Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02933921 2016-06-20
Methods of Treating Women for Hypoactive Sexual Desire Disorder (HSDD)
with Bupropion and Trazodone Combination Treatment
Cross-Reference to Related Patent Applications
This application is related and claims priority to U.S. provisional
Application No. 62/351,904,
filed on June 17, 2016 and entitled "Methods of Treating Women for Hypoactive
Sexual Desire
Disorder (HSDD) with Bupropion and Trazadone Combination Treatment", which is
incorporated herein by reference in its entirety.
This application is also related to U.S. Patent Application No. 14/045,677,
filed on October 3,
2013 and entitled "Treatment Regimens", and U.S. Patent Application No.
14/120,112, filed on
August 6, 2013 and entitled "Treatment Regimens", each of which is
incorporated herein by
reference in its entirety as if fully set forth herein.
Background
Hypoactive sexual desire disorder (HSDD) is one of, if not, the most common
sexual dysfunction
problems presented today to clinicians for diagnosis and treatment. HSDD
affects men and
women of all ages. According to myVMC, it is estimated that approximately 20%
of men and
33% of women are affected by low or absent sexual desire. See "Hypoactive
Sexual Desire
Disorder (HSDD)", reported at http://www.myvinc.com/diseases/hypoactive-sexual-
desire-
disorder-hsdd/.
HSDD is defined as "a deficiency or absence of sexual fantasies and desire for
sexual activity.
The disturbance must cause marked distress or interpersonal difficulty." See
Diagnostic and
Statistical Manual of the American Psychiatric Association (DSM-IV-TR), 4th
Ed., Text Rev.
Washington, DC: American Psychiatric Association, 2000; and International
Classification of
Diseases (ICD-10, F52.0).
HSDD can have serious deleterious effects on the overall health of women,
their quality of life,
and the well-being of their personal relationships. The lack of sexual desire
in women may not
only cause severe psychological, emotional and/or relationship distress which,
in some cases, can
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be severe and debilitating, it can negatively impact their personal
relationships, quality of life,
and well-being. HSDD can be a major impediment to life satisfaction and
happiness.
[0004] Thus, Clinicians need to understand the implications and address the
concerns of their
patients.
Unlike other physical disorders, HSDD diagnosis is generally a subjective
diagnosis by the
health care provider. HSDD diagnosis therefore typically relies upon clinical
judgment based on
the individual's characteristics, the interpersonal determinants including
relationship, the life and
home context, and the cultural setting. Women with HSDD typically have a
decline in sexual
thoughts, a decline in interest in initiating sexual relations, and a decline
in being receptive to a
partner's initiation.
While HSDD is the most common sexual disorder for women of all ages, to date,
it has been
difficult to address and the prevalence rates have varied from study to study,
as exemplified
above and as follows. For example, Segraves and Woodard referenced reports
that HSDD
affects between about 5.4% and about 13.6% women. See Segraves R, Woodard T:
Female
hypoactive sexual desire disorder: history and current status. J Sex Med,
3(3):408-418 (2006).
West et al. reports that HSDD affects about 8.3% women. See West SL, D'Aloisio
AA, Agans
RP, Kalsbeek WD, Borisov NN, Thorp JM: Prevalence of low sexual desire and
hypoactive
sexual desire disorder in a nationally representative sample of US women. Arch
Intern Med.,
168(13):1441-1449 (2008). The Prevalence of Female Sexual Problems Associated
with
Distress and Determinants of Treatment Seeking study (the PRESIDE Study)
reports that HSDD
affects about 8.9% of women between the ages of 18 to 44, about 12.3% of women
between the
ages of 45 to 64, and about 7.4% of women who are 65 years in age or older.
Shifren JL, Monz
BU, Russo PA, Segreti A, Johannes CB: Sexual problems and distress in United
States women:
prevalence and correlates. Obstet Gynecol., 112(5):970-978 (2008). Meanwhile,
the
International Society for Sexual Medicine reports that HSDD affects about 10%
of all women.
See "Hypoactive Sexual Desire Disorder In Women", as reported at
http://www.issminfo/who-
we-are/public-policy/hypoactive-sexual-desire-disorder-in-women/. See also
West SL1,
D'Aloisio AA, Agans RP, Kalsbeek WD, Borisov NN, Thorp JM: Prevalence of low
sexual
desire and hypoactive sexual desire disorder in a nationally representative
sample of US women.
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Arch Intern Med., 168(13):1441-9 (July 14, 2008). The variation in prevalence
between studies
could be due to differences in, for example, the definition of HSDD utilized,
data collection
methods utilized, age-groups studied, and other selected criteria utilized.
On August 18, 2015, the FDA approved Addyi (flibanserin) to treat acquired,
generalized
hypoactive sexual desire disorder (HSDD) in premenopausal women. See
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm. To
date,
Addyi (flibanserin) is the first and only treatment approved by the FDA to
treat HSDD.
Unfortunately, Addyi (flibanserin) so far has not apparently enjoyed the same
level of success
as Viagra or other phosphodiesterase (PDE) inhibitors for the treatment of
erectile dysfunction
in men. Rather, the sales for Addyi (flibanserin), since launch, have been
met with what
appears to be considerable disappointment. See, e.g., "Selling 'Female
Viagra': Agreement With
FDA Forces Sprout Pharmaceuticals To Market Its Low Sexual Desire Pill In New
Ways", as
reported at http://www.ibtimes.com/selling-female-viagra-agreement-fda-forces-
sprout-
pharmaceuticals-market-its-low-2147020; "Why Sales of 'Female Viagra' Addyi
Have Been So
Anticlimactic", as reported at http://time.com/money/4116171/female-viagra-
addyi-sales/; "The
Female Libido Pill Is No Viagra", as reported at
http://www.bloomberg.com/news/articles/2015-
11-17/valeant-s-newest-problem-the-female-libido-pill-isn-t-selling; "Female
Sex Drug Addyi
Not Sprouting Sales for Valeant (VRX)", as reported at
http://www.biospace.com/News/female-
sex-drug-addyi-not-sprouting-sales-for/399895; and "Pill for Low Libido in
Women Goes on
Sale on Saturday", as reported at
https://www.nlm.nih.gov/medlineplus/news/fullstory 155191.html.
According to the article entitled "Five Studies: Does Flibanserin Provide Real
Sexual Benefits
for Women?", as reported in Pacific Standard, the Addyi (flibanserin) placebo-
controlled trials
in HSDD showed only about a 7% improvement over placebo. More specifically,
"Nile trial
found a trend among outcomes: Women achieved an average of one more
"satisfying sexual
event" per month on flibanserin. These could include any type of genital
stimulation. More than
23 percent of women on flibanserin felt that they were "very much" or "much"
improved,
compared with 16.2 percent on placebo." See http://www.psmag.com/health-and-
behavior/is-
flibanserin-the-real-deal-or-a-pharmaceutical-ploy. In that same Pacific
Standard article, it
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suggests that `Thesearch suggests that the now-FDA-approved female libido-
booster is¨at least
in part¨a pharmaceutical ploy." See http://www.psmag.com/health-and-
behavior/is-flibanserin-
the-real-deal-or-a-pharmaceutical-ploy.
Thus, notwithstanding the overwhelming and growing need to effectively treat
women for
HSDD, and the approval of Addyi0 (flibanserin) by the FDA, such a treatment
still remains
elusive and unmet. Consequently, it is apparent that HSDD needs greater
attention from
healthcare professionals across all clinical disciplines. It is equally
apparent that there still is a
need for an effective HSDD treatment that can be prescribed to women to treat
women for
HSDD with therapeutic confidence.
