DESC:“IMPROVED ORAL COMPOSITIONS OF BEMPEDOIC ACID AND METHOD OF MANUFACTURING THEREOF”

FIELD OF THE INVENTION:
The present invention relates to oral formulations of Bempedoic Acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient. Further, the invention relates to providing an economical and technically advanced dosage form over existing dosage forms. The present invention further provides such compositions for the treatment of various cardiovascular diseases.

BACKGROUND OF THE INVENTION:
Bempedoic Acid (also known as ETC-1002) is a substituted alpha-omega-dicarboxylic acid that is pentadecane dioic acid. Bempedoic Acid is chemically known with its IUPAC name as 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid and is represented structurally as below:

Bempedoic Acid (CAS: 738606-46-7), is disclosed earlier during 2003 in WO2004/067489. The said PCT (patent cooperation treaty) patent publication discloses Bempedoic Acid for the first time.
Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor. Bempedoic acid is currently being other in United States under the brand name NEXLETOL® as 180 mg tablet by Esperion Therapeutics Inc. It is 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.
The recommended dose of Bempedoic Acid is 180 mg orally once daily with or without food. Each film-coated tablet of NEXLETOL contains 180 mg of bempedoic
acid and the following inactive ingredients: colloidal silicon dioxide, hydroxyl propyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film coating comprises of partially hydrolyzed polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.
Bempedoic Acid is very much sticky in nature and hence, it is very much difficult for the formulation scientist to develop the stable and easy flowable composition for the same.
US7335799 first time discloses the molecule Bempedoic acid or a salt, hydrate or solvate thereof.
US8497301 discloses that Bempedoic Acid may be used in the treatment of lowering LDL levels and thereby reducing cholesterol level in the blood of mammals. More specifically in US9000041, it is disclosed that Bempedoic Acid may be used for treating a cardiovascular disease and dyslipidemia by oral administration of Bempedoic acid. Further, US10118881 discloses a method for treating hypercholesterolemia by administering Bempedoic acid.
IN201917053385 discloses a granulated composition comprising Bempedoic acid admixed with a lubricant selected from sodium stearyl fumarate, colloidal silicon dioxide and magnesium stearate, which reduces or eliminates the stickiness problem. This Indian patent application has considered a limitation that any one lubricant selected from sodium stearyl fumarate, colloidal silicon dioxide and magnesium stearate must be used in intra-granular portion otherwise there will be stickiness problem.
IN202011045799 claims the pharmaceutical composition of Bempedoic Acid wherein the composition is free of colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate. Further, this Indian patent application claims that the intra-granular portion of the claimed composition is free of lubricant. However, this patent application failed to disclose the stability data which may question to the stability of final composition.
IN202017037792 claims the composition of Bempedoic Acid in capsule dosage form. This composition is sustained release formulation. Here, hypromellose type polymer is used to prepare the sustained release formulation. The elimination half-life of Bempedoic Acid is 21 ± 11 hours at steady-state. Hence, actually, the drug itself has sustained release capacity and hence, no surprising effect is shown by this patent application.
At present, Bempedoic Acid is other as immediate release dosage form only. Looking at the limitations of the prior-arts as described herein above, there is an unmet need for the preparation of new and improved dosage form of Bempedoic Acid. Therefore, by providing the solution to the above problem, the inventors of the present invention have successfully developed an oral dosage form of Bempedoic Acid which have the least sticking property.
The present invention discloses the administration of Bempedoic Acid in an oral tablet form that does not use sophisticated techniques and is economically affordable compared to other dosage form. Further, the formulated tablet dosage form prepared as per the present invention provides greater stability when compared with other Bempedoic Acid formulation. Moreover, the oral route is the preferred one for administration in patients with hypercholesterolemia or atherosclerotic cardiovascular disease.
The present invention incorporates a synergistic combination of Bempedoic Acid along with Neusilin (magnesium aluminometasilicate) that reduce sticky nature of the drug. This combination also increases solubility of Bempedoic Acid by providing better dissolution profile and thereby reducing usage of hazardous organic solvents during preparation of tablet. Moreover, the present invention resulted in achieving higher stability of Bempedoic Acid as comparing to other dosage form. Moreover, as per the present invention, solubility and stability of this patient compliant Bempedoic Acid formulation is proven higher when compared to prior art inventions.

OBJECTIVES OF THE INVENTION:
The principal object of the present invention is to provide oral dosage forms comprising Bempedoic acid and one or more pharmaceutically acceptable excipients, where in oral dosage forms includes solid oral dosage forms as well as other oral dosage forms.
The prime object of the present invention is to provide improved oral pharmaceutical formulations of Bempedoic Acid and pharmaceutically acceptable salt thereof in the form of tablet.
Other objective of the present invention is to provide the composition of Bempedoic acid an economical and advanced dosage form over existing dosage form.
In yet another general object of the present invention is to provide a problem solution approach over the existing dosage form.
Still another aspect of the present invention is provided oral solid dosage form which is in the form of tablet with improved test having high patient complaints.
In some object, the present disclosure provides for a granulated composition wherein the composition further comprises a pharmaceutically acceptable excipient.
One more objective of the present invention is to incorporate the use of Neusilin UFL2 to reduce the stickiness of the composition.
Yet another object of the present invention is provided composition which is used as medicament and process for preparation.
One more aspect of the present invention is to provide an oral dosage form with enhanced dissolution and stability profile.

