DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
“ FILM COATED TABLET OF BEMPEDOIC ACID”
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
V-ENSURE PHARMA TECHNOLOGIES PRIVATE LIMITED INDIAN A-63, MIDC, TTC Industrial Area, Kopar Khairane, Navi Mumbai -400705, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION

COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed

TITLE OF THE INVENTION
Film coated tablet of bempedoic acid.

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical formulation comprising: a) bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients; b) optionally comprising Ezetimibe or its pharmaceutically acceptable salts thereof; c) optionally comprising statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin; wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.
The invention moreover relates to improve poor flow property of the bempedoic acid or its pharmaceutically acceptable salt thereof and reduce stickiness of bempedoic acid or its salt thereof.

BACKGROUND OF THE INVENTION
Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by inhibition of cholesterol synthesis in the liver. The chemical name of bempedoic acid is 8- hydroxy-2, 2, 14, 14- tetramethyl-pentadecanedioic acid.
The structural formula of Bempedoic acid is as follows:

Bempedoic acid is used to treat hypercholesterolemia in conjunction with diet and the highest tolerated statin medication with established atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia.

Bempedoic acid has low melting point, poor flow and stickiness. It is poorly water soluble which comes under Biopharmaceutical Classification System (BCS) Class II drug.

Esperion Therapeutics Inc. EP3630070A1 application relates to granulated composition of Bempedoic acid admixed with a lubricant selected from the group consisting of: colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate prior to granulation. More specifically EP3630070A1 application covers Bempedoic acid granules prepared by using colloidal silicon dioxide to reduce stickiness of bempedoic acid. Further comprises Ezetimibe granules preparation. Apart from Bempedoic acid granules and Ezetimibe granules extragranular portion is prepared by using lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate.

Esperion Therapeutics Inc. another European application EP3752133 A1 relates to immediate release formulation by using colloidal silicon dioxide, magnesium stearate in the core and sustained release formulation of bempedoic acid by using polymeric matrix of hydroxypropylmethylcellulose.

Synthon’s PCT Application No. WO2023036980 A1 relates to pharmaceutical composition comprising bempedoic acid and magnesium alumino-metasilicate. The WO2023036980 A1 application covers intragranular portion comprises magnesium alumino-metasilicate, low-substituted hydroxypropylcellulose, lactose monohydrate, sodium starch glycolate, povidone and extragranular portion comprises magnesium alumino-metasilicate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide.

Mankind Pharma’s Indian Patent Publication No. IN202011045799 relates to a pharmaceutical composition comprising bempedoic acid or pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipient, wherein the intragranular portion of the said composition is free of colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate. Further extragranular portion comprises colloidal silicon dioxide, sodium starch glycolate, talc, calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate.

There is still requirement to prepare improved pharmaceutical formulation of bempedoic acid or pharmaceutically acceptable salt thereof to reduce the stickiness, to improve flow the properties and deliver improved dissolution profile of finished formulation of bempedoic acid or its pharmaceutically acceptable salt thereof, wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

OBJECT OF THE INVENTION
The object of the present invention relates to a pharmaceutical formulation comprising: a) bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients; b) optionally comprising Ezetimibe or its pharmaceutically acceptable salts thereof; c) optionally comprising statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin; wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

SUMMARY OF THE INVENTION
The summary of the present invention relates to a pharmaceutical formulation comprising: a) bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients; b) optionally comprising Ezetimibe or its pharmaceutically acceptable salts thereof; c) optionally comprising statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin; wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

In one embodiment of the present invention relates to improve poor flow property of the bempedoic acid or its pharmaceutically acceptable salt thereof and reduce stickiness of bempedoic acid or its salt thereof.

In another embodiment of the present invention related to a pharmaceutical formulation of bempedoic acid or pharmaceutically acceptable salts thereof comprises one or more pharmaceutically acceptable excipients selected from the group consisting of but are not limited to fillers, binders, disintegrants, glidants and plasticizers.