Summary of the Invention
The present invention overcomes the drawbacks and disadvantages of the current
state of
treatments of women for HSDD through the discovery of a novel and effective
combination
treatment for treating women for HSDD.
Generally speaking, the novel combination treatments of the present invention
comprise treating
women for HSDD, who are in need of HSDD treatment, with a combination of two
drugs,
namely, bupropion and trazodone, in accordance with specific treatment
regimens. Specifically,
the combination treatments of the present invention comprise administering to
a woman
bupropion either once or twice daily and trazodone once daily, each in amounts
effective to treat
the woman for HSDD. More specifically, and in accordance with the present
invention, the
bupropion is administered to a woman in the morning or in the morning and
again about 8 hours
later in the latter part of the afternoon in two equal dosage amounts and the
trazodone is
administered to the woman at night, preferably at bedtime, in a single dosage
amount. Even
more specifically, the bupropion dosage strength that is used in accordance
with the present
invention to treat women for HSDD, whether administered once daily or twice
daily, is 150 mg,
and the trazodone dosage strength that is used in accordance with the present
invention to treat
women for HSDD is 75 mg or 150 mg. Preferably, both the bupropion and
trazodone are oral
extended release (ER) or sustained release (SR) dosage forms, and the women
that are treated for
HSDD are premenopausal women.
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The moderate dose treatment regimen in accordance with the present invention,
i.e., oral
bupropion 150 mg twice daily (preferably ER or SR), wherein the first
bupropion dosing is
administered in the morning and the second bupropion dosing is administered
about 8 hours
thereafter, and oral trazodone 150 mg once daily (preferably ER or SR),
wherein the trazodone is
administered once daily at bedtime, is referred to herein as "Moderate Dose
Lorexys". The
lower dose treatment regimen in accordance with the present invention, i.e.,
oral bupropion 150
mg once daily (preferably ER or SR), wherein the bupropion is administered
once daily in the
morning, and oral trazodone 75 mg once daily (preferably ER or SR), wherein
the trazodone is
administered once daily at night at bedtime, is referred to herein as "Low
Dose Lorexys". Thus,
the present invention contemplates a daily treatment combination dosage range
of between about
75 mg and about 150 mg of trazodone and between about 150 mg and 300 mg of
bupropion
administered daily. While the trazodone is preferably administered at night
and most preferably
at bedtime and the bupropion is preferably administered in the morning and/or
at night, and more
preferably in the morning, the present invention contemplates the
administration of both
trazodone and bupropion together at any time of the day either in separate
dosage forms or in a
unitary dosage form that contains both drugs.
Uniquely, the novel combination treatments of the present invention show
unexpected
superiority over the HSDD treatments for woman available heretofore in
efficacy and/or
inducing fewer or no side effects. In an HSDD clinical trial for premenopausal
women to test
safety and efficacy of the Moderate Dose Lorexys and the Low Dose Lorexys, in
which standard
measures of sexual desire and sexual distress were used, the percentage of
women treated with
Low Dose Lorexys and Moderate Dose Lorexys who met responder criteria were at
about 76%
and about 88%, respectively. In contrast, only 36% and 45%, respectively, of
the same women,
who were treated with only bupropion SR at the same dosage strengths and in
accordance with
the same treatment regimens, met responder criteria.
These advantages of the present invention are not just highly statistically
significant, p 0.01,
they are highly unexpected. The % of women who met the criteria for remission
on Low Dose
Lorexys and Moderate Dose Lorexys showed similar advantage over bupropion
treatment.
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In addition, the Low Dose Lorexys and Moderate Dose Lorexys treatments of the
present
invention are also an advantage over prior treatments in how rapidly patients
responded.
Remission typically takes at least 3 months with other treatments, but, with
the Low Dose
Lorexys and Moderate Dose Lorexys treatments of the present invention, about
58% of the
treated women surprisingly met remission criteria within about 4 weeks.
As to side effects, the main side effects of concern to the FDA for drugs in
this field have been
related to over-sedation, i.e., somnolence, fatigue, dizziness, depression,
accidents, and fainting,
all of which worsen with alcohol. However, surprisingly and quite unexpected,
no sedative-type
side effect during the clinical trial was rated as severe for the women
treated with the Low Dose
Lorexys and Moderate Dose Lorexys of the present invention. Also quite
surprising and
unexpected, treatment of the women with the Low Dose Lorexys and Moderate Dose
Lorexys of
the present invention during the clinical trial did not lead to
discontinuation and no depression,
fainting, or accidents were observed.
A "Responder", as used herein, means a sexual desire Responder, one who
improve by 2 points
on the standard scale from 2-10. Responder is defined on the desire subscale
of the Female
Sexual Function Inventory; the subscale ranges from 2 (desire at very low or
none and almost
never or never) to 10 (desire at very high and almost always or always).
A "Remitter", as used herein is one whose score is at least 5.
Alternatively, a sexual distress Responder is one who improves by one point on
the standard
scale from 0 to 4. The measure is the "bothered by low sexual desire" item of
the Female Sexual
Distress Scale - Revised, and it ranges from 4, always, to 0, never, and a
Remitter is one whose
score is no higher than 2, occasionally.
In one aspect, the invention provides compositions and methods of treating a
subject suffering
from or susceptible to a sexual disorder or symptom thereof (e.g., HSDD,
erectile disorder,
sexual interest arousal disorder, FSD, MSD, and the like) comprising
administering to a subject
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in need thereof a therapeutically effective amount of a composition delineated
herein.
In one aspect, the invention provides a composition comprising a 5-HT2A
antagonist, a
norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable
carrier. In
another aspect the composition is that wherein the 5-HT2A antagonist is also a
5-HTIA receptor
agonist. In another aspect the composition is that comprising trazodone and
bupropion. In
another aspect the composition is that comprising trazodone in a dosage range
of 25-450 mg and
bupropion in a dosage range of 200-450 mg. In another aspect the composition
is that comprising
trazodone in a dosage range of 25-450 mg and bupropion in a dosage range of 25-
450 mg.
In one embodiment, the composition is that comprising bupropion, comprising
bupropion in a
dosage range of 200-450 mg; comprising bupropion in a dosage range of 225-300
mg; or
comprising bupropion in a dosage range of 200-275 mg; comprising bupropion in
a dosage range
of 100-450 mg; comprising bupropion in a dosage range of 100-275 mg;
comprising bupropion
in a dosage range of 25-275 mg; comprising bupropion in a dosage range of XX-
YY mg,
wherein XX is an integer between 5 and 400 and YY is an integer between 50 and
450.
In one embodiment, the composition is that comprising trazodone, comprising
trazodone in a
dosage range of 25-450 mg; comprising trazodone in a dosage range of 75-150
mg; or
comprising trazodone in a dosage range of 50-100 mg; comprising trazodone in a
dosage range
of XX-YY mg, wherein XX is an integer between 25 and 400 and YY is an integer
between 50
and 450.
In one aspect, the invention provides a method of treating a subject suffering
from or susceptible
to a hypoactive sexual desire disorder (HSDD) comprising administering to a
subject in need
thereof a therapeutically effective amount of a composition comprising a 5-
HT2A antagonist, a
norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable
carrier. In one
aspect, one compound is both a 5-HT2A antagonist and a 5-HTIA receptor agonist
(e.g.,
trazodone). In another aspect, the norepinephrine-dopamine reuptake inhibitor
is also a alpha
adrenergic blocker (e.g., bupropion).
