U.S. patent application number 15/354703 was filed with the patent office on 2017-06-15 for treatment of sexual dysfunction and for improved sexual quality of life.
This patent application is currently assigned to ReJoy. The applicant listed for this patent is ReJoy. Invention is credited to Ofer A. GOREN, John McCoy.
Application Number | 20170165253 15/354703 |
Document ID | / |
Family ID | 57503852 |
Filed Date | 2017-06-15 |
United States Patent
Application |
20170165253 |
Kind Code |
A1 |
GOREN; Ofer A. ; et
al. |
June 15, 2017 |
TREATMENT OF SEXUAL DYSFUNCTION AND FOR IMPROVED SEXUAL QUALITY OF
LIFE
Abstract
Compositions and methods for treating sexual dysfunction and
enhancing sexual satisfaction using topical application of alpha-1
adrenergic receptor agonists, muscarinic acetylcholine receptor
agonists, nicotinic acetylcholine receptor agonists, and
cholinesterase inhibitors are disclosed.
Inventors: |
GOREN; Ofer A.; (Irvine,
CA) ; McCoy; John; (Irvine, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ReJoy |
Irvine |
CA |
US |
|
|
Assignee: |
ReJoy
Irvine
CA
|
Family ID: |
57503852 |
Appl. No.: |
15/354703 |
Filed: |
November 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2016/036970 |
Jun 10, 2016 |
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15354703 |
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62317698 |
Apr 4, 2016 |
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62297598 |
Feb 19, 2016 |
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62222494 |
Sep 23, 2015 |
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62213927 |
Sep 3, 2015 |
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62211470 |
Aug 28, 2015 |
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62203728 |
Aug 11, 2015 |
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62188233 |
Jul 2, 2015 |
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62175806 |
Jun 15, 2015 |
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62174262 |
Jun 11, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/221 20130101;
A61K 31/465 20130101; A61K 9/0041 20130101; A61K 31/166 20130101;
A61K 9/0009 20130101; A61K 31/445 20130101; A61K 31/4174 20130101;
A61K 9/0014 20130101; A61K 31/4178 20130101; A61K 31/137 20130101;
A61K 31/439 20130101; A61P 15/00 20180101 |
International
Class: |
A61K 31/465 20060101
A61K031/465; A61K 31/137 20060101 A61K031/137; A61K 31/4174
20060101 A61K031/4174; A61K 31/166 20060101 A61K031/166; A61K
31/445 20060101 A61K031/445; A61K 31/4178 20060101 A61K031/4178;
A61K 31/439 20060101 A61K031/439; A61K 9/00 20060101 A61K009/00;
A61K 31/221 20060101 A61K031/221 |
Claims
1. A method of increasing sexual satisfaction in a female subject
comprising applying a therapeutically effective amount of an active
agent selected from the group consisting of muscarinic
acetylcholine receptor agonists, nicotinic acetylcholine receptor
agonists, and cholinesterase inhibitors topically to a
nipple-areola complex of the female subject.
2. The method of claim 1, wherein the method results in the female
subject having increased sexual self-esteem, increased
self-perception of femininity, and/or increased self-esteem.
3. The method of claim 1, wherein the female subject has undergone
breast surgery prior to application of the active agent and the
surgery resulted in a reduction of nipple sensitivity.
4. The method of claim 1, wherein the active agent is applied in a
sufficient amount to cause erection of the nipple or increased
nipple sensitivity.
5. The method of claim 1, or wherein the active agent is a
muscarinic acetylcholine receptor agonist selected from the group
consisting of muscarinic acetylcholine receptor M.sub.2 agonists
and muscarinic acetylcholine receptor M.sub.3 agonists.
6. The method of claim 1, or wherein the active agent is a
muscarinic acetylcholine receptor agonist selected from the group
consisting of NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC
11-1314, xanomeline, sabcomeline, arecaidine propargyl ester,
acetylcholine, arecoline, oxotremorine, McN-A-343, milameline,
oxotremorine-M, methylfurmethide, bethanechol, carbachol,
furtrethonium, methacholine, aceclidine, pilocarpine, and
muscarine.
7. The method of claim 1, or wherein the active agent is a
nicotinic acetylcholine receptor agonist selected from the group
consisting of varenicline tartrate, galantamine hydrobromide,
nicotine, carbachol, suxamethonium chloride (succinylcholine
chloride), and epibatidine.
8. The method of claim 1, or wherein the active agent is a
cholinesterase inhibitor selected from the group consisting of
physostigmine, neostigmine, edrophonium, pyridostigmine,
echotihiophate, ambenonium, demecarium, tacrine, donepezil,
rivastigmine, galantamine, and pralidoxime.
9. The method of claim 1, wherein the female subject has reduced
sensitivity at the nipple-areola complex before applying the active
agent.
10. A method of treating female sexual dysfunction, the method
comprising applying a therapeutically effective amount of an active
agent selected from the group consisting of muscarinic
acetylcholine receptor agonists, nicotinic acetylcholine receptor
agonists, and cholinesterase inhibitors topically to a
nipple-areola complex of a female subject in need of such
treatment.
11. The method of claim 10, wherein the composition is applied in a
sufficient amount to cause erection of the nipple or increased
nipple sensitivity.
12. The method of claim 10, wherein the active agent is a
muscarinic acetylcholine receptor agonist selected from the group
consisting of muscarinic acetylcholine receptor M.sub.2 agonists
and muscarinic acetylcholine receptor M.sub.3 agonists.
13. The method of claim 10, wherein the active agent is a
muscarinic acetylcholine receptor agonist selected from the group
consisting of NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC
11-1314, xanomeline, sabcomeline, arecaidine propargyl ester,
acetylcholine, arecoline, oxotremorine, McN-A-343, milameline,
oxotremorine-M, methylfurmethide, bethanechol, carbachol,
furtrethonium, methacholine, aceclidine, pilocarpine, and
muscarine.
14. The method of claim 10, wherein the active agent is a nicotinic
acetylcholine receptor agonist selected from the group consisting
of varenicline tartrate, galantamine hydrobromide, nicotine,
carbachol, suxamethonium chloride (succinylcholine chloride), and
epibatidine.
15. The method of claim 10, wherein the active agent is a
cholinesterase inhibitor selected from the group consisting of
physostigmine, neostigmine, edrophonium, pyridostigmine,
echotihiophate, ambenonium, demecarium, tacrine, donepezil,
rivastigmine, galantamine, and pralidoxime.
16. The method of claim 10, wherein the female sexual dysfunction
is selected from the group consisting of female sexual arousal
disorder (FSAD), female sexual interest/arousal disorder (FSIAD),
female orgasmic disorder (FOD) and female hypoactive sexual desire
disorder (FHSDD).
17. A method of reducing or alleviating a symptom of female sexual
dysfunction, the method comprising applying a therapeutically
effective amount of an active agent selected from the group
consisting of muscarinic acetylcholine receptor agonists, nicotinic
acetylcholine receptor agonists, and cholinesterase inhibitors
topically to a nipple-areola complex of a female subject in need of
such treatment.
18. The method of claim 17, wherein the symptom of female sexual
dysfunction is a symptom of female hypoactive sexual desire
disorder (FHSDD), female sexual interest/arousal disorder (FSIAD),
female orgasmic disorder (FOD) or female sexual arousal disorder
(FSAD).
19. The method of claim 17, wherein the symptom of female sexual
dysfunction is a symptom of female sexual interest/arousal disorder
selected from the group consisting of (1) absent/reduced interest
in sexual activity; (2) absent/reduced sexual/erotic thoughts or
fantasies; (3) no/reduced initiation of sexual activity, and
typically unreceptive to a partner's attempts to initiate; (4)
absent/reduced sexual excitement/pleasure during sexual activity in
almost all or all sexual encounters; (5) absent/reduced sexual
interest/arousal in response to any internal or external
sexual/erotic cues; and (6) absent/reduced genital or nongenital
sensations during sexual activity in almost all or all sexual
encounters.
20. The method of claim 17, wherein the active agent is applied in
a sufficient amount to cause erection of the nipple or increased
nipple sensitivity.
21. The method of claim 17, wherein the active agent is a
muscarinic acetylcholine receptor agonist selected from the group
consisting of muscarinic acetylcholine receptor M.sub.2 agonists
and muscarinic acetylcholine receptor M.sub.3 agonists.
22. The method of claim 17, wherein the active agent is a
muscarinic acetylcholine receptor agonist selected from the group
consisting of NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC
11-1314, xanomeline, sabcomeline, arecaidine propargyl ester,
acetylcholine, arecoline, oxotremorine, McN-A-343, milameline,
oxotremorine-M, methylfurmethide, bethanechol, carbachol,
furtrethonium, methacholine, aceclidine, pilocarpine, and
muscarine.
23. The method of claim 17, wherein the active agent is a nicotinic
acetylcholine receptor agonist selected from the group consisting
of varenicline tartrate, galantamine hydrobromide, nicotine,
carbachol, suxamethonium chloride (succinylcholine chloride), and
epibatidine.
24. The method of claim 17, wherein the active agent is a
cholinesterase inhibitor selected from the group consisting of
physostigmine, neostigmine, edrophonium, pyridostigmine,
echotihiophate, ambenonium, demecarium, tacrine, donepezil,
rivastigmine, galantamine, and pralidoxime.
25. A method of causing erection of nipples, increasing nipple
sensitivity, increasing duration of orgasm, reducing time to
orgasm, and/or increasing oxytocin release related to sexual
activity in a female subject comprising applying an effective
amount of an active agent selected from the group consisting of
muscarinic acetylcholine receptor agonists, nicotinic acetylcholine
receptor agonists, and cholinesterase inhibitors topically to a
nipple-areola complex of the female subject.
26. The method of claim 25, wherein the method is to increase
nipple sensitivity in a female subject that had breast surgery.
27. The method of claim 25, wherein the method is to increase
nipple sensitivity in a female subject who has not undergone breast
surgery.
28. A method for treating neuropathy in the nipple areola complex
in a female subject comprising applying an effective amount of an
active agent selected from the group consisting of muscarinic
acetylcholine receptor agonists, nicotinic acetylcholine receptor
agonists, and cholinesterase inhibitors topically to a
nipple-areola complex of the female subject.
29. The method of claim 25, wherein the active agent is applied in
a sufficient amount to cause erection of the nipple.
30. The method of claim 25, wherein the active agent is a
muscarinic acetylcholine receptor agonist selected from the group
consisting of muscarinic acetylcholine receptor M.sub.2 agonists
and muscarinic acetylcholine receptor M.sub.3 agonists.
31. The method of claim 25, wherein the active agent is a
muscarinic acetylcholine receptor agonist selected from the group
consisting of NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC
11-1314, xanomeline, sabcomeline, arecaidine propargyl ester,
acetylcholine, arecoline, oxotremorine, McN-A-343, milameline,
oxotremorine-M, methylfurmethide, bethanechol, carbachol,
furtrethonium, methacholine, aceclidine, pilocarpine, and
muscarine.
32. The method of claim 25, wherein the active agent is a nicotinic
acetylcholine receptor agonist selected from the group consisting
of varenicline tartrate, galantamine hydrobromide, nicotine,
carbachol, suxamethonium chloride (succinylcholine chloride), and
epibatidine.
33. The method of claim 25, wherein the active agent is a
cholinesterase inhibitor selected from the group consisting of
physostigmine, neostigmine, edrophonium, pyridostigmine,
echotihiophate, ambenonium, demecarium, tacrine, donepezil,
rivastigmine, galantamine, and pralidoxime.
34. The method of one of claim 1, wherein the composition is
applied within one hour prior to a sexual activity.
35. The method of one of claim 1, wherein the subject is a
premenopausal female.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This is a continuation-in-part application of, and claims
the benefit of, PCT/US/2016/036970 filed on Jun. 10, 2016, which
claims the benefit of U.S. Provisional Application No. 62/317,698
filed on Apr. 4, 2016, 62/297,598 filed on Feb. 19, 2016, U.S.
Provisional Application No. 62/222,494 filed on Sep. 23, 2015, U.S.
Provisional Application No. 62/213,927 filed on Sep. 3, 2015, U.S.
Provisional Application No. 62/211,470 filed on Aug. 28, 2015, U.S.
Provisional Application No. 62/203,728 filed on Aug. 11, 2015, U.S.
Provisional Application No. 62/188,233 filed on Jul. 2, 2015, U.S.
Provisional Application No. 62/175,806 filed on Jun. 15, 2015, and
U.S. Provisional Application No. 62/174,262 filed on Jun. 11, 2015,
and the entire content of each application referenced above is
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present disclosure relates to methods to treat sexual
dysfunction, particularly female sexual dysfunction, and related
disorders and conditions pertaining to sexual activity and sexual
satisfaction, and methods to enhance sexual satisfaction,
particularly female sexual satisfaction.
BACKGROUND DISCUSSION
[0003] Female sexual dysfunction (FSD) is a prevalent problem,
afflicting approximately 40% of women. There are few treatment
options. See Kyan J. Allandadi et al., "Female Sexual Dysfunction:
Therapeutic Options and Experimental Challenges," Cardiovasc
Hematol Agents Med Chem. 2009 Oct. 7 (4): 260-269. FSD can be
classified under many subtypes. For example, female sexual arousal
disorder (FSAD) is a disorder characterized by a persistent
inability to attain sexual arousal or to maintain arousal until the
completion of a sexual activity. Female Sexual Interest/Arousal
Disorder (FSIAD) is a diagnosis found when a subject experiences a
lack of or significantly reduced sexual interest or arousal. Female
hypoactive sexual desire disorder (FHSDD) is a general loss of
interest in sexual activity. Other subtypes exist, for example,
anorgasmia, a difficulty achieving orgasm.
[0004] Currently, off-label use of testosterone has been
prescribed. A therapy approved by the FDA in August 2015 is the
Sprout Pharmaceuticals, Inc. product Addyi.TM. (flibanserin 100
mg), a once-daily, non-hormonal pill for the treatment of acquired,
generalized hypoactive sexual desire disorder in premenopausal
women. In addition, there are several drugs that were the subject
of clinical trials that affect signaling in the brain. See Wright,
J. J., O'Connor, K. M. (2015), "Female sexual dysfunction," Medical
Clinics of North America, 99(3), 607-628. Because both hormonal and
psycho-affective drugs can be associated with serious negative side
effects, alternative treatment options would be desired for
treating this prevalent condition.
[0005] The arousal phase of the female sexual response cycle
involves genital mechanisms, such as clitoral, labial, and vaginal
engorgement, as well as non-genital peripheral mechanisms, such as
increases in body secretions, cutaneous vasodilation, and nipple
sensitivity with or without nipple erection. Nipple sensitivity and
erection occurs via activation of adrenergic nerves and the
cholinergic nerves. It has been shown in pigs that both adrenergic
and cholinergic neurons innervate the mammary gland. Smooth muscles
in the nipple areola complex are contracted, thereby erecting the
nipple. Agonists of the adrenergic receptors directly stimulate the
smooth muscle. Acetylcholine and acetylcholine receptor agonists
act via axon reflexes to stimulate smooth muscle contraction.
Acetylcholine acts on the nerves in the central nervous system as a
substance mediating the propagation of impulses across the
ganglionic synapse, but it also has a second pharmacological
effect, which is mediated through an axon reflex. Axon reflexes are
peripheral nervous system impulses independent of the central
nervous system. See Rothman and Coon, "Axon Reflex Responses to
Acetyl Choline in the Skin," J. Investigative Dermatology, 3: 79-97
(1940). Additionally, the mammary glands and the nipple are ducts.
Acetylcholine directly stimulates ducts.
