WO2008075320A2

WO2008075320A2 - Antilipidemic pharmaceutical compositions and process for preparation thereof

Info

Publication number: WO2008075320A2
Application number: PCT/IB2007/055298
Authority: WO
Inventors: Sumit Madan; Ravinder Singh; Puneet Tyagi; Vinod Kumar Arora
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2006-12-21
Filing date: 2007-12-21
Publication date: 2008-06-26
Also published as: WO2008075320A3

Abstract

The present invention relates to a new process for preparing an oral pharmaceutical composition comprising fenofibrate alone or in combination with at least one other antilipidemic agent in a single dosage form that can be conveniently administered once or twice in a day.

Description

ANTILIPIDEMIC PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR

PREPARATION THEREOF

Field of the Invention The present invention relates to a new process for preparing an oral pharmaceutical composition comprising fenofibrate alone or in combination with at least one other antilipidemic agent in a single dosage form that can be conveniently administered once or twice in a day.

Background of the Invention In humans, cholesterol and triglycerides (TG) are part of lipoprotein complexes in the bloodstream, and can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein, (LDL) and very- low-density lipoprotein (VLDL) fractions. Cholesterol and triglycerides are synthesized in the liver, incorporated into VLDL, and released into the plasma. High levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo-B, a membrane complex for LDL-C) promote human atherosclerosis, and decreased levels of HDL-C and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis.

Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above about 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases or risk factors, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/LDL ratios. Fenofibrate is recommended in the treatment of hyperlipidemia and hypercholesterolemia. Its chemical name is isopropyl 2-(4-(4-chlorobenzoyl) phenoxy)-2- methylpropionate, and is disclosed in U.S. Patent 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. 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. PCT Publication No. WO 82/01649 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 No. 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. Patent 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 μm.

U.S. Patent 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 μm in diameter) within a multilayer layer inert matrix.

European Patent Application No. 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. European Patent Application No. 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, through intimately mixing the fenofibrate and surfactant, micronized separately.

The process of European Patent No. 0 330 532 led to a new dosage form in which the active ingredient, co-micronized with a solid surfactant, had improved fenofibrate dissolution, and thus increased bioavailability, which made it possible, to decrease the daily dose of the medicament: respective 67 mg and 200 mg instead of 100 mg and 300 nig.

Despite the diversity of available cholesterol-lowering therapies, a significant proportion of the hyper cholesterolemic population is not achieving the recommended target cholesterol levels. 17% to 73% of treated patients actually meet their target levels, but the people of greatest risk (patients with known Coronary Heart Disease) rarely achieve their target levels (Fletcher B et al. Circulation., 112, 3184-3209 (2005)).Thus, there is a continued search for effective, better-tolerated drugs or combination of drugs for the treatment of patients with hypercholesterolemia. Patients with severe primary hypercholesterolemia often present with blood levels of LDL cholesterol greater than 190 mg/dl (4.9 mmol/L) and triglyceride levels up to 350 mg/dl (3.9 mmol/L). The use of diet and single-drug therapy does not always decrease LDL cholesterol and triglycerides adequately enough to reach targeted values in patients with primary severe hypercholesterolemia with or without a concomitant increase in triglycerides. In these patients a combination of complementary fibrate therapy and other antilipidaemic therapy is desirable.

Moreover, studies have shown that as the number of medications prescribed increases, patient compliance with taking those medications decreases. By providing a simplified dose form with specific classes of medication, there would be the potential benefit of improved compliance as well as medication synergy.

Raza, et al. disclosed in WO 00/45817 safe non-interacting drug combinations of a 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor and a drug that is either an inducer, inhibitor, or substrate of cytochrome P 450. Particular combinations are useful in treating hyperlipidemia in humans who are receiving immunosuppressive chemotherapy.

