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:
NOVEL PHARMACEUTICAL FORMULATION COMPRISING
COMBINATION OF ROSIGLITAZONE 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, rosiglitazone or pharmaceutically
acceptable salt thereof and metformin or pharmaceutically acceptable salt
thereof wherein the metformin is present in an extended release form and
rosiglitazone 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, rosiglitazone or pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salt thereof wherein the metformin is present in an extended release form and rosiglitazone is present in an immediate release form.

Rosiglitazone maleate is an oral antidiabetic agent, which acts primarily by increasing insulin sensitivity. Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione,(Z)-2-butenedioate (1:1) of formula 1. Rosiglitazone improves glycemic control while reducing circulating insulin levels. Pharmacologic studies in animal models indicate that rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the a-glucosidase inhibitors.

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 Application 20040106660 disclose a pharmaceutical dosage form comprising and antihyperglycemic drug and at least one pharmaceutically acceptable excipient, a seal coat applied to the controlled release core and an immediate release thiazolidinedione derivative containing coating applied to the seal coating.
US Application 20050226928 disclose pharmaceutical dosage form comprising a controlled release core comprising an antihyperglycemic drug and at least one pharmaceutically acceptable excipient and an immediate release thiazolidinedione derivative and a low viscosity water-soluble binder wherein not less than 85% of the thiazolidinedione is released from the dosage form within 45 minutes when tested according to United States Pharmacopoeia 26, with Apparatus 1 at 100 rpm, 37°C and 900ml of 0.3M KCI-HCI Buffer, pH 2.0.
US Patent No. 6,166,042 discloses a method for treating glycometabolism disorders in a mammal comprising administering to a mammal a therapeutically effective amount of an insulin sensitivity enhancer in combination with a biguanide.
Diabetes is a chronic disease with diverse pathologic manifestations and is accompanied by lipid metabolism disorders and circulatory disorders as well as glycometabolism disorders. As the results, diabetes tends to progress entailing various complications in many cases. Therefore, it is necessary to select the drug of choice for the prevailing disease state in each individual case. However, this selection is often difficult in clinical settings because single use of each individual drug cannot bring sufficient effects in some disease states and there are various problems such as side effect which is caused by an increased dose or a long-term administration.
There are two major classes of oral antidiabetic drugs available, thiazolidinediones (TZDs) and biguanidines. The thiazolidinediones (TZDs) or
3

'glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma), a nuclear receptor. Rosiglitazone is a drug of thiazolidinedione class. Metformin is the drug of biguanide class and act by decreasing gluconeogenesis and by increasing peripheral utilization of glucose, and as they require endogenous islet cell activity.
When biguanides and thiazolidinediones were combined together, they work by decreasing the liver's production of glucose, decreasing the small intestines' absorption of glucose, improving body's ability to use insulin, and by improving body's insulin sensitivity. Thus rosiglitazone-metformin combination has been demonstrated to be synergistic when compared with the use of individual agents separately.
The present invention now relates to pharmaceutical composition for oral administration in the form of a single unit dosage form comprising combination of rosiglitazone or pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salt thereof such that metformin is present in an extended release form and rosiglitazone is present in an immediate release form. The two layers are present without any separating layer or seal coat in between the immediate release layer and the extended release layer. Sodium starch glycolate was used as superdisintegrant in the immediate release layer both intragranularly and extragranularly which helps in fast disintegration and in turn fast dissolution of the active ingredient.
4

In one of the aspects of the present invention there is provided a solid dosage form for oral administration comprising:
a) a controlled release core comprising metformin or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable excipient;
b) an immediate release layer comprising rosiglitazone or pharmaceutically acceptable salt thereof as an active ingredient,
wherein the said immediate release layer and the said extended release layer are further compressed into layered dosage form without any intermediate layer or seal coat in between the two layers.
The therapeutically effective amount of rosiglitazone maleate and metformin hydrochloride is included in this combination. The pharmaceutical compositions containing the rosiglitazone 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 formulated without any separating layer in between the two active layers. Use of superdisintegrants both intra and extragranularly such as sodium starch glycolate helps in immediate disintegration and further fast release of the active ingredients from the immediate release layer.
The combination can be employed in admixture with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients can be diluent, superdisintegrant, filler, binder, lubricant, sweetener, coloring and flavoring agent, glidant, rate controlling polymers and the like. Suitable superdisintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone 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
5

