Claims:We claim:
1. A pharmaceutical composition, comprising solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients.
2. The pharmaceutical composition according to claim 1, wherein solifenacin or a pharmaceutically acceptable salt thereof is solifenacin succinate.
3. The pharmaceutical composition according to claim 1, wherein silodosin or a pharmaceutically acceptable salt thereof is silodosin.
4. The pharmaceutical composition according to claim 1, wherein the composition comprises solifenacin succinate and silodosin.
5. A pharmaceutical composition, comprising solifenacin or a pharmaceutically acceptable salt thereof in an amount of 1mg to 50mg and silodosin or a pharmaceutically acceptable salt thereof in an amount of 1mg to 50 mg as active ingredients.
6. The pharmaceutical composition according to claim 5, comprising 2mg, 2.5mg, 3mg, 5mg, 6mg, 9mg or 10mg of solifenacin succinate.
7. The pharmaceutical composition according to claim 5, comprising 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or 10mg of silodosin.
8. A pharmaceutical composition, comprising solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients together with a pharmaceutically acceptable excipient, wherein the composition is for oral administration.
9. The pharmaceutical composition according to claim 6, wherein the composition is a solid oral dosage form selected from the group consisting of granules, powder, pellets, mini-tablet, capsule and tablet.
10. The pharmaceutical composition according to claim 1, wherein the composition is used for treatment of lower urinary tract symptoms associated with prostatic hypertrophy. , Description:Combination of Solifenacin and Silodosin

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition containing silodosin, or its pharmaceutically acceptable salt, and solifenacin, or its pharmaceutically acceptable salt, as active ingredients and its use as an agent to improve lower urinary tract symptoms associated with prostatic hypertrophy. Further, the pharmaceutical composition comprising silodosin or its pharmaceutically acceptable salts and solifenacin or its pharmaceutically acceptable salts is bio-equivalent to the simultaneously administered individual composition for both the drug.

BACKGROUND OF THE INVENTION
Solifenacin is a quinuclidine derivative having the chemical name (1R, 3'R)-3'-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro- 2-isoquinoline carboxylate. Solifenacin or salts thereof are reported to have an excellent selective antagonistic action against muscarine M3 receptors and are useful as prophylactic or therapeutic agents of urinary diseases such as nervous pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, bladder contracture, and chronic cystitis as well as respiratory diseases such as chronic occlusive lung diseases, chronic bronchitis, asthma and rhinitis. Synthesis of a series of quinuclidine derivatives including solifenacin or salts thereof is disclosed in US6017927.

Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Solifenacin is approved as succinate salt, available in various markets under brand name of Vesicare® marketed by Astellas Pharma. It is available in two strengths, 5 mg and 10 mg of solifenacin succinate, and formulated as tablets for oral administration. It is used for treating contraction of overactive bladder with associated problems such as increased urination frequency and urge incontinence.

Silodosin is an indoline derivative having chemical name 1 - (3-hydroxypropyl) -5 - [(2R) - ({2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] indoline -7-carboxamide. Silodosin is highly uroselective for the alpha (1A) receptors located in the prostate, [urethrae and bladder trigone in the lower urinary tract]. Blocking these receptors relaxes the smooth muscles, resulting in an improvement in urine flow and a reduction in Benign prostate hyperplasia. The selective binding of silodosin to the alpha (1A) receptors is substantially greater than the binding to the cardiovascular-associated alpha (1B) receptors and thereby maximizes target organ activity while minimizing the potential for blood pressure effects. The production of silodosin is for example disclosed in the basic patent US5387603, in which also the use of silodosin for the treatment of dysuria is described.

Silodosin is used for the treatment of dysuria, has selective suppressing activities on the contraction of urethra smooth muscles, and is an extremely useful compound as a medicament for treating dysuria without causing strong hypotensive activities or orthostatic hypotension. Silodosin is approved in USA for 4 mg twice daily dosing and 8 mg once daily dosing to treat symptoms associated with benign prostatic hyperplasia (“BPH”) and is marketed by Allergan under the tradename Rapaflo®.

The proposed invention is to provide a combination formulation comprising solifenacin or its pharmaceutically acceptable salts thereof and silodosin or its pharmaceutically acceptable salts thereof for better management of lower urinary tract symptoms associated with prostatic hypertrophy, especially benign prostatic hyperplasia and other related diseases.

SUMMARY OF THE INVENTION
It is an object of the invention to provide a pharmaceutical composition comprising silodosin or its pharmaceutically acceptable salts and solifenacin or its pharmaceutically acceptable salts.

