FORM 2
Patent Act 1970
(Act 39 of 70)
Complete Specifications
Section 10


" A pharmaceutical composition containing anti-diabetic substance for oral administration."
Applicant: - Unichem Laboratories Ltd., an Indian company having office at Mahalaxmi Chambers , 2nd Floor,22,Bhulabhai Desai Road, Mumbai 400026, India.
The following specification particularly describes the nature of this invention and the manner in which it is to be performed :-

Background of Invention:
The present invention relates to a pharmaceutical composition comprising of one or more anti-diabetic substance as a modified release dosage form for oral administration and a process for the preparation thereof.
For many disease states the ideal dosage regimen is that by which an acceptable therapeutic concentration of the drug at the site(s) of action is attained immediately and is then maintained constant for the duration of the treatment. Provided dose administered and frequency of administration are correct, therapeutic "steady - state" plasma concentrations of a drug can be achieved promptly and maintained by the repetitive administration of conventional per oral dosage forms. However, there are a number of potential limitations associated with conventional per oral dosage forms such as increased frequency of dosing leading to patient non-compliance, sea-saw effect of profiles of drug in blood after every dosing leading to either inadequate bio-availability or increased incidences of adverse reactions. These limitations have led pharmaceutical scientists to consider presenting therapeutically active molecules in "extended - release" preparations or drug delivery systems.
Metformin is an oral anti-hyper glycemic drug used in the management of Type 2 diabetic subjects (non-insulin dependent diabetes mellitus; NIDDM) lowering both basal and post prandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization).
Metformin treated patients show significant improvement in all parameters of glycemic control, stabilization or decrease in body weight and a tendency to improve in the lipid profile particularly when base line values are abnormally elevated and therefore is widely permitted.

However, being short acting drug, metformin requires twice - daily (b.i.d) or three times-a-day (t.i.d) dosing. Adverse events associated with metformin use are often gastro intestinal in nature (eg. Anorexia, nausea, vomiting and occasionally diarrhoea etc). These adverse events may be partially avoided by either administrating appropriate maintenance dose to patients timely or using an extended release dosage form.
The main object of the present invention is to provide an improved pharmaceutical composition comprising of an anti-diabetic biguanide substance (such as metformin hydrochloride) as modified release oral dosage form either singly or in combination with another drugs as rapid release and a process for the preparation thereof.
Several patents and bibliographic references disclose sustained/extended release dosage forms containing metformin hydrochloride . WO 2004006921, US 6676966, WO 03099214, US 20030219482, US 20030171407, WO 03072083, US 6524618, WO 02036100, J.Controlled Release (2002) : 80(1-3):p119-128, US 20010018070, WO 01056544, WO 0132158, US 6099862, EP 976345, US 5955106, WO 03028704, US 6475521, WO 0236100, US 20010024659, US 20030021841, US 2003118647, US 2003104059, US 2003170302, US 6056977 and US 6403121. These teach diverse modified release metformin formulations containing ingredients selected from cellulose derivatives viz. hydroxy propyl methyl cellulose, ethyl cellulose, polymethacrylates and methacylic acid co polymers, waxes, gums, povidone and the like as release retarding excipients and employ matrix or barrier / lamination coating techniques for modifying the metformin release.
The inventions disclosed in the above patents have severe limitations such as ; WO 02036100, WO 0236100 and US 20010024659 use osmotic delivery technology for extending / sustaining the release of metformin either using laser

drill method, which is an extremely expensive procedure leading to high end product cost.
WO 03072083, J.Controlled Release (2002) : 80( 1-3):p119-128, WO 03028704, WO 0236100, US 20010024659, US 20030021841 use semi-permeable membrane of acrylates and acrylic acid copolymer and other bio-nondegradable polymers. As metformin therapy is of a permanent nature, the preferred choice of rate control polymer should always be a harmless material suitable for human consumption.
WO 03099214, US 20030219482, US 6524618, WO 02036100, US 20010018070, WO 01056544, WO 0132158, US 6099862, EP 976345, DE 4432757,WO 03028704, US 6475521, US20030021841, US 2003118647, US 2003104059 use cellulose polymers, gums, polyoxy ethylene derivatives that have inherently wide range of viscosity. Moreover functionality of cellulose polymers is also pH dependent as they degrade in the acid pH of the stomach. Yet another limitation of cellulose, cellulose derivatives, gums etc. are that they swell rapidly and entrap drugs for sustaining their release. Hence, to a limited extent they may be useful if a single drug is present in the formulation but in case of multi-ingredient products where in differential release of drugs are essential these cellulose, gums etc tend to protract dissolution of all drugs leading to wrong bio-availability profiles when administered to a patient.
Administration of metformin as modified release and another anti-diabetic drug as rapid release tablets has been disclosed in WO 2004006921. This patent discloses a process of producing coated compositions of metformin hydrochloride in combination with pioglitazone. Pioglitazone hydrochloride is dispersed in a coating solution contaning ethanol and applied on the surface of a core tablet containing metformin hydrochloride. This process has severe limitation as it leaves large amounts of residual organic vapour in the product. Moreover, coating techniques normally involves 20- 30 % excess use of coating