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.
The dosage form can be prepared by direct compression, dry granulation or by wet granulation or other processes known in the art. The extended release layer may be prepared by wet granulation method and the process comprises of mixing of all the ingredients including active ingredient, preparation of aqueous gelatin solution for use as a binder, granulating the above mix, drying the granules, lubricating with suitable lubricant followed by compression.
The immediate release layer may be prepared by wet granulation method and comprises of mixing of active ingredient, superdisintegrant along with other excipients, granulating the mix with aqueous hypromellose E-5 solution, drying the granules with the help of fluid bed drier, mixing these dried granules with superdisintegrant, microcrystalline cellulose and lubricant followed by compression.
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 - Rosiglitazone maleate (Immediate release layer)
6

Example 1 Example 2
Sr. No. Ingredients Quantity / Tablet in mg Quantity / Tablet in mg
1. Rosiglitazone Maleate 2.800 5.600
2. Sodium starch glycolate (Type A) 10.000 10.000
3. Lactose monohydrate 333.000 330.200
1. Hypromellose (E-5) 6.400 6.400
2. Iron oxide yellow 0.400 0.400
3. Purified water q.s. q.s.
4. Microcrystalline cellulose (Avicel PH101) 34.720 34.720
5. Sodium starch glycolate (Type A) 10.000 10.000
6. Magnesium stearate 2.680 2.680
Total 400.000 400.000
Table 2 - Metformin hydrochloride (Extended release layer)

Sr. No. Ingredients Quantity / Tablet in mg
1 Metformin Hydrochloride 500.000
2 Microcrystalline Cellulose 100.000
3 Magnesium Stearate 10.000
4 Sodium carboxy methylcelluloseHigh viscosity App 20,000cps of 2% solution 110.000
5 Hydroxypropyl methylcellulose K-100 M 200.000

6 Gelatin (160-180 bloom) soft gelatin capsules grade 40.000
7 Povidone K-30 40.000
8 Purified water

Process for preparing Immediate release layer-
1) Rosiglitazone maleate, lactose monohydrate, sodium starch glycolate and yellow iron oxide were passed through # 40 and mixed geometrically hgddfbdfgeometricageometrically.
2) Hypromellose E-5 was dissolved in purified water and this solution used as binder.
3) Above blend was transferred to rapid mixer granulator and binder was
added slowly to the blend, granulated the mixture properly for 5.0 minutes.
4) Granules were dried using fluidized bed drier at 55±5°C.
5) Sodium starch glycolate, microcrystalline cellulose were added to the dried granules and granules were lubricated with magnesium stearate.
6) Lubricated granules were further compressed into tablets.
Process for preparing Extended release layer-
1) Metformin hydrochloride, sodium carboxymethyl cellulose, hydroxypropyl
methylcellulose K-100 M, microcrystalline cellulose and povidone K-30 were sifted through a sieve and mixed properly.
2) Gelatin was soaked in water, boiled, cooled to 50 to 60°C and this solution
was used as binder for the preparation of granules.
3) Binder solution was added slowly to above blend and granules were
prepared.
4) Granules were dried in the fluid bed drier at 60°C.
5) Further these granules were mixed with magnesium stearate, and compressed into tablets on rotary machine.

WE CLAIM:
1. A solid dosage form for oral administration comprising:
c) a controlled release core comprising metformin or pharmaceutical^ acceptable salt thereof along with pharmaceutically acceptable excipient;
d) an immediate release layer comprising rosiglitazone or pharmaceutically acceptable salt thereof as an active ingredient along with pharmaceutically acceptable excipient,
wherein the said immediate release layer and the said extended release layer are further compressed into layered dosage form without any intermediate layer or seal coat in between the two layers.
2. A dosage form according to claim 1, wherein the metformin is present in the form of metformin hydrochloride.
3. A dosage form according to claim 1, wherein the rosiglitazone is present in the form of rosiglitazone maleate.

4. A dosage form according to claim 1, wherein the immediate release layer further comprises of superdisintegrant.
5. A dosage form according to claim 4, wherein the superdisintegrant is selected from sodium starch glycolate, croscarmellose sodium, crospovidone and the like.

6. A dosage form according to claim 1, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, binders, plasticizers, opacifiers and colorants.
7. A dosage form according to claim 1, wherein the diluent is selected from pharmaceutically acceptable inert filler, such as one or more of microcrystalline
9

cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, maltodextrin and mixtures thereof.
8. A dosage form according to claim 1, wherein the binder is selected from one or more of polyvinyl pyrrolidone, lactose, starches, gums, waxes, gelatin and mixtures thereof.
9. A dosage form according to claim 1, wherein the composition is selected from a group consisting of a tablet, caplet, capsule and a granular form.
Dated this 28TH day of June, 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
10