DESC:The term “Bempedoic acid” as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The term “Ezetimibe” as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The term, "pharmaceutically acceptable excipients" as used herein refers to diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, co-solvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavoring agents, antioxidants, colorants, solubilizers, plasticizer or dispersing agents and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.

The term "diluent" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The diluents of instant invention includes, but are not limited to inorganic phosphates such as dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "disintegrant" employed in a composition of the present invention is capable of facilitating the breakup of a pharmaceutical composition prepared from the composition when placed in contact with an aqueous medium. The disintegrants of instant invention includes, but are not limited to alginic acid or sodium alginate; cellulose or cellulose derivatives such as carboxymethylcellulose sodium, microcrystalline cellulose, croscarmellose sodium, powdered cellulose or croscarmellose; iron exchange resin such as amberlite, gums such as agar, locust bean, karaya, pectin and tragacanth, crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, i.e., cross-linked l-ethenyl-2-pyrrolidinone); Pregelatinized starch, sodium starch glycolate or starch.

The term "binder" employed in a composition of the present invention is capable for holding the ingredients together and forming the granules with required mechanical strength. The binders of instant invention include, but are not limited to, but are not limited to, polyvinylpyrrolidone (povidone), polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC) and cellulose ethers.

The term "lubricant" employed in a composition of the present invention is capable of preventing the ingredients from clumping together and from sticking to the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a compression machine. Preferred lubricants of instant invention includes, but are not limited to fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, aluminum stearate, stearic acid or hydrogenated vegetable oil; polyalkylene glycols such as polyethylene glycol (PEG) or sodium benzoate and the like.

The term "composition" or "pharmaceutical composition" or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The term "excipient" means a pharmacologically inactive component such as diluent, disintegrant, carrier, filler, lubricant, binder, and solvent, coating agent or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 11 % and about 40 % means 36 % to 44 %.

The term "oral dosage forms" includes all conventional oral solid dosage forms like Tablet, Capsule, Syrups, Suspension, Granules, Pill, Caplet, Pellets, Powder, Sachet, or any other orally ingestible dosage form comprising Bempedoic acid and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The terms “treat” and “treating” as used herein refers are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a Tablet, capsule, Syrups, Suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising Bempedoic acid or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The term "Parenteral dosage forms” includes all conventional oral solid dosage forms like a
Intramuscular injection, Intravenous injection, subcutaneous injection any other Parenteral dosage forms comprising Bempedoic acid or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

Dual granulation technique is a process where in the two granulations are involved in the manufacturing process.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The present invention relates to process for preparation of Bempedoic acid and Ezetimibe or its pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients.

In certain exemplary embodiments, the pharmaceutical composition comprises, or is in the form of a pharmaceutically acceptable salt, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).

In certain exemplary embodiments, the exemplary compound (Bempedoic acid) contain an acidic group as well as a basic group, the compound can form internal salts, which can also be used in the compositions and methods described herein. When an exemplary compound contains a hydrogen-donating heteroatom (e.g., NH), salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the exemplary compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth, incorporated herein by reference. Physiologically acceptable salts of the exemplary compounds are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts.

In certain embodiment the present invention relates to a process for preparation comprising a pharmaceutically acceptable excipient and a compound disclosed herein, pharmaceutical composition is in the form of solid dosage form, semi-solid dosage form and liquid dosage form.

In certain embodiments compounds described herein can be formulated in a variety of ways. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, or lotions and the like. In certain embodiments, the formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms, such as solutions, syrups, suspension etc. can also be utilized. In another embodiment, the formulation is administered topically. Suitable topical formulations include, but are not limited to lotions, ointments, creams, and gels.

In an another embodiment the solid oral pharmaceutical composition is in the form of tablet comprising Bempedoic acid or pharmaceutically acceptable salts in combination with Ezetimibe and one or more pharmaceutically acceptable excipients.

In an another embodiment the solid oral pharmaceutical composition is in the form of capsule comprising Bempedoic acid or pharmaceutically acceptable salts in combination with Ezetimibe and one or more pharmaceutically acceptable excipients.

In an another embodiment the present invention relates to a process for preparation of Bempedoic Acid and Ezetimibe composition and diluent, lubricant, disintegrants, binders and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention relates to a process for preparation of Bempedoic acid or its pharmaceutically acceptable salts in combination with Ezetimibe, microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, low substituted hydroxy propyl cellulose, hydroxy propyl cellulose, povidone K 30, sodium lauryl sulphate and steric acid and one or more pharmaceutically acceptable excipients.

In yet another embodiment of the pharmaceutical composition of the present invention can be formulated as dosage forms which include, but are not limited to, powders, granules, pills, tablets, coated tablets, capsules, pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, elixirs and the like.

In further embodiments of the present invention relates to the pharmaceutical compositions is prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of Bempedoic acid the active ingredient will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for Bempedoic acid or pharmaceutically acceptable salts or derivatives thereof, alone or in combination with Ezetimibe.

