DESC:TECHNICAL FIELD OF THE INVENTION
This invention relates to a process of preparing solid oral pharmaceutical compositions comprising metformin or pharmaceutically acceptable salt thereof. The composition of the invention comprises a solid oral dosage form which provides sustained release of the metformin. Specifically, the composition is provided in the form of sustained release tablet. Such compositions exhibit reproducible sustained release profile and improved storage stability. The invention also includes a method of treating type-2 diabetes mellitus by administering the composition to a patient in need thereof.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a common disorder more prevalent in developed countries. In the United States diabetes mellitus affects approximately 7.5 million people. It is characterized by its clinical manifestations, namely the non-insulin-dependent or maturity onset form, also known as Type 2 diabetes and the insulin-dependent or juvenile onset form, also known as Type 1 diabetes. Type 2 diabetes is a disease characterized by high-circulating blood glucose, insulin and corticosteroid levels.
As therapeutic agents for diabetes mellitus, those which promote insulin secretion such as sulfonylurea agent and sulfonylamide agent, those which promote insulin resistance such as thiazolidione agent and biguanide agent, those which improve postcibal hyperglycemia such as. Alpha-glucosidase inhibitor and the like have been known, and for the treatment of diabetes mellitus, these agents are used either solely or in combination.
Metformin is the member of the biguanide class of an oral antihyperglycemics and available in various salt forms, e.g. hydrochloride. Metformin is used in the management of type 2 diabetes mellitus. It is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Chemically, metformin hydrochloride is 1-carbamimidamido-N,N-dimethylmethanimidamide hydrochloride with the following structure:

Pharmacologic mechanism of action of metformin is different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
U.S. Patent No. 6,340,475 discloses a controlled-release oral drug dosage formulation designed for gastric retention and controlled delivery of metformin into the gastric cavity.
Extended-release formulations of metformin are disclosed in several other U.S. Patent No.s 6,635,280; 6,866,866; 6,475,521 and 6,660,300.
The use of metformin hydrochloride in sustained release tablets dosage form for the treatment of diabetes is known since years, but the daily dose of metformin is considerably very high which may gives a very large size, shape and weight to the final dosage form. This large size, shape and weight of the dosage form of metformin hydrochloride sometimes leads into the patient non-compliance, acceptability of medication regimens or could lead to medication errors. While taking patient compliance in concern US FDA has issued guidance for Size, Shape and Other Physical Attributes of Generic Tablets and Capsules. Hence development of low weight and size dosage form is necessary.
Metformin Hydrochloride is water soluble drug, sustaining the release of Metformin or pharmaceutically acceptable salt thereof with minimum amount of release controlling polymer is a difficult task. The daily recommended starting dose of metformin is very high, 500 mg to 850 mg for children, adults and adolescents which are administered several times in a day depending on the diabetic condition of the individual. The maximum recommended dose of metformin hydrochloride is 3 grams daily, taken in three divided doses. Thus, high bulk or large size dosage form may impair patient compliance specifically in case of children and elderly as small bulk dosage form is usually recommended for them.
To develop a sustained release dosage form of metformin with less amount of rate controlling polymer is a challenging task.
Therefore there exists a dire need to develop novel dosage forms of metformin which will have small size, appropriate shape and low weight of the final composition.
Hence it is an object of the invention to provide a novel dosage form of metformin or pharmaceutically acceptable salt thereof which will have small size, shape and weight of the final composition.
The invention also provides process for preparing pharmaceutical compositions comprising pharmaceutically effective amounts of metformin or pharmaceutically acceptable salt thereof.
The inventors of the invention have surprisingly found that it is possible to formulate a stable sustained release pharmaceutical composition of metformin or pharmaceutically acceptable salt thereof, which is having very small size, shape and low weight of the final dosage form, and also the formulation exhibits superior chemical and physical stability.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a solid pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof.
In another general aspect, there is provided a solid pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical composition is in sustained release form.
In another general aspect, there is provided a solid pharmaceutical composition comprising:
(a) metformin or pharmaceutically acceptable salt thereof;
(b) one or more polymer and/or combinations thereof.
In another general aspect, there is provided a solid pharmaceutical composition comprising:
(a) metformin or pharmaceutically acceptable salt thereof;
(b) one or more polymer and/or combinations thereof; and
(c) one or more pharmaceutically acceptable excipients.
In another general aspect, there is provided a solid pharmaceutical composition comprising:
(a) metformin or pharmaceutically acceptable salt thereof;
(b) one or more polymer and/or combinations thereof;
(c) one or more pharmaceutically acceptable excipients; and
(d) optionally, an outer film coating.
In another general aspect, there is provided a process of preparing a solid pharmaceutical composition comprising:
a) metformin or pharmaceutically acceptable salt thereof;
b) one or more polymer comprising hydroxylpropyl methyl cellulose or acrylic acid polymer or combination thereof; and
c) one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the range of 70% w/w to 90% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the range of 70% w/w to 80% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the range of 70% w/w or 75% w/w or 80% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the amount of 76% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the hydroxylpropyl methyl cellulose is present in the range of 3% w/w to 8% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the hydroxylpropyl methyl cellulose is present in the range of 4% w/w to 6% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the hydroxylpropyl methyl cellulose is present in the amount of 4.5% w/w or 4.6% w/w or 4.7% w/w or 4.8% w/w or 4.9% w/w or 5% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the range of 7% w/w to 20% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the range of 8% w/w to 20% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the range of 10% w/w to 15% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the amount of 10.8% w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the range of 14.15% w/w of the composition.

