FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
A PHARMACEUTICAL COMPOSITION COMPRISING A COMBINATION OF DAPOXETINE AND PHQSPHODIESTERASE-V INHIBITOR
2. APPLICANT (S):
(a) NAME: AJANTA PHARMA LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Ajanta House, Charkop, Kandivali (West),
Mumbai - 400 067.
Provisional

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The following specification describes the invention.

Field of the Invention:
This invention relates to a combination of dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof and a compound belonging to the class of phosphodiesterase-V inhibitors and/or their isomers, enantiomers, pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such combinations; processes for their preparation; and methods of using such compositions for the treatment of patients suffering from sexual dysfunction and related disorders.
Background of the Invention:
Combination therapy affords the physician and patient the' opportunity to more effectively treat diseases that may stern from more than one cause. When used correctly and appropriately, combination therapy can lead to better outcomes than monotherapy by treating more than one cause of the disease and/or by synergistically enhancing the action of one of the component drugs. Combination therapy also can lead to a better outcome by reducing noncompliance by the patient to a particular regimen.
Premature ejaculation (PE) is a common form of male sexual dysfunction. According to the International Society for Sexual Medicine (ISSM) ejaculation in less than 60 seconds from start of intercourse is "premature" and is a sexual dysfunction affecting 30 % of the world's adult men. Indian surveys have shown that 10 % of all adult males in the country suffer from some sort of sexual dysfunction, a large chunk of which nearly 7 % would be of PE. Conventional selective serotonin reuptake inhibitor (SSRI) antidepressants are commonly used to treat this condition (WO0117521, US20050215617). A new serotonin transporter inhibitor, dapoxetine has been developed specifically for the treatment of PE. Chemically it is (-'-)-N,N-dimethyl-alpha-(2-(l -naphtha lenyloxy)ethyl)-benzenemethanamine and is available as a hydrochloride salt. Dapoxetine is effective when taken on demand, 1-3 h before intercourse. Men with PE receiving dapoxetine 30 or 60mg experienced increased intravaginal ejaculatory latency and
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higher levels of control over ejaculation and satisfaction with sexual intercourse. (Pryor J L, Althof S E, Steidle C, Miloslavshy M, Kell S., J. Urol. 2005; 173(Suppl): 201)

(I) Erectile dysfunction (ED) is another common form of male sexual dysfunction.
Phosphodiesterase (PDE)-V inhibitors, including sildenafil (VIAGRAs; Pfizer Inc.,
New York, NY, USA) or tadalafil (CIALISs; Lilly ICOS, LLC, Indianapolis, IN,
USA) are commonly used to treat this condition. Chemically sildenafil is l-((3-
(4,7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo(4,3-d)pyrimidin-5-yl)-4-
ethoxy-phenyl)sulfonyl)-4-i'nethylpiperazine. Commercially, it is available as
citrate salt.

(II)

(III)

