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 DOSAGE FORM COMPRISING COMBINATION OF
GLIMEPIRIDE AND METFORMIN
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 solid oral dosage form comprising a
combination of antidiabetic agents, glimepiride and metformin or
pharmaceutically acceptable salt thereof wherein the metformin is present in
an extended release form and glimepiride is present in an immediate release
form.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention provides a solid oral dosage form comprising a combination of antidiabetic agents, glimepiride and metformin or pharmaceutically acceptable salt thereof wherein the metformin is present in an extended release form and glimepiride is present in an immediate release form.

Glimepiride is an oral blood-glucose-lowering drug of the sulfonylurea class. Glimepiride chemically is 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea of Formula 1. Glimepiride is indicated as an adjunct to diet and exercise to lower the blood glucose in patients with noninsulin-dependent (Type 2) diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled by diet and exercise alone. Glimepiride may be used concomitantly with metformin when diet, exercise, and glimepiride or metformin alone do not result in adequate glycemic control. Glimepiride is also indicated for use in combination with insulin to lower blood glucose in patients whose hyperglycemia cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent. Combined use of glimepiride and insulin may increase the potential for hypoglycemia.

Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride chemically is, (N,N-dimethylimidodicarbonimidicdiamide monohydrochloride) of formula 2 and is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or (alpha)-glucosidase inhibitors. Metformin hydrochloride is indicated as an adjunct to diet and exercise to lower blood glucose. It can be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults.


US Patent No 6,284,275, and US Patent No 6,099,862, both describe a combination for the simultaneous controlled release of a biguanide and a sulfonylurea. The composition comprises a core containing the two active agents along with other excipients and a semipermeable controlled release coating from which the release of the active agents is controlled by the presence of at least one passageway in the coat.
US Application No 20060002998 disclose a solid pharmaceutical dosage form for oral administration comprising an extended release layer comprising a biguanide and an immediate release layer comprising sulfonylurea such that a seal coat is present between an immediate release layer and an extended release layer.
US Application No 20040086562 disclose a method of administration of two or more therapeutically active agents comprising orally administering to a patient a spaced drug delivery system wherein at least one therapeutically active agent is released immediately upon oral administration of the spaced drug delivery system, and at least one second therapeutically active agent is released as a pulse at a predetermined time after oral administration.
PCT Patent Application WO2005/102273 discloses a pharmaceutical dosage form comprising a biguanide, one or more rate controlling polymers and one or more pharmaceutically acceptable excipients; and an immediate release core comprising a sulfonylurea and one or more pharmaceutically acceptable excipients, wherein the immediate release core is covered by the extended release portion from all sides except one surface.
Diabetes mellitus is a term generally used to refer a metabolic disorder characterized by hyperglycemia, which occurs due to insulin deficiency, insulin resistance and reduced glucose tolerance. There are two main groups of oral antidiabetic drugs available, sulfonylureas and biguanidines. The use of sulfonylureas in treating type 2 diabetes is established as an effective means of
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controlling hypoglycemia. Sulfonylureas act by stimulating insulin release and are thus only effective with some residual pancreatic beta-cell activity. Glimepiride is the drug of sulphonylurea class. Biguanide metformin acts by decreasing gluconeogenesis and by increasing peripheral utilization of glucose, and as they require endogenous islet cell activity.
However, most of the type 2 diabetes patients treated with only sulfonylureas do not succeed in bringing their glucose level to normal, and need to complement their treatment with a second agent, and a combined tablet would be an advantage. On the other hand it has been found that combining glimepiride and metformin is more effective than monotherapy with either of the two medications.
The present invention now relates to pharmaceutical composition for oral administration in the form of solid unit dosage form comprising a combination of glimepiride and metformin hydrochloride such that metformin is present in an extended release form and glimepiride is present in an immediate release form. Glimepiride is used in the form of complex with beta-cyclodextrin, which helps to increase its aqueous solubility and further it releases immediately upon ingestion. Metformin is present in an extended release form so that it is released in a sustained fashion over a period of time.
In one of the aspects of the present invention there is provided a solid pharmaceutical dosage form for oral administration comprising:
a) an immediate release layer comprising glimepiride; and
b) an extended release core comprising metformin or pharmaceutical^ acceptable salt thereof;
wherein the glimepiride is present in the form of complex with cyclodextrins or derivatives thereof.
The therapeutically effective amount of glimepiride and metformin hydrochloride is included in this combination. The pharmaceutical compositions comprising the
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glimepiride and metformin hydrochloride disclosed herein are administered orally. The extended release layer may be a core and the immediate release layer covers at least a portion of the core. The dosage form may be a bilayered dosage form. The combination can be employed in admixture with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant, sweetener, polymers, coloring and flavoring agent, glidant and the like. Suitable diluents include pharmaceutically acceptable inert fillers, such as one or more of microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, dextrose, maltodextrin and mixtures thereof. Suitable binders may include one or more of polyvinyl pyrrolidone, lactose, starches, gums, waxes, gelatin, polymers and mixtures thereof. Suitable lubricants include one or more of colloidal silicon dioxide, talc, stearic acid, magnesium stearate, magnesium silicate, polyethylene, sodium benzoate, sodium lauryl sulphate, fumaric acid, zinc stearate, paraffin, and mixtures thereof. Suitable glidants include, for example, one or more of talc or magnesium stearate and colloidal silicon dioxide. Suitable coloring and flavoring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those skilled in the art.
Glimepiride has poor aqueous solubility and slow dissolution rate which leads to irreproducible clinical response or therapeutic failure in some cases due to subtherapeutic plasma drug levels. Complexation of glimepiride with cyclodextrins or derivatives thereof leads to great enhancement in dissolution rate, increased duration of action and improvement of therapeutic efficacy of the drug. Suitable cyclodextrin derivatives may be selected from hydroxypropyl-p-cyclodextrin, (3-cyclodextrin, a-cyclodextrin, hydroxypropyl- a -cyclodextrin and the like.
The dosage form can be prepared by direct compression, dry granulation or by wet granulation. The extended release layer may be prepared by wet granulation
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method. Metformin hydrochloride, Sodium carboxy methylcellulose, Hydroxypropyl methylcellulose K-100 M, Microcrystalline cellulose and Povidone K-30 were sifted through suitable sieve and mixed properly. Aqueous gelatin solution was used as binder and granules were prepared. These granules were dried and lubricated with magnesium stearate and compressed.
The immediate release layer may be prepared by mixing glimepiride, beta-cyclodextrin, lactose monohydrate, and red iron oxide in a suitable mixer. Povidone K-30 was dissolved in isopropyl alcohol and this solution was used as binder. Granules were prepared, dried and mixed with sodium starch glycolate, microcrystalline cellulose. Further these granules were lubricated with magnesium stearate and compressed.
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.
EXAMPLES
The composition of the batches is provided in Table 1 and 2. Table 1 - Glimepiride (Immediate release layer)

