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:
PHARMACEUTICAL COMPOSITIONS OF REPAGLINIDE OR SALT THEREOF
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 a pharmaceutical composition comprising repaglinide or salt thereof along with pharmaceutically acceptable excipients, wherein repaglinide has a particle size D90 of less than or equal to 50 microns.
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 a pharmaceutical composition comprising repaglinide or salt thereof along with pharmaceutically acceptable excipients, wherein repaglinide has a particle size D90 of less than or equal to 50 microns.
Repaglinide is an oral blood glucose-lowering drug of the meglitinide class used in the management of type 2 diabetes mellitus (also known as non-insulin dependent diabetes mellitus or NIDDM). Repaglinide is chemically unrelated to the oral sulfonylurea insulin secretagogues. Repaglinide is a white to off-white powder with molecular formula C27 H36 N2 04 and a molecular weight of 452.6. Repaglinide (PRANDIN®) is indicated as an adjunct to diet and exercise to lower the blood glucose in patients with type 2 diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled satisfactorily by diet and exercise alone. Its structural formula is

US Patent No 5,312,924, 6,143,769 and RE37035 provide pharmaceutical compositions and method of lowering the level of glucose using repaglinide or salt thereof.
US Patent No 6,677,358 provides a pharmaceutical composition comprising repaglinide and metformin together with a suitable carrier.
US Application 2004102477 (the 477 application) describe crystalline form II, III and amorphous form of S-repaglinide.
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The present inventors have noticed that when repaglinide having a particle size D90 of greater than 50 microns is used; it resulted in appreciable decrease in percent drug release of repaglinide.
The present inventors have now surprisingly found that when repaglinide repaglinide having a particle size D90 of less than or equal to 50 microns is used, it results in improved percent drug release of repaglinide.
One of the aspects of the present invention provides a pharmaceutical composition comprising repaglinide or salt thereof along with pharmaceutically acceptable excipients, wherein repaglinide has a particle size D90 of less than or equal to 50 microns.
The term D90 as used herein means that 90% of the particles have a particle size less than a particular range mentioned. D90 less than 50 microns means 90% of the particles have a particle size less than 50 microns.
In another aspect of the present invention there is provided a pharmaceutical composition, which comprises of granules of repaglinide or salt thereof along with pharmaceutically acceptable excipients.
In another aspect of the invention there is provided a pharmaceutical composition, which comprises of granules of repaglinide or salt thereof along with pharmaceutically acceptable excipients, wherein the granules of repaglinide or salt thereof along with other pharmaceutically acceptable excipients have bulk density of 0.3 to 1.0 g/cc.
The pharmaceutical composition of the present invention can be present in the form of tablet, capsule, powder, disc, caplet, granules and pellets.
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The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, solubilizers, bases, lubricants, disintegrants, and glidants.
Suitable binder may be selected from a group comprising one or more of, povidone, starch, stearic acid, gums, celluloses and the like.
Suitable filler may be selected from a group comprising one or more of, microcrystalline cellulose, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable solubilizer may be selected from a group comprising one or more of, benzyl benzoate, cyclodextrins, glyceryl monostearates, poloxamers, sorbitan esters and the like.
Suitable bases may be selected from a group comprising one or more of, hydroxides of alkali metals, diethanolamine, meglumine, lysine, arginine, ethanolamine, triethanolamine and the like.
Suitable lubricant may be selected from a group comprising one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate and the like.
Suitable glidant may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and the like.
The pharmaceutical composition of the present invention can be prepared by mixing repaglinide with other excipients, compacting the pre-mix through
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compactor, breaking the flakes into granules and finally lubricating the granules and compressing the final blend.
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.
EXAMPLE 1
Table 1: Composition of repaglinide tablets (0.5mg).

S. No Ingredients Quantity/tablet (% w/w)
1 Repaglinide 0.3-2
2 Dicalcium phosphate 15-25
3 Microcrystalline cellulose 25-50
4 Maize Starch 10-25
5 Polyvinyl pyrrolidone 2-7
6 Cross linked povidone 1-6
7 Polyethylene polypropylene glycol polymer (Poloxamer) 1-5
8 1 -Deoxy-1 -(methylamino)-D-glucitol (Meglumine) 1-5
9 Talc 0.25-1
10 Cross linked povidone 0.5-2.5
11 Talc 0.5-2.5
Procedure: Repaglinide, dicalcium phosphate, microcrystalline cellulose, maize starch, polyvinyl pyrrolidone, crospovidone, meglumine and poloxamer are mixed. This pre-mix is compacted through roll compactor to form. The flakes are milled through multimill to form granules. Granules are lubricated with talc and finally compressed into tablets using suitable tooling.
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EXAMPLE 2
Table 2: Composition of repaglinide tablets (1.0mg).

