CA2645318A1 - Pharmaceutical formulations containing metformin - Google Patents

Abstract

Controlled delivery and instant release combination compositions of metformin or salts thereof and glimepiride and the process of making the same are disclosed. Metformin and glimepiride are granulated with a binder and further dispersed in a rate-controlling matrix that results in a controlled release formulation that increases patient compliance. In a further illustrative embodiment metformin and glimepiride are formulated in an instant release presentation using pharmaceutical excipients known in the art.

Description

PHARMACEUTICAL FORMULATIONS CONTAINING METFORMIN
RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application No.
60/780,944 filed on March 9, 2006, the contents of which are incorporated in their entirety by reference.
FIELD OF INVENTION:
The present invention relates to combination compositions of pharmaceutical therapeutics and the process of making the same. In particular, the present invention relates to metformin and salts thereof essentially combined with other commonly known oral anti-diabetic compounds. This combination composition can be formulated in an instant release formulation or granulated and combined with an extended release polymer and further dispersed in a rate-controlling matrix.

BACKGROUND OF 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 as the disorder progresses injections of exogenous insulin.
Another agent known as a biguanide also is used to decrease hepatic glucose production as well as intestinal absorption of glucose. It has now been discovered that combination therapy with a biguanide and a sulfonylreas results in dramatic improvement in glycemic control, and that even better control and patient compliance can be achieved by using a combination comprised of a biguanide, and a sulfonylurea. Accordingly, such combinations are especially useful in treating diabetes and associated complications.

SUMMARY OF THE INVENTION
This invention provides a method of treating diabetes by administering to a subject in need of treatment a single dosage form having a combination of a sulfonylurea together with a biguanide anti-diabetic agent such as metformin. The sulfonylureas are a class of compounds that have been widely employed to treat diabetes. Such compounds are well known, for example as described in U.S. Pat. Nos. 3,454,635, 3,669,966, 2,968,158, 3,501,495, 3,708,486, 3,668,215, 3,654,357, and 3,097,242, all of which are incorporated in their entirety by reference. Preferred sulfonylureas to be employed in the combinations of this invention are glyburide, gliquidone, glipizide, tolbutamide, tolazamide, glisoxepid, chlorpropamide, glibornuride, gliclazide, glimepiride, phenbutamide, and tolcyclamide.
According to this invention, the foregoing sulfonylureas are used in combination with a biguanide to treat diabetes with improved patient compliance thereby improving glycemic control.
Metformin Hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C4HtiN5=HCl and a molecular weight of 165.63. It is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. Metformin is a biguanide that is not chemically or pharmacologically related to any other classes of oral anti-hyperglycemic agents. It is absorbed mainly from the small intestine.
Metformin is stable in vivo and it does not bind to plasma proteins and is therefore excreted unchanged in the urine. It has a half-life of 1.3 to 4.5 hours. The maximum recommended daily dose of metformin is about 4 gms. Metformin is anti-hypererglycemic and it improves glucose tolerance in patients with type II diabetes, lowering both basal and postprandial plasma glucose. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type II diabetes or normal subjects.
Hence it is a drug of choice in controlling type II diabetes and is widely prescribed by physicians all over the world. It is presented in both instant release and extended release formulations. The extended release formulations have been developed to increase patient compliance.
The present invention addresses the problems with patient compliance with biguamide, such as metformin in combination with other orally active hypoglycemic agents used in combination therapy and provides a single formulation composition of metformin and in combination with a sulphonylurea, eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glimepiride or glicazide, which improves patient compliance with the convenience of a single formulation. In particular in a preferred combination according to the invention is metformin in combination with glimepiride. In a further preferred combination according to the invention the metformin in combination with glimepiride is formulated in an extended release formulation.