SUMMARY OF THE INVENTION:
Notwithstanding of wide research on Bempedoic acid as reported in prior-art publications, there is an unmet need to develop a patient compliant oral solid dosage form, here in specifically oral solid dosage form of pharmaceutical composition for Bempedoic acid with technical advancement which provide fast dissolution for immediate action as well as good stability for long term storage. This dosage form also increases patient compliance because patient feels difficulty and pains in taking other available dosage form when he or she is outdoor. Thus, the present invention has solved the problem that is present in the prior-arts as well as in the existing other formulations.
Accordingly, the present invention provides novel oral solid compositions of Bempedoic acid as an active pharmaceutical Ingredient preferably as solid oral dosage form with pharmaceutically acceptable excipients and method of preparation thereof.
The present invention discloses improved oral compositions of Bempedoic Acid preferably as oral solid dosage form with pharmaceutically acceptable excipients and method of preparation thereof.
In another general aspect, a pharmaceutical composition as per the present invention may be in the form of tablet, capsule, caplet, pellets, beads, granules or powder.
In one general aspect, a pharmaceutical composition comprising Bempedoic Acid and one or more pharmaceutically acceptable excipients wherein the composition is in the form of a capsule or a tablet, more preferably it is in the tablet form.
In another general aspect, above-mentioned pharmaceutical composition is optionally provided with barrier coating.
In another general aspect, a pharmaceutical composition as per the present invention comprises Bempedoic Acid or pharmaceutically acceptable salt thereof.
Embodiments of the pharmaceutical composition may include Bempedoic acid as an active ingredient with one or more selected from pharmaceutically acceptable excipients like diluents, vehicles, Fillers, Solubilizers, stabilizers / anti-oxidants, suspending / thickening agents, chelating / complexing agents, solubility enhancing agents, permeability enhancers, preservatives, glidants, active carriers, sweeteners, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents, Binders, granulating fluid, disintegrant, Adsorbents , colorants, solvents, co-solvents and the like.
Another object of the present invention is to provide technically advanced patient-compliant dosage forms over existing dosage form and prior-arts.
According to another aspect, there is provided a process for preparing a pharmaceutical composition comprising bempedoic acid or pharmaceutically acceptable salt thereof, wherein the process comprising the steps of:
(a) granulating bempedoic acid and optionally one or more pharmaceutically acceptable excipient;
(b) blending the granules with one or more pharmaceutically acceptable excipient to form Intra-granular and extra-granular portion; and
(c) compressing the granules into tablet; wherein the sticking problem is not observed and/or avoid.
The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.
References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.
The term "drug" or “active ingredient” or “active pharmaceutical ingredient (API)” herein refers to Bempedoic acid or a pharmaceutically acceptable salt thereof.
The term "Bempedoic acid" as used herein according to the present invention includes, Bempedoic acid in the form of free base, a pharmaceutically acceptable salt thereof, amorphous, crystalline, any isomer, derivative, hydrate, solvate or prodrug or a combination thereof.
The term “oral solid dosage forms” as may include one or more of forms of tablet, capsule, caplet, pellets, beads, granules, sachets, lozenges, pills, Dry powder inhaler or powder, chewable and like.
In accordance with the present invention, an oral solid pharmaceutical composition of Bempedoic acid comprising of Bempedoic acid as an active ingredient with pharmaceutically acceptable excipients in oral solid dosage forms, preferably herein present invention in tablet form.
Bempedoic Acid, chemically known as, 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, is a small lipophilic molecule with molecular weight 344.5 g/mol with solubility in ethanol and isopropanol. Bempedoic Acid is considered a Bio-pharmaceutics Classification System (BCS) Class II drug substance due to its poor solubility in water and higher lipid permeability. Bempedoic acid exhibits low solubility below pH 6.0. The elimination half-life of Bempedoic Acid is 21 ± 11 hours at steady-state.
In accordance with the present invention, an oral pharmaceutical composition of Bempedoic acid comprising of Bempedoic acid as an active ingredient with pharmaceutically acceptable excipients.
Excipients used in pharmaceutical composition for oral administration of pharmaceutically acceptable excipients in pharmaceutical formulations are physiologically inert compounds that are included in the formulation to facilitate the administration of the dosage form, e.g., pourability, palatability, to protect the formulation from issues regarding physical and chemical stability and to enhance the solubility of the therapeutic agent. Pharmaceutical compositions commonly contain a wide range of excipients, the details of which are provided below.
The term "pharmaceutically acceptable excipients" as used herein, refers to excipients those are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise of diluents, vehicles, Fillers, Solubilizers, stabilizers / anti-oxidants, suspending / thickening agents, chelating / complexing agents, solubility enhancing agents, permeability enhancers, preservatives, glidants, active carriers, sweeteners, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents, Binders, granulating fluid, disintegrant, adsorbents , colorants, solvents, co-solvents and the like and combinations thereof.
At the time of preparation of the dosage form, the excipients of tablet are mainly divided into three parts according to their uses in the manufacturing process (A) intra-granular excipients, (B) excipients used in binder solution, binder solution, blending and (C) extra-granular ingredients. The list of excipients used are listed in tables below however it is not limited to the said excipients.
Diluents/ fillers are added where the quantity of active ingredient is small or difficult to compress. Where the amount of active ingredient is small, the overall tableting properties are in large measure determined by the filler. Because of problems encountered with bioavailability of hydrophobic drugs of low water solubility, water-soluble diluents are used as fillers for these tablets. Further, suitable fillers or diluents may include one or more of sugars such as lactose, sucrose glucose, fructose, dextrose, galactose, starch; cellulose derivatives such as microcrystalline cellulose; microcrystalline cellulose PH 101 or microcrystalline cellulose 101, microcrystalline cellulose 112, lactose monohydrate (pharmatose 200M), Foremost NF fast Flo (Lactose Modified, spray Dried 316, carbonates like calcium carbonate; sugar alcohols such as mannitol, sorbitol, erythritol; magnesium carbonate, calcium phosphates kaolin, magnesium oxide, and combination thereof. Furthermore, the present invention comprises about 1.0 mg to 60 mg of diluents/ fillers of the total composition, preferably 4.00 mg to 42.00 mg of diluents/ fillers of the total composition.
Binders give adhesiveness to the powder during the preliminary granulation and to the compressed tablet. They add to the cohesive strength already available in the diluent. While binders may be added dry, they are more effective when added out of solution. The most effective dry binder is microcrystalline cellulose, which is commonly used for preparing tablets by direct compression. Binding agents can be added in two ways depending on the method of granulation: (1) As a powder as in slugging or in dry granulation methods. (2) As a solution to the mixed powders as in wet granulation. Further, suitable binders or polymers may include one or more of hydroxyl ethyl cellulose (HEC), hydroxyl propyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), Hydroxy propyl cellulose SSL, Sucrose NF, Starch NF, carbomers, dextrin, ethyl cellulose, methylcellulose, Lactose monohydrate NF EP, JP, povidone, shellac, zein, gelatin, polymethacrylates, polyvinylpyrrolidone or povidone, pre-gelatinized starch, sodium alginate, gums, synthetic resins, silicic acid, hydrophilic polymers and the like. Furthermore, the present invention comprises about 2.00 mg to 20.00 mg of binders/ polymers of the total composition, preferably 5.00 mg to 14.00 mg of binders/ polymers of the total composition.
A disintegrating agent assists in the fragmentation of the tablet after administration. Sometimes effervescent mixtures are used as disintegrating agents in soluble tablet systems. Further, suitable disintegrating agents may include one or more of crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate (type A), Microcrystalline cellulose (MCC) NF, EP, JP: 101, 102, 12 (DC) and the like. Furthermore, the present invention comprises about 1.00 mg to 20.00 mg of disintegrating agents of the total composition, preferably 3.00 mg to 18.00 mg of disintegrating agents of the total composition.
Glidants are materials that are added to tablet formulations in order to improve the flow properties of the granulations. They act by reducing inter particulate friction. Further, suitable gliding agents and lubricating agents may include one or more of Neusilin UFL2 (magnesium aluminometasilicate), talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide (Aerosil 200) , finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, Silicon dioxide colloidal NF, Cellulose powder NF, kaolin; and the like. Furthermore, the present invention comprises about 1.00 mg to 20.00 mg of glidants of the total composition, preferably 2.5 mg to 11.5 mg of glidants of the total composition.
Adsorbents are substances included in a formulation that are capable of holding quantities of fluids in an apparently dry state. Oil-soluble drugs, fluid extracts, or oils can be mixed with adsorbents and then granulated and compressed into tablets. Fumed silica, microcrystalline cellulose, magnesium carbonate, kaolin, and bentonite, Neusilin UFL2 (magnesium aluminometasilicate) are examples of commonly employed adsorbents. Further, the present invention comprises about 5.00 mg to 15.00 mg of adsorbents of the total composition, preferably 6.00 mg to 12.00 of adsorbents of the total composition.
Solvents play key roles in designing drug delivery systems (DDSs). They are used as the reaction media in the preparation of DDSs and as vehicles for delivery of problematic drugs. The number of pharmaceutically acceptable solvents is limited and developing new green ones is of a great of interest. Specifically organic solvents are commonly used in the pharmaceutical industry as reaction media, in separation and purification of synthesis products and also for cleaning of equipment. This paper presents some aspects of organic solvents utilization in an active pharmaceutical ingredient and a drug product manufacturing process. Sometimes a drug must be applied as an ointment, swallowed in a syrup or injected as a liquid. Solvents are uniquely able to dissolve drugs safely and effectively into these medicinal formulations. Further, Solvent Suitable organic solvents for preparing binding solution may include one or more of water, organic solvents such as ethanol, isopropyl alcohol, acetone, propylene glycol, Glycerin and the like. Furthermore, the present invention comprises about 20.00 mg to 200.00 mg of solvents/vehicles/ granulating fluid of the total composition, preferably 35.00 mg to 190.00 mg of solvent/vehicles/ granulating fluid of the total composition.
Colorants are often added to tablet formulation value or for product identification. Both FD&C and lakes are used. Most dyes are photosensitive when exposed to light. The Federal Food and Drug Administration (FDA) regulates the colorants employed in drugs. Further, suitable colorants may include one or more colorants are DR COAT HSP, Quinoline Yellow WS, Carmoisine, Ponceau 4R, Patent Blue V, and like. Furthermore, the present invention comprises about 1.00 mg to 15.00 mg of colorants of the total composition, preferably 5.00 mg to 10.00 mg of colorants of the total composition.
One embodiment of the present invention may include a pharmaceutical composition comprising 100 mg to 1500 mg of Bempedoic Acid, preferably 100 mg to 500 mg with pharmaceutically acceptable excipients.
Another embodiment of the present invention may include a pharmaceutical composition comprising Bempedoic Acid with pharmaceutically acceptable excipients but devoid of sodium stearyl fumarate, colloidal silicon dioxide and magnesium stearate in intra-granular portion.
The pharmaceutical formulations as described herein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet granulation, dry granulation or hot melt granulation. Further, the present invention and/or pharmaceutical composition is prepared by wet granulation method.
Another embodiment describes an oral pharmaceutical formulation comprising Bempedoic Acid with pharmaceutically acceptable excipients, in the form of a tablet, granules, beads, pellets, powder, particles, agglomerates, microspheres, minitablets, capsules and the like and in the present invention more preferably it is in the tablet form.
In another embodiment, the process comprises a step for providing Bempedoic Acid, wherein the Bempedoic Acid is contained in a tablet that may be prepared by the steps comprising:
The other object of the present invention is to provide oral dosage form of Bempedoic acid formulation and thereby reducing the cost of final formulations by providing an economic significant dosage form over existing dosage form and prior-arts.
In general embodiment, pharmaceutical composition as per the present invention is in the form of an oral solid dosage comprising:
(A) Dispense all the raw material.
(B) Sifting Active pharmaceutical ingredient with pharmaceutically acceptable excipients.
(C) Binder solution preparation by one or more pharmaceutically acceptable binders.
(D) Transfer the material of step-c into rapid mixer granulator by wet granulation.
(E) Blending and lubrication of step-D mixture.
(F) Compress the step-D with rotary compression machine.
(G) Add coating material in the step- F which is compress material.
(H) Finally prepared solid oral dosage form in the tablet form.
In another embodiment, the process comprises a step for providing above-mentioned formulation, wherein the formulation is a tablet that may be prepared by the steps comprising:
(A) Dispense all the raw material.
(B) Sifting:
Co-sift Bempedoic Acid IH, Lactose Monohydrate (Granulac 200), Microcrystalline Cellulose (Avicel PH 101) & Sodium Starch Glycolate (Type A) through #30 sieve using vibro sifter and collect the sifted material.
(C) Binder Solution Preparation:
1. Sift Hydroxypropyl Cellulose SSL through #30 sieve using vibro sifter and collect the sifted material.
2. Take purified water in glass beaker separately.
3. Add Hydroxypropyl Cellulose SSL of step 1 in to Purified Water of step 2 under stirring using stirrer and continue stirring till clear solution observed.

