Claims:1. A modified release pharmaceutical composition comprising Pregabalin, hydrophilic release controlling polymers.

2. The composition as claimed in claim 1, wherein said composition does not contain hydrophobic release controlling polymers.

3. The composition as claimed in claim 1, wherein said hydrophilic release controlling polymers are present in extragranular portion.

4. The composition as claimed in claim 1, wherein said hydrophilic release controlling polymers are selected from one or more of hydroxypropyl methylcellulose, carbopol, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, xanthan gum, guar gum, sodium alginate.

5. A modified release pharmaceutical composition comprising Pregabalin, mixture of low viscosity and high viscosity hydrophilic release controlling polymers, wherein the ratio of low viscosity and high viscosity hydrophilic release controlling polymers is from about 1:1 to about 5:1.

6. The composition as claimed in claim 5, wherein said low viscosity hydrophilic release controlling polymers are selected from low viscosity hydroxypropyl methylcellulose which comprises one or more of METHOCEL K3LV, METHOCEL K100LV, METHOCEL E3LV, METHOCEL E5LV, METHOCEL E6LV, METHOCEL E15LV, METHOCEL E50LV, BENECEL K100LV PH PRM and High viscosity hydrophilic release controlling polymers are selected from high viscosity hydroxypropyl methylcellulose which comprises one or more of METHOCEL K4M, METHOCEL K15M, METHOCEL K100M, METHOCEL K200M, METHOCEL E4M, METHOCEL E10M, BENECEL K250 PH PRM, BENECEL K750 PH PRM, BENECEL K1500 PH PRM, BENECEL E4M Pharm, BENECEL E10M Pharm.

7. A modified release pharmaceutical composition comprising from about 10% to about 50% by weight of Pregabalin, from about 10% to about 80% by weight of hydrophilic release controlling polymers, and from about 1% to about 80% by weight of one or more pharmaceutically acceptable excipients selected from diluents, binders, disintegrants, glidants and lubricants.

8. The composition as claimed in claim 7, wherein said composition is prepared by wet granulation process.

9. The composition as claimed in claim 8, wherein said composition is prepared by
a) co-sifting Pregabalin, diluent and other excipients,
b) granulating the above blend using binder solution,
c) milling and sizing the granules obtained in step (b) followed by pre-lubrication with hydrophilic release controlling polymers and other remaining excipients,
d) lubricating the above blend and compressing into tablet,
e) coating the tablet with film forming polymers.

10. The composition as claimed in claim 7, which comprises Pregabalin from about 20% to about 40% by weight, mixture of low and high viscosity hydroxypropyl methylcellulose from about 30% to about 45% by weight, carbopol from about 10% to about 20% by weight, hydroxypropyl methylcellulose E15 from about 0.5% to about 2% by weight, low substituted hydroxypropyl cellulose from about 3% to about 8% by weight, microcrystalline cellulose from about 5% to about 10% by weight, colloidal silicon dioxide from about 1.5% to about 3% by weight, and magnesium stearate from about 0.5% to about 2% by weight.
, Description:FIELD OF THE INVENTION
The present invention relates to modified release formulation of Pregabalin and process for its preparation wherein said formulation does not contain hydrophobic release controlling polymer.
BACKGROUND OF THE INVENTION
Pregabalin is chemically known as (S)-3-aminomethyl-5-methyl-hexanoic acid and has a molecular weight of 159.23 with the following structural formula:

Pregabalin is indicated for the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia and as an adjunctive treatment for partial onset seizures in adults. Binding to the alpha2-delta subunit (an auxiliary subunit of voltage-gated calcium channels) may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals.
Pregabalin and its use are disclosed in U.S. Pat. No. 6,197,819.
Currently, Pregabalin is available as an immediate release formulation (capsules) which is administered two or three times daily and extended release formulation (tablets), which is administered once daily.
Many patients receiving pregabalin two or more times daily would likely benefit from once daily dosing. Once daily dosing improves patient compliance, especially for elderly patients and for patients taking multiple medications. It also decreases or prevent potentially undesirable dose-related effects by reducing peak blood levels (Cmax) and also increase drug efficacy by increasing minimum plasma concentrations (Cmin).
Several approaches have been explored in the art for a once daily dosage form of pregabalin.
U.S. Patent No. 8,945,620 discloses a Pregabalin formulation for once daily oral dosing containing polyvinyl acetate and polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and polyethylene oxide. Further, the formulation is retained in the stomach for a longer period than an IR formulation.
U.S. Publication No. 2010,0255067 describes pharmaceutical compositions comprising Pregabalin, a hydrophobic release controlling agent, and other pharmaceutically acceptable excipients.
U.S. Patent No. 9,393,205 discloses gastroretentive tablet comprising Pregabalin, at least one swellable polymer, and other pharmaceutically acceptable excipients. Gastroretentive tablet further comprise a gas generating agent.

PCT Publication No. WO 2011,151708 describes gastroretentive dosage form comprising a GABA analog, at least one swelling agent, and at least one non-swelling release retardant.
All the compositions in the art used either specialized technologies or processes like hot melt extrusion or gastro-retention etc. and special excipients like Polyethylene oxide, crospovidone, hydrophobic release controlling agents like hydrogenated vegetable oil, ethyl cellulose etc.
However, the present inventors have developed a modified release composition for once daily administration comprising Pregabalin and conventional release controlling polymers.
OBJECTIVES OF THE INVENTION
The main objective of the invention is to provide a modified release pharmaceutical composition comprising Pregabalin, conventional release controlling polymers and process of preparing the same using wet granulation.

SUMMARY OF THE INVENTION
The present invention provides a modified release pharmaceutical composition comprising Pregabalin, conventional release controlling polymers and process of preparing the same using wet granulation.
In one aspect, the present invention provides a modified release pharmaceutical composition comprising Pregabalin, wherein conventional release controlling polymers are hydrophilic release controlling polymers.
In another aspect, the present invention provides modified release pharmaceutical composition comprising Pregabalin and hydrophilic release controlling polymers, wherein said composition does not contain hydrophobic release controlling polymers.
In one aspect, the present invention provides a modified release pharmaceutical composition comprising Pregabalin and hydrophilic release controlling polymers, wherein said hydrophilic release controlling polymers are present in extragranular portion.
In a more preferred aspect, the present invention provides a modified release pharmaceutical composition comprising Pregabalin and hydrophilic release controlling polymers, wherein said hydrophilic release controlling polymers are low and high viscosity hydrophilic release controlling polymers.
In a most preferred aspect, the present invention provides a modified release pharmaceutical composition comprising Pregabalin and mixture of low viscosity and high viscosity hydrophilic release controlling polymers, wherein the ratio of low viscosity and high viscosity hydrophilic release controlling polymers is from about 1:1 to about 5:1.
In another aspect, the present invention provides a modified release pharmaceutical composition comprising;
from about 10% to about 50% by weight of Pregabalin,
from about 10% to about 80% by weight of hydrophilic release controlling polymers, and
from about 1% to about 80% by weight of one or more pharmaceutically acceptable excipients,
wherein said composition is prepared by wet granulation process.
In a more preferred aspect, the present invention provides a modified release pharmaceutical composition comprising;
Pregabalin,
mixture of low and/or high viscosity hydroxypropyl methylcellulose as a release controlling polymer,
Hydroxypropyl methylcellulose (Methocel E15) as a binder,
Low substituted hydroxypropyl cellulose as a binder,
Carbopol as a release controlling polymer,
Microcrystalline cellulose as a diluent,
Colloidal silicon dioxide as a granulation aid, and
Magnesium stearate as a lubricant.
In yet another aspect, the present invention provides a process for the preparation of modified release pharmaceutical composition of Pregabalin comprising;
a. Co-sifting Pregabalin, diluent and other excipients,
b. Granulating the above blend using binder solution,
c. Milling and sizing the granules obtained in step (b) followed by pre-lubrication with hydrophilic release controlling polymers and other remaining excipients,
d. Lubricating the above blend and compressing into tablet.
e. Coating the tablet with film forming polymers.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 01: Dissolution profile of test (Example 1) and reference formulations (LYRICA CR®).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to a modified release composition for once daily administration comprising Pregabalin and conventional release controlling polymers, prepared using wet granulation process. Particularly, compositions of the present invention do not contain hydrophobic release controlling polymers. Also, excipients used in the present compositions are of low cost and the manufacturing process is less time consuming.
Unless otherwise indicated, this disclosure uses the following definitions.