Glimepiride is an oral blood-glucose lowering drug of the sulfonylureas 'class.
Glimepiride is a white to yellowish-white crystalline, odorless to practically odorless powder that can be incorporated into combination tablets in doses of 1 mg, 2mg and 4mg strengths for oral administration. Glimepiride can be administered up to 8mg per day in divided doses or up to 8mg in an extended release formulation. Chemically, glimepiride is identified as 1 { {p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyI]sulfonyl]-3-(trans-4-methylcyclohexy)urea. The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also pay a role in the activity of sulfonylureas such as glimepiride.
According to an aspect of the present invention, there is provided a method of treatment of hyperglycemic patients comprising administering the tablets having a combination of orally active hypoglycemic agents of varied doses made according to the invention in divided doses or in an extended release formulation once daily to patients in need thereof.
It is thus a further object of the present invention to provide instant release or controlled release compositions of metformin in combination with other orally active hypoglycemic agents or a pharmaceutically acceptable salts thereof.
A further object of the present invention is to provide controlled or instant release compositions of metformin and other orally active hypoglycemic agents that are simple to manufacture without involving cost intensive methods of preparation.
Another object of the present invention is to provide controlled or instant release compositions of metformin in combination with other orally active hypoglycemic agents that are simple to manufacture and have good compressibility that results in good hardness tablets that can withstand the rigors of coating.

DETAILED DESCRIPTION:
Although biguanides such as phenformin or buformin or pharmaceutically acceptable salts thereof, may be used for the purpose of the this invention, the preferred drug, having high water solubility for use herein is metformin or pharmaceutically acceptable salts such as metformin hydrochloride, metformin fumarate, and metformin succinate.
Metformin can be used in varying doses such as 500 mg, 750 mg, 850 mg, and 1000 mg in instant release formulations and up to 4000mg per day in extended release formulations. It is contemplated within the scope of the invention that where desired, metformin or a salt thereof may be used in combination with another antihyperglycemic agent, which may be administered orally in the same dosage form in accordance with the present invention.
The present composition according to the invention can be either an instant release formulation or a controlled release formulation which is essentially comprised of one or more binders in an amount within the range of from with about 0.1% to about 10%
binder , preferably about 0.2% to about 5 % 2-4% binder and most preferably about 0.25%
to about 4.5% binder by weight of the composition. Binders usually are low viscosity polymers or non-polymeric materials and therefore they do not extend the release of a drug. Although binders improve appearance, hardness & friability of the preparation they are usually not intended to influence the disintegration or dissolution roles of active substance.
Binders which are suitable for use herein include but are not limited to copovidone or polyvinyl pyrrolidone (PVP). Copovidone is a white or yellowish-white spray-dried powder that has a relatively fine particle size and good flow properties. It has a typical slight odor .
and a faint taste in aqueous solutions. Because of the ratio of vinylpyrrolidone to vinyl acetate in copovidone, it is almost as universally soluble as polyvinyl pyrrolidone. It dissolves in extremely hydrophilic liquids such as water as well as in more hydrophobic solvents such as butanol. Copovidone has a molecular weight ranging from about 45000 to about 70000 and is available commercially in different grades and trade names such as Kollidon VA 64.
It is contemplated within the scope of the invention that other binders such as polyvinyl pyrrolidone (PVP) with a molecular weight ranging from about 4000 to about 1500000 and preferably about 30,000-1500000 can be used as a binder.
Polyvinylpyrrolidone is available in different grades based on K-value and molecular weights such as polyvinyl pyrrolidone with K value of 24-26, 29-32 or 85-95.
Preferably polyvinyl pyrrolidone with K value 85-95 (Plasdone K-90/D , Kollidon 90F ) can be used in the present invention having high molecular weight (1,000,000-1,500,000) and greater binding capacity.
It is also contemplated that other binders can be used such as but not limited to hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, sodium carboxy methyl cellulose, starches such as corn starch, modified corn starch, sugars, gum acacia and the like.

