The present invention relates to a process of preparing an oral pharmaceutical composition of fenofibrate having an improved dissolution profile.
Fenoflbrate, 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, is useful for the treatment of adult endogenous hyperlipidaemia, hypercholestrolaemia and hypertriglyceridaemia. The usual daily dosage is 67 mg administered in two or three doses or 200 mg once per day.
Fenoflbrate is practically insoluble in water and exhibits a low rate of dissolution in aqueous media (including gastrointestinal fluids) that results in inadequate bioavailability after oral ingestion.
Several ways of increasing the rate of dissolution of drugs having low solubility in water have been disclosed in the prior art.
US Patent 4,895,726 assigned to Fournier Innovation et Synergic discloses a fenofibrate composition wherein fenofibrate is co-micronized with a surfactant, in order to improve its solubility. This patent emphasizes that co-micronizing fenofibrate with a solid surfactant improves fenofibrate bioavailability to a much greater extent than either by adding a surfactant to micronized fenofibrate or intimately mixing fenofibrate and surfactant, micronized separately.
In order to further improve the solubility and bioavailability of fenofibrate, Laboratories Fournier in their US Patent 6,074,670 found that this could be achieved by spraying a suspension of the active on a hydro-soluble carrier.
US Patent 6,277,405 also assigned to Laboratories Fournier, SA discloses an immediate release fenofibrate composition comprising an inert hydro-soluble carrier covered with at least one layer containing fenofibrate in a micronized from having a size less than 20 urn, a hydrophilic polymer and optionally a surfactant.

We have unexpectedly found that contrary to the earlier reports, the use of a hydro-soluble carrier is not a prerequisite for improving the bioavailability of fenofibrate and that it is possible to make fenofibrate formulations having improved solubility and bioavailability by spraying a suspension of fenofibrate onto an inert hydro-insoluble carrier. The composition thus obtained was found to posses a release profile similar to that reported in Fournier's US patents 6,074,670 and 6,277,405.
It is an object of the present invention to provide a process for the preparation of a fenofibrate composition comprising layering an inert hydro-insoluble carrier with at least one layer containing fenofibrate in a micronized form, a hydrophilic polymer and a surfactant.
It is a further object of the present invention to provide a process for the preparation of a composition of fenofibrate comprising layering micronized fenofibrate on a hydro-insoluble carrier wherein the composition has a dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes, as measured using rotating blade method at 75 rpm according to European Pharmacopoeia in a dissolution medium constituted by water with 2% by weight of Polysorbate 80 or with 0.025M sodium lauryl sulphate
It is yet another object of the present invention to disclose a process for preparing a tablet formulation of fenofibrate wherein the micronized fenofibrate, hydrophilic polymer and surfactant are dispersed in water and the dispersion is sprayed onto an inert hydro-insoluble carrier and the granulate thus obtained is mixed with a disintegrant, glidant and lubricant, and compressed to form tablets.
Micronized fenofibrate as described in accordance with this invention has a mean particle size of less than 20 µm. In accordance with another embodiment of the invention the mean particle size is less than 10 µm. The composition comprises from about 20% to about 45% by weight of micronized fenofibrate.
According to this invention, the expression "inert hydro-insoluble carrier" means any pharmaceutically acceptable excipients, water insoluble and inert. Examples of water

insoluble carriers include, but are not limited to, microcrystalline cellulose, dicalcium phosphate, partially pregelatinized starch, and other suitable synthetic and organic polymers.
The hydro-insoluble carrier may be present in an amount from about 20% to about 60% w/w of the total weight of the pharmaceutical composition.
"Hydrophilic polymer", according to this invention should be taken to mean any high molecular weight substance having sufficient affinity towards water. Examples of such polymers include hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, gelatin and their mixtures.
The hydrophilic polymer may be present in an amount from about 10% to about 45% w/w of the total weight of the pharmaceutical composition.
A surfactant, according to this invention may be amphoteric, non-ionic, cationic or anionic. Examples of such surfactants are: sodium lauryl sulphate, monoleate, monolaurate, monopalmitate, monostearate or other esters of polyoxyethylene sorbitan, polyethylene glycol laurate, lecithins, propylene glycol alginate, bile acids, phospholipids, propylene glycol laurate, etc. Mixtures of surfactants are also suitable.
The surfactant may be present in an amount from about 0.5% to about 3% by weight of the total weight of the pharmaceutical composition.
The process according to this invention comprises spraying a suspension of active ingredient, in micronized form, and a hydrophilic polymer, onto a hydro-insoluble carrier resulting in a pharmaceutical composition of fenofibrate with improved dissolution profile.

