FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising i) silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, ii) one or more diluents, jii) one or more surfactants, iv) Hydrogenated vegetable oil, and optionally one or more other pharmaceutically acceptable excipients and process of preparation thereof.
The present invention relates to a 3table capsule dosage tbrm comprising non-granular pharmaceutical composition of silodosin and process of preparation thereof.
The present invention relates to a pharmaceutical composition comprising i) silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, ii) one or more diluents, iii) one or more surfactants, iv) Hydrogenated vegetable oil, and optionally one or more other pharmaceutically acceptable excipients, for the treatment of benign prostatic hyperplasia, dysuria associated with prostate hypertrophy, bladder celvix sclerosis, chronic prostatitis, neurogenic bladder and the like.
BACKGROUND OF THE INVENTION
Silodosin is an indoline derivative having trie molecular formula C25H32F3N3O4 and the following chemical structure: [Formula (I)]
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
fib
Watson labs under the trade name Rapaflo . 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.
Silodosin (KMD-3213) is an a-adrenergic antagonist that has high selectivity for the o.|A receptor relative to UJB and a)D receptors. It is known that KMD-3213, which is contained as an active ingredient in a solid oral dosage form for the treatment of dysuria of the present invention, 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.
US5387603 of Kissei pharmaceutical covers 1, 5, 7-trisubstituted indoline compounds and salts thereof and also a pharmaceutical composition comprising silodosin for the treatment of dysuria.
US5403847 of Synaptic pharmaceutical corporation covers use of ct\c specific compounds to treat benign prostatic hyperlasia.
US20120064154 of Kissei pharmaceutical covers a capsule which comprises: a composition comprising (1) a granule consisting essentially of a) as an active ingredient, an indoline compound represented by the formula:
b) D-mannitol and c) partially pregelatinized starch; and (2) d) a lubricant selected from magnesium stearate, calcium stearate or talc, and e) sodium lauryl sulfate; and a light-shielding capsule shell containing titanium oxide as a light shielding agent; wherein 85% dissolution time is not more than 15 minutes in a dissolution test according to method 2 (paddle method) of the Japanese pharmacopoeia in a condition using water as a test medium and a paddle speed of 50 rpm, and said composition is encapsulated in said light-shielding capsule shell containing not less than 3.0% by weight of titanium oxide based on the total weight of said light-shielding capsule shell.

WO2014006635 of Hetero covers a solid oral'composition comprising: i) silodosin, ii) sodium stearyl fumarate as lubricant, and iii) one or more pharmaceutically acceptable excipients.
US20140243383 of Cadila covers a stable pharmaceutical composition comprising: (a) plurality of granules comprising silodosin or salts thereof and one or more pharmaceutical excipients; and (b) an extragranular portion comprising one or more lubricants and optionally one or more surfactants, wherein the granules arc free of partially pregelatinized starch.
WO2015152680 of Hanmi pharma covers a granule comprising silodosin; alkaline inorganic salt as a stabilizer; and a pharmaceutically acceptable excipient
US20160045446 of Kissei pharmaceutical covers an .oral administration preparation with masked bitterness of silodosin, wherein the masked particle obtained by granulating or coating a drug particle comprising a fine powder of silodosin with a coating agent comprising a non-enteric polymer
However, none of the aforementioned prior art documents describe simple and stable non-granular silodosin compositions having comparative dissolution and bioequivalence profiles to that of Rapaflo capsules.
The present invention relates to a stable non-granular silodosin compositions of silodosin and process of preparation thereof.
The present invention also relates to stable non-granular silodosin compositions comprising hydrogenated vegetable oil (Luritab j and/or stable non-granular silodosin compositions encapsulated in capsule shell containing less than 3.0% by weight of titanium oxide based on the total weight of said capsule shell. The stable non-granular silodosin compositions of the present invention have comparative dissolution and bioequivalence profiles to that of Rapaflo capsules.