Another object of the invention is to provide combination use and combination therapy with silodosin, or its pharmaceutically acceptable salts, and solifenacin, or its pharmaceutically acceptable salts, for improvement of lower urinary tract symptoms associated with prostatic hypertrophy

Another object of the invention is to provide a pharmaceutical composition comprising silodosin or its pharmaceutically acceptable salts and solifenacin or its pharmaceutically acceptable salts which is bio-equivalent to the simultaneously administered individual composition for both the drug.

DETAILED DESCRIPTION OF THE INVENTION
Benign prostatic hyperplasia (BPH) is non-cancerous growth of the prostate gland, which most typically occurs in middle-aged and elderly men. The symptoms of BPH include, for example, weak or intermittent urinary stream (flow rate), straining when urinating, a hesitation before urine flow starts, a sense that the bladder has not emptied completely, and dribbling at the end of urination or leakage afterward.

The prostate gland is a male organ surrounding the urethra between the neck of the bladder and the external urethral sphincter muscle. Prostatic adenoma observed in prostatic hypertrophy is a benign tumour originating from the transitional zone (internal gland) of the prostate, and its growth depends on male hormones (androgens), but its detailed etiological mechanisms have yet to be clarified.

Lower urinary tract symptoms associated with benign prostatic hyperplasia is a common condition in men over the age of 50 years. It occurs in approximately 20% of men younger than 65 years and in 40% of men more than 65 years of age. Development of prostatic hypertrophy is considered to arise mainly from direct urethral compression (mechanical occlusion) due to hypertrophy of the adenoma and from an intra-urethral pressure increase (functional occlusion) due to excessive contraction of the prostate and urethra via sympathetic nerves, and the like.

The present invention relates to a pharmaceutical composition silodosin, or a pharmaceutically acceptable salt thereof and solifenacin, or a pharmaceutically acceptable salt thereof. One of the major objectives of this invention is to improve the lower urinary tract symptoms associated with prostatic hypertrophy and related diseases. The present invention composition contains a combination of two improving agent for lower urinary tract symptoms associated with prostatic hypertrophy, which contain silodosin, or its pharmaceutically acceptable salt, and solifenacin, or its pharmaceutically acceptable salt.

Additionally, the present invention relates to use of silodosin, or a pharmaceutically acceptable salt thereof, and solifenacin, or a pharmaceutically acceptable salt thereof, for manufacturing of a pharmaceutical composition for improvement of lower urinary tract symptoms associated with prostatic hypertrophy, and a method for improving lower urinary tract symptoms associated with prostatic hypertrophy comprising administering an effective dose of silodosin, or a pharmaceutically acceptable salt thereof, and solifenacin, or a pharmaceutically acceptable salt thereof to patients.

A combination of solifenacin or salts thereof being a selective and competitive antagonistic action against muscarine M3 receptors and silodosin being highly uroselective for the alpha (1A) receptors located in the prostate is used for treatment of Lower urinary tract symptoms.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients. In one specific embodiment, a pharmaceutical composition comprises solifenacin succinate and silodosin.

Specific examples of the “pharmaceutically acceptable salts” in “silodosin or a pharmaceutically acceptable salt thereof” and “solifenacin or a pharmaceutically acceptable salt thereof” include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminium, or with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and salts with various amino acids and amino acid derivatives such as acetylleucine, ammonium salts, and others.

Furthermore, the “pharmaceutically acceptable salts” in “silodosin or a pharmaceutically acceptable salt thereof” and “solifenacin or a pharmaceutically acceptable salt thereof” may be various hydrates, solvates and polymorphic crystalloids, which are all included as an active ingredient of the pharmaceutical composition of the present invention. The present invention also includes a pharmaceutical composition containing various radioactive or non-radioactive isotope-labelled compounds.

In another embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt thereof is solifenacin succinate.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt thereof is present in an amount of 1 mg to 100 mg, preferably 1 mg to 50 mg, more preferably 1 gm to 25mg. In certain embodiments, the solifenacin or a pharmaceutically acceptable salt thereof herein are provided in the composition is about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 63.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10.0 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, or any range derivable therein. In further embodiments, the daily dosages appropriate for the solifenacin or a pharmaceutically acceptable salt thereof described herein are from about 0.001 to about 10 mg/kg per body weight.