(D) Wet granulation:
1. Transfer the material of step- (C) into the Rapid Mixer Granulator and carry out dry mixing process.
2. Carry out wet granulation of dry mix of step 1 with use of binder solution of step- (C) in rapid mixer granulator. If require add additional Purified Water till granulation end point achieved.
3. Sift the dried granules of step 8 through #20 sieve using vibro sifter and collect the #20 sieve passed. Further, Mill the #20 sieve retained materials of step 9 through Uniconemill / multi mill equip with 1 mm screen and collect the milled materials.
4. Sift the milled materials of step 10 through #20 sieve and mix it with previously #20 passed material of step 3.
(E) Blending & Lubrication:
1. Co-sift Microcrystalline cellulose 112, colloidal Silicone Dioxide and Sodium Starch Glycolate (Type A) through #30 sieve using vibro sifter and collect the sifted materials
2. Lubricate the blend of step 1 with sifted Magnesium Stearate for 5 minutes at 15 RPM.
(F) Compression:
Compress the lubricated blend of step- (E) with use of Single Rotary Compression Machine.
(G) Film coating:
Disperse coloring material i.e., DR COAT HSP in Purified Water under stirring and continue stirring for 45 minutes to get homogeneous coating dispersion.
(H) Finally carry out the film coated oral dosage form, which in the form of a tablet to provide the final dosage form.
The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. All percentages stated in this specification are by weight, unless otherwise specified. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:
EXAMPLE-1: Selection of Lubricants in intra-granular portion to avoid sticking in granulation
Bempedoic acid is BCS Class II compounds which means that it is poorly soluble in water and highly permeable. The inventors of the present invention observed that in the solid state, Bempedoic acid exhibits poor flow characteristics and is very sticky. The observed stickiness adversely impacts various stages during development of pharmaceutical formulations including weighing, blending, granulation and compression. These problems adversely impact drug manufacturing operations, notably tablet compression (low rpm operation, weight variation, frequent machine stoppage; etc.). Standard granulation of Bempedoic acid only marginally reduces the sticky behavior thereby improving processability. Bempedoic acid also has a relatively low melting point, 88 - 91 °C, and as such contributes to the diminished plasticity of the bulk.
The inventors of the present invention have observed that due to cohesive property of the Bempedoic Acid, without addition of any lubricants, there is sticking problem not only in compression but also in granulation process as well.
Hence, to decide the best combinations of lubricants, the inventors of the present invention undergone a series of experiments wherein various lubricants were randomly selected and added to the intra-granular portion as well as extra-granular portion. These lubricants were admixed with Bempedoic acid wherein blending time was also varied and the appropriate lubricant was selected along with minimum blending time wherein least sticking was observed.
The inventors of the present invention carried out following series of experiments and their results are reported accordingly in below table-1 and table-2.
Table-1: Selection of Lubricants in Intra-granular Portion
Intra-granular portion Blending time with Bempedoic Acid Sticking tendency in granulation
Only Bempedoic Acid free of Lubricants - +++++
Magnesium alumino metasilicate 15 min +++
30 min +
45 min ++
Colloidal Silicon Dioxide 15 min ++++
30 min +++
45 min ++
Sodium Stearyl Fumarate 15 min ++++
30 min ++++
45 min +++
Magnesium Stearate 15 min ++++
30 min ++++
45 min +++
Talc 15 min ++++
30 min +++
45 min ++
From above experiments, the inventors of the present invention surprisingly observed that Bempedoic acid without addition of any of the lubricant shown very high sticky nature and hence, granulation was very much difficult. Therefore, the inventors of the present invention have experimented to check which lubricant and in which admixing / blending time with Bempedoic acid provides better results in lowest time. Therefore, from above table-1, the inventors of the present invention surprisingly found that when Magnesium alumino metasilicate is admixed or blended with Bempedoic acid for 30 minutes, the lowest sticking is observed. Hence, based on above experiments, Magnesium alumino metasilicate was selected in intra-granular portion for further experiments.

