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 COMPOSITIONS OF FENOFIBRATE WITH WETTING AGENT
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 comprising unmicronized fenofibrate in admixture with wetting agent and one or more pharmaceutically acceptable excipients, wherein the said admixture is not comicronized before processing.
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 comprising unmicronized fenofibrate in admixture with wetting agent and one or more pharmaceutically acceptable excipients, wherein the said admixture is not comicronized before processing.
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. Its chemical name is 2-[4-(4-Chlorobenzoyl) phenoxy]-2-methylpropanoic acid 1-methylethyl ester. 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 provide nanoparticulate 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 U.S. Application US2004071771 describe co-micronizing the fenofibrate with surface-active agents.
U.S. Patent No 6,555,135 describes co-micronized mixture of fenofibrate with pharmaceutically acceptable excipient that is not a surfactant.
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U.S. Patent Nos. 6,074,670, 6,277,405 and others describe micronized fenofibrate coated onto hydrosoluble carriers with optional surface-active agents.
U.S. Patent No 6,828,334 describe inclusion complex of fenofibrate with cyclodextrins.
U.S. Patent No 6,027,747 describes solid dispersion of fenofibrate.
U.S. Patent Application 20040087656 describes fenofibrate of particle size less than 2000 nm with an improved bioavailability.
U.S. Application 20060222706 and U.S. 20060222707 describe fenofibrate in intimate association with menthol or surfactant mixture.
U.S. Application 20040057998, 20040058005 and US2004137055 describe micronized fenofibrate compositions.
U.S. Application 20030138496 micronized fenofibrate with inert hydrosoluble carriers.
Several other patents and applications describe specific formulations of micronized fenofibrate with specific polymeric or surface-active agent additives while several others describe emulsion and suspension formulations of fenofibrate.
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 the fenofibrate formulation have surprisingly found that when fenofibrate is mixed with wetting agent, it results in increased solubility of fenofibrate in aqueous fluids which in turn leads to
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significant increase in bioavailability. It was further observed that there is no need to co-micronize the mixture to increase the surface area.
One of the aspects of the present invention provides a pharmaceutical composition comprising unmicronized fenofibrate or salt thereof in admixture with wetting agent and one or more pharmaceutically acceptable excipients, wherein the said admixture is not comicronized before processing.
The term unmicronized fenofibrate as used herein refers to fenofibrate, which is as such not subjected to size reduction by any means.
Suitable wetting agents may be one or more of anionic, cationic or non-ionic surface-active agents or surfactants. Wetting agent may further include one or more of gum acacia, guar gum, xanthan gum, kaolin, bentonite, hectorite, tragacanth, sodium alginate, pectin and the like.
Suitable anionic surfactants may be one or more of sodium dodecyl sulfate (SDS), sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates, sodium stearate, potassium stearate, sodium oleate and the like.
Suitable cationic surfactants may be one or more of benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, benzethonium chloride, cetrimide and the like.
Suitable non-ionic surfactants may be one or more of poloxamers, polyoxyethylene sorbitan fatty acid esters, fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, cholesterol and the like.
In another aspect of the present invention there is provided a process of preparing pharmaceutical composition comprising:
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a) mixing unmicronized fenofibrate with wetting agent and optionally with other excipients,
b) converting the pre-mix of step a) in to granules,
c) converting the granules of step b) in to suitable dosage form.
In yet another aspect of the present invention there is provided a pharmaceutical composition, comprising unmicronized fenofibrate or salt thereof in admixture with wetting agent and one or more pharmaceutically acceptable excipients, wherein the said mixture is not comicronized before processing; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% of fenofibrate is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of 0.05M SLS in water at 37 °C ± 0.5°C.
The pharmaceutical composition of the present invention can be present in the form of tablet, capsule, powder, disc, caplet, granules, pellets and other dosage forms suitable for oral administration.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include one or more of fillers, binders, lubricants, disintegrants, and glidants.
Suitable filler may be one or more of 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 glidant may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and the like.
The pharmaceutical composition of the present invention can be prepared by mixing fenofibrate with wetting agent, compacting the pre-mix through compactor and sizing the flakes in to granules. Granules thus obtained are either granulated with binder, dried, mixed with other pharmaceutically acceptable excipients, or granules are directly mixed with other pharmaceutically acceptable excipients, lubricated and compressed.
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 (48mg, 145 mg)

