FORM 2
THE PATENT ACT 1970
(39 of 1970)&The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PREPARATION OF PHARMACEUTICAL FORMULATION OF
FENOFIBRATE BY MELT GRANULATION
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition of fenofibrate or
salt thereof comprising non-micronized fenofibrate, polyethylene glycol or
derivative thereof and sorbitol in admixture with one or more pharmaceutically
acceptable excipients.
The following specification Part Icularly describes the invention and the manner
in which it is to be performed.

4. Description
The present invention provides a pharmaceutical composition of fenofibrate or salt thereof comprising non-micronized fenofibrate, polyethylene glycol or derivative thereof and sorbitol in admixture with one or more pharmaceutically acceptable excipients.
Fenofibrate is a lipid-regulating agent. The empirical formula is C20H21O4C1 and the molecular weight is 360.83. Fenofibrate is insoluble in water and its melting point is 79-82°C. The chemical name of fenofibrate is 2-[4-(4-Chlorobenzoyl) phenoxy]-2-methylpropanoic acid 1-methylethyl ester (Formula I). Fenofibrate is a white solid which is stable under ordinary conditions and its structural formula is:

FORMULA I
U.S. Patent No 5,145,684, 6,375,986, 6,969,529, 6,592,903, and 6,368,620 provide nanoPart Iculate compositions of fenofibrate.
U.S. Patent No 6,277,405, 6,652,881, 7,037,529, 7,041,319, 6,589,552 and 6,531,158 describe micronized fenofibrate compositions.
U.S. Patent Nos. 4,895,726, 5,880,148, and 7,189, 412 describe co-micronizing the fenofibrate with surface-active agents.
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U.S. Patent Nos. 6,074,670, and 6,277,405 describe micronized fenofibrate coated onto hydrosoluble carriers with optional surface-active agents.
U.S. Patent No 6,828,334 and U.S. Application 2004142903 describes inclusion complex of micronized fenofibrate with cyclodextrin.
Several other International (PCT) Publications describe formulations of fenofibrate or process for preparing fenofibrate formulations such as WO2007075171, WO2007073389, and WO2005002541.
Several other patents describe formulations of fenofibrate or process for preparing fenofibrate formulations such as U.S. Patent Nos. 4,800,079, 4,961,890, 5,827,536, 5,545,628, 6,372,251, 6,531,158, 6,696,084, 6,555,135, 6,719,999, 6,027,747, 6,814,977, 6,838,091, 6,451,339, 6,383,517, 6,682,761, 6,982,281, 6,465,011, 6,444,225, 6,368,622, 7,022,337, and 7,101,574.
Several other applications describe formulations of fenofibrate or process for preparing fenofibrate formulations such as U.S. Patent Applications 2002119199, 2003180367, 2003031705, 20030082215, 20030138496, 2003224059, 20040092597, 20040057999, 20040087656, 20040057998, 2004137055, 20040058005, 2004091535, 2004115264, 2005276974, 2004058009, 2005171193, 2005112192, 2006177512, 20060222706, 2006110444, 20060222707, 20060280791, 2007015833, 2007015834, 20070071812, 20070026062, 20070014854, 20070014864, 20070014853, 2007048384, 2007049636, 2007077307, 20060280791, 20060280790, 2007128278, 20070148234 and 20070148211.
Fenofibrate is poorly soluble drug. Due to its poor hydrosolubility, fenofibrate poses problem of low dissolution. It is also poorly absorbed in the digestive tract and consequently its bioavailability is incomplete and irregular.
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The present inventors while working on fenofibrate formulation have noticed that when non-micronized fenofibrate is melt granulated with polyethylene glycol (PEG) or derivative thereof in presence of sorbitol. The so obtained melt has significantly low melting point when compared to a simple mix of non-micronized fenofibrate, PEG and sorbitol. Additionally the so obtained melt has significantly reduced the crystallinity of the fenofibrate. Further reduction in melting point and crystallinity significantly enhances the solubility, dissolution and bioavailability of fenofibrate.
The present inventors have further noticed that the reduction in the crystallinity of fenofibrate is significantly better when fenofibrate was melted with PEG or derivative thereof in presence of sorbitol as compared to melting fenofibrate with PEG or derivative thereof in the absence of sorbitol.
One of the aspects of the present invention provides a pharmaceutical composition comprising non-micronized fenofibrate or salt thereof, polyethylene glycol or derivative thereof and sorbitol.
For the present invention, the term 'non-micronized fenofibrate' as used herein means fenofibrate having Particle size greater than or equal to about 50pm and fenofibrate is not subjected to any comminution techniques that are well known to person skilled in the art and include but not limited to milling, spray drying, high pressure homogenization .
Suitable polyethylene glycol (PEG) or derivatives thereof may include all PEGs that are liquid at room temperature or that melt upto about 70°C. Suitable polyethylene glycol (PEG) or derivatives thereof comprise one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyglycolyzed glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes, and the like.
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Another aspect of the present invention provides a process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:
a) melting non-micronized fenofibrate, polyethylene glycol or derivative thereof, and sorbitol;
b) granulating the melt of step a) by adsorbing it on one or more pharmaceutically acceptable excipients.
Suitable polyethylene glycol (PEG) or derivatives thereof may include all PEGs that are liquid at room temperature or that melt upto about 70°C. Suitable polyethylene glycol (PEG) or derivatives thereof comprise one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyglycolyzed glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes, and the like.
The one or more pharmaceutically acceptable excipients may include one or more of surfactants, fillers, binders, lubricants, disintegrants, and glidants.
Suitable surfactant in the process of the present invention are those known to ordinary skilled in the art and include but not limited to amphoteric, non-ionic, cationic or anionic surfactants. Examples of such surfactants are sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the like. Mixtures of surfactants are also suitable.
Suitable filler may be one or more of, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
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Suitable binder may be one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable lubricant may be one or more of, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
Suitable disintegrant may be one or more of, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable glidant may be one or more of, colloidal silicon dioxide, talc or cornstarch and the like.
Another aspect of the present invention provides a process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:
a) melting non-micronized fenofibrate, polyethylene glycol or derivative thereof, and sorbitol;
b) granulating the melt of step a) by adsorbing it on one or more pharmaceutical^ acceptable carrier;
c) layering the granules of step b) with one or more pharmaceutically acceptable excipients.
Suitable polyethylene glycol (PEG) or derivatives thereof may include all PEGs that are liquid at room temperature or that melt upto about 70°C. Suitable polyethylene glycol (PEG) or derivatives thereof comprise one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyglycolyzed glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes, and the like.
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The one or more pharmaceutically acceptable carrier may include one or more of fillers, binders, lubricants, disintegrants, and glidants.
Suitable surfactant in the process of the present invention are those known to ordinary skilled in the art and include but not limited to amphoteric, non-ionic, cationic or anionic surfactants. Examples of such surfactants are sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the like. Mixtures of surfactants are also suitable.
Suitable filler may be one or more of, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable binder may be one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable lubricant may be one or more of, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
Suitable disintegrant may be one or more of, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable glidant may be one or more of, colloidal silicon dioxide, talc or cornstarch and the like.
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The one or more pharmaceutically acceptable excipients may include one or more of surfactants, fillers, binders, lubricants, disintegrants, and glidants.
Suitable filler may be one or more of, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable binder may be one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable lubricant may be one or more of, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
Suitable disintegrant may be one or more of, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable glidant may be one or more of, colloidal silicon dioxide, talc or cornstarch and the like.
The composition of the present invention can be prepared by melt granulation. The composition of the present invention can be prepared by melting non-micronized fenofibrate, polyethylene glycol or derivative thereof, sorbitol and one or more pharmaceutically acceptable binder. The obtained molten mass can be granulated by adsorbing on one or more pharmaceutically acceptable excipients.
The composition of the present invention can also be prepared by melting non-micronized fenofibrate, polyethylene glycol or derivative thereof, sorbitol and one or more pharmaceutically acceptable binder. The obtained molten mass can be granulated by adsorbing on one or more pharmaceutically acceptable carrier. The resulting granules can be coated with a layer of surfactant.
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The granules obtained by melt granulation can be optionally mixed with one or more pharmaceutically acceptable excipients. The resulting mixture can be filled into capsule or compressed to make tablet.
The pharmaceutical composition of the present invention is meant for oral administration and can be present in the form of tablet, capsule, caplet, granules, suspension and pellets.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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Example-1
Table-1 Composition of Fenofibrate Tablets

