U.S. patent application number 10/996757 was filed with the patent office on 2005-09-29 for methods of using rapid-onset selective serotonin reuptake inhibitors for treating sexual dysfunction.
This patent application is currently assigned to APBI Holdings, LLC. Invention is credited to Thor, Karl Bruce.
Application Number | 20050215617 10/996757 |
Document ID | / |
Family ID | 22542905 |
Filed Date | 2005-09-29 |
United States Patent
Application |
20050215617 |
Kind Code |
A1 |
Thor, Karl Bruce |
September 29, 2005 |
Methods of using rapid-onset selective serotonin reuptake
inhibitors for treating sexual dysfunction
Abstract
Methods for the prevention, treatment, or management of sexual
dysfunction, such as premature ejaculation, by administering to a
patient in need of therapy a therapeutically effective amount of a
rapid-onset selective serotonin reuptake inhibitor on an as-needed
basis shortly before sexual activity.
Inventors: |
Thor, Karl Bruce;
(Morrisville, NC) |
Correspondence
Address: |
SHERIDAN ROSS PC
1560 BROADWAY
SUITE 1200
DENVER
CO
80202
|
Assignee: |
APBI Holdings, LLC
|
Family ID: |
22542905 |
Appl. No.: |
10/996757 |
Filed: |
November 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10996757 |
Nov 24, 2004 |
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10049427 |
May 6, 2002 |
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10049427 |
May 6, 2002 |
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PCT/US00/20788 |
Aug 22, 2000 |
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60152435 |
Sep 3, 1999 |
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Current U.S.
Class: |
514/419 |
Current CPC
Class: |
A61K 31/557 20130101;
A61K 45/06 20130101; A61P 15/08 20180101; A61K 31/138 20130101;
A61K 31/135 20130101; A61K 31/138 20130101; A61K 31/505 20130101;
A61P 43/00 20180101; A61P 15/00 20180101; A61K 31/135 20130101;
A61K 2300/00 20130101; A61P 15/10 20180101; A61K 31/135
20130101 |
Class at
Publication: |
514/419 |
International
Class: |
A61K 031/405 |
Claims
What is claimed is:
1. A method of treating or managing sexual dysfunction in a mammal
in need of treatment comprising administering on an as-needed basis
to the mammal an amount of a rapid-onset selective serotonin
reuptake inhibitor that is therapeutically effective in the absence
of a priming dose.
2. The method of claim 1, wherein the mammal is a human male.
3. The method of claim 1, wherein the rapid-onset selective
serotonin reuptake inhibitor is short acting.
4. The method of claim 1, wherein the rapid-onset selective
serotonin reuptake inhibitor is delivered in a rapid release
formulation.
5. The method of claim 1, comprising the additional step of
administering a therapeutically effective amount of a second
therapeutic agent for treating or managing a sexual
dysfunction.
6. A method of treating or managing sexual dysfunction in a mammal
in need of such treatment comprising administering on an as-needed
basis to the mammal a therapeutically effective amount of
dapoxetine or a pharmaceutically acceptable salt thereof.
7. The method of claim 6, wherein the mammal is a human male.
8. The method of claim 6, comprising the additional step of
administering a therapeutically effective amount of a second
therapeutic agent for treating or managing sexual dysfunction.
9. The method according to claim 6, wherein the therapeutically
effective amount of dapoxetine is from about 0.001 mg to about 350
mg.
10. The method of 6, wherein the therapeutically effective amount
of dapoxetine or its pharmaceutically acceptable salt is from about
0.01 mg to about 200 mg.
11. The method of 6, wherein the therapeutically effective amount
of dapoxetine or its pharmaceutically acceptable salt is from about
0.1 mg to about 120 mg.
12. The method of claim 1 1, wherein dapoxetine or its
pharmaceutically acceptable salt is administered orally.
13. The method of claim 12, wherein dapoxetine or its
pharmaceutically acceptable salt is administered in an solid oral
dosage form.
14. The method of claim 13, wherein dapoxetine or its
pharmaceutically acceptable salt is administered as a tablet or a
capsule.
15. The method of claim 6, wherein dapoxetine or its
pharmaceutically acceptable salt is delivered as a rapid release
formulation.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/049,427, filed May 6, 2002, which is a national stage
application under 35 U.S.C .sctn. 371 of International Application
No. PCT/US00/20788, filed Aug. 22, 2000, which claims the benefit
of priority to U.S. Provisional Patent Application No. 60/152,435,
filed Sep. 3, 1999, each of which is incorporated herein, in its
entirety, by this reference.
FIELD OF THE INVENTION
[0002] The invention relates to methods for the prevention,
treatment, or management of sexual dysfunction in mammals,
particularly premature ejaculation in men, by administering a
therapeutically effective amount of a rapid onset selective
serotonin reuptake inhibitor, or a pharmaceutically acceptable salt
o thereof, on an as-needed basis shortly before sexual
activity.
BACKGROUND OF THE INVENTION
[0003] A normal erection occurs as a result of a coordinated
vascular event in the penis, which is usually triggered neurally
and includes vasodilation and smooth muscle relaxation in the penis
and its supplying arterial vessels. Arterial inflow causes
enlargement of the substance of the corpora cavernosa. Venous
outflow is trapped by this enlargement, permitting sustained high
blood pressures in the penis normally sufficient to cause rigidity.
Muscles in the perineum also assist in creating and maintaining
penile rigidity. Erection may also be induced centrally in the
nervous system by sexual thoughts or fantasy, and is usually
reinforced locally by reflex mechanisms. Erectile mechanics in
women are substantially similar for the clitoris. In men, however,
ejaculation typically occurs with an orgasm.
[0004] Premature ejaculation, however, is one of the most common
sexual complaints. It is estimated to affect up to 30 to 40 percent
of men, i.e., approximately 36 million American men (Derogatis, L.
R., Med. Aspects Hum. Sexuality, 14:1168-76 (1980); Frank E., et
al., Engl. J. Med., 299:111-115 (1978); Schein, M., et al., Fam.
Pract. Res. J., 7(3): 122-134 (1988)). Premature ejaculation means
persistent or recurrent ejaculation with minimal sexual stimulation
before, upon, or shortly after penetration, and before the person
wishes it. Such ejaculation that occurs sooner than desired is
often disappointing and can lead to other sexual dysfunctions
including erectile difficulties, female inorgasmia, low sexual
desire, and sexual aversion (Rust J., et al., Br. J. Psychiat,
152:629-631 (1988)). Behavioral therapy, such as the Semans pause
maneuver, the Masters and Johnson pause-squeeze technique or the
Kaplan stop-start method, is considered the gold standard for the
treatment of premature ejaculation (Seftel, A. D., Altohob, S. E.,
"Premature Ejaculation", Diagnosis and Management of Male Sexual
Dysfunction, Edited by J. J. Mulcahy, New York, N.Y., Igaku-Shoin,
(1997) Chapter 11, pages 196-203). While these techniques are
harmless, usually painless, and are successful at rates of 60 to
95% (ibid; Hawton, K., et al., Behav. Res. Ther., 24:377 (1986)),
they require partner cooperation and improvement is short-lived
(Bancroft, J. and Coles, L., Brit. Med. J. 1:1575 (1976) and De
Amicus, L. A., et al., Arch. Sex. Behav., 14:467 (1985)).
[0005] Premature ejaculation rarely has a physical cause, however,
prostate gland inflammation or nervous system disorders may be
involved. Treatment may involve certain selective serotonin
reuptake inhibitors, such as fluoxetine, paroxetine, or sertraline
(Merck Manual of Medical Information at 421-422, Home Edition,
Merck Research Laboratories (1997)); see also U.S. Pat. No.
5,597,826 (sertraline), U.S. Pat. No. 5,276,042 (paroxetine), and
U.S. Pat. No. 5,151,448 (fluoxetine).
[0006] Although ejaculation latency is affected by psychological
and/or cognitive mechanisms, somatic factors are also involved
(Althof, S. E., Psychiatr. Clin. N. Amer., 18(1):85-94 (1995);
Rowland, D. L., et al., J. Sex. Marital. Ther., 19:189 (1993)).
Ejaculation is mediated partly through a neural reflex stimulated
by sensory input to the penis, and terminating in smooth and
striated muscle contractions that produce seminal emission and
expulsion. Segraves hypothesized that increased serotoninergic
activation may be associated with orgasmic inhibition (Arch. Gen.
Psychiatry., 46:275-284 (1989)) and reports that ejaculation seems
to be mediated by alpha-receptor activation, presumably at a
peripheral level with cholinergic fibers playing a modulatory role.
Serotoninergic system involvement in ejaculation could occur at the
level of the brain or spinal cord.
[0007] Several psychiatric drugs have been reported to have side
effects of inhibiting ejaculation. Thus, oral pharmacotherapy for
premature ejaculation using tricyclic antidepressants or certain
selective serotonin re-uptake inhibitor drugs has been studied as
an alternative to behavioral therapy (See, e.g., Merck Manual of
Medical Information at 421-422, Home Edition, Merck Research
Laboratories (1997)). Open-label and controlled studies have
reported that these compounds increase intravaginal ejaculatory
latency effectively while avoiding side effects in subjects with
premature ejaculation.
[0008] For example, U.S. Pat. No. 5,672,612 discloses amorphous
paroxetine hydrochloride-ethanol compositions for use as a
therapeutic agent for premature ejaculation. This reference also
reports that sexual dysfunction typically associated with
antidepressants, including delayed and completely abolished
ejaculation, has been the subject of numerous case reports,
studies, and articles. See, e.g., Depression, 2:233-240
(1994/1995); J. Clin. Psychiatry, 54:209-212 (1993); J. Clin.