[0006] The role of nipple stimulation in influencing sexual desire
and arousal in women prior to and during intercourse has been
reported in the literature. Eighty-two percent of surveyed women
report that stimulation of their nipples caused or enhanced their
sexual arousal. See Levin, R., Meston, C. (2006), "Nipple/Breast
stimulation and sexual arousal in young men and women," Journal of
Sexual Medicine, 3(3), 450-454; Levin, R. (2006), "The
breast/nipple/areola complex and human sexuality," Sexual and
Relationship Therapy, 21(2), 237-249. In addition, stimulation of a
women's nipple has been shown to correlate with increased oxytocin
levels in blood serum. See Stein, J. L., Bardeguez, A. D., Verma,
U. L., Tegani, N. (1990), "Nipple stimulation for labor
augmentation," Journal of Reproductive Medicine, 35(7), 710-714.
Oxytocin is a peptide hormone shown to play a role in sexual
satisfaction and desire.
[0007] In addition to sexual dysfunctions described above, women
may have low sexual interest, desire or arousal, fewer and/or less
intense orgasms, or general lack of sexual satisfaction due to a
coexisting medical or psychiatric condition, such as women who have
had breast surgery that reduces or eliminates sensitivity at the
nipple-areola complex. There is a need for pharmaceutical treatment
to restore or increase sensitivity in such subjects.
[0008] U.S. Pat. No. 4,853,216 (Koslo et al.) reports topical
application of alpha-1 adrenergic receptor agonists ("A1AR
agonists") to a hair-bearing skin area to facilitate the physical
or chemical handling of the hair. The purpose is to activate the
pilomotor effect and erect the hair on the skin. This may be
applied as a pretreatment prior to shaving or incorporated into a
shaving composition, such as shaving cream. U.S. Pat. No. 4,853,216
discloses that suitable A1AR agonists include phenylephrine and
methoxamine. See U.S. Pat. No. 4,853,216 at col. 2 lines 46-48.
WO2004041259 (Thurlow et al.) describes the use of
alpha-1adrenergic receptor antagonists for the treatment of FSD.
The reference does not describe application of the antagonist to at
least a portion of the nipple-areola complex, and focuses rather on
inhibitors of receptors in the vaginal tissue. It is unexpected
from this teaching that an A1AR agonist would be useful for
treatment of FSD when applied to at least a portion of the
nipple-areola complex.
[0009] A1AR agonists bind to .alpha.1-receptors on vascular smooth
muscle and induce smooth muscle cell contraction, thus mimicking
the effects of sympathetic neuron activation of smooth muscles via
adrenergic receptors. Phenylephrine is a selective A1AR agonist.
Phenylephrine is used as a decongestant, for which it is sold as an
oral medicine or a nasal spray. Phenylephrine is also sold as a
topical ointment to prevent or reduce symptoms of hemorrhoids.
Phenylephrine is used as an eye drop to dilate the pupil to
facilitate visualization of the retina. US Patent Application Pub.
2004/0198706 (Carrara et al.) discloses formulations for providing
transdermal or transmucosal delivery of active agents. The
formulations treat symptoms of hormonal disorders including female
sexual desire disorder. The active agents may be selected from a
large group of therapeutic agents, one of which is phenylephrine.
The reference does not describe application of the transdermal or
transmucal dosage forms to the nipple-areola complex. It is
unexpected from this teaching that an MAR agonist such a
phenylephrine would be useful for treatment of FSD when applied to
the nipple-areola complex.
SUMMARY
[0010] The present disclosure concerns a method of increasing
sexual satisfaction in a female subject comprising applying a
therapeutically effective amount of an active agent selected from
the group consisting of muscarinic acetylcholine receptor agonists,
nicotinic acetylcholine receptor agonists, and cholinesterase
inhibitors topically to a nipple-areola complex of the female
subject, such as in one further embodiment a female subject who has
undergone breast surgery that resulted in reduced nipple sensation.
In another embodiment, the present disclosure concerns a method of
treating sexual dysfunction, in some embodiments a method of
treating female sexual dysfunction, the method comprising applying
a therapeutically effective amount of an active agent selected from
the group consisting of muscarinic acetylcholine receptor agonists,
nicotinic acetylcholine receptor agonists, and cholinesterase
inhibitors topically to a nipple-areola complex of a subject, such
as a female subject, in need of such treatment. In another
embodiment, the disclosure concerns a method of reducing or
alleviating a symptom of sexual dysfunction, in some embodiments a
symptom of female sexual dysfunction, the method comprising
applying a therapeutically effective amount of an active agent
selected from the group consisting of muscarinic acetylcholine
receptor agonists, nicotinic acetylcholine receptor agonists, and
cholinesterase inhibitors topically to a nipple-areola complex of a
subject, such as a female subject, in need of such treatment. In a
further embodiment, the disclosure concerns a method of causing
erection of nipples, increasing nipple sensitivity, increasing
duration of orgasm, reducing time to orgasm, and/or increasing
oxytocin release related to sexual activity in a subject, in some
embodiments a female subject, comprising applying an effective
amount of an active agent selected from the group consisting of
muscarinic acetylcholine receptor agonists, nicotinic acetylcholine
receptor agonists, and cholinesterase inhibitors topically to a
nipple-areola complex of the subject. In one embodiment, the method
is to increase nipple sensitivity in a female subject that had
breast surgery. The disclosure also concerns compounds and
compositions for use in any of the methods disclosed herein.
BRIEF DESCRIPTION OF THE FIGURE(S)
[0011] FIG. 1 is a diagram identifying areas of the nipple-areola
complex. FIG. 1 shows points corresponding to the four areolar
quadrants (P1-P4) and the nipple (P5), in right and left breasts.
P1, areola superolateral point; P2, areola superomedial point; P3,
areola inferomedial point; P4, areola inferolateral point; P5,
nipple.
DETAILED DESCRIPTION
Methods of Use
[0012] The present disclosure relates to methods to treat or reduce
sexual dysfunction and related disorders pertaining to sexual
activity and sexual satisfaction, and methods to enhance or
increase sexual satisfaction, in some embodiments female sexual
satisfaction. The present disclosure also relates to methods to
treat women having reduced sensitivity of the breast or
particularly of the nipple-areola complex, such as treating women
having reduced or absent sensitivity at the nipple-areola complex,
to increase their sexual satisfaction, to increase sexual
self-confidence, to increase nipple sensitivity, to increase
duration of orgasm, to reduce time to orgasm, to increase intensity
of orgasm, and to improve sexual quality of life.
[0013] As used herein, the terms "female sexual dysfunction" or
"FSD" refer generally to the impairment of the sexual function in a
female. Sexual dysfunction in females includes inhibited orgasm.
Female sexual dysfunction includes, but is not limited to, a number
of categories of diseases, conditions and disorders including
female hypoactive sexual desire disorder (FHSDD or HSDD, used
interchangeably herein), female orgasmic disorder (FOD), sexual
anhedonia, female sexual interest/arousal disorder (FSIAD), and
female sexual arousal disorder (FSAD). Hypoactive sexual desire
disorder includes a disorder in which sexual fantasies and desire
for sexual activity are persistently or recurrently diminished or
absent, causing marked distress or interpersonal difficulties.
Sexual anhedonia includes decreased or absent pleasure in sexual
activity. Sexual arousal disorder can be caused by reduced
estrogen, illness, or treatment with diuretics, antihistamines,
antidepressants, or antihypertensive agents. The woman can
experience mild, moderate, or severe FSD.
[0014] In one embodiment, FSD, FSAD, FOD and FHSDD are as defined
in the Diagnostic and Statistical Manual of Mental Disorders (DSM),
4th edition, the contents of which definitions are incorporated
herein by reference. In another embodiment, the disorder is female
sexual interest/arousal disorder (FSIAD), which encompasses FSAD
and FHSDD. FOD and FSIAD are defined in the Diagnostic and
Statistical Manual of Mental Disorders (DSM), 5th edition, the
contents of which definitions are hereby incorporated herein by
reference. The diagnostic criteria for FSIAD include a lack of, or
significantly reduced, sexual interest/arousal, as manifested by at
least three of the following: (1) absent/reduced interest in sexual
activity; (2) absent/reduced sexual/erotic thoughts or fantasies;
(3) no/reduced initiation of sexual activity, and typically
unreceptive to a partner's attempts to initiate; (4) absent/reduced
sexual excitement/pleasure during sexual activity in almost all or
all sexual encounters; (5) absent/reduced sexual interest/arousal
in response to any internal or external sexual/erotic cues; and (6)
absent/reduced genital or nongenital sensations during sexual
activity in almost all or all sexual encounters. In FSIAD, these
symptoms have persisted for a minimum duration of approximately six
months and cause the subject significant distress. The diagnostic
criteria for FOD are as follows:
[0015] A. Presence of either of the following symptoms and
experienced on almost all or all (approximately 75%-100%) occasions
of sexual activity (in identified situational contexts or, if
generalized, in all contexts): (1). Marked delay in, marked
infrequency of, or absence of orgasm. (2). Markedly reduced
intensity of orgasmic sensations.
[0016] B. The symptoms in Criterion A have persisted for a minimum
duration of approximately 6 months.
[0017] C. The symptoms in Criterion A cause clinically significant
distress in the individual.
[0018] D. The sexual dysfunction is not better explained by a
nonsexual mental disorder or as a consequence of severe
relationship distress (e.g., partner violence) or other significant
stressors and is not attributable to the effects of a
substance/medication or another medical condition.
[0019] The diagnosis of FOD also asks the clinician to specify
whether (1) Lifelong: The disturbance has been present since the
individual became sexually active or (2) Acquired: The disturbance
began after a period of relatively normal sexual function. Also,
the clinician is to specify whether (1) Generalized: Not limited to
certain types of stimulation, situations, or partners or (2)
Situational: Only occurs with certain types of stimulation,
situations, or partners. The clinician is to specify if the subject
never experienced an orgasm under any situation. The clinician is
also to specify the current severity: (1) Mild: Evidence of mild
distress over the symptoms in Criterion A, (2) Moderate: Evidence
of moderate distress over the symptoms in Criterion A, (3) Severe:
Evidence of severe or extreme distress over the symptoms in
Criterion A. As reported in the Diagnostic and Statistical Manual
of Mental Disorders (DSM), 5th edition, page 431, selective
serotonin reuptake inhibitors (SSRIs) are known to delay or inhibit
orgasm in women.
[0020] According to certain of the methods disclosed herein, to
treat female sexual dysfunction disorder(s) or to enhance female
sexual satisfaction, a topical composition of an active agent is
applied to the woman's nipple-areola complex. In one aspect of the
invention there is a method of treating FSD, preferably FSIAD,
FSAD, FSOD, or FHSDD, comprising administering to a subject in need
of such treatment an effective amount of an active agent as defined
herein topically to the nipple-areola complex. As used herein,
applying a composition to a nipple-areola complex includes applying
to the nipple, the areola, or both the nipple and the areola, and
to all or a portion of the nipple, the areola, or both the nipple
and the areola. For example, the composition may be applied to the
areola area only, the base of the nipple only, to half the areola
only or applied to more than half of the areola and not the nipple.
In one embodiment, the composition is applied to only one of a
subject's nipple-areola complexes. The term "nipple-areola complex"
or "NAC" includes both the nipple and areola. The nipple-areola
complex varies in dimension among individuals. The female
nipple-areola complex is located at the prominence of the breast
mound. See Anongporn Nimboriboonporn, "Nipple-areola complex
reconstruction," Gland Surgery 2014; 3(1), pp. 35-42. The nipple
itself may project as much as greater than or equal to 1 cm, with a
diameter of approximately 4-7 mm. The areola consists of pigmented
skin surrounding the nipple proper and is on average approximately
4.2-4.5 cm in diameter. The smooth muscle morphology in the
nipple-areola complex is described, for example, in M. Tezer, et
al., "Smooth muscle morphology in the nipple-areola complex," J.
Morphol. Sci., 2011, vol. 28, no. 3, p. 171-175.
[0021] In other embodiments, the invention is directed to methods
of increasing female sexual satisfaction, causing erection of
nipples, increasing nipple sensitivity, increasing duration of
orgasm, reducing time to orgasm, increasing intensity of orgasm
and/or increasing oxytocin release related to sexual activity by
administering an active agent according to the present disclosure
topically to the nipple areola complex of a female subject. In one
particular embodiment, the invention is directed to methods of
treating neuropathy, and particularly neuropathy at the nipple
areola complex or just at the nipple. In other embodiments, the
invention is directed to methods of increasing female sexual
self-esteem and/or increasing a female subject's self-perception of
femininity by administering an active agent according to the
present disclosure topically to the nipple areola complex of a
female subject. In another embodiment, the invention is directed to
methods of increasing female self-esteem by administering an active
agent according to the present disclosure topically to the nipple
areola complex of a female subject.
[0022] Enhancement of female sexual satisfaction, female sexual
self-esteem, female self-esteem, and female self-perception of
femininity can be measured by patient questionnaires to determine
if the subject's quality of life, particularly in sexual matters,
is enhanced by the present therapeutic methods. Enhancement can
also be determined by a change from baseline in the number of
satisfying sexual events (SSE), a change from baseline in the level
of sexual interest or desire, a change from baseline in the level
of sexual arousal, or a change from baseline in the level of
distress from sexual activities. Baseline may be defined as a
four-week no-treatment phase or a four-week placebo run-in phase.
Changes from baseline typically refer to the treatment responses
obtained during the last four weeks of a double-blinded treatment
period relative to baseline. The time period used for assessing
baseline (e.g., four weeks) should be the same as the time period
used for assessing treatment responses (e.g., four weeks at the end
of the treatment period). Enhancement of self-esteem or female
sexual self-esteem may be measured by any one of the questionnaires
and scales available in the art such as, without limitation, those
disclosed in Heatherton, T. F. & Polivy, J. (1991) "Development
and validation of a scale for measuring state self-esteem," J.
Personality and Social Psychology, 60, 895-910; Rosenberg's
Self-Esteem Scale found on Oct. 30, 2016 at
http://www.wwnorton.com/college/psych/psychsci/media/rosenberg.htm;
and Rosenberg self-esteem scale published in Rosenberg, M. "Society
and the adolescent self-image," Princeton University Press,
Princeton, N.J. (1965). In one embodiment, the questionnaire is
completed by the female subject at a time prior to application of
the active agent and prior to one or more episodes of sexual
intimacy, and then the questionnaire is completed again by the same
subject after the application of the active agent and the
occurrence of one or more episodes of sexual intimacy.
[0023] In one embodiment, the women subjects to be treated by the
methods described herein have reduced sensitivity of the
nipple-areola complex. Sensitivity may be considered as reduced
relative to (1) sensitivity measured in a control group, such as a
control group of women of comparable age, sexual activity, and
health, particularly breast health or nerve health, to those
undergoing the treatment or (2) sensitivity as measured before an
event, such as before an operation, injury, or other biological
change to a breast or a nipple-areola complex. Any of the known
techniques for measuring breast sensitivity may be used to
determine if the subject presents with reduced sensitivity. For
example, studies have measured the sensitivity of the nipple-areola
complex to pressure before and after mammoplasty with a
superomedial pedicle. See, e.g., Ferreira, M C et al., "Sensibility
of the breast after reduction mammoplasty," Ann Plast Surg 2003; 51
(1):1-5. A quantitative analysis of post-operative changes in
breast sensitivity and female sexual function was reported in
Garcia, E S et al., "Sensitivity of the nipple-areola complex and
sexual function following reduction mammoplasty," Aesthetic Surgery
Journal 35(7) (2015) NP193-NP202. In Garcia et al., skin
sensitivity tests were performed in a quiet environment and the
nipple-areola complex was tested for four sensory modalities: light
touch, temperature (hot and cold), vibration, and pressure. Id. at
NP194. Sensitivity was measured using Semmes-Weinstein filaments
(SORRI, BAURU, SP, Brazil, INPI.7.102.105), corresponding to
threshold/potential skin pressure values of 0.05, 0.2, 2, 4, 10,
and 300 grams (Garcia, at FIG. 2). The monofilament was used to
exert pressure until it bent, and the pressure was maintained for 5
seconds. The perceived pressure value was recorded. Pressure
response of less than 9 g/mm.sup.2 was considered sensitive, and
greater than 9 g/mm.sup.2 was considered to show reduced
sensitivity.
