl acetamide dipotassium salt,
2-[(2,6-dipropyl-4-hydroxymethyl)-phenoxy]-2-(4-phenoxyphenyl)-acetic
acid,
2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(4-phenylphenyl)acetic
acid,
2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3-carboxyphenyl)-aceti-
c acid,
2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3,4-ethylenedioxyphen-
yl)acetic acid,
2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3,4,5-trimeth-
oxyphenyl)acetic acid,
2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3,4-me-
thylenedioxyphenyl)acetic acid,
N-(4-dimethylaminobenzenesulfonyl)-2-(4-me-
thoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)
acetamide,
N-(2-methylbenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4--
methylenedioxyphenyl)acetamide,
N-(2-methoxycarbonyl-benzenesulfonyl)-2-(4-
-methoxy-carbonyl-2-propylphenoxy)-2-(3,4-methylenedioxy-phenyl)acetamide,
N-(2-chlorobenzene-sulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-
-methylenedioxyphenyl)acetamide, and others, as described in U.S.
Pat. No. 5,565,485; and certain isooxazoles, oxazoles, thiazoles,
isothiazoles and imidazoles, as described, for example, in U.S.
Pat. No. 6,136,828. Numerous other endothelin antagonists may be
used as secondary agents herein, and will be known to those of
ordinary skill in the art and/or are described in the pertinent
patents, literature and texts.
[0281] Peptidyl drugs include the peptidyl hormones activin,
amylin, angiotensin, atrial natriuretic peptide (ANP), calcitonin,
calcitonin gene-related peptide, calcitonin N-terminal flanking
peptide, ciliary neurotrophic factor (CNTF), corticotropin
(adrenocorticotropin hormone, ACTH), corticotropin-releasing factor
(CRF or CRH), epidermal growth factor (EGF), follicle-stimulating
hormone (FSH), gastrin, gastrin inhibitory peptide (GIP),
gastrin-releasing peptide, gonadotropin-releasing factor (GnRF or
GNRH), growth hormone releasing factor (GRF, GRH), human chorionic
gonadotropin (hCH), inhibin A, inhibin B, insulin, luteinizing
hormone (LH), luteinizing hormone-releasing hormone (LHRH),
.alpha.-melanocyte-stimulating hormone,
.beta.-melanocyte-stimulating hormone,
.gamma.-melanocyte-stimulating hormone, melatonin, motilin,
oxytocin (pitocin), pancreatic polypeptide, parathyroid hormone
(PTH), placental lactogen, prolactin (PRL), prolactin-release
inhibiting factor (PIF), prolactin-releasing factor (PRF),
secretin, somatotropin (growth hormone, GH), somatostatin (SIF,
growth hormone-release inhibiting factor, GIF), thyrotropin
(thyroid-stimulating hormone, TSH), thyrotropin-releasing factor
(TRH or TRF), thyroxine, and vasopressin. Other peptidyl drugs are
the cytokines, e.g., colony stimulating factor 4, heparin binding
neurotrophic factor (HBNF), interferon-.alpha., interferon
.alpha.-2a, interferon .alpha.-2b, interferon .alpha.-n3,
interferon-.beta., etc., interleukin-1, interleukin-2,
interleukin-3, interleukin-4, interleukin-5, interleukin-6, etc.,
tumor necrosis factor, tumor necrosis factor-.alpha., granuloycte
colony-stimulating factor (G-CSF), granulocyte-macrophage
colony-stimulating factor (GM-CSF), macrophage colony-stimulating
factor, midkine (MD), and thymopoietin.
[0282] Selective androgen receptor modulators (SARMs) include
LGD2226 and/or LGD1331, both available from Ligand Pharmaceuticals
(San Diego, Calif.). See Negro-Villar et al. (1999) J. Clin.
Endocrinol. & Metabol. 84(10):3459-62.
[0283] Suitable neuropeptides include bradykinin, kallidin, des-
Arg.sup.9-bradykinin, des-Arg.sup.10-kallidin,
des-Arg.sup.9-[Leu.sup.8]-- bradykinin, [D-Phe.sup.7]-bradykinin,
HOE 140, neuropeptide Y, calcitonin gene-related peptide (cGRP),
enkaphalins and related opioid peptides such as
Met.sup.5-enkaphalin, Leu.sup.5-enkephalin, .alpha.-, .beta.- and
.gamma.-endorphin, .alpha.- and .beta.- neo-endorphin, and
dynorphin, as well as the neurotransmitters GABA
(.gamma.-aminobutyric acid), glycine, glutamate, acetylcholine,
dopamine, epinephrine, 5-hydroxytryptamine, substance P, serotonin,
and catecholamines.