Farmer, M. and Dejager, S. in Am. /. Cardiol. (2000), 85(1), 53-57 reported that the addition of fluvastatin to micronized fenofibrate results in substantial improvement in atherogenic plasma lipids levels in severe primary hypercholesterolemia and is well tolerated. Patients received micronized fenofibrate 200 mg, fluvastatin 20 mg plus micronized fenofibrate 200 mg, or fluvastatin 40 mg plus micronized fenofibrate 200 mg. However, the fenofibrate and the statin were administered in separate dosage forms.

European Patent Application No. 0 475 148 Al discloses that tablets containing pravastatin in combination with tablets of a fibric acid derivative were useful for prevention or treatment of type III hyperlipoproteinemia. European Patent No. 0 455 042 Al discloses a combination of pravastatin and fenofibrate in a single capsule for the treatment of dyslipidemia. However, the combination is prepared by grinding a tablet of pravastatin and a tablet of fenofibrate to a powder for use in a single capsule, and this form of fenofibrate exhibits a food effect.

Ippen et al describe in WO 00/37078 a combination of the 3 -hydroxy- 3- methylglutaryl-coenzyme A inhibitor, cerivastatin with fenofibrate and to its use in the prophylaxis and treatment of disorders and diseases of lipid metabolism. The tablets containing the two actives are prepared by standard wet granulation. Such forms of fenofibrate exhibit a food effect.

A combination regimen of ezetimibe and fenofibrate was recently approved by the U.S. Food and Drug Administration for treatment of mixed hyperlipidemia. This powerful lipid-modifying therapy takes advantage of the different mechanisms of action of the two individual components. Ezetimibe selectively inhibits intestinal uptake of dietary and biliary cholesterol, and exerts its effect most notably on the LDL-C. Fenofibrate activates the peroxisome proliferators-activated receptor alpha (PPAR-alpha), thereby increasing the tissue lipoprotein lipase activity and breakdown of triglycerides in VLDL. The combination therapy of ezetimibe and fenofibrate has an excellent safety profile and exhibits potent synergistic actions on multiple lipid risk factors and represents another alternative in the clinical management of mixed hyperlipidemia.

It is desirable to develop a medication therapy and method of administering the therapy which would be formed by combination of these agents that are beneficial and/or synergistic in patients with Coronary Artery Disease or an equivalent thereof. Such a medication therapy would provide a combination of the benefits of all of the therapeutic agents in a single pill or other dosage form(s), while also significantly reducing the problems of administration and possibly improving patient compliances. In the present invention we have developed a new process for preparing a pharmaceutical composition comprising fenofibrate. It is also found that the composition of the present invention may be combined with other antilipidemic agents to form a combined single dosage form that could significantly enhance patient compliance especially in patients with mixed hyperlipidaemia. Summary of the Invention

In one general aspect there is provided a process for preparing an oral pharmaceutical composition comprising fenofibrate, wherein the process 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.

Embodiments of the process may include one or more of the following features. For example, the process may optionally comprise at least one other antilipidemic agent to form a combined mixture of fenofibrate and at least one other antilipidemic agent in a single dosage form that can be conveniently administered once or twice in a day.

In another general aspect there is provided a process for preparing an oral pharmaceutical composition comprising fenofibrate and at least one other antilipidemic agent, wherein the process 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,

(iv) drying the granules of step (iii) and blending with one or more pharmaceutically acceptable excipients, (v) combining the material of step (iv) with at least one other antilipidemic agent and optionally with one or more pharmaceutically acceptable excipients, and

(vi) compressing the mixture of step (v) into tablets or filling into capsules.

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 antilipidemic agents other than fenofibrate in preparing the combined single dosage form may include one or more of cholesterol absorption inhibitors, cholesterol modifying agents, angiotensin II antagonists, bile acid sequestrants and combinations thereof.

The cholesterol absorption inhibitor may be a selective cholesterol absorption inhibitor, particularly ezetimibe. The cholesterol modifying agents may be statins selected from one or more of simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, rosuvastatin, atorvastatin, and dihydrocompactin.

