WO2024042061A1 - Polythérapie d'obicetrapib et d'ézétimibe et compositions pharmaceutiques à dose fixe - Google Patents

Polythérapie d'obicetrapib et d'ézétimibe et compositions pharmaceutiques à dose fixe Download PDF

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Publication number
WO2024042061A1
WO2024042061A1 PCT/EP2023/073000 EP2023073000W WO2024042061A1 WO 2024042061 A1 WO2024042061 A1 WO 2024042061A1 EP 2023073000 W EP2023073000 W EP 2023073000W WO 2024042061 A1 WO2024042061 A1 WO 2024042061A1
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Prior art keywords
obicetrapib
ezetimibe
pharmaceutical composition
anyone
subject
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PCT/EP2023/073000
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English (en)
Inventor
Joanne Lesley CRAIG
Sheng CUI
Michael Harvey Davidson
Marc DITMARSCH
Johannes Jacob Pieter KASTELEIN
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Newamsterdam Pharma B.V.
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Priority claimed from PCT/EP2022/075957 external-priority patent/WO2024041746A1/fr
Application filed by Newamsterdam Pharma B.V. filed Critical Newamsterdam Pharma B.V.
Publication of WO2024042061A1 publication Critical patent/WO2024042061A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present disclosure relates to a fixed dose pharmaceutical composition
  • a fixed dose pharmaceutical composition comprising obicetrapib and ezetimibe, and its use for preparation of medicaments and treatment of subjects requiring reduction of LDL cholesterol or in patients with heterozygous familial hypercholesterolemia (HeFH) and/or with established atherosclerotic cardiovascular disease (ASCVD).
  • HeFH heterozygous familial hypercholesterolemia
  • ASCVD atherosclerotic cardiovascular disease
  • CVD cardiovascular disease
  • LDL-C low-density lipoprotein cholesterol
  • CAIs Cholesterol Absorption Inhibitors
  • CAIs prevent the uptake of cholesterol from the small intestine by blocking the uptake of micellar cholesterol, which reduces the incorporation of cholesterol esters into chylomicrons and chylomicron remnants.
  • CAIs reduce the amount of cholesterol that is circulated back to the liver, which in turn increases the activity of hepatic LDL-receptors and increases the clearance of LDL cholesterol particles from the bloodstream.
  • a known example of a CAI is ezetimibe, previously known as compound "Sch-58235” of Schering-Plough, and marketed amongst others under the brand names Ezetrol and Zetia (Merck Sharp & Dohme / Merck).
  • ezetimibe is (3R,4S)-l-(4- fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2- one.
  • Ezetimibe is administered frequently either as a mono-therapy, or in an add-on combination therapy.
  • the ezetimibe dosage form is a tablet comprising 10 mg ezetimibe, for oral administration.
  • CETP Cholesteryl Ester Transfer Protein
  • an aspect of the present invention provides methods of treating comprising the concomitant administration of obicetrapib and ezetimibe.
  • Combination therapy requires co-administration of multiple pills as per the exact instructions of the physician prescribing such therapy to a patient. Since each drug in the combination therapy may have its own set of instructions, it is often cumbersome for the patients to follow such instructions for a long time, and this is further complicated for treatment of chronic diseases such as those requiring lipid lowering, and for the patient or a caregiver of patient. Such difficulties usually result into non-compliance, thereby compromised efficacy, increased risk of adverse reactions, and in many cases, development of resistant or altered sensitivity of target receptors/proteins.
  • APIs active pharmaceutical ingredients
  • Physicochemical incompatibility of the active ingredients includes the challenges arising due to differences in the physicochemical properties and behaviour of the APIs, for example, pKa, logP, solubility, hygroscopicity, light sensitivity, particle-size, flowability, compressibility, melting point or any such other parameters of one active ingredient that may not be suitable for the stability of another API in the formulation.
  • the total quantity of excipients that can be used to achieve the desired stability and dissolution of each API from the fixed dose formulation is limited because the size and shape of the dosage form needs to be controlled within the proportions of routinely administered pills.
  • Incompatibility of some excipients for one or more drugs in a fixed dose combination further limits the options for formulation scientists. This is more challenging when one or both APIs have poor water solubility, have differences in their solubility or dissolution pattern, for example one soluble and one insoluble or poorly soluble drug; or one lipophilic and another hydrophilic drug. Interactions of one drug or its impurities with another drug or its impurities in a fixed dose combination can further affect the stability, solubility, efficacy or solubility of one or both the drugs.
  • Ezetimibe is a practically insoluble drug and poor solubility across the physiological pH range. Ezetimibe is also incompatible with many commonly used excipients and presents stability problems, for example presence of polyethylene glycol (PEG) in coating layers can cause increase in the tetrahydropyran impurity of ezetimibe. Furthermore, ezetimibe is an inherently non-compressible and poorly flowable API (see for example EP 2168573 Al), thereby preparing tablet formulations of ezetimibe quite challenging.
  • PEG polyethylene glycol
  • Obicetrapib also has poor water solubility at physiological pH range and exerts a negative effect on the dissolution of ezetimibe (unpublished data).
  • no fixed dose combination of ezetimibe and obicetrapib is known in the art that (i) can be stabilized over a long period of time without substantial increase in the levels of harmful impurities, (ii) is devoid of any significant API-API, API-excipient or excipient-excipient interactions which can render such composition unsuitable for human use, (iii) can consistently provide desired dissolution profile of each of the two ingredients during its shelf-life which is comparable or better than the formulation of a single drug, (iv) which is easy to formulate and does not pose challenges in terms of processability of the ingredients during formulation and scale-up for manufacturing, (v) that is capable of achieving desired bioavailability upon oral administration to humans and is bioequivalent with the same dose of both active ingredients when co-administered as two separate formulations for each drug, and
  • One aspect of the invention thus relates to a fixed dose pharmaceutical composition
  • 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, pharmaceutically acceptable excipients, such as fixed dose pharmaceutical compositions wherein the composition is a dual component composition, and wherein one of the components comprises ezetimibe and another component comprises obicetrapib.
  • An embodiment relates to a fixed dose pharmaceutical composition
  • 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, pharmaceutically acceptable excipients, wherein at least about 60%, preferably at least about 70% and more preferably at least about 80% of ezetimibe is dissolved within about 30 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of about 75 rpm at 37 ⁇ 0.5°C.
  • An embodiment relates to a fixed dose pharmaceutical composition
  • 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, pharmaceutically acceptable excipients, wherein upon oral administration of the said composition to a subject, 90% confidence interval for the geometric mean of the area under the curve (AUC 0- ⁇ and/or AUC 0-t) and/or Cmax for obicetrapib is within a range of 75%-125%, preferably 80%-125%, and more preferably 90%-l 10% of the area under the curve (AUC0- ⁇ and/or AUC 0-t) and/or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered
  • Another embodiment relates to a fixed-dose pharmaceutical composition
  • 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, pharmaceutically acceptable excipients, wherein upon oral administration of the said composition to a subject, 90% confidence interval for the geometric mean of area under the curve (AUC 0- ⁇ and/or AUC o-t) and/or Cmax for ezetimibe and/or ezetimibe glucoronide is within a range of 75% - 125%, preferably 80% - 125%, and more preferably 90% - 110% of the area under the curve (AUC 0- ⁇ and/or AUC o-t) and/or Cmax, respectively, of ezetimibe and/or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference comprises
  • the fixed dose pharmaceutical compositions of ezetimibe and obicetrapib can be made to remain stable over a long period of time without substantial increase in the levels of harmful impurities or without formation of new impurities in substantial quantities. It has also been surprisingly found that the fixed dose pharmaceutical compositions of ezetimibe and obicetrapib are devoid of any significant API-API interactions, drug-excipient interactions and/or excipient-excipient interactions which could render the formulation unsuitable for use.
  • the said pharmaceutical composition consistently provides a dissolution profile for ezetimibe as well as obicetrapib for the entire period of its shelf life, which is equivalent to the dissolution achieved by a formulation comprising just the single drug. Since, the said stable composition provides desired dissolution profile through a single pill, it surprisingly overcomes the problems associated with co- administration of multiple pills of single drug formulations, such as poor patient compliance, sub-optimal therapeutic outcome and enhanced risk of undesired adverse effects such as development of resistance or hypersensitivity of the receptors. This makes the said fixed dose composition particularly relevant treatment for chronic treatment of patients requiring lipid lowering therapy having, therefore making such therapy suitable.
  • a second aspect relates to a fixed dose pharmaceutical composition
  • 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, pharmaceutically acceptable excipients, for use in reducing LDL cholesterol in patients requiring a reduction in LDL cholesterol and/or increase in HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and/or patients with established atherosclerotic cardiovascular disease (ASCVD).
  • HeFH heterozygous familial hypercholesterolemia
  • ASCVD atherosclerotic cardiovascular disease
  • the present invention also provides methods of treating a subject in need thereof, said method comprising the concomitant treatment of 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 the fixed dose pharmaceutical composition as defined herein. More in particular, the invention concerns the following aspects.
  • One aspect of the invention concerns a method for the prophylactic and/or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, said method comprising the concomitant treatment of 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.
  • said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a pharmaceutical composition
  • 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, for use in a method for the prophylactic and/or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, wherein the method comprises the concomitant treatment of the 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.
  • said pharmaceutical composition is the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a method of synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising the concomitant treatment of 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.
  • said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and/or obicetrapib or a pharmaceutically acceptable salt, solvate thereof or co-crystal thereof, for use in a method of synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising the concomitant administration of 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 method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a method of synergistically slowing the development and/or progression of CVD, more in particular ASCVD, and/or synergistically reducing the risk and/or occurrence of CVD related events, in particular ASCVD related events, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof.
  • said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a pharmaceutical composition
  • 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, for use in a method of synergistically slowing the development and/or progression of CVD, more in particular ASCVD, and/or synergistically reducing the risk and/or occurrence of CVD related events, in particular ASCVD related events, in a subject in need thereof, said method comprising the concomitant treatment of the 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.
  • said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a method of enhancement, preferably the synergistic enhancement, of 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 the concomitant treatment of the subject with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.
  • said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of enhancement, preferably the synergistic enhancement, of 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 the concomitant administration of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.
  • said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a method of enhancement, preferably the synergistic enhancement, of the therapeutic efficacy of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in particular of the therapeutic efficacy in the treatment and/or prevention of CVD, more in particular ASCVD, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof.
  • said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of enhancement, preferably the synergistic enhancement of the therapeutic efficacy of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in particular of the therapeutic efficacy in the treatment and/or prevention of CVD, more in particular ASCVD, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof.
  • said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.
  • a further aspect of the invention concerns 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 manufacture of a medicament for use in any one of the afore defined methods.
  • said medicament is the fixed dose pharmaceutical composition as defined herein.
  • kits comprising a package containing a plurality of pharmaceutical unit dosage forms comprising or a pharmaceutically acceptable salt, hydrate or solvate thereof, such as the fixed dose pharmaceutical compositions as defined herein, as well as a leaflet containing printed instructions to repeatedly self-administer said unit dosage forms in order to treat and/or prevent CVD, in particular ASCVD, by combined obicetrapib treatment and ezetimibe therapy.
  • the salt of obicetrapib, contained in the present pharmaceutical compositions, used in the present methods, contained in the unit dosage forms (comprised in the pharmaceutical kit), etc. is an amorphous calcium salt of obicetrapib.
  • Obicetrapib also referred to as “TA-8995”, has the following chemical name and chemical structure:
  • Ezetimibe also referred to as “Sch-58235”, has the following chemical name and chemical structure:
  • Both obicetrapib and ezetimibe may also be used as different salt forms, solvates or co- crystals. They may also be formulated as pro-drugs.
  • apolipoprotein as used herein has its conventional meaning and refers to proteins that bind lipids to form lipoproteins.
  • apolipoprotein B as used herein has its conventional meaning and refers to the protein encoded by the ApoB gene.
  • composition as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.
  • pharmaceutically acceptable as used herein has its conventional meaning and refers to compounds, material, compositions and/or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • carrier as used herein has its conventional meaning and refers to a pharmaceutically acceptable diluent, adjuvant, excipient or vehicle with which a pharmaceutically active ingredient is administered.
  • excipient as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid oral dosage formulation.
  • salt as used herein has its conventional meaning and includes the acid addition and base salts of a pharmaceutically active compound.
  • solvent as used herein has its conventional meaning and refers to a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute.
  • solvent molecules include water, alcohols, nitriles and polar organic solvents.
  • subject refers to humans suffering from or at risk for a certain disease or disorder.
  • term “"subject” and “”patient” herein are used interchangeably.
  • the term "increased risk’ has its conventional meaning and refers to a situation where a subject, preferably a human subject, either male or female, based on his or her risk profile (including an LDL-chole sterol level above 70 mg/dL, such as above 2.6 mmol/1 [100.54 mg/dL]), such that the subject is at an increased risk of suffering a cardiovascular event, compared to those with lower levels.
  • a subject preferably a human subject, either male or female
  • his or her risk profile including an LDL-chole sterol level above 70 mg/dL, such as above 2.6 mmol/1 [100.54 mg/dL]
  • treatment has its conventional meaning and refers to curative, palliative and prophylactic treatment.
  • cardiovascular disease as used herein has its conventional meaning and includes clinical manifestations of arteriosclerosis, peripheral vascular disease angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and cerebral stroke.
  • cardiovascular event as used herein has its conventional meaning and refers to occurrence of myocardial infarction, stroke, coronary death or the necessity to undergo a coronary revascularization (Ference, 2017).
  • hypocholesterolemia as used herein has its conventional meaning and refers to the condition in which high levels of cholesterol are present in the blood.
  • hypolipidaemia as used herein has its conventional meaning and refers to the condition in which there are high amounts of lipids found in the blood.
  • mixed dyslipidaemia has its conventional meaning and refers to the condition in which there are elevations of LDL cholesterol and triglyceride levels that are accompanied by low levels of HDL cholesterol in the blood.
  • statin intolerant has its conventional meaning and refers to subjects inability to tolerate two or more statins, one at a low dose, due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin was discontinued, reference is in this regard also made to the similar definition approved by the FDA in the bempedoic acid (Esperion) phase III trial.
  • CAI cholesterol absorption inhibitor'
  • CETP inhibitor cholesterol ester transfer protein inhibitor
  • 'unit dosage form has its conventional meaning and refers to a dosage form which has the capacity of being administered to a subject, preferably a human, to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising the therapeutic agent, i.e. obicetrapib or combination of therapeutic agents, such as obicetrapib and ezetimibe.
  • the therapeutic agent i.e. obicetrapib or combination of therapeutic agents, such as obicetrapib and ezetimibe.
  • 'fixed dose combination has its conventional meaning and refers to a combination of defined doses of two or more drugs or active ingredients presented in a single dosage unit (e.g. a tablet or a capsule) and administered as such.
  • 'free dose combination as used herein has its conventional meaning and refers to a combination of two drugs or active ingredients administered simultaneously but as two distinct dosage units.
  • an effective amount or “therapeutically effective amount” refers to an amount that is sufficient to effect treatment, as defined herein, when administered to a mammal in need of such treatment.
  • the therapeutically effective amount will vary depending upon the patient being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • Such chiral centers may be of either the (R) or (S) configurations, or may be a mixture thereof.
  • the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (5) form.
  • the present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not.
  • An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound according to the present disclosure are those 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 C1, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I.
  • Particular isotopic variants of a compound according to the present disclosure especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body.
  • any of the embodiments described herein are meant to include, a single stereoisomer, a mixture of stereoisomers and/or an isotopic form of the compounds.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the 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 specified, the term “about” means within plus or minus 10% of a the explicitly recited value, rounded either up or down to the nearest integer.
  • Figure 1 Cumulative undersize curve of small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib
  • Figure 2 Retain curve for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib
  • Figure 4 Comparison of dissolution profile of obicetrapib by discriminatory dissolution method pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib
  • Figure 18 % cumulative undersize curve of small-scale batch of 10 mg 16zetimibe and 10 mg obicetrapib fixed composition
  • Figure 49 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.
  • Figure 50 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.
  • Figure 51 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.
  • Figure 52 is an infrared spectrum of amorphous obicetrapib hemicalcium.
  • Figure 53 is a 'H-NMR spectrum of amorphous obicetrapib hemicalcium.
  • Figure 54 is an x-ray powder diffraction pattern of crystalline obicetrapib hemicalcium.
  • Figure 55 is an x-ray powder diffraction pattern stackplot from a stability study of crystalline obicetrapib hemicalcium.
  • Figure 56 is an x-ray powder diffraction pattern stackplot from a stability study of amorphous obicetrapib hemicalcium.
  • Figure 57 is a polarized light micrograph of amorphous obicetrapib hemicalcium.
  • Figure 58 is a polarized light micrograph of crystalline obicetrapib hemicalcium.
  • Figure 59 is a thermogravimetric analysis plot of amorphous obicetrapib hemicalcium.
  • Figure 60 is a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium.
  • Figure 61 a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium.
  • Figure 62 is a modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obicetrapib hemicalcium.
  • Figure 63 is a solid-state 13 C-NMR spectrum of amorphous and crystalline obicetrapib hemi calcium.
  • Figure 64 is a solid-state 13 C-NMR spectrum of crystalline obicetrapib hemicalcium.
  • Figure 65 is a solid-state 13 C-NMR spectrum of amorphous obicetrapib hemicalcium.
  • Figure 66 is an x-ray powder diffraction pattern of crystalline obicetrapib HC1 and at least partially desolvated crystalline obicetrapib HC1.
  • Figure 67 is an x-ray powder diffraction pattern of crystalline obicetrapib HC1.
  • Figure 68 is an x-ray powder diffraction pattern of crystalline Compound ID.
  • Figure 69 is 'H-NMR spectrum of Compound ID.
  • a first aspect relates to a fixed dose pharmaceutical composition
  • 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 one or more pharmaceutically acceptable excipients.
  • 90% confidence interval for the geometric mean of the area under the curve (AUC o-® and/or AUC o-t) and/or Cmax for obicetrapib is within a range of about 75%-125%, preferably about 80%-125%, and more preferably about 90%-l 10% of the area under the curve (AUCo-® and/or AUC o-t) and/or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate
  • 90% confidence interval for the geometric mean of area under the curve (AUC o-® and/or AUC o-t) and/or Cmax for ezetimibe and/or ezetimibe glucoronide is within a range of about 75% - 125%, preferably about 80% - 125%, and more preferably about 90% - 110% of the area under the curve (AUC o-® and/or AUC o-t) and/or Cmax, respectively, of ezetimibe and/or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a
  • Ezetimibe is practically insoluble in water and with poor solubility across the physiological pH range. Achieving desired dissolution and thereby bioavailability in in vivo conditions is quite challenging for ezetimibe. This problem is further enhanced as obicetrapib slows down the rate of dissolution and the total amount of ezetimibe that can be dissolved (unpublished data).
  • At least about 60%, preferably at least about 70% and more preferably at least about 80% of ezetimibe is dissolved within about 20 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of 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 is dissolved within about 15 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 1000 ml solution comprising phosphate buffer solution of pH 6.8 + 0.2 %w/v Polysorbate 80 at a rotation speed of about 75 rpm at 37 ⁇ 0.5°C.
  • Ezetimibe is inherently a poorly/non-compressible API (see for example EP 2168573 Al) along with poor flowability.
  • the fixed dose pharmaceutical composition may comprise a combination of 1 to 10 mg obicetrapib and 5 to 20 mg ezetimibe. In a preferred embodiment, the composition comprises 5 mg obicetrapib and 10 mg ezetimibe. In a more preferred embodiment the composition comprises 10 mg obicetrapib and 10 mg ezetimibe.
  • the pharmaceutical composition is provided as a unit dosage form comprising 5 mg obicetrapib and 10 mg ezetimibe. In a more preferred embodiment the composition is provided as a unit dosage form comprising 10 mg obicetrapib and 10 mg ezetimibe.
