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: REPAGLINIDE COMPOSITIONS
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, which comprises of granules of repaglinide or salt thereof along with pharmaceutical acceptable excipients, wherein the granules of repaglinide or salt thereof along with other pharmaceutical acceptable excipients are prepared by dry granulation method.
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, 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 are prepared by dry granulation method.
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 O4 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.
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US Application 2004102477 (the '477 application) describe crystalline form II, III and amorphous form of S-repaglinide.
The present inventors have noticed that repaglinide poses stability problem i.e. there is a significant increase in impurities irrespective of whether the method used is aqueous or non-aqueous wet granulation.
The present inventors have now surprisingly found, when repaglinide tablets are prepared by dry granulation technique, it results in improved stability of the product. The tablets prepared by this method have controlled total impurities and individual impurities.
One of the aspects of the present invention provides 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 are prepared by dry granulation method.
In yet another aspect of the present invention there is provided a process of preparing pharmaceutical composition, wherein the process comprises of
a) dry mixing repaglinide or salt thereof with other pharmaceutically acceptable excipients to form a premix;
b) compacting the premix formed in step (a), optionally in the presence of one or more excipients to form flakes; and
c) breaking the flakes formed in step (b), optionally in the presence of one or more excipients, to form granules;
d) lubricating the granules formed in step (c), optionally in the presence of one or more excipients, to form a pharmaceutical composition.
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 (0.5mq).

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, which comprises of granules of repaglinide or salt thereof along with pharmaceutically acceptable excipients, wherein granules of repaglinide or salt thereof along with pharmaceutically acceptable excipients are prepared by dry granulation method.
2. A process of preparing pharmaceutical composition, wherein the process comprises of

a) dry mixing repaglinide or salt thereof with other pharmaceutically acceptable excipients to form a premix;
b) compacting the premix formed in step (a), optionally in the presence of one or more excipients to form flakes; and
c) breaking the flakes formed in step (b), optionally I the presence of one or more excipients, to form granules;
d) lubricating the granules formed in step (c), optionally in the presence of one or more excipients, to form a pharmaceutical composition.

3. A pharmaceutical composition of claim 1 and 2 comprises one or more of a tablet, capsule, powder, disc, caplet, granule and pellet.
4. A pharmaceutical composition of claim 1 and 2, wherein pharmaceutically acceptable excipients are binders, fillers, solubilizers, bases, lubricants, disintegrants, and glidants.
5. A pharmaceutical composition of claim 4, wherein binders are selected from a group comprising one or more of, povidone, starch, stearic acid, gums, celluloses and the like.
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6. A pharmaceutical composition of claim 4, 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.
7. A pharmaceutical composition of claim 4, wherein solubilizers are selected from a group comprising one or more of, benzyl benzoate, cyclodextrins, glyceryl monostearates, poloxamers, sorbitan esters and the like.
8. A pharmaceutical composition of claim 4, wherein bases are selected a group comprising one or more of, hydroxides of alkali metals, diethanolamine, meglumine, lysine, arginine, ethanolamine, triethanolamine and the like.
9. A pharmaceutical composition of claim 4, 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 22TH day of December, 2006

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