While, chemically tadalafil is (6R,12aR)-,6-(l,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino(1,2':l,6)pyrido(3,4-b)indole-l,4-dione.
A significant proportion of men with PE also present with ED. A large survey that included 12,134 men from the United States, Germany, and Italy recently found
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that 7.2% of men met the criteria for both PE and ED. Overall, 32% of men with PE also reported ED, whereas 44% of men with ED also reported PE.
The present invention relates to a combination of dapoxetine or its isomer or enantiomer or pharmaceutically acceptable salt and phosphodiesterase-V inhibitor or their pharmaceutically acceptable salts; pharmaceutical compositions comprising such combinations; processes for their preparation; and methods of using such compositions.
Object of the Invention:
Proper treatment of PE and ED involves not just inhibiting early ejaculation and erectile dysfunction, 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 SSPJ4 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 SSPJ's 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. Dapoxetine, a SSRI is useful in management of PE). On the other hand, ED can be effectively treated by phosphodiesterase-V inhibitors. It is thus desirable to prescribe dapoxetine and phosphodiesterase-V inhibitor in combination. Hence there is need to have a pharmaceutical composition containing such combinations.
One major object of the present invention is to provide a pharmaceutical composition comprising dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof, a compound belonging to the class of phosphodiesterase-V inhibitor and/or their isomers, enantiomers, pharmaceutically
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acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients.
Another major object of the present invention is to provide a process for the preparation of a pharmaceutical composition comprising dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof, a compound belonging to the class of phosphodiesterase-V inhibitor .and/or their isomers, enantiomers, pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptably excipients.
The pharmaceutical composition disclosed in the present invention contains dapoxetine and/or its isorners, enantiomers, pharmaceutically acceptable salts thereof is present in an imniediate release form, or in an extended release form, or partly in an immediate release form and partly an extended release form. On the other hand, phosphodiesterase-V inhibitor is piesent in an immediate release form.
Phosphodiesterase-V inhibitor is selected from either sildenafil or tadalafil, or isomer or enantiomer or phfirmaceulically acceptable salts thereof.
The pharmaceutical composition of the present invention can be formulated as tablets, troches, dispersions, suspensions, solutions, capsules, caplets, cachets, patches, gel caps, syrups, elixirs, gels, powders, magmas, lccenges, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal or oral sprays, aerosols, and the like.
Summary of the Invention;
The present invention represents a pharmaceutical composition comprising dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof, and a compound belonging to the class of phosphodiesterase-V inhibitor and/or their isomers, enantiomers, pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients.
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The present invention relates to a process for the preparation of a pharmaceutical composition comprising dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof, a compound belonging to the class of phosphodiesterase-V inhibitor and/or their isomers, enantiomers, pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients.
In above said composition dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof is present in an immediate release form, or in an extended release form, or partly in an immediate release form and partly an extended release form. Dapoxetine may be present in a dosage range of 2-60 mg.
The said composition contains phosphodiesterase-V inhibitor in an immediate release form.
Phosphodiesterase-V inhibitor is selected from either sildenafil or tadalafil, or isomer or enantiomer or pharmaceutically acceptable salts thereof. Sildenafil is present in a dosage range of 20-200 mg while tadalafil may be present in a dosage range of 2-20 mg.
The pharmaceutical composition of the present invention can be formulated as 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.
Another aspect of the invention is to provide a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salt thereof in a single dosage unit comprising the steps of
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a) blending dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients;
b) optionally granulating the blend by wet granulation or dry granulation;
c) lubricating the blend of step a) or the granules of step b); and
d) compressing into or filling into a solid dosage form.
In another aspect, there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salt thereof in a single dosage unit comprising the steps of
a) blending dapoxetine or its isomer or enantiomer or pharmaceutically acceptable
salt thereof with one or more pharmaceutical excipients;
b) blending sildenafil or tadalafil, or their isomer or enantiomer or
pharmaceutically acceptable salt thereof with one or more pharmaceutical
excipients;
c) optionally granulating separately the blend of step a) and step b) by wet granulation or dry granulation;
d) lubricating separately the blend of step a) and step b) or the granules of step c); and
e) compressing into or filling into a solid dosage form.
The pharmaceutical composition may be provided in the form of tablets wherein the dapoxetine and sildenafil or tadalafil are processed to form a bilayer or multilayer or inlay tablet. Alternatively, the pharmaceutical composition may be provided in the form of tablets wherein the dapoxetine and sildenafil or tadalafil are separated by layer or a membrane of a physiologically acceptable inert material.
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In another aspect, there is a provided a process for preparation of pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salts thereof comprising the steps of
a) extruding dapoxetine with suitable excipients,
b) breaking the extruded cylinders into an appropriate length and transforming them into spheroids,
c) coating the spheroids with an extended release polymer coating,
d) optionally, seal coating the spheroids of step c),
e) coating the spheroid of step c) or d) with a drug layer comprising sildenafil or tadalafil, and
f) filling these spheroids into capsules or compressing them into tablets.
In another aspect, there is provided a process for preparing a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salts thereof comprising the steps of
a) extruding dapoxetine and extended release polymer with suitable excipients,
b) breaking the extruded cylinders into an appropriate length and transforming them into spheroids,
c) optionally, seal coating the spheroids of step b),
d) coating the spheroid of step b) or c) with a drug layer comprising sildenafil or tadalafil, and
e) filing these spheroids into capsules or compressing them into tablets.
The pharmaceutical composition may be provided in the form of tablets wherein dapoxetine and sildenafil or tadalafil are separated by a layer or a membrane of a physiologically acceptable inert material.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer Or pharmaceutically acceptable salts thereof comprising the steps of
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a) blending dapoxetine with one or more pharinaceutically inert excipients,
b) optionally granulating the blend,
c) lubricating the blend or granules,
d) compressing the lubricated blend of step c) into tablet,
e) optionally coating the core with suitable inert excipients,
f) dispersing or dissolving sildenafil or tadalafil and other inert excipients in a suitable solvent system, and