[0024] In one embodiment, the invention is directed to methods for
the manufacture of compositions, particularly pharmaceutical
compositions, for the treatment or reduction of any of the
disorders or conditions recited herein comprising mixing the active
agent with a pharmaceutically acceptable excipient, such as water,
mineral oil, or a surfactant.
[0025] In one embodiment, the method comprises (1) applying an
active agent selected from the group consisting of alpha-1
adrenergic receptor agonists (e.g., without limitation,
synephrine), muscarinic acetylcholine receptor agonists (e.g.,
without limitation, non-specific or specific agonists of (a)
muscarinic acetylcholine receptor M.sub.3 and/or of (b) muscarinic
acetylcholine receptor M.sub.2), nicotinic acetylcholine receptor
agonists, the acetylcholine receptor agonist neuropeptide-Y, and
cholinesterase inhibitors on a test site on the skin of a person;
wherein the test site is not in the nipple areola complex; and (2)
30 to 60 minutes after applying, observing whether the person's
skin shows goosebumps or pilioerection at the site; wherein if
pilioerection or goosebumps are observed, then diagnosing the
person as likely to be a successful candidate for use of the
alpha-1 adrenergic receptor agonist, muscarinic acetylcholine
receptor agonist, nicotinic acetylcholine receptor agonist,
neuropeptide-Y, or cholinesterase inhibitor for any of the many
methods of treatment or prevention described herein. This method
may be combined with any of the other methods of treatment or
prevention described herein to provide an initial diagnosis of
those people most likely to benefit from the treatment and
enhancement methods described. In such combination methods, the
treatment steps only proceed if the person's skin shows goosebumps
or pilioerection at the test site. The step of application to a
site on the skin may be, in one embodiment, applying a bandage or
patch coated with the active agent selected from the group
consisting of alpha-1 adrenergic receptor agonists, muscarinic
acetylcholine receptor agonists, nicotinic acetylcholine receptor
agonists, acetylcholine receptor agonist that is neuropeptide-Y,
and cholinesterase inhibitors to the person's arm or thigh. In
other embodiments of any composition or method involving an alpha-1
adrenergic receptor agonist, the agonist is synephrine or
phenylephrine.
[0026] The subjects to be treated with the present invention
include humans, and in certain embodiments are pre-, per- and
post-menopausal women or men. In one embodiment, the woman is
concomitantly on hormone replacement therapy. In another embodiment
she is not on concomitant hormone replacement therapy. The methods
disclosed may be useful for women who have diminished or absent
breast sensation, such as women having low nipple sensitivity, or
having reduced sensitivity at the nipple-areola complex. Low
sensitivity is a sensitivity below the average, such as below one
standard deviation, obtained from a representative sample of
subjects, for example by measuring nipple sensitivity in a healthy
population of women using the monofilament test described herein. A
sensitivity value may be obtained by measuring sensitivity on
several locations on the nipple areola complex and averaging them.
In one embodiment, the women being treated have low nipple
sensitivity after breast surgery, which as used herein includes
breast implants.
[0027] In one preferred embodiment, the subjects to be treated are
women who have experienced breast surgery, particularly women who
after breast surgery experience reduced or absent nipple
sensitivity. The breast surgery may be of any type, such as without
limitation mastectomy, nipple sparing mastectomy, skin-sparing
mastectomy, prophylactic mastectomy, breast reconstruction, breast
augmentation, and lumpectomy. For women who have experienced breast
surgery, successful therapy in the present methods can be
determined by measuring increased sensitivity in the NAC, such as
by quantitative measurement using the monofilament test disclosed
above in Garcia et al., or the test in the examples herein, or by
patient reports of increased quality of life, such as by increased
sexual satisfaction as shown using one or more of the measurements
or patient reports discussed herein. In another embodiment, the
disclosed methods may be used in women with high breast or
nipple-areola sensitivity, such as to enhance sexual satisfaction.
In one further embodiment, the subjects to be treated are women
with neuropathy, in particular women with neuropathy at the nipple
areola complex.
[0028] In another embodiment, the subjects to be treated is a
mammal, such as non-human primates (particularly higher primates),
sheep, dog, rodent (e.g. mouse or rat), guinea pig, goat, pig, cat,
rabbits, cow, and panda. Treatment in non-human mammals may be
desirable to accelerate conception during mating. Treatment may
also be desirable to induce labor in a mammal, including a
human.
[0029] In one embodiment, the subject to be treated is a human or
animal concomitantly taking one or more SSRI or antidepressants,
such as antidepressants used in the treatment of major depressive
disorder and anxiety disorders. SSRIs may cause a variety of sexual
dysfunction, such as anorgasmia, erectile dysfunction, diminished
libido, genital numbness, and sexual anhedonia (pleasureless
orgasm). To minimize or reduce these side effects, one of the
active agents of the present disclosure according to any of the
methods of administration disclosed herein may also be administered
to the subject concomitantly with the SSRI therapy. By
"concomitantly" is meant herein to be administered in the same day,
week or month, not necessarily at the same time of day, however.
SSRIs include the following: citalopram, fluvoxamine, escitalopram,
paroxetine, sertraline, fluoxetine, and dapoxetine. The
compositions and methods of the present disclosure may also be used
with a subject who concomitantly is taking tricyclic
antidepressants or serotonin-noradrenaline reuptake inhibitors
(SNRIs). Examples of SNRIs include the following: venlafaxine;
desvenlafaxine, duloxetine, milnacipran, levomilnacipran, and
sibutramine.
[0030] The active agents described herein may be applied once every
one, two, three, four, six, eight, ten or twelve hours, or once
daily, twice daily, or once every other day. The frequency of
administration may be determined by one skilled in the art using
pharmacokinetic data available or generated using standard
procedures. Routine pharmacological testing may be performed to
determine if dosages of more than once or twice daily are advisable
and if so the amount of each dosage, in view of the potential for a
rebound effect. It should be noted that increased sexual arousal
can be delayed with respect to nipple erection after the
application of the composition described herein. For example,
increased sexual arousal can occur about 10-45 minutes after nipple
erection or increased nipple sensitivity. The formulations of
active agent described herein may be applied as needed. In one
embodiment, the formulation is applied prior to a sexual activity,
such as about 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, or 6.0
hours prior to sexual activity, or between 0.25-1.0, 0.5-1.0,
0.5-1.5, 1.0-2.0, or 1.0-4.0 hours prior to sexual activity.
Examples of sexual activities include, but are not limited to,
foreplay, sexual intercourse, and masturbation. In case of
sensitivity of the nipple-areola complex to the formulation, it may
be advisable that following use the next administration occur after
48-72 hours has passed. In another embodiment, the active agent
first exerts its effect within about ten minutes of application to
the nipple-areola complex. In further embodiments, the active agent
first exerts its effects between five and thirty minutes after
application. In one embodiment, the active agent exerts an effect
on the nipple-areola complex for a time period of about one-two
hours after application, or from about ten minutes to about one
hour, or from about ten minutes to about two hours, or from about
ten minutes to about three hours after application.
[0031] As used herein, the terms "treat," "treatment," or
"treating" refer to therapeutic treatments, wherein the object is
to reverse, alleviate, ameliorate, inhibit, slow down or stop the
progression or severity of a disease or condition, e.g., FSD. The
term "treating" includes reducing or alleviating at least one
adverse effect or symptom of a disease or condition, e.g., FSD.
Treatment is generally "effective" if one or more symptoms are
reduced. That is, "treatment" includes the improvement of symptoms.
Beneficial or desired clinical results include, but are not limited
to, alleviation of one or more symptom(s) and diminishment of
extent of disease. For example, treatment of FSD is considered
effective if the number of satisfying sexual events (SSE) is
increased from baseline in a sampled time (e.g. 4 weeks), in a
significant manner. Other established metrics to determine
treatment efficacy for FSD include, for example, FSFI (female
sexual function index), SAL (Sexual Activity Log), SAR (Sexual
Activity Record), FSDS (Female Sexual Distress Scale), and the
FSDS-R (Female Sexual Distress Scale Revised). Treatment may occur
even if nipple erection is not obtained. Setting the smooth muscle
underlying the nipple-areola complex without nipple erection is
believed sufficient to elicit the desirable biological response in
a subject, such as a female subject, and therefore to "treat" or
"enhance" according to the methods disclosed herein.
[0032] In one embodiment, a therapeutic effect is seen when the
difference from baseline is a "minimally important difference" or
"MIN" defined in: DeRogatis, L. R., Graziottin, A., Bitzer, J.,
Schmitt, S., Koochaki, P. E., Rodenberg, C. (2009), "Clinically
relevant changes in sexual desire, satisfying sexual activity and
personal distress as measured by the profile of female sexual
function, sexual activity log, and personal distress scale in
postmenopausal women with hypoactive sexual desire disorder,"
Journal of Sexual Medicine, 6, 175-183, the contents of which are
incorporated herein by reference. Such a change may be small but
meaningful to subjects.
Active Agents
[0033] Useful active agents for the methods of use disclosed herein
include agonists of muscarinic acetylcholine receptors (mAChRs),
agonists of nicotinic acetylcholine receptor (also referred to
herein as nicotinic receptors or nAChRs), acetylcholine receptor
agonists such as neuropeptide-Y, and cholinesterase inhibitors. The
agonists may be selective or nonselective agonists of mAChRs or
nAChRs. In other embodiments, a prodrug that is activated to become
a mAChR or nAChR agonist or a cholinesterase inhibitor can be
utilized. Any of the active agents disclosed herein may be used in
combination with another active agent disclosed herein, including
in combination with another active agent of the same type (such as
without limitation one muscarinic acetylcholine receptor agonist in
combination with a second muscarinic acetylcholine receptor
agonist) or in combination with a different type of active agent
(such as without limitation a muscarinic acetylcholine receptor
agonist with a nicotinic acetylcholine receptor agonist). By
"combination" is meant that the active agents are applied within
about one hour of each other to the skin, or at substantially the
same time to the skin, or otherwise such that the combined active
agents are expected to show effect on the NAC at the same time.
[0034] Muscarinic acetylcholine receptors (mAChRs) and nicotinic
acetylcholine receptors (nAChRs) are acetylcholine receptors of an
autonomic nervous system that can be manipulated by agonists.
[0035] mAChRs are found in tissues innervated by postganglionic
parasympathetic neurons, in presynaptic noradrenergic and
cholinergic nerve terminals, in non-innervated sites in vascular
endothelium, and in the central nervous system. There are subtypes
of muscarinic receptors, which are typically referred to as M.sub.1
(e.g., M.sub.1, M.sub.2, M.sub.3, M.sub.4, and M.sub.5). Muscarinic
receptor agonists that may be used to treat sexual dysfunction and
increase sexual satisfaction according to the present compositions
and methods include without limitation NNC 11-1585, NNC 11-1607,
pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline, arecaidine
propargyl ester, acetylcholine, arecoline, oxotremorine, McN-A-343,
milameline, oxotremorine-M, methylfurmethide, bethanechol,
carbachol, furtrethonium, methacholine, aceclidine, pilocarpine,
and muscarine. It has been discovered that at least M.sub.2-type
agonists and M.sub.3-type agonists can be used to induce direct
smooth muscle contraction.
[0036] Suitable M.sub.2 agonists for the compositions and methods
of the present disclosure include, but are not limited to,
methacholine,
(2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine
3-sulfoxide methyl iodide, [.sup.3H]oxotremorine-M, NNC 11-1585,
NNC 11-1607, pentylthio-TZTP, methacholine, NNC 11-1314,
xanomeline, oxotremorine, acetylcholine, arecaidine propargyl
ester, carbachol, McN-A-343, arecoline, methylfurmethide,
pilocarpine, furtrethonium, bethanechol, iperoxo, aceclidine,
[18F]FP-TZTP, and berberine. Suitable M.sub.3 agonists for the
compositions and methods of the present disclosure include, but are
not limited to, NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC
11-1314, xanomeline, sabcomeline, arecaidine propargyl ester,
acetylcholine, arecoline, oxotremorine, McN-A-343, milameline,
oxotremorine-M, methylfurmethide, bethanechol, carbachol,
furtrethonium, methacholine, aceclidine, L-689,660 (mixed
M.sub.1/M.sub.3 agonist), and pilocarpine.
[0037] Nicotinic acetylcholine receptors are located in sympathetic
and parasympathetic ganglia, in the adrenal medulla, in the
neuromuscular junction of the skeletal muscle, and in the central
nervous system. Nicotinic acetylcholine receptors are ligand-gated
ion channels whose activation results in a rapid increase in
cellular permeability to sodium and calcium. They are pentameric
arrays of one to four distinct but homologous subunits, surrounding
an internal channel. The a subunit, which has binding sites for
ACh, is present in at least two copies. Agonist molecules induce a
conformational change that opens the channel. Antagonist molecules
may bind to these sites, but do not elicit the conformational
change.
[0038] There are at least two subtypes of nicotinic receptors,
generally referred to as N.sub.M and N.sub.N. The N.sub.M nicotinic
receptor mediates skeletal muscle stimulation, while the N.sub.N
nicotinic receptor mediates stimulation of the ganglia of the
autonomic nervous system. Useful nicotinic receptor agonists to
treat sexual dysfunction and the other conditions and disorders
disclosed herein include without limitation: varenicline tartrate,
galantamine hydrobromide, nicotine, carbachol, suxamethonium
chloride (succinylcholine chloride), and epibatidine.
[0039] In another embodiment, the active agent useful for treatment
of the disorders and diseases described herein is neuropeptide-Y,
which is an acetylcholine receptor agonist. In one embodiment, the
present disclosure concerns one of the methods disclosed herein,
such as a method for treating sexual dysfunction, particularly
female sexual dysfunction, comprising applying a therapeutically
effective amount of an active agent selected from the group
consisting of neuropeptide-Y, muscarinic acetylcholine receptor
agonists, nicotinic acetylcholine receptor agonists, and
cholinesterase inhibitors topically to a nipple-areola complex of a
female subject in need of such treatment.
[0040] In another embodiment, the active agent used in the
inventive methods herein is an A1AR agonist. "Alpha-1 adrenergic
receptor agonist" or "A1AR agonist" refers to a ligand that binds
the alpha-1adrenergic receptor on smooth muscle cells and activates
smooth muscle contraction. In some embodiments, the AIAR agonist is
selective for the alpha-1adrenergic receptor. Additionally, the
term "alpha-1 adrenergic receptor agonist" can include agents that
when applied will induce the release of endogenous alpha-1
adrenergic receptor agonists (e.g. epinephrine) that activates
smooth muscle contraction or agents that when applied inhibit the
"re-uptake" or degradation of endogenous alpha-1adrenergic receptor
agonists (e.g. epinephrine) that activates smooth muscle
contraction. In another embodiment, the active agent used is a
"smooth muscle agonist," which is an agent that promotes or results
in contraction of the smooth muscle including smooth muscle of the
nipple-areola complex. Thus, an alpha-1adrenergic receptor agonist
that promotes or results in smooth muscle contraction is a smooth
muscle agonist, but so also are, e.g., an alpha 2 adrenergic
receptor agonist that promotes smooth muscle contraction, agents
that that induce the release of endogenous alpha 2 adrenergic
receptor agonist that results in smooth muscle contraction, and
agents that inhibit the re-uptake or degradation of endogenous
alpha 2 adrenergic receptor agonists that activate smooth muscle
contraction. Suitable A1AR agonists for use in the present
description include without limitation phenylephrine, phenylephrine
pivalate, amediphrine, synephrine, cirazoline, desvenlafaxine,
etilfrine, metaraminol, methoxamine, naphazoline, oxymetazoline,
pseudoephrine, m-synephrine, p-synephrine, octopamine, hordenine,
tetrahydrozoline, isometheptene, metaraminol, nicergoline,
ergonovine, levonordefrin, phendimetrazine, methoxamine, midodrine,
clonidine, pergolide, xylometazoline, droxidopa, epinephrine,
mephentermine, 4-methoxyamphetamine, benzphetamine, naphazoline,
apraclondine, bromocriptine, oxymetazoline, phenylpropanolamine,
pseudoephedrine, dipivefrin, noradrenaline, chloroethylclonidine,
norepinephrine, A61603, NS-49, [.sup.125I]HEAT, noradrenaline,
adrenaline, clonidine, St 587, SKF 89748, 6-fluoro-noradrenaline,
methylnoradrenaline, inanidine, NS-49, amidephrine, and dabuzalgron
and dopamine. In certain embodiments, the A1AR agonist is
synephrine, or is selected from phenylephrine, synephrine,
oxymetazoline, and methoxamine. In one embodiment, the therapeutic
agent is norepinephrine. Another suitable therapeutic agent for use
in the inventive methods herein is extract of Bitter orange (Citrus
aurantium), which contains synephrine alkaloids and
para-octopamine. See Satoh, Y., Tashiro, S., Satoh, M., Fujimoto,
Y., Xu, J. Y., and Ikekawa, T. [Studies on the bioactive
constituents of Aurantii Fructus Immaturus]. Yakugaku Zasshi 1996;
116(3):244-250. In one embodiment, the method is for treating
neuropathy in a female subject comprising administering a
therapeutically effective amount of an A1AR agonist, such as
without limitation phenylephrine, to the female subject.