In another general aspect, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 70% to 80% w/w of metformin or pharmaceutically acceptable salt thereof;
b) 4% to 6 % w/w of hydroxylpropyl methyl cellulose;
c) 8% to 20% w/w of carboxypolymethylene polymer; and
d) one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 500 mg of metformin or pharmaceutically acceptable salt thereof;
b) 30mg of hydroxylpropyl methyl cellulose;
c) 92mg of carboxypolymethylene polymer; and
d) one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 1000mg metformin or pharmaceutically acceptable salt thereof;
b) 60mg hydroxylpropyl methyl cellulose;
c) 135mg carboxypolymethylene polymer; and
d) one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 500mg metformin or pharmaceutically acceptable salt thereof;
b) 30mg hydroxylpropyl methyl cellulose;
c) 92mg carboxypolymethylene polymer;
d) 20mg polyvinyl pyrrolidone;
e)10mg microcrystalline cellulose; 4.75mg colloidal silicon dioxide; 3.25mg magnesium stearate; and
f) one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 1000mg metformin or pharmaceutically acceptable salt thereof;
b) 60mg hydroxylpropyl methyl cellulose;
c) 135mg carboxypolymethylene polymer;
d) 40mg polyvinyl pyrrolidone;
e) 20mg microcrystalline cellulose; 9mg colloidal silicon dioxide; 6.25mg magnesium stearate; and
f) one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a pharmaceutical composition; wherein the composition exhibits a dissolution profile such that 25% to 45% of metformin or a pharmaceutically acceptable salt thereof is released within 1 hour; about 55% to about 75% of metformin or a pharmaceutically acceptable salt thereof is released within 3 hours and at least 80% of metformin or a pharmaceutically acceptable salt thereof is released within 10 hours; when the release rate is measured in dissolution apparatus type 2 at 100 rpm using 900 ml of phosphate buffer having pH 6.8 at 37°C ± 0.5°C as dissolution medium.

In another general aspect, there is provided a pharmaceutical composition; wherein the composition is present in the form of powder, tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, minitablets or premixed powder filled in capsule.
In another embodiment, there is provided a process for preparing a pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
(a) milling the metformin or pharmaceutically acceptable salt thereof;
(b) mixing the metformin or pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients;
(c) granulating the mixture using suitable binder solution; and
(d) drying to get granules which on lubrication compressed to form the tablet.

