WO2009024889A2

WO2009024889A2 - Pharmaceutical composition comprising a hmg-coa reductase inhibitor and ezetimibe

Info

Publication number: WO2009024889A2
Application number: PCT/IB2008/053198
Authority: WO
Inventors: Sumit Madan; Arno Appavoo Enose; Vikas Batra; Anupam Trehan; Vinod Arora
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2007-08-21
Filing date: 2008-08-08
Publication date: 2009-02-26
Also published as: WO2009024889A3

Abstract

This invention relates to a pharmaceutical composition of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof and an alkaline earth metal salt additive; and a second component comprising granules of ezetimibe. Further, it relates to a pharmaceutical composition for oral administration comprising ezetimibe and an alkaline earth metal salt additive.

Description

PHARMACEUTICAL COMPOSITION COMPRISING A HMG-CoA REDUCTASE INHIBITOR AND EZETIMIBE

Field of the Invention

This invention relates to pharmaceutical compositions comprising a HMG-CoA reductase inhibitor and ezetimibe, and processes for the preparation of the same.

Background of the Invention

Ezetimibe, chemically, l-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)- hydroxypropyl]-4(S)-(4-hydroxyphenyl) -2-azetidinone, is a cholesterol absorption inhibitor. The therapeutic uses of ezetimibe and related compounds, and their preparations were disclosed in U.S. Patent No. 5,767,115. Ezetimibe is commercially available as 10 mg tablets. It is sold under the name Zetia™. Ezetimibe is available in the U.S. in a combination with simvastatin, sold under the trade name Vytorin™.

HMG-CoA reductase inhibitors are currently among the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. The mechanism of action of HMG-CoA reductase inhibitors has been elucidated in some detail. It is believed that HMG-CoA reductase inhibitors disrupt the biosynthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase"). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol.

Consequently, its inhibition leads to a reduction in the rate of formation of cholesterol in the liver.

The main HMG-CoA reductase inhibitors currently used in therapeutics are: pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and cerivastatin. Lovastatin, simvastatin and pravastatin are derived from fungi, whereas fluvastatin and atorvastatin have an entirely synthetic origin. Simvastatin is a chemically modified 2,2-dimethyl- butyrate analogue of lovastatin. Pravastatin is a purified active metabolite of mevastatin with an open hydroxyacid instead of a lactone ring.

Pravastatin sodium (sold in the U.S. under the trademark Pravachol™) is sensitive to a low pH environment and will degrade to form its lactone and various isomers. Joshi et al., stated in U.S. Patent No. 5,180,589, that in order to stabilize the pharmaceutical composition of pravastatin, it is necessary to add one or more basifying agents to impart a pH of at least 9.

Atorvastatin, which is an inhibitor of the enzyme 3 -hydroxy- 3 -methyl glutaryl coenzyme A reductase (HMG-CoA reductase), is commercially available for the treatment of primary hypercholesterolemia, dysbetalipoproteinemia and homozygous familial hypercholesterolemia. Atorvastatin is commercially available as 10 mg, 20 mg, 40 mg and 80 mg tablets. It is sold under the name Lipitor™.

Various attempts have been made to stabilize atorvastatin. PCT Publication No. WO 00/35425 discloses attempts to stabilize statin formulations using buffering agents capable of providing a pH in the range from 7 to 11.

U.S. Patent Nos. 5,686,104 and 6,126,971 disclose oral pharmaceutical formulations of atorvastatin in which the formulation is described as being stabilized by the addition of a pharmaceutically acceptable alkaline earth metal salt.

International application WO 03/068191 discloses a pharmaceutical composition of atorvastatin comprising alkali metal salt additives.

U.S. Patent Publication No. 2002/0169134 discloses a pharmaceutical composition for the treatment or prevention of sitosterolemia comprising ezetimibe and lipid lowering agents including atorvastatin.

U.S. Patent No. 7,229,982 discloses a pharmaceutical composition comprising ezetimibe, simvastatin, BHA, and citric acid, wherein the composition is free of ascorbic acid.

PCT Publication WO 2006/134604 discloses a pharmaceutical composition of ezetimibe with various statins such as atorvastatin, simvastatin and rosuvastatin. The pharmaceutical composition discloses a tablet of ezetimibe and statin wherein all the excipients are blended with active ingredients, granulated and compressed into suitable size tablets.

