Field of the Invention

Technical field of the present invention relates to pharmaceutical composition comprising combination of sildenafil or its pharmaceutically acceptable salt and dapoxetine or its pharmaceutically acceptable salt thereof.

Background of the Invention

Sildenafil citrate developed by Pfizer is commercially available as VIAGRA , a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) is indicated for the treatment of erectile dysfunction in male. Its chemical name is l-[[3-(6,7-dihydro-l-methyl-7-oxo-3-propyl-l//-pyrazolo [4,3-d| pyrimidin-5-yl)-4ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate, having a molecular weight of 666.7 with the following structural formula:

Dapoxetine, a short-acting selective serotonin reuptake inhibitor (SSRI) is used in treatment of premature ejaculation in men. Its chemical name is (S)-(+)-N,N-dimethyl-.alpha.-[2-(l-naphthalenyloxy) ethyl-benzenemethanamine with molecular formula of C21H23NO HC1, corresponding to a molecular weight of 341.88 and having the following structural formula:

® Dapoxetine is marketed under the trade name PRILIGY in Europe by Janssen- Cilag in the form of oral tablets.

US Patent 5,250,534 assigned to Pfizer claims sildenafil citrate as substance and its use for the treatment of angina, hypertension, heart failure or atherosclerosis.

US Patent 6,469,012 assigned to Pfizer claims use of sildenafil citrate for the treatment of erectile dysfunction in male.

US Patent 7,718,705 assigned to Eli-Lilly claims use of dapoxetine for the treatment of sexual dysfunction, in particular premature ejaculation.

Sildenafil and Dapoxetine have been clinically studied internationally in erectile dysfunction and premature ejaculation respectively. Sildenafil is efficacious and safe in the treatment of erectile dysfunction with multiple and varying etiologies, ages and co-morbid conditions but, will be effective in premature ejaculation only if there is associated erectile dysfunction.

Dapoxetine is efficacious and safe in the treatment of both lifelong and acquired premature ejaculation. However, it has modest efficacy when given alone in premature ejaculation associated with erectile dysfunction.

Both erectile dysfunction and premature ejaculation are the most commonly occurring male sexual dysfunction and often are co-existent. Thus a fixed-dose combination of sildenafil and dapoxetine is likely to be effective and safe in the treatment of premature ejaculation with co-existent erectile dysfunction.

Combination of sildenafil and dapoxetine is not available commercially, hence considering the requirement of such a combination, inventors of the present invention have developed composition of this combination and further evaluated it by performing clinical studies.

Summary of the Invention

In one embodiment, the present invention provides pharmaceutical composition comprising sildenafil, dapoxetine and one or more pharmaceutically acceptable excipients.

The present invention also relates to method of treatment for co-existent erectile dysfunction with premature ejaculation comprising therapeutically effective amount of sildenafil, dapoxetine and one or more pharmaceutically acceptable excipients.

One aspect of the present invention relates to pharmaceutical composition comprising 50mg/100mg of sildenafil with 30mg/60mg of dapoxetine.

Another aspect of the present invention relates to oral pharmaceutical composition comprising sildenafil citrate having a particle size d% less than 60 urn and dapoxetine hydrochloride having a particle size dpo less than 10 um and one or more pharmaceutically acceptable excipients.

In yet another aspect the present invention relates to pharmaceutical composition comprising 50mg/100mg of sildenafil with 30mg/60mg of dapoxetine, dibasic calcium phosphate and one or more pharmaceutically acceptable excipients.

In one embodiment the present invention relates to pharmaceutical composition comprising sildenafil, dapoxetine, dissolution enhancer(s), disintegrant(s) and one or more excipient (s) selected from diluent(s), lubricant(s), and glidant(s).

Accordingly, the present invention relates to pharmaceutical composition in the form of tablet comprising 15 wt% to 40 wt% of sildenafil citrate, 5 wt% to 30 wt% of dapoxetine hydrochloride, 15 wt% to 40 wt% of dibasic calcium phosphate and 1 wt% to 10 wt% of disintegrant/super disintegrant based on total weight of the composition.

Accordingly, the present invention also relates to pharmaceutical composition comprising i) sildenafil ii) dapoxetine iii) dibasic calcium phosphate iv) microcrystalline cellulose v) croscarmellose sodium vi) magnesium stearate and vii) colloidal silicon dioxide.

In another embodiment the present invention relates to process for preparing pharmaceutical composition comprising sildenafil, dapoxetine and one or more pharmaceutically acceptable excipients, where in the process involves dry granulation or direct compression.

Dry granulation process for preparing pharmaceutical composition comprising sildenafil and dapoxetine, involves: (i) sifting and blending the active ingredients with one or more excipients, (ii) compressing the blended mixture of step (i) to form slugs and then sizing the resulting slugs to form granules; (iii) blending the granules with remaining portion of the excipients; and (iv) finally compressing the granules of step (iii) in to tablets.

Alternatively, dry granulation involves; compacting active ingredients and other excipients in a roller compactor; and the compacts obtained were passed through ASTM Sieve # 20 to obtain granules. The granules were lubricated and compressed into tablets using compression machine.

