Technical Field of the Invention
The present invention relates to process for preparing an oral pharmaceutical composition comprising fenofibrate and 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), 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. 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.
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. 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 urn.
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 urn 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.
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, through intimately mixing the fenofibrate and surfactant, micronized separately.
The process of EP 033,532 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 mg.
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 low density lipoprotein (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. Thus, the invention should result in decreased mortality and morbidity through improved patient compliance and combination medication benefits.
Raza, et al. in WO 0045817 disclosed 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.
Farnier, M. and Dejager, S. in Am. J. 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 fenoflbrate 200 mg, fluvastatin 20 mg plus micronized fenoftbrate 200 mg, or fluvastatin 40 mg plus micronized fenoflbrate 200 mg. However, the fenoflbrate and the statin were administered in separate dosage forms.
EP 0 475 148 A1 discloses that tablets containing pravastatin in combination with tablets of a fibric acid derivative were useful for prevention or treatment of type III hyperlipoproteinemia.
EP 0 455 042 Al discloses a combination of pravastatin and fenoflbrate in a single capsule for the treatment of dyslipidemia. However, the combination is prepared by grinding a tablet of pravastatin and a tablet of fenoflbrate to a powder for use in a single capsule, and this form of fenoflbrate exhibits a food effect.
Ippen et al in WO 0037078 describe a combination of the 3-hydroxy-3-methylglutaryl-coenzyme A inhibitor, cerivastatin with fenoflbrate 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 fenoflbrate exhibit a food effect.
The ezetimibe and fenoflbrate combination regimen 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 low-density lipoprotein cholesterol (LDL-C). Fenoflbrate activates the peroxisome proliferators-activated receptor alpha (PPAR-alpha), thereby increasing the tissue lipoprotein lipase activity and breakdown of triglycerides in very low-density lipoproteins (VLDL). The combination therapy of ezetimibe and fenoflbrate 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.
The above references show continuing need to find safe, highly bioavailable, effective pharmaceutical compositions for the prophylaxis or treatment of cardiovascular diseases. As a result, 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.
Therefore, it is an object of this invention to provide a pharmaceutical composition of fenofibrate and other antilipidemic agents in a combined single dosage form that could significantly enhance patient compliance with therapeutic regimens, especially in patients with mixed hyperlipidaemia as compared to single treatment regime.
It is another object of this invention to provide a process of preparing an oral pharmaceutical composition comprising fenofibrate and other antilipidemic agents which involves simple techniques and low cost production. Advantageously, the composition of the present invention exhibits satisfactory dissolution and absorption characteristics.
Summary of the Invention
In one general aspect there is provided a process for preparing an oral pharmaceutical composition comprising fenofibrate and at least one other antilipidemic agent in a single dosage form that can be conveniently administered once or twice in a day.
It is another aspect to provide 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) (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.
Embodiments of the process may include one or more of the following features. For example, the antilipidemic agents other than fenofibrate may include one or more of cholesterol absorption inhibitors, cholesterol modifying agents, angiotensin II antagonists or bile acid sequestrants.
The cholesterol absorption inhibitor may be selective cholesterol absorption inhibitor, particularly ezetimibe.
The cholesterol modifying agents may be one or more of statins selected from one or more of simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, rosuvastatin, atorvastatin, atorvastatin calcium and dihydrocompactin. Particularly statins include atorvastatin, rosuvastatin, lovastatin, pravastatin, simvastatin and fluvastatin. More particularly the statin is rosuvastatin and atorvastatin.
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. Particularly the angiotensin II antagonist is losartan potassium.
The bile acid sequestrants may be one or more of cholestyramine and colestipol.
In the pharmaceutical composition of the present invention, the dosage of fenofibrate may be selected from the range of about 30 to SOOmg 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, and more particularly the dosage of fenofibrate per therapeutic unit is 145mg.
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 surfactant utilized in preparing fenofibrate granules may be 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 composition prepared in the said processes may be optionally further coated with one or more film forming agents.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 of fenofibrate and at least one 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 invention relates to a process of preparing an oral pharmaceutical composition comprising fenofibrate and at least one other antilipidemic agent, that has an ease of administering in a convenient single dosage form.
The fenofibrate granules prepared in the present process 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 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 detailed technology of preparing fenofibrate composition is described in our co-pending Indian Patent Application No. 2752/DEL/2006 Dt. Dec. 21, 2006, which is incorporated herein entirety.
The process for preparing the oral pharmaceutical composition comprising fenofibrate
and other antilipidemic agent involves 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.
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
t
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 granules of 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 and antilipidemic agents other than fenofibrate 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 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 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 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 oral pharmaceutical 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 oral pharmaceutical composition 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. EXAMPLE 1:
Preparation of Fenofibrate granules -1 Composition:

(Table Removed)
Procedure:
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:
Preparation of Fenofibrate granules - II
Composition:

(Table Removed)
Procedure:
Fenofibrate, polyvinyl pyrrolidone and docusate sodium were dissolved in isopropyl alcohol and stirred to get a clear solution.
The solution of step 1 was sprayed over the mixture of microcrysatlline cellulose,
sodium lauryl sulfate and ferric oxide red, to form fenofibrate granules.
2. 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.
EXAMPLE 3:
Preparation of Ezetimibe granules
Composition:

(Table Removed)
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. 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.
EXAMPLE 4:
Preparation of Atorvastatin granules
Composition:

(Table Removed)
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.
4. EXAMPLE 5:
Preparation of Rosuvastatin granules
Composition:

(Table Removed)
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.
4. EXAMPLE 6:
Preparation of Losartan granules
Composition:
(Table Removed)
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.
EXAMPLE 7:

(Table Removed)
EXAMPLE 8:
The granules of Example 1 (fenofibrate granules) and Example 3 (ezetimibe granules) were compressed using specified tools to get bilayered tablets. The tablets were coated with coating composition specified in Example 7.
EXAMPLE 9:
The granules of Example 1 (fenofibrate granules) and Example 3 (ezetimibe granules) were mixed together homogenously and compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified in Example 7.
EXAMPLE 10:
The granules of Example 1 (fenofibrate granules) and Example 3 (ezetimibe granules) were compressed into minitablets separately. Both the tablets were coated with coating composition specified in Example 7. These coated minitablets were filled in desired size of capsules in the desired ratio.
EXAMPLE 11:
The granules of Example 1 (fenofibrate granules) were compressed into minitablets. These minitablets and granules of Example 3 (ezetimibe granules) were mixed together in the desired ratio and filled in desired size of capsules.
EXAMPLE 12:
The granules of Example 3 (ezetimibe granules) were compressed into minitablets. These minitablets and granules of Example 1 (fenofibrate granules) were mixed together in the desired ratio and filled in desired size of capsules.
EXAMPLE 13:
The granules of Example 2 (fenofibrate granules) and Example 4 (atrovastatin granules) were compressed using specified tools to get bilayered tablets. The tablets were coated with coating composition specified in Example 7.
EXAMPLE 14:
The granules of Example 2 (fenofibrate granules) and Example 4 (atrovastatin granules) were mixed together homogenously and compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified in Example 7.
EXAMPLE 15:
The granules of Example 1 (fenofibrate granules) and Example 5 (rosuvastatin granules) were compressed using specified tools to get bilayered tablets. The tablets were coated with coating composition specified in Example 7.
EXAMPLE 16:
The granules of Example 1 (fenofibrate granules) and Example 5 (rosuvastatin granules) were mixed together homogenously and compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified in Example 7.
EXAMPLE 17:
The granules of Example 1 (fenofibrate granules) and Example 6 (losartan granules) were compressed using specified tools to get bilayered tablets. The tablets were coated with coating composition specified in Example 7.
EXAMPLE 18:
The granules of Example 1 (fenofibrate granules) and Example 6 (losartan granules) were mixed together homogenously and compressed using specified tools to get monolithic tablets. The tablets were coated with coating composition specified in Example 7.
EXAMPLE 19:
The granules of Example 1 (fenofibrate granules) and Example 6 (losartan granules) were compressed into minitablets separately. Both the tablets were coated with coating
composition specified in Example 7. These coated minitablets were filled in desired size of capsules in the desired ratio.
EXAMPLE 20:
The granules of Example 1 (fenofibrate granules) were compressed into minitablets. These minitablets and granules of Example 6 (losartan granules) were mixed together in the desired ratio and filled in desired size of capsules.
EXAMPLE 21:
The granules of Example 6 (losartan granules) were compressed into minitablets. These minitablets and granules of Example 1 (fenofibrate granules) were mixed together in the desired ratio and filled in desired size of capsules.
EXAMPLE 22:
The granules of Example 1 (fenofibrate granules), Example 3 (ezetimibe granules) and Example 4 (atorvastatin granules) were compressed using specified tools to get trilayered tablets. The tablets were coated with coating composition specified in Example 7.
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 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.
2. The process according to claim 1 wherein the other antilipidemic agent comprises
one or more of cholesterol absorption inhibitors, cholesterol modifying agents,
angiotensin II antagonists and bile acid sequestrants.
3. The process according to claim 1 wherein the surfactant comprises one or more of
anionic, cationic, zwitterionic and nonionic surfactants.
4. 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.
5. 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.
6. 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.
7. 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.
8. The process according to claim 1 wherein the fenoflbrate granules are combined
with at least one other antilipidemic agent as one or more of coating on granules,
minitablets, multiple-compression tablets, monolithic tablets or multiparticulates.
9. The process according to claim 1 wherein composition is coated with one or more
layers comprising film forming agents.
10. An oral pharmaceutical composition comprising fenoflbrate and at least one other
antilipidemic agent prepared by a process substantially as described and
illustrated herein.