[0041] Additionally, derivatives of alpha-1adrenergic receptor
agonists, muscarinic acetylcholine receptor agonists, nicotinic
acetylcholine receptor agonists, or cholinesterase inhibitors can
be utilized including derivatives of the compounds mentioned above.
In other embodiments, a prodrug that is activated to become an A1AR
agonist, muscarinic acetylcholine receptor agonist, nicotinic
acetylcholine receptor agonist, or cholinesterase inhibitor can be
utilized. Midodrine, phenylephrine oxazolidine, and phenylephrine
pivalate are examples of three such prodrugs. Phenylephrine
pivalate is an A1AR agonist in addition to being a prodrug of
phenylephrine. A particular prodrug can be activated by endogenous
enzymes in the skin such as Caspase-1. Another embodiment is a
method for reducing or ceasing erection of the nipple following
administration of alpha-1 adrenergic receptor agonist(s) comprising
applying a therapeutically effective amount of an alpha-1adrenergic
receptor antagonist or a beta adrenergic receptor agonist to the
nipple areola complex. Such a method may be useful, for example, in
the event of an overdose of alpha-1adrenergic receptor agonist.
[0042] As used herein, a "prodrug" refers to compounds that can be
converted via some chemical or physiological process (e.g.,
enzymatic processes and metabolic hydrolysis) to an active agent.
Thus, the term "prodrug" also refers to a precursor of a
biologically active compound that is pharmaceutically acceptable. A
prodrug may be inactive when administered to a subject, i.e. an
ester, but is converted in vivo to an active compound, for example,
by hydrolysis to the free carboxylic acid or free hydroxyl. The
prodrug compound often offers advantages of solubility, tissue
compatibility or delayed release in an organism. The term "prodrug"
is also meant to include any covalently bonded carriers, which
release the active compound in vivo when such prodrug is
administered to a subject. Prodrugs of an active compound may be
prepared by modifying functional groups present in the active
compound in such a way that the modifications are cleaved, either
in routine manipulation or in vivo, to the parent active compound.
Prodrugs include compounds wherein a hydroxy, amino or mercapto
group is bonded to any group that, when the prodrug of the active
compound is administered to a subject, cleaves to form a free
hydroxy, free amino or free mercapto group, respectively. Examples
of prodrugs include, but are not limited to, acetate, formate and
benzoate derivatives of an alcohol or acetamide, formamide and
benzamide derivatives of an amine functional group in the active
compound and the like. See Harper, "Drug Latentiation" in Jucker,
ed. Progress in Drug Research 4:221-294 (1962); Morozowich et al,
"Application of Physical Organic Principles to Prodrug Design" in
E. B. Roche ed. Design of Biopharmaceutical Properties through
Prodrugs and Analogs, APHA Acad. Pharm. Sci. 40 (1977);
Bioreversible Carriers in Drug in Drug Design, Theory and
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Gangwar et al., "Pro-drug, molecular structure and percutaneous
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anticancer agents," Adv. Drug Delivery Rev. 19(2): 241-273 (1996);
Stella et al., "Prodrugs. Do they have advantages in clinical
practice?" Drugs 29(5): 455-73 (1985); Tan et al. "Development and
optimization of anti-HIV nucleoside analogs and prodrugs: A review
of their cellular pharmacology, structure-activity relationships
and pharmacokinetics," Adv. Drug Delivery Rev. 39(1-3): 117-151
(1999); Taylor, "Improved passive oral drug delivery via prodrugs,"
Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino and
Borchardt, "Prodrug strategies to enhance the intestinal absorption
of peptides," Drug Discovery Today 2(4): 148-155 (1997); Wiebe and
Knaus, "Concepts for the design of anti-HIV nucleoside prodrugs for
treating cephalic HIV infection," Adv. Drug Delivery Rev.:
39(I-3):63-80 (1999); Waller et al., "Prodrugs," Br. J. Clin.
Pharmac. 28: 497-507 (1989), which are incorporated by reference
herein in their entireties.
[0043] Other agents or approaches can be used to contract the
smooth muscle to erect nipples for the treatment of FSD or the
enhancement of sexual satisfaction. As noted above, any agent or
treatment that stimulates smooth muscle contraction is of potential
use in methods of treating FSD or enhancing sexual satisfaction as
described herein.
[0044] In another embodiment, the smooth muscle of the
nipple-areola complex can be contracted by stimulating or
activating a cold receptor. This is believed to stimulate the
pilomotor reflex to result in contraction of the smooth muscle and
erection of the nipple. A cold receptor can be stimulated, for
example, by activating the TRPM8 channel. Exemplary agents that can
stimulate a cold receptor include, but are not limited to, menthol
and icilin. Compositions and methods for stimulating a cold
receptor are disclosed, for example, in U.S. Pat. No. 4,034,109
(Rowsell et al.).
[0045] Without limiting the invention in any way, it is believed
that the smooth muscle in and surrounding the nipple areola complex
is served by or associated with both noradrenergic fibers and a
cholinergic system, and therefore agents that stimulate release of
transmitters from these systems or that activate the axon reflex
can be used to stimulate smooth muscle contraction and thereby
increase sensitivity in the nipple areola complex. Thus,
alpha-1adrenergic agonists and cholinergic receptor agonists,
including, but not limited to acetylcholine and other
neurotransmitters that stimulate smooth muscle contraction are
contemplated for use in the methods and compositions described
herein. The alpha-1adrenergic receptor is a postsynaptic G
protein-coupled receptor on the surface of smooth muscle cells.
Agonists of other G protein-coupled receptors involved in smooth
muscle contraction (e.g., post-synaptic alpha 2 adrenergic
receptors) can also be used to stimulate contraction of the smooth
muscles and thus erection of the nipple when applied to the
nipple-areola complex. Examples of agonists of the postsynaptic
alpha 2 adrenergic receptor include but are not limited to, 4-NEMD,
7-Me-marsanidine, agmatine, apraclonidine, brimonidine, clonidine,
detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine,
lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol,
rilmenidine, romifidine, talipexole, tizanidine, tolonidine,
xylazine, brimonidine, amitraz, chloroethylclonidine and
xylometazoline. In some embodiments, an antagonist of the
presynaptic alpha 2 adrenergic receptor that inhibits negative
feedback of noradrenaline release from the presynaptic neuron can
also be used to stimulate smooth muscle cell contraction. Such
antagonists include aripiprazole, asenapine, atipamezole,
cirazoline, clozapine, efaroxan, idazoxan, lurasidone, melperone,
minserin, mirtazapine, napitane, olanzapine, paliperidone,
phenyoxybenzamine, phentolamine, piribedil, rauwolscine,
risperidone, rotigotine, quetiapine, norquetiapine, setipiline,
tolazoline, yohimbine, ziprasidone, and zotepine. In some
embodiments, an alpha-1agonist/alpha 2 partial agonist, such as
oxymetazoline, is contemplated for use with the methods described
herein. To the extent that it would be disadvantageous to
administer these or other agents systemically, they can be
administered in a formulation that permits uptake by the smooth
muscle of at least a portion of the nipple-areola complex in the
dermis but limits systemic uptake.
[0046] The muscarinic and nicotinic receptor agonists mimic
acetylcholine effect by stimulating the relevant receptors
themselves or by acting through the axon reflex. Another way of
accomplishing the same thing is to reduce the destruction of
acetylcholine (Ach) following its release. This can be achieved by
cholinesterase inhibitors, which are also called the
anticholinesterases. They mimic the effect of combined muscarinic
and nicotinic agonists. By inhibiting acetylcholinesterase and
pseudocholinesterase, these drugs allow ACh to build up at its
receptors. Thus, they result in enhancement of both muscarinic and
nicotinic agonist effect. Suitable cholinesterase inhibitors for
the present methods and compositions include without limitation
physostigmine, neostigmine, edrophonium, pyridostigmine,
echotihiophate, ambenonium, demecarium, tacrine, donepezil,
rivastigmine, galantamine, and pralidoxime.
[0047] The glands in the NAC respond to Ach. Without intending to
be limited, it is believed the present inventive methods and
compositions work by the mechanism that agonists of the muscarinic
receptors, particularly agonists of the muscarinic receptor types
M.sub.2 and M.sub.3, and cholinesterase inhibitors induce response
in the NAC through the activity of the cholinergic pathway on the
mammary glands and ducts of the nipple and therefore induce the
desired sexual response.
[0048] It should be noted that the agonists and inhibitors
described herein also encompass their pharmaceutically acceptable
inorganic or organic salts. Representative salts include the
hydrobromide, hydrochloride, sulfate, bisulfate, phosphate,
nitrate, acetate, succinate, valerate, oleate, palm itate,
stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,
maleate, fumarate, succinate, tartrate, napthylate, mesylate,
glucoheptonate, lactobionate, and laurylsulphonate salts and the
like. For example, phenylephrine may be administered in its
hydrochloride salt form.
Formulations and Dosages
[0049] The present disclosure also pertains to pharmaceutical
compositions of the active agents discussed herein. The
formulations or compositions of the present disclosure include a
therapeutically effective amount of one or more active agents and a
pharmaceutically acceptable excipient. Formulation guidance may be
found in Remington: The Science and Practice of Pharmacy,
Pharmaceutical Press (2012), Allen (ed.). The compositions may be
of any sort useful for topical delivery to the nipple-areola
complex, such as, without limitation, a gel, cream, emulsion,
transdermal patch, spray, foam, ointment, or aerosol. In one
preferred formulation, the composition is a gel. In some
embodiments, the active agent is present in a transdermal patch
that is sized and designed to fit smoothly around the nipple. The
transdermal patch may provide immediate release or sustained
release of the active agent. In another embodiment, the active
agent is applied to a substrate such as a bandage having an
exterior and an interior surface, where the interior surface is
coated with the active agent and a surrounding adhesive section.
The adhesive section preferably is adjacent to, but not comingled
with, the coating of active agent. The substrate is then applied to
the nipple areola complex such that the interior surface of the
substrate is placed on the skin and active agent is in contact with
the nipple areola complex. In one embodiment, this substrate is
shaped like a donut with a circular shape having a central circle
cut-out. The coated substrate is applied to the nipple-areola
complex such that much of the nipple (at least 50%) is not in
contact with the therapeutic agent because the nipple extends
through the hole in the bandage. This embodiment is particularly
desirable for patients for whom the nipple is particularly
sensitive. In this embodiment, the substrate is ring shaped and
comprises two surfaces, an exterior and an interior surface, the
exterior surface preferably comprising a water-resistant plastic
coating and the interior surface coated with the active agent along
a central portion closest to the center of the ring and a
circumferential surface extending along the broadest circumference
of the substrate that contains an adhesive that provides adhesion,
removably, to human skin surface. The active agent present on the
substrate may be in a formulation that is a gel, solution, cream,
etc. In one of these embodiments, the substrate coated with active
agent is applied to the areola for 10, 15, 20, 25, 30, 40, or 45
minutes and then removed, or for less than 10, less than 15, less
than 20, less than 25, less than 30, or less than 45 minutes and
then removed. The substrate may be disposed after application. In
other embodiments, the active agent can be included in ointments or
other topical creams that could be applied to at least a portion of
the nipple-areola complex so that it can be absorbed into the skin
and stimulate the smooth muscle. In other embodiments, the active
agent can be in a liquid spray or aerosol medium, such as a metered
spray, such as is found for example in Evamist.RTM. estradiol
transdermal spray. The spray may contain an alcohol, water, or a
water/alcohol mixture as a vehicle for the active agent.
[0050] In some embodiments, the composition is provided in a
delivery device that has a roller ball connected to a container
holding the composition such that the composition may be applied to
the nipple-areola complex by rolling the ball directly on the
complex. For example, the roller ball device may have a generally
cylindrical container that holds a liquid formulation of one or
more active agents therein and has an open upper end and a lower
end. A roller ball is rotatably disposed in the container and
protrudes from the upper end of the container. A cap portion has a
closed upper end and an open lower end. The lower end of the cap
portion is removably coupled to the upper end of the container.
Devices such as these are well known in the art. See, e.g., U.S.
Pat. No. 6,095,708 (Butaud); U.S. Pat. No. 5,007,775 (Thompson);
U.S. Pat. No. 4,664,547 (Rosenwinkel); U.S. Design Pat. No. 333,977
(Gatrost); and U.S. Design Pat. No. 292,069 (Keeler).
[0051] In one embodiment, the compositions are formulated for quick
delivery through the dermis to the smooth muscles, such as for
delivery of 60%, 70%, 75%, 80%, 85% or more of the active agent
through the dermis within 5, 4, 3, 2 or 1 hour of application to
the nipple-areola complex. In another embodiment, at least 80% of
the active agent is delivered through the dermis on average after
three hours as measured with an in vitro release test using a Franz
cell such as discussed in the examples herein.
[0052] Formulations may be prepared according to the knowledge and
skill of those in the art. In some embodiments, the compositions
can further comprise a flavoring agent. One example of the
flavoring agent is a sweetening agent, such as monoammonium
glycyrrhizinate. In liquid and gel formulations, the bulk excipient
that serves as a medium for conveying the active ingredient is the
vehicle. Suitable vehicles for topical gels and creams include
petrolatum and mineral oil.
[0053] Penetration enhancers may be used in the present
compositions to increase the permeability of the dermal surface to
a active agent, and are often proton accepting solvents such as
dimethyl sulfoxide (DMSO) and dimethylacetamide. Chemical
permeation enhancers facilitate drug permeation across the skin by
increasing drug partitioning into the barrier domain of the stratum
corneum and/or increasing drug diffusivity in the barrier domain of
the stratum corneum. Several mechanisms of action are known:
increasing fluidity of stratum corneum lipid bilayers, extraction
of intercellular lipids, increase of drug's thermodynamic activity,
increase in stratum corneum hydration, alteration of proteinaceous
corneocyte components and others. Permeation enhancers are
conventionally divided into several groups based on their chemical
structure rather than the mechanism of action. More than 300
substances have been shown to have skin permeabilization potential.
Enhancers fall into the following general categories: alcohols
(ethanol, pentanol, benzyl alcohol, lauryl alcohol, propylene
glycols and glycerol), fatty acids (oleic acid, linoleic acid,
valeric acid and lauric acid), amines (diethanolamine and
triethanolamine), esters (isopropyl palmitate, isopropyl myristate
and ethyl acetate), amides (1-dodecylazacycloheptane-2-one
[Azone.RTM.], urea, dimethylacetamide, dimethylformamide and
pyrrolidone derivatives), hydrocarbons (alkanes and squalene),
surfactants (sodium laureate, cetyltrimethylammonium bromide,
Brij.RTM. nonionic polyoxyethylene surfactant, Tween.RTM. polyol
and sodium cholate), terpenes (D-limonene, carvone and anise oil),
sulfoxides (dimethyl sulfoxide) and phospholipids (lecithine).