In certain embodiments, the solifenacin or a pharmaceutically acceptable salt thereof, more specifically solifenacin succinate herein are provided in the composition is present in an amount of 2mg, 2.5mg, 3mg, 5mg, 6mg, 9mg or 10mg.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt thereof is present in the range of 1% to 50% w/w of the pharmaceutical composition, preferably 5% to 40% and more preferably 5% to 25% w/w of the pharmaceutical composition. In certain embodiments, the solifenacin or a pharmaceutically acceptable salt thereof herein are provided in the composition is about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w of the pharmaceutical composition.

In another embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein silodosin or a pharmaceutically acceptable salt thereof is silodosin.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein silodosin or a pharmaceutically acceptable salt thereof is present in an amount of 0.5 mg to 100 mg, preferably 1 mg to 50 mg, more preferably 1 mg to 25mg. In certain embodiments, the silodosin or a pharmaceutically acceptable salt thereof herein are provided in the composition is about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 63.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10.0 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, or any range derivable therein. In further embodiments, the daily dosages appropriate for the silodosin or a pharmaceutically acceptable salt thereof described herein are from about 0.001 to about 10 mg/kg per body weight.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein silodosin or a pharmaceutically acceptable salt thereof is present in the range of 1% to 60% w/w of the pharmaceutical composition, preferably 5% to 50% and more preferably 5% to 30% w/w of the pharmaceutical composition. In certain embodiments, the silodosin or a pharmaceutically acceptable salt thereof herein are provided in the composition is about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w or about 60% w/w of the pharmaceutical composition.

In certain embodiments, the silodosin or a pharmaceutically acceptable salt thereof herein are provided in the composition is present in an amount of 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or 10mg.

In one embodiment, a pharmaceutical composition, comprising solifenacin or a pharmaceutically acceptable salt thereof in an amount of 1mg to 100mg and silodosin or a pharmaceutically acceptable salt thereof in an amount of 1 mg to 100 mg as active ingredients.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt thereof is present in an amount of 1 mg to 100 mg, preferably 1 mg to 50 mg, more preferably 1 gm to 25mg and wherein silodosin or a pharmaceutically acceptable salt thereof is present in an amount of 0.5 mg to 100 mg, preferably 1 mg to 50 mg, more preferably 1 mg to 25mg.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt thereof is present in the range of 1% to 50% w/w of the pharmaceutical composition, preferably 5% to 40% and more preferably 5% to 25% w/w of the pharmaceutical composition and wherein silodosin or a pharmaceutically acceptable salt thereof is present in the range of 1% to 60% w/w of the pharmaceutical composition, preferably 5% to 50% and more preferably 5% to 30% w/w of the pharmaceutical composition.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt thereof is present in an amount of 2mg, 2.5mg, 3mg, 5mg, 6mg, 9mg or 10mg and wherein silodosin or a pharmaceutically acceptable salt thereof is present in an amount 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or 10mg.

In one embodiment, a pharmaceutical composition comprises 5 mg of solifenacin succinate and 4 mg of silodosin. In another embodiment, a pharmaceutical composition comprises 5 mg of solifenacin succinate and 8 mg of silodosin. In another embodiment, a pharmaceutical composition comprises 10 mg of solifenacin succinate and 4 mg of silodosin. In another embodiment, a pharmaceutical composition comprises 10 mg of solifenacin succinate and 8 mg of silodosin.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof is present in ratio of 10: 1 to 1:10.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof is present in ratio of 2.5:1, 1.25: or 1:1.6.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients wherein solifenacin or a pharmaceutically acceptable salt and silodosin or a pharmaceutically acceptable salt thereof combinedly is present in the range of 1% to 90% w/w of the pharmaceutical composition, preferably 5% to 70% and more preferably 5% to 50% w/w of the pharmaceutical composition. In certain embodiments, the solifenacin or a pharmaceutically acceptable salt and silodosin or a pharmaceutically acceptable salt thereof combinedly herein are provided in the composition is about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w or about 60% w/w of the pharmaceutical composition.

Administration can be performed orally in the forms of tablets, pills, capsules, granules, powders, liquids and the like, or parenterally in the forms of intra-articular, intravenous, or intramuscular injections, suppositories, ophthalmic solutions, ointments, percutaneous liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, or inhalants. Oral administration can be cited as a preferred aspect.

