FIELD OF INVENTION

The invention relates to controlled release compositions comprising metformin or its pharmaceutically acceptable salts in combination with pioglitazone or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient and to their process of preparation.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Metformin, chemically known as N, 7V-dimethylimidodicarbonimidic diamide, is disclosed in U.S. Patent No. 3,174,901. It is used as a first-line drug for the treatment of Type 2 diabetes. It is basically marketed in high strength such as 500, 750, 850 and 1000 mg strengths and used once or twice daily due to its short half-life. It can be marketed in single as well as in combination with other antidiabetic drugs for the treatment of type 2 diabetes.

Metformin is commercially available under the trade name GLUCOPHAGE™ in the form of oral tablet as well as GLUMETZA™ in the form of extended release tablet in the U.S.

Pioglitazone belongs to a class of thiazolidinedione (TZD) with hypoglycemic action. Chemically, it is known as (/?S)-5-(4-[2-(5-ethylpyridin-2-yl) ethoxy] benzyl) thiazolidine-2, 4-dione and is disclosed in U.S. Patent No 4,687,777.

Pioglitazone is commercially available under the trade names "Actos" in the USA and UK, "Glustin" in Europe,"Glizone" and "Pioz" in India by Zydus and USV respectively and "Zactos" in Mexico by Takeda

A combination of metformin extended release and pioglitazone is commercially marketed in the US under the trade name ActoplusMet XR as an oral tablet containing dose strength of 1000/30mg and 1000/15mg in order to help for the treatment of Type 2 diabetes.

Several prior arts, disclosing compositions comprising combination of metformin and pioglitazone, are discussed below.

US 6,099,859 discloses a controlled release antihyperglycemic tablet comprising a core containing the antihyperglycemic drug with semi-permeable membrane coating having at least one passage-way.

US 2009/0246232 discloses pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with other antidiabetics differing from the enhancer in the mechanism of action, which shows a potent depressive effect on diabetic hyperglycemia and is useful for prophylaxis and treatment of diabetes.

US 2005/0226928, US 2004/0106660 and US 2005/0249809 disclose a pharmaceutical dosage form comprising an antihyperglycemic drug and thiazolidinedione derivative. Preferably an osmotic tablet, with or without a gelling or expanding polymer.

WO 99/47125 and US 6,099,862 relate to a controlled release pharmaceutical tablet containing antihyperglycemic drug and a hypoglycemic drug that does not contain an expanding or gelling polymer layer and comprising a core containing the antihyperglycemic drug and the hypoglycemic drug, a semi¬permeable coating membrane surrounding the core and at least one passage-way in the membrane to allow the drugs to be released from the core.

The above prior art references disclose various controlled release compositions comprising combination of metformin and pioglitazone in the form of osmotic tablet suitable for oral administration typically consisting of a tablet core that is coated with a semi-permeable membrane and having a passage-way drilled on it by means of a laser beam or other suitable technique. The rate at which the core absorbs water depends on the osmotic pressure generated by the core components and the permeability of the membrane coating. As the core absorbs water, it expands in volume, which pushes the drug solution or suspension out of the
tablet through the passage-way.

The drilling of passage-way in semi-permeable membrane is conventionally carried out as a separate step, using laser beams or high speed mechanical drills. The release of drug from the dosage form depends on the size of the passage-way. It is difficult to get uniform and centered passage-ways always. Moreover, the mechanical or laser drilling technique involves separate equipments which is quite expensive.

To obviate the need for complicated laser drilling, the inventors of the invention have successfully developed a controlled release composition in the form of a tablet comprising a combination of metformin in an extended release form and pioglitazone in an immediate release form, wherein the tablet is devoid of any passage-way in the semi-permeable membrane coating enveloping said metformin or anywhere on the coated tablet and further said tablet is bioequivalent to the commercially available ActoplusMet XR™.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to controlled release compositions comprising metformin or its pharmaceutically acceptable salts in combination with pioglitazone or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient and to their process of preparation

Particularly, the invention relates to controlled release compositions comprising a combination of metformin and pioglitazone, wherein the composition preferably in the form of a tablet is devoid of any passage.

