DESC:FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising Saroglitazar or a pharmaceutically acceptable salt thereof. The present invention, more particularly, relates to tablet formulation comprising Saroglitazar or a pharmaceutically acceptable salt thereof, methods of preparation thereof, and their use in medical therapy.

BACKGROUND OF THE INVENTION

Saroglitazar is a dual regulator that corrects both the lipid profile and the glycemic indices. The chemical name for Saroglitazar is Benzenepropanoic acid, a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-1H- pyrrol-1-yl]ethoxy].

Saroglitazar is indicated for the treatment of Noncirrhotic Non-Alcoholic Steatohepatitis, Non-alcoholic Fatty Liver Disease (NAFLD) with comorbidities (like obesity, Type 2 Diabetes Mellitus, Dyslipidemia or Metabolic Syndrome), and high cholesterol in diabetes (diabetic dyslipidemia).

IN220639 discloses Saroglitazar or a pharmaceutically acceptable salt thereof and IN299505 specifically discloses magnesium salt of Saroglitazar.

IN312723 discloses stable pharmaceutical compositions of a suitable hypolipidemic agent, specifically, stable pharmaceutical composition of Saroglitazar with alkalinizers or pH modifying agents along with a stabilizer, wherein the stabilizer is selected from antioxidants or chelating agents, and the alkalinizers or pH modifying agents is used to maintain the pH of the formulation above 7. The composition is used primarily for triglyceride lowering, with concomitant beneficial effect on glucose lowering and cholesterol lowering.

IN363777 discloses a pharmaceutical composition of Saroglitazar with suitable additives and a stabilizer, wherein the stabilizer is selected from antioxidants or chelating agents. Further discloses the use of composition for treating and preventing disorder such as nonalcoholic fatty liver disease (NAFLD) including fatty liver (steatosis), nonalcoholic steatohepatitis (NASH), and cirrhosis (advanced scarring of the liver).

IN201621012604 discloses a pharmaceutical composition of Saroglitazar with alkalinizers or pH modifying agents along with a stabilizer, wherein the stabilizer is selected from antioxidants or chelating agents, and the alkalinizers or pH modifying agents is used to maintain the pH of the formulation above 7. The composition is used for prevention or treatment of a disease or condition related with disorders of IBO.

Despite the above mentioned prior art disclosing various pharmaceutical compositions of Saroglitazar or a pharmaceutically acceptable salt thereof comprising alkalinizers or pH modifying agents along with a stabilizers selected from antioxidants or chelating agents, there still exists a need for a stable oral pharmaceutical composition of Saroglitazar or a pharmaceutically acceptable salt thereof which ensures the desired therapeutic effect, when correctly administered, without using any conventional alkalinizers, pH modifying agents and/or stabilizers such as antioxidants or chelating agents.

The inventors of the present invention surprisingly found that a stable pharmaceutical composition of saroglitazar or a pharmaceutically acceptable salt thereof can be made without using the conventional alkalinizers, pH modifying agents or stabilizing excipients as disclosed in prior art.

OBJECT OF THE INVENTION

It is an object of the present invention to provide a stable pharmaceutical composition comprising Saroglitazar or a pharmaceutically acceptable salt thereof, and process for preparing such composition for the treatment of Noncirrhotic Non-Alcoholic Steatohepatitis, Non-alcoholic Fatty Liver Disease (NAFLD) with comorbidities (like obesity, Type 2 Diabetes Mellitus, Dyslipidemia or Metabolic Syndrome), and high cholesterol in diabetes (diabetic dyslipidemia).

It is another object of the present invention to provide a stable pharmaceutical composition, for oral administration comprising:
a) Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) one or more adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) Diluents or mixture thereof;
d) Binder;
e) Disintegrant;
f) one or more pharmaceutically acceptable excipients.

It is another object of the present invention to provide a stable pharmaceutical composition, for oral administration comprising:
a) about 4.2 mg of Saroglitazar or a pharmaceutically acceptable salt thereof;
b) about 15 mg of Adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) about 67 mg of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 3 mg of Polyvinylpyrrolidone K-30;
e) about 8 mg of Croscarmellose Sodium;
f) about 1 mg of talc;
g) about 1 mg of Aerosil 200;
h) about 1 mg of Magnesium stearate.

