FIELD OF THE INVENTION
The present invention relates to an orally administered pharmaceutical composition that is a triple combination of antidiabetic agents in which one of the antidiabetic agents is present in an extended release form and the other antidiabetic agents are present in an immediate release form.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, insulin resistance, and is often associated with other disorders such as obesity, hypertension, hyperlipidemia, as well as complications such as cardiovascular disease, retinopathy, neuropathy, and nephropathy. The disease is progressive in nature, and can often be controlled initially by diet alone, but generally requires treatment with drugs such as sulfonylureas and injections of exogenous insulin. Two major forms of diabetes mellitus are now recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone that regulates glucose utilization, and patients with Type I diabetes are dependent on exogenous insulin for survival. Type II diabetes, or non-insulin-dependent diabetes (NIDDM), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin (i.e. insulin resistance). Insulin resistance is a major susceptibility trait for NIDDM and is also a contributing factor in arteriosclerosis, hypertension, lipid disorders and polycystic ovarian syndrome.
Biguanides have been the most widely used class of antidiabetics, they act by increasing insulin activity in peripheral tissues, reducing hepatic glucose output due to inhibition of gluconeogenesis and reducing the absorption of glucose from the intestine. Metformin, phenformin, buformin, etc. belong to this group. Metformin has been widely prescribed for lowering blood glucose in patients with non-insulin-dependent diabetes (NIDDM), marketed in 500, 850 or and 1000 mg strengths as conventional tablets and in 500, 750 and 1000 mg strengths as extended release tablets.
Glitazones have also been widely used in the treatment of NIDDM. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several NIDDM animal models, resulting in the correction of elevated plasma levels of glucose, triglycerides and nonesterified fatty acids without the occurrence of hypoglycemia. These agents, also known generically as thiazolidinediones, such as troglitazone, rosiglitazone and pioglitazone, work by increasing the sensitivity of peripheral tissues, such as skeletal muscle, towards insulin. Pioglitazone, the most widely used glitazone, is normally administered at doses from about 15 mg to about 45 mg, given as a single dose once per day. Another glitazone, rosiglitazone is administered at doses of about 5 mg to about 10 mg per day.
Biguanides and thiazolidinediones are commercially available in the form of tablets of the individual drugs, either immediate release (IR) formulations or in some cases controlled release (CR) formulations, to be administered orally to patients in need thereof, in protocols calling for the single administration of the individual ingredient. Metformin monotherapy is used as a first line treatment in diabetic patients but may be supplemented with other drugs when the secondary failure of the therapy sets in. A combination therapy of a biguanide and a glitazone has a synergistic effect on glucose control, since both agents act by different but complementary mechanisms. The method of treating diabetes by employing combinations of biguanides and glitazones has been demonstrated in clinical evaluation (WO 00/27401 and U.S. Pat. No. 6,011,049). Pharmaceutical compositions having combinations of biguanides and thiazolidinediones providing controlled or immediate release of both of the drugs are known in the art.
It is now common, to go from two oral agents to a combination of three oral agents. The most common triple therapy regimen consists of an insulin secretagouge, eg. Sulfonylurea, metformin and a glitazone.
Sulfonylureas, represented principally by glipizide, glimepiride, glyburide, glibornuride, glisoxepide, gliclazide acetohexamide, chlorpropamide, tolazamide and tolbutamide,
among others, help in controlling or managing NIDDM by stimulating the release of endogenous insulin from the beta cells of the pancreas.
Glyburide, glipizide and glimepiride, the newer sulfonylureas are as effective at lowering plasma glucose concentrations as first generation agents but are more potent, better tolerated and associated with a lower risk of adverse effects. Amongst these, the unique properties of glimepiride provide advantages over others of the same class. Its hydroxy-metabolite has very little hypoglycemic activity therefore it causes fewer hypoglycemic episodes while achieving glycemic control. It is relatively safe in elderly patients with mild renal failure. The other advantage with glimepiride is its long life (9 hour), which allows this drug to be used as once daily treatment (1-6 mg/kg). A possible third advantage with this drug is that it has no effect on human vascular ATP-dependent K+ channels. Theoretically it will not have any deleterious effect on vascular responses during ischemia.