Metformin hydrochloride granules prepared with copovidone (copolyvidone, Kollidon VA 64) have been found to have a good compressibility. Metformin is essentially granulated with suitable binders, the binder concentration ranging from h about 0.1% to about 10%
binder, preferably about 0.2% to about 5 % 2-4% binder and most preferably about 0.25% to about 4.5% binder. Although concentrations above 4% can give also give binding effect, there appears to be no substantial increase in binding. It is contemplated within the scope of the disclosure that multiple granulation steps can be preformed to improve compressibility.
The solvent used with the binder for granulation is preferably water. It is contemplated that other solvents such as isopropyl alcohol or the like can also be employed.
Metformin granules so formed are uniformly dispersed in a controlled release matrix comprising of rate controlling polymers. In a further illustrative embodiment according to the disclosure Metformin granules so formed are uniformly dispersed in a controlled release matrix comprising of rate controlling polymers along with free metformin.
"Controlled-release" as used herein to describe a method and composition for making an active ingredient available to the biological system of a host. A
controlled release preparation according to the present invention is one that achieves slow release of a drug over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery. This admixture is typically compressed under pressure to produce a tablet. Drug is released from this tablet by diffusion and erosion. For drugs of relatively high solubility, the preferred polymeric matrices are those with a relatively high molecular weight. With such systems, release of the drug is achieved by allowing the gastric fluid to diffuse into the matrix where fluid dissolves the matrix-held drug and then diffuses outward while the matrix retains its integrity, or disintegrates at a rate that is considerably slower than the rate at which the drug is dissolved from matrix. Controlled release is thus achieved by the integrity of the matrix and the need for the gastric fluid to diffuse into the matrix to reach the drug.
In the present invention swelling and expanding system is employed. It is contemplated within the scope of the invention that other compositions for controlled or extended release may be employed. The controlled release gastro-retentive swelling system of the present invention employs a combination of rate controlling polymers, which swell voluminously in presence of gastric contents to increase the dosage form size such that it precludes its passage through the pylorus. The term "rate-controlling polymer"
as used herein includes hydrophilic polymers that are capable of retarding the release of inetformin hydrochloride in combination with other anti-diabetic agents in vivo when metformin hydrochloride and other anti-diabetic agents are dispersed in a polymeric matrix formed from the rate controlling polymers.
Preferred polymers for the controlled release system of high solubility drug of the present invention are those which ensure rapid hydration of the polymer matrix to minimize variable and undesirable burst of combination drugs, yet effectively control the release of drugs within a combination being liberated from the discrete particles or drug granules. The hydrophilic water-soluble polymers may be used individually or in combination.
Examples of polymers suitable for this invention include the polymers well known in the pharmaceutical art for their release retarding properties and may be selected from the group comprising acrylic polymers such as available as Eudragit RS, Eudragit RL, natural gums as xanthan gum, karaya gum, locust bean gum, guar gum, gelan gum, gum arabic, tragacanth, carrageenan, pectin, carboxymethyl cellulose (CMC) agar, alginic acid, sodium alginate polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, vinyl acetate copolymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof.
Preferred polymers with appropriate hydration characteristics include hydroxypropylmethylcellulose 2208 USP (hydroxypropylmethylcellulose with a methoxyl content of 19-24% and a hydroxypropyl content of 7-12%), viscosity grades ranging from about 4000 to about 100,000cps and hydroxypropylmethylcellulose 2910 USP
(hydroxypropylmethylcellulose with a methoxyl content of 28-30% and a hydroxypropyl content of 7-12%), viscosity grades ranging from about 3 to about 150 cps.
Another preferred polymer is sodium carboxy methylcellulose having viscosity of about cps.
The amount of polymer relative to the drug may vary depending on the release rate desired, nature of the polymers and their physicochemical characteristics. The amount of the polymer in the dosage form generally varies from about 10% to about 50% by weight of the composition. Preferably, the amount of polymers varies from about 15% to about 45% by weight of the dosage form. Most preferably, the amount of polymer is about 20%
to about 24% by weight of the dosage form. The polymer concentration can be reduced as they are utilized optimally due to their incorporation in dry form.