In another embodiment, there is provided a process for preparing a pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
(a) milling the metformin or pharmaceutically acceptable salt thereof;
(b) mixing the metformin or pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients;
(c) granulating the mixture using suitable binder solution;
(d) drying to get granules which on lubrication compressed to form the tablet; and
(e) optionally, coating the tablet with suitable film coating.
In another general aspect, the coating layer is applied by spray coating; perforated pan coaters or fluid bed coaters can be used.

In general aspect there is provided a method of treating type-2 diabetes mellitus in a patient which method comprising administering the pharmaceutical composition as substantially described herein to the patient.

DETAILED DESCRIPTION OF THE INVENTION
The term "metformin" used throughout the specification refers to not only metformin per se, but also their other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
The compositions of the invention can be prepared together with at least one pharmaceutically acceptable excipient or as oral, parental, inhalation dosage forms comprising the active agent. The pharmaceutical compositions of the invention can be prepared in solid forms comprising tablet; capsule; enterically coated or modified-release tablets; controlled-release tablet, extended-release tablet; delayed-release tablet; slow or fast-release tablet; fast soluble tablet; effervescent tablet; effervescent granule; fast soluble powder mixture; water-soluble powder, tablet, or granule; granule; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; micro tablet in capsule or dry powder mixture to prepare syrup; orodispersible tablet; film tablet or combinations thereof; or in any one of liquid forms such as syrup or suspension.
As used herein, the term “sustained release” refers to a pharmaceutical composition which release active over a specific period of time that conforms to a particular pattern of release to effect a therapeutic outcome. The time period may include, but is not limited to, hours, days.
As used herein, the term "treatment" refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.

Pharmaceutical excipients that can be used in the pharmaceutical composition of the invention can be selected from a group comprising one or more binding agents (binders), disintegrants, lubricants, one or more diluents, glidants, wetting agents, coating agents, anti-adhesive agents, swelling agent, viscosity enhancing agents, filling agents, drying agents, rate controlling polymer agent, surfactants, cosolvents, acidifier, alkaliser, stabilizing agents, pH regulators, flavouring agent, sweeteners, emulgators, antifoaming agents, antioxidants, protective agents, solvents or solvent combinations, colouring agents and complexing agents or the combinations thereof.
The disintegrants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate or combinations thereof.
The binders that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, copovidone, starch or combinations thereof.
The diluents that can be used in the pharmaceutical compositions according to the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch and starch derivatives, sodium chloride, sucrose, talc, xylitol or the combinations thereof.
The lubricants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.
The glidants that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, magnesium trisilicate, cornstarch, talc and the like or combinations thereof.
The release controlling substances which can be used may be selected from the group consisting of hydrophilic agents (e.g. water-soluble polymers), lipophilic agents (water-insoluble polymers) and inert matrix agents, wherein the hydrophilic agents are selected from the group of pharmaceutical excipients which generate a gel in contact with water, including cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like; noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; acrylic acid polymers and copolymers, polyethylene oxide and mixtures thereof; the lipophilic agents are selected from the group consisting of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin, hydrogenated vegetable, castor, cottonseed oils, glyceryl behenate and the like; ethyl cellulose; acrylic acid polymers and copolymers (available commercially under Eudragit® brand); and mixtures thereof; and the inert agents are selected from the group consisting of thermoplastic polymers, which are insoluble and indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.
The solid dosage forms of the invention can be coated with coatings such as protective coating, enteric-coating, moisture barrier coating, film-coating and/or those designed to provide various release properties (such as fast-release, slow-release, controlled-release) afterwards.
The pharmaceutical compositions of the invention are prepared by wet or dry processing methods. In general aspect of the invention the pharmaceutical compositions are prepared by wet processing methods. In a class of this aspect the pharmaceutical compositions are prepared by wet granulation methods. With wet granulation either high-shear granulation or fluid-bed granulation may be used. In this aspect fluid-bed granulation is employed which has the advantage of affording tablets with higher diametric strength.
In another general aspect the pharmaceutical compositions are prepared by dry processing methods. In a class of this aspect the pharmaceutical compositions are prepared by direct compression or dry granulation methods. Dry granulation is done by using roller compaction.
The pharmaceutical compositions obtained by the dry or wet processing methods may be compressed into tablets, encapsulated, or metered into sachets.