g) coating the cores of step e) with a drug layer of sildenafil or tadalafil from step f)-
The pharmaceutical composition may be provided in the form of capsules wherein the dapoxetine composition is in the form of tablets, minitablets, granules or pellets and the sildenafil or tadalafil composition is in the form of the powder, granules, minitablets or pellets.
In another embodiment there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil or pharmaceuticslly acceptable salts thereof comprising the steps of
a) blending dapoxetine with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a;
c) lubricating the blend or granules of step b;
d) compressing the lubricated blend of step c into suitable size tablet;
e) blending sildenafil or tadalafil and one or more pharmaceutically inert
excipients; and
f) filling the tablet and sildenafil or tadalafil powder blend into a capsule.
The beads or tablets as described above may have an additional non-functional coating such as polyethylene glycol for protection or to improve the aesthetic appeal of the product. The non functional coating may also help in overcoming a common problem of the rupturing or cracking of release controlling
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layers/membrane or fragmentation of the core due to mechanical stress generated during compression of cores to tablet or filling into a capsule/sachet.
In yet another embodiment there is provided a kit comprising a plurality of separate pharmaceutical compositions, wherein at least one of said composition contains dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof and at least another of said composition contains a compound belonging to the class of phosphodiesterase-V inhibitor and/or their isomers, enantiomers, pharmaceutically acceptable salts thereof, and said compositions optionally contain a pharmaceutical excipient.
The details of one or more embodiments of the inventions are set forth in the description below.
Detailed Description of the Invention:
The present invention represents a pharmaceutical composition comprising dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof, a compound belonging to the class of phosphodiesterase-V inhibitor and/or their isomers, enantiomers, pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients.
According to one particular aspect of the invention, there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof, a compound belonging to the class of phosphodiesterase-V inhibitor and/or their isomers, enantiomers, pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients.
In above said composition dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof is present in an immediate release form,
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or in an extended release form, or partly in an immediate release form and partly an extended release form.
The said composition contains phosphodiesterase-V inhibitor in an immediate release form.
Phosphodiesterase-V inhibitor is selected from either sildenafil or tadalafil, or isomer or enantiomer or pharrnaceutically acceptable salts thereof.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising dapoxetine hydrochloride and sildenafil citrate or tadalafil in a dosage form wherein dapoxetine hydrochloride and sildenafil citrate or tadalafil are present as immediate release components of the composition. According to another aspect of the invention, there is provided a pharmaceutical composition comprising dapoxetine hydrochloride and sildenafil citrate or tadalafil in a dosage form wherein dapoxetine hydrochloride and sildenafil citrate or tadalafil are present as immediate release components of the composition.
According to another aspect of the invention, there is provided a process for preparing pharmaceutical composition comprising dapoxetine hydrochloride and sildenafil citrate or tadalafil in a dosage form wherein dapoxetine hydrochloride and sildenafil citrate or tadalafil are present as immediate release components of the composition.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising dapoxetine hydrochloride and sildenafil citrate or tadalafil in a dosage form wherein dapoxetine hydrochloride is present as an extended release component and sildenafil citrate or tadalafil is present as an immediate release component of the composition.
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According to another aspect of the invention, there is provided a process for preparing pharmaceutical composition comprising dapoxetine hydrochloride and sildenafil citrate or tadalafil in a dosage form wherein dapoxetine hydrochloride is present as an extended release component and sildenafil citrate or tadalafil is present as an immediate release component of the composition.
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.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 500 mg, more usually about 25 to about 300 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier. 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.
In particular, the present invention provides pharmaceutical compositions, especially suitable for forming solid dosage forms, comprising from about 6 to about 60% by weight dapoxetine or its isomer or enantiomer or pharinaceutically acceptable salts thereof, and about 10 to about 50% by weight sildenafil or its isomer or enantiorner or pharrnaceiitically acceptable salts thereof, or about 2 to about 20% by weight tadalafil or its isomer or enantiomer or pharinaceutically acceptable salts thereof, and pliaimaceulically acceptable excipients.
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In another aspect, there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salt thereof in a single dosage unit comprising the steps of
a) blending dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients;
b) optionally granulating the- blend by wet granulation or dry granulation;
c) lubricating the blend of step a) or the granules of step b); and
d) compressing into or filling into a solid dosage form.
In yet another aspect, there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salt thereof in a single dosage unit comprising the steps of
a) blending dapoxetine or its isomer or enantiomer or pharmaceutically acceptable
salt thereof with one or more pharmaceutical excipients;
b) blending sildenafil or tadalafil, or their isomer or enantiomer or
pharmaceutically acceptable salt thereof with one or more pharmaceutical
excipients;
c) optionally granulating Separately the blend of step a) and step b) by wet granulation or dry granulation;
d) lubricating separately the blend of step a) and step b) or the granules of step c); and
e) compressing into or filling into a solid dosage form.
The pharmaceutical composition may be provided in the form of tablets wherein the dapoxetine and sildenafil or tadalafil are processed to form a bilayer or multilayer or inlay tablet. Alternatively, the pharmaceutical composition may be provided in the form of tablets wherein the dapoxetine and sildenafil or tadalafil
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are separated by layer or a membrane of a physiologically acceptable inert material.
Therapeutically effective amount of dapoxetine or pharniaceutically acceptable salt thereof ranges from 10-100 mg equivalent to dapoxetine. Therapeutically effective amount of sildenafil or pharniaceutically acceptable salt thereof ranges from 20-200 mg equivalent to sildenafil. Therapeutically effective amount of tadalafil or pharmaceutically acceptable salt thereof ranges from 2.5-50 mg equivalent to tadalafil.
Dapoxetine has a rapid onset of action of approximately 1.5 hours and a short half-life and a dose of 30 or 60 mg 1 -3 hours before intercourse not to be taken more frequently than once every 24 hours.
The dose of sildenafil for erectile dysfunction is 25 mg to 100 mg taken not more than once per day between 30 minutes and 4 hours prior to sexual intercourse. Sildenafil has a half-life of 4 hours.
