U.S. patent application number 13/247387 was filed with the patent office on 2012-01-26 for treatment of comorbid premature ejaculation and erectile dysfunction.
Invention is credited to David Bar-Or, Kevin Bilyard, James V. Winkler.
Application Number | 20120018345 13/247387 |
Document ID | / |
Family ID | 39690490 |
Filed Date | 2012-01-26 |
United States Patent
Application |
20120018345 |
Kind Code |
A1 |
Winkler; James V. ; et
al. |
January 26, 2012 |
Treatment of Comorbid Premature Ejaculation and Erectile
Dysfunction
Abstract
The invention provides a method of treating comorbid premature
ejaculation and erectile dysfunction. In particular, the method
comprises administering an effective amount of a tramadol material
and an effective amount of a phosphodiesterase inhibitor. The
invention also provides a pharmaceutical composition comprising a
pharmaceutically-acceptable carrier, a tramadol material and a
phosphodiesterase inhibitor. The invention further provides a kit
comprising a tramadol material and a phosphodiesterase
inhibitor.
Inventors: |
Winkler; James V.; (Denver,
CO) ; Bilyard; Kevin; (Cheshire, GB) ; Bar-Or;
David; (Englewood, CO) |
Family ID: |
39690490 |
Appl. No.: |
13/247387 |
Filed: |
September 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12029783 |
Feb 12, 2008 |
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13247387 |
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60889369 |
Feb 12, 2007 |
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Current U.S.
Class: |
206/570 |
Current CPC
Class: |
A61K 31/519 20130101;
A61P 15/10 20180101; A61K 31/4985 20130101; A61P 15/12 20180101;
A61P 15/00 20180101; A61K 31/519 20130101; A61K 31/137 20130101;
A61K 31/47 20130101; A61K 31/4985 20130101; A61K 31/53 20130101;
A61K 45/06 20130101; A61K 31/47 20130101; A61K 31/53 20130101; A61K
31/137 20130101; A61P 43/00 20180101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
206/570 |
International
Class: |
B65D 69/00 20060101
B65D069/00 |
Claims
1-12. (canceled)
13. A kit comprising: (a) a container holding a tramadol material
and a phosphodiesterase (PDE) inhibitor; or (b) a first container
holding a tramadol material and a second container holding a
phosphodiesterase (PDE) inhibitor.
14. The kit of claim 13 wherein the tramadol material is tramadol
or a pharmaceutically-acceptable form thereof, and the PDE
inhibitor is a PDE3, PDE4 or PDE5 inhibitor.
15. The kit of claim 14 wherein the PDE inhibitor is a PDE5
inhibitor.
16. The kit of claim 15 wherein the tramadol material is
(.+-.)cis-tramadol or a pharmaceutically-acceptable salt thereof,
and the PDE5 inhibitor is sildenafil or a
pharmaceutically-acceptable form thereof, vardenafil or a
pharmaceutically-acceptable form thereof, tadalafil or a
pharmaceutically-acceptable form thereof, or a combination of two
or more of the foregoing PDE5 inhibitors.
17. The kit of claim 16 wherein the tramadol material is
(.+-.)cis-tramadol hydrochloride, and the PDE5 inhibitor is
sildenafil citrate, vardenafil hydrochloride, tadalafil or a
combination of two or more of the foregoing PDE5 inhibitors.
18. The kit of claim 17 wherein the PDE5 inhibitor is sildenafil
citrate.
19. The kit of claim 13 further comprising instructions for using
the tramadol material and the PDE inhibitor to treat comorbid
premature ejaculation and erectile dysfunction in a male.
Description
RELATED APPLICATION
[0001] This application is a divisional application of U.S.
application Ser. No. 12/029,783, filed Feb. 12, 2008, which claims
priority from U.S. Provisional Patent Application No. 60/889,369
filed Feb. 12, 2007. The entire disclosures of the prior
applications are considered to be part of the disclosure of the
accompanying application and are hereby incorporated by
reference.
FIELD OF THE INVENTION
[0002] The invention relates to a method for treating comorbid
premature ejaculation and erectile dysfunction in a human male. The
method comprises administering both a tramadol material and a
phosphodiesterase inhibitor to the male. The invention also relates
to a pharmaceutical composition comprising a tramadol material and
a phosphodiesterase inhibitor. The invention further relates to a
kit comprising a tramadol material and a phosphodiesterase
inhibitor.
BACKGROUND OF THE INVENTION
[0003] Premature ejaculation is the most common form of male sexual
dysfunction, with an estimated 22-38% of males suffering from it.
It is a debilitating sexual dysfunction which can lead to an
inability to enter into, or sustain, relationships and can cause
psychological damage to sufferers. Premature ejaculation can also
impair reproductive success.
[0004] Erectile dysfunction is also a common form of male sexual
dysfunction, with an estimated 5-15% of males suffering from it.
