WO2019106043A1

WO2019106043A1 - Pharmaceutical composition comprising obeticholic acid

Info

Publication number: WO2019106043A1
Application number: PCT/EP2018/082892
Authority: WO
Inventors: Renate Oppelt; Tobias Martin
Original assignee: Hexal Ag
Priority date: 2017-11-29
Filing date: 2018-11-28
Publication date: 2019-06-06

Abstract

The present invention relates to pharmaceutical compositions comprising obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in dissolved form, processes for preparing the pharmaceutical compositions, and their use in the treatment of FXR-mediated diseases.

Description

Pharmaceutical composition comprising obeticholic acid

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

WO 02/072598 describes obeticholic acid, its preparation and use in the prevention or treatment of FXR-mediated diseases, such as liver diseases and cardiovascular diseases. Obeticholic acid is also referred to as 6a-ethyl-chenodeoxycholic acid, 6- ECDCA, or 3a,7odihydroxy-6oethyl-53-cholan-24-oic acid.

WO 2013/192097 discloses a number of polymorphic forms of obeticholic acid, in particular, form 1 (amorphous form), crystalline forms A, C, D, which are said to be mixed hydrates/solvates containing water and varying amounts of organic solvents, and crystalline forms F and G. All crystalline forms A, C, D, F and G were found to be unsuitable as pharmaceutical ingredients.

WO 2017/008773 describes the crystalline polymorphic forms I-2 and I-3 of obeticholic acid. WO 2017/092702 discloses obeticholic acid having crystal form II. WO

2017/11 1979 relates to crystalline forms named A, C, D, F, G and I. WO 2017/1 15324 defines crystalline forms called alpha, beta, gamma and delta.

Even if not all of the above mentioned crystalline forms would prove to be distinct forms, the above documents illustrate that obeticholic acid occurs in a number of polymorphic forms, not all of which are suitable as pharmaceutical ingredients.

Accordingly, there is a risk that one polymorphic form converts into another polymorphic form during preparation of obeticholic acid itself and/or during manufacturing of a pharmaceutical composition comprising obeticholic acid. A polymorphic conversion can be caused, for example, by contact with a solvent or by mechanical stress during mixing and compression steps. As a result, the desired pharmaceutically acceptable polymorphic form may convert into a pharmaceutically unsuitable polymorphic form or into another pharmaceutically acceptable polymorphic form which, however, has different properties, such as a different solubility and different bioavailability.

In view of the above, the object underlying the present invention is to provide a pharmaceutical composition comprising obeticholic acid in a form which is not susceptible to polymorphic conversion, provides rapid release of the obeticholic acid from the pharmaceutical composition into the patient's gastrointestinal tract, thus allowing fast onset of the therapeutic effect, is easy to administer to the patient, thus enhancing patient compliance which in turn ensures therapeutic success, and which pharmaceutical composition can be prepared without the risk that such a polymorphic conversion occurs during manufacturing, and which pharmaceutical composition can be prepared in a simple and cost efficient manner, i.e. with a low number of excipients, thus reducing analytical validation procedures, and with an efficient manufacturing process requiring a low number of process steps and standard manufacturing equipment.

SUMMARY OF THE INVENTION

The above objects have been solved by providing a pharmaceutical composition comprising obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof, wherein the obeticholic acid, the pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof is present in dissolved form.

In the pharmaceutical composition of the present invention, the obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof is neither present in crystalline form nor in amorphous form. Accordingly,

transformations from one crystalline form into another crystalline form or transformations from a crystalline form into the amorphous form or from the amorphous form into a crystalline form are prevented. DETAILED DESCRIPTION OF THE INVENTION

Any reference to "obeticholic acid" made herein includes the pharmaceutically acceptable salts, solvates, solvated salts and amino acid conjugates of obeticholic acid.

Preferably, any reference to "obeticholic acid" made herein includes the

pharmaceutically acceptable salts of obeticholic acid and the amino acid conjugates of obeticholic acid.

Obeticholic acid can be prepared as described, for example, in WO 02/072598.

Pharmaceutically acceptable salts of obeticholic acid include, without limitation, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc salts; and salts made from N,N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine,

ethylendiamine, meglumine, procaine, diethylamine, diisopropylamine, tert-butylamine, di-n-butylamine, 3-dimethylamino-1 -propylamine, cyclohexylamine, dicyclohexylamine, morpholine, N-tertbutylbenzylamine, N-benzylmethylamine, (R)-omethylbenzylamine, (S)-omethylbenzylamine, benzylamine, dibenzylamine and octylamine.

The solvates of obeticholic acid include solvates of a single solvent and mixed solvates (solvates of more than one solvent). Hydrates are the preferred solvates. The solvated salts of obeticholic acid include, without limitation, solvates of the aforementioned salts, for example the solvates, preferably the hydrates, of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc salts; and the solvates, preferably the hydrates, of salts made from N,N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylendiamine, meglumine, procaine, diethylamine, diisopropylamine, tert-butylamine, di-n-butylamine, 3-dimethylamino-1 -propylamine, cyclohexylamine, dicyclohexylamine, morpholine, N-tertbutylbenzylamine, N-benzylmethylamine, (R)-o methylbenzylamine, (S)-omethylbenzylamine, benzylamine, dibenzylamine and octylamine.

Amino acid conjugates of obeticholic acid include, without limitation, glyco-obeticholic acid and tauro-obeticholic acid (i.e. conjugates of obeticholic acid with glycine or taurine). Preferred pharmaceutical compositions of the present invention comprise obeticholic acid or an amino acid conjugate thereof, particularly preferred pharmaceutical compositions of the present invention comprise obeticholic acid.