In one another embodiment of the present invention relates to a process of preparation of pharmaceutical formulation comprising the steps of:
a) blending bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients;
b) further optionally blending the Ezetimibe with one or more pharmaceutically acceptable excipients;
c) in addition to step b) pharmaceutical formulation optionally comprises statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin;
wherein the composition is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

In further aspect of the present invention relates to the pharmaceutical formulation is in the form of tablets, minitablets, pellets, capsules, granules or spheroids.

In one another aspect of the present invention relates to the said pharmaceutical formulation is optionally coated with water soluble or water insoluble polymers.

DETAILED DESCRIPTION OF THE INVENTION

The detailed description of the present invention relates to a pharmaceutical formulation comprising: a) bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients; b) optionally comprising Ezetimibe or its pharmaceutically acceptable salts thereof; c) optionally comprising statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin; wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

In one embodiment of the present invention relates to improve poor flow property of the bempedoic acid or its pharmaceutically acceptable salt thereof and reduce stickiness of bempedoic acid or its salt thereof, wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide. The stickiness of bempedoic acid or its pharmaceutically acceptable salt thereof has been overcome by admixing monometal silicates, magnesium citrate, talc or starch. The monometal silicates used in the present invention is selected from the group consisting of, but are not limited to, calcium silicate, magnesium silicate, and aluminosilicate.

The adsorbents used in the present invention may be selected from the group consisting of, but are not limited to, monometal silicates such as calcium silicate, magnesium silicate, aluminosilicate, magnesium citrate, talc or starch.

In another embodiment of the present invention relates to a pharmaceutical formulation comprises the lubricants is selected from the group consisting of, but are not limited to, magnesium palmitate, magnesium oleate, hydrogenated castor oil, glyceryl behenate, mineral oil, polyethylene monostearate, sodium benzoate, mineral oil, magnesium stearate, sodium stearyl fumarate.

In another embodiment of the present invention related to a pharmaceutical formulation of bempedoic acid or pharmaceutically acceptable salts thereof comprises one or more pharmaceutically acceptable excipients selected from the group consisting of but are not limited to fillers, binders, disintegrants, glidants and plasticizers.

The fillers used in the present invention is selected from the group consisting of, but are not limited to, calcium lactate, calcium phosphate, calcium sulfate, dextrose, erythritol, isomalt, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polyethylene glycol, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, talc, trehalose, xylitol, cellulose or its derivatives such as hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose.

The binders used in the present invention is selected from the group consisting of, but are not limited to, acacia, alginic acid, sodium alginate, ammonium alginate, calcium carbonate, carbomers, povidone, starch, dextrose, sucrose, zein, carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, polyvinyl pyrrolidine, and combinations thereof.

The disintegrants used in the present invention is selected from the group consisting of, but are not limited to, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, carboxymethylcellulose sodium.

The glidants used in the present invention may be selected from the group consisting of, but are not limited to, talc, aluminium oxide, magnesium oxide, magnesium trisilicate.

The plasticizer(s) used in the present invention may be selected from the group consisting of, but are not limited to, cellulose acetate phthalate, diethyl phthalate, phthalate esters, triethyl citrate, dibutyl sebacate, polyethylene glycol, glycerol, triacetin, tributyl citrate, glycerol, propylene glycol, and combinations thereof.

In one another embodiment of the present invention relates to a process of preparation of pharmaceutical formulation comprising the steps of:
a) blending bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients;
b) further optionally blending the Ezetimibe with one or more pharmaceutically acceptable excipients;
c) in addition to step b) pharmaceutical formulation optionally comprises statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin;
wherein the composition is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

In further aspect of the present invention relates to the pharmaceutical formulation is in the form of tablets, minitablets, pellets, capsules, granules or spheroids.

In one another aspect of the present invention relates to the said pharmaceutical formulation is optionally coated with coating agents. The coating agents are selected from water soluble or water insoluble polymers, film-forming agents, pigments/opacifier such as iron oxide, titanium dioxide, zinc oxide, a plasticizer and one or more other pharmaceutically acceptable excipients.

