Technical Field of the Invention
The present invention relates to a new process for preparing fenofibrate compositions with enhanced dissolution and absorption characteristics.
Background of the Invention
Fenofibrate, is recommended in the treatment of hyperlipidemia and hypercholesterolemia. It corresponds to the nomenclature isopropyl 2-(4-(4-chlorobenzoyl) phenoxy)-2-methylpropionate, and is disclosed in U.S. Pat. No. 4,058,552.
Fenofibrate acts as a potent lipid modulator agent offering unique and significant clinical advantages over existing products in the fibrate class of drugs. Fenofibrate produces substantial reductions in plasma triglyceride levels in hypertriglyceridemic patients and in plasma cholesterol and LDL-cholesterol in hypercholesterolemic and mixed dyslipidemic patients. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid. The compositions of this invention are also useful in the reduction of uric acid levels.
Fenofibrate is a prodrug that is absorbed and then hydrolyzed by tissue and plasma esterases to fenofibric acid, its active metabolite or active species. Fenofibric acid, responsible for the pharmacological activity, has a plasma half-life of about 20 hours. Fenofibrate suffer from the disadvantage of being poorly soluble in an aqueous medium, thus having an insufficient dissolution profile and, consequently, poor bioavailability within the organism, following oral administration. The therapeutic dose required to be administered must thus be increased in order to obviate this disadvantage. This particularly applies to numerous hypolipemiant active ingredients, such as those belonging to the fibrate family. Indeed, due to it poor hydrosolubility, fenofibrate is poorly absorbed in the digestive tract and consequently its bioavailability is incomplete, irregular and often varies from one person to another.
To improve the dissolution profile of fenofibrate and its bioavailability, thereby reducing the dose requiring to be administered, it would be useful to increase its dissolution so that it could attain a level close to 100%.
Fenofibrate formulations have been prepared in several different ways in order to improve its bioavailability.
PCX Publication No. WO82/01649 discloses 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 fenofibrate, admixed with an excipient and with a second microporous outer layer of an edible polymer.
European Patent Application 724,877 describes fenofibrate powder co-micronized with a wetting agent in association with a vitamin E component (tocopherol and/or its organic acid ester) for treating or preventing disorders associated with lipoprotein oxidation.
U.S. Pat. No. 4,800,079 describes a medicinal composition in the form of granules with controlled release of fenofibrate. Each granule includes an inert core, a layer based on fenofibrate and a protective layer. Fenofibrate is present in the form of crystalline microparticles of dimensions not greater than 30 |a.m.
U.S. Pat. No. 4,961,890 describes a process for preparing a controlled release formulation containing fenofibrate in an intermediate layer in the form of crystalline microparticles (less than 30 (im in diameter) within a multilayer layer inert matrix.
European Patent Application 904,781 describes a process for making granules of a solid dispersion of a disintegrant in molten fenofibrate by blending a solid dispersing agent into molten fenofibrate, cooling and solidifying the bulk mixture in a tray, and then milling the solid through a screen to produce granules. Disintegrants include polymers such as starch, croscarmellose sodium, sodium starch glycolate, and crospovidone. Such disintegrants are slow to swell and dissolve in aqueous media. Furthermore, when crosslinked as in the case of crospovidone, a polymeric disintegrant will not be uniformly dissolved in molten drug but rather at best will form micro-domains in molten fenofibrate. In addition, polymeric materials can exhibit phase separation phenomena when distributed in a substance with which there is not complete compatibility.
European Patent Application 330,532 discloses a method for improving bioavailability of fenofibrate. This patent describes the effect of co-micronizing fenofibrate with a surfactant, for example sodium laurylsulfate in order to improve fenofibrate solubility and thereby increase its
bioavailability. This patent teaches that co-micronizing fenofibrate with a solid surfactant improves fenofibrate bioavailability to a much greater extent than the improvement that would be obtained either by adding a surfactant, or through solely micronizing the fenofibrate, or, yet again, through intimately mixing the fenofibrate and surfactant, micronized separately.
The process of EP 033,532 leads to a new dosage form in which the active ingredient, co-micronized with a solid surfactant, has improved fenofibrate dissolution, and thus increased bioavailability, which makes it possible, for a given level of effectiveness, to decrease the daily dose of the medicament: respective 67 mg and 200 mg instead of 100 mg and 300 mg.
However, the preparation method in that patent is not completely satisfactory in as much as it does not lead to complete bioavailability of the active ingredient, and suffers from several disadvantages. The technique of co-micronizing fenofibrate with a solid surfactant does, it is true, improve dissolution of the active ingredient, but this dissolution remains, however, incomplete.
In the present invention, the process of preparing fenofibrate composition involves simple techniques and low cost production. Advantageously, the composition of the present invention have enhanced dissolution and absorption characteristics, than those formulations of such agents prepared by the prior art techniques.
Summary of the Invention
It is one of the aspects to provide a process for preparing fenofibrate composition, comprising
the steps of:
(i) preparing a solution comprising fenofibrate, a surfactant and a hydrophilic polymer,
(ii) homogenizing the solution of step (i) with one or more solvents,
(iii) spraying the homogenized solution of step (ii) over one or more inert carriers,
(iv) drying the granules of step (iii) and blending with one or more pharmaceutically
acceptable excipients, (v) compressing the mixture of step (iv) into tablets or filling into capsules.
Embodiments of the process may include one or more of the following features. For example, the surfactant utilized is an anionic surfactant and more particularly, the surfactant is sodium lauryl sulfate.
The inert carriers may be one or more pharmaceutically acceptable materials of water-soluble, water-insoluble and combinations thereof.
The pharmaceutically acceptable excipients may be one or more of fillers, binders, disintegrants, lubricants, glidants, coloring agents and flavoring agents.
According to one of the embodiments, the fenofibrate composition prepared in the said process may be optionally further coated with one or more film forming agents.