In an another embodiment of the present invention relates to a process for preparation of Bempedoic Acid and Ezetimibe composition, where in the said composition comprising of Bempedoic Acid or its salts and Ezetimibe or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient, the present invention further relates to methods of preparing and administering such pharmaceutical compositions.

In an another embodiment of the present invention relates to a process for preparation of Bempedoic Acid and Ezetimibe composition, where in the said composition comprising of Bempedoic Acid or its salts and Ezetimibe or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient, where in the formulation process involves the granulation of Bempedoic acid to the obtained Bempedoic acid granules the Ezetimibe drug dispersion is added to obtained desirable granules, further to this extra granular excipients to added and punched in to mono layer tablet dosage form.

In an another embodiment of the present invention relates to a formulation process for preparation of Bempedoic acid or its pharmaceutically acceptable salt thereof in combination with Ezetimibe and one or more pharmaceutically acceptable excipient, where in the formulation process involves the dual granulation technique.

In an another embodiment of the present invention relates to a formulation process for preparation of Bempedoic acid or its pharmaceutically acceptable salt thereof in combination with Ezetimibe and one or more pharmaceutically acceptable excipient, where in the formulation process comprising drug dispersion with Ezetimibe with other excipients.

In an another embodiment of the present invention relates to a process for preparation of Bempedoic Acid and Ezetimibe composition, where in the said composition comprising of Bempedoic Acid or its salts and Ezetimibe or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient, where in the formulation process involves the granulation of Bempedoic acid to the obtained Bempedoic acid granules the Ezetimibe drug dispersion is added to obtained desirable granules, further to this extra granular excipients to added and punched in to mono layer tablet dosage form.

In an another embodiment of the present invention relates to a process for preparation of Bempedoic acid in combination with Ezetimibe wherein said composition comprises:
(a) Bempedoic acid or its pharmaceutical salt thereof,
(b) Ezetimibe or its pharmaceutical salt thereof,
(b) One or more diluents;
(c) One or more disintegrant;
(d) One or more binder;
(e) One or more lubricant; and
(f) Optionally one or more pharmaceutical acceptable excipients.

In an another embodiment of the present invention relates to a process for preparation of Bempedoic acid in combination with Ezetimibe wherein said composition comprises:
(a) from about 35% to about 60% of Bempedoic acid or its pharmaceutical salt thereof,
(b) from about 1% to about 5% of Ezetimibe or its pharmaceutical salt thereof
(b) from about 10 % to about 30 % of one or more diluents;
(c) from 5 % to about 15 % of disintegrant;
(d) from about 1 % to about 10 % binder;
(e) from about 0.5 % to about 2 % lubricant; and
(f) optionally one or more pharmaceutical acceptable excipients.

In an another embodiment of the present invention relates to a process for preparation of Bempedoic Acid and Ezetimibe composition, where in the said composition comprising of Bempedoic Acid or its salts and Ezetimibe or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient as defined above is used for the treatment of heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease and for lowering of LDL-C.

In an another embodiment of the present invention relates to an oral pharmaceutical composition as defined above having dissolution more than 85% within 30 minutes.

In an another embodiment of the present invention relates to a process for preparation of Bempedoic acid in combination with Ezetimibe, wherein the process relates to sift the Bempedoic acid with the excipients and dry mixing, prepare the binder solution of HPC in water and granulate by adding the binder solution to obtain desirable granules, prepare the drug dispersion preparation with povidone and add Ezetimibe and add to the above said granules with wet mill to obtain the granules of Bempedoic acid and Ezetimibe to which the extra granular material is added with blending, lubricate the obtained mixture, compress the lubricated granules and coat with film coating material.

Dissolution profile of Bempedoic acid and Ezetimibe Tablets:
Bempedoic acid &Ezetimibe Tablets 180 mg/10 mg
B. No BDETI1-0186-006 (Bempedoic acid) BDETI1-0186-006 (Ezetimibe)
Conditions : 900 mL of p H 6.6 P.B. with USP II (paddle) with 50 RPM Conditions : 900 mL of p H 4.5 Acetate buffer with 0.45% SLS with 50 rpm
S.No 5 min 10 min 15 min 20 min 30 min 45 min S.No 5 min 10 min 15 min 20 min 30 min 45 min
Mean of 6 tablets 39 77 90 94 96 96 Mean of 6 tablets 26 60 76 84 92 97
SD 9.51 7.85 2.98 1.56 1.38 1.47 SD 7.10 8.64 6.30 4.66 2.50 1.07
%RSD 24.6 10.2 3.3 1.7 1.4 1.5 %RSD 27.5 14.5 8.3 5.5 2.7 1.1
Min 26.9 64.8 86.2 91.2 93.5 93.5 Min 18.7 46.8 64.5 75.7 87.8 95.1
Max 48.9 87.0 93.6 95.6 97.2 97.7 Max 37.5 72.1 83.3 89.8 95.0 97.9

