FIELD OF THE INVENTION
The present invention provides a pharmaceutical composition comprising obeticholic acid and one or more pharmaceutical acceptable excipients.

BACKGROUND OF THE INVENTION
The Farnesoid X receptor (FXR), also known as the bile acid receptor (BAR), is a member of the nuclear receptor superfamily of ligand-activated transcription factors. FXR forms with retinoid X receptor (RXR) a heterodimer receptor crucial for bile acid homeostasis. FXR is expressed in various tissues including the liver, kidney, intestine, colon, ovary, and adrenal gland, and is activated by a variety of naturally occurring bile acids, including the primary bile acid chenodeoxycholic acid (CDCA) and its taurine and glycine conjugates. Upon activation, the FXR-RXR heterodimer binds the promoter region of target genes and regulates their expression.

6-Ethyl-chenodeoxycholic acid (6-ECDCA, or obeticholic acid, or OCA), a bile acid derivative, is useful for the treatment or prevention of a FXR mediated disease or condition, cardiovascular disease or cholestatic liver disease, and for reducing HDL cholesterol, for lowering triglycerides in a mammal, or for inhibition of fibrosis.

US 7,138,390 of Intercept discloses obeticholic acid (OCA) and US 9,238,673 discloses the composition of obeticholic acid Form 1 and a pharmaceutically acceptable carrier.

PCT application number 2016/176208 discloses compositions of obeticholic acid comprising obeticholic acid and intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprising obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, microcrystalline cellulose, and one or more additional pharmaceutical excipients, and the extra-granular portion comprising microcrystalline cellulose and one or more additional pharmaceutical excipients.

The present invention is focussed on the preparation of a solid oral dosage form of obeticholic acid composition in a simple and cost effective method.

Moreover, the present invention is focussed towards the formation of obeticholic acid compositions by a method that results into desirable dissolution profile and solubility, and possessing advantageous storage stability.

OBJECT OF THE INVENTION
The main aspect of the present invention is to provide a composition of obeticholic acid in a simple and cost effective way.

Another aspect of the present invention is to provide a composition of obeticholic acid by direct compression process.

One another aspect of the present invention is to provide a composition of obeticholic acid by wet/dry granulation process.

One aspect of the present invention is to provide a solid oral dosage form of obeticholic acid wherein the composition is substantially free of microcrystalline cellulose.

One another aspect of the invention to provide a compressed obeticholic acid tablet having an acceptable dissolution profile as well as acceptable degrees of hardness.

SUMMARY OF THE INVENTION
The present invention relates to a composition of obeticholic acid comprising obeticholic acid with pharmaceutical acceptable excipients wherein said composition is prepared by direct compression process.

In another aspect, the present invention relates to the composition of obeticholic acid or its pharmaceutically acceptable salt, solvate, or conjugate thereof, along with one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising diluents, binders, glidants, disintegrants, surfactants and lubricants.

In another aspect, present invention relates to preparation of a solid oral dosage form of obeticholic acid wherein the composition is substantially free of microcrystalline cellulose.

In one another aspect, the present invention relates to a pharmaceutical composition comprising obeticholic acid and one or more pharmaceutical acceptable excipients wherein said composition is prepared by dry or wet granulation process.

In one another aspect, the present invention relates to a composition of obeticholic acid wherein said composition is substantially free of diluents.

DETAILED DESCRIPTION
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

The term “Solvates” as used in the context of the present invention means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Obeticholic acid may have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcohol solvate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate. Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

Accordingly, in main embodiment, the present invention provides a pharmaceutical composition comprising obeticholic acid and one or more pharmaceutical acceptable excipients wherein said composition is prepared by direct compression process.

In other aspect, the present invention relates to the composition of obeticholic acid or its pharmaceutically acceptable salt, solvate, or conjugate thereof, along with one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising diluents, binders, glidants, disintegrants, surfactants and lubricants.

In another embodiment, the composition is produced by compression of a formulation containing the drug and certain excipients selected to aid in the processing and release of the drugs. In addition to the active or therapeutic ingredients, composition may contain a number of inert materials known as excipients. They may be classified according to the role they play in the final tablet.

In one another embodiment, the present invention relates to a pharmaceutical composition comprising of obeticholic acid or a pharmaceutically acceptable salt, solvate, or conjugate thereof, wherein the formulation is administered orally.

In other embodiment, the diluent can be any diluent known in the art. Non-limiting examples of diluents include starch, spray dried lactose, modified starch, pregelatinized starch, microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, calcium phospahte dihydrate, dibasic calcium phosphate anhydrous SG (spherically granulated), tribasic calcium phosphate, calcium phosphate, lactose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, and sucrose, hydroxypropyl methyl cellulose and/or a combination thereof.

Suitable binder in a tablet composition of the present invention may be one or more compounds which are capable of facilitating granulation into aggregates and/or more free-flowing particles and include cellulose, carboxymethylcellulose sodium, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyl propyl methylcellulose, methylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch, alginic acid, sodium alginate, gelatin and the like.

Suitable disintegrant in a tablet composition of the present invention may be one or more compounds which are capable of facilitating the breakup of a tablet prepared from the composition when placed in contact with an aqueous medium and include cellulose, carboxymethylcellulose sodium, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, pregelatinized starch, low substituted hydroxypropylcellulose, sodium starch glycolate, starch and the like.

Suitable glidants according to the invention are silicon dioxide, particularly colloidal silicon dioxide (e.g. Aerosil®, Cab-O-Sil®), stearic acid as well as salts thereof including sodium stearate, calcium stearate, zinc stearate, magnesium stearate, magnesium silicate, calcium silicate, magnesium trisilicate and talc.

Suitable lubricants according to the invention are stearic acid as well as slats thereof including talc, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, glyceryl monostearate, particularly magnesium stearate, polyethylene glycols, hydrogenated castor oil, fatty acid for e.g. fumaric acid, and salts of fatty acids, in particular the calcium, magnesium, sodium or potassium salts thereof, for example calcium behenate, calcium stearate, sodium stearyl fumarate or magnesium stearate (for example HyQual®, Mallinckrodt), glycerides such as glyceryl behenate (Compritol® 888), Dynasan® 118 or Boeson® VP.

Suitable surfactants according to the present invention include sodium lauryl sulfate, sodium dodecyl sulfate, ammonium lauryl sulfate, benzalkonium chloride, alkyl poly (ethylene oxide), copolymers of poly (ethylene oxide) and poly (propylene oxide) commercially called as poloxamers or poloxamines, fatty alcohols, polysorbates e.g., Tween 20, Tween 80, or mixtures thereof.

In one embodiment, the pharmaceutical composition may comprise a coating agent such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents and delayed release coating agents or a coating composition comprising any combination thereof. In another embodiment, the coating agent can be any coating agent known in the art. Examples of coating agents include, but are not limited to, saccharose used alone or together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof; cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone; polysaccharides such as pullulan; hydroxypropyl methyl cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate; carboxymethyl ethyl cellulose; cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; natural substances such as shellac; titanium dioxide; polyvinyl alcohol (e.g., Opadry®); polyethylene glycol; talc; lecithin; and/or combinations thereof.

In one embodiment, the present invention relates to a pharmaceutical formulation of obeticholic acid or a pharmaceutically acceptable salt, solvate, or conjugate thereof, wherein the formulation is substantially free of microcrystalline cellulose.

In further embodiment, the present invention relates to a direct compression process for making an obeticholic acid composition wherein said process comprises the steps of: (1) premixing said obeticholic acid and the main portion of pharmaceutically acceptable excipients in a mixer to obtain a blend; (2) optionally dry screening the blend through a screen in order to segregate cohesive particles and to improve content uniformity; (3) mixing the blend of step (1) or (2) in a mixer, optionally by adding remaining pharmaceutically acceptable excipients to the blend and continuing mixing; (4) tableting the final blend of step (3) by compressing it on a suitable tablet press to produce the tablet cores; (5) optionally film coating of tablet cores of step (4) with a film coat.

In a preferred embodiment, the obeticholic acid used in the composition can be crystalline or amorphous or mixture thereof.

In one of the preferred embodiment, the present invention relates to a pharmaceutical composition comprising obeticholic acid or its pharmaceutically acceptable salt, solvate, or conjugate thereof, wherein the obeticholic acid is having the D90 less than about 200 µm.

In more preferred embodiment, the present invention relates to a pharmaceutical composition comprising obeticholic acid or its pharmaceutically acceptable salt, solvate, or conjugate thereof, wherein the obeticholic acid is having D90 between 2.0 to 150 µm.

In one another embodiment, the present invention provides the composition of obeticholic acid comprising of obeticholic acid or its pharmaceutically acceptable salt, solvate or conjugate thereof, along with the other pharmaceutically acceptable excipients, wherein said composition can be prepared by dry granulation process.

The dry granulation process according to the present invention may include the steps of: (1) mixing obeticholic acid with either all or a portion of the pharmaceutically acceptable excipients in a mixer; (2) compaction/slugging of the blend of step (1); (3) reducing the ribbons/slugs obtained during step (2) to granules by suitable milling or sieving steps; (4) optionally mixing the granules of step (3) with the remaining pharmaceutically acceptable excipients in a mixer to obtain the final blend; (5) tableting the granules of step (3) or the final blend of step (4) by compressing it on a suitable tablet press to produce the tablet cores; (6) optionally film-coating of the tablet cores of step (5) with a film coat.

In one another embodiment, the present invention provides the composition of obeticholic acid comprising of obeticholic acid or its pharmaceutically acceptable salt, solvate or conjugate thereof, along with one or more pharmaceutically acceptable excipients, wherein said composition can be prepared by wet granulation process.

The wet granulation according to the process of the present invention may include the steps of: (1) premixing obeticholic acid and the main portion of the pharmaceutically acceptable excipients in a mixer to obtain a blend; (2) granulating the blend of step (1) by adding a granulation liquid/binder solution; (3) drying the granules of step (2); (4) optionally dry sieving of the dried granules of step (3); (5) mixing the dried granules of (4) with the remaining excipients in a mixer to obtain the final blend; (6) tableting the final blend of step (5) by compressing it on a suitable tablet press to produce tablets cores; (7) optionally film coating of the tablet cores of step (6) with a film coat.

In one another embodiment, the present invention provides the composition of obeticholic acid comprising of obeticholic acid or its pharmaceutically acceptable salt, solvate or conjugate thereof, along with one or more pharmaceutically acceptable excipients, wherein said composition is substantially free of diluents.

In another embodiment, the present invention relates to a method of treating or preventing an FXR mediated disease or condition in a subject comprise of administering oral dosage form comprising the composition of obeticholic acid prepared as per the process of the present invention. The disease or condition is selected from biliary atresia, cholestatic liver disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, primary biliary cirrhosis (PBC), liver damage due to progressive fibrosis, liver fibrosis, and cardiovascular diseases including atherosclerosis, arteriosclerosis, hypercholesteremia, and hyperlipidemia. The present invention relates to a method for lowering triglycerides in a subject comprise of administering oral dosage form comprising the composition of obeticholic acid prepared as per the process of the present invention.

In another embodiment, the present invention further relates to composition of obeticholic acid wherein said composition comprises of microcrystalline cellulose only in extra granular portion.

In further embodiment, the obeticholic acid used in the composition prepared by direct compression/wet granulation/dry granulation process is crystalline in nature and is substantially free of amorphous form of obeticholic acid.

In further embodiment, the obeticholic acid used in the composition prepared by direct compression/wet granulation/dry granulation process is amorphous in nature and is substantially free of crystalline form of obeticholic acid.

In a preferred embodiment, the dissolution profile, content uniformity, stability and the like of the prepared obeticholic acid composition accord with standards prescribed in Food and Drug Administration of United States of America.

In yet another embodiment, the direct compressed obeticholic acid composition prepared according to the present invention is bioequivalent to marketed formulation.

In still another embodiment, the direct compressed obeticholic acid composition prepared according to the present invention possess dissolution of more than 85% in less than 30 min.

The invention will now be described in more detail by way of the following non-limiting examples.
EXAMPLE 1
Ingredients Quantity (mg/tablet)
Obeticholic acid 50.0
Sodium starch glycolate 17.0
Hydroxypropyl methyl cellulose 25.0
Magnesium stearate 3.0
Colloidal silicon dioxide 5.0

Procedure:
(1) premixing obeticholic acid and the main portion of pharmaceutically acceptable excipients in a mixer to obtain a blend;
(2) optionally dry screening the blend through a screen in order to segregate cohesive particles and to improve content uniformity;
(3) mixing the blend of step (1) or (2) in a mixer, optionally by adding remaining pharmaceutically acceptable excipients to the blend and continuing mixing;
(4) tableting the final blend of step (3) by compressing it on a suitable tablet press to produce the tablet cores;
(5) optionally film coating of tablet cores of step (4) with a film coat.

EXAMPLE 2
Ingredients Quantity (mg/tablet)
Intragranular portion
Obeticholic acid 25.0
Sodium starch glycolate 10.0
Hydroxypropyl methyl cellulose 15.0
Extragranular portion
Microcrystalline cellulose 45.0
Magnesium stearate 2.0
Colloidal silicon dioxide 3.0
Purified water q.s.

Procedure:
(1) premixing obeticholic acid, sodium starch glycolate in a mixer to obtain a blend;
(2) granulating the blend of step (1) by adding binder solution prepared by dissolving hydroxypropyl methyl cellulose in purified water;
(3) drying the granules of step (2);
(4) optionally dry sieving of the dried granules of step (3);
(5) mixing the dried granules of (4) with microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide in a mixer to obtain the final blend;
(6) tableting the final blend of step (5) by compressing it on a suitable tablet press to produce tablets cores;
(7) optionally film coating of the tablet cores of step (6) with a film coat.

WE CLAIM
1. A composition comprising obeticholic acid and one or more pharmaceutically acceptable excipients, wherein said composition is substantially free of diluent.

2. The composition as claimed in claim 1, wherein said composition is substantially free of microcrystalline cellulose.

3. The composition as claimed in claim 1, wherein said pharmaceutically acceptable excipients are selected from the group comprising binders, glidants, disintegrants, surfactants and lubricants.

4. The composition as claimed in claim 1, wherein said obeticholic acid is in crystalline or amorphous form.

5. The composition as claimed in claim 1, wherein said obeticholic acid is having D90 less than about 200 µm.

6. The composition as claimed in claim 1, wherein said composition releases more than 85% of drug in less than 30 min.

7. The composition as claimed in claim 1, wherein said composition is prepared by direct compression process comprising the steps of. (1) premixing said obeticholic acid and the main portion of pharmaceutically acceptable excipients in a mixer to obtain a blend; (2) optionally dry screening the blend through a screen in order to segregate cohesive particles and to improve content uniformity; (3) mixing the blend of step (1) or (2) in a mixer, optionally by adding remaining pharmaceutically acceptable excipients to the blend and continuing mixing; (4) tableting the final blend of step (3) by compressing it on a suitable tablet press to produce the tablet cores; (5) optionally film coating of tablet cores of step (4) with a film coat.

8. The composition as claimed in claim 1, wherein said composition is prepared by dry or wet granulation process.

9. A composition comprising intragranular portion and extragranular portion, wherein said intragranular portion comprises obeticholic acid and one or more pharmaceutically acceptable excipients other than microcrystalline cellulose, and extra granular portion comprises one or more pharmaceutically acceptable excipients.

10. The composition as claimed in claim 9, wherein said pharmaceutically acceptable excipients are selected from the group comprising diluents, binders, glidants, disintegrants, surfactants and lubricants.