solids to compensate for the loss during coatina operation. This could lead to inaccuracy of dosage of the 2nd anti-diabetic drug (as it would be dependent upon the efficiency and thickness of coating film over the metformin core tablet). Any inefficiency in the drug coating operation could lead to non-uniformity of dosage of the drug or dose dumping leading to hypo-glycemic shock in a patient.
Hence there is a need to formulate a dosage form of metformin or its pharmaceutical^ effective salts either alone or in combination with other anti¬diabetic agents which exhibits modified release of metformin and accurately programmed release of other drug(s) from a multi-ingredient solid oral formulation and is precise as well as accurate in the delivery of all drugs from the dosage form and employs an industrially feasible cost-effective process.
Metformin hydrochloride has intrinsically poor permeability in the lower portion of the gastro-intestinal tract (git) leading to absorption almost exclusively in the upper part of the git. It is also very freely water soluble. These two difficulties are further compounded by the high unit doses (500 -1500 mg per tablet) usually required for metformin hydrochloride. The situation becomes more complicated when metformin as modified (slow) release is present in combination with another anti-diabetic or other pharmaceutically active substance which is to be administered as rapid release.
In addition, metformin hydrochloride intrinsically has poor compressibility and tends to produce capping during tablet compression. Hence, metformin tablet formulations be it conventional or modified release have to be particularly designed so as to achieve all the desired tablet characteristic in addition to exhibiting desired release rate of metformin.
There are few patents cited in prior art that disclose methods to over come capping during compression of tablets containing metformin viz. US 6117451 provides a direct compression tabletting process capable of giving tablets having

adequate hardness. This formulation employs specific particle size and density range excipients to improve the flow and compressibility characteristics. Use of these excipients not only adds to the cost but also makes the process cumbersome.
PCT application WO 99/47128 describes a method for preparing a biphasic controlled release of metformin from the tablet. This formulation provides the desired extended release and tackles the problem of capping but may result in segregation of granules/ particles due to different particle size and densities during compression. Content uniformity can be difficult to achieve. Moreover , large number of processing steps and high processing times can lead to increased manufacturing costs.
US 5955106 discloses a pharmaceutical composition containing metformin and method of producing the composition where in the metformin granules have a residual moisture content of about 0.5- 3% by weight which is disclosed as critical to avoid capping of the tablets. Presence of this moisture may be suitable for metformin tablet but any other drug in combination with metformin may therefore be subjected to a probable risk of degradation there by leading to a product with unacceptable quality characteristics.
Therefore, there is also a need to formulate a dosage form which exhibits modified (slow) release of metformin without impacting the fast/programmed release of other drug(s) from a multi-ingredient solid oral dosage formulation and also gives a dosage form with acceptable product characteristics, aesthetic appeal and reduced friability.
All the known metformin compositions disclosed in the prior art do not present a single improved composition wherein all of the afore-mentioned disadvantages/ limitations are resolved.

The present invention also deals with formulation of a dosage form of modified release of anti-diabetic biguanide either alone or in combination with other drugs such as anti-diabetic agent(s) as immediate release that is precise and accurate in drug delivery, does not lead to dose dumping, overcomes capping and layer separation problems during tabletting, does not employ cellulose, gums, waxes, methacrylates as retard polymer and yet gives an accurate release of all drugs as programmed , can be efficiently used at reduced concentrations in comparison to those disclosed in the prior art, is safe for human consumption and is stable and of acceptable quality for commercial feasibility.
Scope of the invention:
The main object of the present invention is to provide an improved pharmaceutical composition comprising of an anti-diabetic biguanide substance such as metformin or its hydrochloride salt or other pharmaceutically effective salt or prodrug as modified (slow) release oral dosage form either singly or in combination with other drugs such as another anti-diabetic agents so as to ensure slow release of the biguanide without impacting the fast release of the other drug(s).
Another object of the present invention is to provide a process of preparation of an improved pharmaceutical composition of an anti-diabetic biguanide such as metformin or its hydrochloride salt or other pharmaceutical ly effective salt or pro¬drug as modified release oral dosage form either singly or in combination with other drugs.
Still another object of the present invention is to provide a process of preparation of modified release dosage form containing anti-hyper glycemic agent(s) that does not employ a cellulose derivative, gum, wax, methacrylate as release retardant.

Yet another object of the present invention is to provide a process of preparation of modified (slow) release dosage form containing an anti-hyper glycemic biguanide that contains excipients capable of retarding release of the drug(s) as well as yield strength / hardness to the composition and has good compressibility, reduced friability and does not produce separation of layers when produced as a bilayered tablet composition.
Yet another object of the present invention is to provide a process of preparation of a modified (slow) release pharmaceutical dosage form containing anti-hyper glycemic biguanide or a pharmaceutically acceptable salt or a derivative or a pro¬drug thereof that produces composition with good aesthetic appeal, has industrial feasibility and is cost-effective
Yet another object of the present invention is to provide a process of preparation of modified (slow) release dosage form of an anti-hyper glycemic biguanide such as metformin or its hydrochloride salt or other pharmaceutical ly effective salt or pro-drug that can provide continuous and non-pulsating therapeutic levels of the drug to a mammal in need of such treatment over a twelve-hour or twenty-four hour period.
It is a further object of the present invention to develop a process to obtain modified (slow) release pharmaceutical composition containing anti-hyper glycemic drug or a pharmaceutical ly acceptable or derivative or pro-drug thereof, which is stable and of acceptable quality.
Accordingly the present invention provides an improved pharmaceutical composition containing an anti-diabetic substance such as metformin or buformin or its pharmaceutical ly acceptable salt or pro-drug useful as a modified release oral dosage form either singly or in combination with other drugs and comprises of:

i. 0.1 % to 75 % by weight of bulking agent
ii. 0.1 % to 15 % by weight of disintegrant
iii. 0.1 % to 20 % by weight of a binder
iv. 0.1 % to 15 % by weight of wetting agent
v. 0.1 % to 40 % by weight of carbopol
vi. 0.05 % to 15 % by weight of lubricant
vii. 0.1 % to 5 % by weight of glidant
viii. 0.1% to 45% of a lipid
The invention further provides a process for the preparation of improved pharmaceutical composition containing anti-diabetic biguanide substance which comprises :-
i. Sifting the desired amount of the anti-diabetic biguanide agent through
a sieve, ii. Coating the sieved anti-diabetic biguanide agent with the desired
amount of lipid dissolved in an organic solvent to get uniform coated
granules, iii. Granulating the resulting coated anti-diabetic biguanide agent using
the desired amount of the binder and screening the resulting wet mass
from a sieve and drying, iv. Mixing the granules of step iii, with the desired amount of release
retard polymer, other excipients and lubricants and compressed into
tablets or alternately filled into capsules, v. Alternatively, lipid may be melted and used for coating the drug in step
ii and the coated drug may be further used for granulation of step iii,
mixed with the desired amount of retard polymer, lubricating and
additive materials and compressed into tablets or filled into capsules, vi. Granules of other drugs may be compressed along with the slow
release biguanide granules a bi-layered tablet or filled into capsules.

The amount of anti- diabetic biguanide such as metformin or its pharmaceutical ly effective salt or pro-drug may be used in a concentration of 500 mg to about 2500 mg as the free compound or as a pharmaceutically acceptable salt thereof.
The amount of anti- diabetic biguanide such as buformin or its pharmaceutically effective salt or pro-drug may be used in a concentration of 50 mg to about 1000 mg as the free compound or a pharmaceutically acceptable salt thereof.
Detailed description of the invention :-
The present invention relates to an improved pharmaceutical composition comprising of an anti-diabetic biguanide its pharmaceutically active salt or pro¬drug as modified (slow) release oral dosage form either singly or in combination with other drug(s) so as to ensure slow release of the biguanide without impacting the fast release of the other drug(s) and provides a process of preparation of this improved composition.
The amount of anti- diabetic biguanide used may be metformin or its pharmaceutically effective salt or prodrug in a concentration of 500 mg to about 2500 mg, preferably from about 500 mg to about 2000 mg more preferably from about 500 mg to about 1700 mg as the free compound of the pharmaceutically acceptable salt thereof.
The amount of anti- diabetic biguanide used may be buformin or its pharmaceutically effective salt or pro-drug in a concentration of 50 mg to about 1000 mg, preferably from about 50 mg to about 500 mg more preferably from about 50 mg to about 300 mg as the free compound of the pharmaceutically acceptable salt thereof.

The other anti-diabetic drugs present in combination with the biguanide may be therapeutically'effective concentrations of gliclazide or glipizide, glimeperide or glyburide or pioglitazone or rosiglitazone or nateglinide or repaglinide or ezetimib.
The invention disclosed in the present invention is so designed as to achieve the following features :
1. The composition provides effective control of NIDDM blood glucose levels in humans and mammals. The composition provides continuous and non-pulsating therapeutic levels of drug over twelve - hour or twenty four hour period .
2. The composition comprising of modified (slow) release metformin or its pharmaceutically effective salt can be administered alone or in combination with other drugs such as another anti-diabetic agent as immediate release as a tablet or capsule dosage form.
3. The composition is stable and is of an acceptable quality for administering to humans and mammals. The process of preparing this improved composition is also feasible for commercial scale manufacturing of the product.
4. In contrast to the formulations disclosed in prior art, the present formulation avoids the use of hydropropylcellulose or hydroxypropyl methyl cellulose or ethyl cellulose or their derivatives , gum, wax, methacryllate as release retardant agents and achieves the slow release of the anti-diabetic biguanide substance (with out impacting the fast release of other drugs) from the multi-ingredient composition by the judicious use of the polymer such as carbopol grade 971,974. Use of carbopol in combination with a lipid in the slow release metformin composition further improves the tablet characteristics by imparting better hardness to the tablets there by preventing capping, layer separation and chipping.