EXAMPLE-2: Selection of Lubricants in extra-granular portion to avoid sticking in compression
After achieving the less sticking in granulation process, the next challenge stood before the inventors of the present intention was to achieve least sticking in compression process as well. From above experiments reported in table-2, the inventors of the present invention surprisingly observed that Bempedoic acid granules without addition of any of the lubricant shown very high sticky nature and hence, compression was very much difficult. Therefore, the inventors of the present invention have experimented to check which lubricant and in which admixing / blending time with Bempedoic acid granules provides better results in lowest time. The results of the experiments are shown as below:
Table-2: Selection of Lubricants in Extra-granular Portion
Extra-granular portion Blending time with Bempedoic Acid granules Sticking tendency in Compression
Only Bempedoic Acid granules free of Lubricants - +++++
Magnesium alumino metasilicate 15 min +++
30 min ++
45 min ++
Colloidal Silicon Dioxide 15 min +++
30 min +
45 min +
Sodium Stearyl Fumarate 15 min ++++
30 min +++
45 min ++
Magnesium Stearate 15 min +++
30 min +
45 min +
Talc 15 min +++
30 min ++
45 min ++
From above table-2, the inventors of the present invention surprisingly found that when colloidal silicon dioxide and magnesium stearate are admixed or blended with Bempedoic acid for 30 minutes, the lowest sticking is observed during the compression process. Hence, based on above experiments, colloidal silicon dioxide (Aerosil) and magnesium stearate were selected in extra-granular portion for further experiments.

