Ombactrapib and ezetimibe combined treatment and fixed dose pharmaceutical composition

Abstract

The present disclosure relates to a stable pharmaceutical composition comprising a fixed dose combination of olbistetrapib and ezetimibe or a salt, solvate, or derivative of olbistetrapib and ezetimibe. The disclosure further describes the use of ezetimibe and Eubiquitrapib, for example in such fixed dose combinations, for the preparation of an agent for the treatment of a subject in need of lowering LDL-cholesterol or a subject suffering from hyperlipidemia or mixed dyslipidemia, and methods of treatment for the subject.

Description

Technical Field

[0001] The present disclosure relates to a fixed-dose pharmaceutical composition comprising obicetrapib and ezetimibe and its use for preparing a medicament required for a subject in need of reducing LDL cholesterol or an in-patient suffering from heterozygous familial hypercholesterolemia (HeFH) and / or diagnosed with atherosclerotic cardiovascular disease (ASCVD), and for treating the subject or in-patient. Background Art

[0002] Despite therapeutic advances, cardiovascular disease (CVD) remains the leading cause of death globally, with over 17 million deaths annually. For many years, abnormal cholesterol levels have been known to be associated with an increased risk of cardiovascular diseases (CVD) such as cardiomyopathy, atherosclerosis, and myocardial infarction. In particular, individuals with high levels of low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol in combination with low levels of high-density lipoprotein (HDL) cholesterol have been observed to have the highest risk of cardiovascular disease.

[0003] In primary and secondary prevention of cardiovascular events, reducing low-density lipoprotein cholesterol (LDL-C) is a primary goal of therapy. Although statin therapy is the main means of reducing LDL-C, a significant percentage of patients taking the statin drug formulations either fail to achieve the target lipid levels of statin therapy or are partially or completely intolerant to statins. To reduce the risk of recurrence of non-fatal or fatal cardiovascular disease, such patients are recommended to use alternative lipid-lowering drug formulations in combination.

[0004] One class of alternative therapeutic drug formulations is cholesterol absorption inhibitors (CAI). CAI prevents the uptake of cholesterol by the small intestine by blocking the uptake of micellar cholesterol, thereby reducing the inclusion of cholesterol esters in chylomicrons and chylomicron remnants. CAI reduces the amount of cholesterol recycled back to the liver, thereby increasing the activity of hepatic LDL receptors and increasing the clearance of LDL cholesterol particles from the bloodstream.

[0005] Known examples of CAs are ezetimibe, which was formerly known as the compound "Sch-58235" of Schering-Plough and is marketed under brand names such as Ezetrol and Zetia (Merck Sharp & Dohme / Merck) in many products. The IUPAC name of ezetimibe is (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one. Ezetimibe is often administered as a monotherapy or an add-on combination therapy. Generally, the ezetimibe dosage form is a tablet containing 10 mg of ezetimibe for oral administration.

[0006] Another therapeutic pharmaceutical preparation is an inhibitor of cholesteryl ester transfer protein (CETP). CETP is a plasma protein mainly secreted by the liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to particles containing apolipoprotein B (ApoB) (mainly LDL and VLDL) in exchange for triglyceride (TG), thereby reducing the cholesterol content in HDL and favoring the cholesterol content in (V)LDL. Therefore, it has been hypothesized that CETP inhibition preserves the cholesteryl esters in HDL-C and reduces the cholesterol content of the atherogenic ApoB fraction.

[0007] Although there is evidence to support the potential of CETP inhibition in reducing cardiovascular morbidity, the clinical development of CETP inhibitors has not been easy, and multiple CETP inhibitors have been abandoned at various stages of clinical development. Obicetrapib (also known as TA-8995) is currently under clinical evaluation.

[0008] In the treatment of subjects with hyperlipidemia or mixed dyslipidemia, there is still a need for improved therapies to reduce the risk of cardiovascular events, for example, by combination therapies.

[0009] As will be explained in more detail below, the inventors of the present invention have found that the combination treatment with obicetrapib and ezetimibe results in a significant improvement in the blood lipid profile, and thus, generally speaking, aspects of the present invention provide a treatment method comprising the concomitant administration of obicetrapib and ezetimibe.

[0010] Combination therapies require the co - administration of multiple pills according to the exact instructions of the doctor prescribing such treatment to a patient. Since each drug in a combination therapy may have its own set of instructions for use, it is often cumbersome for a patient to follow such instructions over a long period of time, and this is even more complex for the treatment of chronic diseases (such as chronic diseases requiring lipid - lowering) and for the patient or the patient's caregiver. Such difficulties often lead to non - compliance with medical orders, which impairs the efficacy, increases the risk of adverse reactions, and in many cases, generates resistance or alters the sensitivity of the target receptor / protein.

[0011] Preparing a fixed - dose combination of different drugs in a single pharmaceutical dosage form is often challenging due to the presence of multiple factors such as: physicochemical incompatibilities of the active pharmaceutical ingredients (APIs), such as API - API interactions; excipient - excipient interactions and drug - excipient interactions. Physicochemical incompatibilities of the active ingredients include challenges arising from differences in the physicochemical properties and behaviors of the APIs. For example, the pKa, logP, solubility, hygroscopicity, photosensitivity, particle size, flowability, compressibility, melting point, or any such other parameter of one active ingredient may not be suitable for the stability of another API in the formulation. Compared with preparing a stable formulation with a single API, the total amount of excipients available to achieve the required stability and dissolution of each API in a fixed - dose formulation is limited because the size and shape of the dosage form need to be controlled within the range of the proportions of the conventionally administered pills. Incompatibilities of some excipients of one or more drugs in a fixed - dose combination further limit the choices of formulation scientists. Greater challenges exist in this regard when the water solubility, solubility, or dissolution pattern of one or two APIs is poor or different (e.g., one is a soluble drug while one is insoluble or poorly soluble; or one is a lipophilic drug while the other is a hydrophilic drug). In a fixed - dose combination, the interaction of one drug or its impurities with another drug or its impurities can further affect the stability, efficacy, or solubility of one or both drugs.

[0012] Ezetimibe is an almost insoluble drug and has low solubility over the entire physiological pH range. Ezetimibe is also incompatible with many commonly used excipients and has stability problems. For example, the presence of polyethylene glycol (PEG) in the coating layer can lead to an increase in the tetrahydropyran impurities of ezetimibe. In addition, ezetimibe is an inherently incompressible and poorly flowable API (see, for example, EP 2168573 A1), so preparing tablet formulations of ezetimibe is quite challenging.

[0013] Obeticholic acid also has poor water solubility within the physiological pH range and has a negative impact on the solubility of ezetimibe (unpublished data). To the applicant's knowledge, no fixed-dose combination of ezetimibe and obeticholic acid that meets the following criteria has been found in the art: (i) can remain stable over a long period of time without a significant increase in the level of harmful impurities, (ii) does not have any significant API-API interactions, API-excipient interactions, or excipient-excipient interactions that would render such a composition unsuitable for human use, (iii) can consistently provide the desired dissolution profiles of each of the two components throughout its shelf life, which is comparable to or better than that of a formulation with a single drug, (iv) is easy to formulate and does not pose challenges to the processability of the components during formulation and scale-up for manufacture, (v) can achieve the desired bioavailability when administered orally by humans as two separate formulations of each drug and is bioequivalent to the same dose of the two active ingredients, and (vi) provides improved patient compliance, thereby demonstrating equivalent or superior therapeutic effects over a long period without the side effects of a single-drug formulation with multiple pills, such as poor patient compliance leading to resistance or hypersensitivity of the receptor / protein due to long-term and irregular exposure of the receptor / protein to such a drug and its metabolites at sub-therapeutic or toxic levels.

[0014] Accordingly, there remains a need for a fixed-dose combination formulation of ezetimibe and obeticholic acid that meets all of the above criteria for the treatment of subjects with hyperlipidemia or mixed dyslipidemia and for reducing the risk of cardiovascular events. Summary of the Invention

[0015] As already mentioned above, the inventors of the present invention have found that the combination therapy with obicetrapib and ezetimibe results in a significant improvement in the lipid profile even in subjects who do not respond adequately to (high-intensity) statin therapy (e.g., hypo-responders to high-intensity statin (HIS)). More particularly, as described in the experimental section of this document, it has now been shown in a Phase 2b clinical trial (“ROSE2”; NCT05266586) that the combination of obicetrapib (10 mg) and ezetimibe (10 mg) is well tolerated and reduces the median LDL-C by 59%, clearly demonstrating a supra additive effect. In particular, the median LDL-C in patients treated with obicetrapib was reduced by 39%, which means that the additional use of ezetimibe on top of obicetrapib further / incrementally reduces the (median) LDL-C by approximately 32%. This (greatly) exceeds the LDL-C reduction normally obtained with ezetimibe: with ezetimibe monotherapy, the LDL-C level is typically reduced by 15% to 22% (in patients with hyperlipidemia), while when used in combination with statins, ezetimibe typically further reduces the LDL-C level incrementally by 15% to 20% (see, for example, Catapano et al., European Heart Journal (2016) 37, 2999–3058). A significant increase in ApoB and Lp(a) levels was also demonstrated in the trial.

[0016] Accordingly, one aspect of the present invention relates to a fixed-dose pharmaceutical composition comprising: obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and a pharmaceutically acceptable excipient, such as a fixed-dose pharmaceutical composition wherein the composition is a two-component composition and one of the components comprises ezetimibe and the other component comprises obicetrapib.

[0017] One embodiment relates to a fixed-dose pharmaceutical composition comprising: obeticholic acid or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and a pharmaceutically acceptable excipient, wherein when the pharmaceutical composition is dissolved in 500 ml of solution in a USP Type II apparatus at about 75 rpm at 37 ± 0.5 °C, at least about 60%, preferably at least about 70%, and more preferably at least about 80% of the ezetimibe is dissolved within about 30 minutes, and the solution comprises 0.45% SLS in 0.05 M sodium acetate buffer at pH 4.5.

[0018] One embodiment relates to a fixed-dose pharmaceutical composition comprising: obeticholic acid or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and a pharmaceutically acceptable excipient, wherein upon oral administration of the composition to a subject, the 90% confidence intervals of the geometric mean of the area under the curve (AUC0-∞ and / or AUC0-t) and / or Cmax of obeticholic acid are respectively within the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of the area under the curve (AUC0-∞ and / or AUC0-t) and / or Cmax of obeticholic acid obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference pharmaceutical composition comprises an equivalent dose of obeticholic acid or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or simultaneously or sequentially in combination with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or is administered in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0019] Another embodiment relates to a fixed-dose pharmaceutical composition comprising: obeticholic acid or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and a pharmaceutically acceptable excipient, wherein upon oral administration of the composition to a subject, the 90% confidence intervals of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of ezetimibe and / or ezetimibe glucuronide are respectively those obtained upon oral administration of a reference pharmaceutical composition to a similar subject for the area under the curve (AUC 0-∞ and / or AUC0-t ) and / or in the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of Cmax, wherein the reference pharmaceutical composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or concomitantly or sequentially in combination with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0020] Surprisingly, it has been found that a fixed-dose pharmaceutical composition of ezetimibe and obicetrapib can be kept stable over a long period of time without a significant increase in the level of harmful impurities or the formation of a large amount of new impurities. It has also been surprisingly found that the fixed-dose pharmaceutical composition of ezetimibe and obicetrapib has no significant API-API interactions, drug-excipient interactions and / or excipient-excipient interactions that would render the formulation unsuitable for use.

[0021] Even more surprisingly, it has been found that the pharmaceutical composition consistently provides the dissolution profiles of ezetimibe and obicetrapib throughout its shelf life, which is equivalent to the solubility achieved by formulations comprising only a single drug. Since the stable composition provides the required dissolution profile through a single pill, it surprisingly overcomes the problems associated with the co-administration of multiple pills of a single-drug formulation, such as poor patient compliance, suboptimal therapeutic efficacy and an increased risk of undesirable side effects (e.g., receptor resistance or hypersensitivity). This makes the fixed-dose composition particularly relevant for the chronic treatment of patients in need of lipid-lowering therapy, and thus makes such a therapy applicable.

[0022] A second aspect relates to a fixed-dose pharmaceutical composition comprising: obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and a pharmaceutically acceptable excipient, the fixed-dose pharmaceutical composition being for reducing LDL cholesterol in patients in need of reducing LDL cholesterol and / or increasing HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0023] The present invention also provides a method of treating a subject in need thereof, the method comprising co-treating the subject with obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof and ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, preferably in the form of a fixed-dose pharmaceutical composition as defined herein.

[0024] More particularly, the present invention relates to the following aspects.

[0025] One aspect of the present invention relates to a method for prophylactic and / or therapeutic treatment of a subject suffering from CVD, particularly ASCVD, or at risk of developing CVD, particularly ASCVD, the method comprising co-administering to the subject obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof and ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, the method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0026] Another aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, the pharmaceutical composition for use in a method for prophylactic and / or therapeutic treatment of a subject suffering from CVD, particularly ASCVD, or at risk of developing CVD, particularly ASCVD, wherein the method comprises co-administering to the subject ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof and obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, the pharmaceutical composition is a fixed-dose pharmaceutical composition as defined herein.

[0027] Yet another aspect of the present invention relates to a method for synergistically reducing the plasma LDL-C level of a subject in need thereof, the method comprising co-administering to the subject ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof and obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, the method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0028] Yet another aspect of the present invention relates to a pharmaceutical composition comprising: ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof and / or obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, the pharmaceutical composition for use in a method for synergistically reducing the plasma LDL-C level of a subject in need thereof, the method comprising co-administering ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof and / or obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, the method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0029] Another aspect of the present invention relates to a method for synergistically slowing the development and / or progression of CVD (more particularly ASCVD) and / or synergistically reducing the risk and / or occurrence of CVD-related events (particularly ASCVD-related events) in a subject in need thereof, said method comprising co-administering ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof and obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, said method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0030] Another aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, said pharmaceutical composition for use in a method for synergistically slowing the development and / or progression of CVD (more particularly ASCVD) and / or synergistically reducing the risk and / or occurrence of CVD-related events (particularly ASCVD-related events) in a subject in need thereof, said method comprising co-treating said subject with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof and obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment, said method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0031] Another aspect of the present invention relates to a method for enhancing, preferably synergistically enhancing, the LDL-C lowering effect of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof in a subject in need thereof, said method comprising co-treating said subject with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, said method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0032] Another aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, said pharmaceutical composition for use in a method for enhancing, preferably synergistically enhancing, the LDL-C lowering effect of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof in a subject in need thereof, said method comprising co-administering ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, said method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0033] Another aspect of the present invention relates to a method for enhancing, preferably synergistically enhancing, the therapeutic efficacy of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, particularly in the treatment and / or prevention of CVD, more particularly ASCVD, in a subject in need thereof, said method comprising co-administering ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, the method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0034] Another aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, said pharmaceutical composition for use in a method for enhancing, preferably synergistically enhancing, the therapeutic efficacy of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, particularly in the treatment and / or prevention of CVD, more particularly ASCVD, in a subject in need thereof, said method comprising co-administering ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, the method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0035] Yet another aspect of the present invention relates to the use of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in the preparation of a medicament for use in any of the methods defined above. In a preferred embodiment of the present invention, the medicament is a fixed-dose pharmaceutical composition as defined herein.

[0036] Other aspects of the present invention relate to a kit, said kit comprising: a package containing a plurality of pharmaceutical unit dosage forms, said pharmaceutical unit dosage forms comprising a pharmaceutically acceptable salt, hydrate or solvate, such as a fixed-dose pharmaceutical composition as defined herein; and a leaflet containing printed instructions for use, said kit for repeated self-administration of said unit dosage forms to treat and / or prevent CVD, particularly ASCVD, by combining obicetrapib treatment with ezetimibe therapy.

[0037] It is to be understood that such aspects of the present invention, unless otherwise expressly stated, relate to the same compositions, the same methods of treatment, the same subjects, etc.

[0038] In certain preferred embodiments of the present invention, the salt of obicetrapib included in the pharmaceutical composition of the present invention, for use in the method of the present invention, included in the unit dosage form (included in the pharmaceutical kit), etc., is the amorphous calcium salt of obicetrapib.

[0039] Based on the following specific embodiments and the appended experimental section, specific details and preferred embodiments of the above methods, as well as the compositions and pharmaceutical kits used therein, will become apparent to those skilled in the art.

[0040] Definitions

[0041] Obeticholic acid, also known as "TA-8995", has the following chemical name and chemical structure:

[0042]

[0043] {4-[(2-{[3,5-Bis(trifluoromethyl)benzyl][(2R,4S)-1-(ethoxycarbonyl)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]amino}pyrimidin-5-yl)oxy]butanoic acid}

[0044] Ezetimibe, also known as "Sch-58235", has the following chemical name and chemical structure:

[0045]

[0046] (3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

[0047] Both obeticholic acid and ezetimibe can also be used as different salt forms, solvates or co-crystals. Obeticholic acid and ezetimibe can also be formulated as prodrugs.

[0048] As used herein, the term "apolipoprotein" has its conventional meaning and refers to a protein that binds lipids to form lipoproteins.

[0049] As used herein, the term "apolipoprotein B" (ApoB) has its conventional meaning and refers to the protein encoded by the ApoB gene.

[0050] As used herein, the term "pharmaceutical composition" has its conventional meaning and refers to a pharmaceutically acceptable composition.

[0051] As used herein, the term "pharmaceutically acceptable" has its conventional meaning and refers to the following compounds, materials, compositions and / or dosage forms: within the scope of reasonable medical judgment, suitable for contact with mammalian (especially human) tissues, without excessive toxicity, irritation, allergic reactions and other problem complications, and having a reasonable benefit / risk ratio.

[0052] The term "carrier" as used herein has its conventional meaning and refers to a pharmaceutically acceptable diluent, adjuvant, excipient or vehicle administered together with a pharmaceutically active ingredient.

[0053] The term "excipient" as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient commonly used in pharmaceutical technology for preparing particulate, solid or liquid oral dosage forms.

[0054] The term "salt" as used herein has its conventional meaning and includes acid addition salts and base salts of pharmaceutically active compounds.

[0055] The term "solvate" as used herein has its conventional meaning and refers to a compound formed by solvation, such as a combination of solvent molecules with solute molecules or ions. Well-known solvent molecules include water, alcohols, nitriles and polar organic solvents.

[0056] The term "subject" as used herein refers to a human being suffering from a disease or disorder or at risk of suffering from a disease or disorder. The term "subject" and "patient" are used interchangeably herein.

[0057] The term "increased risk" has its conventional meaning and refers to a situation in which a subject, preferably a human subject (male or female), based on its risk profile (including an LDL-cholesterol level higher than 70 mg / dL, such as higher than 2.6 mmol / l [100.54 mg / dL]), is at an increased risk of experiencing a cardiovascular event compared to a subject with a lower level.

[0058] The term "treatment" as used herein has its conventional meaning and refers to curative treatment, palliative treatment and prophylactic treatment.

[0059] The term "cardiovascular disease" as used herein has its conventional meaning and includes atherosclerosis, peripheral vascular disease, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and the clinical manifestations of stroke.

[0060] As used herein, the term "cardiovascular event" has its conventional meaning and refers to the occurrence of myocardial infarction, stroke, coronary death, or the need for coronary revascularization (Ference, 2017).

[0061] As used herein, the term "hypercholesterolemia" has its conventional meaning and refers to a disease in which there are high levels of cholesterol in the blood.

[0062] As used herein, the term "hyperlipidaemia" has its conventional meaning and refers to a disease in which high levels of lipids are found in the blood.

[0063] As used herein, the term "mixed dyslipidaemia" has its conventional meaning and refers to a disease in which there are elevated levels of LDL cholesterol and triglycerides in the blood, along with low levels of HDL cholesterol.

[0064] As used herein, the term "statin intolerant" has its conventional meaning and refers to a subject who is unable to tolerate two or more statins, one of which is at a low dose, due to the presence of adverse safety effects that begin or increase during statin therapy and resolve or improve upon discontinuation of the statin. In this regard, reference is also made to a similar definition approved by the FDA in the bempedoic acid (Esperion) Phase III trial.

[0065] As used herein, the term "cholesterol absorption inhibitor" (CAI) has its conventional meaning and refers to a compound that reduces LDL-C by blocking the intestinal and biliary absorption of cholesterol. A known cholesterol absorption inhibitor is ezetimibe.

[0066] As used herein, the term "cholesteryl ester transfer protein inhibitor" (CETP inhibitor) has its conventional meaning and refers to a class of compounds that inhibit the CETP receptor in mammals. A known CETP inhibitor is obicetrapib.

[0067] The term "unit dosage form" has its conventional meaning and refers to a dosage form that can be effectively administered to a subject (preferably a human), which can be easily handled and packaged and remains as a physically and chemically stable unit dose comprising a therapeutic pharmaceutical preparation (i.e., obicetrapib or a combination of therapeutic pharmaceutical preparations (e.g., obicetrapib and ezetimibe)).

[0068] As used herein, the term "fixed dose combination" has its conventional meaning and refers to a combination of two or more drugs or active ingredients in defined doses that are present in a single dosage unit (e.g., a tablet or a capsule) and are administered in this manner.

[0069] As used herein, the term "free dose combination" has its conventional meaning and refers to a combination of two drugs or active ingredients that are administered simultaneously but as two distinct dosage units.

[0070] The term "effective amount" or "therapeutically effective amount" means an amount sufficient to achieve a treatment as defined herein when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the patient being treated, the patient's weight and age, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0071] Unless otherwise specifically stated, when a compound can exist in alternative tautomeric, regioisomeric, and / or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, when a compound is described as a specific optical isomer, D- or L-, both optical isomers are intended to be covered herein. For example, when a compound is described as having one of two tautomeric forms, both tautomers are intended to be covered herein. Thus, the compounds provided herein can be enantiomerically pure, or can be a stereoisomeric or diastereomeric mixture. The compounds provided herein can contain chiral centers. Such chiral centers can be in the (R) configuration or the (S) configuration, or can be a mixture of the (R) and (S) configurations. The chiral centers of the compounds provided herein can undergo epimerization in vivo. Thus, those skilled in the art will recognize that for a compound that undergoes epimerization in vivo, administration of the compound in its (R) form is equivalent to administration of the compound in its (S) form.

[0072] This disclosure also encompasses all suitable isotopic variants of the compounds according to this disclosure, whether or not the isotopic variants are radioactive. Isotopic variants of the compounds according to this disclosure are understood to mean compounds in which at least one atom in the compounds according to this disclosure has been exchanged with another atom having the same atomic number but having an atomic mass different from the atomic mass that is normally or predominantly present in nature. Examples of isotopes that can be incorporated into the compounds according to this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131I. Specific isotopic variants of the compounds according to the disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be useful, for example, for examining the mechanism of action or the distribution of the active compound in the body. Using 3 H, 14 C and / or 18 F isotopes labeled compounds are suitable for this purpose. In addition, incorporation of isotopes (e.g., deuterium) can produce particular therapeutic benefits due to the greater metabolic stability of the compound (e.g., an extended half-life in the body or a reduced active dose required). In some embodiments, the hydrogen atoms of the compounds set forth herein may be replaced by deuterium atoms. In certain embodiments, unless otherwise stated, "deuterated" as applied to a chemical group means a chemical group of a deuterium-rich isotope in which the amount of deuterium is significantly greater than its natural abundance. Isotopic variants of the compounds according to the disclosure can be prepared by various methods using corresponding isotopic modifications of specific reagents and / or starting compounds, including, for example, the methods set forth below and in the working examples.

[0073] Accordingly, any of the embodiments described herein are intended to include single stereoisomers, mixtures of stereoisomers, and / or isotopic forms of the compounds.

[0074] Unless otherwise stated, the term "about" or "approximately" means an acceptable error of a particular value as determined by a person of ordinary skill in the art, which depends in part on how the particular value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1%, or 0.05% of a given value or range. Unless otherwise stated, the term "about" means within ±10% of the explicitly recited value, rounded up or down to the nearest integer. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 Cumulative undersize distribution curve of a small-scale batch of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib

[0076] Figure 2 Retention curve of a small-scale batch of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib

[0077] Figure 3For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of ezetimibe at pH 6.8 by the differential dissolution method

[0078] Figure 4 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of obeticholic acid at pH 6.8 by the differential dissolution method

[0079] Figure 5 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of ezetimibe at pH 4.5 by differential dissolution

[0080] Figure 6 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of obeticholic acid in the stress stability study of batch a4459 / 05 / 05 at pH 6.8

[0081] Figure 7 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of obeticholic acid in the stress stability study of batch a4459 / 05 / 06 at pH 6.8

[0082] Figure 8 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of obeticholic acid in the stress stability study of batch a4459 / 05 / 07 at pH 6.8

[0083] Figure 9 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of obeticholic acid in the stress stability study of batch a4459 / 05 / 08 at pH 6.8

[0084] Figure 10 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of ezetimibe in the stress stability study of batch a4459 / 05 / 05 at pH 6.8

[0085] Figure 11 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obeticholic acid, compare the dissolution profiles of ezetimibe in the stress stability study of batch a4459 / 05 / 06 at pH 6.8

[0086] Figure 12For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib, compare the ezetimibe dissolution profiles of the stress stability study of batch a4459 / 05 / 07 at pH 6.8

[0087] Figure 13 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib, compare the ezetimibe dissolution profiles of the stress stability study of batch a4459 / 05 / 08 at pH 6.8

[0088] Figure 14 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib, compare the ezetimibe dissolution profiles of the stress stability study of batch a4459 / 05 / 05 at pH 4.5

[0089] Figure 15 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib, compare the ezetimibe dissolution profiles of the stress stability study of batch a4459 / 05 / 06 at pH 4.5

[0090] Figure 16 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib, compare the ezetimibe dissolution profiles of the stress stability study of batch a4459 / 05 / 07 at pH 4.5

[0091] Figure 17 For small-scale batches of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib, compare the ezetimibe dissolution profiles of the stress stability study of batch a4459 / 05 / 08 at pH 4.5

[0092] Figure 18 Cumulative undersize distribution curve % of small-scale batches of a fixed composition of 10 mg ezetimibe and 10 mg obicetrapib

[0093] Figure 19 Obicetrapib dissolution profile of small-scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed-dose composition

[0094] Figure 20 Ezetimibe dissolution profile (50 rpm) of small-scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed-dose composition

[0095] Figure 21 Ezetimibe dissolution profile (75 rpm) of small-scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed-dose composition

[0096] Figure 22 For the small-scale 10 mg ezetimibe and 10 mg obeticholic acid (free acid) fixed-dose combination, stress stability dissolution results of obeticholic acid prototype C 200BN A4459 / 19 / 03

[0097] Figure 23 For the small-scale 10 mg ezetimibe and 10 mg obeticholic acid (free acid) fixed-dose combination, stress stability dissolution results of obeticholic acid prototype C scale-up BN A4459 / 19 / 02

[0098] Figure 24 For the small-scale 10 mg ezetimibe and 10 mg obeticholic acid (free acid) fixed-dose combination, stress stability dissolution results of ezetimibe prototype C scale-up BN A4459 / 19 / 02

[0099] Figure 25 For the small-scale 10 mg ezetimibe and 10 mg obeticholic acid (free acid) fixed-dose combination, stress stability dissolution results of ezetimibe prototype C scale-up BN A4459 / 19 / 02

[0100] Figure 26 Cumulative undersize distribution curve of small-scale FDC1 composition

[0101] Figure 27 Dissolution curve of obeticholic acid of FDC1 prototype

[0102] Figure 28 Dissolution curve of ezetimibe of FDC1 prototype

[0103] Figure 29 Cumulative undersize distribution curve of small-scale FDC2 composition

[0104] Figure 30 Dissolution curve of obeticholic acid of small-scale FDC2 composition

[0105] Figure 31 Dissolution curve of ezetimibe of small-scale FDC2 composition

[0106] Figure 32 Dissolution curve of obeticholic acid of small-scale FDC2 coated tablets obtained by differential method

[0107] Figure 33 Dissolution curve of obeticholic acid of small-scale FDC2 coated tablets obtained by QC method

[0108] Figure 34 Dissolution curve of ezetimibe of small-scale FDC2 coated tablets obtained by QC method

[0109] Figure 35 Dissolution profile of obeticholic acid in the small-scale prototype 2 of FDC2 coated tablets according to stress stability

[0110] Figure 36 Dissolution profile of ezetimibe in the prototype 2 of FDC2 coated tablets according to stress stability Figure 37 Cumulative undersize distribution curve of the scaled-up batch

[0111] Figure 38 Dissolution profile of obeticholic acid in FDC1 granules from the scaled-up batch

[0112] Figure 39 Dissolution profile of ezetimibe in FDC1 granules from the scaled-up batch

[0113] Figure 40 Dissolution profile of ezetimibe in the FDC2 final blend from the scaled-up batch

[0114] Figure 41 Dissolution profile of obeticholic acid in the uncoated tablets of FDC1 scaled-up batch at different compression forces Figure 42 Dissolution profile of ezetimibe in the uncoated tablets of FDC1 scaled-up batch at different compression forces Figure 43 Dissolution profile of obeticholic acid in the uncoated tablets of FDC2 scaled-up batch at different compression forces Figure 44 Dissolution profile of ezetimibe in the uncoated tablets of FDC2 scaled-up batch at different compression forces Figure 45 Cumulative undersize distribution curve of the technical batch

[0115] Figure 46 Dissolution profile of obeticholic acid in the FDC1 and FDC2 technical batches

[0116] Figure 47 Dissolution profile of obeticholic acid in the FDC1 and FDC2 technical batches

[0117] Figure 48 Particle size distribution (PSD) data of the granules from the technical batch

[0118] Figure 49 X-ray powder diffraction pattern of amorphous obeticholic acid hemicalcium

[0119] Figure 50 X-ray powder diffraction pattern of amorphous obeticholic acid hemicalcium

[0120] Figure 51 X-ray powder diffraction pattern of amorphous obeticholic acid hemicalcium

[0121] Figure 52 Infrared spectrum of amorphous obeticholic acid hemicalcium

[0122] Figure 53 1H-NMR spectrum of amorphous obeticholic acid hemicalcium 1 1H-NMR spectrum

[0123] Figure 54 X-ray powder diffraction pattern of crystalline obeticholic acid hemicalcium

[0124] Figure 55 Stacked X-ray powder diffraction patterns based on the stability study of crystalline obeticholic acid hemicalcium

[0125] Figure 56 Stacked X-ray powder diffraction patterns based on the stability study of amorphous obeticholic acid hemicalcium

[0126] Figure 57 Polarized light micrograph of amorphous obeticholic acid hemicalcium

[0127] Figure 58 Polarized light micrograph of crystalline obeticholic acid hemicalcium

[0128] Figure 59 Thermogravimetric analysis of amorphous obeticholic acid hemicalcium

[0129] Figure 60 Modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obeticholic acid hemicalcium

[0130] Figure 61 Modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obeticholic acid hemicalcium

[0131] Figure 62 Modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obeticholic acid hemicalcium

[0132] Figure 63 Solid-state 13 13C-NMR spectra of amorphous and crystalline obeticholic acid hemicalcium

[0133] Figure 64 Solid-state 13 13C-NMR spectrum of crystalline obeticholic acid hemicalcium

[0134] Figure 65 Solid-state 13 13C-NMR spectrum of amorphous obeticholic acid hemicalcium

[0135] Figure 66 X-ray powder diffraction pattern of crystalline obeticholic acid HCl and at least partially desolvated crystalline obeticholic acid HCl

[0136] Figure 67 X-ray powder diffraction pattern of crystalline obeticholic acid HCl

[0137] Figure 68 is the X-ray powder diffraction pattern of crystalline compound 1D.