Additional excipients that are although not essential for the present invention, are required for the tableting process as known to those skilled in art, and may be suitably included.
The composition of the invention therefore typically includes pharmaceutically acceptable excipients. As is well known to those skilled in the art, pharmaceutical excipients are routinely incorporated into solid dosage forms. This is done to ease the manufacturing process as well as to improve the performance of the dosage form. Common excipients include diluents, lubricants, granulating aids, colorants, flavorants, surfactants, pH adjusters, anti-adherents and gildants etc. Such excipients are routinely used in the dosage forms of this invention.
The present invention may additionally include one or more fillers or excipients in an amount within the range of from about 0 to about 90% by weight and preferably from about I
to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose.
As the composition is in the form of a tablet, it may include one or more tableting lubricants in an amount within the range of from about 0.2 to about 8% and preferably from about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and the like and mixtures thereof. Other conventional pharmaceutical ingredients, which may optionally be present, include preservatives, stabilizers, and FD &C colors etc.
The composition made according to the present invention may be formulated as tablets within a capsule or a tablet. Most preferably, the composition is a tablet. The tablet may optionally be coated with a thin layer of a film forming polymer or a pharmaceutical excipient. The controlled release preparation according to the invention may conveniently be film coated using any film coating material conventional in the pharmaceutical art. It is contemplated that the film coating can be formulated to delay the release of any drug for a selected period of time that is desirable for therapeutic reasons. Preferably an aqueous film coating is used.
The dosage form of present invention is a solid dosage form, preferably a tablet, which may vary in shape such as oval, triangle, almond, peanut, parallelogram, pentagonal, hexagonal, and trapezoidal. The preferred shapes are oval and parallelogram forms.

A controlled release preparation according to the present invention is one that achieves slow release of a drug or drugs in combination over an extended period of time, thereby extending the duration of drug or drugs action over that achieved by conventional delivery. Preferably, such a preparation maintains a drug concentration in the blood within the therapeutic range for 12 hours or more.
Tablets formulated according to the invention allow for controlled release metformin hydrochloride in combination with other anti-diabetic agents over at least a twelve-hour period following oral administration.
Another preferred dissolution rate in vitro upon release of the controlled release preparation for administration twice daily according to the invention is between 5 and 50%
(by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 1 hour, between 10 and 75% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 2 hours, between 20 and 95% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 4 hours, between 40 and 100% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 8 hours, more than 50% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 12 hours, more than 70% (by weight) released after 18 hours and more than 80% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 24 hours. In one illustrative embodiment the glimepiride is released as follows:
1 hour greater than about 10%; 4 hours greater than about 25%; 6 hours greater than about 40%; and 12 hours greater than 60%.
Tablets formulated according to the invention allow for controlled release metformin hydrochloride over at least a twelve-hour period following oral administration, the in vitro release rate preferably corresponds to the following % rate of metformin hydrochloride released as shown in Table 1:

TABLE I
TIME (H) % RELEASED

Yet another preferred preparation particularly suited for once-a-day dosing has an in-vitro release rate corresponding to the following % rate of metformin hydrochloride released as shown in Table 2:

TIME (H) % RELEASED

A still farther preferred preparation in accordance with the invention is also particularly suited for once-a-day dosing has an in vitro release rate corresponding to the following % rate of metformin hydrochloride released as shown in Table 3:

TIME (H) % RELEASED

24 >80 Another preferred dissolution rate in vitro upon release of the controlled release preparation for administration twice daily according to the invention is between 5 and 50%
(by weight) metformin hydrochloride released after 1 hour, between 10 and 75%
(by weight) metformin hydrochloride released after 2 hours, between 20 and 95% (by weight) metformin hydrochloride released after 4 hours, between 40 and 100% (by weight) metformin hydrochloride released after 8 hours, more than 50% (by weight) metformin hydrochloride released after 12 hours, more than 70% (by weight) released after 18 hours and more than 80% (by weight) metformin hydrochloride released after 24 hours.
A formulation in accordance with the invention suitable for once a day or twice a day dosing and may have a Tn,,_, of 3 to 10 hours, preferably 2 to 7 hours.
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. The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations.
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington:
The Science and Practice of Pharmacy, 19'h Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa.,1995.
The pharmaceutical compositions may be specifically forinulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. I:iquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermai patches, implants etc. A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as I to 3 times per day may contain from 0.05 to about 3000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration. The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is a base addition salt of a compound having the utility of a free acid. When a compound of the formula (I) contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above. For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about I g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. A typical tablet that may be prepared by conventional tableting techniques may contain:

Claims (23)

1. A pharmaceutical composition comprising, a first active ingredient comprising a sulfonylurea or a pharmaceutically acceptable salt thereof as active ingredient, a second active ingredient a comprising biguamide or a pharmaceutically acceptable salt thereof as active ingredient as active ingredient.