EXAMPLE- 3:
Sr. No. Ingredients %w/w mg/tab
Intragranular Ingredients
1 Bempedoic Acid 60.00 180.00
2 Neusilin UFL2 (magnesium aluminometasilicate) 3.00 9.00
3 Microcrystalline Cellulose PH 101 14.20 42.60
4 Sodium starch Glycolate Type A 5.33 16.00
Total weight of Dry Mix 82.53 247.60
Binder Solution
5 Povidone (Kollidon® 30) 2.00 6.00
6 Purified Water Q. S Q. S
Total weight of Dried Granules 84.53 253.60
Blending
7 Foremost NF Fast Flo®
(Lactose Modified, Spray Dried 316) 11.00 33.00
8 Colloidal Silicon Dioxide 1.00 3.00
9 Sodium starch Glycolate Type A 2.67 8.00
Lubrication
10 Magnesium stearate 0.80 2.40
Total Weight of Uncoated Tablet 100.00 300.00
Process for preparation:
Step-1: Preparation of dry blend for granulation:
Bempedoic Acid, Neusilin UFL2 (magnesium aluminometasilicate), Microcrystalline cellulose, Sodium starch Glycolate were mixed and sifted to form the dry blend for granulation which was then filled in rapid mixer granulator (RMG) or fluidized bed processor (FBP).
Step-2: Preparation of binding solution:
Povidone (Kollidon® 30) was added into Purified water under stirring to prepare binding solution.