Sr. No Ingredients Example 1 Example 2
Quantity /Tablet inmg Quantity /Tablet inmg
1. Glimepiride 1.000 2.000
2. Beta-cyclodextrin 21.640 21.640
3. Lactose monohydrate 302.08 301.08
4. Povidone K-30 8.000 8.000

5. Iron oxide red 0.200 0.200
6. Isopropyl alcohol q.s. q.s.
7. Microcrystalline cellulose (AvicelPH101) 47.040 47.040
8. Sodium starch glycolate (Type A) 16.040 16.040
9. Magnesium stearate 4.000 4.000
Table 2 - Metformin hydrochloride (Extended release layer)

Sr. No. ingredients Example 1 Example 2
Quantity /Tablet inmg Quantity /Tablet inmg
1 Metformin Hydrochloride 500.000 500.000
2 Microcrystalline Cellulose 100.000 100.000
3 Magnesium Stearate 10.000 10.000
4 Sodium carboxy methylcelluloseHigh viscosity App 20,000cps of 2% solution 110.000 110.000
5 Hydroxypropyl methylcellulose K-100 M 200.000 200.000
6 Gelatin (160-180 bloom) soft gelatin capsules grade 40.000 40.000
7 Povidone K-30 40.000 40.000
8 Purified water
Procedure for the preparation of Immediate Release Layer -
1. Glimepiride, beta-cyclodextrin, lactose monohydrate, and red iron oxide were mixed geometrically and passed through #40.

2. Povidone K-30 was dissolved in isopropyl alcohol and this solution was used as binder.
3. This binder solution was added slowly to the above blend and granules were prepared using rapid mixer granulator.
4. Granules were dried using fluid bed drier at 55°C±5°C. Loss on drying was NMT 2.0%.
5. Dried granules were mixed with sodium starch glycolate and microcrystalline cellulose using stainless steel double cone blender for 5minutes.
6. Further magnesium stearate was added as lubricant and granules were lubricated.
7. Tablets were compressed using rotary tablet machine.
Procedure for the preparation of Extended Release Layer -
1. Metformin hydrochloride, sodium carboxy methylcellulose K-100 M, microcrystalline cellulose and povidone K-30 were sifted through a suitable sieve and mixed properly.
2. Gelatin was soaked in water for 1.30 hours, boiled and cooled to 50-60°C and this solution was used as binder.
3. This binder solution was added slowly to the above blend and granules were prepared using rapid mixer granulator.
4. Granules were dried using fluid bed drier at 55°C±5°C. Loss on drying was NMT 3.2%.
5. Further magnesium stearate was added as lubricant and granules were lubricated.
6. Tablets were compressed using rotary tablet machine.
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WE CLAIM:
1. A solid pharmaceutical dosage form for oral administration comprising:
a) an immediate release layer comprising glimepiride; and
b) an extended release core comprising metformin or pharmaceutically acceptable salt thereof;
wherein the glimepiride is present in the form of complex with cyclodextrins or derivatives thereof.
2. A dosage form of claim 1, wherein the cyclodextrin is p-cyclodextrin.
3. A dosage form of claim 1, wherein the immediate release outer layer comprises film forming polymers and optionally other pharmaceutically acceptable excipients.
4. A dosage form of claim 1, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, binders, plasticizers, opacifiers and colorants.
5. A dosage form of claim 1, wherein the diluent is selected from pharmaceutically acceptable inert filler, such as one or more of microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, maltodextrin and mixtures thereof.
6. A dosage form of claim 1, wherein the binder is selected from one or more of polyvinyl pyrrolidone, lactose, starches, gums, waxes, gelatin and mixtures thereof.
7. A dosage form of claim 1, wherein the extended release layer comprises rate-controlling polymers along with some other suitable excipients.
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8. A dosage form of claim 1, wherein the rate controlling polymer is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, waxes and the like.
9. A dosage form of claim 1 is layered tablet.
10. A dosage form of claim 1, comprising metformin hydrochloride and
glimepiride in a weight ratio of 500:1.

Dated this 28TH day of June, 2006

For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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