Summary of the Invention

Statins can tend to be relatively unstable, and their degradation may be catalyzed by several parameters like oxygen, humidity, acidity and temperature. Alternate compositions are presented herein wherein the atorvastatin component is prepared separately and then blended with ezetimibe granules. Further, ezetimibe is also susceptible to degradation in the presence of alkali metal salts whereas it can be stable in the presence of alkaline earth metal salt additives. Alternate compositions of HMG-CoA reductase inhibitor and ezetimibe have now been developed wherein the composition comprises two components. One component comprises a HMG-CoA reductase inhibitor and the second component comprises granules of ezetimibe.

Hence, in one aspect, there are provided pharmaceutical compositions of HMG- CoA reductase inhibitors and ezetimibe for oral administration comprising: a) a first component comprising an HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof; and b) a second component comprising granules of ezetimibe.

In another aspect, there are provided processes for the preparation of pharmaceutical composition of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising: combining a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof; with a second component comprising granules of ezetimibe.

In another aspect, there are provided methods of treating primary hypercholesterolemia and homozygous familial hypercholesterolemia comprising orally administering to a patient, a pharmaceutical composition of HMG-CoA reductase inhibitor and ezetimibe comprising: a) a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof; and b) a second component comprising granules of ezetimibe. In another aspect, there are provided pharmaceutical compositions for oral administration comprising ezetimibe and at least one alkaline earth metal salt additive.

In another aspect, there are provided pharmaceutical compositions of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising a) a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof and at least one alkaline earth metal salt additive; and b) a second component comprising granules of ezetimibe. In another aspect, there are provided processes for the preparation of pharmaceutical compositions of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising: a) combining a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof and at least one alkaline earth metal salt additive, with a second component comprising granules of ezetimibe.

In another aspect, there are provided methods of treating primary hypercholesterolemia and homozygous familial hypercholesterolemia comprising orally administering to a patient, pharmaceutical compositions of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising: a) a first component comprising HMG-CoA reductase inhibitor and at least one alkaline earth metal salt additive, and b) a second component comprising granules of ezetimibe.

Detailed Description

During initial experimentation with atorvastatin composition comprising sodium carbonate and ezetimibe, it was discovered that ezetimibe can undergo degradation in the presence of alkali metal salt additives (such as sodium carbonate), whereas degradation was not observed in the presence of alkaline earth metal additives. The data is given in the table below indicating the impurity values of ezetimibe under various conditions (experimental details are given in Comparative Example 1). Table 1: Stability of Ezetimibe Under Various Conditions

As used herein, the term "HMG-CoA reductase inhibitor" refers to atorvastatin, rosuvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, and cerivastatin. Pharmaceutically acceptable base addition salts of HMG-CoA reductase inhibitors may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N-1-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine. These may exist in any of the solid state forms available such as amorphous or any other polymorphic form. They can be present in the composition in an amount up to about 50% by weight of the composition.

As used herein, the term "Ezetimibe" refers to include any polymorphic form available of ezetimibe such as anhydrous, hydrated or amorphous form. It is present in the composition in an amount 5-20% by weight of HMG-CoA reductase inhibitor component and in an amount 1-10% by weight of total composition.

The HMG-CoA reductase inhibitor and ezetimibe combination is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, TG, and non-HDL-C levels, and to increase HDL-C levels in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia. It is also indicated for the reduction of elevated total-C and LDL-C levels in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments.

HMG-CoA reductase inhibitor or ezetimibe, for example, can be milled to obtain a desired particle size. The desired size is obtained either directly through the synthesis or by using conventional milling techniques, such as air-jet milling, ball milling, cad milling, multi milling and other suitable size-reduction techniques. The particle size of the atorvastatin can be reduced to particle size dgo of, for example, less than or equal to about 200 μm, and more particularly to particle size of between approximately 5 μm and 50 μm. The particle size of rosuvastatin used may be dgo less than about 60 μm, more particularly less than about 20 μm. Ezetimibe may have a particle size dgo of less than about 10 μm. The size of the particles may be analyzed using a conventional particle size analyzer (e.g., a Malvern Master Sizer).

The term "alkaline earth metal salt additives", as used herein, can include calcium carbonate, calcium hydroxide, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide or mixtures thereof. The amount of alkaline earth metal salt additives may vary from about 0.1 to about 30% by weight of the HMG-CoA reductase component, or for example, from about 1-10% by weight of the HMG-CoA reductase component.