  • the dose of either obicetrapib or ezetimibe is mentioned in this disclosure as mg and/or in relative amounts (by weight), it means obicetrapib or ezetimib in its free form.
  • the said dose shall mean a dose equivalent to the weight of ezetimibe or obicetrapib in its free form, respectively.
  • the pharmaceutical composition is provided in the form of a solid oral dosage selected form caplets, minitablets, lozenges, granules, beads, pellets, tablets, capsules, pill, and the like, or liquid oral dosage forms which may be used for the pharmaceutical preparation include, but are not limited to drinks, solutions, suspensions, syrups, beverages and emulsions.
  • the solid oral dosage form is provided as a dual component pharmaceutical composition.
  • one of the components of the dual component pharmaceutical composition comprises ezetimibe and another component comprises obicetrapib.
  • only one of the components of the dual component pharmaceutical composition comprises both ezetimibe and obicetrapib.
  • the two component composition is a bilayer tablet formulation.
  • ezetimibe is present in one of the two layers and obicetrapib in the other layer of bilayer tablet.
  • the two component system is capsule formulation.
  • the capsule may have two types of granules wherein one granule type comprises ezetimibe and another granule type comprises obicetrapib.
  • the capsule may comprise two different type of blends or minitablets each comprising ezetimibe or obicetrapib, and optionally, such blends or minitablets may be filled in two components of a capsule which are segregated from each other.
  • each blend or minitablet is filled in a smaller capsule or such blend is compressed into a tablet/caplet/minitablet and then the tablets/caplets/minitablets are filled in a capsule formulation .
  • the fixed dose pharmaceutical composition is a compressed tablet formulation comprising an extragranular component and an intragranular component.
  • the intragranular component comprises ezetimibe and extragranular component comprises obicetrapib.
  • the intragranular component comprises both ezetimibe and obicetrapib.
  • the intragranular component comprises obicetrapib and the extragranular component comprises ezetimibe.
  • the extragranular component comprises both ezetimibe and obicetrapib.
  • intragranular components and extragranular components are present in a ratio from about 1 :99 to about 99: 1, preferably about 3: 97 to about 97:3, and more preferably from about 5:95 to about 95:5.
  • intragranular components and extragranular components are present in a ratio from about 10:90 to about 90: 10, preferably about 20:80 to about 80:20 or about 30:70 to about 70:30, and even more preferably about 40:60 to about 60:40 or about 50:50.
  • Intragranular refers to being or occurring within granules of the composition i.e. granules comprising a first set of pharmaceutically acceptable excipients including but not limited to a binder, a disintegrant, a diluent, a glidant and a solvent, and optionally one or more pharmaceutically acceptable active ingredients, in this case ezetimibe and/or obicetrapib.
  • Extra granular refers to addition of pharmaceutically acceptable component to a material following granulation i.e. an extra-granular fraction comprising a second set of pharmaceutically acceptable excipients including but not limited to a disintegrant, a diluent, a lubricant, a glidant or the like.
  • the extra-granular component may comprise one or more pharmaceutically acceptable active ingredients, in this case ezetimibe and/or obicetrapib.
  • the pharmaceutical composition can be obtained by a known conventional method like dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot-melt extrusion or the like.
  • the composition is obtained by wet granulation followed by compression of the granules in a tablet formulation or filling such granules in a capsule.
  • the pharmaceutical composition comprises ezetimibe as anhydrous ezetimibe. In another embodiment, the pharmaceutical composition comprises ezetimibe as ezetimibe hydrate, preferably ezetimibe monohydrate. In yet another embodiment, the pharmaceutical composition comprises a mixture of ezetimibe anhydrous and ezetimibe hydrate, preferably ezetimibe monohydrate.
  • the molar ratio of anhydrous ezetimibe: ezetimibe hydrate, preferably ezetimibe monohydrate, in the pharmaceutical composition could 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.
  • the composition is substantially free of the ezetimibe hydrate and about 100% of ezetimibe is in the form of ezetimibe anhydrous. In another preferred embodiment, about 99.5% ezetimibe is present in the form of ezetimibe anhydrous and about 0.5% of ezetimibe is present in the form of ezetimibe hydrate, preferably ezetimibe monohydrate. In a more preferred embodiment, the composition is substantially free of the ezetimibe anhydrous and about 100% of ezetimibe is in the form of ezetimibe hydrate, preferably ezetimibe monohydrate.
  • Ezetimibe or obicetrapib or both could be present in the form of a pharmaceutically acceptable salt, solvate or a co-crystal thereof.
  • Solvates include but are not limited to hydrates.
  • “salt” refers to a compound prepared by the reaction of an organic acid or base drug with a pharmaceutically acceptable mineral or organic acid or base; as used herein, “salt” includes hydrates and solvates of the salts.
  • Exemplary pharmaceutically acceptable mineral or organic acids or bases are as listed in Tables 1-8 in Handbook of Pharmaceutical Salts, P. H. Stahl and C. G. Wermuth (eds.), VHCA, Zurich 2002, pp. 334-345.
  • a pharmaceutically acceptable salt of obicetrapib or ezetimibe may be readily prepared by mixing together solutions of such compounds and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • salts include, but are not limited to, hydrochloride, phosphate, sulfate, mesylate, esylate and besylate salt forms.
  • the composition comprises obicetrapib as an alkali metal or alkali earth metal salt of obicetrapib, preferably obicetrapib sodium, obicetrapib potassium or obicetrapib calcium, and more preferably obicetrapib calcium salt.
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion, with the exception that, if specifically stated, the active pharmaceutical ingredient may be a liquid at room temperature.
  • the co-crystals may comprise a co-crystal former H-bonded to obicetrapib and/or ezetimibe.
  • the co-crystal former may be H-bonded directly to the active pharmaceutical ingredient or may be H-bonded to an additional molecule which is bound to obicetrapib and/or ezetimibe.
  • a co-crystal could be made between obicetrapib and ezetimibe or their salts or solvates. Solvates of active compounds that do not further comprise a co-crystal former are not co-crystals.
  • the co-crystals may also be a co-crystal between a co-crystal former and a salt of ezetimibe or obicetrapib or both.
  • Other modes of molecular recognition may also be present including, pi- stacking, guest-host complexation and van der Waals interactions.
  • the co-crystal comprises two co-crystal formers.
  • Co-crystal formers include, but are not limited to a free acid, free base, or zwitter ion; a salt, an inorganic base addition salt such as sodium, potassium, lithium, calcium, magnesium, ammonium, aluminum salts or organic base addition salts, or an inorganic acid addition salts such as HBr, HC1, sulfuric, nitric, or phosphoric acid addition salts or an organic acid addition salt such as acetic, proprionic, pyruvic, malanic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, methanesulfonic, ethanesulforic, stearic or lactic acid addition salt; an anhydrate or hydrate of a free form or salt, or more specifically, for example, a hemihydrate, monohydrate, dihydrate, trihydrate, quadrahydrate, pentahydrate; or a solvate of a free form or salt.
  • a salt such as sodium, potassium, lithium,
  • the ratio of active ingredient to co-crystal former may be stoichiometric or non-stoichiometric for the purposes. For example, 1 :1, 1 : 1.5, 1 :2 and 2:1 ratios of active ingredient (obicetrapib or ezetimibe or both, including theirs salts or solvates): co-crystal former are acceptable.
  • the said fixed dose pharmaceutical composition comprises either ezetimibe or obicetrapib, or both as a micronized API.
  • Particle size distribution for such micronized API can be determined by a skilled person using the methods commonly 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.
  • LD laser diffraction
  • DLS dynamic light scattering
  • DIA dynamic image analysis
  • sieve analysis a sieve analysis
  • the method employed is laser diffraction dry powder dispersion which provides the particle size distributions by measuring the angular variation in 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 and small particles scatter light at large angles.
  • the angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating a cumulative undersize discrete distribution curve that gives particle size distribution by volume.
  • the particle size from this method is usually reported as a volume equivalent sphere diameter (Dv).
  • the most common percentiles reported are the DvlO, Dv50 and Dv90 (also referred as Xio, X50 and X90).
  • Dv90 means 90% of the particles by volume are below a particular size & 10% above;
  • Dv50 means 50% of the particles by volume are below a particular size & 50% above
  • DvlO means 10% of the particles by volume are below this size & 90% above.
  • the composition comprises micronized ezetimibe having a Dv90 not more than 10 pm, preferably in the range of 4- 10 pm, more preferably not more than 8.5 pm; Dv50 not more than 4 pm, preferably in the range of about 1-4 pm more, more preferably not more than 3.8pm, and DvlO not more than 1pm.
  • the composition comprises micronized obicetrapib having a Dv90 not more than 14 pm, preferably in the range of about 5-14 pm; Dv50 not more than 5pm, preferably in the range of about 3-5pm; and DvlO not more than 3pm.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
  • Excipients include but are not limited to one or more binders, surfactants, disintegrants, glidant, lubricant, diluent, chelating agents, desiccants or absorbents.
  • binders include but are not limited to one or more binders, surfactants, disintegrants, glidant, lubricant, diluent, chelating agents, desiccants or absorbents.
  • the one or more binders used in the pharmaceutical composition are preferably selected from cellulose derivatives such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, glucose, sucrose, lactose dextrose, xylitol, sorbitol, maltitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites.
  • cellulose derivatives such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, glucose, sucrose, lactose dextrose, xylitol, sorbitol, maltitol, polymethacrylates, polyvinylpyrrol
  • the binder is polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone. In a more preferred embodiment, the binder is copovidone. In an even more preferred embodiment, the binder is Kollidon 30.
  • the binders may typically be present in an amount 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 granule composition in one embodiment and by weight of the total tablet in another embodiment.
  • the one or more surfactants used in the composition preferably are the 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, palmitic, stearic and oleic acid or salts thereof, polyethylene glycol glycerides, polyoxyethylene monoesters, polyoxyethylethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oils, polyethylene glycol having molecular weight in the range of about 2000 to 10000, propylene glycol caprylates, glycerol oleates and caprylates, esters of glycerol and fatty acids.
  • 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 sulphate.
  • the surfactant is sodium lauryl sulphate such as Kolliphor SLS.
  • the surfactants typically may be present in an amount from about 0.2% to 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 granule composition in one embodiment and by weight of the total tablet in another embodiment.
  • the composition comprises a binder : surfactant ratio in the range of about 0.05:5.0 to about 5.0: 0.05, preferably from about 0.5:4.5 to about 4.5: 0.5, more preferably from about 1 :4 to about 4:1, even more preferably from about 1 :2 to about 2:1 and most preferably about 1 : 1.
  • binder: surfactants may be for the granule composition such as intragranular composition or the extragranular composition or for the total composition of the tablet.
  • the pharmaceutical composition typically further comprises one or more disintegrants selected from cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium carboxyl methylcellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate or pregelatinized starch.
  • the disintegrant is croscarmellose sodium or sodium starch glycolate.
  • the disintegrant is sodium starch glycolate.
  • the disintegrants may be present in an amount from about 0.5% to about 10%, from about 1% to about 8%, from about 2% to about 5%, preferably 2% to about 3%, from about 4% to about 5%, or from about 7% to about 8% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.
  • the one or more diluents used in the pharmaceutical composition preferably are selected from the group consisting of: an inorganic phosphates like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof in particular lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomaltose, or celluloses like microcrystalline cellulose or powdered celluloses or the like.
  • the diluent selected from Lactose such as lactose monohydrate, microcrystalline cellulose and mannitol, or a mixture thereof.
  • intragranular component comprises microcrystalline cellulose and lactose monohydrate as diluent.
  • microcrystalline cellulose and mannitol are present as diluent in the extragranular component.
  • the diluents may present in an amount from about 10% to about 95%, preferably from about 40% to about 90%, more preferably from about 60% to about 85%, even more preferably from about 70% to about 85% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.
  • the pharmaceutical composition may optionally be film-coated using techniques well known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating may also be performed using the hot melt technique.
  • the film coat comprises film-forming polymers, one or more pharmaceutically acceptable excipients and pharmaceutically acceptable solvents.
  • film-forming agents include, but are not limited to, cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose; polyvinyl alcohol, waxes; fat substances; or mixtures thereof.
  • commercially available coating compositions comprising film forming polymers marketed under various trade names, such as Opadry®, may be used for coating.
  • solvents used for preparing the coating solution are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
  • the film coating is a primary alcohol free coating.
  • the primary alcohol free coating is a coating made using water.
  • Glidants present in the pharmaceutical dosage form preferably are selected from silicon dioxide, talc, magnesium stearate and the like.
  • a preferred glidant is silicon dioxide such as Aerosil® or magnesium stearate such as Ligamed MF 2V or a mixture thereof.
  • Glidants may typically be present in amount from about 0.1% to 10%, from about 0.% to about 5%, or from about 1% to about 2% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.
  • Lubricants present in the pharmaceutical composition are preferably selected from fatty acids or fatty acid derivatives, such as alkali and earth alkali salts of stearic, lauric and/or palmitic acid and the like.
  • a preferred lubricant is magnesium stearate and may typically be present in amount from about 0.1% to 10%, from about 0.% to about 5% or from about 1% to about 2% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.
  • Stability is an essential quality attribute for pharmaceutical formulations that determines the shelf life of the composition during which the composition is suitable for its intended use both from an efficacy and a safety point of view.
  • stability of a pharmaceutical composition of a stable pharmaceutical composition means that one or more parameters governing the physical and chemical integrity of the active pharmaceutical ingredients (APIs) remain within a pharmaceutically acceptable criteria during the shelf life of the product.
  • one or more such parameters are selected from identification of the active ingredient(s) in the composition by methods, for example, HPLC and/or UV spectroscopy; visual appearance of the composition, assay percentage of the active ingredient(s) in the composition, individual and/or total percentage of the related substances and/or impurities in the composition, content uniformity of the composition with respect to the active ingredient(s), dissolution rate, microbial limits, and the like.
  • compositions often lose their efficacy and/or safety over time because of the loss or degradation or conversion of the active ingredient(s) into impurities commonly known as related substance(s).
  • a stable fixed dose pharmaceutical composition retains at least up to about 90%(w/w) of the claimed potency for ezetimibe as well as obicetrapib.
  • Ezetimibe is known to give rise to stability problems associated with its formulations because of interactions with excipients and/or the combination drug partner. It has been surprisingly found that the fixed dose pharmaceutical composition effectively controls the levels of individual and total related substances of ezetimibe during the preparation as well as storage of the fixed dose composition.
  • the stable fixed dose pharmaceutical composition has not more than about 5% (w/w), preferably not more than about 2%(w/w), more preferably not more than about 1% (w/w) and even more preferably not more than about 0.2% (w/w) of an individual related substance of ezetimibe; and not more than about 5% (w/w), preferably not more than about 2%(w/w), more preferably not more than about l%(w/w), and even more preferably not more than about 0.5%(w/w) of total related substances of ezetimibe.
  • the fixed dose pharmaceutical composition comprising ezetimibe and obicetrapib wherein the ezetimibe tetrahydropyran analog impurity is 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).
  • the stable fixed dose pharmaceutical composition has not more than about 5% (w/w), preferably not more than about 2%(w/w), more preferably not more than about 0.5% (w/w), even more preferably not more than about 0.3%(w/w), and most preferably not more than about 0.2%(w/w) of any unspecified individual obicetrapib related substance; and not more than about 5%(w/w), preferably not more than about 2%(w/w), more preferably not more than about l%(w/w), and even more preferably not more than about 0.5%(w/w) of total related substances of obicetrapib.
  • the pharmaceutical composition remains stable for at least up to 1 month, preferably at least up to 3 months, more preferably at least upto 6 months under stability conditions of 40°C temperature and 75% relative humidity.
  • the composition remains stable at least up to 3 months, preferably at least upto 6 months under stability conditions of 40°C temperature and 75% relative humidity.
  • the composition remains stable for at least up to 3 months, 6 months or 12 months under stability conditions of 25°C temperature and 60% relative humidity.
  • the composition remains stable for at least up to 6 months, 12 months, 18 months or 24 months at room temperature.
  • the pharmaceutical composition is a tablet formulation comprising or consisting of: a. an intragranular component comprising: i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ii. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe monohydrate equivalent to ezetimibe 10 mg; iii.
  • a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w/w the granule of intragranular component, preferable 3-6% w/w, more preferably about 4.5+0.5% w/w;
  • 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.
  • An extragranular component comprising: i. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4%-6% w/w sodium starch glycolate; ii. optionally, a lubricant, preferably magnesium stearate, more preferably about l%-2% w/w magnesium stearate; iii. optionally, a glidant, preferably colloidal silicon dioxide or talk or both, more preferably about l%-2% w/w colloidal silicon dioxide or talk or both; iv.
  • a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4%-6% w/w sodium starch glycolate
  • a lubricant preferably magnesium stearate, more preferably about l%-2% w/w magnesium stearate
  • the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.
  • the pharmaceutical composition comprises tablet formulation comprising or consisting of: a. an intragranular component comprising: i. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; ii. a binder and a surfactant in a ratio of 1 : 1, preferably the binder and the surfactant each are about 1+0.5% w/w of the granule of intragranular component; more preferably the binder is 1+0.5% w/w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w/w sodium lauryl sulphate; iii.
  • an intragranular component comprising: i. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; ii. a binder and a surfactant in a ratio of 1 : 1,
  • a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w/w the granule of intragranular component, preferable 3-6% 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.
  • an extra-granular component comprising: i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ii. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4%-6% w/w sodium starch glycollate; iii. optionally, a lubricant, preferably magnesium stearate, more preferably about 1% w/w magnesium stearate; iv. optionally, a glidant, preferably colloidal silicon dioxide or talk or both, more preferably about l%-2% w/w colloidal silicon dioxide or talk or both; v.
  • the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.
  • the pharmaceutical composition is a tablet formulation comprising or consisting of a. an intragranular component comprising: i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ii. a binder and a surfactant in a ratio of 1 : 1, preferably the binder and the surfactant each are about 1+0.5% w/w of the granule of intragranular component; more preferably the binder is 1+0.5% w/w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w/w sodium lauryl sulphate; iii.
  • an intragranular component comprising: i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ii. a binder and a surfactant in a ratio of 1 : 1, preferably the binder and the surfactant each are about 1+0.5% w/w of the granule of intragranular component; more preferably the binder is
  • a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w/w the granule of intragranular component, preferable 3-6% 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.
  • an extra-granular component comprising: i. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg ii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; even more preferably about 4%-6% w/w sodium starch glycollate iii. optionally, a lubricant, preferably magnesium stearate, more preferably about 1-2% w/w magnesium stearate iv.
  • the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.
  • Another aspect relates to a pharmaceutical composition
  • a pharmaceutical composition comprising obicetrapib and ezetimibe or pharmaceutically acceptable salts, solvates or co-crystals thereof and a pharmaceutically acceptable carrier for use in the treatment of subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and/or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).
  • HeFH familial hypercholesterolemia
  • CV atherosclerotic cardiovascular
  • a second aspect relates to the use of a fixed dose pharmaceutical composition
  • 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 one or more pharmaceutically acceptable excipients for preparation of a medicament for treatment of subjects requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol.
  • the said subjects are suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).
  • HeFH heterozygous familial hypercholesterolemia
  • ASCVD established atherosclerotic cardiovascular disease
  • the said subjects are partially or completely intolerant to statins.
  • the use of a pharmaceutical composition is for treatment of subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and/or maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).
  • HeFH heterozygous familial hypercholesterolemia
  • CV established atherosclerotic cardiovascular
  • a third aspect relates to a method of treatment of subjects requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol, wherein the method comprises administering to the said subject a therapeutically effective dose of 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 one or more pharmaceutically acceptable excipients.
  • 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 one or more pharmaceutically acceptable excipients.
  • the said method is for the treatment of subjects suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).
  • hyperlipidemia or mixed dyslipidemia heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).
  • HeFH heterozygous familial hypercholesterolemia
  • ASCVD established atherosclerotic cardiovascular disease
  • the subject requires additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and/or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).