The term “pregabalin” refers to (S)-3-aminomethyl-5-methyl-hexanoic acid or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof.
The term “modified release” include, inter alia, extended release, delayed release, sustained release, controlled release, prolonged release, programmed release or their combination.
The term “conventional release controlling polymers” refers to polymers which are readily available with low cost and do not require any specialized process or processing equipment.
The term “low viscosity hydrophilic release controlling polymers” refers to polymers having viscosity of 120cps or less, measured by using 2% aqueous solution at 200c.
The term “high viscosity hydrophilic release controlling polymers” refers to polymers having viscosity more than 120cps, measured by using 2% aqueous solution at 200c.
The term “f2” refers to Similarity factor which is calculated using the following formula:

The term “% by weight” refers to % by weight of total pharmaceutical composition.
The pharmaceutical compositions according to the present invention, includes therapeutically effective amount of pregabalin, further comprise one or more pharmaceutically acceptable excipients selected from group consisting of hydrophilic release controlling polymers, diluents, binders, disintegrants, glidants and lubricants or any other excipients known in the art.
Suitable examples of hydrophilic release controlling polymers include one or more of low viscosity polymers, high viscosity polymers and other polymers.
Low viscosity hydrophilic release controlling polymers are selected from one or more of hydroxypropyl methylcellulose available under various trade names such as METHOCEL K3LV, METHOCEL K100LV, METHOCEL E3LV, METHOCEL E5LV, METHOCEL E6LV, METHOCEL E15LV, METHOCEL E50LV and BENECEL K100LV PH PRM etc.
High viscosity hydrophilic release controlling polymers are selected from one or more of Hydroxypropyl methylcellulose available under various trade names such as METHOCEL K4M, METHOCEL K15M, METHOCEL K100M, METHOCEL K200M, METHOCEL E4M, METHOCEL E10M and BENECEL K250 PH PRM, BENECEL K750 PH PRM, BENECEL K1500 PH PRM, BENECEL E4M Pharm, BENECEL E10M Pharm etc.
Other hydrophilic release controlling polymers are selected from one or more of carbopols available under various grades like carbopol 71G, 934P, 971P etc., hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, xanthan gum, guar gum, sodium alginate, preferably hydroxypropyl methylcellulose, more preferably mixture of low and high viscosity hydroxypropyl methylcellulose.
Suitable examples of diluents include microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, or combinations thereof, preferably microcrystalline cellulose.
Suitable examples of binders include polyvinylpyrrolidone, starch mucilage, pregelatinized starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, methyl cellulose, hydroxylpropyl methyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, carbopols, or combinations thereof, preferably hydroxypropyl methylcellulose or low-substituted hydroxypropyl cellulose or both.
Suitable examples of disintegrants include silicified microcrystalline cellulose, microcrystalline cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose or combinations thereof.
Suitable examples of lubricants and/or glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc or combinations thereof, preferably magnesium stearate.
The compositions of the present invention are in the form of tablets, dispersible tablets, capsules, granules, beads and pellets, preferably tablets.
The tablets described herein may be prepared by conventional tableting techniques using commonly available equipment known to the person skilled in the art. The process may comprise involving granulation, direct compression, preferably wet granulation.
The tablets are coated. Coating may comprise any conventional coating formulations and will include one or more film-formers, such as Hydroxypropyl methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose and the like and one or more plasticizers, such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate, castor oil and the like and any other excipients known to person skilled in the art. Preferably coating is carried out using Opadry® from Colorcon.
In one aspect, the present invention provides a modified release pharmaceutical composition comprising;
from about 10% to about 50% by weight of Pregabalin,
from about 10% to about 80% by weight of hydrophilic release controlling polymers, and
from about 1% to about 80% by weight of one or more pharmaceutically acceptable excipients,
wherein said composition is prepared by wet granulation process.
In another aspect, the present invention provides a modified release pharmaceutical composition comprising;
Pregabalin from about 20% to about 40% by weight,
mixture of low and high viscosity hydroxypropyl methylcellulose from about 30% to about 45% by weight,
Carbopol from about 10% to about 20% by weight,
Hydroxypropyl methylcellulose (Methocel E15) from about 0.5% to about 2% by weight,
Low substituted hydroxypropyl cellulose from about 3% to about 8% by weight,
Microcrystalline cellulose from about 5% to about 10% by weight,
Colloidal silicon dioxide from about 1.5% to about 3% by weight, and
Magnesium stearate from about 0.5% to about 2% by weight.
The following examples are intended to be illustrative and non-limiting:

