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 SALTS THEREOF COMPRISING ADSORBENT AND POLYETHYLENE GLYCOL
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 salts thereof comprising fenofibrate, pharmaceutically acceptable adsorbent and polyethylene glycol.
The following specification Particularly describes the invention and the manner in which it is to be performed.
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4. Description
The present invention provides a pharmaceutical composition of fenofibrate or salts thereof comprising fenofibrate, pharmaceutically acceptable adsorbent and polyethylene glycol .
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:




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 pharmaceutically acceptable adsorbent and polyethylene glycol (PEG) or
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derivative thereof is alternately coated with a layer of fenofibrate and surfactant, it resulted in significant increase in the solubility of fenofibrate in aqueous fluids which in turn leads to significant increase in percent drug release of fenofibrate and hence increased bioavailability.
The present inventors have further noticed that when pharmaceutically acceptable adsorbent and PEG or derivative thereof is alternately coated with a layer of fenofibrate and surfactant, the surfactant remains available with fenofibrate for longer duration of time when compared to fenofibrate formulation wherein pharmaceutically acceptable adsorbent and PEG or derivative thereof is coated with single layer of fenofibrate followed by single layer of surfactant.
One of the aspects of the present invention provides a pharmaceutical composition of fenofibrate or salts thereof comprising fenofibrate, pharmaceutically acceptable adsorbent and polyethylene glycol or derivative thereof.
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 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.
Suitable pharmaceutically acceptable adsorbents may include one or more of colloidal silicon dioxide, calcium silicate, magnesium aluminum silicate, porous ceramics, polypropylene foams, cellulose, cellulose derivatives, polyols, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, calcium carbonate, calcium phosphate, calcium sulfate.
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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.
Another aspect of the present invention provides a pharmaceutical composition of fenofibrate or salts thereof comprising fenofibrate, pharmaceutically acceptable adsorbent and polyethylene glycol or derivative thereof wherein the said adsorbent and polyethylene glycol or derivative thereof is alternately coated with fenofibrate and surfactant.
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 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 50pm.
Suitable pharmaceutically acceptable adsorbents may include one or more of colloidal silicon dioxide, calcium silicate, magnesium aluminum silicate, porous ceramics, polypropylene foams, cellulose, cellulose derivatives, polyols, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, calcium carbonate, calcium phosphate, calcium sulfate.
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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 surfactants 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. Suitable surfactants include one or more of 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.
The 1 to 99% w/w of total solution of fenofibrate and surfactant can be alternately coated on pharmaceutically acceptable adsorbent and polyethylene glycol (PEG) or derivatives thereof.
Another aspect of the present invention provides a process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:
a) preparing a solution of fenofibrate comprising fenofibrate and optionally one or more pharmaceutically acceptable excipients;
b) preparing a solution of surfactant comprising one or more surfactants and optionally one or more pharmaceutically acceptable excipients;
c) alternately coating the solution of step a) and step b) on pharmaceutically acceptable adsorbent and polyethylene glycol (PEG) or derivatives thereof.
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The one or more pharmaceutically acceptable excipients may include one or more of fillers, binders, lubricants, disintegrants, and glidants.
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.
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.
In the process of the present invention the solution of fenofibrate can be prepared by dissolving fenofibrate and optionally one or more pharmaceutically acceptable excipients in a suitable solvent. The selected solvent should be the one in which fenofibrate and one or more pharmaceutically acceptable excipients are soluble while the pharmaceutically acceptable adsorbent should not be soluble or only sparingly soluble. The term "soluble" and "sparingly soluble" as used herein refers to descriptive terms of solubility as per United States Pharmacopoeia (USP 29/NF 24).
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In the process of the present invention the solution of surfactant and optionally one or more pharmaceutically acceptable excipients can be prepared by using one or more solvents in which they are soluble. The term "soluble" as used herein refers to descriptive term of solubility as per United States Pharmacopoeia (USP 29/NF 24).
Suitable solvents in the process of the present invention are those known to ordinary skilled in the art and include but not limited to one or more of water, methanol, ethanol, isopropanol, acetone, ether, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methylene chloride and the like.
In the process of the present invention the pharmaceutically acceptable adsorbent and polyethylene glycol (PEG) or derivatives thereof is alternately coated with a solution of fenofibrate and surfactant by the methods known in the art and include but not limited to Glatt processor, rapid mixer granulator (RMG) and the like.
The pharmaceutical composition of the present invention can be prepared by alternately coating a solution of fenofibrate and surfactant on pharmaceutically acceptable adsorbent and polyethylene glycol (PEG) or derivatives thereof. The solution of fenofibrate can be adsorbed on pharmaceutically acceptable adsorbent and PEG followed by coating with a solution of surfactant or vice-versa. The process of adsorption or coating is repeated one after the other. The alternately coated pharmaceutically acceptable adsorbent and PEG can be further optionally coated with a layer of surfactant and optionally mixed with one or more pharmaceutically acceptable excipients. The obtained blend can be filled into capsule or compressed to make a tablet. The obtained tablets can be optionally coated with opadry.
The pharmaceutical composition of the present invention is meant for oral administration and can be present in the form of tablet, capsule, powder, disc, caplet, granules 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.
Example-1
Table-1 Composition of Fenofibrate Tablets