Psychopharmacol, 3:76-79 (1983). SSRI antidepressants seem to be a
safe treatment option for patients with premature ejaculation,
particularly in cases with failed psychological treatment, although
other anti-anxiety drugs, such as chlordiazepoxide (LIBRIUM.TM.)
and diazepam (VALIUM.TM.) are not suitable for the treatment of
premature ejaculation. See also Clin. Neuropharmacology,
20(5):466-471 (1997) (treatment of premature ejaculation with
fluoxetine) and Clin. Neuropharmacology, 20(3):210-214 (mianserin
for treatment of sexual dysfunction induced by SSRIs).
[0009] U.S. Pat. No. 5,151,448 discloses the chronic administration
of fluoxetine, preferably orally, in an amount in the range of
about 5 mg to about 80 mg per day, preferably about 20 mg per day
for the treatment of premature ejaculation. The compositions are
administered for a time period of at least about 3 months,
preferably for at least about 6 months. In some instances,
fluoxetine is administered chronically as long as the patient
remains sexually active.
[0010] U.S. Pat. No. 5,276,042 discloses the chronic administration
of paroxetine, preferably orally, in an amount in the range of
about 3 mg to about 30 mg per day, preferably about 10 mg per day
for the treatment of premature ejaculation. The compositions are
administered for a time period of at least about 3 months,
preferably for at least about 6 months. In some instances,
paroxetine is administered chronically as long as the patient
remains sexually active.
[0011] U.S. Pat. No. 5,597,826 discloses the administration of
sertraline and an agonist or antagonist of the serotonin 1 (5-HT1)
receptor and the use of such compositions for treating or
preventing a condition selected from a large list of disorders
including sexual dysfunction, such as premature ejaculation. These
compositions are disclosed to be administered daily, for example,
one to four times daily.
[0012] McMahon reports that 37 potent men with premature
ejaculation were treated with 50 mg oral sertraline and placebo in
a controlled randomized single-blind crossover trial. Chronic open
label treatment was continued in 29 patients that achieved an
increase in ejaculatory latency over pretreatment levels with
active drug. McMahon, J. Urology, 159(6):1935-1938 (1998). McMahon
concluded that sertraline appeared to be a useful and well
tolerated oral treatment for premature ejaculation after 1 to 2
weeks, with several patients maintaining that control after chronic
treatment for several months.
[0013] U.S. Pat. Nos. 5,770,606 and 5,624,677 disclose psychogenic
impotence or erectile dysfunction that can be identified in
patients and treated, without substantial undesirable side effects,
by sublingual administration of apomorphine dosage forms to
maintain a plasma concentration of no more than about 5.5 nanograms
per mL.
[0014] Certain selective serotonin re-uptake inhibitors have been
reported as being useful for various indications. For example, U.S.
Pat. No. 5,135,947 discloses 1-phenyl naphthalonyloxypropanamines
and methods of using the same for treating a variety of disorders
that have been linked to decreased neurotransmission of serotonin
in mammals, including obesity, depression, alcoholism, pain, memory
loss, anxiety, smoking, and the like.
[0015] The above-discussed references primarily concern the chronic
administration of therapeutic agents for the treatment of premature
ejaculation, but do not discuss administration on an as-needed
basis. As discussed above, treatment of premature ejaculation can
involve administration of certain selective serotonin reuptake
inhibitors, such as fluoxetine, paroxetine, or sertraline, to delay
ejaculation. This type of drug works by increasing the amount of
serotonin in the body and can be administered daily (Merck Manual
ofMedical Information at 421-422, Home Edition, Merck Research
Laboratories (1997)).
[0016] Paick et al. recently reported that self-therapy with
sertraline tablets was investigated by chronic administration
followed by as-needed administration on the day of intercourse.
Paick, J. S., et al., J. Urology, 159(S5):241 (June, 1998).
[0017] This study was conducted with 24 males for six weeks, and
the authors reported that 50 mg doses were administered for 2 weeks
followed by self therapy with 50 mg or 100 mg of sertraline
as-needed at 5 p.m. in treatment of premature ejaculation. The
authors concluded that such therapy could possibly be as attractive
as self-injection therapy in the treatment of erectile
dysfunction.
[0018] McMahon and Touma, J. Urol., 161:1826-1839 (1999) showed in
26 patients suffering from premature ejaculation that prn dosing
with a 20 mg paroxetine tablet 3-4 hours prior to intercourse
resulted in a statistically significant increase in ejaculatory
latency in the second through fourth weeks of 10 paroxetine
treatment but not in the first week, indicating that 1-2 weeks of
priming doses of paroxetine are required. Frequency of intercourse
was significantly increased only after 3 weeks of prn paroxetine
therapy.
[0019] In a subsequent paper, McMahon and Touma, International J.
Impotence Research, 11:241-246 (1999), showed that 20 mg prn
paroxetine improved ejaculatory latency in only 42% of their
patients and the increase in ejaculatory latency was only reported
as being statistically significant after 4 weeks of treatment,
again indicating the need for "priming doses" of paroxetine. In
addition, 37% of patients that initially showed improvement in
ejaculatory latency with continuous dosing of paroxetine
subsequently lost benefit after switching to prn dosing. Similarly,
Salem, et al., J. Urol., 163(S4), 197 (2000), showed that 100% of
patients that initially showed improvement in ejaculatory latency
with continuous dosing of fluoxetine subsequently lost benefit
after switching to prn dosing.
[0020] Proper treatment of premature ejaculation involves not just
inhibiting early ejaculation, but in ensuring that the patient has
increased control over the timing of the ejaculation. The available
options for treating premature ejaculation also typically require
daily dosage to maintain suitable plasma levels. The daily or
chronic use of conventional SSRIs and related compounds for such
therapy may result in adverse effects expected with high or
continuing dosages of such compounds. In addition, chronic or daily
administration of conventional SSRIs is a burdensome requirement on
the patient. Furthermore, the latency period, from time of dosing
to engaging in sexual activity, associated with conventional SSRIs
is another hurdle which the patient must deal with. Finally, not
experiencing benefit from a drug with a single, or the first,
administration of drug is also burdensome. It is thus desired to
find a compound and method for sexual dysfunction therapy, in
particular, to provide increased control over ejaculatory timing.
In particular, it is desired to achieve the beneficial therapeutic
effect of preventing, treating, or managing sexual dysfunction
while reducing or avoiding adverse effects associated with the
present protocols for administration of sexual dysfunction therapy.
In particular, it is desirable to consistently achieve the maximum
therapeutic response within a convenient time frame following
administration of a drug therapy immediately before to 4 hours on
an as-needed basis to allow a patient to coordinate drug therapy
with the timing of intercourse following a single, or the first,
dose.
SUMMARY OF THE INVENTION
[0021] The invention encompasses methods and compounds employing as
needed dosing, also known as pro re nata dosing (referred to herein
as "prn dosing"), to prevent, treat, and manage sexual dysfunction
therapy. Without wishing to be bound by theory, it is believed that
these methods and compounds provide therapy by accomplishing at
least one of the following: increasing the effect of monoamines in
the mammal, increasing serotonin in the mammal, or inhibiting or
avoiding reuptake of serotonin into nerve terminals in the mammal.
Prn dosing reduces and/or avoids adverse effects that can occur
with chronic therapy of a therapeutic agent. Thus, the methods of
preventing, treating, or managing sexual dysfunction comprise
administering a therapeutically effective amount of the active
agent to a patient in need of therapy immediately prior to, to
about 12 hours prior to, the patient's anticipated sexual activity
according to the invention. Preferably a therapeutically effective
amount of the active agent is administered to a patient in need of
therapy immediately prior to, to about 10 hours prior to, the
patient's anticipated sexual activity, more preferably immediately
prior to, to about 8 hours prior to, the patient's anticipated
sexual activity, and most preferably immediately prior to, to about
4 hours prior to, the patient's anticipated sexual activity. In
addition, a therapeutically effective amount of the active agent
can be administered to a patient in need of therapy immediately
prior to the patient's anticipated sexual activity. Thus, the
present invention eliminates the need for chronic or daily
administration of the active agent prior to anticipated sexual
activity.
[0022] Typically, the patient is a mammal, such as a dog, horse,
rat, mouse, or human, but in particular, the patient is a human. In
a preferred embodiment, the human is male with or at risk of sexual
dysfunction, such as premature ejaculation.
[0023] One embodiment of the present invention is a method of
treating or managing sexual dysfunction in a mammal in need of
treatment which comprises administering on an as-needed basis to
the mammal a therapeutically effective amount of a rapid-onset
selective selective serotonin reuptake inhibitor. An example of a
rapid-onset selective serotonin reuptake inhibitor is dapoxetine or
a pharmaceutically acceptable salt thereof. As used herein the term
"dapoxetine" refers to the compound of the following formula. 1
[0024] which is also referred to as
(S)-(+)-NN-Dimethyl-1-phenyl-3-(1-naph- thalenyloxy)propanamine or
as (S)-(+)-N,N-Dimethyl-.alpha.-[2-(1-naphthale-
nyloxy)ethyl-benzenemethanamine. It is understood by one of
ordinary skill in the art that the method of the present invention
includes the administration of a rapid-onset selective serotonin
reuptake inhibitor, such as dapoxetine as the free base or as a
pharmaceutically acceptable salt thereof, such as the HCl salt.
