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:PHARMACEUTICAL COMPOSITION OF FENOFIBRATE OR SALTSTHEREOF PREPARED BY EXTRUSION SPHERONIZATION
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 DESCRIPTIONThe present invention provides a pharmaceutical composition comprisingspheroid cores of fenofibrate or salts thereof and one or more spheronizingaid.
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 comprising spheroid cores of fenofibrate or salts thereof and one or more spheronizing aid.
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.
U.S. Patent Nos. 6,074,670, and 6,277,405 describe micronized fenofibrate coated onto hydrosoluble carriers with optional surface-active agents.
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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.
The present inventors while working on fenofibrate formulation have noticed that when spheroid cores of fenofibrate and one or more spheronizing agent is prepared by melt extrusion or extrusion spheronization, the so obtained spheroid cores have significantly reduced melting point as compared to the simple
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spheroids. Additionally the so obtained spheroid cores have significantly reduced the crystallinity of the fenofibrate. The reduction in melting point and crystallinity significantly enhances the solubility, dissolution and bioavailability of fenofibrate.
The present inventors have anticipated that as the spheroid cores are in pellet form they may remain suspended in the gastric fluid for longer duration of time that may result in increased absorption of fenofibrate and hence increased bioavailability.
One of the aspects of the present invention provides a pharmaceutical composition comprising spheroid cores of fenofibrate or salts thereof and one or more spheronizing aid.
Another aspect of the present invention provides a process for preparing pharmaceutical composition comprising spheroid cores of fenofibrate or salts thereof and one or more spheronizing aid wherein the said process comprises:
a) blending a mixture comprising fenofibrate or salts thereof and one or more spheronizing aid;
b) extruding and spheronizing the blend of step a) to give spheroid cores.
For the present invention, the term 'spheroid cores' is conventional in the pharmaceutical art and means a spherical granule, pellet, core and the like.
The pharmaceutical composition of the present invention comprises of fenofibrate or salt thereof as an active ingredient.
Fenofibrate can be present in micronized or non-micronized form. Micronized form means fenofibrate is subjected to comminution techniques that are well known to person skilled in the art and include but not limited to milling, spray drying, high pressure homogenization and the like. The Part Icle size of micronized fenofibrate is less than 50pm. Non-micronized form means
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fenofibrate is not subjected to any comminution techniques well known to person skilled in the art. The Part Icle size of non-micronized fenofibrate is greater than or equal to about 50um.
The spheronizing aid of the present invention may comprise any pharmaceutically acceptable material, which may be spheronized together with the active ingredient to form spheroid cores.
The spheronizing aid may comprise one or more of surfactants, fillers, binders, lubricants, disintegrants, glidants, plasticizers, pharmaceutically acceptable sugars, polyethylene glycols or derivative thereof, polymers 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, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the like. Mixtures of surfactants are also suitable.
Suitable filler may include 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 include one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable lubricant may include one or more of, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
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Suitable disintegrant may include one or more of, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable glidant may include one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable plasticizer may include one or more of diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, microcrystalline cellulose and the like.
The one or more pharmaceutically acceptable sugar may include one or more of sucrose, glucose, fructose, galactose, maltose, isomaltose, cellobiose, melibiose, gentiobiose, lactose, sorbitol, mannitol and the like.
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 polymers may include one or more of hydrophilic or hydrophobic polymers.
The hydrophilic polymers may include one or more of cellulose ethers, carbohydrate gum, polyuronic acid salts and mixtures, thereof. Suitable cellulose ethers include one or more of methylhydroxypropylcelluloses, hydroxyethylcelluloses, hydroxypropylcellulose, methylcelluloses, ethylcelluloses, and carboxymethylcelluloses, and the like. Suitable carbohydrate gums include
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one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof.
The hydrophobic polymers include one or more of cellulose ethers, acrylic acid polymers, aliphatic alcohols and natural or synthetic wax or oil. Suitable acrylic acid polymers include any suitable acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Suitable aliphatic alcohols include stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol and mixtures, thereof. Suitable natural or synthetic wax or oil include hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax, Carnauba wax or glyceryl monostearate.
Blending of fenofibrate or salts thereof and one or more spheronizing aid can be carried out using double cone blender or by any other suitable blending techniques known in the art.
Extruding and spheronizing of fenofibrate or salts thereof and one or more spheronizing aid blend, can be carried out by using extruder and spheronizer or by any other suitable techniques known in the art.
The spheroid cores can be optionally coated with one or more functional or nonfunctional coat to make immediate release, controlled release, sustained release dosage forms.
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The functional coat may include one or more of one or more hydrophilic polymers, hydrophobic polymers, enteric polymers, and the like.
The hydrophilic polymers may include one or more of cellulose ethers, carbohydrate gum, polyuronic acid salts and mixtures, thereof. Suitable cellulose ethers include one or more of methylhydroxypropylcelluloses, hydroxyethylcelluloses, hydroxypropylcellulose, methylcelluloses, ethylcelluloses, and carboxymethylcelluloses, and the like. Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof.
The hydrophobic polymers include one or more of cellulose ethers, acrylic acid polymers, aliphatic alcohols and natural or synthetic wax or oil. Suitable acrylic acid polymers include any suitable acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Suitable aliphatic alcohols include stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol and mixtures, thereof. Suitable natural or synthetic wax or oil include hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax, Carnauba wax or glyceryl monostearate.
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The enteric polymers include, for example, one or more of cellulose acetate phthalate, shellac, Hydroxypropyl methylcellulose phthalate, and acrylic acid polymers like Eudragit.
The non-functional coat may include one or more of plasticizers, surfactants, tack-modifiers and the like. Suitable plasticizer may include one or more of diethylphthalate, dibutyl sebacate and the like. Suitable surfactant may include one or more of sorbitan trioleate, sorbitan monolaurate, polysorbate 80 (Tween 80.TM.), poloxamers, sodium lauryl sulphate, sodium dioctylsulfosuccinate (DOSS), cremophore RH 40 and the like. Suitable tack-modifiers may include one or more of talc, colloidal anhydrous silica, opadry and the like.
The spheroid cores can be optionally mixed with one or more pharmaceutically acceptable excipients. 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 include 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 include one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable lubricant may include 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 include one or more of, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable glidant may include one or more of colloidal silicon dioxide, talc or cornstarch and the like.
The composition of the present invention can be prepared by blending fenofibrate or salt thereof with one or more spheronizing agent and extruding the blend through extruder followed by spheronizing to get spheroid cores. The spheroid cores can be optionally coated with one or more functional or non-functional coat. The spheroid cores can be optionally mixed with one or more pharmaceutically acceptable excipients. The resulting mixture can be filled into capsules or compressed to tablet using a suitable tooling.
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, pellets, controlled release tablets or capsules, sustained release tablets or capsules.
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. Poloxamer 1-25
4. Lactose monohydrate 5-25
5. Sodium lauryl sulfate 1-25
6. Docusate Sodium 1-25
Part II
7. Prosolv SMCC 90 1-20
8. Crospovidone 1-20
9. Magnesium Stearate 1-20
Procedure: Fenofibrate, PEG 6000, Poloxamer, Lactose monohydrate, Sodium lauryl sulfate and Docusate Sodium were blended together and passed through the extruder to get an extrudate. The obtained extrudate was passed through the spheronizer to get spheroid cores and dried. The spheroid cores were then blended with Prosolv SMCC 90 and Crospovidone and then lubricated with magnesium stearate. The obtained blend was compressed to tablets using suitable tooling and tablets were 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. Lactose monohydrate 5-25
Part II
4. Poloxamer 1-25
5. Sodium lauryl sulfate 1-25
6. Docusate Sodium 1-25
Part III
7. Prosolv SMCC 90 1-20
8. Crospovidone 1-20
9. Magnesium Stearate 1-20
Procedure: Fenofibrate, PEG 6000 and Lactose monohydrate were blended together and passed through the extruder to get an extrudate. The obtained extrudate was passed through the spheronizer to get spheroid cores and dried. The spheroid cores were coated with a solution of Poloxamer, Sodium lauryl sulfate, and Docusate Sodium and dried. The coated spheroid cores were blended with Prosolv SMCC 90 and Crospovidone and then lubricated with magnesium stearate. The obtained blend was compressed to tablets using suitable tooling and tablets were coated with aqueous dispersion of opadry.
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WE CLAIM:
1. A pharmaceutical composition comprising spheroid cores of fenofibrate or salts thereof and one or more spheronizing aid.
2. A process for preparing pharmaceutical composition comprising spheroid cores of fenofibrate or salts thereof and one or more spheronizing aid wherein the said process comprises:

a) blending a mixture comprising fenofibrate or salts thereof and one or more spheronizing aid;
b) extruding and spheronizing the blend of step a) to give spheroid cores.

3. The pharmaceutical composition and process of claim 1 and 2, wherein fenofibrate is in micronized or non-micronized form.
4. The pharmaceutical composition and process of claim 1 and 2, wherein spheronizing aid comprises one or more of surfactants, fillers, binders, lubricants, disintegrants, glidants, plasticizers, pharmaceutically acceptable sugars, polyethylene glycols or derivative thereof, polymers.
5. The process of claim 2, further comprising one or more functional coat or non-functional coat.
6. The process of claim 5, wherein functional coat comprises one or more of hydrophilic polymers, hydrophobic polymers, enteric polymers.
7. The process of claim 5, wherein the non-functional coat comprises one or more of plasticizers, surfactants, tack-modifiers.
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8. The process of claim 2, further comprising one or more pharmaceutically acceptable excipients.
9. The process of claim 8, wherein pharmaceutically acceptable excipients comprises one or more of surfactants, fillers, binders, lubricants, disintegrants, glidants.
10. The pharmaceutical composition of claim 1, wherein the composition is tablet, capsule, caplet, granules, suspension, pellets, controlled release tablets or capsules, sustained release tablets or capsules.

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Abstract
The present invention provides a pharmaceutical composition comprising spheroid cores of fenofibrate or salts thereof and one or more spheronizing aid wherein the said composition is prepared by extrusion spheronization.
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