[0284] One or more amino acids may be included in the present
formulations. As used herein, the term "amino acid" includes the
conventional amino acids, e.g., phenylalanine, leucine, isoleucine,
methionine, valine, serine, proline, threonine, alanine, tyrosine,
histidine, glutamine, asparagine, lysine, aspartic acid, glutamic
acid, cysteine, tryptophan, arginine, and glycine, with arginine
being particularly preferred. In addition, the term "amino acid"
will also include amino acid derivatives, e.g., 1-naphthylalanine,
2-naphthylalanine, 3-pyridylalanine, 4-hydroxyproline,
O-phosphoserine, N-acetylserine, N-formylmethionine,
3-methylhistidine, 5-hydroxylysine, and nor-leucine, in addition to
stereoisomers (e.g., D-amino acids) of the twenty conventional
amino acids. Combinations of any of the foregoing are contemplated
as well. Preferred amino acids are the neuroactive amino acids
.gamma.-aminobutyric acid (GABA), glycine, .beta.-alanine, taurine,
and glutamate.
[0285] Suitable serotonin agonists include, but are not limited to
2-methyl serotonin, buspirone, ipsaperone, tiaspirone, gepirone,
ergot alkaloids, 8-hydroxy-(2-N,N-dipropyl-amino)-tetraline,
1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride,
sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride,
mezacopride, and combinations thereof. Suitable serotonin
antagonists include, for example, ondansetron, granisetron,
metoclopramide, tropisetron, dolasetron, palonosetron,
trimethobenzamide, methysergide, risperidone, ketanserin,
ritanserin, clozapine, amitriptyline, MDL 100,907
(R(+)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperid-
ine-methanol) (Marion Merrell Dow), azatadine, cyproheptadine,
fenclonine, chlorpromazine, mianserin and combinations thereof.
[0286] Representative ergot alkaloids include ergotamine and
ergotamine analogs, e.g., acetergamine, brazergoline, bromerguride,
cianergoline, delorgotrile, dihydroergotamine, disulergine,
ergonovine, ergonovine maleate, ergotamine tartrate, etisulergine,
lergotrile, lysergide, mesulergine, metergoline, metergotamine,
nicergoline, pergolide, propisergide, proterguride and
terguride.
[0287] Calcium channel blockers that are suitable for use according
to the present invention include, without limitation, amlodipine,
felodipine, isradipine, nicardipine, nifedipine, nimodipine,
nisoldipine, nitrendipine, bepridil, diltiazem, verapamil, and
combinations thereof.
[0288] Potassium channel openers include, but are not limited to,
pinacidil, diazoxide, cromakalim, nicorandil, minoxidil,
(N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridyl-guanidine (P-1075),
and N-cyano-N'-(2-nitroxyethyl)-3-pridinecarboximidamide
monomethanesulfonate (KRN 2391).
[0289] Potassium channel blockers include tedisamil, agitoxin-2,
apamin, BDS-I, BDS-II, charybdotoxin, .alpha.-dendrotoxin,
.beta.-dendrotoxin, .gamma.-dendrotoxin, .delta.-dendrotoxin,
dendrotoxin-I, dendrotoxin-K, E-4031, iberiotoxin, kaliotoxin,
MCD-peptide, margatoxin, noxiustoxin, paxilline, penitrem A,
stichodactyla, tertiapin, tityustoxin K alpha, verruculogen, and
combinations thereof. Although all of the active agents are
available commercially, most of the listed potassium channel
blockers are available from Alomone Labs (Jerusalem, Israel).
[0290] Suitable dopamine agonists include, for example, levodopa,
bromocriptine, pergolide, apomorphine, piribedil, pramipexole,
ropinirole, and combinations thereof. Dopamine antagonists include,
without limitation, spiroperidol, benperidol, trifluperidol,
pimozide, fluphenazine, droperidol, haloperidol, thiothixene,
trifluperazine, moperone, prochlorperazine, molindone,
thioridazine, clozapine, chlorpromazine, promazine, sulpiride,
clebopride, chlorpromazine, spiperone, flupenthixol, and
combinations thereof.
