Claims:1. A solid oral dosage form comprising a combination of metformin and glimepiride in 2 different layers, wherein both layers are separated by a separating layer comprising at least one particulate excipient.
2. A solid dosage form as claimed in claim 1 in which metformin is presented as modified release form and glimepiride is presented as immediate release form in 2 different layers, wherein both layers are separated by a separating layer comprising at least one particulate excipient.
3. A solid dosage form as claimed in claim 1 in which metformin hydrochloride is presented as modified release form and glimepiride is presented as immediate release form in 2 different layers, wherein both layers are separated by a separating layer comprising at least one particulate excipient water soluble diluent and/or disintegrant.
4. A solid dosage form as claimed in claim 1 in which metformin hydrochloride is presented as modified release core tablet and glimepiride is presented as immediate release coat over core tablet of metformin, wherein core and glimepiride layers are separated by a separating layer comprising at least one particulate excipient lactose and/or sodium starch glycolate.
5. A solid oral dosage form comprising a combination of metformin and glimepiride wherein dosage form comprises a) metformin hydrochloride as modified release core tablet, b) glimepiride as immediate release coat over core tablet, c) separating layer comprising at least one particulate excipient.
6. A solid oral dosage form as claimed in claim 5 in which separating layer comprises lactose and/or sodium starch glycolate.
7. A solid oral dosage form as claimed in claim 5 in which a) modified release tablet core comprises metformin hydrochloride, cellulose polymer; b) separating layer comprising diluent, cellulose polymer, disintegrant; c) immediate release coat comprises glimepiride, diluent, cellulose polymer, disintegrant.
8. A solid oral dosage form as claimed in claim 5 in which a) modified release tablet core comprises metformin hydrochloride, hydroxypropyl methylcellulose; b) separating layer comprising lactose, hydroxypropyl methylcellulose, sodium starch glycolate; c) immediate release coat comprises glimepiride, lactose, hydroxypropyl methylcellulose, sodium starch glycolate.
9. A solid dosage form as claimed in claim 5 in which immediate release coat comprises solubility enhancing excipient.
10. A solid dosage form as claimed in claim 5 in which immediate release coat comprises polysorbate. , Description:Field of invention
The present invention provides solid oral pharmaceutical composition of metformin and glimepiride wherein metformin is present as modified release form and glimepiride is present in immediate release form; and metformin in modified release form is presented as core tablet and glimepiride is presented as immediate release form over metformin modified release form, with an intermediate layer comprising lactose and/or sodium starch glycolate to ensure the final composition provides consistent desired modified and immediate release of actives respectively.

Background of invention
Metformin hydrochloride (N,N-dimethylimidodicarbonimidicdiamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antidiabetic agents. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula of metformin hydrochloride is:

Metformin is available as immediate release, modified release formulations; there are several combination products available along with alogliptin, canagliflozin, dapagliflozin, empagliflozin, glipizide, linagliptin, pioglitazone, repaglinide, rosiglitazone, saxagliptin, sitagliptin, and others.

Glimepiride is an oral antidiabetic drug of the sulfonylurea class. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder. Chemically, glimepiride is 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans- 4-methylcyclohexyl)urea with a molecular weight of 490.62. The molecular formula for glimepiride is C24H34N4O5S. Glimepiride is practically insoluble in water. The structural formula of glimepiride is:

Glimepiride is available as immediate release formulation, there are several combination products available along with pioglitazone, rosiglitazone and others.

Commercially combination of metformin extended release and glimepiride immediate release tablets are available as bilayer tablets to meet respective release profiles of both active substances. Bilayer tablets have technical limitation that ratio of layers that leads to higher weight of overall tablet resulting in bigger tablets that are difficult to swallow.

Detailed description
The present invention relates to a solid oral dosage form of modified release metformin and immediate release glimepiride.

In an embodiment of the invention, modified release metformin and immediate release glimepiride are presented in two separate layers, wherein both layers are separated by a separating layer comprising water soluble diluent and/or disintegrant.

In another embodiment of the invention, modified release metformin is presented as core tablet and immediate release glimepiride is coated over metformin core tablet, wherein both are separated by a separating layer comprising water soluble diluent and/or disintegrant.

In an embodiment of the invention, metformin used is metformin hydrochloride.

In yet another embodiment of the invention, metformin hydrochloride per tablet is in the range of 250 mg to 1000mg.

In another embodiment of the invention, glimepiride per tablet is in the range of 1mg to 4mg.

In an embodiment different proportions of metformin hydrochloride to glimepiride per tablet are but not limited to 1000:1 or 1000:2 or 500:1 or 500:2.

In one embodiment of the invention, active substance used in immediate release layer may include but not limited to alogliptin, atorvastatin, canagliflozin, dapagliflozin, empagliflozin, glipizide, glyburide, linagliptin, lovastatin, pioglitazone, repaglinide, rosiglitazone, saxagliptin, simvastatin, sitagliptin, pitavastatin, rosuvastatin, and their pharmaceutical salts thereof.

Modified release core tablets of metformin hydrochloride of present invention comprise hydroxypropyl methylcellulose and are manufactured either by direct compression, dry granulation or wet granulation methods.

Immediate release glimepiride layer of present invention is coated over metformin layer using aqueous or non-aqueous or combinations thereof, either in solution form or fine dispersion form.

Immediate release glimepiride layer of present invention comprises water soluble diluent and/or disintegrant.