S.No. Ingredients Qty/tablet (%w/w)
Part-I
1 Fenofibrate (unmicronized) 20-70
2 Poloxamer 5-50
Part-ll
4 Lactose 20-70
5 Silicified microcrystalline cellulose 5-70
6 Crospovidone 1-6
7 Povidone 0.1-10
8 Purified water q.s.
9 Magnesium stearate 0.1-3
10 Opadry 0.5-5
Procedure: Unmicronized fenofibrate and poloxamer are co-sifted and mixed in double cone blender. Above pre-mix is compacted through roll compactor and sizing is carried out to break flakes in to granules using multi mill or oscillating granulator. Granules thus obtained are blended with pre-sifted lactose, silicified microcrystalline cellulose, crospovidone in rapid mixer granulator and granulated with binder solution in rapid mixer granulator. The granules are dried, milled and blended with pre-sifted crospovidone. Then granules are lubricated with magnesium stearate and final blend is compressed in to tablets using suitable tooling and coated with aqueous dispersion of Opadry.
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Example-2
Table-2 Composition of Fenofibrate Tablets (48mg, 145 mg)

S.No. Ingredients Qty/tablet (%w/w)
Part-I
1 Fenofibrate (unmicronized) 20-70
2 Poloxamer 5-50
Part-ll
4 Lactose 20-70
5 Silicified microcrystalline cellulose 5-70
6 Crospovidone 1-6
7 Magnesium stearate 0.1-3
8 Opadry 0.5-5
Procedure: Unmicronized fenofibrate and poloxamer are co-sifted and mixed in double cone blender. Above pre-mix is compacted through roll compactor and sizing is carried out to break flakes in to granules using multi mill or oscillating granulator. Granules thus obtained are blended with pre-sifted lactose, silicified microcrystalline cellulose, crospovidone in double cone blender and lubricated with magnesium stearate and final blend is compressed in to tablets using suitable tooling and coated with aqueous dispersion of Opadry.
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Table 3: Dissolution data of Fenofibrate tablets (145mg)

Time (min) % drug released (Example-I) % drug released (Example-ll)
10 25 31
20 60 66
30 80 83
45 92 96
Table 3 provides the dissolution data for fenofibrate tablets (145mg) prepared as per the formula given in Table 1 and 2. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 1000 ml of 0.05M SLS in water at 37 °C ± 0.5°C was used as medium.
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WE CLAIM:
1) A pharmaceutical composition comprising unmicronized fenofibrate or salt thereof in admixture with wetting agent and one or more pharmaceutically acceptable excipients, wherein the said admixture is not comicronized before processing.
2) The pharmaceutical composition of claim 1, wherein the wetting agent is a surface-active agent.
3) The pharmaceutical composition of claim 2, wherein the surface-active agent is anionic, cationic, or non-ionic.
4) The surface active agent of claim 3, wherein the anionic surface active agent comprises one or more of sodium dodecyl sulfate, sodium laurate, dialkylsodium sulfosuccinates, sodium stearate, potassium stearate, sodium oleate.
5) The surface active agent of claim 3, wherein the cationic surface active agent comprises one or more of benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, benzethonium chloride, cetrimide.
6) The surface-active agent of claim 3, where in the non-ionic surface-active agent comprises one or more of poloxamers, polyoxyethylene sorbitan fatty acid esters, fatty alcohols, glyceryl esters.
7) The pharmaceutical composition of claim 1, wherein the wetting agent comprises one or more of gum acacia, guar gum, xanthan gum, kaolin, bentonite, hectorite, tragacanth, sodium alginate, pectin.
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8) A process of preparing pharmaceutical composition comprising:
a) mixing unmicronized fenofibrate with wetting agent and optionally with other excipients,
b) converting the pre-mix of step a) in to granules,
c) converting the granules of step b) in suitable dosage form.

9) A pharmaceutical composition, comprising unmicronized fenofibrate in admixture with wetting agent and one or more pharmaceutically acceptable excipients, wherein the said mixture is not comicronized before processing; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% of fenofibrate is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of 0.05M SLS in water at 37 °C ± 0.5°C.
10) The pharmaceutical composition of claim 1 comprises one or more of a tablet, capsules, powder, disc, caplet, granules, pellets and other dosage forms suitable for oral administration.

Dated this 26th day of February, 2007 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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