[0025] The embodiment preferably encompasses the treatment,
prevention, and/or management of such disorders using a single unit
dosage form that contains dapoxetine, or a pharmaceutically
acceptable salt thereof. The methods of administering dapoxetine,
or a pharmaceutically acceptable salt thereof, are also useful in
combination with an additional therapeutic agent, such as a
conventional selective serotonin reuptake inhibitor (as used herein
the term "SSRI" refers to selective serotonin reuptake inhibitor)
for the treatment, prevention, or management of sexual dysfunction,
such as premature ejaculation. The invention encompasses the
treatment, prevention, and/or management of sexual dysfunction and
the symptoms thereof using dapoxetine. The invention preferably
encompasses the treatment, prevention, and/or management of such
disorders using a single unit dosage form that contains dapoxetine,
or a pharmaceutically acceptable salt thereof. However, it should
be recognized that combination therapy by separate administration
of the compositions of the invention and an additional therapeutic
agent, such as another SSRI, is also contemplated. The methods and
compositions described herein are believed to provide superior or
improved therapy over prior art methods and compositions involving
paroxetine, fluoxetine, venlafaxine, fluvoxamine, or sertraline in
the absence of dapoxetine, or a pharmaceutically acceptable salt
thereof.
[0026] The present invention further provides a method of treating
or managing sexual dysfunction in a mammal in need of treatment
which comprises administering on an as-needed basis to the mammal a
therapeutically effective amount of a rapid-onset selective
serotonin reuptake inhibitor.
[0027] The present invention provides an improvement in flexibility
of timing with regard to when the therapeutically effective amount
of the rapid-onset selective serotonin reuptake inhibitor is taken
in relation to the patient's participation in sexual activity, and
thus, represents an improvement in the dosing schedule.
[0028] The present invention also provides an unexpected benefit
with prn dosing with dapoxetine over either prn dosing or
continuous dosing with non-rapid onset SSRIs, such as paroxetine,
fluoxetine, and sertraline, in that the improvement in ejaculatory
latency with prn dosing with dapoxetine occurs after the very first
dose or a single dose.
[0029] The present invention also shows an improvement in the
ability of prn dosed SSRIs, preferably dapoxetine, to treat the
full range of PE patients, such as those who consider themselves
severe (see tables 13a and 13b) or moderate (see tables 14a and
14b), and patients who have a baseline ejaculatory latency of less
than one minute (see tables 10a and 10b) or less than two minutes
(see tables 11a and 11b). Dapoxetine also increased ejaculatory
latency in patients with baseline latencies greater than or equal
to one minute (see tables 16a and 16b) or greater than or equal to
two minutes (see tables 15a and 15b). This latter data establishes
that administration of a rapid-onset SSRI would be of benefit to a
male who does not suffer from premature ejaculation per se, but
still wishes to prolong ejaculation.
[0030] The present invention provides additional benefit in
allowing administration of a therapeutically effective dose of a
rapid-onset SSRI, without causing accumulation of the drug when
administered on a daily basis, through the drug's demonstration of
a short half-life. An example of a rapid-onset SSRI with a short
half-life is dapoxetine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 shows rapid-onset to reach peak plasma concentration
followed by rapid metabolism (i.e. short half-life) in 20
volunteers who had taken a dose of 40 mg dapoxetine at time zero of
the 14th day of daily dosing.
[0032] FIG. 2 depicts the ejaculatory latency change in minutes vs.
time after dosing for placebo, 20 mg Dapoxetine, and 40 mg
dapoxetine.
DETAILED DESCRIPTION OF THE INVENTION
[0033] The present invention represents an improvement in overall
therapy relative to sexual dysfunction treatment technology
presently available.
[0034] According to another aspect, the present invention provides
the use of a rapid-onset selective serotonin reuptake inhibitor, or
a pharmaceutically acceptable salt thereof, on an as-needed basis,
for the manufacture of a medicament for treatment or management of
sexual dysfunction.
[0035] According to yet another aspect, the present invention
provides the use of a rapid-onset selective serotonin reuptake
inhibitor, or a pharmaceutically acceptable salt thereof, on an
as-needed basis, for treatment or management of sexual
dysfunction.
[0036] The present invention further provides an article of
manufacture comprising packaging material and a pharmaceutical
agent contained within said packaging material, wherein said
pharmaceutical agent is effective for treating premature
ejaculation in a human male, and wherein said packaging material
comprises a label which indicates that said pharmaceutical agent
can be used for treating premature ejaculation in a human male, and
wherein said pharmaceutical agent comprises a rapid-onset selective
serotonin reuptake inhibitor or a pharmaceutically acceptable salt
thereof.
[0037] The invention encompasses methods of preventing, treating,
or managing sexual dysfunction in a mammal in need of therapy by
administering as-needed a therapeutically effective amount of a
rapid-onset selective serotonin reuptake inhibitor, or a
pharmaceutically acceptable salt thereof. A rapid-onset selective
serotonin reuptake inhibitor is administered to a mammal to, for
example, increase the effect of monoamines, increase or enhance the
effects of serotonin, and/or to inhibit or avoid the reuptake of
serotonin into nerve terminals. In particular, the invention
encompasses compounds and methods of administering as-needed a
therapeutically effective amount of a rapid-onset selective
serotonin reuptake inhibitor, or a pharmaceutically acceptable salt
thereof, to a human in need of therapy to prevent, treat, or manage
sexual dysfunction. A suitable rapid-onset selective serotonin
reuptake inhibitor of the present invention is dapoxetine. The
invention is discussed in more detail below. For clarity of
discussion, the specific example of dapoxetine is used herein to
exemplify the use of rapid-onset selective serotonin reuptake
inhibitors with the present invention. The present invention also
includes rapid-onset selective serotonin reuptake inhibitors that
are short acting selective serotonin reuptake inhibitors.
[0038] The present invention includes use of dapoxetine, in
particular (a)
(+)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine, or a
pharmaceutically acceptable salt thereof; (b)
(S)-(+)-N,N-dimethyl-1-phen- yl-3-(1-naphthalenyloxy)-propanamine
(dapoxetine), or a pharmaceutically acceptable salt thereof; and
(c) (R)-(-)-N,N-dimethyl-1-phenyl-3-(1-napht-
halenyloxy)-propanamine, or a pharmaceutically acceptable salt
thereof, as well as any active metabolites thereof. In particular,
the active metabolites include, but are not limited to, mono
desmethyl dapoxetine and di-desmethyl dapoxetine. Typically, the
compound administered will include only one of these alternative
forms, but may include more than one in varying amounts.
[0039] As used herein the terms "Me", "Et", "Pr", "EtOAc", "THF",
and "DMF" refer to methyl, ethyl, propyl, ethyl acetate,
tetrahydrofuran and dimethylformamide respectively.
[0040] As used herein the term "sexual activity" refers to an
activity involving sexual arousal wherein the patient desires to
avoid sexual dysfunction, such as premature ejaculation. Examples
of sexual activity are intercourse, masturbation, sexual
intercourse, and the like. Sexual intercourse is preferred.
[0041] As used herein the term "sexual arousal" refers to
engorgement of a sexual organ. Examples of sexual organs are the
penis and clitoris.
[0042] As used herein the term "engorgement" refers to an increase
in blood flow to a sexual organ.
[0043] As used herein the term "intercourse" refers to physical
stimulation between individuals that involves the genitalia of at
least one person, such as intromission.
[0044] As used herein the term "intromission" refers to the
insertion or period of insertion of the penis into an orifice. An
example of an orifice is the vagina.
[0045] As used herein the term "a rapid-onset selective serotonin
reuptake inhibitor" refers to a drug with a pharmacokinetic profile
wherein Tmax is consistently less than about 4 hours. In
alternative embodiments, "a rapid-onset selective serotonin
reuptake inhibitor" refers to a drug with a pharmacokinetic profile
wherein Tmax is consistently less than about 3 hours or
consistently less than about 2 hours. Dapoxetine is an example of a
rapid-onset selective serotonin reuptake inhibitor.
[0046] As used herein the term "a short acting selective serotonin
reuptake inhibitor" refers to a drug with a pharmacokinetic profile
wherein T.sub.1/2 is less than about 20 hours. In alternative
embodiments, "a short acting selective serotonin reuptake
inhibitor" refers to a drug with a pharmacokinetic profile wherein
T.sub.1/2 is less than about 13 hours or less than about 7
hours.
[0047] The term "racemic" as used herein, means a mixture of the
(R) and (S) enantiomers of a compound where the (R) and (S)
enantiomers are present in approximately a 1:1 ratio.
[0048] The term "substantially free of its (R) stereoisomer" as
used herein, means for example, that the compound contains a
significantly greater proportion of dapoxetine in relation to its
(R) stereoisomer. In a preferred embodiment of the present
invention, the compound contains at least about 90% by weight of
dapoxetine and about 10% by weight or less of its (R) stereoisomer.
In a more preferred embodiment of the present invention, the term
"substantially free of its (R) stereoisomer" as used herein, means
that the compound contains at least about 95% by weight of
dapoxetine and about 5% by weight or less of its (R) stereoisomer.
In a most preferred embodiment, the term "substantially free of its
(R) stereoisomer" as used herein, means that the compound contains
at least about 99% by weight of dapoxetine and about 1% or less of
its (R) stereoisomer. In a most especially preferred embodiment,
the term "substantially free of its (R) stereoisomer" as used
herein, means that the compound contains nearly 100% by weight of
dapoxetine.