The composition according to this invention can additionally contain other excipients conventionally used in the pharmaceutical and chemical fields which is compatible with the active ingredient, such as disintegrants, glidants, lubricants, binders, fillers, pigments, wetting agents, buffers, etc.
Examples of disintegrants used include those conventionally known in the art, such as croscarmellose sodium, cross-linked polyvinyl pyrrolidone and sodium starch glycolate.
The glidants used in accordance with the present invention include those conventionally known in the art such as starch, talc, stearates and colloidal silica.
Examples of lubricants used in the compositions include stearic acid, talc, magnesium stearate, sodium stearyl fumarate, mineral oil and the like or mixtures thereof.
Examples of binders include those conventionally known in the art such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, gelatin, polyvinyl pyrrolidone and the like.
Examples of fillers used in accordance with the present invention include microcrystalline cellulose, lactose, starch, cross-linked polyvinyl pyrrolidone, etc.
The composition in accordance with the present invention may be filled into capsules, formulated as dry syrups, suspensions or mixed with other pharmaceutically acceptable excipients and compressed to tablets. The tablets may further be coated. Examples of some film forming polymers that can be used for tablet coating are cellulose derivatives (hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and their derivatives), acrylic and methacrylic copolymers of different molecular weights.

The compositions according to the invention comprise, based on the total composition weight, an inert hydro-insoluble carrier representing 20 to 60% by weight, micronized fenofibrate representing from 20 to 45% by weight, hydrophilic polymer representing from 10 to 45% by weight and the surfactant representing 0.5 to 3% by weight.
Accordingly, the present invention relates to a process for the preparation of an oral pharmaceutical composition of fenofibrate with improved dissolution profile comprising:
a. mixing micronised fenofibrate, 10 to 45 % w/w of a hydrophilic polymer, 0.5 to 5%
w/w of a surfactant, to obtain a solution or dispersion, and
b. layering said solution or dispersion on to an inert hydro-insoluble carrier used as 15 to
60% w/w, to obtain granulates,
C. optionally mixing said granulates with pharmaceutically accepted excipients selected
from the group consisting of fillers, binders, disintegrants, lubricants, glidants,
colourants and flavouring agents, to obtain a mixture, d. processing said mixture or said granulates as herein described, to obtain said
pharmaceutical composition having a dissolution of at least 20% in 10 minutes, at
least 50% in 20 minutes and at least 75% in 30 minutes.
The following examples will further exemplify the invention and are not intended to limit the scope of the invention.
EXAMPLE 1

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Sodium lauryl sulphate was dissolved in water and the micronized fenoflbrate was added to it while stirring continuously. Following this, polyvinylpyrrolidone was added while still agitating to form a dispersion.
The fenoflbrate suspension was sprayed onto starch 1500 (partially pregelatinized starch) in Glatt process technology using bottom spray. The granulate thus obtained was mixed with disintegrant, glidant and lubricant and compressed to form tablets. The tablets thus obtained were film coated.
Tablets of this example (I) were compared with Fournier's marketed tablets (II) formulation made in accordance with the invention disclosed in US 6,277,405 for dissolution rate. The rotating blade method (European Pharmacopoeia) is used under the following conditions: volume of medium: 1000 ml; medium temperature: 37°C; blade rotation speed: 75 rpm; samples taken: every 2.5 minutes. Determination of the amount dissolved is carried out by spectrophotometry. Tests are repeated 6 times over".
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From the results, it is clearly evident that over 95% drug is released in 20 minutes in both the formulations and I and II show substantially similar dissolution profiles. The formulation containing the hydro-insoluble core also gives a dissolution profile similar to that claimed in US 6,277,405.
EXAMPLE 2

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Fenofibrate (micronized) suspension was prepared in a similar way as in Example 1 and it was sprayed onto microcrystalline cellulose powder in Glatt process technology using bottom spray. The granulate was mixed with a disintegrant, glidant and lubricant and compressed to form tablets. These tablets were film coated.