The two components are further processed to obtain the pharmaceutical composition such as a monolayer tablet, bilayer tablet, capsule, pill and the like. The HMG-CoA reductase inhibitor component may be in the form of granules; or may be in the form of blend. Ezetimibe granules may be prepared by granulation using granulating fluid or a binder solution or by dry granulation process such as roller compaction or slugging. The pharmaceutical composition may further comprise pharmaceutically acceptable inert excipients. The term "pharmaceutically acceptable inert excipient", as used herein, includes substances known in the art as diluents, binders, disintegrants, stabilizers, surfactants and lubricants/glidants. The excipients are selected based on the desired physical aspects of the final tablets; e.g., obtaining a tablet with desired hardness and friability, being rapidly dispersible and easily swallowed, etc.

The term "stabilizer", as used herein, means an agent that stabilizes the drug, for example, chelating agents, photoprotectants and antioxidants. Examples of suitable antioxidants can include, for example, butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, propyl gallate, tocopherol, citric acid, malic acid, ascorbic acid or mixtures thereof. The antioxidants can be present at concentrations of, for example, from about 0.01% to about 5% by weight. The antioxidants may be dissolved in organic solvents such as, for example, ethanol, isopropanol, n-propanol, acetone, ethyl acetate or mixtures thereof and sprayed on to pharmaceutically acceptable inert excipients. These antioxidants may be present in either or both the components.

Examples of chelating agents can include, for example, disodium EDTA, edetic acid, citric acid, and combinations thereof. The chelating agents can be present at a concentration of up to approximately 10% by weight of the composition, for example, from about 0.01 to about 5% by weight.

The term "photoprotectant", as used herein, means an agent for the protection from light. Examples can include metal oxides such as titanium oxide, ferric oxide or zinc oxide. The photoprotectant can be present at a concentration of up to approximately 10% by weight of the composition, for example, from about 0.01 to about 5% by weight.

Examples of suitable binders can include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth or sodium alginate or mixtures thereof.

Examples of diluents can include mannitol, pregelatinized starch, lactose, cellulose powdered, microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, sorbitol, starch, sucrose, or sugar compressible or mixtures thereof.

Examples of suitable disintegrants can include croscarmellose sodium, starch, crospovidone or sodium starch glycolate or mixtures thereof.

Examples of suitable surfactants can include polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene -polyoxypropylene copolymer, or sodium lauryl sulphate or mixtures thereof. The concentration of surfactant may vary from 1-10% by weight of the composition. Examples of lubricants and glidants can include magnesium stearate, sodium stearyl fumarate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, or mixtures thereof.

Other suitable binders, diluents, disintegrants, surfactants, lubricants, or glidants would be known to those of skill in the art. The HMG-CoA reductase inhibitor and ezetimibe may be present in the same matrix or may be separated by one or more pharmaceutically acceptable inert excipients.

In one of the embodiments, there is a provided a pharmaceutical composition in the form of a monolayer tablet comprising: a) a first component comprising HMG-CoA reductase inhibitor and an alkaline earth metal additive; and b) a second component comprising ezetimibe granules.

In one of the embodiments, there is provided a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of HMG-CoA reductase inhibitor component a) blending HMG-CoA reductase inhibitor, an alkaline earth metal additive and one or more pharmaceutically acceptable inert excipients; b) optionally, granulating the blend of step a); ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating the blend; c) optionally, adding extragranular excipients; iii) Blending the components of step i) and ii); and iv) Lubricating the blend of step iii) and compressing into suitable size tablets. The pharmaceutical composition may be provided in the form of a tablet wherein

HMG-CoA reductase inhibitor and ezetimibe are processed to form a bilayer tablet.

In one of the embodiments, there is provided a pharmaceutical composition in the form of a bilayer tablet wherein a) the first layer comprises HMG-CoA reductase inhibitor and an alkaline earth metal additive; and b) the second layer comprises ezetimibe granules.

In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of HMG-CoA reductase inhibitor component a) blending HMG-CoA reductase inhibitor, an alkaline earth metal additive and one or more pharmaceutically acceptable inert excipients; b) optionally granulating the blend; c) lubricating the blend or granules; ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating the blend; c) lubricating the blend or granules; and iii) Compressing the two components of step i) and ii) into a bilayer tablet.