  • HeFH heterozygous familial hypercholesterolemia
  • CV atherosclerotic cardiovascular
  • the said are partially or completely intolerant to statins.
  • a fourth aspect relates to a fixed dose combination pharmaceutical composition of obicetrapib and ezetimibe, wherein the said pharmaceutical composition is considered to be suitable for the said use according to the second aspect or said method of treatment according to the third aspect, when: a. the fixed dose pharmaceutical composition is orally administered to a subject; b. the concentration of obicetrapib in the subject’s blood is determined 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 c.
  • AUC area-under the curve
  • a fifth aspect relates to a fixed dose combination pharmaceutical composition of obicetrapib and ezetimibe, wherein the said pharmaceutical composition is considered to be suitable for the said use according to the second aspect or said method of treatment according to the third aspect, when: a. the said fixed dose pharmaceutical composition is orally administered to a subject, ezetimibe and/or ezetimibe glucoronide in the subject’s blood is determined at one or more time points after administration to provide a set of ezetimibe and/or ezetimibe glucoronide concentration/time data points, respectively, to provide an area-under the curve (AUC) for ezetimibe and/or ezetimibe glucoronide, respectively; and, b.
  • AUC area-under the curve
  • t for AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours ( AUC0-72), 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 AUC0- ⁇ , preferably 48 hours (AUC 0-48), and more preferably 72 hours (AUC0-72) or AUC0- ⁇ .
  • the subject is a healthy human subject, preferably a non-tobacco, non-nicotine using adult male or female human, more preferably of 18-65 years of age, and optionally, the said human has a body mass index of 18.5 to 29.9 Kg/m 2 .
  • the subject is human requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol.
  • the is human is suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).
  • HeFH heterozygous familial hypercholesterolemia
  • ASCVD established atherosclerotic cardiovascular disease
  • the said human is partially or completely intolerant to statins.
  • the human subject has LDL-cholesterol levels ⁇ 70 mg/dL, and optionally the said humans are not adequately controlled by their current lipid-modifying therapies.
  • the subject in need thereof may be administered with the said composition 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 subject is administered with the said composition to deliver a daily oral dose of 10 mg obicetrapib and 10 mg ezetimibe.
  • the dissolution profile of ezetimibe from the fixed dose combination was found to be non-inferior or sometime superior as compared to the commercial formulation of ezetimibe (Zetia®) which is discussed in detail in the examples section. It was also surprisingly found that the fixed dose combination composition disclosed herein is bioequivalent to a combination of monotherapy drugs co-administered to human subjects.
  • the confidence intervals (90%) on the geometric mean ratios for AUCo-t, AUCo- ⁇ and Cmax for obicetrapib, ezetimibe and ezetimibe glucoronide from two of the representative compositions - FDC1 and FDC2 were found to be within a range of 75%-125%, preferably 80%-125%, and more preferably 90%-110% of AUCo-t, AUCo- ⁇ and Cmax of obicetrapib, ezetimibe and ezetimibe glucoronide, respectively as obtained from co-administration of single drug formulations of same dose of ezetimibe and obicetrapib, which is discussed in detail in the examples section below.
  • the invention provides methods for the curative and/or prophylactic treatment of a subject in need thereof. More in particular, the invention provides methods for the treatment and/or prevention of cardiovascular disease, in particular Atherosclerotic cardiovascular disease, in such subjects, using the compositions as defined herein. The invention further provides methods for the treatment and/or prevention of one or more symptoms associated with (atherosclerotic) cardiovascular disease, in such subjects, using the compositions as defined herein. The invention further provides methods for the treatment and/or prevention of one or more pathologies associated with and/or caused by (atherosclerotic) cardiovascular disease, in such subjects, using the compositions as defined herein.
  • cardiovascular disease in particular Atherosclerotic cardiovascular disease
  • the invention further provides methods for the treatment and/or prevention of one or more symptoms associated with (atherosclerotic) cardiovascular disease, in such subjects, using the compositions as defined herein.
  • the invention further provides methods for the treatment and/or prevention of one or more pathologies associated with and/or caused by (atherosclerotic)
  • the invention further provides methods for the treatment and/or prevention of one or more aetiological factors associated with (atherosclerotic) cardiovascular disease, such as elevated LDL-C levels and/or elevated ApoB levels, in such subjects, using the compositions as defined herein.
  • the invention further provides methods for mitigating and/or ameliorating resistance or hypo-responsiveness to statin therapy, in particular high intensity statin therapy, in such subjects, using the compositions as defined herein.
  • treat when used in conjunction with a specific disease or symptom (for example: “method of treating disease . . .”) refers to curing, alleviating or abrogating said disease and/or accompanying symptoms, diminishing extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, ameliorating the disease state, prolonging survival (as compared to expected survival without treatment), etc.
  • prevent refers to reducing the risk for a subject to acquire a disease and/or accompanying symptoms, delaying the moment a subject acquires disease, etc.
  • treat when used in relation to a patient or subject (for example: “method of treating a subject”), typically refers to the act of administering a therapeutic compound to said patient or subject for whatever therapeutic and/or prophylactic purpose.
  • cardiovascular disease has its conventional meaning as referring to a disease or condition in which the function of a subject's cardiovascular system becomes impaired.
  • cardiovascular diseases include thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the chambers of the heart); 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; ischemic sudden death; transient
  • the term “atherosclerotic cardiovascular disease” refers to a specific subset of cardiovascular diseases that include atherosclerosis as a component or precursor to the particular type of cardiovascular disease.
  • Atherosclerosis is a chronic inflammatory response that occurs in the walls of arterial blood vessels associated with retained LDL-C. It involves the formation of atheromatous plaques that can lead to narrowing ("stenosis") of the artery, and can eventually lead to partial or complete closure of the arterial opening and/or plaque ruptures.
  • Atherosclerotic diseases or disorders include the consequences of atheromatous plaque formation and rupture including, without limitation, stenosis or narrowing of arteries, heart failure, aneurysm formation including aortic aneurysm, aortic dissection, and ischemic events such as myocardial infarction and stroke.
  • the atherosclerotic cardiovascular disease and/or pathology associated with atherosclerotic cardiovascular disease that may advantageously be treated and/or prevented according to the present invention is selected from the group consisting of arteriosclerosis, peripheral vascular disease, hyperlipidemia, mixed dyslipidemia betalipoproteinemia, hypoalphalipoproteinemia, hypercholesteremia, hypertriglyceridemia, familial-hypercholesteremia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and cerebral stroke.
  • the methods of the present invention are effective in and/or intended for reducing and/or normalizing LDL-C plasma levels. More in particular, the methods are effective in and/or intended for reducing LDL-C plasma levels, with at least 5 %, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably 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 %.
  • the methods are effective in and/or intended for reducing LDL-C plasma levels, with at least 5 mg/dL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably 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.
  • the methods are effective in and/or intended for reducing LDL-C plasma levels, 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.
  • ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof
  • obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof
  • the present methods of administering ezetimibe (or a pharmaceutically acceptable salt, solvate or co-crystal thereof), in order to enhance the LDL-C lowering effect of obicetrapib as defined herein, are effective in and/or intended for further reducing LDL-C plasma levels, with at least 20 %, as compared to methods based on therapy with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, alone (or, at least, without ezetimibe), more preferably at least 22.5 %, at least 25 %, at least 26 %, at least 27 %, at least 28 %, at least 29 % or at least 30 %.
  • these methods are effective in and/or intended for further reducing LDL-C plasma levels, with at least 20 mg/dL as compared to methods based on therapy with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, alone (or, at least, without ezetimibe), more preferably 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.
  • the methods are effective in and/or intended for reducing and/or normalizing ApoB plasma levels. More in particular, the methods are effective in and/or intended for reducing ApoB plasma levels, with at least 5 %, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably at least 10 %, at least 15 %, at least 20 %, at least 22.5 %, at least 25 % or at least 27.5 %.
  • the methods are effective in and/or intended for reducing ApoB plasma levels, with at least 5 mg/dL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably 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.
  • the methods are effective in and/or intended for reducing ApoB plasma levels, 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.
  • the methods are effective in and/or intended for reducing and/or normalizing Lp(a) plasma levels. More in particular, the methods are effective in and/or intended for reducing Lp(a) plasma levels, with at least 5 %, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably at least 7.5 %, at least 10 %, at least 12.5 %, at least 15 %, at least 17.5 % or at least 20 %.
  • the methods are effective in and/or intended for reducing Lp(a) plasma levels, with at least 5 nmol/L, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably 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.
  • the methods are effective in and/or intended for reducing Lp(a) plasma levels, 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.
  • the methods are effective in and/or intended for mitigating and/or ameliorating resistance or hypo-responsiveness to statin therapy, in particular high intensity statin therapy.
  • High intensity statin therapy is a term conventionally used in the art to denote the regimens based on the highest allowed dosages of the statins having the highest efficacy in reducing LDL-C, notably regimens that typically display a LDL-C reduction > 50 % in normally responsive subjects.
  • statins currently used in clinical practice only 20 mg (daily) or 40 mg (daily) of rosuvastatin and 40 mg (daily) or 80 mg (daily) of atorvastatin meet the criteria.
  • hypo-responsiveness to HIS therapy means that a subject receiving HIS therapy fails to reach a 35 % LDL-C reduction, preferably it means that a subject receiving HIS therapy fails to reach a 30 % LDL-C reduction, a 25 % LDL-C reduction, a 20 % LDL-C reduction, a 15 % LDL-C reduction, or a 10 % LDL-C reduction.
  • Mitigating and/or ameliorating hypo-responsiveness to HIS therapy means that the difference between the subject’s response (LDL-C reduction) and the (average) response of normo- responsive subjects is reduced.
  • the methods are effective in and/or intended for normalizing the responsiveness to statin therapy.
  • the methods of the invention are directed at the treatment and/or prevention of a subject suffering from or at risk of suffering from CVD, in particular ASCVD.
  • a subject refers to a living organism, typically a mammal, in particular a human subject, suffering from or prone to a disease or condition that can be treated by using the composition provided herein.
  • the subject is a subject that has been diagnosed with CVD, in particular ASCVD.
  • the subject is a subject that is considered to be at risk, typically at above-average risk, of developing CVD, in particular ASCVD, as can e.g. be judged by healthcare professionals.
  • the subject is a subject suffering from one or more conditions known to bear a causal and/or epidemiological correlation with the occurrence of (AS)CVD, such as diabetes, hypertension, hypercholesterolemia, including, overweight/obesity, metabolic syndrome, etc.
  • AS epidemiological correlation with the occurrence of (AS)CVD
  • the subject is a subject that is genetically predisposed to develop (AS)CVD.
  • the subject is a subject prone to develop (AS)CVD as a consequence of life-style / habitual factors, such as unhealthy diet, lack of exercise, alcohol consumption, smoking.
  • the subject to be treated has elevated plasma levels of LDL-C, typically an LDL-C plasma 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.
  • the subject has an LDL-C plasma level that is at least 125 % of the average LDL-C plasma level in healthy subjects, e.g. at least 150 %, at least 175 %, or at least 200 %.
  • Normal LDL-C (reference) values typically depend on gender and age.
  • the subject to be treated has elevated plasma levels of ApoB, typically an ApoB plasma 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.
  • the subject has an ApoB plasma level that is at least 125 % of the average ApoB plasma level in healthy subjects, e.g. at least 150 %, at least 175 %, or at least 200 %.
  • Normal ApoB (reference) values typically depend on gender and age.
  • the subject to be treated has elevated plasma levels of non-HDL-C, typically a non-HDL-C plasma 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.
  • the subject has a non-HDL-C plasma level that is at least 125 % of the average non-HDL-C plasma level in healthy subjects, e.g. at least 150 %, at least 175 %, or at least 200 %.
  • Normal non-HDL-C (reference) values typically depend on gender and age.
  • the subject is human male. In another embodiment of the invention, the subject is human female.
  • the subject is at increased risk based on age, such as a subject being over 35 years of age, over 40 years of age, over 45 years of age, over 50 years of age, over 55 years of age, over 60 years of age, over 65 years of age or over 70 years of age; typically in combination with one or more other risk factors as defined herein.
  • the subjects to be treated display hypo-responsiveness to statin therapy, in particular HIS therapy.
  • High intensity statin therapy is a term conventionally used in the art, to denote the regimens based on the highest allowed dosages of statins having the highest efficacy in reducing LDL-C, notably regimens that typically display a LDL-C reduction > 50 % in normally responsive subjects.
  • statin therapy 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.
  • the subject is a subject that is receiving HIS therapy and fails to reach a 35 % LDL-C reduction, preferably a subject receiving HIS therapy that fails to reach a 30 % LDL-C reduction, a 25 % LDL-C reduction, a 20 % LDL-C reduction, a 15 % LDL-C reduction, or a 10 % LDL-C reduction.
  • the subject s hypo-responsiveness to statin therapy, in particular HIS therapy, is established after at least 1 month of (continuous) HIS therapy, more preferably at least 2 months, at least 3 months, at least 4 months, at least 5 months or at least 6 months.
  • compositions comprising obicetrapib or a salt or solvate/hydrate thereof, preferably any composition as defined herein before.
  • the method comprises the administration of obicetrapib in 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, e.g. about 10 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose.
  • the method comprises the administration of obicetrapib in 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 a salt, solvate or co-crystal of obicetrapib in the equipotent dose.
  • the method comprises the administration of obicetrapib in a dose within the range of 1-100 mg, 2-50 mg, 3-50 mg, 4-25 mg, 4.5-15 mg or 5-10 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose.
  • the method comprises the administration of obicetrapib in a dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose.
  • the method comprises the administration obicetrapib in a dose of 5, 7.5, 10, 12.5 or 15 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose.
  • the treatment comprises the repeated administration of the composition containing obicetrapib or a salt, hydrate or solvate thereof, preferably in a dose within the ranges defined herein before.
  • the treatment comprises the repeated administration of the composition, preferably in a dose within the ranges defined herein before, at a frequency of at least once every two days or at least once every day.
  • the treatment comprises the repeated administration of the composition, preferably in the dose as defined herein before, at a frequency of once to four times every day.
  • the method comprises the once or twice daily administration of the composition containing obicetrapib or a salt, hydrate or solvate thereof, in the dose ranges as defined here above, most preferably twice daily.
  • the method comprises the administration of obicetrapib at a daily dosage 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, e.g. about 10 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage.
  • the method comprises the administration of obicetrapib at a daily dosage 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 a salt, solvate or co-crystal of obicetrapib in the equipotent dosage.
  • the method comprises the administration of obicetrapib at a daily dosage within the range of 1-100 mg, 2-50 mg, 3-50 mg, 4-25 mg, 4.5-15 mg or 5-10 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage.
  • the method comprises the administration of obicetrapib at a daily dosage of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage.
  • the method comprises the administration of obicetrapib at a daily dosage of 4 of 5, 7.5, 10, 12.5 or 15 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage.
  • the methods of the invention further comprises the concurrent treatment with ezetimibe.
  • ezetimibe and obicetrapib may be administered at or around the same time, sequentially or concurrently, or they may be administered at different time points.
  • the frequency and administration intervals of obicetrapib and ezetimibe are equal, more preferably each is administered once daily, still more preferably at the same time of the day, sequentially or concurrently as two separate unit dosage forms, preferably in the form of the fixed dose combination product as defined herein.
  • the methods of the invention comprise the administration of ezetimibe at a daily dosage of 1-30 mg, 2-25 mg, 3-20 mg, 4- 17.5 mg, or 5-15 mg e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg, most preferably about 10 mg; or a salt, solvate or co-crystal of ezetimibe, in the equipotent dosage.
  • the methods of the invention in some embodiments, further comprises the concurrent treatment with a HMG CoA reductase inhibitor, preferably concurrent HIS therapy.
  • the HMG CoA reductase inhibitor and obicetrapib may be administered at or around the same time, sequentially or concurrently, or they may be administered at different time points.
  • the frequency and administration intervals of obicetrapib and the HMG CoA reductase inhibitor are equal, more preferably each is administered once daily, still more preferably at the same time of the day, sequentially or concurrently as two separate unit dosage forms, or in the form of a fixed dose combination product.
  • the methods of the invention comprise the administration of rosuvastatin at a daily dosage of 10-50 mg, 15-45 mg, 17.5-42.5 mg, or 20-40 mg, e.g. 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 mg, most preferably about 20 mg or 40 mg; or a salt, solvate or co-crystal of rosuvastatin in the equipotent dosage.
  • the methods of the invention comprise the administration of atorvastatin at a daily dosage of 30-90 mg, 35-85 mg, 37.5-82.5 mg, or 40-80 mg, e.g.
  • the methods of the invention do not comprise the concomitant treatment with a HMG CoA reductase inhibitor.
  • the daily doses indicated herein may be contained in a single unit dosage form as well as in a plurality of unit dosage forms.
  • the method comprises the administration of obicetrapib (or a salt, hydrate or solvate thereof) in the dosages recited herein once daily.
  • methods are also envisaged comprising the administration of 2 unit dose forms, each comprising approximately half of the daily dosage as indicated above, at certain pre-determined moments during the day, e.g. one in the morning, such as shortly after the subject wakes up, and one in the evening, such as around the time the subject has his evening meal or goes to sleep.
  • Embodiments wherein unit dosage forms are used comprising higher amounts of obicetrapib and/or ezetimibe than the daily dose indicated herein are also contemplated. This may e.g. involve the use of extended release dosage forms that remain in the body and keep releasing the active ingredient for a sufficiently long time.
  • methods and/or compositions for use according to the invention comprise the administration, preferably the repeated administration, of obicetrapib and ezetimibe (or a salt, hydrate or solvate thereof), preferably in the form of the fixed dose pharmaceutical composition as defined herein, to the subject, at a dose and frequency effective to reduce the subject’s LDL-C plasma levels, the subject’s ApoB plasma levels and/or the subjects Lp(a) plasma levels, more preferably to accomplish a reduction in one or more of the subject’s LDL-C plasma levels, the subject’s ApoB plasma levels and/or the subjects Lp(a) plasma levels within the ranges recited herein elsewhere.
  • these treatments comprise the repeated administration of obicetrapib and ezetimibe (or a salt, hydrate or solvate of obicetrapib and/or ezetimibe), preferably in the form of the fixed dose pharmaceutical composition as defined herein, in accordance with the above-defined regimens, during 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 year, at least three year, at least 5 year, at least 10 year, at least 20 year, at least 30 year.
  • treatment may be continued for as long as it is deemed beneficial to the subj ect’ s overall health and well-being (as determined by appropriately qualified healthcare professional), e.g. for the rest of the subject’s life.
  • Another aspect of the invention is directed to a pharmaceutical kit comprising a package containing a plurality of unit dosage forms and a leaflet, wherein said unit dosage forms contain the pharmaceutical composition according to the invention and wherein said leaflet contains printed instructions to repeatedly self-administer said unit dosage forms in order to accomplish any of the therapeutic objectives as defined herein, such as to treat and/or prevent any cardiac disease or dysfunction as defined herein.
  • the pharmaceutical kit comprises a container, such as a cardboard box, holding one or more blister packs, said one or more blister packs containing a plurality of solid unit dosage forms as defined herein before, preferably a plurality of tablets as defined herein before.
  • the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12 of at least 15 of said unit dosage forms, e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms.
  • the pharmaceutical kit only comprises unit dosage forms as defined herein that contain obicetrapib as the sole active ingredient.
  • the pharmaceutical kit only comprises a plurality of unit dosage forms as defined herein that contain obicetrapib (or a salt, hydrate or solvate thereof) as the sole active ingredient and a plurality, preferably an equal number, of unit dosage forms that contain ezetimibe as the sole active, typically in the dose amounts recited herein elsewhere.
