FORM 2
THE PATENTS ACT, 1970
(39 Of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10,and Rule 13]
Title
PHARMACEUTICAL FORMULATIONS COMPRISING METFORMIN AND
GLIBENCLAMIDE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention

PHARMACEUTICAL FORMULATIONS COMPRISING METFORMIN AND
GLIBENCLAMIDE
FIELD OF THE INVENTION
The invention relates to the field of pharmaceutical sciences particularly to the solid oral formulation of metformin and glibenclamide.
BACKGROUND OF THE INVENTION
There are two main groups of oral antidiabetic drugs available: these are the sulphonylureas and the biguanides. Sulphonylureas act by stimulating insulin release and are thus only effective with some residual pancreatic beta-cell activity; examples of sulphonylureas available are glibenclamide, gliclazide, tolbutamide, glipizide, tolazamide, gliquidone and chlorpropamide. The biguanides, such as metformin, act by decreasing gluconeogenesis and by increasing peripheral utilisation of glucose, and as they require endogenous insulin they are only effective with some residual pancreatic islet cell activity.
Glyburide, also known as glibenclamide, is chemically defined as 5-chloro-N-[2-[4-[[[(cyclohexylamino)-carbonyl]amino]sulfonyl]phenyl]ethyl]-2-methoxy-benzamide (Merck Index, Tenth Edition, p. 642).
The initial treatment of non-insulin dependent diabetes involves diet control and exercise. Only after this has been shown to be inadequate are oral antidiabetic drugs used, and then only to complement the effect of diet and not replace it. Monotherapy with an oral antidiabetic can be an effective treatment for many years. However the efficiency can decrease with time. Due to sulphonylureas and biguanides having complementary modes of action, combined therapy is now an established form of treatment for non-insulin dependent diabetes.
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A combination of metformin with glibenclamide has been disclosed in WO 97/17975 for the treatment of type II diabetes with a defined ratio of the two active ingredients, which is a requirement in order to obtain an optimum therapeutic effect. This prior art defines an optimum therapeutic ratio of metformin hydrochloride to glibenclamide of 100:1, for example 500 mg of metformin hydrochloride with 5 mg glibenclamide in a single dosage unit.
Metformin being highly water soluble do not pose any problem of bioavailability. Glibenclamide being poorly water soluble (solubility is 0.1 mg/ml in water at 25.degree. C.--practically insoluble as defined by the USP) drug has bioavailability problems such that its bioavailability varies depending on its particle size. Moreover, the bioavailability of metformin and glibenclamide in the combination is different to that of bioavailability of glibenclamide when administered alone.
US 3,979,520 discloses the tablet formulation comprising glibenclamide with a surface area of about 3 to 10 m.sup.2 /g. This patent does not disclose the compositions comprising metformin and glibenclamide.
US 6,303,146 assigned to LIPHA discloses that the selection of a specific size fraction of glibenclamide enables the production of a solid oral dosage form comprising a combination of metformin and glibenclamide, and in particular a tablet, exhibiting glibenclamide bioavailability comparable to the bioavailability obtained with the separated administration of metformin and glibenclamide, when judged by the area under the curve of the in-vivo analysis. This patent discloses the solid oral dosage form comprising a combination of metformin and glibenclamide in which the size of the glibenclamide is such that at most 10% of the particles are less than 2 micron and at most 10% of the particles are greater than 60 micron, so that the
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glibenclamide bioavailability is comparable to the glibenclamide bioavailability obtained with a separate administration of metformin and glibenclamide.
The US 6,830,760 assigned to LIPHA discloses the solid oral dosage form comprising a combination of metformin and glibenclamide with particle size distribution of 25 % particles between 3 to 11 micron, 50 % particles between 6 to 23 micron and 75 % particles between 15 to 46 micron and at most 10 % particles above 60 microns. This patent discloses that specifically, the physical form of glyburide, which is the subject matter of this invention, is glyburide having a defined particle size distribution. This particle size distribution provides an enhanced rate of dissolution of the glyburide compared to bulk glyburide, and it provides reproducible bioavailability in vivo.
Thus it is evident form the prior art that formulations comprise combination of glibenclamide and metformin poses problems of bioavailability compared to bioavailability of glibenclamide alone. Thus the prior art discloses various formulations having different particle size distributions. The prior art reveal that when combination of metformin and glibenclamide is to be formulated it is difficult to predict which particle size distribution of glibenclamide would result in bioequivalent formulation to that of Glucovance. It is known in the pharmaceutical art that achieving bioequivalent formulation, particularly when one of the ingredients in the combination is poorly water soluble, is difficult to predict.
SUMMARY OF THE INVENTION
In one embodiment there is provided pharmaceutical formulations comprising metformin and glibenclamide in which the particle size of the glibenclamide is
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such at least 15 % particles are less than 2 micron and at least 90% particles are less than 10 micron, so that the glibenclamide bioavailability is comparable to the commercially available Glucovance formulation in US market comprising metformin and glibenclamide.
In another embodiment there is provided pharmaceutical formulations comprising metformin and glibenclamide in which the particle size of the glibenclamide is such that at least 20 % particles are less than 2 micron and at least 90% particles are less than 10 micron, so that the glibenclamide bioavailability is comparable to the commercially available Glucovance formulation in US market comprising metformin and glibenclamide.
In still another embodiment there is provided pharmaceutical formulations comprising metformin and micronized glibenclamide wherein the glibenclamide is present as intragranular and extragranaular form.
The further embodiments relates to the process of preparation of pharmaceutical formulations comprising metformin and glibenclamide and method of using such compositions.
DETAILED DESCRIPTION OF THE INVENTION
The formulation of the present invention comprises metformin and glibenclamide in immediate release form. The formulation is in the form of an oral dosage form and may be in the form of tablet, capsule or such like. The formulation comprises combination of metformin and glibenclamide, at lest one diluent, at least one binder, at least one disintegrant and at least one lubricant.
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The metformin may range form 250 to 1000 mg per tablet, preferably 250 to 500 mg. The glibenclamide may range from 1 to 5 mg per tablet, preferable 1.25 to 5 mg.
The diluent may be selected from microcrystalline cellulose; sugar or sugar alcohols like lactose, mannitol or xylitol; starch or starch derivatives and such like. The diluent may range from 0.5 to 35 %, preferably 2 to 6 %.
The binder may be selected from cellulose derivatives like hydroxypropyl methylcellulose, hydroxypropyl cellulose; polyvinyl pyrrolidone, gums like xanthan gum, alginates or agar and such like. The binder may range from 2 to 10 %, preferably 4 to 5 %.
The disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, crospovidone or pregelatinized starch. The disintegrant may range from 1 to 10 %, preferably 6 to 7 %.
The lubricants/glidant may be selected from magnesium stearate, talc or colloidal silicon dioxide. The lubricant may vary from 0.5 to 7 %, preferably 2 to 5 %.
The formulations are preferably in the form of tablet, which may be optionally coated. The tablet may be bilayered tablet with metformin and glibenclamide being present in two different layers. Preferably the tablets are matrix tablet containing metformin and glibenclamide in the single layer along with pharmaceutically accepted excipients.
The following examples are provided to further illustrate the invention, and are not intended to limit the scope of the invention.
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Example 1:
Tablet formulation of metformin and glibenclamide