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In one aspect, the invention provides a method of treating a subject suffering
from or susceptible
to a hypoactive sexual desire disorder (HSDD) comprising administering to a
subject in need
thereof a therapeutically effective amount of a composition comprising a 5-
HTIA receptor
agonist, a 5-HT2A antagonist, and a pharmaceutically acceptable carrier. In
one aspect, one
compound is the 5-HTIA receptor agonist and the 5-HT2A antagonist (e.g.,
trazodone).
In aspects, the method is that wherein the sexual disorder (SD) is female
sexual disorder (FSD).
In aspects, the method is that wherein the SD is female orgasm disorder (FOD);
wherein the SD
is female sexual arousal disorder (FSAD); or wherein the SD is sexual pain
disorder or
dysfunction. In aspects, the method is that wherein the FSD includes one or
more simultaneous
dysfunctions of sexual desire, arousal, orgasm, and/or pain. In aspects, the
method is that
wherein the SD is male sexual disorder (MSD).
Another aspect is a method of treating a disease, disorder or symptom thereof
described in the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) in a subject
comprising
administering to the subject a compound or composition herein.
Another aspect is a method of treating erectile dysfunction (ED) in a subject
comprising
administering to the subject a compound or composition herein.
Another aspect is a method of treating male HSDD in a subject comprising
administering to the
subject a compound or composition herein.
Another aspect is an extended release composition comprising a 5-HT2A
antagonist, a
norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable
carrier.
In one aspect, the invention provides a composition comprising the 5-HTIA
receptor agonist and
5-HT2A antagonist nefazodone and a pharmaceutically acceptable carrier.
In one aspect, the invention provides a composition comprising the 5-HTIA
receptor agonist and
5-HT2A antagonist mirtazapine and a pharmaceutically acceptable carrier.
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Other aspects include those, wherein the composition is administered orally;
wherein the
composition is administered topically; wherein the subject is diagnosed and
being treated for
depression; wherein the subject is not undergoing treatment for depression;
wherein the subject
is concurrently prescribed an additional therapeutic agent; or wherein the
subject is concurrently
not prescribed an additional therapeutic agent; wherein the subject is
concurrently administered
an additional therapeutic agent; or wherein the subject is concurrently not
administered an
additional therapeutic agent.
In one aspect, the invention provides a composition comprising a 5-HTIA
receptor agonist, a 5-
HT2A antagonist, and a pharmaceutically acceptable carrier.
In one embodiment, the composition is that comprising bupropion, comprising
bupropion in a
dosage range of 100-450 mg qd; comprising bupropion in a dosage range of 200-
450 mg qd;
comprising bupropion in a dosage range of 100-300 mg qd; comprising bupropion
in a dosage
range of 225-300 mg qd; comprising bupropion in a dosage range of 100-275 mg
qd; or
comprising bupropion in a dosage range of 200-275 mg qd; comprising bupropion
in a dosage
range of XX-YY mg qd, wherein XX is an integer between 5 and 400 and YY is an
integer
between 50 and 450.
In one embodiment, the composition is that comprising trazodone, comprising
trazodone in a
dosage range of 25-450 mg qd; comprising trazodone in a dosage range of 75-150
mg qd; or
comprising trazodone in a dosage range of 50-100 mg qd; comprising trazodone
in a dosage
range of XX-YY mg qd, wherein XX is an integer between 25 and 400 and YY is an
integer
between 50 and 450.
In one embodiment, the composition is that comprising bupropion and trazodone,
comprising
bupropion in a dosage range of 50-450 mg and trazodone in a dosage range of 25-
450 mg;
comprising bupropion in a dosage range of 200-450 mg and trazodone in a dosage
range of 25-
450 mg; comprising bupropion in a dosage range of 100-300 mg qd and comprising
trazodone in
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a dosage range of 75-150 mg qd; comprising bupropion in a dosage range of 225-
300 mg qd and
comprising trazodone in a dosage range of 75-150 mg qd; comprising bupropion
in a dosage
range of 100-275 mg qd and comprising trazodone in a dosage range of 50-100 mg
qd; or
comprising bupropion in a dosage range of 200-275 mg qd and comprising
trazodone in a dosage
range of 50-100 mg qd.
In one aspect, the invention provides a method of making a composition
comprising combining a
5-HT2A antagonist, a norepinephrine-dopamine reuptake inhibitor, and a
pharmaceutically
acceptable carrier. In one aspect, the invention provides a method of making a
composition
comprising combining a 5-HTIA receptor agonist, 5-HT2A antagonist, and a
pharmaceutically
acceptable carrier. In one aspect, the invention provides a method of making a
composition
comprising combining a 5-HTIA receptor agonist, and a pharmaceutically
acceptable carrier. In
one aspect, the invention provides a method of making a composition comprising
combining a 5-
HTIA antagonist, and a pharmaceutically acceptable carrier.
In one aspect, the method of making a composition comprises combining a 5-HTIA
receptor
agonist, a norepinephrine-dopamine reuptake inhibitor and a pharmaceutically
acceptable carrier
such that the composition comprises a range of 25-450 of a 5-HTIA receptor
agonist. In another
aspect, the method of making comprises combining a 5-HT2A antagonist and a
pharmaceutically
acceptable carrier such that the composition comprises a range of 25-450 mg of
a 5-HT2A
antagonist and a norepinephrine-dopamine reuptake inhibitor.
In one embodiment, the method comprises combining bupropion, trazodone, and a
pharmaceutically acceptable carrier.
In one aspect, the invention provides a kit comprising a composition
delineated herein and a
label providing instructions for administration of the composition to a
subject for treating or
ameliorating HSDD or symptoms thereof in the subject.
In another aspect, the invention provides a method of treating hypoactive
sexual desire disorder
(HSDD) in a subject comprising administering to the subject a 5-HTiA receptor
agonist, and a 5-
CA 02933921 2016-06-20
HT2A antagonist. The methods herein can further comprise those wherein the
subject is identified
as in need of such treatment, and those wherein the subject is treated upon
administration of the
compounds and/or compositions herein. The methods can include those wherein
the subject has
not previously been administered the compounds and/or compositions herein, or
wherein the
subject has not previously been administered the compounds and/or compositions
herein at the
stated dosage levels or administration regimens.
In another embodiment, the invention a method of treating a subject suffering
from or
susceptible to a hypoactive sexual desire disorder (HSDD) comprising
administering to a subject
in need thereof a therapeutically effective amount of a composition comprising
any one of a 5-
HT2A antagonist, a norepinephrine-dopamine reuptake inhibitor, a 5-HTIA
receptor agonist, an
endocrine active agent, or any combination thereof and a pharmaceutically
acceptable carrier.
In another aspect, the invention provides a method of treating hypoactive
sexual desire disorder
(HSDD) in a subject comprising administering to the subject a therapeutically
effective amount
of any one of a 5-HT2A antagonist, a norepinephrine-dopamine reuptake
inhibitor, a 5-HTIA
receptor agonist, an endocrine active agent, or any combination thereof.
In aspects the endocrine agent is testosterone, which can be in an amount of a
dosage range of 25
to 1000 mg.
In aspects, the subject is that wherein the subject is not being treated with
a selective serotonin
reuptake inhibitor (SSRI) agent.
In aspects, the subject is that wherein the subject is being treated with a
selective serotonin
reuptake inhibitor (S SRI) agent.
In aspects, the subject is that wherein the subject is identified as having
selective serotonin
reuptake inhibitor (SSRI) agent induced HSDD.
In aspects, the subject is that wherein the subject is being treated with a
PDE-5 inhibitor
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compound (i.e., sildenafil, tadalafil, and the like).