The water soluble polymers used in the coating according to the present invention is selected from the group consisting of, but are not limited to, hydroxypropylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, modified starch, polyvinyl alcohol, xanthan gum, or polyethylene oxide, polyvinylpyrrolidone (PVP), carboxyvinyl polymer, poloxamer, methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, carrageenans, xanthan gum, and mixtures of one or more thereof.

The water insoluble polymers used in the coating according to the present invention is selected from the group consisting of, but are not limited to, acrylic acid polymers, polymethacrylates or methacrylic acid copolymers, ethylcellulose, cellulose acetate, hydroxypropylcellulose succinate, hydroxypropylmethylcellulose succinate, alginate, acacia, chitosan, carmellose sodium, carmellose calcium, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, shellac and derivatives and mixtures thereof.
The term “adsorbent” used herein means “an agent used to bind another component form within a pharmaceutical formulation, acting as a carrier.”

The term “formulation” used herein means that it is a pharmaceutical formulation which is suitable for administration to a patient. Other terms such as “composition” or “dosage form” are used herein interchangeably.

EXAMPLES:
The present invention is specifically illustrated by way of the following examples but the present invention is not limited to the content thereof.
Example 1:
Sr. No Ingredients Function mg/tab %w/w
Intragranular Part
1. Bempedoic acid API 180 54.55
2. Lactose Monohydrate Filler 28.5 8.64
3. Microcrystalline cellulose 101 Filler 41.25 12.5
4. Sodium starch glycolate Disintegrant 8.25 2.5
5. Calcium Silicate Glidant 11.55 3.5
Granulating Fluid
6. Water Solvent QS -
7. Hydroxypropyl cellulose Binder 9.9 3
Extragranular Part
8. Sodium starch glycolate Disintegrant 9.9 3
9. Microcrystalline cellulose 102 Filler 34.05 10.32
10. Calcium Silicate Glidant 3.3 1
11. Magnesium stearate Lubricant 3.3 1
Weight of Core tablet 330 100
Film Coating
12. Opadry II Film Coating 10 3.03
Weight of Coated tablet 340 -

Example 1: Manufacturing Process
i) The pharmaceutical formulation of Bempedoic acid is prepared by sifting the intragranular part as bempedoic acid, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and calcium silicate through #40 mesh;
ii) Granulating fluid is prepared by using hydroxypropyl cellulose with sufficient amount of water;
iii) Granulate the intragranular part in a rapid mixer granulator using granulating fluid;
iv) Sifting the extragranular part as sodium starch glycolate, microcrystalline cellulose, and calcium silicate through #40 mesh;
v) Blend the dried granules of intragranular part along with extragranular part, and the blend is lubricated with magnesium stearate;
vi) The lubricated blend obtained in step v) is compressed into the tablets and coated with film coating.

Example 2:
Sr. No Ingredients Function mg/tab %w/w
Intragranular
1. Bempedoic acid API 180 54.55
2. Lactose Monohydrate Filler 28.5 8.64
3. Microcrystalline cellulose 101 Filler 52.8 16
4. Sodium starch glycolate Disintegrant 8.25 2.5
Granulating Fluid
5. Water Solvent QS -
6. Hydroxypropyl cellulose Binder 9.9 3
Extragranular
7. Sodium starch glycolate Disintegrant 9.9 3
8. Microcrystalline cellulose 102 Filler 37.35 11.32
9. Magnesium stearate Lubricant 3.3 1
Weight of Core tablet 330 100
Film Coating
10. Opadry II Film Coating 10 3.03
Weight of Coated tablet 340 -

Example 2: Manufacturing Process
i) The pharmaceutical formulation of Bempedoic acid is prepared by sifting the intragranular part as bempedoic acid, lactose monohydrate, microcrystalline cellulose, and sodium starch glycolate through #40 mesh;
ii) Granulating fluid is prepared by using hydroxypropyl cellulose with sufficient amount of water;
iii) Granulate the intragranular part in a rapid mixer granulator using granulating fluid;
iv) Sifting the extragranular part as sodium starch glycolate, and microcrystalline cellulose through #40 mesh;
v) Blend the dried granules of intragranular part along with extragranular part, and the blend is lubricated with magnesium stearate;
vi) The lubricated blend obtained in step v) is compressed into the tablets and coated with film coating.