[0049] The term "substantially free of its (S) stereoisomer" as
used herein, means for example, that the compound contains a
significantly greater proportion of
(R)-(-)N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-- propanamine in
relation to its (S) stereoisomer. In a preferred embodiment of the
present invention, the compound contains at least about 90% by
weight of
(R)-(-)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine and
about 10% by weight or less of its (S) stereoisomer. In a more
preferred embodiment of the present invention, the term
"substantially free of its (S) stereoisomer" as used herein, means
that the compound contains at least about 95% by weight of
(R)-(-)-N,N-dimethyl-1-phenyl-3-- (1-naphthalenyloxy)-propanamine
and about 5% by weight or less of its (S) stereoisomer. In a most
preferred embodiment, the term "substantially free of its (S)
stereoisomer" as used herein, means that the compound contains at
least about 99% by weight of (R)-(-)-N,N-dimethyl-1-phenyl-3--
(1-naphthalenyloxy)-propanamine and about 1% or less of its (S)
stereoisomer. In a most especially preferred embodiment, the term
"substantially free of its (S) stereoisomer" as used herein, means
that the compound contains nearly 100% by weight of
(R)-(-)-N,N-dimethyl-1-phe-
nyl-3-(1-naphthalenyloxy)-propanamine.
[0050] Dapoxetine and its pharmaceutically acceptable salts can be
readily prepared by procedures well known to those of ordinary
skill in the art. See for example U.S. Pat. No. 5,135,947, issued
Aug. 4, 1992 the disclosure of which is incorporated herein by
reference. In addition, for preparation of various useful
intermediates of dapoxetine, see U.S. Pat. No. 5,292,962, issued
Mar. 8, 1994 the disclosure of which is incorporated herein by
reference.
[0051] In one embodiment of the present invention, a rapid-onset
selective serotonin reuptake inhibitor or a pharmaceutically
acceptable salt thereof can be administered to an animal in
combination with a compound capable of increasing or enhancing the
effect of monoamines or serotonin in the mammal. Preferred
monoamine-increasing compounds include, but are not limited to,
amitriptyline (ELAVIL.TM. and VANATRIP.TM.), amitriptyline and
chlordiazepoxide (LIMBITROL.TM.), amitriptyline and perphenazine
(ETRAFON.TM. and TRIAVIL.TM.), amoxapine (ASENDIN.TM.),
clomipramine (ANAFRANIL.TM.), citalopram (CELEXA.TM.), dapoxetine,
desipramine (NORPRAMIN.TM. and PERTOFRANE.TM.), doxepin
(ADAPIM.TM., SINEQUAN.TM., XEPDIN.TM., and ZONALON.TM.),
duloxetine, fluoxetine (PROZAC.TM.), fluvoxamine (LUVOX.TM.),
imipramine (JANIMINE.TM., TOFRANIL.TM., and TOFRANIL-PM.TM.),
isocarboxazid (MARPLAN.TM.), mirtazapine (REMERON.TM.),
nortriptyline (PAMELOR.TM.), paroxetine (PAXIL.TM.), phenelzine
(NARDIL.TM.), protriptyline (VIVACTIL.TM.), refazodone
(SERZONE.TM.), selegiline (ALZENE.TM., CAREBEX.TM., DEPRENYL.TM.,
and ELDEPRYL.TM.), sertraline (ZOLOF.TM.), tranylcypromine
(PARNATE.TM.), trazadone (DESYREL.TM.), trimipramine
(SURMONTIL.TM.), and venlafaxine (EFFEXOR.TM.).
[0052] It should also be recognized for all embodiments herein that
combination therapy by separate administration of the compounds of
the invention and an additional therapeutic agent, such as one or
more drugs (e.g., yohimbine) for a second, different sexual
dysfunction is also contemplated.
[0053] The various compounds enumerated above with a tradename are
generally commercially available. The remaining compounds may be
readily prepared or obtained by those of ordinary skill in the
pharmaceutical art. For example, one of ordinary skill in the art
is readily able to synthesize dapoxetine, or a pharmaceutically
acceptable salt thereof, as well as metabolites or the optically
pure stereoisomers or salts thereof, for use in the compounds and
methods of the invention, such as by following the teachings of
U.S. Pat. No. 5,135,947. See also W. J. Wheeler, et al., "A Chiral
Synthesis of Dapoxetine Hydrochloride, a Serotonin Re-uptake
Inhibitor, and its .sup.14C Isotopomer," J. Labeled Compounds
Radiopharmaceuticals, 31(4):305-315 (1992).
[0054] The terms "composition(s)," "active agent(s)," and
"compound(s)," as used herein, each encompass: (a) composition(s)
to increase the effect of monoamines; (b) composition(s) to
increase serotonin in the mammal; (c) composition(s) that inhibit
or avoid the reuptake of serotonin into nerve terminals in the
mammal; and (d) serotonin-selective re-uptake inhibitor(s); or a
pharmaceutically acceptable salt thereof. The terms
"composition(s)," "active agent(s)," and "compound(s)" also include
any optically pure isomer, or a pharmaceutically acceptable salt
thereof, as well as any active metabolite, or a pharmaceutically
acceptable salt thereof, of the above-noted compound(s).
[0055] The term "additional therapeutic agent(s)," as used herein,
refers to the use of compounds that may be used in addition to the
compound to prevent, treat, or manage sexual dysfunction in a
patient in need of therapy. For example, yohimbine or nitric oxide
may be used for erectile dysfunction therapy in addition to a
compound as discussed herein according to the invention. Other
suitable additional therapeutic agents include, but are not limited
to, eicosanoids, such as alprostadil, and phosphodiesterase
inhibitors, such as sildenafil citrate (VIAGRA.TM.) and IC 351.
[0056] The term "pharmaceutically acceptable salt" as used herein,
refers to salts of the compounds disclosed herein which are
substantially non-toxic to living organisms. Typical
pharmaceutically acceptable salts include those salts prepared by
reaction of the compounds of the present invention with a
pharmaceutically acceptable mineral or organic acid. Such salts are
known as acid addition salts. Pharmaceutically acceptable salts
also include compounds that have been formulated to have a Tmax of
less than about 4 hours.
[0057] Acids commonly employed to form acid addition salts are
inorganic acids such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and
organic acids such as p-toluenesulfonic, methanesulfonic acid,
oxalic acid, p-bromophenyisulfonic acid, carbonic acid, succinic
acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts are the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, bromide, iodide, acetate, propionate, decanoate,
caprylate, acrylate, formate, hydrochloride, dihydrochloride,
isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,
succinate, suberate, sebacate, fumarate, maleate,
butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,
methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate,
xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,
citrate, lactate, .alpha.-hydroxybutyrate, glycolate, tartrate,
methanesulfonate, propanesuffonate, naphthalene-1-sulfonate,
napththalene-2-sulfonate, mandelate and the like. Preferred
pharmaceutically acceptable acid addition salts are those formed
with mineral acids such as hydrochloric acid and hydrobromic acid,
and those formed with organic acids such as maleic acid and
methanesulfonic acid.
[0058] It should be recognized that the particular counterion
forming a part of any salt of this invention is usually not of a
critical nature, so long as the salt as a whole is
pharmacologically acceptable and as long as the counterion does not
contribute undesired qualities to the salt as a whole. It is
further understood that the above salts may form hydrates or exist
in a substantially anhydrous form.
[0059] The pharmaceutical compounds used in the methods of the
present invention, which are sterile where appropriate, include any
of the above-listed compounds, or a pharmaceutically acceptable
salt thereof, as the active ingredient. The compounds may also
contain a pharmaceutically acceptable carrier or excipient, and
optionally, other therapeutic ingredients.
[0060] The compounds for use in the methods of the present
invention can include suitable excipients or carriers such as
starches, sugars, microcrystalline cellulose, diluents, granulating
agents, lubricants, binders, disintegrating agents, and the like.
Examples of such excipients include water, saline, Ringer's
solution, dextrose solution, Hank's solution, and other aqueous
physiologically balanced salt solutions. Nonaqueous vehicles, such
as fixed oils, sesame oil, ethyl oleate, or triglycerides may also
be used. Other useful formulations include suspensions containing
viscosity-enhancing agents, such as sodium carboxymethylcellulose,
sorbitol, or dextran. Excipients can also contain minor amounts of
additives, such as substances that enhance isotonicity and chemical
stability. Examples of buffers include phosphate buffer,
bicarbonate buffer and Tris buffer, while examples of preservatives
include thimerosal, o-cresol, formalin and benzyl alcohol. Standard
formulations can either be liquid injectables or solids, which can
be taken up in a suitable liquid as a suspension or solution for
injection. Thus, in a non-liquid formulation, the excipient can
comprise dextrose, human serum albumin, preservatives, etc., to
which sterile water or saline can be added prior to
administration.
[0061] Dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, caplets, cachets, patches, gel
caps, syrups, elixirs, gels, powders, magmas, lozenges, ointments,
creams, pastes, plasters, lotions, discs, suppositories, nasal or
oral sprays, aerosols, and the like.
[0062] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit form, in
which case solid pharmaceutical carriers are employed. If desired,
tablets may be coated by standard aqueous or non-aqueous
techniques.
[0063] In addition to the common dosage forms set out above, the
compounds of the present invention may also be administered to
facilitate as-needed administration by controlled release means or
delivery devices that are well known to those of ordinary skill in
the art, such as those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;
5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and
5,733,566, the disclosures of which are each incorporated herein by
express reference thereto. These pharmaceutical compositions can be
used to provide slow or controlled-release of one or more of the
active ingredients therein using, for example, hydropropylmethyl
cellulose, other polymer matrices, gels, permeable membranes,
osmotic systems, multilayer coatings, microparticles, liposomes,
microspheres, or the like, or a combination thereof to provide the
desired release profile in varying proportions. Suitable
controlled-release formulations known to those of ordinary skill in
the art, including those described herein, may be readily selected
for use with the pharmaceutical compounds and methods of the
invention. Thus, single unit dosage forms suitable for oral
administration, such as tablets, capsules, gelcaps, caplets, and
the like, that are adapted for controlled-release are encompassed
by the present invention. The term "controlled-release
formulation(s)," as used herein, means a formulation adapted to
provide extended release of the active ingredient(s) during the
need for therapy. For example, but in no way intended to limit the
invention, a controlled-release formulation according to the
invention might release active ingredient(s) over a 2 to 8 hour
period of time.
