FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule13)
1. TITLE OF THE INVENTION:PHARMACEUTICAL COMPOSITION OF FENOFIBRATE OR SALTS THEREOF COMPRISING CYCLODEXTRIN AND PHARMACEUTIC ALLY ACCEPTABLE CARRIER
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 of fenofibrate or salt thereof comprising non-micronized fenofibrate, cyclodextrin or derivative thereof and pharmaceutically acceptable carrier.
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 a pharmaceutical composition of fenofibrate or salt thereof comprising non-micronized fenofibrate, cyclodextrin or derivative thereof and pharmaceutically acceptable carrier.
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 a portion of total non-micronized fenofibrate is complexed with cyclodextrin or derivative thereof to form Premix A and the remaining portion in part or full of
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non-micronized fenofibrate is melt granulated with pharmaceutically acceptable carrier to form Premix B. Premix A and Premix B are mixed together. The so obtained mix has increased solubility 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 a remaining portion in part or full of non-micronized fenofibrate is melt granulated with pharmaceutically acceptable carrier. The so obtained mix has significantly low melting point when compared to a simple mix of non-micronized fenofibrate and pharmaceutically acceptable carrier. Additionally the so obtained mix has significantly reduced the crystallinity of the fenofibrate. Further 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, cyclodextrin or derivative thereof and one or more pharmaceutically acceptable carrier.
For the present invention, the term 'non-micronized fenofibrate' as used herein means fenofibrate having Part Icle 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 cyclodextrin or derivatives thereof may include one or more of hydroxypropyl-P-cyclodextrin, P-cyclodextrin, a-cyclodextrin, hydroxypropyl- a -cyclodextrin and the like.
The one or more pharmaceutically acceptable carrier comprises one or more of Polyethylene glycols (PEGs), Polyethylene glycol derivatives, poloxamines, polyvinyl alcohol, polyvinyl alcohol copolymer, polyvinyl pyrrolidone, polyvinyl
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pyrrolidone vinyl acetate copolymers, acrylate polymers, cellulosic polymers, chitosan, phosphatidylcholines, miglyol, polyester polymers or copolymers, saccharides and the like.
Suitable polyethylene glycols (PEGs) may include all PEGs that are liquid at room temperature or that melt upto about 70oC. Suitable polyethylene glycols (PEGs) comprise one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and the like.
Suitable polyethylene glycol (PEG) derivatives may include one or more of polyglycolyzed glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes and the like.
Suitable cellulosic polymers may include one or more of methylcellulose,
ethylcellulose, methylhydroxypropylcelluloses, hydroxyethylcelluloses,
hydroxypropylcellulose, carboxymethylcelluloses and the like.
Suitable acrylate polymers may include one or more of 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), glycidyl methacrylate copolymers and the like.
Another aspect of the present invention provides a pharmaceutical composition of fenofibrate or salts thereof comprising non-micronized fenofibrate, cyclodextrin or derivative thereof and pharmaceutically acceptable carrier wherein the said composition is prepared by (a) complexing a portion of total non-micronized fenofibrate with cyclodextrin or derivative thereof and melt granulating the
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remaining portion in part or full of non-micronized fenofibrate with pharmaceutical^ acceptable carrier (b) mixing both the portions.
For the present invention, the term 'portion' as used herein refers to 1-99% of total non-micronized fenofibrate used in the formulation that needs to be complexed with cyclodextrin or derivative thereof.
For the present invention, the term 'remaining portion' as used herein refers to 1-99% of total non-micronized fenofibrate used in the formulation that needs to be melt granulated with one or more pharmaceutically acceptable carrier.
Another aspect of the present invention provides a process for preparing pharmaceutical composition of fenofibrate salts thereof wherein the said process comprises:
a) preparing premix (A) by complexing a portion of total non-micronized fenofibrate with cyclodextrin or derivative thereof;
b) preparing premix (B) by
(i) melting remaining portion in full or part of non-micronized fenofibrate with one or more pharmaceutically acceptable carrier,
(ii) mixing the melt of step b)(i) with a solution comprising one or more pharmaceutically acceptable sugar,
(iii) adsorbing the mixture of step b)(ii) on one or more pharmaceutically acceptable excipients;
c) Mixing premix (A) and premix (B).
For the present invention, the term 'premix (A)' as used herein refers to inclusion complex of a portion of total non-micronized fenofibrate with cyclodextrin or derivative thereof.
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For the present invention, the term 'premix (B)' as used herein refers to melt granulation of remaining portion in full or part of non-micronized fenofibrate with one or more pharmaceutically acceptable carrier.
Premix (A) and Premix (B) can be mixed together in the ratio of 1:99 to 99:1.
The one or more pharmaceutically acceptable carrier comprises one or more of Polyethylene glycols (PEGs), Polyethylene glycol derivatives, poloxamines, polyvinyl alcohol, polyvinyl alcohol copolymer, polyvinyl pyrrolidone, polyvinyl pyrrolidone vinyl acetate copolymers, acrylate polymers, cellulosic polymers, chitosan, phosphatidylcholines, miglyol, polyester polymers or copolymers, saccharides and the like.
Suitable polyethylene glycols (PEGs) may include all PEGs that are liquid at room temperature or that melt upto about 70°C. Suitable polyethylene glycols (PEGs) comprise one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and the like.
Suitable polyethylene glycol (PEG) derivatives may include one or more of polyglycolyzed glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes and the like.
Suitable cellulosic polymers may include one or more of methylcellulose,
ethylcellulose, methylhydroxypropylcelluloses, hydroxyethylcelluloses,
hydroxypropylcellulose, carboxymethylcelluloses and the like.
Suitable acrylate polymers may include one or more of 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
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methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers and the like.
The 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 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.
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.
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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 complexing a portion of total non-micronized fenofibrate with cyclodextrin or derivative thereof to make an inclusion complex and melt granulating the remaining portion in part or full of non-micronized fenofibrate with pharmaceutically acceptable carrier.
The inclusion complex of a portion of total non-micronized fenofibrate with P-cyclodextrin can be prepared by dissolving fenofibrate and cyclodextrin or derivative thereof in a suitable solvent followed by mixing and drying. The formed inclusion complex can be mixed with one or more pharmaceutically acceptable excipients. The inclusion complex can also be prepared by methods well known in the art.
The solvents may include one or more of water, methanol, ethanol, isopropanol, acetone, ether, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methylene chloride and the like.
The melt granulation can be done by, dissolving the remaining portion in part or full of non-micronized fenofibrate in one or more pharmaceutically acceptable carrier by melting. The obtained melt can be mixed with a solution of pharmaceutically acceptable sugar and one or more pharmaceutically acceptable excipients to get a molten mixture. The obtained mixture can be granulated by adsorbing it on one or more pharmaceutically acceptable excipients.
The inclusion complex and granules obtained by melt granulation can be mixed together and can be optionally mixed with one or more pharmaceutically
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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. Beta Cyclodextrin 5-60
Part II
3. Fenofibrate 5-50
4. PEG 6000 5-50
Part III
5. HPMC 1-25
6. Sucrose 1-25
Part IV
7. Lactose monohydrate 5-25
8. Crospovidone 5-25
9. Poloxamer 1-25
10. Sodium Lauryl Sulfate 1-25
11. Docusate Sodium 1-25
Part V
12. Prosolv SMCC 90 1-20
13. Crospovidone 1-20
14. Magnesium Stearate 1-20
* Fenofibrate is non-micronized having Particle size greater than or equal to 50pm
Procedure: Fenofibrate and Beta cyclodextrin were dissolved in suitable solvent and mixed followed by drying to make an inclusion complex. PEG 6000 and Fenofibrate were melted in a water bath to get a molten mass. Sucrose and HPMC was dissolved in suitable solvent and was added to the molten mass. The obtained molten mass was adsorbed on lactose monohydrate, Crospovidone, Poloxamer, Sodium Lauryl Sulfate and Docusate sodium in Rapid Granulator Mixer to get uniform granules. The obtained granules were mixed with the inclusion complex, Prosolv SMCC 90 and Crospovidone. The resulting blend was lubricated with Magnesium stearate and compressed into tablets using proposed 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. Beta Cyclodextrin 5-60
3. Prosolv SMCC 90 5-30
4. Crospovidone 0.5-5
5. Magnesium Stearate 0.5-5
Part II
6. Fenofibrate 5-50
7. PEG 6000 5-50
Part III
8. HPMC 1-25
9. Sucrose 1-25
Part IV
10. Lactose monohydrate 5-25
11. Poloxamer 1-25
12. Sodium Lauryl Sulfate 1-25
13. Docusate Sodium 1-25
Part V
14. Prosolv SMCC 90 1-20
15. Crospovidone 1-20
16. Magnesium Stearate 1-20
* Fenofibrate is non-micronized 50pm

having Particle size greater than or equal to

Procedure: Fenofibrate and Beta cyclodextrin were dissolved in suitable solvent and mixed followed by drying to make an inclusion complex. Prosolv SMCC 90 and Crospovidone were sifted and added to the inclusion complex and the resulting mixture was lubricated with Magnesium Stearate to form Premix (A). PEG 6000 and Fenofibrate were melted in a water bath to get a molten mass. Sucrose and HPMC were dissolved in suitable solvent and was added to the molten mass. The obtained mixture was adsorbed on lactose monohydrate, Poloxamer, Sodium Lauryl Sulfate and Docusate sodium in Rapid Granulator Mixer to get uniform granules (Premix B). The obtained granules were mixed Premix (A), Prosolv SMCC 90 and Crospovidone. The resulting blend was lubricated with Magnesium stearate and compressed into tablets using proposed tooling. The tablets can be optionally coated with aqueous dispersion of Opadry.