The prevalence of erectile dysfunction increases with age and
certain medical conditions, such as heart disease, hypertension and
diabetes.
[0005] Men often suffer from both premature ejaculation and
erectile dysfunction. It has been reported that from about 25 to
about 45% of men with premature ejaculation also suffer from
erectile dysfunction (Fasolo et al., J. Sex. Med., 2:376-382
(2005); Shabsigh and Perelman, J. Sex Res., Volume 43, Number 1
(February 2006); Porst et al., European Urology , 51(3):816-824
(March 2007; published online July 2006)), and that over half of
men with erectile dysfunction also suffer from premature
ejaculation (Shabsigh and Perelman, J. Sex Res., Volume 43, Number
1 (February 2006)). Men who suffer from both premature ejaculation
and erectile dysfunction have lower scores for quality of life and
sexual enjoyment compared to those with either premature
ejaculation or erectile dysfunction alone. Id.
SUMMARY OF THE INVENTION
[0006] The invention provides a method of treating comorbid
premature ejaculation and erectile dysfunction in a human male. In
particular, the method comprises administering an effective amount
of a tramadol material and an effective amount of a
phosphodiesterase inhibitor to the male an effective time prior to
sexual activity.
[0007] The invention also provides a pharmaceutical composition.
The composition comprises a pharmaceutically-acceptable carrier, a
tramadol material and a phosphodiesterase inhibitor.
[0008] The invention further provides a kit comprising a tramadol
material and a phosphodiesterase inhibitor. The kit may comprise
one or more containers, each of which contains both the tramadol
material and the phosphodiesterase inhibitor. Alternatively, the
kit may comprise a container holding the tramadol material and a
different container holding the phosphodiesterase inhibitor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows stereoisomers of tramadol.
DETAILED DESCRIPTION OF THE PRESENTLY-PREFERRED EMBODIMENTS OF THE
INVENTION
[0010] As used herein, the term "premature ejaculation" means a
sexual dysfunction wherein a male is unable to control the
ejaculatory process to a degree sufficient to satisfy a partner
and/or himself. Premature ejaculation refers to persistent or
recurring ejaculation with minimal stimulation and/or that occurs
sooner than desired, before or shortly after penetration during
sexual intercourse, causing distress to one or both partners. See
Montague, et al. J. Urol., 172:290-294 (2004); Diagnostic and
Statistical Manual of Mental Disorders, 4.sup.th ed., American
Psychiatric Association, Washington, D.C. (2000). The term includes
"congenital," "lifelong," "primary" and "acquired" premature
ejaculation.
[0011] Although a variety of specific criteria have been proposed
for diagnosing premature ejaculation, no one criterion or group of
criteria is yet universally accepted. Specific proposed criteria
include: (i) ejaculation prior to penetration or within ten to
twenty strokes after intromission; (ii) ejaculation in less than
1-2 minutes; and (iii) ejaculation 50% of the time more rapidly
than the female is able to have an orgasm if she has no orgasmic
dysfunction. See, e.g., U.S. Pat. Nos. 6,037,360 and 5,151,448;
Male Infertility and Sexual Dysfunction, page 356 (Springer-Verlag
1997); Diagnostic and Statistical Manual of Mental Disorders
(American Psychiatric Association 1994). More recently, an
intravaginal ejaculatory latency time (`IELT` or `WELT`) measured
by stopwatch of less than 2 minutes combined with evidence of
distress or interpersonal difficulty has been used for the
diagnosis of premature ejaculation in clinical studies. See Pryor,
et al., Lancet, 368(9539):929-937 (Sep. 9, 2006). One report
suggests that men with an IELT of less than 1 minute have
"definite" premature ejaculation and that men with an IELT between
1 and 1.5 minutes have "probable" premature ejaculation, whereas
the severity of the premature ejaculation (such as
"non-symptomatic," "mild," "moderate" and "severe") should be
defined in terms of associated psychological problems. Waldinger,
et al., J. Sex. Med., 2(4):498-507 (2005). Various self-reported
outcome questionnaires, also referred to as patient-reported
outcomes, for diagnosing premature ejaculation have been developed.
See Althof, et al., Urol. Clin. North Am., 34(4):581-589 (November
2007). The Premature Ejaculation Diagnostic Tool (PEDT) is one such
questionnaire. It has recently been validated and indicates that
scores of 9 and 10 are "probable" premature ejaculation and scores
equal to or greater than 11 are diagnostic of premature
ejaculation. See Symonds et al., Eur. Urol., 52:565-573 (2007) and
Symonds et al., Int. J. Impot. Res., 19:521-5 (2007) (includes a
copy of the questionnaire). This questionnaire evaluates lack of
control, frequency of premature ejaculation, minimal sexual
stimulation, distress and interpersonal difficulties. Presently,
the inventors consider that the best criteria for diagnosing
premature ejaculation are a short IELT plus a PEDT score of 9 or
greater. The exact definition of a short IELT is expected to vary
depending on geographic area and/or cultural differences, and can
be determined empirically. For the United States, the inventors
presently consider that the best definition of a short IELT is an
IELT of less than 2 minutes in greater than 50% of coital attempts
as measured using a stopwatch.