  • the pharmaceutical kit only comprises a plurality of unit dosage forms as defined, wherein each unit dosage form comprises obicetrapib (or a salt, hydrate or solvate thereof) and ezetimibe (or a salt, hydrate or solvate thereof), more preferably a plurality of the fixed dose pharmaceutical composition as defined herein.
  • kits as defined herein may further comprise a plurality of unit dosage forms that contain a HMG CoA reductase inhibitor as the sole active, preferably atorvastatin or rosuvastatin (or a salt, hydrate or solvate thereof), typically in the dose amounts recited herein elsewhere.
  • a HMG CoA reductase inhibitor as the sole active, preferably atorvastatin or rosuvastatin (or a salt, hydrate or solvate thereof), typically in the dose amounts recited herein elsewhere.
  • the pharmaceutical kit comprises a leaflet inserted into the container, typically a patient information leaflet containing printed information, which information may include a description of the form and composition of the unit dosage forms contained in the kit, an indication of the therapeutic indications for which the product is intended, instructions as to how the product is to be used and information and warnings concerning adverse effects and contraindications associated with the use.
  • the leaflet that is part of the kit according to the invention, will typically contain the information concerning the therapeutic indications, uses, treatment regimens, etc. as described here above in relation to the methods of treatment of the present invention.
  • the leaflet contains printed instructions to repeatedly (self- administer the unit dosage forms in order to treat and/or prevent CVD, in particular ASCVD.
  • obicetrapib as contained in the present pharmaceutical compositions, as used in the present methods, as contained in the unit dosage forms (comprised in the pharmaceutical kit), etc., is a salt form of obicetrapib, more particularly an amorphous obicetrapib calcium salt, in particular, amorphous obicetrapib hemicalcium.
  • the amorphous obicetrapib hemicalcium of the disclosure is different from and can be distinguished from the crystalline obicetrapib hemicalcium disclosed in U.S. Patent Number 7,872,126.
  • a common technique used to distinguish crystalline from amorphous materials is x- ray powder diffraction. However, this technique has limitations, especially when the crystalline material is disordered.
  • 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 features that are associated with amorphous materials.
  • the x-ray powder diffraction pattern from Figure 50 has peaks at about 3.4°20, about 7.O°20, and about 9.2°20.
  • another sample of Figure 51 has x-ray powder diffraction peaks also at about 3.4°20, about 7.O°20, and about 9.2°20.
  • the x- ray powder diffraction patterns of any of Figure 49 or Figure 50 or Figure 51 may be used to characterize amorphous obicetrapib hemicalcium, provided, however, occasionally, a sharp higher angle peak is present, such as at about 31.7°20 is found (such as in Figure 50), and that peak, when present, is due to sodium chloride.
  • Example 11.18, Example 11.19, Example 11.20, and Example 11.21 set forth various x-ray powder diffraction procedures.
  • the procedure of Example 11.18 was generally used to collect the data set forth in Figures 49, 54, 55, and 56;
  • Example 11.19 was generally used for Figure 50;
  • Example 11.20 was used generally used for Figure 51; and
  • Example 11.21 was generally used for Figures 66, 67, and 68 (with Figure 68 being for Compound ID rather than crystalline obicetrapib HC1).
  • amorphous in “amorphous obicetrapib hemicalcium” does not mean that the material has no order whatsoever. As shown by the presence of peaks in the x- ray powder diffraction pattern, there is still some order in the sample. Thus, as used herein, the term “amorphous” in “amorphous obicetrapib hemicalcium” does not mean that the x-ray powder diffraction pattern must contain purely an amorphous halo (but may contain halo-like features). Rather, it means that there is disorder, but the amorphous phase is distinguishable from the crystalline phase as discussed below.
  • PLM polarized light microscopy
  • a material is viewed through polarized light, and by viewing the material through cross-polarizers, one can differentiate between materials that are anisotropic (e.g., crystals) or isotropic (e.g., amorphous compounds).
  • Anisotropic materials when exposed to polarized light through cross polarizers, exhibit birefringence which manifests itself by exhibiting color change through cross polarizers.
  • Isotropic materials do not show birefringence and exhibit no color change when exposed to polarized light.
  • Figure 57 amorphous obicetrapib hemicalcium was analyzed by polarized light microscopy as set forth in Example 11.17.
  • Figure 57 shows, the materials under study do not birefringe indicating that the material is amorphous.
  • Figure 58 is a polarized light micrograph of crystalline obicetrapib hemicalcium made in accordance with Example 11.16.
  • the particles shown in Figure 58 (which is in black and white) exhibits a much brighter contrast. In the corresponding color version, that figure is multicolored.
  • Figure 58 indicates crystallinity.
  • crystals in Figure 58 are larger than the particles provided in the amorphous obicetrapib hemicalcium polarized light micrograph of Figure 57. Accordingly, PLM and/or the lack of birefringence can be used to characterize amorphous obicetrapib hemicalcium.
  • mDSC modulated differential scanning calorimetry
  • mDSC modulated Differential Scanning Calorimetry
  • the term “about” generally refers to a variability of plus or minus 1°C.
  • crystalline obicetrapib hemicalcium has a higher glass transition temperature under the same conditions, and three measurements in Figure 62 indicate a range between about 118°C and about 125.5°C.
  • the glass transition temperature of amorphous obicetrapib hemicalcium is between about 109°C and 112°C when measured with a pinhole.
  • the glass transition temperature of amorphous obicetrapib hemicalcium was found to be about 111°C (111.32°C at the midpoint) and is shown in Figure 61. The onset was measured to be about 102°C (101.62°C) and the endpoint about 118°C (117.58°C)
  • the glass transition temperature of amorphous obicetrapib hemicalcium may also be measured using mDSC with a closed pan.
  • the type of sample preparation may affect the measured glass transition temperature. In such cases, the glass transition temperature decreases to temperatures of less than about 100°C and in particular between about 70°C and about 92°C depending on humidity.
  • FIG. 59 is a thermogravimetric analysis thermogram of amorphous obicetrapib hemicalcium showing a weight loss of less than 1% when heated to about 200°C. Such weight losses may be, for example, between about 0.8% and about 0.95% including between about 0.84% and about 0.92%. In Figure 59, the weight loss was determined to be about 0.85%. This particular material was found to have a water content of about 1.5%. In some embodiments, the water content of may be higher and include a range from about 0% to about 5% water by weight, including up to about 4% by weight, up to about 3% by weight, and between about 0.5% and 1.5% by weight.
  • TGA thermogravimetric analysis
  • Solid-state 13 C-NMR spectroscopy is another technique which may be used to characterize amorphous materials.
  • Figure 63 shows a solid-state 13 C-NMR spectrum of both crystalline and amorphous obicetrapib hemicalcium with Figure 64 and Figure 65 showing the crystalline and amorphous obicetrapib hemicalcium separately. There are at least two differences in the spectra.
  • the crystalline phase has a peak at about 22.1 ppm and which not present in the amorphous phase.
  • a peak at about 29.5 ppm in the crystalline phase is pronounced while not nearly so in the amorphous phase.
  • the absence of a solid-state 13 C-NMR peak at about 22.1 ppm and/or the absence of a pronounced peak at about 29.5 ppm may be used to characterize amorphous obicetrapib hemicalcium.
  • a solid-state 13 C- NMR spectrum substantially the same as that of Figure 65 may be used to characterize amorphous obicetrapib hemicalcium.
  • the absence of a peak in this context does not mean there is necessarily no intensity of, for example, 22.1 ppm or 29.5 ppm, but rather the intensity is not pronounced as it is in the crystalline obicetrapib hemicalcium 13 C-NMR spectrum.
  • the properties of crystalline materials also typically differ from those of amorphous materials. Thermodynamically, crystalline materials are more physically stable than amorphous materials. Accordingly, there is a thermodynamic driving force to convert amorphous compounds into crystalline ones. Under accelerated stress conditions, if there would be a physical conversion of solid form, one would therefore generally expect it to be from amorphous to crystalline. However, with obicetrapib hemicalcium, the reverse is the case.
  • Figure 54 is a plot of x-ray powder diffraction pattern taken of crystalline obicetrapib hemicalcium
  • Figure 55 is a plot of x-ray powder diffraction patterns taken of crystalline obicetrapib hemicalcium under stress conditions.
  • Pattern 1 is an x-ray powder diffraction pattern of a sample of amorphous obicetrapib hemicalcium
  • Pattern 2 is the x-ray powder diffraction pattern of a sample of crystalline obicetrapib hemicalcium.
  • pattern 3 the sample of crystalline obicetrapib hemicalcium was exposed to 70°C at 75% relative humidity for one day.
  • the x-ray powder diffraction pattern shows the near total loss of crystallinity in that day.
  • the result remains the same as seen in pattern 4.
  • Pattern 1 was taken before the sample was placed on stability. Exposing that material to the same 70°C and 75% relative humidity conditions did not trigger a crystallization and the material remained amorphous after 7 days (pattern 2) and 14 days (pattern 3).
  • pattern 2 Exposing that material to the same 70°C and 75% relative humidity conditions did not trigger a crystallization and the material remained amorphous after 7 days (pattern 2) and 14 days (pattern 3).
  • amorphous obicetrapib hemicalcium is more physically stable than crystalline obicetrapib hemicalcium under typical pharmaceutical use and processing conditions.
  • amorphous obicetrapib hemicalcium is more suitable for pharmaceutical development and use than the corresponding crystalline phases.
  • amorphous obicetrapib hemicalcium is more soluble than the highly insoluble crystalline obicetrapib hemicalcium.
  • solubility is especially challenging with obicetrapib.
  • the solubility of obicetrapib has been measured to be substantially less than 0.1 mg/mL in water. It would be desirable to have a solid form of obicetrapib that would deliver a larger amount of obicetrapib.
  • solubility is a thermodynamic quantity of a material
  • Such measurements provide the solubility under metastable conditions and provide information, for example, of the amount of material undergoing dissolution as a function of time.
  • the amorphous form has a higher kinetic solubility and dissolution rate than the crystalline form (and by extension obicetrapib itself). Both crystalline and amorphous obicetrapib hemicalcium kinetic solubility determinations were made in biorelevant media at different pHs, namely at about 5.0 (FeSSIF conditions) and at pH of about 6.5 (FaSSIF) conditions as set forth in Example 11.28.
  • Table W shows the measured solubility of two different batches of amorphous obicetrapib hemicalcium versus crystalline obicetrapib hemicalcium over the course of 2 hours in FeSSIF media at 37°C. In both cases, the amorphous obicetrapib hemicalcium had a higher concentration in solution than the corresponding crystalline material for all time points measured.
  • the concentrations in Table W are those of obicetrapib (i.e., the free acid).
  • Table X shows a similar experiment at 37°C but in FaSSIF media at a pH of 6.5. As with Table W, in both batches, the amorphous obicetrapib hemicalcium had a higher concentration in solution than the corresponding crystalline material for all time points measured. The concentrations in Table X are those of obicetrapib (i.e., the free acid).
  • amorphous obicetrapib hemicalcium dissolves faster than the corresponding crystalline phase, more drug is available for immediate use and potentially higher bioavailability in the amorphous phase than in the crystalline phase.
  • Amorphous obicetrapib hemicalcium is also advantageous because, unlike many amorphous organic compounds, it does not readily pick up moisture. When exposed to relative humidities approaching 90%, moisture uptake has been measured to be typically less than about 5% for example. This lack of hygroscopicity is favorable because it does not require any special handling or storage conditions. Other drawbacks commonly associated with manufacturing and using amorphous materials are similarly not present. For example, amorphous materials are often challenging to make chemically pure. Here, however, amorphous obicetrapib hemicalcium can be made routinely with chemical purities of 99.9% or higher.
  • substantially pure amorphous obicetrapib hemicalcium there is provided substantially pure amorphous obicetrapib hemicalcium.
  • the chemical purity of substantially pure amorphous obicetrapib hemicalcium is 99.9% or greater.
  • a method of preparing an amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium, wherein the method comprises: treating obicetrapib with an acid to form a salt, solvate, or composition; isolating the resulting salt, solvate or composition; and treating that salt, solvate, or composition with a calcium source to create an amorphous obicetrapib calcium salt, such as amorphous obicetrapib hemicalcium.
  • the resulting salt can then be isolated.
  • Examples of calcium sources include calcium salts such as halogenated calcium salts and soluble calcium salts.
  • the calcium source is calcium chloride.
  • an amorphous salt of obicetrapib calcium such as amorphous obicetrapib hemicalcium has been found to occur when there is an intermediate salt, solvate or composition (such composition comprising the corresponding acid used to make a salt).
  • Treating obicetrapib directly with a calcium base such as calcium hydroxide has not been found to be a viable way of making an amorphous salt of obicetrapib calcium due to either low solubility, the weakness of the bases available or both. Rather, it has been found that by deploying an intermediate salt, such as a sodium salt, the preparation of amorphous obicetrapib hemicalcium is viable.
  • the use of the salt, solvate, or composition enables the production of a highly pure amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium.
  • Exemplary salts that may be made as an intermediate include those from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), a sulfate (e.g., methyl sulfate), a halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate,
  • the intermediate when the intermediate is a solvate or a composition, then the corresponding acids may be used or present.
  • the intermediate when a solvate, the intermediate may further include a solvent such as an organic solvent or water, in which case the solvate would be a hydrate.
  • a solvent such as an organic solvent or water, in which case the solvate would be a hydrate.
  • organic solvent is CPME (cyclopentyl methyl ether).
  • the intermediate is a solvate of an acid.
  • the intermediate is a solvate of an acid and an organic solvent.
  • the intermediate is a solvate comprising an acid and a solvent.
  • the acid is hydrochloric acid and a solvent is CPME.
  • the disclosure includes methods for preparing amorphous obicetrapib calcium salts, such as amorphous obicetrapib hemicalcium.
  • the disclosure further includes amorphous obicetrapib calcium salts, including amorphous obicetrapib hemicalcium, so prepared.
  • an intermediate referred to herein as crystalline obicetrapib HC1 is used in the processes for preparing amorphous obicetrapib calcium, such as amorphous obicetrapib hemicalcium.
  • amorphous obicetrapib hemicalcium is prepared via a chemical synthesis where an intermediate is used denoted by Formula (IH):
  • y varies such that the mass percent of HC1 varies from 0.01% to 8% by weight and is believed to further include an associated organic solvent such as by way of a solvate.
  • y varies from 0.002 to 1.5.
  • y varies from 0.3 to 1.
  • y varies from 0.4 to 0.6, including between 0.5 and 0.6.
  • Formula (IH), as a solvate is isolated in its crystalline form.
  • the solvent is CPME.
  • Other solvents which may form solvates include toluene and heptane.
  • Obicetrapib HC1 as typically prepared herein is crystalline.
  • the term crystalline obicetrapib HC1 may include CPME as a solvate when CPME is used in the preparation of crystalline obicetrapib HC1.
  • the solvate is of an organic solvent and in many embodiments, that solvent is CPME.
  • the disclosure provides for compositions comprising crystalline obicetrapib HC1.
  • Formula (IH) is referred to as obicetrapib HC1 and when crystalline, it is referred to as crystalline obicetrapib HC1.
  • crystalline HC1 obicetrapib is a mixed salt solvate. It has been found that when CPME is used to deliver HC1 in the reaction to create Formula (IH), the chloride content of Formula (IH) ranges between about 2.5% and 3.0% by weight which is below what one would expect for a neutral salt - namely about 4.8% by weight.
  • crystalline obicetrapib HC1 when CPME is so used, it is found in the material when crystallized.
  • the resulting crystalline Formula (IH) material is referred to as crystalline obicetrapib HC1, those x-ray powder diffraction pattern are seen in Figure 66.
  • An advantage of using crystalline obicetrapib HC1 as an intermediate is that the resulting amorphous obicetrapib hemicalcium has a chemical purity which is routinely 99.9% pure or greater. Chemical purity is the quantitative representation of whether other chemical entities other than the compound being measured are present.
  • a chemical purity of 99.9% amorphous obicetrapib hemicalcium means that not more than 0.1% of the compounds in a sample of amorphous obicetrapib hemicalcium are other entities.
  • Physical purity refers to the amount of other solid forms of the same compound present which, in the case of amorphous obicetrapib hemicalcium, the other solid form being crystalline obicetrapib hemicalcium.
  • the disclosure herein provides for amorphous obicetrapib hemicalcium which is physically pure meaning it is free or substantially free of crystalline obicetrapib hemicalcium. Unless otherwise stated herein, the purity measurements provided herein are measurements of chemical purity.
  • HC1 obicetrapib is not limited to crystalline obicetrapib HC1. Indeed, upon desolvation, crystalline obicetrapib HC1 may become amorphous.
  • pattern 2 reflects crystalline obicetrapib HC1 subject to a mild drying treatment whereby surface solvent was removed and it can be seen that this compound is crystalline.
  • the sample whose x-ray powder diffraction was measured in pattern 1 was subject to a stronger drying treatment at 48 hours at 55°C at a pressure of 2mbar. As is apparent, this drying changed the material from crystalline to amorphous, likely due to loss of HC1 and a desolvation of CPME.
  • 1 H-NMR spectroscopy for example, was used to show the presence of CPME in the top pattern, but was substantially absent in the lower, amorphous pattern.
  • the amorphous pattern therefore, represents HC1 obicetrapib which is not crystalline obicetrapib. It may be obicetrapib, but is believed to have HC1 associated with the obicetrapib as a solvate and thus is HC1 obicetrapib, but with a lower chloride content than typically found in the ranges found for crystalline obicetrapib HC1. In some embodiments, that chloride content is less than 0.1% by weight such as between about 0.01% and 0.1% by weight.
  • Crystalline obicetrapib HC1 may be characterized by an x-ray powder diffraction pattern comprising a peak at about 9.8°2 ⁇ .
  • crystalline obicetrapib HC1 may be characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 8.1°20, about 9.8°2 ⁇ , about 13.8°2 ⁇ , about 16.7°2 ⁇ , or about 19.5°2 ⁇ .
  • Table Y provides illustrative peaks which may be present in crystalline obicetrapib HC1.
  • crystalline obicetrapib HC1 may be characterized by an x-ray powder diffraction pattern substantially the same as that in Figure 67, although it is believed that the material analyzed in Figure 67 was measured in such a way that a peak between about 4.3°2 ⁇ and about 4.7°2 ⁇ was not measured.
  • Table Y Another intermediate used in the preparation of obicetrapib is that of Formula (VI) wherein Y 1 is a protecting group (e.g., as described herein); A n ' is an anion; and n is an integer from 1-3.
  • Y 1 is a protecting group (e.g., as described herein); A n ' is an anion; and n is an integer from 1-3.
  • the compound of Formula (VI) is a mesylate salt where n is 1, Y 1 is t-butyl, and has the structure of Compound ID:
  • a 'H-NMR spectrum of Compound ID (in solution) can be found in Figure 69.
  • Crystalline Compound ID may be characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 5.2°20 or about 9.1°20.
  • crystalline Compound ID may be characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 5.2°20, about 9.1°20, about 15.9°20, about 16.5°20, about 17.2°20, about 18.6°20, and about 19.2°20.
  • Table Z provides illustrative peaks which may be present in crystalline Compound ID (with the peak at about 5.2°20 not measured due to instrument limitations in reflection mode).
  • crystalline Compound ID may be characterized by an x-ray powder diffraction pattern substantially the same as Figure 68.
  • Crystalline compounds such as crystalline Compound ID and a crystalline obicetrapib HC1, for example, may be characterized by x-ray powder diffraction.
  • An x-ray powder diffraction pattern is an x-y graph with °20 (diffraction angle) on the x-axis and intensity on the y-axis.
  • the peaks are usually represented and referred to by their position on the x-axis rather than the intensity of peaks on the y-axis because peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is not typically used to characterize solid forms.
  • the data from x-ray powder diffraction may be used in multiple ways to characterize crystalline forms.
  • the entire x-ray powder diffraction pattern output from a diffractometer may be used to characterize a crystalline obicetrapib HC1 compound or a crystalline Compound ID.
