DESC:Present invention provides a pharmaceutical composition comprising Bempedoic acid or its pharmaceutically acceptable salt, Rosuvastatin or its pharmaceutically acceptable salt, ezetimibe or its pharmaceutically acceptable salt and optionally one or more pharmaceutically acceptable excipient.

The present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the oral pharmaceutical composition is a bilayer tablet composition.

The present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof and one or more pharmaceutically acceptable excipients, which is suitable in the treatment or prevention of cardiovascular disease or reducing the risk of cardiovascular disease.

Present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is a fixed dose combination.

Present invention provides a pharmaceutical composition, wherein the composition is in the form of a tablet.

Present invention relates to a solid oral pharmaceutical composition comprising the pharmaceutically acceptable excipients is selected from diluents, binders, disintegrant, surfactants, lubricants, glidants and coloring agents and the like or mixture thereof and optionally a pharmaceutical acceptable excipient.

Pharmaceutical composition of present invention is a monolayer tablet, bilayer tablet or trilayer tablet.

The present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and a third agent selected from the group of statins refer to Atorvastatin, Rosuvastatin, Fluvastatin, Pravastatin, Simvastatin.

The term “Bempedoic acid”, “ezetimibe”, “Rosuvastatin” used herein refers to a pharmaceutically active molecule as well as its pharmaceutically acceptable salts, esters, amides, prodrugs, metabolites, enantiomers, polymorphs, analogues, etc. that induce a desired pharmacological or physiological effect. The term also includes all polymorphic forms, whether crystalline or amorphous.

Statins include, but are not limited to, Rosuvastatin, Atorvastatin, simvastatin, pravastatin, lovastatin, Fluvastatin and Pitavastatin. The dosage of Rosuvastatin (5 mg - 40 mg), atorvastatin (10 mg - 80 mg), simvastatin (5 mg - 80 mg), pravastatin (10 mg - 80 mg), lovastatin (20 mg40 mg), Fluvastatin (20 mg -80 mg), Pitavastatin (1 mg - 4 mg), may be used in any embodiment or aspect disclosed herein.

The pharmaceutical composition comprises Bempedoic acid or its pharmaceutical acceptable salt in an amount from about 1 mg to about 1000 mg, preferably from about 50 mg to about 500 mg. According to one embodiment, Bempedoic acid is present in amount of about 120 mg. According to another embodiment, Bempedoic acid is present in amount of about 180 mg.

The pharmaceutical composition comprises Rosuvastatin or its pharmaceutical acceptable salt
in an amount from about 1 mg to about 100 mg. According to one embodiment Rosuvastatin is
present in amount of about 60 mg. According to one embodiment Rosuvastatin is present in
amount of about 40 mg.

The pharmaceutical composition comprises ezetimibe or its pharmaceutical acceptable salt in an amount from about 1 mg to about 100 mg. According to one embodiment ezetimibe is present in amount of about 10 mg.

Another objective of the present invention relates to pharmaceutical composition of Bempedoic acid, Ezetimibe and Rosuvastatin where there is no drug-drug interaction between Bempedoic acid, Rosuvastatin and Ezetimibe, Rosuvastatin.
The pharmaceutical composition contains Bempedoic acid, ezetimibe and Rosuvastatin having particle size of D90 less than 200µ (microns).

The pharmaceutical composition of the present invention is a fixed dose combination.

Alternatively, the combinations of the present invention can be manufactured or administered as separate pharmaceutical compositions of the respective pharmaceutically active agent, which can be administered simultaneously, sequentially or separated with time.

The pharmaceutical compositions of present invention can be prepared using wet granulation (aqueous or non-aqueous), dry granulation/roller compaction/slugging, direct compression or any other conventional technique used in manufacturing pharmaceutical dosage forms.

The pharmaceutical compositions can be in the form of matrix or reservoir and/or combinations thereof.

