FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
ORAL DOSAGE FORM OF TAMSULOSIN OR SALT THEREOF IN THE FORM OF MICROTABLETS
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides pharmaceutical composition in the form of microtablets comprising tamsulosin or salt thereof along with pharmaceutically acceptable carriers.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides pharmaceutical composition in the form of microtablets comprising tamsulosin or salt thereof along with pharmaceutical^ acceptable carriers.
Tamsulosin hydrochloride is an antagonist of alphas adrenoceptors in the prostate. Tamsulosin HCI is (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl] amino] propyl]-2-methoxybenzenesulfonamide, monohydrochloride of formula 1. Tamsulosin HCI is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). It is not indicated for the treatment of hypertension. (R)-tamsulosin hydrochloride is marketed under various trade names, including FLOMAX (Boehringer Ingelheim) in the U.S., HARNAL (Yamanouchi) in Japan and OMNIC (Yamanouchi) in Europe, for treatment of symptoms of benign prostatic hyperplasia such as urinary volume and frequency problems. The approved drug products include a capsule dosage form for oral administration that comprises 0.4 mg of the tamsulosin hydrochloride. The capsule provides controlled release of the tamsulosin and is a once daily dosage form, although two capsules can be used if needed; i.e. a maximum single daily administration of 0.8 mg.

FORMULA 1
U.S. Pat. No. 4,772,475 (EP 194838, EP 533297) discloses controlled-release pharmaceutical dosage forms comprising multiple granulate units containing
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tamsulosin, microcrystalline cellulose and a release-controlling agent. The granulate gradually releases tamsulosin from the granulate matrix. The patent suggests that an enteric coating is not needed.
U. S. Application No. 20050100606 discloses a controlled-release formulation of tamsulosin hydrochloride, which comprises a granular core; and a drug-coating layer coated on the granular core.
U.S. Pat. No. 6,328,979 discloses a sustained-release composition which includes an ionic drug such as tamsulosin hydrochloride and an ionic substance having an opposite charge to that of the ionic drug for increasing hydrophobicity of the ionic drug.
European Patent Application EP 1596849 A1 discloses a controlled release pharmaceutical composition of tamsulosin comprising a spheroid core, one or more of rate controlling polymers, and an enteric coating over the spheroid core, process for preparation of the pharmaceutical composition and method of treating symptoms of benign prostatic hyperplasia comprising administering a controlled-release pharmaceutical composition of tamsulosin.
The present invention provides pharmaceutical composition in the form of microtablets comprising tamsulosin or salt thereof, and an enteric coating wherein the said microtablets are with or without intermediate layer or seal coat between the drug core and the enteric coat.
In one of the aspects of the present invention there is provided a solid dosage form in the form of enteric coated microtablets for oral administration comprising tamsulosin or salt thereof along with pharmaceuticals acceptable excipients wherein the said microtablets are free of an intermediate layer or seal coat between the drug core and the enteric coat.
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Tamsulosin can be present in the form of tamsulosin hydrochloride. The usual recommended dose of tamsulosin hydrochloride is used for the preparation of formulation. The pharmaceutically acceptable enteric coat forming polymers can be selected from methacrylic acid/methyl methacrylate copolymers such as Eudragit L or cellulose derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methyl methacrylate, ethyl methacrylate, lauryl methacrylate and other suitable polymers. The enteric coating is present in an amount of from about 1 to about 20 weight percent (%), based on the total weight of the microtablets. Pharmaceutically acceptable excipients can be filler, binder, lubricant, disintegrant, glidant, plasticizers and the like.
The said microtablets have a tablet size of about 1mm to 4mm, and a tablet weight of about 1 to 50mg.
Preferred fillers include, but are not limited to, microcrystalline cellulose, starch, dibasic calcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, dextrose, sucrose, lactose, mannitol, sorbitol and the like.
Preferred binders include, but are not limited to, starches, e.g., potato starch, wheat starch and corn starch; gums, such as gum tragacanth, acacia gum and gelatin; polyvinyl pyrrolidone, purified water and the like.
The lubricant is preferably selected from calcium stearate, magnesium stearate, sodium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, polyethylene glycol, sodium benzoate, stearic acid and talc. A combination of lubricants may also be used.
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Preferred plasticizers include, but are not limited to, citric and tartaric acid esters such as acetyl-triethyl citrate, acetyl tributyl citrate; glycerol and glycerol esters; phthalic acid esters and the like. A combination of plasticizers may also be used.
The dosage form can be prepared by dry granulation, wet granulation or by direct compression. The microtablets may be prepared by wet granulation method. Aqueous solution of tamsulosin hydrochloride was prepared and this solution was layered on microcrystalline cellulose followed by granulating the blend with Eudragit L 30 D 55. Granules were dried and lubricated with magnesium stearate. These granules were compressed into microtablets using multi-tip punches. Further the microtablets were coated using enteric coating solution.
The process of coating may be performed in any suitable equipment such as, in a fluid bed coater, or preferably on a coating pan employing polymer solutions in water or in suitable organic solvents or using latex dispersions of these polymers. The results of the coating procedure may be routinely checked by withdrawing sample of the microtablets. Coating was applied till approximately 3% weight gain was achieved.
The microtablets are enclosed inside a capsule, for example, a gelatin capsule. For this any capsule conventionally employed in the pharmaceutical formulation field can be used.
The microtablets may have dissolution of about 100% in about 6 hours when measured in a USP Type II apparatus at 50 rpm using 500 ml of pH 6.8 phosphate buffer as dissolution medium.
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.
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EXAMPLE
Composition of batches is provided in Table 1.
Table 1 - Tamsulosin hydrochloride 0.4mg enteric-coated micro tablets