Tadalafil has a half-life of 17.5 hours and is available in 5, 10, or 20 mg doses. Due to its 36-hour effect it is also known as the weekend pill. As with sildenafil it is recommended that tadalafil be used no more than once daily.
In another aspect, there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salts thereof in a single dosage unit comprising the steps of
a) coating an inert core with a drug layer comprising dapoxetine,
b) coating the core with a polymeric coating to provide for extended release of the drug,
c) optionally, coating the core of step b) with a seal coat,
d) coaling cores of step b) or c) with a drug layer comprising sildenafil or tadalafil,
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e) optionally, coating the cores of step d) with a seal coat, and
f) filling the beads of step d) or e) into capsules or compressing into tablets.
The pharmaceutical composition may be provided in the form of capsules wherein
the capsule comprises beads comprising dapoxetine and sildenafil or tadalafil.
The pharmaceutical composition may be provided in the form of capsules wherein the capsule comprises two beads viz. one of dapoxetine and another of sildenafil or tadalafil.
In another aspect, there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salts thereof in a single dosage unit comprising the steps of
a) coating an inert core with a drug layer comprising, sildenafil or tadalafil
b) coating an inert core with a drug layer comprising dapoxetine,
c) coating the cores of step b) with an extended release layer, and
d) filling the beads of step a) and c) into capsules.
The inert core described here can be water insoluble, soluble or swellable.
Water insoluble core includes silicon dioxide, small particles of glass, or plastic resin particles such as polypropylene or polyethylene. Water-soluble core includes sugar spheres such as glucose, mannitol, lactose, xylitol, dextrose, sucrose and salt cores such as sodium chloride, potassium chloride. Water swellable core may be made up of hydroxypropyl methylcellulose, microciystalline cellulose or starch. Inert core may have a diameter ranging from about 150-600 urn, preferably about 250-425 um.
The pharmaceutical composition may be provided in the form of capsules or tablets wherein the capsule or tablet comprises spheroids.
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In another aspect, there is a provided a process for preparation of pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salts thereof comprising the steps of
a) extruding dapoxetine with suitable excipients,
b) breaking the extruded cylinders into an appropriate length and transforming
them into spheroids,
c) coating the spheroids with an extended release polymer coating,
d) optionally, seal coating the spheroids of step c),
e) coating the spheroid of step c) or d) with a drug layer comprising sildenafil or tadalafil, and
f) filling these spheroids into capsules or compressing them into tablets.
In another aspect, there is provided a process for preparing a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salts thereof comprising the steps of
a) extruding dapoxetine and extended release polymer with suitable excipients,
b) breaking the extruded cylinders into an appropriate length and transforming them into spheroids,
c) optionally, seal coating the spheroids of step b),
d) coating the spheroid of step b) or c) with a drug layer comprising sildenafil or tadalafil, and
e) filing these spheroids into capsules or compressing them into tablets.
The pharmaceutical composition may be provided in the form of tablets wherein dapoxetine and sildenafil or tadalafil are separated by a layer or a membrane of a physiologically acceptable inert material.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salts thereof comprising the steps of
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a) blending dapoxetine with one or more pharmaceutically inert excipients,
b) optionally granulating the blend,
c) lubricating the blend or granules,
d) compressing the lubricated blend of step c) into tablet,
e) optionally coating the core with suitable inert excipients,
f) dispersing or dissolving sildenafil or tadalafil and other inert excipients in a suitable solvent system, and
g) coating the cores of step e) with a drug layer of sildenafil or tadalafil from step
f).
The pharmaceutical composition may be provided in the form of capsules wherein the dapoxetine composition is in the form of tablets, minitablets, granules or pellets and the sildenafil or tadalafil composition is in the form of the powder, granules, minitablets or pellets.
In another embodiment there is provided a process for the preparation of a pharmaceutical composition comprising dapoxetine and sildenafil or tadalafil or pharmaceutically acceptable salts thereof comprising the steps of
a) blending dapoxetine with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a;
c) lubricating the blend or granules of step b;
d) compressing the lubricated blend of step c into suitable size tablet;
e) blending sildenafil or tadalafil and one or more pharmaceutically inert
excipients; and
f) filling the tablet and sildenafil or tadalafil powder blend into a capsule.
The beads or tablets as described above may have an additional non-functional coating such as polyethylene glycol for protection or to improve the aesthetic appeal of the product. The non functional coating may aho help in overcoming a common problem of the rupturing or cracking of release controlling
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layers/membrane or fragmentation of the core due to mechanical stress generated during compression of cores to tablet or filling into a capsule/sachet.
The above said solid compositions are optionally film coated with film forming polymers.
Single dosage unit as used herein includes tablet, capsule, pills and the like. This single dosage unit is suitable for once a clay administration.
Yet another aspect of the invention is to provide a kit comprising a plurality of separate pharmaceutical compositions, wherein at least one of said composition contains dapoxetine and/or its isomers, enantiomers, pharmaceutically acceptable salts thereof and at least another of said composition contains a compound belonging to the class of phosphodiecterase-V inhibitor and/or their isomers, enantiomers, pharmaceutically acceptable salts thereof, and said compositions optionally contain a pharmaceutical excipienl. The said compositions provided in the kit may be taken one after another or in a span of upto S hours.
In yet another aspect of the invention there is provided a pharmaceutical composition in the form of chewable tablets comprising dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceutically acceptable salts thereof and one or more sweetening agents. Optionally, the formulation may contain one or more polyalcohols, surfactants, colorants, flavors, flavor enhancers, or taste modifying agents including taste masking agents.
The above said solid compositions contain dapoxetine about 6 to 60 %, and sildenafil 10 to 50 % or tadalafil 2 to 20 % per total weight of solid composition.
Another aspect of the present invention is to provide a solid oral dosage form comprising dapoxetine hydrochloride and sildenafil citrate wherein the sildenafil is released at a faster rate compared to dapoxetine.
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Another aspect of the present invention is to provide a solid oral dosage form comprising dapoxetine hydrochloride and tadalafil wherein the tadalafil is released at a faster rate compared to dapoxetine.
Another aspect of the present invention is to provide a solid oral dosage form comprising dapoxetine hydrochloride and sildenafil citrate or tadalafil wherein dapoxetine may he enteric coated to provide less than 10 % release within 2 hours of dosing.
The dissolution profiles for such a composition comprising dapoxetine hydrochloride and sildenafil citrate is given below.
Table 1. Dissolution profile of dapoxetine I-IC1 in a composition comprising dapoxetine hydrochloride and sildenafil citrate

