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:
SOLID ORAL DOSAGE FORM COMPRISING COMBINATION OF PIOGLITAZONE 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, pioglitazone or pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salt thereof wherein the metformin is present in an extended release form and pioglitazone is present in an immediate release form.
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 solid oral dosage form comprising a combination of antidiabetic agents, pioglitazone or pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salt thereof wherein the metformin is present in an extended release form and pioglitazone is present in an immediate release form.
Pioglitazone hydrochloride is an oral antihyperglycemic agent that acts primarily
by decreasing insulin resistance. Pioglitazone is used in the management of type
2 diabetes. Pharmacological studies indicate that pioglitazone improves
sensitivity to insulin in muscle and adipose tissue and inhibits hepatic
gluconeogenesis. Pioglitazone improves glycemic control while reducing
circulating insulin levels. Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-
pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride of formula 1 belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, biguanides, or the a-glucosidase inhibitors. The molecule contains one asymmetric center, and the synthetic compound is a racemate. The two enantiomers of pioglitazone interconvert in vivo.

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
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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.
PCT Application No. WO 2003005995 discloses a core formulation comprising pioglitazone hydrochloride or pharmaceutically acceptable salt thereof as an active ingredient, a core, at least a portion of which is enclosed by said first layer,
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comprising a biguanide as an active ingredient; and a modulating polymer comprising a silicate which is associated with at least one of said active ingredients.
Diabetes mellitus is a medical disorder characterized by varying or persistent hyperglycemia (high blood sugar levels) resulting from the defective secretion or action of the hormone insulin. A major feature of type 2 diabetes is a lack of sensitivity to insulin by the cells of the body, particularly fat and muscle cells. Thus, larger quantities of insulin are produced as an attempt to get these cells to recognize that insulin is, in fact, present. In addition to the problems with an increase in insulin resistance, the release of insulin by the pancreas may also be defective and suboptimal. In fact, there is a known steady decline in beta cell production of insulin in type 2 diabetes that contributes to worsening glucose control. Finally, the liver in these patients continues to produce glucose through a process called gluconeogenesis despite elevated glucose levels. This control of gluconeogenesis becomes compromised.
There are two major classes of oral antidiabetic drugs available, thiazolidinediones (TZDs) and biguanidines. The thiazolidinediones (TZDs) or '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. Pioglitazone is a drug of thiazolidinedione class. Pioglitazone acts by increasing the sensitivity (responsiveness) of cells to insulin. It improves sensitivity to insulin in muscle and fat tissue. These drugs have been effective in lowering blood sugars in patients with type 2 diabetes
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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 pioglitazone-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 pioglitazone or pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salt thereof such that metformin is present in an extended release form and pioglitazone 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.
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 pioglitazone 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 pioglitazone hydrochloride and metformin hydrochloride is included in this combination. The pharmaceutical compositions containing the pioglitazone and metformin hydrochloride disclosed herein are
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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.
The combination can be employed in admixture with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant, sweetener, coloring and flavoring agent, glidant, rate controlling polymers 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.
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 the process comprises of mixing pioglitazone or salt thereof with lactose monohydrate, granulating it with aqueous solution of hydroxypropyl cellulose,
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drying the granules, mixing it with carboxy methylcellulose calcium and colloidal silicon dioxide, further lubricating with magnesium stearate and compressing into tablets.
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.
Table1-Pioglitazone hydrochloride (Immediate release layer)

Sr. No. Ingredients Example 1 Example 2
Quantity / Tablet in mg Quantity / Tablet in mg
1. Pioglitazone hydrochloride 16.540 33.080
2. Lactose monohydrate 366.380 349.840
3. Hydroxypropyl cellulose (Klucel-LF) 4.000 4.000
4. Iron oxide red 0.400 0.400
5. Carboxymethyl cellulose calcium 8.000 2.00
6. Colloidal silicon dioxide (Aerosil-200) 2.000 0.500
7. Magnesium stearate 2.680 0.67
8. Purified water q. s. q. s.
Total 400.000 400.000
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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 methylcellulose(High 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 - - - - - - - - -
Total 1000.00
Process for preparing Immediate release layer-
1) Pioglitazone hydrochloride, lactose monohydrate and yellow iron oxide were passed through # 40 and mixed geometrically.
2) Hydroxy propyl cellulose (Klucel-LF) was dissolved in purified water and this solution was 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) Carboxy methylcellulose calcium and colloidal silicon dioxide were added to the dried granules and granules were lubricated with magnesium stearate.
6) Lubricated granules were further compressed into tablets.
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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.
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WE CLAIM:
1. A solid dosage form for oral administration comprising:
a) a controlled release core comprising metformin or pharmaceutically
acceptable salt thereof along with pharmaceutically acceptable
excipients;
b) an immediate release layer comprising pioglitazone or pharmaceutically
acceptable salt thereof as an active ingredient along with
pharmaceutically acceptable excipients;
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 pioglitazone is present in the form of pioglitazone hydrochloride.
4. A dosage form according to claim 1, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, binders, lubricants, glidants and colorants.
5. A dosage form according to claim 1, wherein the diluent is selected from pharmaceutically acceptable inert filler, such as one or more of carboxy methylcellulose calcium, microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, maltodextrin and mixtures thereof.
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6. 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.
7. 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.
8. A dosage form according to claim 1, wherein the metformin or salt thereof and pioglitazone or salt thereof is present in therapeutically effective amount.
Dated this 28TH day of June, 2006 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory

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