SUMMARY OF INVENTION
Aspects of the present invention relates to pharmaceutical compositions comprising of silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient.
Aspects of the present invention relates to a pharmaceutical composition comprising i) silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, ii) one or more diluents, iii) one or more surfactants, iv) Hydrogcnatcd vegetable oil, and optionally one or more other pharmaceutically acceptable excipients.
Aspects of the present invention relates to a pharmaceutical composition comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, wherein the said composition is highly stable.
Aspects of the present invention relates to stable non-granular compositions of silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient and one or more pharmaceutically acceptable excipients.
Aspects of the present invention relates to a stable capsule dosage form comprising non-granular composition of silodosin, mannitol, pregelatinized starch, sodium lauryl sulfate and hydrogenated vegetable oil.
Aspects of the present invention relates to a process of preparing a composition of silodosin comprising:
a) Blending silodosin with one or more pharmaceutically acceptable excipients;
b) Lubricating the blend of step (a) with hydrogenated vegetable oil; and
c) Preparing the lubricated blend of step (b) into a suitable dosage form.
Aspects of the present invention relates to a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, wherein the capsule shell comprising less than 3.0% by weight of titanium oxide based on the total weight of said capsule shell.

Aspects of the present invention relates to a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, and at least 70% of the active ingredient is released in not more than about 60 minutes when subjected to a dissolution test in USP Type-2 Apparatus (paddle method) using 900 ml of 0.1N HC1 as the dissolution mediaand at a paddle speed of 50 rpm.
Aspects of the present invention relates to a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, and the said capsule comprising not more than about 0.15% of known impurities, not more than about 0.10% of any individual unknown impurity and not more than about 0.30% of total impurity.
Aspects of the present invention relates to a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, and is • useful for treatment of benign prostatic hyperplasia, dysuria associated with prostate hypertrophy, bladder celvix sclerosis, chronic prostatitis, neurogenic bladder.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, "a" or "an" means one or more unless otherwise specified.
Open terms such as "include," "including," "contain," "containing" and the like mean "comprising".
The term "treatment" or "treating" refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disorder.
The term "administering" or "administration" means providing a drug to a patient in a manner that is pharmacologically useful.

The term "patient" or "subject" means an animal, preferably a mammal, more ■ preferably human, in need of therapeutic intervention.
The term "Dosage form" means one or more compounds in a medium, carrier, vehicle, or device suitable for administration to a patient. "Oral dosage form" means a dosage form suitable for oral administration.
The term "or" can be conjunctive or disjunctive. The term "and" can be conjunctive.
The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
As used herein, the term "silodosin" is used in broad sense to include not only the silodosin per se but also its pharmaceutical^ acceptable salts, pharmaceutical^ acceptable solvates, pharmaceutical^ acceptable hydrates, pharmaceutical^ acceptable enantiomers, pharmaceutical^ acceptable derivatives, pharmaceutical^ acceptable polymorphs and pharmaceutical^ acceptable "prodrugs thereof, and also its various crystalline and/or amorphous forms and/or mixtures thereof.
Typically, silodosin is sieved and/or milled to control its particle size. In a preferred embodiment silodosin has a particle size distribution of d(lO) NMT 50 urn, d(50) NMT 250 urn and d(90) NMT 500 um, or d(10) NMT 20um, d(50) NMT 100 urn and d(90) NMT 250 um. In an embodiment, d(90) is about 5-50um measured using the laser diffraction particle size analyzer such as Mastersizer 2000 (Malvern Instruments).
The term "prodrug" means an ester or carbonate, which is formed by reacting one or more hydroxy groups of the compound of the Formula (I) with an acylating agent substituted by an alkyl, an alkoxy or an aryl by a conventional method to produce acetate, pivalate, methylcarbonate, benzoate, etc. Further, the prodrug includes also an ester or amide, which is similarly formed by reacting one or more hydroxy groups of the compound of the Formula (I) with an .alpha.-amino acid or a .beta.-amino acid, etc. using a condensing agent by a conventional method. In addition,. t]ie..prodrug includes^lso^ether, which is similarly formed