In an embodiment of the invention, the controlled release compositions comprising a combination of metformin and pioglitazone, wherein metformin composition is in the form of controlled release core, preferably an osmotic tablet, coated with pioglitazone dispersion.

In an embodiment of the invention, there is provided controlled release compositions comprising a combination of metformin and pioglitazone, wherein metformin is present in a controlled release form while pioglitazone is present in an immediate release form.

In an embodiment of the invention, there is provided a process for preparing controlled release compositions comprising a combination of metformin and pioglitazone, wherein the composition, preferably in the form of a tablet is devoid of any passage-way.

Yet another objective of the invention is to provide controlled release compositions comprising a combination of metformin and pioglitazone, wherein the composition, preferably in the form of a tablet is devoid of any passage-way; and said tablet is designed in such a way that it complies with the reference product ActoplusMet XR™ in terms of in vivo parameters like bioequivalence and in vitro parameters like dissolution.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to controlled release compositions comprising metformin or its pharmaceutically acceptable salts in combination with pioglitazone or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient and to their process of preparation

The invention relates to controlled release compositions in the form of a tablet comprising a combination of metformin hydrochloride and pioglitazone hydrochloride, wherein the tablet is devoid of any passage-way.

Preferably, the invention relates to controlled release compositions in form of tablets comprising a combination of metformin hydrochloride and pioglitazone hydrochloride, wherein the tablet is devoid of any passage-way.

More preferably, the invention relates to controlled release compositions in form of tablets comprising a combination of metformin and pioglitazone, wherein the core of metformin is surrounded by a semi-permeable membrane coating layer which is further coated with sustained release coating layer followed by a layer of pioglitazone, wherein said tablet is devoid of any passage-way.

Metformin as used in the invention includes metformin base and its pharmaceutically acceptable salts or its combinations thereof. Preferably metformin according to the invention is used in form of metformin hydrochloride.

Pioglitazone as used in the invention includes pioglitazone base and its pharmaceutically acceptable salts or its combinations thereof. Preferably pioglitazone according to the invention is used in form of pioglitazone hydrochloride.

"Pharmaceutical composition" as described herein, includes dosage forms such as tablets, osmotic tablets, mini-tablets, layered tablets, inlay tablets, coated tablets, capsules, pellets, beads, pills, powders, and granules. Preferably, it relates to a tablet or osmotic tablet.

The term "core" as used herein according to the invention implies a conventional monolithic or layered tablet which does not have any functional and/or aesthetic coating layer over it.

The term "passage-way" as used herein includes an aperture, orifice, bore, hole or a weaken area created within the semi-permeable membrane or any other coating layer over said semi-permeable membrane enveloping the tablet to allow the release of the drug from the tablet core.

In one embodiment, the tablet core includes metformin hydrochloride and one or more pharmaceutically acceptable excipients such as diluents, binding agent, lubricants and surfactant, wherein said tablet core is designed to release metformin in an extended release manner.

Binders used include, but are not limited to polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polymethacrylate, polyvinyl alcohol, waxes and the like. The preferred binding agents are water soluble materials such as polyvinyl pyrrolidone.

Surfactants used include, but are not limited to sodium lauryl sulfate, quaternary ammonium salts, polysorbates, sorbitan esters, poloxamer, betaines, higher fatty alcohols such as cetyl alcohol and oleyl alcohol and the like. The preferred surfactant is sodium lauryl sulfate.

Diluents used include, but are not limited to microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pre-gelatinized starch, mannitol, sorbitol, dextrate, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like.

Lubricants used include, but are not limited to magnesium stearate, sodium stearate, calcium stearate, sodium stearyl fumarate, talc or silica and the like.

Further, the tablet core is preferably coated with a polymeric coating to form a semi-permeable membrane enveloping/ surrounding said tablet completely which membrane is devoid of any passage-way.

The tablet core comprising metformin is surrounded by a semi-permeable membrane consisting of a semi-permeable membrane-forming polymer, flux enhancer, anti-tacking agents, and at least one plasticizer capable of improving film-forming properties of the polymers and again coated over with a pioglitazone drug layer.

