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:
MELT GRANULATION PROCESS OF FENOFIBRATE OR SALTS
THEREOF
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 pharmaceutical composition of fenofibrate or
salts thereof comprising non-micronized fenofibrate, Polyethylene glycol or
derivative thereof, and one or more surfactants. The present invention also
provides a process of preparing pharmaceutical composition of fenofibrate or
salts thereof.
The following specification Part Icularly describes the invention and the manner
in which it is to be performed.
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4. Description
The present invention provides pharmaceutical composition of fenofibrate or salts thereof comprising non-micronized fenofibrate, Polyethylene glycol or derivative thereof and one or more surfactants. The present invention also provides a process of preparing pharmaceutical composition of fenofibrate or salts thereof.
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, the obtained melt has significantly low melting point when compared to a simple mix of non-micronized fenofibrate and PEG. Additionally the so obtained melt has significantly reduced the crystallinity of the fenofibrate. The reduction in melting point and crystallinity significantly enhances the solubility, dissolution and bioavailability of fenofibrate.
One of the aspects of the present invention provides a pharmaceutical composition of fenofibrate or salts thereof comprising non-micronized fenofibrate, polyethylene glycol or derivative thereof and one or more surfactant.
For the present invention, the term 'non-micronized fenofibrate' as used herein means fenofibrate having Particle size greater than or equal to about 50um 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.
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,
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polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the like. Mixtures of surfactants are also suitable.
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 with polyethylene glycol or derivative thereof;
b) mixing the melt of step a) with a solution comprising one or more surfactant;
c) granulating the mixture of step b) by adsorbing it on one or more pharmaceutically acceptable carrier.
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 with polyethylene glycol or
derivative thereof in presence of sorbitol;
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b) mixing the melt of step a) with a solution comprising one or more
surfactant,
c) granulating the mixture of step b) by adsorbing it on one or more
pharmaceutically acceptable carrier.
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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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.
The one or more pharmaceutically acceptable carrier may include one or more of fillers, binders, lubricants, disintegrants, glidants, pharmaceutically acceptable sugars and the like.
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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Suitable pharmaceutically acceptable sugar may include one or more of sucrose, glucose, fructose, galactose, maltose, isomaltose, cellobiose, melibiose, gentiobiose, lactose, sorbitol, mannitol 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 with polyethylene glycol or derivative thereof. The obtained melt is mixed with a solution comprising one or more surfactant. The obtained mixture can be granulated, by adsorbing it on one or more pharmaceutically acceptable carrier. The obtained granules can be optionally coated and optionally mixed with one or more pharmaceutically acceptable excipients. The resulting mixture can be filled into capsule or compressed to make tablet.
The composition of the present invention can also be prepared by melting non-micronized fenofibrate with polyethylene glycol or derivative thereof in presence of sorbitol. The obtained melt is mixed with a solution comprising one or more surfactant. The obtained mixture can be granulated, by adsorbing it on one or more pharmaceutically acceptable carrier. The obtained granules can be optionally coated and optionally mixed with one or more pharmaceutically acceptable excipients.
The solution comprising one or more surfactant may optionally contain one or more pharmaceutically acceptable sugar.
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.
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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
Part II
3. Poloxamer 5-40
4. Sodium Lauryl Sulfate 1-20
5. Docusate Sodium 1-20
6. Povidone K-30 0.5-20
Part III
7. Lactose monohydrate 5-40
8. Crospovidone 5-40
Part IV
9. Prosolv SMCC 90 1-25
10. Crospovidone 1-25
11. Magnesium Stearate 1-15
* Fenofibrate is non-micronized having Particle size greater than or equal to 50um
Procedure: Fenofibrate and PEG were melted in a water bath to get a molten mass. Poloxamer, Sodium Lauryl Sulfate, Docusate Sodium and Povidone K-30 were dissolved in suitable solvent and the solution was added to the molten mass and homogenized. The obtained mixture was adsorbed on lactose monohydrate and Crospovidone 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. Part II
5. Poloxamer 5-40
6. Sodium Lauryl Sulfate 1-20
7. Docusate Sodium 1-20
8. Povidone K-30 0.5-20
9. Part III
10. Lactose monohydrate 5-40
11. Crospovidone 5-40
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 50pm
Procedure: Fenofibrate and PEG were melted in a water bath to get a molten mass and to it solution of sorbitol was added. Poloxamer, Sodium Lauryl Sulfate, Docusate Sodium and Povidone K-30 were dissolved in suitable solvent and the solution was added to the molten mass and homogenized. The obtained mixture was adsorbed on lactose monohydrate and Crospovidone 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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CLAIM:
1. A pharmaceutical composition of fenofibrate or salts thereof comprising non-micronized fenofibrate, polyethylene glycol or derivative thereof and one or more surfactant.
2. A process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:

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

4. The pharmaceutical composition of claim 1, further comprising sorbitol.
5. The pharmaceutical composition and process of claim 1-3, wherein fenofibrate is having Particle size greater than or equal to about 50um.
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6. The pharmaceutical composition and 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.
7. The pharmaceutical composition and process of claim 1-3, wherein the surfactant comprises one or more of amphoteric, non-ionic, cationic or anionic surfactants.
8. The process of claim 2 and 3, wherein pharmaceutically acceptable carrier comprises one or more of binders, lubricants, disintegrants, glidants, sugars.


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Abstract
The present invention provides pharmaceutical composition of fenofibrate or salts thereof comprising non-micronized fenofibrate, Polyethylene glycol or derivative thereof, and one or more surfactants. The present invention also provides a process of preparing pharmaceutical composition of fenofibrate or salts thereof.
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