Direct compression process for preparing pharmaceutical composition comprising sildenafil and dapoxetine, involves: sifting and blending the active ingredients with one or more excipients and compressing the blended mixture in to tablets.

Detailed Description of the Invention

The term "sexual dysfunction'" as used herein according to the present invention includes erectile dysfunction (ED) and premature ejaculation (PE). Premature ejaculation (PE) is defined as the persistent or recurrent onset of orgasm and ejaculation with minimal sexual stimulation before on or shortly after penetration and before the person wishes it. According to the International Society for Sexual Medicine (ISSM) ejaculation in less than 60 seconds from start of intercourse is "premature". Erectile dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse.

The term " sildenafil " as used herein according to the present invention includes sildenafil in the form of free base, in the form of a pharmaceutically acceptable salt thereof, amorphous sildenafil citrate, crystalline sildenafil citrate or any isomer, derivative, hydrate, solvate, or prodrug or combinations thereof.

The term " dapoxetine " as used herein according to the present invention includes dapoxetine in the form of free base, in the form of a pharmaceutically acceptable salt thereof, amorphous dapoxetine hydrochloride, crystalline dapoxetine hydrochloride or any isomer, derivative, hydrate, solvate, or prodrug or combinations thereof.

Pharmaceutical compositions of the present invention include solid dosage forms such as tablets, capsules, granules, MUPS, pellets, solid dispersions, beads, particles, mini-tablets, or orally disintegrating tablets, as well as liquid dosage forms such as solutions, suspensions, syrups and the like.

The present invention relates to pharmaceutical composition comprising sildenafil, dapoxetine and one or more pharmaceutically acceptable excipients.

The recommended dose of sildenafil for erectile dysfunction is 50 mg, taken as needed, between 30 minutes and 4 hours prior to sexual intercourse and dapoxetine for premature ejaculation is 30 mg or 60 mg, 1 -3 hours before intercourse.

The present invention relates to pharmaceutical composition comprising 50mg/100mg of sildenafil with 30mg/60mg of dapoxetine.

The present invention also relates to oral pharmaceutical composition comprising sildenafil having a particle size d90 less than 60 μm and dapoxetine having a particle size d90 less than 10 μm.

Particle size can be reduced and/or controlled using techniques such as milling. Desired particle size for sildenafil and dapoxetine can be obtained by suitable micronization techniques known in the art such as dry milling, wet milling, air jet milling, sieving, homogenizing using a homogenizer such as rotor-stator and/or high pressure homogenizer such as a MICROFLUIDIZER and the like. Micronized sildenafil and dapoxetine provides good in vitro end release and in vivo bioavailability.

The present invention provides pharmaceutical composition comprising sildenafil, dapoxetine, dissolution enhancer, disintegrant and one or more excipients selected from diluent(s), binder(s), lubricant(s), and glidant(s).

The term "dissolution enhancer" means an excipient, which when included in the composition, increases the rate of dissolution of the drug. Accordingly, dibasic calcium phosphate in an amount of about 15-40% by weight based on the total weight of the composition was found to be effective in enhancing the dissolution rate.

Suitable disintegrants include, by way of example and without limitation, polacrillin potassium, croscarmellose sodium, crospovidone (e.g., KOLLIDON®, POLYPLASDONE®), polyvinylpyrrolidone, sodium starch glycolate (e.g., PRIMOGEL, EXPLOTAB®), hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium, starches such as corn starch, potato starch, pre-gelatinized and modified starches, clays, bentonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. Amberlite™), alginates, gums such as agar, guar, locust bean, karaya, pectin, tragacanth and the like or combinations thereof.

Suitable diluents include talc, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose), calcium sulfate, xylitol, lactitol, starch, pregelatinized starch, kaolin, sucrose, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like and mixtures thereof.

Suitable binders include, by way of example and without limitation, lactose, starches such as corn starch, potato starch, modified starches, sugars, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, sodium alginate, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, ethyl cellulose, gelatin, liquid glucose, povidone, pregelatinized starch and combination thereof.

Suitable lubricants include, by way of example and without limitation, calcium stearate, magnesium stearate, sodium stearyl fumarate, zinc stearate, mineral oil, stearic acid, fumaric acid, palmitic acid, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like or combinations thereof.

Suitable glidants include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc and the like or combinations thereof.

In particular, the present invention provides pharmaceutical composition comprising 15 wt% to 40 wt% of sildenafil citrate, 5 wt% to 30 wt% of dapoxetine hydrochloride, 15 wt% to 40 wt% of dibasic calcium phosphate and 1 wt% to 10 wt% of disintegrant/super disintegrant.

Accordingly, the present invention also relates to pharmaceutical composition comprising i) sildenafil ii) dapoxetine iii) dibasic calcium phosphate iv) microcrystalline cellulose v) croscarmellose sodium vi) magnesium stearate and vii) colloidal silicon dioxide.

The present invention further provides a process for preparing pharmaceutical composition of sildenafil and dapoxetine either by dry granulation or direct compression.