Glimepiride, being an insulin secretagouge, makes more insulin available for better utilization by the two insulin sensitizers, pioglitazone and metformin and hence enhances the actions of the insulin sensitizers. Moreover there is reduced incidence of side effects due to reduced dosage requirements of individual drugs. The triple combinations can be given as once a day administration and hence improves patient compliance.
Triple combination of drugs comprising biguanide in combination with sulfonylurea and glitazone have been described. US patent 6,011,049 and European patent EP 1514550A2 disclose combinations of a glitazone, a biguanide and a sulfonylurea, useful for treating diabetes mellitus and improving glycemic control.
Combinations comprising combinations of two antidiabetic agents, biguanide (extended-release) with either a glitazone or a sulfonylurea (immediate-release) are disclosed in applications published as WO 04/045608 and WO 04/045662, respectively. These applications are incorporated herein by reference in their entirety.
Although combination therapy comprising two antidiabetic agents is well known in the art and are convenient to formulate, it is challenging to develop a triple combination of a high dose, water-soluble drug with a narrow absorption window limited to either stomach and/or upper intestine in combination with immediate release drugs belonging to different classes in a single dosage form that exhibits prolonged release. WO 05/009412, filed by Wockhardt, discloses pharmaceutical compositions comprising three components of which at least one is a slow release therapeutic agent. The three components exemplified include metformin, pioglitazone and glimepiride.
For preparing a single dosage form for the combination of a biguanide, a glitazone and a sulfonylurea, the biguanide, which has a shorter half-life needs to be administered in a controlled or extended release form; whereas sulfonylurea, particularly glimepiride, and glitazone, particularly pioglitazone which have longer half-lives, need to be administered in immediate release form. Further there is a large disparity between the doses and solubility of the biguanide and the other two immediate release antidiabetic drugs, hence it is difficult to formulate these together in a single dosage form.
SUMMARY OF THE INVENTION
In one general aspect there is provided a solid pharmaceutical dosage form for oral administration of a biguanide, glitazone and sulfonylurea in a single dosage unit.
The dosage form includes an extended release portion comprising: a biguanide; and an immediate release portion comprising glitazone and sulfonylurea.
Embodiments of the dosage form may include one or more of the following features. For example, the biguanide may be one or more of metformin, phenformin, and buformin and, in particular, metformin. The glitazone may be one or more of pioglitazone, rosiglitazone, troglitazone, ciglitazone and englitazone, and in particular pioglitazone. The sulfonylurea may be one or more of glipizide, glimepiride, glibornuride, glyburide,
glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide and tolbutamide and, in particular, glimepiride.
According to yet another aspect, pharmaceutical compositions are provided which can incorporate a high dose of biguanide for extended release in combination with glitazone and sulfonylurea for immediate release and are of acceptable size, making it convenient for oral administration as a single unit.
It is one general aspect to provide an oral solid dosage form comprising:
(a) an extended release portion comprising biguanide, and,
(b) an immediate release portion comprising glitazone and sulfonylurea.
In one of the embodiments, the oral solid dosage form is provided as bilayered or multilayered tablets. The extended release portion forms one layer and the immediate release portion forms the second layer. Alternatively, a seal-coat layer or an inert layer may be incorporated between the two portions to form multilayered tablets.
Since the immediate release portion comprises highly water insoluble actives, glitazone and sulfonylurea, suitable pharmaceutically acceptable surfactants are incorporated in this portion to achieve rapid dispersibility and improved solubility.
In another embodiment, the extended release portion is present as a core completely surrounded by the immediate release portion. The immediate release portion is applied as a coating in a solution or suspension. Alternatively, the immediate release portion is compressed over the core.
It is another aspect to provide an oral solid dosage form comprising:
(a) an extended-release core comprising biguanide;
(b) optionally a seal-coat surrounding the core; and
(c) an immediate-release coating applied to the core comprising glitazone, sulfonylurea, film-forming polymer (s), surfactants and plasticizer.