Time (min) Average (% of dapoxetine HC1 released) Range of % of dapoxetine HC1 released over 12 samples
3 62 59-64
6 85 82-87
9 99 98-101
12 100 99-101
15 101 100-101
30 101 100-101
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Table 2. Dissolution profile of sildenafil citrate in a composition comprising dapoxetine hydrochloride and sildenafil citrate

Time (min) Average (% of sildenafil citrate released) Range of % of sildenafil citrate released over 12 samples
3 75 72 - 78
6 96 92-97
9 100 98-101
12 100 99-101
15 101 100-101
30 100 100-101
A clinical trial is proposed to be executed in a crossover fashion to evaluate the clinical efficacy of the composition over plain sildenafil or dapoxetine. This will be a randomised, double-blind, double-dummy, placebo-controlled, 4-period cross¬over, single-centre trial conducted in patients with diagnosed PE and ED. The trial involved 4 treatments: sildenafil 100 mg; dapoxetine 60 mg; sildenafil 100 mg plus dapoxetine 60 mg; and placebo. For each patient the total duration of the trial was 12 weeks, comprising a 2-week screening period followed by four 7-day, double-blind, double-dummy, randomized treatment periods, each period being separated by a 2-week washout period. All patients were to receive each of the 4 treatments. Prospective patients were observed during the 2-week screening period to assess their suitability for the trial; those who failed the entry criteria were not permitted to re-enter the trial. Patients were assessed at entry to the trial (Visit 1), at the beginning of the randomised period (Visit 2), and after each of the 4 randomised treatment periods: Visits 3, 4, 5, and 6, respectively. Similarly, a clinical trial is proposed to be executed in a crossover fashion to evaluate the clinical efficacy of the composition over plain tadalafil or dapoxetine.
The term 'extended release' as used herein includes.any release other than immediate release and covers the slow release of drug over an extended period of time, and includes both controlled and sustained release.
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The term "pharmaceutically inert excipient" as used herein includes substances known in the art as diluents, binders, disintegrants, coloring agents, flavoring agents, stabilizers, extended release polymers, surfactants, lubricants/glidants, plasticizers and preservatives for pharmaceutical compositions.
The diluent may be one or more of lactose, starch, mannitol, sorbitol, dextrose rnonohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose- based diluents, monobasic calcium sulphate rnonohydrate, calcium sulphate dihydrate, calcium lactate trihydrate, powdered cellulose, and the like.
The binding agent is selected from those commonly known in the art, and is used to impart sufficient cohesion to the powders to permit normal processing, such as sizing, lubrication, compression, and packaging, but still permit the composition to disintegrate and dissolve upon ingestion. Examples of suitable binding agents include one or more of acacia, tragacanth, sucrose, gelatin, glucose, starch, alginic acid, polyethylene glycol, guar gum, polysaccharides, bentonites, polyvinylpyrrolidone, and cellulose ethers such as hydroxypropyl methylcellulose and hydroxypropyl cellulose. The binding agent preferably is present at from about 0.05 % to about 50 % w/w of the formulation, although variations outside this range may be used.
The disintegrants may be one or more of starches, sodium starch glycolate, clays, celluloses such as purified cellulose, methylcellulose and sodium carboxymethylcellulose, alginates, pre-gelatinized corn starches, crospovidone, and gums. Disintegianls can be added at any suitable step during the preparation of the pharmaceutical composition, particularly prior to granulation or during the lubrication step prior to compression or filling of the dosage form. The disintegrant may be present either or both of intragranularly and extragranularly.
Croscarmellose sodium and sodium starch glycolate is one preferred disintegrant and may be present at from about 0.5 % to about 7 % w/w of the formulation. The
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use of disintegrant intragranularly as well as extragranularly enhances the disintegration time appreciably. The exlragranular disintegrant is present at from about 0.5 % to about 3 % w/w of the formulation, and preferably the disintegrant or disintegrants are present at about 1.5 % to about 2.5 % w/w of the formulation.
The pharmaceutical composition optionally comprises one or more lubricants and /or glidants. Suitable lubricants and/or glidants include glyceryl behenate, metallic stearate such as magnesium stearate, stearic acid, hydrogenated vegetable oils, talc, v/axes, boric acid, sodium benzoate, polyethylene glycols and sodium stearyl fumarate. The lubricant used in the present formulation is present in an amount of about 0.1 % to about 2.0% w/w and preferably from about 0.1 % to about 1.5% w/w. Use of magnesium stearate as lubricant is particularly desirable.
Examples of extended release polymers include water soluble polymers and water insoluble polymers. Specific examples of water-soluble polymers include polyvinylpyrrolidone, hydroxy propylcellulose, hydroxypropyl methylcellulose, methylcellulose, vinyl acetate copolymers, polysaccharides (such as alginate, xanthum gum), polyethylene oxide, maleic anhydride, methyl vinyl ether copolymers and derivatives and mixtures thereof. Specific example of water-insoluble polymers include acrylates such as methacrylates, methacrylic acid copolymers, acrylic acid copolymers; cellulose derivatives such ethylcellulose or cellulose acetate; polyethylene, and high molecular weight polyvinylalcohols.
Coating may be performed by applying one or more film forming polymers, with or without other pharmaceulically inert excipients, as a solution/dispersion in a suitable solvent system using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidizecl bed processor; or dip coating.
Examples of plasticizers include polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl phthalate, clibutyl sebacate and the like.
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The polyalcohol used in the present composition comprises of xylitol, sucralose, glycerol, polyethlene glycol, propylene glycol, glycerol rnonoesters with fatty acids or other pharmaceutically acceptable polyalcohols or mixtures thereof.
Sweetening agent may be of natural or artificial source. Examples are sugar, dextrose, lactose, mannitol, sucrose, xylitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, sodium cyclamate and honey or mixtures thereof.
The flavors which may be added optionally in the composition are selected from the essential oils or water soluble extracts of menthol, wintergreen, peppermint, sweet mint, spearmint, vanillin, cherry, chocolate, cinnamon, clove, lemon, orange, raspberry, rose, spice, violet, herbal, fruit, strawberry, grape, pineapple, peach, kiwi, papaya, mango, coconut, apple, coffee, plum, watermelon, nuts, durean, green tea, grapefruit, banana, butter, camomile. The effect of flavors may be enhanced using flavor enhancers like tartaric acid, citric acid vanillin, or the like.
Taste masking agents may be incorporated in the said composition whenever taste making is desired. Examples of taste masking agents include resins.
Colorants which may optionally be mixed in the composition must be safe in terms of toxicity and should be accepted by the Food and Drug Administration for use in pharmaceutical and cosmetic compositions.
The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
Examples I to VI
Hard gelatin capsules can be prepared using the formulae I to VI as given in Table
1. The active ingredients can be sieved and blended with the excipients given in the
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Table 1. The mixture can be filled into suitably sized two-piece hard gelatin capsules using suitable machinery.
Table 1