WE CLAIM:

1. A pharmaceutical formulation comprising:
a) bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients;
b) optionally comprising Ezetimibe or its pharmaceutically acceptable salts thereof;
c) optionally comprising statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin;
wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

2. A pharmaceutical formulation as claimed in claim 1, monometal silicates selected from the group consisting of calcium silicate, magnesium silicate, aluminosilicate.

3. A pharmaceutical formulation of bempedoic acid as claimed in claim 1, lubricants selected from the group consisting of but are not limited to, magnesium palmitate, magnesium oleate, hydrogenated castor oil, glyceryl behenate, mineral oil, polyethylene monostearate, sodium benzoate, mineral oil.

4. A pharmaceutical formulation of bempedoic acid as claimed in claim 1, one or more pharmaceutically acceptable excipients selected from the group consisting of but are not limited to fillers, binders, disintegrants, glidants and plasticizers.

5. A process of preparation of pharmaceutical formulation comprising the steps of:
a) blending bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients;
b) further optionally blending the Ezetimibe with one or more pharmaceutically acceptable excipients;
c) in addition to step b) pharmaceutical formulation optionally comprises statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin;
wherein the composition is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

6. A pharmaceutical formulation as claimed in claim 1, wherein the said formulation is in the form of tablets, minitablets, pellets, capsules, granules or spheroids.

7. A pharmaceutical formulation as claimed in claim 1, wherein said formulation is optionally coated with water soluble or water insoluble polymers.

Dated this: 27th day of November, 2024

Vijaykumar Shivpuje
IN/PA-1096
Agent for the Applicant
To
The Controller of Patents
The Patent Office, Mumbai

ABSTRACT
FILM COATED TABLET OF BEMPEDOIC ACID
The present invention relates to a pharmaceutical formulation comprising: a) bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients; b) optionally comprising Ezetimibe or its pharmaceutically acceptable salts thereof; c) optionally comprising statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin; wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide. The invention furthermore relates to improve poor flow property of the bempedoic acid or its pharmaceutically acceptable salt thereof and reduce stickiness of bempedoic acid or its salt thereof.

,CLAIMS:WE CLAIM:

1. A pharmaceutical formulation comprising:
a) bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients;
b) optionally comprising Ezetimibe or its pharmaceutically acceptable salts thereof;
c) optionally comprising statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin;
wherein the formulation is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

2. A pharmaceutical formulation as claimed in claim 1, monometal silicates selected from the group consisting of calcium silicate, magnesium silicate, aluminosilicate.

3. A pharmaceutical formulation of bempedoic acid as claimed in claim 1, lubricants selected from the group consisting of but are not limited to, magnesium palmitate, magnesium oleate, hydrogenated castor oil, glyceryl behenate, mineral oil, polyethylene monostearate, sodium benzoate, mineral oil.

4. A pharmaceutical formulation of bempedoic acid as claimed in claim 1, one or more pharmaceutically acceptable excipients selected from the group consisting of but are not limited to fillers, binders, disintegrants, glidants and plasticizers.

5. A process of preparation of pharmaceutical formulation comprising the steps of:
a) blending bempedoic acid or pharmaceutically acceptable salts thereof admixed with monometal silicates, magnesium citrate, talc or starch and lubricants, optionally one or more pharmaceutically acceptable excipients;
b) further optionally blending the Ezetimibe with one or more pharmaceutically acceptable excipients;
c) in addition to step b) pharmaceutical formulation optionally comprises statins selected from the group consisting of rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, roxadustat, mevastatin, pitavastatin;
wherein the composition is devoid of magnesium aluminometasilicate, colloidal silicon dioxide.

6. A pharmaceutical formulation as claimed in claim 1, wherein the said formulation is in the form of tablets, minitablets, pellets, capsules, granules or spheroids.

7. A pharmaceutical formulation as claimed in claim 1, wherein said formulation is optionally coated with water soluble or water insoluble polymers.