S. No Ingredients Qty/tab (% w/w)
Part I
1. Fenofibrate* 5-50
2. PEG 6000 5-50
3. Sorbitol 0.5-20
4. Povidone K-30 0.5-20
Part II
5. Lactose monohydrate 5-40
6. Crospovidone 5-40
7. Poloxamer 5-40
8. Sodium Lauryl Sulfate 1-20
9. Cremophore RH 40 5-40
10. Docusate Sodium 1-20
Part III
11. Prosolv SMCC 90 1-25
12. Crospovidone 1-25
13. Magnesium Stearate 1-15
* Fenofibrate is non-micronized having Particle size greater than or equal to 50um
Procedure: Fenofibrate, PEG 6000 and sorbitol were melted in a water bath to get a molten mass and solution of Povidone K-30 was added to the molten mass and homogenized. The obtained molten mass was adsorbed on lactose monohydrate, Crospovidone, Poloxamer, Sodium Lauryl Sulfate, Cremophore RH 40 and Docusate sodium in Rapid Granulator Mixer to get uniform granules. The obtained granules were mixed with Prosolv SMCC 90 and Crospovidone. The resulting blend was lubricated with Magnesium stearate and compressed into tablets using suitable tooling. The tablets can be optionally coated with aqueous dispersion of Opadry.
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Example-2
Table-2 Composition of Fenofibrate Tablets

S. No Ingredients Qty/tab (% w/w)
Part I
1. Fenofibrate* 5-50
2. PEG 6000 5-50
3. Sorbitol 0.5-20
4. Povidone K-30 0.5-20
5. Part II
6. Lactose monohydrate 5-40
7. Crospovidone 5-40
Part III
8. Poloxamer 5-40
9. Sodium Lauryl Sulfate 1-20
10. Cremophore RH 40 5-40
11. Docusate Sodium 1-20
12. Part IV
13. Prosolv SMCC 90 1-25
14. Crospovidone 1-25
15. Magnesium Stearate 1-15
* Fenofibrate is non-micronized having Particle size greater than or equal to 50um
Procedure: Fenofibrate, PEG 6000 and sorbitol were melted in a water bath to get a molten mass and solution of Povidone K-30 was added to the molten mass and homogenized. The obtained molten mass was adsorbed on lactose monohydrate, Crospovidone in Rapid Granulator Mixer to get uniform granules. The obtained granules were coated with solution of Poloxamer, Sodium Lauryl Sulfate, Cremophore RH 40 and Docusate sodium and dried. The coated granules were mixed with Prosolv SMCC 90 and Crospovidone. The resulting blend was lubricated with Magnesium stearate and compressed into tablets using suitable tooling. The tablets can be optionally coated with aqueous dispersion of Opadry.
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WE CLAIM:
1. A pharmaceutical composition comprising non-micronized fenofibrate or salt thereof, polyethylene glycol or derivative thereof and sorbitol.
2. A process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:

a) melting non-micronized fenofibrate, polyethylene glycol or derivative thereof and sorbitol;
b) granulating the melt of step a) by adsorbing it on one or more pharmaceutically acceptable excipients.
3. A process for preparing pharmaceutical composition of fenofibrate or salts
thereof wherein the said process comprises:
a) melting non-micronized fenofibrate, polyethylene glycol or derivative thereof and sorbitol;
b) granulating the melt of step a) by adsorbing it on one or more pharmaceutically acceptable carrier;
c) layering the granules of step b) with one or more pharmaceutically acceptable excipients.

4. The pharmaceutical composition and the process of claim 1-3, wherein fenofibrate is having Particle size greater than or equal to about 50pm.
5. The pharmaceutical composition and the process of claim 1-3, wherein polyethylene glycol or derivative comprises one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyglycolyzed glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes.
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The process of claim 2 and 3, wherein pharmaceutically acceptable excipients comprises one or more of surfactants, fillers, binders, lubricants, disintegrants, glidants.
The process of claim 3, wherein pharmaceutically acceptable carrier comprises one or more of fillers, binders, lubricants, disintegrants, glidants.

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Abstract
The present invention provides a pharmaceutical composition of fenofibrate or salt thereof comprising non-micronized fenofibrate, polyethylene glycol or derivative thereof and sorbitol in admixture with one or more pharmaceutically acceptable excipients. The present invention also provides a process of preparing the said pharmaceutical composition.
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