The angiotensin II antagonists may be selected from one or more of losartan potassium, saralasin acetate, candesartan cilexetil, valsartan, candesartan, eprosartan, irbesartan, tasosartan or telmisartan.

The bile acid sequestrants may be one or more of cholestyramine and colestipol.

The dosage of fenofibrate in the pharmaceutical composition of the present invention may be selected from the range of about 30 to 300mg per therapeutic unit. Particularly the dosage may be selected from 40 mg, 43 mg, 48 mg, 50 mg, 54 mg, 67 mg, 100 mg, 10 mg, 120 mg, 130 mg, 134 mg, 145 mg, 150 mg, 160 mg and 200 mg per therapeutic unit.

The antilipidemic agent may be combined with the fenofibrate granules in a variety of ways. For example, it can be incorporated into an exterior coating over the granules, minitablets or tablets. The antilipidemic agent can be incorporated along with fenofibrate granules into multiple-compression tablets or monolithic tablets. A multiple-compression tablet can exist as a layered tablet, compression-coated tablet or as a inlay tablet. The antilipidemic agents may be present in the form of multiparticulates, such as particles, pellets, powder, beads or granules along with the fenofibrate granules prepared according to the process of the invention. A barrier may be included between the fenofibrate granules and the other antilipidemic agent in case of instability between the two actives. The barrier is a physical barrier around one or both of the actives. In one or the embodiments, the barrier is a coating around at least one of the two actives.

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 composition prepared in said processes may be optionally further coated with one or more film forming agents.

In another general aspect there is provided an oral pharmaceutical composition of fenofibrate and at least one other antilipidemic agent in a single dosage form, in which the fenofibrate exhibits pharmacokinetic parameters comparable to the commercially available TRICOR^® 145mg tablets (Fenofibrate 145mg tablets, Abbott Laboratories, USA) and complies with the USFDA criteria set for bioequivalence.

In another general aspect there is provided an oral pharmaceutical composition of fenofibrate and at least one other antilipidemic agent in a single dosage form, in which the other antilipidemic agent atorvastain exhibits pharmacokinetic parameters comparable to the commercially available LIPITOR lOmg tablets (Atorvastatin calcium lOmg tablets, Pfizer Inc, USA) and complies with the USFDA criteria set for bioequivalence.

It is yet another aspect to provide a method of treating hyperlipidaemic, dyslipidimic or mixed hyperlipidaemia conditions by administering to a person in need thereof, an oral pharmaceutical composition comprising fenofibrate. The composition may further include one or more other antilipidemic agent in a single dosage form.

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 an oral pharmaceutical composition comprising fenofibrate, involves solubilizing fenofibrate along with surfactant and hydrophilic polymer in a solution and spraying the solubilized fenofibrate over the inert carriers for preparing the granules. This technique provides the active fenofibrate readily available in the solubilized form as soon as it enters the gastro-intestinal region.

The present process for preparing an oral pharmaceutical composition comprising fenofibrate involves the steps of:

(v) compressing the mixture of step (iv) into tablets or filling into capsules.

In one embodiment the process comprises an additional step of combining at least one other antilipidemic agent to form a combined mixture of fenofibrate and at least one other antilipidemic agent in a single dosage form. This combined single dosage form has an ease of administering, especially to geriatrics and has an enhanced patient compliance with therapeutic regimens.

The process for preparing the oral pharmaceutical composition comprising fenofibrate and other antilipidemic agent involves the steps of:

(ii) homogenizing the solution of step (i) with one or more solvents,

(v) combining the material of step (iv) with at least one other antilipidemic agent and optionally with one or more pharmaceutically acceptable excipients, and

(vi) compressing the mixture of step (v) into tablets or filling into capsules.

The antilipidemic agents other than fenofibrate may include one or more of cholesterol absorption inhibitors, cholesterol modifying agents, angiotensin II antagonists, bile acid sequestrants and the like. 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, docusate sodium, 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 other antilipidemic agents which are used in combination with fenofibrate are optionally mixed with one or more pharmaceutically acceptable excipients and prepared in accordance with any pharmaceutically acceptable technique that achieves uniform blending, e.g. dry blending, wet granulation and dry granulation.