Examples:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1:
Manufacturing Formula (Wet granulation):
S.No. Ingredients Qty per Unit (mg) % w/w
Ezetimibe Portion
Intra-granular
1. Bempedoic acid 180.00 48.00
2. Microcrystalline cellulose 102 13.75 3.67
3. Lactose monohydrate 46.75 14.33
4. Low Substituted Hydroxy propyl cellulose (L-HPC) 7.50 2.00
5. Sodium starch glycolate type A 25.34 6.76
Granulation - I
6. Hydroxy propyl cellulose (Klucel LF) 7.50 2.00
7. Purified water q.s. q.s.
Granulation – II with Drug dispersion
8. Ezetimibe 10.00 2.67
9. Povidone K 30 1.00 0.27
10. Sodium lauryl sulphate 2.00 0.53
11. Purified water Q.S --
Extra granular
12. Microcrystalline cellulose 200 37.50 10.00
13. Sodium starch glycolate type A 37.50 10.00
14. Stearic Acid 6.66 1.78
Core Tablet Weight (mg) 375.50 100.00
Film Coating
15. Opadry II AMB 88A505053 Blue 9.39 --
16. Purified water Q.S --
Coated Tablet Weight (mg) 384.89 --

Brief Manufacturing Procedure:
Sifting
i. Co-sift Bempedoic acid, Lactose monohydrate, Hydroxy propyl cellulose (L-HPC), Sodium starch glycolate and Microcrystalline cellulose 101 through sieve # 40 ASTM (425 µm).
Dry mixing
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.
Granulation - I
Binder Preparation
iii. Dissolve Hydroxy propyl cellulose (Klucel LF) in 50% (dry mix weight) of purified water under stirring and stir until a clear dispersion is formed.
iv. Granulate step-ii dry mix by using HPC dispersion by the following granulation parameters.
Drying
v. Dry the granules at inlet temperature of 40°C - 60°C in Fluid bed dryer until the Loss of drying (LOD) of the granules reaches 1.0 - 3.0 % w/w at 105°C.
Sizing and Milling
vi. Sift the step-vii dried granules through sieve #30 ASTM (600 µm) and collect retains and fines separately.
vii. Mill the retentions of step-viii by using multi mill fitted with 1.0 mm screen at slow 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).
viii. Load the Milled granules of step vii in RMG.
Granulation - II
Drug dispersion preparation
ix. Dissolve Povidone K-30 in 40% (dry mix weight) of purified water under stirring and stir until a clear solution is formed.
x. To step ix, add Sodium lauryl sulphate and stir until form a clear solution is formed. Take precaution to avoid formation of foam.
xi. To step x, add Ezetimibe and then homogenize the solution for 30 minutes to form smooth homogeneous dispersion and add the remaining 10% of purified water for rinsing purpose.
xii. Granulate step-viii by using step-xi drug dispersion by the following granulation parameters.
Wet Milling
xiii. Unload the wet mass from Rapid mixer granulator and mill through multi mill fitted with 6.0 mm screen at medium speed.
Drying
xiv. Dry the granules at inlet temperature of 40°C - 60°C in Fluid bed dryer until the Loss of drying (LOD) of the granules reaches 1.0 - 3.0 % w/w at 105°C.
Sizing and Milling
xv. Sift the step-xiv dried granules through sieve #30 ASTM (600 µm) and collect retains and fines separately.
xvi. Mill the retentions of step-xv by using multi mill fitted with 1.0 mm screen at slow 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
xvii. Co-sift Microcrystalline cellulose, Sodium starch glycolate through sieve #40 ASTM (425 µm).
xviii. Sift Stearic Acid through sieve #60 ASTM (250 µm).
Blending and Lubrication
xix. Load the granules of step-xvi, and step-xvii into blender and mix for 5 minutes at slow speed.
xx. Add pre sifted lubricant of step-xviii to above material of step-xii and mix for 5 minutes at slow speed.
Compression
xxi. Compress the lubricated blend with suitable punches and parameters
Film Coating:
xxii. Coat the tablets of xxii with film coating material.
,CLAIMS:1) A process for the preparation of pharmaceutical composition comprising of Bempedoic acid or its salt and Ezetimibe or its salt, one or more pharmaceutically acceptable excipients, where in the formulation process involves the dual granulation technique.

2) The process for the preparation of pharmaceutical composition as claimed in claim 1, where in the Bempedoic acid granules are prepared by wet granulation and second granulation is prepared by using Ezetimibe drug dispersion.

3) The process for the preparation of pharmaceutical composition as claimed in claim 1, where in the composition comprises:
(a) about 35% to 60% of Bempedoic acid or its pharmaceutical salt thereof,
(b) about 1% to 5% of Ezetimibe or its pharmaceutical salt thereof,
(b) about 10 % to 30 % of one or more diluents;
(c) about 5 % to 15 % of disintegrant;
(d) about 1 % to 10 % binder;
(e) about 0.5 % to 2 % lubricant; and
(f) optionally one or more pharmaceutical acceptable excipients.

4) The process for the preparation of pharmaceutical composition as claimed in claim 1, where in the composition is a tablet or capsule dosage form.

5) The process for the preparation of pharmaceutical composition contain Bempedoic acid and Ezetimibe as claimed in claim 1, where in the pharmaceutical preparation which is suitable in the treatment or prevention of cardiovascular disease or reducing the risk of cardiovascular disease.