Hydration of the stratum corneum is important. A fully hydrated
stratum corneum (under occlusion) presents lesser diffusional
resistance to a drug than its dehydrated counterpart.
[0054] In some embodiments, the composition further comprises an
exfoliating agent to promote abrasion of the surface of the skin to
increase the permeability of the dermal surface to a therapeutic
agent. Examples of the exfoliating agent include (1) inorganic
and/or metallic particles such as: boron nitride, in body-centered
cubic form (Borazon.RTM.); aluminosilicate (e.g. nepheline);
zircon; mixed oxides of aluminum such as emery; zinc oxide;
aluminum oxides such as aluminas or corundum; titanium oxide;
titanium oxide coated mica; carbides, in particular silicon carbide
(carborundum); or other metal oxides; metals, and metal alloys such
as iron shot, steel shot, and in particular perlite; silicates such
as glass, quartz, sand, or vermiculite; calcium carbonate (e.g.
Bora-Bora sand or Rose de Brignoles sand) or magnesium carbonate;
sodium chloride; pumice stone; amorphous silica; diamond; ceramics,
and (2) organic particles such as: fruit stones, in particular
apricot stones, e.g. Scrubami.RTM. apricot; wood cellulose, e.g.
ground bamboo stem; coconut shell, e.g. coconut exfoliator; polyam
ides, in particular Nylon-6; sugars; plastic microbeads, e.g.
polyethylenes or polypropylenes; ground walnut; ground apricot
seed; ground shells, and (3) mixed particles associating organic
and inorganic compounds, and particles coated in the above
compounds. The exfoliating agents may be in the form of microbeads
of less than five millimeters in its largest dimension that have an
exfoliating effect.
[0055] In one embodiment, the active agent is incorporated into
capsules or other slow release vehicles in the composition that
allow the chemical or agent to be slowly released into the dermis.
Capsules or vehicles that encapsulate the active agent can include,
but are not limited to, liposomes, non-ionic liposomes, niosomes,
novasome I, erythromycin-Zn complex, microspheres, nanoparticles,
solid lipid nanoparticles, and nanoemulsions.
[0056] The dosage applied to each nipple-areola complex on a female
or male patient will be specific for the different active agents
disclosed herein. One of ordinary skill may use standard practices
and testing to determine an acceptable dosage. In one embodiment,
the dosage applied on a nipple-areola complex is between 0.1-15,
10-15, 5-20, 10-20, 0.1-5.0, 0.2-0.8, 0.4 -5.0, 0.4-4.0, 0.4-3.0,
0.4-2.0, 0.4-1.0, 0.4-0.8, 0.6-5.0, 0.6-4.0, 0.6-3.0, 0.6-1.0,
1.0-5.0, 1.0-4.0, 1.0-3.0, 1.0-2.0, 1.5-5.0, 1.5-4.0, 1.5-3.0,
1.5-2.0, 1.5-3.5, 0.1-2.0, 0.2-2.0, 0.3-2.0, 0.5-2.0, 0.6-2.0,
0.7-2.0, 0.8-2.0, 0.9-2.0, 1.1-2.0, 1.2-2.0, 1.3-2.0, 1.4-2.0,
1.5-2.0, 1.6-2.0, 1.7-2.0, 1.8-2.0, or 1.9-2.0 mg/cm.sup.2 of
active agent. In one embodiment, the active agent is phenylephrine,
oxymetazoline or synephrine and the dosage applied on a
nipple-areola complex is between 0.05-5.0, 0.1-5.0, 0.4 -5.0,
0.4-4.0, 0.4-3.0, 0.4-2.0, 0.4-1.0, 0.4-0.8, 0.6-5.0, 0.6-4.0,
0.6-3.0, 0.6-1.0, 1.0-5.0, 1.0-4.0, 1.0-3.0, 1.0-2.0, 1.5-5.0,
1.5-4.0, 1.5-3.0, 1.5-2.0, 1.5-3.5, 0.1-2.0, 0.2-2.0, 0.3-2.0,
0.5-2.0, 0.6-2.0, 0.7-2.0, 0.8-2.0, 0.9-2.0, 1.1-2.0, 1.2-2.0,
1.3-2.0, 1.4-2.0, 1.5-2.0, 1.6-2.0, 1.7-2.0, 1.8-2.0, or 1.9-2.0
mg/cm.sup.2. In one embodiment the dosage of the active agent is
0.1-2.0, 0.5-2.0, 1.0-2.0, 0.1-1.0, 0.2-1.0, 0.3-1.0, 0.4-1.0,
0.5-1.0, 0.6-1.0, 0.7-1.0, 0.8-1.0, 0.9-1.0, 0.1-0.9, 0.2-0.9,
0.2-0.8, 0.2-0.7, 0.3-0.9, 0.3-0.8, 0.3-0.7, 0.4-0.9, 0.4-0.8,
0.5-0.9, 0.5-0.8, 0.5-0.7, or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,
0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or
2.0 mg/cm.sup.2. In one embodiment when the active agent is
phenylephrine, methoxamine or oxymetazoline, the dosage of the
active agent is 0.1-2.0, 0.5-2.0, 1.0-2.0, 0.1-1.0, 0.2-1.0,
0.3-1.0, 0.4-1.0, 0.5-1.0, 0.6-1.0, 0.7-1.0, 0.8-1.0, 0.9-1.0,
0.1-0.9, 0.2-0.9, 0.2-0.8, 0.2-0.7, 0.3-0.9, 0.3-0.8, 0.3-0.7,
0.4-0.9, 0.4-0.8, 0.5-0.9, 0.5-0.8, 0.5-0.7, or about 0.1, 0.2,
0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,
1.6, 1.7, 1.8, 1.9, or 2.0 mg/cm.sup.2. In another embodiment the
active agent is phenylephrine HCl and the dosage is 0.1-2.0,
0.5-2.0, 1.0-2.0, 0.1-1.0, 0.2-1.0, 0.3-1.0, 0.4-1.0, 0.5-1.0,
0.6-1.0, 0.7-1.0, 0.8-1.0, 0.9-1.0, 0.1-0.9, 0.2-0.9, 0.2-0.8,
0.2-0.7, 0.3-0.9, 0.3-0.8, 0.3-0.7, 0.4-0.9, 0.4-0.8, 0.5-0.9,
0.5-0.8, 0.5-0.7, or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,
0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0
mg/cm.sup.2. Under this dosage measurement, a smaller dimension of
the nipple-areola complex will result in a lower total dose.
[0057] As measured by in vitro release testing (IVRT), the dosage
that penetrates the stratum may be about 90, 80, 70, 60, 50, 40 or
30% of the dosage topically applied. In one embodiment, the dosage
that penetrates the stratum is between 0.1-1.0, 0.2-1.0, 0.3-0.9,
0.4-0.8, 0.5-1.0, 0.6-1.1, 0.01-1.0, or 0.01-0.1 mg/cm.sup.2, or is
approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9
mg/cm.sup.2.
[0058] The active agent can be applied in a transdermal patch of
any appropriate size and formulation that allows for administration
of a therapeutically effective amount of one or more active agents.
In one embodiment, the nipple-areola complex may be measured and a
circle of the appropriate size of a transdermal patch applied to
encompass the entire nipple-areola surface. In certain embodiments,
the circular transdermal patches are 8, 12 and 16 cm in diameter.
In other embodiments, the circular transdermal patch is 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cm in diameter, or
is a size ranging from 5-10, 6-11, 7-12, 8-13, 9-14, 10-15, 11-16,
12-17, 13-18, 14-19, or 15-20 cm in diameter. Based on a
transdermal patch or occlusive covering of a therapeutic
composition of 8 cm in diameter, a total dosage of 5 mg may be
applied in one embodiment. Similarly, a patch 12 cm in diameter may
apply a total dose of 7.5 mg and a patch of 16 cm may apply a total
dose of 10 mg.
[0059] In one embodiment, the active agent is present in the
composition for topical administration at a concentration of
0.025-1.0, 0.05-1.0, 0.025-2.0, 0.05-2.0, 0.05-3.0, 0.05-4.0,
0.5-1.0, 0.5-2.0, 0.5-3.0, 0.1-40.0, 0.1-35.0, 0.1-25.0, 0.1-10.0,
0.1-15.0, 0.1-5.0, 1.0-25.0, 1.0-10.0, 1.0-15.0, 1.0-5.0, 5.0-25.0,
5.0-10.0, 5.0-15.0, 5.0-10, 5.0-15.0, 5.0-20.0, 10.0-20.0,
20.0-30.0, 25.0-30.0, 30.0-40.0, 10.0-40.0, or 35.0-40.0% by
weight, or approximately 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0,
9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0,
20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0,
31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, or 40% by
weight. In one embodiment, the active agent is phenylephrine,
synephrine or a pharmaceutically acceptable salt or hydrate thereof
and is in a composition at a concentration of 5% to 10% or 10% to
30% therapeutic agent by total weight of the composition. In one
embodiment, the composition comprises an A1AR agonist in a
concentration of about 0.25, 0.33, 0.5, 1.0, 2.0 or 2.5% by weight.
In one embodiment, the composition comprises methoxamine or
oxymetazoline (such as oxymetazoline HCl) in a concentration of
about 0.025-1.0, 0.05-1.0, 0.025-2.0, 0.05-3.0, 0.05-5.0, 0.05-4.0,
0.1-5.0 or 0.5-2.0% by weight or in a concentration of about 0.025,
0.05, 0.25, 0.33, 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0%
by weight. In one embodiment, the active agent is midodrine and is
present in the composition at a concentration of 0.025-5.0,
0.05-5.0, 0.1-5.0, 0.2-5.0, 0.025-2.0, 0.05-2.0, 0.2-2.0 or
0.1-3.0% by weight. As is readily understood by the person of
ordinary skill in the field, the concentration of active agent in a
composition can vary depending on the particular active agent used
and the efficacy of the composition containing it to deliver the
agent through the dermis.
[0060] In one embodiment, the method is to treat female sexual
dysfunction, preferably female sexual arousal disorder (FSAD),
female sexual interest/arousal disorder (FSIAD), female orgasmic
disorder (FOD) or female hypoactive sexual desire disorder (FHSDD),
by applying a therapeutically effective amount of one or more
active agents selected from the following: an A1AR agonist, such as
phenylephrine; a muscarinic acetylcholine receptor agonist; a
nicotinic acetylcholine receptor agonist; and a cholinesterase
inhibitor, topically to a nipple-areola complex of a female subject
in need of such treatment, such as a premenopausal woman, in an
amount of 0.2-0.8 mg/cm.sup.2 active agent per surface area of the
nipple-areola complex. In another embodiment, the method is to
treat treating female sexual dysfunction, preferably female sexual
arousal disorder (FSAD), female sexual interest/arousal disorder
(FSIAD), female orgasmic disorder (FOD) or female hypoactive sexual
desire disorder (FHSDD), by applying a therapeutically effective
amount of one or more active agents from the following: an A1AR
agonist, such as phenylephrine, a muscarinic acetylcholine receptor
agonist, a nicotinic acetylcholine receptor agonist, and a
cholinesterase inhibitor, topically to a nipple-areola complex of a
female subject in need of such treatment, such as a postmenopausal
woman, in an amount of 0.2-0.8 mg/cm.sup.2 therapeutic agent per
surface area of the nipple-areola complex. In a further embodiment,
the method is to reduce or alleviate a symptom of female sexual
dysfunction, such as (1) absent/reduced interest in sexual
activity; (2) absent/reduced sexual/erotic thoughts or fantasies;
(3) no/reduced initiation of sexual activity, and typically
unreceptive to a partner's attempts to initiate; (4) absent/reduced
sexual excitement/pleasure during sexual activity in almost all or
all sexual encounters; (5) absent/reduced sexual interest/arousal
in response to any internal or external sexual/erotic cues; or (6)
absent/reduced genital or nongenital sensations during sexual
activity in almost all or all sexual encounters, the method
comprising applying a therapeutically effective amount of one or
more active agents selected from the following: an A1AR agonist,
such as phenylephrine, a muscarinic acetylcholine receptor agonist,
a nicotinic acetylcholine receptor agonist, and a cholinesterase
inhibitor, in a dosage of 0.2-0.8 mg/cm.sup.2, topically to a
nipple-areola complex of a female subject in need of such
treatment. In yet a further embodiment, the method is for causing
erection of nipples, increasing nipple sensitivity, and/or
increasing oxytocin release related to sexual activity in a female
subject, such as a premenopausal or postmenopausal woman,
comprising applying an effective amount of one or more active
agents selected from the following: an A1AR agonist, such as
phenylephrine, a muscarinic acetylcholine receptor agonist, a
nicotinic acetylcholine receptor agonist, and a cholinesterase
inhibitor, topically to a nipple-areola complex of the female
subject in an amount of 0.2-0.8 mg/cm.sup.2.
[0061] In yet another embodiment, the method is to treat female
sexual dysfunction, preferably female sexual arousal disorder
(FSAD), female sexual interest/arousal disorder (FSIAD), female
orgasmic disorder (FOD) or female hypoactive sexual desire disorder
(FHSDD), by applying a therapeutically effective amount of one or
more active agents selected from the following: an A1AR agonist,
such as phenylephrine, a muscarinic acetylcholine receptor agonist,
a nicotinic acetylcholine receptor agonist, and/or a cholinesterase
inhibitor topically to a nipple-areola complex of a female subject
in need of such treatment, such as a premenopausal woman. In at
least one embodiment, the method is to reduce or alleviate a
symptom of female sexual dysfunction, such as (1) absent/reduced
interest in sexual activity; (2) absent/reduced sexual/erotic
thoughts or fantasies; (3) no/reduced initiation of sexual
activity, and typically unreceptive to a partner's attempts to
initiate; (4) absent/reduced sexual excitement/pleasure during
sexual activity in almost all or all sexual encounters; (5)
absent/reduced sexual interest/arousal in response to any internal
or external sexual/erotic cues; or (6) absent/reduced genital or
nongenital sensations during sexual activity in almost all or all
sexual encounters, the method comprising applying a therapeutically
effective amount of one or more active agents selected from the
following: an A1AR agonist, such as phenylephrine, a muscarinic
acetylcholine receptor agonist, a nicotinic acetylcholine receptor
agonist, and/or a cholinesterase inhibitor. In yet a further
embodiment, the method is for causing erection of nipples,
increasing nipple sensitivity, and/or increasing oxytocin release
related to sexual activity in a female subject, such as a
premenopausal or postmenopausal woman, comprising applying an
effective amount of one or more active agents selected from the
following: an Al AR agonist, such as phenylephrine, a muscarinic
acetylcholine receptor agonist, a nicotinic acetylcholine receptor
agonist, and a cholinesterase inhibitor.
[0062] The pH of the formulation will be determined following
procedures known in the art to provide for stability of the active
agent and allow for skin penetration of the agent. Phenylephrine,
for example, may be formulated at a pH of less than 6, particularly
if it is concentrated at 10% or more by weight of the formulation.
In one embodiment, phenylephrine is formulated at 10% by weight or
higher in a liquid solution that does not contain ethanol and has a
pH of less than 6, preferably 5.5 or between 4.9 and 5.5, 4.9 and
5.6, 4.9 and 5.7, 4.9 and 5.8, 4.9 and 5.9, 5.0 and 5.8, 5.0 and
5.9, 5.1 and 5.8, 5.1 and 5.7, 5.2 and 5.8, 5.3 and 5.8, 5.3 and
5.7, or 5.4 and 5.6.
[0063] The term "consisting of" refers to compositions, methods,
and respective components thereof as described herein, which are
exclusive of any element not recited in that description of the
embodiment.
[0064] As used herein the term "consisting essentially of" refers
to those elements required for a given embodiment. The term permits
the presence of elements that do not materially affect the basic
and novel or functional characteristic(s) of that embodiment.