Ingredients mg/capsule

Formula I Formula II Formula III Formula IV Formula
V Formula VI
Dapoxetine I-IC1 33.6 33.6 67.2 67.2 -- --
Dapoxetine oxalate 100
Dapoxetine tartrate 100
Sildenafil citrate 140.5 140.5
Tadalafil -- 20 -- 20 20 20
Dried starch 60.9 31.4 22.3 42.8 40 40
Microcrystalline cellulose 50 50 50 50 50 50
Croscarmellose sodium 10 10 10 10 10 10
Magnesium stearate 5 5 10 10 5 5
Fill weight 300 150 300 200 225 225
Examples VII to X
Tablets can be prepared using the formulae VII to X as given in Table 2. The active ingredients can be sieved and blended with the excipients given in the Table 2 until a uniform blend is formed. The dry blend is subjected to granulation with the help of povidone and isopropyl alcohol. The dry granules are then screened and blended with magnesium stearate and talc. The resulting granules are then compressed into tablets of desired shape. The resulting tablets are then subjected to film coating with solution of HPMC
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Table 2

Ingredients mg/tablet

Formula VII Formula VIII Formula IX Formula X
Dapoxetine I-IC1 33.6 33.6 67.2 67.2
Sildenafil citrate 140.5 -- 140.5 --
Tadalafil — 20 -- 20
Microcrystalline cellulose 75.9 46.4 42.3 62.8
Croscarmellose sodium 25 25 25 25
Magnesium stearate 8 8 S S
Povidone 7 7 7 7
Isopropyl alcohol q. s. q. s. q. s. q. s.
Talc o 0 8 8 8
HPMC 2 2 2 2
Methylene chloride q. s. q. s. q. s. q. s.
Tablet weight 300 150 300 200
Example XI and XII
Eilayer tablets can be prepared using the formulae XI and XII as given in Table 3. Dapoxetine can be sieved and blended with the excipients given in the Table 3 until a uniform blend is formed. The dry blend is subjected to granulation with the help of povidone and isopropyl alcohol. The dry granules are then screened and blended v/ith magnesium stearate. The resulting granules are then compressed into tablets of desired shape to form a first layer. Sildenafil citrate or tadalafil can be sieved and blended with the excipients given in the Table 3 until a uniform blend is formed. The dry blend is subjected to granulation. The dry granules are then screened and blended with magnesium stearate. The resulting granules are then compressed over first layer to form a second layer.
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Table 3

(First layer) Ingredients mg/tablet (Second layer) Ingredients mg/tablet

Formula XI
Formula XI
Dapoxetine HO 67.2 Sildenafil citrate 140.5
Microcrystalline cellulose 37.8 Sodium starch glycolate 28.8
HPMC 60 Povidone 8.4
Carbopol-27G 40 Yellow oxide of iron 2
Povidone 12 Microcrystalline cellulose 281.1
Magnesium stearate J Magnesium stearate 9.6
Isopropyl alcohol q. s. Purified talc 9.6
Isopropyl alcohol q. s.
Layer weight 220 Layer weight 480
Tablet weight 700 mg
Example XII
Bilayer tablets can be prepared using the formulae XII as given in Table 4. Dapoxetine can be sieved and blended with the excipients given in the Table 4 until a uniform blend is formed. The dry blend is subjected to granulation with the help of povidone and isopropyl alcohol. The dry granules are then screened and blended with magnesium stearate. The resulting granules are then compressed into tablets of desired shape to form a first layer. Taclalafil can be sieved and blended with the excipients given in the Table 3 until a uniform blend is formed. The dry blend is subjected to granulation. The dry granules are then screened and blended with magnesium stearate. The resulting granules are then compressed over first layer to form a second layer.
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Table 4