It is yet another aspect to provide a layered tablet for the combination of biguanide, sulfonylurea and glitazone comprising:
a layer comprising biguanide, rate-controlling polymers and pharmaceutically
acceptable excipients, and
another layer comprising sulfonylurea, glitazone and pharmaceutically acceptable
excipients;
wherein the tablet provides extended release of metformin and immediate-release of
glitazone and sulfonylurea.
In yet another embodiment, the immediate release portion is surrounded by the extended release portion in such a manner that only one surface of the immediate release portion is exposed, i.e. tablet within a tablet.
In yet another embodiment, the immediate release portion and the extended release portion are provided as separate beads, pellets, particles, granules or tablets to be filled inside a capsule. Alternatively, multiple units of the extended release portion may be prepared and these units are coated or layered with the immediate release portion.
In another general aspect a process is provided for preparing an oral solid dosage form comprising:
(a) blending biguanide with rate-controlling polymers,
(b) granulating the blend,
(c) compressing to form a core,
(d) layering glitazone and sulfonylurea on the surface of the core, wherein the coating comprises glitazone, sulfonylurea, film-forming polymer (s), surfactants and plasticizer.
Alternatively, an inert layer or seal-coat layer may be incorporated between the core and the glitazone-sulfonylurea layer.
It is another aspect to provide a process for preparing bilayered tablet for the combination of biguanide, glitazone and sulfonylurea, said process comprising:
(a) dispersing biguanide in a solid matrix to form granules/blend which provides extended release of the biguanide,
(b) blending/ granulating glitazone and sulfonylurea with pharmaceutical^ acceptable excipients to form granules/blend which provides immediate release of glitazone and sulfonylurea,
(c) compressing the two granules/blend to form bilayered tablet.
Alternatively, an inert layer or seal-coat layer may be incorporated between the two granules/blend to form multilayered tablets.
It is yet another aspect to provide a process for preparing a tablet within a tablet for the combination of biguanide, glitazone and sulfonylurea, said process comprising:
(a) granulating glitazone, sulfonylurea and pharmaceutically acceptable excipients to form granules,
(b) compressing the glitazone and sulfonylurea granules to form immediate release core,
(c) granulating biguanide, rate-controlling polymers and pharmaceutically acceptable excipients to form granules,
(d) compressing biguanide granules around the immediate release core tablet such that one surface of the immediate release core tablets remains exposed.
In another general aspect there is provided a method of treating non- insulin dependent diabetes meliitus in a patient in need thereof wherein the dosage form provides extended-release of the biguanide and immediate release of the glitazone and sulfonylurea.
The oral solid dosage form may further include one or more of insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, stating, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, a novel therapeutic triple combination drug delivery system comprising different classes of drugs is addressed. Anti-diabetic drugs given in an extended and/or immediate release belonging to different classes of antidiabetic agents, which act by different mechanisms of action, resulting in a better level of glycemic control is described.
Hydrophobic therapeutic agents, i.e., therapeutic compounds having poor solubility in aqueous solution, can be difficult to formulate in a dosage form that provides effective administration of the therapeutic agent to patients. A well-designed formulation must, at a minimum, be capable of presenting a therapeutically effective amount of the hydrophobic compound to the desired absorption site, in an absorbable form. Even this minimal functionality is difficult to achieve when delivery of the hydrophobic therapeutic agent requires interaction with aqueous physiological environments, such as gastric and intestinal fluids. Pharmaceutical compositions for delivery of such hydrophobic therapeutic agents must carry the hydrophobic compound through the aqueous environment, while maintaining the hydrophobic compound in an absorbable form, and avoiding the use of physiologically harmful solvents or excipients.
A similar problem is faced in formulating extended release dosage forms for highly soluble therapeutic agents. The high solubility of the therapeutic agent requires the incorporation of a high percentage of a rate-controlling polymer to achieve a desired release profile and prolonged effect. Further, it is difficult to control the initial burst of the drug from the formulation.