[0012] As used herein, the term "erectile dysfunction" means the
consistent or recurrent inability to achieve and/or maintain a
penile erection sufficient to permit satisfactory sexual
intercourse or activity. "Erectile dysfunction" is also used herein
to mean the partial, temporary or episodic absence of a penile
erection.
[0013] The erectile function (EF) domain of the International Index
of Erectile Function (IIEF) has been developed and validated as a
patient-based questionnaire that is now widely use for the
diagnosis of erectile dysfunction. The EF domain of the IIEF has
demonstrated test reliability and validity with a high degree of
sensitivity and specificity. In particular, men scoring 25 or less
are classified as having ED and those scoring above 25 are
classified as not having ED (sensitivity=0.97; specificity=0.88).
Further, responses to IMF erectile function questions can classify
erectile dysfunction into five diagnostic categories: no erectile
dysfunction (score 26-30); `mild` erectile dysfunction (score
22-25); `mild-to-moderate` erectile dysfunction (score 17-21);
`moderate` erectile dysfunction (score 11-16); and `severe`
erectile dysfunction (score 6-10). See Rosen, et al., Int. J.
Impot. Res., 14(4):226-244 (August 2002) and Rosen, et al.,
Urology, 49:822-830 (1997) (includes a copy of the IIEF
questionnaire and an identification of the EF questions). Another
subset of the IIEF called the Sexual Health Inventory for Men
(SHIM) was also developed and validated as a diagnostic tool that
is now widely use for the diagnosis of erectile dysfunction. Men
scoring 21 or less are classified as having ED and those scoring
above 21 are classified as not having ED (sensitivity=0.98;
specificity=0.88). Further, responses to SHIM questions can
classify erectile dysfunction into five diagnostic categories: no
erectile dysfunction (score 22-25); `mild` erectile dysfunction
(score 17-21); `mild-to-moderate` erectile dysfunction (score
12-16); `moderate` erectile dysfunction (score 8-11); and `severe`
erectile dysfunction (score 5-7). See Rosen, et al., Int. J. Impot.
Res., 14(4):226-244 (August 2002) (identifies the SHIM questions)
and Rosen, et al., Urology, 49:822-830 (1997) (includes a copy of
the IIEF questionnaire). Accordingly, erectile dysfunction can be
diagnosed using the EF score and/or the SHIM score, and the
severity of erectile dysfunction can also be assessed using these
scores.
[0014] As used herein, the term "comorbid" means that two diseases
coexist or are found in the same person. "Comorbid premature
ejaculation and erectile dysfunction" means that premature
ejaculation and erectile dysfunction coexist or are found in the
same human male, i.e, that a single human male experiences, tends
to experience, or has a history of experiencing, both premature
ejaculation and erectile dysfunction.
[0015] The term "tramadol material" is used herein to refer to
2-[dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol
("tramadol") and all pharmaceutically-acceptable forms and
derivatives of tramadol. In particular, the term includes the
N-oxide derivative ("tramadol N-oxide") and the O-desmethyl
derivative ("O-desmethyl tramadol"). The term also includes the
solvates, polymorphs, and pharmaceutically-acceptable acid addition
salts of tramadol and its derivatives. The term further includes
all of the stereoisomers of any of the foregoing, including
individual stereoisomers (including individual enantiomers) and
mixtures of stereoisomers (including the racemates).
[0016] The stereoisomers of tramadol are shown in FIG. 1. There
appears to be some discrepancy in the literature regarding the
nomenclature of the individual stereoisomers of tramadol. For the
purposes of the present application, the designations of "cis" and
"trans" stereoisomers of tramadol are made in reference to the
relative positions of the dimethylamino and the hydroxy
substituents on the cyclohexane ring within the tramadol molecule.
As shown in FIG. 1, the R,R and S,S enantiomers will be referred to
herein as the "cis" isomers while the R,S and S,R isomers will be
referred to herein as the "trans" isomers. As also shown in FIG. 1,
the R,R isomer of tramadol will be referred to herein as the "+"
cis isomer and the S,S isomer will be referred to as the "-" cis
isomer. It is presently understood that R,S and S,R isomers are not
optically active.
[0017] Presently preferred is tramadol and the acid addition salts
thereof, particularly the hydrochloride. Even more preferred is
(.+-.)cis-tramadol, the acid addition salts, particularly the
hydrochloride, and the individual enantiomers.
[0018] Methods of making tramadol, tramadol N-oxide, and
O-desmethyl tramadol are well known. See, e.g., U.S. Pat. Nos.