In aspects, the subject is that wherein the subject is not concurrently being
treated with a PDE-5
inhibitor compound (i.e., sildenafil, tadalafil, and the like).
In aspects, the subject is that wherein the subject is being treated with an
endocrine agent (e.g.,
testosterone).
In aspects, the subject is that wherein the subject is not concurrently being
treated with an
endocrine agent (e.g., testosterone).
In another aspect, the methods herein comprise taking a sample (i.e., fluid,
blood, urine, saliva,
tissue, etc.) and assessing a biological marker (i.e., liver enzymes, CYP3A4,
and/or a genetic
marker of the transport, receptor type, receptor density, receptor affinity,
metabolism, or activity
of serotonin, serotonin lA or 2A subtype, dopamine, or a receptor subtype of
dopamine) to
measure health status of the subject either prior to, during or after
administration of the
compositions herein.
Brief Description of the Figures
The foregoing and other objects, advantages and features of the present
invention,
and the manner in which the same are accomplished, will become more readily
apparent
upon consideration of the following detailed description of the invention
taken in
conjunction with the accompanying figures and example, which illustrate
embodiments,
wherein:
FIG. 1 summarizes the results of a Phase ha 3-way open label cross-over study
in which
proprietary combinations of trazodone and bupropion were used to treat
premenopausal women
for hypoactive sexual desire disorder (HSDD);
FIG. 2 summarizes the design and doses of the Phase ha 3-way open label cross-
over
study;
FIG. 3 summarizes the entry criteria: inclusions of the Phase Ha 3-way open
label cross-
over study;
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FIG. 4 summarizes the entry criteria: exclusions of the Phase Ha 3-way open
label cross-
over study;
FIG. 5 depicts a graph showing sample size: 30 for > 80% power to detect a
delta of 35%
between control (bupropion) and Low Dose Lorexys and Moderate Dose Lorexys of
the Phase
ha 3-way open label cross-over study;
FIG. 6 summarizes the dispositions of the patients in the of the Phase ha 3-
way open
label cross-over study;
FIG. 7 summarizes the % responders for Moderate Dose Lorexys vs Bupropion of
the
Phase Ha 3-way open label cross-over study;
FIG. 8 summarizes the % of patients reaching remission for Low Dose Lorexys vs
Bupropion of the Phase Ha 3-way open label cross-over study;
FIG. 9 summarizes Low Dose Lorexys intermediate efficacy as to patients'
global
impression of change, that is, % improved, for all those patients with an end
of study evaluation
of the Phase Ha 3-way open label cross-over study;
FIG. 10 summarizes the adverse events of the Phase ha 3-way open label cross-
over
study; and
FIG. 11 summarizes the conclusions of the Phase Ha 3-way open label cross-over
study.
Detailed Description of the Invention
The present inventors have now discovered a therapeutic strategy that
addresses hypoactive
sexual desire disorder (HSDD) in a woman and, in particular, a pre-menopausal
woman.
The present invention relates, at least in part, to the discovery that a
combination of a 5-HT2A
antagonist (which is optionally a 5-HTIA receptor agonist), a norepinephrine-
dopamine reuptake
inhibitor, (and optionally an endocrine active agent) provides unexpected
superior and
synergistic results in addressing hypoactive sexual desire disorder (HSDD) in
a subject.
1. Definitions
Before further description of the present invention, and in order that the
invention may be more
readily understood, certain terms are first defined and collected here for
convenience.
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The term "administration" or "administering" includes routes of introducing
the compound of the
invention(s) to a subject to perform their intended function. Examples of
routes of administration
that may be used include injection (subcutaneous, intravenous, parenterally,
intraperitoneally,
intrathecal), oral, buccal, sublingual, inhalation, rectal and transdermal.
The pharmaceutical
preparations may be given by forms suitable for each administration route. For
example, these
preparations are administered in tablets or capsule form, by injection,
inhalation, eye lotion,
ointment, suppository, etc. administration by injection, infusion or
inhalation; topical by lotion or
ointment; and rectal by suppositories. Oral administration is preferred. The
injection can be bolus
or can be continuous infusion. Depending on the route of administration, the
compound of the
invention can be coated with or disposed in a selected material to protect it
from natural
conditions which may detrimentally effect its ability to perform its intended
function. The
compound of the invention can be administered alone, or in conjunction with
either another
agent as described above or with a pharmaceutically-acceptable carrier, or
both. The compound
of the invention can be administered prior to the administration of the other
agent,
simultaneously with the agent, or after the administration of the agent.
Furthermore, the
compound of the invention can also be administered in a pro-drug form which is
converted into
its active metabolite, or more active metabolite in vivo.
The language "biological activities" of a compound of the invention includes
all activities
elicited by compound of the inventions in a responsive cell. It includes
genomic and non-
genomic activities elicited by these compounds.
"Biological composition" or "biological sample" refers to a composition
containing or derived
from cells or biopolymers. Cell-containing compositions include, for example,
mammalian
blood, red cell concentrates, platelet concentrates, leukocyte concentrates,
blood cell proteins,
blood plasma, platelet-rich plasma, a plasma concentrate, a precipitate from
any fractionation of
the plasma, a supernatant from any fractionation of the plasma, blood plasma
protein fractions,
purified or partially purified blood proteins or other components, serum,
semen, mammalian
colostrum, milk, saliva, placental extracts, a cryoprecipitate, a
cryosupernatant, a cell lysate,
mammalian cell culture or culture medium, products of fermentation, ascites
fluid, proteins
induced in blood cells, and products produced in cell culture by normal or
transformed cells
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(e.g., via recombinant DNA or monoclonal antibody technology). Biological
compositions can
be cell-free. In a preferred embodiment, a suitable biological composition or
biological sample is
a red blood cell suspension. In some embodiments, the blood cell suspension
includes
mammalian blood cells. Preferably, the blood cells are obtained from a human,
a non-human
primate, a dog, a cat, a horse, a cow, a goat, a sheep or a pig. In preferred
embodiments, the
blood cell suspension includes red blood cells and/or platelets and/or
leukocytes and/or bone
marrow cells.
The term "effective amount" includes an amount effective, at dosages and for
periods of time
necessary, to achieve the desired result, e.g., sufficient to treat a
hypoactive sexual desire
disorder in a subject. An effective amount of compound of the invention may
vary according to
factors such as the disease state, age, and weight of the subject, and the
ability of the compound
of the invention to elicit a desired response in the subject. Dosage regimens
may be adjusted to
provide the optimum therapeutic response. An effective amount is also one in
which any toxic or
detrimental effects (e.g., side effects) of the compound of the invention are
outweighed by the
therapeutically beneficial effects.
A therapeutically effective amount of compound of the invention (i.e., an
effective dosage) may
range from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25
mg/kg body
weight, more preferably about 0.1 to 20 mg/kg body weight, and even more
preferably about 1 to
mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
The skilled
artisan will appreciate that certain factors may influence the dosage required
to effectively treat a
subject, including but not limited to the severity of the disease or disorder,
previous treatments,
the general health and/or age of the subject, and other diseases present.
Moreover, treatment of a
subject with a therapeutically effective amount of a compound of the invention
can include a
single treatment or, preferably, can include a series of treatments. In one
example, a subject is
treated with a compound of the invention in the range of between about 0.1 to
20 mg/kg body
weight, one time per week for between about 1 to 10 weeks, preferably between
2 to 8 weeks,
more preferably between about 3 to 7 weeks, and even more preferably for about
4, 5, or 6
weeks. It will also be appreciated that the effective dosage of a compound of
the invention used
for treatment may increase or decrease over the course of a particular
treatment. Administration
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regimens herein where designated are in accordance with the following
abbreviations: SID or
QD=Once a day; BID=Twice a day, TID=Three times a day; QID=Four times a day;
q.h.s=every
night.