[0291] Non-androgenic steroids that may be administered as
secondary active agents include progestins and estrogens. Suitable
estrogens include synthetic and natural estrogens such as:
estradiol (i.e., 1,3,5-estratriene-3,17.beta.-diol, or
"17.beta.-estradiol") and its esters, including estradiol benzoate,
valerate, cypionate, heptanoate, decanoate, acetate and diacetate;
17.alpha.-estradiol; ethinylestradiol (i.e.,
17.alpha.-ethinylestradiol) and esters and ethers thereof,
including ethinylestradiol 3-acetate and ethinylestradiol
3-benzoate; estriol and estriol succinate; polyestrol phosphate;
estrone and its esters and derivatives, including estrone acetate,
estrone sulfate, and piperazine estrone sulfate; quinestrol;
mestranol; and conjugated equine estrogens. Suitable progestins
include acetoxypregnenolone, allylestrenol, anagestone acetate,
chlormadinone acetate, cyproterone, cyproterone acetate,
desogestrel, dihydrogesterone, dimethisterone, ethisterone
(17.alpha.-ethinyltestosterone), ethynodiol diacetate, flurogestone
acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone
acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone,
hydroxymethylprogesterone acetate, 3-ketodesogestrel,
levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone
acetate, megestrol, megestrol acetate, melengestrol acetate,
norethindrone, norethindrone acetate, norethisterone,
norethisterone acetate, norethynodrel, norgestimate, norgestrel,
norgestrienone, normethisterone, and progesterone. It is generally
desirable to co-administer a progestin along with an estrogen so
that the estrogen is not "unopposed." As is well known in the art,
estrogen-based therapies are known to increase the risk of
endometrial hyperplasia and cancer, as well as the risk of breast
cancer, in treated individuals. Co-administration of estrogenic
agents with a progestin has been found to decrease the
aforementioned risks.
[0292] The primary vasoactive agent--i.e., VIP or an agonist
thereof--and the additional active agent or agents may be
incorporated into a single formulation, or they may be administered
separately, either simultaneously or sequentially. In a preferred
embodiment, an androgenic agent is administered prior to
administration of VIP or a VIP agonist, i.e., the androgenic agent
is administered as a pretreatment. In a particularly preferred
embodiment, such a method involves administration of an androgenic
agent, e.g., via oral or topical (preferably vulvar and/or vaginal)
administration, followed by topical (again, preferably vulvar
and/or vaginal) administration of VIP or a VIP agonist.
[0293] The formulations herein are administered by topical
application to the vulvar region and/or by vaginal drug
administration. These pharmaceutical formulations will typically
contain one or more pharmaceutically acceptable carriers suited to
the particular type of formulation, i.e., gel, ointment,
suppository, or the like. The vehicles are comprised of materials
of naturally occurring or synthetic origin that do not adversely
affect the active agent or other components of the formulation.
Suitable carriers for use herein include water, silicone, waxes,
petroleum jelly, polyethylene glycol, propylene glycol, liposomes,
sugars such as mannitol and lactose, and a variety of other
materials, again depending, on the specific type of formulation
used. As described in Section IV, infra, dosage forms used for
administration to the vulvar region and/or vagina may be used to
deliver drug on an as-needed, on-demand basis, and/or throughout an
extended, sustained release profile.
[0294] The formulations may also include a chemical compound to
enhance permeation of the active agent through the mucosal tissue,
i.e., a "permeation enhancer." Suitable permeation enhancers
include those generally useful in conjunction with topical,
transdermal or transmucosal drug delivery. Examples of suitable
permeation enhancers include the following: sulfoxides such as
dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C.sub.10MSO);
ethers such as diethylene glycol monoethyl ether (available
commercially as Transcutol.RTM.) and diethylene glycol monomethyl
ether; surfactants such as sodium laurate, sodium lauryl sulfate,
cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer
(231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No.
4,783,450); the 1-substituted azacycloheptan-2-ones, particularly
1-n-dodecylcyclaza-cycloheptan-2-one (available under the trademark
Azone.RTM. from Nelson Research & Development Co., Irvine,
Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and
4,557,934); alcohols such as ethanol, propanol, octanol, decanol,
benzyl alcohol, and the like; fatty acids such as lauric acid,
oleic acid and valeric acid; fatty acid esters such as isopropyl
myristate, isopropyl palmitate, methylpropionate, and ethyl oleate;
polyols and esters thereof such as propylene glycol, ethylene
glycol, glycerol, butanediol, polyethylene glycol, and polyethylene
glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343);
amides and other nitrogenous compounds such as urea,
dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone,
1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and
triethanolamine; terpenes; alkanones; and organic acids,
particularly salicylic acid and salicylates, citric acid and
succinic acid. Mixtures of two or more enhancers may also be
used.
