FORM 2
THE PATENT ACT 11970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION OF FENOFIBRATE OR SALT THEREOF WITH AN INERT CORE
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 an immediate release pharmaceutical composition of fenofibrate comprising an inert core with at least one layer containing fenofibrate in non-micronized form in admixture with pharmaceutically acceptable excipients and optionally one or more layers.
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 an immediate release pharmaceutical composition of fenofibrate comprising an inert core with at least one layer containing fenofibrate in non-micronized form in admixture with pharmaceutically acceptable excipients and optionally one or more layers.
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 No 4,961,890 describe controlled release formulation of fenofibrate in which the medicine being in the form of a granule that comprises an inert core in its center, a protective outer coating and an intermediate layer based on fenofibrate. Fenofibrate is in micronized form.
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U.S. Patent Nos. 4,895,726, 4,800,079, 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.
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 and U.S. Patent Application 20070026062 describes solid dispersion of fenofibrate.
U.S. Patent No 6,465,011 describes formulations comprising lipid-regulating agents.
U.S. Patent Nos. 6,368,622, 6,383,517 and U.S. Patent Applications 2005112192, 2006177512 describes process for preparing solid formulations of lipid-regulating agents.
U.S. Application 20030138496 and International (PCT) Publication WO2004028506 describes micronized fenofibrate with inert hydrosoluble carriers.
U.S. Patent Application 20040087656 describes fenofibrate of particle size less than 2000 nm with an improved bioavailability.
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U.S. Application 20040057998 and US2004137055 describe micronized fenofibrate compositions.
U.S. Application 20060222706 and U.S. 20060222707 describe fenofibrate in intimate association with menthol or surfactant mixture.
International (PCT) Publication WO2005002541 describes process for preparing solid formulations of lipid-regulating agents.
International (PCT) Publication WO82/01649 describes a fenofibrate formulation having granules that are comprised of a neutral core that is a mixture of saccharose and starch. The neutral core is covered with a first layer of micronized fenofibrate, admixed with an excipient and with a second microporous outer layer of an edible polymer.
Several other patents and applications describe formulations of fenofibrate or process for preparing fenofibrate formulations such as U.S. Patent Applications 20060280791, 2007015833, 2007015834, 20070014864, 20070014854, 20070014853, 2007048384, 2007049636, European Patent Application No. EP0793958B1.
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 an inert core like sugar spheres or microcrystalline cellulose spheres is coated with hydrophobic drug like fenofibrate provides large surface area resulting in increased solubility of fenofibrate in aqueous fluids which in turn leads to significant increase in percent drug release of fenofibrate and hence increased bioavailability. Moreover, the fenofibrate that is being coated onto an inert core is present in non-micronized form.
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One of the aspects of present invention provides an immediate release pharmaceutical composition of fenofibrate comprising an inert core with at least one layer containing fenofibrate in non-micronized form in admixture with pharmaceutically acceptable excipients and optionally one or more layers.
Another aspect of the present invention provides an immediate release pharmaceutical composition of fenofibrate comprising an inert core with at least one layer containing fenofibrate in non-micronized form, one or more layers containing surfactant and optionally one or more pharmaceutically acceptable excipients.
For the present invention, the term 'Fenofibrate' as used herein refers to having particle size greater than or equal to about 150pm.
For the present invention, the term 'inert core' as used herein means any excipient, pharmaceutically inert, crystalline or amorphous, in a particulate form, not leading to a chemical reaction under the operating conditions employed. The inert core of the present invention include those known to ordinary skilled in the art and examples of such inert cores include but not limited to one or more of hydrosoluble, hydro-insoluble, swellable cores or combination thereof.
Hydro-soluble cores comprise one or more of sugar spheres, derivatives of sugars, such as xylitol, lactose, saccharose, hydrolyzed starch (maltodextrin) or mixtures of two or more thereof.
Hydro-insoluble cores comprise one or more of glass, silicon dioxide, plastic resin particles, ethylcellulose coated microcrystalline cellulose spheres, dicalcium phosphate, pregelatinized starch or mixtures of two or more thereof.
Swellable inert core comprise one or more of hydroxypropyl methylcellulose, microcrystalline cellulose, starch or mixtures of two or more thereof.
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For the present invention, the term 'one or more layers' as used herein means layer(s) comprising one or more pharmaceutically acceptable excipients either alone or in combination with drug.
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.
Another aspect of the present invention provides a process for preparing immediate release pharmaceutical composition of fenofibrate wherein the said process comprises the steps of:
a) dissolving fenofibrate and optionally one or more binders in one or more organic solvents to form a solution
b) coating an inert core with solution of step a)
c) layering the core of step b) with solution or dispersion of one or more surfactants
d) optionally adding one or more pharmaceutically acceptable excipients to step c)
Another aspect of the present invention provides a process for preparing immediate release pharmaceutical composition of fenofibrate wherein the said process comprises the steps of:
a) dissolving fenofibrate and optionally one or more pharmaceutically acceptable excipients in one or more organic solvents to form a solution
b) coating an inert core with solution of step a)
c) optionally adding one or more pharmaceutically acceptable excipients to step b).
In the process of the present invention the solution of fenofibrate can be prepared by dissolving fenofibrate, binder and/or surfactant in a solvent in which the fenofibrate, binder and/or surfactant are soluble. The term "soluble" as used
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herein refers to descriptive terms of solubility as per United States Pharmacopoeia (USP 29/NF 24).
The one or more binders 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 polyvinylpyrrolidone, Hydroxypropyl methylcellulose, Hydroxypropyl cellulose, Plasdone S-630.
Suitable organic 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 methanol, ethanol, isopropanol, acetone, ether, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methylene chloride.
In the process of the present invention the inert core can be coated with drug solution by using methods known to ordinary skilled in the art and include but not
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limited Glatt processor, rapid mixer granulator (RMG) and the like.
In the process of the present invention the solution of surfactant can be prepared using one or more solvents in which the surfactant is soluble. The term "soluble" as used herein refers to descriptive term of solubility as per United States Pharmacopoeia (USP 29/NF 24).
In the process of the present invention, layering of drug coated inert core with surfactant solution can be done using methods known to ordinary skilled in the art and include but not limited Glatt processor, rapid mixer granulator (RMG) and the like.
The one or more surfactants 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
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another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer.RTM., etc. Mixtures of surfactants are also suitable.
The one or more pharmaceutically acceptable excipients include one or more of fillers, binders, lubricants, disintegrants, surfactants, polymers and glidants.
Suitable filler may be one or more of, microcrystalline cellulose, solidified 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 surfactants may be one or more of, sodium docusate, sodium lauryl sulfate, sodium laurate, sodium stearate, sodium oleate, polyoxyethylene sorbitan esters, fatty alcohols, fatty acid esters of fatty alcohols and the like.
Suitable polymers are those known to ordinary skilled in the art.
Suitable glidant may be one or more of, colloidal silicon dioxide, talc or cornstarch and the like.
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The pharmaceutical composition of the present invention can be prepared by dissolving fenofibrate, binder and/or surfactant in suitable solvent. The obtained solution is coated onto inert core using Glatt processor. The drug coated inert cores are optionally layered with a surfactant solution using Glatt processor. The obtained pellets are blended with pharmaceutical^ acceptable excipients, lubricated and compressed to form tablet. The obtained tablets can be optionally coated with aqueous dispersion of opadry.
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 (48 mg, 145 mg)

S.No. Ingredients Qty/tablet (%w/w)
Part I
1. Fenofibrate 20-70
2. PVP K-30 1-30
3. Sugar spheres 10-100
4. Acetone q.s
5. I PA q.s
Part II
6. Docusate Sodium 0.05-5
7. Sodium Lauryl Sulphate 0.1-10
8. Acetone q.s
9. Water q.s
Part III Extragranular
10 Microcrystalline Cellulose 10-50
11 Crospovidone 1-10
12 Magnesium stearate 0.1-2
13 Opadry 0.5-5
Procedure: Fenofibrate and polyvinylpyrrolidone (PVP K-30) are dissolved in sufficient quantity of acetone and isopropyl alcohol (IPA) to get clear solution. Fenofibrate solution is coated on sugar spheres using Glatt processor (Step 1). Docusate sodium and sodium lauryl sulphate are dissolved in sufficient quantity of acetone and water mixture (step 2). The obtained solution is layered onto drug coated cores of step 1 using Glatt processor. The obtained pellets are blended with presifted microcrystalline cellulose and crospovidone. Above blend is lubricated with magnesium stearate and compressed to form tablet using suitable tooling. Compressed tablets are 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 20-70
2. PVP K-30 1-30
3. Microcrystalline cellulose spheres 10-100
4. Acetone q.s
5. I PA q.s
Part II
6. Docusate Sodium 0.05-5
7. Sodium Lauryl Sulphate 0.1-10
8. Acetone q.s
9. Water q.s
Part III Extragranular
10 Microcrystalline Cellulose 10-50
11 Crospovidone 1-10
12 Magnesium stearate 0.1-2
13 Opadry 0.5-5
Procedure: Fenofibrate and polyvinylpyrrolidone (PVP K-30) are dissolved in sufficient quantity of acetone and isopropyl alcohol (IPA) to get clear solution. Fenofibrate solution is coated on microcrystalline cellulose spheres using Glatl processor (Step 1). Docusate sodium and sodium lauryl sulphate are dissolved ir sufficient quantity of acetone and water mixture (step 2). The obtained solution is layered onto drug coated cores of step 1 using Glatt processor. The obtained pellets are blended with presifted microcrystalline cellulose and crospovidone. Above blend is lubricated with magnesium stearate and compressed to form tablet using suitable tooling. Compressed tablets are coated with aqueous dispersion of Opadry.