  • a smaller subset of such data may also be, and typically is, suitable for characterizing such compounds.
  • a collection of one or more peaks from such a pattern may be used to so characterize these compounds.
  • the phrase “one or more peaks” of a list of peaks from an x-ray powder diffraction pattern are provided, what is generally meant is that any combination of the peaks listed may be used for characterization.
  • the fact that other peaks are present in the x-ray powder diffraction pattern generally does not negate or otherwise limit that characterization.
  • variability in the position of peaks on the x-axis may derive 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 yield slightly different diffractograms, and different x-ray instruments may operate using different parameters and these may lead to slightly different diffraction patterns from the same crystalline solid.
  • crystalline Compound ID may be further characterized by an x- ray powder diffraction pattern substantially the same as the x-ray powder pattern as that of Figure 68.
  • a method of preparing an amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium, wherein the method comprises: i. treating obicetrapib with HC1 to obtain crystalline obicetrapib HC1; ii. isolating crystalline obicetrapib HC1; iii. preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium, from the crystalline obicetrapib HC1 isolated in step (ii); and iv.
  • amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium.
  • a method of preparing obicetrapib wherein the method comprises:
  • steps (a)-(d) of the subject method are performed in a solvent, and intermediate compounds of Formulae (IV), (V) and (VIII) do not need to be isolated from their respective solvents if they are to be processed further to end products.
  • the intermediate compound of Formula (VI) may be isolated from the solvent as a salt in solid form, such that it can be washed to remove impurities. This isolation step ensures sufficient purity of downstream products.
  • the subject process does not need to comprise purification steps using chromatography, such as column chromatography to achieve the chemical purity levels described herein.
  • the method includes step (i), treating obicetrapib with HC1 in an organic solvent to obtain crystalline obicetrapib HC1.
  • crystalline obicetrapib HC1 has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, or even more.
  • the HC1 in step (i) is in a suitable solvent.
  • solvent may be an aqueous solvent or an organic solvent.
  • the organic solvent used in step (i) comprises a mixture of a solvent and an anti-solvent.
  • the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl- tetrahydrofuran, di chloromethane, 1,4-di oxane, 1,2-diflurobenzene, toluene, hexafluoroisopropanol, and water.
  • the anti-solvent is selected from n- heptane, n-hexane, n-pentane, and cyclohexane.
  • the HC1 has sufficient solubility in the anti-solvent such that it can be used as a suitable solvent.
  • the organic solvent used in step (i) comprises a mixture of cyclopentyl methyl ether and n-heptane.
  • the organic solvent used in step (i) further comprises toluene. In some embodiments, toluene is the majority component of the organic solvent.
  • step (i) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane , raising the temperature to between 35°C and 40°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, then adding further n-heptane as an anti-solvent.
  • a small portion of the reaction mixture can optionally be extracted, cooled to a temperature of between 10°C and 15°C, to obtain a slurry of crystals of crystalline obicetrapib HC1 in a mixture of cyclopentyl methyl ether and n-heptane (referred to herein as a “seed crystal slurry”).
  • seed crystal slurry a mixture of cyclopentyl methyl ether and n-heptane
  • all or a portion of the seed crystal slurry of crystalline obicetrapib HC1 can then be added back to the reaction mixture.
  • the seeds assist with nucleation but are not required.
  • the resulting reaction mixture is then cooled to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HC1 from the system under agitation.
  • the crystalline obicetrapib HC1 is crystallized over a period of 12 hours or more, with subsequent filtration (e.g., through a filter dryer), one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane , and drying.
  • a wet filter cake of crystalline obicetrapib HC1 is dried in vacuo in steps using temperatures of 25°C-30°C, 30°C-40°C, 40°C-50°C then 50°C-55°C, such as 25°C, 35°C, 46°C, and 54°C.
  • the method of preparing crystalline obicetrapib HC1 comprises the addition of seed crystals (e.g., as a seed crystal slurry).
  • the seed crystals of an HC1 compound can be formed as a slurry by following step (i) as set out above and after addition of dry HC1 in cyclopentyl methyl ether and anti-solvent n-heptane , extracting a small portion of the reaction mixture, cooling to a temperature between 10°C and 15°C, to provide a slurry of crystals of crystalline obicetrapib HC1 in cyclopentyl methyl ether and n-heptane .
  • step (i) comprises providing crystalline obicetrapib HC1 in a mixture of cyclopentyl methyl ether and n-heptane , raising the temperature to between 35°C and 45°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, addition of further n-heptane as anti-solvent, and the optional addition of seed crystals of an HC1 compound (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HC1 from the system under agitation.
  • an HC1 compound e.g., as a seed crystal slurry prepared as described herein
  • the crystalline obicetrapib HC1 is crystallized over a period of 12 hours or more, with subsequent filtration, one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane , and drying.
  • crystalline obicetrapib HC1 is dried in vacuo.
  • crystalline obicetrapib HC1 is subjected to drying in a vacuum drying cabinet at 25 mbar pressure and at a temperature of 55°C for 10 hours or more.
  • the crystalline obicetrapib HC1 includes less than 0.1 weight percent residual cyclopentyl methyl ether.
  • step (i) comprises providing the solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 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) (such as toluene), less than 1 weight percent of n-heptane based on weight of solution, addition of n-heptane , raising the temperature to 35°C to 45°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to 50°C to 55°C, addition of further n-heptane as anti-solvent, optional addition of seed crystals of a crystalline obicetrapib HC1 (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 10°C and 15°C, followed by crystallizing crystalline obicetrapib HC1 from the system under agitation
  • the crystalline obicetrapib HC1 from step (i) is isolated in step (ii).
  • the isolated crystalline obicetrapib HC1 has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, 99.7%, or even more.
  • Another embodiment of the disclosure concerns the crystalline obicetrapib HC1, obtained by or obtainable by the process as defined herein.
  • Still another embodiment of the disclosure is directed to HC1 obicetrapib, including crystalline obicetrapib HC1.
  • the crystalline obicetrapib HC1 is stored at controlled room temperature and under a nitrogen atmosphere and is protected from moisture to prevent the formation of an amorphous solid such as from desolvation.
  • the method includes step (iii)-(iv), preparing an amorphous calcium salt of obicetrapib from crystalline obicetrapib HC1 isolated in step (ii), and isolating an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium.
  • the amorphous calcium salt of obicetrapib is in the form of amorphous obicetrapib hemicalcium:
  • step (iii) includes the following steps:
  • step (iii-1) converting crystalline obicetrapib HC1 of step (ii) to provide obicetrapib in an organic solvent
  • step, (iii-1) comprises the following steps:
  • step (aa) providing crystalline obicetrapib HC1, as isolated in step (ii); (bb) dissolving crystalline obicetrapib HC1 in a mixture of water and isopropyl acetate under agitation.
  • step (bb) is conducted at a temperature between 15°C and 25°C;
  • step (dd) performing two or more distillations on the washed organic phase resulting from step (cc) at a temperature of 50°C or lower (such as 30°C or lower), with intermediate additions of ethanol, to obtain a solution of obicetrapib in ethanol.
  • step, (iii-2) comprises the following steps:
  • step (ee) adding an aqueous NaOH solution to the solution obtained in step (dd) and agitating the resulting mixture, such as at a temperature between 20°C and 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib;
  • step (ff) optionally filtering the solution obtained in step (ee).
  • step, (iii-3) comprises the following steps:
  • step (hh) cooling the CaCb solution obtained in step (gg) to a temperature from 8°C to 12°C and adding via a filter to the solution obtained in step (ff) or (ee) under agitation at said temperature;
  • step (ii) stirring the slurry resulting from step (hh) for about 1 to about 10 hours.
  • the stirring is conducted at a temperature between 8°C and 12°C;
  • step (jj) isolating the solids from the slurry obtained in step (ii) by filtration.
  • the isolating is conducted at a temperature between 8°C and 12°C;
  • step (kk) washing the filtration residue obtained in step (jj) with water in one or more washing steps.
  • the washing is conducted at a temperature between 8°C and 12°C; and (11) drying the washed residue obtained in step (kk), such as in vacuo at a temperature from 40°C to 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours, or 200 hours, or even more), to obtain amorphous obicetrapib hemicalcium (also sometimes referred to herein as compound 3).
  • amorphous obicetrapib hemicalcium is submitted to a subsequent reworking procedure.
  • amorphous obicetrapib hemicalcium is further reworked by dissolving in ethanol (such as twice the weight of ethanol relative to amorphous obicetrapib hemicalcium) at a temperature of 25°C to 50°C, followed by cooling to 10°C to 15°C, followed by filtering into a mixture of aqueous calcium chloride solution and ethyl acetate, also cooled to 10°C to 15°C, followed by filtering, washing with water and drying in vacuo at 45°C or less for 20 hours or more.
  • ethanol such as twice the weight of ethanol relative to amorphous obicetrapib hemicalcium
  • amorphous obicetrapib hemicalcium is isolated with a purity of 95% or more, such as a purity of 95.5% or more, 96% or more, 96.5% or more, 97% or more, 97.5% or more, 98% or more, 98.5% or more, 99% or more, 99.1% or more, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more.
  • amorphous obicetrapib hemicalcium is subjected to a milling process.
  • the milling process is adapted (e.g., parameters such as feed rate, venturi pressure and mill pressure are adapted) to allow production of micronized amorphous obicetrapib hemicalcium.
  • step (a) of the process for preparing obicetrapib according to the present disclosure the compound of Formula (II), or a salt thereof, is coupled with a compound of Formula (III) to provide a compound of Formula (IV) (where X 1 is a leaving group and Y 1 is protecting group, e.g., as described herein).
  • Step (a) of the subject method starts with a compound of Formula (II) (2R,4S)-4-amino- 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline), or a salt thereof:
  • the compound of Formula (II) can for example be obtained using a process as disclosed in WO2016/024858A1 or in W02007/116922A1, both of which are incorporated herein by reference in their entirety.
  • the compound of Formula (II) can be obtained from a corresponding salt that is stable and can be obtained in pure and solid form.
  • the solid form can be amorphous or crystalline.
  • the compound of Formula (II) is obtained from a corresponding crystalline salt.
  • the compound of Formula (II) provided in step (a) is a salt of the Formula (IIA) or (IIB): wherein A m ' is an anion and n is an integer from 1-3.
  • the compound of Formula (II) provided in step (a) is a salt of Formula (IIA).
  • the compound of Formula (IIA) is used directly in the coupling reaction with the compound of Formula (III) without performing a desalting step.
  • the compound of Formula (II) provided in step (a) is a salt of Formula (IIB).
  • the compound of Formula (IIB) is used directly in the coupling reaction with the compound of Formula (III) without performing a desalting step.
  • 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 carried out before the coupling reaction of step (a):
  • step (pre-a2) desalting the compound of Formula (IIA) or (IIB) to obtain the compound of Formula (II), wherein the reaction in step (pre-a2) is performed in an organic solvent, the compound of Formula (II) is not isolated from the organic solvent, and the process does not comprise chromatography.
  • 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).
  • the salts of Formula (IIA) or (IIB), are chosen from salts with an anion A m ' selected from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), a sulfate (e.g., methylsulfate), a halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pan
  • the salts of Formula (IIA) or (IIB), are chosen from salts with an anion A m ' selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.
  • the salts of Formula (IIA) or (IIB), are chosen from salts with an anion A m ' selected from chloride, bromide, bitartrate, and mesylate.
  • m is 1.
  • the salt is of Formula (IIA), and the anion A m ' is mesylate, where m is 1.
  • the mesylate (MSA) salt (also referred to herein as compound 1A, shown below) can be obtained via a process as disclosed in WO2016/024858A1 or in WO2007/116922A1, the disclosures of which are incorporated herein by reference in their entirety.
  • the desalting of a compound of Formula (IIA) or (IIB) in step (pre-a2) is performed in a mixture of an aqueous sodium hydroxide solution and an organic solvent chosen from toluene, dichloromethane, cyclopentyl methyl ether, isopropyl ether, t- butyl methyl ether, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, chlorobenzene and combinations thereof, followed by heating the mixture then cooling the mixture, and allowing the system to phase separate, and separating off the aqueous phase.
  • the solvent is toluene.
  • the reaction mixture is heated to a temperature between 45°C and 60°C, then cooled to a temperature between 15°C and 40°C.
  • the organic phase obtained after separating off the aqueous phase is subjected to one or more aqueous washing steps wherein each aqueous washing step is followed by separating off the aqueous phase, such as one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and subsequently one or more washing steps with deionized water, again followed by separating off the aqueous phase.
  • the resulting washed organic phase is then optionally subjected to distillation to reduce the water content to below 1000 ppm, based on the weight of the solution.
  • a small amount of water remains in the organic phase with the compound of Formula (II) and the subsequent coupling with a compound of Formula (III) proceeds in the presence of this small amount of water.
  • the desalting reaction in step (pre-2a) is performed on the mesylate salt (Compound 1A) in a mixture of an aqueous sodium hydroxide solution and toluene, at a temperature between 45°C and 60°C, followed by cooling the mixture to a temperature between 15°C and 25°C, allowing the system to phase separate, and separating off the aqueous phase.
  • the toluene phase obtained after separating off the aqueous phase is then optionally subjected to one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and subsequently one or more washing steps with deionized water, again followed by separating off the aqueous phase, after which the resulting washed toluene phase is subjected to distillation at a temperature between 50°C and 65°C under reduced pressure to reduce the water content to below 1000 ppm, based on the weight of the total amount of the solution.
  • a small amount of water remains in the toluene with the compound of Formula (II) and the subsequent coupling reaction with a compound of Formula (III) proceeds in the presence of this small amount of water.
  • step (a) the compound of Formula (II), or a salt thereof (e.g., compound of Formula (IIA) or (IIB), such as the mesylate salt 1A), is coupled with a compound of Formula (III) to provide a compound of Formula (IV).
  • this process is carried out in an organic solvent.
  • the coupling partner of Formula (III) in step (a) includes a leaving group (X 1 ). It will be understood that any convenient leaving group may find use in the present disclosure for X 1 .
  • the leaving group (X 1 ) in the compound of Formula (III) is selected from a halogen, a carbamate, and a substituted sulfonyloxy group.
  • the leaving group (X 1 ) in the compound of Formula (III) is a sulfonyloxy group selected from a methanesulfonyloxy, p-toluenesulfonyloxy or a trifluoromethanesulfonyloxy group.
  • 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 ).
  • protecting group refers to any group which when bound to a functional group such as a carboxylic acid moiety of the compounds (including intermediates thereof) prevents reactions from occurring at the functional group and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the functional group e.g., the carboxylic acid moiety.
  • carboxylic acid protecting groups include conventional substituents such as t-butyl esters, methyl esters, ethyl esters, benzyl esters, allyl esters, 1,1 -di ethylallyl esters, 2,2,2-trifluro ethyl esters, phenyl esters, 4-methoxybenzyl esters, silyl esters, ortho esters, esters of 2, 6-di substituted phenols (e.g., 2,6- dimethylphenol) and any other groups that can be introduced chemically onto a carboxylic acid group or like functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • substituents such as t-butyl esters, methyl esters, ethyl esters, benzyl esters, allyl esters, 1,1 -di ethylallyl esters, 2,2,2-trifluro ethyl esters, phenyl
  • any convenient protecting group e.g., ester group
  • a carboxylic acid moiety may find use in the present disclosure for Y 1 , and the selection of appropriate protecting groups can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis, 4 th Ed., by T. W. Greene and P. G. M. Wuts (John Wiley & Sons, New York, 1999), in Protecting Group Chemistry, 1st Ed., by Jeremy Robertson (Oxford University Press, 2000); and in March's Advanced Organic chemistry: Reactions Mechanisms, and Structure, 8th Ed., by Michael B.
  • the protecting group (Y1) is selected from an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an allyl group, a substituted allyl group, and a silyl group.
  • the protecting group (Y1) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluro ethyl, phenyl, 4-methoxybenzyl ester, a 2,6-disubstituted phenol, and a silyl group.
  • the protecting group (Y1) is a t-butyl group.
  • the compound of Formula (III) is of the structure 1B below: 1B .
  • the solvent is selected from toluene, t-butanol, 1,4- dioxane, xylene, N-methyl-2-pyrrolidone, dimethylformamide, water, tetrahydrofuran, and combinations thereof.
  • the solvent is a mixture of organic solvent toluene and organic co-solvent t- butanol.
  • steps (pre-a1) and (pre-a2) are performed before step (a), the compound of Formula (II) is already present in the required solvent, because the same organic solvents are used in steps (pre-a2) and (a) or because of a solvent swap in step (pre-a2).
  • more organic solvent and for example an organic co-solvent can be added in step (a).
  • an organic co-solvent can also be added during a solvent swap in step (pre-a2).
  • steps (pre-a1) and (pre-a2) are performed before step (a) and the compound of Formula (II) is present in toluene.
  • the coupling reaction in step (a) typically is a catalyzed reaction.
  • the reaction is a palladium-catalyzed coupling reaction in the presence of a base.
  • Suitable examples of palladium catalysts are for example tris(dibenzylideneacetone)dipalladium and Pd(II)acetate.
  • Suitable bases include organic bases (e.g., sodium t-butoxide, and potassium t- butoxide) and inorganic bases (e.g., K3PO4 , K3PO4 ⁇ H2O, sodium carbonate , potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH).
  • anhydrous K3PO4 is used as a base.
  • the particle size distribution is such that 90% of the particles are smaller than between about 140 and about 307 microns including between about 140 and about 170 microns, including about 160 and about 290 microns, and about 180 and about 220 microns, and about 200 and about 210 microns. In some embodiments, 90% of the particles are less than 205 microns. In these and other embodiments, 50% of the particles are between about 35 and about 173 microns or smaller, including between about 35 and about 40 microns. In these and other embodiments, 10% of the particles between about 7 and about 74 microns including between about 7 and about 10 microns.
  • the compound of Formula (II) is reacted in step (a) with a compound of Formula (III) in a solvent (e.g., an organic solvent), using a palladium catalyst, a base.
  • the reaction mixture further includes a ligand.
  • the compound of Formula (IIA) or (IIB) is reacted in step (a) with a compound of Formula (III) in a solvent (e.g., an organic solvent), using a palladium catalyst, a base.
  • the reaction mixture further includes a ligand.
  • the desalted compound of Formula (II) is reacted in step (a) with a compound of Formula (III) in the solvent (e.g., an organic solvent), using Pd(II)acetate, either (S)-BINAP [(S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] or rac-BINAP as a ligand.
  • solvent e.g., an organic solvent
  • (S)-BINAP is used as the ligand, and a base selected from sodium t- butoxide, potassium t-butoxide, anhydrous K3PO4, K 3 PO 4 ⁇ H 2 O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH and NaOH.
  • a salt of Formula (IIA) or (IIB) is reacted in step (a) with a compound of Formula (III) in the solvent (e.g., an organic solvent), using Pd(II)acetate, either (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.
  • a compound of Formula (III) in the solvent e.g., an organic solvent
  • (S)- BINAP is used as the ligand, and a base selected from sodium t-butoxide, potassium t-butoxide, anhydrous K3PO4, K 3 PO 4 ⁇ H 2 O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH and NaOH.
  • the salt of Formula (IIA) is the mesylate salt, Compound 1A.
  • the reaction in step (a) is performed at a temperature from 70°C and 80°C, optionally under a nitrogen atmosphere, for 2 or more hours.
  • the compound of Formula (II) or salt of Formula (IIA) is reacted in step (a) with a compound of Formula (III) wherein X1 is Cl and Y1 is t-butyl, in a mixture of organic solvent toluene and organic co-solvent t-butanol, using Pd(II)acetate as catalyst, (S)- BINAP as a ligand, and anhydrous K 3 PO 4 or K3PO4 ⁇ H2O as a base, at a temperature between 70°C and 80°C, under a nitrogen atmosphere, for 2 or more hours.