Use of stearic acid a lipid, in combination with carbopol a release retard polymer, coupled as a tablet hardner is a novel property employed in the process of this improved composition. On comparing the friability data of marketed tablets containing HPMC and the like indicated that chipping, layer separation and high friability as against 'nil' friability exhibited by the tablets prepared using the process disclosed in the present invention.
The technology employed in this improved composition of the present invention is unique sandwich type delivery system that is a membrane/ matrix hybrid system activated by hydration and gives constant drug release versus time. The composition is so formulated using the correct excipients in appropriate concentration so as to give desired slow release for metformin and rapid release of other drugs from a multi-ingredient anti-diabetic oral dosage form.
The bi-layer tablet delivery system comprises of one layer containing drug(s) as a rapid release and other layer comprising of anti-diabetic biguanide such as metformin hydrochloride or the like, coated with a lipid membrane forming the drug reservoir.This is then dispersed in a rate controlling swell-able polymer matrix that gets activated by hydration. The release of the drug gets activated by the hydration induced swelling of the polymer and is modulated/ controlled by membrane permeation- matrix diffusion push-pull effect.
Alternately, the composition can also be formulated as a single tablet or capsule while following the sandwich type mechanisms exhibiting modified release of metformin and the like anti-diabetic substances for administration in NIDDM diabetic humans and mammals.
The pharmaceutical composition of the present invention comprises of anti¬diabetic biguanide as slow release and other drug(s) as rapid release as an oral dosage form which comprises of:

i. 0.1 % to 75 % by weight of bulking agent
ii. 0.1 % to 15 % by weight of disintegrant
iii. 0.1 % to 20 % by weight of a binder
iv. 0.1 % to 15 % by weight of wetting agent
v. 0.1 % to 40 % by weight of carbopol
vi. 0.05 % to 15 % by weight of lubricant
vii. 0.1 % to 5 % by weight of glidant
viii. 0.1 % to 45 % by weight of a lipid
The bulking agent used may be selected from microcrystalline cellulose, dicalcium phosphate, starch, lactose and the like. The amount of the bulking agent used may be in the range of 0.1 % to 75 % by weight, preferably 0.1 % to 50 % of microcrystalline cellulose and preferably 0.1 % to 25 % of dicalcium phosphate
The disintegrant used may be selected from sodium starch glycollate, crospovidone, croscarmellose sodium or calcium, starch, pollacrin and the like. The amount of disintegrant used ranges from 0.1 % to 15 % by weight but preferably 0.1 % to 10 % by weight of sodium starch glycollate .
The binder used may be selected from starch, polyvinyl pyrollidone, gelatin and the like. The amount of binder used ranges from 0.1 % to 20 % by weight but preferably 0.1 % to 5 % by weight of polyvinyl pyrollidone.
The wetting agent used may be selected from polysorbate 20 or 60 or 80, sodium lauryl sulphate, lutrol, cremophore 40, diocytyl sodium sulfo succinate,doccusate sodium and the like. The amount of wetting agent used ranges from 0.1 % to 15 % by weight but preferably 0.1 % to 5 % by weight of polysorbate 80.
The amount of carbopol used may range from 0.1 % to 40 % by weight.

The pharmaceutical composition disclosed in the presented invention has been evaluated in vitro for its assay, dissolution profile in surrogate biological fluids as well as impurities using high performance liquid chromatography (HPLC) techniques.
Results of the analysis of modified release metformin hydrochloride tablets
(1000mg) as disclosed in the invention is as follows :
(a)Assay of Metformin hydrochloride: 98.49%
(b)Dissolution profile in 900 ml Phosphate buffer pH 7.5 , USP apparatus II, 75
rpm> 2 Hours:- 25% (Limit 10-40 %)
4 Hours:- 54% (Limit 20-65 %)
8 Hours:- 70% (Limit 50-100 %)
12 Hours:- 82% (Limit NLT 75%) (a) Related substances:- Less than 1% (Total impurities)
The results of analysis of pharmaceutical composition containing metformin
hydrochloride (500mg) slow release and rapid release of pioglitazone
hydrochlorie (15mg) and glimeperide (2mg) as disclosed in the present invention
are as follows:
(a)Assay of Metformin hydrochloride:- 100.1 %
(b)Assay of pioglitazone hydrochloride: 101 .0 %
©Assay of glimepiride:-102.87%
(d)Dissolution of Metformin hydrochloride in 900ml Phosphate buffer pH 7.5,USP
apparatus II, 75 rpm :-
2 Hours:- 23 % (Limit 10-40%)
4 Hours:- 53 % (Limit 20-65%)
8 Hours:- 68 % (Limit 50-100%)
12 Hours:- 83 % (Limit NLT 75%) (e)Dissolution in 900ml of 0.1 N HCI, USP apparatus II, 75 rpm : of Glimepiride :- 94% ; of Pioglitazone hudrochloride : 100 . % (f) Related impurities:- Total impurities less than 1%