(First layer) Ingredients mg/tablet (Second layer) Ingredients mg/tablet

Formula XII
Formula XII
Dapoxetine HC1 67.2 Tadalafil 20.0
Microcrystalline cellulose 37.8 Lactose 70.5
HPMC 60 Povidone 5
Carbopol-27G 40 Yellow oxide of iron 2
Povidone 12 Microcrystalline cellulose 135
Magnesium stearate J3 Croscarmellose sodium 10
Isopropyl alcohol q. s. Sodium lauryl sulpahte 2.5
Magnesium stearate 5
water q. s.
Layer weight 220 Layer weight 250
Tablet weight 470 mg
Examples XIII and XIV
Trilayer tablets can be prepared by compressing microcrystalline cellulose (100
mg) as a middle layer in bilayer tablets described in examples XI and XII.
Example XV
Flard gelatin capsule containing two tablets each for dapoxetine and sildenafil or tadalafil. Tablet of dapoxetine is prepared using the formula XV. Dapoxetine can be sieved and blended with the excipients given in the Table 4 until a uniform blend is formed. The dry blend is subjected to granulation with the help of povidone and isopropyl alcohol. The dry granules are then screened and blended with magnesium stearate. The resulting granules are then compressed into tablets of desired shape. Similarly, tablets of sildenafil and tadalafil were prepared according to formula XVI and XVII.
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Table 5

Ingredients mg/composition

Formula XV Formula XVI Formula XVII
Dapoxetine HC1 33.6 -- --
Sildenafil citrate -- 140.5 --
Tadalafil -- — 20
Microcrystalline cellulose 66.4 59.5 35
Croscarmellose sodium 25 25 20
Magnesium stearate 8 S 8
Povidone 7 7 7
Isopropyl alcohol q. s. q. s. q. s.
Talc 8 8 8
HPMC 2 2 2
Methylene chloride q. s. q. s. q. s.
Tablet weight 150 250 100
Example XVI
Hard gelatin capsule containing a dapoxetine tablet (prepared according to example XV) and granules of sildenafil or tadalafil (prepared according to example XV) can be prepared.
Example XVII
Hard gelatin capsule containing a sildenafil or tadalafil tablet (prepared according to example XV) and dapoxetine granules (prepared according to example XV) can be prepared.
Example XVIII
Hard gelatin capsule containing a dapoxetine granules (prepared according to example XV) and granules of sildenafil or tadalafil (prepared according to example XV) can be prepared.
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Example XIX
Hard gelatin capsule can be prepared that is containing a nd dapoxetine tablet
(prepared according to example XV) and powder of sildenafil or tadalafil, or vise
versa.
Example XX
An aerosol solution is prepared containing the following components:

Ingredient Weight (%)
Dapoxetine (HC1 salt) 0.25
Tadalafil 0.1
Ethanol 29.65
Propellant 22 (chlorodifluromethane) 70.00
Total 100
The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30° C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are than fitted to the container.
Example XXI
Suppositories may be made as follows:

Ingredient Qty (mg/suppository)
Dapoxetine (oxalate salt) 100
Sildenafil citrate 100
Saturated fatly acid glycerides 2000
Total weight 2200
The active ingredients is passed through sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
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Example XXII
Suspensions are made as follows:

Ingredient Qty (mg / 5ml)
Dapoxetine (oxalate) 30
Sildenafil citrate 100
Na carboxymethyl cellulose 50
Syrup 1.25 ml
Benzoic acid solution 0.10 ml
Flavor q.s.
Color q.s.
Purified water 5.0
Example XXIII
Table 6

Ingredient Quantity (mg/tablet)
Dapoxetine HCl 33.6
Sildenafil citrate 140.5
Microerystalline cellulose 75
HPMC 60
Eudragit 40
Magnesium stearate 5
Talc 5
IPA/water q.s.
Dapoxetine HCl, HPMC and microerystalline cellulose are mixed and subjected to wet granulation. The dried granules are coated using eudragit dispersion. These granules and sildenafil citrate are mixed and compressed into a table or filled in the capsules.
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Example XXIV
Chewable tablets may be prepared as follows.