  • a compound of Formula (III) wherein X1 is Cl and Y1 is t-butyl in a mixture of organic solvent toluene and organic co-solvent t-butanol, using Pd(II)acetate as catalyst, (S)- BINAP as a ligand, and anhydrous K 3 PO 4 or K3PO4 ⁇ H2O as a base
  • the one or more aqueous washing steps comprise one or more washing steps with water, preferably deionized water, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous HCl solution, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and finally one or more washing steps with again deionized water, followed by separating off the aqueous phase.
  • water preferably deionized water
  • step (a) is performed in an organic solvent different from the solvent used in step (b)
  • the organic solvent used in step (a) is swapped in step (a) with the organic solvent applied in step (b), such that the compound of Formula (IV) remains in solution.
  • at least part of the (organic) solvent used in step (a) is evaporated, such as by using distillation at reduced pressure, and the organic solvent of step (b) is added, such that the compound of Formula (IV) remains in solution during the solvent swap.
  • This process can be performed by continuously evaporating the (organic) solvent used in step (a) and by continuously adding the organic solvent of step (b), for example until the amount of the (organic) solvent used in step (a), based on the total amount of solvent, is below a certain threshold value.
  • this process can be performed batch-wise in more than one steps of evaporating part of the (organic) solvent used in step (a) and subsequently adding part of the organic solvent used in step (b), for example until the amount of the (organic) solvent used in step (a), based on the total amount of solvent, is below a certain threshold value.
  • the solvent used in step (a) is a mixture of organic solvent toluene and organic co-solvent t-butanol.
  • the t-butanol is removed from the organic phase comprising the compound of Formula (IV) during the washing steps.
  • the remaining organic solvent toluene is swapped with acetonitrile by distilling off in two or more steps, at a temperature between 50°C and 65°C under reduced pressure, part of the toluene with intermediate addition of acetonitrile, in an amount to obtain a solvent mixture with less than about 20 weight percent toluene, based on the combined weight of the solvents, such that the compound of Formula (IV) remains in solution.
  • Y 1 is t-butyl.
  • step (b) of the method for preparing a compound of Formula (I) according to the disclosure the compound of Formula (IV) is converted to the carbamate of Formula (V) in an organic solvent, and subsequently isolated as a solid salt of Formula (VI) (where Y 1 is a protecting group, e.g., as described herein).
  • the organic solvent used in step (b) is selected from acetonitrile, chlorobenzene, toluene, V-methyl-2 -pyrrolidone, xylene, 1,4-di oxane, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, t- butyl methyl ether, and combinations thereof.
  • the organic solvent is acetonitrile or a mixture of chlorobenzene and dichloromethane.
  • the compound of Formula (IV) is already provided in step (a) in the organic solvent used in step (b), either because the same organic solvents are used in steps (a) and (b) or because of a solvent swap in step (a).
  • Y 1 is t-butyl.
  • the organic solvent used in step (b) is a mixture of acetonitrile toluene, with less than about 20 weight percent toluene, based on the combined weight of the organic solvents.
  • the conversion of the compound of Formula (IV) to the corresponding carbamate with Formula (V) in step (b) is performed in acetonitrile with less than about 20 weight percent toluene, based on the combined weight of the organic solvents, with an excess ethyl chloroformate in the presence of pyridine, at a temperature between 10°C and 20°C.
  • step (b) is performed in an organic solvent different from the organic solvent used in step (c)
  • the organic solvent used in step (b) is swapped in step (b) with the organic solvent applied in step (c), such that the compound of Formula (V) remains in solution.
  • step (b) In some embodiments where the organic solvents used in steps (b) and (c) are different, at least part of the organic solvent used in step (b) is evaporated, such as by distillation at 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 swap.
  • This process can be performed by continuously evaporating the organic solvent used in step (b) and by continuously adding the organic solvent of step (c), for example until the amount of the organic solvent used in step (b), based on the total amount of organic solvent, is below a certain threshold value.
  • this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (b) and subsequently adding part of the organic solvent used in step (c), for example until the amount of the organic solvent used in step (b), based on the total amount of organic solvent, is below a certain threshold value.
  • the resulting mixture is preferably subjected to one or more treatments with an aqueous sodium chloride and/or HC1 solution, followed by separating off the aqueous phase, and subsequently to one or more treatments with an aqueous bicarbonate solution, followed by separating off the aqueous phase.
  • the conversion of the compound of Formula (IV) to the corresponding carbamate with Formula (V) in step (b) is performed in acetonitrile with an excess of ethyl chloroformate in the presence of pyridine, at a temperature between 10°C and 20°C, and this solvent is swapped in step (b) with isopropyl acetate by distilling off in two or more steps, at a temperature of 60°C or less under reduced pressure, part of the acetonitrile with intermediate addition of isopropyl acetate, in an amount to obtain a solution of the compound of Formula (V) in isopropyl acetate, wherein the solution may be subjected to one or more treatments with an aqueous NaCl/HCl solution, followed by separating off the aqueous phase, and subsequently to one or more treatments with an aqueous bicarbonate solution, followed by separating off the aqueous phase.
  • the salt of Formula (VI) is chosen from salts with an anion A n ' selected from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate and mesylate), a sulfate (e.g., methyl sulfate), a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stea
  • the salt of Formula (VI) is chosen from salts with an anion A n ' selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.
  • the salt of Formula (VI) is chosen from salt with an anion A n ' selected from chloride, bromide, bitartrate, and mesylate.
  • the salt from of Formula (VI) is the mesylate salt including the crystalline mesylate salt thereof, Compound ID:
  • n 1
  • the organic solvent used in the conversion of Formula (V) to (VI) is not particularly limited, but in some embodiments is selected from cyclopentyl methyl ether, isopropyl ether, t- butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof.
  • isopropyl acetate or a mixture comprising dichloromethane, n-heptane and isopropyl alcohol, such as a mixture of chlorobenzene, dichloromethane, n-heptane and isopropyl alcohol is used. It is noted that, the compound of Formula (V) is already provided in organic solvent owing to the solvent swap described herein before.
  • the organic solvent used in the conversion of compound of Formula (V) to its corresponding salt of Formula (VI) selected from cyclopentyl methyl ether, isopropyl ether, /-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, with less than about 20 weight percent toluene and less than about 7 weight percent acetonitrile, based on the combined weight of the solvents.
  • the solvent is a mixture of isopropyl acetate, toluene and acetonitrile, with less than about 20 weight percent toluene and less than about 7 weight percent acetonitrile, based on the combined weight of the solvents.
  • an organic co-solvent different from the organic solvent already used in step (b) is preferred to add an organic co-solvent different from the organic solvent already used in step (b).
  • organic co-solvents are selected from cyclopentyl methyl ether, isopropyl ether, /-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, such as methyl /-butyl ether.
  • the need and advantages of using an organic co-solvent depend on the particular organic solvent already used in step (b). In certain cases, the use of a co-solvent can be dispensed with.
  • the organic solvent for the conversion of a compound of Formula (V) to its corresponding salt of Formula (VI) comprises isopropyl acetate and methyl /-butyl ether as an organic co-solvent.
  • an acid is added to form the salts of Formula (VI) defined supra.
  • the acid is selected from ditartartic acid, sulfuric acids, sulfonic acids, hydrogen bromide and hydrogen chloride.
  • the acid is methanesulfonic acid.
  • the salt of Formula (VI) can be obtained in crystalline form, part of the acid needed to form the salt of Formula (VI) can be added before the crystallization and part during the crystallization.
  • the solid form of the salt of Formula (VI) is isolated by crystallization if the salt of Formula (VI) can be obtained in crystalline form, filtration, one or more optional washing steps of the filtration residue, and drying.
  • the compound of Formula (V) is converted to the corresponding mesylate salt according to Formula (VI) with methanesulfonic acid in an organic solvent mixture of isopropyl acetate and methyl /-butyl ether with less than about 20 weight percent toluene and less than 7 weight percent acetonitrile, based on the combined weight of the organic solvents, followed by crystallizing the mesylate salt according to Compound ID from the organic solvent, with subsequent filtration, one or more optional washing steps of the filtration residue, and drying.
  • crystallization is induced by adding seed crystals of the salt according to Formula (VI).
  • crystallizing the salt according to Formula (VI) and obtaining the crystalline form of the salt according to Formula (VI) is performed by adding the acid needed to form the salts, by agitating the resulting mixture for more than 60 minutes at a temperature from 20°C to 25°C, by allowing crystallization under agitation at a temperature between 15°C and 25°C for more than 120 minutes, followed by subjecting the resulting slurry to vacuum filtration, wherein the filtration residue is washed one or more times with the same organic solvent that is used to crystallize the salt according to Formula (VI) from, and by vacuum drying the crystalline form of the salt according to Formula (VI).
  • the invention concerns the salt according to Formula (VI), wherein A”' is an anion, wherein n is an integer from 1-3.
  • the compound is the crystalline mesylate (MSA) salt of Formula (VI) (e.g., Compound ID as described herein).
  • crystallizing the mesylate salt of Formula (VI) from an organic solvent mixture of isopropyl acetate and methyl /-butyl ether and obtaining the crystalline form of the mesylate salt according to Compound ID is performed by adding methanesulfonic acid needed to form the salt, agitating the resulting mixture for more than 60 minutes at a temperature between 15°C and 25°C (e.g., 20°C), then allowing crystallization under agitation at a temperature between 15°C and 25°C for more than 120 minutes.
  • the resulting slurry is subjected to vacuum filtration, wherein the filtration residue is washed one or more times with a mixture of isopropyl acetate and methyl /-butyl ether, and dried under vacuum to provide a crystalline form of the mesylate salt according to Compound ID.
  • the compound of Formula (VI) is obtained in a yield of at least 70%, based on the number of moles of the compound of Formula (II). In some embodiments, the compound of Formula (VI) is obtained with a purity of 99% or more, such as a purity of 99.1% or more, 99.2% or more, 99.3% or more, 99.5% or more, or even more.
  • step (c) of the process according to the present disclosure the isolated salt of Formula (VI), or the desalted derivative thereof (e.g., the compound according to Formula (V)), is alkylated with a compound of Formula (VII) to provide a compound of Formula (VIII): where, X 2 is a leaving group and Y 1 is a protecting group (e.g., as described herein).
  • the isolated solid form of the salt according to Formula (VI), such as a crystalline form of the salt according to Formula (VI) (such as the crystalline mesylate salt, Compound ID), is reacted directly with a compound of Formula (VII) in an organic solvent, to form a compound of Formula (VIII) (i.e., without a desalting step).
  • the isolated solid form of the salt according to Formula (VI), such as a crystalline form of the salt according to Formula (VI) (such as the crystalline mesylate salt, Compound ID), is desalted and reacted with a compound of Formula (VII) in an organic solvent, to form a compound of Formula (VIII). Desalting the compound of Formula (VI) results in a compound according to Formula (V).
  • the desalting process and the subsequent reaction with a compound of Formula (V) are performed in the same organic solvent.
  • the organic solvent is selected from xylene, n-hexane, toluene, heptanes (mix of isomers), n-heptane , dichloromethane, chlorobenzene, and combinations thereof.
  • the organic solvent is toluene or n-heptane .
  • 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.
  • the base is selected from alkali metal hydrides, alkali metal hydroxides, alkali earth metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and amines. In some embodiments, the base is chosen from alkali metal alkoxides. In some embodiments, the base is sodium /-pentoxide or a mixture of sodium t- butoxide, and potassium /-butoxide.
  • the solid-liquid phase-transfer catalyst is selected from t- butylammonium hydrogensulfate, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, a crown ether, and combinations thereof.
  • the catalyst is t- butylammonium hydrogensulfate.
  • the reaction of the compound of Formula (V) or (VI) with the compound of Formula (VII) is performed at a temperature between 0°C and 25°C (such as from 5°C to 20°C).
  • the coupling partner of Formula (VII) in step (c) includes a leaving group X2.
  • the leaving group X2 in the compound of Formula (VII) is selected from a halogen, and a substituted sulfonyloxy group.
  • the leaving group X2 in the compound of Formula (VII) is a substituted sulfonyloxy group selected from a methanesulfonyloxy, p-toluenesulfonyloxy or a trifluoromethanesulfonyloxy group.
  • the leaving group X2 is a halogen.
  • the halogen is bromide.
  • the compound of Formula (VII) is of the structure 1E below.
  • the desalting of the compound of Formula (VI) and the subsequent reaction with a compound of Formula (VII) in step (c) is performed in toluene as an organic solvent in the presence of a base and a catalyst at a temperature from 5°C to 25°C.
  • the desalting of the compound of Formula (VI) and the subsequent reaction with a compound of Formula (VII) in step (c) is performed in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogensulfate as a catalyst at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.
  • Y1 is t-butyl.
  • the alkylation of a compound of Formula (VI) (i.e., without an additional desalting step) with a compound of Formula (VII) in step (c) is performed in toluene as an organic solvent in the presence of a base and a catalyst at a temperature from 5°C to 25°C.
  • the alkylation of a compound of Formula (VI) with a compound of Formula (VII) in step (c) is performed in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogensulfate as a catalyst at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.
  • step (c) includes providing crystalline 1D, desalting this compound and reacting the desalted compound with a compound of Formula (VII) wherein X2 is Br in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t- butylammonium hydrogensulfate as a catalyst, at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.
  • X2 is Br in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t- butylammonium hydrogensulfate as a catalyst, at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.
  • step (c) includes reacting crystalline 1D with a compound of Formula (VII) wherein X2 is Br in toluene as an organic solvent in the presence of sodium t- pentoxide as a base and t-butylammonium hydrogensulfate as a catalyst, at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.
  • the base is the last reagent added to the reaction mixture. Without being bound to any particular theory, the inventors have discovered that by adding the base as the last reagent, the number of equivalents of both the base and the compound of Formula (VII) used in the reaction mixture can be reduced.
  • step (c) results in the production of a compound of Formula (VIII) in an organic solvent.
  • Y1 is t-butyl.
  • this reaction mixture is subjected in step (c) to one or more aqueous washing steps to remove impurities, followed by separating off the aqueous phase, and optionally one or more filtration steps, to obtain a washed reaction mixture comprising the compound of Formula (VIII) in the organic solvent.
  • the reaction mixture comprising the compound of Formula (VIII) in the organic solvent is concentrated by distilling off part of the organic phase to obtain a concentrated reaction mixture comprising the compound of Formula (VIII) in the organic solvent.
  • the organic solvent comprises from 30 to 40 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture.
  • the organic solvent comprises 34 to 37 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture.
  • the one or more aqueous washing steps, the optionally one or more filtration steps, and the concentration step are preferably combined such that a washed and concentrated reaction mixture comprising the compound of Formula (VIII) in the organic solvent is obtained.
  • the organic solvent includes from 30 to 40 weight percent of the compound of Formula (VIII).
  • the organic solvent includes from 34 to 37 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture.
  • the one or more aqueous washing steps comprise one or more washing steps with an aqueous acetic acid solution.
  • the reaction mixture comprising the compound of Formula (VIII) in toluene as an organic solvent is subjected in step (c) to one or more aqueous washing steps with an aqueous acetic acid solution followed by separating off the aqueous phase, and subsequently by distilling off part of the toluene, typically at a temperature from 75°C to 90°C under reduced pressure, to obtain a washed and concentrated reaction mixture comprising the compound of Formula (VIII) in toluene with from 30 to 40 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture.
  • the concentrated mixture includes from 34 to 37 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture.
  • step (c) is performed in an organic solvent different from the organic solvent used in step (d)
  • the organic solvent used in step (c) is swapped in step (c) with the organic solvent applied in step (d) such that the compound of Formula (VIII) remains in solution.
  • step (c) wherein the organic solvents used in steps (c) and (d) are different, at least part of the organic solvent used in step (c) is evaporated, preferably using distillation at 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 swap.
  • This process can be performed by continuously evaporating the organic solvent used in step (c) and by continuously adding the organic solvent of step (d), for example until the amount of the organic solvent used in step (c), based on the total amount of organic solvent, is below a certain threshold value.
  • this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (c) and subsequently adding part of the organic solvent used in step (d), for example until the amount of the organic solvent used in step (c), based on the total amount of organic solvent, is below a certain threshold value.
  • 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, e.g., as described herein).
  • the selection of the first organic solvent used in step (d) is not particularly limited.
  • the first organic solvent is not an ether or an ester.
  • the first organic solvent is toluene or a mixture of n-heptane and acetic acid.
  • the compound of Formula (VIII) is already provided in step (c) in the first solvent used in step (d), either because the same organic solvents are used in steps (c) and (d) or because of a solvent swap in step (c).
  • the first organic solvent as defined hereinbefore with from 30 to 40 weight percent of the compound of Formula (VIII), such as from 34 to 37 weight percent, based on the weight of the reaction mixture, is provided in step (d).
  • toluene as a first organic solvent with from 30 to 40 weight percent of the compound of Formula (VIII), such as from 34 to 37 weight percent, based on the weight of the reaction mixture, is provided in step (d).
  • any convenient protecting group for a carboxylic acid such as an ester moiety, may find use as Y 1 in the compound of Formula (VIII).
  • the selection of an appropriate protecting group for a carboxylic acid can be readily determined by one skilled in the art.
  • the protecting group (Y 1 ) is selected from an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an allyl group, a substituted allyl group, and a silyl group.
  • the protecting group (Y 1 ) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluro ethyl, phenyl, 4-methoxybenzyl ester, a 2,6-disubstituted phenol, and a silyl group.
  • the protecting group Y 1 is t- butyl.
  • the conversion of the compound of Formula (VIII) to obicetrapib is performed by contacting the compound of Formula (VIII) in the first organic solvent, such as toluene or a mixture of n-heptane and acetic acid, with acetic acid (AcOH) and dry HC1 under agitation.
  • the reaction mixture is heated to a temperature between 40°C and 55°C and the resulting mixture is maintained at this temperature under agitation for at least 3 hours.
  • Obicetrapib can be isolated from the resulting mixture using techniques known to the skilled person.
  • the resulting mixture comprising obicetrapib is subjected in step (d) to one or more aqueous washing steps.
  • the one or more aqueous washing steps in step (d) are performed as follows:
  • reaction mixture comprising obicetrapib is cooled to a temperature between 15°C and 25°C, and subsequently a mixture of n-heptane, acetonitrile and water is added followed by agitating the resulting mixture for more than 15 minutes at this temperature;
  • step (BB) the system obtained in step (AA) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;
  • step (CC) a mixture of n-heptane, acetonitrile, toluene and water is added to the aqueous phase obtained in step (BB), followed by agitating the resulting system for more than 15 minutes at a temperature between 15°C and 25°C;
  • step (DD) the system obtained in step (CC) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;
  • step (EE) the organic phase obtained in step (BB) and the organic phase obtained in step (DD) are combined, water is added, and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C;
  • step (FF) the system obtained in step (EE) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;
  • step (GG) water is added to the organic phase obtained in step (FF) and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C;
  • step (HH) the system obtained in step (GG) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;
  • step (II) an aqueous solution of sodium citrate tribasic dihydrate is added to the organic phase obtained in step (HH) followed by agitating the resulting mixture for more than 15 minutes at a temperature between 15°C and 25°C;
  • step (JJ) the system obtained in step (II) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;
  • step (KK) water is added to the organic phase obtained in step (JJ) and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C;
  • step (KK) the system obtained in step (KK) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated.
  • Steps (AA) to (LL) in this embodiment result in a washed compound of Formula (I) in an organic solvent mixture comprising n-heptane , acetonitrile and the first organic solvent.
  • the first solvent is toluene.
  • the organic solvent mixture is swapped in a subsequent step (MM) with CPME such that obicetrapib remains in solution.
  • step (LL) is followed by step (MM) wherein at least part of the solvents in the organic solvent mixture obtained in step (LL) is evaporated, such as by distillation at reduced pressure, and wherein cyclopentyl methyl ether is added, such that obicetrapib remains in solution during the solvent swap.
  • the process results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent based on the weight of the solution.