In one embodiment, there is provided a solid pharmaceutical composition comprising:
(a) metformin or pharmaceutically acceptable salt thereof;
(b) one or more polymer and/or combinations thereof.
In another embodiment, there is provided a solid pharmaceutical composition comprising:
(a) metformin or pharmaceutically acceptable salt thereof;
(b) one or more polymer and/or combinations thereof; and
(c) one or more pharmaceutically acceptable excipients.
In another embodiment, there is provided a solid pharmaceutical composition comprising:
(a) metformin or pharmaceutically acceptable salt thereof;
(b) one or more polymer and/or combinations thereof;
(c) one or more pharmaceutically acceptable excipients; and
(d) optionally, an outer film coating.
In another embodiment, there is provided a solid pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical composition is in sustained release form.
In another embodiment, there is provided a process of preparing a solid pharmaceutical composition comprising:
a) metformin or pharmaceutically acceptable salt thereof;
b) one or more polymer comprising hydroxylpropyl methyl cellulose or acrylic acid polymer or combination thereof; and
c) one or more pharmaceutically acceptable excipients.

In another embodiment, there is provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the range of 70% w/w to 90% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the range of 70% w/w to 80% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the range of 70% w/w or 75% w/w or 80% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the amount of 76% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the hydroxylpropyl methyl cellulose is present in the range of 3% w/w to 8% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the hydroxylpropyl methyl cellulose is present in the range of 4% w/w to 6% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the hydroxylpropyl methyl cellulose is present in the amount of 4.5% w/w or 4.6% w/w or 4.7% w/w or 4.8% w/w or 4.9% w/w or 5% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the range of 7% w/w to 20% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the range of 8% w/w to 20% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the range of 10% w/w to 15% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the amount of 10.8% w/w of the composition.

In another embodiment, there is provided a pharmaceutical composition; wherein the acrylic acid polymer is carboxypolymethylene polymer, and is present in the range of 14.15% w/w of the composition.

In another embodiment, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 70% to 80% w/w of metformin or pharmaceutically acceptable salt thereof;
b) 4% to 6 % w/w of hydroxylpropyl methyl cellulose;
c) 8% to 20% w/w of carboxypolymethylene polymer; and
d) one or more pharmaceutically acceptable excipients.

In another embodiment, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 500 mg of metformin or pharmaceutically acceptable salt thereof;
b) 30mg of hydroxylpropyl methyl cellulose;
c) 92mg of carboxypolymethylene polymer; and
d) one or more pharmaceutically acceptable excipients.

In another embodiment, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 1000mg metformin or pharmaceutically acceptable salt thereof;
b) 60mg hydroxylpropyl methyl cellulose;
c) 135mg carboxypolymethylene polymer; and
d) one or more pharmaceutically acceptable excipients.

In another embodiment, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 500mg metformin or pharmaceutically acceptable salt thereof;
b) 30mg hydroxylpropyl methyl cellulose;
c) 92mg carboxypolymethylene polymer;
d) 20mg polyvinyl pyrrolidone;
e)10mg microcrystalline cellulose; 4.75mg colloidal silicon dioxide; 3.25mg magnesium stearate; and
f) one or more pharmaceutically acceptable excipients.

In another embodiment, there is provided a process of preparing a sustained release pharmaceutical composition comprising:
a) 1000mg metformin or pharmaceutically acceptable salt thereof;
b) 60mg hydroxylpropyl methyl cellulose;
c) 135mg carboxypolymethylene polymer;
d) 40mg polyvinyl pyrrolidone;
e)20mg microcrystalline cellulose; 9mg colloidal silicon dioxide; 6.25mg magnesium stearate; and
f) one or more pharmaceutically acceptable excipients.