3,652,589, 3,830,934, 5,223,541, 5,336,691, 5,723,668, 5,728,885,
and 5,874,620, the complete disclosures of which are incorporated
herein by reference. Tramadol is also commercially available from
several sources, including Gruenenthal GmbH, Aschen, Germany.
[0019] The pharmaceutically-acceptable acid addition salts are
prepared by conventional methods well known in the art using
pharmaceutically-acceptable, substantially non-toxic, organic and
inorganic acids. Such acids include hydrochloric acid, nitric acid,
sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid,
propionic acid, maleic acid, malonic acid, succinic acid, citric
acid, tartaric acid, malic acid, benzoic acid, salicylic acid,
phthalic acid, nicotinic acid, etc. Preferred is hydrochloric acid,
and tramadol hydrochloride is the most preferred compound for
practicing the invention.
[0020] Phosphodiesterases (PDEs) are a class of intracellular
enzymes involved in the metabolism of the second messenger
nucleotides cAMP and cGMP. The PDEs have now been classified into
eleven major families, Types I-XI. The members of the families vary
in their tissue, cellular and subcellular distribution, as well as
their links to the cAMP and cGMP pathways. For example, PDE type
III (PDE3), PDE type IV (PDE4) and PDE type V (PDE5) are found in
the corpus cavernosum, with PDE5 being the most abundant.
[0021] A "phosphodiesterase inhibitor" is an agent that is capable
of inhibiting or reducing, selectively or nonselectively, the
activity of a PDE. Suitable PDE inhibitors for use in the present
invention include those described in U.S. Pat. Nos. 5,250,534,
5,859,006, 6,140,329, 6,362,178, 6,403,597, 6,469,012, 6,821,975,
6,943,166 and 6,943,171, the complete disclosures of which are
incorporated herein by reference. Methods of making PDE inhibitors
are known. See, e.g., U.S. Pat. Nos. 5,250,534, 5,859,006,
6,140,329, 6,362,178, 6,403,597, 6,469,012, 6,821,975, 6,943,166
and 6,943,171. The PDE inhibitor used in the present invention is
preferably an inhibitor of PDE3, PDE4 and/or PDE5. More preferably,
the PDE inhibitor is a selective inhibitor of PDE5. Even more
preferably, the inhibitor is sildenafil, vardenafil and/or
tadalafil, and pharmaceutically-acceptable forms (e.g., salts,
solvates, stereoisomers (individual isomers and mixtures of
isomers), etc.) of them. Most preferably, the inhibitor is
sildenafil citrate (e.g., Viagra.RTM. sildenafil citrate; Pfizer),
vardenafil hydrochloride (e.g., Levitra.RTM. vardenafil HCl;
Schering-Plough) and/or tadalafil (e.g., Cialis.RTM.; Lilly
ICOS).
[0022] To treat comorbid premature ejaculation and erectile
dysfunction, an effective amount of a tramadol material and an
effective amount of a phosphodiesterase inhibitor are administered
to a male an effective time prior to sexual activity. The two drugs
may be administered simultaneously or sequentially in any order.
They may be administered separately, by the same or different modes
of administration, or they may be administered in combination in a
single dosage form by a single route of administration. Preferred
is a single dose of each drug taken orally prior to sexual
activity. By an "effective amount" is meant a nontoxic, but
sufficient, amount of each of the two drugs to delay ejaculation
and to reduce the incidence or severity of erectile dysfunction. By
an "effective time" is meant the range of time prior to sexual
activity during which each of the two drugs must be administered so
that they will be effective to delay ejaculation and reduce the
incidence of erectile dysfunction. An effective amount of
(.+-.)cis-tramadol HCl is from about 1 mg to about 250 mg,
preferably from about 10 mg to about 200 mg, more preferably from
about 25 mg to about 150 mg, given orally from about 30 minutes to
about 24 hours before sexual activity. An effective amount of
Viagra.RTM. sildenafil citrate is from about 5 mg to about 500 mg,
preferably from about 25 mg to about 100 mg, given orally from
about 30 minutes to about 4 hours before sexual activity. An
effective amount of Levitra.RTM. vardenafil hydrochloride is from
about 1 mg to about 100 mg, preferably from about 5 mg to about 20
mg, given orally from about 30 minutes to about 2 hours before
sexual activity. An effective amount of Cialis.RTM. tadalafil is
from about 1 mg to about 100 mg, preferably from about 5 mg to
about 20 mg, given orally from about 30 minutes to about 36 hours
before sexual activity. However, it is understood by those skilled
in the art that the dosage amount will vary with the particular
form of tramadol employed and the particular phosphodiesterase
inhibitor employed, the route(s) of administration, the timing of
the administration, the identity of any other drugs being
administered, the severity of the premature ejaculation and
erectile dysfunction conditions, the age, size and condition of the
patient, and like factors known in the medical art. In general, a
suitable dose will be that amount of the compound which is the
lowest dose effective to delay ejaculation and reduce the incidence
or severity of erectile dysfunction without toxicity. However, the
dosage, route of administration, etc., will be determined by an
attending physician within the scope of sound medical judgment.