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WE CLAIM:
1. A pharmaceutical composition of fenofibrate or salts thereof comprising non-micronized fenofibrate, cyclodextrin or derivative thereof and one or more pharmaceutically acceptable carrier.
2. A pharmaceutical composition of fenofibrate or salts thereof comprising non-micronized fenofibrate, cyclodextrin or derivative thereof and pharmaceutically acceptable carrier wherein the said composition is prepared by (a) complexing a portion of total non-micronized fenofibrate with cyclodextrin or derivative thereof and melt granulating the remaining portion in part or full of non-micronized fenofibrate with pharmaceutically acceptable carrier (b) mixing both the portions.
3. A process for preparing pharmaceutical composition of fenofibrate salts thereof wherein the said process comprises:

a) preparing premix (A) by complexing a portion of total non-micronized fenofibrate with cyclodextrin or derivative thereof;
b) preparing premix (B) by
(i) melting remaining portion in full or part of non-micronized fenofibrate with one or more pharmaceutically acceptable carrier,
(ii) mixing the melt of step b)(i) with a solution comprising one or more pharmaceutically acceptable sugar,
(iii) adsorbing the mixture of step b)(ii) on one or more pharmaceutically acceptable excipients;
c) Mixing premix (A) and premix (B).
4. The pharmaceutical composition and the process of claim 1-3, wherein
fenofibrate is having Particle size greater than or equal to about 50um.
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5. The pharmaceutical composition and the process of claim 1-3, wherein cyclodextrin or derivative thereof comprises one or more of hydroxypropyl-(3-cyclodextrin, B-cyclodextrin, a-cyclodextrin, hydroxypropyl- a -cyclodextrin.
6. The pharmaceutical composition and the process of claim 1-3, pharmaceutically acceptable carrier comprises one or more of Polyethylene glycols (PEGs), Polyethylene glycol derivatives, poloxamines, polyvinyl alcohol, polyvinyl alcohol copolymer, polyvinyl pyrrolidone, polyvinyl pyrrolidone vinyl acetate copolymers, acrylate polymers, cellulosic polymers, chitosan, phosphatidylcholines, miglyol, polyester polymers or copolymers, saccharides.
7. The process of claim 3, wherein pharmaceutically acceptable sugar comprises one or more of sucrose, glucose, fructose, galactose, maltose, isomaltose, cellobiose, melibiose, gentiobiose, lactose, sorbitol, mannitol.
8. The process of claim 3, wherein pharmaceutically acceptable excipients comprises one or more of surfactants, fillers, binders, lubricants, disintegrants, glidants.
9. The process of claim 3, wherein Premix (A) and Premix (B) are mixed in the ratio of 1:99 to 99:1.

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Abstract
A pharmaceutical composition of fenofibrate or salts thereof comprising non-micronized fenofibrate, cyclodextrin or derivative thereof and pharmaceutically acceptable carrier wherein the said composition is prepared by (a) complexing a portion of total non-micronized fenofibrate with cyclodextrin or derivative thereof and melt granulating the remaining portion in part or full of non-micronized fenofibrate with pharmaceutically acceptable carrier (b) mixing both the portions.
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