Examples
Example 1: Pregabalin extended release tablets:
Table 1
S.NO Ingredients Quantity (mg/tablet)
1 Pregabalin 330.00
2 Colloidal silicon dioxide 22.00
3 Low substituted hydroxypropyl cellulose
(L-HPC) (LH 21) 25.00
4 Microcrystalline cellulose 62.00
4 Hydroxypropyl methylcellulose (HPMC)
(Methocel E15) 10.00
5 Purified Water q.s.
6 Hydroxypropyl methylcellulose
(Methocel K4M) 190.00
7 Hydroxypropyl Methylcellulose
(Methocel K100LV Premium) 215.40
8 Low substituted hydroxypropyl cellulose
(LH 21) 25.00
9 Carbopol 71G 150.00
10 Microcrystalline cellulose 20.00
11 Magnesium Stearate 10.60
Tablet weight (Core) 1060.0
12 Opadry II Pink (85F540430) 40.00
13 Purified water q.s.
Tablet weight (Coated) 1100.0

Manufacturing procedure:
1) Pregabalin, colloidal silicon dioxide, L-HPC and microcrystalline cellulose were loaded into fluid bed processor and mixed for 10 minutes.
2) HPMC E15 is dissolved in purified water.
3) The dry mix of step (1) is granulated using binder solution of step (2) by top spray granulation.
4) The dried granules of step (3) were mixed with HPMC K4M, HPMC K100LV, L-HPC, carbopol 71g, microcrystalline cellulose for 10 minutes.
6) Magnesium stearate is added to blend of step (4) and mixed for 5 min.
7) Compressed the blend of step (6) into tablets.
8) The tablets of step (7) are coated using Opadry Pink.

Comparison of in-vitro dissolution profile:
The Pregabalin extended release tablets of example 1 and reference product (LYRICA CR®) were subjected to dissolution studies in 900 ml of 0.06M HCl at 37°C ± 0.5°C using USP apparatus II with paddle speed at 50 rpm.
Table 2: The comparative dissolution data:

Time (hr) Drug released (Percent w/w)
LYRICA CR® Example 1
0 00 00
0.5 11.0 9.8
1 17.5 16.0
2 28.0 25.6
3 36.3 33.5
4 43.8 39.7
6 54.5 50.8
8 64.2 59.7
10 71.4 67.4
12 78.5 74.0
14 82.2 79.1
16 86.8 84.3
24 98.7 97.9
26 98.4 100.1
30 98.4 104.6

Based on the above results, the release profile of Pregabalin extended release tablets of example 1 is found to be similar to Reference product with the f2 (similarity factor) value of 74.