  • the concentration of obicetrapib in cyclopentyl methyl ether is from 33 and 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent, and less than 1 weight percent of n-heptane based on the weight of the solution.
  • This process can be performed by continuously evaporating the solvents in the organic solvent mixture obtained in step (LL) and by continuously adding cyclopentyl methyl ether, for example until the amount of specific solvents in the organic solvent mixture, based on the total amount of organic solvents, is below a certain threshold value.
  • this process can be performed batch-wise in more than one steps of evaporating part of the solvents in the organic solvent mixture obtained in step (LL) and by subsequently adding cyclopentyl methyl ether, for example until the amount of specific solvents in the organic solvent mixture, based on the total amount of solvent, is below a certain threshold value.
  • the first organic solvent is toluene
  • step (LL) is followed by step (MM) wherein at least part of the n-heptane , acetonitrile and toluene in the organic solvent mixture obtained in step (LL) is evaporated, such as by distillation at a temperature of 45°C or lower and at reduced pressure (in-vacuo), with intermediate additions of cyclopentyl methyl ether, such that obicetrapib remains in solution during the solvent swap, resulting in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent.
  • the concentration of obicetrapib in cyclopentyl methyl is from 33 to 37 weight percent based on the weight of the solution, with 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.
  • step (d) is followed by step (e)-(f), wherein obicetrapib is treated with HCl such as in a suitable solvent.
  • a suitable solvent may be an aqueous solvent or an organic solvent.
  • the use of an organic solvent provides crystalline obicetrapib HCl.
  • the organic solvent used in step (e) comprises a mixture of a solvent and an anti-solvent.
  • the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2- pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-diflurobenzene, toluene, hexafluoroisopropanol, and water.
  • the anti-solvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane.
  • the HCl has sufficient solubility in the anti-solvent such that it can be used as a suitable solvent.
  • the organic solvent used in step (e) comprises a mixture of cyclopentyl methyl ether and n-heptane .
  • the organic solvent used in step (e) further comprises toluene.
  • step (e) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane , raising the temperature to between 35°C and 40°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, then adding further n-heptane as an anti-solvent.
  • a small portion of the reaction mixture can be extracted, cooled to a temperature of between 10°C and 15°C, to obtain a slurry of crystals of crystalline obicetrapib HC1 in a mixture cyclopentyl methyl ether and n-heptane (referred to herein as a “seed crystal slurry”).
  • seed crystal slurry a mixture cyclopentyl methyl ether and n-heptane
  • all or a portion of the seed crystal slurry of crystalline obicetrapib HC1 can then be added as seed crystals back to the reaction mixture.
  • the seeds assist with nucleation but are not required and thus the process described herein can be done without seeding.
  • the resulting reaction mixture is then cooled to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HC1 from the system under agitation.
  • the crystalline obicetrapib HC1 is crystallized over a period of 12 hours or more, with subsequent filtration (e.g., through a filter dryer), one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane , and drying.
  • a wet filter cake of crystalline obicetrapib HC1 is dried in vacuo in steps using temperatures of 25°C- 30°C, 30°C-40°C, 40°C-50°C then 50°C-55°C, such as 25°C, 35°C, 46°C, and 54°C.
  • the method of preparing crystalline obicetrapib HC1 comprises the addition of seed crystals (e.g., as a seed crystal slurry).
  • the seed crystals of crystalline obicetrapib HC1 can be formed as a slurry by following step (i) as set out above and after addition of dry HC1 in cyclopentyl methyl ether and anti-solvent n-heptane , extracting a small portion of the reaction mixture, cooling to a temperature between 10°C and 15°C, to provide a slurry of crystals of crystalline obicetrapib HC1 in cyclopentyl methyl ether and n- heptane.
  • the organic solvent used in step (e) comprises a mixture of cyclopentyl methyl ether and n-heptane .
  • step (e) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane , raising the temperature to 35°C-45°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to 50°C-55°C, addition of further n-heptane as anti-solvent, the optional addition of seed crystals of crystalline obicetrapib HC1 (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HC1 from the system under agitation.
  • step (e) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and
  • the crystalline obicetrapib HC1 is crystallized over a period of at least 12 hours, with subsequent filtration, one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane , and drying.
  • the crystalline obicetrapib HC1 is dried in vacuo.
  • the crystalline obicetrapib HC1 is subjected to drying in a vacuum drying cabinet at 25 mbar pressure and at a temperature of 55°C for 10 hours or more.
  • the crystalline obicetrapib HC1 includes less than 0.1 weight percent residual cyclopentyl methyl ether.
  • step (MM) of step (d) results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 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), and less than 1 weight percent of n- heptane.
  • step (MM) of step (d) results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 to 37 weight percent, based on the weight of the solution, less than 1 weight percent of toluene, and less than 1 weight percent of n-heptane .
  • These solutions can, after addition of n-heptane , advantageously be used in step (e).
  • the n-heptane can also be added in step (d).
  • step (e) comprises providing the solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 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) (such as toluene), and less than 1 weight percent of n-heptane , addition of n-heptane , raising the temperature to 35°C to 45°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to 50°C to 55°C, addition of further n-heptane as anti-solvent, the optional addition of seed crystals of crystalline obicetrapib HC1 (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib
  • a wet filter cake of crystalline obicetrapib HC1 is dried in vacuo in steps using temperatures of 25°C-30°C, 30°C- 40°C, 40°C-50°C then 50°C-55°C, such as 25°C, 35°C, 46°C, and 54°C.
  • step (f) comprises the following steps:
  • step (cc) adding an aqueous NaOH solution to the solution obtained in step (bb) and agitating the resulting mixture, such as at a temperature from 20°C to 25°C for at least 4 hours, to obtain a solution of the sodium salt obicetrapib;
  • step (dd) optionally filtering the solution obtained in step (cc);
  • step (ff) cooling the CaC12 solution obtained in step (ee) to a temperature between 8°C and 12oC and adding via a filter to the solution obtained in step (dd) (or (cc)) under agitation at said temperature;
  • step (gg) stirring the slurry resulting from step (ff) for about 1 to about 10 hours.
  • the slurry is stirred at a temperature between 8°C and 12°C;
  • step (hh) isolating the solids from the slurry obtained in step (gg) by filtration.
  • the isolating is conducted at a temperature between 8°C and 12°C;
  • step (ii) washing the filtration residue obtained in step (hh) with water in one or more washing steps.
  • the washing is conducted at a temperature between 8°C and 12°C;
  • step (jj) drying the washed residue obtained in step (ii), such as in vacuo at a temperature between 40°C and 50°C for more than 16 hours (such as 200 hours or more), to obtain amorphous obicetrapib hemicalcium.
  • crystalline obicetrapib HC1 is isolated in step (f) with a purity of 98% or more, such as 98.5% or more, 99% or more 99.5% or more, or even more.
  • Another embodiment of the disclosure concerns the crystalline obicetrapib HC1 obtained by or obtainable by the process as defined herein.
  • Still another embodiment of the disclosure is directed to crystalline obicetrapib HC1.
  • crystalline obicetrapib HC1 is stored at controlled room temperature and under a nitrogen atmosphere and is protected from moisture to prevent the formation of an amorphous solid, because crystalline obicetrapib HC1 including crystalline obicetrapib HC1 is hygroscopic.
  • step (f) is followed by steps (g)-(h), wherein the crystalline obicetrapib HC1 is converted to amorphous obicetrapib hemicalcium (Formula IB):
  • step (g) the preparation of amorphous obicetrapib hemicalcium includes steps (g 1 )-(g3) as set out below:
  • step (gl) converting crystalline obicetrapib HC1 of step (f) to obicetrapib in an organic solvent
  • step, (gl) comprises the following steps:
  • step (aa) providing crystalline obicetrapib HC1 as defined or obtained in step (f);
  • step (bb) dissolving crystalline obicetrapib HC1 in a mixture of water and isopropyl acetate under agitation.
  • step (bb) is conducted at a temperature between 15°C and 25°C;
  • step (cc) allowing phase separation and subjecting the resulting organic phase to one or more subsequent washing steps with water, wherein each washing step is followed by separating off the aqueous phase, resulting in a washed organic phase; and
  • step, (g2) comprises the following steps:
  • step (ee) adding an aqueous NaOH solution to the solution obtained in step (dd) and agitating the resulting mixture, such as at a temperature between 20°C and 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib;
  • step (ff) optionally filtering the solution obtained in step (ee).
  • step, (g3) comprises the following steps:
  • step (hh) cooling the CaC12 solution obtained in step (gg) to a temperature from 8°C to 12°C and adding via a filter to the solution obtained in step (ff) or (ee) under agitation at said temperature;
  • step (ii) stirring the slurry resulting from step (hh) for about 1 to 10 hours.
  • the stirring is conducted at a temperature between 8°C and 12°C;
  • step (jj) isolating the solids from the slurry obtained in step (ii) by filtration.
  • the isolating is conducted at a temperature between 8°C and 12°C;
  • step (kk) washing the filtration residue obtained in step (jj) with water in one or more washing steps.
  • the washing is conducted at a temperature between 8°C and 12°C;
  • step (kk) drying the washed residue obtained in step (kk), such as in vacuo at a temperature from 40°C to 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours, or 200 hours, or even more), to obtain the amorphous obicetrapib hemicalcium (also sometimes referred to herein as compound 3).
  • step (g) comprises the following steps:
  • step (aa) providing crystalline obicetrapib HC1, as defined or obtained in step (f);
  • step (cc) adding an aqueous NaOH solution to the solution obtained in step (bb) and agitating the resulting mixture, such as at a temperature from 20°C to 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib;
  • step (dd) optionally filtering the solution obtained in step (cc);
  • step (ff) cooling the CaC12 solution obtained in step (ee) to a temperature between 8°C and 12oC and adding via a filter to the solution obtained in step (dd) or (cc) under agitation at said temperature;
  • step (gg) stirring the slurry resulting from step (ff) for about 1 to 10 hours.
  • the slurry is stirred at a temperature between 8°C and 12°C;
  • step (hh) isolating the solids from the slurry obtained in step (gg) by filtration.
  • the isolating is conducted at a temperature between 8°C and 12°C;
  • step (ii) washing the filtration residue obtained in step (hh) with water in one or more washing steps.
  • the washing is conducted at a temperature between 8°C and 12°C;
  • step (jj) drying the washed residue obtained in step (ii), such as in vacuo at a temperature between 40°C and 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours, or 200 hours, or even more), to obtain the amorphous hemicalcium-salt of Formula (IB).
  • amorphous obicetrapib hemicalcium is stored sealed at a temperature of less than 30°C and protected from light. In some embodiments, amorphous obicetrapib hemicalcium is submitted to a subsequent reworking procedure.
  • amorphous obicetrapib hemicalcium is further reworked by dissolving in ethanol (such as twice the weight of ethanol relative to amorphous obicetrapib hemicalcium at a temperature of 25°C to 50°C, followed by cooling to 10°C to 15°C, followed by filtering into a mixture of aqueous calcium chloride solution and ethyl acetate, also cooled to 10°C to 15°C, followed by filtering, washing with water and drying in vacuo at 45°C or less for 20 hours or more.
  • ethanol such as twice the weight of ethanol relative to amorphous obicetrapib hemicalcium at a temperature of 25°C to 50°C, followed by cooling to 10°C to 15°C, followed by filtering into a mixture of aqueous calcium chloride solution and ethyl acetate, also cooled to 10°C to 15°C, followed by filtering, washing with water and drying in vacuo at 45
  • amorphous obicetrapib hemicalcium is processed to achieve a particle size distribution.
  • processing is by milling. Examples of milling include hammer milling, ball milling, and jet milling.
  • spray drying may be used to achieve a particle size distribution.
  • spray-dried amorphous obicetrapib hemicalcium is provided.
  • An example of jet-milled amorphous obicetrapib hemicalcium is provided in Example 11.14.
  • unmilled amorphous obicetrapib hemicalcium is provided. In many embodiments of the disclosure, milled amorphous obicetrapib hemicalcium is provided.
  • the particle size distribution of amorphous obicetrapib 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.
  • 90% of the particles have a diameter between about 6 microns and 15 microns.
  • the particle size distribution of amorphous obicetrapib 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.
  • the particle size distribution of amorphous obicetrapib hemicalcium is such that 10% of the particles have a diameter of about 2 microns or less.
  • Amorphous obicetrapib hemicalcium of the disclosure can be made with high chemical purity according to the processes of the disclosure.
  • levels of purity include greater than 98.0 % pure such as 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 more.
  • the highest level of purities such as greater than 99.8% or 99.9% pure are more readily achieved with processes where crystalline obicetrapib HC1 is used as an intermediate.
  • amorphous calcium salts of obicetrapib including amorphous obicetrapib hemicalcium.
  • New intermediates for use in the synthesis of obicetrapib and salts thereof are also provided.
  • obicetrapib as contained in the present pharmaceutical compositions, as used in the present methods, as contained in the unit dosage forms (comprised in the pharmaceutical kit), etc., is a salt form of obicetrapib, more particularly a salt as described by one or more of the non-limiting clauses that follow:
  • Clause 7 The amorphous obicetrapib hemicalcium of clauses 2-5, having an x-ray powder diffraction pattern comprising one or more x-ray powder diffraction peaks at about 3.4°2 ⁇ , about 7.0°2 ⁇ , and about 9.2°2 ⁇ .
  • Clause 8 The amorphous obicetrapib hemicalcium of clauses 2-7, wherein the amorphous obicetrapib hemicalcium does not birefringe.
  • Clause 9 The amorphous obicetrapib hemicalcium of clauses 2-8, having a glass transition temperature at a value between about 107°C and about 112°C.
  • Clause 10 The amorphous obicetrapib hemicalcium of clause 9, wherein the glass transition temperature is measured with modulated differential scanning calorimetry.
  • Clause 11 The amorphous obicetrapib hemicalcium of clause 10, wherein the measurement with modulated differential scanning calorimetry uses a sample pan which is open.
  • Clause 13 The amorphous obicetrapib hemicalcium of clauses 8-12, wherein the glass transition temperature is at a value between about 110°C and about 112°C.
  • Clause 14 The amorphous obicetrapib hemicalcium of clauses 2-13, having a glass transition temperature of less than about 100°C when measured by differential scanning calorimetry using a closed sample pan.
  • Clause 15 The amorphous obicetrapib hemicalcium of clause 14, having 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.
  • Clause 16 The amorphous obicetrapib hemicalcium of clauses 2-15, having a loss in weight of less than about 1% when heated to about 200°C.
  • Clause 18 The amorphous obicetrapib hemicalcium of clause 17, wherein the weight loss is between about 0.84% and about 0.92%.
  • Clause 19 The amorphous obicetrapib hemicalcium of clauses 2-18, having a water content of less than about 5%.
  • Clause 20 The amorphous obicetrapib hemicalcium of clause 19, having a water content of less than about 4%.
  • Clause 21 The amorphous obicetrapib hemicalcium of clause 20, having a water content of less than about 3%.
  • Clause 22 The amorphous obicetrapib hemicalcium of clause 19, having a water content of between about 0.5% and about 1.5%.
  • Clause 23 The amorphous obicetrapib hemicalcium of clauses 2-22, in a bulk form or formulated composition having a particle size distribution wherein about 90% of the particles have a diameter of about 15 microns or less.
  • Clause 24 The amorphous obicetrapib hemicalcium of clause 23, wherein about 90% of the particles have a diameter of between about 6 microns and about 15 microns.
  • Clause 25 The amorphous obicetrapib hemicalcium of clause 24, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 14 microns or less.
  • Clause 26 The amorphous obicetrapib hemicalcium of clause 25, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 13 microns or less.
  • Clause 27 The amorphous obicetrapib hemicalcium of clause 26, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 12 microns or less.
  • Clause 28 The amorphous obicetrapib hemicalcium of clause 27, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 11 microns or less.
  • Clause 29 The amorphous obicetrapib hemicalcium of clause 28, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 10 microns or less.
  • Clause 30 The amorphous obicetrapib hemicalcium of clause 29, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 9 microns or less.
  • Clause 31 The amorphous obicetrapib hemicalcium of clause 30, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 8 microns or less.
  • Clause 32 The amorphous obicetrapib hemicalcium of clause 31, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 7 microns or less.
  • Clause 33 The amorphous obicetrapib hemicalcium of clause 32, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 6 microns or less.
  • Clause 34 The amorphous obicetrapib hemicalcium of clause 33, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 5 microns or less.
  • Clause 35 The amorphous obicetrapib hemicalcium of clause 34, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 4 microns or less.
  • Clause 36 The amorphous obicetrapib hemicalcium of clause 35, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 3 microns or less.
  • Clause 37 The amorphous obicetrapib hemicalcium of clauses 2-36, in a bulk form or formulated composition having a particle size distribution wherein about 50% of the particles have a diameter of about 5 microns or less.
  • Clause 38 The amorphous obicetrapib hemicalcium of clause 37, having a particle size distribution wherein about 50% of the particles have a diameter of about 4 microns or less.
  • Clause 39 The amorphous obicetrapib hemicalcium of clause 38, having a particle size distribution wherein about 50% of the particles have a diameter of about 3 microns or less.
  • Clause 40 The amorphous obicetrapib hemicalcium of clauses 2-39, in a bulk form or formulated composition having a particle size distribution wherein about 10% of the particles have a diameter of about 2 microns or less.
  • Clause 42 The amorphous obicetrapib hemicalcium of clause 41, having a chemical purity of at least 99.0%.
  • Clause 44 The amorphous obicetrapib hemicalcium of clause 43, having a chemical purity of at least 99.6%.
  • Clause 45 The amorphous obicetrapib hemicalcium of clause 44, having a chemical purity of at least 99.7%.
  • Clause 46 The amorphous obicetrapib hemicalcium of clause 45, having a chemical purity of at least 99.8%.
  • Clause 47 The amorphous obicetrapib hemicalcium of clause 46, having a chemical purity of at least 99.9%.
  • Clause 50 The amorphous obicetrapib hemicalcium of clauses 2-49, having a solid-state 13 C- NMR spectrum where no peak is present at about 29.5 ppm.
  • Clause 53 The amorphous obicetrapib hemicalcium of clauses 2-50, wherein the amorphous obicetrapib hemicalcium has been milled.
  • Clause 54 The amorphous obicetrapib hemicalcium of clauses 2-50 or 53, wherein the amorphous obicetrapib hemicalcium has been jet milled.
  • Amorphous obicetrapib hemicalcium prepared by a synthetic process wherein an intermediate in the process comprises crystalline obicetrapib HC1.
  • Clause 62 HC1 obicetrapib of clauses 58-61, wherein the weight percent of HC1 is between about 0.01% and about 8%.
  • Clause 63 A composition comprising crystalline obicetrapib HC1 of any one of clauses 58-62.
  • Clause 64 The crystalline obicetrapib HC1 of clause 58-60 or 62-63, wherein the crystalline obicetrapib HC1 is a solvate.
  • Clause 65 The crystalline obicetrapib HC1 of clause 64, wherein the solvate comprises obicetrapib and hydrochloric acid.
  • Clause 68 The solvate of any one of clauses 61, or 64-67, wherein the solvent of the solvate is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether (CPME), N-methyl-2 -pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl- tetrahydrofuran, di chloromethane, 1,4-di oxane, 1,2-diflurobenzene, toluene, and hexafluoroi sopropanol .
  • the solvent of the solvate is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl
  • Clause 70 The crystalline obicetrapib HC1 of any one of clauses 58-59 or 61-69, having an x- ray powder diffraction pattern substantially the same as that in Figure 67.
  • Clause 71 The crystalline obicetrapib HC1 of any one of clauses 58-59 or 61-69, having an x- ray powder diffraction pattern comprising a peak at about 9.8°2 ⁇ .
  • Clause 72 The crystalline obicetrapib HC1 of any one of clauses 58-59, 61-69 or 71, having an x-ray powder diffraction pattern comprising one or more peaks at about 8.1°20, about 9.8°2 ⁇ , about 13.8°2 ⁇ , about 16.7°2 ⁇ , and about 19.5°2 ⁇ .