The pharmaceutically acceptable excipient is selected from the group comprising diluents/fillers, binders, disintegrants, glidants, lubricants, stabilizers, antioxidants, solubilizers/surfactants/wetting agents, plasticizers, solvents and/or combinations thereof.
Suitable diluents/fillers include, but are not limited to starch, pregelatinized starch, powdered celluloses, polysaccharides, dibasic calcium phosphate anhydrous or dihydrate/ calcium hydrogen phosphate, magnesium stearate, calcium phosphate, tricalcium phosphate anhydrous, calcium carbonate, calcium citrate, tricalcium citrate, magnesium carbonate, lactose monohydrate, lactose anhydrous, microcrystalline cellulose, mannitol, dextrose, dextrin, maltodextrin, sucrose, sorbitol, xylitol, lactitol. inositol, Di basic Calcium Phosphate, Lactose monohydrate, dextrates, lactitol, maltodextrin, trehalose, and/or combinations thereof. Further, the amount of diluent is preferably in the range of 10% w/w to 90% w/w by weight of the composition.
Suitable binders include, but are not limited to acacia, alginic acid, agar, calcium carrageenan, dextrin, gelatin, liquid glucose, gum, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, pectin, polyethylene glycol, povidone, Polysorbate 80, starch, pregelatinized starch and/or combinations thereof. Further, the amount of binder is preferably in the range of 0.5% w/w to 50% w/w by weight of the composition.

Suitable disintegrants include, but are not limited to sodium starch glycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, calcium and sodium carboxymethylcellulose, pregelatinized starch, magnesium trisilicate, crospovidone, cornstarch, potato starch and/or combinations thereof. Further, the amount of disintegrant is preferably in the range of 1% w/w to 25% w/w by weight of the composition.

Suitable lubricants/glidants may comprise but not limited to magnesium stearate, colloidal silicon dioxide, aluminum silicate, sodium stearyl fumarate, colloidal silicon dioxide, stearic acid, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, starch, sodium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, fatty acid, fumaric acid, glyseryl palmito sulphate and/or combinations thereof. Further, the amount of lubricant is preferably in the range of 0.01% w/w to 20% w/w by weight of the composition.

Suitable solubilizers/surfactants include but are not limited to poloxamer, polysorbate, povidone, cremophore, soluplus, lecithin, sodium lauryl sulfate, polyethylene glycol and/or
combinations thereof.

Suitable solvents include but are not limited to purified water, methanol, ethanol, isopropyl
alcohol, methylene chloride/ dichloromethane, chloroform, ethyl acetate, acetone and/or
mixtures thereof.

Suitable plasticizers include but are not limited to, dibutyl sebacate; vegetable oil, e.g., castor
oil or glycerol/glycerin; or a glyceryl ester of a fatty acid, e.g., glyceryl triacetate or glyceryl
monoricinoleate, polyethylene glycol, triethyl citrate, acetyl tributyl citrate, talc and/or mixtures thereof.

Suitable stabilizers include but are not limited to organic carboxylic acid selected from the group comprising tartaric acid, fumaric acid, maleic acid and citric acid; phosphate salt such as dibasic phosphate; hydroxides (such as sodium, potassium, calcium or aluminium hydroxides); calcium salts of organic and inorganic acids (such as calcium acetate, calcium lactate, calcium succinate, calcium fumarate, calcium carbonate) and their magnesium or aluminium equivalents.

Suitable antioxidants include but are not limited to ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, propyl gallate and alpha-tocopherol.

The pharmaceutical compositions of the present invention are meant for oral administration.

The compositions can be in the form of tablets, capsules, tablets filled in capsule, mini tablets
filled in capsule, sachets containing powder or granules, pellets, and the like.

The pharmaceutical compositions of present invention can be a monolayer tablet, bilayer tablet
or trilayer tablet.

The composition can be administered alone or in combination either with one or more other lipid lowering drugs, simultaneously or sequentially or in fixed dose combination. The other lipid lowering drugs, include, but are not limited Statin such as Rosuvastatin, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Simvastatin; Selective cholesterol absorption inhibitors such as Ezetimibe; fibric acid derivatives such as fenofibrate, gemfibrozil, clofibrate, bezafibrat, ciprofibrate; bile acid sequestrants such as cholestyramine, colestipol, colesevelam; nicotinic acid; PCKS9 inhibitor such as evolocumab, alirocumab; omega 3 fatty acids and/or combinations thereof.
The present invention also provides kits which include one or more compositions described
herein, in suitable packaging, and can further comprise written material that can include instructions for use and other related literature.

The pharmaceutical composition of the present invention is meant for once daily or twice daily administration.

The pharmaceutical compositions of the present invention may be film coated with various film coating materials known in the art e.g. commercially available Opadry®. The coating may contain film-forming agents, pigments/opacifier such as iron oxide, titanium dioxide, zinc oxide, a plasticizer and one or more other pharmaceutically acceptable excipient.