by reacting one or more hydroxy groups of the compound of the Formula (I) with a condensing agent via a conventional method.
The term "pharmaceutically acceptable" means molecular entities and compositions that are of sufficient purity and quality for use in the formulation of a composition or medicament of the present invention. Since both human use (clinical and over-the-counter) and veterinary use are equally included within the scope of the present invention, a formulation would include a composition or medicament for either human or veterinary use.
The term "pharmaceutically acceptable salt" refers includes, for example, such pharmaceutically acceptable salts wherein compounds having a carboxy group include inorganic salts such as sodium salts, potassium salts and calcium salts, and organic salts which are formed with organic amines such as morpholine and piperidine. Of the indoline compounds of the present invention, compounds wherein R represents a substituted or unsubstituted acyl group or a furoyl group can be converted into mono-acid addition salts formed by hydrochloric acid, hydrobromic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, succinic acid, tartaric acid, 2,4-dimethylbenzenesulfonic acid, 2,5-dimethylbenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 1-butanesulfonic acid, fumaric acid, glutamic acid, aspartic acid and the like.
To provide a more concise description, some of the.quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
The term "non-granular" refers to compositions which are not prepared by granulation techniques like wet granulation and dry granulation. The non-granular compositions of present invention are prepared by simple mixing process.
The term "stable" refers to compositions mean chemically stable having controlled levels of drug impurities as specified and/or accepted bv.drue regulatory agencies.

The term "impurity" for silodosin relates to known impurities and/or unknown impurities. For example the known impurities include Dehydro Silodosin, Des (3-hydroxypropyl) Silodosin and Cyano Silodosin.
The term "OGD" refers to Office of generic drugs.
. In embodiments, the present invention provides pharmaceutical compositions comprising of silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient.
In embodiments, the present invention provides a pharmaceutical composition ■ comprising i) silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, ii) one or more diluents, iii) one or more surfactants, iv) Hydrogenated vegetable oil, and optionally one or more other pharmaceutically acceptable excipients.
In embodiments, the present invention provides a stable non-granular compositions of silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient and one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions of silodosin of the present invention include any number of excipients, including, but not limited to, diluents or fillers, surfactants, binders, disintegrants, glidants, surfactants, lubricants and mixtures thereof.
Diluents: Various useful fillers or diluents include but are not limited to lactose, mannitol, sorbitol, xylitol, pregelatinized starch, maize starch, potato starch, rice starch, wheat starch, powdered celluloses, dibasic calcium phosphate, calcium phosphate, calcium carbonate, magnesium carbonate, microcrystalline cellulose and the like and mixtures thereof; more preferably selected from mannitol and pregelatinized starch.
In one of the particular embodiments, the present invention provides a stable non-granular pharmaceutical composition of silodosin comprising mannitol and pregelatinized starch.

Surfactants: Various useful surfactants include but are not limited to sodium lauryl sulfate, polyethyleneglycol, polyoxyethylene polyoxypropylene glycol, triethyl citrate and combinations thereof.
In one of the preferred embodiments, the present invention provides a stable non-granular pharmaceutical composition of silodosin comprising sodium lauryl sulfate.
Binders: Various useful binders include but are not limited to pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, powdered acacia, gelatin, guar gum, carbomers.
Disintegrants: Various useful disintegrants include but are not limited to pregelatinized starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Glidants: One or more glidants, which improve the flow of a powder blend can be used. Useful glidants include but are not limited to, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica.
The stable non-granular pharmaceutical composition of silodosin of present invention are devoid of magnesium stearate.
In one of the embodiments, the present invention provides a pharmaceutical composition comprising of silodosin comprising Hydrogenated vegetable oil as lubricant.
In one of the embodiments, the present invention provides a stable pharmaceutical composition of silodosin comprising Hydrogenated vegetable oil as lubricant and devoid of magnesium stearate.
In embodiments, the present invention provides a pharmaceutical composition comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, wherein the said composition is highly stable.