Sr. No. Ingredient Mg/capsule % w/w
CORE
1 Tamsulosin hydrochloride 0.4 0.17
2 Microcrystalline cellulose (AvicelpH 101) 146.9 63.37
3 Magnesium stearate 5.7 2.45
4 Eudragit L 30 D 55 250ml=75 32.25
5 Purified water q.s. -
Total Weight (mg) 228
ENTERIC COAT
1 Eudragit L 30 D 55 20ml=6 2.58
2 Tri ethyl citrate 0.3 0.12
3 Talc 0.48 0.20
4 Purified water q.s. -
Total Fil Weight (mg) 231.78 -
Procedure -
a) Preparation of core-
1) Tamsulosin hydrochloride was dissolved in purified water.
2) Microcrystalline cellulose was sifted through # 60.
3) Drug layering was carried out over microcrystalline cellulose using tamsulosin hydrochloride solution.
4) This blend dried, sifted and was further granulated with Eudragit L 30 D 55.
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5) Granules were dried at 60°C and lubricated with 60 # passed magnesium stearate.
6) This blend was further compressed into microtablets using multi-tip punches of desired shape and size.
b) Enteric coating-
1) Eudragit L 30 D 55 was diluted with in purified water.
2) Tri ethyl citrate and talc was further added to this solution.
3) Coating was applied till the desired weight gain is achieved.
Dissolution study -
The capsules filled with microtablets were evaluated in a dissolution study. Each capsule was placed in a USP type II dissolution apparatus containing 500ml of pH 6.8 phosphate buffer, and these were rotated at 50 rpm for 6 hours. Samples were taken every 0, 1, 2, 4 and 6 hours and the amount of tamsulosin hydrochloride released was determined. The dissolution profile of Flomax® and tamsulosin hydrochloride microtablet was summarized in table 2.
Table 2 - Dissolution data of the microtablets prepared as per the present invention

Time (hrs) Flomax® release (%) Tamsulosin hydrochloride microtablets release (%)
0 0 0
1 28 32
2 52 61
4 85 83
6 103 99
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WE CLAIM:
1) A solid dosage form in the form of enteric coated microtablets for oral administration comprising tamsulosin or salt thereof along with pharmaceutically acceptable excipients wherein the said microtablets are free of an intermediate layer or seal coat between the drug core and the enteric coat.
2) A dosage form according to claim 1, wherein the tamsulosin is in the form of tamsulosin hydrochloride.
3) A dosage form according to claim 1, wherein the microtablets have a tablet size of about 1 to 4mm.
4) A dosage form according to claim 1, wherein the enteric coating is present in an amount from about 1 to 20 weight percent, based on the total weight of the microtablet.
5) A dosage form according to claim 1, wherein the enteric coating additionally comprises plasticizer.
6) A dosage form according to claim 1, wherein the microtablet can be present with an intermediate layer in between the core and the enteric coat.
7) A dosage form according to claim 1, wherein the microtablets are enclosed within a capsule.
8) A dosage form according to claim 1, wherein the excipient is selected from the group consisting of binders, diluents, fillers, plasticizers, enteric coating agents, lubricants, glidants and the like.
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9) A dosage form according to claim 1, wherein lubricant may be one or more of
magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated
vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate.
10) A dosage form according to claim 1, wherein enteric coating forming
polymers can be selected from methacrylic acid/methyl methacrylate copolymers
such as Eudragit L or cellulose derivatives such as carboxymethyl cellulose,
cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and other
suitable polymers.

Dated this 28th day of June, 2006 For Wockhardt Limited
(Yatendra Kumar) Authorized Signatory
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