FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
PROVISIONAL SPECIFICATION (SECTION 10 and rule 13)
"PHARMACEUTICAL COMPOSITIONS COMPRISING STEROL
INHIBITORS"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House, HDO - Corporate Bldg,
Wing -A, B.D. Sawant Marg,
Chakala, Andheri (East),
Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF
THE INVENTION

FIELD OF INVENTION
Present invention relates to the pharmaceutical composition comprising sterol inhibition inhibitor, preferably Ezetimibe and its pharmaceutical^ acceptable salts and to the process of manufacturing such compositions

OH
(I)

Ezetimibe is a novel selective cholesterol absorption inhibitor that effectively blocks intestinal absorption of dietary and biliary cholesterol. Ezetimibe undergoes glucuronidation to a single metabolite and is localized in the intestinal wall, where it prevents cholesterol absorption. Enterohepatic recirculation of ezetimibe and the glucoronide ensures repeated delivery to the site of action and limits peripheral exposure. Ezetimibe does not affect the absorption of fat-soluble vitamins or triglycerides. Ezetimibe is available under trade name ZETIA marketed by Merck/Schering-plough pharmaceuticals (MSP Singapore).
DESCRIPTION OF THE RELATED ART
U.S. Patent 5,767,115, 5,624,920, 5,668,990, 5, 656,624 and 5,688,787, respectively, disclose hydroxy-substituted azetidinone compounds and substituted, & beta-lactam compounds useful for lowering cholesterol and/or in inhibiting the formation of cholesterol- containing lesions in mammalian arterial walls. Ezetimibe is one among several compounds described in said patents. U.S. Patent 5,846,966 and 5,661,145, respectively, disclose hydroxy-substituted azetidinone compounds or substituted &beta-lactam compounds in combination with HMG CoA reductase inhibitors for preventing or treating atherosclerosis and reducing plasma cholesterol levels.
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PCT application published as WO00/38725 discloses cardiovascular therapeutic combinations including an ileal bile acid transport inhibitor or cholesteryl ester transport protein inhibitor in combination with a fibric acid derivative, nicotinic acid derivative, microsomal triglyceride transfer protein inhibitor, cholesterol absorption antagonist, phytosterol, stanol, antihypertensive agent or bile acid sequestrant.
U.S. Pat. No. 5,698,527 discloses ergostanone derivatives substituted with disaccharides as cholesterol absorption inhibitors, employed alone or in combination with certain other cholesterol lowering agents, which are useful in the treatment of hypercholesterolemia and related disorders.
U.S.Pat. No.7030106 is directed to compositions and therapeutic combinations comprising PPAR activator(s) and certain sterol absorption inhibitors for treating vascular and lipidemic conditions. The patent describes common formula for tablets comprising sterol absorption inhibitors. The formula thus disclosed in patent comprised of lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and sodium lauryl sulphate and magnesium stearate.
We have surprisingly found that there is very limited prior art available with respect to the formulation of ezetimibe. The current prior art doesn't reveal the effect of particle size on dissolution of tablets. In accordance with the said invention we have identified the particle size of ezetimibe required for adequate dissolution. In one more embodiment of the invention we have provided the composition comprising Ezetimibe without Microcrystalline cellulose.
OBJECTIVE OF THE INVENTION:
The objective of present invention is to provide pharmaceutical composition comprising ezetimibe and its pharmaceutically acceptable salts having specific particle size.
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Yet another objective of the present invention is to provide pharmaceutical composition comprising ezetimibe or its pharmaceutically acceptable salt wherein the 90% particles are not more than 25 microns.
Still another objective of the present invention is to provide an oral pharmaceutical composition comprising ezetimibe or its pharmaceutically acceptable salt wherein the 90% particles are not more than 15 microns.
Further object of the present invention is to provide an oral pharmaceutical composition comprising ezetimibe or its pharmaceutically acceptable salt wherein the 90% of particles are not more than 7 microns.
Further object of the present invention is to provide an oral pharmaceutical composition comprising ezetimibe or its pharmaceutically acceptable salt wherein the 90% of particles are not more than 7 microns and 50% particles are not more than 5 microns.
Another objective of present invention is to provide a pharmaceutical composition substantially free from microcrystalline cellulose or crystalline cellulose.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention is directed to pharmaceutical composition comprising at least one sterol inhibitor particularly of ezetimibe having specific particle size. In one embodiment, the pharmaceutical composition contains ezetimibe of which 90% of particles are not more than 25 microns, in an another embodiment the pharmaceutical composition contains ezetimibe of which 90% of particles are not more than 15 microns, the pharmaceutical composition contains ezetimibe of which 90% of particles are not more than 10 microns. In a most preferred embodiment 90% of particles are not more than 7 microns.
In the present invention one embodiment, the pharmaceutical composition contains ezetimibe of which 50% of particles are not more than 10 microns, in an another
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embodiment the pharmaceutical composition contains ezetimibe of which 50% of particles are not more than 7 microns, the pharmaceutical composition contains ezetimibe of which 50% of particles are not more than 4 microns.
The present invention is also directed to process of making pharmaceutical composition by direct compression and / or by wet granulation process.
The pharmaceutically acceptable excipients that may be used in the present invention include "diluents" such as lactose, dicalcium phosphate, calcium sulfate, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, powdered sugar and the like and mixtures thereof.
The pharmaceutically acceptable excipients that may be used in the present invention include "disintegrant" such as carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose croscarmellose sodium), sodium starch glycolate(e.g. Explotab.RTM),crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate and starch, wherein sodium starch glycolate is most preffered.
The "binder" can be selected from one or more of polyvinylpyrrolidone, starch mucilage,
pregelatinized starch, sodium alginate, alginic acid, acacia mucilage, tragacanth,
hydroxypropyl methyl cellulose, carboxymethylcellulose sodium,
carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylate, carboxyvinyl polymers like carbopols and combinations thereof.
Suitable "lubricants" include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.
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The obtained pharmaceutical composition of ezetimibe was tested for its dissolution profile against Zetia by using USP II apparatus at 100 RPM.
Initially few experiments were carried out for ezetimibe having particle size about 25 microns which showed release of the drug about 40-50%, based on such release profile obtained ezetimibe was micronized and pharmaceutical dosage form was prepared. The example mentioned below demonstrates some illustrative procedures for preparing the pharmaceutical compositions described herein. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention. The pharmaceutical compositions of present invention can be prepared with techniques well known in the art, preferably, direct compression, dry granulation and wet granulation.
EXAMPLE 1:
Particle Size (D 0.9) =6 micron