[0138] Figure 69 is of compound 1D 1 1H-NMR spectrum. Detailed implementation mode

[0139] Fixed-dose pharmaceutical composition of the present invention

[0140] The first aspect relates to a fixed-dose pharmaceutical composition, which comprises obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients.

[0141] In one of the examples, when the fixed-dose pharmaceutical composition is orally administered to a subject, the 90% confidence interval of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of obicetrapib is respectively within the range of about 75% to 125%, preferably about 80% to 125%, and more preferably about 90% to 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of obicetrapib obtained when a reference pharmaceutical composition is orally administered to a similar subject, wherein the reference pharmaceutical composition comprises an equivalent dose of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or simultaneously or sequentially in combination with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or in the form of a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0142] In another example, when the fixed pharmaceutical composition is orally administered to a subject, the 90% confidence interval of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of ezetimibe and / or ezetimibe glucuronide is respectively the area under the curve (AUC 0-∞ and / or AUC 0-t)and / or in the range of about 75% to 125%, preferably about 80% to 125%, and more preferably about 90% to 110% of Cmax, wherein the reference pharmaceutical composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or co-administered simultaneously or sequentially with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or is administered in the form of a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0143] Ezetimibe is poorly soluble in water and has poor solubility throughout the physiological pH range. It is extremely challenging to achieve the required solubility and thus bioavailability under in vivo conditions for ezetimibe. This problem is further exacerbated as obicetrapib reduces the dissolution rate and total amount of soluble ezetimibe (unpublished data). It has surprisingly been found that when the pharmaceutical composition is dissolved in 500 ml of solution in a USP type II apparatus at about 75 rpm at 37 ± 0.5 °C, at least about 60%, preferably at least about 70%, and more preferably at least about 80% of the ezetimibe from the fixed-dose pharmaceutical composition dissolves within about 30 minutes, the solution comprising 0.45% SLS in 0.05 M sodium acetate buffer at pH 4.5. In a preferred embodiment, it has surprisingly been found that when the pharmaceutical composition is dissolved in 500 ml of solution in a USP type II apparatus at about 75 rpm at 37 ± 0.5 °C, at least about 60%, preferably at least about 70%, and more preferably at least about 80% of the ezetimibe from the fixed-dose pharmaceutical composition dissolves within about 20 minutes, the solution comprising 0.45% SLS in 0.05 M sodium acetate buffer at pH 4.5.

[0144] In addition, it has surprisingly been found that when the pharmaceutical composition is dissolved in 1000 ml of solution in a USP type II apparatus at about 75 rpm at 37 ± 0.5°C, at least about 70%, preferably at least about 80%, more preferably at least about 85%, and even more preferably at least about 90% of obicetrapib from the fixed-dose pharmaceutical composition is dissolved within about 30 minutes, the solution comprising phosphate buffer solution at pH 6.8 + 0.2% w / v polysorbate 80. In a preferred embodiment, it has surprisingly been found that when the pharmaceutical composition is dissolved in 1000 ml of solution in a USP type II apparatus at about 75 rpm at 37 ± 0.5°C, at least about 70%, preferably at least about 80%, and more preferably at least about 85% of obicetrapib from the fixed-dose pharmaceutical composition is dissolved within about 15 minutes, the solution comprising phosphate buffer solution at pH 6.8 + 0.2% w / v polysorbate 80.

[0145] Ezetimibe is essentially a poorly compressible / incompressible API (see, for example, EP 2168573 A1) and has poor flowability. Thus, it is extremely challenging for formulation scientists to prepare a tablet formulation of ezetimibe that not only meets the requirements of hardness, disintegration time, friability, shape, and size but also provides the desired stability and solubility. It has surprisingly been found that the composition not only meets the required specifications for solubility and stability suitable for the claimed use but also complies with the criteria of processability parameters (i.e., flowability, compressibility, disintegration time, friability, hardness, shape, and size).

[0146] The fixed-dose pharmaceutical composition may comprise a combination of 1 mg to 10 mg of obicetrapib and 5 mg to 20 mg of ezetimibe. In a preferred embodiment, the composition comprises 5 mg of obicetrapib and 10 mg of ezetimibe. In a more preferred embodiment, the composition comprises 10 mg of obicetrapib and 10 mg of ezetimibe.

[0147] In a preferred embodiment, the pharmaceutical composition is provided in a unit dosage form comprising 5 mg of obicetrapib and 10 mg of ezetimibe. In a more preferred embodiment, the composition is provided in a unit dosage form comprising 10 mg of obicetrapib and 10 mg of ezetimibe.

[0148] Whenever the dose of obicetrapib or ezetimibe is mentioned in mg and / or relative amounts (by weight) in the present disclosure, it means obicetrapib or ezetimibe in its free form. Whenever a salt, solvate, or co-crystal of ezetimibe or obicetrapib is used, for the purposes hereof, the dose shall mean the dose equivalent to the weight of ezetimibe or obicetrapib in its free form, respectively.

[0149] In certain embodiments, the pharmaceutical composition is provided in a solid oral dosage form selected from caplets, mini - tablets, tablets, granules, beads, pellets, tablets, capsules, pills, etc., or in a liquid oral dosage form useful for pharmaceutical preparation, the liquid oral dosage form including but not limited to drinks, solutions, suspensions, syrups, beverages, and emulsions.

[0150] In one embodiment, the solid oral dosage form is provided as a two - component pharmaceutical composition. In a preferred embodiment, one component of the two - component pharmaceutical composition comprises ezetimibe and the other component comprises obicetrapib. In another preferred embodiment, only one of the components in the two - component pharmaceutical composition comprises both ezetimibe and obicetrapib.

[0151] In certain embodiments, the two - component composition is a bilayer tablet formulation. In a preferred embodiment, ezetimibe is present in one of the two layers of the bilayer tablet and obicetrapib is present in the other layer.

[0152] In another embodiment, the two - component system is a capsule formulation. In a preferred embodiment, the capsule can have two types of granules, where one type of granule comprises ezetimibe and the other type of granule comprises obicetrapib. In yet another preferred embodiment, the capsule can comprise two different types of blends or mini - tablets each comprising ezetimibe or obicetrapib, and optionally, such blends or mini - tablets can be filled into two separate components of the capsule. In some embodiments, each blend or mini - tablet is filled into a smaller capsule, or such blends are pressed into tablets / caplets / mini - tablets and then the tablets / caplets / mini - tablets are filled into a capsule formulation.

[0153] In another embodiment, the fixed - dose pharmaceutical composition is a compressed tablet formulation comprising an extra - granular component and an intra - granular component. In a preferred embodiment, the intra - granular component comprises ezetimibe and the extra - granular component comprises obicetrapib. In a more preferred embodiment, the intra - granular component comprises both ezetimibe and obicetrapib. In another embodiment, the intra - granular component comprises obicetrapib and the extra - granular component comprises ezetimibe. In yet another embodiment, the extra - granular component comprises both ezetimibe and obicetrapib.

[0154] The components within the granules and the components outside the granules are present in a ratio of from about 1:99 to about 99:1, preferably from about 3:97 to about 97:3, and more preferably from about 5:95 to about 95:5. In another embodiment, the components within the granules and the components outside the granules are present in a ratio of from about 10:90 to about 90:10, preferably from about 20:80 to about 80:20 or from about 30:70 to about 70:30, and even more preferably from about 40:60 to about 60:40 or about 50:50.

[0155] The term "within the granules" means within or present in the granules of the composition, which granules include a first group of pharmaceutically acceptable excipients (including but not limited to binders, disintegrants, diluents, glidants and solvents) and optionally include one or more pharmaceutically acceptable active ingredients (ezetimibe and / or obicetrapib in this case).

[0156] The term "outside the granules" means the addition of pharmaceutically acceptable components to the material after granulation, i.e., the outside of the granules portion includes a second group of pharmaceutically acceptable excipients (including but not limited to disintegrants, diluents, lubricants, glidants, etc.). Optionally, the components outside the granules may include one or more pharmaceutically acceptable active ingredients (ezetimibe and / or obicetrapib in this case).

[0157] The pharmaceutical composition can be obtained by known conventional methods such as dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot melt extrusion, etc. In a preferred embodiment, the composition is obtained by wet granulation and then pressing the granules into a tablet formulation or filling such granules into a capsule.

[0158] In one embodiment, the pharmaceutical composition comprises ezetimibe in the anhydrous form of ezetimibe. In another embodiment, the pharmaceutical composition comprises ezetimibe hydrate, preferably ezetimibe in the form of ezetimibe monohydrate. In yet another embodiment, the pharmaceutical composition comprises a mixture of anhydrous ezetimibe and ezetimibe hydrate (preferably ezetimibe monohydrate). The molar ratio of anhydrous ezetimibe: ezetimibe hydrate (preferably ezetimibe monohydrate) in the pharmaceutical composition can be in the range of 100:0 to 0:100, 99.09:0.01 to 0.01:99.09, 99.08:0.02 to 0.02:99.08, 99.07:0.03 to 0.03:99.07, 99.06:0.04 to 0.04:99.06, 99.05:0.05 to 0.05:99.05, 99.04:0.06 to 0.06:99.04, 99.03:0.07 to 0.07:99.03, 99.02:0.08 to 0.02:99.02, 99.01:0.09 to 0.09:99.01, 99:1 to 1:99, 98:2 to 2:98, 90:10 to 10:90, 70:30 to 30:70 or 50:50. In a preferred embodiment, the composition is substantially free of ezetimibe hydrate and approximately 100% of the ezetimibe is in the form of anhydrous ezetimibe. In another preferred embodiment, approximately 99.5% of the ezetimibe is present in the form of anhydrous ezetimibe and approximately 0.5% of the ezetimibe is present in the form of ezetimibe hydrate (preferably ezetimibe monohydrate). In a more preferred embodiment, the composition is substantially free of anhydrous ezetimibe and approximately 100% of the ezetimibe is in the form of ezetimibe hydrate, preferably ezetimibe monohydrate.

[0159] Ezetimibe or obeticholic acid or both ezetimibe and obeticholic acid may exist in the form of their pharmaceutically acceptable salts, solvates or co-crystals. Solvates include, but are not limited to, hydrates. In addition, "salt" refers to a compound prepared by reacting an organic acid or basic drug with a pharmaceutically acceptable mineral acid or base or organic acid or base; the "salt" used herein includes hydrates and solvates of salts. Exemplary pharmaceutically acceptable mineral acids or bases or organic acids or bases are listed in Tables 1 to 8 in Handbook of Pharmaceutical Salts (edited by P.H. Stahl and C.G. Wermuth, VHCA, Zurich 2002, pages 334 - 345). Pharmaceutically acceptable salts of obeticholic acid or ezetimibe can be readily prepared by appropriately mixing solutions of such compounds with the desired acid or base. The salt can precipitate out of the solution and be collected by filtration, or can be recovered by evaporation of the solvent. In one embodiment, the salts include, but are not limited to, hydrochloride, phosphate, sulfate, mesylate salt, esylate salt and besylate salt forms. In a preferred embodiment, the composition comprises obeticholic acid in the form of an alkali metal or alkaline earth metal salt of obeticholic acid, preferably obeticholic acid sodium, obeticholic acid potassium or obeticholic acid calcium, and more preferably obeticholic acid calcium salt. The term "co-crystal" as used herein means a crystalline material composed of two or more distinct solids at room temperature, each solid having distinct physical properties (such as structure, melting point and heat of fusion), but there are special cases where the active pharmaceutical ingredient can be a liquid at room temperature when specifically stated. Co-crystals can include co-crystal formers H-bonded to obeticholic acid and / or ezetimibe. The co-crystal former can be directly H-bonded to the active pharmaceutical ingredient, or can be H-bonded to another molecule that binds to obeticholic acid and / or ezetimibe. In one of the embodiments, a co-crystal can be formed between obeticholic acid and ezetimibe or a salt or solvate of obeticholic acid and ezetimibe. A solvate of an active compound that does not further include a co-crystal former is not a co-crystal. Co-crystals can also be co-crystals between a co-crystal former and a salt of ezetimibe or a salt of obeticholic acid or a salt of both ezetimibe and obeticholic acid. There can also be other modes of molecular recognition, including π-stacking, guest-host complexation and van der Waals interaction.Among the interactions listed above, hydrogen bonding is the main interaction in the formation of co-crystals, whereby a non-covalent bond is formed between a hydrogen bond donor in one moiety and a hydrogen bond acceptor in another moiety. In another embodiment, the co-crystal comprises two co-crystal formers. Co-crystal formers include, but are not limited to: free acids, free bases or zwitterions; salts, inorganic base addition salts (such as sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts, ammonium salts, aluminum salts) or organic base addition salts, or inorganic acid addition salts (such as, HBr addition salts, HCl addition salts, sulfuric acid addition salts, nitric acid addition salts or phosphoric acid addition salts), or organic acid addition salts (such as, acetic acid addition salts, propionic acid addition salts, pyruvic acid addition salts, malonic acid addition salts, succinic acid addition salts, malic acid addition salts, maleic acid addition salts, fumaric acid addition salts, tartaric acid addition salts, citric acid addition salts, benzoic acid addition salts, methanesulfonic acid addition salts, ethanesulfonic acid addition salts, stearic acid addition salts or lactic acid addition salts); anhydrates or hydrates in free form (or more particularly, for example, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, pentahydrates) or salts; or solvates or salts in free form. For the purposes described, the ratio of the active ingredient to the co-crystal former may be stoichiometric or non-stoichiometric. For example, ratios of active ingredient (obeticholic acid or ezetimibe or both obeticholic acid and ezetimibe, including their salts or solvates): co-crystal former of 1:1, 1:1.5, 1:2 and 2:1 are acceptable.

[0160] In one of the embodiments, the fixed-dose pharmaceutical composition comprises ezetimibe or obicetrapib or both ezetimibe and obicetrapib as micronized API. The particle size distribution of this micronized API can be determined by those skilled in the art using methods well known in the art. These methods include, but are not limited to, laser diffraction (LD), dynamic light scattering (DLS), dynamic image analysis (DIA), or sieve analysis. Preferably, the method employed is laser diffraction dry powder dispersion, which provides the particle size distribution by measuring the angular variation of the intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam, while small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the particle size, which generates a cumulative undersize discrete distribution curve that gives the particle size distribution by volume. The particle size obtained according to this method is typically recorded as the volume equivalent spherical diameter (Dv). The most commonly recorded percentiles are Dv10, Dv50, and Dv90 (also referred to as X 10 、X 50 、and X 90 ). Dv90 means that 90% of the particles are smaller than a specific size by volume and 10% of the particles are larger than the specific size; Dv50 means that 50% of the particles are smaller than a specific size by volume and 50% of the particles are larger than the specific size, and Dv10 means that 10% of the particles are smaller than this size by volume and 90% of the particles are larger than this size.

[0161] In a preferred embodiment, the composition comprises micronized ezetimibe having a Dv90 of no more than 10 μm, preferably in the range of 4 μm to 10 μm, more preferably no more than 8.5 μm; a Dv50 of no more than 4 μm, preferably in the range of about 1 μm to 4 μm, more preferably no more than 3.8 μm; and a Dv10 of no more than 1 μm.

[0162] In another preferred embodiment, the composition comprises micronized obicetrapib having a Dv90 of no more than 14 μm, preferably in the range of about 5 μm to 14 μm; a Dv50 of no more than 5 μm, preferably in the range of about 3 μm to 5 μm; and a Dv10 of no more than 3 μm.

[0163] The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. Excipients include, but are not limited to, one or more binders, surfactants, disintegrants, glidants, lubricants, diluents, chelating agents, desiccants, or absorbents. The following references, which are hereby incorporated by reference in their entirety, disclose techniques and excipients for formulating oral dosage forms. See The Handbook of Pharmaceutical Excipients, 9th Edition, edited by Rowe et al., American Pharmaceuticals Association (2020); and "Remington: The Science and Practice of Pharmacy", 22nd Edition, edited by Gennaro, Lippincott Williams & Wilkins (2013).

[0164] One or more binders for use in the pharmaceutical composition are preferably selected from: cellulose derivatives such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxyethylcellulose; gelatin, glucose, sucrose, lactose, dextrose, xylitol, sorbitol, maltitol, polymethacrylates, copolymers of polyvinylpyrrolidone and polyvinylpyrrolidone, starch paste, pregelatinized starch, tragacanth, alginic acid, and salts of alginic acid such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonite. In a preferred embodiment, the binder is polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone. In a more preferred embodiment, the binder is copovidone. In an even more preferred embodiment, the binder is Kollidon 30.

[0165] The binder can generally be present in an amount of from about 0.2% to about 10%, from about 0.5% to about 5%, from about 0.5% to about 2%, or from about 0.5% to about 1%, preferably about 1.0 ± 0.5%, by weight of the particulate composition in one embodiment and by weight of the total tablet in another embodiment.

[0166] The one or more surfactants used in the composition are preferably surfactants having an HLB value selected from at least about 15, at least about 20, at least about 30, or at least about 40. One or more such surfactants are selected from: lauric acid or salts of lauric acid, palmitic acid or salts of palmitic acid, stearic acid or salts of stearic acid, and oleic acid or salts of oleic acid, polyethylene glycol glycerol esters, polyoxyethylene monoesters, polyoxyethylenemonostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oil, polyethylene glycol having a molecular weight in the range of about 2000 to 10000, propylene glycol octanoate, glycerol oleate and octanoate, esters of glycerol and fatty acids. In a preferred embodiment, one or more surfactants are selected from dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, polysorbate 40, or polysorbate 80, or sodium lauryl sulfate. In a more preferred embodiment, the surfactant is sodium lauryl sulfate, such as Kolliphor SLS.

[0167] The surfactant can generally be present in one embodiment in an amount of about 0.2% to 10%, about 0.5% to about 5%, about 0.5% to about 2%, or about 0.5% to about 1%, preferably about 1.0 ± 0.5%, by weight of the particulate composition and in another embodiment by weight of the total tablet.

[0168] In one of the embodiments, the composition comprises a binder:surfactant ratio in the range of about 0.05:5.0 to about 5.0:0.05, preferably about 0.5:4.5 to about 4.5:0.5, more preferably about 1:4 to about 4:1, even more preferably about 1:2 to about 2:1, and most preferably about 1:1. Such a ratio of binder:surfactant can be used for the particulate composition (e.g., the composition within the particle or the composition outside the particle) or for the total composition of the tablet.

[0169] The pharmaceutical composition generally further comprises one or more disintegrants selected from: crospovidone, croscarmellose sodium, calcium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate, or pregelatinized starch. In a preferred embodiment, the disintegrant is croscarmellose sodium or sodium starch glycolate. In a more preferred embodiment, the disintegrant is sodium starch glycolate.

[0170] The disintegrant can be present in one embodiment in an amount of about 0.5% to about 10%, about 1% to about 8%, about 2% to about 5%, preferably 2% to about 3%, about 4% to about 5%, or about 7% to about 8%, by weight of the particulate composition and in another embodiment by weight of the total tablet.

[0171] The one or more diluents for use in the pharmaceutical composition are preferably selected from the group consisting of: inorganic phosphates such as calcium hydrogen phosphate; or sugars or sugar analogs and their derivatives, particularly lactose (e.g., lactose monohydrate or anhydrous lactose), dextrose, sorbitol, mannitol, sucrose, maltodextrin, isomaltose; or celluloses such as microcrystalline cellulose or powdered cellulose, etc. In a preferred embodiment, the diluent is selected from lactose (e.g., lactose monohydrate), microcrystalline cellulose and mannitol or mixtures thereof. In a more preferred embodiment, the intragranular components include microcrystalline cellulose and lactose monohydrate as diluents. In another preferred embodiment, microcrystalline cellulose and mannitol are present as diluents in the extragranular components. The diluent may be present in one embodiment in an amount of about 10% to about 95%, preferably about 40% to about 90%, more preferably about 60% to about 85%, even more preferably about 70% to about 85% by weight of the particulate composition and in another embodiment by weight of the total tablet.

[0172] The pharmaceutical composition may optionally be film-coated using techniques well known in the art (e.g., spraying in a conventional coating pan or fluid bed processor or dip coating). As an alternative, hot melt techniques may also be used to perform the coating. The film coating comprises a film-forming polymer, one or more pharmaceutically acceptable excipients and a pharmaceutically acceptable solvent. Examples of film-forming agents include, but are not limited to: cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and ethylcellulose; polyvinyl alcohol, waxes; fatty substances; or mixtures thereof. As an alternative, commercially available coating compositions comprising film-forming polymers marketed under various trade names (e.g., ) may be used for coating.

[0173] Examples of solvents for preparing the coating solution are selected from methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, chloroform, dichloromethane, water or mixtures thereof. In a preferred embodiment, the film coating is a coating free of primary alcohols. Preferably, the coating free of primary alcohols is a coating made with water.

[0174] The glidants present in the pharmaceutical dosage form are preferably selected from silica, talc, magnesium stearate, etc. Preferred glidants are silica (e.g., ) or magnesium stearate (e.g., Ligamed MF 2V) or mixtures thereof. The glidant is typically present in one embodiment in an amount of about 0.1% to 10%, about 0.% to about 5%, or about 1% to about 2% by weight of the particulate composition and in another embodiment by weight of the total tablet.

[0175] The lubricant present in the pharmaceutical composition is preferably selected from fatty acids or fatty acid derivatives, such as alkali metal salts and alkaline earth metal salts of stearic acid, alkali metal salts and alkaline earth metal salts of lauric acid, and / or alkali metal salts and alkaline earth metal salts of palmitic acid, etc. A preferred lubricant is magnesium stearate, and the lubricant may generally be present in an amount of about 0.1% to 10%, about 0% to about 5%, or about 1% to about 2% by weight of the particulate composition in one embodiment and by weight of the total tablets in another embodiment.

[0176] Stability is an essential quality attribute of pharmaceutical formulations, which determines the shelf life of the composition during which the composition is suitable for its intended use from both the perspectives of efficacy and safety. The term stability of a pharmaceutical composition means that during the shelf life of the product, one or more parameters that govern the physical and chemical integrity of the active pharmaceutical ingredient (API) remain within pharmaceutically acceptable standards. Generally, one or more such parameters are selected from: identifying the active ingredient in the composition by methods such as HPLC and / or ultraviolet (UV) spectroscopy; the visual appearance of the composition, the assay percentage of the active ingredient in the composition, the individual percentages and / or total percentages of related substances and / or impurities in the composition, the content uniformity of the composition with respect to the active ingredient, the dissolution rate, the microbial limit, etc.

[0177] Pharmaceutical compositions often lose their efficacy and / or safety over time due to loss or degradation of the active ingredient or conversion of the active ingredient into impurities commonly referred to as related substances. A stable fixed-dose pharmaceutical composition retains at least up to about 90% (w / w) of the claimed potency of ezetimibe and obicetrapib.

[0178] It is known that ezetimibe can cause stability problems related to its formulations due to interactions with excipients and / or combination drug partners. It has surprisingly been found that during the preparation and storage of fixed-dose compositions, the fixed-dose pharmaceutical compositions effectively control the levels of individual related substances and total related substances of ezetimibe. In an embodiment, the stable fixed-dose pharmaceutical composition has an individual related substance of ezetimibe of no more than about 5% (w / w), preferably no more than about 2% (w / w), more preferably no more than about 1% (w / w), and even more preferably no more than about 0.2% (w / w); and a total related substance of ezetimibe of no more than about 5% (w / w), preferably no more than about 2% (w / w), more preferably no more than about 1% (w / w), and even more preferably no more than about 0.5% (w / w). In a preferred embodiment, the fixed-dose pharmaceutical composition comprises ezetimibe and obicetrapib, wherein the ezetimibe tetrahydropyran analogue impurity is no more than about 2% (w / w), preferably no more than about 0.5% (w / w), more preferably no more than about 0.3% (w / w), and even more preferably no more than about 0.2% (w / w).

[0179] In another embodiment, the stable fixed-dose pharmaceutical composition has any unspecified individual obicetrapib related substance of no more than about 5% (w / w), preferably no more than about 2% (w / w), more preferably no more than about 0.5% (w / w), even more preferably no more than about 0.3% (w / w), and most preferably no more than about 0.2% (w / w); and a total related substance of obicetrapib of no more than about 5% (w / w), preferably no more than about 2% (w / w), more preferably no more than about 1% (w / w), and even more preferably no more than about 0.5% (w / w).

[0180] It has surprisingly been found that the pharmaceutical composition remains stable for at least up to 1 month, preferably at least up to 3 months, more preferably at least up to 6 months under the stability conditions of 40 °C temperature and 75% relative humidity. In a preferred embodiment, the composition remains stable for at least up to 3 months, preferably at least up to 6 months under the stability conditions of 40 °C temperature and 75% relative humidity. In another preferred embodiment, the composition remains stable for at least up to 3 months, 6 months or 12 months under the stability conditions of 25 °C temperature and 60% relative humidity. In yet another preferred embodiment, the composition remains stable for at least up to 6 months, 12 months, 18 months or 24 months at room temperature.

[0181] In a preferred embodiment, the pharmaceutical composition is a tablet formulation, and the tablet formulation comprises or consists of the following:

[0182] a. Excipients outside the granules, which comprise:

[0183] i. Calcium obeticholic acid equivalent to 10 mg of obeticholic acid free acid;

[0184] ii. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe monohydrate equivalent to 10 mg of ezetimibe;

[0185] iii. A binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each account for about 1 ± 0.5% w / w of the particles of the components within the granules; more preferably, the binder is polyvinylpyrrolidone or povidone at 1 ± 0.5% w / w, and the surfactant is sodium lauryl sulfate at 1 ± 0.5% w / w;

[0186] iv. A disintegrant selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the particles of the components within the granules, preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w;

[0187] v. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol;

[0188] b. Components outside the granules, including:

[0189] i. A disintegrant selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably sodium starch glycolate at about 4% w / w to 6% w / w;

[0190] ii. Optionally a lubricant, preferably magnesium stearate, more preferably magnesium stearate at about 1% w / w to 2% w / w;

[0191] iii. Optionally a glidant, preferably colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc, more preferably colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc at about 1% w / w to 2% w / w;

[0192] iv. Optionally one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose, even more preferably about 20% w / w to about 50% w / w of microcrystalline cellulose and about 1% to about 20% of mannitol.

[0193] c. Optionally, the pharmaceutical composition comprises a film coating, preferably the film coating is free of primary alcohols, more preferably the film coating is free of polyethylene glycol.

[0194] In another preferred embodiment, the pharmaceutical composition comprises a tablet formulation, the tablet formulation comprising or consisting of:

[0195] a. Extra-granular components, which include:

[0196] i. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to 10 mg of ezetimibe;

[0197] ii. A binder and a surfactant in a ratio of 1:1, preferably each of the binder and the surfactant accounts for about 1 ± 0.5% w / w of the granules of the intra-granular components; more preferably, the binder is polyvinylpyrrolidone or povidone at 1 ± 0.5% w / w, and the surfactant is sodium lauryl sulfate at 1 ± 0.5% w / w;

[0198] iii. A disintegrant selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the granules of the intra-granular components, preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w;

[0199] iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol;

[0200] b. Extra-granular components, including:

[0201] i. Obeticholic acid calcium equivalent to 10 mg of obeticholic acid free acid;

[0202] ii. A disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably sodium starch glycolate at about 4% w / w to 6% w / w;

[0203] iii. Optionally a lubricant, preferably magnesium stearate, more preferably magnesium stearate at about 1% w / w;

[0204] iv. Optionally a glidant, preferably colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc, more preferably colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc at about 1% w / w to 2% w / w;

[0205] v. Optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose, even more preferably about 20% w / w to about 50% w / w of microcrystalline cellulose and about 1% to about 20% of mannitol.

[0206] c. Optionally, the pharmaceutical composition comprises a film coating, preferably the film coating does not contain primary alcohols, more preferably the film coating does not contain polyethylene glycol.

[0207] In yet another preferred embodiment, the pharmaceutical composition is a tablet formulation, the tablet formulation comprising the following or consisting of:

[0208] a. Excipients outside the granules, which include:

[0209] i. Calcium obeticholic acid equivalent to 10 mg of obeticholic acid free acid;

[0210] ii. A binder and a surfactant in a ratio of 1:1, preferably each of the binder and the surfactant accounts for about 1 ± 0.5% w / w of the granules of the excipients inside the granules; more preferably, the binder is 1 ± 0.5% w / w of polyvinylpyrrolidone or polyvinylpyrrolidine, and the surfactant is 1 ± 0.5% w / w of sodium lauryl sulfate;

[0211] iii. A disintegrant selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the granules of the excipients inside the granules, preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w;

[0212] iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol;

[0213] b. Excipients outside the granules, including:

[0214] i. Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate equivalent to 10 mg of ezetimibe;

[0215] ii. A disintegrant selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; even more preferably sodium starch glycolate at about 4% w / w to 6% w / w

[0216] iii. Optionally a lubricant, preferably magnesium stearate, more preferably magnesium stearate at about 1% w / w to 2% w / w

[0217] iv. Optionally a glidant, preferably colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc, more preferably about 1% to 2% of colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc;

[0218] v. Optionally one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose, even more preferably about 20% w / w to about 50% w / w of microcrystalline cellulose and about 1% to about 20% of mannitol.

[0219] c. Optionally, the pharmaceutical composition comprises a film coating, preferably the film coating is free of primary alcohols, more preferably the film coating is free of polyethylene glycol.

[0220] On the other hand, there is provided a pharmaceutical composition comprising obicetrapib and ezetimibe or a salt, solvate or co-crystal of obicetrapib and a pharmaceutically acceptable carrier, the pharmaceutical composition being used for treating a subject in need of additional reduction of low density lipoprotein cholesterol as an adjunct to diet and / or maximum tolerated lipid-lowering therapy, the maximum tolerated lipid-lowering therapy being used for treating adults with heterozygous familial hypercholesterolemia (HeFH) or diagnosed with atherosclerotic cardiovascular (CV) disease (ASCVD).

[0221] The second aspect relates to the use of a fixed-dose pharmaceutical composition in the preparation of a medicament for treating a subject in need of reducing LDL cholesterol and / or increasing HDL cholesterol, the fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients.

[0222] In one of the examples, the subject has or had hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or was diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0223] In one embodiment, the subject is partially or completely intolerant to statins.

[0224] In one embodiment, the use of the pharmaceutical composition is for treating a subject in need of additional reduction of low-density lipoprotein cholesterol as an adjunctive therapy to diet and / or maximum tolerated lipid-lowering therapy, the maximum tolerated lipid-lowering therapy being for treating adults with heterozygous familial hypercholesterolemia (HeFH) or diagnosed with atherosclerotic cardiovascular (CV) disease (ASCVD).

[0225] A third aspect relates to a method of treating a subject in need of reducing LDL cholesterol and / or increasing HDL cholesterol, wherein the method comprises administering to the subject a therapeutically effective dose of a fixed-dose pharmaceutical composition, the fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients.

[0226] In one of the embodiments, the method is for treating a subject having or suffering from hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0227] In one embodiment, the subject is in need of additional reduction of low-density lipoprotein cholesterol as an adjunctive therapy to diet and / or maximum tolerated lipid-lowering therapy, the maximum tolerated lipid-lowering therapy being for treating adults with heterozygous familial hypercholesterolemia (HeFH) or diagnosed with atherosclerotic cardiovascular (CV) disease (ASCVD).

[0228] In one embodiment, the subject is partially or completely intolerant to statins.