[0065] The singular terms "a," "an," and "the" include plural
referents unless context clearly indicates otherwise. Similarly,
the word "or" is intended to include "and" unless the context
clearly indicates otherwise. Although methods and materials similar
or equivalent to those described herein can be used in the practice
or testing of this disclosure, suitable methods and materials are
described below. The abbreviation, "e.g." is derived from the Latin
exempli gratia, and is used herein to indicate a non-limiting
example. Thus, the abbreviation "e.g." is synonymous with the term
"for example."
[0066] Measurement of the strength of nipple smooth muscle
contraction can be performed, if necessary, via myograph adapted
for that purpose. Examples are described in, e.g., Zeveke &
Gladysheva, Bull. Exp. Biol. Med. 71: 102-105 (1971) and Hellmann,
J. Physiol. 169: 603-620 (1963). Measurement of nipple sensitivity
can be performed, if necessary, via Semmes-Weinstein monofilament
test adapted for that purpose. Other methods for measuring nipple
sensitivity (i.e., sensibility) have been described. Examples are
described in, e.g., Mofid, Dellon, Elias & Nahabedian, Plast
Reconstr Surg. 109(7):2283-2288 (2002).
[0067] Efficacy of treatment for FSD and enhancement of sexual
satisfaction can be determined by monitoring the number of
satisfying sexual events (SSE) in a given experimental period. For
example, a questionnaire may be administered by a clinician asking
the number of SSEs a patient has experienced in a given four-week
period. A treatment can thus be applied for another four-week
period and the questionnaire can be re-assessed at the end of the
treatment. An increase in SSE from baseline can then be evaluated,
for example, in a statistically significantly large cohort. As but
one example, an average increase from 6 to 6.7 SSEs would show
efficacy of a treatment. Similarly, secondary endpoints could
include questionnaires assessing sexual satisfaction, e.g., change
from baseline to end-of-study in arousal domain score, female
sexual function index, satisfaction with arousal, desire domain
from female sexual function index, satisfaction with desire,
quality of relationship with partner, and a female sexual distress
scale. Other established metrics to determine treatment efficacy
for FSD can also be used, and they include, for example, FSFI
(female sexual function index), SAL (Sexual Activity Log), SAR
(Sexual Activity Record), FSDS (Female Sexual Distress Scale), and
the FSDS-R (Female Sexual Distress Scale Revised).
[0068] Other parameters to measure or quantify sexual arousal in
females include arousal domain score from female sexual function
index, satisfaction with arousal, desire domain from female sexual
function index, satisfaction with desire as measured, quality of
relationship with partner, change in hormone levels such as
oxytocin, length of time of nipple erection. A treatment is
considered effective if any one or a combination of these
parameters is increased as compared to a reference level that is
measured in the absence of the treatment.
[0069] Active agents can optionally be administered by
iontophoresis, which uses an electric field to drive the passage of
ionic agents or drugs into the skin. As but one example,
iontophoresis has been used to deliver agents such as phenylephrine
to the skin to stimulate smooth muscle contraction. See, e.g.,
Siepmann et al., Neurology Apr. 25, 2012; 78(Meeting Abstracts 1):
P05.197. Thus, in one embodiment, the present disclosure relates to
an iontophoresis device for transdermal delivery that dispenses one
or more active agents that are selected from the following: A1AR
agonists, such as phenylephrine; muscarinic acetylcholine receptor
agonists; nicotinic acetylcholine receptor agonists; and
cholinesterase inhibitors. The iontophoresis device can comprise
one or more metal contacts. Optionally, the iontophoresis device
can comprise one or more compartments for containing the active
agent(s). For example, the iontophoeresis device can comprise one
or more compartments for containing at least one of an A1AR
agonist, a muscarinic receptor agonist, a nicotinic receptor
agonist, and a cholinesterase inhibitor.
[0070] Penetration enhancement of the active agents across the
stratum corneum can be achieved by applying an electric field
gradient across the skin. This iontophoresis method is well
established in the literature. See Nitin Dixit, Vikas Bali, Sanjula
Baboota, Alka Ahuja and Javed Ali (2007), "Iontophoresis--An
Approach for Controlled Drug Delivery: A Review", Current Drug
Delivery, 4, 1-10. For example, phenylephrine hydrochloride, a
selective alpha-1adrenergic receptor agonist, has been successfully
iontophorised across the stratum corneum and delivered to the
arrector pili muscle producing piloerection on the forearm. See T.
Siepmann, C. H. Gibbons, B. M. Illigens, J. A. Lafo, C. M. Brown,
and R. Freeman (2012), "Quantitative Pilomotor Axon-Reflex Test--A
Novel Test of Pilomotor Function", Archives of Neurology (2012),
69(11), 1488-1492. The advantage of using iontophoresis is that the
concentrations of active agent required to penetrate the stratum
corneum are typically much lower than those needed with other
topical formulations. For example, a 1% w/v concentration of
phenylephrine hydrochloride can activate the piloerection on the
forearm when iontophoresis in used. See T. Siepmann, Archives of
Neurology (2012), supra.
[0071] In one embodiment of the present invention, a solution of
one or more active agents that are selected from the following:
A1AR agonists, such as phenylephrine; muscarinic acetylcholine
receptor agonists; nicotinic acetylcholine receptor agonists; and
cholinesterase inhibitors is placed in an iontophoresis patch
specifically designed for the nipple areola complex. Devices such
as these are well known in the art. See, e.g., U.S. Pat. No.
8,442,629 B2 (Suzuki); U.S. Pat. No. 4,968,297 A (Jacobsen); US
Patent U.S. Pat. No. 8,362,027 B2 (Inagi); U.S. Pat. No. 4,419,092
A (Jacobsen); U.S. Pat. No. 8,423,131 B2 (Mir Imran); U.S. Pat. No.
5,087,242 A (Tomasz); U.S. Pat. No. 5,248,295 A (Jacobsen). It is
important to note that the net charge of the drug must be matched
with the like charged terminal of the iontophoretic device. For
example, if a solution of phenylephrine hydrochloride is used, the
solution should be placed on the positively charged electrode of
the iontophoresis patch. During iontophoresis, an electric field
drives the charged drug molecules across the stratum corneum. This
method of delivering the active agent that is an A1AR agonist, such
as phenylephrine, a muscarinic acetylcholine receptor agonist, a
nicotinic acetylcholine receptor agonist, and/or a cholinesterase
inhibitor on or in an iotophoresis patch is believed to be useful
with any of the inventive methods of use disclosed herein, as is
apparent to one of ordinary skill in the art.
[0072] In one embodiment of the invention, electroporation is used
to enhance the permeability of the stratus corneum. During
electroporation, an electric current is applied to the skin,
creating pores in the stratum corneum that facilitate diffusion of
the drug molecules. The drug may diffuse across the stratum corneum
by static diffusion. In an embodiment, electroporation is combined
with iontophoresis, and the drug is further driven through the
stratus corneum by an electric field. It should be understood that
electroporation may be used to enhance permeability of any of the
therapeutic compositions disclosed herein, with or without the
added use of iontophoresis.
[0073] In one embodiment of the invention, a voltage of about 30 V
to about 500 V are applied to the skin for electroporation. In an
embodiment, the voltage is pulsed for a short duration. In some
embodiments, the short duration is in a range of greater than 0 ms
to about 300 ms.
Electrical Stimulation
[0074] In one embodiment of the invention, the smooth muscle can be
contracted via electrical stimulation to at least a portion of the
nipple-areola complex of the breast. The electrical stimulation can
be controlled, e.g., by a unit. Examples of applying electrical
forces to contract the smooth muscles are described in, for
example, US Patent Application Pub. US2013/0199348 published on
Aug. 8, 2013, titled Pilomotor Effect Stimulating Device and
Method. In some embodiments, the voltage or amplitude of the signal
applied can be in the range of 35 to 75 volts, 25 to 50 volts, 10
to 30 volts or other suitable ranges to reach the threshold for
muscle contraction. The current applied by a device as disclosed
herein can, in some embodiments, preferably be in the microamps to
avoid electrocution of the user. A frequency of 10 KHz to 15 KHz
can be applied, or a lower or higher frequency. In some
embodiments, the pulse length applied will be from 1 to 50
milliseconds, 1 to 100 milliseconds, or other suitable lengths to
contract smooth muscle of at least a portion of the nipple-areola
complex or any other pilomotor effective amount of current. In some
embodiments, a control unit will automatically pulse the electrical
stimulation at random intervals that are enough to keep the smooth
muscle relatively contracted. In other embodiments, the pulses will
be spaced out enough to allow the smooth muscle to relax in between
pulses.
[0075] In one embodiment, the electrical stimulation device can be
built into a bra. A female subject can wear the bra with the
electrical stimulation device and promote stimulation by turning on
the device.
[0076] It should be noted that combinations of the above methods
and active agents can be used to promote the contraction of the
smooth muscle and achieve the desired therapeutic results and
enhancement of sexual satisfaction.
[0077] The various methods and techniques described above provide a
number of ways to carry out the invention. Of course, it is to be
understood that not necessarily all objectives or advantages
described can be achieved in accordance with any particular
embodiment described herein. Thus, for example, those skilled in
the art will recognize that the methods can be performed in a
manner that achieves or optimizes one advantage or group of
advantages as taught herein without necessarily achieving other
objectives or advantages as taught or suggested herein. A variety
of alternatives are mentioned herein. It is to be understood that
some embodiments specifically include one, another, or several
features, while others specifically exclude one, another, or
several features, while still others mitigate a particular feature
by inclusion of one, another, or several advantageous features.
[0078] All patents, patent applications, publications of patent
applications, and other published material, such as articles and
books referenced herein are hereby incorporated herein by this
reference in their entireties. Should there be any inconsistency or
conflict between the description, definition, and/or the use of a
term associated with any of the incorporated material and that
associated with the present document, the description, definition,
and/or the use of the term in the present document shall
prevail.
EXAMPLES
[0079] The following examples illustrate some embodiments and
aspects of the invention. It will be apparent to those skilled in
the relevant art that various modifications, additions,
substitutions, and the like can be performed without altering the
spirit or scope of the invention, and such modifications and
variations are encompassed within the scope of the invention as
defined in the claims which follow. The technology disclosed herein
is further illustrated by the following examples which in no way
should be construed as being further limiting.
Example 1
Transdermal Delivery of 10% Phenylephrine Solution
[0080] Transdermal penetration of a particular formulation can be
assessed with in vitro release testing (IVRT) using a Franz cell.
See Bartosova and Bajagar, "Transdermal Drug Delivery In Vitro
Using Diffusion Cells," Current Medicinal Chemistry, 2012, 19,
4671-4677.
[0081] In order to determine the dermal absorption and
bioavailability of topically applied 10% Phenylephrine
Hydrochloride solution, we used an IVRT experimental setup with
both skin excised from pig ears and a synthetic skin model (Maine
Manufacturing, LLC, Me., USA). In both models (see table below),
the maximal skin absorption in 24 hours did not exceed 83%.
[0082] In the example, the following data was obtained from a Franz
cell diffusion experiment using excised pigskin barrier. A 50
microliter aliquot of a phenylephrine solution was allowed to
penetrate through 9 mm diameter sample of pigskin into a 5 mL
reservoir of phosphate buffered saline. Phenylephrine concentration
was determined in the reservoir by measuring the optical absorbance
at 214 nm at time points subsequent to the application of the
formulation. In the following example the test solution was 10%
(w/w) phenylephrine, 10% (w/w) Dimethyl Isosorbide, and 80% (w/w)
ethanol. From the data below, it can be concluded that the
formulation can be deemed "successful" because 82% of the applied
drug penetrated the pigskin membrane in 3 hours. The experiment was
run in triplicate. The average of all three data is shown. It is
envisioned that additional studies may be undertaken with other
models of in vitro release testing or with variations of the same
model to compare with the data reported below.
TABLE-US-00001 TABLE 1 IVRT skin penetration model (pig skin) of
10% Phenylephrine HCl solution. Penetration (%) Time (h) Sample 1
Sample 2 Sample 3 Average 1 32.3% 2.1% 0.7% 11.7% 2 80.6% 89.0%
13.6% 61.1% 3 78.9% 87.5% 81.9% 82.8% 4 78.6% 83.4% 81.1% 81.0% 5
78.5% 86.0% 81.3% 81.9% 24 81.3% 83.1% 80.3% 81.6%
[0083] Therefore, if a subject is to apply 0.1 mL of the drug
solution and not remove it for a period of 24 hours (which is
unlikely to occur), she will experience an average absorption of
8.3 mg of Phenylephrine HCl per nipple-areola complex or 16.6 mg
total absorption over 24 hours. In comparison, in the United
States, Over-the-Counter (OTC) Sudafed phenylephrine contains 10 mg
phenylephrine hydrochloride oral tablets indicated for
administration of 10 mg to 20 mg every 4 hours. The oral dosage is
approximately 40% systemically bioavailable. Assuming one
Sudafed.RTM. PE phenylephrine tablet every 4 hours or 60 mg per
day, the total dosage will be 24 mg. The dosage proposed in the
present study will result in approximately 45% less systemic
Phenylephrine HCl exposure compared to the oral OTC drug.
[0084] In addition, while the percent of ocular absorption has not
been determined, the 10% ophthalmic solution approved by the US FDA
was found safe based on assuming complete absorption of 21 mg
Phenylephrine HCl per day, which is also higher than the absorption
at the dosage disclosed herein for the treatment of FSD.
[0085] Finally, it should be noted that systemic bioavailability of
topically applied Phenylephrine HCl is likely to be far lower than
the maximal estimated amount due to the local vasoconstriction
effect of the drug; hence, the reduced systemic absorption.
Example 2
[0086] A study of the blood pressure and heart rate of five
patients receiving topical application on the nipple-areola complex
was made. The composition applied was 0.1 mL of a 10% phenylephrine
solution for a total dosage of 10 mg phenylephrine HCl. Blood
pressure and heart rate were measured at baseline (T=0), after 15
minutes and 30 minutes. No significant change in blood pressure or
heart rate was detected in any of the subjects.
[0087] This data supports the safety of the topically applied
dosage (.about.15-20 mg) of phenylephrine. The applied dosage does
not provide for an increase in systemic heart rate or blood
pressure.
TABLE-US-00002 TABLE 2 0.1 mL 10% PHCI Subject Nr. BP (T = 0) BP (T
= 15) BP (T = 30) HR (T = 0) HR (T = 15) HR (T = 30) 1 115/80
112/76 117/75 82 69 74 2 119/78 122/77 122/78 81 77 80 3 116/76
117/72 128/77 74 75 68 4 116/74 120/72 116/68 51 53 58 5 100/67
99/67 97/63 63 68 69
Example 3
[0088] A pilot study was conducted to assess the dosage of topical
phenylephrine solution required to elicit nipple erection and
sensitivity. Five subjects ages 18-70 participated in the study.
Two subjects were post-menopausal and the reminder three were
pre-menopausal. Subjects were not hypertensive, pregnant or
breastfeeding. Three formulations were used: Formula A: 0% topical
phenylephrine hydrochloride solution; Formula B: 5% topical
phenylephrine hydrochloride solution; Formula C: 10% topical
phenylephrine hydrochloride solution.
[0089] The study was conducted over 3 days. On day 1, subjects were
instructed to apply on the left nipple Formula A and on the right
nipple Formula B. On day 2, subjects were instructed to apply on
the left nipple Formula A and on the right nipple Formula C. On day
3, subjects were instructed to apply on the left nipple Formula B
and on the right nipple Formula C. 0.1 mL of each formula was
applied with a cotton swab to the nipple areole complex. Table 3
summarizes the finding from this study. The 10% topical
phenylephrine solution (Formula C) elicited a clinical response in
all subjects while the 5% and placebo formulations (Formula A and
B) failed to elicit a response. With the 10% topical phenylephrine
solution, response in nipple erection and sensitivity was obtained
in less than 30 minutes and lasted for 3-4 hours.
