FIELD OF THE INVENTION:

The present invention relates to a pharmaceutical composition comprising Tamsulosin and its
pharmaceutically acceptable salts thereof. The present invention specifically relates to
controlled release pharmaceutical composition comprising Tamsulosin, release controlling
polymers and hydrophobic pore forming agent and a process for the preparation thereof.

BACKGROUND OF THE INVENTION:

Tamsulosin is, chemically known as 5-[2-[[2-(2-ethoxy phenoxy) ethyl] amino] propyl]-2-
methoxy-benzene-sulfonamide represented by a structural formula I

Tamsulosin hydrochloride is an alpha adrenoceptor blocking agent developed by Yamanouchi pharmaceutical company and is used for the treatment of benign prostatic hyperplasia.

Tamsulosin is first disclosed in EP 34432 and U.S. patent no. 4,731,478 as pharmaceutically
active substance having alpha-adrenergic blocking activity that is useful for treatment of cardiac insufficiencies and benign prostatic hyperplasia.

Tamsulosin administered as Flomaxtra XL, which is absorbed from the intestine and is approximately 55 - 59% bioavailable. A consistent slow release of tamsulosin is maintained over the whole pH range encountered in the gastro - intestinal tract with little fluctuation over 24 hours. The rate and extent of absorption of tamsulosin administered as Flomaxtra XL is not affected by food. . Due to its pharmacokinetic properties, tamsulosin hydrochloride is administered to patients in the form of an oral, controlled-release pharmaceutically composition, suitable for a once-daily administration.

Tamsulosin shows linear kinetics. After a single dose of Flomaxtra XL in the fasted state, plasma levels of tamsulosin peak at a median time of 6 hours. Steady state is reached by day 4 of multiple dosing, plasma levels of Tamsulosin peak at 4 to 6 hours in the fasted and fed state. Peak plasma levels increase from approximately 6 ng/ml after the first dose to 11 ng/ml in steady state. As a result of the prolonged release characteristics of Flomaxtra XL, the trough concentration of tamsulosin in plasma amounts to 40% of the peak plasma concentration under fasted and fed conditions.

Flomaxtra XL is formulated as an Oral Controlled Absorption System (OCAS) and is a prolonged release tablet of the non-ionic gel matrix type, which contains Macrogol 7,000,000, Macrogol 8000, butyl hydroxyl toluene, magnesium stearate, colloidal silica anhydrous, hypromellose and iron oxide yellow. The Macrogol 7,000,000 grade is not commonly available grade and handling of such a high viscosity grade during processing is very difficult.

EP 1441713 and DE 20221486 discloses a monolithic pharmaceutical tablet, comprising 0.1- 10 mg of tamsulosin or a pharmaceutically acceptable salt thereof, 10-90 wt. % of hydroxyl propyl methyl cellulose (HPMC), the total tablet mass being 10-300 mg which exhibits dissolution profile such that in each of SIF, FasSIF, FeSSIF not more than 60% of Tamsulosin is released within 2 hrs. Nevertheless, it does not disclose anything about extending the drug release over the period of 24 hrs.

EP 1523994 discloses the manufacturing of a controlled release preparation comprising particles comprised of a drug, PEO with molecular mass above 2,000,000 and a specific size controlling agent obtained by sizing. The powder particles obtained by sizing are prepared by re-binding of smaller PEO particles back to bigger PEO particles. PEO with molecular mass above 2,000,000 becomes very sticky when exposed to moisture during processing and stability.

In consideration of prior art, the present inventors have found that many problems are encountered during manufacturing of controlled release composition of Tamsulosin using Macrogol 7,000,000 which is not commonly available grade commercially. Therefore, there is need for best composition for the preparation of controlled release pharmaceutical composition comprising Tamsulosin which releases Tamsulosin over the period of 24 hrs with commonly available excipients, with ease in manufacturing method.

The present inventors have found that the controlled release composition of tamsulosin can be prepared using commonly available excipients with ease of preparation in a more economic way.

OBJECTIVE OF THE INVENTION:

The main object of the present invention is to provide a pharmaceutical composition comprising tamsulosin or its pharmaceutically acceptable salts.

Another object of the present invention is to provide a process for the preparation of pharmaceutical composition comprising tamsulosin or its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION:

The first aspect of the present invention is to provide controlled release pharmaceutical composition comprising tamsulosin or its pharmaceutically acceptable salts.