S. No Ingredients Quantity/tablet (% w/w)
1 Repaglinide 0.3-2
2 Dicalcium phosphate 15-25
3 Microcrystalline cellulose 25-50
4 Maize Starch 10-25
5 Polyvinyl pyrrolidone 2-7
6 Cross linked povidone 1-6
7 Polyethylene polypropylene glycol polymer (Poloxamer) 1-5
8 1 -Deoxy-1 -(methylamino)-D-glucitol (Meglumine) 1-5
9 Talc 0.25-1
10 Iron oxide Yellow 0.05-0.25
11 Cross linked povidone 0.5-2.5
12 Talc 0.5-2.5
Procedure: Repaglinide, dicalcium phosphate, microcrystalline cellulose, maize starch, polyvinyl pyrrolidone, crospovidone, meglumine, poloxamer and iron oxide yellow are mixed. This pre-mix is compacted through roll compactor to form flakes. The flakes are milled through multimill to form granules. Granules are lubricated with talc and finally compressed into tablets using suitable tooling.
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EXAMPLE 3
Table 3: Composition of repaglinide tablets (2.0mg).

S. No Ingredients Quantity/tablet (% w/w)
1 Repaglinide 0.3-2
2 Dicalcium phosphate 15-25
3 Microcrystalline cellulose 25-50
4 Maize Starch 10-25
5 Polyvinyl pyrrolidone 2-7
6 Cross linked povidone 1-6
7 Polyethylene polypropylene glycol polymer (Poloxamer) 1-5
8 1 -Deoxy-1 -(methylamino)-D-glucitol (Meglumine) 1-5
9 Talc 0.25-1
10 Iron oxide Red 0.05-0.25
11 Cross linked povidone 0.5-2.5
12 Talc 0.5-2.5
Procedure: Repaglinide, dicalcium phosphate, microcrystalline cellulose, maize starch, polyvinyl pyrrolidone, crospovidone, meglumine, poloxamer and iron oxide red are mixed. This pre-mix is compacted through roll compactor to form flakes. The flakes are milled through multimill to form granules. Granules are lubricated with talc and finally compressed into tablets using suitable tooling.
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WE CLAIM:
1. A pharmaceutical composition comprising repaglinide or salt thereof along with pharmaceutically acceptable excipients, wherein repaglinide has a particle size D90 of less than or equal to 50 microns.
2. A pharmaceutical composition, which comprises of granules of repaglinide or salt thereof along with pharmaceutically acceptable excipients.
3. A pharmaceutical composition, which comprises of granules of repaglinide or salt thereof along with pharmaceutically acceptable excipients, wherein
the granules of repaglinide or salt thereof along with other pharmaceutically acceptable excipients have bulk density of 0.3 to 1.0 g/cc.
4. A pharmaceutical composition of claim 1, 2 and 3 comprises one or more of a tablet, capsule, powder, disc, caplet, granule and pellet.
5. A pharmaceutical composition of claim 1, 2 and 3, wherein pharmaceutically acceptable excipients are binders, fillers, solubilizers, bases, lubricants, disintegrants, and glidants.
6. A pharmaceutical composition of claim 5, wherein binders are selected from a group comprising one or more of, povidone, starch, stearic acid, gums, celluloses and the like.
7. A pharmaceutical composition of claim 5, wherein fillers are selected from a group comprising one or more of, microcrystalline cellulose, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
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8. A pharmaceutical composition of claim 5, wherein solubilizers are selected from a group comprising one or more of, benzyl benzoate, cyclodextrins, glyceryl monostearates, poloxamers, sorbitan esters and the like.
9. A pharmaceutical composition of claim 5, wherein bases are selected a group comprising one or more of, hydroxides of alkali metals, diethanolamine, meglumine, lysine, arginine, ethanolamine, triethanolamine and the like.
10. A pharmaceutical composition of claim 5, wherein lubricants are selected from a group comprising one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate and the like.


Dated this 27th day of December, 2006

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