Ingredients Quantity in mg/Tab
Sildenafil Citrate * 140.48
Mask IC-MK-9014 (Instacoat) 210.75
Purified Water -
Dapoxetine HC1 33.6
Mannitol 42.57
Croscarmellose sodium 10.00
Citric acid monohydrate 6.00
Sodium chloride 6.00
Aspartame 10.00
Monoammonium Glycerrhizinate 10.00
Sucralose 18.00
Sucrose (Pharma grade) 40.00
Colloidal Silicon Dioxide (Aerosil 200) 2.00
Microcrystalline cellulose (Vivapur 102) 20.00
Lake sunset yellow 20.00
P.V.P. K-30 10.00
Isopropyl alcohol
Trusil Orange ASV flavour 0.60
Croscarmellose sodium 10.00
Colloidal Silicon Dioxide (Aerosil 200 ) 1.00
Purified Talc 3.00
Magnesium Stearate 6.00
Total Weight of (ablet 600.00 mg
Mix a part of sildenafil citrate with Instacoat MK 9014 in purified water to form a sildenafil citrate mask complex. The resultant complex is dried and sized. This complex is then mixed with the remaining 50% sildenafil citrate, dapoxetine
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hydrochloride, mannitol, microcrystalline cellulose, citric acid monohydrate, sodium chloride, aspartame, monoammoniurn glycerrhizinate, sucralose, sucrose, croscarmellose sodium and colours for a period of 15 minutes. The dry mix is granulated with a binder solution of povidone (PVPK30) in isopropyl alcohol, dried in a fluidized bed drier and sifted. The granules are lubricated by addition of croscarmellose sodium, colloidal silicon dioxide, purified talc and flavours and mixed in the octagonal blender for 15 minutes, followed by addition of magnesium stearate and further mixing for 5 minutes. The lubricated mass is then compressed into tablets using suitable tooling.
To evaluate the clinical efficacy of the composition over plain sildenafil/tadalafil or dapoxetine a clinical trial is proposed to be executed in a crossover fashion.
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We claim:
1. A pharmaceutical composition comprising dapoxetine or its isomer or
enantiomer or pharmaceiitically acceptable salt thereof, phosphodiesterase-V
inhibitor or their pharmaceiitically acceptable salts and optionally one or more
pharmaceiitically acceptable excipients.
2. A process for the preparation of a pharmaceutical composition comprising
dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or
pharmaceiitically acceptable salt thereof in a single dosage unit comprising the
steps of
a) blending dapoxetine and sildenafil or tadalafil, or pharmaceiitically
acceptable salt thereof with one or more pharmaceutical excipients;
b) optionally granulating the blend by wet granulation or dry granulation;
c) lubricating the blend of step a) or the granules of step b); and
d) compressing into or filling into a solid dosage form.
3. A process for the preparation of a pharmaceutical composition comprising
dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or
pharmaceiitically acceptable salt thereof in a single dosage unit comprising the
steps of
a) blending dapoxetine or its isomer or enantiomer or pharmaceiitically acceptable salt thereof with one or more pharmaceutical excipients;
b) blending sildenafil or tadalafil, or their isomer or enantiomer or pharmaceiitically acceptable salt thereof with one or more pharmaceutical excipients;

c) optionally granulating separately the blend of step a) and step b) by wet granulation or dry granulation;
d) lubricating separately the blend of step a) and step b) or the granules of step c); and
e) compressing into or filling into a solid dosage form.
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4. A process for preparation of pharmaceutical composition comprising dapoxetine
and sildenafil or tadalafil, or their isomer or enantiomer or pharrnaceiitically
acceptable salts thereof comprising the steps of
a) extruding dapoxetine with suitable excipients,
b) breaking the extruded cylinders into an appropriate length and transforming them into spheroids,
c) coating the spheroids with an extended release polymer coating,
d) optionally, seal coating the spheroids of step e),
e) coating the spheroid of step c) or d) with a drug layer comprising sildenafil or tadalafil, and
f) filling these spheroids into capsules or compressing them into tablets.
5. A process for preparing a pharmaceutical composition comprising dapoxetine
and sildenafil or tadalafil, or their isomer or enantiomer or pharmaceulically
acceptable salts thereof comprising the steps of
a) extruding dapoxetine and extended release polymer with suitable excipients,
b) breaking the extruded cylinders into an appropriate length and transforming them into spheroids,
c) optionally, seal coating the spheroids of step b),
d) coating the spheroid of step b) or c) with a drug layer comprising sildenafil or tadalafil, and
e) filing these spheroids into capsules or compressing them into tablets.
6. A process for the preparation of a pharmaceutical composition comprising
dapoxetine and sildenafil or tadalafil, or their isomer or enantiomer or
pharrnaceiitically acceptable salts thereof comprising the steps of
a) blending dapoxetine with one or more pharmaceutically inert excipients,
b) optionally granulating the blend,
c) lubricating the blend or granules,
d) compressing the lubricated blend of step c)'into tablet,
e) optionally coating the core with suitable inert excipients,
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f) dispersing or dissolving sildenafil or tadalafil and other inert excipients in a suitable solvent system, and
g) coating the cores of step e) with a drug layer of sildenafil or tadalafil from step f).
7. A process for the preparation of a pharmaceutical composition comprising
dapoxetine and sildenafil or tadalafil or pharrnaceutically acceptable salts thereof
comprising the steps of
a) blending dapoxetine with one or more pharrnaceutically inert excipients;
b) optionally granulating the blend of step a;
c) lubricating the blend or granules of step b;
d) compressing the lubricated blend of step c into suitable size tablet;
e) blending sildenafil or tadalafil and one or more pharrnaceutically inert excipients; and
f) filling the tablet and sildenafil or tadalafil powder blend into a capsule.

8. A kit comprising a plurality of separate pharmaceutical compositions, wherein at least one of said composition contains dapoxetine and/or its isomers, enantiomers, pharrnaceutically acceptable salts thereof and at least another of said composition contains a compound belonging to the class of phosphodiesterase-V inhibitor and/or their isomers, enantiomers, pharrnaceutically acceptable salts thereof, and said compositions optionally contain a pharmaceutical excipient.
9. According to claim S the said compositions provided in the kit may be taken one after another or in a span of up to 8 hours.
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10. A method of treating or managing sexual dysfunction in a mammal in need > such treatment comprising administering on as-needed basis to the mammal therapeutically effective amount of dapoxetine or its isomer or enantiomer i pharmaceutically acceptable salt thereof, phosphodiesterase-V inhibitor and/< their isomers, enantiomers, pharmaceutically acceptable salts thereof.


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(Dr.Eswaran K Iyer) GM- Intellectual Property For Ajanta Pharma Limited