Second aspect of the present invention is to provide controlled release tablets comprising tamsulosin, release rate controlling polymers and hydrophobic pore forming agents.

Third aspect of the present invention is to provide a process for the preparation of controlled release pharmaceutical composition comprising Tamsulosin.

Fourth aspect of the present invention is to provide a use of such pharmaceutical composition for the prevention or treatment of benign prostatic hyperplasia and other related states or conditions.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides a pharmaceutical composition comprising Tamsulosin, release controlling polymers and hydrophobic pore forming agent.

According to the first embodiment of the invention, control release polymers are selected from the group of acrylates and methacrylates and copolymers thereof with various co monomers. The copolymers of acrylates and methacrylates are commercially available from Evonik Pharma GmbH, Weiterstadt Germany marketed under the trademark EUDRAGIT (Registered Trademark of Rohm Pharma GmbH). Especially preferred polymers are the 1:1- up to 1:2-copolymer of methacrylic acid and methyl methacrylate which is resistant to gastric juice and soluble in intestinal juices and which is formed from monomers selected from the group consisting of methacrylic acid and methacrylic acid lower alkyl esters and copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups which is pH independent polymer. The l:l-copolymers are marketed in the EUDRAGIT L series. The corresponding 1:2-copolymers are marketed in the EUDRAGIT S series. The copolymer of ethyl acrylate, methyl methacrylate and low content of methacrylic acid ester with quaternary ammonium groups are marketed in the Eudragit RS and RL series.

Especially preferred polymers are the l:l-copolymer of methacrylic acid and methyl methacrylate which is marketed under the product name EUDRAGIT L 100, the 1:2- copolymer of methacrylic acid and methyl methacrylate which is marketed under the product name EUDRAGIT S 100, the copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups which is marketed under the product name EUDRAGIT RS PO and EUDRAGIT RL PO. The combination of these Eudragit polymers enables controlled time release of active ingredient by pH independent swelling.

The second embodiment of the present invention comprises hydrophobic pore forming agent selected from group of anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, kaolin, hydrous silicon dioxide, calcium silicate, magnesium silicate, light anhydrous silicate, magnesium metasilicate aluminate, magnesium carbonate, calcium carbonate, silicone dioxide, bentonite, calcium sulfate, activated carbon or mesoporous Silica, wherein only one such item type can be used or two or more can be combined together preferably calcium hydrogen phosphate dihydrate as it helps in extending the drug release beyond 24 hrs of time.

According to another embodiment, the controlled release pharmaceutical composition of tamsulosin includes matrix forming agents, binders, dispersing agents, glidants, plasticizers, lubricants, surfactants, disintegrants, film coating agents and coloring agents. As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.

According to other embodiment of the present invention matrix forming agents include, but are not limited to hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearine, tripalmitine, trimyristine, wax, lanolin, glyceryl palmitostearate, glyceryl stearate, polyglyceryl diisostearate, diethylene glycol monostearate, ethylene glycol monostearate and any mixture thereof.

An especially preferred matrix forming agents are selected from hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearine, tripalmitine, trimyristine and any mixture thereof. Lubritab® is a registered trademark used for Hydrogenated Vegetable Oils. Lubritab® serves as matrix forming agent so that the release of Tamsulosin from the matrix takes place in controlled manner.

According to one embodiment of the present invention binders include, but are not limited to, acacia, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioners sugar, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxy ethyl methyl cellulose, hydroxylpropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, poloxamer, polydextrose, polyethylene oxide, polymethyl acrylates, povidone, sodium alginate, starch, pregelantized starch, stearic acid, sucrose, sunflower oil, zein and mixtures thereof.

In another embodiment of the present invention lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.

According to another embodiment of the present invention disintegrants include, but are not limited to alginic acid, crosslinked polyvinyl pyrrolidone, com starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol® Primellose®.), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, maize starch and modified starches, methyl cellulose, microcrystalline cellulose, polyacrilin potassium, potato starch, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab), pregelatinized starch, starch and mixtures thereof.

According to another embodiment of the present invention diluents include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium chaim glyceride, microcrystalline cellulose, polydextrose, polymethylacrylates, potassium chloride, powdered cellulose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelantized starch, sterilizable maize, sucrose, sugar spheres, talc, tragacanth, trehalose, tribasic calcium phosphate, xylitol and mixtures thereof.