v. The granules of step iv can also be mixed with granules of rapid release anti-diabetic or other drugs and compressed into bi-layered tablets or filled into capsules.
vi. Alternatively, stearic acid may be melted at 40 - 90 degrees centigrade and used for coating the anti-diabetic biguanide and the coated drug may be further used for granulation of step iii, mixed with the desired amount of release retard polymer, lubricating and other additive materials and compressing into tablets or filled into capsules.
The other anti-diabetic drugs present in combination with the biguanide may be therapeutically effective concentrations of gliclazide or glipizide, glimeperide or glyburide or pioglitazone or rosiglitazone or nateglinide or repaglinide or ezetimib. The anti-diabetic drugs disclosed in the present invention may also be combined with vitamins such as vitamin B12 or B3 or B6 or B1 or B2 or folic acid or their derivatives.
The process disclosed in the present invention involves use of the anti-hyper glycemic biguanide substance or its derivative or salt or pro-drug with and may or may not contain at least one further active ingredient.
The composition prepared by the present process may also contain other formulation additives viz. preservatives, colors, flavours, pH adjusters in addition to the earlier listed bulking agents, binders, wetting agents, lubricants glidants, lipid and levigating agents.
Examples of levigating agent without limitation include water, pharmaceutical grade edible oils such corn oil, cotton seed oil, peanut oil, arachis oil and the like, triglycerides, isopropyl myristate, mineral oil, water-isopropanol mixture, water-ethyl alcohol mixture may be used, but preferably water and isopropanol may be used in the composition of the present invention.

The results of analysis of pharmaceutical composition containing metformin
hydrochloride (1000mg) slow release and rapid release of glimeperide (2mg) as
disclosed in the present invention are as follows:
(a)Assay of Metformin hydrochloride:- 100.1%
(b) Assay of glimepiride:-102.87%
© Dissolution of Metformin hydrochloride in 900ml Phosphate buffer pH 7.5
USP apparatus II, 75 rpm :-
2 Hours:- 27% (Limit 10-40%)
4 Hours:- 50% (Limit 20-65%)
8 Hours:- 65% (Limit 50-100%)
12 Hours:- 89% (Limit NLT 75%) (d) Dissolution of Glimepiride In 900ml of 0.1 N HCI, USP apparatus II, 75 rpm paddle:- 96% (e)Related impurities:- Total impurities less than 1%
The pharmaceutical composition so produced as disclosed in the present invention has been evaluated for stability at several combinations of temperature and related impurity as per standard stability test guidelines prescribed by ICH (International conference on harmonization). The stability samples were analyzed by validated chromatographic techniques viz. assay as well as dissolution and related substances. The results are as follows : at the end of 6 months exposure to 40°C ± 2°C / 75 ±5% RH.

Tests Results Acceptance criteria

Initial 1 3 months

Assay
Metformin Hydrochloride(500mg) 100.1 % 99.40 % 95-110%w/w
Glimepiride (2mg) 102.87% 101.33% 95-110%w/w
Pioglitazone hydrochloride (15mg) 101.0% 100.3% 95-110%w/w

The lubricant used may be selected from hydrogenated castor oils, magnesium or calcium stearate, boricin, compritol, stearic acid and the like. The amount of lubricant used ranges from 0.05 % to 7 % by weight but preferably 0.05 % to 7 % by weight of magnesium stearate.
The glidant used may be selected from colloidal silicon dioxide, talc and the like. The amount of glidant used ranges from 0.1 % to 5 % by weight but preferably 0.1 % to 3 % by weight of talc.
The lipid used may be selected from stearic acid, cetostearyl alcohol, glyceryl behemate, glyceryl monostearate, glyceryl palmitate and the like. The amount of lipid used ranges from 0.1 to 45 % by weight but preferably stearic acid in 0.1% to 35 % by weight
According to the invention there is provided a process for the preparation of improved pharmaceutical composition containing an anti-diabetic biguanide substance which comprises :-
i. Sifting the desired amount of the anti-diabetic biguanide agent through
a 60 mesh sieve, ii. Coating the sieved anti-diabetic biguanide agent with the desired
amount of stearic acid dissolved in sufficient isopropanol or any other
organic solvent to get uniform coated granules, iii. Granulating the resulting coated anti-diabetic biguanide agent using
the desired amount of the binder and screening the resulting wet mass
from 8 to10 mesh sieve and drying the same at 40 - 80 degrees
centigrade till the moisture content in the dried granules is at 3.0 -3.5
% by weight, iv. Mixing the granules of step iii, with the desired amount of release
retard polymer, lubricating and other additive materials and
compressing into tablets or filled into capsules.

Dissolution Profile -
Metformin '■* -
Hydrochloride
2 hours 23% 25% 10-40%
4 hours 53% 58% 20- 65 %
8 hours 68% 70% 50-100%
12 hours 83% 89% Not less than 75 %
Dissolution
Pioglitazone 100% 97% Not less than 70 % in 30
Hydrochloride minutes
Glimepiride 94% 95% Not less than 70 % in 30 minutes
Related substances <1 % <1 % NMT 2 % (total impurities)
The pharmaceutical composition so produced as disclosed in the present invention shows assay, dissolution profile and related substance / impurities well within acceptance criteria even after exposure to 40°C+ 2°C/75% ± 5% RH for 6 months which is extrapolated to 24 months of shelf life as per ICH guidelines. The pharmaceutical composition so disclosed in the present invention is therefore stable, of acceptable quality, accurate in dosing and does not lead to dose dumping over shelf life storage.
Pilot trials of the process of preparation of the pharmaceutical composition as disclosed in the present invention were conducted using standard tabletting machines and were found to be easy, simple and feasible to implement on industrial scale.

