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 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 non-micronized fenofibrate or salts thereof, and one or more vehicles optionally with one or. more pharmaceutically 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 non-micronized fenofibrate or salts thereof, and one or more vehicles optionally with one or more pharmaceutically 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
FORMULA I
Fenofibrate is practically insoluble in water and exhibits a low rate of dissolution in aqueous media that results in inadequate bioavailability after oral ingestion. This low rate of dissolution of fenofibrate in aqueous media is also found in gastrointestinal fluids. Chemically, fenofibrate is 2-[4-(4-Chlorobenzoyl) phenoxy]-2-methylpropanoic acid 1-methylethyl ester of formula I. Several methods of increasing the rate of dissolution of drugs having low solubility in water and other aqueous media have been disclosed in the prior art.


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.
The present inventors while working on fenofibrate formulation have noticed that when fenofibrate is dissolved in vehicle at specific temperature, and further processed with pharmaceutically acceptable excipients, the obtained fenofibrate product has significantly reduced the crystallinity of the fenofibrate. The reduction in 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-micronised fenofibrate, one or more vehicles along with pharmaceutically acceptable excipients.
For the present invention, the term 'non-micronized fenofibrate' as used herein means fenofibrate having particle size greater than or equal to about 50um 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 vehicles in the process of the present invention are those known to ordinary skilled in the art. Examples of such vehicles are polyethylene glycolor derivatives thereof, poloxamer, cremophore RH 40, vitamin E TPGS and the like. Mixtures of vehicles 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) melting vehicle at temperature less than melting point of fenofibrate to form a clear solution;
2) dissolving non-micronized fenofibrate in solution of step 1) at temperature which is below the melting point of the fenofibrate;
3) spraying the fenofibrate solution onto the suitable filler;
4) mixing with one or more pharmaceutical^ acceptable excipients.
Another aspect of the present invention provides a pharmaceutical composition of fenofibrate or salts thereof comprising non-micronised fenofibrate, polyethylene glycol and its derivatives along with pharmaceutically acceptable excipients.
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-polyoxyethylene, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylene, and the like.
Another aspect of the present invention provides a process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:
1) melting the mixture of polyethylene glycol and its derivatives at temperature less than melting point of fenofibrate to form a clear solution;
2) dissolving non-micronized fenofibrate in solution of step 1) at temperature which is below the melting point of the fenofibrate;
3) spraying the fenofibrate solution onto the suitable filler;


4) mixing with one or more pharmaceutically acceptable excipients.
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 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 composition of the present invention can be prepared by dissolving non-micronized fenofibrate in a clear solution of one or more melted surfactants. The obtained solution 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 pharmaceutical^ acceptable excipients. The resulting mixture can be filled into capsule or compressed to make tablet.
The composition of the present invention can also be prepared by dissolving non-micronized fenofibrate with mixture of polyethylene glycol and one or more surfactant. The obtained solution 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. PEG 6000 5 to 70


3. Vitamin E TPGS 2 to 50
4 Starch 1500/Lactose 10 to 70
Part II Extragranular
5 Prosolv SMCC 90 10 to 50
6 Crospovidone (Polyplasdone INF 10) 1 to 10
7 Aerosil 200 1 to 5
8 Magnesium stearate 0.1 to 2
Average weight of Core Tablet
Opadry Weight gain 3.0 %of core
Procedure -
Mixture of PEG 6000 + Vitamin E TPGS were melted together at 60-70°C to form a clear Solution. Fenofibrate was dissolved in above solution at 60-70°C (below the melting point of Fenofibrate).Starch 1500/Lactose were loaded in Fluid bed processor and above solution of Fenofibrate was sprayed onto starch 1500/Lactose. During spraying the temperature of the solution was maintained at 70-75°C. 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
Example-2
Table-2 Composition of Fenofibrate Tablets

SN Ingredients Workable range (%)
Parti
1. Fenofibrate 10 to 70
2. PEG 6000 5 to 70
3. Cremophore RH 40 2 to 50


4 Starch 1500/Lactose/Calcium Silicate 10 to 70
Part II Extragranular
5 Prosolv SMCC 90 10 to 50
6 Crospovidone (PolyplasdonelNFlO) 1 to 10
7 Aerosil 200 1 to 5
8 Magnesium stearate 0.1 to 2
Average weight of Core Tablet
Opadry Weight gain 3.0 %of core
Procedure -
Mixture of PEG 6000 and Cremophore RH 40 was melted together at 60-70°C to form a clear Solution. Fenofibrate was dissolved in above solution at 60-70°C (below the melting point of Fenofibrate). Mixture of starch 1500, Lactose and Calcium Silicate was loaded in Fluid bed processor and above solution of Fenofibrate was sprayed onto the starch 1500, Lactose and Calcium Silicate mixture. During spraying the temperature of the solution was maintained at 70-75°C. 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
Example-3
Table-3 Composition of Fenofibrate Tablets