Oral administration is typically preferred, because of ease of administration and greater compliance. Oral dosage forms may be solid or liquid (e.g. syrup). Exemplary solid oral dosage forms include, but are not limited to, tablets, capsules (both hard gelatin and soft gelatin), sachets, lozenges, powders, pills, or granules, and the solid dosage form can be, for example, a fast melt dosage form, controlled release dosage form, lyophilized dosage form, delayed release dosage form, extended release dosage form, pulsatile release dosage form, mixed immediate release and controlled release dosage form, or a combination thereof.

As compositions for oral administration, tablets, pills, capsules, powders, granules, liquids and the like are used. In these solid compositions, the effective ingredient is mixed with at least one of inert carriers, excipients or other additives and the like for usual drug formulation.

The composition may be manufactured by various methods such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization and layering. The process may be carried out under ambient conditions of temperature and humidity.

According to another embodiment of the above aspect, the dosage form is powder, tablet, capsule, pellets, granules, solution, suspension or a mixture thereof. The composition may be a single layer, bilayer, or multilayer tablet or it may be a capsule filled with powder, granules, liquid or mini-tablet. Multilayer tablets include tablets having a shell-and-core configuration in which a core is fully encased by a shell. Tablets may also have a coating with or without the pharmaceutically active agent.

In one of the embodiment, the composition is a capsule dosage form. In a certain embodiment, the capsule is filled with powder, granules, pellets, mini-tablet or soft gel capsules of both the drugs, optionally with one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of powder,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of powder, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of pellets,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of powder, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of powder,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of pellets, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of pellets,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of pellets, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of powder,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of min-tablet, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of mini-tablet,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of powder, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of mini-tablet,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of mini-tablet, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of mini-tablet,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of pellets, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of pellets,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of mini-tablet, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of solution or suspension in soft gelatin capsule,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of mini-tablet, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of mini-tablet,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of solution or suspension in soft gelatin capsule, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of solution or suspension in soft gelatin capsule,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of pellets, and
(c) optionally one or more excipients.

In one embodiment, a capsule comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof in form of pellets,
(b) silodosin or a pharmaceutically acceptable salt thereof in the form of solution or suspension in soft gelatin capsule, and
(c) optionally one or more excipients.

According to another embodiment of the above aspect, the capsules are prepared by conventional processes known in the art. Powder, pellets, granules, mini-tablets and soft-gelatin capsules are prepared by known methods and filled into capsule shells. The capsules shells are can be gelatin, HPMC, Eudragit or any other polymer based.

In one of the embodiment, the composition is a tablet dosage form. The composition can be a single layer, bilayer, or multilayer tablet.
In one embodiment, a tablet comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof,
(b) silodosin or a pharmaceutically acceptable salt thereof, and
(c) optionally one or more excipients.

In one embodiment, a tablet comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof,
(b) silodosin or a pharmaceutically acceptable salt thereof, and
(c) optionally one or more excipients
wherein the tablet is a bilayer tablet and each layer comprises one the drug

In one embodiment, a tablet comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof,
(b) silodosin or a pharmaceutically acceptable salt thereof, and
(c) optionally one or more excipients
wherein the tablet is a multilayer tablet and two layers of the drug is separated by a layer of inert layer.

In one embodiment, a tablet comprises:
(a) solifenacin or a pharmaceutically acceptable salt thereof is a core tablet,
(b) silodosin or a pharmaceutically acceptable salt thereof is a coating layer over the core tablet, and
(c) optionally a separation layer between core tablet and coating layer.

In one embodiment, a tablet comprises:
(a) silodosin or a pharmaceutically acceptable salt thereof is a core tablet,
(b) solifenacin or a pharmaceutically acceptable salt thereof is a coating layer over the core tablet, and
(c) optionally a separation layer between core tablet and coating layer.

According to another embodiment of the above aspect, the tablets are prepared by conventional processes of direct compression, dry granulation, wet granulation or any other methods known in the art.

In another embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients together with a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be prepared by usually employed methods with silodosin or its pharmaceutically acceptable salts and solifenacin or its pharmaceutically acceptable salts along with carriers, excipients, or other additives for usual drug formulation. The composition comprises pharmaceutically acceptable excipients that are routinely used and are selected from the group comprising diluents, binders, disintegrants, lubricants/glidants, and combinations thereof.

Non limiting examples of binders include starches such as potato starch, wheat starch, corn starch, celluloses such as hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.

Fillers or diluents include, but are not limited to dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate or mixtures thereof.

Lubricants may be selected from, but are not limited to, those conventionally known in the art such as magnesium, aluminium or calcium or zinc stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc or mixtures thereof.

Glidants include, but are not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel or mixtures thereof.

