FORM 2
THE PATENT ACT 1970
(39 of 1970)&The Patents Rules, 2003
PATENT OF ADDITION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION OF FENOFIBRATE COMPRISING
PREGELATINIZED STARCH AS ADSORBENT
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 of fenofibrate or
pharmaceutically acceptable salts thereof comprising fenofibrate adsorbed on
a pharmaceutically acceptable adsorbent wherein the said adsorbent is
pregelatinized starch.
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 of fenofibrate or pharmaceutically acceptable salts thereof comprising fenofibrate adsorbed on a pharmaceutically acceptable adsorbent wherein the said adsorbent is pregelatinized starch.
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 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 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 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 describe micronized fenofibrate with inert hydrosoluble carriers.
U.S. Patent Application 20040087656 describes fenofibrate of Part Icle size less than 2000 nm with an improved bioavailability.
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.
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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.
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 fenofibrate is adsorbed on pregelatinized starch, it adheres to various interPart Icle and intraPart Icle pores present on the surface of pregelatinized starch that provides large exposed surface area for drug loading 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. Also, it was found by the present inventors that the composition of fenofibrate comprising fenofibrate adsorbed on pregelatinized starch exhibits similar dissolution profile as that of Tricor® tablets (commercially available fenofibrate tablets).
The present inventors have further noticed that the composition of present invention is bioequivalent to Tricor® tablets (commercially available fenofibrate tablets).
One of the aspects of the present invention provides a pharmaceutical composition comprising fenofibrate or pharmaceutically acceptable salts thereof and pharmaceutically acceptable adsorbent wherein the said adsorbent is pregelatinized starch.
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
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person skilled in the art and include but not limited to milling, spray drying, high pressure homogenization.
Another aspect of the present invention provides a process for preparing pharmaceutical composition of fenofibrate or pharmaceutically acceptable salts thereof 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) adsorbing solution of step a) on pregelatinized starch to obtain adsorbate of fenofibrate and optionally drying
c) layering the adsorbate of fenofibrate of step b) with a solution or dispersion of one or more surfactants
d) optionally adding one or more pharmaceutically acceptable excipients to step c).
For the present invention, the term 'adsorbate' as used herein refers to a physical mixture and/or a complex in which fenofibrate is adhered to or adsorbed on a surface of a pharmaceutically acceptable adsorbent.
In the process of the present invention the solution of fenofibrate can be prepared by dissolving fenofibrate and binder in a solvent in which the fenofibrate and binder are soluble while the adsorbent should not be soluble or only sparingly soluble in this solvent. The term "soluble" and "sparingly soluble" as used 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, ethylcellulose, low molecular weight Hydroxypropyl methylcellulose.
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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 fenofibrate solution can be adsorbed on pregelatinized starch using methods known to ordinary skilled in the art and include but not limited Glatt processor, rapid mixer granulator (RMG) and the like.
The adsorbate of fenofibrate contains fenofibrate in an amount of about 1% to about 70% by weight and pharmaceutical^ acceptable adsorbent from about 30% to about 99% by weight.
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 the adsorbate of fenofibrate 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 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.
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The one or more pharmaceutically acceptable excipients include one or more of fillers, binders, lubricants, disintegrants, and glidants.
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.
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.
The pharmaceutical composition of the present invention can be prepared by dissolving fenofibrate and binder in suitable solvent and adsorbing the obtained solution on pregelatinized starch using Glatt processor. Wet mass thus obtained is dried and the obtained adsorbate of fenofibrate is layered with a surfactant solution using Glatt processor. Wet mass thus obtained is dried, blended with other pharmaceutically acceptable excipients, lubricated and compressed to form
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tablet. The obtained tablets can be optionally coated with aqueous dispersion of opadry.
Another aspect of the present invention there is provided a pharmaceutical composition of fenofibrate or pharmaceutically acceptable salts thereof and pharmaceutically acceptable adsorbent wherein the said adsorbent is pregelatinized starch; 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 composition of the present invention 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 said composition exhibits similar dissolution profile as that of Tricor® tablets (commercially available fenofibrate tablets).
Another aspect of the present invention there is provided a pharmaceutical composition of fenofibrate or pharmaceutically acceptable salts thereof which when administered to human subjects in the fed state at the dose of 145mg presents (a) the mean area under the 96 hour AUC curve is in the range from about 56.02 to about 268.23 (ug*hr/ml); (b) the mean area under the AUC curve extrapolated to infinite time is in the range from about 59.07 to about 291.33 (ug*hr/ml) and; (c) the maximum plasma concentration is in the range from about 3.886 to about 20.703 ug/ml.
The pharmaceutical composition of the present invention comprising 145mg of fenofibrate, pregelatinized starch as adsorbent can be used to make formulations such as tablets or capsules. For tablets comprising about 145 mg fenofibrate administered orally to human subjects in a fed state, the pharmacokinetics based on the plasma concentration of fenofibric acid was determined and is shown in
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Table 3. The composition of the present invention was found to be bioequivalent to commercially available Tricor Tablets.
The geometric mean of the ratio of the AUC 0-96h for the formulation of the present invention administered orally to a group of human subjects in a fasted state versus the AUC 0-96h of Tricor® 145 mg tablets administered orally to the group of human subjects in the fasted state is about 0.80 to about 1.25, preferably about 1.
Similarly, the geometric mean of the ratio of the AUC.O-infinity for a formulation of the present invention when orally administered to a group of human subjects in a fed state versus the AUC. 0-infinity of Tricor® 145 mg tablets administered orally to the group of human subjects in the fed state is about 0.80 to about 1.25, preferably about 1.
Also similarly, the geometric mean of the ratio of Cmax for the formulation of the present invention administered orally to a group of human subjects in a fed state versus the Cmax for Tricor® 145 mg tablets administered orally to the group of human subjects in the fed state is about 0.80 to about 1.25, preferably about 1.
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 20-70
2. PVP K-30 1-30
3. Pregelatinized starch 5-70
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 adsorbed on Pregelatinized starch using Glatt processor. Wet mass thus obtained is tray dried overnight in an oven at 35-40°C (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 dried mass obtained in step 1 using Glatt processor and then dried. Dried mass is sieved through ASTM 30 mesh and blended with presifted microcrystalline cellulose and crospovidone in rapid mixer granulator. 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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Table 2: Dissolution data of Fenofibrate tablets (145mg) and Tricor® Tablets (145mg)