Therefore, there exists a need for pharmaceutical compositions for oral administration that include a combination of a hydrophobic, water- insoluble therapeutic agents, i.e., a
glitazone and sulfonylurea, in an immediate release form and a highly water-soluble therapeutic agent, i.e., a biguanide, in an extended-release form that has the characteristics of achieving an effect over twenty four hours after once daily administration.
The pharmaceutical compositions of the present invention can be administered orally in the form of tablets, such as coated tablets or bilayered tablets, or in the form of capsules containing pellets, beads, granules, multiparticulates, tablets, or powder. A better control and patient compliance is achieved by: a) Using an extended/controlled release agent which is a candidate for an extended release regimen in combination with b) more than one immediate release drugs preferably having a long elimination half life.
Biguanide, as used herein, includes metformin, phenformin and buformin including their salts, solvates, hydrates, and polymorphs. Particularly, the biguanide used is metformin. Metformin as used herein may include base per se or a pharmaceutically acceptable salt selected from amongst hydrochloride, fumarate, hydrobromide, succinate or maleate. The daily effective dose of metformin may range from about 500 mg to about 2550 mg and, in particular, the dose may be a single dose of about 500 mg to about 1000 mg. The biguanide may be present in an amount from about 20% to about 80% by weight of the total composition.
The biguanide may be incorporated in an extended release portion by dispersing in a rate-controlling polymer matrix, as described in our pending applications published as WO 03/28704 and WO 03/039527. Alternatively, the biguanide may be layered onto pharmaceutically acceptable inert cores or seeds in admixture with rate-controlling polymers or surrounded by rate-controlling polymers.
The term matrix as used herein refers to a uniform mixture of biguanide, rate-controlling polymers and optionally other excipients.
Glitazone as employed herein is intended to include, but is not limited to, pioglitazone, rosiglitazone, troglitazone, ciglitazone and englitazone. In particular the glitazone used may be pioglitazone. The daily effective dose of pioglitazone may range from 5 mg to 50
mg and, in particular, the dose may be a single dose of 10 mg to 45 mg. The glitazone may be present in an amount of from about 0.5% to about 10% by weight of the total composition.
Sulfonylurea as used herein is intended to include, but is not limited to, glipizide, glimepiride, glibornuride, glyburide, glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide and tolbutamide. In particular, the sulfonylurea used may be glimepiride. The daily effective dose of glimepiride may range from 1 mg to 10 mg and, in particular, the dose may be a single dose of about 2 mg to about 4 mg. The sulfonylurea may be present in an amount from about 0.05% to about 10% by weight of the total composition.
Since sulfonylureas and glitazones are poorly soluble, better results may be obtained if its particle size of sulfonylureas is equal to or less than about 10 microns and particle size of glitazones is equal to or less than 40 microns. Size reduction or micronization may be carried out in any of the conventionally known mills, such as ball mill, colloid mill, grinding mill, air jet mill, roller mill, impact mill, etc.
Rate-controlling polymers may be selected from hydrophilic or hydrophobic polymers. The hydrophilic polymers may be selected from cellulose derivatives such as ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and sodium carboxy methylcellulose of different degrees of substitution and molecular weights or similar materials. These polymers may be used alone or in combination. The hydrophobic polymers may be selected from ethylcellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, poly (alkyl) methacrylate, waxes, shellac and hydrogenated vegetable oils.
The rate-controlling polymers may constitute from about 10% to about 30% of the total composition.
The matrix may be made by any pharmaceutically acceptable technique that achieves uniform blending, e.g. dry blending, wet granulation, compaction and fluid bed
granulation. The matrix may be formulated as plurality of discrete or aggregated particles, pellets, beads or granules. Alternatively the matrix may be compressed into tablets.
The pharmaceutically acceptable excipients may include one or more of diluents, binders, lubricants, glidants, colorants and flavouring agents.
Suitable diluents may be selected from any such pharmaceutically acceptable excipients, which give bulk to the composition and improve compressibility. These may be selected from starch and starch derivatives, dicalcium phosphate, calcium sulphate, sorbitol, microcrystalline cellulose, lactose, glucose, mannitol, alginates, alkali earth metal salts, clay, polyethylene glycols or similar materials.