TABLE-US-00003 TABLE 3 Day 1 Day 2 Day 3 Subject Formula Formula
Formula Formula Formula Formula Nr. A B A C B C 001 NR NR NR R NR R
002 NR NR NR R NR R 003 NR NR NR R NR R 004 NR NR NR R NR R 005 NR
NR NR R NR R R = Response i.e., nipple erection NR = No
Response
Example 4
[0090] An additional pilot study was conducted to assess the safety
and efficacy of topical phenylephrine applied to the nipple-areole
complex for the treatment of female sexual dysfunction. Nine women
subjects ages 18-70 participated in the study. Two subjects were
post-menopausal and the remaining seven were pre-menopausal.
Subjects were not suffering from clinical depression, hypertension,
pregnant, breastfeeding or currently taking testosterone, SSRIs, or
other antidepressants. 0.1 mL of 10% topical phenylephrine
hydrochloride solution was applied with a cotton swab to each
nipple areole complex (a total dosage of 20 mg was applied
topically). Subjects were instructed to apply the solution
approximately 1 hour before sexual activity. The duration of the
study was for a period of one week. The number of Satisfying Sexual
Events (SSE) determined by a Sexual Activity Record (SAR) was
recorded. In addition, a modified Female Sexual Function Index
(FSFI) desire domain questionnaire was administered. Table 4
summarizes the change in SSEs from baseline as well as Adverse
Events (AE). All subjects reported increased nipple sensitivity
within 30 minutes after the application of the topical
phenylephrine solution. The nipples remained sensitive up to 3 to 4
hours. In one subject, with initial slightly painful nipple
erection, the sensitivity persisted for approximately 8 hours.
Seven subjects reported significant change in the number of SSEs
from baseline. Subjects reporting increase in the number of SSEs
also reported increased desire possibly attributed to the
hypothesized mechanism of action of oxytocin release as a result of
nipple erection.
TABLE-US-00004 TABLE 4 Number of SSE Number of SSE Subject Nr.
(baseline) (1 week) 001 1 3 002 0 2 003 0 1 004 2 4 005 1 3 006 2 2
007 1 1 008 3 6 009 2 3
Example 5
Protocols for Clinical Studies
Primary Outcome Measures:
[0091] Number of satisfying sexual events (SSE) determined from
Sexual Activity Record (SAR).
Secondary Outcome Measures:
[0092] Female Sexual Function Index (FSFI); Female Sexual Distress
Scale, Revised (FSDS-R); Sexual Quality of Life-Female
(SQOL-F).
Efficacy Parameters
[0093] During the first site visit, week 4 site visit and week 8
site visit, the primary investigator (PI) will instruct the subject
in the use of the sexual activity record (SAR). In addition, during
week 4 site visit and week 8 site final visit, the PI will
administer standardized patient reported outcomes (PROs) of
FSD.
PROs:
Sexual Activity Record (SAR):
[0094] The SAR was developed to measure the frequency of successful
and satisfactory sexual events as a primary end point in clinical
trials of sexual dysfunction. The SAR is a brief form that is
completed after the respondent engages in sexual activity. Its
seven items assess the respondent's experience of the most recent
sexual encounter in the areas of sexual arousal, orgasm, and
overall satisfaction with sexual arousal. Respondents indicate
whether sexual events include self-stimulation, partnered sexual
activity, or a combination of both.
Female Sexual Function Index (FSFI):
[0095] The FSFI is a 19-item multidimensional self-report
instrument (Table 5) used to assess women's sexual function in six
domains: desire, arousal, lubrication, orgasm, satisfaction, and
pain. The instrument yields scores for each of these six domains as
well as a total score. The FSFI has demonstrated good test-retest
reliability (a=0.79-0.88). Rosen et al., 2000, "The Female Sexual
Function Index (FSFI): A multidimensional self-report instrument
for the assessment of female sexual function," Journal of Sex and
Marital Therapy, 26, 191-208; Wiegel, M., Meston, C., & Rosen,
R., 2005, "The Female Sexual Function Index: Cross-validation and
development of clinical cut-off scores," Journal of Sex &
Marital Therapy, 31, 1-20.
TABLE-US-00005 TABLE 5 FSFI Question Response Options 1. Over the
past 4 weeks, 5 = Almost always or always how often did you feel
sexual 4 = Most times (more than half the time) desire or interest?
3 = Sometimes (about half the time) 2 = A few times (less than half
the time) 1 = Almost never or never 2. Over the past 4 weeks, 5 =
Very high how would you rate your level 4 = High (degree) of sexual
desire or 3 = Moderate interest? 2 = Low 1 = Very low or none at
all 3. Over the past 4 weeks, 0 = No sexual activity how often did
you feel 5 = Almost always or always sexually aroused ("turned 4 =
Most times (more than half the time) on") during sexual activity 3
= Sometimes (about half the time) or intercourse? 2 = A few times
(less than half the time) 1 = Almost never or never 4. Over the
past 4 weeks, 0 = No sexual activity how would you rate your level
5 = Very high of sexual arousal ("turn 4 = High on") during sexual
activity 3 = Moderate or intercourse? 2 = Low 1 = Very low or none
at all 5. Over the past 4 weeks, 0 = No sexual activity how
confident were you about 5 = Very high confidence becoming sexually
aroused 4 = High confidence during sexual activity or 3 = Moderate
confidence intercourse? 2 = Low confidence 1 = Very low or no
confidence 6. Over the past 4 weeks, 0 = No sexual activity how
often have you been 5 = Almost always or always satisfied with your
arousal 4 = Most times (more than half the time) (excitement)
during sexual 3 = Sometimes (about half the time) activity or
intercourse? 2 = A few times (less than half the time) 1 = Almost
never or never 7. Over the past 4 weeks, 0 = No sexual activity how
often did you become 5 = Almost always or always lubricated ("wet")
4 = Most times (more than half the time) during sexual activity or
3 = Sometimes (about half the time) intercourse? 2 = A few times
(less than half the time) 1 = Almost never or never 8. Over the
past 4 weeks, 0 = No sexual activity how difficult was it to become
1 = Extremely difficult or impossible lubricated ("wet") 2 = Very
difficult during sexual activity or 3 = Difficult intercourse? 4 =
Slightly difficult 5 = Not difficult 9. Over the past 4 weeks, 0 =
No sexual activity how often did you maintain 5 = Almost always or
always your lubrication ("wetness") 4 = Most times (more than half
the time) until completion of sexual 3 = Sometimes (about half the
time) activity or intercourse? 2 = A few times (less than half the
time) 1 = Almost never or never 10. Over the past 4 weeks, 0 = No
sexual activity how difficult was it to 1 = Extremely difficult or
impossible maintain your lubrication 2 = Very difficult ("wetness")
3 = Difficult until completion of sexual 4 = Slightly difficult
activity or intercourse? 5 = Not difficult 11. Over the past 4
weeks, 0 = No sexual activity when you had sexual 5 = Almost always
or always stimulation or intercourse, 4 = Most times (more than
half the time) how often did you reach 3 = Sometimes (about half
the time) orgasm (climax)? 2 = A few times (less than half the
time) 1 = Almost never or never 12. Over the past 4 weeks, 0 = No
sexual activity when you had sexual 1 = Extremely difficult or
impossible stimulation or intercourse, 2 = Very difficult how
difficult was it for you 3 = Difficult to reach orgasm (climax)? 4
= Slightly difficult 5 = Not difficult 13. Over the past 4 weeks, 0
= No sexual activity how satisfied were you with 5 = Very satisfied
your ability to reach orgasm 4 = Moderately satisfied (climax)
during sexual activity 3 = About equally satisfied and or
intercourse? dissatisfied 2 = Moderately dissatisfied 1 = Very
dissatisfied 14. Over the past 4 weeks, 0 = No sexual activity how
satisfied have you been 5 = Very satisfied with the amount of
emotional 4 = Moderately satisfied closeness during sexual 3 =
About equally satisfied and activity between you and your
dissatisfied partner? 2 = Moderately dissatisfied 1 = Very
dissatisfied 15. Over the past 4 weeks, 5 = Very satisfied how
satisfied have you been 4 = Moderately satisfied with your sexual
relationship 3 = About equally satisfied and with your partner?
dissatisfied 2 = Moderately dissatisfied 1 = Very dissatisfied 16.
Over the past 4 weeks, 5 = Very satisfied how satisfied have you
been 4 = Moderately satisfied with your overall sexual life? 3 =
About equally satisfied and dissatisfied 2 = Moderately
dissatisfied 1 = Very dissatisfied 17. Over the past 4 weeks, 0 =
Did not attempt intercourse how often did you experience 1 = Almost
always or always discomfort or pain during 2 = Most times (more
than half the time) vaginal penetration? 3 = Sometimes (about half
the time) 4 = A few times (less than half the time) 5 = Almost
never or never 18. Over the past 4 weeks, 0 = Did not attempt
intercourse how often did you experience 1 = Almost always or
always discomfort or pain following 2 = Most times (more than half
the time) vaginal penetration? 3 = Sometimes (about half the time)
4 = A few times (less than half the time) 5 = Almost never or never
19. Over the past 4 weeks, 0 = Did not attempt intercourse how
would you rate your level 1 = Very high (degree) of discomfort or
pain 2 = High during or following vaginal 3 = Moderate penetration?
4 = Low = Very low or none at all
[0096] The individual domain scores and full scale (overall) score
of the FSFI can be derived from the computational formula outlined
in Table 4. For individual domain scores, add the scores of the
individual items that comprise the domain and multiply the sum by
the domain factor (see below). Add the six domain scores to obtain
the full scale score. It should be noted that within the individual
domains, a domain score of zero indicates that the subject reported
having no sexual activity during the past month. Subject scores can
be entered in the right-hand column. Significant positive changes
in score reflect efficacy of the methods of treatment described
herein.
TABLE-US-00006 TABLE 6 Score Minimum Maximum Domain Questions Range
Factor Score Score Score Desire 1, 2 1-5 0.6 1.2 6.0 Arousal 3, 4,
5, 6 0-5 0.3 0 6.0 Lubrication 7, 8, 9, 10 0-5 0.3 0 6.0 Orgasm 11,
12, 13 0-5 0.4 0 6.0 Satisfaction 14, 15, 16 0 (or 1)-5 0.4 0.8 6.0
Pain 17, 18, 19 0-5 0.4 0 6.0 Full Scale Score Range 2.0 36.0
Female Sexual Distress Scale-Revised (FSDS-R):
[0097] The FSDS (original version) is a self-report questionnaire
developed to measure sexually related personal distress in women.
Response choices are "never," "rarely," "occasionally,"
"frequently," and "always." The questionnaire is scored by summing
the item responses (scaled such that "never" equals 0 and "always"
equals 4). The FSDS-R differs from the FSDS in that it includes one
additional question that asks women to rate distress related to low
sexual desire. This modification is more consistent with diagnosis
of HSDD. Significant improvement in score indicates therapeutic
efficacy.
Sexual Quality of Life--Female (SQoL-F):
[0098] The SQoL-F is an 18-item questionnaire developed to assess
the sexual quality of life women, specifically to assess sexual
confidence, emotional well-being and relationship issues. The
instrument has been validated for use in a broad range of women
with Female Sexual Arousal Disorder and Hypoactive Sexual Desire
Disorder. Significant improvement in score indicates therapeutic
efficacy.
Example 6
[0099] A pilot study was conducted to assess the optimal pH of
topical phenylephrine solution required to elicit smooth muscle
contraction on the skin. A series of 10% phenylephrine solutions
were prepared in phosphate buffer solutions of varied pH. pH 4.6,
4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, and 6.6 were used.
Areas of skin on the subjects forearm were marked with a surgical
pen. 50 microliter of each solution were applied to the marked area
of skin and allowed to dry. After one hour the sites of application
were visually inspected for the appearance of the pilomotor effect
(i.e., "goose bumps"). The results are summarized in the table
below:
TABLE-US-00007 TABLE 7 pH of 10% Phenylephrine Solution Results
after 1 hour 4.6 None 4.8 Slight 5.0 Strong 5.2 Strong 5.4 Strong
5.6 Slight 5.8 Slight 6.0 None 6.2 None 6.4 None 6.6 None
Example 7
[0100] Oxymetazoline HCl 0.1%, 0.2%, 0.5%. A study was conducted to
assess the dosage of topical oxymetazoline solution required to
elicit nipple erection and sensitivity. Five premenopausal subjects
participated in the study. Subjects were not hypertensive, pregnant
or breastfeeding. Three formulations were used: Formula A: 0.1%
topical oxymetazoline hydrochloride solution; Formula B: 0.2%
topical oxymetazoline hydrochloride solution; Formula C: 0.5%
topical oxymetazoline hydrochloride solution.
[0101] The study was conducted over 3 days. On day 1, subjects were
instructed to apply Formula A to both areolas. On day 2, subjects
were instructed to apply Formula B to both areolas. On day 3,
subjects were instructed to apply Formula C to both areolas. 0.1 mL
of each formula was applied using a metered dosage dispenser to
each areola. Table 8 summarizes the finding from this study. The
0.5% topical oxymetazoline solution (Formula C) elicited a clinical
response in 4 out of 5 subjects while the 0.1% and 0.2%
formulations (Formula A and B) failed to elicit a response. With
the 0.5% topical oxymetazoline solution, response in nipple
erection and sensitivity was obtained approximately within 1 hour
and lasted over 8 hours.
TABLE-US-00008 TABLE 8 Subject Nr. Formula A Formula B Formula C 1
NR NR R 2 NR NR NR 3 NR NR R 4 NR NR R 5 NR NR R R = response,
i.e., nipple erection/increased sensitivity NR = no response
[0102] Due to the long acting effect of oxymetazoline it may be
beneficial to apply once daily, every other day, or as needed prior
to sexual activity or for restoration of sensation for patients
that have lost or reduced sensitivity due to surgery or breast
trauma.
Example 8
[0103] Phenylephrine HCl 15%. A study was conducted to evaluate the
effect of Phenylephrine HCl 15% on the FSFI orgasm domain. Three
premenopausal subjects participated in the study. Subjects were not
hypertensive, pregnant or breastfeeding.
TABLE-US-00009 TABLE 9 Phenylephrine FSFI Orgasm Domain Study FSFI
Scale How FSFI Scale How Often Orgasm Difficult to Reach was
Reached Inter- Orgasm Inter- Subject Nr. Baseline vention Baseline
vention 1 2 4 4 5 2 1 4 3 4 3 2 5 2 5
[0104] In addition, 3 of 5 subjects that have previously reported
to experience no increased sensitivity or nipple erection following
application of 10% Phenylephrine HCl, have reported increased
sensitivity and nipple erection following application of 15%
Phenylephrine HCl. No adverse events were reported.
[0105] Due to the shorter lasting acting effect of phenylephrine
compared to oxymetazoline it may be beneficial to apply as needed
prior to sexual activity. However, due to report of nipple
sensitivity as long as 12 hours past application, it may be
beneficial to apply phenylephrine daily.
Example 9
Synephrine HCl 50%.
[0106] A study was conducted to assess the dosage of topical
synephrine solution required to elicit nipple erection and
sensitivity. Five premenopausal subjects participated in the study.
Subjects were not hypertensive, pregnant or breastfeeding. Two
formulations were used: Formula A: 40% topical synephrine
hydrochloride solution; Formula B: 50% topical synephrine
hydrochloride solution.
[0107] The study was conducted over 2 days. On day 1, subjects were
instructed to apply Formula A to both areolas. On day 2, subjects
were instructed to apply Formula B to both areolas. 0.1 mL of each
formula was applied using a metered dosage dispenser to each
areola. Table 10 summarizes the finding from this study. The 50%
topical synephrine hydrochloride solution (Formula B) elicited a
clinical response in 4 out of 5 subjects while Formula A failed to
elicit a response.
TABLE-US-00010 TABLE 10 Synephrine Study Subject Nr. Formula A
Formula B 1 NR R 2 NR R 3 NR R 4 NR NR 5 NR R NR = No Response R =
Response i.e., nipple erection/increased sensitivity
Example 10
[0108] Erection of the Nipple Areola Complex with 1% Phenylephrine
Hydrochloride Solution
[0109] In the following experiment, a commercially available
iontophoresis patch was used to erect the nipple of a female
subject.