In another embodiment, there is provided a pharmaceutical composition; wherein the composition exhibits a dissolution profile such that 25% to 45% of metformin or a pharmaceutically acceptable salt thereof is released within 1 hour; about 55% to about 75% of metformin or a pharmaceutically acceptable salt thereof is released within 3 hours and at least 80% of metformin or a pharmaceutically acceptable salt thereof is released within 10 hours; when the release rate is measured in dissolution apparatus type 2 at 100 rpm using 900 ml of phosphate buffer having pH 6.8 at 37°C ± 0.5°C as dissolution medium.

In another embodiment, there is provided a pharmaceutical composition; wherein the composition is present in the form of powder, tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, minitablets or premixed powder filled in capsule.
In another embodiment, there is provided a process for preparing a pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
(a) milling the metformin or pharmaceutically acceptable salt thereof;
(b) mixing the metformin or pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients;
(c) granulating the mixture using suitable binder solution; and
(d) drying to get granules which on lubrication compressed to form the tablet.
In another embodiment, there is provided a process for preparing a pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
(a) milling the metformin or pharmaceutically acceptable salt thereof;
(b) mixing the metformin or pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients;
(c) granulating the mixture using suitable binder solution;
(d) drying to get granules which on lubrication compressed to form the tablet; and
(e) optionally, coating the tablet with suitable film coating.
The pharmaceutical tablet compositions of the invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients known in the pharmaceutical formulation art. According to the desired properties of the pharmaceutical composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparing tablet compositions. Such ingredients include, but are not limited to, diluents, compression aids, glidants, disintegrants, lubricants, flavors, flavor enhancers, sweeteners, and preservatives.
In another embodiment, the coating layer is applied by spray coating; perforated pan coaters or fluid bed coaters can be used.
The term "tablet" as used herein is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.
In another embodiment, there is provided a method of treating type-2 diabetes mellitus in a patient which method comprising administering the pharmaceutical composition in accordance with the invention.
The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
In accordance with the Invention tablet formulations are set out below –
EXAMPLES
Example 1: Metformin Sustained Release Tablet
Table 1
Sr. No. Ingredients Quantity (mg/tablet)
Dry Mix
1 Metformin Hydrochloride 500.00
2 Microcrystalline Cellulose 5-15
3 Hydroxy Propyl Methyl Cellulose K100M 20-40
Binder
4 Polyvinyl Pyrrolidone (K- 90) 5-15
5 Purified water q. s.
Lubrication
6 Carboxymethylene Carbomer (Carbopol 971P) 40-60
7 Carboxymethylene Carbomer (Carbopol 71G) 30-55
8 Colloidal Silicone Dioxide 2-7
9 Magnesium Stearate 1.5-4.5
Total weight of Tablet 630-670

Procedure:
Metformin hydrochloride was milled through multi-mill (1mm screen). Microcrystalline cellulose and hypromellose was sifted through #40 mesh. Polyvinyl pyrrolidone was dissolved in purified water. Metformin, microcrystalline cellulose and hypromellose were mixed in rapid mixer granulator & were granulates using the binder solution. The granules were then dried in fluidized bed dryer. The dried granules were then passed through #16 mesh. The retention was milled through 3.0 mm screen followed by 1.5 mm screen. Carbopol 971P was sifted through #16 mesh & Carbopol 71G and colloidal silicon dioxide was sifted through #30 mesh. The sized granules, carbopol and colloidal silicon dioxide were blended for 10 minutes. Magnesium stearate was then added in blender and mixed for about 3 minutes. This blend was then compressed by using compression machine.
Example 2: Metformin Sustained Release Tablet
Table 2
Sr. No. Ingredients Quantity (mg/tablet)
Dry Mix
1 Metformin Hydrochloride 1000.00
2 Microcrystalline Cellulose 15-25
3 Hydroxy Propyl Methyl Cellulose K100M 45-75
Binder
4 Polyvinyl Pyrrolidone (K- 90) 15-25
5 Purified water q. s.
Lubrication
6 Carboxymethylene Carbomer (Carbopol 971P) 80-110
7 Carboxymethylene Carbomer (Carbopol 71G) 30-50
8 Colloidal Silicone Dioxide 6-12
9 Magnesium Stearate 4-9
Total weight of Tablet 1220-1280