Dry granulation process for preparing pharmaceutical composition involves: (i) sifting and blending the active ingredients with one or more excipients, (ii) compressing the blended mixture of step (i) to form slugs and then sizing the resulting slugs to form granules; (iii) blending the granules with remaining portion of the excipients; and (iv) finally compressing the granules of step (iii) in to tablets.

Alternatively, dry granulation involves; compacting active ingredients and other excipients in a roller compactor; and the compacts obtained were passed through ASTM Sieve # 20 to obtain granules. The granules were lubricated and compressed into tablets using compression machine.

Direct compression process involves: sifting and blending the active ingredients with one or more excipients and compressing the blended mixture in to tablets.

Coating may be optionally performed by applying one or more film forming polymers with or without other inert excipients, using any conventional coating technique known in the art.

Pharmaceutical composition comprising therapeutically effective amount of sildenafil in combination with dapoxetine is useful in the treatment of sexual dysfunction to the individual in need of such treatment.

The invention is further exemplified with following examples and is not intended to limit the scope of the invention.

EXAMPLES

Example 1-4:

Compositions of sildenafil and dapoxetine tablets prepared by dry granulation using solubility enhancer (dibasic calcium phosphate) in an amount of more than 15wt% based on total weight of the tablet.



Brief manufacturing process:
i) Intra granular materials were sifted and blended together,
ii) the blended material of step no (i) was slugged/ compacted and the resulted slugs/ compacts were milled using multimill or cone mill, iii) milled granules of step (ii) were sifted through # 20 mesh completely, iv) extra granular materials were sifted together through # 40 mesh, v) extra granular magnesium stearate was sifted through # 60 mesh, vi) materials of step (iii), (iv) and (v) were blended together and finally compressed into tablets, vii) compressed tablets were optionally coated with film coating and clear coating.

Table 1

Dissolution Profiles of sildenafil and dapoxetine tablets prepared according to examples 1-4 in 900ml of 0.1 N HCL using paddle method at 50 rpm.

Example 5-6 (Comparative examples):

Compositions of sildenafil and dapoxetine tablets prepared by dry granulation using solubility enhancer (dibasic calcium phosphate) in an amount of about, less than 15wt% based on total weight of the tablet.


Manufacturing process: Same as given for example 1-4.

Table 2

Dissolution Profiles of sildenafil and dapoxetine tablets prepared according to example 5 and 6 in 900ml of 0.1N HCL using paddle method at 50 rpm.

SIL-Sildenafil and DAP-Dapoxetine.

We claim:

1. A Pharmaceutical composition comprising sildenafil, dapoxetine and one or more pharmaceutically acceptable excipients.

2. A method for the treatment of sexual dysfunction comprising administering to the individual in need of such treatment a therapeutically effective amount of sildenafil in combination with dapoxetine.

3. A pharmaceutical composition comprising sildenafil citrate having a particle size dgo less than 60 urn, dapoxetine hydrochloride having a particle size dgo less than 10 urn and one or more pharmaceutically acceptable excipients.

4. A Pharmaceutical composition comprising,

i) 50mg/100mg of sildenafil,
ii) 30mg/60mg of dapoxetine,
iii) dibasic calcium phosphate and
iv) one or more pharmaceutically acceptable excipients.

5. A Pharmaceutical composition in the form of tablet comprising based on total weight of the composition,

i) 15 wt% to 40 wt% of sildenafil citrate,

ii) 5wt%to30wt% of dapoxetine hydrochloride,

iii) 15 wt% to 40 wt% of dibasic calcium phosphate as dissolution enhancer and

iv) 1 wt% to 10 wt% of disintegrant/super disintegrant.

6. A tablet composition comprising; i) sildenafil citrate having a particle size d90 less than 60 μm ii) dapoxetine hydrochloride having a particle size d90 less than 10 urn iii) dibasic calcium phosphate iv) microcrystalline cellulose v) croscarmellose sodium vi) magnesium stearate and vii) colloidal silicon dioxide.

7. A solid oral composition comprising sildenafil citrate in combination with dapoxetine hydrochloride and one or more excipient (s) wherein the composition is prepared either by dry granulation or direct compression.

8. A process for the preparation of pharmaceutical composition comprising sildenafil citrate, dapoxetine hydrochloride and one or more pharmaceutically acceptable excipients; comprises: (a) sifting and blending the active ingredients with one or more excipients (b) compressing/slugging the blended mixture of step (a) and then sizing the resulting slugs/compacts to form granules; (c) blending the granules with all or none or remaining portion of the excipients; and (d) finally compressing the granules of step (c) in to tablets.

9. The pharmaceutical composition according to any of the preceding claims, where in pharmaceutically acceptable excipient is selected from a dissolution enhancer, a disintegrant, a diluent, a lubricant and a glidant or mixtures thereof.

10. The pharmaceutical composition according to any of the preceding claims include solid dosage forms such as tablets, capsules, granules, MUPS, pellets, solid dispersions, beads, particles, mini-tablets, or orally disintegrating tablets.