In dry blending the active ingredient and excipients are blended together and compressed. The wet granulation method involves mixing active ingredient and excipients, with a solution or dispersion of a wet binder and then granulating into desired size granules. The resulting granulated material is dried, and blended with other excipients, for example lubricants and colorants, before combining with fenofibrate portion. The granules may also be prepared by the techniques known in the field of art, for example, simple granulation, followed by sieving; drug layering; extrusion and marumerization or spheronization; rotogranulation; pelletization; micropelletization, etc. These steps may be carried out in the conventional manner. The dry granulation process comprises compacting active agent with one or more pharmaceutically acceptable excipient(s) by using any suitable apparatus, for example, roller compactor such as a chilsonator or drop roller; or a conventional tablet press. The techniques may be involve roller compaction or slugging; sizing the compacts into granules by milling.

The prepared granules of fenofibrate with or without antilipidemic agents are optionally mixed with one or more pharmaceutically acceptable excipients and 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.

The combined fenofibrate and at least one other antilipidemic agent tablets may be monolithic, bilayered or multilayered tablets. The mutilayered tablets can exist as a layered tablet, as a compression-coated tablet, or as an inlay tablet.

A layered tablet is a tablet which is made up of two or more distinct layers or discrete zones of granulation compressed together with the individual layers lying one on top of another. Such conventional layered tablets are generally prepared by compressing a granulation onto a previously compressed granulation. The operation may be repeated to produce multilayered tablets of more than two layers. A layered tablet has at least two layers or discrete zones one of which is made from fenofibrate and another of which is made from other antilipidemic agent.

A compression-coated tablet is a tablet which is made up of an inner core and one or more outer coats wherein the inner core is completely surrounded by the outer coat or coats. These tablets have at least two discrete zones of granulation compressed together, i.e., an inner core zone and an outer coat zone. Such tablets are prepared by feeding a previously compressed inner core into a special tableting machine and compressing one or more other granulation coats around the preformed inner core. A variation of the compression-coated tablet is the inlay tablet, also referred to as a dot, or bull's-eye tablet. Instead of an inner core zone being completely surrounded by an outer coat, one surface of the zone corresponding to an inner core zone is exposed. These tablets have at least two discrete zones of granulation compressed together. The preparation of inlay tablets is similar to the preparation of compression-coated tablets except that a surface of coating is eliminated.

The two actives may be present in the form of multiparticulates, such as particles, pellets, slugs, powder, beads or granules. The coated or uncoated multiparticulates of fenofibrate and other antilipidemic agent can be filled into capsules. Alternatively, the multiparticulates can be compressed into tablets. The term "pharmaceutically acceptable excipients" as used herein includes 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 oral pharmaceutical composition comprising fenofibrate 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 oral pharmaceutical composition comprising fenofibrate alone or in combination with other antilipidemic agents prepared according to the present invention may be used to treat hyperlipidaemic or dyslipidimic conditions. 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.

EXAMPLES

Example 1

Granules I:

Preparation of Fenofibrate Granules I

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, to get fenofibrate granulate mixture. Example 2

Granules II:

Preparation of Fenofibrate Granules II

Composition:

Procedure:

1. Fenofibrate, polyvinyl pyrrolidone and docusate sodium were dissolved in isopropyl alcohol and stirred to get a clear solution.

2. The solution of step 1 was sprayed over the mixture of microcrysatlline cellulose, sodium lauryl sulfate and ferric oxide red, to form fenofibrate granules. 3. The dried granules of step 2 were sifted and mixed with cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate, to get fenofibrate granulate mixture. Granules III:

Preparation of Ezetimibe Granules

Composition:

Procedure: 1. Ezetimibe, croscarmellose sodium and lactose were mixed together to get a uniform mixture.