[0295] In some cases, the formulations may include an enzyme
inhibitor, i.e., a compound effective to inhibit enzymes present in
the vagina or vulvar area that could degrade or metabolize the
active agent. That is, inhibitors of enzymes that decrease or
eliminate the activity of the active agent may be included in the
formulation so as to effectively inhibit the action of those
enzymes. Such compounds include, for example, fatty acids, fatty
acid esters, and NAD inhibitors.
[0296] The formulations may be in the form of an ointment, cream,
emulsion, lotion, gel, solid, solution, suspension, foam or
liposomal formulation. Alternatively, the formulations may be
contained within a vaginal ring (e.g., as disclosed in U.S. Pat.
No. 5,188,835 to Lindskog et al., assigned to Kabi Pharmacia AB),
or within a tampon, suppository, sponge, pillow, puff, or osmotic
pump system; these platforms are useful solely for vaginal
delivery.
[0297] Ointments 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. 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
1034-1038, 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, reference may be had to Remington: The Science and Practice
of Pharmacy for further information.
[0298] Lotions are preparations that may be applied without
friction, and are typically liquid or semiliquid preparations in
which solid particles, including the active agent, are present in a
water or alcohol base. Lotions are usually suspensions of solids,
and preferably, for the present purpose, comprise a liquid oily
emulsion of the oil-in-water type. It is generally necessary that
the insoluble matter in a lotion be finely divided. Lotions will
typically contain suspending agents to produce better dispersions
as well as compounds useful for localizing the active agent in
contact with the skin, e.g., methylcellulose, sodium
carboxymethylcellulose, or the like.
[0299] Pharmaceutical emulsion formulations are generally formed
from a dispersed phase (e.g., a pharmacologically active agent), a
dispersion medium and an emulsifying agent. If desired, emulsion
stabilizers can be included in the formulation as well. A number of
pharmaceutically useful emulsions are known in the art, including
oil-in-water (o/w) formulations, water-in-oil (w/o) formulations
and multiple emulsions such as w/o/w or o/w/o formulations.
Emulsifying agents suitable for use in such formulations include,
but are not limited to, TWEEN 60.RTM., Span 80.RTM., cetostearyl
alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl
sulfate.
[0300] Pharmaceutical creams are, as known in the art, viscous
liquid 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 sometimes
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.
[0301] The above pharmaceutical formulations are formed by
dispersing the finely divided or dissolved active agent uniformly
throughout the vehicle or base using conventional techniques,
typically by a levigating the agent with a small quantity of the
base to form a concentrate, which is then diluted geometrically
with further base. Alternatively, a mechanical mixer may be used.
Creams, lotions and emulsions are formed by way of a two-phase heat
system, wherein oil-phase ingredients are combined under heat to
provide a liquified, uniform system. The aqueous-phase ingredients
are separately combined using heat. The oil and aqueous phases are
then added together with constant agitation and allowed to cool. At
this point, concentrated agents may be added as a slurry. Volatile
or aromatic materials can be added after the emulsion has
sufficiently cooled. Preparation of such pharmaceutical
formulations is within the general skill of the art.
[0302] The active agent can also be incorporated into a gel
formulation using known techniques. Two-phase gel systems generally
comprise a suspension or network of small, discrete particles
interpenetrated by a liquid to provide a dispersed phase and a
liquid phase. Single-phase gel systems are formed by distributing
organic macromolecules uniformly throughout a liquid such that
there are no apparent boundaries between the dispersed and liquid
phases. Suitable gelling agents for use herein include synthetic
macromolecules (e.g., Carbomers.RTM., polyvinyl alcohols and
polyoxyethylene-polyoxypropylene copolymers), gums such as
tragacanth, as well as sodium alginate, gelatin, methylcellulose,
sodium carboxymethylcellulose, methylhydroxyethyl cellulose and
hydroxyethyl cellulose. 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 or
stirring, or combinations thereof.
[0303] Liposomes are microscopic vesicles having a lipid wall
comprising a lipid bilayer, and can be used as drug delivery
systems herein as well. Generally, liposome formulations are
preferred for poorly soluble or insoluble pharmaceutical agents.