The pharmaceutical composition may be provided in the form of a capsule wherein HMG-CoA reductase inhibitor component is in the form of tablet and ezetimibe component is in the form of the granules. In one of the embodiments, there is a provided a pharmaceutical composition in the form of a capsule comprising: a) a tablet comprising HMG-CoA reductase inhibitor and an alkaline earth metal additive; and b) ezetimibe granules. In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of atorvastatin component a) blending atorvastatin, an alkaline earth metal additive and one or more pharmaceutically acceptable inert excipients; b) optionally granulating the blend; c) lubricating the blend or granules; d) compressing into suitable size tablet; ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating ezetimibe and drying the granules; iii) Filling the atorvastatin tablet of step i) and ezetimibe granule of step ii) into a capsule.

In one of the embodiments, there is a provided a pharmaceutical composition in the form of a capsule comprising: a) a blend of HMG-CoA reductase inhibitor and alkaline earth metal additive; and b) a tablet comprising ezetimibe granules.

In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of HMG-CoA reductase inhibitor component a) blending HMG-CoA reductase inhibitor, an alkaline earth metal additive and one or more pharmaceutically acceptable inert excipients; b) optionally granulating the blend; ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating the blend; c) lubricating the blend or granules; and d) compressing into suitable size tablet; iii) Filling the HMG-CoA reductase inhibitor component of step i) and ezetimibe tablet of step ii) into a capsule.

In one of the embodiments, there is a provided a pharmaceutical composition in the form of a capsule comprising: i) a tablet of HMG-CoA reductase inhibitor and alkaline earth metal additive; and ii) a tablet comprising ezetimibe granules.

In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of atorvastatin component a) blending atorvastatin and one or more pharmaceutically acceptable inert excipients; b) optionally granulating the blend using roller compactor or slugging; c) compressing the blend or granules into suitable size tablets; ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating the blend; c) lubricating the blend or granules, d) compressing into suitable size tablet, iii) Filling the atorvastatin tablet of step i) and ezetimibe tablet of step ii) into a capsule.

The pharmaceutical composition may be further film coated with functional or non functional layer. The coating may be selected from amongst one or more of those suitable coating materials known in the art. For example, the coating material can be Opadry or Opadry AMB (aqueous moisture barrier). Examples of coloring agents include any FDA approved colors for oral use. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically acceptable inert excipients, as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.

The pharmaceutical composition may be packaged in unit dosage pack such as blister or into multiunit dosage pack such as bottle. The bottle may be an oxygen permeable container such as HDPE bottle or oxygen impermeable container such as Polyethylene and ethylene vinyl alcohol or glass bottle. The packaging may further comprise oxygen absorbers or desiccants.

The following examples illustrate the invention but do not limit the scope of the invention.

EXAMPLES

Comparative Example 1 : A. Ezetimibe Blend

Procedure:

1. Ezetimibe was mixed with croscarmellose sodium and lactose and was transferred to rapid mixer granulator and mixed for 15 minutes.

2. Povidone and sodium lauryl sulfate were dissolved in purified water till clear solution was obtained. 3. Blend of step 1 was granulated with the binder solution of step 2 and the granules so obtained were dried.

4. Microcrystalline cellulose; croscarmellose sodium and magnesium stearate were mixed with blend of step 3. B. Ezetimibe Blend with Sodium Carbonate

The ezetimibe blend prepared above was blended with sodium carbonate (6.5 g) and mixed till a uniform blend was obtained.

C. Ezetimibe Blend with Calcium Carbonate

The ezetimibe blend prepared above was blended with calcium carbonate (7.5 g) and mixed till a uniform blend was obtained.

D. Spiked Samples - Ezetimibe Blend with Sodium Carbonate

Amount equivalent to eight tablets of the ezetimibe blend and sodium carbonate were dispersed in tetrahydrofuran and then acetonitrile was added and filtered. The clear solution was used for HPLC analysis and total impurity was determined. All the samples were analyzed by HPLC method using an Inertsil ODS column.