Procedure:
The tablets of 1000mg metformin were prepared in a similar manner as that of the procedure mentioned for preparation of example 1 of this invention.

Example 3: Metformin Sustained Release Tablet
Table 3
Sr. No. Ingredients 500 mg (mg/tablet) 1000 mg (mg/tablet)
Dry Mix
1 Metformin Hydrochloride 500.00 1000.00
2 Microcrystalline Cellulose 10.00 20.00
3 Hypromellose K100M 30.00 60.00
Binder
4 Polyvinyl Pyrrolidone (K- 90) 10.00 20.00
5 Purified water q.s q.s
Lubrication
6 Carboxymethylene Carbomer
(Carbopol 971P) 50.00 95.00
7 Carboxymethylene Carbomer
(Carbopol 71G) 42.00 39.75
8 Colloidal Silicone Dioxide 4.75 9.00
9 Magnesium Stearate 3.25 6.25
Total 650.00 1250.00

Procedure:
The tablets of 500 mg and 1000mg metformin were prepared in a similar manner as that of the procedure mentioned for preparation of example 1 of this invention.
Dissolution Data
The dissolution data of metformin tablet of example 1, 2 and 3 was obtained by using dissolution Apparatus Type 2 (Basket) in a 900ml phosphate buffer pH 6.8 at 100 rpm, and is mentioned below in table 4
Table 4
Time Points (Hour) Dissolution (%)
1 34-40
3 59-68
10 87-93

,CLAIMS:1. A process of preparing a sustained release pharmaceutical composition comprising:
a) metformin or pharmaceutically acceptable salt thereof;
b) one or more polymer comprising hydroxylpropyl methyl cellulose or acrylic acid polymer or combination thereof; and
c) one or more pharmaceutically acceptable excipients.

2. A process for preparing a pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
(a) milling the metformin or pharmaceutically acceptable salt thereof;
(b) mixing the metformin or pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients;
(c) granulating the mixture using suitable binder solution; and
(d) drying to get granules which on lubrication compressed to form the tablet.
3. A process for preparing a pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
(a) milling the metformin or pharmaceutically acceptable salt thereof;
(b) mixing the metformin or pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients;
(c) granulating the mixture using suitable binder solution;
(d) drying to get granules which on lubrication compressed to form the tablet; and
(e) optionally, coating the tablet with suitable film coating.
4. A process of preparing a sustained release pharmaceutical composition according to claim 1 comprising:
a) 70% to 80% w/w of metformin or pharmaceutically acceptable salt thereof;
b) 4% to 6 % w/w of hydroxylpropyl methyl cellulose;
c) 8% to 20% w/w of carboxypolymethylene polymer; and
d) one or more pharmaceutically acceptable excipients.

5. A process of preparing a sustained release pharmaceutical composition according to claim 1 comprising:
a) 500 mg of metformin or pharmaceutically acceptable salt thereof;
b) 30mg of hydroxylpropyl methyl cellulose;
c) 92mg of carboxypolymethylene polymer; and
d) one or more pharmaceutically acceptable excipients.

6. A process of preparing a sustained release pharmaceutical composition according to claim 1 comprising:
a) 1000mg metformin or pharmaceutically acceptable salt thereof;
b) 60mg hydroxylpropyl methyl cellulose;
c) 135mg carboxypolymethylene polymer (carbopol); and
d) one or more pharmaceutically acceptable excipients.