FORM 2



MS

THE PATENTS ACT 1970
As amended by the Patents (Amendment) Act, 2002
COMPLETE SPECIFICATION
(See Section 10; Rule 13)
TITLE
A process of producing a sustained release composition of metformin hydrochloride
APPLICANTS
USV Limited, BSD Marg, Govandi, Mumbai 400088, Maharashtra, India, an Indian Company
INVENTORS
Dr Gidwani Suresh Kumar, Singnurkar Purushottam and Tewari Prashant Kumar, USV Limited, BSD Marg, Govandi, Mumbai 400088, Maharashtra, India, all Indian Nationals
The following specification particularly describes the nature of this invention and the manner in which it is to be nerformed

This invention relates to a process of producing a sustained release composition of metformin hydrochloride.
The composition of the invention provides sustained release of metformin hydrochloride over a prolonged period of time.
Metformin hydrochloride is a well known biguanide derivative (1,1-dimethylbiguanide monohydrochloride) which is widely used as oral antihtperglycemic agent in the management of noninsulin dependent diabetes mellitus (NIDDM).
Metformin hydrochloride being a highly water soluble drug ( >300 mg/ml at 25° C) leads to the difficulty in making a sustained release dosage form.
Marketed preparations available earlier with 850 mg dose of metformin hydrochloride having label of retard tablets (Glucophase RTM retard) have not been able to demonstrate any advantage in a limited volunteer trials. This probably attributable to poor choice of polymers and low dosage, desired for sustained action.
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US Patent No 5,955,106 by Moeckel, J. describes the process of making metformin hydrochloride 850 mg retard tablet containing hydrocolloid forming retarding agents and further control of release provided by film envelop. It however does not provide any justification for using 850 mg dose of metformin hydrochloride for delayed release preparation and the expected release rates from such compositions. This patent also does not give any invitro and in-vivo data to support its claims. Literature survey indicates metformin hydrochloride has only 40% to 60% bioavailability with high renal clearance. Hence the dose 850 mg may be insufficient to achieve therapeutic plasma concentration, around 1 ug/ml for a sufficient period of time and might require to take such tablets twice or thrice a day.
PCT Publication No 99/47128 by Timmins et al describes biphasic controlled release delivery system for metformin Irochloride with inner solid particulate phase and outer solid tinuous phase utilizing hydrophilic and hydrophobic polymers. ;se tablets are hydrodynamicaly balanced and swells upto roximately three times its dry size following hydration. However,
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The dose of metformin hydrochloride is calculated by considering the following pharmacokinetic values from the literature.
Plasma concentration Cmax = 1.02ug/ml
Elimination half life tlA = 6.2 hours
Volume of distribution Vd = 275 litrs
Renal clearance = 552 ± 139 Litrs / min
Total clearance = 1300ml/min
Using Dobrinska and Welling model, the calculated loading dose is
283 mg and maintenance dose is 759 mg and the total dose is 1040 mg
of metformin hydrochloride for achieving sustained release effect for 24
hours.
The object of the present invention is to prepare palatable and swallowable pharmaceutical preparation containing as high as approximately 1.0 gm metformin by suitable technology showing demonstrable release rate and facilitated in-vivo absorption for the desired period. The emphasis is to develop simple monolithic system composed of hydrophobic material and other excipients with improved
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kinetics of extended release dosage forms and with highest possible content of active substance and the simplest method of producing it.
According to the invention there is provided a process of
producing a sustained release composition of metformin hydrochloride A
with a hyrophobic material, the composition being configured to exhibit in-vitro drug release characteristics of the metformin hydrochloride while in gastic fluid having a pH of 1.2 for a first hour and then in phosphate buffer having a pH of 6.8, the in-vitro drug release characteristics after the first, second, third, fourth, fifth, sixth, seventh and eighth hours being 38 - 45%> release by the first hour, 50 - 56%> release by the second hour, 62 - 68%> release by the third hour, 70 - 75%o release by the fourth floor, 80 - 85%o release by the sixth hour, 85 - 90% release by the seventh hour, 91-95%> release by the eighth hour and 96 - 100%) release by the eighth hour, the process comprising :
i) granulating 60 to 85%) by weight of metformin hydrochloride and 15 to 40%o by weight of hydrophobic material in an aqueous or organic solvent by hot melt granulation or by extrusion and ii) drying the granulated product.
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The sustained release composition of the invention is a homogeneous or single phase system composed of active drug in an amount within the range of 60 to 85% by weight, preferably 70 to 80% by weight, and one or more hydrophobic materials in an amount within the range of about 15 to 40% by weight, preferably 20 to 30% by weight based on the weight of the active substance.
Hydrophobic materials which may be employed for the sustained release system in the present invention include, but not limited to hydrophobic polymers such as stearic acid, glycerylmonostearate, glyceryl behenate, glyceryl monooleate, glyceryl palmitostearate, microcrystalline wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, tristearin, waxes, polyethylene powder, polyvinyl chloride, shellac, rosin, and the like.