The semi-permeable membrane surrounding the core can also include film forming agent and flux-enhancing agent. The flux enhancing agent can increase the volume of fluid imbibed into the core to enable the dosage form to dispense metformin through the porous membrane.

The film forming agents can be a water-soluble material or an enteric material. Examples of the preferred materials that are useful as film formers are selected from ethyl cellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acetate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate and cellulose acetate butyrate. A preferred film forming agent is cellulose acetate.

Flux enhancing agents used include, but are not limited to sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol and the like. A preferred flux-enhancing agent is polyethylene glycol.

The use of the plasticizer in combination with the film forming polymer to form the external membrane around the core of the tablet, results in a membrane which allows the water to be imbibed into the core of the tablet even in the absence of a passage-way. The semi-permeable membrane-forming polymer is permeable to aqueous fluids but substantially impermeable to the components of the core.

Plasticizers used include, but are not limited to triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyl oxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate and the like.

Anti-tacking agents used include, but are not limited to talc, colloidal silicon dioxide, titanium dioxide and the like.

Further, the tablet core with semi-permeable membrane is coated with a sustained release coating. The sustained release coating comprises an aqueous dispersion of a plasticized hydrophobic polymer selected from the group consisting of ethyl cellulose, a polymer or copolymer of acrylates or methacrylates, and a mixture thereof.

Further, the tablet core can optionally be coated with a film coat/seal coat, which provides an aesthetic appeal or can also provide some functional role such as moisture protection, taste masking or any interactions etc. The film/seal coat may comprise polymers such as cellulose derivatives such as one which is commercially available as Opadry™.

In another embodiment of the invention, pioglitazone is coated onto the semi-permeable membrane of tablet core, where in the pioglitazone coating should be applied as a solution or in dispersion form.

The pioglitazone coating solution or dispersion also contain a surfactant, filler, disintegrant, binder, pore former and other pharmaceutically acceptable excipients.

Pore forming agent used include, but are not limited to water-soluble material such as sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid copolymer, poloxamer and the like.

Suitable disintegrants include sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, starch, calcium carboxymethlycellulose, croscarmellose sodium and the like.

Although pharmaceutically acceptable coatings can be obtained when the pioglitazone coat is applied directly to the semi-permeable membrane of a tablet core, a preferred approach is to first coat the semi-permeable membrane with sustained release coat and a film/seal coat, prior to the application of the pioglitazone coating.

The tablet core imbibes aqueous fluids from the surrounding environment across the membrane and dissolves the drug. The pioglitazone layer is dissolved; water is then taken up through the membrane, which in turn dissolves the metformin and excipients in the core formulation. The dissolved metformin is released through the pores which are formed in the semi-permeable membrane insitu. The rate of drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane.

In yet another embodiment, the invention relates to a process for preparing controlled release compositions in form of tablets comprising a combination of metformin and pioglitazone, wherein the tablet is devoid of any passage-way. The process in general involves the following basic steps:

i. preparing a core comprising metformin and one or more pharmaceutically acceptable excipients;

ii. over-coating said core of step i with a semi-permeable membrane;

iii. over-coating said semi-permeable membrane of step ii with a sustained release coat; which is optionally followed by seal coat layer;

iv. over-coating said sustained release coated core of step iii with a drug layer comprising pioglitazone and one or more pharmaceutically acceptable excipients. v. optionally a seal coating layer over said drug layer.

More preferably, in another embodiment, the invention relates to a process for preparing a controlled release tablet comprising a combination of metformin and pioglitazone, wherein said tablet is devoid of any passage-way. Said process involves the following detailed steps:

A) Tablet core is prepared as follows:
1. Sifting and mixing metformin hydrochloride and one or more pharmaceutically acceptable excipients in a top spray granulator;
2. Granulating the mixture of step 1 using a binder solution;
3. Drying granules obtained in step 2;
4. Blending granules of step 3 with extra granular excipients;
5. Compressing the blend of step 4 to obtain tablets comprising metformin hydrochloride;

B) Semi-permeable membrane coating:

6. Dissolving cellulose acetate in acetone;
7. Dispersing talc and dissolving polyethylene glycol, triacetin in purified water;
8. Adding the aqueous phase of step no. 7 into the content of step no. 6 and stirring to get uniform dispersion;
9. Coating the core tablet of step no 5 with the dispersion of step no. 8 in automatic coating machine till the desired weight build up is achieved;

Q Sustained release coating:

10. Dissolving hydroxypropyl methylcellulose in purified water;
11. Dispersing talc and dissolving polyethylene glycol in purified water;
12. Adding the aqueous phase of step no. 10 into the content of step no. 11 and stir to get uniform dispersion;
13. Adding the dispersion of methacrylic acid copolymer type C into the content of step no. 12 and stirring to get uniform dispersion;
14. Coating the semi-permeable membrane coated tablets of step no. 9 with the dispersion of step no. 13 in automatic coating machine till the desired weight build up is achieved;

D) Film/seal coating:

15. Dissolving and dispersing Opadry™ in purified water with stirring;
16. Coating the sustained release coated tablets of step no. 14 with the dispersion of step no. 15 in automatic coating machine till the desired weight build up is achieved;

E) Pioglitazone coating:

17. Dissolving and dispersing mannitol, polyethylene glycol, hydroxypropyl methylcellulose, sodium chloride, crospovidone and polysorbate 80 in purified water with stirring;
18. Dispersing pioglitazone HC1 into the content of step no. 17 and stirring to get uniform dispersion;
19. Coating the film coated tablets of step no. 16 with the dispersion of step no. 18 in an automatic coating machine till the desired weight build up is achieved.

The following examples illustrate specific aspects and some embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and is not intended to limit the scope of the invention in any manner.

Example-1

Brief Manufacturing Process:

A. Core:

1. Delump and Sift the Metformin Hydrochloride and Lactose monohydrate through Quadro-co-mill / mechanical sifter fitted with suitable screen.

2. Dissolve Povidone in Isopropyl alcohol using pneumatic stirrer, till a clear solution is formed.

3. Disperse Sodium lauryl sulphate in the solution of Step 2 using pneumatic stirrer till a uniform dispersion is formed.

4. Load the material of step 1 in to bowel of top spray granulator.

5. Granulate the material of step 4 using binder solution of step 3 in top spray granulator. An additional quantity of purified water is sprayed to get suitable granules.

6. Dry the wet granules of step 5 at 40°C - 60°C to achieve the LOD of NMT 2.5% (IR moisture balance at 105°C).

7. Sift the dried granules of step 6 through Quadro-co-mill / mechanical sifter fitted with suitable screen.

8. Blend the material of Step 7 along with the Magnesium stearate in bin blender.

9. If lumps were observed in blend before compression, delump with sifting through vibro sifter fitted with suitable mesh.

10. Compress the blend of step 9 into tablet.

B. Semi-Permeable membrane coating:

11. Dissolve cellulose acetate in acetone using pneumatic stirrer till a clear solution is formed.

12. Dissolve polyethylene glycol in purified water using stirrer still a clear solution is formed.

13. Add solution of step 12 to solution of step 11 under continuous stirring using pneumatic stirrer till a Clear solution is formed.

14. Add Triacetin to solution of step 13 under continuous stirring using pneumatic stirrer till a Clear solution is formed.

15. To the resulting solution of step 13 add Talc under continuous stirring using pneumatic stirrer till a uniform dispersion is formed.

16. Coat the core tablets of step 10 with coating dispersion of step 15 in automatic coating machine, till the desired weight build up is obtained.

C. SR Coating:

17. Dissolve Hydroxypropyl Methyl Cellulose in purified water under continuous stirring still a clear solution is formed.

18. Add polyethylene glycol and Talc to solution of step 17 under continuous stirring using pneumatic stirrer till a uniform dispersion is formed.

19. Take Methacrylic Acid Copolymer Dispersion and filter through suitable mesh or screen and add the dispersion of step
18 under continuous stirring using pneumatic stirrer till a uniform dispersion is formed.