Liposomal preparations for use in the instant invention include
cationic (positively charged), anionic (negatively charged) and
neutral preparations. Cationic liposomes are readily available. For
example, N[1-2,3-dioleyloxy)propyl]-N,N,N-triethyl- ammonium
("DOTMA") liposomes are available under the tradename
Lipofectin.RTM. (GIBCO BRL, Grand Island, N.Y.). Similarly, anionic
and neutral liposomes are readily available as well, e.g., from
Avanti Polar Lipids (Birmingham, Ala.), or can be easily prepared
using readily available materials. Such materials include
phosphatidyl choline, cholesterol, phosphatidyl ethanolamine,
dioleoylphosphatidyl choline ("DOPC"), dioleoylphosphatidyl
glycerol ("DOPG"), dioleoylphoshatidyl ethanolamine ("DOPE"), among
others. These materials can also be mixed with DOTMA in appropriate
ratios. Methods for making liposomes using these materials are well
known in the art.
[0304] Vaginal suppositories are typically manufactured with
polyethylene glycol (PEG), polyethylene oxide and/or other low
melting point or water-soluble polymers including fatty acid
esters. Suppositories may also be applied to the vulvar region, in
which case these dosage forms, which are solid at ambient
temperature, rapidly melts when placed on the clitoris and within
the vulvar region.
[0305] Typically, compositions and dosage forms for vulvar and/or
vaginal administration will contain the active agent in a
concentration such that an effective amount of the agent is
delivered with a single application. For example, the composition
or dosage form will generally contain sufficient active agent such
that an effective amount of the agent is delivered by application
of about 0.1 g to 1.0 g. Thus, for delivering about 1.0 .mu.g to
about 100 mg, preferably about 0.05 mg to about 50 mg, most
preferably about 1.0 mg to about 25 mg, of the composition or
dosage form will contain the active agent at a concentration in the
range of about 1.0 .mu.g/g to about 1.0 g/g, preferably 50 .mu.g/g
to about 500 mg/g, most preferably about 1.0 mg/g to about 250
mg/g.
[0306] Delivery of an "as-needed" or "on-demand" dose with topical
formulations intended for application to the vulvar region, and/or
with vaginal suppositories, is effected by using the appropriate
carrier and, when necessary, excipients, for the particular active
agent. For example, the active agent's affinity to the carrier must
be lower than its affinity to the treated body surface. Optimally,
the agent will have a relatively high affinity for the mucosal
surface to which it is applied, and a relatively low affinity for
the particular carrier. As the affinity of the agent for the body
surface remains constant (assuming the agent does not change, e.g.,
hydrolyze, etc., upon contact with the body surface), a suitable
carrier for use in the formulations described herein can be
determined by routinely testing a series of different carriers
containing the active agent and selecting those carriers that
provide the greatest flux of the active agent to the intended
tissue, e.g., clitoral tissue. Additionally, one or more permeation
enhancers and/or detergents may also be present in the formulation
to ensure a rate of delivery sufficient for on-demand
administration. A combination of these approaches as well as other
approaches may be used to effect delivery of an on-demand dose.
[0307] Once the initial, on-demand dose is delivered, the drug
delivery system, if present, and/or any remaining formulation may
be removed or may remain in place, depending on the preferences of
the individual. Alternatively, the formulation and optional drug
delivery system may be designed to provide both initial "on-demand"
release of the active agent, i.e., as a single, bolus dose, as well
as sustained release thereafter, e.g., pulsatile, continuous or
cyclical drug release. Such systems can include, for example,
osmotic release systems that are capable of delivering an initial,
on-demand release of the active agent in addition to variable
amounts of the agent in a pulsatile manner thereafter.
[0308] Other drug delivery platforms capable of providing an
initial release of drug followed by a pulsatile, continuous or
cyclical agent release profile include those formed from
bioerodible polymers, wherein the active agent is dispersed within
a polymer matrix that is surrounded by an immediate release coating
of the agent. The immediate release coating ensures effective
on-demand administration. The polymers forming the matrix are
selected such that they bioerode in the presence of moisture, and
provide for sustained agent release at readily predictable
rates.
[0309] More particularly, release of the active agent can be
controlled by dissolution (bioerosion) of a polymer using either
encapsulated dissolution control or matrix dissolution control. In
encapsulated dissolution control, the on-demand dose of the active
agent is located within an outer polymeric or wax membrane that
dissolves to provide an initial release of the agent. When the
encapsulating membrane comprising an initial release of the agent
has dissolved, a core containing additional active agent is then
available for release and adsorption across the epithelial or
mucosal surfaces of the vagina or vulvar area. Bioerodible coating
materials may be selected from a variety of natural and synthetic
polymers, depending on the agent to be coated and the desired
release characteristics. Exemplary coating materials include
gelatins, carnauba wax, shellacs, ethylcellulose, cellulose acetate
phthalate or cellulose acetate butyrate. Following the immediate
release of the agent, a uniform sustained release of the agent can
be attained by compressing a population of particles of the agent
with varying membrane thickness (e.g., varying erosion times) into
a tablet form for a single administration.