Diluents used in the present invention include but not limited to lactose, mannitol, sorbitol, maltitol, xylitol, starch, povidone, cellulose and cellulose derivatives, and various grades of calcium phosphates.

Binders used in the present invention include but not limited to gums such as acacia, gelatine, xanthine, starch and derivatives of starch, various grades of povidones, celluloses and its derivatives, and the like.

Disintegrants used in the present invention include but not limited to starch and starch derivatives, sodium starch glycolate, povidone grades, cellulose derivatives, croscarmellose sodium, silicon dioxides and the like.

Solubility enhancing excipients of the invention include but not limited to poloxamers, PEG and its derivatives, sodium lauryl sulphates, polysorbates, cyclodextrins, starches, cellulose derivatives, povidone derivatives, acidifiers or alkalizers and the like.

Core tablets of the invention are prepared either by direct compression, dry granulation or wet granulation using rapid mixer granulator or fluid bed processor and the like.

Immediate release layer of second active substance is prepared as clear solution, fine dispersion either in water or alcohols such as isopropyl alcohol, methanol, ethanol or acetone, methylene chloride, dimethyl sulfoxide either alone in combination with each other in various ratios and the like.

Examples
Positive control example 1
Material Qty mg per unit
Microcrystalline cellulose 559
Lactose monohydrate 455
Dicalcium phosphate 195
Sodium starch glycolate 52
Magnesium stearate 26
Colloidal silicon dioxide 13

Core placebo tablets were prepared using above composition by direct blending and compression process.
Material Qty mg per unit
Glimepiride 2
Lactose 15
Sodium starch glycolate 3
Hydroxypropyl methylcellulose 5cps 26
Polyethylene glycol 400 1.5
Talc 0.4
Tween 80 1.2

Glimepiride, lactose, sodium starch glycolate, hydroxypropyl methylcellulose, polyethylene glycol, talc were sifted through 40# screen. Above sifted materials were added to purified water to make it 13% w/v dispersion under stirring. Tween 80 was added to above dispersion under stirring. This dispersion was sprayed on to above manufactured core placebo tablets.

Release profiles were generated.
Time in minutes % drug released
5 64
10 85
15 88
20 90
30 90
45 90

Control example 2
Metformin core tablets
Material Qty mg per unit
Metformin hydrochloride 1000
HPMC K200 M 240
HPMC 5 cps 8
Purified water Qs
Sodium carboxy methylcellulose 26
Magnesium stearate 26

Metformin core tablets were prepared using above composition by granulating blend of metformin and HPMC K200 M, using HPMC 5cps dispersion in water using rapid mixer granulator, dried milled granules were blended with SCMC and magnesium stearate and compressed.
Conventional separating layer
Material Qty mg per unit
Opadry clear 35
Purified water Qs

Opadry clear was dispersed in water to make it 13% w/v dispersion under stirring and coated over above metformin core tablets to form a separating layer.

Glimepiride layer
Material Qty mg per unit
Glimepiride 2
Lactose 15
Sodium starch glycolate 3
Hydroxypropyl methylcellulose 5cps 26
Polyethylene glycol 400 1.5
Talc 0.4
Tween 80 1.2

Glimepiride, lactose, sodium starch glycolate, hydroxypropyl methylcellulose, polyethylene glycol, talc were sifted through 40# screen. Above sifted materials were added to purified water to make it 13% w/v dispersion under stirring. Tween 80 was added to above dispersion under stirring. This dispersion was sprayed on to above manufactured core placebo tablets.

Release profiles were generated.
Time in minutes % drug released
5 23
10 41
15 51
20 -
30 61
45 62

Complete release was not achieved.

Example 3
Metformin core tablets
Material Qty mg per unit
Metformin hydrochloride 1000
HPMC K200 M 240
HPMC 5 cps 8
Purified water Qs
Sodium carboxy methylcellulose 26
Magnesium stearate 26

Metformin core tablets were prepared using above composition by granulating blend of metformin and HPMC K200 M, using HPMC 5cps dispersion in water using rapid mixer granulator, dried milled granules were blended with SCMC and magnesium stearate and compressed.
Separating layer
Material Qty mg per unit
Lactose 17
Sodium starch glycolate 3
Hydroxypropyl methylcellulose 5cps 26
Polyethylene glycol 400 1.5
Talc 0.4
Tween 80 1.2
Purified water Qs

Lactose, sodium starch glycolate, hydroxypropyl methylcellulose, polyethylene glycol, talc were sifted through 40# screen. Above sifted materials were added to purified water to make it 13% w/v dispersion under stirring.

This dispersion was sprayed on to above manufactured metformin core tablets.
Glimepiride layer
Material Qty mg per unit
Glimepiride 2
Lactose 15
Sodium starch glycolate 3
Hydroxypropyl methylcellulose 5cps 26
Polyethylene glycol 400 1.5
Talc 0.4
Tween 80 1.2

Glimepiride, lactose, sodium starch glycolate, hydroxypropyl methylcellulose, polyethylene glycol, talc were sifted through 40# screen. Above sifted materials were added to purified water to make 13% w/v dispersion under stirring. Tween 80 was added to above dispersion under stirring. This dispersion is sprayed on to above manufactured metformin tablets coated with separating layer.

Release profiles were generated.
Time in minutes % drug released
5 33
10 49
15 70
20 76
30 93
45 100

Complete release was achieved.