Step-3: Preparation of granules:
Binding solution prepared as per step-2 was admixed with dry blend prepared in step-1 in a granulator (RMG or FBP). The granules were dried and sized.
Step-4: Lubrication:
The dried and sized granules prepared as per step-3 were lubricated with Foremost NF Fast Flo® Lactose Modified, Spray Dried 316, Colloidal silicon dioxide and magnesium stearate.
Step-5: Compression:
The lubricated granules prepared as per step-4 were subjected to compression to form tablets.
Step-6: Coating:
The tablets prepared as per step-5 were coated with pharmaceutically acceptable coating agents.

EXAMPLE- 4:
Sr. No. Ingredients %w/w mg/tab
Intragranular Ingredients
1 Bempedoic Acid 60.00 180.00
2 Neusilin UFL2 (magnesium aluminometasilicate) 3.67 11.00
3 Microcrystalline Cellulose PH 101 13.13 39.40
4 Sodium starch Glycolate Type A 5.33 16.00
Total weight of Dry Mix 82.13 246.40
Binder Solution
5 Povidone (Kollidon® 30) 2.00 6.00
6 Purified Water Q. S Q. S
Total weight of Dried Granules 84.13 252.40
Blending
7 Foremost NF Fast Flo®
(Lactose Modified, Spray Dried 316) 11.00 33.00
8 Colloidal Silicon Dioxide 1.00 3.00
9 Sodium starch Glycolate Type A 2.67 8.00
Lubrication
10 Magnesium stearate 1.20 3.60
Total Weight of Uncoated Tablet 100.00 300.00
Process for preparation:
Step-1: Preparation of dry blend for granulation:
Bempedoic Acid, Neusilin UFL2 (magnesium aluminometasilicate), Microcrystalline cellulose, Sodium starch Glycolate were mixed for 10 minutes and sifted to form the dry blend for granulation which was then filled in rapid mixer granulator (RMG) or fluidized bed processor (FBP).

Step-2: Preparation of binding solution:
Povidone (Kollidon® 30) was added into Purified water under stirring to prepare binding solution.

Step-3: Preparation of granules:
Binding solution prepared as per step-2 was admixed with dry blend prepared in step-1 in a granulator (RMG or FBP). The granules were dried and sized.

Step-4: Lubrication:
The dried and sized granules prepared as per step-3 were lubricated with Foremost NF Fast Flo® Lactose Modified, Spray Dried 316, Colloidal silicon dioxide and magnesium stearate.

Step-5: Compression:
The lubricated granules prepared as per step-4 were subjected to compression to form tablets.

Step-6: Coating:
The tablets prepared as per step-5 were coated with pharmaceutically acceptable coating agents.

EXAMPLE- 5:
Sr. No. Ingredients %w/w mg/tab
Intragranular Ingredients
1 Bempedoic Acid 60.00 180.00
2 Neusilin UFL2 (magnesium aluminometasilicate) 3.67 11.00
3 Microcrystalline Cellulose PH 101 13.13 39.40
4 Sodium starch Glycolate Type A 5.33 16.00
Total weight of Dry Mix 82.13 246.40
Binder Solution
5 Povidone (Kollidon® 30) 2.00 6.00
6 Purified Water Q. S Q. S
Total weight of Dried Granules 84.13 252.40
Blending
7 Foremost NF Fast Flo®
(Lactose Modified, Spray Dried 316) 11.00 33.00
8 Colloidal Silicon Dioxide 1.00 3.00
9 Sodium starch Glycolate Type A 2.67 8.00
Lubrication
10 Magnesium stearate 1.20 3.60
Total Weight of Uncoated Tablet 100.00 300.00
Process for preparation:
Step-1: Preparation of dry blend for granulation:
Bempedoic Acid and Neusilin UFL2 (magnesium aluminometasilicate) was mixed together for 15 mins for uniform covering the API particles with Neusilin UFL2 to avoid stickiness during the compression and then added other Intragranular materials. Microcrystalline cellulose, Sodium starch Glycolate were mixed for 10 minutes with above material and sifted to form the dry blend for granulation which was then filled in rapid mixer granulator (RMG) or fluidized bed processor (FBP).

Step-2: Preparation of binding solution:
Povidone (Kollidon® 30) was added into Purified water under stirring to prepare binding solution.

Step-3: Preparation of granules:
Binding solution prepared as per step-2 was admixed with dry blend prepared in step-1 in a granulator (RMG or FBP). The granules were dried and sized.

Step-4: Lubrication:
The dried and sized granules prepared as per step-3 were lubricated with Foremost NF Fast Flo® Lactose Modified, Spray Dried 316, Colloidal silicon dioxide and magnesium stearate.

Step-5: Compression:
The lubricated granules prepared as per step-4 were subjected to compression to form tablets.