[0064] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts.
[0065] Ideally, the use of an optimally designed controlled-release
preparation in medical treatment according to the invention is
characterized by a minimum of drug substance being employed to cure
or control the condition during the need for therapy. Advantages of
controlled-release formulations according to the invention may
include: 1) activity of the drug that is extended for the duration
of the need for therapy; 2) reduction of peak plasma concentration
of the active ingredient(s); and 3) increased patient
compliance.
[0066] Most controlled-release formulations are designed to
initially release an amount of drug that promptly produces the
desired therapeutic effect, and gradually and continually release
of other amounts of drug to maintain this level of therapeutic
effect over a period of time sufficient to provide the as-needed
therapy. In order to maintain this constant level of drug in the
body while needed for therapy, the drug must be released from the
dosage form at a rate that will replace the amount of drug being
metabolized and excreted from the body. The drug must also be
released at a sufficient rate to facilitate absorption into the
bloodstream during the need for therapy.
[0067] The controlled-release of an active ingredient may be
stimulated by various inducers, for example pH, temperature,
enzymes, water, or other physiological conditions or compounds. The
term "controlled-release component," as used herein, means a
compound or compounds, including, but not limited to, polymers,
polymer matrices, gels, permeable membranes, liposomes,
microspheres, or the like, or a combination thereof, that
facilitates the controlled-release of the active ingredient
as-needed for therapy.
[0068] In addition, it is understood that the compounds of the
present invention may be administered as rapidly disintegrating or
dissolving pharmaceutical dosage forms which are readily prepared
by one of ordinary skill in the art. Such formulations are useful,
for example, for human patients who have difficulty swallowing
conventional tablets or capsules, and are also useful for the
sublingual and buccal administration of drugs.
[0069] Observations from the final analyses of the study cited in
the example section allow one to predict that a non-rapid onset
SSRI formulated to provide rapid-onset selective serotonin reuptake
inhibition would be expected to provide substantial benefit over
current formulations of non-rapid onset SSRIs. Thus, a further
embodiment of the present invention is the delivery of a non-rapid
onset SSRI, such as fluoxetine, paroxetine, or sertraline, in a
rapid release formulation.
[0070] For example, freeze-dried or lyophilized dosage forms are
generally known to rapidly dissolve or disintegrate in the mouth.
These forms consist of a porous matrix of a water-soluble or
water-dispersible carrier material which is impregnated with a unit
dose of the active compound. These dosage forms are prepared by
first adding the active compound to a solution comprising the
carrier material and a suitable solvent, typically water. The
resulting composition is then subjected to a freeze drying
procedure whereby the solvent sublimes under a high vacuum.
[0071] In addition, U.S. Pat. No. 4,866,046, issued Sep. 12, 1989,
describes an aspirin tablet, for example, that rapidly dissolves in
the oral, preferably sublingual, cavity within 2-60 seconds. This
tablet provides rapid absorption of aspirin from the saliva into
the blood stream. The sublingual tablet is prepared by compressing
into slugs a mixture of starch (10% moisture), acetylsalicylic
acid, flavor and sweetener. The slugs are then ground (14-16 Mesh
size) and recompressed into tablets. An amino acid may also be used
with the aspirin for its solubilizing and a taste-neutralizing
effects.
[0072] U.S. Pat. No. 5,082,667, issued Jan. 21, 1992, discusses a
tablet triturate dosage that dissolves quickly in the buccal
cavity. The form includes a porous, cementatory network of a
water-soluble but ethanol-insoluble carbohydrate, which contains
discrete particles of the active compound that have been coated
with a triglyceride coating. The discrete particles are prepared by
suspending the active ingredient in molten triglyceride. The
discrete particles are mixed with the carbohydrate and a temporary
liquid binder to form a damp mass. The mass is then shaped into a
tablet and dried to form the tablet triturate. This tablet
triturate method is limited, however, to active compounds that are
not sensitive to the melting temperature of the triglyceride.
[0073] Pharmaceutical compositions for use in the methods of the
present invention may be prepared by any of the methods of
pharmacy, but all methods include the step of bringing into
association the active ingredient with the carrier which
constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation.
[0074] For example, a tablet may be prepared by compression or
molding, optionally, with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable
machine the active ingredient in a free-flowing form, such as
powder or granules, optionally mixed with a binder, lubricant,
inert diluent, surface active or dispersing agent. Molded tablets
may be made by molding, in a suitable machine, a mixture of the
powdered compound moistened with an inert liquid diluent.
[0075] The administration of these compositions in the methods of
the present invention may be either concurrent or sequential, e.g.,
a rapid-onset selective serotonin reuptake inhibitor, or a
pharmaceutically acceptable salt thereof, may be administered as a
combination (a single unit dosage), or concurrently but separately,
with one or more additional therapeutic agents, such as one or more
drugs for erectile dysfunction or low libido, for the prevention,
treatment, or management of sexual dysfunction. The compounds of
the invention may also be provided by the sequential administration
of one of the compounds discussed above and one or more additional
therapeutic agents suitable for the prevention, treatment, or
management of a sexual dysfunction in any possible order. The
compositions administered in each of these methods may be
concurrent, sequential, or in any combination of concurrent and/or
sequential.
[0076] The terms "as-needed," "as-needed basis," "prn," and "prn
dosing," as used herein, mean administering a therapeutically
effective amount of a rapid onset selective serotonin reuptake
inhibitor according to the invention at a time interval sufficient
to provide an improved therapeutic profile, i.e., improved therapy,
in the prevention, treatment, or management of sexual dysfunction
while avoiding priming doses, chronic administration, and/or
overdosing. As used herein, the term "therapeutically effective
amount," means the amount of a rapid onset selective serotonin
reuptake inhibitor or a pharmaceutically acceptable salt thereof,
that provides a therapeutic benefit in the treatment, prevention,
or management of one or more sexual dysfunctions or the symptoms of
the one or more sexual dysfunctions. The term "sexual dysfunction,"
as used herein, includes, but is not limited to, premature
ejaculation, retarded ejaculation (male), inhibited orgasm
(female), low sexual desire, sexual aversion, dyspareunia, and
vaginismus. In particular, sexual dysfunction means premature
ejaculation. The term "premature ejaculation," as used herein,
means intravaginal ejaculation latency of less than 2 minutes that
has occurred in greater than 50% of intercourse for at least the
previous 6 months. The term is also used in accordance with DSM IV
to mean: (1) persistent or recurrent ejaculation with minimal
sexual stimulation before, on, or shortly after penetration and
before the person wishes it, which must account for factors that
affect duration of the excitement phase, such as age, novelty of
the sexual partner or situation, and recent frequency of sexual
activity; (2) the disturbance causes marked distress or
interpersonal difficulty; and (3) the premature ejaculation is not
due exclusively to the direct effects of a substance (e.g.,
withdrawal from opioids).
[0077] One embodiment of the present invention is prn dosing of a
rapid-onset selective serotonin reuptake inhibitor, or a
pharmaceutically acceptable salt thereof, prior to sexual activity.
A preferred method includes prn dosing of a rapid-onset selective
serotonin reuptake inhibitor from immediately prior to, to about 12
hours prior to, sexual activity.
[0078] A more preferred method includes prn dosing immediately
prior to, to about 10 hours prior to, sexual activity. A more
preferred method includes prn dosing immediately prior to, to about
8 hours prior to, sexual activity. A most especially preferred
method includes prn dosing immediately prior to, to about 4 hours
prior to, sexual activity.
[0079] Those of ordinary skill in the art are well aware of a
suitable time interval for dosing purposes as discussed herein,
which may depend on other therapeutic compositions being taken by
the patient. By way of example, and in no way intended to be
limiting, a suitable time interval might be about 1 to 4 hours
prior to the need for therapy, but not more than once per day.
[0080] The amount of a dose of a rapid-onset selective serotonin
reuptake inhibitor, or a pharmaceutically acceptable salt thereof,
in prn dosing is an amount suitable for management of a disorder or
condition. The amount will vary with the severity of the condition
to be treated and the route of administration.
[0081] The dose and dose frequency will also vary according to the
age, body weight, and response of the individual patient. A
suitable dose range can be readily determined by one of ordinary
skill in the art. In general, the total dose for a rapid-onset
selective serotonin reuptake inhibitor, or a pharmaceutically
acceptable salt thereof, for the conditions described herein,
ranges from about 0.001 mg to about 350 mg, preferably from about
0.01 mg to about 200 mg, more preferably from about 0.01 mg to
about 120 mg, and most especially preferred about 1 mg to about 80
mg, administered in single or divided doses as needed. These
dosages are preferably adapted for self-administration as needed by
the patient.
[0082] It is further recommended that patients aged over 65 years,
and those with impaired renal or hepatic function, initially
receive low doses, and that they then be titrated based on
individual response(s) or blood level(s). It may be necessary to
use dosages outside these ranges in some cases, as will be apparent
to those lo skilled in the art. Further, it is noted that the
clinician or treating physician will know how and when to adjust,
interrupt, or terminate therapy in conjunction with individual
patient response.
EXAMPLES
[0083] The efficacy of a prn dosing method of the present invention
can be tested in a variety of ways. For example, a skilled artisan
could compare responses with and without administration of a prn
dose of dapoxetine, or a pharmaceutically acceptable salt thereof,
(within a time frame compatible with the pharmacokinetics of
dapoxetine). Suitable responses to compare include, for example,
determining latency from initiation of sexual activity until time
of ejaculation with a chronometer, by determining the number of
pelvic thrusts associated with intercourse, by counting the number
of times ejaculation occurs prior to penetration, or through the
use of a question or series of questions posed to the patients.
[0084] The efficacy of a prn dosing method with dapoxetine, or a
pharmaceutically acceptable salt thereof, can be determined, for
example, as follows. In vivo testing of human subjects can be
conducted via a double-blind, randomized, placebo-controlled safety
and efficacy study at 2 to 15 sites. To ensure 128 evaluable
subjects, approximately 168 subjects can be randomized to one of
four treatments: placebo, 20 mg or 40 mg dapoxetine. The study can
include a screening visit, a lead-in period of 4 weeks or less in
which intercourse was attempted at least 4 times, and a treatment
period of 4 weeks or less in which intercourse was attempted at
least 4 times. Subjects should be healthy men at least 18 years of
age with a diagnosis of premature ejaculation.
[0085] Subjects should be instructed to take study medication (one
dose is 2 tablets of either placebo, 10 mg or 20 mg dapoxetine)
within 1-3 hours of anticipated sexual activity. Study medication
is not taken more than 1 time per day. Subjects can be stratified
at the time of enrollment in a 1:1:1 ratio of placebo and 2 doses
of dapoxetine. Efficacy of dapoxetine, or a pharmaceutically
acceptable salt thereof, can be assessed by comparing ejaculatory
latencies recorded with a stopwatch by the partner and recorded in
an event log.
[0086] The patient-perceived-benefit of prn dosing method with
dapoxetine, or a pharmaceutically acceptable salt thereof, can be
determined, for example, through administration of a global
satisfaction question, such as,
[0087] "How would you complete the following statement?
[0088] The new bottle of medication that I received at my previous
visit made my premature ejaculation problem.
[0089] ______ much better
[0090] ______ better
[0091] ______ slightly better
[0092] ______ the same
[0093] ______ slightly worse
[0094] ______ worse
[0095] ______ much worse"
[0096] In addition, the patient-perceived-benefit of prn dosing
method with dapoxetine, or a pharmaceutically acceptable salt
thereof, can be determined, for example, through administration of
a psychometric quality of life instrument, such as a premature
ejaculation questionnaire (PEQ).
[0097] Subjects should be healthy men at least 18 years of age with
a diagnosis of premature ejaculation as defined by DSM IV. Subjects
who meet the selection criteria can provide a medical history and
have psychosexual and physical examinations at screening. Efficacy
of dapoxetine, or a pharmaceutically acceptable salt thereof, can
be assessed by comparing ejaculatory latencies recorded with a
stopwatch by the partner and recorded in an event log. Safety can
be assessed by clinical laboratory analyses, vital signs, and
adverse experience reports collected throughout the study. A
physical examination, including chest x-ray and ECG, can be
performed at the final visit.
[0098] Each subject should comply with the following criteria,
premature ejaculation as defined in the DSM IV or intravaginal
ejaculation latency over 2 minutes that occurred in over 50% of
intercourse for at least the previous 6 months, as noted by both
Subject and Partner/Spouse. Criteria for Premature Ejaculation
should be as follows: (1) persistent or recurrent ejaculation with
minimal sexual stimulation before, on, or shortly after penetration
and before the person wishes it. The clinician must take into
account factors that affect duration of the excitement phase, such
as age, novelty of the sexual partner or situation, and recent
frequency of sexual activity; (2) the disturbance causes marked
distress or interpersonal difficulty; and (3) the premature
ejaculation is not due exclusively to the direct effects of a
substance (e.g., withdrawal from opioids).
[0099] Subjects in the study should be heterosexual male, at least
18 years of age in a stable, monogamous, sexual relationship for at
least 6 months. The Subject and Partner/Spouse should both agree to
attempt at least 4 vaginal intercourses between visit 1 and visit 2
(which can be no longer than 4 weeks time) and 4 vaginal
intercourses between visit 2 and visit 3, visit 3 and visit 4, and
visit 4 and visit 5 (none of which can be longer than 4 weeks
time). The Subject and Partner should be capable of understanding
and complying with the protocol and both have understood and signed
the informed consent document. If Partner/Spouse is of childbearing
potential (i.e., not postmenopausal or not surgically sterile) and
Subject is not sterile, Subject and/or Partner should use an
acceptable form of birth control (condom, oral contraceptives).
Subject and Partner should agree to use the same form of birth
control throughout the study.
[0100] Subjects meeting any of the following criteria should be
excluded from the study, any clinically significant abnormalities,
history or presence of cardiac or vascular disease, hypertension,
hepatic, renal pulmonary, neurological or endocrinologic diseases,
significantly abnormal ECG at screening, a history of alcohol/drug
abuse within previous 6 months; average consumption of more than 2
drinks per day, a presence of major psychiatric disorders (e.g.,
schizophrenia, depression), concurrent erectile dysfunction,
urethritis, chronic prostatitus, pelvic surgery or trauma/injury to
spinal cord, positive hepatitis B surface antigen (HB sAg), HCV, or
human immunodeficiency virus (HIV) test results, has a known
hypersensitivity to dapoxetine or other SSRIs, has received any
investigational drugs within the previous 30 days, is unwilling or
unable to cooperate fully with the Investigator, is taking the
anti-hypertensive drugs, guanethidine or reserpine, or has evidence
of any medical condition that would interfere with premature
ejaculation, such as Subjects taking any of the medications within
the stated washout period listed below in Table 1.
1TABLE 1 Medications Medication/Treatment Washout Period Over the
counter cough/cold preparations 7 days Antiepileptics (e.g.,
phenytoin) 30 days Antispasmodics (e.g., procyclidine) 30 days
Barbiturates (e.g., phenobarbital) 30 days Cimetidine 30 days Other
Investigational Drugs 30 days Prescription or over the counter diet
30 days medications or treatments Sedating antihistamines 30 days
Warfarin-like compounds (e.g., Coumadin) 30 days Lithium 30 days
Selective Serotonin Re-uptake Inhibitors 30 days [SSRIs] (e.g.,
ZOLOFT, PAXIL, PROZAC] Tncyclicm Antidepressants (e.g., Coxefen, 30
days Nortriptylene, Amitriptyline) Monoamine Oxidase Inhibitors
[MAOls] 30 days (Nardil, Pamate, etc.) Antihypertensives:
.alpha.-blockers; clonidine; .alpha.- 30 days methyl DOPA, or
13-blockers
[0101] Subjects can be stratified at the time of enrollment in a
1:1:1 ratio of placebo and 2 doses of dapoxetine. Both the
Investigator and Subject should be blinded from study drug
assignment.
[0102] Vital signs assessments include blood pressure, heart rate,
respiration, and body temperature and these can be determined at
Screening and visits 2, 3, 4, and 5. Blood pressure and heart rate
measurements can be obtained with the Subject recumbent and
sitting. Oral body temperature (degrees Fahrenheit) may be measured
as part of each set of vital sign measurements specified above.
Laboratory analysis of standard assays can be done at Screening and
visits 2, 3, 4, and 5. Patients can be given event logs and
stopwatches at visit 1 to record the time study medication is
taken, when intercourse is attempted, and the ejaculatory latency,
defined as the time from intromission to ejaculation. The patient
and partner can initial each event in the event log. Questionnaires
should be administered at visits 1, 2, 3, 4, and 5 at the
investigative site. Subjects can be given 6 doses of study drug
(i.e., 12 capsules) at visit 2.
[0103] Subjects should self-administer the study medication within
1-3 hours of anticipated sexual activity. The study drug should not
be taken more than one time per day. Dosing can be captured by the
Subject in his event log. Dosing information in the Subject's event
log can be compared to the amount of drug left at visit 3.
[0104] Subjects cannot take any of the medications listed in the
table in the Exclusion Criteria section within the specified
washout period. Subjects should not take new medications (i.e.,
medications started within 30 days prior to study start or at some
point during the study) or stop taking any medications during the
course of this study. Use of all medications (over-the-counter,
prescription, and herbal) can be recorded on the concomitant
medication page of the case report form.
[0105] Comparisons can be made between absolute values for
placebo-treated versus each of the dapoxetine-treated groups.
[0106] Subjects can be required to attempt intercourse on at least
4 occasions across a maximum time period of 4 weeks during the
lead-in period. After 4 attempts at intercourse, the subjects
should return for visit 2. Event logs should be collected,
subject/partner global satisfaction recorded, and the quality of
life questionnaire administered. The subject should be randomized
to one of 18 dosing regimens of placebo or dapoxetine (20 or 40 mg
pm). After 4-6 attempts at intercourse across a maximum time period
of 4 weeks, the subject should return for visit 3. Event logs
should be collected, subject/partner global satisfaction recorded,
and the quality of life questionnaire administered. The next dose
of placebo or dapoxetine should then be distributed. After 4-6
attempts at intercourse across a maximum time period of 4 weeks,
the subject should return for visit 4. This pattern can be repeated
until the patient has received placebo and both doses of
dapoxetine.
[0107] Measures for "ejaculatory latency" and "number of thrusts
prior to ejaculation" should be recorded as the average of the 4-6
events recorded in the event logs for that treatment period.
Subjects who ejaculated prior to intromission should have a zero
recorded for both "ejaculatory latency" and "number of thrusts
prior to ejaculation." "Measures for Subject and Partner
satisfaction scores (global impression)" and "Subject and Partner
ejaculatory (or sexual) quality-of-life questionnaire" for each
treatment period should be based on the score collected at the
visit immediately following each treatment period.