Tablets of this example were subjected to dissolution studies using rotating blade method at 50 rpm according to European Pharmacopoeia in a dissolution medium constituted by 1000 ml water containing 0.025M sodium lauryl sulphate.
(Table Removed)
The results clearly indicate that although the speed was reduced from 75 rpm to 50 rpm, more than 90% of the drug is still released in 45 minutes. Thus, it can be concluded that the formulation containing hydro-insoluble core gives a similar dissolution profile to that claimed in US 6,277,405 even at a slower speed.
The present invention is not limited to the embodiments described. Those skilled in the art will find it apparent that various modifications and variations can be made to the formulations of this invention. Thus, the present invention is intended to cover such modifications and variations, provided they come under the scope of the appended claims.

WE CLAIM:
1. A process of preparation of pharmaceutical composition comprising layering an inert
hydro-insoluble carrier with at least one layer containing micronized fenofibrate, a
surfactant and a hydrophilic polymer.
2. A process according to Claim 1, wherein the pharmaceutical composition is in the
form of granules inside a capsule.
3. A process according to Claim 1, wherein the pharmaceutical composition is in the
form of granules for dry syrup or suspension.
4. A process as described in Claim 1 wherein the hydro-insoluble carrier is selected from
the group comprising microcrystalline cellulose, dicalcium phosphate, partially
pregelatinized starch or a mixture thereof.
5. A process as described in Claim 1 wherein the hydro-insoluble carrier is present in an
amount of 20 to 60% by weight.
6. A process as described in Claim 1 wherein the hydrophilic polymer is
polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
polyvinyl alcohol, gelatin, or a mixture thereof.
7. A process as described in Claim 1 wherein the hydrophilic polymer is present in an
amount of 10 to 45% by weight.
8. A process as described in Claim 1 wherein the surfactant is selected from the group
comprising sodium lauryl sulphate, polyoxyethylene sorbitan esters, sodium
monopalmitate, polyethylene glycol laurate, sodium monopalmitate, polyethylene

glycol laurate, lecithins, propylene glycol alginate, bile acids, phospholipids, propylene glycol laurate, or a mixture thereof.
9. A process as described in Claim 1 wherein the surfactant is present in an amount of
0.5 to 3% by weight.
10. A process as described in Claim 1 wherein the pharmaceutical composition can
additionally contain other excipients conventionally used in the pharmaceutical and
chemical fields such as disintegrants, glidants, lubricants, binders, fillers, pigments,
wetting agents, buffers, etc.
11. A process as described in Claim 1 wherein the disintegrant is selected from the group
consisting of croscarmellose sodium, crospovidone, sodium starch glycolate or a
mixture thereof.

12. A process as described in Claim 1 wherein the glidant is selected from the group
consisting of starch, talc, stearates, colloidal silica and mixtures thereof.
13. A process as described in Claim 1 wherein the lubricant is selected from the group
consisting of stearic acid, talc, magnesium stearate, sodium stearyl fumarate, mineral
oil and the like or mixtures thereof.
14. A process as described in Claim 1 wherein the binder is selected from the group
consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, gelatin,
polyvinyl pyrrolidone and the like.
15. A process as described in Claim 1 wherein the filler is selected from the group
consisting of microcrystalline cellulose, lactose, starch, cross-linked polyvinyl
pyrrolidone, etc.
16. A process of preparing a pharmaceutical composition comprising layering micronized
fenofibrate on a hydro-insoluble carrier wherein the composition has a dissolution of
at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30
minutes, as measured using rotating blade method at 75 rpm according to European
Pharmacopoeia in a dissolution medium constituted by water with 2% by weight
polysorbate 80 or 0.025M sodium lauryl sulphate.
17. A process for preparing an immediate-release fenofibrate composition comprising
layering an inert hydro-insoluble carrier with at least one layer comprising fenofibrate
in a micronized form having a mean particle size less than 20 µm, a hydrophilic
polymer and a surfactant; wherein based on the total composition weight, the inert .
hydro-insoluble carrier represents 20 to 60 % by weight, micronized fenofibrate
represents from 20 to 45% by weight, hydrophilic polymer represents from 10 to 45%
by weight and the surfactant represents 0.5 to 3% by weight.
18. A process for preparing a tablet formulation of fenofibrate wherein the micronized
fenofibrate, hydrophilic polymer and a surfactant are dispersed in water and the
dispersion is sprayed onto an inert hydro-insoluble carrier and the granulate thus
obtained is mixed with disintegrants, glidants, lubricants, binders, fillers, and
compressed to form tablets.
19. A process as described and exemplified herein.