[0229] A fourth aspect relates to a fixed-dose combination pharmaceutical composition of obicetrapib and ezetimibe, wherein the pharmaceutical composition is considered suitable for the use according to the second aspect or the treatment method according to the third aspect in the following cases:

[0230] a. The fixed-dose pharmaceutical composition is administered orally to the subject;

[0231] b. Measuring the concentration of obicetrapib in the blood of the subject at one or more time points after administration to provide a set of obicetrapib concentration / time data points to provide an area-under the curve (AUC); and

[0232] c. The 90% confidence intervals for the geometric mean of the area under the curve (AUC0-∞ and / or AUC0-t) and / or Cmax of obeticholic acid are respectively within the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of the area under the curve (AUC0-∞ and / or AUC0-t) and / or Cmax of obeticholic acid obtained when the reference pharmaceutical composition is orally administered to similar subjects, wherein the reference pharmaceutical composition comprises an equivalent dose of obeticholic acid or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or co-administered simultaneously or sequentially with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or administered in the form of a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0233] The fifth aspect relates to a fixed-dose combination pharmaceutical composition of obeticholic acid and ezetimibe, wherein the pharmaceutical composition is considered suitable for the use according to the second aspect or the treatment method according to the third aspect in the following cases:

[0234] a. The fixed-dose pharmaceutical composition is orally administered to a subject, and ezetimibe and / or ezetimibe glucuronide in the blood of the subject are measured at one or more time points after administration to respectively provide a set of ezetimibe and / or ezetimibe glucuronide concentration / time data points so as to respectively provide the area under the curve (AUC) of ezetimibe and / or ezetimibe glucuronide; and

[0235] b. The 90% confidence intervals for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of ezetimibe and / or ezetimibe glucuronide are respectively within the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of ezetimibe and / or ezetimibe glucuronide obtained when the reference pharmaceutical composition is orally administered to similar subjects, wherein the reference pharmaceutical composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or co-administered simultaneously or sequentially with another pharmaceutical composition comprising obeticholic acid or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or administered in the form of a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0236] In one embodiment of the use according to the above aspects, t of AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC 0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0-336) or AUC 0-∞, preferably 48 hours (AUC 0-48), and more preferably 72 hours (AUC 0-72) or AUC 0-∞.

[0237] In one embodiment, the subject is a healthy human subject, preferably an adult man or woman who does not use tobacco or nicotine, more preferably between 18 and 65 years of age, and optionally, the human has a body mass index of 18.5 to 29.9 Kg / m 2 2.

[0238] In another embodiment, the subject is a person in need of reducing LDL cholesterol and / or increasing HDL cholesterol. In a preferred embodiment, the person is suffering from or has hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or has been diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0239] In one embodiment, the person is partially or completely intolerant to statins.

[0240] Preferably, the LDL-cholesterol level of the human subject is ≥ 70 mg / dL, and optionally, the human is not adequately controlled by their current lipid-lowering therapy.

[0241] For the use of the pharmaceutical composition or the treatment method according to other aspects, the composition can be administered to a subject in need thereof to deliver a total daily oral dose of 5 mg obicetrapib and 10 mg ezetimibe, 10 mg obicetrapib and 10 mg ezetimibe, or 20 mg obicetrapib and 20 mg ezetimibe, preferably the composition is administered to the subject to deliver a daily oral dose of 10 mg obicetrapib and 10 mg ezetimibe.

[0242] It has surprisingly been found that: compared to the commercially available ezetimibe formulations discussed in detail in the Examples section It was found that the dissolution profile of ezetimibe from the fixed-dose combination was not poor, or sometimes even better. It was also surprisingly found that the fixed-dose combination compositions disclosed herein are bioequivalent to combinations of single-therapy drugs co-administered to human subjects. The confidence intervals (90%) of the geometric mean ratios of AUC0-t, AUC0-∞, and Cmax of obicetrapib, ezetimibe, and ezetimibe glucuronide from two representative compositions, FDC1 and FDC2, were respectively within the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of the AUC0-t, AUC0-∞, and Cmax of obicetrapib, ezetimibe, and ezetimibe glucuronide obtained when co-administering single-drug formulations of ezetimibe and obicetrapib at the same dose, which will be discussed in detail in the experimental section below.

[0243] The fixed-dose combination pharmaceutical composition of obicetrapib and ezetimibe will be further illustrated below by non-limiting examples.

[0244] Treatment method of the present invention

[0245] As described in the previous part herein, the present invention provides a method for curative and / or prophylactic treatment of a subject in need thereof. More particularly, the present invention provides a method for treating and / or preventing cardiovascular diseases, particularly atherosclerotic cardiovascular diseases, in such subjects using the compositions defined herein. The present invention further provides a method for treating and / or preventing one or more symptoms associated with (atherosclerotic) cardiovascular diseases in such subjects using the compositions defined herein. The present invention further provides a method for treating and / or preventing one or more conditions associated with and / or caused by (atherosclerotic) cardiovascular diseases in such subjects using the compositions defined herein. The present invention further provides a method for treating and / or preventing one or more etiological factors associated with (atherosclerotic) cardiovascular diseases (e.g., elevated LDL-C levels and / or elevated ApoB levels) in such subjects using the compositions defined herein. The present invention further provides a method for reducing and / or improving the resistance or hyporesponsiveness of such subjects to statin therapy, particularly high-intensity statin therapy, using the compositions defined herein.

[0246] The term "treat, treating or treatment" used in connection with a particular disease or symptom (e.g., "a method of treating a disease...") refers to curing, alleviating or eliminating the disease and / or the accompanying symptoms, reducing the degree of the disease, stabilizing the state of the disease (i.e., not worsening), delaying or slowing the progression of the disease, improving the state of the disease, prolonging survival (compared to the expected survival without treatment), etc. The term "prevent, preventing or prevention" as used herein refers to reducing the risk of a subject contracting a disease and / or developing accompanying symptoms, delaying the time when a subject contracts a disease, etc. The term "treat, treating or treatment" with respect to a patient or subject (e.g., "a method of treating a subject") generally refers to the act of administering a therapeutic compound to the patient or subject for any therapeutic and / or prophylactic purpose.

[0247] The term "cardiovascular disease" as used herein has its conventional meaning and refers to a disease or disorder in which the function of the cardiovascular system of a subject is impaired. Examples of cardiovascular diseases include thromboembolic diseases (e.g., arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease or thromboembolic disease in the ventricle); atherosclerosis; hypertensive heart disease; coronary artery disease; carotid artery disease; stroke; peripheral artery disease involving atherosclerosis; restenosis; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (first or recurrent); acute myocardial infarction (AMI); myocardial infarction; ischemic heart disease; cardiac ischemia; ischemia; sudden ischemic death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary thrombosis; cerebral artery thrombosis, cerebral embolism; renal embolism; pulmonary embolism, etc.

[0248] As used herein, the term "atherosclerotic cardiovascular disease" refers to a specific subset of cardiovascular diseases that include atherosclerosis as a component or precursor of a specific type of cardiovascular disease. Atherosclerosis is a chronic inflammatory response that occurs in the arterial vessel wall in relation to retained LDL-C. It involves the formation of atherosclerotic plaques, which can lead to narrowing of the artery ("stenosis") and can ultimately result in partial or complete closure of the arterial opening and / or plaque rupture. Thus, atherosclerotic diseases or conditions include the consequences of atherosclerotic plaque formation and rupture, including but not limited to arterial stenosis or narrowing, heart failure, aneurysm formation including aortic aneurysm, aortic dissection, and ischemic events (e.g., myocardial infarction and stroke).

[0249] In particularly preferred embodiments, the atherosclerotic cardiovascular diseases and / or pathologies associated with atherosclerotic cardiovascular diseases that can be advantageously treated and / or prevented according to the present invention are selected from the group consisting of arteriosclerosis, peripheral vascular disease, hyperlipidemia, mixed dyslipidemia, beta-lipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, and cerebrovascular accident.

[0250] As will be apparent from the teachings of the present invention, the methods of the present invention are effective and / or are intended to reduce and / or normalize the plasma level of LDL-C. More particularly, the methods are effective and / or are intended to reduce the plasma level of LDL-C by at least 5% from baseline, where baseline is defined as the start of treatment with obicetrapib and ezetimibe, more preferably by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%. In further embodiments, the methods are effective and / or are intended to reduce the plasma level of LDL-C by at least 5 mg / dL from baseline, where baseline is defined as the start of treatment with obicetrapib and ezetimibe, more preferably by at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 25 mg / dL, at least 30 mg / dL, at least 35 mg / dL, or at least 40 mg / dL. In further embodiments, the methods are effective and / or are intended to reduce the plasma level of LDL-C to a level below 85 mg / dL, preferably below 80 mg / dL, below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 55 mg / dL, or below 50 mg / dL.

[0251] As will be apparent from the teachings of the present invention, administration of ezetimibe (or a pharmaceutically acceptable salt, solvate or co-crystal thereof) in addition to obicetrapib (or a pharmaceutically acceptable salt, solvate or co-crystal thereof) will significantly enhance LDL-C lowering, particularly supra-additively or synergistically. More particularly, in order to enhance the LDL-C lowering effect of obicetrapib as defined herein, the methods of the present invention for administering ezetimibe (or a pharmaceutically acceptable salt, solvate or co-crystal thereof) effectively and / or are designed to further reduce the LDL-C plasma level by at least 20%, more preferably by at least 22.5%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29% or at least 30% compared to methods of therapy based on the use of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof alone (or at least without ezetimibe). In a further embodiment, compared to methods of therapy based on the use of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof alone (or at least without ezetimibe), these methods effectively and / or are designed to further reduce the LDL-C plasma level by at least 20 mg / dL, more preferably by at least 22.5 mg / dL, at least 25 mg / dL, at least 27.5 mg / dL, at least 30 mg / dL, at least 32.5 mg / dL or at least 35 mg / dL.

[0252] In a preferred embodiment of the present invention, the methods effectively and / or are designed to reduce and / or normalize the ApoB plasma level. More particularly, the methods effectively and / or are designed to reduce the ApoB plasma level by at least 5% from baseline, where baseline is defined as the start of treatment with obicetrapib and ezetimibe, more preferably by at least 10%, at least 15%, at least 20%, at least 22.5%, at least 25% or at least 27.5%. In a further embodiment, the methods effectively and / or are designed to reduce the ApoB plasma level by at least 5 mg / dL from baseline, where baseline is defined as the start of treatment with obicetrapib and ezetimibe, more preferably by at least 5 mg / dL, at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 22.5 mg / dL, at least 25 mg / dL or at least 27.5 mg / dL. In a further embodiment, the methods effectively and / or are designed to reduce the ApoB plasma level to a level below 80 mg / dL, preferably below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 57.5 mg / dL or below 55 mg / dL.

[0253] In a preferred embodiment of the present invention, the method effectively and / or is intended to reduce and / or normalize the Lp(a) plasma level. More particularly, the method effectively and / or is intended to reduce the Lp(a) plasma level by at least 5% from baseline, where baseline is defined as the start of treatment with obicetrapib and ezetimibe, more preferably by at least 7.5%, at least 10%, at least 12.5%, at least 15%, at least 17.5% or at least 20%. In a further embodiment, the method effectively and / or is intended to reduce the Lp(a) plasma level by at least 5 nmol / L from baseline, where baseline is defined as the start of treatment with obicetrapib and ezetimibe, more preferably by at least 10 nmol / L, at least 15 nmol / L, at least 20 nmol / L, at least 25 nmol / L, at least 30 nmol / L, at least 35 nmol / L or at least 40 nmol / L. In a further embodiment, the method effectively and / or is intended to reduce the Lp(a) plasma level to a level below 110 nmol / L, preferably below 105 nmol / L, below 100 nmol / L, below 95 nmol / L, below 90 nmol / L, below 85 nmol / L or below 80 nmol / L.

[0254] In some embodiments of the present invention, the method effectively and / or is intended to alleviate and / or improve resistance or hypo - responsiveness to statin therapy, particularly high - intensity statin therapy. High - intensity statin therapy is a term conventionally used in the art to denote a regimen of statins based on the highest allowable dose of statins having the highest efficacy in reducing LDL - C, particularly a regimen that typically shows an LDL - C reduction of ≥50% in normally responsive subjects. Among the statins currently used in clinical practice, only rosuvastatin at 20 mg (daily) or 40 mg (daily) and atorvastatin at 40 mg (daily) or 80 mg (daily) meet the criteria. In the context of the present invention, hypo - responsiveness to HIS therapy means that a subject receiving HIS therapy fails to achieve an LDL - C reduction of 35%, preferably it means that a subject receiving HIS therapy fails to achieve an LDL - C reduction of 30%, an LDL - C reduction of 25%, an LDL - C reduction of 20%, an LDL - C reduction of 15% or an LDL - C reduction of 10%. Alleviating and / or improving hypo - responsiveness to HIS therapy means reducing the difference between the response (LDL - C reduction) of the subject and the (average) response of normally responsive subjects. In a further embodiment of the present invention, the method effectively and / or is intended to normalize the response to statin therapy.

[0255] As previously described herein, the methods of the invention are directed to treating and / or preventing in a subject having CVD, particularly ASCVD, or at risk of having CVD, particularly ASCVD.

[0256] The term "subject" refers to a living organism, typically a mammal, particularly a human subject, having or susceptible to a disease or condition treatable with the compositions provided herein.

[0257] In a particularly preferred embodiment of the invention, the subject is a subject diagnosed with CVD, particularly ASCVD.

[0258] In some further preferred embodiments of the invention, the subject is a subject considered to be at risk (generally having above-average risk) of having CVD, particularly ASCVD, which can be determined, for example, by a healthcare professional.

[0259] In a preferred embodiment of the invention, the subject is a subject having one or more conditions known to be causally and / or epidemiologically associated with the development of (AS)CVD, such as diabetes, hypertension, hypercholesterolemia, including overweight / obesity, metabolic syndrome, etc. In some further preferred embodiments of the invention, the subject is a subject genetically predisposed to having (AS)CVD. In some further preferred embodiments of the invention, the subject is a subject susceptible to having (AS)CVD due to lifestyle / habitual factors (e.g., unhealthy diet, lack of exercise, alcohol consumption, smoking).

[0260] According to a preferred embodiment of the invention, the subject to be treated has elevated plasma LDL-C levels, typically having a plasma LDL-C level of at least 70 mg / dL, more preferably at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL or at least 100 mg / dL. Additionally, according to a preferred embodiment of the invention, the subject's plasma LDL-C level is at least 125% of the average plasma LDL-C level of a healthy subject, such as at least 150%, at least 175% or at least 200%. Normal LDL-C (reference) values generally depend on gender and age.

[0261] According to a preferred embodiment of the present invention, the subject to be treated has elevated plasma ApoB levels, typically having a plasma ApoB level of at least 70 mg / dL, more preferably at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL or at least 100 mg / dL. Additionally, according to a preferred embodiment of the present invention, the subject's plasma ApoB level is at least 125% of the average plasma ApoB level of healthy subjects, such as at least 150%, at least 175% or at least 200%. Normal ApoB (reference) values typically depend on gender and age.

[0262] According to a preferred embodiment of the present invention, the subject to be treated has elevated plasma non-HDL-C levels, typically having a plasma non-HDL-C level of at least 100 mg / dL, more preferably at least 105 mg / dL, at least 110 mg / dL, at least 115 mg / dL, at least 120 mg / dL, at least 125 mg / dL or at least 130 mg / dL. Additionally, according to a preferred embodiment of the present invention, the subject's plasma non-HDL-C level is at least 125% of the average plasma non-HDL-C level of healthy subjects, such as at least 150%, at least 175% or at least 200%. Normal non-HDL-C (reference) values typically depend on gender and age.

[0263] In one embodiment of the present invention, the subject is a human male. In another embodiment of the present invention, the subject is a human female.

[0264] In still other preferred embodiments of the present invention, typically in combination with one or more other risk factors defined herein, the subject is at increased risk based on age (e.g., the subject is over 35 years old, over 40 years old, over 45 years old, over 50 years old, over 55 years old, over 60 years old, over 65 years old or over 70 years old).

[0265] According to certain embodiments of the present invention, the subject to be treated shows low responsiveness to statin therapy, particularly HIS therapy. High-intensity statin therapy is a term conventionally used in the art to indicate a regimen of statins based on the highest allowable dose that has the highest efficacy in reducing LDL-C, particularly a regimen that typically shows an LDL-C reduction of ≥ 50% in normally responsive subjects. In current clinical practice, only rosuvastatin 20 mg / day or 40 mg / day and atorvastatin 40 mg / day or 80 mg / day are considered HIS therapy. In a preferred embodiment of the present invention, the subject is a subject who is receiving HIS therapy and fails to achieve a 35% reduction in LDL-C, preferably a subject who receives HIS therapy and fails to achieve a 30%, 25%, 20%, 15% or 10% reduction in LDL-C. In a preferred embodiment of the present invention, the low responsiveness of the subject to statin therapy, particularly HIS therapy, is established after at least 1 month (consecutive) of HIS therapy, more preferably after at least 2 months, at least 3 months, at least 4 months, at least 5 months or at least 6 months.

[0266] Each aspect of the invention as defined herein relates to a method of treatment comprising administering (usually repeatedly) a composition comprising obicetrapib or a salt or solvate / hydrate of obicetrapib (preferably any composition as previously defined herein).

[0267] Thus, in a particularly preferred embodiment of the present invention, the method comprises administering obeticholic acid at a dose of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg or at least 9 mg, such as about 10 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose. According to various aspects of the present invention, the method comprises administering obeticholic acid at a dose of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less, or 11 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose. According to various aspects of the present invention, the method comprises administering obeticholic acid at a dose within the range of 1 mg to 100 mg, 2 mg to 50 mg, 3 mg to 50 mg, 4 mg to 25 mg, 4.5 mg to 15 mg or 5 mg to 10 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose. In certain preferred embodiments, the method comprises administering obeticholic acid at a dose of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose. In certain particularly preferred embodiments, the method comprises administering obeticholic acid at a dose of 5 mg, 7.5 mg, 10 mg, 12.5 mg or 15 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose.

[0268] In a particularly preferred embodiment of the present invention, the treatment comprises preferably repeating the administration of a composition comprising obeticholic acid or a salt, hydrate or solvate of obeticholic acid at a dose within the ranges previously defined herein. In a particularly preferred embodiment of the present invention, the treatment comprises preferably repeating the administration of the composition at a frequency of at least once every two days or at least once a day at a dose within the ranges previously defined herein. In a particularly preferred embodiment of the present invention, the treatment comprises preferably repeating the administration of the composition at a frequency of once to four times a day at the dose previously defined herein. In a particularly preferred embodiment of the present invention, the method comprises administering a composition comprising obeticholic acid or a salt, hydrate or solvate of obeticholic acid once or twice a day at the dose range defined above herein, most preferably twice a day.

[0269] Thus, in a particularly preferred embodiment of the present invention, the method comprises administering obeticholic acid at a daily dose of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg or at least 9 mg, such as about 10 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose. According to various aspects of the present invention, the method comprises administering obeticholic acid at a daily dose of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less, or 11 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose. According to various aspects of the present invention, the method comprises administering obeticholic acid at a daily dose within the range of 1 mg to 100 mg, 2 mg to 50 mg, 3 mg to 50 mg, 4 mg to 25 mg, 4.5 mg to 15 mg or 5 mg to 10 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose. In certain preferred embodiments, the method comprises administering obeticholic acid at a daily dose of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose. In certain particularly preferred embodiments, the method comprises administering obeticholic acid at a daily dose of 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg or 15 mg; or administering a salt, solvate or co-crystal of obeticholic acid at an equivalent dose.

[0270] As will be apparent to those skilled in the art, based on the teachings of the present invention, the method of the present invention further comprises co-treatment with ezetimibe. To this end, ezetimibe and obicetrapib (or a therapeutically acceptable salt, solvate or co-crystal of ezetimibe and obicetrapib) may be administered simultaneously or approximately simultaneously, sequentially or concurrently, or ezetimibe and obicetrapib may be administered at different time points. In a preferred embodiment of the present invention, the frequency and dosing intervals of obicetrapib and ezetimibe are equal, more preferably each is administered once daily, even more preferably at the same time of day, and are administered sequentially or concurrently in two separate unit dosage forms, preferably in the form of a fixed-dose combination product as defined herein. In a preferred embodiment, the method of the present invention comprises administering ezetimibe at a daily dose of 1 mg to 30 mg, 2 mg to 25 mg, 3 mg to 20 mg, 4 mg to 17.5 mg or 5 mg to 15 mg, such as 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg, most preferably about 10 mg; or administering a salt, solvate or co-crystal of ezetimibe at an equivalent dose.

[0271] As will be apparent to those skilled in the art, based on the teachings of the present invention, in some embodiments, the method of the present invention further comprises co-treatment with an HMG CoA reductase inhibitor, preferably co-HIS therapy. To this end, the HMG CoA reductase inhibitor and obicetrapib (or a therapeutically acceptable salt, solvate or co-crystal thereof) may be administered simultaneously or approximately simultaneously, sequentially or concurrently, or may be administered at different time points. In a preferred embodiment of the present invention, the frequency and dosing interval of obicetrapib and the HMG CoA reductase inhibitor are equal, more preferably each administered once daily, even more preferably at the same time of day, administered sequentially or concurrently in two separate unit dosage forms, or in the form of a fixed-dose combination product. In a preferred embodiment, the method of the present invention comprises administering rosuvastatin at a daily dose of 10 mg to 50 mg, 15 mg to 45 mg, 17.5 mg to 42.5 mg or 20 mg to 40 mg, such as 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg or 45 mg, most preferably about 20 mg or 40 mg; or administering a salt, solvate or co-crystal of rosuvastatin at an equivalent dose. In a preferred embodiment, the method of the present invention comprises administering atorvastatin at a daily dose of 30 mg to 90 mg, 35 mg to 85 mg, 37.5 mg to 82.5 mg or 40 mg to 80 mg, such as 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg or 85 mg, most preferably about 40 mg or 80 mg; or administering a salt, solvate or co-crystal of atorvastatin at an equivalent dose. In certain preferred embodiments, the method of the present invention does not comprise concomitant treatment with an HMG CoA reductase inhibitor.

[0272] As will be apparent to those skilled in the art, based on the teachings of the present invention, the daily doses shown herein can be included in a single unit dosage form or in multiple unit dosage forms. In the most preferred embodiments of the present invention, the method comprises administering obicetrapib (or a salt, hydrate or solvate of obicetrapib) once daily at the doses described herein. However, methods are also contemplated that include administering two unit dosage forms at certain predetermined times of the day, each unit dosage form comprising approximately half of the daily dose as described above, for example, one unit dosage form is administered in the morning (e.g., shortly after the subject wakes up) and the other unit dosage form is administered in the evening (e.g., around the time the subject has dinner or goes to bed). Embodiments are also contemplated in which unit dosage forms are used that comprise higher amounts of obicetrapib and / or ezetimibe compared to the daily doses shown herein. This can include, for example, the use of extended release dosage forms that are retained in the body and continuously release the active ingredient for a sufficient length of time.

[0273] In embodiments, there is provided the use of a method and / or composition according to the present invention, wherein the method and / or use comprises administering to a subject, preferably repeatedly, obicetrapib and ezetimibe (or salts, hydrates or solvates of obicetrapib and ezetimibe) in a dosage and frequency effective to reduce the plasma level of LDL-C, the plasma level of ApoB and / or the plasma level of Lp(a) of the subject, preferably in the form of a fixed dose pharmaceutical composition as defined herein, thereby more preferably reducing one or more of the plasma level of LDL-C, the plasma level of ApoB and / or the plasma level of Lp(a) of the subject to within the ranges described elsewhere herein. In particularly preferred embodiments of the present invention, these treatments comprise repeatedly administering obicetrapib and ezetimibe (or salts and / or solvates of obicetrapib and ezetimibe) in the form of a fixed dose pharmaceutical composition as defined herein according to the above regimens for a period of at least one month, at least three months, at least four months, at least six months, at least nine months, at least one year, at least two years, at least three years, at least 5 years, at least 10 years, at least 20 years, at least 30 years. There is no particular upper limit; the treatment can continue as long as it is considered beneficial to the overall health and well-being of the subject (as determined by a duly qualified healthcare professional), for example, for the remainder of the subject's life.

[0274] Drug kit of the present invention

[0275] Another aspect of the present invention relates to a pharmaceutical kit, said pharmaceutical kit comprising a package containing a plurality of unit dosage forms and a package insert, wherein said unit dosage forms contain a pharmaceutical composition according to the present invention, and wherein said package insert contains printed instructions for guiding repeated self - administration of said unit dosage forms to achieve any therapeutic purpose as defined herein, such as treating and / or preventing any heart disease or dysfunction as defined herein.

[0276] According to an embodiment of the present invention, the pharmaceutical kit comprises a container (e.g., a cardboard box) containing one or more blister packs, said one or more blister packs containing a plurality of solid unit dosage forms as previously defined herein, preferably containing a plurality of tablets as previously defined herein. In a particularly preferred embodiment of the present invention, the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12 or at least 15 of said unit dosage forms, for example, comprising 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms. In one embodiment of the present invention, the pharmaceutical kit only comprises unit dosage forms containing obicetrapib as the sole active ingredient as defined herein. In one embodiment of the present invention, the pharmaceutical kit generally comprises, at the dosage levels described elsewhere herein, only a plurality of unit dosage forms containing obicetrapib (or a salt, hydrate or solvate of obicetrapib) as the sole active ingredient as defined herein, and a plurality (preferably an equal number) of unit dosage forms containing ezetimibe as the sole active ingredient. In one embodiment of the present invention, the pharmaceutical kit only comprises a plurality of defined unit dosage forms, wherein each unit dosage form comprises obicetrapib (or a salt, hydrate or solvate of obicetrapib) and ezetimibe (or a salt, hydrate or solvate of ezetimibe), more preferably comprising a plurality of fixed - dose pharmaceutical compositions as defined herein. In some embodiments, the pharmaceutical kit as defined herein may further comprise, at the dosage levels described elsewhere herein, a plurality of unit dosage forms containing an HMG CoA reductase inhibitor as the sole active ingredient, preferably containing atorvastatin or rosuvastatin (or salts, hydrates or solvates of atorvastatin and rosuvastatin).

[0277] According to the present invention, the pharmaceutical kit includes a package insert placed in a container, which is typically a patient information package insert containing printed information. The information may include descriptions of the form and composition of the unit dosage forms contained in the kit, indications of the intended therapeutic indications of the product, instructions on how to use the product, and information and warnings regarding side effects and contraindications associated with use. Those of ordinary skill in the art will understand that, based on the information provided herein, the package insert as part of the kit according to the present invention will typically contain information regarding therapeutic indications, uses, treatment regimens, etc. as described above herein regarding the treatment methods of the present invention. In a particularly preferred embodiment of the present invention, the package insert contains printed instructions for guiding the repeated (self-) administration of the unit dosage forms for the treatment and / or prevention of CVD, particularly ASCVD.

[0278] Hereinafter, the treatment methods of the present invention based on the combination therapy of obicetrapib and ezetimibe will be further illustrated by non-limiting examples.

[0279] Amorphous calcium salt form of obeticholic acid

[0280] In certain preferred embodiments of the present invention, obicetrapib included in the pharmaceutical compositions of the present invention, for use in the methods of the present invention, included in unit dosage forms (included in pharmaceutical kits), etc. is in the form of a salt of obicetrapib, more particularly amorphous obicetrapib calcium salt, especially amorphous obicetrapib hemicalcium.

[0281] The amorphous obicetrapib hemicalcium disclosed herein is different from the crystalline obicetrapib hemicalcium disclosed in U.S. Patent No. 7,872,126 and can be distinguished from the crystalline obicetrapib hemicalcium. A commonly used technique for distinguishing crystalline materials from amorphous materials is X-ray powder diffraction. However, such a technique has limitations, especially when the crystalline material is disordered. In the case of amorphous obicetrapib hemicalcium, X-ray powder diffraction patterns of two different lots of amorphous obicetrapib hemicalcium are provided in Figure 49 and Figure 50 These patterns have the familiar "halo" type characteristics associated with amorphous materials. Figure 50 The X-ray powder diffraction pattern in Figure 51 has peaks at approximately 3.4° 2θ, approximately 7.0° 2θ, and approximately 9.2° 2θ. Similarly, Figure 49 or Figure 50 or Figure 51The X-ray powder diffraction pattern of any of them can be used to characterize amorphous obeticholic acid hemicalcium, however, if occasionally sharp higher angle peaks occur, for example, the peak is found at about 31.7° 2θ (e.g., in Figure 50 ), then the peak (when present) is caused by sodium chloride. In Figure 51 , in another sample of amorphous obeticholic acid hemicalcium, peaks at about 3.4° 2θ, about 7.0° 2θ and about 9.2° 2θ were identified. In Figure 51 , the peak at about 5.6° 2θ was determined to be caused by Kapton foil, which was used in the measurement setup described in Example 11.20. The X-ray powder pattern of crystalline obeticholic acid hemicalcium prepared in Example 11.16 is shown in Figure 54 . It also exhibits halo-like behavior, which may indicate disorder for a crystalline compound.

[0282] Examples 11.18, 11.19, 11.20 and 11.21 illustrate various X-ray powder diffraction procedures. The procedure of Example 11.18 is generally used to collect the data described in Figure 49 , Figure 54 , Figure 55 and Figure 56 ; Example 11.19 is usually used for Figure 50 ; Example 11.20 is usually used for Figure 51 ; and Example 11.21 is usually used for Figure 66 , Figure 67 and Figure 68 ( Figure 68 is for Compound 1D rather than crystalline obeticholic acid HCl).

[0283] The use of the term "amorphous" in "amorphous obeticholic acid hemicalcium" does not mean that the material has no order. As shown by the presence of peaks in the X-ray powder diffraction pattern, there is still a certain degree of order in the sample. Therefore, as used herein, the term "amorphous" in "amorphous obeticholic acid hemicalcium" does not mean that the X-ray powder diffraction pattern must contain only amorphous halos (but may contain halo-like features). Rather, this means that there is disorder, but as described below, the amorphous phase can be distinguished from the crystalline phase.

[0284] Another technique that can be used to distinguish crystalline materials from amorphous materials is polarized light microscopy ("PLM"). In PLM, materials are observed through polarized light, and anisotropic materials (e.g., crystals) or isotropic materials (e.g., amorphous compounds) can be distinguished by observing the materials through a cross-polarizer. When an anisotropic material is exposed to polarized light passing through a cross-polarizer, it exhibits birefringence, which is evidenced by a color change when passing through the cross-polarizer. On the other hand, isotropic materials do not show birefringence and do not show a color change when exposed to polarized light.

[0285] In Figure 57 , as described in Example 11.17, amorphous obeticholic acid hemicalcium was analyzed by polarized light microscopy. As Figure 57 shown, the material studied did not exhibit birefringence, indicating that the material was amorphous. In contrast, Figure 58 is a polarized light micrograph of crystalline obeticholic acid hemicalcium prepared according to Example 11.16. Notably, Figure 58 the particles shown therein (which are black and white) exhibit a brighter contrast. In the corresponding color version, the pattern is multicolored. Therefore, Figure 58 indicates crystallinity. In addition, Figure 58 the crystals in Figure 57 are larger than the particles provided in the polarized light micrograph of amorphous obeticholic acid hemicalcium in

[0286] Other techniques can also be further used to distinguish amorphous obeticholic acid hemicalcium from crystalline obeticholic acid hemicalcium, and thus other techniques can be used to characterize amorphous obeticholic acid hemicalcium. One such technique is modulated differential scanning calorimetry, also known as "mDSC". The difference in the heat required to raise the temperature of a sample relative to a reference is measured as a function of temperature and can be measured using modulated differential scanning calorimetry (mDSC). In an mDSC thermogram, the glass transition temperature can also be measured, and the glass transition temperature can be used to characterize amorphous materials. In Figure 60 (the procedure of which is described in Example 11.25), an open sample holder was used to measure the mDSC thermogram of amorphous obeticholic acid hemicalcium, allowing volatile gases to escape during the measurement. In Figure 60 , the opening was formed by piercing the lid on a pan to create a pinhole. The glass transition temperature of this sample was recorded to be approximately 110 °C.

[0287] Regarding thermal measurements, the term "about" generally refers to a variability of ±1°C. In contrast, crystalline obeticholic acid hemicalcium has a higher glass transition temperature under the same conditions, and Figure 62 Three measurements in [reference] indicate a range between about 118°C and about 125.5°C. In some embodiments, when measurements are made with a pinhole, the glass transition temperature of amorphous obeticholic acid hemicalcium is between about 109°C and 112°C. In one sample, at example 11.26, the glass transition temperature of amorphous obeticholic acid hemicalcium was found to be about 111°C (midpoint 111.32°C) and is shown in Figure 61 [reference]. The onset temperature was measured to be about 102°C (101.62°C), and the end temperature was about 118°C (117.58°C).

[0288] The glass transition temperature of amorphous obeticholic acid hemicalcium can also be measured using a hermetically sealed pan and mDSC. The type of sample preparation may affect the measured glass transition temperature. In such cases, the glass transition temperature decreases below about 100°C depending on humidity and particularly ranges between about 70°C and about 92°C.

[0289] Other thermal techniques can also be used to analyze and characterize amorphous obeticholic acid hemicalcium, such as using thermogravimetric analysis (TGA). Figure 59 [Figure] is the thermogravimetric analysis thermogram of amorphous obeticholic acid hemicalcium, which shows a weight loss of less than 1% when heated to about 200°C. Such weight loss can be, for example, between about 0.8% and about 0.95% (including between about 0.84% and about 0.92%). In Figure 59 [reference], the weight loss was determined to be about 0.85%. The water content of this particular material was found to be about 1.5%. In some embodiments, the water content can be higher and includes a range from about 0 wt% to about 5 wt%, including up to about 4 wt%, up to about 3 wt%, and between about 0.5 wt% and 1.5 wt%.

[0290] Solid state 13 13C-NMR spectroscopy is another technique that can be used to characterize amorphous materials. Figure 63 [Figure] shows the solid state 13 13C-NMR spectra of both crystalline obeticholic acid hemicalcium and amorphous obeticholic acid hemicalcium, where Figure 64 and Figure 65Crystalline obeticholic acid hemicalcium and amorphous obeticholic acid hemicalcium are shown respectively. There are at least two differences in the spectra. The crystalline phase has a peak at about 22.1 ppm, while the peak does not exist in the amorphous phase. In addition, the peak at about 29.5 ppm in the crystalline phase is obvious, while the peak is not so obvious in the amorphous phase. Therefore, the absence of a solid-state 13 C-NMR peak at about 22.1 ppm and / or the absence of an obvious peak at about 29.5 ppm can be used to characterize amorphous obeticholic acid hemicalcium. In addition, a solid-state Figure 65 substantially the same as that shown 13 C-NMR spectrum can be used to characterize amorphous obeticholic acid hemicalcium. The absence of a peak in this context does not mean that there must be no intensity at, for example, 22.1 ppm or 29.5 ppm, but that the intensity is not as obvious as in the 13 C-NMR spectrum of crystalline obeticholic acid hemicalcium.

[0291] The properties of crystalline materials are usually also different from those of amorphous materials. Thermodynamically, crystalline materials are more physically stable than amorphous materials. Therefore, there is a thermodynamic driving force to convert amorphous compounds into crystalline compounds. Under accelerated stress conditions, if there is a physical transformation of the solid form, it is usually expected that the physical transformation will be from amorphous to crystalline. However, for obeticholic acid hemicalcium, the situation is exactly the opposite.

[0292] Figure 54 is a schema of the X-ray powder diffraction pattern of the obtained crystalline obeticholic acid hemicalcium, while Figure 55 is a schema of the X-ray powder diffraction pattern of crystalline obeticholic acid hemicalcium obtained under stress conditions. In Figure 55 , four diffraction patterns are shown based on the stability study described in Example 11.27. Pattern 1 is the X-ray powder diffraction pattern of a sample of amorphous obeticholic acid hemicalcium. Pattern 2 is the X-ray powder diffraction pattern of a sample of crystalline obeticholic acid hemicalcium. In Pattern 3, a sample of crystalline obeticholic acid hemicalcium was exposed to 70 °C at 75% relative humidity for one day. As can be seen from Pattern 3, the X-ray powder diffraction pattern shows that almost all crystallinity is lost within the day. After 7 days under the same conditions, the result is still the same as that seen in Pattern 4. For Figure 56 the shown amorphous obeticholic acid hemicalcium, a similar experiment was carried out. Pattern 1 is the stability obtained before placing the sample. Exposing the material to the same conditions of 70 °C and 75% relative humidity does not trigger crystallization, and the material remains amorphous after 7 days (Pattern 2) and 14 days (Pattern 3). Therefore, these experiments show that, contrary to expectations, the amorphous form of obeticholic acid hemicalcium is more stable than the crystalline obeticholic acid hemicalcium.

[0293] In some embodiments of the present disclosure, stable amorphous obeticholic acid hemicalcium is provided herein. In these embodiments, the amorphous obeticholic acid hemicalcium is more physically stable than the crystalline obeticholic acid hemicalcium under typical drug use and processing conditions.

[0294] Without wishing to be bound by theory, kinetics may render the amorphous phase kinetically stable relative to the thermodynamically more stable crystalline phase, at least under drug-related processing and use conditions. The result of such a stability profile is that amorphous obeticholic acid hemicalcium is more suitable for drug development and use than the corresponding crystalline phase. Despite being physically more resilient, amorphous obeticholic acid hemicalcium is more soluble than the highly insoluble crystalline obeticholic acid hemicalcium.

[0295] The solubility of obeticholic acid is particularly challenging. For example, at 20 °C, the solubility of obeticholic acid in water has been measured to be substantially less than 0.1 mg / mL. There is a desire for a solid form of obeticholic acid that will deliver a greater amount of obeticholic acid.

[0296] Although solubility is a thermodynamic quantity of a material, the dynamic solubility of a material can be measured without necessarily reaching thermodynamic equilibrium. Such measurements provide the solubility under metastable conditions and provide information such as the amount of material that dissolves over time.

[0297] The amorphous form has a higher dynamic solubility and dissolution rate (and by extension obeticholic acid itself) than the crystalline form. As described in Example 11.28, dynamic solubility measurements of both crystalline obeticholic acid hemicalcium and amorphous obeticholic acid hemicalcium were performed in a biologically relevant medium at different pHs (i.e., at a pH of about 5.0 (FeSSIF conditions) and at a pH of about 6.5 (FaSSIF) conditions).

[0298] Table W shows the solubilities measured for two different batches of amorphous obeticholic acid hemicalcium and crystalline obeticholic acid hemicalcium over the course of 2 hours in FeSSIF medium at 37 °C. In both cases, the amorphous obeticholic acid hemicalcium had a higher concentration in solution than the corresponding crystalline material at all measured time points. The concentrations in Table W are the concentrations of obeticholic acid (i.e., the free acid).

[0299] Table W – Dynamic Solubilities of Crystalline Obeticholic Acid Hemicalcium and Amorphous Obeticholic Acid Hemicalcium in FeSSIF (pH 5.0) at 37 °C

[0300]

[0301] Table X shows a similar experiment at 37 °C, but the experiment was conducted in FaSSIF medium at pH 6.5. As with Table W, in both batches, at all measured time points, the concentration of amorphous obeticholic acid hemicalcium in solution was higher than that of the corresponding crystalline material. The concentrations in Table X are the concentrations of obeticholic acid (i.e., the free acid).

[0302] Table X - Dynamic Solubility of Crystalline and Amorphous Obeticholic Acid Hemicalcium in FaSSIF (pH 6.5) at 37 °C

[0303]

[0304] Since amorphous obeticholic acid hemicalcium dissolves faster than the corresponding crystalline phase, more drug is available for immediate use, and the bioavailability in the amorphous phase may be higher than that in the crystalline phase.

[0305] Unlike many amorphous organic compounds, amorphous obeticholic acid hemicalcium does not readily absorb moisture, and amorphous obeticholic acid hemicalcium is thus advantageous. For example, when exposed to a relative humidity of nearly 90%, the measured moisture absorption rate is generally less than about 5%. This lack of hygroscopicity is advantageous because it does not require any special handling or storage conditions. Similarly, there are no other drawbacks typically associated with the manufacture and use of amorphous materials. For example, amorphous materials are often challenging to achieve chemical purity. Here, however, amorphous obeticholic acid hemicalcium can be prepared in a conventional manner with a chemical purity of 99.9% or higher.

[0306] In some embodiments of the present disclosure, substantially pure amorphous obeticholic acid hemicalcium is provided. In these and other embodiments, the chemical purity of the substantially pure amorphous obeticholic acid hemicalcium is 99.9% or higher.

[0307] In many aspects of the present disclosure, a method for preparing an amorphous calcium salt of obeticholic acid, such as amorphous obeticholic acid hemicalcium, is provided, wherein the method comprises: treating obeticholic acid with an acid to form a salt, solvate, or composition; separating the resulting salt, solvate, or composition; and treating the salt, solvate, or composition with a calcium source to produce an amorphous calcium salt of obeticholic acid, such as amorphous obeticholic acid hemicalcium. The resulting salt can then be isolated.

[0308] Examples of calcium sources include calcium salts, such as calcium halide salts and soluble calcium salts. In many embodiments, the calcium source is calcium chloride.

[0309] It has been found that when there is an intermediate salt, solvate or composition (such compositions include the corresponding acids used to prepare the salts), amorphous salts of obisertopib calcium are prepared, such as amorphous obisertopib hemicalcium. It has not been found that the direct treatment of obisertopib with a calcium base (e.g., calcium hydroxide) is a viable method for preparing amorphous salts of obisertopib calcium because of low solubility, weaknesses in the available base, or both. Instead, it has been found that it is feasible to prepare amorphous obisertopib hemicalcium by formulating an intermediate salt (e.g., the sodium salt). However, even in the case of using the sodium salt, for purity and yield purposes, it is preferred to utilize additional salts or salt form exchanges related to the sodium salt of obisertopib (e.g., using compositions or solvates rather than the actual salt). In particular, the use of salts, solvates or compositions enables the production of high-purity amorphous calcium salts of obisertopib, such as amorphous obisertopib hemicalcium.

[0310] Exemplary salts that can be prepared as intermediates include salts from the following: sulfonates (e.g., benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, ethanesulfonate, edisylate or methanesulfonate), sulfates (e.g., methyl sulfate), halogens (e.g., chloride, iodide or bromide), acetates, aspartates, benzoates, bicarbonates, bitartrates, carbonates, citrates, decanoates, fumarates, glucoheptonates, glucuronates, glutamates, glycolates, hexanoates, hydroxynaphthoates, isethionates, lactates, lactobionates, malates, maleates, mandelates, mucates, nitrates, octanoates, oleates, pamoates, pantothenates, phosphates, polygalacturonates, propionates, salicylates, stearates, succinates, tartrates or teoclates. When the intermediate is a system solvate or composition, the corresponding acid can be used or be present. Additionally, when the intermediate is a system solvate, the intermediate can further include a solvent (e.g., an organic solvent) or water, in which case the solvate will be a hydrate. One such organic solvent is cyclopentyl methyl ether (CPME).

[0311] In some embodiments, the intermediate is a system solvate of an acid. In these and other embodiments, the intermediate is a system solvate of an acid and an organic solvent. In some specific embodiments, the intermediate system includes a solvate of an acid and a solvent. In some of these embodiments, the acid is hydrochloric acid and the solvent is CPME.

[0312] In many aspects of the present disclosure, the present disclosure includes methods for preparing amorphous obeticholic acid calcium salts, such as amorphous obeticholic acid hemicalcium. The present disclosure further includes amorphous obeticholic acid calcium salts so prepared, including amorphous obeticholic acid hemicalcium. In one such preparation, an intermediate herein referred to as crystalline obeticholic acid HCl is used in the process of preparing amorphous obeticholic acid calcium (e.g., amorphous obeticholic acid hemicalcium).

[0313] In many aspects of the present disclosure, amorphous obeticholic acid hemicalcium is prepared by chemical synthesis, wherein an intermediate represented by formula (IH) is used:

[0314]

[0315] wherein y varies such that the mass percentage of HCl varies from 0.01 wt% to 8 wt%, and is believed to more particularly include associated organic solvents, e.g., in the form of a solvate. In some embodiments, y varies from 0.002 to 1.5. In some embodiments, y varies from 0.3 to 1. In some embodiments, y varies from 0.4 to 0.6 (including between 0.5 and 0.6). In some embodiments, formula (IH) as a solvate is isolated in its crystalline form. In many embodiments, the solvent is CPME. Other solvents that can form solvates include toluene and heptane.

[0316] Obeticholic acid HCl typically prepared herein is crystalline. Additionally, when CPME is used in the preparation of crystalline obeticholic acid HCl, the term crystalline obeticholic acid HCl can include CPME as a solvate. In formula (IH), the solvate is a solvate of an organic solvent, and in many embodiments, the solvent is CPME. In some embodiments, the present disclosure provides a composition comprising crystalline obeticholic acid HCl.

[0317] Formula (IH) is referred to as obeticholic acid HCl, and when it is crystalline, it is referred to as crystalline obeticholic acid HCl.

[0318] Without being bound by theory, it is believed that crystalline HCl obeticholic acid is a mixed salt solvate. It has been found that when CPME is used to deliver HCl in the reaction to form formula (IH), the chloride content of formula (IH) is in the range of between about 2.5 wt% and 3.0 wt%, which is lower than what would be expected for a neutral salt, i.e., about 4.8 wt%.

[0319] In many embodiments, when CPME is so used, it is found in the material upon crystallization. When CPME is used in the reaction to deliver dry HCl and is thus found in the crystalline material, the resulting crystalline formula (IH) material is referred to as crystalline obeticholic acid HCl, and these X-ray powder diffraction patterns are at Figure 66It can be seen from [Figure 0]. The advantage of using crystalline obeticholic acid HCl as an intermediate is that the resulting amorphous obeticholic acid hemicalcium usually has a chemical purity of 99.9% or higher. Chemical purity is a quantitative representation of the presence of other chemical entities in addition to the compound being measured. For example, amorphous obeticholic acid hemicalcium with a chemical purity of 99.9% means that no more than 0.1% of the compounds in the sample of amorphous obeticholic acid hemicalcium are other entities. Physical purity refers to the amount of other solid forms of the same compound present. In the case of amorphous obeticholic acid hemicalcium, the other solid form is crystalline obeticholic acid hemicalcium. The disclosures herein provide physically pure amorphous obeticholic acid hemicalcium, which means that the amorphous obeticholic acid hemicalcium does not contain or substantially does not contain crystalline obeticholic acid hemicalcium. Unless otherwise specified herein, the purity measurements provided herein are measurements of chemical purity.

[0320] The obeticholic acid HCl used herein is not limited to crystalline obeticholic acid HCl. In fact, upon desolvation, crystalline obeticholic acid HCl may become amorphous.

[0321] Under stress, crystalline obeticholic acid HCl loses its crystallinity. In Figure 66 , Spectrum 2 reflects crystalline obeticholic acid HCl that has undergone a mild drying treatment to remove surface solvent, and it can be seen that this compound is crystalline. In contrast, the sample whose X-ray powder diffraction was measured in Spectrum 1 was subjected to a stronger drying treatment at 55 °C and a pressure of 2 mbar for 48 hours. Apparently, such drying may cause the material to change from crystalline to amorphous due to the loss of HCl and the desolvation of CPME. For example, using 1 1H-NMR spectroscopy shows the presence of CPME in the top spectrum, but substantially no CPME in the lower amorphous spectrum. Therefore, the amorphous spectrum represents obeticholic acid HCl that is not crystalline obeticholic acid. It may be obeticholic acid, but it is believed to have HCl bound to obeticholic acid as a solvate, and thus is obeticholic acid HCl, but has a lower chloride content than that typically found in the range of crystalline obeticholic acid HCl. In some embodiments, the chloride content is less than 0.1 wt%, for example, in the range of about 0.01 wt% to 0.1 wt%.

[0322] Crystalline obeticholic acid HCl can be characterized by an X-ray powder diffraction pattern that includes a peak at about 9.8° 2θ. In some embodiments, crystalline obeticholic acid HCl can be characterized by an X-ray powder diffraction pattern that includes one or more peaks at about 8.1° 2θ, about 9.8° 2θ, about 13.8° 2θ, about 16.7° 2θ, or about 19.5° 2θ. Table Y provides exemplary peaks that may be present in crystalline obeticholic acid HCl. In some embodiments, crystalline obeticholic acid HCl can be characterized by a pattern that isFigure 67 characterized by substantially the same X-ray powder diffraction pattern, but it is believed that Figure 67 the materials analyzed in [reference] were measured in such a way that no peaks between approximately 4.3° 2θ and approximately 4.7° 2θ were detected.

[0323] Table Y

[0324] °2θ Intensity 8.1 950 9.8 1650 13.8 2000 16.7 2900 19.5 4100 21.1 3700 21.6 3800 22.4 3600 24.9 1950 26.6 1850

[0325] An intermediate of formula (VI) for preparing obisertoparib

[0326]

[0327] wherein Y 1 is a protecting group (e.g., as described herein); A n- is an anion; and n is an integer from 1 to 3.

[0328] In one embodiment, the compound of formula (VI) is a mesylate, wherein n is 1, Y 1 is tert-butyl, and has the structure of Compound 1D:

[0329]

[0330] The 1H-NMR spectrum of Compound 1D (in solution) can be found in Figure 69 . The crystalline Compound 1D can be characterized by an X-ray powder diffraction pattern including one or more peaks at approximately 5.2° 2θ or approximately 9.1° 2θ. In some embodiments, the crystalline Compound 1D can be characterized by an X-ray powder diffraction pattern including one or more peaks at approximately 5.2° 2θ, approximately 9.1° 2θ, approximately 15.9° 2θ, approximately 16.5° 2θ, approximately 17.2° 2θ, approximately 18.6° 2θ, and approximately 19.2° 2θ. Table Z provides exemplary peaks that may be present in the crystalline Compound 1D (the peak at approximately 5.2° 2θ was not measured due to instrumental limitations in the reflection mode). In some embodiments, the crystalline Compound 1D can be characterized by an X-ray powder diffraction pattern substantially the same as 1 that of Figure 68 .

[0331] Table Z

[0332]

[0333]

[0334] Crystalline compounds (e.g., crystalline compound 1D and crystalline obeticholic acid HCl) can be characterized, for example, by X-ray powder diffraction. An X-ray powder diffraction pattern is an x-y plot where 2θ (diffraction angle) is on the x-axis and intensity is on the y-axis. Peaks are typically represented and referred to by their position on the x-axis rather than the peak intensity on the y-axis because peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee and Web, pages 255 to 257 (2003)). Thus, intensity is generally not used to characterize solid forms. Data from X-ray powder diffraction can be used in a variety of ways to characterize crystalline forms. For example, the entire X-ray powder diffraction pattern output from a diffractometer can be used to characterize crystalline obeticholic acid HCl compound or crystalline compound 1D. However, a smaller subset of such data may also be suitable and is generally suitable for characterizing such compounds. For example, a collection of one or more peaks from such a pattern can be used to so characterize these compounds. When the phrase "one or more peaks" is provided from a list of peaks in an X-ray powder diffraction pattern, it is generally meant that any combination of the listed peaks can be used for the characterization. Additionally, the fact that other peaks are present in the X-ray powder diffraction pattern generally does not negate or otherwise limit the characterization.

[0335] In addition to the variability in peak intensity, there can also be variability in the peak position on the x-axis. However, such variability is typically taken into account when reporting the position of peaks for characterization purposes. Such variability in the peak position along the x-axis can arise from several sources (e.g., sample preparation, particle size, moisture content, solvent content, instrument parameters, data analysis software, and sample orientation). For example, samples of the same crystalline material prepared under different conditions may produce slightly different diffraction patterns, and different X-ray instruments may operate using different parameters, and such factors can result in slightly different diffraction patterns from the same crystalline solid. Due to such sources of variability, the word "about" is typically used before the peak in 2θ when reporting X-ray diffraction peaks. For the purpose of reporting data herein, the value is typically ±0.2° 2θ, and whenever an exposure is made herein, whether or not the word "about" is present, it is intended to report the value with such variability. In some cases, the variability may be higher, depending on the instrument conditions, including the maintenance of the instrument.

[0336] In some embodiments, crystalline compound 1D can be further characterized by an X-ray powder diffraction pattern that is substantially the same as Figure 68 the X-ray powder pattern of.

[0337] In many aspects of the present disclosure, a method for preparing an amorphous calcium salt of obeticholic acid, such as amorphous obeticholic acid hemicalcium, is provided, wherein the method comprises:

[0338] i. Treat obeticholic acid with HCl to obtain crystalline obeticholic acid HCl;

[0339] ii. Isolate the crystalline obeticholic acid HCl;

[0340] iii. Prepare an amorphous calcium salt of obeticholic acid, such as amorphous obeticholic acid hemicalcium, from the crystalline obeticholic acid HCl isolated in step (ii); and

[0341] iv. Isolate the amorphous calcium salt of obeticholic acid, such as amorphous obeticholic acid hemicalcium.

[0342] In other aspects of the present disclosure, a method for preparing obeticholic acid is provided, wherein the method comprises:

[0343] (a) Prepare a compound of formula (IV) by coupling a compound of formula (II) or a salt thereof with a compound of formula (III);

[0344]

[0345] wherein X 1 is a leaving group, and Y 1 is a protecting group;

[0346] (b) Prepare a carbamate of formula (V) from the compound of formula (IV) and isolate it in the form of a solid salt of formula (VI):

[0347]

[0348] wherein Y 1 is a protecting group, A n- is an anion, and wherein n is an integer from 1 to 3;

[0349] (c) Optionally desalt the compound of formula (VI) and alkylate it with a compound of formula (VII) to provide a compound of formula (VIII):

[0350]

[0351] wherein, X 2 is a leaving group, Y 1 is a protecting group; and

[0352] (d) Convert the compound of formula (VIII) to obeticholic acid, wherein reaction steps (a) to (d) are carried out in an organic solvent, optionally without isolating compounds (IV), (V) and (VIII) from the organic solvent, and wherein the process does not need to include chromatography.

[0353] The reactions in steps (a) to (d) of the subject method are carried out in a solvent, and if the intermediate compounds of formula (IV), (V) and (VIII) are to be further processed into the final product, it is not necessary to separate the intermediate compounds of formula (IV), (V) and (VIII) from their respective solvents. This means that any solvent exchange between reaction steps (x) and (x + 1) is carried out by evaporating at least a portion of the solvent used in step (x) and gradually adding the solvent of step (x + 1), such that the compounds remain in solution during the solvent exchange. The intermediate compound of formula (VI) can be separated from the solvent as a salt in solid form, such that the intermediate compound of formula (VI) can be washed to remove impurities. This separation step ensures sufficient purity of the downstream product. The subject process does not need to include a purification step using chromatography (e.g., column chromatography) to achieve the chemical purity levels described herein.

[0354] Method for preparing amorphous calcium salts such as amorphous obeticholic acid hemicalcium - steps (i) to (iv) of aspect (i) to (ii)

[0355] In some embodiments of a method for preparing an amorphous calcium salt of obicetrapib (e.g., amorphous obicetrapib hemicalcium), the method comprises step (i): treating obicetrapib with HCl in an organic solvent to obtain crystalline obicetrapib HCl.

[0356] In some embodiments, crystalline obicetrapib HCl has a purity of 98% or higher, such as 98.5% or higher, 99% or higher, 99.5% or higher, or even higher.

[0357] In some embodiments, the HCl in step (i) is in a suitable solvent. Such a solvent can be an aqueous solvent or an organic solvent. In some embodiments, the organic solvent used in step (i) comprises a mixture of a solvent and an anti-solvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the anti-solvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane.

[0358] In some embodiments, the HCl has sufficient solubility in the anti-solvent such that it can be used as a suitable solvent. In some embodiments, the organic solvent used in step (i) comprises a mixture of cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (i) further comprises toluene. In some embodiments, toluene is the major component of the organic solvent.

[0359] In some embodiments, step (i) includes: providing obeticholic acid in a mixture of cyclopentyl methyl ether and n - heptane, raising the temperature to between 35°C and 40°C while stirring, adding dry HCl in cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, and then adding additional n - heptane as an anti - solvent. Optionally, a small portion of the reaction mixture is extracted and cooled to a temperature between 10°C and 15°C to obtain a slurry of crystals of crystalline obeticholic acid HCl in a mixture of cyclopentyl methyl ether and n - heptane (referred to herein as "seed crystal slurry"). Optionally, then all or a portion of the seed crystal slurry of crystalline obeticholic acid HCl is added back to the reaction mixture. The seed aids in nucleation but is not essential. The resulting reaction mixture is then cooled to a temperature between 5°C and 15°C (e.g., 10°C to 15°C), and then crystalline obeticholic acid HCl is crystallized from the system while stirring. In some embodiments, crystalline obeticholic acid HCl crystallizes over a period of 12 hours or longer, followed by filtration (e.g., through a filter dryer), one or more optional washing steps (e.g., washing with a mixture of cyclopentyl methyl ether and n - heptane), and drying. In some cases, the wet filter cake of crystalline obeticholic acid HCl is vacuum - dried in multiple steps using temperatures of 25°C to 30°C, 30°C to 40°C, 40°C to 50°C, and then 50°C to 55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0360] In some embodiments, the method for preparing crystalline obeticholic acid HCl includes adding a seed (e.g., as a seed crystal slurry). The seed of the HCl compound can be formed into a slurry by following step (i) as stated above, and after adding dry HCl in cyclopentyl methyl ether and an anti - solvent n - heptane, extracting a small portion of the reaction mixture and cooling it to a temperature between 10°C and 15°C to provide a slurry of crystals of crystalline obeticholic acid HCl in cyclopentyl methyl ether and n - heptane.

[0361] Thus, in one embodiment, step (i) comprises providing crystalline obeticholic acid HCl in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to between 35 °C and 45 °C while stirring, adding dry HCl in cyclopentyl methyl ether and raising the temperature again to between 50 °C and 55 °C, adding additional n-heptane as an anti-solvent, and optionally adding seeds of the HCl compound (e.g., as a seed slurry prepared as described herein), cooling to a temperature between 5 °C and 15 °C (e.g., 10 °C to 15 °C), and then crystallizing crystalline obeticholic acid HCl from the system while stirring. In some embodiments, the crystalline obeticholic acid HCl crystallizes over a period of 12 hours or longer, followed by filtration, one or more optional washing steps (e.g., washing with a mixture of cyclopentyl methyl ether and n-heptane), and drying. In some embodiments, the crystalline obeticholic acid HCl is dried under vacuum. In some embodiments, the crystalline obeticholic acid HCl is dried in a vacuum drying oven at a pressure of 25 mbar and a temperature of 55 °C for 10 hours or longer. In some embodiments, after the drying procedure, the crystalline obeticholic acid HCl comprises less than 0.1 weight percent of residual cyclopentyl methyl ether.

[0362] In some embodiments, step (i) comprises: providing a solution of obeticholic acid in cyclopentyl methyl ether having a concentration between 30 weight percent and 40 weight percent, e.g., 33 weight percent to 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent used in step (d) (e.g., toluene), less than 1 weight percent of n-heptane based on the weight of the solution, adding n-heptane, raising the temperature to 35 °C to 45 °C while stirring, adding dry HCl in cyclopentyl methyl ether and raising the temperature again to 50 °C to 55 °C, adding additional n-heptane as an anti-solvent, optionally adding seeds of crystalline obeticholic acid HCl (e.g., as a seed slurry prepared as described herein), cooling to a temperature between 10 °C and 15 °C, and then crystallizing crystalline obeticholic acid HCl from the system while stirring, e.g., over a period of at least 12 hours, followed by filtration, one or more washing steps with a mixture of cyclopentyl methyl ether and n-heptane, and drying, e.g., under vacuum. In some embodiments, the amount of toluene is significantly greater.

[0363] In some embodiments, in step (ii), the crystalline obeticholic acid HCl from step (i) is separated. In some embodiments, the separated crystalline obeticholic acid HCl has a purity of 98% or higher, e.g., 98.5% or higher, 99% or higher, 99.5% or higher, 99.7% or even higher.

[0364] Another embodiment of the disclosure relates to crystalline obeticholic acid HCl obtained by or obtainable by the methods defined herein.

[0365] Another embodiment of the disclosure relates to obeticholic acid HCl, including crystalline obeticholic acid HCl.

[0366] In some embodiments, crystalline obeticholic acid HCl is stored at controlled room temperature and under a nitrogen atmosphere and protected from moisture to prevent the formation of an amorphous solid, for example, by desolvation.

[0367] Method for preparing amorphous calcium salts of obeticholic acid such as amorphous obeticholic acid hemicalcium - aspects (i) to (iv) Steps (iii) to (iv)

[0368] In some embodiments of a method for preparing an amorphous calcium salt of obeticholic acid (e.g., amorphous obeticholic acid hemicalcium), the method comprises steps (iii) to (iv): preparing an amorphous calcium salt of obeticholic acid from crystalline obeticholic acid HCl isolated in step (ii), and isolating the amorphous calcium salt of obeticholic acid (e.g., amorphous obeticholic acid hemicalcium).

[0369] In some embodiments of a method for isolating the amorphous calcium salt of obeticholic acid according to step (iv), the amorphous calcium salt of obeticholic acid is in the form of amorphous obeticholic acid hemicalcium:

[0370]

[0371] In some embodiments of a method for preparing obeticholic acid, step (iii) comprises the following steps:

[0372] (iii-1) converting the crystalline obeticholic acid HCl of step (ii) to provide obeticholic acid in an organic solvent;

[0373] (iii-2) treating the obeticholic acid in the organic solvent with an aqueous sodium hydroxide solution to form the sodium salt of obeticholic acid; and

[0374] (iii-3) treating the sodium salt of obeticholic acid with an aqueous calcium chloride solution to form amorphous obeticholic acid hemicalcium;

[0375] wherein the compounds in steps (iii-1) and (iii-2) are not isolated.

[0376] Thus, in some embodiments, step (iii-1) comprises the following steps:

[0377] (aa) providing the crystalline obeticholic acid HCl isolated in step (ii);

[0378] (bb) While stirring, dissolve crystalline obeticholic acid HCl in a mixture of water and isopropyl acetate. In some embodiments, step (bb) is carried out at a temperature between 15 °C and 25 °C;

[0379] (cc) Allow phase separation to occur and perform one or more subsequent washing steps on the resulting organic phase with water, where the aqueous phase is separated after each washing step to obtain a washed organic phase; and

[0380] (dd) At a temperature of 50 °C or lower (e.g., 30 °C or lower), perform distillation two or more times on the washed organic phase obtained from step (cc), with the intermediate addition of ethanol, to obtain a solution of obeticholic acid in ethanol.

[0381] In some embodiments, step (iii-2) comprises the following steps:

[0382] (ee) Add an aqueous NaOH solution to the solution obtained in step (dd) and stir the resulting mixture, for example, at a temperature between 20 °C and 25 °C for at least 4 hours to obtain a solution of the sodium salt of obeticholic acid; and

[0383] (ff) Optionally filter the solution obtained in step (ee).

[0384] In some embodiments, step (iii-3) comprises the following steps:

[0385] (gg) Prepare a CaCl 2 solution by adding deionized water to CaCl 2 , then add ethyl acetate as a co-solvent and stir the resulting mixture for 10 minutes to 30 minutes;

[0386] (hh) Cool the CaCl 2 solution obtained in step (gg) to a temperature of 8 °C to 12 °C and add it, while stirring, via a filter to the solution obtained in step (ff) or (ee) at said temperature;

[0387] (ii) Stir the slurry obtained from step (hh) for about 1 hour to about 10 hours. In some embodiments of step (ii), the stirring is carried out at a temperature between 8 °C and 12 °C;

[0388] (jj) Separate the solid from the slurry obtained in step (ii) by filtration. In some embodiments of step (jj), the separation is carried out at a temperature between 8 °C and 12 °C;

[0389] (kk)Washing the filtration residue obtained in step (jj) with water in one or more washing steps. In some embodiments of step (kk), the washing is carried out at a temperature between 8 °C and 12 °C; and

[0390] (ll)Drying the washed residue obtained in step (kk) in vacuo at a temperature, for example, between 40 °C and 50 °C for more than 16 hours (e.g., 50 hours, 100 hours, 150 hours or 200 hours, or even longer) to obtain amorphous obeticholic acid hemicalcium (which is sometimes also referred to herein as Compound 3).

[0391] In some embodiments, a subsequent reprocessing procedure is carried out on the amorphous obeticholic acid hemicalcium. In some embodiments, the amorphous obeticholic acid hemicalcium is further reprocessed by dissolving it in ethanol (e.g., ethanol twice the weight of the amorphous obeticholic acid hemicalcium) at a temperature between 25 °C and 50 °C, then cooling to between 10 °C and 15 °C, then filtering into a mixture of an aqueous calcium chloride solution and ethyl acetate that is also cooled to between 10 °C and 15 °C, then filtering, washing with water and drying in vacuo at a temperature of 45 °C or lower for 20 hours or longer.

[0392] In some embodiments of step (iv), amorphous obeticholic acid hemicalcium with a purity of 95% or higher, for example, 95.5% or higher, 96% or higher, 96.5% or higher, 97% or higher, 97.5% or higher, 98% or higher, 98.5% or higher, 99% or higher, 99.1% or higher, 99.2% or higher, 99.3% or higher, 99.4% or higher, 99.5% or higher, 99.6% or higher, 99.7% or higher, 99.8% or higher, or 99.9% or higher is isolated.

[0393] In some embodiments, a grinding treatment is carried out on the amorphous obeticholic acid hemicalcium. In some embodiments, the grinding treatment is adapted (e.g., adapting parameters such as feed rate, venturi pressure and grinding pressure) so as to enable the production of micronized amorphous obeticholic acid hemicalcium.

[0394] Method for preparing obeticholic acid - step (a) of aspects (a) to (d)

[0395] In step (a) of the process for preparing obeticholic acid according to the present disclosure, a compound of formula (II) or a salt thereof is coupled with a compound of formula (III) to provide a compound of formula (IV) (wherein, for example, as described herein, X 1 is a leaving group and Y 1 is a protecting group).

[0396]

[0397] Step (a) of the subject method starts from the compound of formula (II) (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline) or a salt thereof:

[0398]

[0399] The compound of formula (II) can be obtained, for example, using the processes disclosed in WO 2016 / 024858 A1 or WO 2007 / 116922 A1, which are incorporated herein by reference in their entireties. In some embodiments, the compound of formula (II) can be obtained from a stable corresponding salt and can be obtained in pure and solid form. The solid form can be amorphous or crystalline. In some embodiments, the compound of formula (II) is obtained from the corresponding crystalline salt.

[0400] In some embodiments, the compound of formula (II) provided in step (a) is a salt of formula (IIA) or (IIB):

[0401]

[0402] wherein A m- is an anion and n is an integer from 1 to 3.

[0403] In some embodiments, the compound of formula (II) provided in step (a) is a salt of formula (IIA). In some embodiments, the compound of formula (IIA) is directly used in the coupling reaction with the compound of formula (III) without performing a desalting step.

[0404] In some embodiments, the compound of formula (II) provided in step (a) is a salt of formula (IIB). In some embodiments, the compound of formula (IIB) is directly used in the coupling reaction with the compound of formula (III) without performing a desalting step.

[0405] In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIA) or (IIB). In some embodiments, the following steps are performed before the coupling reaction in step (a):

[0406] (pre-a1) Provide a compound of formula (IIA) or (IIB):

[0407]

[0408] (pre-a2) Desalt the compound of formula (IIA) or (IIB) to obtain the compound of formula (II),

[0409] Wherein the reaction in step (pre-a2) is carried out in an organic solvent, the compound of formula (II) is not separated from the organic solvent, and the process does not include chromatography.

[0410] In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIA). In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIB).

[0411] In some embodiments, the salt of formula (IIA) or (IIB) is selected from salts having anion A m- wherein the anion is selected from: sulfonate (e.g., benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, ethanesulfonate, ethanedisulfonate or methanesulfonate), sulfate (e.g., methyl sulfate), halogen (e.g., chloride, iodide or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, glucoheptanoate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, hydroxyethylsulfonate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate and theophyllinate.

[0412] In some embodiments, the salt of formula (IIA) or (IIB) is selected from salts having anion A m- wherein the anion is selected from chloride, bromide, bitartrate, sulfate and sulfonate.

[0413] In some embodiments, the salt of formula (IIA) or (IIB) is selected from salts having anion A m- wherein the anion is selected from chloride, bromide, bitartrate and methanesulfonate.

[0414] In some embodiments of the salt of formula (IIA) or (IIB), m is 1.

[0415] In some embodiments, the salt has the formula (IIA), and anion A m- is methanesulfonate, where m is 1. The methanesulfonate (mesylate, MSA) salt (also referred to herein as Compound 1A, as shown below) can be obtained by the process disclosed in WO 2016 / 024858A1 or WO 2007 / 116922 A1, which are incorporated herein by reference in their entireties.

[0416]

[0417] In some embodiments, the desalting of the compound of formula (IIA) or (IIB) in step (pre-a2) is carried out in a mixture of an aqueous sodium hydroxide solution and an organic solvent selected from toluene, dichloromethane, cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, chlorobenzene, and combinations thereof. Subsequently, the mixture is heated, then cooled, and the system is allowed to phase-separate, and the aqueous phase is separated. In some embodiments, the solvent is toluene. In some embodiments, the reaction mixture is heated to a temperature between 45 °C and 60 °C and then cooled to a temperature between 15 °C and 40 °C.

[0418] In some embodiments, the organic phase obtained after separating the aqueous phase is subjected to one or more aqueous washing steps, where the aqueous phase is separated after each aqueous washing step. For example, one or more aqueous washing steps are carried out using an aqueous sodium chloride solution, followed by separation of the aqueous phase, and then one or more aqueous washing steps are carried out using deionized water, followed by separation of the aqueous phase again. Then, optionally, the resulting washed organic phase is distilled to reduce the water content to less than 1000 ppm by weight of the solution. Alternatively, in some embodiments, a small amount of water remains in the organic phase of the compound of formula (II), and the coupling with the compound of formula (III) is then carried out in the presence of this small amount of water.

[0419] In some embodiments, the desalting reaction in step (pre-2a) is carried out on the mesylate (Compound 1A) in a mixture of an aqueous sodium hydroxide solution and toluene at a temperature between 45 °C and 60 °C. Subsequently, the mixture is cooled to a temperature between 15 °C and 25 °C, the system is allowed to phase-separate, and the aqueous phase is separated. Then, optionally, the toluene phase obtained after separating the aqueous phase is subjected to one or more washing steps using an aqueous sodium chloride solution, followed by separation of the aqueous phase, and then one or more washing steps are carried out using deionized water, followed by separation of the aqueous phase again. Thereafter, the resulting washed toluene phase is distilled under reduced pressure at a temperature between 50 °C and 65 °C to reduce the water content to less than 1000 ppm by weight of the total amount of the solution. Alternatively, a small amount of water remains in the toluene of the compound of formula (II), and the coupling reaction with the compound of formula (III) is then carried out in the presence of this small amount of water.

[0420] As described above, in step (a), the compound of formula (II) or a salt thereof (e.g., the compound of formula (IIA) or (IIB), such as mesylate 1A) is coupled with the compound of formula (III) to provide the compound of formula (IV). In some embodiments, this process is carried out in an organic solvent.

[0421] The coupling partner of formula (III) in step (a) includes a leaving group (X 1 ). It should be understood that any convenient leaving group can be used for X in this disclosure 1 . In some embodiments, the leaving group (X 1 ) in the compound of formula (III) is selected from halogen, carbamate, and substituted sulfonyloxy. In some embodiments, the leaving group (X 1 ) in the compound of formula (III) is a sulfonyloxy selected from methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy. In some embodiments, the leaving group (X 1 ) is a carbamate. In some embodiments, the leaving group (X 1 ) is a halogen. In certain embodiments, the halogen is chloride. The coupling partner of formula (III) in step (a) also includes a protecting group (Y 1 ). The term "protecting group" refers to any group that prevents reaction at a functional group (e.g., the carboxylic acid moiety of a compound (including its intermediates)) when attached to the functional group, and the protecting group can be removed by conventional chemical or enzymatic steps to reconstitute the functional group such as the carboxylic acid moiety. The particular removable protecting group employed is not critical, and examples of carboxylic acid protecting groups include conventional substituents such as tert-butyl ester, methyl ester, ethyl ester, benzyl ester, allyl ester, 1,1-diethylallyl ester, 2,2,2-trifluoroethyl ester, phenyl ester, 4-methoxybenzyl ester, silyl ester, ortho ester, esters of 2,6-disubstituted phenols (e.g., 2,6-dimethylphenol), and any other group that can be chemically introduced onto a carboxylic acid group or similar functionality and subsequently selectively removed under mild conditions compatible with the nature of the product by chemical or enzymatic methods. It should be understood that any convenient protecting group for the carboxylic acid moiety (e.g., an ester group) can be used for Y in this disclosure 1, and those skilled in the art can easily determine the selection of appropriate protecting groups. Suitable groups for such purposes are discussed in standard textbooks in the chemical field, such as Protective Groups in Organic Synthesis by T.W. Greene and P.G.M. Wuts, 4th Edition, (John Wiley & Sons, New York, 1999), included in Protecting Group Chemistry by Jeremy Robertson, 1st Edition, (Oxford University Press, 2000); and included in March's Advanced Organic chemistry: Reactions Mechanisms, and Structure by Michael B. Smith, 8th Edition, (Wiley-Interscience Publication, 2001). In some embodiments, the protecting group (Y 1 ) is selected from alkyl, substituted alkyl, aryl, substituted aryl, allyl, substituted allyl, and silyl. In some embodiments, the protecting group (Y 1 ) is selected from tert-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl, 2,6-disubstituted phenol, and silyl. In some embodiments, the protecting group (Y 1 ) is tert-butyl. In some embodiments, the compound of formula (III) has the following structure 1B:

[0422]

[0423] In some embodiments of the coupling reaction in step (a), the solvent is selected from toluene, tert-butanol, 1,4-dioxane, xylene, N-methyl-2-pyrrolidone, dimethylformamide, water, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of the organic solvent toluene and the organic co-solvent tert-butanol.

[0424] Since the same organic solvent is used in steps (pre-a2) and (a), or since a solvent exchange is carried out in step (pre-a2), if steps (pre-a1) and (pre-a2) are carried out before step (a), the compound of formula (II) is already present in the desired solvent. If desired, more organic solvent and, for example, an organic co-solvent may be added in step (a). As will be understood by those skilled in the art, an organic co-solvent may also be added during the solvent exchange in step (pre-a2). In some embodiments, steps (pre-a1) and (pre-a2) are carried out before step (a), and the compound of formula (II) is present in toluene.

[0425] The coupling reaction in step (a) is generally a catalytic reaction. In some embodiments, the reaction is a palladium-catalyzed coupling reaction carried out in the presence of a base. Suitable examples of palladium catalysts are, for example, tris(dibenzylideneacetone)dipalladium and palladium(II) acetate. Suitable bases include organic bases (e.g., sodium tert-butoxide and potassium tert-butoxide) and inorganic bases (e.g., K 3 PO 4 、K 3 PO 4 ·H 2 O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH).

[0426] In many embodiments, anhydrous K3PO4 is used as the base. In many such embodiments, the particle size distribution is such that 90% of the particles are less than between about 140 microns and about 307 microns (including between about 140 microns and about 170 microns, including between about 160 microns and about 290 microns, and between about 180 microns and about 220 microns, and between about 200 microns and about 210 microns). In some embodiments, 90% of the particles are less than 205 microns.

[0427] In these and other embodiments, 50% of the particles are between about 35 microns and about 173 microns or less than that range, including between about 35 microns and about 40 microns.

[0428] In these and other embodiments, 10% of the particles are between about 7 microns and about 74 microns, including between about 7 microns and about 10 microns.

[0429] In some embodiments, the compound of formula (II) is reacted with the compound of formula (III) in a solvent (e.g., an organic solvent) using a palladium catalyst and a base in step (a). In some embodiments, the reaction mixture further comprises a ligand.

[0430] In some embodiments, the compound of formula (IIA) or (IIB) is reacted with the compound of formula (III) in a solvent (eg, an organic solvent) using a palladium catalyst and a base in step (a). In some embodiments, the reaction mixture further comprises a ligand.

[0431] In some embodiments, the desalted compound of formula (II) is reacted with the compound of formula (III) in a solvent (e.g., an organic solvent) using palladium (II) acetate, (S)-BINAP [(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl] or rac-BINAP as a ligand in step (a). In some embodiments, (S)-BINAP is used as a ligand, and the base is selected from sodium tert-butoxide, potassium tert-butoxide, anhydrous K 3 PO 4 , K 3 PO 4 ·H 2 O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH.

[0432] In some embodiments, the salt of formula (IIA) or (IIB) is reacted with the compound of formula (III) in a solvent (e.g., an organic solvent) using palladium (II) acetate, (S)-BINAP [(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl], (R)-BINAP [(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl] or rac-BINAP as a ligand in step (a). In some embodiments, (S)-BINAP is used as a ligand, and the base is selected from sodium tert-butoxide, potassium tert-butoxide, anhydrous K 3 PO 4 , K 3 PO 4 ·H 2 O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH and NaOH. In some embodiments, the salt of formula (IIA) is a mesylate salt, ie, compound 1A.

[0433] In some embodiments, the reaction in step (a) is performed at a temperature of 70° C. to 80° C., optionally under a nitrogen atmosphere, for 2 hours or more.

[0434] In some embodiments, the compound of formula (II) or the salt of formula (IIA) is prepared in step (a) at a temperature between 70° C. and 80° C. under a nitrogen atmosphere using palladium (II) acetate as a catalyst, (S)-BINAP as a ligand, and anhydrous K 3 PO 4 or K 3 PO 4·H 2 O reacts with the compound of formula (III) in a mixture of the organic solvent toluene and the organic co-solvent tert-butanol as a base for 2 hours or longer, where X 1 is Cl, and Y 1 is tert-butyl.

[0435] In some embodiments, the one or more water washing steps include one or more washing steps with water (preferably deionized water), followed by separation of the aqueous phase, followed by one or more washing steps with an aqueous HCl solution, followed by separation of the aqueous phase, followed by one or more washing steps with an aqueous sodium chloride solution, followed by separation of the aqueous phase, and finally one or more washing steps with deionized water again, followed by separation of the aqueous phase.

[0436] If tert-butanol is used as the organic co-solvent in step (a), this organic co-solvent is removed from the organic phase during the washing step.

[0437] If step (a) is carried out in an organic solvent different from the solvent used in step (b), the organic solvent used in step (a) is exchanged in step (a) with the organic solvent applied to step (b) such that the compound of formula (IV) remains in solution.

[0438] In some embodiments where the (organic) solvents used in steps (a) and (b) are different, at least a portion of the (organic) solvent used in step (a) is evaporated, for example using distillation under reduced pressure, and the organic solvent of step (b) is added such that the compound of formula (IV) remains in solution during the solvent exchange. This process can be carried out by continuously evaporating the (organic) solvent used in step (a) and continuously adding the organic solvent of step (b), for example until the amount of the (organic) solvent used in step (a) is below a certain threshold based on the total amount of the solvent. As an alternative, this process can be carried out batchwise in more than one of the following steps: evaporating a portion of the (organic) solvent used in step (a) and then adding a portion of the organic solvent used in step (b), for example until the amount of the (organic) solvent used in step (a) is below a certain threshold based on the total amount of the solvent.

[0439] In some embodiments, the solvent used in step (a) is a mixture of the organic solvent toluene and the organic co-solvent tert-butanol. During the washing step, tert-butanol is removed from the organic phase comprising the compound of formula (IV).

[0440] In some embodiments of step (a), acetonitrile is used to exchange the remaining organic solvent toluene by distilling off a portion of toluene in two or more steps under reduced pressure at a temperature between 50 °C and 65 °C and adding acetonitrile in the middle, wherein the amount of acetonitrile added is such that a solvent mixture containing less than about 20 weight percent toluene based on the combined weight of the solvents is obtained, so that the compound of formula (IV) remains in solution. In some embodiments of the compound of formula (IV), Y 1 is tert-butyl.

[0441] Method for preparing obeticholic acid - step (b) from aspects (a) to (d)

[0442] In step (b) of the method for preparing the compound of formula (I) according to the present disclosure, the compound of formula (IV) is converted to a carbamate of formula (V) in an organic solvent and then separated into a solid salt of formula (VI) (wherein Y 1 is a protecting group as described herein, for example).

[0443]

[0444] In some embodiments, the organic solvent used in step (b) is selected from acetonitrile, chlorobenzene, toluene, N-methyl-2-pyrrolidone, xylene, 1,4-dioxane, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, tert-butyl methyl ether, and combinations thereof. In some embodiments, the organic solvent is a mixture of acetonitrile or chlorobenzene and dichloromethane.

[0445] As previously explained herein, since the same organic solvent is used in steps (a) and (b), or since a solvent exchange is carried out in step (a), the compound of formula (IV) has been provided in the organic solvent used in step (b) in step (a). In some embodiments of the compounds of formula (IV), (V), and (VI), Y 1 is tert-butyl.

[0446] In some embodiments, the organic solvent used in step (b) is a mixture of acetonitrile and toluene with less than about 20 weight percent toluene based on the combined weight of the organic solvents.

[0447] In some embodiments, the conversion of the compound of formula (IV) to the corresponding carbamate of formula (V) in step (b) is carried out in acetonitrile at a temperature between 10 °C and 20 °C in the presence of pyridine, and less than about 20 weight percent of toluene and an excess of ethyl chloroformate based on the combined weight of the organic solvents.

[0448] If step (b) is carried out in an organic solvent different from the organic solvent used in step (c), the organic solvent used in step (b) is exchanged in step (b) with the organic solvent applied in step (c) such that the compound of formula (V) remains in solution.

[0449] In some embodiments in which the organic solvents used in steps (b) and (c) are different, at least a portion of the organic solvent used in step (b) is evaporated, for example by distillation carried out under reduced pressure, and the organic solvent of step (c) is added such that the compound of formula (V) remains in solution during the organic solvent exchange. This process can be carried out by continuously evaporating the organic solvent used in step (b) and continuously adding the organic solvent of step (c), for example until the amount of the organic solvent used in step (b) is less than a certain threshold based on the total amount of the organic solvent. As an alternative, this process can be carried out batchwise in more than one of the following steps: evaporating a portion of the organic solvent used in step (b) and subsequently adding a portion of the organic solvent used in step (c), for example until the amount of the organic solvent used in step (b) is less than a certain threshold based on the total amount of the organic solvent.

[0450] The resulting mixture is preferably treated one or more times with an aqueous solution of sodium chloride and / or HCl, followed by separation of the aqueous phase, and subsequently treated one or more times with an aqueous solution of bicarbonate, followed by separation of the aqueous phase.

[0451] In some embodiments, the conversion of the compound of formula (IV) to the corresponding carbamate of formula (V) in step (b) is carried out in acetonitrile with an excess of ethyl chloroformate in the presence of pyridine at a temperature between 10 °C and 20 °C, and in step (b) this solvent is exchanged with isopropyl acetate by distilling off in two or more steps under reduced pressure at a temperature of 60 °C or lower a portion of the acetonitrile and adding in a certain amount of isopropyl acetate in the middle to obtain a solution of the compound of formula (V) in isopropyl acetate, wherein the solution can be treated one or more times with an aqueous NaCl / HCl solution, followed by separation of the aqueous phase, and subsequently treated one or more times with an aqueous bicarbonate solution, followed by separation of the aqueous phase.

[0452] Next, the compound of formula (V) dissolved in an organic solvent is converted to the corresponding salt according to formula (VI), where A n- is an anion and n is an integer from 1 to 3. The solid form of the salt according to formula (VI) is then isolated as a solid form.

[0453] In some embodiments, the salt of formula (VI) is selected from those having the anion A n-salts, wherein the anion An- is selected from sulfonate (e.g., benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, ethanesulfonate, ethanedisulfonate or methanesulfonate), sulfate (e.g., methyl sulfate), halogen, acetate, aspartate, benzoate, hydrogencarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, glucoheptanoate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, hydroxyethylsulfonate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate and theophyllinate.

[0454] In some embodiments, the salts of formula (VI) are selected from salts having anion A n- salts, wherein the anion is selected from chloride, bromide, bitartrate, sulfate and sulfonate.

[0455] In some embodiments, the salts of formula (VI) are selected from salts having anion A n- salts, wherein the anion is selected from chloride, bromide, bitartrate and methanesulfonate.

[0456] In some embodiments, the salt form of formula (VI) is methanesulfonate, including its crystalline methanesulfonate, i.e., Compound 1D:

[0457]

[0458] In some embodiments of the salts of formula (VI), n is 1.

[0459] The organic solvents used in the conversion of formula (V) to (VI) are not particularly limited, but in some embodiments are selected from cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate and combinations thereof. In some embodiments, isopropyl acetate or a mixture including dichloromethane, n-heptane and isopropanol is used, e.g., a mixture of chlorobenzene, dichloromethane, n-heptane and isopropanol. It should be noted that due to the solvent exchange previously described herein, the compound of formula (V) has been provided in the organic solvent.

[0460] Thus, in some embodiments, the organic solvents used to convert the compound of formula (V) to its corresponding salt of formula (VI) are selected from cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate and combinations thereof, having less than about 20 weight percent toluene and less than about 7 weight percent acetonitrile based on the combined weight of the solvents. In some embodiments, the solvent is a mixture of isopropyl acetate, toluene and acetonitrile, having less than about 20 weight percent toluene and less than about 7 weight percent acetonitrile based on the combined weight of the solvents.

[0461] In some embodiments, an organic cosolvent different from the organic solvent already used in step (b) is preferably added. Exemplary organic cosolvents are selected from cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, such as methyl tert-butyl ether. As will be understood by those skilled in the art, the need for and advantages of using an organic cosolvent depend on the particular organic solvent already used in step (b). In certain instances, the use of a cosolvent may be omitted.

[0462] In some embodiments, the organic solvents for converting the compound of formula (V) to its corresponding salt of formula (VI) include isopropyl acetate and methyl tert-butyl ether as organic cosolvents.

[0463] Subsequently, an acid is added to form the salt of formula (VI) as defined above. In some embodiments, the acid is selected from ditartaric acid, sulfuric acid, sulfonic acid, hydrogen bromide, and hydrogen chloride. In some embodiments, the acid is methanesulfonic acid. In embodiments where the salt of formula (VI) can be obtained in crystalline form, a portion of the acid required to form the salt of formula (VI) may be added before crystallization and a portion during crystallization.

[0464] The salt of formula (VI) in solid form is isolated by crystallization (if a crystalline form of the salt of formula (VI) is obtainable), filtration, one or more optional filtration residue washing steps, and drying.

[0465] In some embodiments, in an organic solvent mixture of isopropyl acetate and methyl tert-butyl ether (wherein there is less than about 20 weight percent toluene and less than 7 weight percent acetonitrile based on the combined weight of the organic solvents), the compound of formula (V) is converted to the corresponding methanesulfonate salt according to formula (VI) using methanesulfonic acid, followed by crystallization of the methanesulfonate salt of Compound 1D from the organic solvent, followed by filtration, one or more optional washing steps of the filtration residue, and drying.

[0466] In some embodiments where the salt according to formula (VI) can be obtained in crystalline form, crystallization is induced by adding seeds of the salt according to formula (VI).

[0467] In some embodiments in which the salt according to formula (VI) can be obtained in crystalline form, crystallization of the salt according to formula (VI) and obtaining the crystalline form of the salt according to formula (VI) are carried out by the following means: adding the acid required to form the salt, stirring the resulting mixture at a temperature of 20 °C to 25 °C for more than 60 minutes, allowing crystallization to occur with stirring at a temperature between 15 °C and 25 °C for more than 120 minutes, then subjecting the resulting slurry to vacuum filtration, wherein the filter residue is washed one or more times with the same organic solvent used to crystallize the salt according to formula (VI), and the crystalline form of the salt according to formula (VI) is dried under vacuum.

[0468] In embodiments, the present invention relates to a salt according to formula (VI), wherein A n- is an anion, where n is an integer from 1 to 3. In some embodiments, the compound is the crystalline methanesulfonic acid (MSA) salt of formula (VI) (e.g., compound 1D as described herein).

[0469] In some embodiments, crystallization of the methanesulfonate of formula (VI) from an organic solvent mixture of isopropyl acetate and methyl tert-butyl ether and obtaining the crystalline form of the methanesulfonate according to compound 1D are carried out by the following means: adding methanesulfonic acid required to form the salt, stirring the resulting mixture at a temperature between 15 °C and 25 °C (e.g., 20 °C) for more than 60 minutes, then allowing crystallization to occur with stirring at a temperature between 15 °C and 25 °C for more than 120 minutes. The resulting slurry is subjected to vacuum filtration, wherein the filter residue is washed one or more times with a mixture of isopropyl acetate and methyl tert-butyl ether, and dried under vacuum to provide the crystalline form of the methanesulfonate according to compound 1D.

[0470] In some embodiments, the compound of formula (VI) is obtained in a yield of at least 70% based on the molar amount of the compound of formula (II). In some embodiments, the compound of formula (VI) is obtained with a purity of 99% or higher, such as 99.1% or higher, 99.2% or higher, 99.3% or higher, 99.5% or higher, or even higher.

[0471] Method for preparing obeticholic acid - step (c) of aspects (a) to (d)

[0472] In step (c) of the process according to the present disclosure, the isolated salt of formula (VI) or its desalted derivative (e.g., the compound according to formula (V)) is alkylated with a compound of formula (VII) to provide a compound of formula (VIII):

[0473]

[0474] wherein, X 2 is a leaving group, and Y1 is a protecting group (e.g., as described herein).

[0475] In some embodiments of step (c), the isolated solid form of the salt according to formula (VI) (e.g., the crystalline form of the salt according to formula (VI), such as crystalline methanesulfonate, i.e., compound 1D) is directly reacted with the compound of formula (VII) in an organic solvent to form the compound of formula (VIII) (i.e., without a desalting step).

[0476] In some embodiments of step (c), the isolated solid form of the salt according to formula (VI) (e.g., the crystalline form of the salt according to formula (VI), such as crystalline methanesulfonate, i.e., compound 1D) is desalted and reacted with the compound of formula (VII) in an organic solvent to form the compound of formula (VIII). Desalting the compound of formula (VI) gives the compound according to formula (V).

[0477] When a desalting step is performed on the compound of formula (VI), the desalting process and the subsequent reaction with the compound of formula (V) are carried out in the same organic solvent. In some embodiments, the organic solvent is selected from xylene, n-hexane, toluene, heptane (a mixture of isomers), n-heptane, dichloromethane, chlorobenzene, and combinations thereof. In some embodiments, the organic solvent is toluene or n-heptane.

[0478] In some embodiments, step (c) is carried out in the presence of a base. In some embodiments, step (c) is carried out in the presence of a solid-liquid phase transfer catalyst.

[0479] In some embodiments, the base is selected from alkali metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, and amines. In some embodiments, the base is selected from alkali metal alkoxides. In some embodiments, the base is sodium tert-pentoxide or a mixture of sodium tert-butoxide and potassium tert-butoxide.

[0480] In some embodiments, the solid-liquid phase transfer catalyst is selected from ammonium tert-butyl sulfate, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, crown ether, and combinations thereof. In some embodiments, the catalyst is ammonium tert-butyl sulfate.

[0481] In some embodiments, the reaction of the compound of formula (V) or (VI) with the compound of formula (VII) is carried out at a temperature between 0 °C and 25 °C (e.g., 5 °C to 20 °C).

[0482] The coupling partner of formula (VII) in step (c) includes the leaving group X 2 . It should be understood that any convenient leaving group can be used for X in this disclosure 2。In some embodiments, the leaving group X in the compound of formula (VII) 2 is selected from halogen and substituted sulfonyloxy. In some embodiments, the leaving group X in the compound of formula (VII) 2 is a substituted sulfonyloxy selected from methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy. In some embodiments, the leaving group X 2 is halogen. In certain embodiments, the halogen is bromide. In some embodiments, the compound of formula (VII) has the following structure 1E.

[0483]

[0484] In some embodiments, the desalting of the compound of formula (VI) and subsequent reaction with the compound of formula (VII) in step (c) are carried out in toluene as an organic solvent at a temperature of 5 °C to 25 °C in the presence of a base and a catalyst. In some embodiments, the desalting of the compound of formula (VI) and subsequent reaction with the compound of formula (VII) in step (c) are carried out at a temperature between 5 °C and 25 °C in the presence of sodium tert-amylate as the base and ammonium tert-butyl hydrogen sulfate as the catalyst in toluene as an organic solvent with stirring for about 1 hour to 8 hours. In some embodiments of the compound of formula (VI), Y 1 is tert-butyl.

[0485] In some embodiments, the alkylation of the compound of formula (VI) with the compound of formula (VII) (i.e., without an additional desalting step) in step (c) is carried out in toluene as an organic solvent at a temperature of 5 °C to 25 °C in the presence of a base and a catalyst. In some embodiments, the alkylation of the compound of formula (VI) with the compound of formula (VII) in step (c) is carried out at a temperature between 5 °C and 25 °C in the presence of sodium tert-amylate as the base and ammonium tert-butyl hydrogen sulfate as the catalyst in toluene as an organic solvent with stirring for about 1 hour to 8 hours.

[0486] In some embodiments, step (c) includes providing Crystal 1D, desalting this compound, and reacting the desalted compound with the compound of formula (VII) (where X 2 is Br) at a temperature between 5 °C and 25 °C in the presence of sodium tert-amylate as the base and ammonium tert-butyl hydrogen sulfate as the catalyst in toluene as an organic solvent with stirring for about 1 hour to 8 hours.

[0487] In some embodiments, step (c) includes reacting Crystal 1D with the compound of formula (VII) (where X 2is carried out at a temperature between 5 °C and 25 °C in toluene as an organic solvent with sodium tert - pentoxide as a base and ammonium tert - butyl hydrogen sulfate as a catalyst while stirring for about 1 hour to 8 hours.

[0488] In some embodiments of step (c), the base is the last reagent added to the reaction mixture. Without being bound by any particular theory, the inventors of the present invention have found that by adding the base as the last reagent, the equivalent amounts of both the base and the compound of formula (VII) used in the reaction mixture can be reduced. Reducing the equivalent amount of the compound of formula (VII) in turn reduces the risk of introducing formula (VII) - related impurities into the final product.

[0489] Thus, step (c) results in the production of the compound of formula (VIII) in an organic solvent. In some embodiments of the compound of formula (VIII), Y 1 is tert - butyl. In some embodiments, this reaction mixture undergoes one or more water - washing steps in step (c) to remove impurities, followed by separation of the aqueous phase, and optionally one or more filtration steps, to obtain a washed reaction mixture comprising the compound of formula (VIII) in an organic solvent. In some embodiments, the reaction mixture comprising the compound of formula (VIII) in an organic solvent is concentrated by distilling off a portion of the organic phase to obtain a concentrated reaction mixture comprising the compound of formula (VIII) in an organic solvent. In some embodiments, based on the weight of the reaction mixture, the organic solvent comprises 30 wt% to 40 wt% of the compound of formula (VIII). In some embodiments, based on the weight of the reaction mixture, the organic solvent comprises 34 wt% to 37 wt% of the compound of formula (VIII).

[0490] Preferably, the one or more water - washing steps, the optionally carried out one or more filtration steps, and the concentration step are combined to obtain a washed and concentrated reaction mixture comprising the compound of formula (VIII) in an organic solvent. In some cases, the organic solvent comprises 30 wt% to 40 wt% of the compound of formula (VIII). In some embodiments, based on the weight of the reaction mixture, the organic solvent comprises 34 wt% to 37 wt% of the compound of formula (VIII).

[0491] In some embodiments, the one or more water - washing steps include one or more washing steps with an aqueous acetic acid solution.

[0492] In some embodiments, in step (c), the reaction mixture comprising the compound of formula (VIII) in toluene as an organic solvent is subjected to one or more water washing steps with an aqueous acetic acid solution, followed by separation of the aqueous phase, and then generally distilling off a portion of the toluene under reduced pressure at a temperature of 75 °C to 90 °C to obtain a washed and concentrated reaction mixture comprising the compound of formula (VIII) in toluene, wherein the content of the compound of formula (VIII) is 30 weight percent to 40 weight percent based on the weight of the reaction mixture. In some embodiments, the concentrated mixture comprises 34 weight percent to 37 weight percent of the compound of formula (VIII) based on the weight of the reaction mixture.

[0493] If step (c) is carried out in an organic solvent different from the organic solvent used in step (d), the organic solvent used in step (c) is exchanged in step (c) with the organic solvent applied in step (d) such that the compound of formula (VIII) remains in solution.

[0494] In some embodiments where the organic solvents used in steps (c) and (d) are different, at least a portion of the organic solvent used in step (c) is preferably evaporated by distillation carried out under reduced pressure, and the organic solvent of step (d) is added such that the compound of formula (VIII) remains in solution during the organic solvent exchange. This process can be carried out by continuously evaporating the organic solvent used in step (c) and continuously adding the organic solvent of step (d), for example until the amount of the organic solvent used in step (c) is less than a certain threshold based on the total amount of the organic solvents. As an alternative, this process can be carried out batchwise in more than one of the following steps: evaporating a portion of the organic solvent used in step (c) and then adding a portion of the organic solvent used in step (d), for example until the amount of the organic solvent used in step (c) is less than a certain threshold based on the total amount of the organic solvents.

[0495] Method for preparing the compound of formula (I) - step (d) of aspects (a) to (d)

[0496] In step (d) of the process according to the present disclosure, the compound of formula (VIII) is converted to obicetrapib in a first organic solvent (where Y 1 is a protecting group as described herein, for example).

[0497]

[0498] The choice of the first organic solvent used in step (d) is not particularly limited. In some embodiments, the first organic solvent is not an ether or an ester. In some embodiments, the first organic solvent is toluene or a mixture of n-heptane and acetic acid. As previously explained herein, since the same organic solvent is used in steps (c) and (d), or since a solvent exchange is carried out in step (c), the compound of formula (VIII) has been provided in the first solvent used in step (d) in step (c).

[0499] Thus, in some embodiments, the first organic solvent as defined hereinbefore is provided in step (d), and based on the weight of the reaction mixture, the first organic solvent has 30 wt% to 40 wt% of the compound of formula (VIII), for example 34 wt% to 37 wt% of the compound of formula (VIII).

[0500] In some embodiments, toluene is provided as the first organic solvent in step (d), and based on the weight of the reaction mixture, the toluene has 30 wt% to 40 wt%, for example 34 wt% to 37 wt% of the compound of formula (VIII).

[0501] Any convenient protecting group for the carboxylic acid (e.g., an ester moiety) can be used as Y in the compound of formula (VIII). 1 . As disclosed herein, the choice of a suitable protecting group for the carboxylic acid can be readily determined by those skilled in the art. In some embodiments of formula (VIII), the protecting group (Y 1 ) is selected from alkyl, substituted alkyl, aryl, substituted aryl, allyl, substituted allyl, and silyl. In some embodiments of formula (VIII), the protecting group (Y 1 ) is selected from tert-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl, 2,6-disubstituted phenol, and silyl. In some embodiments of the compound of formula (VIII), the protecting group Y 1 is tert-butyl. In some embodiments, the conversion of the compound of formula (VIII) to obisertopib is carried out by contacting the compound of formula (VIII) with acetic acid (AcOH) and dry HCl in a first organic solvent (e.g., toluene or a mixture of n-heptane and acetic acid) while stirring. In some embodiments, the reaction mixture is heated to a temperature between 40 °C and 55 °C and the resulting mixture is maintained at this temperature for at least 3 hours while stirring.

[0502] Obisertopib can be isolated from the resulting mixture using techniques known to those skilled in the art.

[0503] In some embodiments, in step (d), the resulting mixture comprising obicetrapib is subjected to one or more water washing steps. In some embodiments, the one or more water washing steps in step (d) are carried out as follows:

[0504] (AA) Cool the reaction mixture comprising obicetrapib to a temperature between 15 °C and 25 °C, and then add a mixture of n - heptane, acetonitrile and water, and then stir the resulting mixture at this temperature for more than 15 minutes;

[0505] (BB) Allow the system obtained in step (AA) to phase - separate into an organic phase and an aqueous phase, and separate the two phases;

[0506] (CC) Add a mixture of n - heptane, acetonitrile, toluene and water to the aqueous phase obtained in step (BB), and then stir the resulting system at a temperature between 15 °C and 25 °C for more than 15 minutes;

[0507] (DD) Allow the system obtained in step (CC) to phase - separate into an organic phase and an aqueous phase, and separate the two phases;

[0508] (EE) Combine the organic phase obtained in step (BB) with the organic phase obtained in step (DD), add water, and stir the resulting system at a temperature between 15 °C and 25 °C for more than 15 minutes;

[0509] (FF) Allow the system obtained in step (EE) to phase - separate into an organic phase and an aqueous phase, and separate the two phases;

[0510] (GG) Add water to the organic phase obtained in step (FF), and stir the resulting system at a temperature between 15 °C and 25 °C for more than 15 minutes;

[0511] (HH) Allow the system obtained in step (GG) to phase - separate into an organic phase and an aqueous phase, and separate the two phases;

[0512] (II) Add an aqueous solution of trisodium citrate dihydrate to the organic phase obtained in step (HH), and then stir the resulting mixture at a temperature between 15 °C and 25 °C for more than 15 minutes;

[0513] (JJ) Allow the system obtained in step (II) to phase - separate into an organic phase and an aqueous phase, and separate the two phases;

[0514] (KK) Add water to the organic phase obtained in step (JJ), and stir the resulting system at a temperature between 15 °C and 25 °C for more than 15 minutes; and

[0515] (LL) allows the system obtained in step (KK) to phase-separate into an organic phase and an aqueous phase, and separates the two phases.

[0516] Steps (AA) through (LL) in this example produce a washed compound of formula (I) in an organic solvent mixture comprising n-heptane, acetonitrile, and a first organic solvent. In some examples, the first solvent is toluene.

[0517] In some examples where the first organic solvent is no longer predominantly composed of cyclopentyl methyl ether, the organic solvent mixture is exchanged with CPME in a subsequent step (MM) such that obeticholic acid remains in solution.

[0518] Thus, in some examples, step (MM) is carried out after step (LL), where at least a portion of the solvent in the organic solvent mixture obtained in step (LL) is evaporated, for example by distillation under reduced pressure, and where cyclopentyl methyl ether is added such that obeticholic acid remains in solution during the solvent exchange. In some examples, the process forms a solution of obeticholic acid in cyclopentyl methyl ether at a concentration between 30 weight percent and 40 weight percent based on the weight of the solution. In some examples, the concentration of obeticholic acid in cyclopentyl methyl ether is from 33 weight percent to 37 weight percent based on the weight of the solution, with less than 1 weight percent of the first organic solvent, and less than 1 weight percent of n-heptane present based on the weight of the solution.

[0519] This process can be carried out by continuously evaporating the solvent in the organic solvent mixture obtained in step (LL) and by continuously adding cyclopentyl methyl ether, for example until the amount of a particular solvent in the organic solvent mixture is below a certain threshold based on the total amount of the organic solvents. As an alternative, this process can be carried out batchwise in more than one of the following steps: evaporating a portion of the solvent in the organic solvent mixture obtained in step (LL) and subsequently adding cyclopentyl methyl ether, for example until the amount of a particular solvent in the organic solvent mixture is below a certain threshold based on the total amount of the solvents.

[0520] In some embodiments, the first organic solvent is toluene, and step (MM) is carried out after step (LL), wherein at least a portion of n-heptane, acetonitrile, and toluene in the organic solvent mixture obtained in step (LL) is evaporated, for example, by distillation at a temperature of 45 °C or lower and under reduced pressure (in vacuo), with the intermediate addition of cyclopentyl methyl ether, such that obeticholic acid remains in solution during the solvent exchange, thereby obtaining a solution of obeticholic acid in cyclopentyl methyl ether at a concentration between 30 weight percent and 40 weight percent. In some embodiments, based on the weight of the solution, the concentration of obeticholic acid in cyclopentyl methyl ether is from 33 weight percent to 37 weight percent, and the solution has less than 0.5 weight percent of toluene, less than 0.5 weight percent of acetonitrile, and less than 2.7 weight percent of n-heptane.

[0521] Method for preparing crystalline obeticholic acid HCl - steps (e) to (f) other than aspects (a) to (d)

[0522] In some embodiments of the subject method, steps (e) to (f) are carried out after step (d), wherein obeticholic acid is treated with HCl, for example, in a suitable solvent. Such a solvent can be an aqueous solvent or an organic solvent. In some embodiments, using an organic solvent provides crystalline obeticholic acid HCl.

[0523] In some embodiments, the organic solvent used in step (e) comprises a mixture of a solvent and an anti-solvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the anti-solvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane. In some embodiments, HCl has sufficient solubility in the anti-solvent such that it can be used as a suitable solvent. In some embodiments, the organic solvent used in step (e) comprises a mixture of cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (e) further comprises toluene.

[0524] In some embodiments, step (e) comprises: providing obeticholic acid in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to between 35 °C and 40 °C while stirring, adding dry HCl in cyclopentyl methyl ether, and raising the temperature again to between 50 °C and 55 °C, and then adding additional n-heptane as an anti-solvent. At this time, a small portion of the reaction mixture can be extracted and cooled to a temperature between 10 °C and 15 °C to obtain a slurry of crystals of crystalline obeticholic acid HCl in a mixture of cyclopentyl methyl ether and n-heptane (referred to herein as "seed slurry"). Optionally, then all or a portion of the seed slurry of crystalline obeticholic acid HCl can be added back to the reaction mixture as seeds. Seeding aids nucleation but is not required, and thus the processes described herein can be carried out without seeding. The resulting reaction mixture is then cooled to a temperature between 5 °C and 15 °C (e.g., 10 °C to 15 °C), and then crystalline obeticholic acid HCl is crystallized from the system while stirring. In some embodiments, crystalline obeticholic acid HCl crystallizes over a period of 12 hours or longer, followed by filtration (e.g., through a filter dryer), one or more optional washing steps (e.g., washing with a mixture of cyclopentyl methyl ether and n-heptane), and drying. In some cases, the wet filter cake of crystalline obeticholic acid HCl is vacuum dried in multiple steps using temperatures of 25 °C to 30 °C, 30 °C to 40 °C, 40 °C to 50 °C, and then 50 °C to 55 °C, such as 25 °C, 35 °C, 46 °C, and 54 °C.

[0525] Thus, in some embodiments, the method for preparing crystalline obeticholic acid HCl comprises adding seeds (e.g., as a seed slurry). Seeds of crystalline obeticholic acid HCl can be formed into a slurry by following the steps (i) stated above, and after adding dry HCl in cyclopentyl methyl ether and an anti-solvent n-heptane, extracting a small portion of the reaction mixture and cooling it to a temperature between 10 °C and 15 °C to provide a slurry of crystals of crystalline obeticholic acid HCl in cyclopentyl methyl ether and n-heptane.

[0526] In some embodiments, the organic solvent used in step (e) comprises a mixture of cyclopentyl methyl ether and n-heptane. Thus, in one embodiment, step (e) comprises providing obeticholic acid in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to a temperature of 35 °C to 45 °C while stirring, adding dry HCl in cyclopentyl methyl ether and raising the temperature again to 50 °C to 55 °C, adding additional n-heptane as an anti-solvent, optionally adding seeds of crystalline obeticholic acid HCl (e.g., as a seed slurry prepared as described herein), cooling to a temperature between 5 °C and 15 °C (e.g., 10 °C to 15 °C), and then crystallizing crystalline obeticholic acid HCl from the system while stirring. In some embodiments, crystalline obeticholic acid HCl crystallizes over a period of at least 12 hours, followed by filtration, one or more optional washing steps (e.g., washing with a mixture of cyclopentyl methyl ether and n-heptane), and drying. In some embodiments, crystalline obeticholic acid HCl is dried under vacuum. In some embodiments, crystalline obeticholic acid HCl is dried in a vacuum oven at a pressure of 25 mbar and a temperature of 55 °C for 10 hours or longer. In some embodiments, after the drying procedure, crystalline obeticholic acid HCl comprises less than 0.1 weight percent of residual cyclopentyl methyl ether.

[0527] In some embodiments previously described herein, step (MM) of step (d) forms a solution of obeticholic acid in cyclopentyl methyl ether at a concentration between 30 weight percent and 40 weight percent, e.g., 33 weight percent to 37 weight percent, based on the weight of the solution, the solution comprising less than 1 weight percent of the first organic solvent used in step (d) and less than 1 weight percent of n-heptane. In some embodiments previously described herein, step (MM) of step (d) forms a solution of obeticholic acid in cyclopentyl methyl ether at a concentration between 30 weight percent and 40 weight percent, e.g., 33 weight percent to 37 weight percent, based on the weight of the solution, the solution comprising less than 1 weight percent of toluene and less than 1 weight percent of n-heptane. After adding n-heptane, these solutions can be advantageously used in step (e). As will be understood by those skilled in the art, n-heptane can also be added in step (d).

[0528] Thus, in some embodiments, step (e) comprises forming a solution of obeticholic acid in cyclopentyl methyl ether at a concentration between 30 wt% and 40 wt%, e.g., between 33 wt% and 37 wt%, by weight of the solution, the solution comprising less than 1 wt% of the first organic solvent (e.g., toluene) used in step (d) and less than 1 wt% of n-heptane, adding n-heptane, raising the temperature to 35°C to 45°C while stirring, adding dry HCl in cyclopentyl methyl ether and raising the temperature again to 50°C to 55°C, adding additional n-heptane as an anti-solvent, optionally adding seeds of crystalline obeticholic acid HCl (e.g., as a seed slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (e.g., 10°C to 15°C), and then crystallizing crystalline obeticholic acid HCl from the system while stirring, e.g., over a period of at least 12 hours, followed by filtration, performing one or more washing steps with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some cases, the wet filter cake of crystalline obeticholic acid HCl is vacuum dried in multiple steps using temperatures of 25°C to 30°C, 30°C to 40°C, 40°C to 50°C, and then 50°C to 55°C, e.g., 25°C, 35°C, 46°C, and 54°C.

[0529] In some embodiments, step (f) comprises the steps of:

[0530] (aa) providing crystalline obeticholic acid HCl;

[0531] (bb) dissolving crystalline obeticholic acid HCl in ethanol while stirring. In some embodiments, the temperature is between 15°C and 25°C;

[0532] (cc) adding an aqueous NaOH solution to the solution obtained in step (bb) and stirring the resulting mixture, e.g., at a temperature of 20°C to 25°C, for at least 4 hours to obtain a solution of the sodium salt of obeticholic acid;

[0533] (dd) optionally filtering the solution obtained in step (cc);

[0534] (ee) preparing a CaCl2 solution by adding deionized water to CaCl2 while stirring, then adding ethyl acetate as a co-solvent and stirring the resulting mixture for 10 minutes to 30 minutes;

[0535] (ff) cooling the CaCl2 solution obtained in step (ee) to a temperature between 8°C and 12°C and adding it, while stirring at said temperature, via a filter to the solution obtained in step (dd) (or (cc));

[0536] (gg) Stir the slurry obtained from step (ff) for about 1 hour to about 10 hours. In some embodiments, the slurry is stirred at a temperature between 8 °C and 12 °C;

[0537] (hh) Separate the solid from the slurry obtained in step (gg) by filtration. In some embodiments, the separation is carried out at a temperature between 8 °C and 12 °C;

[0538] (ii) Wash the filtration residue obtained in step (hh) with water in one or more washing steps. In some embodiments, the washing is carried out at a temperature between 8 °C and 12 °C; and

[0539] (jj) Dry the washed residue obtained in step (ii) in vacuo at a temperature between 40 °C and 50 °C for more than 16 hours (e.g., 200 hours or longer) to obtain amorphous obeticholic acid hemicalcium.

[0540] In some embodiments of the subject method, crystalline obeticholic acid HCl having a purity of 98% or higher, such as 98.5% or higher, 99% or higher, 99.5% or higher, or even higher, is separated in step (f).

[0541] Another embodiment of the present disclosure relates to crystalline obeticholic acid HCl obtainable or obtained by the process defined herein.

[0542] Yet another embodiment of the present disclosure relates to crystalline obeticholic acid HCl.

[0543] In some embodiments, crystalline obeticholic acid HCl is stored at a controlled room temperature and under a nitrogen atmosphere and protected from moisture to prevent the formation of amorphous solids because crystalline obeticholic acid HCl, including crystalline obeticholic acid HCl, is hygroscopic.

[0544] Method for preparing amorphous obeticholic acid hemicalcium - steps (g) to (h) other than aspects (a) to (f)

[0545] In some embodiments of the subject method, steps (g) to (h) are carried out after step (f), in which crystalline obeticholic acid HCl is converted to amorphous obeticholic acid hemicalcium (Formula IB):

[0546]

[0547] In some embodiments of step (g), the preparation of amorphous obeticholic acid hemicalcium comprises steps (g1) to (g3) as described below:

[0548] (g1) Convert the crystalline obeticholic acid HCl from step (f) to obeticholic acid in an organic solvent;

[0549] (g2) Treat obeticholic acid in an organic solvent with an aqueous sodium hydroxide solution to form the sodium salt of obeticholic acid; and

[0550] (g3) Treat the sodium salt of obeticholic acid with an aqueous calcium chloride solution to form amorphous obeticholic acid hemicalcium;

[0551] wherein the compounds in steps (g1) and (g2) are not separated.

[0552] Thus, in some embodiments, step (g1) comprises the following steps:

[0553] (aa) Provide crystalline obeticholic acid HCl as defined or obtained in step (f);

[0554] (bb) Dissolve crystalline obeticholic acid HCl in a mixture of water and isopropyl acetate while stirring. In some embodiments, step (bb) is carried out at a temperature between 15 °C and 25 °C;

[0555] (cc) Allow phase separation and perform one or more subsequent washing steps on the resulting organic phase with water, wherein the aqueous phase is separated after each washing step to obtain the washed organic phase; and

[0556] (dd) Carry out distillation two or more times on the washed organic phase obtained from step (cc) at a temperature of 50 °C or lower (e.g., 30 °C or lower), with the addition of ethanol in between, to obtain a solution of the obeticholic acid compound in ethanol. In some embodiments, step (g2) comprises the following steps:

[0557] (ee) Add an aqueous NaOH solution to the solution obtained in step (dd) and stir the resulting mixture, for example, at a temperature between 20 °C and 25 °C for at least 4 hours to obtain a solution of the sodium salt of obeticholic acid; and

[0558] (ff) Optionally filter the solution obtained in step (ee).

[0559] In some embodiments, step (g3) comprises the following steps:

[0560] (gg) Prepare a CaCl2 solution by adding deionized water to CaCl2 while stirring, then add ethyl acetate as a co-solvent and stir the resulting mixture for 10 minutes to 30 minutes;

[0561] (hh)Cool the CaCl₂ solution obtained in step (gg) to a temperature of 8 °C to 12 °C and add it to the solution obtained in step (ff) or (ee) via a filter while stirring at said temperature;

[0562] (ii)Stir the slurry obtained from step (hh) for about 1 hour to 10 hours. In some embodiments of step (ii), the stirring is carried out at a temperature between 8 °C and 12 °C;

[0563] (jj)Separate the solid from the slurry obtained in step (ii) by filtration. In some embodiments of step (jj), the separation is carried out at a temperature between 8 °C and 12 °C;

[0564] (kk)Wash the filter residue obtained in step (jj) with water in one or more washing steps. In some embodiments of step (kk), the washing is carried out at a temperature between 8 °C and 12 °C; and

[0565] (ll)Dry the washed residue obtained in step (kk) in vacuo at a temperature of, for example, 40 °C to 50 °C for more than 16 hours (e.g., 50 hours, 100 hours, 150 hours or 200 hours, or even longer) to obtain amorphous obeticholic acid hemicalcium (sometimes also referred to herein as Compound 3).

[0566] In some embodiments, step (g) comprises the following steps:

[0567] (aa)Provide crystalline obeticholic acid HCl as defined or obtained in step (f);

[0568] (bb)Dissolve crystalline obeticholic acid HCl in ethanol while stirring. In some embodiments, the temperature is between 15 °C and 25 °C;

[0569] (cc)Add an aqueous NaOH solution to the solution obtained in step (bb) and stir the resulting mixture, for example, at a temperature of 20 °C to 25 °C for at least 4 hours to obtain a solution of the sodium salt of obeticholic acid;

[0570] (dd)Optionally filter the solution obtained in step (cc);

[0571] (ee)Prepare a CaCl₂ solution by adding deionized water to CaCl₂ while stirring, then add ethyl acetate as a co-solvent and stir the resulting mixture for 10 minutes to 30 minutes;

[0572] (ff) Cool the CaCl₂ solution obtained in step (ee) to a temperature between 8 °C and 12 °C and add it, while stirring at said temperature, via a filter to the solution obtained in step (dd) or (cc);

[0573] (gg) Stir the slurry obtained from step (ff) for about 1 hour to 10 hours. In some embodiments, stir the slurry at a temperature between 8 °C and 12 °C;

[0574] (hh) Separate the solid from the slurry obtained in step (gg) by filtration. In some embodiments, the separation is carried out at a temperature between 8 °C and 12 °C;

[0575] (ii) Wash the filter residue obtained in step (hh) with water in one or more washing steps. In some embodiments, the washing is carried out at a temperature between 8 °C and 12 °C; and

[0576] (jj) Dry the washed residue obtained in step (ii) in vacuo, for example at a temperature between 40 °C and 50 °C, for more than 16 hours (e.g., 50 hours, 100 hours, 150 hours or 200 hours, or even longer), to obtain the amorphous semi-calcium salt of formula (IB).

[0577] In some embodiments, amorphous obeticholic acid semi-calcium salt is stored sealed and protected from light at a temperature below 30 °C.

[0578] In some embodiments, a subsequent reprocessing procedure is carried out on the amorphous obeticholic acid semi-calcium salt. In some embodiments, the amorphous obeticholic acid semi-calcium salt is further reprocessed by dissolving it in ethanol (e.g., ethanol in an amount twice the weight of the amorphous obeticholic acid semi-calcium salt) at a temperature of 25 °C to 50 °C, then cooling to 10 °C to 15 °C, then filtering into a mixture of an aqueous calcium chloride solution and ethyl acetate which is also cooled to 10 °C to 15 °C, then filtering, washing with water and drying in vacuo at a temperature of 45 °C or lower for 20 hours or longer.

[0579] In many embodiments of the present disclosure, the amorphous obeticholic acid semi-calcium salt is processed to achieve a particle size distribution. In many embodiments, such processing is carried out by grinding. Examples of grinding include hammer milling, ball milling and jet milling. In other embodiments, spray drying may be used to achieve a particle size distribution. Thus, in some embodiments of the present disclosure, spray-dried amorphous obeticholic acid semi-calcium salt is provided. An example of jet-milled amorphous obeticholic acid semi-calcium salt is provided in Example 11.14.

[0580] In many embodiments of the present disclosure, unground amorphous obeticholic acid hemicalcium is provided. In many embodiments of the present disclosure, ground amorphous obeticholic acid hemicalcium is provided.

[0581] In many embodiments, the particle size distribution of amorphous obeticholic acid hemicalcium is such that 90% of the particles have a diameter of about 15 microns or less. In these and other embodiments, 90% of the particles have a diameter of about 14 microns or less, 13 microns or less, 12 microns or less, 11 microns or less, 10 microns or less, 9 microns or less, 8 microns or less, 7 microns or less, 6 microns or less, 5 microns or less, 4 microns or less, or 3 microns or less.

[0582] In some embodiments, 90% of the particles have a diameter between about 6 microns and 15 microns.

[0583] In these and other embodiments, the particle size distribution of amorphous obeticholic acid hemicalcium is such that 50% of the particles have a diameter of about 5 microns or less, such as for example 4 microns or less or 3 microns or less.

[0584] In these and other embodiments, the particle size distribution of amorphous obeticholic acid hemicalcium is such that 10% of the particles have a diameter of about 2 microns or less.

[0585] According to the process of the present disclosure, the amorphous obeticholic acid hemicalcium of the present disclosure can be made with high chemical purity. Such purity levels include a purity greater than 98.0%, such as a purity greater than 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% or higher. The highest levels of purity, such as a purity greater than 99.8% or 99.9%, can be more readily achieved by a process in which crystalline obeticholic acid HCl is used as an intermediate.

[0586] As described above, amorphous calcium salts of obeticholic acid, including amorphous obeticholic acid hemicalcium, are also provided herein. New intermediates for the synthesis of obeticholic acid and salts of obeticholic acid are also provided.

[0587] Accordingly, the subject method has been described with reference to certain embodiments discussed above. It will be recognized that various modifications and alternative forms well known to those skilled in the art can be readily made to these embodiments.

[0588] In certain preferred embodiments of the present invention, obeticholic acid included in the pharmaceutical compositions of the present invention, used in the methods of the present invention, included in unit dosage forms (including in pharmaceutical kits), etc. is in the form of a salt of obeticholic acid, more particularly a salt described by one or more of the following non-limiting clauses:

[0589] Clause 1. An amorphous calcium salt of obeticholic acid.

[0590] Clause 2. An amorphous obeticholic acid hemicalcium.

[0591] Clause 3. A stable amorphous obeticholic acid hemicalcium.

[0592] Clause 4. A substantially pure amorphous obeticholic acid hemicalcium.

[0593] Clause 5. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 4, which is substantially free of any crystalline salts of obeticholic acid hemicalcium.

[0594] Clause 6. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 5, which has an X-ray powder diffraction pattern substantially the same as that of Figure 49 ...

[0595] Clause 7. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 5, which has an X-ray powder diffraction pattern including one or more X-ray powder diffraction peaks at about 3.4° 2θ, about 7.0° 2θ, and about 9.2° 2θ.

[0596] Clause 8. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 7, wherein the amorphous obeticholic acid hemicalcium does not exhibit birefringence.

[0597] Clause 9. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 8, which has a glass transition temperature at a value between about 107 °C and about 112 °C.

[0598] Clause 10. The amorphous obeticholic acid hemicalcium as described in Clause 9, wherein the glass transition temperature is measured by modulated differential scanning calorimetry.

[0599] Clause 11. The amorphous obeticholic acid hemicalcium as described in Clause 10, wherein the measurement by modulated differential scanning calorimetry is performed using an open sample pan vessel.

[0600] Clause 12. The amorphous obeticholic acid hemicalcium as described in Clause 11, wherein the opening is a pinhole.

[0601] Clause 13. The amorphous obeticholic acid hemicalcium as described in Clauses 8 to 12, wherein the glass transition temperature is at a value between about 110 °C and about 112 °C.

[0602] Clause 14. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 13 has a glass transition temperature of less than about 100 °C when measured by differential scanning calorimetry using a closed sample pan vessel.

[0603] Clause 15. The amorphous obeticholic acid hemicalcium salt as described in Clause 14 has a glass transition temperature at a value between about 70 °C and about 92 °C when measured by differential scanning calorimetry using a closed sample pan vessel.

[0604] Clause 16. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 15 has a weight loss of less than about 1% when heated to about 200 °C.

[0605] Clause 17. The amorphous obeticholic acid hemicalcium salt as described in Clause 16, wherein the weight loss is between about 0.8% and about 0.95%.

[0606] Clause 18. The amorphous obeticholic acid hemicalcium salt as described in Clause 17, wherein the weight loss is between about 0.84% and about 0.92%.

[0607] Clause 19. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 18 has a water content of less than about 5%.

[0608] Clause 20. The amorphous obeticholic acid hemicalcium salt as described in Clause 19 has a water content of less than about 4%.

[0609] Clause 21. The amorphous obeticholic acid hemicalcium salt as described in Clause 20 has a water content of less than about 3%.

[0610] Clause 22. The amorphous obeticholic acid hemicalcium salt as described in Clause 19 has a water content between about 0.5% and about 1.5%.

[0611] Clause 23. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 22 is in the form of a bulk or formulated composition and has a particle size distribution in which about 90% of the particles have a diameter of about 15 microns or less.

[0612] Clause 24. The amorphous obeticholic acid hemicalcium salt as described in Clause 23, wherein about 90% of the particles have a diameter between about 6 microns and about 15 microns.

[0613] Clause 25. The amorphous obeticholic acid hemicalcium salt as described in Clause 24 has a particle size distribution in which about 90% or more of the particles have a diameter of about 14 microns or less.

[0614] Clause 26. The amorphous obeticholic acid hemicalcium salt as described in Clause 25 has a particle size distribution in which about 90% or more of the particles have a diameter of about 13 microns or less.

[0615] Clause 27. The amorphous obeticholic acid hemicalcium as described in Clause 26 has a particle size distribution in which about 90% or more of the particles have a diameter of about 12 microns or less.

[0616] Clause 28. The amorphous obeticholic acid hemicalcium as described in Clause 27 has a particle size distribution in which about 90% or more of the particles have a diameter of about 11 microns or less.

[0617] Clause 29. The amorphous obeticholic acid hemicalcium as described in Clause 28 has a particle size distribution in which about 90% or more of the particles have a diameter of about 10 microns or less.

[0618] Clause 30. The amorphous obeticholic acid hemicalcium as described in Clause 29 has a particle size distribution in which about 90% or more of the particles have a diameter of about 9 microns or less.

[0619] Clause 31. The amorphous obeticholic acid hemicalcium as described in Clause 30 has a particle size distribution in which about 90% or more of the particles have a diameter of about 8 microns or less.

[0620] Clause 32. The amorphous obeticholic acid hemicalcium as described in Clause 31 has a particle size distribution in which about 90% or more of the particles have a diameter of about 7 microns or less.

[0621] Clause 33. The amorphous obeticholic acid hemicalcium as described in Clause 32 has a particle size distribution in which about 90% or more of the particles have a diameter of about 6 microns or less.

[0622] Clause 34. The amorphous obeticholic acid hemicalcium as described in Clause 33 has a particle size distribution in which about 90% or more of the particles have a diameter of about 5 microns or less.

[0623] Clause 35. The amorphous obeticholic acid hemicalcium as described in Clause 34 has a particle size distribution in which about 90% or more of the particles have a diameter of about 4 microns or less.

[0624] Clause 36. The amorphous obeticholic acid hemicalcium as described in Clause 35 has a particle size distribution in which about 90% or more of the particles have a diameter of about 3 microns or less.

[0625] Clause 37. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 36 is in the form of a bulk or a formulated composition and has a particle size distribution in which about 50% of the particles have a diameter of about 5 microns or less.

[0626] Clause 38. The amorphous obeticholic acid hemicalcium as described in Clause 37 has a particle size distribution in which about 50% of the particles have a diameter of about 4 microns or less.

[0627] Clause 39. The amorphous obeticholic acid hemicalcium salt as described in Clause 38 has a particle size distribution in which about 50% of the particles have a diameter of about 3 microns or less.

[0628] Clause 40. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 39 is in the form of a bulk or a formulated composition and has a particle size distribution in which about 10% of the particles have a diameter of about 2 microns or less.

[0629] Clause 41. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 40 has a chemical purity of at least 98.0%.

[0630] Clause 42. The amorphous obeticholic acid hemicalcium salt as described in Clause 41 has a chemical purity of at least 99.0%.

[0631] Clause 43. The amorphous obeticholic acid hemicalcium salt as described in Clause 42 has a chemical purity of at least 99.5%.

[0632] Clause 44. The amorphous obeticholic acid hemicalcium salt as described in Clause 43 has a chemical purity of at least 99.6%.

[0633] Clause 45. The amorphous obeticholic acid hemicalcium salt as described in Clause 44 has a chemical purity of at least 99.7%.

[0634] Clause 46. The amorphous obeticholic acid hemicalcium salt as described in Clause 45 has a chemical purity of at least 99.8%.

[0635] Clause 47. The amorphous obeticholic acid hemicalcium salt as described in Clause 46 has a chemical purity of at least 99.9%.

[0636] Clause 48. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 47 has a solid-state Figure 65 C-NMR spectrum substantially the same as that of 13 the solid-state 13 C-NMR spectrum.

[0637] Clause 49. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 48 has a solid-state 13 C-NMR spectrum in which there is no peak at about 22.1 ppm.

[0638] Clause 50. The amorphous obeticholic acid hemicalcium salt as described in Clauses 2 to 49 has a solid-state 13 C-NMR spectrum in which there is no peak at about 29.5 ppm.

[0639] Clause 51. An unground amorphous obeticholic acid hemicalcium salt.

[0640] Clause 52. A milled amorphous obeticholic acid hemicalcium.

[0641] Clause 53. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 50, wherein the amorphous obeticholic acid hemicalcium has been milled.

[0642] Clause 54. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 50 or 53, wherein the amorphous obeticholic acid hemicalcium has been jet-milled.

[0643] Clause 55. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 50 or 53 to 54, wherein the amorphous obeticholic acid hemicalcium has been spray-dried.

[0644] Clause 56. An amorphous obeticholic acid hemicalcium prepared by a synthetic process, wherein the intermediate in the process includes crystalline obeticholic acid HCl.

[0645] Clause 57. The amorphous obeticholic acid hemicalcium as described in Clauses 2 to 56, wherein the amorphous obeticholic acid hemicalcium is prepared by a synthetic process, and the intermediate in the process includes crystalline obeticholic acid HCl.

[0646] Clause 58. An obeticholic acid HCl.

[0647] Clause 59. A crystalline obeticholic acid HCl.

[0648] Clause 60. An amorphous HCl obeticholic acid compound.

[0649] Clause 61. A solvate of the HCl obeticholic acid as described in Clauses 58 to 60.

[0650] Clause 62. The HCl obeticholic acid as described in Clauses 58 to 61, wherein the weight percentage of HCl is between about 0.01% and about 8%.

[0651] Clause 63. A composition comprising the crystalline obeticholic acid HCl as described in any one of Clauses 58 to 62.

[0652] Clause 64. The crystalline obeticholic acid HCl as described in Clauses 58 to 60 or 62 to 63, wherein the crystalline obeticholic acid HCl is a solvate.

[0653] Clause 65. The crystalline obeticholic acid HCl as described in Clause 64, wherein the solvate includes obeticholic acid and hydrochloric acid.

[0654] Clause 66. The crystalline obeticholic acid HCl as described in Clause 65, wherein the solvate includes an organic solvent.

[0655] Clause 67. Crystalline obeticholic acid HCl as described in Clause 66, wherein the solvate comprises a solvent in which the solubility is sufficient to dissolve sufficient HCl to deliver sufficient HCl to produce crystalline obeticholic acid HCl.

[0656] Clause 68. The solvate as described in any one of Clauses 61 or 64 to 67, wherein the solvent of the solvate is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether (CPME), N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, and hexafluoroisopropanol.

[0657] Clause 69. Crystalline obeticholic acid HCl as described in Clause 68, wherein the solvent is CPME.

[0658] Clause 70. Crystalline obeticholic acid HCl as described in any one of Clauses 58 to 59 or 61 to 69, which has an X-ray powder diffraction pattern substantially the same as that of Figure 67 the X-ray powder diffraction pattern in.

[0659] Clause 71. Crystalline obeticholic acid HCl as described in any one of Clauses 58 to 59 or 61 to 69, which has an X-ray powder diffraction pattern including a peak at about 9.8° 2θ.

[0660] Clause 72. Crystalline obeticholic acid HCl as described in any one of Clauses 58 to 59, 61 to 69 or 71, which has an X-ray powder diffraction pattern including one or more peaks at about 8.1° 2θ, about 9.8° 2θ, about 13.8° 2θ, about 16.7° 2θ and about 19.5° 2θ.

[0661] Clause 73. A salt according to formula (VI):

[0662]

[0663] wherein Y 1 is a protecting group, An- is an anion; and n is an integer from 1 to 3.

[0664] Clause 74. The salt as described in Clause 73, wherein the compound is the mesylate salt having the following structure (Compound 1D):

[0665]

[0666] Clause 75. The crystalline mesylate salt of Compound 1D as described in Clause 74.

[0667] Clause 76. The crystalline mesylate salt of Compound 1D as described in Clause 75, which has a powder diffraction pattern substantially the same as any one of the four X-ray powder patterns shown in Figure 68 .

[0668] Clause 77. The crystalline mesylate salt of Compound 1D as described in Clause 75, which has an X-ray powder diffraction pattern including one or more peaks at about 5.2° 2θ and about 9.1° 2θ.

[0669] Clause 78. The crystalline mesylate salt of Compound 1D as described in Clauses 75 to 77, which has an X-ray powder diffraction pattern including one or more peaks at about 9.1° 2θ, about 15.9° 2θ, about 16.5° 2θ, about 17.2° 2θ, about 18.6° 2θ and about 19.2° 2θ.

[0670] In certain preferred embodiments of the present invention, obicetrapib included in the pharmaceutical compositions of the present invention, used in the methods of the present invention, included in unit dosage forms (including in pharmaceutical kits), etc. is in the form of a salt of obicetrapib, more particularly a salt prepared by using one or more of the methods described in the following non-limiting clauses:

[0671] Clause 79. A method for preparing obicetrapib, wherein the method comprises:

[0672] (a) preparing a compound of formula (IV) by coupling a compound of formula (II) or a salt thereof with a compound of formula (III):

[0673]

[0674] wherein X 1 is a leaving group, and Y 1 is a protecting group;

[0675] (b) preparing a carbamate of formula (V) from the compound of formula (IV) and separating it in the form of a solid salt of formula (VI):

[0676]

[0677] wherein Y 1 is a protecting group, An- is an anion, and n is an integer from 1 to 3;

[0678] (c) optionally desalting the compound of formula (VI) and alkylating it with a compound of formula (VII) to provide a compound of formula (VIII):

[0679]

[0680] wherein, X 2is a leaving group, and Y 1 is a protecting group; and

[0681] (d) converting the compound of formula (VIII) into obicetrapib, wherein reaction steps (a) to (d) are carried out in an organic solvent, and the compounds (IV), (V) and (VIII) are optionally not isolated from the organic solvent, and wherein the process does not require chromatography.

[0682] Clause 80. The method according to clause 79, wherein the compound of formula (II) in step (a) is obtained by applying the following steps before step (a):

[0683] (pre-a1) providing a compound of formula (IIA) or (IIB):

[0684]

[0685] (pre-a2) desalting the compound of formula (IIA) or (IIB) to obtain the compound of formula (II);

[0686] wherein the reaction in step (pre-a2) is carried out in an organic solvent, and the compound of formula (II) is optionally not isolated from the organic solvent, and the process does not require chromatography.

[0687] Clause 81. The method according to clause 80, wherein the salt of formula (IIA) or (IIB) is selected from salts having an anion Am-, and the anion Am- is selected from: sulfonate, sulfate, halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, caprate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, caproate, hydroxynaphthoate, hydroxyethylsulfonate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, caprylate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate and theophyllinate; wherein the sulfonate may be benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, ethanesulfonate, ethanedisulfonate or methanesulfonate; the sulfate may be methylsulfate; and the halogen may be chloride, iodide or bromide.

[0688] Clause 82. The method according to clause 81, wherein the salt having an anion A m- is selected from chloride, bromide, bitartrate, sulfate and sulfonate.

[0689] Clause 83. The method according to clause 82, wherein the salt having an anion A m- is selected from chloride, bromide, bitartrate and methanesulfonate.

[0690] Clause 84. A method as described in any one of Clauses 79 to 83, wherein Y in the compounds of formulas (III) to (VI) and (VIII) 1 is selected from alkyl, substituted alkyl, aryl, substituted aryl, allyl, substituted allyl, and silyl.

[0691] Clause 85. A method as described in Clause 84, wherein Y in the compounds of formulas (III) to (VI) and (VIII) 1 is selected from tert-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl, 2,6-disubstituted phenol, and silyl.

[0692] Clause 86. A method as described in Clause 85, wherein Y in the compounds of formulas (III) to (VI) and (VIII) 1 is tert-butyl.

[0693] Clause 87. A method as described in any one of Clauses 79 to 86, wherein the salt of formula (VI) is selected from salts having anion A n- wherein anion A n- is selected from: sulfonate, sulfate, halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, caprate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, caproate, hydroxynaphthoate, hydroxyethylsulfonate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, caprylate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and theophyllinate; wherein the sulfonate may be benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, ethanesulfonate, ethanedisulfonate, or methanesulfonate; the sulfate may be methyl sulfate; and the halogen may be chloride, iodide, or bromide.

[0694] Clause 88. A method as described in Clause 87, wherein the salt having anion A n- is selected from chloride, bromide, bitartrate, sulfate, and sulfonate.

[0695] Clause 89. A method as described in Clause 87, wherein the salt having anion A n- is selected from chloride, bromide, bitartrate, and methanesulfonate.

[0696] Clause 90. A method as described in Clause 87, wherein the salt form of formula (VI) is methanesulfonate, i.e., Compound 1D:

[0697]

[0698] Clause 91. The method as described in Clause 90, wherein the mesylate is crystalline.

[0699] Clause 92. The method as described in any one of Clauses 79 to 91, wherein X in the compound of formula (III) 1 is selected from halogen, carbamate, and substituted sulfonyloxy.

[0700] Clause 93. The method as described in Clause 92, wherein X in the compound of formula (III) 1 is halogen.

[0701] Clause 94. The method as described in Clause 93, wherein the halogen is chloride.

[0702] Clause 95. The method as described in any one of Clauses 79 to 94, wherein X in the compound of formula (VII) 2 is selected from halogen and substituted sulfonyloxy.

[0703] Clause 96. The method as described in Clause 95, wherein X in the compound of formula (III) 2 is halogen.

[0704] Clause 97. The method as described in Clause 96, wherein the halogen is bromide.

[0705] Clause 98. A method for preparing the amorphous hemicalcium salt of obeticholic acid, wherein the method comprises:

[0706] (i) treating obeticholic acid with HCl to obtain the crystalline obeticholic acid HCl compound;

[0707] (ii) separating the crystalline obeticholic acid HCl compound;

[0708] (iii) preparing the amorphous hemicalcium salt of obeticholic acid from the crystalline obeticholic acid HCl compound separated in step (ii); and

[0709] (iv) separating the amorphous hemicalcium salt of obeticholic acid.

[0710] Clause 99. The method as described in Clause 98, wherein the crystalline obeticholic acid HCl compound separated in step (ii) comprises the compound of formula (IH):

[0711]

[0712] wherein y varies from 0.002 to 1.5.

[0713] Clause 100. The method as described in Clause 98 or 99, wherein the preparation of the amorphous semi-calcium salt of formula (I) in step (iii) comprises the following steps:

[0714] (iii-1) Converting the crystalline obeticholic acid HCl compound of step (ii) to provide obeticholic acid in one or more suitable solvents selected from organic solvents and aqueous solvents;

[0715] (iii-2) Treating obeticholic acid in an organic solvent with an aqueous sodium hydroxide solution to form the sodium salt of obeticholic acid; and

[0716] (iii-3) Treating the sodium salt of obeticholic acid with an aqueous calcium chloride solution to form the amorphous semi-calcium salt of obeticholic acid;

[0717] wherein the compounds in steps (iii-1) and (iii-2) are optionally not separated.

[0718] Clause 101. The method as described in any one of Clauses 98 to 100, wherein the amorphous semi-calcium salt of obeticholic acid is amorphous obeticholic acid semi-calcium.

[0719] Clause 102. The method as described in any one of Clauses 98 to 101, wherein the amorphous calcium salt of obeticholic acid is separated with a chemical purity of at least 99%.

[0720] Clause 103. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is separated with a purity of at least 99.1%.

[0721] Clause 104. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is separated with a purity of at least 99.2%.

[0722] Clause 105. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is separated with a purity of at least 99.3%.

[0723] Clause 106. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is separated with a purity of at least 99.4%.

[0724] Clause 107. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is separated with a purity of at least 99.5%.

[0725] Clause 108. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is separated with a purity of at least 99.6%.

[0726] Clause 109. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is separated with a purity of at least 99.7%.

[0727] Clause 110. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is isolated with a purity of at least 99.8%.

[0728] Clause 111. The method as described in Clause 102, wherein the amorphous calcium salt of obeticholic acid is isolated with a purity of at least 99.9%.

[0729] Clause 112. The method as described in any one of Clauses 102 to 111, wherein the amorphous calcium salt of obeticholic acid is amorphous obeticholic acid hemicalcium.

[0730] Clause 113. A pharmaceutical composition comprising the amorphous salt of calcium obeticholate as described in any one of Clauses 1 to 57, and one or more pharmaceutically acceptable carriers.

[0731] Clause 114. The pharmaceutical composition as described in Clause 113, wherein the amorphous salt of calcium obeticholate is amorphous obeticholic acid hemicalcium.

[0732] Clause 115. A method for treating a subject suffering from cardiovascular disease or at increased risk of developing cardiovascular disease, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition as described in Clause 113 or 114.

[0733] Clause 116. An amorphous calcium salt of obeticholic acid, prepared according to the process as described in any one of Clauses 79 to 112.

[0734] Clause 117. The amorphous calcium salt as described in Clause 116, which is amorphous obeticholic acid hemicalcium.

[0735] Clause 118. A method for preparing an amorphous calcium salt of obeticholic acid, comprising treating obeticholic acid with an acid to form a salt, solvate, composition or combination thereof of obeticholic acid; isolating the salt, solvate, composition or combination thereof; and treating the salt, solvate, composition or combination thereof with a calcium source to form an amorphous obeticholic acid hemicalcium salt.

[0736] Clause 119. The method as described in Clause 118, wherein the calcium source is calcium chloride.

[0737] Clause 120. A salt, solvate, composition or combination thereof, comprising obeticholic acid and a free acid.

[0738] Clause 121. The salt as described in Clause 120.

[0739] Clause 122. The solvate as described in Clause 120.

[0740] Clause 123. The composition as described in Clause 120.

[0741] Clause 124. The salt, solvate, composition or combination thereof as described in Clause 120, wherein the free acid is selected from sulfonic acid, sulfuric acid, haloacid, acetic acid, aspartic acid, benzoic acid, bicarbonic acid, acid tartrate, carbonic acid, citric acid, capric acid, fumaric acid, gluceptic acid, gluconic acid, glutamic acid, glycolic acid, caproic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, mucic acid, nitric acid, caprylic acid, oleic acid, pamoic acid, pantothenic acid, phosphic acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, tartric acid and teoclic acid; wherein the sulfonic acid may be benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, ethanedisulfonic acid or methanesulfonic acid; the sulfuric acid is methylsulfuric acid; and the haloacid may be HCl, HBr or HI.

[0742] Clause 125. The method as described in Clause 118, wherein the calcium source is a calcium halide salt.

[0743] Clause 126. The method as described in Clause 118, wherein the calcium source is a soluble calcium salt.

[0744] Clause 127. The method as described in Clause 118, wherein the calcium source is a calcium salt.

[0745] This disclosure may further be the method described by one or more of the foregoing non - restrictive clauses.

[0746] Examples

[0747] Analytical and physical characterization methods:

[0748] The methods used throughout the study are summarized in Table A. The specific parameters and conditions for the analytical and physical assessments for each non - restrictive example are set forth in the relevant section of this example.

[0749] Table A

[0750]

[0751] XRPD

[0752] XRPD analysis was performed in transmission mode on an X'pertPro / Empyrean X-ray diffractometer (PANalytical) equipped with an X’Celerator detector using the standard XRPD Aptuit method. The data was evaluated using Highscore Plus software. The instrument parameters used are listed in Table B below.

[0753] Table B

[0754]

[0755]

[0756] Particle Size Distribution (PSD)

[0757] PSD analysis was performed on a new Sympatec Helos laser diffraction instrument equipped with a RODOS / M for dispersion and an ASPIROS or VIBRI for sample delivery. Powder dispersion was achieved by using compressed air and a spray gun utilizing the Venturi effect. The details of the PSD method are listed in Table C.

[0758] Table C

[0759]

[0760]

[0761] Differential Dissolution Method (Obeticholic Acid) at pH 6.8 Table D

[0762]

[0763] Differential Dissolution Method (Ezetimibe) at pH 4.5 Table E

[0764]

[0765]

[0766] QC Dissolution Method (Obeticholic Acid) at pH 6.8 Table F

[0767] Instrument parameters Value Equipment USP Apparatus II Dissolution medium Phosphate buffer solution at pH 6.8 + 0.2% w / v polysorbate 80 Volume of dissolution medium [mL] 1000 Temperature of dissolution medium [°C] 37±0.5 Rotation speed [rpm] 75 – infinity 250 rpm Sampling time [minutes] 15; 30; 45; 60 and 70 (70' is infinity at 250 rpm) Sampling volume [mL] 1 Separation technique (*) PVDF 0.45 μm membrane Pre - wet volume of filter [mL] 9 (sample 10 mL and return the first 9 mL to the container) Detection HPLC - UV

[0768] QC Dissolution Method (Ezetimibe) at pH 4.5 Table G

[0769] Instrument parameters Value Equipment USP Apparatus II Dissolution medium Acetate buffer solution at pH 4.5 + 0.45% w / v SLS Volume of dissolution medium [mL] 500 Temperature of dissolution medium [°C] 37±0.5 Rotation speed [rpm] 75 – infinity 250 rpm Sampling time [minutes] 15; 30; 45; 60 and 70 (70' being the infinite point). Sampling volume [mL] 1 Separation technique (*) ww / PTFE 0.45 Filter pre-wetting volume [mL] 9 (Sampling 10 mL and returning the first 9 mL to the container) Detection HPLC-UV

[0770] Assay and Impurities / Related Substances (Obeticholic Acid) Table H

[0771]

[0772]

[0773] Assay and Impurities / Related Substances (Ezetimibe) Table I

[0774]

[0775]

[0776] Example 1

[0777] Fixed-dose combination tablets of 10 mg ezetimibe and 5 mg obeticholic acid (small-scale batch of approximately 500 g)

[0778] High-shear granulation and fluidized-bed drying

[0779] Four prototype formulations were evaluated. The excipients contained in the granules were a plastic filler (Avicel PH101), a brittle filler (Pharmatose 200M), a binder (Colidon 30), a disintegrant (glycolys), and a surfactant (Kolliphor SLS fine). In the initial four trials (granule batches A4459 / 05 / 01, A4459 / 05 / 02, A4459 / 05 / 03, and A4459 / 05 / 04), the amounts of plastic and brittle fillers were evaluated at high or low levels, and two high-shear granulation processing conditions were tested. In the last two trials (granule batches A4459 / 07 / 01 and A4459 / 08 / 01), the formulations were prepared at a high lactose level and a lower impeller speed (according to processing condition 2). The composition and addition method of the excipients were modified as detailed in Table 1.

[0780] The materials were dispensed to the target weight, and ezetimibe, obeticholic acid, and the excipients within the granules were manually sieved and transferred to the granulation bowl. The granulation solution was prepared by dissolving the required excipients in water.

[0781] Small-scale granules were dried using a STREA fluidized-bed granulator, and the material was fluidized in the bowl by adjusting the air volume as needed until the LOD of the dried granules was equal to or lower than the initial LOD. The inlet temperature, product temperature, exhaust temperature, and air flow volume were recorded throughout the drying period. After drying, the granules were tested for particle homogeneity of API, LOD, sieve analysis, TBD, and XRPD.

[0782] Preparation and tabletting of the final blend

[0783] The final blend was prepared by accurately weighing the required amounts of the particulate excipients. Then, the excipients (except magnesium stearate (MgSt)) were manually sieved, added together with the granules to a bin of suitable volume, and blended using a Pharmatech mixer. MgSt was sieved separately and added to the bin. For tabletting, a single punch compression machine (specifically, an EK0 tabletting machine) was used to generate the compression curve and manufacture tablets with a target weight of 150.0 mg. Based on the information collected for the compression curve, small-scale tablet manufacturing was carried out. These tablets were tested for appearance, assay and impurity content, differential solubility, ezetimibe USP tablet dissolution method, content uniformity, and water content by KF and XRPD. All the produced intermediates and uncoated tablets were stored in double-layer low density polyethylene (LDPE) bags sealed with cable ties and transferred to aluminum bags sealed with silica gel.

[0784] Table 1: Composition (% w / w) of granules and tablets for small-scale 10 mg ezetimibe and 5 mg obicetrapib trials

[0785]

[0786]

[0787] Results:

[0788] Small-scale trials for the development of 10 mg ezetimibe, 5 mg obicetrapib tablets

[0789] Small-scale batches of granule production were successfully carried out. During granulation, the energy consumption increased after the addition of the granulation solution, and after drying, the LOD of the granules was lower than the initial LOD (Table 2). Compared with granule batches A4459 / 05 / 03 and A4459 / 05 / 04, granules A4459 / 05 / 01 and A4459 / 05 / 02 presented coarser particles. This was related to the higher lactose level in the formulation rather than the granulation parameters (process condition 1 vs. process condition 2). As the amounts of binder and water used for granulation decreased and the level of surfactant increased, granule batches A4459 / 07 / 01 and A4459 / 08 / 01 (manufactured with a higher level of lactose) presented particles containing a larger proportion of fines ( Figure 1 and Figure 2)。In short, tablets with a higher microcrystalline cellulose content (batches A4459 / 05 / 07 and A4459 / 05 / 08) had faster disintegration times, lower friability, and higher hardness values compared to tablets with a higher lactose content (batches A4459 / 05 / 05 and A4459 / 05 / 06). Overall, these tablet batches presented a suitable appearance. Tablet batches A4459 / 07 / 02 and A4459 / 08 / 02 (containing a high level of lactose) showed faster disintegration times and a suitable dissolution profile for both drug substances. However, due to capping and failed friability tests, the hardness and friability of the tablets could not be improved to an acceptable level. The tablet hardness was lower compared to that obtained with previous trials (batches A4459 / 05 / 05 and A4459 / 05 / 06).

[0790] Table 2: LOD for the small-scale trial of 10 mg ezetimibe and 5 mg obicetrapib

[0791]

[0792] Particle characterization

[0793] Chemical characterization analysis

[0794] Homogeneity tests were performed on the particles of both obicetrapib and ezetimibe, and the results are shown in Table 3. Both APIs were homogeneously dispersed in the particles, and batch A4459 / 05 / 03 obtained the maximum RSD% value, but the maximum RSD% value was still within the typical acceptable range for particle homogeneity.

[0795] Table 3: Particle uniformity of 500 g batch-scale prototypes

[0796]

[0797]

[0798] Physical property characterization

[0799] As shown in Table 4, small amounts of ezetimibe (EZE) hydrate were found in all wet granule samples. However, during the drying process, the formed EZE hydrate converted back to anhydrous EZE, except for batch 05 / 01 where a small amount of the hydrate polymorphic form still seemed to be present.

[0800] Table 4. Summary of XRPD data for small-scale 10 mg ezetimibe and 5 mg obicetrapib blends, as well as wet and dry granules

[0801]

[0802] Tablet characterization

[0803] Chemical Characterization Analysis

[0804] The characterization results of the pilot batches are presented in Table 5. The results of assays and impurities were as expected and the impurity profiles were consistent with both input APIs. All prototypes were also found to have homogeneous API content as the AV values ​​of the content uniformity results were significantly lower than the AV requirements of the pharmacopoeia. The water content results were found to be in the range of 4.5% to 5.0% and no defects were observed in appearance.

[0805] The dissolution profiles of orbicetrapib showed similar dissolution trends for prototypes A4459 / 05 / 08, A4459 / 05 / 06, and A4459 / 05 / 07, with prototype A4459 / 05 / 08 (high Avicel content and low impeller speed) dissolving rapidly in the range of 5 to 15 minutes. Prototype A4459 / 05 / 05 (high lactose and high impeller speed) dissolved significantly more slowly. The dissolution results of the USP ezetimibe method at pH 4.5 were consistent with those observed at pH 6.8. Significant improvements in solubility characterization were observed for prototype 3 batch A4459 / 07 / 02 (4% binder) and prototype 4 batch A4459 / 08 / 02 (1% binder), indicating that the distribution profile of prototype 4 is consistent with the reference commercial ezetimibe tablets. The dissolution profiles are presented in Figure 3 , Figure 4 and Figure 5 The assay, content uniformity, and impurity profiles of both orbicetrapib and ezetimibe showed no significant differences among the four formulations.

[0806] Table 5: Small-scale characterization results of 10 mg ezetimibe and 5 mg orbitrapi

[0807]

[0808]

[0809]

[0810] Stress stability

[0811] Prototype 1 and Prototype 2 with different process conditions were evaluated in a stress stability study with the following design

[0812] Table 6: Stress stability study design

[0813]

[0814] key:

[0815] T = Appearance, assay, and related substances, differential solubility were tested, water content was tested by KF, and form was examined by XRPD

[0816] (T) = Optional tests

[0817] The results are recorded in Tables 7, 8, and 9.

[0818] Table 7: Results of Appearance, Assay, and Water Content for 10 mg Ezetimibe and 5 mg Obeticholic Acid on a Small Scale

[0819]

[0820]

[0821] Table 8: Impurity Profile for 10 mg Ezetimibe and 5 mg Obeticholic Acid on a Small Scale

[0822]

[0823]

[0824] Table 9: Solubility Characterization Results for Stress Stability of 10 mg Ezetimibe and 5 mg Obeticholic Acid on a Small Scale

[0825]

[0826]

[0827]

[0828]

[0829] Table 9 (continued): Solubility Characterization Results for Stress Stability of 10 mg Ezetimibe and 5 mg Obeticholic Acid on a Small Scale

[0830]

[0831]

[0832]

[0833] Physical Property Characterization

[0834] Except for prototype tablet A4459 / 05 / 05 (where a small amount of EZE hydrate was observed in the sample at the initial time point and all placed stable samples), for other tablet prototypes, a small amount of EZE hydrate form appeared at the 3-week (3WK) and 4-week (4WK) time points. The XRPD data are summarized in Table 10.

[0835] Table 10: Summary of XRPD data for stress stability of 10 mg ezetimibe and 5 mg obeticholic acid tablets on a small scale

[0836]

[0837]

[0838] Example 2

[0839] Fixed-dose combination of 10 mg ezetimibe and 10 mg obeticholic acid tablets (small-scale batch of approximately 500 g)

[0840] Details of the prototype formulations manufactured in this set of experiments are summarized in Tables 11 and 12. The key modification to the formulation composition was to increase the dose strength of obeticholic acid (free acid) from 5.0 mg to 10.0 mg.

[0841] High-shear granulation and fluidized bed drying

[0842] These trials were carried out on a small scale batch (batch size of 500 g) according to Process Condition 2. However, Batch A4459 / 16 / 02 (referred to as "Prototype C scale-up") was carried out on a batch size of 2 Kg.

[0843] The powder was manually sieved, loaded into the granulation bowl and mixed for 5 minutes. The granulation solution was sprayed at the required spray rate and wet agglomeration was carried out before drying the material in a fluidized bed dryer. The inlet air temperature and air volume were adjusted as required to fluidize the dried granules until their LOD was equal to or lower than the initial LOD. The granules were characterized for content uniformity of API, LOD (soon after milling), sieve analysis, TBD and XRPD. Granule batches A4459 / 13 / 01 (Prototype A) and A4459 / 16 / 02 (Prototype C scale-up) were divided into two equal samples to produce the final blends required to make 150 mg tablets and 200 mg tablets.

[0844] Preparation of final blend, tableting and coating

[0845] The final blend was prepared by accurately weighing the granule excipients to produce tablets with the required composition. The excipients were manually sieved and mixed using a hopper of appropriate volume. The lubricant (MgSt) was sieved separately and added to the bowl for mixing. A single punch press was used to generate the compression curve and produce small-scale batches of tablets. The friability, disintegration time, hardness, appearance and thickness of the tablets were monitored throughout the processing. The differential solubility of the tablets, ezetimibe USP tablet dissolution method and XRPD were tested.

[0846] Three selected tablet batches (Prototype B, Prototype C scale-up, and Prototype C scale-up 200) were coated with 20% w / w Opadry AMB II white aqueous suspension. Coating process parameters and tablet weight gain were monitored throughout the processing. XRPD of the coated tablets, differential solubility of obeticholic acid, and ezetimibe USP tablet dissolution method were tested at a paddle speed of 75 rpm.

[0847] All produced intermediates and final drug products were stored in double-layer LDPE bags sealed with cable ties and transferred to heat-sealed aluminum bags containing silica gel.

[0848] Table 11: Composition (% w / w) of granules and tablets of 10 mg ezetimibe and 10 mg obeticholic acid on a small scale

[0849]

[0850] * Water does not appear in the tablets; Inner = materials added as dry powder, Outer = materials dissolved in water for granulation; ** Added in a lower amount due to equipment problems

[0851] Table 12 Composition (% w / w) of granules and tablets of 10 mg ezetimibe and 10 mg obeticholic acid

[0852]

[0853] * Water does not appear in the tablets; Inner = materials added as dry powder, Outer = materials dissolved in water for granulation Results:

[0854] These granulation tests were successfully carried out. Overall, the PSD of the granules was similar to that of batch A4459 / 08 / 01 (Prototype 4) and showed a relatively large amount of fines ( Figure 18 ). Compared with batch A4459 / 08 / 02 (Prototype 4, condition 2), the tablet batches had comparable disintegration times, higher hardness, and lower friability values at similar compression forces. The tablets did not exhibit any serious defects (e.g., capping, lamination). Upon careful inspection, the coated tablets presented a smooth white surface without any visual external defects.

[0855] Granule characterization

[0856] Chemical characterization analysis

[0857] Homogeneity tests were performed on the granules of both obeticholic acid and ezetimibe, and the results are shown in Table 13. Analyses were performed with n = 6, except for the scale-up batches which were performed with n = 10.

[0858] Physical property characterization

[0859] The XRPD data of the developed prototypes are summarized in Table 14. The EZE hydrate could be observed in the samples before or during the granulation process. However, the amount of the detected EZE hydrate always seemed to be extremely limited.

[0860] Tablet Characterization

[0861] Chemical Characterization Analysis

[0862] The characterization results of the small-scale batches are shown in Table 15. Dissolution tests were performed on the prototypes. The dissolution results of obeticholic acid showed that all the tested prototypes had similar dissolution profiles, with minor differences regarded as analytical variability. For ezetimibe, Prototypes D and C obtained the most promising results, with Prototype C achieving promising results meeting USP specification Q = 80 + 5 within 30 minutes in three vessels. This most promising prototype was also characterized using the USP dissolution method conditions for ezetimibe at a higher paddle speed of 75 rpm. This is because the USP method developed for lighter tablets seems to over-discriminate tablets with a target weight up to 200 mg compared to the developed fixed-dose combinations. The results showed a dissolution profile consistent with that of the current commercial formulation.

[0863] Physical Property Characterization

[0864] Except for Prototypes C and the 200 mg scaled-up batch of C shown in Table 16, all the produced small-scale prototype tablets contained a small amount of EZE hydrate.

[0865] Table 13: Granule Uniformity of the Developed Prototypes of 10 mg Ezetimibe and 10 mg (Free Acid) Obeticholic Acid

[0866]

[0867]

[0868] Table 14: Summary of XRPD Data of the Developed Prototypes of 10 mg Ezetimibe and 10 mg (Free Acid) Obeticholic Acid

[0869]

[0870]

[0871] Table 15: Dissolution Characterization Results of Small-Scale 10 mg Ezetimibe and 10 mg Obeticholic Acid (Free Acid)

[0872]

[0873]

[0874]

[0875]

[0876] Table 16: Summary of XRPD Data for Small-Scale Tablet Prototype Batches

[0877] Sample Batch ID XRPD Tablet prototype A A4459 / 14 / 01 OBI + anhydrous EZE + a small amount of EZE hydrate Tablet prototype A 200 mg A4459 / 14 / 04 OBI + anhydrous EZE + a small amount of EZE hydrate Tablet prototype B A4459 / 14 / 02 OBI + anhydrous EZE + a small amount of EZE hydrate Tablet prototype C A4459 / 14 / 03 OBI + anhydrous EZE Tablet prototype C scale-up A4459 / 16 / 03 OBI + anhydrous EZE Tablet prototype C scale-up 200 mg A4459 / 18 / 03 OBI + anhydrous EZE + a small amount of EZE hydrate Tablet prototype C 2% SLS A4459 / 18 / 01 OBI + anhydrous EZE + a small amount of EZE hydrate Tablet prototype D A4459 / 18 / 02 OBI + anhydrous EZE + a small amount of EZE hydrate

[0878] Stress Stability

[0879] Based on the process tablet compression parameters and solubility data, the following tablet prototypes were selected to evaluate the feasibility of the coating process:

[0880] A4459 / 16 / 03 (150 mg / tablet, prototype C scale-up)

[0881] A4459 / 18 / 03 (200 mg / tablet prototype C scale-up / 200 mg),

[0882] And subsequent stress stability studies were then conducted using the following design for stability settings. The results are shown in Tables 17 and 18.

[0883] Table 17: Stress Stability Study Design

[0884]

[0885]

[0886] Key:

[0887] T = Appearance, assay, and related substances, content uniformity (only at the initial stage), differential solubility were tested, water content was tested by KF, and form checks were performed by XRPD

[0888] (T) = Optional test

[0889] Table 18: Results of Assay, Water Content, and Visual Appearance of Small-Scale 10 mg Ezetimibe and 10 mg Obeticholic Acid (Free Acid) Prototype C 200 and Prototype C Scale-Up Stress Stability

[0890]

[0891]

[0892] Table 19: Results of Impurity Profiles of Small-Scale 10 mg Ezetimibe and 10 mg Obeticholic Acid (Free Acid) Prototype C 200 and Prototype C Scale-Up Stress Stability

[0893]

[0894] N.D. = Not detected

[0895] Table 20: Solubility Characterization Results of Small-Scale 10 mg Ezetimibe and 10 mg Obicetrapib (Free Acid) Prototype C 200 and Prototype C Scale-Up Stress Stability

[0896]

[0897]

[0898] Physical Property Characterization

[0899] The XRPD data of the samples with stress stability during storage are summarized in Table 21. When exposed to the condition of 40 °C / 75% RH for 2 weeks, both of these two prototype tablets presented ezetimibe hydrate. However, once packaged, no polymorphic transformation occurred until stored for 4 weeks.

[0900] Table 21 Summary of XRPD Data of Prototype C 200 and Scale-Up with Stress Stability during Storage

[0901]

[0902] Example 3

[0903] Fixed-dose combination of 10 mg ezetimibe and 10 mg obicetrapib obtained by co-granulation of drug substance / active ingredient (FDC1) (small-scale batch of approximately 500 g)

[0904] High-shear granulation, drying, preparation of the final blend, and tableting

[0905] Three compositions (Composition 1 Batch A4459 / 20 / 02, Composition 2 Batch A4459 / 20 / 03, and Composition 3 Batch A4459 / 20 / 04) were prepared as summarized in Table 22. The prototype formulation composition selected for these compositions was the prototype formulation composition of "Prototype C" (e.g., granule batch A4459 / 13 / 03). The preparation and characterization (LOD and XRPD) of the granules were described in the previous section (small-scale manufacturing). The content uniformity, LOD, sieve analysis, TBD, and XRPD of the granules were tested. As described in the previous example, the blend for tableting and compression curve and small-batch tablets with a tablet weight of 150 mg were manufactured. The content uniformity, XRPD, solubility of the tablets were tested and the water content was tested by KF. All the produced intermediates and final drug products were stored as described in the previous sections.

[0906] Table 22: Composition (% w / w) of Granules and Tablets of FDC1 Compositions

[0907]

[0908] *Water is not present in the final product. All excipients used for granulation are added in dry powder form

[0909] Results

[0910] High-shear granulation was successfully carried out. The drying step was carried out without any problems, and after 15 minutes of drying, the LOD of the granules was lower than the initial LOD. Generally, despite increasing the impeller speed (Composition 1)( Figure 26 ), the wet coalescence time (Composition 2), or the amount of granulating agent (Composition 3), the granules still presented a relatively large amount of fines. The tablet friability, disintegration time, thickness, and hardness of these tablet batches were found to be similar.

[0911] Granule chemical characterization

[0912] The granules were tested for homogeneity, and it was found that obeticholic acid and ezetimibe were homogeneously dispersed.

[0913] Physical property characterization

[0914] The XRPD data of the blend / granule prototype FDC1 method are summarized in Table 23. Eze hydrate was only present in the wet granule samples. All three prototypes showed similar flowability.

[0915] Tablet chemical characterization

[0916] The results of the chemical characterization of the FDC1 tablets are shown in Table 24. The results of the analytical characterization did not show any significant differences between the three compositions.

[0917] Physical property characterization

[0918] The XRPD data of the tablets from the FDC1 composition are summarized in Table 25. Eze hydrate was not present in any of the samples.

[0919] Table 23: Summary of XRPD data of granules from FDC1 composition

[0920]

[0921] Table 24: Results of chemical characterization of FDC1 composition

[0922]

[0923]

[0924] Table 25: Summary of XRPD data of granules from FDC1 composition

[0925]

[0926]

[0927] Example 4

[0928] A fixed-dose combination (FDC2) of 10 mg ezetimibe and 10 mg obicetrapib obtained by forming ezetimibe into granules and adding obicetrapib outside the granules

[0929] High-shear granulation and drying

[0930] Three compositions were prepared as summarized in Table 26. The excipients contained in the granules were the same as those used in the granule manufacture for the FDC1 method. The formulation composition of these granules reflected the formulation composition of the FDC1 granule "Prototype C". The methods of high-shear granulation, granule drying, and milling have been described in the previous section. The content uniformity (ezetimibe only), sieve analysis, TBD, and XRPD of the granules were tested.

[0931] Preparation of the final blend, tableting, and coating

[0932] The components of the formulation outside the granules are listed below:

[0933] - Obicetrapib

[0934] - Plastic filler (Avicel PH 200)

[0935] - Brittle filler (Pearlitol 200SD)

[0936] - Disintegrant (Glycolys)

[0937] - Galant (Glydant) (Aerosil 200)

[0938] - Lubricant (Ligamed MF-2-V)

[0939] The final blend was prepared by accurately weighing the components outside the granules (excipients and API) and screening them. The excipients and granules were loaded into a hopper of appropriate volume and blended using a Pharmatech mixer. Then, the lubricant (MgSt) was added to the hopper and mixed.

[0940] To generate the compression curve and manufacture small batches of tablets, a single-station press (EK0) equipped with a 9.0 mm round punch (R = 11) was used. The target tablet weight was 230 mg, and throughout the process, tablet friability, disintegration time, hardness, appearance and thickness, as well as the individual tablet weight and the tablet weight of ten tablets were monitored.

[0941] The content uniformity of the tablets (stratified samples: beginning, middle, and end of production), XRPD, solubility, and water content were tested by KF.

[0942] The tablets were coated with a 20% w / w Opadry AMB II white aqueous suspension to the desired target weight gain (target weight gain 3% w / w, limit 2% w / w to 4% w / w). The coating suspension and coating method were described in the previous section. Coating parameters and the weight gain of the tablets were monitored throughout the processing. The XRPD, solubility, appearance, content uniformity of the coated tablets were tested, and the water content was tested by KF.

[0943] All produced intermediates and final drug products were stored in double-layer LDPE bags with silica and transferred to heat-sealed aluminum bags.

[0944] Table 26: Composition (% w / w) of granules, tablets, and coated tablets of the FDC2 composition

[0945]

[0946]

[0947] *Water does not appear in the final product. All excipients used for granulation were added in dry powder form

[0948] Results

[0949] High-shear granulation of the FDC2 composition was successfully carried out. The drying step was carried out without any problems, and after drying for about 16 minutes, the LOD of the granules was lower than the initial LOD. The granules showed a relatively large amount of fines ( Figure 29 ). The values of disintegration time and thickness were similar between batches of FDC2 tablets.

[0950] Granule chemical characterization

[0951] The homogeneity of both obicetrapib and ezetimibe in the A4459 / 20 / 01 blend was tested and found to be homogeneously dispersed. Results for the other two granules were not collected.

[0952] Tablet chemical characterization

[0953] The results of the chemical characterization of prototype 1 of the FDC2 tablets are shown in Tables 27 and 28. The results of the analytical characterization did not show any significant differences between the three prototypes of FDC2.

[0954] Physical property characterization

[0955] The XRPD data of the blends / granules from the FDC2 composition are summarized in Table 29. The XRPD data of the tablets from the FDC2 method are summarized in Table 30. A small amount of Eze hydrate is present in Prototype 1.

[0956] Table 27: Results of the analytical characterization of uncoated FDC2

[0957]

[0958]

[0959]

[0960] Table 28: Results of the analytical characterization of coated FDC2

[0961]

[0962]

[0963]

[0964] Table 29: Summary of XRPD data of granules from FDC2 composition

[0965] Sample Batch ID XRPD Prototype 1 final dry granules A4459 / 20 / 01 OBI + anhydrous EZE + a small amount of EZE hydrate Prototype 2 final dry granules A4459 / 25 / 01 OBI + anhydrous EZE Prototype 3 final dry granules A4459 / 25 / 02 OBI + anhydrous EZE

[0966] Table 30: Summary of XRPD data of tablets from FDC2 composition

[0967]

[0968] Stress stability

[0969] Prototype 2 coated tablets were selected for stress stability studies using the following design

[0970] Table 31: Stress stability study design

[0971]

[0972] Key:

[0973] T = Appearance, assay, related substances, differential solubility were tested, water content was tested by KF, and form was examined by XRPD

[0974] (T) = Optional test

[0975] The results are recorded in Tables 66, 67, and 68.

[0976] Table 32: Results of assay, water content, and visual appearance of Prototype 2 FDC2 stress stability

[0977]

[0978] Table 33: Results of impurity profile for stress stability of Prototype 2 FDC2

[0979]

[0980]

[0981] N.D. = Not detected

[0982] Table 34: Results of dissolution characterization for stress stability of Prototype 2 FDC2

[0983]

[0984] Example 5

[0985] A fixed-dose combination (FDC3) of 10 mg ezetimibe and 10 mg obeticholic acid obtained by granulating obeticholic acid and adding ezetimibe outside the granules

[0986] Prototype compositions were prepared as summarized in Table 35. The granulation method was according to Process Condition 2 as described above. The methods of high-shear granulation, particle drying, and milling have been described in the previous section. The content uniformity (of obeticholic acid only), sieve analysis, TBD, and XRPD of the granules were tested.

[0987] Preparation of the final blend, tableting, and coating

[0988] The final blend was prepared by accurately weighing the extra-granular components (excipients and API) and sieving them. The excipients and granules were loaded into a hopper of appropriate volume and blended using a Pharmatech mixer. Then, the lubricant (MgSt) was added to the hopper and mixed.

[0989] To generate the compression curve and produce a small batch of tablets, a single-punch press was used. The target tablet weight was 230 mg, and throughout the process, tablet friability, disintegration time, hardness, appearance, and thickness, as well as the individual tablet weight and the tablet weight of ten tablets, were monitored. The content uniformity (stratified samples: beginning, middle, and end of production), XRPD, solubility, and water content were tested by the KF method for the tablets.

[0990] Tablets were coated with a 20% w / w Opadry AMB II white aqueous suspension to achieve the desired target weight gain. The coating suspension and coating method have been described in the previous section. Coating parameters and the weight gain of the tablets were monitored throughout the processing. The XRPD, solubility, appearance, content uniformity of the coated tablets were tested, and the water content was tested by the KF method.

[0991] All the intermediates and final drug products produced are stored in double-layer LDPE bags with silica and transferred to heat-sealed aluminum bags.

[0992] Table 35: Composition (% w / w) of granules, tablets and coated tablets of FDC3 composition

[0993]

[0994]

[0995] **Or lactose***Optional example 6

[0996] A fixed-dose combination (FDC4) of 10 mg ezetimibe and 10 mg obeticholic acid as a bilayer tablet obtained by granulating ezetimibe and obeticholic acid separately and then compressing

[0997] Prototype compositions were prepared as summarized in Table 36. The granulation method for ezetimibe was the same as that described above for FDC1, and the granulation method for obeticholic acid was the same as that described above for FDC3. The methods of high-shear granulation, particle drying and milling were the same as those described for FDC1 in the previous section. The granules were then fed into the compressor via two hoppers. The die was filled with the first type of granules and then slightly compressed. Then the second type of granules was filled, and subsequent compression was carried out according to the method explained in the previous examples. The content uniformity (ezetimibe or obeticholic acid), sieve analysis, TBD and XRPD of the individual granules were tested. The granules were compressed according to the above method to form tablets. The content uniformity (stratified samples: beginning, middle and end of production), XRPD, solubility of the tablets were tested, and the water content was tested by KF.

[0998] The tablets were coated with a 20% w / w Opadry AMB II...

Claims

1. A fixed-dose pharmaceutical composition, said pharmaceutical composition comprising the following or consisting of the following Components: a. Obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, b. Ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and c. One or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, wherein when the pharmaceutical composition is orally administered to a subject, the 90% confidence interval of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax is within the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of obeticholic acid obtained when a reference pharmaceutical composition is orally administered to a similar subject, wherein the reference pharmaceutical composition comprises an equivalent dose of obeticholic acid or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or simultaneously or sequentially in combination with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or is administered in the form of a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

3. The pharmaceutical composition according to any one of the preceding claims, wherein upon oral administration of the pharmaceutical composition to a subject, the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or the geometric mean of Cmax of ezetimibe and / or ezetimibe glucuronide are respectively within the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of ezetimibe and / or ezetimibe glucuronide respectively obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference pharmaceutical composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or co-administered simultaneously or sequentially with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or is administered in the form of a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

4. The pharmaceutical composition according to any one of the preceding claims, said pharmaceutical composition being for use in the treatment of a subject in need of reducing LDL cholesterol and / or increasing HDL cholesterol, wherein the pharmaceutical composition is considered suitable for said use in the following circumstances: a. The fixed-dose pharmaceutical composition is orally administered to the subject; b. The concentration of obicetrapib in the plasma of the subject is measured at one or more time points after administration to provide a set of obicetrapib concentration / time data points so as to provide the area under the curve (AUC); and c. The area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or the 90% confidence interval of the geometric mean of Cmax is respectively within the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax obtained when orally administering a reference pharmaceutical composition to similar subjects, wherein the reference pharmaceutical composition comprises an equivalent dose of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or simultaneously or sequentially in combination with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or is administered in the form of a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

5. The pharmaceutical composition according to any one of the preceding claims, said pharmaceutical composition being for use in the treatment of a subject in need of reducing LDL cholesterol and / or increasing HDL cholesterol, wherein the pharmaceutical composition is considered suitable for said use in the following circumstances: a. The fixed-dose pharmaceutical composition is orally administered to the subject; b. The concentration of ezetimibe and / or ezetimibe glucuronide in the plasma of the subject is measured at one or more time points after administration to provide a set of ezetimibe and / or ezetimibe glucuronide concentration / time data points respectively, so as to provide the area under the curve (AUC) of ezetimibe and / or ezetimibe glucuronide respectively; and c. The area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or the 90% confidence interval of the geometric mean of Cmax are respectively within the range of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax of ezetimibe and / or ezetimibe glucuronide obtained when orally administering a reference pharmaceutical composition to similar subjects, wherein the reference pharmaceutical composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference pharmaceutical composition is administered alone, or simultaneously or sequentially in combination with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or is administered in the form of a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

6. The pharmaceutical composition according to any one of the preceding claims, wherein the use of said pharmaceutical composition is for reducing LDL cholesterol and / or increasing HDL cholesterol in a person suffering from heterozygous familial hypercholesterolemia (HeFH) and / or diagnosed with atherosclerotic cardiovascular disease (ASCVD).

7. The pharmaceutical composition according to any one of the preceding claims, wherein t of AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC 0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0-336) or AUC 0-∞, preferably 48 hours (AUC 0-48), and more preferably AUC 0-∞.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the subject is a human, preferably a healthy human, more preferably a human in need of reducing LDL cholesterol and / or increasing HDL cholesterol, a human suffering from heterozygous familial hypercholesterolemia (HeFH) and / or diagnosed with atherosclerotic cardiovascular disease (ASCVD).

9. The pharmaceutical composition according to any one of the preceding claims, wherein the subject is a healthy adult man or woman aged 18 to 65 who does not use tobacco or nicotine, and optionally, the person has a body mass index of 18.5 to 29.9 Kg / m 2 2.

10. The pharmaceutical composition according to any one of the preceding claims, wherein the LDL cholesterol level of the human in need of reducing LDL cholesterol, and / or the human suffering from heterozygous familial hypercholesterolemia (HeFH), and / or the human diagnosed with atherosclerotic cardiovascular disease (ASCVD) is ≥ 70 mg / dL, and optionally, the human is not adequately controlled by their current lipid-lowering therapy.

11. The pharmaceutical composition according to any one of the preceding claims, wherein when the pharmaceutical composition is dissolved in 500 ml of solution in a USP type II apparatus at 37 ± 0.5 °C at a rotation speed of about 75 rpm, at least about 60%, preferably at least about 70%, and more preferably at least about 80% of ezetimibe is dissolved within about 30 minutes, and the solution comprises 0.45% of SLS in 0.05 M sodium acetate buffer at pH 4.

5.

12. The pharmaceutical composition according to any one of the preceding claims, wherein when the pharmaceutical composition is dissolved in 1000 ml of solution in a USP type II apparatus at 37 ± 0.5 °C at a rotation speed of about 75 rpm, at least about 70%, preferably at least about 80%, and more preferably at least about 85% of obicetrapib is dissolved within about 15 minutes, and the solution comprises phosphate buffer solution at pH 6.8 + 0.2% w / v of polysorbate 80.

13. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises 1 mg to 20 mg of obicetrapib and 5 mg to 20 mg of ezetimibe, preferably the pharmaceutical composition comprises 5 mg of obicetrapib and 10 mg of ezetimibe or 10 mg of obicetrapib and 10 mg of ezetimibe.

14. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is provided in unit dosage forms comprising 1 mg to 20 mg of obicetrapib and 5 mg to 20 mg of ezetimibe, preferably the unit dosage form comprises 5 mg of obicetrapib and 10 mg of ezetimibe, or 10 mg of obicetrapib and 10 mg of ezetimibe.

15. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises not more than about 2% (w / w), preferably not more than about 0.5% (w / w), more preferably not more than about 0.3% (w / w), even more preferably not more than about 0.2% (w / w) of ezetimibe tetrahydropyran analog as an impurity.

16. The pharmaceutical composition according to any one of the preceding claims, wherein ezetimibe or obicetrapib, or both ezetimibe and obicetrapib are micronized.

17. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises micronized ezetimibe, and the micronized ezetimibe has a Dv of not more than 10 μm, preferably in the range of 4 μm to 10 μm, more preferably not more than 8.5 μm 90 ; a Dv of not more than 4 μm, preferably in the range of about 1 μm to 4 μm, more preferably not more than 3.8 μm 50 ; and a Dv of not more than 1 μm 10 .

18. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises micronized obeticholic acid, and the micronized obeticholic acid has a Dv of not more than 14 μm, preferably in the range of about 5 μm to 14 μm 90 ; a Dv of not more than 5 μm, preferably in the range of about 3 μm to 5 μm 50 ; and a Dv of not more than 3 μm 10 .

19. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises ezetimibe in the form of anhydrous ezetimibe, ezetimibe monohydrate, or a mixture thereof.

20. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises obeticholic acid in the form of an alkali metal or alkaline earth metal salt of obeticholic acid, preferably comprises sodium obeticholic acid, potassium obeticholic acid or calcium obeticholic acid, and more preferably comprises the calcium salt of obeticholic acid.

21. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is a two-component composition, and wherein one component in the two-component composition comprises ezetimibe, and the other component comprises obeticholic acid.

22. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is a two-component composition, and wherein one component in the two-component composition comprises both ezetimibe and obeticholic acid.

23. The pharmaceutical composition according to any one of claims 21 to 22, wherein the two-component composition is a bilayer tablet formulation, a capsule formulation comprising two types of granules or consisting of two types of granules, or a tablet formulation comprising an extra-granular component and an intra-granular component.

24. The pharmaceutical composition according to claim 22, wherein: a. the intra-granular component comprises ezetimibe, and the extra-granular component comprises obeticholic acid; or the intra-granular component comprises both ezetimibe and obeticholic acid; and the extra-granular component comprises only excipients.

25. The pharmaceutical composition according to claim 22, wherein: a. the intra-granular component comprises obeticholic acid, and the extra-granular component comprises ezetimibe; or b. the extra-granular component comprises both ezetimibe and obeticholic acid, and the intra-granular component comprises only excipients.

26. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition further comprises one or more binders and surfactants, wherein preferably the ratio of binder:surfactant in the intra-granular component is in the range of about 0.05:5.0 to about 5.0:0.05, preferably about 0.5:4.5 to about 4.5:0.5, more preferably about 1:4 to about 4:1, even more preferably about 1:2 to about 2:1, and most preferably about 1:

1.

27. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition further comprises one or more binders selected from the following: cellulose derivatives, preferably selected from methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylate, polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone, starch paste, sucrose, sorbitol, pregelatinized starch, tragacanth, alginic acid and salts of alginic acid such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonite, preferably the binder is polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone, more preferably the binder is copovidone, and even more preferably the binder is kollidon 30.

28. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition further comprises one or more surfactants having an HLB value of at least 15, at least 20, at least 30 or at least 40; preferably, the one or more surfactants are selected from lauric acid or a salt thereof, palmitic acid or a salt thereof, stearic acid or a salt thereof, and oleic acid or a salt thereof, polyethylene glycol glycerol esters, polyoxyethylene monoesters, polyoxyethylenemono stearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oil, polyethylene glycol having a molecular weight in the range of about 2000 to 10000, propylene glycol octanoate, glycerol oleate and octanoate, esters of glycerol and fatty acids; more preferably, the one or more surfactants are selected from dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, polysorbate 40 or polysorbate 80 or sodium lauryl sulfate; and even more preferably, the surfactant is sodium lauryl sulfate.

29. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition further comprises one or more disintegrants selected from crospovidone, croscarmellose sodium, calcium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, preferably the disintegrant is croscarmellose sodium or sodium starch glycolate, and more preferably the disintegrant is sodium starch glycolate.

30. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition remains stable at 40 °C / 75% relative humidity for at least 1 month, preferably at least 3 months and more preferably at least 6 months, or remains stable at 25 °C / 60% relative humidity for at least 3 months, preferably at least 6 months and more preferably at least 12 months.

31. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is a tablet formulation, the tablet formulation comprising the following or consisting of the following Composition: a. Components within the granules, which include: i. Calcium obeticholic acid equivalent to 10 mg of obeticholic acid free acid; ii. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to 10 mg of ezetimibe; iii. A binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each account for about 1 ± 0.5% w / w of the granules of the components within the granules; more preferably, the binder is polyvinylpyrrolidone or povidone at 1 ± 0.5% w / w, and the surfactant is sodium lauryl sulfate at 1 ± 0.5% w / w. iv. Disintegrants selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the particles of the components within the granules, preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; v. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. Components outside the granules, which include: i. Disintegrants selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; ii. Optionally a lubricant, preferably magnesium stearate, iii. Optionally a glidant, preferably colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc; iv. Optionally one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose; c. Optionally, the pharmaceutical composition comprises a film coating, preferably the film coating does not contain primary alcohols, more preferably the film coating does not contain polyethylene glycol.

32. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises a tablet formulation, the tablet formulation comprising the following or consisting of the following Composition: a. Components within the granules, which include: i. Anhydrous ezetimibe equivalent to 10 mg of ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate; ii. A binder and a surfactant in a ratio of 1:1, preferably each of the binder and the surfactant accounts for about 1 ± 0.5% w / w of the particles of the components within the granules; more preferably, the binder is polyvinylpyrrolidone or polyvinylpyridine ketone at 1 ± 0.5% w / w, and the surfactant is sodium lauryl sulfate at 1 ± 0.5% w / w; iii. Disintegrants selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the particles of the components within the granules, preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. Components outside the granules, which include: i. Obeticholic acid calcium equivalent to 10 mg of obeticholic acid free acid; ii. Disintegrants selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; iii. Optionally, a lubricant, preferably magnesium stearate, iv. Optionally, a glidant, preferably colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc; v. Optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose; c. Optionally, the pharmaceutical composition comprises a film coating, preferably the film coating does not contain primary alcohols, more preferably the film coating does not contain polyethylene glycol.

33. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises a tablet formulation, the tablet formulation comprising the following or consisting of the following Composition: a. Intra-granular components, which include: i. Calcium obeticholic acid equivalent to 10 mg of obeticholic acid free acid; ii. A binder and a surfactant in a ratio of 1:1, preferably each of the binder and the surfactant accounts for about 1 ± 0.5% w / w of the granules of the intra-granular components; more preferably, the binder is polyvinylpyrrolidone or polyvinylpyridine ketone at 1 ± 0.5% w / w, and the surfactant is sodium lauryl sulfate at 1 ± 0.5% w / w; iii. A disintegrant selected from sodium croscarmellose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the granules of the intra-granular components, preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. Extra-granular components, which include: i. Anhydrous ezetimibe equivalent to 10 mg of ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate; ii. A disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; iii. Optionally, a lubricant, preferably magnesium stearate, iv. Optionally, a glidant, preferably colloidal silicon dioxide or talc or both colloidal silicon dioxide and talc; v. Optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose; c. Optionally, the pharmaceutical composition comprises a film coating, preferably the film coating does not contain primary alcohols, more preferably the film coating does not contain polyethylene glycol.

34. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is used for treating a subject in need of reducing LDL cholesterol and / or increasing HDL cholesterol, preferably the subject suffering from hyperlipidemia or mixed dyslipidemia.

35. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is used for reducing LDL cholesterol in a patient in need of reducing LDL cholesterol and / or increasing HDL cholesterol, a patient suffering from heterozygous familial hypercholesterolemia (HeFH), and / or a patient diagnosed with atherosclerotic cardiovascular disease (ASCVD).

36. Use of the pharmaceutical composition according to any one of the preceding claims in the preparation of a medicament for treating a subject suffering from hyperlipidemia or mixed dyslipidemia.

37. Use of the pharmaceutical composition according to any one of the preceding claims in the preparation of a medicament for reducing LDL cholesterol in a subject in need of reducing LDL cholesterol and / or increasing HDL cholesterol, a subject suffering from heterozygous familial hypercholesterolemia (HeFH), and / or a subject diagnosed with atherosclerotic cardiovascular disease (ASCVD).

38. Use of the pharmaceutical composition according to any one of the preceding claims in the preparation of a medicament for reducing the risk of cardiovascular events.

39. The use according to any one of the preceding claims, wherein the subject suffers from mild dyslipidemia.

40. A method for treating a subject in need of reducing LDL cholesterol and / or increasing HDL cholesterol, a subject suffering from heterozygous familial hypercholesterolemia (HeFH), and / or a subject diagnosed with atherosclerotic cardiovascular disease (ASCVD), wherein the method comprises administering to the patient in need a therapeutically effective dose of the pharmaceutical composition according to any one of the preceding claims.

41. A method for treating a subject suffering from hyperlipidemia or mixed dyslipidemia, wherein the method comprises administering to the patient in need the pharmaceutical composition according to any one of the preceding claims.

42. Use of the pharmaceutical composition according to any one of the preceding claims in the preparation of a medicament or a treatment method, wherein the LDL-cholesterol level of the subject is ≥ 50 mg / dL, preferably ≥ 70 mg / dL, and optionally, the person is not adequately controlled by their current lipid-lowering therapy.

43. Use of the pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is administered to the subject in need to deliver a total daily oral dose of 5 mg obicetrapib and 10 mg ezetimibe, 10 mg obicetrapib and 10 mg ezetimibe, or 20 mg obicetrapib and 20 mg ezetimibe, preferably the pharmaceutical composition is administered to the subject to deliver a daily oral dose of 10 mg obicetrapib and 10 mg ezetimibe.

44. Use of a pharmaceutical composition as described in any one of the preceding claims, wherein the subject in need is a subject in need of additional reduction of low density lipoprotein cholesterol as an adjunctive therapy to diet and / or maximum tolerated lipid-lowering therapy for treating adults with heterozygous familial hypercholesterolemia (HeFH) or diagnosed with atherosclerotic cardiovascular (CV) disease (ASCVD).

45. A pharmaceutical composition comprising obicetrapib and ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and a pharmaceutically acceptable carrier, for use in the treatment of a subject in need of additional reduction of low density lipoprotein cholesterol as an adjunctive therapy to diet and / or maximum tolerated lipid-lowering therapy for treating adults with heterozygous familial hypercholesterolemia (HeFH) or diagnosed with atherosclerotic cardiovascular (CV) disease (ASCVD).

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