According to one more embodiment of the present invention surfactants comprises non-ionic surfactants like alkyl poly(ethylene oxide),a poly(ethyleneoxide), Copolymers of poly(ethylene oxide) and poly(propylene oxide) (commercially called Poloxamers or Poloxamines), alkyl polyglucosides like octly glucoside, decyl maltoside, fatty alcohols like Cetyl alcohol, oleyl alcohol, Cocamide MEA, Cocamide DEA, Polysorbates like Tween 20, Tween 80; anionic surfactants such as Perfluorooctanoate, perfluorooctanesulfonate, sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, alkyl benzene sulfonate, soaps or fatty acid salts and cationic surfactants such as Cetyl trimethylammonium bromide, cetylpyridinium chloride, polyethoxylated tallow amine, benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide, predominantly C14 alkyl).

According to further embodiment of the present invention solvent comprises: Isopropyl alcohol, ethanol, n-butanol, acetone, purified water or combination thereof.

In the one preferred embodiment the pharmaceutical composition comprising tamsulosin suited for oral administration like tablets, capsules, MUPS and sachets.

The compressed tablet can also be film coated. Film coat concentration can be varied up to about 10% to complement the drug amount, and preferably about 2.0% to about 3.5%.

Film coating suspensions include combinations of one, two or three of the following components: carboxymethylcellulose sodium, carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner's sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin, methyl cellulose, microcrystalline wax, Opadry and Opadry II, polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide, and zein.

The tamsulosin present in the composition is normally the (R)-enantiomer of tamsulosin but the (S)-enantiomer as well as mixtures of the two in various proportions or racemic mixtures are also included within the meaning of tamsulosin. As used herein "tamsulosin" is any tamsulosin moiety containing substance that exhibits pharmaceutical activity and specifically includes tamsulosin free base, pharmaceutically acceptable salts thereof , especially pharmaceutically acceptable acid addition salts thereof and mixtures or combinations of two or more of any such tamsulosin substances. Examples of useful tamsulosin pharmaceutically acceptable salts include tamsulosin hydrochloride, tamsulosin bromide, tamsulosin methane sulfonate, tamsulosin tosylate, tamsulosin besylate, tamsulosin acetate, tamsulosin maleate, tamsulosin tartrate and tamsulosin citrate.

The amount of tamsulosin present in the composition ranges from 0.1 to 1.5%. In absolute terms, the amount of tamsulosin is generally within range of 0.1 to 1.2 mg, typically 0.3 to 1.2 mg, and preferably 0.3 to 0.8 mg, expressed in amount of free base. For example 0.4 mg of tamsulosin hydrochloride is preferred amount of tamsulosin which corresponds to 0.367 mg of tamsulosin free base.

Futher embodiment of the present invention provides a process for manufacturing the controlled release pharmaceutical composition of Tamsulosin comprising the following steps:

(1) screening the pharmaceutically acceptable excipients;

(2) dry mixing the content of step (1);

(3) preparing a binder solution, dispersing tamsulosin in to the binder solution;

(4) adding the binder solution of step (3) to the dry blend of step (2);

(5) granulating the content of step (2) using binder solution;

(6) drying the granules obtained from step (5);

(7) screening the granules obtained from step (6);

(8) screening the lubricant and adding and mixing lubricant with the screened granules;

(9) optionally, compressing the content of step (8) to tablets;

(10) optionally, film coating of the tablets obtained from step (9).

In one embodiment, the dry mixing can be carried out using high shear mixer, rapid mixer granulator and planetary mixers preferably using rapid mixer granulator. The granules can be prepared using high shear mixer, rapid mixer granulator, fluid bed granulator or extrusion- spheronization, preferably by rapid mixer granulator.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non- limiting examples.
Example 1: Preparation of 0.4 mg tablets of Tamsulosin hydrochloride:

The process for the preparation of example 1 is as follows:

(1) Calcium hydrogen phosphate dihydrate, Lubritab, Eudragit RS PO and Eudragit L 100 were screened through a 30 mesh screen;

(2) The content of step (1) was mixed in a rapid mixer granulator with an impeller speed set at 150 rpm for 5 minutes;