Step-6: Coating:
The tablets prepared as per step-5 were coated with pharmaceutically acceptable coating agents.

EXAMPLE- 6:
Sr. No. Ingredients Qty./tab (mg) % w/w
Intra-granular materials
1. Bempedoic acid 180.00 55.38
2. Lactose monohydrate (Pharmatose 200M) 15.00 4.62
3. Microcrystalline cellulose 101 42.00 12.92
4. Sodium starch glycolate (type A) 5.00 1.54
5. Hydroxyl propyl cellulose SSL 13.00 4.00
6. Purified water q. s -
Extra-granular material
1. Microcrystalline cellulose 112 49.00 15.08
2. Sodium starch glycolate (type A) 4.00 1.23
3. Colloidal silicon dioxide (Aerosil 200) 10.00 3.08
4. Magnesium stearate 7.00 2.15
Total weight of core tablets 325.00 100.00
Film coating
1. DR COAT HSP 9.75 -
2. Purified water q. s -
Total weight of coated tablets 334.75 -
q.s * As per requirement of the composition preparation.
Process for preparation:
Step-1: Dispense all the raw material.

Step-2: Sifting:
Co-sift Bempedoic Acid IH, Lactose Monohydrate (Granulac 200), Microcrystalline Cellulose (Avicel PH 101) & Sodium Starch Glycolate (Type A) through #30 sieve using vibro sifter and collect the sifted material.

Step- 3: Binder Solution Preparation:
a. Sift Hydroxypropyl Cellulose SSL through #30 sieve using vibro sifter and collect the sifted material.
b. Take purified water in glass beaker separately.
c. Add Hydroxypropyl Cellulose SSL of step- a in to Purified Water of step- b under stirring using stirrer and continue stirring till clear solution observed.

Step- 4: Wet granulation:
a. Transfer the material of step- 3 into the Rapid Mixer Granulator and carry out dry mixing process.
b. Carry out wet granulation of dry mix of step- a with use of binder solution of step- 3 in rapid mixer granulator. If require add additional Purified Water till granulation end point achieved.
c. Sift the dried granules of step- b through #20 sieve using vibro sifter and collect the #20 sieve passed. Further, Mill the #20 sieve retained materials of step 9 through Uniconemill / multi mill equip with 1 mm screen and collect the milled materials.
d. Sift the milled materials of step- c through #20 sieve and mix it with previously #20 passed material of step 3.

Step- 5: Blending & Lubrication:
a. Co-sift Microcrystalline cellulose 112, colloidal Silicone Dioxide and Sodium Starch Glycolate (Type A) through #30 sieve using vibro sifter and collect the sifted materials
b. Lubricate the blend of step- a with sifted Magnesium Stearate for 5 minutes at 15 RPM.

Step-6: Compression:
Compress the lubricated blend of step- 5 with use of Single Rotary Compression Machine.

Step-7: Film coating:
Disperse coloring material i.e., DRCOAT HSP in Purified Water under stirring and continue stirring for 45 minutes to get homogeneous coating dispersion. Finally carry out the film coated oral dosage form, which in the form of a tablet to provide the final dosage form.

TEST EXAMPLE-1: STRESS STABILITY TESTING
Formulations prepared as per the example-5 were placed under stress stability testing for 15 days at 60°C. Following are the assay and dissolution results for the same:
Sr. No. Parameter Initial After 15 days at 60°C
01. % Assay 101.72 100.69
02. Dissolution Rate
After 15 min 99.1 78.2
After 30 min 102.6 91.2
After 45 min 102.7 95.6
03. % Total Impurities 0.62 1.18

The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described. The following examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.
,CLAIMS:We Claim:
1. A pharmaceutical composition of bempedoic acid oral solid dosage forms comprising bempedoic acid or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, where in more preferable pharmaceutically acceptable excipients may comprise of diluents/ fillers, binders/ polymers, disintegrating agents, glidants, adsorbents, solvents/ vehicles/ granulating fluids, colorants and combinations thereof.

2. A pharmaceutical composition in the form of tablet of bempedoic acid comprising:
a. 100 mg to 1500 mg of bempedoic acid, wherein more preferable 100 mg to 500 mg of bempedoic acid,
b. 1.0 mg to 60 mg of diluents/ fillers, wherein more preferable 4.00 mg to 42.00 mg of diluents/ fillers,
c. 2.00 mg to 20.00 mg of binders/ polymers, wherein more preferable 5.00 mg to 14.00 mg of binders/ polymers,
d. 1.00 mg to 20.00 mg of disintegrating agents, wherein more preferable 3.00 mg to 18.00 mg of disintegrating agents,
e. 1.00 mg to 20.00 mg of glidants, wherein more preferable 2.5 mg to 11.5 mg of glidants,
f. 5.00 mg to 15.00 mg of adsorbents, wherein more preferable 6.00 mg to 12.00 of adsorbents,
g. 20.00 mg to 200.00 mg of solvents/vehicles/ granulating fluid, where in more preferable 35.00 mg to 190.00 mg of solvent/vehicles/ granulating fluid,
h. 1.00 mg to 15.00 mg of colorants, wherein more preferable 5.00 mg to 10.00 mg of colorants.