It is another object of the present invention to provide a stable pharmaceutical composition, for oral administration comprising:
a) about 1-10 mg of Saroglitazar or a pharmaceutically acceptable salt thereof;
b) about 5-20 mg of Adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) about 15-75 mg of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 1-10 mg of Polyvinylpyrrolidone K-30;
e) about 4-15 mg of Croscarmellose Sodium;
f) about 0.5-10 mg of talc;
g) about 0.5-7 mg of Aerosil 200;
h) about 0.5- 5 mg of Magnesium stearate.

It is another object of the present invention to provide a stable pharmaceutical composition, for oral administration comprising:
a) about 4.2% w/w of Saroglitazar Calcium;
b) about 15% w/w of Neusilin S2 (Magnesium Alumino metasilicate);
c) about 67 % w/w of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 3% w/w of Polyvinylpyrrolidone K-30
e) about 8% w/w of Croscarmellose Sodium
f) about 1% w/w of talc
g) about 1% w/w of Aerosil 200
h) about 1% w/w of Magnesium stearate

It is another object of the present invention to provide a stable pharmaceutical composition, for oral administration comprising:
a) about 1-10% w/w of Saroglitazar Calcium;
b) about 5-20% w/w of Neusilin S2 (Magnesium Alumino metasilicate);
c) about 15-75% w/w of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof
d) about 1-10% w/w of Polyvinylpyrrolidone K-30;
e) about 4-15% w/w of Croscarmellose Sodium;
f) about 0.5-10% w/w of talc;
g) about 0.5-7% w/w of Aerosil 200
h) about 0.5-5% w/w of Magnesium stearate

It is also another object of the present invention to provide a process for preparing stable pharmaceutical composition using different methods such as direct compression, dry granulation or wet granulation, comprising-
a) Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) one or more adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) Diluents or mixture thereof;
d) Binder;
e) Disintegrant;
f) one or more pharmaceutically acceptable excipients.

It is yet another object of the present invention to provide a tablet composition comprising Saroglitazar or a pharmaceutically acceptable salt thereof used for the treatment of Noncirrhotic Non-Alcoholic Steatohepatitis, Non-alcoholic Fatty Liver Disease (NAFLD) with comorbidities (like obesity, Type 2 Diabetes Mellitus, Dyslipidemia or Metabolic Syndrome), and high cholesterol in diabetes (diabetic dyslipidemia).

It is yet another object of the present invention to provide a stable pharmaceutical composition of Saroglitazar calcium, which uses a new and different beneficial formulation and is still bioequivalent to the commercially available compositions in India i.e. LIPAGLYNTM tablets and BILYPSA® tablets.

SUMMARY OF THE INVENTION

The present invention provides the following aspects, subject-matters and preferred embodiments, which respectively taken alone or in combination, further contribute to solving the object of the present invention.

The present invention provides a stable pharmaceutical composition comprising Saroglitazar or a pharmaceutically acceptable salt thereof and a process for preparing thereof.

The present invention provides a pharmaceutical composition comprising Saroglitazar or a pharmaceutically acceptable salt thereof which surprisingly shows an improved stability.

More particularly, the present invention relates to
A) A stable pharmaceutical composition comprising:
i. Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
ii. one or more adsorbent;
iii. Diluents or mixture thereof;
iv. Binder;
v. Disintegrant;
vi. one or more pharmaceutically acceptable excipients.

B) The stable pharmaceutical composition according to A), wherein the one or more adsorbent is selected from Magnesium-Aluminometasilicate, Hydrated aluminum silicate and mixtures thereof.

C) The stable pharmaceutical composition according to A), wherein the composition is in tablet dosage form.

D) The stable pharmaceutical composition according to A), wherein the one or more pharmaceutically acceptable excipient(s) is selected from diluent, binder, disintegrant, lubricant and the like.

E) The stable pharmaceutical composition according to A), wherein the diluent is lactose monohydrate.

F) The stable pharmaceutical composition according to A), wherein the binder is polyvinylpyrrolidone.

G) The stable pharmaceutical composition according to A), wherein the lubricant is magnesium stearate, talc and colloidal silicon dioxide.

H) The stable pharmaceutical composition according to A), wherein the composition is suitable for use in the treatment of Noncirrhotic Non-Alcoholic Steatohepatitis, Non-alcoholic Fatty Liver Disease (NAFLD) with comorbidities (like obesity, Type 2 Diabetes Mellitus, Dyslipidemia or Metabolic Syndrome), and high cholesterol in diabetes (diabetic dyslipidemia).

In one aspect of the present invention, there is provided a stable pharmaceutical composition, for oral administration comprising:
a) Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) one or more adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) Diluents or mixture thereof;
d) Binder;
e) Disintegrant;
f) one or more pharmaceutically acceptable excipients.

In another aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) about 4.2 mg of Saroglitazar or a pharmaceutically acceptable salt thereof;
b) about 15 mg of Adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) about 67 mg of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 3 mg of Polyvinylpyrrolidone K-30;
e) about 8 mg of Croscarmellose Sodium;
f) about 1 mg of talc;
g) about 1 mg of Aerosil 200;
h) about 1 mg of Magnesium stearate.

In yet another aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) about 1-10 mg of Saroglitazar or a pharmaceutically acceptable salt thereof;
b) about 5-20 mg of Adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) about 15-75 mg of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 1-10 mg of Polyvinylpyrrolidone K-30;
e) about 4-15 mg of Croscarmellose Sodium;
f) about 0.5-10 mg of talc;
g) about 0.5-7 mg of Aerosil 200;
h) about 0.5- 5 mg of Magnesium stearate.

In one aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) about 4.2% w/w of Saroglitazar Calcium;
b) about 15% w/w Neusilin S2 (Magnesium Alumino metasilicate);
c) about 67 % w/w of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 3% w/w of Polyvinylpyrrolidone K-30
e) about 8% w/w of Croscarmellose Sodium
f) about 1% w/w of talc
g) about 1% w/w of Aerosil 200
h) about 1% w/w of Magnesium stearate

In another aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) about 1-10% w/w of Saroglitazar Calcium;
b) about 5-20% w/w Neusilin S2 (Magnesium Alumino metasilicate);
c) about 15-75% w/w of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof
d) about 1-10% w/w of Polyvinylpyrrolidone K-30;
e) about 4-15% w/w of Croscarmellose Sodium;
f) about 0.5-10% w/w of talc;
g) about 0.5-7% w/w of Aerosil 200
h) about 0.5-5% w/w of Magnesium stearate

In yet another aspect of the present invention there is provided a process for preparing stable pharmaceutical composition using different methods such as direct compression, dry granulation or wet granulation, comprising-
a) Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) one or more adsorbent;
c) Diluents or mixture thereof;
d) Binder;
e) Disintegrant;
f) one or more pharmaceutically acceptable excipients.

DESCRIPTION OF THE INVENTION

Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas, or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is to describe particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the step" includes reference to one or more steps and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their availability to the applicant before the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by the prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

According to one aspect, the present invention provides a stable pharmaceutical composition for oral administration comprising:
a) Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) one or more adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) Diluents or mixture thereof;
d) Binder;
e) Disintegrant;
f) one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form.

The term "stable" as used herein refers to a pharmaceutical composition of the present invention, which after 3 or 6 months storage at 40 ± 2°C / 75 ± 5 % RH, 30 ± 2°C / 75 ± 5 % RH and 25 ± 2°C / 75 ± 5 % RH has at least 90, 95, or 98% of the initial amount of active ingredient (here, Saroglitazar) and the amount of Sulfoxide impurity is Not More than 1%.

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

The compositions in accordance with the present invention can be prepared either by direct compression, dry granulation or wet granulation method.

As term “active ingredient” as used herein means an ingredient or compound having an intended biological effect. “Active ingredient” may be broadly construed to include an active compound and vice versa. Such active ingredients or active compounds are thus considered to be “biologically active”.

The term "pharmaceutically acceptable salt" is suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of a reasonable medical evaluation, and has a reasonable benefit. Pharmaceutically acceptable salts of the saroglitazar of the present invention include alkali or alkaline earth metal salts selected from lithium, barium, strontium, zinc, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, metformin-l-glutamic acid, sodium, potassium, calcium, lysine, arginine, guanidine and its derivatives, tromethamine, d?ethanolamine, choline, ammonium, substituted ammonium salts, or an aluminium salts; or ammonium salt or organic amines salts selected from methylamine, dimethylamine, ethylamine, diethylamine, 1,2-ethanediamine, n-propylamine, isopropylamine, diisopropylamine, N-methyl isopropylamine, n-butylamine, t-butylamine, 2-butamine, 1,2-ethanediamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N- (4-aminobutyl) guanidine, dicyclohexylamine, benzene- methanamine, ethanolamine, diethanolamine, tris- (hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, L-alanine, L- lysine, D-lysine, L-arginine, L-histidine, L-threonine, 2-thiopheneethanamine, (2S)- 3,3-dimethyl-2-butanamine, cyclopentanamine, and cycloheptanamine.

The term "excipient" as used herein means a pharmacologically inactive component such as, but not limited to, a diluent or filler, binder, disintegrant, lubricant, glidant, surfactant, colorant, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic, and are acceptable for human use.

The term “adsorbent” as used herein is meant to encompass a substance that has the ability to condense or hold molecules of other substances on its surface or in its inner structure, an activity often referred as “adsorbing” or “absorbing”, respectively. Examples of such adsorbents include Neusilin S2 (Magnesium Alumino metasilicate), Kaolin (Hydrated aluminum silicate) and mixtures thereof.

In one aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) one or more adsorbent;
c) Diluents or mixture thereof;
d) Binder;
e) Disintegrant;
f) one or more pharmaceutically acceptable excipients.

In another aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) about 4.2 mg of Saroglitazar or a pharmaceutically acceptable salt thereof;
b) about 15 mg of Adsorbent such as Neusilin S2 (Magnesium Alumino metasilicate);
c) about 67 mg of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 3 mg of Polyvinylpyrrolidone K-30;
e) about 8 mg of Croscarmellose Sodium;
f) about 1 mg of talc;
g) about 1 mg of Aerosil 200;
h) about 1 mg of Magnesium stearate.

In yet another aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) about 1-10 mg of Saroglitazar or a pharmaceutically acceptable salt thereof;
b) about 5-20 mg of Neusilin S2 (Mag Aluminometasilicate);
c) about 15-75 mg of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 1-10 mg of Polyvinylpyrrolidone K-30;
e) about 4-15 mg of Croscarmellose Sodium;
f) about 0.5-10 mg of talc;
g) about 0.5-7 mg of Aerosil 200;
h) about 0.5- 5mg of Magnesium stearate.

In one aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) about 4.2% w/w of Saroglitazar Calcium;
b) about 15% w/w of Neusilin S2 (Mag Aluminometasilicate);
c) about 67 % w/w of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 3% w/w of Polyvinylpyrrolidone K-30;
e) about 8% w/w of Croscarmellose Sodium;
f) about 1% w/w of talc;
g) about 1% w/w of Aerosil 200;
h) about 1% w/w of Magnesium stearate.

In another aspect of the present invention there is provided a stable pharmaceutical composition, for oral administration comprising:
a) about 1-10% w/w of Saroglitazar or a pharmaceutically acceptable salt thereof;
b) about 5-20% w/w of Neusilin S2 (Mag Aluminometasilicate);
c) about 15-75% w/w of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 1-10% w/w of Polyvinylpyrrolidone K-30;
e) about 4-15% w/w of Croscarmellose Sodium;
f) about 0.5-10% w/w of talc;
g) about 0.5-7% w/w of Aerosil 200;
h) about 0.5-5% w/w of Magnesium stearate.

In yet another aspect of the present invention there is provided a process for preparing stable pharmaceutical composition using different methods such as direct compression, dry granulation or wet granulation, comprising-
a) Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) one or more adsorbent;
c) Diluents or mixture thereof;
d) Binder;
e) Disintegrant;
f) one or more pharmaceutically acceptable excipients.

In a further embodiment, the lubricants used in the composition of the present invention are selected from the group consisting of metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and the like and mixtures thereof.

In a further embodiment, the fillers or diluents used in the composition of the present invention are selected from the group consisting of sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches, and carbohydrate derivatives, polysaccharides (including dextrose and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like. In certain preferred embodiments, the filler or diluent is lactose, microcrystalline cellulose, or a combination thereof. Several types of microcrystalline cellulose are suitable for use in the formulations described herein, for example, microcrystalline cellulose selected from the group consisting of Avicel® types: PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. Several types of lactose are suitable for use in the formulations described herein, for example, lactose is selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flow, directly compressible anhydrous lactose, and modified lactose monohydrate. In one embodiment of the invention, the filler or diluent is a combination of microcrystalline cellulose and lactose.
In a further embodiment, the binders used in the composition of the present invention are selected from the group consisting of cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, ethylcellulose and sodium carboxymethyl cellulose), sugar (including sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), glycol, corn syrup, polysaccharides (including acacia, tragacanth, guar, alginates, and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like. Preferably, the binding agent, if present, is hydroxypropyl cellulose.
In a further embodiment, the disintegrants used in the composition of the present invention are selected from the group consisting of starches, clays, celluloses, alginates, and gums, and crosslinked starches, and polymers, combinations thereof, and the like. Representative disintegrants include microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar, and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like. Preferably, the disintegrant, if present, is cross-linked cellulose, more preferably cross-linked sodium carboxymethylcellulose or croscarmellose sodium.

In a further embodiment, the glidants used in the composition of the present invention are selected from the group consisting of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, or mixtures thereof. Glidant may be used in the range of 0.01 - 10 % w/w of the total weight of the stable oral pharmaceutical composition.

“Colorants” may be selected from, but are not limited to, iron oxide yellow, iron oxide red, titanium dioxide, or mixtures thereof. Colorants may be used in the range of 0.01 - 1.5 % w/w of the total weight of the stable oral pharmaceutical composition.

The pharmaceutical compositions of the present invention may be further coated with a functional or non-functional coating. The coating composition may be comprised of pharmaceutically acceptable excipients such as coating agents, binders, plasticizers, coloring agents, and opacifiers. The total weight gain after coating may be about 1% w/w to 10% w/w of the uncoated pharmaceutical composition.

“Coating agents” which are useful in the coating process, may be selected from, but not limited to, water-soluble polymers such as, but not limited to, polyvinylpyrrolidone or water-soluble cellulose such as, but not limited to, hydroxypropyl methylcellulose or hydroxypropyl cellulose. It may be selected from, but not limited to, soluble agents such as polysorbate 80, polysaccharides such as maltodextrin, acacia, com, sucrose, gelatin, shellac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinylpyrrolidone, vinyl acetate or combinations thereof. These may be applied from aqueous or non-aqueous systems or combinations of the aqueous and non-aqueous systems as appropriate.

Examples of binders for coating layer include cellulose or cellulose derivatives such as, but not limited to, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, and carboxymethyl cellulose sodium, and microcrystalline cellulose, alginic acid, sodium alginate and gelatin, polyvinyl pyrrolidone, crospovidone, starch, pregelatinized starch, or mixtures thereof. Examples of plasticizers for coating include, but are not limited to, propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, or mixtures thereof. Examples of opacifiers for coating include, but are not limited to, titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof. Antitacking agents such as, but are not limited to, talc, stearic acid, magnesium stearate, colloidal silicon dioxide, or the like. Examples of coloring agents for coating include, but are not limited to, FDA-approved colorants such as iron oxide, the lake of tartrazine, allura red, the lake of quinoline yellow, the lake of erythrosine, titanium dioxide, or mixtures thereof. Suitable solvents for the coating include but are not limited to, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, or mixtures thereof.

In further embodiments, the disclosed pharmaceutical compositions are prepared using a “direct compression” refers to the general process of directly compressing the ingredients in the pharmaceutical formulation (i.e., therapeutic agent and excipients) without changing the physical and chemical properties of the therapeutic agent. The therapeutic agent, along with pharmaceutically acceptable excipients, in the form of powders, are blended in a low shear apparatus, for example a twin shell blender. The blended composition is then filled into a die and directly compressed into a by a punch. A tablet press, for example, can accomplish this compression step. Useful excipients in a direct compression process include, but are not limited to fillers, binders, lubricants and glidants.

Another aspect of the present invention provides a tablet formulation comprising Saroglitazar or pharmaceutically acceptable salt thereof, used for the treatment of Noncirrhotic Non-Alcoholic Steatohepatitis, Non-alcoholic Fatty Liver Disease (NAFLD) with comorbidities (like obesity, Type 2 Diabetes Mellitus, Dyslipidemia or Metabolic Syndrome), and high cholesterol in diabetes (diabetic dyslipidemia).

Yet another aspect of the present invention is to provide a process of preparation of tablet formulation comprising Saroglitazar or a pharmaceutically acceptable salt thereof.

Stability study carried out for Saroglitazar calcium tablet provided satisfactory data for all the physical and chemical parameters, wherein initial, 1M, 2M, 3M and 6M stability studies were performed at 40 ± 20C / 75 ± 5 % RH, 300C ± 20C / 75 ± 5 % RH and 25 ± 20C /75 ± 5 %RH.

It should be appreciated that the invention can be embodied / aspects in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

Example 1: Saroglitazar Calcium Tablet Composition

Sr. No. Ingredient Amount (% w/w)
1 Saroglitazar Calcium 1-10
2 Microcrystalline Cellulose 5 - 80
3 Neusilin S2 10 - 50
4 Lactose Monohydrate 5 - 80
5 Polyvinylpyrrolidone 2 - 5
6 Croscarmellose sodium 0.5 - 10
8 Talc 1 - 10
9 Aerosil 0.1 - 2
10 Magnesium Stearate 0.25 - 5

Manufacturing Process:
Saroglitazar calcium and Neusilin S2 (Magnesium Alumino metasilicate) were sifted through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected separately in double Polythene lined labeled container. Above sifted material was added with equal quantity of microcrystalline cellulose through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected in blender. Remaining ingredients were sifted separately through #30 S.S. Sieve which fitted to a Mechanical Sifter and added with above sifted material in blender at slow speed for 20 minutes. Blended material was added with magnesium stearate in blender at slow speed for 3 minutes. The lubricated blend is compressed by using suitable die and punches.

Example 2: Saroglitazar Calcium Tablet Composition

Sr. No. Ingredient Amount (Mg / Tablet)
1 Saroglitazar Calcium 4.17
2 Microcrystalline Cellulose 46.83
3 Neusilin S2 15.00
4 Lactose Monohydrate 20.00
5 Polyvinylpyrrolidone 3.00
6 Croscarmellose sodium 8.00
8 Talc 1.00
9 Aerosil 1.00
10 Magnesium Stearate 1.00

Manufacturing Process:
Saroglitazar calcium and Neusilin S2 (Magnesium Alumino metasilicate) were sifted through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected separately in double Polythene lined labeled container. Above sifted material was added with equal quantity of microcrystalline cellulose through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected in blender. Remaining ingredients were sifted separately through #30 S.S. Sieve which fitted to a Mechanical Sifter and added with above sifted material in blender at slow speed for 20 minutes. Blended material was added with magnesium stearate in blender at slow speed for 3 minutes. The lubricated blend was compressed by using suitable die and punches.

Example 3: Saroglitazar Magnesium Tablet Composition

Sr. No. Ingredient Amount (%w/w)
1 Saroglitazar Magnesium 1-10
2 Microcrystalline Cellulose 5 - 80
3 Neusilin S2 10 - 50
4 Lactose Monohydrate 5 - 80
5 Polyvinylpyrrolidone 2 - 5
6 Croscarmellose sodium 0.5 - 10
8 Talc 1 - 10
9 Aerosil 0.1 - 2
10 Magnesium Stearate 0.25 - 5

Manufacturing Process:
Saroglitazar Magnesium and Neusilin S2 (Magnesium Alumino metasilicate) were sifted through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected separately in double Polythene lined labeled container. Above sifted material was added with equal quantity of microcrystalline cellulose through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected in blender. Remaining ingredients were sifted separately through #30 S.S. Sieve which fitted to a Mechanical Sifter and added with above sifted material in blender at slow speed for 20 minutes. Blended material was added with magnesium stearate in blender at slow speed for 3 minutes. The lubricated blend is compressed by using suitable die and punches.

Example 4: Saroglitazar Potassium Tablet Composition

Sr. No. Ingredient Amount (%w/w)
1 Saroglitazar Potassium 1-10
2 Microcrystalline Cellulose 5 - 80
3 Neusilin S2 10 - 50
4 Lactose Monohydrate 5 - 80
5 Polyvinylpyrrolidone 2 - 5
6 Croscarmellose sodium 0.5 - 10
8 Talc 1 - 10
9 Aerosil 0.1 - 2
10 Magnesium Stearate 0.25 - 5

Saroglitazar Potassium and Neusilin S2 (Magnesium Alumino metasilicate) were sifted through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected separately in double Polythene lined labeled container. Above sifted material was added with equal quantity of microcrystalline cellulose through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected in blender. Remaining ingredients were sifted separately through #30 S.S. Sieve which fitted to a Mechanical Sifter and added with above sifted material in blender at slow speed for 20 minutes. Blended material was added with magnesium stearate in blender at slow speed for 3 minutes. The lubricated blend is compressed by using suitable die and punches.

Example 5: Saroglitazar Sodium Tablet Composition

Sr. No. Ingredient Amount (%w/w)
1 Saroglitazar Sodium 1-10
2 Microcrystalline Cellulose 5 - 80
3 Neusilin S2 10 - 50
4 Lactose Monohydrate 5 - 80
5 Polyvinylpyrrolidone 2 - 5
6 Croscarmellose sodium 0.5 - 10
8 Talc 1 - 10
9 Aerosil 0.1 - 2
10 Magnesium Stearate 0.25 - 5

Saroglitazar Sodium and Neusilin S2 (Magnesium Alumino metasilicate) were sifted through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected separately in double Polythene lined labeled container. Above sifted material was added with equal quantity of microcrystalline cellulose through #30 S.S. Sieve which fitted to a Mechanical Sifter and collected in blender. Remaining ingredients were sifted separately through #30 S.S. Sieve which fitted to a Mechanical Sifter and added with above sifted material in blender at slow speed for 20 minutes. Blended material was added with magnesium stearate in blender at slow speed for 3 minutes. The lubricated blend is compressed by using suitable die and punches.

The formulations of the invention exemplified in Example 2 were evaluated for stability at conditions of 40 ± 2°C / 75 ± 5 % RH, 30 ± 2°C / 75 ± 5 % RH and 25 ± 2°C / 75 ± 5 % RH for initial, 3M and 6M (months).

A. Stability Study: Example 2 stored at 40 ± 2°C / 75 ± 5 % RH (Accelerated Storage Condition) for Initial, 3M and 6M.
Sr.
No TEST SPECIFICATION Initial 3M 6M
1 Description White to off-white coloured, circular, biconvex, uncoated tablets plain on both sides Complies Complies Complies
2 Identification test The retention time of the major peak of Saroglitazar in the chromatograms of the assay preparation correspond to that in the chromatograms of the standard preparations, as obtained in the assay for Saroglitazar. Complies Complies Complies
3 Uniformity of Weight Not more than 2 of the individual weights deviate from the average weight by more than 7.5% and none deviates by more than 15%. Complies Complies Complies
4 Disintegration time Not more than 15 minutes 1 to 2 minutes 1 to 2 minutes 1 to 2 minutes
5 Dissolution Not less than 70% (D) of labelled amount of Saroglitazar is dissolved in 45 minutes. 99 % 94% 88%
6 Assay: (By HPLC) Saroglitazar:4 mg /Tablet Not less than 90.0 % and not more than 110.0% of labelled amount of Saroglitazar. 98.1 % 97.2% 94.2
7
Related Substances

SRG Sulfoxide: 0.417 0.614 0.918
SRG Ethyl Ester: ND 0.091 0.141
Any Sec Impurity.: 0.384 0.465 0.506
Total Impurity 2.454 3.247 4.700

B. Stability Study: Example 2 at 30 ± 2°C / 75 ± 5 % RH (Intermediate Storage Condition) for Initial, 3M and 6M.
Sr.
No TEST SPECIFICATION Initial 3M 6M
1 Description White to off-white coloured, circular, biconvex, uncoated tablets plain on both sides Complies Complies Complies
2 Identification test The retention time of the major peak of Saroglitazar in the chromatograms of the assay preparation correspond to that in the chromatograms of the standard preparations, as obtained in the assay for Saroglitazar. Complies Complies Complies
3 Uniformity of Weight Not more than 2 of the individual weights deviate from the average weight by more than 7.5% and none deviates by more than 15%. Complies Complies Complies
4 Disintegration time Not more than 15 minutes 1 to 2 minutes 1 to 2 minutes 1 to 2 minutes
5 Dissolution Not less than 70% (D) of labelled amount of Saroglitazar is dissolved in 45 minutes. 99 % 96% 91%
6 Assay: (By HPLC) Saroglitazar:4 mg /Tablet Not less than 90.0 % and not more than 110.0% of labelled amount of Saroglitazar. 98.1 % 98.4% 97.3%
7
Related Substances

SRG Sulfoxide: 0.417 0.486 0.611
SRG Ethyl Ester: ND 0.036 0.063
Any Sec Impurity.: 0.384 0.514 0.762
Total Impurity 2.454 2.753 3.747

C. Stability Study: Example 2 at 25 ± 2°C / 60% ± 5 % RH (Long term Storage Condition) for Initial, 3M and 6M.
Sr.
No TEST SPECIFICATION Initial 3M 6M
1 Description White to off-white coloured, circular, biconvex, uncoated tablets plain on both sides Complies Complies Complies
2 Identification test The retention time of the major peak of Saroglitazar in the chromatograms of the assay preparation, correspond to that in the chromatograms of the standard preparations, as obtained in the assay for Saroglitazar. Complies Complies Complies
3 Uniformity of Weight Not more than 2 of the individual weights deviate from the average weight by more than 7.5% and none deviates by more than 15%. Complies Complies Complies
4 Disintegration time Not more than 15 minutes 1 to 2 minutes 1 to 2 minutes 1 to 2 minutes
5 Dissolution Not less than 70% (D) of labelled amount of Saroglitazar is dissolved in 45 minutes. 99 % 97% 94%
6 Assay: (By HPLC) Saroglitazar:4 mg /Tablet Not less than 90.0 % and not more than 110.0% of labelled amount of Saroglitazar. 98.1 % 99.8% 99.8%
7
Related Substances

SRG Sulfoxide: 0.417 0.416 0.458
SRG Ethyl Ester: ND 0.035 0.018
Any Sec Impurity.: 0.384 0.378 0.566
Total Impurity 2.454 2.401 2.914

Conclusion: All the physical and chemical parameters including the impurity levels were found satisfactory and the initial, 3M and 6M stability data at 400C /75 %RH, 300C ± 20C / 75 ± 5 % RH and 25 ± 20C /75 ± 5 %RH was found to be satisfactory.
,CLAIMS:1. A stable pharmaceutical composition suitable for oral administration comprising:
a) Saroglitazar or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) Magnesium Alumino Metasilicate;
c) Diluents or mixture thereof;
d) Binder;
e) Disintegrant;
f) one or more pharmaceutically acceptable excipients.

2. A stable pharmaceutical composition as in claim 1, wherein Saroglitazar is present at a concentration of about 1-10 mg.

3. A stable pharmaceutical composition as in claim 1, wherein the Magnesium Alumino Metasilicate is present at a concentration of about 5-20 mg.

4. A stable pharmaceutical composition as in claim 1, wherein the diluent is Microcrystalline cellulose and Lactose Monohydrate of combinations thereof at a concentration of about 15-75 mg.

5. A stable pharmaceutical composition as in claim 1, wherein the binder is Polyvinylpyrrolidone K-30 at a concentration of about 1-10 mg.

6. A stable pharmaceutical composition as in claim 1, wherein the Disintegrant is Croscarmellose Sodium at a concentration of about 4-15 mg.

7. A stable pharmaceutical composition as in claim 1, wherein the Glidant is talc at a concentration of about 0.5-10 mg.

8. A stable pharmaceutical composition as in claim 1, wherein the Anti-adherent is Aerosil-200 at a concentration of about 0.5-7 mg.

9. A stable pharmaceutical composition as in claim 1, wherein the Lubricant is Magnesium stearate at a concentration of about 0.5-5 mg.

10. A stable Tablet composition suitable for oral administration comprising:
a) about 4.2 mg of Saroglitazar or a pharmaceutically acceptable salt thereof;
b) about 15 mg of Magnesium Aluminometasilicate;
c) about 67 mg of Microcrystalline Cellulose and Lactose Monohydrate or combinations thereof;
d) about 3 mg of Polyvinylpyrrolidone K-30;
e) about 8 mg of Croscarmellose Sodium;
f) about 1 mg of talc;
g) about 1 mg of Aerosil 200;
h) about 1 mg of Magnesium stearate.