[0108] Capsules or tablets can be prepared that contain placebo, 10
mg or 20 mg dapoxetine. Two capsules or two tablets should be taken
by a Subject 1-3 hours prior to anticipated sexual activity. Other
suitable oral formulations for the present invention are listed in
Tables 2, 3, 4, 5, 6 and 7.
2TABLE 2 Oral Formulation 5 mg 10 mg 20 mg Component capsule
capsule capsule Dapoxetine 5.0 10.0 20.0 Microcrystalline 90.0 90.0
90.0 Cellulose Pre-gelatinized 100.3 97.8 82.8 Starch
Croscarmellose 7.0 7.0 7.0 Magnesium 0.2 0.2 0.2 Stearate
[0109] The active ingredient (e.g., dapoxetine, or a
pharmaceutically acceptable salt thereof) can be sieved and blended
with the excipients listed. The mixture can be filled into suitably
sized two-piece hard gelatin capsules using suitable machinery and
methods well known in the art. See Remington's Pharmaceutical
Sciences, 16th or 18th Editions, each incorporated herein in its
entirety by this reference. Other doses may be prepared by altering
the fill weight and, if necessary, changing the capsule size to
suit.
3TABLE 3 Compressed Tablet Unit Dosage Forms Component 2.5 mg
tablet 5.0 mg tablet 20 mg tablet Dapoxetine 2.5 5.0 20.0
Microcrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized 100.3
97.8 82.8 Starch Croscarmellose 7.0 7.0 7.0 Magnesium 0.2 0.2 0.2
Stearate
[0110] The active ingredient (e.g., dapoxetine, or a
pharmaceutically acceptable salt thereof) can be sieved through a
suitable sieve and blended with the excipients until a uniform
blend is formed. The dry blend can be screened and blended with the
magnesium stearate. The resulting powder blend can then be
compressed into tablets of desired shape and size. Tablets of other
strengths can be prepared by altering the ratio of the active
ingredient to the excipient(s) or modifying the table weight.
4TABLE 4 Tablets Quantity per Tablet in mg. Formula A B C Active
Ingredient: 5.0 10.0 25.0 Dapoxetine Lactose BP 62.0 107.0 137.0
Starch BP 20.0 20.0 25.0 Microcrystalline Cellulose 10.0 10.0 10.0
Hydrogenated Vegetable Oil 1.5 1.5 1.5 Polyvinylpyrrolidinone 1.5
1.5 1.5 Compression Weight 100.0 150.0 200.0
[0111] The active ingredient (e.g., dapoxetine, or a
pharmaceutically acceptable salt thereof) can be sieved through a
suitable sieve and blended with the lactose until a uniform blend
is formed. Suitable volumes of water are added and the powders are
granulated. After drying, the granules are then screened and
blended with the remaining excipients. The resulting granules are
then compressed into tablets of desired shape. Tablets of other
strengths can be prepared by altering the ratio of active
ingredient to the excipient(s) or the compression weight.
5TABLE 5 Tablets Quantity per Tablet in mg. Formula A B C Active
Ingredient: 5.0 10.0 25.0 Dapoxetine Lactose BP 48.5 93.5 83.5
Starch BP 30.0 30.0 60.0 Pregelatinized Maize Starch BP 15.0 15.0
15.0 Magnesium stearate BP 1.5 1.5 1.5 Compression Weight 100.0
150.0 540.0
[0112] The active ingredient (e.g., dapoxetine, or a
pharmaceutically acceptable salt thereof) can be sieved through a
suitable sieve and blended with lactose, starch, and pregelatinized
maize starch until a uniform blend is formed. Suitable volumes of
water are added and the powders are granulated. After drying, the
granules are then screened and blended with the remaining
excipients. The resulting granules are then compressed into tablets
of desired shape. Tablets of other strengths can be prepared by
altering the ratio of active ingredient to excipient(s) or
compression weight.
6TABLE 6 Tablets Quantity per Tablet in mg. Formula A B C Active
Ingredient: 5.0 10.0 25.0 (R)-(--)-N,N-Dimethyl-1-phenyl-3-
(1-naphthalenyloxy)-propanamine Lactose BP 48.5 43.5 78.5 Starch BP
30.0 30.0 30.0 Pregelatinized Maize Starch BP 15.0 15.0 15.0
Magnesium stearate BP 1.5 1.5 1.5 Compression Weight 100.0 100.0
100.0
[0113] The active ingredient,
(R)-(-)-N,N-Dimethyl-1-phenyl-3-(1-naphthale- nyloxy)-propanamine,
can be sieved through a suitable sieve and blended with lactose,
starch, and pregelatinized maize starch until a uniform blend is
formed. Suitable volumes of water are added and the powders
granulated. After drying, the granules are screened and blended
with the remaining excipients. The resulting granules are then
compressed into tablets of desired shape. Tablets of other
strengths can be prepared by altering the ratio of active
ingredient to the excipient(s) or the compression weight.
7TABLE 7 Composition of placebo, 10 mg Dapoxetine, 20 mg
Dapoxetine, and 30 mg Dapoxetine Capsules. 10 mg 20 mg 30 mg
Ingredient Placebo Capsule Capsule Capsule Dapoxetine HCI (mg) NA
11.351 22.702 34.053 Starch, pregelatinized, 223.31 211.959 200.608
189.257 NF (Starch 1500) (mg) Dimethicone, NF (mg) 1.69 1.69 1.69
1.69 (Dow Corning 360 Medical Fluid, 350 cs) Total Fill Weight per
225 225 225 225 Capsule (mg) *The amounts of dapoxetine HCl are
equivalent to the corresponding potencies (10 mg, 20 mg, and 30 mg)
of the free base, dapoxetine.
[0114] Table 7 provides an additional formulation for the placebo
and the 10 mg, 20 mg, and 30 mg capsules of dapoxetine. Dapoxetine
HCl is blended with the excipients listed in Table 7 under
conditions and using techniques well known to one of ordinary skill
in the art. The mixture is then filled into suitably sized hard
gelatin capsules using suitable machinery and methods well known in
the art.
[0115] The Investigator can give the Subject 12 capsules of study
drug at each visit beginning with visit 2 and ending with visit 4.
Twelve capsules should be sufficient supply for the target of 4
attempts at intercourse (8 capsules) plus 2 planned, but aborted,
attempts (4 "extra" capsules). At each subsequent visit, Subjects
should return unused study medication from the previous treatment
period and can be given the next 12 capsules (containing a
different dosage from the previous study periods) of study drug.
The Subject should be allowed a maximum of one dose (two capsules)
per day. Drug administration should be recorded by the Subject in
his event log. Investigator should maintain a dispensing and an
inventory record of all test articles during the study and should
compare amount of study medication returned at these visits to drug
administration record in the Subject's event log. Any unused test
articles should be returned to the sponsor at the end of the
study.
[0116] After first treatment period, patient can be crossed over to
a different dose of study medicine (placebo, 20 mg or 40 mg
dapoxetine). After the second treatment period, patient can be
crossed over to the final study medicine (placebo, 20 mg or 40 mg
dapoxetine).
[0117] Any suitable route of administration may be employed for
providing a mammal with an effective dosage of dapoxetine according
to the methods of the present invention. For example, oral, rectal,
parenteral, epicutaneous, transdermal, subcutaneous, intramuscular,
intranasal, sublingual, buccal, intradural, intraocular,
intrarespiratory, or nasal inhalation and like forms of
administration may be employed. Oral administration is generally
preferred due to ease of administration, particularly where
self-therapy is administered by the mammal.
[0118] As used herein the terms "study drug" or "study medicine"
refer to either the placebo dose, the 20 mg dose of dapoxetine or
the 40 mg dose of dapoxetine.
[0119] The results of an interim analysis of a randomized,
double-blind, three way crossover evaluation of two prn doses of
dapoxetine (20 mg and 40 mg) in the treatment of premature
ejaculation (hereinafter referred to as "PE") are disclosed in
tables 8a and 8b. Each patient is assigned to receive 4 to 6
administrations of each of the 3 study doses, in a random order,
over 3 periods of not more than 4 weeks each. Interim analysis of
the data was conducted following completion of the first treatment
period.
[0120] The study comprised 155 men, aged 19 to 60, presenting with
PE as defined in the DSM IV. All patients were involved in a stable
monogamous sexual relationship of at least 6 months duration and
reported a history of intravaginal ejaculatory latency (hereinafter
referred to as "EL") of less than 2 minutes in greater than half of
their intercourse experiences. History of significant
cardiovascular disease or psychiatric disorder, uncontrolled
hypertension, erectile dysfunction, and substance abuse were
criteria for exclusion.
[0121] During a lead-in period (maximum of 4 weeks), patients were
asked to record ejaculatory latency a minimum of 4 times. Latency
is defined as the time span, as measured by the patient's partner
via a stopwatch, from vaginal intromission to ejaculation. At the
completion of the lead-in period, patients were randomized to
treatment with either 20 mg or 40 mg dapoxetine or placebo. Study
medication was to be ingested 1 to 3 hours prior to a planned
intercourse event. The time study drug was taken and time of
intercourse was recorded in an event log. Patients were instructed
to attempt intercourse at least 4 times over the 4 week treatment
period and were issued a sufficient supply of medication to
complete 6 attempts at intercourse. The outcome of each attempt
(success of intromission and EL) was recorded in the event log
initialed by the patient and his partner. Patients returned to the
study clinic for a follow-up visit after 4 to 6 attempts at
intercourse were completed. At visits 4, 5, and 6 patients were
asked to answer the Global Satisfaction Questions and to complete
the PEQ.