2. Sodium lauryl sulphate and polyvinyl pyrrolidone were dissolved in water and mixed with mixture of step 1 to get ezetimibe granules.

3. The granules prepared in step 2 were dried. 4. The dried granules of step 3 were sifted and mixed with microcrystalline cellulose, croscarmellose sodium, ferric oxide red and magnesium stearate, to get ezetimibe granulate mixture.

Granules IV:

Preparation of Atorvastatin Granules

Composition:

Procedure: 1. Atorvastatin calcium, calcium carbonate, lactose, microcrystalline cellulose and croscarmellose sodium were mixed together to get a uniform dry blend.

2. Polysorbate 80 and Hydroxy proypyl cellulose were dissolved in water and mixed with mixture of step 1 to get atorvastatin granules.

3. The granules of step 2 were dried, sifted and mixed with croscarmellose sodium and magnesium stearate, to get atorvastatin granulate mixture.

Granules V:

Preparation of Rosuvastatin Granules

Composition:

Procedure: 1. Rosuvastatin calcium, microcrystalline cellulose, lactose, dibasic calcium phosphate anhydrous and cross-linked polyvinyl pyrrolidone were mixed together to get a uniform dry blend.

2. To the dry blend of step 1, intragraular magnesium stearate was mixed and compacted using roller compactor. 3. The compacts of step 2 were sized and mixed with extragranular microcrystalline cellulose, cross-linked polyvinyl pyrrolidone and magnesium stearate, to get rosuvastatin granulate mixture.

Granules VI:

Preparation of Losartan Granules

Composition:

Procedure: 1. Losartan potassium, microcrystalline cellulose and lactose were mixed together to get uniform mixture.

2. To the mixture of step 1 magnesium stearate was added, mixed and compacted in roller compactor.

3. The compacts of step 2 were charged in oscillating granulator to get granules of losartan.

4. To the granules of step 3, pregelainised starch and magnesium stearate were added and mixed together, to get losartan granulate mixture.

Coating composition:

Example 3

The Example 1 fenofibrate granules were compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified above. Example 4

The Example 1 fenofibrate granules and Granules III ezetimibe granules were compressed using specified tools to get bilayered tablets. The tablets were coated with coating composition specified above. Example 5

The Example 1 fenofibrate granules and Granules III ezetimibe granules were mixed together homogenously and compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified above.

Example 6 The Example 1 fenofibrate granules and Granules III ezetimibe granules were compressed into minitablets separately. Both the tablets were coated with coating composition specified above. These coated minitablets were filled in desired size of capsules in the desired ratio.

Example 7 The Example 1 fenofibrate granules were compressed into minitablets. These minitablets and granules of Granules III ezetimibe granules were mixed together in the desired ratio and filled in desired size of capsules.

Example 8

The Granules III ezetimibe granules were compressed into minitablets. These minitablets and Example 1 fenofibrate granules were mixed together in the desired ratio and filled in desired size of capsules.

Example 9

The Example 2 fenofibrate granules and Granules IV atrovastatin granules were compressed using specified tools to get bilayered tablets. The tablets were coated with coating composition specified above. Example 10:

The Example 2 fenofibrate granules and Granules IV atrovastatin granules were mixed together homogenously and compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified above. Example 11

The Example 1 fenofibrate granules and Granules V rosuvastatin granules were compressed using specified tools to get bilayered tablets. The tablets were coated with coating composition specified above.

Example 12 The Example 1 fenofibrate granules and Granules V rosuvastatin granules were mixed together homogenously and compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified above.

Example 13

The Example 1 fenofibrate granules and Granules VI losartan granules were compressed using specified tools to get bilayered tablets. The tablets were coated with coating composition specified above.

Example 14:

The Example 1 fenofibrate granules and Granules VI losartan granules were mixed together homogenously and compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified above.