(3) The binder solution was prepared by dissolving povidone in isopropyl alcohol. Tamsulosin hydrochloride was dispersed in the same solution and stirred to get clear solution;

(4) The binder solution of step (3)was slowly added to the dry blend of step (2) for approximately 6-10 minutes;

(5) Granulation was performed in rapid mixer granulator with an impeller speed set at 150 rpm for 5 minutes;

(6) The wet mass obtained was dried in tray dryer by maintaining the product temperature 45 ° C till the loss on drying of the granules was between 0.5- 1.0 percent;

(7) Magnesium stearate was screened through a 30 mesh screen;

(9) The content obtained from step (6) was mixed with the content from step (7) for 2min using a suitable blender; and (10) The lubricated granules were compressed using 8.99 X 6.51 mm Oval shaped concave punch set.

The tablets obtained from Example 1 were subsequently tested for in vitro dissolution rate, measured by Apparatus I (USP Basket Method), using the following parameters:

o Speed: 100 rpm

o Dissolution Media: pH 1.2 buffer for 2 hrs followed by pH 7.2 buffer, with polysorbate

o Volume: 500 ml

o Temperature: 37° C ± 0.5 0 C

Dissolution Rate of Tamsulosin hydrochloride tablets of Example 1:

Example 2: Preparation of 0.4 mg capsules of Tamsulosin hydrochloride:

The process for the preparation of example 2 is as follows:

(1) Calcium hydrogen phosphate dihydrate, Lubritab, Eudragit RS PO were screened
through a 30 mesh screen;

(2) The content step (1) was mixed in a rapid mixer granulator with an impeller speed set
at 150 rpm for 5 minutes;

(3) The binder solution was prepared by dissolving povidone in isopropyl alcohol.

Tamsulosin hydrochloride was dispersed in the same solution and stirred to get clear
solution;

(4) The binder solution of step (3)was slowly added to the dry blend of step (2) for
approximately 6-10 minutes;

(5) Granulation was performed in rapid mixer granulator with an impeller speed set at 150 rpm for 5 minutes;

(6) The wet mass obtained was dried in tray dryer by maintaining the product temperature 45 ° C till the loss on drying of the granules was between 0.5-1 percent;

(7) Magnesium stearate was screened through a 30 mesh screen;

(9) The content obtained from step (6) was mixed with the content from step (7) for 2 min using a suitable blender; and (10) The lubricated granules were filled in the capsule of suitable size.

The capsules obtained from Example 2 were subsequently tested for in vitro dissolution rate, measured by Apparatus I (USP Basket Method), using the following parameters:

o Speed: 100 rpm

o Dissolution Media: pH 1.2 buffer for 2 hrs followed by pH 7.2 buffer, with
polysorbate o Volume: 500 ml o Temperature: 37° C ± 0.5 0 C

Dissolution Rate of Tamsulosin hydrochloride capsule of Example 2

We Claim:

1) A pharmaceutical composition comprising Tamsulosin or its pharmaceutically acceptable salts thereof, release controlling polymers and hydrophobic pore forming agent.

2) A pharmaceutical composition according to claim 1, comprises 0.1 to 1.5% by weight of Tamsulosin or a pharmaceutically acceptable salt thereof.

3) The pharmaceutical composition according to claim 1, wherein the said release controlling polymers are selected from the group comprising of copolymers of acrylates and alkylacrylates, preferably Eudragit polymers.

4) The pharmaceutical composition according to claim 1, wherein the said hydrophobic pore forming agent is selected from group consisting of calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, kaolin, hydrous silicon dioxide, calcium silicate, magnesium silicate, light anhydrous silicate, magnesium metasilicate aluminate, magnesium carbonate, calcium carbonate, silicone dioxide, bentonite, calcium sulfate, activated carbon or mesoporous silica or combination thereof.

5) The pharmaceutical composition according to claim 1, further comprises pharmaceutically acceptable excipients, selected from the group of glidants, lubricants, fillers, binders, disintegrants, diluents, surfactants, and solutions.

6) The pharmaceutical composition according to claim 1, wherein the related dosage forms are selected from the group of capsules, tablets, mups and sachets.

7) The pharmaceutical composition according to claim 1, is used for treating or ameliorating the conditions of benign prostatic hyperplasia and related condition.