[0122] Of the 155 patients randomized, 145 completed the treatment
period. 54 patients were randomized to the placebo group, while 56
and 45 received 20 mg or 40 mg dapoxetine respectively. Although
patients were randomly assigned to treatment sequences in blocks of
6, the imbalance in the number of patients randomized to each group
was due to the random distribution of the 40 mg assignment to later
allocations within the blocks. The intent-to-treat population was
comprised of 143 patients, each of whom had baseline and follow-up
data for analysis. Analysis of EL was conducted on the 138 patients
who had latency data at baseline and at least one post-medication
event. The percentage of patients with data sufficient for
inclusion in the analysis of EL was lower in the 40 mg group than
in either of the other two groups. This difference may be
attributable to the smaller size of the 40 mg group, such that each
patient represents a greater percentage of the whole, rather than
being a function of the dose administered.
[0123] Patients across all three groups attempted intercourse
following ingestion of study drug an average of 4.4 times. Mean
ejaculatory latency at baseline (the average of all recorded EL
during the 4 week lead-in period) was 18 seconds longer in the
placebo group than in either dapoxetine group. An EL evaluable
patient was one who had both a baseline and a follow-up latency
value. It is notable that 22.5%, 16.0% and 13.5% of EL evaluable
patients in the placebo, 20 mg dapoxetine and 40 mg dapoxetine
groups respectively had mean baseline EL above 2 minutes, with some
recording mean values as high as 7 minutes.
[0124] Tables 8a and 8b provide summaries of the ejaculatory
latency in minutes for the baseline and follow-up respectively.
8TABLE 8a Baseline - 4-6 Attempts at Intercourse Lead-in Dapoxetine
Dapoxetine Dapoxetine Placebo 20 mg 40 mg 20 & 40 mg N 51
patients 50 patients 37 patients 87 patient, Mean .+-. S.D. 1.6
.+-. 1.09 1.3 .+-. 0.91 1.3 .+-. 1.24 1.3 .+-. 1.06 (minutes) Range
0.2-5.6 0.1-4.2 0.0-7.0 0-7.0 (minutes)
[0125]
9TABLE 8b Follow-up - 4-6 Attempts at Intercourse Treatment
Dapoxetine Dapoxetine Dapoxetine Placebo 20 mg 40 mg 20 & 40 mg
N 51 patients 50 patients 37 patients 87 patient, Mean .+-. S.D.
2.0 .+-. 1.48 2.3 .+-. 2.26 2.3 .+-. 2.19 2.3 .+-. 2.22 (minutes)
LS Mean 1.74 2.41 2.52 NA (minutes) Range 0.2-7.6 0.1-11.4 0.0-9.8
0.0-11.4 (minutes) P value v. NA 0.0340 0.0228 0.0103 placebo * NA
represents "not applicable." **LS represents "least squares," and
is the mean value with adjustment for differences in baseline and
sample size.
[0126] As summarized in table 8b above, the mean ejaculatory
latency for all intercourse events that followed ingestion of
dapoxetine increased by one minute for both the 20 mg and 40 mg
dapoxetine treatment groups, while EL increased only 24 seconds in
the placebo group. When the data are adjusted for sample size and
baseline differences between treatments, the LS means are 1.74
minutes for placebo, 2.41 for the 20 mg dapoxetine treatment, and
2.52 for the 40 mg dapoxetine treatment. The percentage of patients
achieving increases of at least one minute in EL was higher in the
20 mg (22%) and 40 mg (24%) dapoxetine groups than in the placebo
group (14%).
[0127] Various modifications of the invention in addition to those
shown and described herein will be apparent to those skilled in the
art from the foregoing description. Such modifications are also
intended to fall within the scope of the appended claims. The above
disclosure includes all the information believed to be essential to
enable those skilled in the art to practice the claimed
invention.
[0128] The cited patents or publications may provide further useful
information and, thus, these cited materials are incorporated
herein in their entireties by reference thereto.
[0129] The results of a final analysis of a randomized,
double-blind, three way crossover evaluation of two prn doses of
dapoxetine (20 mg and 40 mg) in the treatment of premature
ejaculation are disclosed in the following tables. The final
analyses of the data was conducted following completion of all 3
treatment periods.
10TABLE 9 Ejaculatory Latency in Minutes for all Patients.
Dapoxetine Dapoxetine Placebo 20 mg 40 mg (LS Mean) (LS Mean) (LS
Mean) Ejaculatory Latency 2.26 2.78 3.19 (minutes p-value v.
placebo for 0.0470 0.0004 ejaculatory latency Change in Latency
0.92 1.43 1.86 (minutes) p-value v. placebo for 0.05424 0.0004
change in latency
[0130]
11TABLE 10a Ejaculatory Latency for Patients with a Baseline of
Less Than One Minute. Dapoxetine Dapoxetine Placebo 20 mg 40 mg (LS
Mean) (LS Mean) (LS Mean) Ejaculatory Latency 1.1 1.2 1.7 (minutes)
p-value v. placebo for 0.009 ejaculatory latency Change in Latency
0.5 0.6 1.3 (minutes) p-value v. placebo for 0.008 change in
latency
[0131]
12TABLE 10b Global Satisfaction for Patients with a Baseline of
Less Than One Minute. Dapoxetin Dapoxetine Placebo 20 mg 40 mg
p-value Better/Much Better 4% 13% 24% <0.001 .gtoreq.Slightly
Better 16% 38% 46% <0.001
[0132]
13TABLE 11a Ejaculatory Latency for Patients with a Baseline of
Less Than Two Minutes. Dapoxetine Dapoxetine Placebo 20 mg 40 mg
(LS Mean) (LS Mean) (LS Mean) Ejaculatory Latency 1.7 2.4 2.5
(minutes) p-value v. placebo for 0.003 ejaculatory latency Change
in Latency 0.8 1.4 1.5 (minutes) p-value v. placebo for 0.003
change in latency
[0133]
14TABLE 11b Global Satisfaction for Patients with a Baseline of
Less Than Two Minutes. Dapoxetin Dapoxetine Placebo 20 mg 40 mg
p-value Better/Much Better 7% 23% 29% <0.001 .gtoreq.Slightly
Better 28% 50% 50% <0.001
[0134] Table 12 reveals that Dapoxetine can effectively and
unexpectedly treat premature ejaculation with the first dose
administered to a patient. Thus, no lead-in period is required in
order to treat premature ejaculation with dapoxetine providing for
effective PRN dosing.
15TABLE 12 Ejaculatory Latency Recorded After Administration of a
Single Dose. Dapoxetine Dapoxetine Placebo 20 mg 40 mg (LS Mean)
(LS Mean) (LS Mean) Ejaculatory Latency 1.54 .+-. 0.24 2.37 .+-.
0.24 1.98 .+-. 0.27 (minutes) p-value v. placebo for 0.015 0.219
ejaculatory latency *p-value for dapoxetine doses combined vs.
placebo = 0.038
[0135]
16TABLE 13a Ejaculatory Latency for "Severe" Patients. Dapoxetine
Dapoxetine Placebo 20 mg 40 mg Baseline (LS Mean) (LS Mean) (LS
Mean) Ejaculatory Latency 1.23 2.10 2.60 3.09 (minutes) p-value,
<0.0028 Placebo vs 40 mg Change in Latency 0.92 1.42 1.93
(minutes) p-value, <0.0026 Placebo vs 40 mg
[0136]
17TABLE 13b Global Satisfaction for "Severe" Patients. Dapoxetine
Dapoxetine Placebo 20 mg 40 mg p-value Better/Much Better 7.3%
17.2% 25.5% <0.0001 .gtoreq.Slightly Better 31.0% 48.5% 54.1%
<0.0001
[0137]
18TABLE 14a Ejaculatory Latency for "Moderate" Patients. Dapoxetine
Dapoxetine Placebo 20 mg 40 mg Baseline (LS Mean) (LS Mean) (LS
Mean) Ejaculatory Latency 1.68 2.10 2.64 2.93 (minutes) p-value,
<0.0405 Placebo vs 40 mg Change in Latency 0.45 0.94 1.27
(minutes) p-value, <0.0516 Placebo vs 40 mg
[0138]
19TABLE 14b Global Satisfaction for "Moderate" Patients. Dapoxetine
Dapoxetine Placebo 20 mg 40 mg p-value Better/Much Better 13.4%
34.4% 50% <0.0076 .gtoreq.Slightly Better 30.1% 51.6% 66.7%
<0.0076
[0139]
20TABLE 15a Ejaculatory Latency for Patients with a Baseline
.gtoreq.Two Minutes. Placebo Dapoxetine 40 mg Baseline (LS Mean)
(LS Mean) Ejaculatory Latency 3.19 5.24 6.59 (minutes) p-value,
0.18 Placebo vs 40 mg Change in Latency 2.12 3.43 (minutes)
p-value, 0.19 Placebo vs 40 mg
[0140]
21TABLE 15b Global Satisfaction for Patients with a Baseline
.gtoreq. Two Minutes. Dapoxetine Placebo 40 mg p-value Better/Much
Better 13% 39.1% 0.09 .gtoreq.Slightly Better 43.4% 65.2% 0.09
[0141]
22TABLE 16a Ejaculatory Latency for Patients with a Baseline
.gtoreq. One Minute. Dapoxetine Placebo 40 mg Baseline (LS Mean)
(LS Mean) Ejaculatory Latency 1.90 3.16 4.24 (minutes) p-value,
0.01 Placebo vs 40 mg Change in Latency 1.32 2.40 (minutes)
p-value, 0.01 Placebo vs 40 mg
[0142]
23TABLE 16b Global Satisfaction for Patients with a Baseline
.gtoreq. One Minute. Dapoxetine Placebo 40 mg p-value Better/Much
Better 11.7% 36.4% <0.001 >Slightly Better 40.6% 65.0%
<0.001
* * * * *