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The pharmaceutical compositions according to the present invention can be used to produce compressed tablets of any shape, preferably oval shape and can be additionally provided with film coat of commonly used hydrophilic coating polymers. The film envelop used cane a taste neutralizing film forming agent to which dies can optionally be added can be used for elegance. The proportion by weight of the film envelop relative to the final tablet is in the usual range of 0.5 to 4.0% by weight preferably 1.0 to 1.5% by weight. Film formers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, cellulose derivatives and the like.
The composition according to the present invention can also be used to produce compressed slugs and filled into capsules.
Auxiliary substances which may be employed for sustained release system in the present invention include, binder, like polyvinyl pyrrolidone, gelatin, gum acacia, Klucel EF (hydroxypropyl cellulose), carboxymethyl cellulose sodium etc; Where as the glidants include, but not limited to colloidal siliconedioxide, talc, starch, and the
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like; lubricants include, but not limited to magnesium stearate, zinc stearate, and the like.
The pharmaceutical dosage form according to the present invention such as tablet, apart from active drug and hydrophobic materials may contain 1.0 to 15% by weight of a binder, preferably 3.0 to 10% by weight; and upto2.0% by weight of glidant preferably 0.5 to 1.05 by weight; and upto 2.0% by weight of lubricants preferably 0.5 to 1.0 % by weight; each in relation to the tablet weight.
In the present invention the pharmaceutical composition, such as tablets are produced by dry mixing of active substance and optionally further auxiliary substance and granulating this mixture with hydrophobic materials by hot melt granulation technique using jacketed rapid mixer granulator at a temperature 40 to 120°C, preferably 60 to 80°C. This is followed by gradually cooling the granulate mass to the room temperature with continuous mixing. The resulting mass is further granulated with aqueous or organic solution of the binder followed by drying and
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into capsule. The tablets can be coated with a film using the standard coating processes and methods such as conventional coating pan or fluid coating process.
The sustained release tablets according to the present invention release metformin hydrochloride in a controlled manner which is suppose to provide an effect over a time period upto 24 hours, preferably over 18 hours as per the calculations.
Us -" ' tformin sustained release formulations as per the invention shows the following in-vitro drug release characteristics when tested in gastric fluid pH 1.2 for first hour and then in phosphate buffer pH 6.8 USP.
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Time (Hrs_ % Release
1 38 -45%
2 50 - 55%
3 62 - 68 %
4 70- 75%
5 80 - 85%
6 85 - 90%
7 91-95%
8 96-100%
Example 1:
225 gm of stearic acid was melted at 70°C temperature. 1000 gm metformin hydrochloride was heated to 70°C in a jacketed rapid mixer granulator and granulated with above melted stearic acid at 70°C temperature. After granulation the granulate mass was mixed continuously with gradual cooling to room temperature.
60 gm of shellac and 25 gm of polyvinyl pyrollidone were dissolved in 150 gm of isopropyl alcohol. This solution was gradually added to
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above metformin stearic acid granulate and mixed till dough mass formed. The resulting dough mass was dried at 45°C for 2 hours and then sized through 2.4 mm screen to break the agglomerates. These sized granules (1310 gm) were blended with 4.0 gm of colloidal siiicone dioxide and 8.0 gm of magnesium stearate and compressed into capsule shape oval tablets of each containing 1000 mg of metformin hydrochloride.
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The in-vitro release of metformin hydrochloride form these tablet was as follows:


Time (Hrs) % Release
1 40%
2 55%
3 65%
4 75%
5 82%
6 89%
7 95%
8 99.5%
Example 2:
225 gm of stearic acid, 1000 gm metformin hydrochloride, 60 gm of shellac and 25 gm of polyvinyl pyrollidone were mixed in the extruder at 70°C and extruded and then gradually cooled to room temperature. The resulting agglomerates were sized through 2.4 mm screen. These sized granules (1310 gm) were blended with 4.0gmof colloidal silicone dioxide and 8.0 gm of magnesium stearate and compressed into capsule shape oval tablets of each containing 1000 mg of metformin hydrochloride.
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I
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I
The in-vitro release of metformin hydrochloride form these tablet was as follows

Time (Hrs) % Release
1 42%
2 57%
3 68%
4 77%
5 84%
6 90%
7 96%
8 100%
Example 3:
250 gm of glyceryl mono stearate was melted at 70°C temperature. 1000 gm metforminhydrochloride was heated to 70°C in a jacketed rapid mixer granulator and granulated with above melted stearic acid at 80°C temperature. After granulation the granulate mass was mixed continuously with gradual cooling to room temperature.
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60 gm of shellac and 25 gm of polyvinyl pyrollidone were dissolved in 150 gm of isopropyl alcohol. This solution was gradually added to above metformin stearic acid granulate and mixed till dough mass formed. The resulting dough mass was dried at 45°C for 2 hours and then sized through 2.4 mm screen to break the agglomerates. These sized granules (1335 gm) were blended with 4.0 gm of colloidal silicone dioxide and 8.0 gm of magnesium stearate and compressed into capsule shape oval tablets of each containing 1000 mg of metformin hydrochloride.
The in-vitro release of metformin hydrochloride form these tablet was as follows:
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Time (Hrs) % Release
1 39%
2 52%
3 61%
4 72%
5 80%
6 88%
7 94%
8 98%
Example 4
175 gmof polyethylene powder, 1000 gm metformin hydrochloride and 25 gm of polyvinyl pyrollidone were mixed in the extruder at 70°C and extruded and then gradually cooled to room temperature. The resulting agglomerates were sized through 2.4 mm screen. These sized granules (1200 gm) were blended with 4.0 gm of colloidal silicone dioxide and 8.0 gm of magnesium stearate and compressed into capsule shape oval tablets of each containing 1000 mg of metformin hydrochloride.
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The in-vitro release of metformin hydrochloride form these tablet was as follows

Time (Hrs) % Release
1 48%
2 54.2%
3 64%
4 73.4%
5 82%
6 90.3%
7 96%
8 99.7%
Example 5:
160 gm of polyvinyl chloride powder, 1000 gm metformin
hydrochloride and 25 gm of polyvinyl pyrollidone were mixed in the extruder at 70°C and extruded and then gradually cooled to room temperature. The resulting agglomerates were sized through 2.4 mm screen. These sized granules (1185 gm) were blended with 4.0 gm of
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colloidal silicone dioxide and 8.0 gm of magnesium stearate and compressed into capsule shape oval tablets of each containing 1000 mg of metformin hydrochloride.
The in-vitro release of metformin hydrochloride form these tablet was as follows

