DESCRIPTION
FIELD OF THE INVENTION
The present invention is directed to a pharmaceutical formulation comprising
Dapoxetine and Tramadol to treat premature ejaculation.
PRIOR ART OF THE RELATED INVENTION
US 7718705 discloses the 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.
U.S. Patent 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.
U.S. Patent No. 5,276,042 discloses the chronic administration of paroxetine.
The compositions are administered for a time period of at least about 3 months.
In some instances, paroxetine is administered chronically as long as the patient
remains sexually active.
U.S. Patent 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 sexual dysfunction, such as premature
ejaculation. These compositions are disclosed to be administered daily, for
example, one to four times daily.
EP 1397126 provides a method of delaying ejaculation. The method comprises
administering an effective amount of a tramadol material to a human male prior
to sexual intercourse. The method is particularly useful for treating premature
ejaculation.
Thus there is a need of the pharmaceutical formulation which is effective in
delaying the ejaculation, when taken just few hours prior to sexual intercourse.
OBJECTIVES OF THE INVENTION

The object of the present invention is to provide a pharmaceutical formulation
for delaying the ejaculation.
Yet another object of the present invention is to provide a formulation which is
having fewer side effects.
Yet another object is to provide a formulation which is not taken for a longer
period to get results; rather taken a few hours before sexual intercourse.
SUMMARY OF THE INVENTION
The present pharmaceutical formulation comprises of selective serotonin *
reuptake inhibitor and a centrally acting opioid for the treatment of premature
ejaculation. The selective serotonin reuptake inhibitor is preferably Dapoxetine
and the centrally acting opioid is preferably Tramadol or its pharmaceutically
acceptable salts.
DETAILED DESCRITION OF THE INVENTION
Premature ejaculation (PE) is a condition in which a man ejaculates earlier than
he or his partner would like him to. Premature ejaculation is also known as rapid
ejaculation, rapid climax, premature climax, or early ejaculation. Premature
ejaculation (PE; also known as rapid ejaculation) is the most common type of
sexual dysfunction in men younger than 40 years. Most professionals who treat
premature ejaculation define this condition as the occurrence of ejaculation
prior to the wishes of both sexual partners. This broad definition thus avoids
specifying a precise duration for sexual relations and reaching a climax, which
is variable and depends on many factors specific to the individuals engaging in
intimate relations. An occasional instance of premature ejaculation might not be
cause for concern, but, if the problem occurs with more than 50% of attempted
sexual relations, a dysfunctional pattern usually exists for which treatment may
be appropriate.
To clarify, a male may reach climax after 8 minutes of sexual intercourse, but
this is not premature ejaculation if his partner regularly climaxes in 5 minutes
and both are satisfied with the timing. Another male might delay his ejaculation
for a maximum of 20 minutes, yet he may consider this premature if his partner,
even with foreplay, requires 35 minutes of stimulation before reaching climax. If
intercourse is the method of sexual stimulation for the second example and the
male climaxes after 20 minutes of intercourse and then loses his erection,

satisfying his partner (at least with intercourse), who needs 35 minutes to climax, is impossible.
Because many females are unable to reach climax at all with vaginal intercourse (no matter how prolonged), this situation may actually represent delayed orgasm in the female partner rather than premature ejaculation in the male; the problem can be either or both, depending on the point of view. This highlights the importance of obtaining a thorough sexual history from the patient (and preferably from the couple).
PE is sometimes confused with erectile dysfunction (ED; impotence), a condition where the man cannot achieve or maintain an erection suitable for sexual intercourse. Men with PE ejaculate with a rigid erection while men with ED may lose their erection prior to ejaculation. Unlike ED, PE is not frequently associated with serious underlying medical conditions like heart disease or diabetes, although it is possible to have both PE and ED. Dapoxetine is indicated for the treatment of premature ejaculation (PE) in men aged 18 to 64 years. The following conditions were met in the clinical studies of PE: a latency of intravaginal ejaculation (IELTS) in less than two minutes, and constant or recurrent ejaculation with minimal sexual stimulation before, during or shortly after penetration and before the patient wishes, and significant personal distress or interpersonal difficulty due to PE, and poor ejaculation control. Dapoxetine mechanism for premature ejaculation is assumed to be linked to inhibition of neuronal reuptake of serotonin and the subsequent strengthening of the neurotransmitter effect on pre-and postsynaptic receptors. Ejaculation in humans is mediated primarily by the sympathetic nervous system. The ejaculation path based on a reflex center in the spinal cord and is mediated by the brainstem, which initially affected by a number of nuclei in the brain. In rats, dapoxetine inhibits the ejaculatory ejection reflex by acting at supraspinal level where the lateral paragigantocellular (LPGi) is a necessary brain structure for effect. Postganglionic sympathetic fibers that innervate the seminal vesicles, vas deferens, prostate, they bulbourethral muscles and bladder neck causing them to contract in a coordinated way to achieve ejaculation. Dapoxetine modulates this ejaculations reflex in rats and increases the Pudendal motoneuron reflex discharges (PMRD) latency and reduced duration of PMRD.