Time (min) % drug released (Example-1) % drug released (Tricor® Tablets)
10 53 56
20 93 99
30 100 100
45 100 100
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 0.05M SLS in water at 37 °C ± 0.5°C was used as medium.
Table 3: Fed Biostudy data of 145mg Fenofibrate Tablets (Sample A) against commercially available Tricor® Tablets

Pharmacokinetic Parameters Example 1 (145mg Fenofibrate Tablets) Tricor® Tablets (145mg)
Mean Geometric mean Mean Geometric mean
Cmax 9.1 8.3 9.46 9.13
AUC 0-t 129.33 117.02 130.66 121.64
AUC 0- «> 136.46 123.01 138.02 127.77
Cmax = Maximum plasma concentration in ug/ml
AUC (o-t) = Area under the plasma concentration time curve from time 0 to t
(t=96hrs).
AUC (o-°° [infinity]) = Area under the plasma concentration time curve from time
0 to infinity.
The pharmaceutical composition of the present invention i.e. Sample A (145mg) was found to be bioequivalent to the innovator tablet (Tricor® Tablets 145mg).
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WE CLAIM:
1) A pharmaceutical composition comprising fenofibrate or pharmaceutical^ acceptable salts thereof and pharmaceutical^ acceptable adsorbent wherein the said adsorbent is pregelatinized starch.
2) A pharmaceutical composition of claim 1 wherein fenofibrate is non-micronized and having Particle size greater than or equal to about 150pm.
3) A process for preparing pharmaceutical composition of fenofibrate or pharmaceutically acceptable salts thereof 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) adsorbing solution of step a) on pregelatinized starch to obtain adsorbate of fenofibrate and optionally drying
c) layering the adsorbate of fenofibrate of step b) with a solution or dispersion of one or more surfactants
d) optionally adding one or more pharmaceutically acceptable excipients to step c).

4) A process of claim 3 wherein binder comprises one or more of polyvinylpyrrolidone, ethylcellulose, low molecular weight Hydroxypropyl methyl cellulose.
5) A process of claim 3 wherein organic solvent comprises one or more of methanol, ethanol, isopropanol, acetone, ether, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methylene chloride.
6) A process of claim 3 wherein adsorbate of fenofibrate contains fenofibrate in an amount from about 1% to about 70% by weight and
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pharmaceutically acceptable adsorbent from about 30% to about 99% by weight.
7) A process of claim 3 wherein surfactants comprises one or more of amphoteric, non-ionic, cationic or anionic surfactants.
8) A process of claim 3 wherein pharmaceutically acceptable excipients comprises one or more of fillers, lubricants, disintegrants, and glidants.
9) A pharmaceutical composition of fenofibrate or pharmaceutically acceptable salts thereof and pharmaceutically acceptable adsorbent wherein the said adsorbent is pregelatinized starch; 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) A pharmaceutical composition of fenofibrate or pharmaceutically acceptable salts thereof which when administered to human subjects in the fed state at the dose of 145mg presents (a) the mean area under the 96 hour AUC curve is in the range from about 56.02 to about 268.23 (ug*hr/ml); (b) the mean area under the AUC curve extrapolated to infinite time is in the range from about 59.07 to about 291.33 (ug*hr/ml) and; (c) the maximum plasma concentration is in the range from about 3.886 to about 20.703 ug/ml.

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Abstract
The present invention provides a pharmaceutical composition of fenofibrate or pharmaceutically acceptable salts thereof comprising fenofibrate adsorbed on a pharmaceutically acceptable adsorbent wherein the said adsorbent is pregelatinized starch. The present invention also provides a process of preparing the said composition.
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