S.No. Ingredients Qty/tablet (%w/w)
Part I
1. Fenofibrate 20-70
2. Pregelatinized starch 5-50
3. PEG 6000 5-50
4. Poloxamer 5-50
5. Povidone K-30 1-30
Part II
6. Docusate Sodium 0.05-5
7. Sodium Lauryl Sulphate 0.1-10
Part III
8. Prosolv SMCC 90 10-50
9. Crospovidone 1-10
10. Magnesium Stearate 0.1-2
Procedure: Fenofibrate and Povidone K-30 were dissolved in suitable solvent to get clear solution. Pregelatinized starch and PEG 6000 were alternately coated with 33% w/w of total poloxamer solution and 33% w/w of total fenofibrate solution till 100% w/w of both the solutions were layered. The obtained granules were further coated with a solution of Docusate sodium and sodium lauryl sulphate and dried. The obtained granules were mixed with Prosolv SMCC 90 and Crospovidone followed by lubricating the granules with Magnesium Stearate. The lubricated granules were compressed into tablets using suitable tooling and optionally coated wit aqueous dispersion of opadry.
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Example-2
Table-2 Composition of Fenofibrate Tablets

S.No. Ingredients Qty/tablet (%w/w)
Part I
1. Fenofibrate 20-70
2. Pregelatinized starch 5-70
3. PEG 6000 5-50
4. Poloxamer 5-50
5. Povidone K-30 1-30
Part II
6. Docusate Sodium 0.05-5
7. Sodium Lauryl Sulphate 0.1-10
Part III
8. Prosolv SMCC 90 10-50
9. Crospovidone 1-10
10. Magnesium Stearate 0.1-2
Procedure: Fenofibrate and Povidone K-30 were dissolved in suitable solvent to get clear solution. Pregelatinized starch and PEG 6000 were alternately coated with 25% w/w of total poloxamer solution and 25% w/w of total fenofibrate solution till 100% w/w of both the solutions were layered. The obtained granules were further coated with a solution of Docusate sodium and sodium lauryl sulphate and dried. The obtained granules were mixed with Prosolv SMCC 90 and Crospovidone followed by lubricating the granules with Magnesium Stearate. The lubricated granules were compressed into tablets using suitable tooling and optionally coated wit aqueous dispersion of opadry.
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WE CLAIM:
1. A pharmaceutical composition of fenofibrate or salts thereof comprising fenofibrate, pharmaceutical^ acceptable adsorbent and polyethylene glycol or derivative thereof.
2. A pharmaceutical composition of fenofibrate or salts thereof comprising fenofibrate, pharmaceutically acceptable adsorbent and polyethylene glycol or derivative thereof wherein the said adsorbent and polyethylene glycol or derivative thereof is alternately coated with fenofibrate and surfactant.
3. A process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:

a) preparing a solution of fenofibrate comprising fenofibrate and optionally one or more pharmaceutically acceptable excipients;
b) preparing a solution of surfactant comprising one or more surfactants and optionally one or more pharmaceutically acceptable excipients;
c) alternately coating the solution of step a) and step b) on pharmaceutically acceptable adsorbent and polyethylene glycol (PEG) or derivatives thereof.

4. The pharmaceutical composition and process of claim 1-3, wherein fenofibrate is in micronized or non-micronized form.
5. The pharmaceutical composition and process of claim 1-3, wherein pharmaceutically acceptable adsorbent comprises one or more of colloidal silicon dioxide, calcium silicate, magnesium aluminum silicate, porous ceramics, polypropylene foams, cellulose, cellulose derivatives, polyols,
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starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, calcium carbonate, calcium phosphate, calcium sulfate.
6. The pharmaceutical composition and process of claim 1-3, wherein polyethylene glycol or derivative thereof 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 2 and 3, wherein surfactant comprise one or more of one or more of 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.
8. The pharmaceutical composition and process of claim 2 and 3, wherein pharmaceutically acceptable adsorbent and polyethylene glycol or derivative thereof is alternately coated with 1 to 99% w/w of total solution of fenofibrate and surfactant.
9. The process of claim 3, wherein pharmaceutically acceptable excipients comprise one or more of fillers, binders, lubricants, disintegrants, and glidants.
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10. The pharmaceutical composition of claim 1 and 2, is meant for oral administration and comprises one or more of a tablet, capsules, powder, disc, caplet, granules, pellets.

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ABSTRACT
The present invention provides a pharmaceutical composition of fenofibrate or salts thereof comprising fenofibrate, pharmaceutically acceptable adsorbent and polyethylene glycol wherein the said adsorbent and polyethylene glycol or derivative thereof is alternately coated with fenofibrate and surfactant. The present invention also provides a process of preparing the said composition.

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