The term "homeostasis" is art-recognized to mean maintenance of static, or
constant, conditions
in an internal environment.
The language "improved biological properties" refers to any activity inherent
in a compound of
the invention that enhances its effectiveness in vivo. In a preferred
embodiment, this term refers
to any qualitative or quantitative improved therapeutic property of a compound
of the invention,
such as reduced toxicity.
The term "modulate" refers to an increase or decrease, e.g., the alteration in
hypoactive sexual
desire disorder and/or symptoms thereof in a subject such that a desired end
result is achieved,
e.g., a therapeutic result.
The term "obtaining" as in "obtaining a compound useful in treating hypoactive
sexual desire
disorder" is intended to include purchasing, synthesizing or otherwise
acquiring the compound.
The phrases "parenteral administration" and "administered parenterally" as
used herein means
modes of administration other than enteral and topical administration, usually
by injection, and
includes, without limitation, intravenous, intramuscular, intraarterial,
intrathecal, intracapsular,
intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular,
intraarticulare, subcapsular, subarachnoid, intraspinal and intrastemal
injection and infusion.
The language "a prophylactically effective amount" of a compound refers to an
amount of a
compound of the invention any formula herein or otherwise described herein
which is effective,
upon single or multiple dose administration to the patient, in preventing or
treating a sexual
disorder.
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The language "reduced toxicity" is intended to include a reduction in any
undesired side effect
elicited by a compound of the invention when administered in vivo.
The term "subject" includes organisms which are capable of suffering from a
sexual disorder or
who could otherwise benefit from the administration of a compound or
composition of the
invention, such as human (male or female) and non-human animals (male or
female). Preferred
humans include human patients suffering from or prone to suffering from
hypoactive sexual
desire disorder or associated state, as described herein. The term "non-human
animals" of the
invention includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice,
and non-mammals,
such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians,
reptiles, etc.
The term "susceptible to a hypoactive sexual desire disorder" is meant to
include subjects at risk
of developing hypoactive sexual desire disorder, e.g., subjects previously
diagnosed as having or
having a family or medical history of hypoactive sexual desire disorder, and
the like.
The phrases "systemic administration, "administered systemically", "peripheral
administration"
and "administered peripherally" as used herein mean the administration of a
compound of the
invention(s), drug or other material, such that it enters the patient's system
and, thus, is subject to
metabolism and other like processes, for example, subcutaneous administration.
The language "therapeutically effective amount" of a compound of the invention
of the invention
refers to an amount of an agent which is effective, upon single or multiple
dose administration to
the patient, in modulating hypoactive sexual desire disorder and/or symptoms
of hypoactive
sexual desire disorder, or in improving the patient (either objectively or
subjectively according to
the patient or health care provider) beyond that expected in the absence of
such treatment.
2. Compounds of the Invention
In one aspect, the invention provides compounds capable of modulating
hypoactive sexual desire
disorder in a subject. Such compounds include a 5-HT2A antagonist, a 5-HTIA
receptor agonist, a
norepinephrine-dopamine reuptake inhibitor, and an endocrine active agent.
Compositions of the
17
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invention further include a pharmaceutically acceptable carrier.
The compounds delineated herein include a 5-HT2A antagonist, that is a
compound that
demonstrates antagonistic activity against the 5-HT2A receptor; a
norepinephrine-dopamine
reuptake inhibitor; that is a compound that exhibits inhibition activity in
norepinephrine-
dopamine reuptake; a 5-HTIA receptor agonist, that is a compound that
demonstrates agonist
activity against the 5-HTIA receptor; and an endocrine active agent, that is
an agent that is active
in modulating the endocrine system.
In one embodiment, the invention provides a compound (e.g., a compound herein)
capable of
modulating hypoactive sexual desire disorder; and pharmaceutically acceptable
esters, salts,
hydrates, solvates, isomers and prodrugs thereof
Naturally occurring or synthetic isomers can be separated in several ways
known in the art.
Methods for separating a racemic mixture of two enantiomers include
chromatography using a
chiral stationary phase (see, e.g., "Chiral Liquid Chromatography," W. J.
Lough, Ed. Chapman
and Hall, New York (1989)). Enantiomers can also be separated by classical
resolution
techniques. For example, formation of diastereomeric salts and fractional
crystallization can be
used to separate enantiomers. For the separation of enantiomers of carboxylic
acids, the
diastereomeric salts can be formed by addition of enantiomerically pure chiral
bases such as
brucine, quinine, ephedrine, strychnine, and the like. Alternatively,
diastereomeric esters can be
formed with enantiomerically pure chiral alcohols such as menthol, followed by
separation of the
diastereomeric esters and hydrolysis to yield the free, enantiomerically
enriched carboxylic acid.
For separation of the optical isomers of amino compounds, addition of chiral
carboxylic or
sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or
lactic acid can result
in formation of the diastereomeric salts.
3. Uses Of The Compounds of the Invention
In one embodiment, the invention provides methods of treating hypoactive
sexual desire disorder
(HSDD) in a subject comprising administering to the subject a composition
delineated herein. In
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certain embodiments, the subject is a mammal, e.g., a primate, e.g., a human.
In aspect, the
disease, disorder or symptom thereof in which the compounds, compositions, and
methods of
treatment relate to is one described in the Diagnostic and Statistical Manual
of Mental Disorders
4<sup>th</sup> edition--Text Revision, (DSM-I-TRV), American Psychiatric
Association.
In certain embodiments, the methods of the invention include administering to
a subject a
therapeutically effective amount of a compound of the invention in combination
with another
pharmaceutically active compound. Examples of pharmaceutically active
compounds include
compounds known to treat hypoactive sexual desire disorder (HSDD) in a
subject. Other
pharmaceutically active compounds that may be used can be found in Harrison's
Principles of
Internal Medicine, Thirteenth Edition, Eds. T. R. Harrison et al. McGraw-Hill
N.Y., NY; and the
Physicians Desk Reference 50th Edition 1997, Oradell N.J., Medical Economics
Co., the
complete contents of which are expressly incorporated herein by reference. The
compound of the
invention and the pharmaceutically active compound may be administered to the
subject in the
same pharmaceutical composition or in different pharmaceutical compositions
(at the same time
or at different times).
Determination of a therapeutically effective hypoactive sexual desire disorder
(HSDD) effective
amount, a prophylactically effective hypoactive sexual desire disorder amount
of the compound
of the invention, can be readily made by the physician or veterinarian (the
"attending clinician"),
as one skilled in the art, by the use of known techniques and by observing
results obtained under
analogous circumstances. The dosages may be varied depending upon the
requirements of the
patient in the judgment of the attending clinician; the severity of the
condition being treated and
the particular compound being employed. In determining the therapeutically
effective hypoactive
sexual desire disorder amount or dose, and the prophylactically effective
hypoactive sexual
desire disorder amount or dose, a number of factors are considered by the
attending clinician,
including, but not limited to: the specific hypoactive sexual desire disorder
involved;
pharmacodynamic characteristics of the particular agent and its mode and route
of
administration; the desired time course of treatment; the species of mammal;
its size, age, and
general health; the specific disease involved; the degree of or involvement or
the severity of the
disease; the response of the individual patient; the particular compound
administered; the mode
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of administration; the bioavailability characteristics of the preparation
administered; the dose
regimen selected; the kind of concurrent treatment (i.e., the interaction of
the compound of the
invention with other co-administered therapeutics); and other relevant
circumstances.