The pharmaceutical composition(s) may optionally contain a surface-active agent or solubilizing agents. Solubilizing agents help to solubilize the active ingredient either in composition or in-situ at the site of absorption or action. Solubilizing agents include but are not limited to surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination thereof. Non-limiting examples of surfactants include water soluble or water dispersible nonionic, semi-polar nonionic, anionic, cationic, amphoteric, or zwitterionic surface active agents or any combination thereof.
The preferred surface active agents include, but are not limited to, copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) and polyoxyethylene (poly(ethylene oxide)) that is well known as poloxamer. However, other agents may also be employed such as dioctyl sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS), polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or other pharmaceutically acceptable surface active agents known to the person skilled in the art. Other solubilizing agents include but not necessarily limited to vitamin E and its derivatives; monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters; nitrogen-containing solvents; phospholipids; glycerol acetates such as acetin, diacetin and triacetin; glycerol fatty acid esters such as mono-, di- and triglycerides and acetylated mono- and di-glycerides; propylene glycol esters; ethylene glycol esters and combinations thereof.

The amount of each type of excipient employed, e.g. glidant, binder, disintegrant, filler or diluent and lubricant may vary within ranges conventional in the art. Thus for example, the amount of glidant may vary within a range of 0.1 to 10% by weight, in particular 0.1 to 5% by weight, e.g. 0.1 to 0.5% by weight; the amount of binder may vary within a range of from about 10 to 45% by weight, e.g. 20 to 30% by weight; the amount of disintegrant may vary within a range of from 0.5 to 5% by weight, e.g. 1% by weight; the amount of filler or diluent may vary within a range of from 10 to 60% by weight; whereas the amount of lubricant may vary within a range of from 0.1 to 5.0% by weight.

The composition of the present invention may be further coated with one or more non-functional coatings. The coating may comprise one or more film-forming polymers and coating additives.

Examples of film-forming polymers include ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes, and methacrylic acid polymers such as Eudragit®. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry®, may also be used.

Coating additives may be selected from the group comprising binders, plasticizers, opacifiers, coloring agents, and lubricants. Examples of plasticizers include acetylated triacetin, triethyl citrate, tributyl citrate, glycerol tributyrate, diacetylated monoglyceride, polyethylene glycols, propylene glycol, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, diethyl oxalate, diethyl phthalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, and combinations thereof. Examples of opacifiers include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, and combinations thereof. Coloring agents include any FDA approved color for oral use.

Specific examples of solvents for granulation or coating include water, acetone, ethanol, methanol, isopropyl alcohol, methylene chloride, and combinations thereof.

These additional excipients are selected based on function and compatibility with the pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety.

Coating may be performed by applying the coating composition as a solution, suspension, or blend using any conventional coating technique known in the art such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, or compression coating

The tablets may be dispensed in packs made with usual packaging materials like high-density polyethylene (HDPE) bottles or blister packs. The package may additionally contain a desiccant.

In one embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof as active ingredients, wherein the composition is used for treatment of lower urinary tract symptoms, specifically for treatment of lower urinary tract symptoms associated with prostatic hypertrophy.

In further embodiments, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof is provided in a composition that is similar, comparable or equivalent to combined marketed composition of solifenacin and silodosin. In other embodiment, a pharmaceutical composition comprises solifenacin or a pharmaceutically acceptable salt thereof and silodosin or a pharmaceutically acceptable salt thereof provides similar, comparable or equivalent pharmacokinetic parameters (e.g., AUC, Cmax, Tmax, Cmax, T1/2) when compared to an effect of simultaneous administration of both individual marketed composition of equal strengths. Similar, comparable or equivalent pharmacokinetic parameters, in some instances, refer to within 50% to 200%, 80% to 150%, 85% to 125%, 90% to 110%, or increments therein, of the given values. It should be recognized that the ranges can, but need not be symmetrical, e.g., 85% to 105%.