[0110] 1. The nipple and areola of each breast were prepared by
cleaning with a sterile alcohol pad.
[0111] 2. Two Inotopatch 80 (Travanti Medical) patches were removed
from packaging.
[0112] 3. The positive electrode of the first patch was filled with
1.3 mL of a 1% phenylephrine hydrochloride.
[0113] 4. The negative electrode of the first patch was filled with
1.3 mL of a saline solution.
[0114] 5. The positive electrode (approximately 1.5 cm diameter)
containing the drug was placed over the nipple areola complex of
the right breast; the negative electrode was placed on the adjacent
breast tissue outside the nipple areola complex of the right
breast.
[0115] 6. Steps 2-5 were repeated, however, both electrodes of the
Inotopatch 80 were filled with 1.3 mL of saline. The patch was
applied to left breast following the procedure of step 5.
[0116] 7. The patches were left in place (adhesive) for 1 hour
(dosage=4.8 A, 80 mA/min).
[0117] 8. After 1 hour the patches were removed.
[0118] After the experiment above, the patient's right nipple was
visibly erect; the left nipple was not. The patient described
increased sensitivity in the right nipple compared to the left
nipple.
Example 11
Restoration of Nipple Sensitivity Post Breast Surgery.
[0119] A case study was conducted to assess the efficacy of a
topical phenylephrine solution in increasing nipple sensitivity in
patients that reported a loss in nipple sensitivity post breast
surgery. Five subjects ages 36-65 participated in the study.
Subjects were asked to rate their nipple sensitivity on a Likert
scale (1-10) before surgery and currently (i.e., after surgery).
Next, patients were asked to apply a 10% phenylephrine solution to
each nipple areola complex. 45 minutes after application of the
drug, patients were asked again to rate their nipple sensitivity on
a Likert scale (1-10). The results of the study are summarized in
Table 11 below.
TABLE-US-00011 TABLE 11 Nipple Sensitivity Post- Breast Pre- Post-
Surgery + Patient Age Size Surgery Type Surgery Surgery Drug 1 65
34 DD Lumpectomy 10 3 8 2 38 36 D Augmentation 9 5 8 3 42 36 C
Augmentation, 8 5 6 Lift 4 36 30 C Augmentation 8 6 6 5 52 38 C
Lumpectomy, 7 0 1 Reduction, Partial Masectomy, Trans Flap
Example 12
[0120] 10%, 15% and 20% Phenylephrine Solutions Applied to
Nipple-Areola Complex.
Method:
[0121] 20 healthy, pre-menopausal females were recruited to the
study. Subjects were instructed to apply either 4 or 6 drops of an
investigational drug to each nipple areola complex. Baseline
blood-pressure, heart rate, nipple erection, nipple sensitivity,
genital lubrication and arousal were measured and recorded. 30
minutes later, blood pressure and heart rate were measured and
recorded. 60 minutes later, blood-pressure, heart rate, nipple
erection, nipple sensitivity, genital lubrication and arousal were
measured and recorded.
[0122] During the study, four parameters of efficacy were measured:
nipple erection, nipple sensitivity, genital lubrication, and
arousal. Efficacy parameters were all patient reported outcomes
measured at 0 and 60 minutes after the application of the
investigational drug. Nipple erection was determined by asking the
patient if they had experienced nipple erection during the 60
minutes after the application of the investigational drug. Nipple
sensitivity was measured with a Likert scale of 1-10 (1 being
"insensitive", 10 being "extremely sensitive/bordering on pain") at
0 and 60 minutes after the application of the investigational drug.
Genital lubrication was measured with a Likert scale of 1-10 (1
being "none", 10 being "excellent") at 0 and 60 minutes after the
application of the investigational drug. Arousal was measured with
a Likert scale of 1-10 (1 being "none", 10 being "extremely
aroused") at 0 and 60 minutes after the application of the
investigational drug. A summary of the efficacy data is presented
in the table below.
[0123] After a 48-hour washout period, subjects repeated the
procedure using 4 or 6 drops of a new arm of the study. The
subjects and the investigator were blinded to the drug assignment
in each arm. In total 6 arms were tested:
[0124] Arm 1--Placebo, 4 drops
[0125] Arm 2--10% Phenylephrine HCl, 4 drops
[0126] Arm 3--15% Phenylephrine HCl, 4 drops
[0127] Arm 4--20% Phenylephrine HCl, 4 drops
[0128] Arm 5--Placebo, 6 drops
[0129] Arm 6--10% Phenylephrine HCl, 6 drops
Results:
[0130] The tables below shows the results of the study. There were
no changes in blood pressure or heart rate of any of the subjects
participating in the study. There was one adverse event (nipple
pain) observed in the 20% Phenylephrine arm.
TABLE-US-00012 TABLE 12 Nipple Erection and Sensitivity, Four Drops
of Investigational Drug (0.114 mL) per NAC Placebo 10% PE 15% PE
20% PE Patient # Erection Sensitivity Erection Sensitivity Erection
Sensibility Erection Sensitivity 1 0 2 0 0 0 0 1 4 2 0 -1 0 0 0 2 3
0 1 1 1 0 2 1 2 4 0 0 0 0 1 3 0 0 5 0 0 0 1 0 0 1 0 6 0 1 0 1 1 2 1
1 7 0 0 1 0 0 0 0 0 9 0 1 1 5 1 5 1 1 10 0 0 0 0 0 2 1 2 11 0 0 0 1
0 0 0 0 12 0 0 0 0 0 0 13 0 0 1 2 0 2 1 2 14 0 0 0 0 0 0 0 0 15 0 0
0 0 0 1 1 1 16 0 0 1 1 1 3 1 4 17 0 0 1 2 1 9 1 9 19 0 0 1 0 0 0 1
2 20 0 0 0 1 1 1 1 1 21 1 2 0 0 22 1 0 1 1 1 3 1 0 # Patients 18 18
19 19 19 19 19 19 Responders 0 1 7 3 8 10 13 8 % Responders 0% 6%
37% 16% 42% 53% 68% 42%
TABLE-US-00013 TABLE 13 Nipple Erection and Sensitivity, Six Drops
of Investigational Drug (0.170 mL) per NAC Placebo 10% PE Patient #
Erection Sensitivity Erection Sensitivity 1 0 0 0 2 2 3 0 0 1 2 4 0
0 1 4 5 0 0 0 0 6 1 1 0 1 7 0 0 0 0 9 1 3 1 3 10 0 0 1 2 11 0 0 12
0 0 0 0 13 1 1 0 0 14 0 0 0 0 15 0 0 16 0 0 1 4 17 1 3 19 0 0 1 1
20 1 1 21 22 # Patients 14 14 16 16 Responders 3 1 8 7 % Responders
21% 7% 50% 44%
[0131] Tables 12 and 13 demonstrate the dose dependent increase in
nipple sensitivity after application of the investigational drug.
Nipple erection data was scored "1" for a positive response to the
question "Did you experience nipple erection after applying the
solution?" It was scored "0" otherwise. Sensitivity data was
tabulated by subtracting the patient reported nipple sensitivity at
60 minutes from the reported value at baseline. Subjects were asked
to rate their level of nipple sensitivity on a scale of 1-10 (1
being "non-sensitive" and 10 being "extremely sensitive, bordering
on pain.") Subjects reporting a sensitivity increase greater than 2
after the application of each investigational drug were considered
sensitivity responders.
TABLE-US-00014 TABLE 14 Change in heart rate 15, 30, and 60 minutes
after the application of four drops of investigational drug (0.114
mL) per NAC Placebo Arm A 10% Arm C HR Delta HR HR Delta HR Patient
# (t = 0) t = 15 t = 30 t = 60 (t = 0) t = 15 t = 30 t = 60 1 57 -5
2 -1 65 -2 0 -10 2 73 -9 -5 -1 63 -3 -2 -2 3 93 -1 -9 -1 90 -10 -12
-7 4 78 -6 0 -7 82 3 13 -1 5 70 7 -2 -2 85 -7 -7 -6 6 68 1 -4 1 72
0 -3 -4 7 68 4 -7 -3 68 3 -7 -4 8 80 10 7 8 74 0 -1 -1 9 63 -4 -9 0
60 3 5 5 10 80 -7 1 -3 68 -1 7 5 11 73 -5 -6 -8 71 -2 -3 -8 12 96 2
-4 -7 74 3 3 7 13 85 -2 -5 2 85 4 3 2 14 102 -3 -9 -13 96 -9 -4 2
15 65 -6 -4 -6 66 -3 -4 -1 16 80 -10 -10 -12 77 -2 -4 -9 17 61 -6
-5 -5 61 -1 -1 -4 18 88 0 -1 0 83 6 -7 -2 19 68 -1 -3 6 74 -5 0 -4
20 87 -3 -8 -2 85 0 7 -6 15% (Arm D) 20% (Arm B) HR Delta HR HR
Delta HR Patient # (t = 0) t = 15 t = 30 t = 60 (t = 0) t = 15 t =
30 t = 60 1 77 -9 -14 -16 84 -15 -20 -21 2 63 1 4 4 64 3 4 3 3 96 0
0 -6 84 -2 -6 1 4 77 -4 -1 -2 79 -1 -14 -13 5 82 -6 -2 -4 71 -2 -3
-21 6 71 4 6 -2 82 -6 7 6 7 80 -15 -10 -7 70 2 1 -1 8 89 -9 -10 -9
81 -4 7 0 9 80 -4 -4 1 80 -10 -1 -8 10 82 -8 -5 -3 82 6 -7 -6 11 82
-5 -2 -2 66 1 10 4 12 79 -3 2 0 80 -7 -9 0 13 92 -9 -12 -10 82 -5 1
-3 14 87 6 8 -6 102 -6 -1 -4 15 71 -1 5 -3 61 -1 3 4 16 72 -2 -2 -2
60 10 10 11 17 55 1 1 2 61 -4 -3 -3 18 76 -3 4 0 99 -3 -9 -6 19 76
-3 3 -6 67 7 6 9 20 80 -9 -8 -11 71 0 1 -2
TABLE-US-00015 TABLE 15 Genital lubrication and arousal, 60 minutes
after the application of different phenylephrine solutions. Placebo
(Arm A) 10% (Arm C) 15% (Arm D) 20% (Arm B) Patient # Lubrication
Arousal Lubrication Arousal Lubrication Arousal Lubrication Arousal
1 0 0 0 0 0 0 1 1 2 -1 -1 0 0 1 0 0 0 3 1 0 1 0 3 0 3 0 4 0 0 0 0 0
0 0 0 5 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 0 0 7 -2 0 0 0 0 0 2 0 8 1 0
1 0 2 0 0 0 9 0 0 0 0 0 0 0 0 10 0 0 0 0 0 0 0 0 11 0 0 0 0 0 0 0 0
12 0 0 0 0 0 0 0 0 13 0 0 0 0 0 0 0 0 14 1 0 0 0 1 0 2 0 15 0 0 0 0
0 0 0 0 16 0 0 0 0 0 0 2 0 17 0 0 0 0 0 -1 0 0 18 0 0 0 0 0 0 0 0
19 0 0 2 0 0 0 0 0 20 0 0 0 0 1 0 0 0 # Patients 20 20 20 20 20 20
20 20 Responders 0 0 1 0 2 0 4 0 Percent 0% 0% 5% 0% 10% 0% 20%
0%
[0132] Genital lubrication was measured with a Likert scale of 1-10
(1 being "none" and 10 being "excellent") at 0 and 60 minutes after
the application of the investigational drug. Arousal was measured
with a Likert scale of 1-10 (1 being "none" and 10 being "extremely
aroused") at 0 and 60 minutes after the application of the
investigational drug. Data are displayed as change from baseline of
the reported values. A subject was considered a responder for
genital lubrication if she reported a change in genital lubrication
of 2 or more.
[0133] A subject was considered a responder for arousal if she
reported a change in arousal of 2 or more.
Example 13
[0134] A study was conducted to assess the effectiveness of
different acetylcholine receptor agonists on eliciting nipple
erection and increasing nipple sensitivity in normal women aged
18-65. Ten subjects were recruited. Each subject was randomly
assigned a single agonist. Each subject self-administered a single
dose of the agonist to one NAC that was self-reported as the least
sensitive (or if no differential sensitivity, then the left NAC).
The agonists were applied in topical solutions to the NAC. The
subject was supervised by a medical professional. Blood pressure
and heart rate were monitored at baseline, 5 minutes, 10 minutes,
and 30 minutes. No changes in blood pressure or heart rate were
detected. Subjects were asked to report if they experienced nipple
erection and sensitivity in less than 10 minutes and if the effect
lasted more or less than 10 minutes. The results are reported in
Table 16. The subjects all responded to the agonists. The effect
was short-lived; however, sensitivity is some of the subjects was
reported up 60 minutes later.
TABLE-US-00016 TABLE 16 Response to acetylcholine receptor
agonists. Nipple Sensitivity Nipple Onset Effect Nipple Sensi- Time
Duration Erection tivity Dosage Agent (min) (min) (Yes/No) (Yes/No)
(mg/cm.sup.2) Acetylcholine <10 <5 Yes Yes 1.3 Nicotine
<10 <10 Yes Yes 5.0 Alpha-Lobeline <10 <10 Yes Yes 1.9
Mecholyl <10 <10 Yes Yes 2.0 Pilocarpine <10 <5 Yes Yes
6.3 Carbachol <10 <10 Yes Yes 0.6 Cevimeline <10 <10
Yes Yes 5.6 Bethanechol <10 <10 Yes Yes 12.5 Methacholine
<10 <10 Yes Yes 0.4 Metaclopramide <10 <10 Yes Yes
3.8
Example 14
A. Measurement of Nipple Sensitivity: Patient Reported Outcomes
(PRO)
[0135] Nipple sensitivity will be measured using the following PRO
efficacy parameters:
Nipple Erection:
[0135] [0136] Each subject will complete a self-report assessment
as to whether or not her nipple is erect.
Nipple Sensitivity:
[0136] [0137] Each subject will self-report her nipple sensitivity
on a Likert scale of 1 to 10: 1 being insensitive, 10 being
extremely sensitive bordering on uncomfortable/pain.
Nipple Pain:
[0137] [0138] Each subject will self-report if she is experiencing
nipple pain.
B. Measurement of Nipple Sensitivity: Quantitative Measurements
[0138] [0139] Nipple sensitivity will also be measured using
quantitative sensitivity measurements such as the following. Skin
sensitivity tests will be performed by the primary investigator in
a quiet environment. During the test, subjects will lay on a
comfortable bed with their eyes closed. The areola will be divided
into four quadrants, with the nipple considered an additional
point, for a total of five regions (FIG. 1). In each region, four
sensory modalities will be tested: light touch, temperature (hot
and cold), vibration, and pressure. The quantitative measurements
will occur at baseline, 30, and 60 minutes following application of
the interventional drug.
Light Touch Modality:
[0140] Sensitivity to light touch will be tested using a wad of
cotton wool passed smoothly over the skin. The subject will be
asked to report feeling the application of the cotton wad.
Temperature Modality:
[0141] Temperature sensitivity will be tested with tubes containing
water heated at 60.degree. C. and crushed ice, respectively, placed
on the skin for two seconds. Subjects will be asked to report if
they can feel each applied tube.
Vibration Modality:
[0142] A tuning fork vibrating at 128 vibrations per second placed
in contact with the skin for two seconds. Subjects will be asked to
report if they can feel vibrations.
Pressure Modality:
[0143] Pressure sensitivity will be measured using Semmes-Weinstein
monofilaments (Fabrication Enterprises, Inc.), corresponding to
threshold/potential skin pressure values of 0.05, 0.2, 2, 4, 10,
and 300 grams. The monofilament is used to exert pressure until it
is bent, and the pressure is maintained for 5 seconds. Starting
with the lightest filament, subjects will be asked to report if
they can feel each of the monofilaments in a stepwise fashion. The
lowest value will be recorded as the pressure threshold for the
region.
* * * * *
References