FIELD OF THE INVENTION
The present invention relates to a composition comprising ezetimibe and atorvastatin.
In particular, the present invention provides an immediate release bilayer tablet comprising one layer of atorvastatin calcium and other layer of ezetimibe and method for the preparation thereof.
BACKGROUND OF THE INVENTION
Ezetimibe of formula I, belongs to a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. It is chemically known as l-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone,
Formula I Ezetimibe is an anti-hyperlipidemic medication suitable for oral use and is being
®
marketed under the trade name ZETIA , which is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF.
Ezetimibe, processes for its preparation, pharmaceutical compositions and its use as a hypocholesterolemic agent are disclosed in European patent EP0720599B1. Further it discloses the use of ezetimibe in combination with HMG-CoA reductase inhibitors such as atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin in reducing the plasma cholesterol levels and in the treatment of atherosclerosis.

Atorvastatin of formula II, is an HMG-CoA reductase inhibitor and is chemically known as [R-(R*,R*)]-2-(4-fluorophenyl)-R,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenyl amino)carbonyl]-lH-pyrrole-l-heptanoic acid.
Formula II
Atorvastatin, processes for its preparation, and the use of atorvastatin as a cholesterol biosynthesis inhibitor are first disclosed in European patent EP409281B1. Atorvastatin is a hypolipidemic drug which is a selective competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Atorvastatin is the only drug in this class that can reduce both elevated LDL cholesterol and triglycerides in patients with hypercholesterolemia.
Ezetimibe lowers serum cholesterol concentration by selectively inhibiting the absorption of cholesterol and phytosterols structurally similar to cholesterol in the intestine. Its mechanism of action is complementary to HMG-CoA reductase inhibitors. So, when ezetimibe and HMG-CoA reductase inhibitors like atorvastatin are co-administered, the cholesterol lowering effect increases synergistically. Also, the plasma levels of LDL-C were significantly reduced, the difference was statistically significant, and atorvastatin and ezetimibe combined with the use of a double dose atorvastatin compared the efficacy of lowering LDL-C similar difference was statistically significant. Thus, atorvastatin combined with ezetimibe and atorvastatin alone compared, can reduce LDL-C to obtain additional benefits, can make more high-risk or very high risk of CHD patients with blood lipid standards.
PCT publication WO 2006/134604 discloses pharmaceutical composition comprising ezetimibe, an HMG-CoA reductase inhibitor in combination with disintegrants and

glidants. HMG-CoA reductase inhibitors are defined as atorvastatin, simvastatin and rosuvastatin. It discloses the formulation of ezetimibe and atorvastatin calcium with excipients like calcium carbonate, lactose, starch, croscarmellose sodium, polyvinylpyrrolidone k-30, isopropyl alcohol, magnesium stearate, colloidal anhydrous silica, crospovidone, hydroxypropylmethylcellulose-15cps, talc, Lake Sunset yellow, titanium dioxide and triacetin.
European patent EP1353696 Bl discloses ezetimibe composition comprising 10% ezetimibe, 55% lactose monohydrate, 20% microcrystalline cellulose, 4% povidone, 8% croscarmellose sodium, 2% sodium lauryl sulfate, and 1% magnesium stearate. This patent does not disclose compositions of ezetimibe with atorvastatin calcium.
European patent application EP1849459 Al discloses a composition comprising ezetimibe co-milled with at least one hydrophilic excipient. Co-milling is carried out with saccharides or polysaccharides, typically starch, to obtain ezetimibe particle size of d(0.9) of less than or equal to about 25 u.m, preferably less than or equal to 10 u.m, and more preferably less than or equal to about 5 u.m. The said mixture is then pressed into slugs and milled and thereafter granulated using a granulation solution of povidone in ethanol. The granules were then dried and mixed with other excipients and compressed into tablets. This patent application makes use of organic solvent to prepare granulation solution and does not disclose compositions of ezetimibe with atorvastatin calcium.
Another European patent EP2217214 Bl discloses pharmaceutical composition of ezetimibe comprising 5 to 20% ezetimibe, 50 to 85% diluent, 3 to 25% disintegrant, 2 to 5% solubility enhancer, 1 to 10% binder and 0.5 to 1% lubricant, with specific particle size of ezetimibe selected from d(0.9) of 9 to 20 u.m and a d(0.5) of 4 to 10 u.m. The said patent makes the use of corn starch paste for the manufacture of

pharmaceutical composition. This patent has not exemplified the compositions of ezetimibe with atorvastatin calcium.
Another European patent EP2229938 Bl discloses pharmaceutical composition of ezetimibe which is free of magnesium stearate having a median particle size of less than or equal to 2 u.m, wherein micronized ezetimibe is finely distributed within the weight ratio of micronized ezetimibe to polyvinylpyrrolidone in the range of between 3:1 to 2:1 (w/w). Further the formulation makes use of sodium stearyl fumarate and colloidal silicon dioxide. This patent too does not disclose compositions of ezetimibe with atorvastatin calcium.
Another European patent EP2231118B2 discloses a pharmaceutical composition using non-micronized ezetimibe suspension. The suspension of ezetimibe is prepared by dissolving ezetimibe in a solvent selected from lower alcohols, amines or ketones, and then solution is added to anti-solvent, recovering the precipitate from resulting suspension, drying the precipitate and suspending in a solvent and suspension is de-agglomerated and homogenized with wet homogenizer. The suspension of ezetimibe is sprayed upon a mixture of solid excipients and forming the mixture into dosage form. The present invention makes use of organic solvent and wet milling for preparing suspension of ezetimibe of desired particle size and does not exemplified compositions of ezetimibe with atorvastatin calcium.
One another European patent EP2328563 Bl discloses combination composition of atorvastatin and ezetimibe, comprising atorvastatin calcium, ezetimibe, lactose, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate. Additionally, in other examples calcium carbonate or silicon dioxide or combination thereof has also been disclosed. The said patent has not disclosed the specific amounts of excipients used for the individual layer of atorvastatin or ezetimibe in the bilayer tablet formulation.

Another European patent application EP3360541 Al discloses bilayer tablet composition comprising one layer of atorvastatin calcium and other layer of ezetimibe, wherein in atorvastatin layer calcium carbonate is added to improve the stability and in ezetimibe layer, high amount of filler and one polymer is added to improve the solubility.
A US patent application 2007/0275052 discloses a pharmaceutical composition comprising micronized ezetimibe of which about 90% of the particles are not more than about 7 microns and of which about 50% of the particles are not more than about 4 microns. In exemplified process ezetimibe, lactose monohydrate, crospovidone or sodium starch glycolate and sodium lauryl sulphate were sifted through mesh #60 to prepare pre granulation blend and granulated using binder solution of povidone in water. Dried the granules and mixed with magnesium stearate and compressed into tablets.
A Chinese patent application CN107875129 A discloses bilayer tablet formulation of atorvastatin and ezetimibe wherein, atorvastatin calcium pellets is prepared using polysorbate 80, hydroxypropyl cellulose, calcium carbonate, microcrystalline cellulose, lactose and sodium carboxymethyl starch. The ezetimibe layer comprises ezetimibe, microcrystalline cellulose, lactose, croscarmellose sodium, povidone, sodium lauryl sulfate, and magnesium stearate.
Another Chinese patent application CN109718215A discloses ezetimibe composition comprises 10% ezetimibe, 55 to 60% lactose, 15 to 20% microcrystalline cellulose, 4 to 8% croscarmellose sodium, 3 to 5% povidone, 2 to 3% sodium lauryl sulfate, 0.5 to 1% magnesium stearate, 0.5 to 1% micronized silica gel. This patent too does not disclose compositions of ezetimibe with atorvastatin calcium.

A recently published PCT publication WO 2019/025512 Al discloses a tablet comprising ezetimibe, wherein weight ratio of stearic acid to silica is 1:1 to 1:3 and a plastic excipient selected from microcrystalline cellulose, powdered cellulose, cyclodextrins, low substituted hydroxypropyl cellulose and maltodextrin have been used along with other excipients. But this publication too does not exemplified compositions of ezetimibe with atorvastatin calcium.
Ezetimibe is reported as practically insoluble in water, which cause it to exhibit a low dissolution rate in aqueous media such as gastrointestinal fluids, which can result in low bioavailability after oral ingestion. When the solid dosage forms, such as tablets, are taken orally, in many cases, the drug must first dissolve in aqueous gastrointestinal fluids before exhibiting its effect. But, because many drugs such as ezetimibe are small organic molecules with low solubility, dissolution problems arise and having low dissolution rates limit their bioavailability. The prior art references as described above have used one or the other factor to solve the solubility issue, either by particle reduction, using non-micronized ezetimibe suspension or using plastic excipients or using solubility enhancer excipients. Most of the references have used ezetimibe blend with other excipients including solubility enhancer excipients and granulated using binder solution. It has been observed that since amount of solubility enhancer is too less, it will not mix properly in the dry blend.
So, there is a need for an improved method to prepare a composition to overcome the solubility problem of ezetimibe or its combination with other therapeutic agents such as HMG-CoA reductase inhibitors, preferably atorvastatin on which ezetimibe has a synergistic effect. The present invention aims is to provide a dosage form by providing composition of ezetimibe and/or its combination with atorvastatin to overcome solubility problem and have desired dissolution profile.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an immediate release bilayer tablet composition comprising one layer of atorvastatin calcium and other layer of ezetimibe.
Another object of present invention is to provide a method for the preparation of bilayer tablet of atorvastatin calcium and ezetimibe.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a pharmaceutical composition comprising ezetimibe and its combination with atorvastatin calcium to provide high stability and solubility.
Accordingly, the present invention provides a pharmaceutical bilayer tablet composition comprising
(i) atorvastatin layer:
a) 05 to 20% w/w atorvastatin calcium,
b) 40 to 60% w/w diluent,
c) 04 to 08% w/w disintegrant,
d) 01 to 04% w/w binder,
e) 0.2 to 0.8% w/w solubilizing agent,
f) 20 to 40% w/w a I ka I ize r,
g) 0.2 to 1.0% w/w lubricant,
h) 0.2 to 1.0%w/wglidant.
(ii) ezetimibe layer:
a) 03 to 10% w/w ezetimibe,
b) 60 to 95% w/w diluent,
c) 03 to 10% w/w disintegrant,

d) 03 to 06% w/w binder,
e) 1.1 to 2.2% w/w solubilizing agent,
f) 0.4 to 1.8% w/w lubricant.
wherein the ezetimibe layer is obtained by a wet granulation process, wherein ezetimibe is dispersed in binder solution comprising a binder and a solubilizing agent.
According to yet another aspect the present invention provides a pharmaceutical bilayer tablet composition comprising:
(i) atorvastatin layer:
a) 05 to 20% w/w atorvastatin calcium,
b) 20 to 30% w/w lactose, preferably as monohydrate and 20 to 30% w/w microcrystalline cellulose,
c) 04 to 08% w/w croscarmellose sodium,
d) 01 to 04% w/w hydroxypropylcellulose,
e) 0.2 to 0.8% w/w polysorbate,
f) 20 to 40% w/w calcium carbonate,
g) 0.2 to 1.0% w/w magnesium stearate,
h) 0.2 to 1.0% w/w silicon dioxide colloidal, (ii) ezetimibe layer:
a) 03 to 10% w/w ezetimibe,
b) 50 to 70% w/w lactose, preferably as monohydrate and 10 to 25% w/w microcrystalline cellulose,
c) 03 to 10% w/w croscarmellose sodium,
d) 03 to 06% w/w povidone,
e) 1.1 to 2.2% w/w sodium lauryl sulfate,
f) 0.4 to 1.8% w/w magnesium stearate.
wherein the ezetimibe layer is obtained by a wet granulation process, wherein ezetimibe is dispersed in binder solution comprising a binder and a solubilizing agent.

According to yet another aspect the present invention provides a process for the preparation of a pharmaceutical bilayer tablet composition, wherein process comprising the following steps:
(i) atorvastatin layer:
a) mixing a suitable binder in purified water;
b) mixing solubilizing agent with solution of step a);
c) granulating the mixture of atorvastatin calcium, suitable diluent, a disintegrant and alkalizer with solution of step b);
d) optionally wet milling the granules of step c);
e) drying the granules of step d);
f) milling the dried granules;
g) sieving the dried granules;
h) blending granules with a suitable glidant and suitable lubricant;
(ii) ezetimibe layer:
a) mixing a suitable binder in purified water to obtain solution;
b) adding solution of solubilizing agent in purified water in step a);
c) adding ezetimibe to solution of step b) to obtain dispersion;
d) preparing dry mix blend of a suitable diluent and disintegrant and passed through a sieve;
e) spraying the dispersion of step c) on the blend of step d) to obtain granules;
f) drying the granules;
g) sieving the dried granules through mesh #60; and
h) mixing the dried granules obtained after shifting through mesh #60 in step g)
with a suitable diluent and a suitable lubricant; (iii) pressing the blend from steps h) subsequently form a bilayer tablet; and (iv) coating the bilayer tablet.

According to yet another aspect the present invention provides a process for the preparation of a pharmaceutical bilayer tablet composition, wherein process comprising the following steps:
(i) atorvastatin layer:
a) mixing hydroxypropylcellulose in purified water;
b) mixing polysorbate 80 with solution step a);
c) granulating the mixture of atorvastatin calcium, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and calcium carbonate with solution of step b);
d) optionally wet milling the granules of step c);
e) drying the granules of step d);
f) milling the dried granules;
g) sieving the dried granules;
h) blending granules with silicon dioxide colloidal and magnesium stearate;
(ii) ezetimibe layer:
a) mixing povidone in purified water to obtain solution;
b) adding solution of sodium lauryl sulfate in purified water in step a);
c) adding ezetimibe to solution of step b) to obtain dispersion;
d) preparing dry mix blend of lactose monohydrate and croscarmellose sodium and passed through a sieve;
e) spraying the dispersion of step c) on the blend of step d) to obtain granules;
f) drying the granules;
g) sieving the dried granules; and
h) mixing the dried granules obtained in step g) with microcrystalline cellulose;
and with magnesium stearate; (iii) pressing the blend from steps h) subsequently to form bilayer tablet; and (iv) coating the bilayer tablet.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel pharmaceutical composition with improved solubility comprising ezetimibe or its combination with atorvastatin calcium for the preparation of a bilayer tablet.
Generally, ezetimibe used for the formulation can be any polymorphic form of ezetimibe. The ezetimibe used can be amorphous or crystalline form. Ezetimibe can be milled or micronized and can have particle size of d(0.9) of less than 30 u.m, preferably less than 20 u.m and more preferably less than 10 u.m.
Atorvastatin calcium used for the formulation can be any polymorphic form. The polymorphic form of atorvastatin calcium can be amorphous or crystalline form, preferably a crystalline form; more preferably form 1 of crystalline atorvastatin calcium trihydrate. Atorvastatin calcium can have particle size of d(0.9) less than 50 u.m, preferably less than 40 u.m, more preferably less than 20 u.m. The composition of ezetimibe or its combination with atorvastatin calcium can be used to provide immediate release bilayer tablet.
According to one aspect, the present invention provides an industrially advantageous and improved pharmaceutical composition comprising ezetimibe, atorvastatin calcium and excipient(s).
In general terms, excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while formulation is developed. The formulations should have no physicochemical incompatibility between active ingredients and excipients.

In view of that, certain amounts of excipients are used for the ezetimibe composition, to overcome the problems of stability and solubility of ezetimibe alone or its combination with atorvastatin calcium for bilayer tablet.
The present invention, formulation overcomes the above significant development challenges and enables formulation that has simultaneously:
a) a better dissolution profile to individual active ingredients,
b) a stable formulation despite the incompatibilities of two component atorvastatin calcium and ezetimibe.
c) a better dissolution profile and shell-life of the final pharmaceutical product.
Generally, the pharmaceutical composition comprises two layers - atorvastatin layer and ezetimibe layer. The atorvastatin layer composition comprises:
a) 05 to 20% w/w atorvastatin calcium,
b) 40 to 60% w/w diluent,
c) 04 to 08% w/w disintegrant,
d) 01 to 04% w/w binder,
e) 0.2 to 0.8% w/w solubilizing agent,
f) 20 to 40% w/w a I ka I ize r,
g) 0.2 to 1.0% w/w lubricant,
h) 0.2 to 1.0%w/wglidant.
The ezetimibe layer composition comprises:
a) 03 to 10% w/w ezetimibe,
b) 60 to 95% w/w diluent,
c) 03 to 10% w/w disintegrant,
d) 03 to 06% w/w binder,

e) 1.1 to 2.2% w/w solubilizing agent,
f) 0.4 to 1.8% w/w lubricant.
Diluent can be selected from microcrystalline cellulose, lactose, lactose monohydrate, microfine cellulose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, spray dried lactose, sodium chloride, sorbitol, talc, lactilol, sucrose, maltose, fructose, xylitol, or mixtures thereof. Preferably, the diluent for atorvastatin layer can be lactose monohydrate, which is taken in 40% to 60%, more preferably 20% to 30%; and microcrystalline cellulose which can be taken 40% to 60%, more preferably 20% to 30%; diluent for ezetimibe layer can be lactose monohydrate, which is taken in 60% to 95%, more preferably 50% to 70%; and microcrystalline cellulose which can be taken 60% to 95%, more preferably 10% to 25%;
Disintegrant can be selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polyacrillin potassium, polyvinyl polypyrrolidone, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch (such as potato starch, corn starch), clays (such as xanthan gum or veegum), or mixtures thereof. Preferably, the disintegrant is croscarmellose sodium, which is taken in 3% to 10%, more preferably 4% to 8% for ezetimibe layer and 4% to 8%, more preferably 5% to 7% for atorvastatin layer.
Binder can be selected from acacia, alginic acid, carboxymethylcellulose sodium, copovidone, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil,

hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, sucrose, dextrose, lactose, maltodextrin, microcrystalline cellulose, methylcellulose, polyethylene glycol, calcium phosphate, sorbitol, xylitol, mannitol, water, or mixtures thereof. Preferably, the binder is povidone for ezetimibe layer which is taken in 3% to 6%, more preferably 4.5% and hydroxypropyl cellulose is for atorvastatin layer which is taken in 1% to 4%, more preferably 1.5 to 2.5%.
Solubilizing agent can be selected from sodium lauryl sulphate, polyoxyethylene glycol esters, sulphate, polysorbate, sorbitan fatty acid esters, polyethylene glycols, or mixtures thereof, preferably, the solubilizing agent is sodium lauryl sulphate for ezetimibe layer which is in 1.1% to 2.2%, more preferably 1.5% and polysorbate is for atorvastatin layer which is 0.2% to 0.8%, more preferably 0.4%.
Lubricant can be selected from magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, aluminium stearate, sodium stearyl fumarate, paraffins, leucine, sodium lauryl sulfate, magnesium lauryl sulfate, sodium chloride, sodium acetate, or mixtures thereof. Preferably, the lubricant is magnesium stearate which is in 0.4% to 1.8%, more preferably 0.5% to 1.5% for ezetimibe layer and 0.2% to 1.0%, more preferably 0.5% for atorvastatin layer.
Alkalizer can be selected from calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide, lithium hydroxide or mixtures thereof. Preferably, the alkalizer is calcium carbonate which is in 20% to 40%, more preferably 30% to 32% for atorvastatin layer.

Glidant can be selected from colloidal silicon dioxide, magnesium trisilicate, powder cellulose, starch, talk, tribasic calcium phosphate, calcium silicate or mixtures thereof. Preferably, the glidant is silicon dioxide colloidal and is taken in 0.2% to 1.0%, more preferably 0.5% for atorvastatin layer.
According to another aspect the present invention provides a process for the preparation of pharmaceutical composition. The method for preparing solid pharmaceutical composition such as tablet or bilayer tablet can be selected from the methods known in the art such as granulation method dry or wet; direct compression method etc. The wet granulation method is preferred over direct compression because it is observed that wet granulation overcomes the problems associated with the physical properties of the individual components in the formulation, such as a low solubility, poor flowing or sticking to the punches. Wet granulation provides a material that has the required flow and cohesive properties necessary to obtain an acceptable solid dosage form, i.e. tablet. Tablet uniformity is generally improved with wet granulation because all of the granules usually contain the same amount of drug. It also avoids separation of the drug from the excipients. In wet granulation, in one way, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water or an aqueous binder solution, which causes the powders to form granules. The resulting granules can be milled, dried and sifted through desired mesh size to obtain the desired particle size. The granules can then be mixed with other excipients and can be pressed to form tablets. In an alternate way, wet granulation technique the granules can be prepared by spraying water or an aqueous binder solution onto the powder blend in fluid bed processor (FBP). The granulate can be milled, dried and sifted through desired mesh size to obtain the desired particle size as above and can then be mixed with other excipients and pressed to form tablets.

The bilayer tablet composition of present invention is prepared by wet granulation spraying method. In one layer, atorvastatin calcium composition and in another layer ezetimibe composition followed by pressing of both the layers and coating of the tablet.
The atorvastatin layer can be prepared by adding a solubilizing agent to clear solution of a binder in purified water to obtain binder solution. The mixture of atorvastatin calcium, diluent, disintegrant and alkalizer can be granulated with binder solution. The resulting granules can be then wet milled through mill and dried in fluid bed drier. The resulting granules can be milled and further dried in fluid bed till loss on drying equals to or less than 2.0% w/w. The dried granules can be shifted through mesh #40. The resulting dried granules can be blended with glidant followed by lubricant.
The ezetimibe layer can be prepared by preparing a blend of diluent and disintegrant. The pre granulation blend was then transferred to the bowl of a fluid bed processor (FBP) followed by mixing for 5-10 minutes in FBP. A suitable binder, and a solubilizing agent can be dissolved in purified water and ezetimibe is added slowly to this binder solution to form dispersion for granulation. The solubilizing agent, binder and ezetimibe can be used in the ratio of 1:2:2.5 to 1:5:10. The drug binder dispersion can be then sprayed at a rate of l-10gm/minute on the resulting blend to obtain the desired granules. The resulting granules can be dried at a temperature of 60°C to 70°C till loss on drying is equal to or less than 3% w/w. The dried granules were then passed through mesh # 60 which was then mixed with a suitable diluent and blended in the bin blender for 10 minutes; followed by blending with a lubricant and blended in the bin blender for 3 minutes. The lubricated blend was compressed into tablets.

In a specific embodiment, the atorvastatin layer can be prepared by adding polysorbate 80 to clear solution of hydroxypropylcellulose in purified water to obtain binder solution. The mixture of atorvastatin calcium, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and calcium carbonate shifted through mesh #22 can be granulated with binder solution. The resulting granules can be then optionally wet milled through mill and dried in fluid bed drier. The resulting granules can be milled and further dried in fluid bed till loss on drying equals to or less than 3.0% w/w. The dried granules can be shifted through mesh #40. The resulting dried granules can be blended with mesh #40 passed silicon dioxide colloidal followed by mesh #60 passed magnesium stearate.
The ezetimibe layer can be prepared by preparing a blend of lactose monohydrate and croscarmellose sodium sifted through mesh # 60. The pre granulation blend was then transferred to the bowl of a fluid bed processor (FBP) followed by mixing for 5-10 minutes in FBP. Povidone K-30 and sodium lauryl sulphate were dissolved in purified water and ezetimibe is added slowly to this binder solution to form dispersion for granulation.
It is advantageous to add ezetimibe to a solution of povidone and solubilizing agent in water to get a uniform dispersion. In most of the prior art processes, ezetimibe, lactose, solubilizing agent such as sodium lauryl sulfate and croscarmellose sodium have been mixed in dry form. Since the amount of solubilizing agent such as sodium lauryl sulfate is too less that it may not mix uniformly if mixed in dry state. It is very convenient to spray the said uniform dispersion over blend in the next steps. The drug binder dispersion can be then sprayed at a rate of l-10gm/minute on the resulting blend to obtain the desired granules. The resulting granules can be dried at a temperature of 60°C to 70°C till loss on drying is equal to or less than 3% w/w. The dried granules were then passed through mesh # 60 which was then mixed with already sifted microcrystalline cellulose through mesh # 60 and blended in the bin

blender for 10 minutes; followed by blending with magnesium stearate and blended in the bin blender for 3 minutes. The lubricated blend was compressed into tablets.
Bilayer table can be then compressed using bilayer compression machine using atorvastatin layer and ezetimibe layer.
The pharmaceutical bilayer tablet composition can be coated to protect the composition against the moisture and light to maintain the stability. Suitable coating ingredients are selected from the group comprising hydroxypropylmethylcellulose, lactose monohydrate, macrogol 4000, macrogol 400, titanium dioxide, polyethylene glycol, talc, titanium dioxide, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), pigments, dyes, iron oxide or mixtures thereof, preferably hydroxypropylmethylcellulose, lactose monohydrate, macrogol 4000, macrogol 400, titanium dioxide, talc. The amount of the film coating is 1.0% to 2.0% by weight.
For bilayer tablet preparation of atorvastatin calcium and ezetimibe, one layer comprises free flowing granules of atorvastatin calcium and other layer comprises of free flowing granules of ezetimibe, wherein the weight ratio of ezetimibe layer to atorvastatin layer is between 0.5 and 5.0 w/w. The amount of atorvastatin calcium in tablet is 3.0% to 10.0% w/w and amount of ezetimibe in tablet is 0.8 to 4.0% w/w.
The hardness of bilayer tablet may range from 100 N to 400 N; preferably from 125 N to 300N, more preferably from 147N to about 260 N.
The resulting free flowing granules of atorvastatin calcium composition or ezetimibe composition can be used alone for individual tablet or capsule preparation or can be used with combination of each other for bilayer tablet composition.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples are provided

herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations that come within the scope of any claims and their equivalents. Examples:
Example 1- Bilayer tablet

Example 2: Bilayer tablet

Example 3: Bilayer tablet
Procedure for preparation of atorvastatin layer:
To a stirred solution of hydroxypropylcellulose in purified water, polysorbate 80 was 5 added slowly and stirred to obtain clear drug binder solution. Mixture of

atorvastatin calcium, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and calcium carbonate were sifted through mesh #22 and loaded in high shear mixture. The resulting mixture was then granulated with binder solution till granules are formed and wet milled through mill. Resulting granules were dried in fluid bed drier and milled. The resulting granules were dried in fluid bed drier till loss on drying equals to or less than 2.0% w/w. The resulting dried granules were shifted through 40# screen. Dried sized granules were then blended with 40# passed colloidal silicon dioxide colloidal in blender. The resulting blend was then blended with 60# passed magnesium stearate to obtain atorvastatin layer.
Procedure for preparation of ezetimibe layer:
To a stirred solution of povidone in purified water, solution of sodium lauryl sulphate in purified water was added slowly and stirred for 10 minutes. To the resulting solution ezetimibe was added slowly and stirred for 30 minutes to obtain drug binder solution. Mixture of lactose monohydrate and croscarmellose sodium passed through mesh #60 was then loaded to fluid bed processor and dried to obtain a blend. On the resulting blend, drug binder dispersion was sprayed to get desired granules. The resulting granules were dried at temperature 105°C till loss on drying is equal to or less than 3.0% w/w and sifted through mesh #60. The dried granules were then mixed with microcrystalline cellulose already passed mesh #60 in blender. The magnesium stearate [passed mesh #60] was then blended with the resulting blend as above to obtain the ezetimibe layer. Atorvastatin calcium in one layer and ezetimibe as other layer were then compressed in bilayer compression machine. The resulting bilayer tablet is then coated using a dispersion of Opadry White [hypromellose, lactose monohydrate, macrogol 4000, titanium dioxide (E171) and macrogol 400 talc] in water.

The resulting bilayer tablets are tested for their dissolution profile against Atozet by
using Dissolution apparatus at 75 rotations per minute [RPM]. As per USFDA, Office
of Generic Drugs dissolution method recommendations, the finalized conditions for
the dissolution of Ezetimibe and Atorvastatin film coated tablets were set as follows:
Apparatus: II (Ph. Eur. /USP Paddles)
Speed: 75 rpm
Dissolution medium: pH 6.8 Phosphate buffer with 0.2% w/v Tween
80
Volume of dissolution medium: 900 mL
Comparative details of Dissolution Profile with ATOZET
Dissolution medium: pH 6.8 Phosphate buffer with 0.2% w/v Tween 80
Dissolution media: 900 ml
Dissolution apparatus: 75 RPM
TABLE-1

TABLE-2
TABLE-3

Example-4: Preparation of ezetimibe tablet
Procedure:
To a stirred solution of povidone in purified water, solution of sodium lauryl sulphate in purified water was added slowly and stirred for 10 minutes. To the resulting solution ezetimibe was added slowly and stirred for 30 minutes to obtain drug binder solution. Mixture of lactose monohydrate and croscarmellose sodium passed through mesh #60 was then loaded to fluid bed processor and dried to obtain the blend. On the resulting blend, drug binder dispersion was sprayed to get desired granules. The resulting granules were dried at temperature 105°C till loss on drying is equal to or less than 3.0% w/w and sifted through mesh #60. The dried granules were then mixed with microcrystalline cellulose already passed mesh #60 in blender. The magnesium stearate [passed mesh #60] was then blended with the resulting blend and the final blend was then compressed in compression machine into a tablet.

WE CLAIM:
1. A pharmaceutical bilayer tablet composition comprising:
(i) atorvastatin layer:
a) 05 to 20% w/w atorvastatin calcium,
b) 40 to 60% w/w diluent,
c) 04 to 08% w/w disintegrant,
d) 01 to 04% w/w binder,
e) 0.2 to 0.8% w/w solubilizing agent,
f) 20 to 40% w/w a I ka I ize r,
g) 0.2 to 1.0% w/w lubricant,
h) 0.2 to 1.0%w/wglidant.
(ii) ezetimibe layer:
a) 03 to 10% w/w ezetimibe,
b) 60 to 95% w/w diluent,
c) 03 to 10% w/w disintegrant,
d) 03 to 06% w/w binder,
e) 1.1 to 2.2% w/w solubilizing agent,
f) 0.4 to 1.8% w/w lubricant.
wherein the ezetimibe layer is obtained by a wet granulation process^
wherein ezetimibe is dispersed in binder solution comprising a binder and solubilizing agent.
2. The pharmaceutical bilayer tablet composition as claimed in claim 1, wherein the weight ratio of ezetimibe layer to atorvastatin layer is between 0.5 to 5.0; the ratio of solubilizing agent, binder and ezetimibe is 1:2:2.5 to 1:5:10.
3. The pharmaceutical bilayer tablet composition as claimed in claim 1, wherein diluent is selected from lactose monohydrate, microcrystalline cellulose or

mixture thereof; disintegrant is croscarmellose sodium; binder is selected from hydroxypropyl cellulose, povidone.
4. The pharmaceutical bilayer tablet composition as claimed in claim 1, wherein solubilizing agent is selected from polysorbate and sodium lauryl sulphate; lubricant is magnesium stearate; alkalizer is calcium carbonate; glidant is silicon dioxide colloidal.
5. A process for the preparation of pharmaceutical bilayer tablet composition, comprising the following steps:
(i) atorvastatin layer:
a) mixing binder in purified water;
b) mixing solubilizing agent with solution step a);
c) granulating the mixture of atorvastatin calcium, diluent, disintegrant and alkalizer with solution of step b);
d) optionally wet milling the granules of step c);
e) drying the granules of step d);
f) milling the dried granules ;
g) sieving the dried granules;
h) blending granules with glidant and lubricant; (ii) ezetimibe layer:
a) mixing binder in purified water to obtain solution;
b) adding solution of solubilizing agent in purified water in step a);
c) adding ezetimibe to solution of step b) to obtain dispersion;
d) preparing dry mix blend of diluent and disintegrant and passing the obtained dry mix blend through a sieve;
e) spraying the dispersion of step c) on the blend of step d) to obtain granules;
f) drying the granules ;
g) sieving the dried granules; and

h) mixing the dried granules obtained in step g) with diluent and with lubricant; (iii) pressing the blend from steps h) subsequently to form bilayer tablet and (iv) optionally coating the bilayer tablet with a film coat.
6. The process for the preparation of pharmaceutical bilayer tablet composition as claimed in claim 5, wherein binder is selected from hydroxypropyl cellulose, povidone.
7. The process for the preparation of pharmaceutical bilayer tablet composition as claimed in claim 5, wherein solubilizing agent is selected from polysorbate and sodium lauryl sulphate.
8. The process for the preparation of pharmaceutical bilayer tablet composition as claimed in claim 5, wherein diluent is selected from lactose monohydrate, microcrystalline cellulose or mixture thereof; distingrant is croscarmellose sodium.
9. The process for the preparation of pharmaceutical bilayer tablet composition as claimed in claim 5, wherein lubricant is magnesium stearate.
10. The process for the preparation of pharmaceutical bilayer tablet composition as claimed in claim 5, wherein alkalizer is calcium carbonate; glidant is silicon dioxide colloidal.