In the pharmaceutical composition of the present invention, the dissolved form of obeticholic acid is preferably a solution of obeticholic acid in a solvent or a mixture of solvents. Within the meaning of the present invention, a solution of obeticholic acid in a solvent or a mixture of solvents is in liquid state (at a temperature of 25°C under atmospheric pressure of 101325 Pa).

In another preferred embodiment of the present invention, the dissolved form is a liquid- in-solid system of obeticholic acid in a solvent or a mixture of solvents. Within the meaning of the present invention, a liquid-in-solid system refers to a solid form of a liquid substance obtained by converting the liquid substance into a dry powder

(preferably a dry, non-adherent, free-flowing powder) by mixing the liquid substance with an adsorbent material. While the liquid-in-solid system is macroscopically in solid form (e.g. in powdered form), the originally liquid substance (or the dissolved substance) remains in liquid form (or in dissolved form). In particular, a liquid-in-solid system can be obtained by mixing obeticholic acid in dissolved form with an adsorbent material resulting in a powder, wherein the obeticholic acid is still present in dissolved form. In other words, the obeticholic acid is not present in the liquid-in-solid system in solid form, such as in crystalline form or in amorphous form.

Preferably, the solvent is a non-volatile solvent. Within the meaning of the present invention, a non-volatile solvent is a solvent having a boiling point of more than 100°C, preferably more than 125°C, more preferably more than 150°C (under atmospheric pressure of 101325 Pa). The mixture of solvents preferably comprises at least one non- volatile solvent as defined above.

In a preferred embodiment, the pharmaceutical composition of the present invention comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent, preferably in a non-volatile solvent.

More preferably, the solvent is selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycols, glyceryl fatty acid esters, propylene glycol fatty acid esters, polyoxylglycerides, polyoxyethylene sorbitan fatty acid esters and mixtures thereof. In case a mixture of solvents is used, the mixture of solvents preferably comprises at least one solvent selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycols, glyceryl fatty acid esters, propylene glycol fatty acid esters, polyoxylglycerides, and polyoxyethylene sorbitan fatty acid esters.

Diethylene glycol monoethyl ether has the structure:

CH₃-CH2-O-CH2-CH2-O-CH2-CH2-OH and is also known under the IUPAC name 2-(2-ethoxyethoxy)ethanol). Its CAS

(Chemical Abstract Service) number is 11 1-90-0.

The polyethylene glycol has preferably a weight average molecular weight of from 180 to 600 g/mol, more preferably of from 350 to 450 g/mol, most preferably of about 400 g/mol. Mixtures of polyethylene glycols having different molecular weights can be used.

The glyceryl fatty acid ester is preferably selected from mono and diglycerides of saturated or unsaturated C₈ to Ci₈fatty acids, for example, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate, glyceryl dicaprate, glyceryl caprylate/caprate (CAS number: 73398-61-5), glyceryl monolaurate, glyceryl dilaurate, glyceryl monomyristate, glyceryl dimyristate, glyceryl monooleate, glyceryl dioleate, glyceryl monopalmitate, glyceryl dipalmitate, glyceryl monostearate, glyceryl distearate, and mixtures thereof. More preferably, the glyceryl fatty acid ester is selected from mono and diglycerides of saturated or unsaturated C₈ to C fatty acids. Particularly preferred are glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate, glyceryl dicaprate, glyceryl caprylate/caprate (CAS number: 73398-61-5), glyceryl monolaurate, glyceryl dilaurate, and mixtures thereof. Most preferred are glyceryl monocaprylate, glyceryl monocaprate, glyceryl dicaprylate, glyceryl dicaprate, glyceryl caprylate/caprate (CAS number: 73398-61-5), and mixtures thereof.

For the avoidance of doubt, the above glyceryl monoesters include the glyceryl-1 - monoesters and glyceryl-2-monoesters (such as glyceryl-1 -monocaprylate and glyceryl- 2-monocaprylate), the above glyceryl diesters include the glyceryl-1 ,3-diesters and glyceryl-1 ,2-diesters (such as the glyceryl-1 ,3-dicaprylate and glyceryl-1 ,2-dicaprylate), and the above glyceryl mixed diesters include the glyceryl-1 ,2-diester, glyceryl-1 ,3- diester and glyceryl-2,1 -diester (such as the glyceryl-1 -caprylate-2-caprate, glyceryl-1 - caprylate-3-caprate and glyceryl-2-caprylate-1-caprate).

The propylene glycol fatty acid ester is preferably selected from esters of propylene glycol with saturated or unsaturated C12 to Ci₆ fatty acids. Propylene glycol monolaurate (CAS Number 27194-74-7) is particularly preferred.

Polyoxylglycerides are mixtures of monoesters, diesters, and triesters of glycerol, and monoesters and diesters of polyethylene glycols. Examples include caprylocaproyl polyoxylglycerides (CAS number: 223129-75-7), lauroyl polyoxylglycerides (CAS number: 57107-95-6), linoleoyl polyoxylglycerides (CAS number: 61789-25-1 ), oleoyl polyoxylglycerides (CAS number: 68424-61-3 and 9004-96-0), stearoyl

polyoxylglycerides (CAS number: 1323-83-7 and 9005-08-7) and mixtures thereof. Caprylocaproyl polyoxylglycerides, linoleoyl polyoxylglycerides, oleoyl

polyoxylglycerides and mixtures thereof are preferred. Caprylocaproyl

polyoxylglycerides are especially preferred. Polyoxylglycerides are described in detail in the "Handbook of Pharmaceutical Excipients" (6th edition), edited by R.C. Rowe, P.J. Sheskey and M.E. Quinn, published by the Pharmaceutical Press and the American Pharmacists Association.

The polyoxyethylene sorbitan fatty acid ester is preferably selected from Polysorbate 20 (Polyoxyethylene 20 sorbitan monolaurate, CAS number: 9005-64-5), Polysorbate 40 (Polyoxyethylene 20 sorbitan monopalmitate, CAS number: 9005-66-7), Polysorbate 60 (Polyoxyethylene 20 sorbitan monostearate, CAS number: 9005-67-8), and Polysorbate 80 (Polyoxyethylene 20 sorbitan monooleate, CAS number: 9005-65-6). Polysorbate 40, Polysorbate 80 and mixtures thereof are preferred, Polysorbate 80 is especially preferred. Polyoxyethylene sorbitan fatty acid esters are described in detail in the "Handbook of Pharmaceutical Excipients" (6th edition), edited by R.C. Rowe, P.J.

Sheskey and M.E. Quinn, published by the Pharmaceutical Press and the American Pharmacists Association.

In a preferred embodiment, the polyethylene glycol has a weight average molecular weight of from 350 to 450 g/mol; the glyceryl fatty acid ester is selected from glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate, glyceryl dicaprate, glyceryl caprylate/caprate, and mixtures thereof; the propylene glycol fatty acid ester is propylene glycol monolaurate; the polyoxylglyceride is selected from caprylocaproyl polyoxylglycerides, linoleoyl polyoxylglycerides, oleoyl polyoxylglycerides and mixtures thereof; and the polyoxyethylene sorbitan fatty acid ester is selected from Polysorbate 40, Polysorbate 80 and mixtures thereof.

In an even more preferred embodiment, the solvent is selected from the group consisting of diethylene glycol monoethyl ether, glyceryl caprylate/caprate, propylene glycol monolaurate, caprylocaproyl polyoxylglycerides, and mixtures thereof.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent or a mixture of solvents or a liquid-in-solid system of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises diethylene glycol monoethyl ether.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent or a mixture of solvents or a liquid-in-solid system of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises glyceryl caprylate/caprate.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent or a mixture of solvents or a liquid-in-solid system of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises caprylocaproyl polyoxylglycerides.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent or a mixture of solvents or a liquid-in-solid system of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises propylene glycol monolaurate.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises diethylene glycol monoethyl ether. In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises glyceryl caprylate/caprate.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises caprylocaproyl polyoxylglycerides.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a solution of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises propylene glycol monolaurate.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a liquid-in-solid system of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises diethylene glycol monoethyl ether.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a liquid-in-solid system of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises glyceryl caprylate/caprate.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a liquid-in-solid system of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises caprylocaproyl polyoxylglycerides.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises obeticholic acid in dissolved form, wherein the dissolved form is a liquid-in-solid system of obeticholic acid in a solvent or a mixture of solvents, and wherein the solvent comprises propylene glycol monolaurate.

The pharmaceutical composition of the present invention is preferably a capsule filled with obeticholic acid in dissolved form. Hard-shelled capsules and soft-shelled capsules can be used. Both of these capsules can be made from aqueous solutions of gelling agents, for example from gelatin or polysaccharides, such as starch. Capsules can be tailored to any specific need, for example, by including plasticizers, coloring agents, preservatives, disintegrants and/or lubricants in the capsule material. Any capsule suitable for oral administration to a patient can be employed in the present invention.

With regard to the capsule size, there is no limitation, provided the capsules can be used for oral administration. Preferably, capsules of standard sizes 1 , 2, 3 or 4, are used, i.e. capsules having a volume of about 0.5 ml, 0.37 ml, 0.30 ml and 0.21 ml, respectively, which are in accordance with DAC/NRF (German Drug Codex (Deutscher Arzneimittel-Codex) / New German Formulary (Neues Rezeptur-Formularium)).

A capsule has the advantage that it can be produced in a simple and efficient manner with a low number of process steps on standard manufacturing equipment. This allows to reduce the costs related to process validation and analytical procedures. Additionally, capsules allow for a fast release of the obeticholic acid into the gastrointestinal tract of the patient's body, thus, producing a quick onset of the therapeutic effect.

Gelatin-based capsules are preferred. Thus, in a preferred embodiment of the present invention, the capsule is a hard gelatin capsule. Hard gelatin capsules have additionally the advantage that the two parts of the capsule may be colored differently, thus allowing a wide variety of color schemes, for example, to differentiate between capsules containing different amounts of the active ingredient obeticholic acid.

In another preferred embodiment of the present invention, the capsule is a soft gelatin capsule. Soft gelatin capsules have additionally the advantage that they are hermetically sealed and cannot be opened.

The capsule can be filled with obeticholic acid dissolved in a solvent or a mixture of solvents, such as the solvents mentioned above. Preferably, obeticholic acid dissolved in a solvent or a mixture of solvents is in liquid state and the capsule is filled with the liquid.

A capsule filled with obeticholic acid dissolved in a solvent or a mixture of solvents has the advantage that only a minimum of pharmaceutical excipients has to be used (obeticholic acid, the solvent or mixture of solvents, and the capsule shell). Alternatively, the capsule can contain an adsorbent material, wherein the obeticholic acid in dissolved form is adsorbed onto the adsorbent material (liquid-in-solid-system).

The adsorbent material, onto which the obeticholic acid in dissolved form is adsorbed, can be present in the form of particles (i.e. in powder form), in the form of granules, in the form of pellets or in the form of minitablets. Granules, pellets and minitablets are preferred.

The advantage of granules, pellets and minitablets is their better flowability compared to particles (powders).

Granules are irregularly shaped agglomerates and include wet granules and dry granules. Granules are, for example, prepared by mixing the adsorbent particles onto which the obeticholic acid in dissolved form is adsorbed with a granulation liquid (wet granules). Alternatively, the adsorbent particles onto which the obeticholic acid in dissolved form is adsorbed are pressed into compacts or flakes and then broken into granules (dry granules).

Pellets are agglomerates having a smooth surface and rounded edges. Pellets have a lower porosity and a narrower particle size distribution compared to granules. They can be prepared, for example, from granules by extrusion and spheronization. Alternatively, a powder mixture can be directly mixed with a binder liquid in an extruder, extruded and spheronized. Pellets can usually have a particle size of from 0.2 to 2 mm.

Minitablets are tablets with a diameter of not more than 3 mm, preferably 1 to 3 mm. Hard gelatine capsules filled with minitablets have the advantage that patients with swallowing problems (e.g. pediatric or elderly patients) can open the capsule and administer the minitablets separately. Additionally, minitablets offer the advantage of being able to combine various release kinetics, for example an immediate release and an extended release by combining minitablets with different release characteristics in one capsule. Minitablets can be prepared in the same manner as normal tablets with the exception that the punch used in the compression step is adapted to the size of the minitablets and produces, for example, 10 minitablets having a diameter of 2 mm instead of 1 normal tablet having a diameter of 10 mm.

In an alternative embodiment, the pharmaceutical composition of the present invention can be a tablet comprising an adsorbent material wherein obeticholic acid in dissolved form is adsorbed onto the adsorbent material. A tablet has the advantage that it may be produced with a breaking notch. Such a breaking notch allows the patient to divide the tablet. Tablets can be produced in any way known to the skilled person, for example, by wet granulation, dry granulation or direct compression.

The tablet may contain a coating. The coating may, for example, comprise polyvinyl alcohol, in particular, partly-hydrolyzed polyvinyl alcohol, and a colorant.

Examples of the adsorbent materials mentioned above include, without limitation, silicon dioxide, magnesium aluminometasilicates and mixtures thereof. A preferred magnesium aluminometasilicate is AI₂0₃-MgCM .7Si0₂-l-l₂0 (CAS number: 1251 1 -31 -8).

Silicon dioxide is the most preferred adsorbent material.

The adsorbent material has preferably a volumetric oil absorption of from 0.3 to 0.9 g oil/ml, more preferably 0.5 to 0.9 g oil/ml, even more preferably 0.7 to 0.9 g oil/ml. The volumetric oil absorption can be measured according to ASTM D 6854.

The adsorbent material has preferably an average particle size of from 5 to 200 pm, more preferably 5 to 100 pm, even more preferably 5 to 50 pm. The average particle size can be measured by laser diffraction, for example, by using a Malvern mastersizer equipment.

The adsorbent material has preferably a bulk density of from 150 to 600 g/l, more preferably 300 to 600 g/l, even more preferably 450 to 600 g/l. The bulk density can be measured according to Ph. Eur. 9.2 chapter 2.9.34 (method 1 ).

The adsorbent material has preferably an average pore volume of from 0.2 to 2.0 cm³/g, more preferably 1 .0 to 2.0 cm³/g, even more preferably 1 .5 to 2.0 cm³/g. The average pore volume can be measured, for example, by using the fluid saturation method.

In the pharmaceutical composition of the present invention, the weight ratio of obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof (API) to the solvent or mixture of solvents (S) (the weight ratio API/S) is preferably 1 :5 to 1 :20, more preferably 1 :6 to 1 :15, even more preferably 1 :6 to 1 :10, most preferably 1 :8 to 1 :10. The pharmaceutical composition of the present invention can additionally comprise one or more excipients selected from the group consisting of solubilizers, emulsifiers, wetting agents, surfactants, fillers, binders, disintegrants, glidants, lubricants, preservatives and mixtures thereof. Examples of the aforementioned excipients are known, for example, from the "Handbook of Pharmaceutical Excipients" (6th edition), edited by R.C. Rowe, P.J. Sheskey and M.E. Quinn, published by the Pharmaceutical Press and the American Pharmacists Association.

Preferably, the pharmaceutical composition of the present invention contains less than 0.2% by weight of any unspecified impurities and less than 0.5% by weight of each of the following impurities:

3a,7odihydroxy-6-ethyliden-53-cholan-24-oic acid,

6-3-ethyl-chenodeoxycholic acid,

3a,73-dihydroxy-6a-ethyl-53-cholan-24-oic acid,

3a,73-dihydroxy-63-ethyl-53-cholan-24-oic acid,

3a(3a,7odihydroxy-6oethyl-53-cholan-24-oyloxy)-7a-hydroxy-6a-ethyl-53-cholan-24- oic acid,

3ohydroxy-6oethyl-7-keto-53-cholan-24-oic acid,

3ohydroxy-63-ethyl-7-keto-53-cholan-24-oic acid,

chenodeoxycholic acid,

6-ethylursodeoxycholic acid.

In a preferred embodiment, the pharmaceutical composition of the present invention is free from obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in amorphous form.

In a further preferred embodiment, the pharmaceutical composition of the present invention is free from obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in crystalline form.

In another preferred embodiment, the pharmaceutical composition of the present invention is free from obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in amorphous form, and is free from obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in crystalline form. Within the meaning of the present invention, the pharmaceutical composition of the present invention is free from obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in amorphous form, if the amorphous form is present in an amount of 0% by weight to less than 1% by weight, preferably 0% by weight to less than 0.5% by weight, more preferably 0% by weight to less than 0.2% by weight, most preferably 0% by weight to less than 0.05% by weight, based on the amount of the obeticholic acid, pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof present in the pharmaceutical

composition.

Within the meaning of the present invention, the pharmaceutical composition of the present invention is free from obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in crystalline form, if the crystalline form is present in an amount of 0% by weight to less than 1 % by weight, preferably 0% by weight to less than 0.5% by weight, more preferably 0% by weight to less than 0.2% by weight, most preferably 0% by weight to less than 0.05% by weight, based on the amount of the obeticholic acid, pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof present in the pharmaceutical

composition.

It is particularly preferred that the amorphous form of obeticholic acid, a

pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof cannot be detected by any method known to the skilled person in the pharmaceutical composition of the present invention (i.e. the amorphous form is below the detection level).

It is further particularly preferred that any crystalline form of obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof cannot be detected by any method known to the skilled person in the pharmaceutical composition of the present invention (i.e. any crystalline form is below the detection level).

It is further particularly preferred that the amorphous form and any crystalline form of obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof cannot be detected by any method known to the skilled person in the pharmaceutical composition of the present invention (i.e. any crystalline form and the amorphous form are below the detection level). In another preferred embodiment, wherein the pharmaceutical composition of the present invention comprises obeticholic acid in dissolved form, the pharmaceutical composition is preferably free from obeticholic acid in amorphous form. In another preferred embodiment, wherein the pharmaceutical composition of the present invention comprises obeticholic acid in dissolved form, the pharmaceutical composition is preferably free from obeticholic acid in crystalline form. In another preferred

embodiment, wherein the pharmaceutical composition of the present invention comprises obeticholic acid in dissolved form, the pharmaceutical composition is free from obeticholic acid in amorphous form and is free from obeticholic acid in crystalline form. Within the meaning of the present invention, the pharmaceutical composition of the present invention is free from obeticholic acid in amorphous form, if the amorphous form is present in an amount of 0% by weight to less than 1 % by weight, preferably 0% by weight to less than 0.5% by weight, more preferably 0% by weight to less than 0.2% by weight, most preferably 0% by weight to less than 0.05% by weight, based on the amount of the obeticholic acid present in the pharmaceutical composition. Within the meaning of the present invention, the pharmaceutical composition of the present invention is free from obeticholic acid in crystalline form, if the crystalline form is present in an amount of 0% by weight to less than 1 % by weight, preferably 0% by weight to less than 0.5% by weight, more preferably 0% by weight to less than 0.2% by weight, most preferably 0% by weight to less than 0.05% by weight, based on the amount of the obeticholic acid present in the pharmaceutical composition. It is particularly preferred that the amorphous form of obeticholic acid cannot be detected by any method known to the skilled person in the pharmaceutical composition of the present invention (i.e. the amorphous form is below the detection level). It is further particularly preferred that any crystalline form of obeticholic acid cannot be detected by any method known to the skilled person in the pharmaceutical composition of the present invention (i.e. any crystalline form is below the detection level). It is further particularly preferred that the amorphous form and any crystalline form of obeticholic acid cannot be detected by any method known to the skilled person in the pharmaceutical composition of the present invention (i.e. any crystalline form and the amorphous form are below the detection level).

In a particularly preferred embodiment, the pharmaceutical composition of the present invention is a capsule, wherein the capsule comprises obeticholic acid in dissolved form, wherein the pharmaceutical composition is free from obeticholic acid in amorphous form and is free from obeticholic acid in crystalline form, and wherein the dissolved form is a solution of obeticholic acid in a solvent comprising caprylocaproyl polyoxylglycerides.

In another particularly preferred embodiment, the pharmaceutical composition of the present invention is a capsule, wherein the capsule comprises obeticholic acid in dissolved form, wherein the pharmaceutical composition is free from obeticholic acid in amorphous form and is free from obeticholic acid in crystalline form, and wherein the dissolved form is a solution of obeticholic acid in a solvent comprising propylene glycol monolaurate.

In another particularly preferred embodiment, the pharmaceutical composition of the present invention is a capsule, wherein the capsule comprises obeticholic acid in dissolved form, wherein the pharmaceutical composition is free from obeticholic acid in amorphous form and is free from obeticholic acid in crystalline form, and wherein the dissolved form is a solution of obeticholic acid in a solvent comprising glyceryl caprylate/caprate.

In another particularly preferred embodiment, the pharmaceutical composition of the present invention is a capsule, wherein the capsule comprises obeticholic acid in dissolved form, wherein the pharmaceutical composition is free from obeticholic acid in amorphous form and is free from obeticholic acid in crystalline form, and wherein the dissolved form is a solution of obeticholic acid in a solvent comprising diethylene glycol monoethyl ether.

The process for preparing a pharmaceutical composition of the present invention may include the following steps:

(a) obeticholic acid is transferred into a dissolved form, for example, by dissolving it in a solvent or mixture of solvents;

(b) the dissolved form obtained in step (a) is converted into a pharmaceutical composition.

Dissolving obeticholic acid in a solvent or a mixture of solvents can be done by any suitable technology, for example by using a mechanical stirrer (such as an overhead stirrer or a magnetic stirrer). Depending on the form of obeticholic acid used (obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof) and depending on the solvent or mixture of solvents used, it may take up to 120 minutes until a clear solution is obtained, in most cases it takes 10 to 60 minutes. In a preferred process of the present invention, the obeticholic acid is dissolved in a solvent or mixture of solvents followed by one of the following steps:

(I) the dissolved obeticholic acid is filled into a capsule, preferably into a hard gelatin capsule or a soft gelatin capsule;

(II) the dissolved obeticholic acid is adsorbed onto an adsorbent material, preferably silicon dioxide, and then filled into a capsule, preferably into a hard gelatin capsule;

(III) the dissolved obeticholic acid is adsorbed onto an adsorbent material, preferably silicon dioxide, granulated to produce granules and the granules are then filled into a capsule, preferably into a hard gelatin capsule;

(IV) the dissolved obeticholic acid is adsorbed onto an adsorbent material, preferably silicon dioxide, pelletized to produce pellets and the pellets are then filled into a capsule, preferably into a hard gelatin capsule;

(V) the dissolved obeticholic acid is adsorbed onto an adsorbent material, preferably silicon dioxide, compressed to produce minitablets and the minitablets are then filled into a capsule, preferably into a hard gelatin capsule;

(VI) the dissolved obeticholic acid is adsorbed onto an adsorbent material, preferably silicon dioxide, and then compressed into a tablet.

Step (VI) may optionally be followed by a coating step.

Obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof is preferably present in the pharmaceutical composition of the present invention in an amount of from 0.1 to 100 mg, preferably in an amount of from 1 to 50 mg, more preferably in an amount of 1 mg, 1.5 mg, 2 mg, 3 mg, 5 mg, 10 mg, 12.5 mg, 20 mg, 25 mg or 50 mg (based on the free acid).

The pharmaceutical composition of the present invention can be used in the treatment of FXR-mediated diseases, such as liver diseases and cardiovascular diseases. The pharmaceutical composition of the present invention can preferably be used in the treatment of hepatic disorders, for example, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), hepatitis B, hepatitis C, parasitic liver disease, drug-induced liver disease (e.g. methotrexate, isoniazid, oxyphenistatin, methyldopa, chlorpromazine, tolbutamide or amiodarone induced liver disease), hereditary cholestasis, and intrahepatic cholestasis of pregnancy in a patient in need thereof. Alternatively, the pharmaceutical composition of the present invention can preferably be used for preventing, reversing or slowing the reduction of bone density in a patient in need thereof, in particular, the pharmaceutical composition of the present invention can be used in the prevention or treatment of osteoporosis in a patient in need thereof.

The pharmaceutical composition of the present invention is preferably administered once daily to a patient in need thereof.

The pharmaceutical composition of the present invention can be used in free or fixed combination with one or more other drugs, such as lipid-lowering agents, cholesterol- lowering agents, anticoagulants, and/or antidiabetic agents.

EXAMPLES

The following examples illustrate the present invention and are not intended to limit the scope of the invention set forth in the claims appended hereto.

Example 1

Hard gelatin capsules (filled with solution)

Obeticholic acid was dissolved in diethylene glycol monoethyl ether by using a magnetic stirrer until a clear solution was formed. This took about 60 minutes. The resulting solution was then directly filled into prefabricated hard gelatin capsules using an encapsulation machine as known to a skilled person, wherein the empty capsules are opened, filled and closed in one step, followed by sealing.

Examples 2 to 4 Example 1 was repeated with the only difference that instead of diethylene glycol monoethyl ether, the following solvents were used:

Example 2: Propylene glycol monolaurate

Example 3: Caprylocaproyl polyoxylglycerides

Example 4: Glyceryl caprylate/caprate

Example 5

Soft gelatin capsules (filled with solution)

Obeticholic acid was dissolved in diethylene glycol monoethyl ether by using an overhead stirrer until a clear solution was formed. This took about 60 minutes. The obtained solution was used as liquid filling material.

The soft gelatin capsules were produced on a conventional rotary die machine, which is fed by two tanks of material: (1 ) the molten gelatin having a temperature of about 60 to 65°C, and (2) the liquid filling material having a temperature of less than 35°C. The molten gelatin flows onto the surface of two separate drums, where flat, solid ribbons of gelatin are formed. The liquid fill material prepared above was then injected into the space between the two ribbons. The injection of the liquid forces the gelatin to expand into the die pockets. As the ribbons continue to pass the heated wedge and are pressed between the die rolls, the capsule halves are sealed together by the application of heat and pressure.

The soft gelatin capsules coming off the encapsulation machine then went through primary and secondary drying processes in drying chambers to remove the excess water from the gelatin shell. Examples 6 to 9

Example 5 was repeated with the only difference that instead of diethylene glycol monoethyl ether, the following solvents were used:

Example 6: Propylene glycol monolaurate

Example 7: Caprylocaproyl polyoxylglycerides

Example 8: Glyceryl caprylate/caprate

Example 9: Polysorbate 80 Example 10

Tablets

Obeticholic acid was dissolved in diethylene glycol monoethyl ether by using an overhead stirrer until a clear solution was formed. This took about 60 minutes.

The solution was then adsorbed onto the silicon dioxide under continuous mixing in a conventional wet granulation equipment (high shear mixer) to prepare a dry, flowable and compressible powder. The silicon dioxide used has the following properties:

Average particle size (Malvern): 50 pm,

Bulk density: 275 g/l,

Average pore volume: 1.7 cm³/g.

The powder, wherein the obeticholic acid is still present in dissolved form, was then mixed with the microcrystalline cellulose and the sodium starch glycolate in a rotary drum mixer for about 10 minutes. Then, the magnesium stearate was added and the components were mixed for about 1 min in a rotary drum mixer. The mixture was finally compressed into tablets using a Kilian rotary tablet press. Example 1 1

Example 10 was repeated with the only difference that instead of diethylene glycol monoethyl ether, caprylocaproyl polyoxylglycerides were used.

Example 12

Hard gelatin capsules (filled with powder)

The solution was then adsorbed onto the silicon dioxide under continuous mixing in a conventional wet granulation equipment (high shear mixer) to prepare a dry, flowable and compressible powder. The silicon dioxide used has the following properties: Average particle size (Malvern): 150 pm,

Bulk density: 275 g/l,

Average pore volume: 1.7 cm³/g.

The powder, wherein the obeticholic acid is still present in dissolved form, was then directly filled into prefabricated hard gelatin capsules using an encapsulation machine as known to a skilled person wherein the empty capsules are opened, filled and closed in one step, followed by sealing. Example 13

Example 12 was repeated with the only difference that instead of silicon dioxide, Al₂0₃-Mg0-1.7Si0₂-H₂0 (CAS number: 12511-31-8) was used as adsorbent material.

The adsorbent material used has the following properties:

Average particle size (Malvern): 100 pm,

Bulk density: 350 g/l.

Example 14

Hard gelatin capsules (filled with granules)

The solution was then adsorbed onto the silicon dioxide under continuous mixing in a conventional wet granulation equipment (high shear mixer) to prepare a dry, flowable and compressible powder. The silicon dioxide used has the following properties: Average particle size (Malvern): 50 pm,

Bulk density: 275 g/l,

Average pore volume: 1.7 cm³/g. The powder, wherein the obeticholic acid is still present in dissolved form, was then mixed with the microcrystalline cellulose in a rotary drum mixer for about 10 minutes. The mixture was then compacted on a roller compactor (Alexander Compactor). The compacted mixture was passed through a 1.0 mm sieve.

The resulting granules were directly filled into prefabricated hard gelatin capsules using an encapsulation machine as known to a skilled person wherein the empty capsules are opened, filled and closed in one step, followed by sealing. Example 15

Hard gelatin capsules (filled with pellets)

Obeticholic acid was dissolved in diethylene glycol monoethyl ether by using an overhead stirrer until a clear solution was formed. This took about 60 minutes. The solution was then adsorbed onto the silicon dioxide under continuous mixing in a conventional wet granulation equipment (high shear mixer) to prepare a dry, flowable and compressible powder. The silicon dioxide used has the following properties:

Average particle size (Malvern): 50 pm,

Bulk density: 275 g/l,

Average pore volume: 1.7 cm³/g.

The powder, wherein the obeticholic acid is still present in dissolved form, was then mixed with the microcrystalline cellulose and the sodium starch glycolate in a rotary drum mixer for about 10 minutes. Then, the magnesium stearate was added and the components were mixed for about 1 min in a rotary drum mixer. The mixture was then compacted on a roller compactor (Alexander Compactor). The compacted mixture was passed through a 1.0 mm sieve. The obtained granules were then formed into pellets by extrusion and spheronization on a conventional pelletizing equipment.

The resulting pellets were directly filled into prefabricated hard gelatin capsules using an encapsulation machine as known to a skilled person wherein the empty capsules are opened, filled and closed in one step, followed by sealing. Example 16

Hard gelatin capsules (filled with minitablets)

Average particle size (Malvern): 50 pm,

Bulk density: 275 g/l,

Average pore volume: 1.7 cm³/g.

The powder, wherein the obeticholic acid is still present in dissolved form, was then mixed with the microcrystalline cellulose and the sodium starch glycolate in a rotary drum mixer for about 10 minutes. Then, the magnesium stearate was added and the components were mixed for about 1 min in a rotary drum mixer. The mixture was finally compressed into minitablets using a rotary tablet press with a punch producing minitablets having a diameter of 2 mm.

The resulting minitablets were then directly filled into prefabricated hard gelatin capsules using an encapsulation machine as known to a skilled person wherein the empty capsules are opened, filled and closed in one step, followed by sealing.

Examples 17 to 20

Example 16 was repeated with the only difference that instead of diethylene glycol monoethyl ether, the following solvents were used:

Example 17: Propylene glycol monolaurate

Example 18: Caprylocaproyl polyoxylglycerides

Example 19: Polysorbate 80

Example 20: Glyceryl caprylate/caprate

Example 21

Example 16 was repeated with the only difference that instead of silicon dioxide, Al₂0₃-Mg0-1.7Si0₂-H₂0 (CAS number: 12511-31-8) was used as adsorbent material. The adsorbent material used has the following properties:

Average particle size (Malvern): 100 pm,

Bulk density: 350 g/l. Example 22

Solutions of obeticholic acid in the following solvents were prepared: a) Obeticholic acid was mixed with caprylocaproyl polyoxylglycerides (CAS number:

223129-75-7) in a weight ratio of 1 : 9 (obeticholic acid : solvent) by using an overhead stirrer until a clear solution was formed. b) Obeticholic acid was mixed with caprylocaproyl polyoxylglycerides (CAS number:

223129-75-7) in a weight ratio of 1 : 7 (obeticholic acid : solvent) by using an overhead stirrer until a clear solution was formed. c) Obeticholic acid was mixed with propylene glycol monolaurate in a weight ratio of 1 :

9 (obeticholic acid : solvent) by using an overhead stirrer until a clear solution was formed. d) Obeticholic acid was mixed with propylene glycol monolaurate in a weight ratio of 1 :

7 (obeticholic acid : solvent) by using an overhead stirrer until a clear solution was formed. e) Obeticholic acid was mixed with glyceryl caprylate/ca prate (CAS number: 73398-61- 5) in a weight ratio of 1 : 9 (obeticholic acid : solvent) by using an overhead stirrer until a clear solution was formed. f) Obeticholic acid was mixed with glyceryl caprylate/ca prate (CAS number: 73398-61- 5) in a weight ratio of 1 : 7 (obeticholic acid : solvent) by using an overhead stirrer until a clear solution was formed.

Solutions a) to f) were stored at 25°C ± 2°C/60% RH ± 5% RH (RH = relative humidity). A clear solution was still present after storage for 3 months in case of all solutions a) to f)·

Reference Example 1

Obeticholic acid was mixed with water in a weight ratio of 1 : 9 (obeticholic acid : water) by using a magnetic stirrer for 60 minutes. The obeticholic acid did not dissolve.

Instead, a foamy suspension was obtained. Reference Example 2

A solvent mixture containing 10 % by volume of water and 90 % by volume of ethanol was prepared. Obeticholic acid was mixed with this water/ethanol solvent mixture in a weight ratio of 1 : 9 (obeticholic acid : solvent mixture) by using a magnetic stirrer for 60 minutes. The obeticholic acid did not dissolve. Instead, a foamy suspension was obtained. Reference Example 3

Obeticholic acid was mixed with glycerol in a weight ratio of 1 : 9 (obeticholic acid : glycerol) by using a magnetic stirrer. It took less than 1 minute until a highly viscous liquid was formed, wherein no further stirring was possible. The obeticholic acid did not dissolve.

Reference Example 4

Obeticholic acid was mixed with eicosapentaenoic acid ethyl ester in a weight ratio of 1 : 9 (obeticholic acid : eicosapentaenoic acid ethyl ester) by using a magnetic stirrer. The obeticholic acid did not dissolve. The experiment had to be terminated after 2.5 minutes because a highly viscous and sticky material was formed, wherein further stirring was impossible.

Claims

1. Pharmaceutical composition comprising obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof,

wherein the obeticholic acid, pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof is present in dissolved form.

2. Pharmaceutical composition according to claim 1 , wherein the dissolved form is a solution of obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in a solvent or a mixture of solvents.

3. Pharmaceutical composition according to claim 1 , wherein the dissolved form is a liquid-in-solid system of obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in a solvent or a mixture of solvents.

4. Pharmaceutical composition according to any of claims 2 to 3, wherein the solvent is a non-volatile solvent having a boiling point of more than 100°C or the mixture of solvents comprises at least one non-volatile solvent having a boiling point of more than 100°C.

5. Pharmaceutical composition according to any of claims 2 to 4, wherein the solvent is selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycols, glyceryl fatty acid esters, propylene glycol fatty acid esters, polyoxylglycerides, polyoxyethylene sorbitan fatty acid esters and mixtures thereof, or the mixture of solvents comprises at least one solvent selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycols, glyceryl fatty acid esters, propylene glycol fatty acid esters, polyoxylglycerides, polyoxyethylene sorbitan fatty acid esters and mixtures thereof.

6. Pharmaceutical composition according to claim 5, wherein the polyethylene glycol has a weight average molecular weight of from 350 to 450 g/mol; the glyceryl fatty acid ester is selected from glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate, glyceryl dicaprate, glyceryl caprylate/caprate, and mixtures thereof; the propylene glycol fatty acid ester is propylene glycol monolaurate; the polyoxylglyceride is selected from caprylocaproyl polyoxylglycerides, linoleoyl polyoxylglycerides, oleoyl polyoxylglycerides and mixtures thereof; and the polyoxyethylene sorbitan fatty acid ester is selected from Polysorbate 40, Polysorbate 80 and mixtures thereof.

7. Pharmaceutical composition according to any of claims 2 to 5, wherein the solvent is selected from the group consisting of diethylene glycol monoethyl ether, propylene glycol monolaurate, caprylocaproyl polyoxylglycerides, glyceryl

caprylate/caprate, and mixtures thereof.

8. Pharmaceutical composition according to any of claims 1 to 7, which is a capsule, preferably a hard gelatin capsule or a soft gelatin capsule, filled with obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in dissolved form.

9. Pharmaceutical composition according to any of claims 1 or 3 to 7, which is a capsule containing an adsorbent material, wherein the obeticholic acid, a

pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in dissolved form is adsorbed onto the adsorbent material.

10. Pharmaceutical composition according to claim 9, which is a capsule containing particles, granules, pellets or minitablets comprising an adsorbent material and obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in dissolved form adsorbed onto the adsorbent material.

1 1. Pharmaceutical composition according to any of claims 1 or 3 to 7, which is a tablet comprising an adsorbent material and obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in dissolved form adsorbed onto the adsorbent material.

12. Pharmaceutical composition according to any of claims 9 to 1 1 , wherein the adsorbent material is selected from silicon dioxide, magnesium aluminometasilicates and mixtures thereof.

13. Pharmaceutical composition according to any of claims 9 to 12, wherein the adsorbent material has an average particle size of from 5 to 200 pm, preferably 5 to 50 pm, a volumetric oil absorption of from 0.3 to 0.9 g oil/ml, a bulk density of from 150 to 600 g/l and/or an average pore volume of from 0.2 to 2.0 cm³/g.

14. Pharmaceutical composition according to any of claims 1 to 13, which is free from obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in amorphous form.

15. Pharmaceutical composition according to any of claims 1 to 14, which is free from obeticholic acid, a pharmaceutically acceptable salt, solvate, solvated salt or amino acid conjugate thereof in crystalline form.