Suitable binders may be selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl celluloses, dextrin, carbohydrate gums, alginates, polyacrylic acid, polyvinylalcohol and similar materials or mixtures thereof.
Suitable lubricants may be selected from talc, magnesium stearate, other alkali earth metal stearates like zinc, calcium stearate etc; sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol and similar materials.
Suitable glidants may be selected from talc and colloidal silicon dioxide.
The inert layer or seal coat provided between the extended release portion of biguanide and the immediate release portion of glitazone and sulfonylurea may include polymers and other pharmaceutically acceptable excipients.
The polymers used in the inert layer or seal coat should be penetrable by gastrointestinal fluids and either soluble or erodible. Suitable polymers that may be used include hydroxypropylmethylcellulose, hydroxypropylcellulose, poly (vinyl) alcohol, polyvinylpyrrolidone, poly (ethylene) oxide, or combinations thereof. The seal coat
around the core may constitute from about 1% to about 5% by weight of the dosage form.
The immediate release drugs glitazone and sulfonylurea may be deposited as a suspension or solution over the extended release biguanide core or over the seal coated core. Deposition can be achieved by coating techniques commonly used in the art, such as spraying, pan coating orfluidized bed coating.
The immediate release coating may comprise film forming polymer(s), plasticizers and other conventional additives such as lubricants, fillers, antiadherents, opacifiers and colorants.
Suitable film forming polymer(s) may be selected from one or more of hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinyl acetate and N-vinyl pyrrolidone copolymer, polyvinyl alcohol or mixtures thereof.
Suitable plasticizers may include one or more of citric acid alkyl esters, glycerol esters, sucrose esters, sorbitan esters, polyethylene glycols or mixtures thereof.
The immediate release coating and the inert or seal coating may be applied as a solution or suspension in a suitable solvent.
Suitable solvents may be selected from water; alcohols like ethyl alcohol, isopropyl alcohol; ketones like acetone or ethyl methyl ketone; chlorinated hydrocarbons like methylene chloride, dichloromethane and trichloroethane or mixtures thereof.
Due to poor dispersibility and solubility of glitazone and sulfonylurea in solvents, the immediate release portion may include suitable surfactants.
The surfactants used may be hydrophilic or hydrophobic. Particularly hydrophilic surfactants may be used.
Hydrophilic surfactants may be selected from the group consisting of non-ionic surfactants, ionic surfactants or mixtures thereof.
The surfactants may be selected from one or more of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; caprylocaproyl macrogolglycerides, polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; and mixtures thereof. In particular the nonionic surfactant used may be polyoxyl 40 hydrogenated castor oil.
The surfactants may constitute from about 0.5% to about 10% by weight of the total composition.
The coated cores may be dried under conditions effective for drying, such as in oven or fluidized bed drier.
Alternatively, the immediate release layer may be applied by press-coating, dry compression or deposition over the extended release core or seal coated extended release core.
In another embodiment, the immediate release drugs may be combined with pharmaceutical^ acceptable excipients and compressed along with the extended release portion as bilayered tablets or an inert layer may be incorporated between the two portions to form multilayered tablets.
The immediate-release layer may additionally comprise pharmaceutically acceptable excipients acting in one or more capacities as diluents, binders, lubricants, surfactants, disintegrants and pigments/colorants.
The solid dosage form may also include an outer protective coating layer which may comprise any conventional coating formulation and will include one or more of film forming polymers or binders and one or more plasticizers.
The following examples illustrate various aspects of the present invention. These examples are for illustration only and should not be construed as limiting the scope of the invention.
Example 1
(Table Removed)
Process:
1. Metformin Hydrochloride was milled through multimill.
2. Milled Metformin Hydrochloride, was sifted with Microcrystalline Cellulose and Sodium Carboxymethyl Cellulose and transferred to a Rapid Mixer Granulator. Purified Water was added to it and granulated to prepare granules.