Effective dosage forms, modes and times of administration, and
dosage amounts can be determined empirically.
[0023] As used herein, "delay ejaculation" means that a male
receiving treatment is able to control the ejaculatory process so
as to prevent ejaculation for a time which is longer than that
normally experienced by the male when not receiving treatment. It
is expected that the male will be able to control the ejaculatory
process to a degree sufficient to better or completely satisfy his
partner. "Delay ejaculation" does not mean to totally prevent
ejaculation.
[0024] As used herein, "reduce the incidence of erectile
dysfunction" means that erectile dysfunction will be prevented in a
male receiving treatment according to the invention or that the
number of incidences of erectile dysfunction will be reduced. As
used herein, "reduce the severity of erectile dysfunction" means
that the severity of erectile dysfunction as measured by the EF
and/or SHIM score is reduced (i.e., the EF or SHIM score
increases).
[0025] The tramadol material and phosphodiesterase inhibitor may be
administered by any suitable route of administration, including
orally, nasally, rectally, parenterally (e.g., intravenously,
subcutaneously, or intramuscularly), topically (i.e., delivery to
the skin or mucosa), transdermally (i.e., delivery by passage of a
drug through the skin into the bloodstream), transmucosally (i.e.,
delivery by passage of a drug through the mucosal tissue into the
bloodstream), intracavernosally (i.e., injection into one or both
corpora of the corpora cavernosal tissues of the penis), and
intarurethrally (i.e., delivery into the urethra). Highly preferred
is oral administration.
[0026] While it is possible for the tramadol material and
phosphodiesterase inhibitor to be administered alone, it is
preferable to administer them (individually or in combination) as a
pharmaceutical formulation (composition). The pharmaceutical
compositions will comprise a tramadol material, a phosphodiesterase
inhibitor or both as the active ingredient(s) in admixture with one
or more pharmaceutically-acceptable carriers and, optionally, with
one or more other compounds, drugs, or other materials. Each
carrier must be "acceptable" in the sense of being compatible with
the other ingredients of the formulation and not injurious to the
male who will take the composition. Pharmaceutically-acceptable
carriers are well known in the art. Regardless of the route of
administration selected, the active ingredient(s) are formulated
into pharmaceutically-acceptable dosage forms by conventional
methods known to those of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences
[0027] Pharmaceutical compositions containing a tramadol material
and methods of making the pharmaceutical compositions have been
described. See, e.g., U.S. Pat. Nos. 3,652,589, 3,830,934,
5,223,541, 5,591,452, 5,601,842, 5,728,885, 6,017,963, 6,090,856,
and 6,156,342, the complete disclosures of which are incorporated
herein by reference. Moreover, pharmaceutical compositions
containing tramadol and pharmaceutically-acceptable salts thereof
are manufactured and sold worldwide. In the United States, (.+-.)
cis-2-[dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol
hydrochloride for oral administration is available from
Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J. 08869, as ULTRAM
tablets. Each ULTRAM tablet contains 50 mg (.+-.)
cis-2-[dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol
hydrochloride and a number of inactive ingredients (corn starch,
hydroxypropyl methylcellulose, lactose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80,
sodium starch glycolate, titanium dioxide and wax). It is
understood that the commercial preparation of tramadol marketed
under the brand name ULTRAM.RTM. consists of a mixture of the R,R
and S,S isomers of tramadol hydrochloride.
[0028] Pharmaceutical compositions containing a phosphodiesterase
inhibitor and methods of making the pharmaceutical compositions
have also been described. See, e.g., U.S. Pat. Nos. 5,250,534,
5,859,006, 6,140,329, 6,362,178, 6,403,597, 6,469,012, 6,821,975,
6,943,166 and 6,943,171, the complete disclosures of which are
incorporated herein by reference. Suitable phosphosdiesterase
inhibitors are also available commercially from, e.g, Pfizer
(Viagra.RTM. sildenafil citrate), Schering-Plough (Levitra.RTM.
vardenafil HCl) and Lilly ICOS (Cialis.RTM. tadalafil).
[0029] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, powders, granules or as a solution or a suspension in an
aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil
liquid emulsions, or as an elixir or syrup, or as pastilles (using
an inert base, such as gelatin and glycerin, or sucrose and
acacia), and the like, each containing a predetermined amount of
the active ingredient(s). Preferred oral administration forms are
tablets and capsules.
[0030] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules and the like), the active ingredient(s) are 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, cetyl alcohol and glycerol
monosterate; (8) absorbents, such as kaolin and bentonite clay; (9)
lubricants, such as 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 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.