3. The pharmaceutical composition in the form of a tablet of bempedoic acid as claimed in claim 2 where in composition comprises diluents/ fillers are selected from sugars such as lactose, sucrose glucose, fructose, dextrose, galactose, starch; cellulose derivatives such as microcrystalline cellulose; microcrystalline cellulose PH 101 or microcrystalline cellulose 101, microcrystalline cellulose 112, lactose monohydrate (pharmatose 200M), Foremost NF fast Flo (Lactose Modified, spray Dried 316, carbonates like calcium carbonate; sugar alcohols such as mannitol, sorbitol, erythritol; magnesium carbonate, calcium phosphates kaolin, magnesium oxide, and combination thereof.

4. The pharmaceutical composition in the form of a tablet of bempedoic acid as claimed in claim 2 where in composition comprises binders/ polymers are selected from hydroxyl ethyl cellulose (HEC), hydroxyl propyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), Hydroxy propyl cellulose SSL, Sucrose NF, Starch NF, carbomers, dextrin, ethyl cellulose, methylcellulose, Lactose monohydrate NF EP, JP, povidone, shellac, zein, gelatin, polymethacrylates, polyvinylpyrrolidone or povidone, pre-gelatinized starch, sodium alginate, gums, synthetic resins, silicic acid, hydrophilic polymers and combination thereof.

5. The pharmaceutical composition in the form of a tablet of bempedoic acid as claimed in claim 2 where in composition comprises disintegrating agents are selected from crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate (type A), Microcrystalline cellulose (MCC) NF, EP, JP: 101, 102, 12 (DC) and combination thereof.

6. The pharmaceutical composition in the form of a tablet of bempedoic acid as claimed in claim 2 where in composition comprises glidants are selected from Neusilin UFL2 (magnesium aluminometasilicate), talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide (Aerosil 200) , finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, and combination thereof.

7. The pharmaceutical composition in the form of a tablet of bempedoic acid as claimed in claim 2 where in composition comprises adsorbents are selected from fumed silica, microcrystalline cellulose, magnesium carbonate, kaolin, and bentonite, Neusilin UFL2 (magnesium aluminometasilicate) and combination thereof.

8. The pharmaceutical composition in the form of a tablet of bempedoic acid as claimed in claim 2 where in composition comprises solvents/vehicles/ granulating fluid are selected from water, ethanol, isopropyl alcohol, acetone, propylene glycol, Glycerine and combination thereof.

9. The pharmaceutical composition in the form of a tablet of bempedoic acid as claimed in claim 2 where in composition comprises colorants are selected from DR COAT HSP, Quinoline Yellow WS, Carmoisine, Ponceau 4R, Patent Blue V, and like.

10. Process for the preparation of tablet of bempedoic acid comprises following steps:
Step-1: Dispense all the raw material.

Step-2: Sifting:
Co-sift Bempedoic Acid IH, Lactose Monohydrate (Granulac 200), Microcrystalline Cellulose (Avicel PH 101) & Sodium Starch Glycolate (Type A) through #30 sieve using vibro sifter and collect the sifted material.

Step- 3: Binder Solution Preparation:
a. Sift Hydroxypropyl Cellulose SSL through #30 sieve using vibro sifter and collect the sifted material.
b. Take purified water in glass beaker separately.
c. Add Hydroxypropyl Cellulose SSL of step- a in to Purified Water of step- b under stirring using stirrer and continue stirring till clear solution observed.

Step- 4: Wet granulation:
a. Transfer the material of step- 3 into the Rapid Mixer Granulator and carry out dry mixing process.
b. Carry out wet granulation of dry mix of step- a with use of binder solution of step- 3 in rapid mixer granulator. If require add additional Purified Water till granulation end point achieved.
c. Sift the dried granules of step- b through #20 sieve using vibro sifter and collect the #20 sieve passed. Further, Mill the #20 sieve retained materials of step 9 through Uniconemill / multi mill equip with 1 mm screen and collect the milled materials.
d. Sift the milled materials of step- c through #20 sieve and mix it with previously #20 passed material of step 3.

Step- 5: Blending & Lubrication:
a. Co-sift Microcrystalline cellulose 112, colloidal Silicone Dioxide and Sodium Starch Glycolate (Type A) through #30 sieve using vibro sifter and collect the sifted materials
b. Lubricate the blend of step- a with sifted Magnesium Stearate for 5 minutes at 15 RPM.

Step-6: Compression:
Compress the lubricated blend of step- 5 with use of Single Rotary Compression Machine.

Step-7: Film coating:
Disperse coloring material i.e., DR COAT HSP in Purified Water under stirring and continue stirring for 45 minutes to get homogeneous coating dispersion. Finally carry out the film coated oral dosage form, which in the form of a tablet to provide the final dosage form.

To,
The Controller of Patents,
The Patent Office,
Mumbai.

________________________________
DR. ARAVIND BADIGER
TECHNICAL DIRECTOR