20. Coat the PM coated tablets of step 16 with coating dispersion of step 19 in automatic coating machine, till the desired weight build up is obtained

D. Film coating 1:

21. Disperse Opadry clear YS-1-7006 into purified water under continues stirring and coat the tablet of step 20 in automatic coating machine, till the desired weight build up is obtained.

E. Pioglitazone coating:

22. Dissolve / disperse Kollicoat IR, Kollidon CLM, Polyethylene glycol 6000 and Sodium chloride in sufficient amount of water.

23. Disperse pioglitazone in purified water under continuous stirring till to get uniform dispersion and passed through colloidal mill.

24. Add the content of step no.23 to step no.22 under continuous stirring till to get uniform dispersion.

25. Coat the film coated tablets of step 21 with coating dispersion of step 24 in automatic coating machine, till the desired weight build up is obtained.

F. Film coating 2:

26. Dissolve Hydroxypropyl Methyl Cellulose in purified water under continuous stirring till a clear solution is formed.

27. Add Lactose monohydrate and polysorbate 80 to solution of step 26 under continuous stirring using pneumatic stirrer till a uniform solution is formed

28. Disperse Kollidon CLM in the solution of step no 27 under continuous stirring till to get uniform dispersion.

29. Coat the pioglitazone coated tablets of step 25 with coating dispersion of step 28 in automatic coating machine, till the desired weight build up is obtained.

Example-2

Brief Manufacturing Process:

A. Core:

1. Delump and Sift the Metformin Hydrochloride and Lactose monohydrate through Quadro-co-mill / mechanical sifter fitted with suitable screen.

2. Dissolve Povidone in Isopropyl alcohol using pneumatic stirrer, till a clear solution is formed.

3. Disperse Sodium lauryl sulphate in the solution of Step 2 using pneumatic stirrer till a uniform dispersion is formed.

4. Load the material of step 1 in to bowel of top spray granulator.

5. Granulate the material of step 4 using binder solution of step 3 in top spray granulator. An additional quantity of purified
water is sprayed to get suitable granules.

6. Dry the wet granules of step 5 at 40°C - 60°C to achieve the LOD of NMT 2.5% (IR moisture balance at 105°C).

7. Sift the dried granules of step 6 through Quadro-co-mill / mechanical sifter fitted with suitable screen.

8. Blend the material of Step 7 along with the Magnesium stearate in bin blender.

9. If lumps were observed in blend before compression, delump with sifting through vibro sifter fitted with suitable mesh.

10. Compress the blend of step 9 into tablet.

B. Semi-Permeable membrane coating:

11. Dissolve cellulose acetate in acetone using pneumatic stirrer till a clear solution is formed.

12. Dissolve polyethylene glycol in purified water using stirrer still a clear solution is formed.

13. Add solution of step 12 to solution of step 11 under continuous stirring using pneumatic stirrer till a Clear solution is formed.

14. Add Triacetin to solution of step 13 under continuous stirring using pneumatic stirrer till a Clear solution is formed.

15. To the resulting solution of step 13 add Talc under continuous stirring using pneumatic stirrer till a uniform dispersion is formed.

16. Coat the core tablets of step 10 with coating dispersion of step 15 in automatic coating machine, till the desired weight build up is obtained.

C. SR Coating:

17. Dissolve Hydroxypropyl Methyl Cellulose in purified water under continuous stirring still a clear solution is formed.

18. Add polyethylene glycol and Talc to solution of step 17 under continuous stirring using pneumatic stirrer till a uniform dispersion is formed.

19. Take Methacrylic Acid Copolymer Dispersion and filter through suitable mesh or screen and add the dispersion of step 18 under continuous stirring using pneumatic stirrer till a uniform dispersion is formed.

20. Coat the PM coated tablets of step 16 with coating dispersion of step 19 in automatic coating machine, till the desired weight build up is obtained

D. Film coating 1:

21. Disperse Opadry clear YS-1-7006 into purified water under continues stirring and coat the tablet of step 20 in automatic coating machine, till the desired weight build up is obtained.

E. Pioglitazone coating:

22. Dissolve / disperse Kollicoat IR, Kollidon CLM, Polyethylene glycol 6000 and Sodium chloride in sufficient amount of water.