Examples of film-forming agents include polyvinyl alcohol, ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit®. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used.

According to one embodiment, the pharmaceutical compositions of the present invention can be in the form of modified release dosage form which include, but not limited to, controlled release, sustained release, extended release, prolonged release dosage form. Various rate controlling agents/techniques known in the art may be used to control the release of the drug from the dosage form.

Suitable release controlling agents, include but are not limited to, cellulose derivatives such as
hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, alginate,
poly(alkylcyanoacrylate), polyethylene, poly(ethylene-co-vinylacetate), poly(hydroxyethyl
methacrylate), poly(hydroxypropylethyl methacrylate), poly(methyl methacrylate), polyurethane, poly(vinyl alcohol), polyvinyl acetate, poly(acrylic acid), polyvinylpyrrolidone,
poly (ethylene oxide), poloxamer, polymethacrylates, gums, waxes, collagen, silicon and/or
combinations thereof.

The pharmaceutical compositions are useful for treating cardiovascular diseases which refer to diseases of the heart and circulatory system. These diseases are often associated with dyslipoproteinemias and/or dyslipidemias. Cardiovascular diseases which the compositions of the present invention are useful for preventing or treating include but are not limited to arteriosclerosis; atherosclerosis; stroke; ischemia; endothelium dysfunctions, in particular those dysfunctions affecting blood vessel elasticity; peripheral vascular disease; coronary heart disease; myocardial infarction; cerebral infarction and restenosis.

In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof and one or more pharmaceutically acceptable excipients.

In one of the embodiments of the present invention relates to the process for the preparation of oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof and one or more pharmaceutically acceptable excipients.

In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the oral pharmaceutical composition is a bilayer tablet composition.

In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin where in the pharmaceutical compositions is a tablet, capsule, powder, solution or suspension.
In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof and one or more pharmaceutically acceptable excipients, which is suitable in the treatment or prevention of cardiovascular disease or reducing the risk of cardiovascular disease.

In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin where in the pharmaceutical compositions is a tablet where all the active ingredients are in single layer (Monolithic tablet) Bilayer tablet or multiple layered tablet.

In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin where in the pharmaceutical composition having two components tablet or capsule and final composition can be tablet in tablet, capsule in capsule, tablet in capsule, minitablet filled in capsule,

In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin where in the pharmaceutical composition where all the active ingredients are present in single form or multiple form.

In one of the embodiments of the present invention relates to a solid oral pharmaceutical composition comprising the pharmaceutically acceptable excipients is selected from diluents, binders, disintegrant, surfactants, lubricants, glidants and coloring agents and the like or mixture thereof and optionally a pharmaceutical acceptable excipient.

In one of the embodiments of the present invention provides a pharmaceutical composition, wherein the ratio between Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof is 18:1:4.
In one of the embodiments of the present invention provides a pharmaceutical composition, wherein Bempedoic acid is present in an amount of about 180 mg; Ezetimibe is present in an amount of about 10 mg and Rosuvastatin is present in an amount of about 40 mg or its pharmaceutical acceptable salts thereof.

In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin with one or more pharmaceutically acceptable excipients, where in the Bempedoic acid and Ezetimibe is present in the one layer (mono layer), Rosuvastatin is present in the another layer (Bilayer Compression).

In one of the embodiments of the present invention relates to the oral pharmaceutical compositions comprising Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof and one or more pharmaceutically acceptable excipients, where in the Bempedoic acid, Ezetimibe layer is prepared by wet granulation process and Rosuvastatin layer is prepared by direct compression process.

In one of the embodiments of the present invention relates to pharmaceutical composition of Bempedoic acid, Ezetimibe and Rosuvastatin where there is no drug-drug interaction between Bempedoic acid, Rosuvastatin and Ezetimibe, Rosuvastatin.

In one of the embodiments of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is a fixed dose combination.

In one of the embodiments of the present invention provides a pharmaceutical composition, wherein the composition is in the form of a tablet.

In one of the embodiments of the present invention the pharmaceutical composition is a monolayer tablet, bilayer tablet or trilayer tablet.

In one of the embodiments of the present invention Bempedoic acid, Rosuvastatin and ezetimibe or their pharmaceutically acceptable salt is present in crystalline form or amorphous form.

Another objective of the present invention is useful for treating cardiovascular diseases.