Dapoxetine effectiveness in the treatment of premature ejaculation has been established in five double-blind, placebo-controlled clinical trials, in which a total of 6081 patients were randomized. The patients were 18 years or older and had had a PE in the majority of sexual intercourse for 6 months before recruitment. Patients had in four of the studies a latency of intra-vaginal ejaculation (IELTS; time from vaginal penetration to the time of intra-vaginal ejaculation) of < 2 minutes in at least 75% of the evaluable intercourse during the baseline period. The fifth study, patients had the same inclusion. However, were not measured IELTS using a stopwatch. Patients with other types of sexual dysfunction, including erectile dysfunction, or those who used other types of pharmacotherapy for the treatment of PE were excluded from all studies. In four of the studies measured the primary efficacy endpoint was mean IELTS using a stopwatch at each intercourse.
The results from all randomized trials were consistent. In a representative study with the longest duration of treatment (24 weeks) randomized 1162 patients, of whom 385 to placebo, 388 to Dapoxetine 30 mg, if necessary, and 389 to Dapoxetine 60 mg if necessary. Mean IELTS at baseline and at study endpoint for any treatment group are shown in Figure 1. The increases in mean average IELTS at the end point at week 24 was statistically significant (p <0.001) in both dapoxetine groups versus placebo. The size of the IELTS extension was related to IELTS at baseline and varied between individual patients. The clinical relevance of the effect of treatment with dapoxetine described below in terms of patient-reported response rates.
Tramadol hydrochloride is a centrally acting opioid analgesic, used in treating moderate to severe pain. The drug has a wide range of applications, including treatment for restless leg syndrome and fibromyalgia.
It was found that when dapoxetine is combined with tramadol, the resulting combination shows a significant synergy in the treatment of premature ejaculation.
The present invention is directed to the pharmaceutical formulation comprising Dapoxetine and Tramadol. Dapoxetine is used either as dapoxetine or its pharmaceutically acceptable salt and is in the range of 15 mg to 80 mg, more preferably 30 mg to 60 mg, whereas Tramadol is used either as tramadol or its

pharmaceutical^ acceptable salt and is in the range 25 mg to 125 mg, more
preferably 50 mg to 100 mg.
The present formulation is prepared by using the suitable pharmaceutical
excipients, along with the said quantity of Active Pharmaceutical Ingredients.
The excipients used may be selected from the group of diluents, binding
agents, disintegrants, and lubricants.
The diluents can be selected from lactose, sucrose, glucose, mannitol, sorbitol,
calcium carbonate, and magnesium stearate.
The binding agents can be selected from polyvinylpyrrolidone (PVP),
polyethylene glycol (PEG), xylitol, sorbitol and maltitol which are mixed with the
appropriate solvent.
The solvent can be selected from purified water or isopropyl alcohol or the
mixture of both.
The disintegrants can be selected from polyvinylpyrrolidone (crospovidone),
crosslinked sodium carboxymethyl cellulose (croscarmellose sodium) and
sodium starch glycolate.
The lubricants can be selected from talc or silica, and fats, e.g. vegetable
stearin, magnesium stearate or stearic acid.
The formulation may be coated or uncoated.
The formulation can be coated with Hydroxypropyl Methyl Cellulose, along with
suitable plasticizer, opacifier, coloring agent and the solvent.
The release of both the said active ingredients from the pharmaceutical
formulations of the present invention can be immediate or modified, controlled,
delayed, sustained, and extended. The release rate for both active drugs can
be the same or different.
The pharmaceutical formulations of the present invention may comprise formed
particles with the same composition or formed particles with different composition and different release rate of said active ingredients.

CLAIMS
1. A pharmaceutical formulation comprising 15 mg to 80 mg of Dapoxtine, preferably 30 to 60 mg, and Tramadol 25 mg to 125 mg, preferably 50 to 100 mg, along with pharmaceutically acceptable excipients.
2 The pharmaceutically acceptable excipients are selected from diluents,
binding agents, disintegrants, and lubricants.
3 The diluents as claimed in claim 2 can be selected from lactose, sucrose,
glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.
4. The binding agents as claimed in claim 2 can be selected from
polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), xylitol, sorbitol
and maltitol which are mixed with the appropriate solvent.
5. The solvent as claimed in claim 4 can be selected from purified water or
isopropyl alcohol or the mixture of both.
6. The disintegrants as claimed in claim 2 can be selected from
polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl
cellulose (croscarmellose sodium) and sodium starch glycolate.
7. The lubricants as claimed in claim 2 can be selected from talc or silica,
and fats, e.g. vegetable stearin, magnesium stearate or stearic acid.
8. The formulation as claimed in claim 1 can be coated with Hydroxypropyl Methyl Cellulose, along with suitable plasticizer, opacifier, coloring agent and the solvent.