Ingredients mg/tablet
Ezetimibe 10
Lactose monohydrate 75
Crospovidone 5
Sodium lauryl sulphate 3
Povidone K-30 6
Purified water q.s
Magnesium Stearate 1
Total 100
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EXAMPLE 2:
Particle Size (D 0.9) =6 micron

Ingredients mg/tablet
Ezetimibe 10
Lactose monohydrate 75
Sodium Starch glycolate 5
Sodium lauryl sulphate 3
Povidone K-30 6
Purified water q.s
Magnesium Stearate 1
Total 100
Procedure:
Ezetimibe, Croscarmellose sodium, Lactose monohydrate, microcrystalline cellulose, and Sodium lauryl sulphate were sifted through ASTM mesh # 60. The pre granulation blend was transferred to the bowl of Rapid mixer granulator (RMG) followed by mixing for 10 min in RMG at slow impeller speed. PVP K30 in purified water was used as the binder solution for granulation; the powder blend was granulated at fast impeller and slow chopper to get desired granules. The granules were then dried in the Fluid Bed Drier till the LOD of the dried granules was found to be less than 3.0%w/w.The dried granules were then passed through ASTM mesh # 30 which was then mixed with Magnesium stearate and blended in the Bin Blender for 3 minutes. This lubricated blend was compressed into tablets.
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Comparative Dissolution Profile of Example 1. Example 2 and ZETIA: Dissolution media (500ml): water Dissolution apparatus: USP II, 50 RPM

TIME (min) EXAMPLE 1 Percent Release EXAMPLE 2 Percent Release ZETIA Percent Release
5 43 38 47
10 65 74 79
15 71 86 85
30 73 86 88
45 72 86 86
60 70 88 84
Recovery 75 95 81
Dated this twenty third (23rd) day of May, 2006
VIJAYmSARE \ MANAGER-iRM Glenmark Pharmaceuticals Limited
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