Examples
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example-1:
Manufacturing Formula:
Bempedoic Acid + Ezetimibe Monolayer portion 180mg/10mg – Wet Granulation (Layer 1)
S.No. Ingredients mg/Tablet % w/w
Granulation -I (Ezetimibe Tablets - 10 mg)
Intra granular Portion
1. Lactose monohydrate 50.00 13.33
2. Microcrystalline cellulose 101 11.00 2.93
3. Sodium Starch Glycolate 6.00 1.6
Binder Solution
4. Ezetimibe 10.00 2.67
5. Povidone K 30 1.00 0.27
6. Sodium lauryl sulfate 2.00 0.53
7. Purified water q.s --
Total weight of granules 80.00
Granulation -II (Bempedoic acid Tablets - 180 mg)
Intra granular Portion
8. Bempedoic acid 180.00 48.00
9. Microcrystalline cellulose 101 9.50 7.34
10. Colloidal silicon dioxide 3.50 0.16
Binder Solution
11. Hydroxy propyl cellulose 12.00 2.90
12. Purified water q.s --
Total weight of granules 205.00 --
Total weight of G1+G2 285.00 --
Extra granular portion
13. Microcrystalline cellulose 102 39.50 8.39
14. Lactose Mono Hydrate 25.00
15. Sodium Starch Glycolate 21.00 1.93
16. Colloidal silicon dioxide 0.50 0.32
17. Magnesium stearate 4.62 1.23
Uncoated tablet weight 375.00 100.00
Rosuvastatin Calcium portion – Direct Compression Process (Layer 2)
S. No Ingredients 180/10mg/40 mg
Pre-lubrication
1. Rosuvastatin Calcium 41.66
2. Microcrystalline Cellulose PH 102 (Pharmacel 102) 100.00
3. Lactose monohydrate Ph. Eur (Flowlac 100) 200.84
4. Di basic Calcium Phosphate Anhydrous Ph. Eur(Direct Compressible Grade) 30.00
5. Crospovidone Ph. Eur (Polyplasdone XL-10) 25.00
Lubrication
6. Magnesium Stearate Ph. Eur (Ligamed MF 2V) 2.50
Core Tablet weight (mg) 400.00
Bilayer Compression
7. Compressed Tablets of Layer 1 of Bempedoic acid + Ezetimibe Portion 375.00
8. Blend for Layer 2 of Rosuvastatin Calcium portion 400.00
Total Bilayer Core Tablet weight(mg) 775.00
Film Coating (3.0% w/w Build up, 15.0% w/w Solid content)
9. Opadry II 85F520340 Pink 23.25
10. Purified water -
Total Bilayer Coated Tablet weight (mg) 798.25

Manufacturing Process (Layer 1)
Granulation-I:
Sifting:
I. Co-sift Microcrystalline cellulose 101, lactose monohydrate and Sodium starch glycolate through 30 # mesh.
II. Load the step I into Rapid mixer granulator and dry mix for 15 minutes.
Binder preparation:
III. Add required quantiry of Purified water, to this add weighed quantity of povidone K30,Ezetimibe and Sodium lauryl sulphate under stirring and continue stirring upto clear solution was formed.
Granulation:
IV. Granulate the step II with step III to attain desired granules and dried the wet granules to attain desired % LOD @ 105°C 1.0 – 3.0 %w/w and mill with 1.50 mm screen until all the dried granules passes through 30# mesh.
Granulation II
Intragranular agents:
V. Co-sift Bemoedoic acid, microcrystalline cellulose 101, lactose monohydrate, sodium starch glycolate and Colloidal silicon dioxide through 30# mesh.
VI. Load the step v into Rapid mixer granulator and dry mix for 15 minutes.
Binder preparation:
VII. Add required quantiry of Purified water, to this add weighed quantity of Hydroxypropyl cellulose under stirring and continue stirring upto clear solution was formed.
VIII. Granulate the step VI with step VII to attain desired granules and dried the wet granules to attain desired % LOD @ 105°C 1.0 – 3.0 %w/w and mill with 1.50 mm screen until all the dried granules passes through 30# mesh.
Extra-granular sifting:
IX. Co-sift microcrystalline cellulose 102, sodium starch glycolate and Colloidal silicon dioxide through #30 mesh.
X. Sift Magnesium stearate through 60# mesh.
Blending:
XI. Blend the step IV (Granulation-I) and step VIII (Granulation-II) in a suitable blender for about 5 minutes and to this add step IX and blend for 15 minutes.
Lubrication:
XII. Blend the step XI materials with step X for 5 minutes.