Time (Hrs) % Release
1 42%
2 53.1%
3 62.5 %
4 72%
5 80%
6 85%
7 94%
8 98.8%
Example 6:
230 gm of hydrogenated castor oil was melted at 70°C temperature.
1000 gm metformin hydrochloride was heated to 70°C in a jacketed
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rapid mixer granulator and granulated with above melted stearic acid at 70°C temperature. After granulation the granulate mass was mixed continuously with gradual cooling to room temperature.
60 gm of shellac and 25 gm of polyvinyl pyrollidone were dissolved in 150 gm of isopropyl alcohol. This solution was gradually added to above metformin stearic acid granulate and mixed till dough mass formed. The resulting dough mass was dried at 45°C for 2 hours and then sized through 2.4 mm screen to break the agglomerates. These sized granules (1315 gm) were blended with 4.0 gm of colloidal silicone dioxide and 8.0 gm of magnesium stearate and compressed into capsule shape oval tablets of each containing 1000 mg of metformin hydrochloride.
The in-vitro release of metformin hydrochloride form these tablet was as follows:
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Time (Hrs) % Release
1 41%
2 53%
3 66%
4 74.9%
5 83%
6 91%
7 96.2%
8 100%
References:
1. Moeckel, J., Gabel, R., Woog, H, [1997], US Patent 5,955,106.
2. Timmins, P., Vyas, K., [1999], World Patent WO 99/47128.
3. Noel, M., (1980), Journal of International Biomedical Information and Data (IBID), 1(1), 9-20.
4. Kenneth, C, Ralph, A.D., (1998), Diabetes Reviews, 6 (2), 89 -131.
5. Nancy C. Sambol, Jaine Chaing, Michael O'Conner, Chui Y Liu (1196), J Clin. Pharmacol., 36,1012-1021.
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6. Physician Desk reference, Edition 58, (2000), Medical economic company Inc. NJ 07645 - 1742, Glucophase®, page 831 - 835.


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We claim:
1. Process of producing a sustained release composition of
A
metformin hydrochloride with a hyrophobic material, the composition being configured to exhibit in-vitro drug release characteristics of the metformin hydrochloride while in gastic fluid having apH of 1.2 for a first hour and then in phosphate buffer having a pH of 6.8, the in-vitro drug release characteristics after the first, second, third, fourth, fifth, sixth, seventh and eighth hours being 38 - 45% release by the first hour, 50 - 56% release by the second hour, 62 - 68% release by the third hour, 70 - 75% release by the fourth floor, 80 - 85% release by the sixth hour, 85 - 90% release by the seventh hour, 91 - 95% release by the eighth hour and 96 - 100% release by the eighth hour, the process comprising:
i) granulating 60 to 85% by weight of metformin hydrochloride and 15 to 40% by weight of hydrophobic material in an aqueous or organic solvent by hot melt granulation or by extrusion and ii) drying the granulated product.

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2. Process of claim 1, wherein the sustained release dose for metformin hydrochloride is at least 1000 mg.
/
3. Process of claim 1, wherein 70 to 80% by weight of metformin hydrochloride and 20 to 30% by weight of hydrophobic material are granulated.
4. Process of claim 1, wherein the hydrophobic material is selected from the group consisting of fatty acids, fatty alcohols, fatty acid esters, hydrogenated oils, waxes and natural resins.
5. Process of claim 4, wherein the hydrophobic material comprises stearic acid, glyceryl monostearate, glyceryl behenate, glyceryl pamitostearate, glyceryl monooleate, microcrystalline wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, tristearin, shellac, rosin, polyvinyl chloride powder, polyethylene powder, and the like.
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6. Process of claim 1, wherein the granulation is carried out alongwith
3 to 10% by weight of binder, 0.5 to 1.5% by weight of glidant and
0.5 to 1.0% by weight of lubricant.
7. Process of claim 1, wherein the granulated product is compressed
into tablet.
Dated this 14th day of February 2002

(Jose M A)
Agent for the Applicants
For Khaitan & Co
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