[0031] 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 compound moistened with an inert liquid
diluent.
[0032] 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(s) 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. 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. These compositions may also be of a composition
so that they release the active ingredient(s) only, or
preferentially, in a certain sequence (e.g., one before the other,
one immediately and the other over time, both over time but with
different release profiles, etc.). Examples of embedding
compositions which can be used include polymeric substances and
waxes. The active ingredient(s) can also be in microencapsulated
form.
[0033] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically-acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient(s), 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.
[0034] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming,
thickening, and preservative agents.
[0035] Suspensions, in addition to the active ingredient(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.
[0036] Formulations of the pharmaceutical compositions of the
invention for rectal administration may be presented as a
suppository, which may be prepared by mixing the active
ingredient(s) with one or more suitable nonirritating excipients or
carriers comprising, for example, cocoa butter, polyethylene
glycol, a suppository wax or salicylate, and which is solid at room
temperature, but liquid at body temperature and, therefore, will
melt in the rectum and release the active ingredient(s).
[0037] Dosage forms for the topical, transdermal or transmucosal
administration of the active ingredient(s) include powders, sprays,
ointments, pastes, creams, lotions, gels, solutions, patches, drops
and inhalants. The active ingredient(s) may be mixed under sterile
conditions with a pharmaceutically-acceptable carrier, and with any
buffers, or propellants which may be required.
[0038] The ointments, pastes, creams and gels may contain, in
addition to the active ingredient(s), 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.
[0039] Powders and sprays can contain, in addition to the active
ingredient(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.
[0040] The active ingredient(s) may also be delivered through the
skin using conventional transdermal drug delivery systems, i.e.,
transdermal patches, wherein the active ingredient(s) are typically
contained within a laminated structure that serves as a drug
delivery device to be affixed to the skin. In such a structure, the
active ingredient(s) are typically contained in a layer, or
"reservoir," underlying an upper backing layer. The laminated
device may contain a single reservoir, or it may contain multiple
reservoirs. In one embodiment, the reservoir comprises a polymeric
matrix of a pharmaceutically acceptable contact adhesive material
that serves to affix the system to the skin during drug delivery.
Examples of suitable skin contact adhesive materials include, but
are not limited to, polyethylenes, polysiloxanes, polyisobutylenes,
polyacrylates, polyurethanes, and the like. Alternatively, the
drug-containing reservoir and skin contact adhesive are present as
separate and distinct layers, with the adhesive underlying the
reservoir which, in this case, may be either a polymeric matrix as
described above, or it may be a liquid or hydrogel reservoir, or
may take some other form.
[0041] The backing layer in these laminates, which serves as the
upper surface of the device, functions as the primary structural
element of the laminated structure and provides the device with
much of its flexibility. The material selected for the backing
material should be selected so that it is substantially impermeable
to the active ingredient and any other materials that are present.
The backing layer may be either occlusive or nonocclusive,
depending on whether it is desired that the skin become hydrated
during drug delivery. The backing is preferably made of a sheet or
film of a preferably flexible elastomeric material. Examples of
polymers that are suitable for the backing layer include
polyethylene, polypropylene, polyesters, and the like.
[0042] During storage and prior to use, the laminated structure
includes a release liner. Immediately prior to use, this layer is
removed from the device to expose the basal surface thereof, either
the drug reservoir or a separate contact adhesive layer, so that
the system may be affixed to the skin. The release liner should be
made from a drug/vehicle impermeable material.
[0043] Transdermal drug delivery devices may be fabricated using
conventional techniques, known in the art, for example by casting a
fluid admixture of adhesive, drug and vehicle onto the backing
layer, followed by lamination of the release liner. Similarly, the
adhesive mixture may be cast onto the release liner, followed by
lamination of the backing layer. Alternatively, the drug reservoir
may be prepared in the absence of drug or excipient, and then
loaded by "soaking" in a drug/vehicle mixture.
[0044] The laminated transdermal drug delivery systems may in
addition contain a skin permeation enhancer. That is, because the
inherent permeability of the skin to some drugs may be too low to
allow therapeutic levels of the drug to pass through a reasonably
sized area of unbroken skin, it is necessary to coadminister a skin
permeation enhancer with such drugs. Suitable enhancers are well
known in the art.
[0045] The pharmaceutical compositions of the invention may also be
administered by nasal aerosol or inhalation. Such compositions are
prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, propellants such
as fluorocarbons or nitrogen, and/or other conventional
solubilizing or dispersing agents.
[0046] Preferred formulations for topical drug delivery are
ointments and creams. Ointments are semisolid preparations which
are typically based on petrolatum or other petroleum derivatives.