Manufacturing Process of Rosuvastatin Calcium (Layer II)
Sifting
1. Co-sift Rosuvastatin Calcium and Pregelatinised starch (Starch 1500) through 425 µm (ASTM mesh no #40).
2. Co-sift step STEP 1 with 50% of Microcrystalline cellulose PH 101 through 425 µm (ASTM mesh no #40
3. Co-sift blend of step 2 with remaining 50% of Microcrystalline cellulose PH 101 and colloidal silicon dioxide through 425 µm (ASTM mesh no #40).
4. Sift Magnesium stearate through 250 µm sieve (ASTM mesh no #60).
Blending
5. Load the sifted materials of step 3 in a low shear blender and blend for 20 minutes.
6. Add sifted Magnesium stearate of step 4 to step 5 and blend for 5 minutes.
7. Unload the lubricated blend of step in a double-layered poly bags and stored in HDPE containers.
Bi Layer Compression (Layer I & Layer II)
8. Compress into Bilayer Tablet with Layer I & Layer II with suitable punches.
Film Coating
9. Prepare the coating dispersion by dispersing Opadry II Pink in purified water under stirring and coat the compressed tablets of step with the coating dispersion.

Example- II:
Manufacturing Formula:
Bempedoic Acid and Ezetimibe Portion 180mg – Wet Granulation (Layer 1)
S.No Ingredients mg/tab % w/w
Intra granular
1. Bempedoic acid1 180.00 55.38
2. Microcrystalline cellulose 1022 13.75 11.20
3. Lactose Monohydrate 53.75 14.33
4. Sodium Starch Glycolate 25.34 6.76
5. Hydroxy Propyl Cellulose 7.50 2.00
Binder Solution
6. Ezetimibe 10.00 2.67
7. Povidone K 30 1.00 0.27
8. Sodium Lauryl Sulphate 2.00 0.53
9. Purified water q.s. -
Extra granular
10. Microcrystalline Cellulose 200 37.00 9.87
11. Sodium Starch Glycolate 37.50 10.00
12. Stearic Acid 50 6.60 1.78
375.00 100.00

Rosuvastatin Calcium portion – Direct Compression Process (Layer 2)
S. No Ingredients mg/unit %w/w
Pre-lubrication
1. Rosuvastatin Calcium 41.66 10.41
2. Microcrystalline Cellulose PH 102 (Pharmacel 102) 100.00 25.00
3. Lactose monohydrate Ph. Eur
(Flowlac 100) 200.84 50.21
4. Di basic Calcium Phosphate Anhydrous Ph. Eur(Direct Compressible Grade) 30.00 7.500
5. Crospovidone Ph. Eur (Polyplasdone XL-10) 25.00 6.25
Lubrication
6. Magnesium Stearate Ph. Eur (Ligamed MF 2V) 2.50 0.62
Core Tablet weight (mg) 400.00 100.00
Bilayer Compression
7. Compressed Tablets of Layer 1 of Bempedoic acid + Ezetimibe Portion 375.00 48.39
8. Blend for Layer 2 of Rosuvastatin Calcium portion 400.00 51.61
Total Bilayer Core Tablet weight(mg) 775.00 --
Film Coating (3.0% w/w Build up, 15.0% w/w Solid content)
9. Opadry II 85F520340 Pink 23.25 3.00
10. Purified water - --
Total Bilayer Coated Tablet weight (mg) 798.25 --

Manufacturing Process (Layer 1)
Sifting
i. Co-sift Bempedoic acid, Microcrystalline cellulose 101, Hydroxy propyl cellulose, Lactose monohydrate and Sodium starch glycolate type A through sieve # 40 ASTM (425 µm).
Dry mixing and Granulation
ii. Load the sifted materials of step-i in Rapid Mixer Granulator and mix for 10 minutes using impeller at slow speed and chopper off.
API Dispersion
iii. Dissolve Povidone K 30 in purified water (50 % w/w of dry mix weight) under stirring and stir until obtain a clear solution.
iv. Add Sodium Lauryl Sulphate in to the above binder solution of step iii under continuous stirring and stir until obtain a clear solution and allow it to settle for 10 minutes to clear the foam formation.
v. Keep the solution of step iv under homogenization and add ezetimibe slowly into the solution, Keep the solution under homogenization for 30 minutes.
vi. Add extra quantity of purified water (10% of dry mix weight) for rinsing purpose and if required, Add additional quantity of purified water (up to 10% of dry mix weight).
vii. Granulate step-ii dry mix by using step-v API Dispersion by the following granulation parameters
Wet Milling
viii. Unload the wet mass from RMG and mill through co-mill fitted with 8.0 mm screen at slow speed. Drying
ix. Dry the granules in FBD until the LOD of the granules reaches 1.0 - 3.0 % w/w at 60°C with following parameters.
Sizing and Milling
x. Sift the step-v dried granules through sieve #30 ASTM (600 µm).
xi. Mill the retentions of step-vi by using co-mill fitted with 1.5 mm screen at slow to medium speed and sift through sieve #30 ASTM (600 µm).
xii. Mill the retentions of step-vii by using co-mill fitted with 1.0 mm screen at medium to fast speed and sift through sieve #30 ASTM (600 µm). Continue this to mill the granules with 1.0 mm screen until all the material passes through sieve #30 ASTM (600 µm).
Sifting of extra-granular material
xiii. Co-sift Microcrystalline cellulose 200 and Sodium starch glycolate type A through sieve #30 ASTM (600 µm).
xiv. Sift Stearic acid through sieve #60 ASTM (250 µm).
Blending and Lubrication
xv. Load the granules of step-xiii and step-xiii materials in blender and mix for 15 minutes.
xvi. Add pre sifted Stearic acid of step-xiv to above material after step xv and mix for 5 minutes.
Manufacturing Process of Rosuvastatin Calcium (Layer II)
Sifting
1. Co-sift Rosuvastatin Calcium and Pregelatinised starch (Starch 1500) through 425 µm (ASTM mesh no #40).
2. Co-sift step STEP 1 with 50% of Microcrystalline cellulose PH 101 through 425 µm (ASTM mesh no #40
3. Co-sift blend of step 2 with remaining 50% of Microcrystalline cellulose PH 101 and colloidal silicon dioxide through 425 µm (ASTM mesh no #40).
4. Sift Magnesium stearate through 250 µm sieve (ASTM mesh no #60).
Blending
5. Load the sifted materials of step 3 in a low shear blender and blend for 20 minutes.
6. Add sifted Magnesium stearate of step 4 to step 5 and blend for 5 minutes.
7. Unload the lubricated blend of step in a double-layered poly bags and stored in HDPE containers.
Bi-Layer Compression (Layer I & Layer II)
8. Compress into Bilayer Tablet with Layer I & Layer II with suitable punches.
,CLAIMS:1) A bilayer pharmaceutical composition comprising Bempedoic acid, Ezetimibe and Rosuvastatin or its pharmaceutical acceptable salts thereof and one or more pharmaceutically acceptable excipients.

2) The bilayer pharmaceutical composition as claimed in claim 1, wherein the Bempedoic acid and Ezetimibe is present in the one layer, Rosuvastatin is present in the another layer.

3) The bilayer pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excepients selected from diluents, binders, disintegrant, surfactants, lubricants, glidants and coloring agents.

4) The bilayer pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excepients selected from lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone, sodium lauryl sulfate, colloidal silicon dioxide, hydroxy propyl cellulose, lactose mono hydrate, magnesium stearate, croscarmellose sodium, di basic calcium phosphate anhydrous.

5) The bilayed pharmaceutical composition as claimed in claim 1, wherein the process of preparation involes:
Bempedoic acid and Ezetimibe layer:
• Blending Bempedoic acid along with intragranular excepients,
• Binding solution was prepared by dispersion Ezetimibe in granulation fluid along with binder and surfactant,
• Granulation of Bempedoic acid blend with above granulation fluid and obtained granules are dried and lubricated alone with extra granular excepients.

Rosuvastatin layer: (Direct compression)
• Pre-lubriction of Rosuvastatin along with excepients, lubricate with magnesium Stearate.
• Compressed tablets of Bempedoic acid; Ezetimibe portion and blend of Rosuvastatin calcium portion in to bilayer tablet.

6) The bilayer pharmaceutical composition as claimed in claim 1, wherein Bepedoic acid granules, Ezetimibe granules are prepared seperately.

7) The bilayer pharmaceutical composition as claimed in claim 1, wherein the composition is used for the treatment or prevention of cardiovascular disease or reducing the risk of cardiovascular disease.