23. Disperse pioglitazone in purified water under continuous stirring till to get uniform dispersion and passed through colloidal mill.

24. Add the content of step no.23 to step no.22 under continuous stirring till to get uniform dispersion.

25. Coat the film coated tablets of step 21 with coating dispersion of step 24 in automatic coating machine, till the desired weight build up is obtained.

F. Film coating 2:

26. Dissolve Hydroxypropyl Methyl Cellulose in purified water under continuous stirring till a clear solution is formed.

27. Add Lactose monohydrate and polysorbate 80 to solution of step 26 under continuous stirring using pneumatic stirrer till a uniform solution is formed

28. Disperse Kollidon CLM in the solution of step no 27 under continuous stirring till to get uniform dispersion.

29. Coat the pioglitazone coated tablets of step 25 with coating dispersion of step 28 in automatic coating machine, till the desired weight build up is obtained.

Example-3

Brief Manufacturing Process:

A. Core:

1. Delump and Sift the Metformin Hydrochloride and Lactose monohydrate through Quadro-co-mill / mechanical sifter fitted with suitable screen.

2. Dissolve Povidone in Isopropyl alcohol using pneumatic stirrer, till a clear solution is formed.

3. Disperse Sodium lauryl sulphate in the solution of Step 2 using pneumatic stirrer till a uniform dispersion is formed.

4. Load the material of step 1 in to bowel of top spray granulator.

5. Granulate the material of step 4 using binder solution of step 3 in top spray granulator. An additional quantity of purified water is sprayed to get suitable granules.

6. Dry the wet granules of step 5 at 40°C - 60°C to achieve the LOD of NMT 2.5% (IR moisture balance at 105°C).

7. Sift the dried granules of step 6 through Quadro-co-mill / mechanical sifter fitted with suitable screen.

8. Blend the material of Step 7 along with the Magnesium stearate in bin blender.

9. If lumps were observed in blend before compression, delump with sifting through vibro sifter fitted with suitable mesh.

10. Compress the blend of step 9 into tablet.

B. Semi-Permeable membrane coating:

11. Dissolve cellulose acetate in acetone using pneumatic stirrer till a clear solution is formed.

12. Dissolve polyethylene glycol in purified water using stirrer still a clear solution is formed.

13. Add solution of step 12 to solution of step 11 under continuous stirring using pneumatic stirrer till a Clear solution is formed.

14. Add Triacetin to solution of step 13 under continuous stirring using pneumatic stirrer till a Clear solution is formed.

15. To the resulting solution of step 13 add Talc under continuous stirring using pneumatic stirrer till a uniform dispersion is
formed.

16. Coat the core tablets of step 10 with coating dispersion of step 15 in automatic coating machine, till the desired weight build up is obtained.

C. SR Coating:

17. Dissolve Hydroxypropyl Methyl Cellulose in purified water under continuous stirring still a clear solution is formed.

18. Add polyethylene glycol and Talc to solution of step 17 under continuous stirring using pneumatic stirrer till a uniform dispersion is formed.

19. Take Methacrylic Acid Copolymer Dispersion and filter through suitable mesh or screen and add the dispersion of step 18 under continuous stirring using pneumatic stirrer till a uniform dispersion is formed.

20. Coat the PM coated tablets of step 16 with coating dispersion of step 19 in automatic coating machine, till the desired weight build up is obtained

P. Film coating 1:

21. Disperse Opadry clear YS-1-7006 into purified water under continues stirring and coat the tablet of step 20 in automatic coating machine, till the desired weight build up is obtained.

E. Pioglitazone coating:

22. Dissolve / disperse Hydroxypropyl Methyl Cellulose, mannitol, Kollidon CLM, Polyethylene glycol 6000 and Sodium chloride in sufficient amount of water.

23. Disperse pioglitazone in purified water under continuous stirring till to get uniform dispersion and passed through colloidal mill.

24. Add the content of step no.23 to step no.22 under continuous stirring till to get uniform dispersion.

25. Coat the film coated tablets of step 21 with coating dispersion of step 24 in automatic coating machine, till the desired weight build up is obtained.