The pharmaceutical composition so produced as disclosed in the present invention metformin hydrochloride (500 mg) + glimeperide (2 mg) bi-layered tablet was evaluated for in vivo availability in 24 healthy human subjects as per the ICH guidelines of good clinical practices and good laboratory practices.
For evaluation of the rate and extent of bio-availability for each subject, pharmacokinetic parameters such Cmax, Tmax, AUC 0-24 and AUCo-inf were estimated from the Metformin + glimepiride plasma concentration - time plot. In addition the terminal phase, terminal elimination rate constant (Kele) and elimination half-life (t ½) were also determined. The plasma samples were analyzed using validated HPLC analytical techniques and the data so obtained was analyzed statistically at 90% confidence interval.
The following table shows data of in vivo study:

Pharmacokinetic parameter Metformin Glimepiride
1- Cmax(ng/ml) 739.603 157.145
2. AUC0-24 (ng x hr/ml) 9053.44 853.40
3. AUC 0-inf (ng x hr/ml) 10227.35 955.847
4.Tmax(Hrs) 4.833 2.458
5. Peak plasma concentration (Hrs) 4.0-5.0 2.0 - 3.0
6. Adverse events None None

Bio-availability as Metformin Glimepiride
1. Extent of absorption (AUCo-24 x hr/ml) 98.8% 97.2%
2. Cmax values 97.22% 97.20%
3. First detention in plasma 30 mins 30 mins.

The in vivo concentration time profile for Metformin hydrochloride and glimeperide from a multi-ingredient composition comprising of metformin hydrochloride (500 mg) + glimeperide (2mg) bilayered tablet as disclosed in the present invention are as follows:

Time (hrs) Concentration in ng/ml in plasma

Metformin Glimepiride
0 0.0 0.0
0.5 150 50
1.0 250 80
1.5 350 110
2.0 430 140
2.5 470 157
3.0 520 115
4.0 610 90
5.0 739 60
6.0 580 55
8.0 550 40
12.0 400 10
16.0 280 5
20.0 210 3
24.0 100 0.0
The above bio-availability and pharmaco-kinetic data prove that the pharmaceutical composition so disclosed in the present invention is efficacious, precise in dosing and also safe for administration to mammals.
The above-specified specification can be better understood with the help of examples 1 -9 . However, these examples do not in any way restrict the broad scope of the invention.

Example 1:
17.21 mg Pioglitazone hydrochloride, 2 mg Glimeperide, 2 mg iron oxide yellow, 100 mg Microcrystalline cellulose, 10 mg sodium starch glycollate, 35 mg dicalcium phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and granulated with water (granules A). 500 mg metformin hydrochloride to be granulated with 10 % polyvinyl pyrollidone solution and 50 mg stearic acid melted at 60°C. The granules may be wet screened through a 8 mesh sieve and dried at 50- 60°C using fluidizeded drier. The dried granules are passed through 20 mesh (granules B) and mixed with 200 mg carbopol , 5 mg talc and 15 mg magnesium stearate and compressed as a bilayered tablet.
Example 2:
34.42 mg Pioglitazone hydrochloride,3mg red iron oxide, 100 mg Microcrystalline cellulose, 10 mg sodium starch glycollate, 35 mg dicalcium phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and granulated with water (granules A). 500 mg metformin hydrochloride to be granulated with 10 % polyvinyl pyrollidone solution and 50 mg stearic acid in isopropyl alcohol. The granules may be wet screened through a 8 mesh sieve and dried at 45-60°C using fluidized ed drier. The dried granules are passed through 20 mesh (granules B) and mixed with 200 mg carbopol,5 mg talc and 15 mg magnesium stearate and compressed as a bi layered tablet.
Examples 3:
34.42 mg Pioglitazone hydrochloride, 3mg erythrosine pink, 100 mg Microcrystalline cellulose, 10 mg sodium starch glycollate, 35 mg dicalcium phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and granulated with water (granules A). 1000 mg metformin hydrochloride to be granulated with 10 % polyvinyl pyrollidone solution and 75 mg stearic acid melted at 60°C. The granules may be wet screened through 8 mesh sieve and dried at 50-60°C using fluidized ed drier. The dried granules are passed through 20 mesh