Example 15:

The Example 1 fenofibrate granules and Granules VI losartan granules were compressed into minitablets separately. Both the tablets were coated with coating composition specified above. These coated minitablets were filled in desired size of capsules in the desired ratio. Example 16

The Example 1 fenofibrate granules were compressed into minitablets. These minitablets and Granules VI losartan granules were mixed together in the desired ratio and filled in desired size of capsules. Example 17

The Granules VI losartan granules were compressed into minitablets. These minitablets and Example 1 fenofibrate granules were mixed together in the desired ratio and filled in desired size of capsules.

Example 18 The Example 1 fenofibrate granules, Granules III ezetimibe granules and Granules

IV atorvastatin granules were compressed using specified tools to get trilayered tablets. The tablets were coated with coating composition specified above.

In vivo bioequivalence study In vivo performance of combined dosage form of Fenofibrate + Atorvasatin bilayered tablets prepared as per the composition of Example 9 (T) was evaluated with respect to the TRICOR^® 145 mg tablets (R) and LIPITOR^® lOmg tablets (R) in healthy male volunteers under fed condition, as per guidelines set by USFDA. Pharmacokinetic parameters C_max (Maximum plasma concentration), AUCo-iast (Area under the plasma concentration vs. time curve from 0 hours to the time of last sample collected) and AUC_mf obs (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 9 (T) vs. TRICOR^® 145mg tablets (R) and LIPITOR® lOmg 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.

Claims

We Claim: 1. A process for preparing an oral pharmaceutical composition comprising fenofibrate, wherein the process 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.

2. A process for preparing an oral pharmaceutical composition comprising fenofibrate and at least one other antilipidemic agent, wherein the process 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) combining the material of step (iv) with at least one other antilipidemic agent and optionally with one or more pharmaceutically acceptable excipients, and (vi) compressing the mixture of step (v) into tablets or filling into capsules.

3. The process according to claim 2, wherein the other antilipidemic agent comprises one or more of cholesterol absorption inhibitors, cholesterol modifying agents, angiotensin II antagonists and bile acid sequestrants.

4. The process according to claim 1 or 2, wherein the surfactant comprises one or more of anionic, cationic, zwitterionic and nonionic surfactants.

5. The process according to claim 1 or 2, 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.

6. The process according to claim 1 or 2, wherein the solvent comprises one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.

7. The process according to claim 1 or 2, wherein the inert carriers comprise one or more pharmaceutically acceptable water-soluble materials, water-insoluble materials and combinations thereof.

8. The process according to claim 1 or 2, wherein the one or more pharmaceutically acceptable excipients comprise one or more of fillers, binders, disintegrants, lubricants, glidants, coloring agents and flavoring agents.

9. The process according to claim 2, wherein the fenofibrate granules are combined with at least one other antilipidemic agent as one or more of coating on granules, mini tablets, multiple-compression tablets, monolithic tablets or multiparticulates.

10. The process according to claim 2, wherein composition optionally comprises a barrier layer in case of instability between fenofibrate granules and the other antilipidemic agent.

11. The process according to claim 1 or 2, wherein the composition optionally further coated with one or more film forming agents.

12. The process according to claim 11, wherein the film forming agents comprises one or more of 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.

13. An oral pharmaceutical composition comprising fenofibrate prepared by the process of claim 1 exhibits pharmacokinetic parameters comparable to the commercially available TRICOR^® 145mg tablets (Fenofibrate 145mg tablets, Abbott Laboratories; USA) and complies with the USFDA criteria set for bioequivalence.

14. An oral pharmaceutical composition comprising fenofibrate and atorvastatin prepared by the process of claim 2 exhibits pharmacokinetic parameters comparable to the commercially available LIPITOR^® lOmg tablets (Atorvastatin lOmg tablets, Pfizer Inc.; USA) and TRICOR^® 145mg tablets (Fenofibrate 145mg tablets, Abbott Laboratories; USA) and complies with the USFDA criteria set for bioequivalence.

15. A method of treating hyperlipidaemic, dyslipidimic or mixed hyperlipidaemia conditions comprising the administration of a pharmaceutical composition prepared by the process of claim 1 or 2.