E. Spiked Samples - Ezetimibe Blend with Calcium Carbonate

Amount equivalent to eight tablets of the ezetimibe blend and calcium carbonate were dispersed in tetrahydrofuran and then acetonitrile was added and filtered. The clear solution was used for HPLC analysis and total impurity was determined. All the samples were analyzed by HPLC method using Inertsil ODS column and the results are given in Table 1 indicating ezetimibe is stable in the presence of alkaline earth metal salts.

Example 1

Procedure: a) Preparation of Atorvastatin Component i) Atorvastatin calcium, calcium carbonate, lactose monohydrate, microcrystalline cellulose and a part of croscarmellose sodium were blended. ii) Hydroxypropyl cellulose and polysorbate 80 were dissolved in water to get a clear solution. iii) The blend of step i) was granulated with solution of step ii). iv) The granules of step iii) were dried. v) The blend of step iv) was blended with remaining part of croscarmellose sodium. b) Preparation of Ezetimibe Component i) Ezetimibe was blended with croscarmellose sodium and lactose, ii) Sodium lauryl sulphate and povidone were dissolved in water. iii) The blend of step i) was granulated with solution of step ii). iv) The granules of step iii) were dried. v) The granules of step iv) were blended with extragranular croscarmellose sodium and microcrystalline cellulose. c) Atorvastatin blend and granules of ezetimibe were blended together and lubricated with magnesium stearate. d) The lubricated blend of step c) was compressed into suitable size tablet. e) The tablet of step d) were coated with a dispersion of Opadry and Sunset Yellow in water.

Example 2

Procedure followed for Example 2 was same as that for example 1.

The total impurity values of ezetimibe for Example 2 were determined for three exhibit batches at 40° C and 75% RH at initial and after 6 months using HPLC method using Inertsil ODS column. The data is given below in Table 2. Table 2: Total Impurity Values of Ezetimibe of Example 2

Example 3

Procedure: a) Preparation of Atorvastatin Component i) Atorvastatin calcium, sodium lauryl sulphate, hydroxypropylcellulose-L, half quantity of croscarmellose sodium and a part of colloidal silicon dioxide and three-fourth quantity of microcrystalline cellulose were blended, ii) Butylated hydroxyanisole and butylated hydroxytoluene were dissolved in isopropyl alcohol. iii) The three fourth quantity of lactose was sifted. iv) The solution of step ii) was added to the bulk of step iii) and mixed. v) The wet mass was dried at 30 C - 40 C in fluidized bed drier and passed through sieve. vi) Calcium carbonate was milled and passed through the sieve. vii)The remaining quantity of microcrystalline cellulose was passed through multimill. viii) The remaining quantity of croscarmellose sodium and remaining part of colloidal silicon dioxide were blended with remaining quantity of lactose, ix) The blends of step i), v)-viii) were mixed together. b) Preparation of Ezetimibe Component i) Ezetimibe was blended with croscarmellose sodium and lactose. ii) Sodium lauryl sulphate and povidone were dissolved in water. iii) The blend of step i) was granulated with solution of step ii). iv) The granules of step iii) were dried. v) The granules of step iv) were blended with extragranular croscarmellose sodium and microcrystalline cellulose. c) Atorvastatin blend and granules of ezetimibe were blended together and lubricated with magnesium stearate. d) The lubricated blend of step c) was compressed into suitable size tablet. e) The tablet of step d) were coated with a dispersion of Opadry and Sunset Yellow in water.

Example 4

Procedure: a) Preparation of Rosuvastatin Component i) Microcrystalline cellulose, lactose monohydrate, dicalcium phosphate and crospovidone were blended together. ii) Rosuvastatin was geometrically mixed with the blend of step i). iii) The blend of step ii) was lubricated with magnesium stearate. iv) The blend of step iii) was compacted in roller compactor to obtain the compacts. v) The compacts were milled to obtain desired granules. b) Preparation of Ezetimibe Component i) Ezetimibe was blended with croscarmellose sodium and lactose, ii) Sodium lauryl sulphate and povidone were dissolved in water, iii) The blend of step i) was granulated with solution of step ii). iv) The granules of step iii) were dried. v) The granules of step iv) were blended with extragranular croscarmellose sodium and microcrystalline cellulose. c) The granules of rosuvastatin and ezetimibe were mixed together. d) Crospovidone, croscarmellose sodium and microcrystalline cellulose were mixed together. e) The blend of step c) and d) were blended together. f) The blend of step e) was lubricated using magnesium stearate and compressed into suitable size tablet. g) Opadry and ferric oxide red were dispersed in water. h) The tablets of step f) were coated with dispersion of step g). While several particular formulations have been described above, it will be apparent that various modifications and combinations of the formulations detailed in the text can be made without departing from the spirit and scope of the invention. For example, additional exemplary tablet formulation is contemplated below.

a) Preparation of Atorvastatin Component: i) Dissolve butylated hydroxyanisole and butylated hydroxytoluene in isopropyl alcohol. ii) Blend about 3/4th quantity of microcrystalline cellulose, pregelatinized starch and colloidal silicon dioxide. iii) Add the solution of step i) to the bulk of step ii and mix. iv) Dry the wet mass at 40 C - 45 C in a fluidized bed drier and pass through a sieve. v) Mill calcium carbonate and passed through a sieve. vi) Pass the remaining l/4^th quantity of microcrystalline cellulose was passed through a multimill. vii) Pass atorvastatin calcium, sodium lauryl sulphate and hydroxypropylcellulose through the screen of a quadro comil. viii)Sieve mannitol and croscarmellose sodium together through a screen. ix) Add the blends of steps v) - vii) to the blend of step viii) and mix together. x) Add the blend of step iv) to the blend of step ix) and mix together, xi) Lubricate the blend of step ix) with magnesium stearate. b) Preparation of Ezetimibe Component i) Blend ezetimibe with croscarmellose sodium and lactose. ii) Dissolve sodium lauryl sulphate and povidone in water, iii) Granulate the blend of step i) with solution of step ii). iv) Dry the granules of step iii). v) Blend the granules of step iv) with croscarmellose sodium. c) Blend atorvastatin blend and granules of ezetimibe and lubricate with magnesium stearate. d) Compress the lubricated blend of step c) into suitable size monolayer tablet. e) Coat the tablet of step d) with a dispersion of Opadry and Sunset Yellow in water.

Claims

WE CLAIM: 1. A pharmaceutical composition of an HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising a. a first component comprising an HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof and an alkaline earth metal salt additive; and b. a second component comprising granules of ezetimibe.

2. The pharmaceutical composition according to claim 1 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, fluvastatin, simvastatin, pravastatin and rosuvastatin.

3. The pharmaceutical composition according to claim 1 wherein the alkaline earth metal salt additive is selected from the group consisting of calcium carbonate, calcium hydroxide, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, or aluminum magnesium hydroxide or mixtures thereof.

4. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition is a tablet, capsule or pill.

5. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition further comprises pharmaceutically acceptable inert excipients selected from diluents, binders, disintegrants, stabilizers, surfactants or lubricants/glidants.

6. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition is prepared by a process comprising the steps of: a) Preparation of an HMG-CoA reductase inhibitor component; i) Blending an HMG-CoA reductase inhibitor and an alkaline earth metal salt additive with pharmaceutically acceptable inert excipients; ii) Optionally, granulating the blend of step a); and b) Preparation of an ezetimibe component i) Blending ezetimibe with other pharmaceutically acceptable inert excipients; ii) Granulating the blend.

7. The pharmaceutical composition according to claim 6 wherein the HMG-CoA reductase inhibitor component and ezetimibe component are compressed into a tablet.

8. The pharmaceutical composition according to claim 6 wherein the HMG-CoA reductase inhibitor component and ezetimibe component are compressed into a bilayer tablet.

9. The pharmaceutical composition according to claim 6 wherein the granules of ezetimibe are prepared using a granulating fluid or a binder solution.

10. The pharmaceutical composition according to claim 6 wherein granules of ezetimibe are prepared by slugging or compaction.

11. The pharmaceutical composition according to claim 6 wherein the pharmaceutical composition is further coated with nonfunctional coating.

12. The pharmaceutical composition according to claim 1, for the treatment of primary hypercholesterolemia or homozygous familial hypercholesterolemia.

13. A pharmaceutical composition for oral administration comprising ezetimibe and an alkaline earth metal salt additive.

14. The pharmaceutical composition according to claim 13 wherein the alkaline earth metal salt additive is selected from the group consisting of calcium carbonate, calcium hydroxide, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, or aluminum magnesium hydroxide or mixtures thereof.

15. The pharmaceutical composition according to claim 13, for the treatment of primary hypercholesterolemia or homozygous familial hypercholesterolemia.