SN Ingredients Qty/Tab (%)
Parti
1. Fenofibrate 10 to 70


2. PEG 6000 5 to 70
3. Tween 80 2 to 50
4 Starch 1500/Lactose/Calcium Silicate 10 to 70
Part II Extragranular
5 Prosolv SMCC 90 10 to 50
6 Crospovidone (Polyplasdone INF 10) 1 to 10
7 Aerosil 200 1 to 5
8 Magnesium stearate 0.1 to 2
Average weight of Core Tablet
Opadry Weight gain 3.0 %of core
Procedure -
Mixture of PEG 6000 + Tween 80 were melted together at 60-70°C to form a clear Solution. Fenofibrate was dissolved in above solution at 60-70°C (below the melting point of Fenofibrate). Mixture of starch 1500, Lactose and Calcium Silicate was loaded in Fluid bed processor and above solution of Fenofibrate was sprayed onto the starch 1500, Lactose and Calcium Silicate mixture. During spraying the temperature of the solution was maintained at 70-75°C. 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
Example-4
Table-4 Composition of Fenofibrate Tablets
SN Ingredients Qty/Tab (%)


Parti
1. Fenofibrate 10 to 70
2. Poloxamer 407 or 188 5 to 70
3. Vitamin E TPGS 2 to 50
4 Starch 1500/Lactose 10 to 70
Part II Extragranular
5 Prosolv SMCC 90 10 to 50
6 Crospovidone (Polyplasdone INF 10) 1 to 10
7 Aerosil 200 1 to5
8 Magnesium stearate 0.1 to 2
Average weight of Core Tablet
Opadry Weight gain 3.0 %of core
Procedure -
Mixture of Poloxamer 407 or 188 and Vitamin E TPGS was melted together at 60-70°C to form a clear Solution. Fenofibrate was dissolved in above solution at 60-70°C (below the melting point of Fenofibrate). Starch 1500/Lactose were loaded in Fluid bed processor and above solution of Fenofibrate was sprayed onto starch 1500/Lactose. During spraying the temperature of the solution was maintained at 70-75°C. 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
Example-5
Table-5 Composition of Fenofibrate Tablets


SN Ingredients Qty/Tab (%)
Parti
1 Fenofibrate 10 to 70
2 Vitamin E TPGS 2 to 50
3 Starch 1500/Lactose 10 to 70
Part II Extragranular
4 Prosolv SMCC 90 10 to 50
5 Crospovidone (Polyplasdone INF 10) 1 to 10
6 Aerosil 200 1 to 5
7 Magnesium stearate 0.1 to 2
Average weight of Core Tablet
8 Opadry Weight gain 3.0 %of core
Procedure -
Vitamin E TPGS was melted at 60-70°C to form a clear Solution. Fenofibrate was dissolved in above solution at 60-70°C (below the melting point of Fenofibrate). Starch 1500/Lactose were loaded in Fluid bed processor and above solution of Fenofibrate was sprayed onto starch 1500/Lactose. During spraying the temperature of the solution was maintained at 70-75°C. 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 6 -Dissolution data of Fenofibrate tablets (145mg) and Tricor® Tablets (145mg)


Table 6 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 1000 ml of 0.025M SLS in water at 37 °C ± 0.5°C was used as a medium.

Time (min) % drug released (Example-4) % drug released (Example-1) % drug released (Tricor® Tablets)
10 28 30 37
20 52 56 85
30 70 76 92
45 92 96 94
60 101 104 95
90 103 107 96
Table 7 -Dissolution data of Fenofibrate tablets (145mg) and Tricor® Tablets (145mg)
Table 7 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-4) % drug released (Example-1) % drug released (Tricor® Tablets)
10 29 27 52


20 47 50 95
30 67 71 98
45 90 92 98
60 97 102 99
90 99 107 99


WE CLAIM:
1. A pharmaceutical composition of fenofibrate or salts thereof comprising non-micronised fenofibrate, one or more vehicles along with pharmaceutically acceptable excipients.
2. A process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:

1) melting vehicle at temperature less than melting point of fenofibrate to form a clear solution;
2) dissolving non-micronized fenofibrate in solution of step 1) at temperature which is below the melting point of the fenofibrate;
3) spraying the fenofibrate solution onto the suitable filler;
4) mixing with one or more pharmaceutically acceptable excipients

3. A pharmaceutical composition of fenofibrate or salts thereof comprising non-micronised fenofibrate, polyethylene glycol and its derivatives along with pharmaceutically acceptable excipients.
4. A process for preparing pharmaceutical composition of fenofibrate or salts thereof wherein the said process comprises:

1) melting the mixture of polyethylene glycol and its derivatives at temperature-less than melting point of fenofibrate to form a clear solution;
2) dissolving non-micronized fenofibrate in solution of step 1) at temperature which is below the melting point of the fenofibrate;
3) spraying the fenofibrate solution onto the suitable filler;
4) mixing with one or more pharmaceutically acceptable excipients
5. The pharmaceutical composition and process of claim 1-4, wherein fenofibrate is having particle size greater than or equal to about 50pm.


6. The pharmaceutical composition and process of claim 1-4, wherein the surfactant comprises one or more of amphoteric, non-ionic, cationic or anionic surfactants.
7.The pharmaceutical composition and process of claim 1-4, wherein the vehicle comprise one or more of polyethylene glycol or derivatives thereof, poloxamer, cremophore RH 40, vitamin E TPGS
8. The pharmaceutical composition and process of claim 1-4, wherein polyethylene glycol or derivative 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.
9. The process of claim 2 and 3, wherein pharmaceutically acceptable excipients comprises one or more of binders, lubricants, disintegrants, glidants, sugars.



Abstract
The present invention provides pharmaceutical composition comprising non-micronized fenofibrate or salts thereof, and one or more vehicles optionally with one or more pharmaceutically acceptable excipients. The present invention also provides a process of preparing such pharmaceutical compositions.