In embodiments, the present invention provides a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, wherein the said composition is highly stable.
In embodiments, the present invention provides a stable capsule dosage form comprising non-granular composition of silodosin, mannitol, pregelatinized starch, sodium lauryl sulfate and hydrogenated vegetable oil.
In embodiments, the present invention provides a process of preparing a composition of silodosin comprising:
a) Blending silodosin with one or more pharmaceutically acceptable excipients;
b) Lubricating the blend of step (a) with hydrogenated vegetable oil; and
c) Preparing the lubricated blend of step (b) into a suitable dosage form.
In one of the particular embodiments, the present invention provides a process of preparing stable non-granular compositions of silodosin comprising the following steps:
a) Co-sifting silodosin and sodium lauryl sulfate;
b) Co-sifting step (a) material with pregelatinized starch;
c) Co-sifting step (b) material with at least a part of mannitol;
d) Co-sifting step (c) material with remaining part of mannitol;
e) Sifting hydrogenated vegetable oil;
f) Blending the sifted material of step (d);
g) Adding sifted hydrogenated vegetable oil to step (f) and blending, and h) Encapsulation of material of step (g) to obtain capsules.
In one of the particular embodiments, the present invention provides a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, wherein the capsule shell comprising less than 3.0% by weight of titanium oxide based on the total weight of said capsule shell.

In one of the particular embodiments, the present invention provides a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl- sulfate and Hydrogenated vegetable oil, wherein the capsule shell comprising less than 2.5% by weight of titanium oxide based on the total weight of said capsule shell.
In one of the particular embodiments, the present invention provides a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, and at least 70% of the active ingredient is released in not more than about 60 minutes when subjected to a dissolution test in USP Type-2 Apparatus (paddle method) using 900 ml of 0.1 N HC1 as the dissolution mediaand at a paddle speed of 50 rpm.
In one of the particular embodiments, the present invention provides a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized* starch, sodium lauryl sulfate and Hydrogenated vegetable oil, wherein the capsule shell comprising about 2.0% to 2.5% by weight of titanium oxide based on the total weight of said capsule shell and the capsule is packed in HDPE containers or opaque PVC blisters.
In one of the particular embodiments, the present invention provides a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, wherein the capsule shell comprising less than 3.0% by weight of titanium oxide based on the total weight of said capsule shell, and the capsule composition of silodosin is chemically stable when stored at 40°C / 75% RH for 6 months.
In one of the particular embodiments, the present invention provides a stable capsule dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt thereof as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate and Hydrogenated vegetable oil, and the said capsule comprising not more than about 0.15% of known impurities, not more than about 0.10% of any individual unknown impurity and not more than about 0.30% of total impurity.

In one of the particular embodiments, the present invention provides a stable c< dosage form comprising silodosin or a prodrug or a pharmaceutically acceptable salt.tl as the active ingredient, mannitol, pregelatinized starch, sodium lauryl sulfate Hydrogenated vegetable oil, and is useful for treatment of benign prostatic hyper] dysuria associated with prostate hypertrophy, bladder celvix sclerosis, chronic pros neurogenic bladder.
The following examples and test examples illustrate the invention in further deta do not restrict the scope of the invention in any manner whatsoever.
Manufacturing Procedure:
Step 1: Silodosin and Sodium lauryl sulfate were co-sifted together.
Step 2: Step-1 material was co-sifted with Pregelatinized starch.
Step 3: Step-2 material was co-sifted with 50% Mannitol.
Step 4: Step-3 material was co-sifted with remaining 50% Mannitol.
Step 5: Hydrogenated vegetable oil was sifted and kept a side.
Step 6: The sifted material of step-4 were blended in a low shear blender.
Step 7: The sifted hydrogenated vegetable oil of step-5 was added to step-6 and blended.

Step 8: The lubricated blend of step-7 was encapsulated into hard gelatin capsule shells
having less than 3.0% by weight of titanium oxide based on the total weight of said capsule
shell.
Step 9: The filled capsules of step 8 were stored in double layered polyethylenebag and
sealed in triple laminated bags.
Step 10: The capsules were packed in HDPE packs and opaque PVC blisters.
Chemical stability of Silodpsin capsules 4mg of example 1: