FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITIONS COMPRISING FENOFIBRATE OR SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: WOCKHARDT LIMITED, D-4, MIDC, CHIKALTHANA,
AURANGABAD (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides pharmaceutical composition comprising micronized fenofibrate or salts thereof, and one or more surfactants other than dioctylsulfosuccinate optionally with other pharmaceutical^ acceptable excipients. The present invention also provides a process of preparing such pharmaceutical compositions.
The following specification particularly describes the invention and the manner in which it is to be performed.


DESCRIPTION
The present invention provides pharmaceutical composition comprising micronized fenofibrate or salts thereof, and one or more surfactants other than dioctylsulfosuccinate optionally with other pharmaceutical^ acceptable excipients. The present invention also provides a process of preparing such pharmaceutical compositions.
Fenofibrate is a lipid-regulating agent, belongs to the family of fibrates or fibric acid derivatives. It is indicated as an adjunctive therapy to diet for the treatment of adult patients with very high elevations of serum triglyceride levels who are at risk of pancreatitis and who do not respond adequately to dietary control. It is particularly useful for the treatment of adult endogenous hyperlipidemia, hypercholesterolemia and hypertriglyceridemia. It is commercially available as oral capsules containing micronized fenofibrate in the strengths of 67 mg, 134 mg and 200 mg
U.S. Patent Nos. 5,145,684; 6,375,986; 6,969,529; and 6,592,903 disclose nanoparticulate compositions of fenofibrate.
U.S. Patent Nos. 6,277,405; 6,652,881; 7,037,529; 7,041,319; 6,589,552; 6,531,158 and U.S. Application Nos. 20040057998 and 2004137055 describe micronized fenofibrate compositions.
U.S. Patent Nos. 4,895,726; 5,880,148 and U.S. Application No. 2004071771 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 and 6,277,405 describe micronized fenofibrate coated onto hydro soluble carriers with optional surface-active agents.
U.S. Patent No. 6,828,334 discloses inclusion complex of fenofibrate with cyclodextrins.
U.S. Patent No. 6,027,747 discloses solid dispersion of fenofibrate.
U.S. Application No. 20040087656 describes fenofibrate of particle size less than 2000 nm with an improved bioavailability.
U.S. Application Nos. 20060222706 and 20060222707 describe fenofibrate in intimate association with menthol or a surfactant mixture.
U.S. Application No. 20030138496 discloses micronized fenofibrate with inert hydro soluble carriers.
The solubility of an active pharmaceutical ingredient influences the bioavailability of the drug. Fenofibrate is a poorly soluble drug. Due to its poor hydrosolubility, the fenofibrate poses problem of low dissolution. It is also poorly absorbed in the digestive tract and consequently its bioavailability is incomplete and irregular. Clearly, there is a need for improved compositions in which the fenofibrate exhibits better dissolution properties.
Further prior art discloses that solid dose nanoparticulate or microparticulate compositions would not disperse properly upon administration and thus lose the benefits of dissolution and bioavailability as formation of clumps or agglomerated particles takes place due to lack of easy dispersibility. Use of dioctylsulfosuccinate (DOSS) along with polymeric stabilizers exhibit easy redispersion of the composition.


The present inventors while working on fenofibrate formulation have noticed that when fenofibrate is mixed with aqueous solution of one or more surfactants other than dioctylsulfosuccinate (DOSS) optionally with other pharmaceutical^ acceptable excipients and then subjected to micronization, the product thus obtained gets easily redispersed into the dispersion medium without exhibiting the problem of agglomeration leading to enhanced solubility and percent release of fenofibrate. This further leads to increased bioavailability of fenofibrate.
One of the aspects of the present invention provides a pharmaceutical composition of fenofibrate or salts thereof comprising micronised fenofibrate, one or more surfactants other than dioctylsulfosuccinate along with pharmaceutically acceptable excipients.
For the present invention, the term 'micronized fenofibrate' as used herein means fenofibrate having particle size less than 1 urn.
Suitable 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 another ester of polyoxyethylene sorbitane, lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40, vitamin E TPGS and the like. Mixtures of surfactants are also suitable.
Another aspect of the present invention provides a process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:
1) dissolving surfactant other than dioctylsulfosuccinate in aqueous solvent to form a clear solution;