Sr. No. Ingredients mg/tablet (5mg) mg/tablet (2.5mg)
1 Metformin Hydrochloride 500.00 500.00
2 Glibenclamide 5.00 2.50
3 Microcrystalline cellulose 22.00 24.50
4 Croscarmellose sodium 15.00 15.00
5 Polyvinyl pyrrdidone K-30 30.00 30.00
6 Purified Water qs. qs.
7 Microcrystalline cellulose 17.00 17.00
8 Croscarmellose sodium 14.00 14.00
9 Colloidal silicon dioxide 10.00 10.00
10 Magnesium Stearate 7.00 7.00
Total (Core tablet) 620.00 620.00
11 Hydroxypropyl methyl cellulose 6 cps 2.75 2.70
12 Hydroxypropyl methyl cellulose E15 LV 2.75 2.70
13 Titanium Dioxide 1.64 2.02
14 Talc 1.36 1.33
15 Polyethylene glycol 6000 0.82 0.75
16 Yellow Oxide of Iron 0.68 -
17 Lake of Sunset Yellow - 0.50
Total (Coated tablet) 630.00 630.00
PROCESS OF PREPARATION:
1. Glibenciaimide was geometrically mixed with croscarmellose sodium, microcrystalline cellulose, and polyvinyl pyrrolidone K-30.
2. Metformin Hydrochloride was passed through 40 mesh sieve and mixed with mixture of step 1.
3. The mixture obtained in step 2 was granulated with purified water, to obtain the wet mass.
4. The wet mass of step 3 was dried to get appropriate loss on drying.
5. The granules of step 4 were sieved through 40 mesh sieve.
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6. The granules of step 5 were lubricated with microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
7. The mixture of step 6 was compressed with appropriate punches (16 X 8 mm capsule shape biconcave with embossing on one side)
8. The tablets of step 7 were coated with film coating.
The particle size distribution of glibenclamide in the above example is given below.