(granules B) and mixed with 250 mg carbopol, 5 mg talc and 25 mg magnesium stearate and compressed as a bi layered tablet.
Example 4:
2 mg Glimeperide , 5mg of yellow iron oxide, 100 mg Microcrystalline cellulose, 10 mg sodium starch glycollate, 35 mg dicalcium phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and granulated with water (granules A). 1000 mg metformin hydrochloride to be granulated with 10 % polyvinyl pyrollidone solution and 75 mg stearic acid melted at 50-60°C. The granules may be wet screened through 10 mesh sieve and dried at 45-60°C using fluidizeded drier. The dried granules are passed through 20 mesh (granules B) and mixed with 250 mg carbopol, 5 mg talc and 25 mg magnesium stearate and compressed as a bilayered tablet.
Example 5:
1 mg Glimeperide,3 mg erythrosine pink, 100 mg Microcrystalline cellulose, 10 mg sodium starch glycollate, 35 mg dicalcium phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and granulated with water (granules A). 500 mg metformin hydrochloride to be granulated with 10 % polyvinyl pyrollidone solution and 50 mg stearic acid in isopropyl alcohol. The granules may be wet screened through 8 mesh sieve and dried at 50-60°C using fluidized ed drier. The dried granules are passed through 20 mesh (granules B) and mixed with 200 mg carbopol , 5 mg talc and 15 mg magnesium stearate and may be filled into hard gelatin capsules.
Example 6:
10 mg Ezetimib, 100 mg Microcrystalline cellulose,3 mg of yellow iron oxide, 10 mg sodium starch glycollate, 35 mg dicalcium phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and granulated with water (granules A). 500 mg metformin hydrochloride to be granulated with 10 % polyvinyl pyrollidone solution and 50 mg stearic acid in isopropyl alcohol. The granules

may be wet screened through a 8 mesh sieve and dried at 45-60°C using fluidized bed drier. The dried granules are passed through 20 mesh (granules B) and mixed with 200 mg carbopol ,5 mg talc, 15 mg magnesium stearate and 50 mg stearic acid and compressed as a bilayered tablet.
Example 7:
10 mg Ezetimib, 100 mg Microcrystalline cellulose,3mg yellow iron oxide, 10 mg sodium starch glycollate, 35 mg dicalcium phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and granulated with water (granules A). 500 mg metformin hydrochloride to be granulated with 10 % polyvinyl pyrollidone solution and 80 mg stearic acid melted at 50-60°C. The granules may be wet screened through a 10 mesh sieve and dried at 50- 60°C using fluidized bed drier. The dried granules are passed through 20 mesh (granules B) and mixed with 200 mg carbopol ,5 mg talc, 15 mg magnesium stearate and 50 mg stearic acid and filled into hard gelatin capsules.
Example 8:
Thiamine mononitrate, Pyridoxine hydrochloride, Riboflavine, cyanocobalamine, vitamin B3 and folic acid in therapeutic quantities, Microcrystalline cellulose, 10 mg sodium starch glycollate, 35 mg dicalcium phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and granulated with water (granules A). 500 mg metformin hydrochloride to be coated with 75 mg of stearic acid melted at 50-60°C and granulated with 10 % polyvinyl pyrollidone soultion in isopropyl alcohol. The granules may be wet screened through 10 mesh sieve and dried at 50-60°C using fluidized bed drier. The dried granules are passed through 20 mesh (granules B) and mixed with 200 mg carbopol ,15 mg magnesium stearate, 5 mg talc and 50 mg stearic acid and filled into capsule.

Example 9
Thiamine mononitrate, Pyridoxine hydrochloride, 3mg of quinoline yellow,
Riboflavine, cyanocobalamine, vitamin B3 and folic acid in therapeutic quantities,
Microcrystalline cellulose, 10 mg sodium starch glycollate, 35 mg dicalcium
phosphate, 10 mg polyvinyl pyrollidone, 4 mg Tween -80, may be mixed and
granulated with water (granules A). 1000 mg metformin hydrochloride to be
coated with 95 mg of stearic acid dissolved in sufficient isopropanol and
granulated with 10 % polyvinyl pyrollidone soultion. The granules may be wet
screened through 8 mesh sieve and dried at 50-60°C using tray drier. The dried
granules are passed through 20 mesh (granules B) and mixed with 200 mg
carbopol,15 mg magnesium stearate, 5 mg talc and 50 mg stearic acid and
compressed into bi-layered tablet.

We Claim:
1. An improved pharmaceutical composition containing an anti-diabetic biguanide
substance as modified or slow release either singly or in combination with other
drugs as a oral dosage form which comprises:
(i) 0.1 % to 75% by weight of bulking agent (ii) 0.1 % to 15 % by weight of disintegrant (iii) 0.1 to 20 % by weight of binder (v) 0.1 % to 15 % by weight by wetting agent (vi) 0.1 % to 40% by weight of carbopal (vii) 0.05 % to 15 % by weight of lubricant and (viii) 0.1 % to 5 % by weight of glidants (ix) 0.1 % to 45 % by weight of lipid
2. An improved composition as claimed in claiml wherein the anti hyperglycemic biguanide or a pharmaceutically acceptable salt or pro-drug thereof used is selected from metformin or buformin or its pharmaceuticaily effective salt.
3. An improved composition as claimed in claims 1 and 2 wherein the amount of
anti hyperglycemic biguanide used is metformin or metformin hydrochloride in a concentration of 500 mg to about 2500mg, preferably from about 500mg to about 2000 mg more preferably from about 500mg to about 1700mg.
4. An improved composition as claimed in claims 1 to 2 wherein the amount of anti hyperglycemic biguanide used is buformin or its physiologically effective salt in a concentration of 50 mg to about 2500 mg, preferably from about 50 mg to about 2000mg more preferably from about 50 mg to about 500 mg
5. An improved composition as claimed in claimsl to 4 wherein the bulking agent used is in the range of 0.1 to 75 % by weight selected from microcrystalline cellulose , dicalcium phosphate, starch and lactose