It is another aspect of the invention is to provide a fenofibrate composition, which exhibits pharmacokinetic parameters comparable to the commercially available TRICOR® 145mg tablets (Fenofibrate 145mg tablets, Abbott Laboratories, USA) and is complying with the USFDA criteria set for bioequivalence.
It is yet another aspect to provide a method of treating hyperlipidaemic or dyslipidimic conditions by administering to a person in need thereof, a pharmaceutical composition of fenofibrate. The composition may further include one or more other antilipidaemic agents.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
The present process for preparing fenofibrate composition that involves solubilizing fenofibrate along with surfactant and hydrophilic polymer in a solution and spraying the solubilized fenofibrate over the inert carriers for preparing the final dosage form. This technique advantageously has enhanced dissolution and absorption characteristics as it provides the active fenofibrate already in the solubilized form as soon as it enters the gastro-intestinal region.
The present process for preparing fenofibrate composition comprises the steps of:
(i) preparing a solution comprising fenofibrate, a surfactant and a hydrophilic polymer,
(ii) homogenizing the solution of step (i) with one or more solvents,
(iii) spraying the homogenized solution of step (ii) over one or more inert carriers,
(iv) drying the granules of step (iii) and blending with one or more pharmaceutically
acceptable excipients, (v) compressing the mixture of step (iv) into tablets or filling into capsules.
The solvents used for preparing of fenofibrate solution include, but are not limited to, methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof. More, particularly the solvent used is water.
Surfactants helps in increasing the solubility of fenofibrate and hereby increases the dissolution rate. The term "surfactant" is used in its conventional sense throughout this invention. Suitable surfactant can be anionic, cationic, zwitterionic and nonionic surfactants. Preferably, the compositions include at least one anionic surfactant. Suitable anionic surfactants include, but are not limited to, alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, sodium lauryl sulfate or sodium dodecylsulfate, alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidylinositol, diphosphatidylglycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid and their salts, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.).
Hydrophilic polymers present along with the fenofibrate solution improves solubility of fenofibrate. It may include, but are not limited to, pharmaceutically acceptable materials like starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, and cellulose derivatives like hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose and mixtures thereof.
Suitable solvents used for homogenizing the fenofibrate solution, which is meant for spraying may include one or more of water; ketones, such as acetone; alcohols such as methanol, ethanol, isopropyl alcohol; chlorinated hydrocarbons, such as methylene chloride and mixtures thereof. In general, the solvent should adequately disperse, or suspend the active ingredient, surfactant and hydrophilic polymers used.
Fenofibrate solution homogenized with organic solvents may be sprayed using coating equipment known is the pharmaceutical arts, such as fluidized bed coaters (Wurster coaters or top-sprayers), pan coaters and rotary granulators. The spray nozzle can be placed in the top, side
walls or the bottom of the spraying chamber and the chamber can be provided with more than one nozzle.
The inert carriers may be fluidised in air, allowing the carrier particle to be carried upwards from the bottom of the spraying chamber. The fluidised core particles are then hit by one or more small droplets of fenofibrate solution optionally containing one or more pharmaceutically excipients, which are ejected from the nozzle. After spraying, the solvent provided on the cores is evaporated to obtain granules of fenofibrate.
The expression "inert carriers" means any excipients, generally water-soluble or water-insoluble, pharmaceutically inert, crystalline or amorphous, in a particulate form, and not leading to a chemical reaction under the operating conditions employed. Combinations of both water-soluble and water-insoluble materials can also be employed.
Examples of water-soluble carrier may include, but are not limited to, cellulose derivatives, starch, gums, alginates, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, carbohydrate based polymers or any other pharmaceutically acceptable water-soluble materials.
Examples of water-insoluble carrier may include, but are not limited to, pregelatinised starch, crospovidone, colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate, dibasic calcium phosphate or any other pharmaceutically acceptable water-insoluble materials.
The pharmaceutically acceptable excipients may be one or more of fillers, binders, disintegrants, lubricants, glidants, coloring agents and flavoring agents.
Suitable examples of fillers include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized and sucrose.
Examples of binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose,
polyvinyl alcohol, pullutan, pregelatinized starch, agar, tragacanth, sodium alginate and propylene glycol.
Examples of disintegrants include, but are not limited to, starch, croscarmellose sodium, crospovidone, sodium starch glycolate or mixtures thereof.
Examples of lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like.
The coloring agents of the present invention may be selected from any FDA approved colors for oral use.
The fenofibrate composition may be formulated into various pharmaceutical preparations for oral administration, e.g., in the form of tablet or capsule in accordance with any of the conventional procedure known in the field of art, for example, milling, sieving, slugging, kneading, granulating, tabletting, coating, etc. These steps may be carried out in the conventional manner. Most preferably the composition is tablet.
The fenofibrate composition prepared by the present invention may be coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
The coating layers over the tablet may be applied as solution/ dispersion of coating ingredients using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor or dip coating.
Example of solvents used for preparing a solution/dispersion of the coating ingredients include, but are not limited to, methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.
Example of film forming agents include, but are not limited to, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; Waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit® RL and RS; or mixture thereof.
Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
The fenofibrate composition according to the present invention may be used to treat hyperlipidaemic or dyslipidimic conditions. The composition according to the present invention comprising fenofibrate may be administered in combination with other medicines, for example, other antilipidaemic agents.
The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.
EXAMPLE 1: Preparation of Fenofibrate 145mg tablets
Composition:

Procedure:
1 . Fenofibrate, polyvinyl pyrrolidone and sodium lauryl sulphate were dissolved in water and stirred to get a clear solution.
2. To the solution of step 1, mixture of Acetone: Dichloromethane (70:30 ratio) was added
under stirring and the stirring was continued for 45 minutes.
3. The solution of step 2 was sprayed over the mixture of pregelatinised starch and lactose,
to form fenofibrate granules.
4. The dried granules of step 3 were sifted and mixed with cross-linked polyvinyl
pyrrolidone, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate.
5. The mixture obtained in step 4 was compressed into tablets.
6. The compressed tablets were coated with the given coating composition.
In vivo bioequivalence study
In vivo performance of Fenofibrate tablets prepared as per the composition of Example 1 (T) was evaluated with respect to the TRICOR 145 mg tablets (R) in healthy male volunteers under fed condition. Pharmacokinetic parameters Cmax (Maximum plasma concentration), AUCo-iast (Area under the plasma concentration vs. time curve from 0 hours to the time of last sample collected) and AUCjnf_0bs (Area under the plasma concentration vs time curve from 0 hours to infinity) were calculated from the data obtained. Statistical analysis was carried out at 90% interval using "SAS" software package. The results of the study are given in Table 1.
Table 1

®
Pharmacokinetic data for tablets of Example 1 (T) vs. TRICOR 145mg tablets (R)

While there has been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.

WE CLAIM:
1. A process for preparing fenofibrate composition comprising the steps of:
(i) preparing a solution comprising fenofibrate, a surfactant and a hydrophilic
polymer,
(ii) homogenizing the solution of step (i) with one or more solvents, (iii) spraying the homogenized solution of step (ii) over one or more inert carriers, (iv) drying the granules of step (iii) and blending with one or more pharmaceutically
acceptable excipients, (v) compressing the mixture of step (iv) into tablets or filling into capsules.
2. The process according to claim 1 wherein the surfactant comprises one or more of
anionic, cationic, zwitterionic and nonionic surfactants.
3. The process according to claim 1 wherein the hydrophilic polymer comprises one or
more of starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene
glycol, acrylic acid derivatives, cellulose derivatives like hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose,
carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose and mixtures
thereof.
4. The process according to claim 1 wherein the solvent comprises one or more of
methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures
thereof.
5. The process according to claim 1 wherein the inert carriers comprise one or more
pharmaceutically acceptable water-soluble materials, water-insoluble materials and
combinations thereof.
6. The process according to claim 1 wherein the one or more pharmaceutically acceptable
excipients comprise one or more of fillers, binders, disintegrants, lubricants, glidants,
coloring agents and flavoring agents.
7. The process according to claim 1 wherein the composition is coated with one or more
layers comprising film forming agents.

8. A fenofibrate composition prepared by a process of claim 1 exhibits pharmacokinetic
parameters comparable to the commercially available TRIG OR® 145mg tablets
(Fenofibrate 145mg tablets, Abbott Laboratories; USA) and is complying with the
USFDA criteria set for bioequivalence.
9. A method of treating hyperlipidaemic or dyslipidimic condition comprising the
administration of a formulation prepared by the process of claim 1.
10. A fenofibrate composition prepared by a process substantially as described and
illustrated herein.