3. The granules were dried in Fluid bed dryer and sized.
4. Hydroxypropylmethylcellulose was sifted and blended with the granules of step 3.
5. The granules of step 4 were lubricated with magnesium stearate and compressed.
6. Coating dispersion for seal coat was made by dispersing opadry in water and the tablets of step 5 were coated till weight builds up of 2 % w/w were achieved.
7. Polyoxyl 40 hydrogenated castor oil was dissolved in purified water. Piogltazone Hydrochloride & Glimepiride were added to this solution under stirring. Opadry was added to this dispersion and stirred continuously.
8. The tablets of step 6 were film coated with the solution of step 7 till weight builds up of 8% w/w.
In-vitro dissolution study
In-vitro release of the tablets (Example 1 (a)) was studied in 900 ml of pH 6.8 phosphate buffer, using USP dissolution apparatus (basket) at 100 rpm; in 900 ml of 0.1 N HCL using USP dissolution apparatus (paddle with a sinker) at 75 rpm and in 900 ml of pH 8.0 phosphate buffer consisting 0.2% sodium lauryl sulphate using USP dissolution apparatus (basket) at 100 rpm for metformin, pioglitazone and glimepiride respectively. The results are listed in Tables 1-3.
Table 1. Dissolution profile of metformin hydrochloride from tablets prepared according to Example 1a in Phosphate buffer pH 6.8 (900 mL), USP basket method at 100 rpm.

(Table Removed)
Table 2. Dissolution profile of pioglitazone from tablets prepared according to Example 1a in 0.1 N Hydrochloric acid (900 ml_), USP basket method at 75 rpm.
(Table Removed)
Table 3. Dissolution profile of glimepiride from tablets prepared according to Example 1a in Phosphate buffer pH 8.0 containing 0.2% sodium lauryl sulphate (900 mL), USP basket method at 100 rpm.
(Table Removed)
Example 2
Bilavered Tablets
(Table Removed)
Process: Metformin blend
1. Metformin Hydrochloride was milled through multimill.
2. Milled Metformin Hydrochloride, Microcrystalline Cellulose and Sodium Carboxymethyl Cellulose were transferred to a Rapid Mixer Granulator. Purified water was added to it and granulated to prepare granules.
3. The granules were dried in fluid bed dryer and sized.
4. Hydroxypropylmethylcellulose was sifted and blended with the granules of step 3 in a low shear mixer.
5. Magnesium Stearate was sifted and mixed with the blend of step 4.
Pioglitazone HCI + Glimepiride blend
1. Pioglitazone Hydrochloride, Glimepiride, Microcrystalline Cellulose, lactose, hydroxy propyl cellulose-l, poly vinyl pyrrolidone & color were sifted and transferred to a Rapid Mixer Granulator. Purified water was added to it and granulated to prepare granules.
2. The granules were dried in fluid bed dryer and sized.
3. Microcrystalline cellulose, sodium starch glycolate and carboxy methylcellulose calcium were sifted and mixed with granules of step 2 in a low shear mixer.
4. Magnesium Stearate was sifted and mixed with the blend of step 3.
Bilayer tablet compression
The two blends, metformin blend and pioglitazone-glimepiride blend were compressed over each other to form bilayered tablets.

WE CLAIM:
1. An oral solid dosage form comprising:
(a) an extended-release portion comprising biguanide, and
(b) an immediate-release portion comprising glitazone and sulfonylurea.

2. The dosage form according to claim 1 wherein the biguanide is selected from amongst metformin, buformin, phenformin or their salts, solvates, hydrates and polymorphs.
3. The dosage form according to claim 1 wherein the sulfonylurea is selected from amongst glipizide, glimepiride, glisoxepide, glyburide, glibonuride, gliclazide, acetohexamide, chlorpropamide, tolazamide and tolbutamide.
4. The dosage form according to claim 1 wherein glitazone is selected from amongst pioglitazone, rosiglitazone, troglitazone, ciglitazone and englitazone.