[0310] In matrix dissolution control, the active agent is dissolved
or dispersed within a matrix of, for example, an erodible wax. The
agent is released for adsorption across the epithelial or mucosal
surfaces of the vagina or vulvar area as the matrix bioerodes. The
rate of agent availability is generally controlled by the rate of
penetration of the dissolution media (i.e., vaginal fluids) into
the matrix, wherein the rate of penetration is dependent on the
porosity of the matrix material. Bioerodible matrix dissolution
delivery systems can be prepared by compressing the active agent
with a slowly soluble polymer carrier into a tablet or suppository
form. There are several methods of preparing drug/wax particles
including congealing and aqueous dispersion techniques. In
congealing methods, the active agent is combined with a wax
material and either spray-congealed, or congealed and then
screened. For an aqueous dispersion, the active agent/wax
combination is sprayed or placed in water and the resulting
particles collected. Matrix dosage formulations can be formed by
compaction or compression of a mixture of active agent, polymer and
excipients. Of course, the active agent will also be located in an
external coating of the matrix formulation to provide for immediate
release of the active agent necessary for on-demand
administration.
[0311] In an alternative embodiment, the pharmaceutical formulation
is administered in the form of biodegradable adhesive film or sheet
that adheres to the vulvar area. Such drug delivery systems are
generally composed of a biodegradable adhesive polymer based on a
polyurethane, a poly(lactic acid), a poly(glycolic acid), a
poly(ortho ester), a polyanhydride, a polyphosphazene, or a mixture
or copolymer thereof. Preferred biodegradable adhesive polymers
include polyurethanes and block copolyurethanes containing peptide
linkages, simple mixtures of polyurethanes and polylactides, and
copolymers of acrylates and mono- or disaccharide residues.
[0312] 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, as explained supra. The unit dose of
any particular active agent will depend, of course, on the active
agent, the needs of the patient, and on the mode of administration.
Those of ordinary skill in the art of pharmaceutical formulation
can readily deduce suitable unit doses for VIP and various VIP
agonists, as well as suitable unit doses for other types of active
agents that may be incorporated into a dosage form of the
invention.
[0313] Drug administration is preferably, although not necessarily,
on an as-needed basis, in which case chronic drug administration is
not involved. 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 0.25 to 72 hours, preferably
about 0.5 to 48 hours, more preferably about 1 to 24 hours, most
preferably about 1 to 12 hours, and optimally about 1 to 4 hours
prior to anticipated sexual activity. As will be appreciated by
those in the fields of pharmacology and drug delivery, the upper
end of the aforementioned ranges will depend on the
pharmacokinetics of the particular active agent administered.
[0314] With a sustained release dosage form, a single "as-needed"
dose can provide therapeutic efficacy over an extended time period
in the range of about 4 to 72 hours, typically in the range of
about 4 to 48 hours, more typically in the range of about 4 to 24
hours, depending on the formulation. The release period may be
varied by the selection and relative quantity of particular
sustained release polymers, as discussed supra.
[0315] As-needed administration as described herein has several
advantages over chronic pharmacologic intervention. First, chronic
administration of some agents, in particular steroids, can result
in serious medical complications and alter the balance of naturally
occurring steroids in the body. Second, patient compliance can be
problematic with a regimented dosing scheme. Furthermore, as-needed
administration is convenient and doses are taken only in
anticipation of sexual activity. Thus, needless expenditure on
wasted dosages is avoided, thereby decreasing the treatment's
overall expense.
[0316] The patient treated may be a woman suffering from some type
of sexual dysfunction or disorder, or may possess "normal" sexual
desire and/or "normal" sexual responsiveness as those terms are
understood defined by clinicians or other experts. For these
"normal" women, the present invention offers heightened sexual
desire and responsiveness relative to her typical sexual
experience. Often, however, the female patient seeking enhanced
sexual desire and responsiveness suffers a sexual dysfunction such
as a condition, disease or disorder that affects one of the four
stages of the female sexual response: excitement, plateau, orgasm,
or resolution. More specifically, the patient may suffer from any
one or more of the following:
[0317] a decrease in or absence of female sexual responsiveness or
female sexual desire;
[0318] a persistent or recurrent deficiency or absence of sexual
fantasies and desire for sexual activity;
[0319] a decrease in the physiological response to sexual
stimulation such as, but not limited to, slowed, decreased or
absent erectile response of the female erectile tissues; slowed,
decrease or absent lubrication of the vagina; slowed decreased or
absent ability to reach orgasm, and decreased intensity of or
pleasure in orgasms;
[0320] frigidity;
[0321] sexual aversion;
[0322] a condition, disease or disorder that may result in
decreased sexual desire and responsiveness including, but not
limited to, the menopausal or post-menopausal state, radiotherapy
of the pelvis, multiple sclerosis, atherosclerosis, pelvic trauma
or surgery, peripheral neuropathies, autonomic neuropathies,
diabetes mellitus, and disorders of the innervation of any of the
sexual organs;
[0323] substance-induced decreases in sexual desire and
responsiveness including, but not limited to, decreases related to
the administration of pharmacologic agents such as, but not limited
to, anti-depressants, neuroleptics, anti-hypertensives, opiates,
alcohol, and any other agent found to decrease or eliminate any
part of the sexual response cycle; and
[0324] primary and secondary anorgasmia.
[0325] In addition to enhancing female sexual desire and
responsiveness, the method, compositions and dosage forms of the
invention are useful in improving the tissue health of the female
genitalia and preventing vaginal atrophy, preventing pain during
intercourse as a result of dyspareunia, and alleviating vaginal
itching and dryness associated with dyspareunia and other
conditions.
[0326] In another embodiment, a packaged kit is provided that
contains the pharmaceutical formulation to be administered, i.e., a
pharmaceutical formulation containing VIP or a VIP agonist for
enhancing female sexual desire and responsiveness, a container
(e.g., a vial, a bottle, a pouch, an envelope, a can, a tube, an
atomizer, an aerosol can, etc.), preferably sealed, for housing the
formulation during storage and prior to use, and instructions for
carrying out drug administration in a manner effective to enhance
sexual desire and responsiveness. The instructions will typically
be written instructions on a package insert, a label, and/or on
other components of the kit.
[0327] 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 transdermal delivery
device). The administration device may be a dropper, a swab, a
stick, or the nozzle or outlet of an atomizer or aerosol can. 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 active agent, or a gel or ointment contained
within a tube. The kit may contain multiple formulations of
different dosages of the same agent. The kit may also contain
multiple formulations of different active agents.
[0328] The present kits will also typically include means for
packaging the individual kit components, i.e., the pharmaceutical
dosage forms, the administration device (if included), and the
written instructions for use. Such packaging means may take the
form of a cardboard or paper box, a plastic or foil pouch, etc.
[0329] 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
that 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.
[0330] All patents, patent applications, patent publications and
non-patent literature references mentioned herein are incorporated
by reference in their entireties.
EXAMPLE 1
[0331] A cream formulation is prepared for the topical
administration of VIP. The cream includes the following
components:
1 VIP 750 mg Beeswax 2.7 g Carbopol .RTM. 934 q.s. 100.0 g
[0332] Mixing is conducted with tile and spatula until a
homogeneous cream mixture is obtained having the prostaglandin
uniformly dispersed throughout the composition.
EXAMPLE 2
[0333] The procedure of Example 1 is repeated except that the
following components are used:
2 Stearyl-VIP 500 mg Polyethylene glycol 400 37.5 g
1,2,6-hexanetriol 20.0 g Polyethylene glycol 4000 q.s. 100.0 g
[0334] Stearyl-VIP is prepared as described in U.S. Pat. No.
5,147,855 to Gozes et al. A homogenous cream mixture is
obtained.
EXAMPLE 3
[0335] The procedure of Example 1 is repeated except that the
following components are used:
3 Stearyl VIP.sub.7-28 750 mg Polyethylene glycol 400 37.0 g
Polyethylene glycol 400 monostearate 26.0 g Polyethylene glycol
4000 q.s. 100.0 g
[0336] Stearyl-VIP is prepared as described in U.S. Pat. No.
5,147,855 to Gozes et al. A homogenous cream mixture is
obtained.
EXAMPLE 4
[0337] The procedure of Example 1 is repeated except that the
following components are used:
4 VIP-Gly-Cys-NH.sub.2 (SEQ. ID NO.: 204) 750 mg Polyethylene
glycol 400 47.5 g Cetyl Alcohol 5.0 g Polyethylene glycol 4000 q.s.
100.0 g
[0338] VIP-Gly-Cys-NH.sub.2 (SEQ. ID NO.: 204) is prepared as
described in U.S. Pat. No. 5,612,314 to Stamler et al. A homogenous
cream mixture is obtained.