2) dissolving binder(s) and filler(s) in aqueous solvent and mixing this solution with the solution from step 1);
3) adding the fenofibrate into the solution of step 2);
4) micronizing the fenofibrate of step 3);
5) spraying the micronised fenofibrate suspension onto the suitable filler;
6) granulating the mixture of step 3) with one or more pharmaceutically acceptable excipients.
Suitable 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 another ester of polyoxyethylene sorbitane, lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40, vitamin E TPGS and the like. Mixtures of surfactants are also suitable.
The suitable micronizers may include one or more of micro fluidizer, dynomill, pressure homogenizer and the like.
The one or more pharmaceutically acceptable carrier may include one or more of fillers, binders, lubricants, disintegrants, glidants, pharmaceutically acceptable sugars and the like.
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.
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.
Suitable pharmaceutical^ acceptable sugar may include one or more of sucrose, glucose, fructose, galactose, maltose, isomaltose, cellobiose, melibiose, gentiobiose, lactose, sorbitol, mannitol and the like.
The composition of the present invention can be prepared by dissolving one or more surfactants into the aqueous solution. Separately dissolving binder(s) and filler(s) in aqueous solution; combining these two aqueous solutions and mixing fenofibrate with this solution; micronizing the fenofibrate with the help of suitable micro fluidizer. The obtained suspension is sprayed onto suitable filler. The obtained mixture can be granulated, with one or more pharmaceutically acceptable excipients. The obtained granules can be optionally coated and optionally mixed with one or more pharmaceutically 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.
Examples: The composition and dissolution data of batches is provided in table 1-7. The following formulations are representatives of the preferred compositions of the present invention. The preparation method of dosage form is detailed below.
Example-1
Table-1 Composition of Fenofibrate Tablets

SN Ingredients Qty/Tab (%)
Parti
1. Fenofibrate 10 to 70
2. Vitamin E TPGS 5 to 50
3. Sucrose 10 to 70
4 Hydroxypropyl methyl cellulose 5 to 25
5 Sodium Lauryl Sulphate 0.1 10
6 Purified Water q.s.
7 Starch 1500 15 to 80
Part II Extragranular
8 Prosolv SMCC 90 5 to 50
9 Crospovidone (Polyplasdone INF 10) 1 to 10
10 Aerosil 200 1 to5
11 Magnesium stearate 0.1 to 2
Opadry Weight gain 3.0 %of core
Procedure -
Vitamin E TPGS was dissolved in purified to form a clear Solution. Hydroxypropylmethyl cellulose and sodium lauryl sulfate was dissolved in purified water and the solution from the above step was mixed with this solution.


Fenofibrate was mixed in above mixture and then subjected to micronization process using microfluidizer. Starch 1500 was loaded in Fluid bed processor and above solution of Fenofibrate was sprayed onto starch 1500. The granules obtained in above step were dried & passed through suitable mesh screen and then were blended with presifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with pre sifted Magnesium Stearate for 2-3 minutes. The lubricated blend was compresses into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to 3 % weight gain
Table 2 -Dissolution data of Fenofibrate tablets (145mg) and Tricor® Tablets (145mg)
Table 2 provides the dissolution data for fenofibrate tablets (145mg) prepared as per the formula given in Table 1 and commercially available Tricor® Tablets. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used, wherein 1000 ml of 0.025M SLS in water at 37 °C ± 0.5°C was used as a medium.

Time (min) % drug released (Example-1) % drug released (Tricor® Tablets)
10 40 37
20 68 85
30 83 92
45 94 94
60 99 95
90 103 96


Table 3-Dissolution data of Fenofibrate tablets (145mg) and Tricor® Tablets (145mg)
Table 3 provides the dissolution data for fenofibrate tablets (145mg) prepared as per the formula given in Table 4 and commercially available Tricor® Tablets. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used, wherein 2000 ml of 0.0125M SLS in water at 37 °C ± 0.5°C was used as a medium.

Time (min) % drug released (Example-1) % drug released (Tricor® Tablets)
10 27 52
20 56 95
30 68 98
45 78 98
60 84 99
90 92 99

WE CLAIM:
1. A pharmaceutical composition comprising micronized fenofibrate or salts thereof, and one or more surfactants other than dioctylsulfosuccinate optionally with other pharmaceutically acceptable excipients.
2. A process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:

1) dissolving surfactant other than dioctylsulfosuccinate in aqueous solvent to form a clear solution;
2) dissolving binder(s) and filler(s) in aqueous solvent and mixing this solution with the solution from step 1);
3) adding the fenofibrate into the solution of step 2);
4) micronizing the fenofibrate of step 3);
5) spraying the micronised fenofibrate suspension onto the suitable filler;
6) granulating the mixture of step 3) with one or more pharmaceutically acceptable excipients.
3. The pharmaceutical composition and process of claim 1-2, wherein fenofibrate is having particle size less than 1pm.
4.The pharmaceutical composition and process of claim 1-2, wherein the surfactant comprise one or more of one or more of sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, and cremophore RH 40.
5. The pharmaceutical composition and process of claim 1-2, wherein pharmaceutically acceptable excipients comprises one or more of binders, lubricants, disintegrants, glidants, sugars.


6. The pharmaceutical composition and process of claim 5, wherein the binders
comprise one or more from povidone, starch, stearic acid, gums,
hydroxypropylmethyl cellulose.
7. The pharmaceutical composition and process of claim 5, wherein the
lubricants comprise one or more from magnesium stearate, zinc stearate,
calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated
vegetable oil, glyceryl behenate.

Abstract
The present invention provides pharmaceutical composition of fenofibrate or salts thereof comprising micronized fenofibrate, one or more surfactants other than dioctylsulfosuccinate along with pharmaceutically acceptable excipients. The present invention also provides a process of preparing pharmaceutical composition of fenofibrate or salts thereof.