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

Example 1: Composition with diluent combination lactose and Mannitol
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Lactose monohydrate 5.2-47.0
4 Mannitol 10.4-93.9
5 Corn starch 0.3-2.7
6 Pregelatinized starch 2.2-19.7
7 Hypromellose 0.2-2.2
8 Sodium lauryl sulfate 0.1-0.9
9 Magnesium stearate 0.1-0.5
10 Sodium Stearyl Fumarate 0.1-1.3
11 Opadry Coating material 0.6-5.2
12 Purified Water QS

Example 2: Composition with combination of lactose and Mannitol as diluent
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Lactose monohydrate 5.2-47.0
4 Mannitol 10.4-93.9
5 Corn starch 0.3-2.7
6 Pregelatinized starch 2.2-19.7
7 Hypromellose 0.2-2.2
8 Sodium lauryl sulfate 0.1-0.9
9 Magnesium stearate 0.1-0.5
10 Sodium Stearyl Fumarate 0.1-1.3
11 Opadry Coating material 0.6-5.2
12 Purified Water QS

Example 3: Composition with Lactose as diluent
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Lactose monohydrate 15.6-140.8
4 Corn starch 0.3-2.7
5 Pregelatinized starch 2.2-19.7
6 Hypromellose 0.2-2.2
7 Sodium lauryl sulfate 0.1-0.9
8 Magnesium stearate 0.1-0.5
9 Sodium Stearyl Fumarate 0.1-1.3
10 Opadry Coating material 0.6-5.2
11 Purified Water QS

Example 4: Composition mannitol as diluent
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Mannitol 0.3-2.7
4 Corn starch 2.2-19.7
5 Pregelatinized starch 0.2-2.2
6 Hypromellose 0.1-0.9
7 Sodium lauryl sulfate 0.1-0.5
8 Magnesium stearate 0.1-1.3
9 Sodium Stearyl Fumarate 0.6-5.2
10 Opadry Coating material 0.3-2.7
11 Purified Water QS

Example 5: Composition with Microcrystalline Cellulose as diluent
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Microcrystalline Cellulose 0.3-2.7
4 Corn starch 2.2-19.7
5 Pregelatinized starch 0.2-2.2
6 Hypromellose 0.1-0.9
7 Sodium lauryl sulfate 0.1-0.5
8 Magnesium stearate 0.1-1.3
9 Sodium Stearyl Fumarate 0.6-5.2
10 Opadry Coating material 0.3-2.7
11 Purified Water QS

Example 6: Composition with Starch as binder
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Lactose monohydrate 5.2-47.0
4 Mannitol 10.4-93.9
5 Corn starch 2.7-24.6
6 Sodium lauryl sulfate 0.1-0.9
7 Magnesium stearate 0.1-0.5
8 Sodium Stearyl Fumarate 0.1-1.3
9 Opadry Coating material 0.6-5.2
10 Purified Water QS

Example 7: Composition with Hypromellose as binder
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Lactose monohydrate 5.2-47.0
4 Mannitol 10.4-93.9
5 Hypromellose 2.7-24.6
6 Sodium lauryl sulfate 0.1-0.9
7 Magnesium stearate 0.1-0.5
8 Sodium Stearyl Fumarate 0.1-1.3
9 Opadry Coating material 0.6-5.2
10 Purified Water QS

Example 8: Composition with Magnesium stearate as Lubricant
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Lactose monohydrate 5.2-47.0
4 Mannitol 10.4-93.9
5 Corn starch 0.3-2.7
6 Pregelatinized starch 2.2-19.7
7 Hypromellose 0.2-2.2
8 Sodium lauryl sulfate 0.1-0.9
9 Magnesium stearate 0.2-1.9
10 Opadry Coating material 0.6-5.2
11 Purified Water QS

Example 9: Composition with Sodium Stearyl Fumarate as Lubricant
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Lactose monohydrate 5.2-47.0
4 Mannitol 10.4-93.9
5 Corn starch 0.3-2.7
6 Pregelatinized starch 2.2-19.7
7 Hypromellose 0.2-2.2
8 Sodium lauryl sulfate 0.1-0.9
9 Sodium Stearyl Fumarate 0.2-1.9
10 Opadry Coating material 0.6-5.2
11 Purified Water QS

Example 10: Composition without Sodium lauryl sulfate
Sr. No. Ingredient % w/w range
1 Solifenacin succinate 0.4-3.6
2 Silodosin 0.3-2.9
3 Lactose monohydrate 5.3-47.9
4 Mannitol 10.4-93.9
5 Corn starch 0.3-2.7
6 Pregelatinized starch 2.2-19.7
7 Hypromellose 0.2-2.2
8 Magnesium stearate 0.1-0.5
9 Sodium Stearyl Fumarate 0.1-1.3
10 Opadry Coating material 0.6-5.2
11 Purified Water QS

As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

The term "about" is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value. The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to "and/or." The terms "comprise," "have" and "include" are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes" and "including," are also open-ended. For example, any method that "comprises," "has" or "includes" one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described.