EXAMPLE 5
[0339] The procedure of Example 1 is repeated except that the
following components are used:
5 VIP-Gly-Cys-NO (SEQ. ID NO.: 203) 750 mg Polyethylene glycol 400
47.5 g Cetyl Alcohol 5.0 g Polyethylene glycol 4000 q.s. 100.0
g
[0340] VIP-Gly-Cys-NO (SEQ. ID NO.: 203) is prepared as described
in U.S. Pat. No. 5,612,314 to Stamler et al. A homogenous cream
mixture is obtained.
EXAMPLE 6
[0341] An ointment formulation is prepared for the topical
administration of VIP. The ointment includes the following
components:
6 VIP 750 mg Anhydrous lanolin 20.0 g Mineral oil 25.0 g White
Petrolatum q.s. 100.0 g
[0342] Mixing is conducted with tile and spatula until a
homogeneous ointment mixture is obtained having the VIP uniformly
dispersed throughout the composition.
EXAMPLE 7
[0343] The procedure of Example 5 is repeated except that the
following components are used:
7 VIP 750 m Diisopropyl Adipate 19.95 g White Petrolatum, USP q.s.
100.0 g
[0344] A homogenous ointment mixture is obtained.
[0345] In the cream and ointment formulations described in Examples
1-6, optional ingredients can include materials such as
antioxidants, viscosity modifiers (e.g., paraffin wax or lanolin
wax), and topical absorption rate modifiers.
EXAMPLE 8
[0346] A vaginal suppository formulation is prepared using a
synthetic or semisynthetic prostaglandin. The suppository includes
the following components:
8 Prostaglandin 0.25 gm Polyethylene glycol 400 37.0 gm Glycerol
gelatin 20.0 gm Polyethylene glycol 4000 q.s. 100.0 gm
[0347] The polyethylene glycol 400 solution containing
prostaglandin is mixed well with glycerol gelatin or similar
suppository base such as macrogol, Witepsol.RTM., or the like, with
a mechanical mixing apparatus, and the mixture is then cooled in a
suppository mold.
EXAMPLE 9
[0348] Suppositories suitable for vaginal administration of a unit
dosage of VIP are made as follows. Twenty mg VIP are mixing the
selected prostaglandin with 250 mg polyethylene glycol, molecular
weight (M.sub.w) approximately 4000, and the mixture is heated to a
temperature just high enough to produce a melt. The melted mixture
is then poured into a mold suitable to provide a suppository, and
allowed to cool. The suppository so provided is a unit dosage form
suitable for vaginal administration.
EXAMPLE 10
[0349] Individuals are assessed and pre-screened to assemble an
experimental group of subjects suffering from sexual dysfunction.
The compositions prepared in Examples 1-9, formulated with VIP or
an analog thereof, are each assessed in the experimental subjects
for their ability to increase uterine or vaginal epithelial blood
flow. The formulations are applied vaginally and to the vulvar
region, and changes in blood flow and/or vaginal fluid production
after application of the vasodilating formulations are determined
using known methods. Increase in vaginal epithelial blood flow is
determined using indirect methods such as photoplethysmography
(Levin (1980) Clinics in Obstet. Gynaecol. 7:213-252), heated
oxygen electrode (Wagner et al. (1978), "Vaginal Fluid" in The
Human Vagina, Evans et al. (eds.), Amsterdam: Elsevier/North
Holland Biomedical Press, pp. 121-137), and direct clearance of
radioactive Xenon (Wagner et al. (1980) Obstet. Gynaecol.
56:621-624). Changes in vulvar blood flow are monitored using laser
Doppler velocimetry (Sarrel, P. M. (1990) Obstet. Gynaecol.
75:26S-32S).
[0350] Decreased vaginal dryness and/or dyspareunia are negatively
correlated with vaginal blood flow rates, wherein increased blood
flow to the vagina correlates with increased lubrication and
decreased frequency and severity of dyspareunia (Sarrel, P. M.
(1990) Obstet. Gynaecol. 75:26S-32S). Accordingly, vulvar blood
flow after treatment is assessed using laser Doppler velocimetry
and compared to baseline levels. Increased vaginal lubrication as a
result of treatment with the vasoactive formulations can also be
assessed using the methods of Semmens et al. (1982) J. Am. Med.
Assoc. 248:445-448. The compositions of Examples 1-9, when assessed
using such methods, are found to substantially increase blood flow
to the vagina and vulvar area and alleviate vaginal dryness.
* * * * *