Dissolution Study:

a) Dissolution of metformin hydrochloride from the tablets prepared according to the invention was compared with the commercially available ActoplusMet XR™ which was tested in 1000ml of phosphate buffer (pH 6.8) using USP Dissolution Apparatus 1 with paddle speed set at 100 rpm and the results are tabulated in table- 1.

b) Dissolution of pioglitazone hydrochloride from the tablets prepared according to the invention was compared with the commercially available ActoplusMet XR™ which was tested in 900ml of 0.3 M HC1, potassium chloride buffer pH 2.0 using USP Dissolution Apparatus 2 with paddle speed set at 75 rpm and the results are tabulated in following table-2.
The samples were periodically withdrawn and spectrophotometrically analyzed for combination of metformin and pioglitazone content and subsequently the mean % drug release versus time was calculated.

Table-1
Table-2

Stability Studies:

The tablets prepared according to the Examples 1 and 2 above were charged on accelerated condition at 40°C/75% RH for 3 months in HDPE bottles for stability studies and the tablets were monitored for the following parameters such as assay, dissolution, water content, related substances and impurities and the results are given in following tables.

Table - 3
Table - 4
Table - 5

Bio-Studies:

The bioequivalence study data for Example 3 (Test) is as follows

1. Study design: two way cross over design both fasting and fed state
2. Reference product: Actoplus met® XR (pioglitazone HC1 and metformin HC1 extended -release) Tablets 30mg/1000mg (Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015.)

WE CLAIM:

1. A controlled release tablet comprising:

i. a core comprising metformin or its pharmaceutically acceptable salts;
ii. a semi-permeable membrane surrounding said core;
iii. a sustained release coating layer over said semi-permeable membrane;
iv. optionally a seal coating layer over said sustained release coating layer;

wherein said tablet is devoid of any passage-way.

2. A controlled release tablet comprising:

i. a core comprising metformin or its pharmaceutically acceptable salts;
ii. a semi-permeable membrane surrounding said core;
iii. a sustained release coating layer over said semi-permeable membrane;
iv. optionally a seal coating layer over said sustained release coating layer;
v. a drug layer over said seal or sustained release coating layer comprising pioglitazone or its pharmaceutically acceptable salts;
vi. optionally a seal coating layer over said drug layer; wherein said tablet is devoid of any passage-way.

3. The controlled release tablet according to claim lor 2, wherein said core comprises one or more pharmaceutically acceptable excipients selected from a group comprising diluents, binders, surfactants, pore-formers glidants and lubricants and combinations thereof.

4. The controlled release tablet according to claim 1 or 2, wherein said semi¬permeable membrane comprises a polymer, a flux enhancing agent and at least one plasticizer.

5. The controlled release tablet according to claim 4, wherein said polymer is selected from a group consisting of ethyl cellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acetate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate or combinations thereof.

6. The controlled release tablet according to claim 4, wherein said flux enhancing agent is selected from a group consisting of sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol or combinations thereof.

7. The controlled release tablet according to claim 4, wherein said plasticizer is selected from a group consisting of triacetin, acetylated monoglycerides, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyl oxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutyl sebacate, triethylcitrate, tributylcitrate, glyceroltributyrate or combinations thereof.

8. The controlled release tablet according to claim 1 or 2, wherein said sustained release coating layer comprises a polymer selected from a group consisting of cellulose ethers, polymer or copolymer of acrylates or combinations thereof.

9. A process for preparing a controlled release tablet comprising metformin or its pharmaceutically acceptable salts in combination with pioglitazone or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient, wherein said process involves the steps of:

i. preparing a core comprising metformin and one or more pharmaceutically acceptable excipients;
ii. over-coating said core of step with a semi-permeable membrane;
iii. over-coating said semi-permeable membrane of step ii with a sustained release coat; which is optionally followed by seal coat layer;
iv. over-coating said sustained release coated core of step iii with a drug layer comprising pioglitazone and one or more pharmaceutically acceptable excipients.
v. optionally a seal coating layer over said drug layer.

10. A controlled release tablet comprising a combination of metformin and pioglitazone as herein described and exemplified.