Size in Microns 0.5 1 2 3 5 10 20
Volume under % 1.09 3.71 18.73 39.37 73.72 99.1 100
Dissolution profile of glibenclamide (500 + 5 mg tablet)
USP type II, 500 ml (pH 4.5 with 1% Sodium lauryl sulphate) at 50 RPM.

Time in minutes % drug released
5 10.6
10 30
15 48.9
20 63.1
30 78.2
45 86.5
60 89.4
Example 2:
Tablet formulation of metformin and Glibenclamide:

Sr. No. Ingredients mg/tablet (5mg) mg/tablet (2.5mg)
1 Metformin Hydrochloride 500.00 500.00
2 Microcrystalline cellulose 22.00 24.50
3 Croscarmellose sodium 15.00 15.00
4 Polyvinyl pyrrdidone 30.00 30.00
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5 Purified Water qs. q.s.
6 Glibenclamide 5.00 2.50
7 Microcrystalline cellulose 17.00 17.00
8 Croscarmellose sodium 14.00 14.00
9 Colloidal silicon dioxide 10.00 10.00
10 Magnesium Stearate 7.00 7.00
Total (Core tablet) 620.00 620.00
11 Hydroxypropyl methyl cellulose 6 cps 2.75 2.70
12 Hydroxypropyl methyl cellulose E15 LV 2.75 2.70
13 Titanium Dioxide 1.64 2.4
14 Talc 1.36 1.33
15 Polyethylene glycol 6000 0.82 0.75
16 Yellow Oxide of Iron 0.68 -
17 Lake of Sunset Yellow - 0.12
Total (Coated tablet) 630.00 630.00
PROCESS OF PREPARATION:
1. Croscarmellose sodium, microcrystalline cellulose, and polyvinyl pyrrolidone K-30 were sifted through 40 mesh screen and mixed together.
2. Metformin Hydrochloride was passed through 40 mesh sieve and mixed with mixture of step 1.
3. The mixture of step 2 was granulated with water.
4. The granules of step 3 were dried till desired loss on drying is obtained.
5. The dried granules of step 3 were sized and mixed with microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and glibenclamide for appropriate time.
6. Then mixture of step 5 was lubricated with magnesium stearate.
7. The lubricated blend of step 5 was compressed to appropriate size (16 X 8 mm capsule shape biconcave with embossing 5/2.5 on one side).
8. The tablets were film coated.
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The particle size distribution of glibenclamide in the above example is given below.

Size in Microns 2 10 60
Volume under % 17.91 99.90 100
Dated this on 17th September, 2005

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ABSTRACT
The present invention relates to a solid oral dosage form comprising a combination of metformin and glibenclamide comprising micronized glibenclamide.