5. The dosage form according to claim 1 wherein the extended-release portion comprises rate-controlling polymers and pharmaceutically acceptable excipients.
6. The dosage form according to claim 5 wherein the rate controlling polymers are hydrophilic, hydrophobic or a combination thereof, wherein the hydrophilic polymers are selected from amongst cellulose derivatives such as hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxy ethyl cellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or combinations thereof; polyvinyl pyrrolidone, polysaccharides, polyalkylene glycols, starch and derivatives thereof and hydrophobic polymers are selected from amongst poly(ethylene)oxide, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, waxes, shellac and hydrogenated vegetable oils.
7. The dosage form according to claim 5 wherein the pharmaceutically acceptable excipients are selected from one or more of diluents, binders, lubricants, glidants, colorants and flavouring agents.
8. The dosage form according to claim 1 wherein inert layer or seal-coat is provided between extended-release portion and immediate-release portion.
9. The dosage form according to claim 1 wherein the extended-release portion is present as a core completely surrounded by immediate-release portions.
10. The dosage form according to claim 1 wherein the extended-release portion forms one layer and immediate-release portion forms the second layer compressed together as bilayered or multilayered tablet.
11. The dosage form according to claim 1 wherein the immediate-release portion is surrounded by the extended-release portion in such a manner that only one surface of the immediate-release portion is exposed.
12. The dosage form according to claim 1 wherein the immediate-release and extended-release portions are provided as separate beads, pellets, particles, granules or tablets to be filled inside a capsule.
13. The dosage form according to claim 1 wherein the immediate-release portion further comprises pharmaceutically acceptable surfactants and other excipients.
14. An oral solid dosage form comprising:

(a) an extended-release core comprising biguanide;
(b) optionally a seal-coat surrounding the core; and
(c) an immediate-release coating applied to the core comprising glitazone, sulfonylurea, film-forming polymer (s), surfactants and plasticizer.
15. The oral solid dosage form according to claim 14 wherein the process for preparing the dosage form comprises the steps of:
(a) blending biguanide with rate-controlling polymers,
(b) granulating the blend,
(c) compressing to form a core,
(d) layering the immediate-release portion of glitazone and sulfonyl urea onto the surface of the core wherein the immediate-release portion comprises glitazone, sulfonylurea, film-forming polymer (s), surfactants and plasticizer.
16.
A layered tablet for the combination of biguanide, sulfonylurea and glitazone comprising:
a layer comprising biguanide, rate-controlling polymers and
pharmaceutically acceptable excipients, and
another layer comprising sulfonylurea, glitazone and pharmaceutically
acceptable excipients; wherein the tablet provides extended release of metformin and immediate-release of glitazone and sulfonylurea.
17.
The layered tablet according to claim 16 wherein the process for preparing the layered tablet for the combination of biguanide, glitazone and sulfonylurea comprises the steps of:
(a) dispersing biguanide in a solid matrix to form granules/blend which provides extended release of the biguanide,
(b) blending/granulating glitazone and sulfonylurea with pharmaceutically acceptable excipients to form granules/blend which provides immediate-release of glitazone and sulfonylurea,
(c) compressing the two granules/blends to form bilayered tablet.
18. The layered tablet according to claim 16 wherein the process for preparing the layered tablet for the combination of biguanide, glitazone and sulfonylurea comprises the steps of:
(a) granulating glitazone, sulfonylurea and pharmaceutically acceptable excipients to form granules,
(b) compressing the glitazone-sulfonylurea granules to form immediate-release core,
(c) granulating biguanide, rate-controlling polymers and pharmaceutically acceptable excipients to form granules,
(d) compressing biguanide granules around the immediate release core tablet such that one surface of the immediate-release core tablets remains exposed.

19. A method of treating non-insulin dependent diabetes mellitus in a patient in need thereof, comprising administering a solid dosage form for the combination of biguanide, sulfonylurea and glitazone, wherein the dosage form provides extended-release of the biguanide and immediate-release of glitazone and sulfonylurea.
20. The method according to claim 19 wherein the solid dosage form may further include one or more of insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors.