DESC:FIELD OF THE INVENTION

The present invention provides pharmaceutical composition comprising bempedoic acid and one or more lipid lowering drug. The present invention further provides method of preparing such composition and its use for treating or reducing the risk of cardiovascular diseases.

BACKGROUND OF THE INVENTION

Bempedoic acid is described chemically as: 8-hydroxy-2,2,14,14 tetramethyl-pentadecanedioic acid.

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor. Bempedoic acid is currently being marketed in United States under the brand name NEXLETOL® as 180 mg tablet. Bempedoic acid and Ezetimibe combination product is currently being marketed in United States under the brand name NEXLIZET® as 180/10 mg tablets. These are indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.

U.S. Patent No. 7,335,799 B2 discloses bempedoic acid or a salt, hydrate or solvate thereof.

U.S. Patent No. 8,497,301 B2 relates to a method of lowering LDL (Low density lipoprotein) levels by administering bempedoic acid or salt thereof.

U.S. Patent No. 9,000,041 B2 relates to a method for treating a cardiovascular disease, dyslipidemia by administering bempedoic acid.

U.S. Patent No. 9,624,152 B2 covers a method of inhibiting sterol synthesis in a patient, comprising administering to a patient bempedoic acid.

U.S. Patent No. 10,118,881 B2 relates to a method for treating hypercholesterolemia by administering bempedoic acid.

Statins inhibit the enzyme hydroxymethylglutaryl (HMG)-CoA reductase and are widely used as lipid lowering drugs. Synthesis routes for statins is known from WO2005047276A2.

Ezetimibe is also known as lipid lowering drug. It works by preventing the absorption of cholesterol in the intestine. Its process of synthesis is disclosed in U.S. Patent No. 5,631,365.

US 20180064671 A1 relates to a fixed dose combination of bempedoic acid and ezetimibe for treating hypercholesterolemia.

US 20180078518 A1 relates to a fixed-dose combination of bempedoic acid and atorvastatin for treating cardiovascular diseases.

For patients with higher cardiovascular risk, aggressive treatment options are recommended. Therefore, there exists a need in the art to develop a new combination of bempedoic acid along with other lipid lowering drugs which is both effective and as well as safe. The advantages of such combinations include, increased reduction of cholesterol and LDL levels as compared to the levels observed when patients are treated with these drugs alone.

SUMMARY OF THE INVENTION

According to one aspect, the present invention provides a pharmaceutical composition comprising bempedoic acid or its pharmaceutically acceptable salt, one or more lipid lowering drug and optionally one or more pharmaceutically acceptable excipient.

According to another aspect, the present invention provides a pharmaceutical composition comprising bempedoic acid or its pharmaceutically acceptable salt, a statin or its pharmaceutically acceptable salt and optionally one or more pharmaceutically acceptable excipient.
According to one embodiment, the present invention provides a pharmaceutical composition comprising bempedoic acid or its pharmaceutically acceptable salt, rosuvastatin or its pharmaceutically acceptable salt and optionally one or more pharmaceutically acceptable excipient.

According to another embodiment, the present invention provides a pharmaceutical composition, wherein bempedoic acid is present in an amount of about 180 mg; and rosuvastatin is present in an amount of about 10 mg.

According to another embodiment, the present invention provides a pharmaceutical composition, wherein bempedoic acid is present in an amount of about 180 mg; and rosuvastatin is present in an amount of about 20 mg.

According to another aspect, the present invention provides a pharmaceutical composition comprising bempedoic acid or its pharmaceutically acceptable salt, a statin or its pharmaceutically acceptable salt, ezetimibe or its pharmaceutically acceptable salt and optionally one or more pharmaceutically acceptable excipient.

According to one embodiment, the 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.

According to another embodiment, the present invention provides a pharmaceutical composition, wherein bempedoic acid is present in an amount of about 180 mg; rosuvastatin is present in an amount of about 10 mg; and ezetimibe is present in an amount of about 10 mg.

According to another embodiment, the present invention provides a pharmaceutical composition, wherein bempedoic acid is present in an amount of about 180 mg; rosuvastatin is present in an amount of about 20 mg; and ezetimibe is present in an amount of about 10 mg.

According to another embodiment, the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is a fixed dose combination.

According to another embodiment, the present invention provides a pharmaceutical composition, wherein the composition is in the form of a tablet.

According to another embodiment, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipient selected from the group comprising diluents/fillers, binders, disintegrants, glidants, lubricants, solubilizers/surfactants/wetting agents, plasticizers, solvents and/or combinations thereof.

According to one embodiment, the pharmaceutical composition of present invention is a monolayer tablet, bilayer tablet or trilayer tablet.

According to one embodiment, bempedoic acid, rosuvastatin or ezetimibe or their pharmaceutically acceptable salt is present in crystalline form or amorphous form.

According to another embodiment, the present invention is useful for treating cardiovascular diseases.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition comprising bempedoic acid or its pharmaceutically acceptable salt and one or more lipid-lowering drug for treating cardiovascular diseases.

The term “bempedoic acid”, “ezetimibe” or “statin” 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 mg- 40 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 20 mg. According to one embodiment rosuvastatin is present in amount of about 10 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.

The pharmaceutical composition contains bempedoic acid having particle size of D90 less than 200µ (microns).

According to one embodiment, 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 pharmaceutical composition of the present invention may comprise a solid dispersion of bemepedoic acid in one or more carrier and optionally including other pharmaceutically acceptable excipient. The carrier can be hydrophilic or hydrophobic or water swellable, which include but not limited to polyethylene glycol (PEG), phospholipids, polyvinylpyrrolidone, cellulose derivatives such as methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethylcellulose, poly (ethylene oxide), carboxyvinyl polymer, carboxymethylethylcellulose, polyvinylalcohol and polyvinylacetate (PVA)/PVP copolymer, guar gum, xanthan gum, sodium alginate, dextrin, cyclodextrin, crospovidone, polyacrylates polymethacrylates, urea, soluplus, sugar, polyols and their polymers, surfactants such as poloxamer, tween, gelucire and/or combinations thereof.

The solid dispersion of bempedoic acid is then combined with one or more other lipid lowering drug along with one or more pharmaceutically acceptable excipient to form combination product.

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, 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, 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, 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, crosslinked polyvinylpyrrolidone, calcium and sodium carboxymethylcellulose, pregelatinized starch, magnesium trisilicate, 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, 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, ethylacetate, 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.

In some embodiments, the combination drugs of the present invention are provided or packaged as separate compositions in separate containers within the kit. In some embodiments, the combination drugs of the present invention are provided or packaged as a single composition within a container in the kit.

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), poloxamers, 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.

The various embodiments of the present invention can be assembled in several different ways.
The following examples will illustrate in more detail the various aspects of the present invention.

EXAMPLE 1:
Ingredient Qty./Tablet
(mg)
Bempedoic granules
Bempedoic acid 180.00
Lactose monohydrate 30.00
Microcrystalline cellulose 48.00
Hydroxypropyl cellulose 12.00
Purified water q.s.
Sodium starch glycolate 15.00
Colloidal silicon dioxide 3.00
Talc 12.00
Rosuvastatin granules
Rosuvastatin calcium 10.42
Lactose monohydrate 58.00
Microcrystalline cellulose 20.00
Calcium hydrogen phosphate 7.00
Crospovidone 5.00
Magnesium stearate 1.25
Ezetimibe granules
Ezetimibe 10.00
Lactose monohydrate 50.00
Microcrystalline cellulose 20.00
Sodium starch glycolate 5.00
Povidone 3.00
Sodium lauryl sulfate 2.00
Purified water q.s.
Film Coating
Opadry 9.000

Brief Manufacturing process
1. Sifting all the ingredients through appropriate sieves.
2. Dry mixing pre-sifted bempedoic acid, lactose monohydrate and microcrystalline cellulose.
3. Adding hydroxylpropyl cellulose to water and keep stirring till uniform dispersion is obtained.
4. Granulating the dry mix of step 2 using dispersion of step 3 to obtain granules.
5. Drying the granules followed by passing through appropriate sieve and then passing through multi mill.
6. Blending the granules of step 5 with sodium starch glycolate, colloidal silicon dioxide and talc to form final blend for bempedoic acid granules.
7. Rosuvastatin, lactose, microcrystalline cellulose, calcium hydrogen phosphate, crospovidone all were blended.
8. The blend obtained in step 7 was lubricated using magnesium stearate to form final blend for rosuvastatin granules.
9. Ezetimibe, lactose, microcrystalline cellulose, sodium starch glycolate were blended.
10. Povidone and sodium lauryl sulfate were dissolved in purified water to form binder solution.
11. Blend of step 9 was granulated using binder solution of step 10 to form final blend for Ezetimibe granules.
12. The final granule blends of step 6, 8 and 11 were finally compressed separately to form tri-layered tablet.

Example 2:
Ingredient
Qty./Tablet
(mg)
Bempedoic acid granules
Bempedoic acid 180.000
Lactose monohydrate 30.000
Microcrystalline cellulose 60.000
Hydroxypropyl cellulose 15.000
Purified Water q.s.
Sodium starch glycolate 9.000
Talc / Calcium stearate / Stearic acid 6.000
Ezetimibe granules
Ezetimibe 10.000
Lactose monohydrate 50.00
Microcrystalline cellulose 11.00
Sodium starch glycolate 5.00
Povidone 2.00
Sodium lauryl sulfate 2.00
Purified water q.s.
Rosuvastatin granules
Rosuvastatin calcium 11.54
Dicalcium phosphate 15.00
Microcrystalline cellulose 50.00
Lactose 25.00
Pre gelatinized starch 16.00
Hydroxypropyl cellulose 3.00
IPA q.s.
Talc 3.00
Sodium starch glycolate 2.00
Film Coating
Opadry 6.000
Purified Water q.s.

Brief Manufacturing process
1. Sifting all the ingredients through appropriate sieves.
2. Mixing pre-sifted bempedoic acid, lactose monohydrate and microcrystalline cellulose.
3. Adding hydroxypropyl cellulose to purified water and keep stirring till a clear solution is obtained.
4. Adding binder of step 3 to dry mix of step 2 to obtain granules
5. Drying the granules and then sifting and milling the granules.
6. Mixing the sifted granules with sodium starch glycolate and or talc / calcium stearate / stearic acid to form final blend for bempedoic acid granules.
7. Ezetimibe, lactose, microcrystalline cellulose, sodium starch glycolate were blended.
8. Povidone and sodium lauryl sulfate were dissolved in purified water to form binder solution.
9. Blend of step 7 was granulated using binder solution of step 8 to form final blend for ezetimibe granules.
10. The final blends of step 6 and 9 were mixed and lubricated using talc to form final blend.
11. Rosuvastatin calcium, dicalcium phosphate, lactose, microcrystalline cellulose, pregelatinized starch were blended.
12. Isopropyl alcohol was taken in container and hydroxypropyl cellulose was added with continuous stirring to obtain binder solution.
13. The blend of step 11 was granulated using binder solution of step 12.
14. The granules were dried and sifted and blended with sodium starch glycolate and lubricated using talc to form final blend for rosuvastatin granules.
15. The final granule blends of step 10 and 14 were compressed to form bi-layered tablet.
16. Film coating the tablets of step 15 using Opadry.

Example 3:

Ingredient
Qty./Tablet
(mg)
Bempedoic acid 180.000
Rosuvastatin calcium 20.84
Ezetimibe 10.00
Lactose monohydrate 30.000
Microcrystalline cellulose 60.000
Sodium starch glycolate 9.000
Povidone / Hydroxypropyl cellulose 15.000
Talc / Calcium stearate / Stearic acid 3.000
Film Coating
Opadry 9.000
Purified Water q.s.

Brief Manufacturing process
1. Sifting all the ingredients through appropriate sieves.
2. Adding pre-sifted bempedoic acid, rosuvastatin calcium, ezetimibe, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone or hydroxypropyl cellulose in a blender and mix for suitable time.
3. Compacting the blended material of step 2 using a suitable compactor and obtain granules of uniform size by sizing.
4. Mixing the sifted granules with talc or calcium stearate or stearic acid in a blender.
5. Compressing the blend of step 4 into tablets using suitable tools.
6. Then film coating the compressed tablets using Opadry.

Example 4:
Bempedoic Acid Part:

Ingredient Qty./Tablet
(mg) – Common blend for 10mg and 20mg Rosuvastatin Tablets
Dry mix
Bempedoic acid 180.000
Lactose monohydrate 30.000
Microcrystalline cellulose 56.000
Sodium starch glycolate 15.000
Binder solution
Hydroxypropyl cellulose 9.000
Purified water q.s.
Prelubrication / Blending
Sodium starch glycolate 15.000

Rosuvastatin Part:
Name of Ingredients Qty./tablet
(10 mg) Qty./tablet
(20 mg)
Rosuvastatin calcium 10.42 20.83
Lactose monohydrate 105.05 94.64
Microcrystalline cellulose 36.20 36.20
Crospovidone 7.00 7.00
Tricalcium phosphate anhydrous 13.21 13.21
Lubrication for Roller compaction
Calcium stearate 1.00 1.00
Bempedoic acid part and Rosuvastatin part (Final lubrication)
Talc 5.00 5.00
Calcium stearate 12.12 12.12
Total 495.00 495.00
Opadry white 15.00 15.00
Coated Tablet Weight 510.00 510.00

Brief Manufacturing process:
Bempedoic acid Part
1. Sifting:
Sift all the ingredients through appropriate sieves.
2. Dry mixing:
Add pre-sifted bempedoic acid, lactose monohydrate, microcrystalline cellulose and sodium starch glycolate in a rapid mixer granulator (RMG) and mix for suitable time.
3. Binder preparation:
Add hydroxypropyl cellulose to water and keep stirring till uniform dispersion is obtained and then use for granulation.
4. Granulation:
Add binder of step 3 to dry mix of step 2 in the RMG and knead as per requirement.
5. Drying:
Firstly, air dry the granules at room temperature then dry the granules at appropriate temperature till required LOD is achieved.
6. Sifting and Milling of Granules:
Pass the granules through appropriate sieve and pass through multi mill till 100% blend passes through the required sieve.
7. Blending:
Mix the sifted granules with sodium starch glycolate and talc.

Rosuvastatin Part:
8. Sifting of Rosuvastatin part:
Add rosuvastatin, lactose monohydrate, microcrystalline cellulose, crospovidone, tricalcium phosphate.
9. Blending:
Blend the above sifted materials for 10 minutes at 10 RPM in blender.
10. Lubrication for Roller compaction:
Lubricate the above blended materials with calcium stearate.
11. Roller compaction:
Compact the above materials to get desired bulk density of granules based on the compaction study.
12. Milling
Mill the above compacts to get the desired bulk density.

Mixing of Bempedoic part and Rosuvastatin part:
13. Now mix both the bempedoic acid granules and rosuvastatin granules and blend it for 10 mins at desired RPM.
14. Lubrication
Lubricate the above materials using calcium stearate and talc for 5 mins at desired RPM.
15. Compression
Compress the lubricated blend using suitable punches and parameters.
16. Coating
Coat the tablets using Opadry.

Example 5:
Bempedoic acid Part:

Ingredient Qty./Tablet
(mg) – Common blend for 10mg and 20mg Rosuvastatin Tablets
Dry mix
Bempedoic acid 180.00
Lactose monohydrate 30.00
Microcrystalline cellulose 46.00
Sodium starch glycolate 15.00
Binder solution
Hydroxypropyl cellulose 9.00
Purified water q.s.
Blending
Sodium starch glycolate 15.00
Talc 5.00
Lubrication
Calcium stearate 10.00
Total 310.00

Rosuvastatin Part
Name of Ingredients Qty./tablet
(10 mg) Qty./tablet
(20 mg)
Rosuvastatin calcium 10.42 20.83
Lactose monohydrate 105.05 94.64
Microcrystalline cellulose 36.20 36.20
Crospovidone 7.00 7.00
Tricalcium phosphate anhydrous 13.21 13.21
Lubrication for Roller compaction
Calcium stearate
Final lubrication
Talc 5.00 5.00
Calcium stearate 12.12 12.12
Total 190.00 190.00
Total Bilayer tablet weight 500.00 500.00
Opadry white 15.00 15.00
Coated Tablet Weight 515.00 515.00

Brief Manufacturing process
Bempedoic Acid Part
1. Sifting:
Sift all the ingredients through appropriate sieves.
2. Dry mixing:
Add pre-sifted bempedoic acid, lactose monohydrate, microcrystalline cellulose and sodium starch glycolate and tricalcium phosphate in a rapid mixer granulator (RMG) and mix for suitable time.
3. Binder preparation:
Add hydroxyl propyl cellulose to water and keep stirring till uniform dispersion is obtained and then use for granulation
4. Granulation:
Add binder of step 3 to dry mix of step 2 in the RMG and knead as per requirement.
5. Drying:
Firstly, air dry the granules at room temperature then dry the granules at appropriate temperature till required LOD is achieved.
6. Sifting and Milling of Granules:
Pass the granules through appropriate sieve and pass through multi mill.
7. Blending:
Mix the sifted granules with sodium starch glycolate, and talc.
8. Lubrication
Lubricate the above blend using calcium stearate.

Rosuvastatin Part:
9. Sifting of Rosuvastatin part:
Add rosuvastatin, lactose monohydrate, microcrystalline cellulose, crospovidone, tricalcium phosphate.
10. Blending:
Blend the above sifted materials for 10 minutes at 10 RPM in blender.
11. Lubrication for Roller compaction:
Lubricate the above blended materials with calcium stearate.
12. Roller compaction:
Compact the above materials to get desired bulk density of granules based on the compaction study.
13. Sifting and Milling of Granules:
Pass the granules through appropriate sieve and pass through multi mill till 100% blend passes through the required sieve.
14. Lubrication
Lubricate the above materials using calcium stearate and talc for 5 mins at 10 RPM.
15. Compression
Compress the lubricated blend of both Bempedoic part and Rosuvastatin part as a Bi-layered tablet using suitable punches and process parameters.
16. Coating
Coat the tablets using Opadry.

Example 6:
Ingredients Qty./tablet
(10 mg) Qty./tablet
(20 mg)
Intragranular
Bempedoic acid 180.000 180.000
Rosuvastatin calcium 10.42 20.83
Lactose monohydrate 30.000 30.000
Microcrystalline cellulose# 64.580 54.170
Sodium starch glycolate 15.000 15.000
Crospovidone XL 5.000 5.000
Tribasic calcium phosphate 10.00 10.00
Lubrication for Roller Compaction
Calcium stearate 10.00 10.00
Prelubrication/Blending
Crospovidone XL 10 5.000 5.000
Talc 5.000 5.000
Lubrication
Calcium stearate 10.00 10.00
Total 360.00 360.00
Coating
Opadry white 10.00 10.00
Coated tablet weight 370.00 370.00

Brief Manufacturing process
1. Sifting:
Sift all the ingredients through appropriate sieves.
2. Dry mixing:
Add pre-sifted bempedoic acid, rosuvastatin, lactose monohydrate and microcrystalline cellulose and sodium starch glycolate and tribasic calcium phosphate.
3. Lubrication for Roller compaction
Lubricate the above blend using calcium stearate.
4. Roller compaction:
Compact the above blend to get a desired compacts.
5. Milling
Mill the compacts using suitable screen to get the desired bulk density.
6. Prelubrication/Blending:
Prelubricate the above milled granules with crospovidone and talc.
7. Lubrication:
Lubricate the above blend using calcium stearate.
8. Compression
Compress the above materials as a monolithic formulation.
9. Coating
Coat the tablets using Opadry.

CLAIMS:WE CLAIM:

1. A pharmaceutical composition comprising Bempedoic acid or its pharmaceutically acceptable salt, one or more lipid lowering drug and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically composition comprises:
diluent in the range of 10% w/w to 90% w/w,
disintegrant is present in the range of 1% w/w to 25% w/w,
lubricant is present in the range of 0.01% w/w to 20% w/w,
optionally a binder is present in the range of 0.5% w/w to 50% w/w,
based on the total weight of the composition.

2. The pharmaceutical composition as claimed in claim 1, wherein one or more lipid lowering drug is selected from the group comprising 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 or a combination thereof.

3. The pharmaceutical composition as claimed in claim 2, wherein one or more lipid lowering is rosuvastatin or its pharmaceutically acceptable salt, ezetimibe or its pharmaceutically acceptable salt, or a combination of both.

4. The pharmaceutical composition as claimed in claim 1, wherein pharmaceutically acceptable excipient further comprises solubilizers, surfactants, plasticizers, antioxidants, glidants or a combination thereof.

5. The pharmaceutical composition as claimed in claim 1, wherein the diluent is selected from the group comprising starch, pregelatinized starch, powdered celluloses, polysaccharides, dibasic calcium phosphate anhydrous or calcium hydrogen phosphate, 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, dextrates, lactitol, maltodextrin, trehalose, or a combination thereof.

6. The pharmaceutical composition as claimed in claim 1, wherein the binder is selected from the group comprising 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, starch, pregelatinized starch, or a combination thereof.

7. The pharmaceutical composition as claimed in claim 1, wherein the disintegrant is selected from the group comprising sodium starch glycolate, croscarmellose sodium, crosslinked polyvinylpyrrolidone, calcium and sodium carboxymethylcellulose, pregelatinized starch, magnesium trisilicate, corn starch, potato starch, or a combination thereof.

8. The pharmaceutical composition as claimed in claim 1, wherein the lubricant is selected from the group comprising magnesium stearate, colloidal silicon dioxide, aluminum silicate, sodium stearyl fumarate, 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 or a combination thereof.

9. The pharmaceutical composition as claimed in claim 1, wherein the Bempedoic acid is having a particle size of D90 less than 200µ.

10. The pharmaceutical composition as claimed in claim 1, wherein the composition is prepared by process selected from wet granulation, dry granulation, or direct compression method.