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Example-3
Table-3 Composition of Fenofibrate Tablets (48mg, 145 mg)

S.No. Ingredients Qty/tablet (%w/w]i
Part I
1. Fenofibrate 20-70
2. PVP K-30 1-30
3. Docusate Sodium 0.05-5
4. Sodium Lauryl Sulphate 0.1-10
5. Microcrystalline cellulose spheres/ sugar spheres 10-100
6. Acetone q.s
7. I PA q.s
Part II Extragranular
10 Microcrystalline Cellulose 10-50
11 Crospovidone 1-10
12 Magnesium stearate 0.1-2
13 Opadry 0.5-5
Procedure: Fenofibrate, polyvinylpyrrolidone (PVP K-30), docusate sodium and sodium lauryl sulphate are dissolved in sufficient quantity of acetone and isopropyl alcohol (IPA) to get clear solution. The obtained solution is coated on microcrystalline cellulose spheres or sugar spheres using Glatt processor. The obtained pellets are blended with presifted microcrystalline cellulose and crospovidone. Above blend is lubricated with magnesium stearate and compressed to form tablet using suitable tooling. Compressed tablets are optionally coated with aqueous dispersion of Opadry.
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WE CLAIM:
1. An immediate release pharmaceutical composition of fenofibrate comprising an inert core with at least one layer containing fenofibrate in non-micronized form in admixture with pharmaceutically acceptable excipients and optionally one or more layers.
2. An immediate release pharmaceutical composition of claim 1 wherein one or more layers comprise one or more of pharmaceutically acceptable
excipients either alone or in combination with drug.
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3. An immediate release pharmaceutical composition of fenofibrate comprising an inert core with at least one layer containing fenofibrate in non-micronized form, one or more layers containing surfactant and optionally one or more pharmaceutically acceptably excipients
4. A process for preparing immediate release pharmaceutical composition of fenofibrate wherein the said process comprises the steps of:

a) dissolving fenofibrate and optionally one or more binders in one or more organic solvents to form a solution
b) coating an inert core with solution of step a)
c) layering the core of step b) with solution or dispersion of one or more surfactants
d) optionally adding one or more pharmaceutically acceptable excipients to step c).
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5. A process for preparing immediate release pharmaceutical composition of fenofibrate wherein the said process comprises the steps of:
a) dissolving fenofibrate and optionally one or more pharmaceutically acceptable excipients in one or more organic solvents to form a solution '
b) coating an inert core with solution of step a)
c) optionally adding one or more pharmaceutically acceptable excipients to step b).

6. A process of claim 4 and 5, wherein binder comprises one or more of polyvinylpyrrolidone, Hydroxypropyl methylcellulose, Hydroxypropyl cellulose, Plasdone S-60.
7. A process of claim 4 and 5, wherein organic solvent comprises one or more of methanol, ethanol, isopropanol, acetone, ether, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methylene chloride.
8. A process of claim 4 and 5, wherein inert cores comprise one or more of hydrosoluble, hydro-insoluble, swellable cores or combination thereof.
9. A process of claim 4 and 5, wherein surfactants comprise one or more of amphoteric, non-ionic, cationic or anionic surfactants.
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10. A process of claim 4 and 5, wherein pharmaceutically acceptable excipients comprises one or more of fillers, lubricants, disintegrants, surfactants, polymers and glidants.
Dated this 20 th day of April, 2007
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