Creams containing the selected active agent(s), are, as known in
the art, viscous liquid or semisolid emulsions, either oil-in-water
or water-in-oil. Cream bases are water-washable, and contain an oil
phase, an emulsifier and an aqueous phase. The oil phase, also
sometimes called the "internal" phase, is generally comprised of
petrolatum and a fatty alcohol such as cetyl or stearyl alcohol;
the aqueous phase usually, although not necessarily, exceeds the
oil phase in volume, and generally contains a humectant. The
emulsifier in a cream formulation is generally a nonionic, anionic,
cationic or amphoteric surfactant. The specific ointment or cream
base to be used, as will be appreciated by those skilled in the
art, is one that will provide for optimum drug delivery. As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and nonsensitizing.
[0047] Formulations for buccal administration include tablets,
lozenges, gels and the like. Alternatively, buccal administration
can be effected using a transmucosal delivery system as known to
those skilled in the art.
[0048] Pharmaceutical compositions suitable for parenteral
administrations comprise the active ingredient(s) in combination
with one or more pharmaceutically-acceptable sterile isotonic
aqueous or non-aqueous solutions, dispersions, suspensions or
emulsions, or sterile powders or other solid forms which may be
reconstituted into sterile injectable solutions or dispersions just
prior to use, which may contain antioxidants, buffers, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0049] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions 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.
[0050] These compositions may also contain adjuvants such as
wetting agents, emulsifying agents and dispersing agents. It may
also be desirable to include isotonic agents, such as sugars,
sodium chloride, and the like in the compositions. In addition,
prolonged absorption of injectable pharmaceutical forms may be
brought about by the inclusion of agents which delay absorption
such as aluminum monosterate and gelatin.
[0051] In some cases, in order to prolong the effect of the active
ingredient(s), it is desirable to slow the absorption of the active
ingredient(s) 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 absorption of the active ingredient(s) 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 active ingredient(s) is accomplished by
dissolving or suspending the drug in an oil vehicle.
[0052] Injectable depot forms are made by forming microencapsule
matrices of the active ingredient(s) in biodegradable polymers such
as polylactide-polyglycolide. Depending on the ratio of active
ingredient(s) to polymer, and the nature of the particular polymer
employed, the rate of release of the active ingredient(s) can be
controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides). Depot injectable
formulations are also prepared by entrapping the active
ingredient(s) in liposomes or microemulsions which are compatible
with body tissue. The injectable materials can be sterilized for
example, by filtration through a bacterial-retaining filter.
[0053] Intracavernosal injection can be carried out by use of a
syringe or any other suitable device. An example of a hypodermic
syringe useful herein, that can be used for simultaneous injection
into both corpora, is described in U.S. Pat. No. 4,127,118. The
injection is made on the dorsum of the penis by placement of the
needle to the side of each dorsal vein and inserting it deep into
the corpora.
[0054] The active ingredient(s) can be administered in a
pharmaceutical formulation suitable for transurethral drug
delivery. The formulation contains one or more selected carriers or
excipients, such as water, silicone, waxes, petroleum jelly,
polyethylene glycol, propylene glycol, liposomes, sugars such as
mannitol and lactose, and/or a variety of other materials, with
polyethylene glycol and derivatives thereof particularly preferred.
It may be desirable to incorporate a transurethral permeation
enhancer in the urethral dosage form. Examples of suitable
transurethral permeation enhancers include dimethylsulfoxide,
dimethyl formaminde, N,N-dimethylacetamide, decylmethylsulfoxide,
polyethylene glycol monolaurate, glycerol monolaurate, lecithin,
the 1-substituted azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Nelson Research & Development Co., Irvine,
Calif.), SEPA.RTM. (available from Macrochem Co., Lexington,
Mass.), alcohols (e.g., ethanol), detergents (such as
Tergitol.RTM., Nonoxynol-9.RTM. and TWEEN-80.RTM.) and the like.
Transurethral formulations may additionally include one or more
enzyme inhibitors effective to inhibit drug-degrading enzymes which
may be present in the urethra. Additional optional components
include excipients, preservatives (e.g., antioxidants), chelating
agents, solubilizing agents (e.g., surfactants), and the like, as
will be appreciated by those skilled in the art of drug formulation
preparation and delivery.
[0055] Transurethral drug administration, as explained in PCT
application WO 91/16021, can be carried out in a number of
different ways using a variety of urethral dosage forms. For
example, the drug can be introduced into the urethra from a
flexible tube, squeeze bottle, pump or aerosol spray. The drug may
also be contained in coatings, pellets or suppositories which are
absorbed, melted or bioeroded in the urethra. In certain
embodiments, the drug is included in a coating on the exterior
surface of a penile insert. Drug delivery devices for administering
a drug transurethrally are described in U.S. Pat. No. 6,037,360 and
PCT application WO 91/16021.