The dosage administration can be in a single dosage form or multiple dosage
forms. The dosages
can be administered concurrently, simultaneously, or sequentially. The dosages
can be a single
dosage immediately prior to sexual activity, or can be one or more doses daily
without regard to
timing prior to sexual activity. Treatment can be initiated with smaller
dosages, which are less
than the optimum dose of the compound. Thereafter, the dosage may be increased
by small
increments until the optimum effect under the circumstances is reached. For
convenience, the
total daily dosage may be divided and administered in portions during the day
if desired. A
therapeutically effective amount and a prophylactically effective amount of a
compound of the
invention of the invention is expected to vary from about 0.1 milligram per
kilogram of body
weight per day (mg/kg/day) to about 100 mg/kg/day.
The identification of those patients who are in need of prophylactic treatment
for hypoactive
sexual desire disorder is well within the ability and knowledge of one skilled
in the art. Certain
of the methods for identification of patients which are at risk of developing
hypoactive sexual
desire disorder which can be treated by the subject method are appreciated in
the medical arts,
such as family history, and the presence of risk factors associated with the
development of that
disease state in the subject patient (e.g., use of antidepressant drugs,
hormonal contraceptives,
antihormonal and/or cytotoxic chemotherapies, sedatives, antipsychotic drugs,
antiepileptic
drugs, mood stabilizer drugs, opioid drugs, alcohol, or narcotic drugs). A
clinician skilled in the
art can readily identify such candidate patients, by the use of, for example,
clinical tests, physical
examination and medical/family history.
As used herein, "obtaining a biological sample from a subject," includes
obtaining a sample for
use in the methods described herein. A biological sample is described above.
In another aspect, a compound of the invention is packaged in a
therapeutically effective amount
with a pharmaceutically acceptable carrier or diluent. The composition may be
formulated for
CA 02933921 2016-06-20
treating a subject suffering from or susceptible to a hypoactive sexual desire
disorder, and
packaged with instructions to treat a subject suffering from or susceptible to
a hypoactive sexual
desire disorder.
The subject may be at risk of a hypoactive sexual desire disorder, may be
exhibiting symptoms
of a hypoactive sexual desire disorder, may be susceptible to a hypoactive
sexual desire disorder
and/or may have been diagnosed with a sexual desire disorder.
If the modulation of the status indicates that the subject may have a
favorable clinical response to
the treatment, the subject may be treated with the compound. For example, the
subject can be
administered therapeutically effective dose or doses of the compound.
Kits of the invention include kits for treating a hypoactive sexual desire
disorder in a subject.
The kit may include a compound of the invention, for example, a compound
described herein,
pharmaceutically acceptable esters, salts, and prodrugs thereof, and
instructions for use. The
instructions for use may include information on dosage, method of delivery,
storage of the kit,
etc. In aspects, the kits (and methods of using them) comprise instructions
indicating that the
compositions and/or treatment methods are contraindicated for (or not to be
administered to)
subjects that: (1) require and/or are taking CYP3A4, CYP 2B6-, or CYP 2D6-
metabolized drugs;
(ii) take any sex hormone other than an approved hormonal contraceptive; (iii)
drink more than
one alcoholic drink per day (e.g., 12-oz beer, 4-oz wine, etc).
Alternatively, the effects of compound of the invention can be characterized
in vivo using
animals models.
4. Pharmaceutical Compositions
The invention also provides a pharmaceutical composition, comprising an
effective amount of a
compound described herein and a pharmaceutically acceptable carrier. In a
further embodiment,
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the effective amount is effective to treat a hypoactive sexual desire
disorder, as described
previously.
In an embodiment, the compound of the invention is administered to the subject
using a
pharmaceutically-acceptable formulation, e.g., a pharmaceutically-acceptable
formulation that
provides sustained delivery of the compound of the invention to a subject for
at least 12 hours,
24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks
after the
pharmaceutically-acceptable formulation is administered to the subject.
In certain embodiments, these pharmaceutical compositions are suitable for
topical or oral,
buccal or sublingual administration to a subject. In other embodiments, as
described in detail
below, the pharmaceutical compositions of the present invention may be
specially formulated for
administration in solid or liquid form, including those adapted for the
following: (1) oral
administration, for example, drenches (aqueous or non-aqueous solutions or
suspensions),
tablets, boluses, powders, granules, pastes; (2) parenteral administration,
for example, by
subcutaneous, intramuscular or intravenous injection as, for example, a
sterile solution or
suspension; (3) topical application, for example, as a cream, ointment or
spray applied to the
skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or
foam; or (5) aerosol,
for example, as an aqueous aerosol, liposomal preparation or solid particles
containing the
compound or composition herein.
The phrase "pharmaceutically acceptable" refers to those compound of the
inventions of the
present invention, compositions containing such compounds, and/or dosage forms
which are,
within the scope of sound medical judgment, suitable for use in contact with
the tissues of human
beings and animals without excessive toxicity, irritation, allergic response,
or other problem or
complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically-acceptable carrier" includes pharmaceutically-
acceptable material,
composition or vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating
material, involved in carrying or transporting the subject chemical from one
organ, or portion of
the body, to another organ, or portion of the body. Each carrier is
"acceptable" in the sense of
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being compatible with the other ingredients of the formulation and not
injurious to the patient.
Some examples of materials which can serve as pharmaceutically-acceptable
carriers include: (1)
sugars, such as lactose, glucose and sucrose; (2) starches, such as corn
starch and potato starch;
(3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose,
ethyl cellulose and
cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
(8) excipients, such as
cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed
oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11)
polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12)
esters, such as ethyl
oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium
hydroxide and
aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic
saline; (18)
Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and
(21) other non-toxic
compatible substances employed in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium
stearate, as well as coloring agents, release agents, coating agents,
sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be present in the
compositions.
Examples of pharmaceutically-acceptable antioxidants include: (1) water
soluble antioxidants,
such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium
metabisulfite, sodium
sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl
palmitate, butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl
gallate, alpha-
tocopherol, and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine
tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the
like.
Compositions containing a compound of the invention(s) include those suitable
for oral, nasal,
topical (including buccal and sublingual), rectal, vaginal, aerosol and/or
parenteral
administration. The compositions may conveniently be presented in unit dosage
form and may be
prepared by any methods well known in the art of pharmacy. The amount of
active ingredient
which can be combined with a carrier material to produce a single dosage form
will vary
depending upon the host being treated, the particular mode of administration.
The amount of
active ingredient which can be combined with a carrier material to produce a
single dosage form
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will generally be that amount of the compound which produces a therapeutic
effect. Generally,
out of one hundred percent, this amount will range from about 1 percent to
about ninety-nine
percent of active ingredient, preferably from about 5 percent to about 70
percent, more
preferably from about 10 percent to about 30 percent.
Methods of preparing these compositions include the step of bringing into
association a
compound of the invention(s) with the carrier and, optionally, one or more
accessory ingredients.
In general, the formulations are prepared by uniformly and intimately bringing
into association a
compound of the invention with liquid carriers, or finely divided solid
carriers, or both, and then,
if necessary, shaping the product.
Compositions of the invention suitable for oral administration may be in the
form of capsules,
cachets, pills, tablets, caplets, gel caps, lozenges (using a flavored basis,
usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a suspension in
an aqueous or non-
aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as
an elixir or syrup, or as
pastilles (using an inert base, such as gelatin and glycerin, or sucrose and
acacia) and/or as mouth
washes and the like, each containing a predetermined amount of a compound of
the invention(s)
as an active ingredient. A compound may also be administered as a bolus,
electuary or paste.