2. The formulation as defined in claim 1 wherein said biguamide is metformin.

3. The formulation as defined in claim 2 wherein said sulfonylurea is glimepiride hydrochloride in an amount ranging from about 1mg to about 8mg and, said metformin is present in an amount ranging from about 10 mg to about 4000 mg.

4. The formulation as defined in claim 2 which further comprises an extended release polymer having a predetermined rate of degradation.

5. The formulation as defined in claim 3, wherein said glimepiride hydrochloride and/or said metformin are present as biodegradable microspheres having a biodegradable shell coating and where said shell coating has a predetermined rate of degradation.

6. A method of administering glimepiride hydrochloride and metformin to a mammal, which comprises treating the mammal with the formulation defined in claim 2.

7. A method for producing a controlled release formulation, which comprises:
(a) producing a first component comprising a biodegradable material having a predetermined rate of degradation to provide a predetermined delay in the time period of release of the contents destined to be enclosed by said component;
(b) producing a second component comprising metformin and having a secondary layer comprising glimepiride hydrochloride partially enclosing said second component;
and (c) combining said first and second component forming an extended release matrix allowing said metformin and glimepiride to be released in a therapeutically acceptable manner.

8. A method of producing a combined formulation of glimepiride hydrochloride and metformin, which comprises:
(a) providing a therapeutic selected amount of metformin or a pharmaceutically acceptable salt thereof; and (b) providing a therapeutic selected amount of glimepiride or a pharmaceutically acceptable salt thereof; and combining said metformin and said glimepiride in a pharmaceutically acceptable binders and exceipents.

9. A method of treating diabetes mellitus in a patient in need thereof, which comprises administering to the patient the formulation of claim 2 wherein said active ingredients are each present in an therapeutically effective amount.

10. A pharmaceutical composition in a single integral unit consisting essentially of a therapeutically effective amount of glimepiride hydrochloride combined with a therapeutically effective amount of metformin.

11. A pharmaceutical composition in a single integral unit consisting essentially of a therapeutically effective amount of glimepiride hydrochloride combined with a therapeutically effective amount of buformin.

12. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the integral composition of claim 10.

13. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the integral composition of claim 11.

14. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the composition of claim 1 wherein the biguamide is phenformin.

15. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the composition of claim 1 wherein the biguamide is buformin.

16. A process for preparing an oral dosage form of metformin in combination with a sulfonylurea or a pharmaceutically acceptable salt thereof wherein the hardness of said oral dosage form is at least about 8kg/cm2 comprising steps of (i) granulating metformin hydrochloride with about 0.1 to about 10% binder (ii) dispersing the resulting granules in one or more rate-controlling hydrophilic polymers;
(iii) blending in a sulfonylurea; and (iv) compressing the composition so obtained into tablets of at least about 8kg/cm2.

17. The process of claim 16 further comprising the step of adding about 0.5 %
to about 4% of unbound metformin or pharmaceutically acceptable salt thereof wherein said unbound metformin is dispersed within said one or more rate-controlling hydrophilic polymers.

18. The process of claim 16 wherein said binder is selected from the group consisting of copovidone, polyvinyl pyrrolidone, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol and sodium carboxy methyl cellulose.

19. The process of claim 16 wherein said binder copovidone.

20. The process of claim 16 further comprising the step of adding one or more tableting lubricants in an amount within the range of from about 0.2 to about 8%

21. The process of claim 16 said hydrophilic polymers is selected from the group consisting of Eudragit RS, Eudragit RL, xanthan gum, karaya gum, locust bean gum, guar gum, gelan gum, gum arabic, tragacanth, carrageenan, pectin, carboxymethyl cellulose, agar, alginic acid, sodium alginate polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, vinyl acetate copolymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof.

22. The process of claim 16 wherein said hydrophilic polymers is selected from the group consisting of hydroxypropylmethylcellulose 2208 USP, hydroxypropylmethylcellulose 2910 USP, sodium carboxy methylcellulose and mixtures thereof.

23. The process of claim 16 wherein said sulfonylurea is glimepiride hydrochloride in an amount ranging from about 1mg to about 8mg and, said metformin is present in an amount ranging from about 10 mg to about 4000 mg.