[0056] Urethral suppository formulations containing polyethylene
glycol or a polyethylene glycol derivative can be used as the
urethral dosage form, and may be conveniently formulated using
conventional techniques, e.g., compression molding, heat molding or
the like, as will be appreciated by those skilled in the art and as
described in the pertinent literature and pharmaceutical texts.
See, for example, Remington: The Science and Practice of Pharmacy,
19th Ed. (Easton, Pa.: Mack Publishing Co., 1995), which discloses
typical methods of preparing pharmaceutical compositions in the
form of urethral suppositories. It is also preferred that urethral
suppositories contain one or more solubilizing agents (e.g., a
nonionic, anionic, cationic or amphoteric surfactant) effective to
increase the solubility of the active ingredient(s) in the
polyethylene glycol or other transurethral vehicle.
[0057] It may be desirable to deliver the active ingredient(s) in a
urethral dosage form which provides for controlled or sustained
release of the agent(s). In such a case, the dosage form typically
comprises a biocompatible, biodegradable material, typically a
biodegradable polymer. Examples of such polymers include polyester,
polyalkylcyanoacrylate, polyorthoester, polyanhydride, albumin,
gelatin and starch. As explained, for example, in PCT application
WO 96/40054, these and other polymers can be used to provide
biodegradable microparticles which enable controlled and sustained
drug release, in turn minimizing the required dosing frequency.
[0058] The method of intraurethral administration may involve an
"active" delivery mechanism such as iontophoresis, electroporation
or phonophoresis. Devices and methods for delivering drugs in this
way are well known in the art. Iontophoretically assisted drug
delivery is, for example, described in PCT application WO 96/40054.
Briefly, the active agent(s) are driven through the urethral wall
by means of an electric current passed from an external electrode
to a second electrode contained within or affixed to a urethral
probe.
[0059] The pharmaceutical formulations may be presented in
unit-dose or multi-dose sealed containers, for example, ampules,
vials and blister packs, and may be stored in a lyophilized
condition requiring only the addition of the sterile liquid
carrier, for example water for injection, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared
from sterile powders, granules and tablets of the type described
above.
[0060] The invention also provides a kit comprising a tramadol
material and a phosphodiesterase inhibitor. The kit may comprise
one or more containers, each of which contains a tramadol material
and a phosphodiesterase inhibitor. In such a case, the tramadol
material and the phosphodiesterase inhibitor are preferably
contained in the same pharmaceutical composition. Alternatively,
the kit may comprise a container holding the tramadol material and
a different container holding the phosphodiesterase inhibitor.
Suitable containers include tubes, ampules, vials, bottles, foil
packets, the wells of a tray and the molded depressions of blister
packs. The kit will also comprise instructions for administration
of the tramadol material and the phosphodiesterase inhibitor to
treat comorbid premature ejaculation and erectile dysfunction. The
container(s) will preferably be contained in a package, such as a
box. The instructions may be attached to, or printed on, one of the
containers, may be printed on a separate sheet of paper inside the
package, or may be attached to or printed on the package.
[0061] It is to be noted that "a" or "an" entity refers to one or
more of that entity. For example, "a container" refers to one or
more containers.
EXAMPLES
Example 1
[0062] A 51-year-old heterosexual male with a long history of
premature ejaculation and erectile dysfunction was evaluated by a
urologist who determined his premature ejaculation was `severe`
(documented intravaginal ejaculatory latency by stopwatch of less
than 1 minute and Premature Ejaculation Diagnostic Tool (PEDT)
score of 15) and co-morbid with `mild to moderate` erectile
dysfunction (International Index of Erectile Function (IIEF)
erectile function (EF) score of 21).
[0063] The subject was initially treated with selective serotonin
reuptake inhibitor (SSRI) medications; however, SSRI treatment was
only partially effective in treating the premature ejaculation and
did not improve his erectile dysfunction. The subject discontinued
all SSRI drugs due to low efficacy and intolerable side effects.
Sildenafil citrate (Viagra.RTM.) 50 mg administered before
intercourse somewhat improved the erectile dysfunction but did not
relieve the severe premature ejaculation, which continued to cause
significant emotional distress for the subject and his sexual
partner.
[0064] At the confidential suggestion of one of the inventors of
the present invention, the urologist subsequently prescribed
tramadol HCl with instructions to self administer a combination of
tramadol HCl 100 mg and sildenafil citrate 50 mg approximately 3
hours before intercourse. The results have been described as
`miraculous` with the subject's only complaint being excessively
delayed ejaculation (`much greater than 10 minutes`) and occasional
anorgasmia. These moderate adverse events of excessively delayed
ejaculation and anorgasmia were not permanent and were no longer
reported after reducing the tramadol HCl dose to 50 mg. The subject
now reports that this combination `works dramatically well` and his
co-morbid condition of premature ejaculation and erectile
dysfunction is successfully treated with a combination of tramadol
HCl 50 mg and sildenafil citrate 50 mg administered before
intercourse.
* * * * *