In solid dosage forms of the invention for oral administration (capsules,
tablets, pills, dragees,
powders, granules and the like), the active ingredient is mixed with one or
more
pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium
phosphate, and/or any
of the following: (1) fillers or extenders, such as starches, lactose,
sucrose, glucose, mannitol,
and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, alginates, gelatin,
polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as
glycerol; (4) disintegrating
agents, such as agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain
silicates, and sodium carbonate; (5) solution retarding agents, such as
paraffin; (6) absorption
accelerators, such as quaternary ammonium compounds; (7) wetting agents, such
as, for
example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as
kaolin and bentonite
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clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid
polyethylene glycols,
sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the
case of capsules,
tablets and pills, the pharmaceutical compositions may also comprise buffering
agents. Solid
compositions of a similar type may also be employed as fillers in soft and
hard-filled gelatin
capsules using such excipients as lactose or milk sugars, as well as high
molecular weight
polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more
accessory
ingredients. Compressed tablets may be prepared using binder (for example,
gelatin or
hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,
disintegrant (for example,
sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),
surface-active or
dispersing agent. Molded tablets may be made by molding in a suitable machine
a mixture of the
powdered active ingredient moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions
of the present
invention, such as dragees, capsules, pills and granules, may optionally be
scored or prepared
with coatings and shells, such as enteric coatings and other coatings well
known in the
pharmaceutical-formulating art. They may also be formulated so as to provide
slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in
varying proportions to provide the desired release profile, other polymer
matrices, liposomes
and/or microspheres. They may be sterilized by, for example, filtration
through a bacteria-
retaining filter, or by incorporating sterilizing agents in the form of
sterile solid compositions
which can be dissolved in sterile water, or some other sterile injectable
medium immediately
before use. These compositions may also optionally contain opacifying agents
and may be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain portion
of the gastrointestinal tract, optionally, in a delayed manner. Examples of
embedding
compositions which can be used include polymeric substances and waxes. The
active ingredient
can also be in micro-encapsulated form, if appropriate, with one or more of
the above-described
excipients.
Liquid dosage forms for oral administration of the compound of the
invention(s) include
CA 02933921 2016-06-20
pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions,
syrups and
elixirs. In addition to the active ingredient, the liquid dosage forms may
contain inert diluents
commonly used in the art, such as, for example, water or other solvents,
solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in
particular, cottonseed,
groundnut, corn, germ, olive, castor and sesame oils), glycerol,
tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
In addition to inert diluents, the oral compositions can include adjuvants
such as wetting agents,
emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming
and preservative
agents.
Suspensions, in addition to the active compound of the invention(s) may
contain suspending
agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene
sorbitol and sorbitan
esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-
agar and tragacanth,
and mixtures thereof
Pharmaceutical compositions of the invention for rectal or vaginal
administration may be
presented as a suppository, which may be prepared by mixing one or more
compound of the
invention(s) with one or more suitable nonirritating excipients or carriers
comprising, for
example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate,
and which is solid
at room temperature, but liquid at body temperature and, therefore, will melt
in the rectum or
vaginal cavity and release the active agent.
Compositions of the present invention which are suitable for vaginal
administration also include
pessaries, tampons, creams, gels, pastes, foams or spray formulations
containing such carriers as
are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of
the invention(s)
include powders, sprays, ointments, pastes, creams, lotions, gels, solutions,
patches and
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inhalants. The active compound of the invention(s) may be mixed under sterile
conditions with a
pharmaceutically-acceptable carrier, and with any preservatives, buffers, or
propellants which
may be required.
The ointments, pastes, creams and gels may contain, in addition to compound of
the invention(s)
of the present invention, excipients, such as animal and vegetable fats, oils,
waxes, paraffins,
starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid,
talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of the invention(s),
excipients such
as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and
polyamide powder, or
mixtures of these substances. Sprays can additionally contain customary
propellants, such as
chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as
butane and propane.
The compound of the invention(s) can be alternatively administered by aerosol.
This is
accomplished by preparing an aqueous aerosol, liposomal preparation or solid
particles
containing the compound. A nonaqueous (e.g., fluorocarbon propellant)
suspension could be
used. Sonic nebulizers are preferred because they minimize exposing the agent
to shear, which
can result in degradation of the compound.
Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or
suspension of the
agent together with conventional pharmaceutically-acceptable carriers and
stabilizers, The
carriers and stabilizers vary with the requirements of the particular
compound, but typically
include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol),
innocuous proteins like
serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as
glycine, buffers, salts,
sugars or sugar alcohols. Aerosols generally are prepared from isotonic
solutions.
Transdermal patches have the added advantage of providing controlled delivery
of a compound
of the invention(s) to the body. Such dosage forms can be made by dissolving
or dispersing the
agent in the proper medium. Absorption enhancers can also be used to increase
the flux of the
active ingredient across the skin. The rate of such flux can be controlled by
either providing a
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CA 02933921 2016-06-20
rate controlling membrane or dispersing the active ingredient in a polymer
matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are
also contemplated
as being within the scope of the invention.
Pharmaceutical compositions of the invention suitable for parenteral
administration comprise one
or more compound of the invention(s) in combination with one or more
pharmaceutically-
acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions,
suspensions or
emulsions, or sterile powders which may be reconstituted into sterile
injectable solutions or
dispersions just prior to use, which may contain antioxidants, buffers,
bacteriostats, solutes
which render the formulation isotonic with the blood of the intended recipient
or suspending or
thickening agents.
Examples of suitable aqueous and nonaqueous carriers, which may be employed in
the
pharmaceutical compositions of the invention include water, ethanol, polyols
(such as glycerol,
propylene glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable
oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
Proper fluidity can be
maintained, for example, by the use of coating materials, such as lecithin, by
the maintenance of
the required particle size in the case of dispersions, and by the use of
surfactants.
These compositions may also contain adjuvants such as preservatives, wetting
agents,
emulsifying agents and dispersing agents. Prevention of the action of
microorganisms may be
ensured by the inclusion of various antibacterial and antifungal agents, for
example, paraben,
chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to
include isotonic
agents, such as sugars, sodium chloride, and the like into the compositions.
In addition,
prolonged absorption of the injectable pharmaceutical form may be brought
about by the
inclusion of agents which delay absorption such as aluminum monostearate and
gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to
slow the absorption of the
drug from subcutaneous or intramuscular injection. This may be accomplished by
the use of a
liquid suspension of crystalline or amorphous material having poor water
solubility. The rate of
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absorption of the drug then depends upon its rate of dissolution which, in
turn, may depend upon
crystal size and crystalline form. Alternatively, delayed absorption of a
parenterally-administered
drug form is accomplished by dissolving or suspending the drug in an oil
vehicle.
Injectable depot forms are made by forming microencapsule matrices of compound
of the
invention(s) in biodegradable polymers such as polylactide-polyglycolide.
Depending on the
ratio of drug to polymer, and the nature of the particular polymer employed,
the rate of drug
release can be controlled. Examples of other biodegradable polymers include
poly(orthoesters)
and poly(anhydrides). Depot injectable formulations are also prepared by
entrapping the drug in
liposomes or microemuisions which are compatible with body tissue.
When the compound of the invention(s) are administered as pharmaceuticals, to
humans and
animals, they can be given per se or as a pharmaceutical composition
containing, for example,
0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination
with a
pharmaceutically-acceptable carrier.
Regardless of the route of administration selected, the compound of the
invention(s), which may
be used in a suitable hydrated form, and/or the pharmaceutical compositions of
the present
invention, are formulated into pharmaceutically-acceptable dosage forms by
conventional
methods known to those of skill in the art.
Actual dosage levels and time course of administration of the active
ingredients in the
pharmaceutical compositions of the invention may be varied so as to obtain an
amount of the
active ingredient which is effective to achieve the desired therapeutic
response for a particular
patient, composition, and mode of administration, without being toxic to the
patient. An
exemplary dose range is from 0.1 to 10 mg per day.
A preferred dose of the compound of the invention for the present invention is
the maximum that
a patient can tolerate and not develop serious side effects. Preferably, the
compound of the
invention of the present invention is administered at a concentration of about
0.001 mg to about
100 mg per kilogram of body weight, about 0.001--about 10 mg/kg or about 0.001
mg--about
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100 mg/kg of body weight. Ranges intermediate to the above-recited values are
also intended to
be part of the invention.
5. Example
The invention is further illustrated by the following example which is
intended to illustrate but
not limit the scope of the invention.
Low Dose Lorexys and High Dose Lorexys
HSDD Clinical Study in Premenopausal Women
We sought to estimate the prevalence of low sexual desire and hypoactive
sexual desire disorder
(HSDD) in US women, focusing on their menopausal status.
Methods:
An open cross-sectional study was performed. From a probability sample of
households, 2207
US women aged 30 to 70 years and in stable relationships (>or=3 months) were
interviewed by
telephone. The analysis focused on 755 premenopausal women and 552 naturally
and 637
surgically menopausal women. Low sexual desire was defined using the Profile
of Female
Sexual Function desire domain, and HSDD was defined using the Profile of
Female Sexual
Function and the Personal Distress Scale.
Results:
Prevalence of low sexual desire ranged from 26.7% among premenopausal women to
52.4%
among naturally menopausal women. The prevalence of HSDD was highest among
surgically
menopausal women (12.5%). Compared with premenopausal women and adjusting for
age,
race/ethnicity, educational level, and smoking status, the prevalence ratios
for HSDD were 2.3
(95% confidence interval, 1.2-4.5) for surgically menopausal women and 1.2
(0.5-2.8) for
naturally menopausal women; the prevalence ratios for low sexual desire were
1.3 (0.9-1.9) and
1.5 (1.0-2.2) for surgically and naturally menopausal women, respectively.
Conclusions:
CA 02933921 2016-06-20
Prevalence of low sexual desire is elevated among surgically and naturally
menopausal women
vs premenopausal women. Distress about low desire (HSDD) appears to be more
than twice as
prevalent among surgically menopausal women vs premenopausal women, although
the estimate
is fairly imprecise.
Hyposexual desire disorder {HSDD) remains without approved pharmacotherapies,
though one
CNS agent, bupropion, is recommended. This study tested the efficacy and
safety of Lorexys, a
proprietary combination of bupropion and trazodone, in premenopausal women.
A clinical study was conducted with Lorexys to treat premenopausal women for
HSDD. The
study's primary objective was to evaluate Lorexys' safety, tolerability and
pro-sexual efficacy as
compared to bupropion, one of its constituent drugs. Other objectives included
exploration of the
onset and duration of action of Lorexys.
The study had an adaptive, three-way crossover, open-label design. It enrolled
30 premenopausal
women who met the DSM-IV-TR criteria for HSDD, and it also assessed patients
for the newly
defined DSM-5 Sexual Interest and Arousal Disorder. Each subject received a
daily dose of
bupropion as an active control for four weeks followed by a week-long washout
period, then
daily administration of a low dose of Lorexys for four weeks followed by
another washout
period, and, finally, a moderate dose of Lorexys for four weeks followed by
another washout
period.
The dosing and treatment regimens for the study were as follows:
Active Control: Bupropion SR 300 mg was administered once daily in the morning
for
four weeks.
Low Dose Lorexys: Low dose Lorexys is combination therapy that consists of two
drugs: buproprion and trazadone. burpropion SR 150 mg was administered once
daily in
the morning and trazadone ER 75 mg was administered once daily at bedtime,
each for
four weeks.
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Moderate Dose Lorexys: Moderate dose Lorexys is also combination therapy that
consist
of two drugs: buproprion and trazadone. burpropion SR 150 mg was administered
twice
daily, once in the morning and once eight (8) hours later, and trazadone ER
150 mg was
administered once daily at bedtime, each for four weeks.
Patients self-evaluated weekly with questionnaires and were assessed during
eight clinic visits.
Outcome measures for efficacy included validated self-rated scales of Sexual
Function and
Sexual Distress and global change. Outcome measures for safety included
comprehensive
evaluations of symptoms and vital signs, plus standard laboratory studies and
electrocardiograms. The study was conducted at two clinical sites in the U.S.
Materials and Methods:
This was an open-label crossover study in non-depressed, otherwise healthy
patients with DSM-
IV-TR HSDD, aged 25-50 years, with four weeks per treatment. With n=30 and 33%
more
Lorexys responders vs. Bupropion SR, the power at a =0.05 was 80%. Four weeks
of Bupropion
SR at 300 mg/day and a washout was followed by four weeks of Lorexys low-dose
(LOR-low),
i.e, Bupropion SR plus Trazodone ER at doses lower than the labeled doses,
followed by another
washout and four weeks of Lorexys moderate-dose (LORmod; 2x LOR-low).The
primary
efficacy endpoint was Female Sexual Function Index Desire domain (FSFI-d); the
key secondary
was Female Sexual Distress Scale-Revised (FSDS-R). Analyses included %
responders and %
remitters from the first baseline, using standard definitions (see Table 1)
for FSFI-d and FSDS-R
item 13 (FSDS-R-i13), plus Patient's Global Impression of Change (PGIC). See
FIGS. 1-11.
Results
Five patients (17%) discontinued for administrative reasons; one (4%)
discontinued for adverse
events, on LOR-mod. Table 1 below shows responder and remitter rates with LOR-
mod; rates
with LOR-low were intermediate and non-significant vs. bupropion.
Conclusion
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Lorexys was highly superior to bupropion in non-depressed, otherwise healthy,
premenopausal HSDD to Bupropion SR alone in the treatment of premenopausal
women for
HSDD. See Table 1 and FIGS. 1-11.
Table 1. Results
Measure Definition LOR-mod Bupropion p-value on
Fisher's Exact
test, 2-tailed
Responders
FSFI-d 2-point increase 76% 38% <0.01
FSDS-R-i13 1-point decrease 88% 45% <0.01
PGIC >=Moderately 58% 24% <0.05
Improved
Remitters
FSFI-d >=5 58% 24% <0.05
FSDS-R-i13 <=2 75% 32% <0.01
The disclosures of each and every patent, patent application and publication
cited herein are
hereby incorporated herein by reference in their entireties.
The recitation of a listing of chemical groups in any definition of a variable
herein includes
definitions of that variable as any single group or combination of listed
groups. The recitation of
an embodiment for a variable herein includes that embodiment as any single
embodiment or in
combination with any other embodiments or portions thereof. The recitation of
an embodiment
herein includes that embodiment as any single embodiment or in combination
with any other
embodiments or portions thereof.
Although the invention has been disclosed with reference to specific
embodiments, it is apparent
that other embodiments and variations of the invention may be devised by
others skilled in the
art without departing from the true spirit and scope of the invention. The
claims are intended to
be construed to include all such embodiments and equivalent variations.
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