6. An improved composition as claimed in claims 1 to 5 wherein the disintegrant
is used is in range from 0.1 % to 15 % by weight selected from croscarmellose sodium or calcium, crospovidone, sodium starch glycollate, starch and pollacrin.
7, An improved composition as claimed in claims 1 to 6 wherein the binder used
ranges from 0.1% to 20 % by weight selected from polyvinyl pyrollidone, starch and gelatin.
8. An improved composition as claimed in claimsl to 7 wherein the wetting agent
used ranges from 0.1 % to 15 % by weight selected from polysorbate 20 or 80
or 60 , cremophore RH 40 or lutrol and docussate sodium.
9. An improved composition as claimed in claims 1 to 8 wherein the amount of
carbopol used ranges from 0.1 % to 40% by weight.
10. An improved composition as claimed in claims 1 to 9 wherein the lubricant used ranges from 0.05 % to 15 % by weight selected from calcium or magnesium stearate , hydrogenated vegetable oil and stearic acid.
11. An improved composition as claimed in claims 1 to 10 wherein the glidants used ranges from 0.1 to 5 % by weight selected from talc and colloidal silicon dioxide.
12. An improved composition as claimed in claims 1 to 11 wherein the lipid
used ranges from 0.1% to 45 % by weight selected from glyceryl
behemate, glyceryl palmitate, cetostearyl alcohol , glyceryl monostearate
or stearic

13. An improved composition as claimed in claims 1 to 12 wherein the bulking
agent is microcrystalline cellulose preferably at 0.1 % to 50 % by weight and dicalcium phosphate preferably at 0.5 to 25 % by weight
14. An improved composition as claimed in claims 1 to 13 wherein the disintegrant used is sodium starch glycollate, preferably at 0.5% to 10 % by weight.
15. An improved composition as claimed in claims 1 to 14 wherein the binder
used is polyvinyl pyrollidone preferably at 0.2 % to 5 % by weight.
16. An improved composition as claimed in claims 1 to 15 wherein the wetting
agent used is polysorbate 80 preferably at 0.1 % to 5 % by weight
17. An improved composition as claimed in claims 1 to 16 wherein the carbopol
is used preferably at 0.1% to 20% by weight.
18. An improved composition as claimed in claims 1 to 17 wherein lubricant used
is magnesium stearate preferably at 0.1% to 7 % by weight.
19. An improved composition as claimed in claims 1 to 18 wherein the lipid used
is stearic acid preferably at 0.1 % to 35 % by weight.
20. An improved composition as claimed in claims 1 to 19 wherein the glidant
used is colloidal silicon dioxide preferably at 0.1 to 3 % by weight.
21. A process for the preparation of improved pharmaceutical composition
claimed in claims 1 to 20, an anti-diabetic biguanide substance as modified
or slow release either singly or in combination with other drugs as a oral
dosage form which comprises:

i. Sifting the desired amount of the anti-diabetic biguanide agent through a sieve.
ii. Coating the sieved anti-diabetic biguanide agent with the desired amount of stearic acid dissolved in sufficient isopropanol or any other organic solvent to get uniform coated granules.
iii. Granulating the resulting coated anti-diabetic biguanide agent using the desired amount of the binder and screening the resulting wet mass from a sieve and drying the same at 25 - 80 degrees centigrade till the moisture content in the dried granules is at 3.0 -3.5 % by weight.
iv. Mixing the granules of step iii, with the desired amount of release retard polymer, lubricating and other additive materials and compressing into tablets or filled into capsules.
v. The granules of step iv can also be mixed with granules of rapid release anti-diabetic or other drugs and compressed into bi-layered tablets or filled into capsules.
vi. Alternatively, stearic acid may be melted and used for coating the anti¬diabetic biguanide and the coated drug may be further used for granulation of step iii, mixed with the desired amount of release retard polymer, lubricating and other additive materials and compressing into tablets or filled into capsules.
22. An improved composition as claimed in claims 1 to 21 where in other drug
used in combination with anti-hyper glycemic biguanide are glypizide,
glyburide or glimeperide or pioglitazone or rosiglitazone or nateglinide or
ezetimib or gliclazide or repaglinide or its pharmaceutically effective salts..
23. An improved composition as claimed in claims 1 to 21 or 22 wherein other
drugs used are vitamin B1, B2 , B3, B6, B12 and folic acid.

24. An improved pharmaceutical composition as claimed in claims 1 to 23 containing an anti-diabetic biguanide as modified or slow release oral dosage form substantially as herein described with reference to the Examples 1 to 9
25. A process for the preparation of an improved pharmaceutical composition as
claimed in claims 1 to 24 containing an anti-diabetic biguanide as modified or slow release oral dosage form substantially as herein described with reference to the Examples 1 to 9


Dated this 11th day of August 2004


BHOOPENDRA KUMAR SHARMA
Executive Director
Unichem Laboratories, Mumbai, India