  • Clause 76 The crystalline mesylate salt of Compound ID of clause 75, having a powder diffraction pattern substantially the same as any of the four x-ray powder patterns set forth in Figure 68.
  • Clause 77 The crystalline mesylate salt of Compound ID of clause 75, having an x-ray powder diffraction pattern comprising one or more peaks at about 5.2°2 ⁇ and about 9.1°20.
  • Clause 78 The crystalline mesylate salt of Compound ID of clauses 75-77 having an x-ray powder diffraction pattern comprising one or more peaks at about 9.1°20, about 15.9°2 ⁇ , about 16.5°2 ⁇ , about 17.2°2 ⁇ , about 18.6°2 ⁇ , and about 19.2°2 ⁇ .
  • obicetrapib as contained in the present pharmaceutical compositions, as used in the present methods, as contained in the unit dosage forms (comprised in the pharmaceutical kit), etc., is a salt form of obicetrapib, more particularly a salt that can be prepared using methods as described by one or more of the non- limiting clauses that follow:
  • 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):
  • step (pre-a2) desalting the compound of Formula (IIA) or (IIB) to obtain the compound of Formula (II); wherein the reaction in step (pre-a2) is performed 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.
  • the salt of Formula (IIA) or (IIB) is chosen from salts with an anion Am- selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsy
  • Clause 82 The method of clause 81, wherein the salt with an anion A m ' is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.
  • Clause 83 The method of clause 82, wherein the salt with an anion A m ' is selected from chloride, bromide, bitartrate, and mesylate.
  • Clause 84 The method of any one of clauses 79-83, wherein Y 1 in the compounds of Formulae (III)-(VI) and (VIII) is selected from an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an allyl group, a substituted allyl group and a silyl group.
  • Clause 85 The method of clause 84, wherein Y 1 in the compounds of Formulae (III)-(VI) and (VIII) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2- trifluroethyl, phenyl, 4-methoxybenzyl ester, a 2, 6-di substituted phenol, and a silyl group.
  • Clause 86 The method of clause 85, wherein Y 1 in the compounds of Formulae (III)-(VI) and (VIII) is t-butyl.
  • Clause 87 The method of any one of clauses 79-86, wherein the salt of Formula (VI) is chosen from salts with an anion A n ' selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, naps
  • Clause 88 The method of clause 87, wherein the salt with an anion A n ' is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.
  • Clause 89 The method of clause 87, wherein the salt with an anion A n ' is selected from chloride, bromide, bitartrate, and mesylate.
  • Clause 92 The method of any one of clauses 79-91, wherein X 1 in the compound of Formula (III) is selected from a halogen, a carbamate, and a substituted sulfonyloxy group.
  • Clause 95 The method of any one of clauses 79-94, wherein X 2 in the compound of Formula (VII) is selected from a halogen and a substituted sulfonyloxy group. Clause 96. The method of clause 95, wherein X 2 in the compound of Formula (III) is a halogen.
  • step (iii) preparing an amorphous hemicalcium salt of obicetrapib from the crystalline obicetrapib HC1 compound isolated in step (ii);
  • Clause 100 The method according to clauses 98 or 99, wherein the preparation of the amorphous hemicalcium salt of Formula (I) in step (iii) comprises the following steps:
  • step (iii- 1 ) converting the crystalline obicetrapib HC1 compound of step (ii) to provide obicetrapib in one or more suitable solvents selected from organic solvents and aqueous solvents;
  • Clause 102 The method of any one of clauses 98-101, wherein the amorphous calcium salt of obicetrapib is isolated with a chemical purity of at least 99%.
  • Clause 103 The method of clause 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.1%.
  • Clause 104 The method of clause 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.2%.
  • Clause 105 The method of clause 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.3%.
  • Clause 106 The method of clause 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.4%.
  • Clause 108 The method of clause 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.6%.
  • Clause 109 The method of clause 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.7%.
  • Clause 110 The method of clause 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.8%.
  • Clause 111 The method of clause 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.9%.
  • Clause 113 A pharmaceutical composition comprising an amorphous salt of obicetrapib calcium of any one of clauses 1-57 and one or more pharmaceutically acceptable carriers.
  • Clause 114 The pharmaceutical composition of clause 113, wherein the amorphous salt of obicetrapib calcium is amorphous obicetrapib hemicalcium.
  • Clause 115 A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising administering a therapeutically effective amount of a pharmaceutical composition according to clauses 113 or 114 to the subject.
  • a method of making an amorphous obicetrapib calcium salt comprising treating obicetrapib with an acid to form a salt, solvate composition, or combination thereof; isolating the salt, solvate, composition, or combination thereof; treating the salt, solvate, composition, or combination thereof with a calcium source to make an amorphous obicetrapib hemicalcium salt.
  • Clause 120 A salt, solvate, composition or combination thereof, comprising obicetrapib and a free acid.
  • Clause 123 The composition of clause 120.
  • Clause 124 The salt, solvate, composition, or combination thereof of clause 120, wherein the free acid is selected from a sulfonic acid, a sulfuric acid, a halogenated acid, acetic acid, aspartic acid, benzoic acid, bicarbonic acid, bitartaric acid, carbonic acid, citric acid, decanoic acid, fumaric acid, gluceptic acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, mucic acid, nitric acid, octanoic acid, oleic acid, pamoic acid, pantothenic acid, phosphic acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, tartric acid, and a teoclic acid; wherein the
  • Clause 127 The method of clause 118, wherein the calcium source is a calcium salt.
  • the present disclosure may further be a method as described by one or more of the preceding non-limiting clauses.
  • PSD analyses were run on a Sympatec Helos laser diffraction instrument equipped with the RODOS/M for dispersion and the ASPIROS or VIBRI for sample delivery.
  • the powder dispersion is achieved by the use of compressed air and through a gun that uses the Venturi effect.
  • PSD method details are listed in table C.
  • the excipients contained in the granule were plastic filler (Avicel PH101), brittle filler (Pharmatose 200M), binder (Kollidon 30), disintegrant (glycolys) and surfactant (Kolliphor SLS fine).
  • plastic filler Avicel PH101
  • brittle filler Pharmatose 200M
  • binder Kollidon 30
  • disintegrant glycolys
  • surfactant Kolliphor SLS fine
  • the materials were dispensed at the target weight and ezetimibe, obicetrapib and the intra- granular excipients were manually sieved and transferred into a granulation bowl.
  • the granulation solution was prepared by solubilising the required excipients in water.
  • the small-scale granules were dried using a STREA fluid bed granulator and the material was fluidised in the bowl by adjusting the air volume as required and until the LOD of the dried granule was equal or lower than the initial LOD.
  • the inlet air temperature, product temperature, exhaust temperature as well as the air flow volume were registered throughout drying. Following drying, the granules were tested for granule homogeneity of APIs, LOD, sieve analysis, TBD and XRPD.
  • the final blends were prepared by weighing accurately the required amount of extra-granular excipients. Then, the excipients (with the exception of Magnessium Stearate (MgSt)) were manually sieved, added with the granule to a bin of suitable volume and blended using a Pharmatech mixer. The MgSt was sieved separately and added to the bin.
  • a single punch compression machine specifically, the EKO tableting machine
  • EKO tableting machine was used to generate the compression profile and manufacture tablets with 150.0 mg target weight. Based on the information collected for the compression profile, a small-scale tablet manufacture was performed.
  • Table 1 Composition (% w/w) of granule and tablet of small scale 10 mg ezetimibe and 5 mg obicetrapib trials
  • the tablet batches A4459/07/02 and A4459/08/02 presented faster time of disintegration and suitable dissolution profile of both drug substances.
  • the hardness and friability of the tablets could not be improved to a level considered acceptable due to capping and failure of the friability test.
  • the tablet hardness was lower compared to that obtained with the previous trials (batch A4459/201705 and A4459/201706).
  • EZE ezetimibe
  • Results for the characterization of the small scale batch are reported in Table 5. Results for assay and impurities met the expectation and the impurity profile was consistent with both input APIs. All the prototypes were also found with an homogenous APIs content as the content uniformity results was with AV values significantly lower than the pharmacopeial requirement of AV. Water content results were found to be in range from 4.5 and 5.0%, and no defects were observed on the appearance.
  • the powders were sieved manually, loaded into the granulation bowl and mixed for 5 mins.
  • the granulation solution was sprayed at the required spray rate and wet massing was conducted prior to drying the material in a fluid bed drier.
  • the inlet air temperature and the air volume was adjusted as required to fluidise the granule that was dried until its LOD was equal or lower than the initial LOD.
  • the granules were characterised as for content uniformity of APIs, LOD (soon after milling), sieve analysis, TBD and XRPD.
  • the granule batch A4459/13/01 (prototype A) and batch A4459/16/02 (prototype C scale-up) were divided in two aliquots to manufacture the final blends required to generate the 150 mg tablet and the 200 mg tablet.
  • the final blend was prepared by weighing accurately the extra-granular excipients to manufacture tablets with the required composition.
  • the excipients were manually sieved and a bin of suitable volume was used for mixing.
  • the lubricant (MgSt) was sieved separately, added to the bowl and mixed.
  • a single punch compression machine was used to generate a compression profile and manufacture a small-scale batch of tablets. The friability, disintegration time, hardness, appearance and thickness of the tablets was monitored throughout processing. The tablets were tested for discriminating dissolution, ezetimibe USP tablet dissolution method and XRPD.
  • Three selected tablet batches (prototype B, prototype C scale-up and prototype C scale-up 200) were coated using a 20% w/w Opadry AMB II white aqueous suspension.
  • the coating process parameters as well as the weight gain of the tablets were monitored throughout processing.
  • the coated tablets were tested for XRPD, discriminating dissolution for obicetrapib, ezetimibe USP tablet dissolution method and ezetimibe USP tablet dissolution method with 75 rpm paddle speed.
  • Table 11 Composition (%w/w) of granule and tablet of small scale 10 mg ezetimibe 10 mg obicetrapib
  • EZE hydrate can be observed in samples before the granulation process or during the granulation. However, the amount of EZE hydrate detected appears always to be very limited.
  • Table 13 Granule uniformity of 10 mg ezetimibe and 10 mg (free acid) obicetrapib development prototypes
  • Table 14 XRPD data summary 10 mg ezetimibe and 10 mg (free acid) obicetrapib development prototypes
  • Table 15 Results of the dissolution characterization of small scale lOmg ezetimibe and
  • compositions Composition 1 batch A4459/20/02, Composition 2 batch A4459/20/03 and Composition 3 batch A4459/20/04
  • the prototype formulation composition selected for these compositions was that of “prototype C” (e.g. granule batch A4459/13/03).
  • the preparation and characterization (LOD and XRPD) of the granules are described in the previous sections (small-scale manufactures).
  • the granules were tested for content uniformity, LOD, sieve analysis, TBD and XRPD.
  • the blend for tableting and the compression profile and manufacture of a small batch of tablets at 150 mg tablet weight was performed as described in the previous example.
  • the high shear granulation was conducted successfully.
  • the drying step was conducted without any issues and, after 15 minutes drying the LOD of the granules was lower than the initial LOD.
  • the and the granules presented a relatively large quantity of fine particles despite the increase of the impeller speed (composition 1) ( Figure 26), the time of wet massing (composition 2) or the quantity of granulating agent (composition 3).
  • composition 1 Figure 26
  • composition 2 the time of wet massing
  • composition 3 the quantity of granulating agent
  • the tablet friability, time of disintegration, thickness and hardness were found to be similar among these tablet batches.
  • Table 23 XRPD data summary of granules from FDC1 compositions
  • Table 25 XRPD data summary of granules of FDC1 compositions
  • compositions were prepared as summarised in Table 26.
  • the excipients contained in the granule were the same of those used for the manufacture of the granule for the FDC1 approach.
  • the formulation composition of these granules reflected that of FDC1 granule “prototype C”.
  • the method of high shear granulation, granule drying, and milling was described in the previous sections.
  • the granules were tested for content uniformity (ezetimibe only), sieve analysis, TBD and XRPD.
  • Plastic filler (Avicel PH 200)
  • the final blend was prepared by weighing accurately and sieving the extra-granular components (excipients and API). The excipients and the granule were loaded in a bin of suitable volume and blended using a Pharmatech mixer. Then, the lubricant (MgSt) was added to the bin and mixed.
  • a single punch compression machine EKO
  • the target tablet weight was 230 mg and, throughout the process, the tablet friability, disintegration time, hardness, appearance end thickness was monitored as well as the individual tablet weight and the tablet weight of ten tablets.
  • the tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.
  • the tablets were coated using a 20% w/w Opadry AMB II white aqueous suspension at the required target weight increase (target weight increase 3% w/w, limits 2% w/w - 4% w/w).
  • the coating suspension and the method of coating was described in the previous section.
  • the coating parameters as well as the weight gain of the tablets was monitored throughout processing.
  • the coated tablets were tested for XRPD, dissolution, appearance, content uniformity and water content by KF.
  • Table 26 Composition (% w/w) of granule, tablet and coated tablet of FDC2 compositions
  • the high shear granulation of the FDC2 compositions was conducted successfully.
  • the drying step was conducted without any issues and, after ca. 16 minutes drying, the LOD of the granules was lower than the initial LOD.
  • the granules showed a relatively large quantity of fine particles (Figure 29).
  • the values of disintegration time and thickness were similar among FDC2 tablet batches.
  • XRPD data of the Blend/granules from FDC2 compositions are summarized in Table 29.
  • XRPD data of the tablets from FDC2 approach are summarized in Table 30. There was a presence of small amount of Eze hydrate in prototype 1.
  • Table 27 Results of the analytical characterization of FDC2 - Uncoated
  • Table 28 Results of the analytical characterization of FDC2- Coated
  • Table 29 XRPD data summary of granules from FDC2 compositions
  • Table 30 XRPD data summary of tablets from FDC2 compositions Stress Stability
  • Prototype 2 coated tablet was selected for the stress stability study with the following design
  • T Tested for appearance, assay & related substances, discriminating dissolution, water content by KF, and form check by XRPD
  • Results are reported in Table 66, Table 67 and Table 68.
  • EXAMPLE 5 Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by granulation of obicetrapib and addition of ezetimib in the extra-granule (FDC3)
  • Prototype compositions were prepared as summarised in Table 35.
  • the method of granulation was as per process condition 2 as described above.
  • the method of high shear granulation, granule drying, and milling was described in the previous sections.
  • the granules were tested for content uniformity (obicetrapib only), sieve analysis, TBD and XRPD. Preparation of final blend, tableting and coating
  • the final blend was prepared by weighing accurately and sieving the extra-granular components (excipients and API). The excipients and the granule were loaded in a bin of suitable volume and blended using a Pharmatech mixer. Then, the lubricant (MgSt) was added to the bin and mixed.
  • the target tablet weight was 230 mg and, throughout the process, the tablet friability, disintegration time, hardness, appearance end thickness was monitored as well as the individual tablet weight and the tablet weight of ten tablets.
  • the tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.
  • the tablets were coated using a 20% w/w Opadry AMB II white aqueous suspension at the required target weight increase.
  • the coating suspension and the method of coating was described in the previous section.
  • the coating parameters as well as the weight gain of the tablets was monitored throughout processing.
  • the coated tablets were tested for XRPD, dissolution, appearance, content uniformity and water content by KF.
  • Table 35 Composition (% w/w) of the granule, tablet and coated tablet of the FDC3 composition
  • the second granule was then filled followed by compression as per the method explained in previous examples.
  • the individual granules were tested for content uniformity (obicetrapib or ezetimibe), sieve analysis, TBD and XRPD.
  • the granules were compressed to form a tablet as per the methods described above.
  • the tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.
  • the tablets were coated using a 20% w/w Opadry AMB II white aqueous suspension at the required target weight increase.
  • the coating suspension and the method of coating was described in the previous section.
  • the coating parameters as well as the weight gain of the tablets was monitored throughout processing.
  • the coated tablets were tested for XRPD, dissolution, appearance, content uniformity and water content by KF.
  • Table 36 Composition (% w/w) of the granule, tablet and coated tablet of the FDC4 composition
  • the API and excipients were dispensed accurately, sieved and added to the granulation bowl according to the approach detailed in the FDC1 and FDC2 formulation approaches above.
  • the parameters of granulation for both the FDC1 and FDC2 approach were identical.
  • the granules were tested for content uniformity (only for the FDC1 approach), LOD, sieve analysis, TBD and XRPD.
  • the final blend of the FDC1 and FDC2 compositions were prepared to manufacture tablets whose batch number and composition is detailed in Table 37.
  • the components of the extra- granule were manually sieved and loaded in a bin of suitable volume.
  • the granule was mixed with the extra-granular materials using a Pharmatech mixer. Then, the FDC2 blend was tested for content uniformity.
  • the tablets were coated using a 20% w/w Opadry AMB II white aqueous suspension at the required target weight increase (target weight increase 3% w/w, limits 2% w/w - 4% w/w).
  • target weight increase 3% w/w, limits 2% w/w - 4% w/w.
  • the coating suspension and the method of coating was described in the previous section.
  • the coating parameters as well as the weight gain of the tablets was monitored throughout processing.
  • the coated tablets were tested for XRPD, dissolution, appearance, assay and impurities, and water content by KF.
  • Table 38 Granule and final blend impurities profile and dissolution result for scale up batches
  • Table 42 Ezetimibe dissolution results for scale-up batch A4459/29/05 (FDC2) at different compression forces
  • Table 43 Obicetrapib dissolution results for scale-up batch A4459/29/05 (FDC2) at different compression forces
  • the components of the FDC1 granule (batch A4459/30/02) and FDC2 granule (batch A4459/30/01) were sieved manually and added to the granulation bowl.
  • the batch size of the granule was 2 kg, and, identical processing condition of granulation were used.
  • the physical mixture was blended for 5 mins at 220 rpm and a LOD testing was executed.
  • the granulating agent purified water
  • a sample for XRPD and LOD was taken. Then, the granule was dried using a fluid bed drier.
  • the drying step was concluded as the LOD of the granule was equal or lower than the initial LOD or below 3% (w/w).
  • the granules were tested for content uniformity (only for FDC1), PSD, LOD, sieve analysis, TBD and XRPD.
  • a rotary press machine was used for the generation of a compression profile and for the tableting campaign.
  • FDC1 tablets 150 mg target tablet weight
  • a 7.0 mm diameter punch was used whereas, for FDC2 tablets (230.0 mg tablet weight) an 8.5 mm diameter punch.
  • the friability, disintegration time, hardness, thickness and appearance of the tablets as well as the individual tablet weight and the tablet weight of ten tablets was monitored during tableting.
  • the tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.
  • the coating suspension was prepared at 20% (w/w) solid content by adding the required quantity of Opadry to water under stirring. The suspension was mixed for no less than 45 minutes and its visual homogeneity confirmed. Then, the spray rate of the coating suspension was measured. The coating suspension was kept under stirring all the time. The weight gain of the tablets was monitored throughout the manufacture and spraying was stopped as the required target gain (3% w/w, 2% w/w - 4% w/w limits) was achieved. The coated tablets were visually inspected and tested for XRPD, dissolution, appearance, content uniformity, and water content by KF.
  • HDPE High Density Polyethylene
  • HDPE High Density Polyethylene
  • Table 49 Composition (% w/w) of the granule, tablet and coated tablet of the FDC1 and
  • the high shear granulation of the technical batches was conducted successfully and no issues occurred during the process.
  • the powder consumption was comparable to that observed in the scale-up batches.
  • the drying process was executed within 45 mins as the LOD of the granule was lower than 3%.
  • the granules showed similar PSD values and the quantity of fine particles was relatively large (e.g. the quantity of particles smaller than 125 pm was ca. 70 % - 73 %) ( Figure 45). No relevant differences were observed in comparison to the scale-up batches.
  • the granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe, and were found to be homogeneously dispersed.
  • Table 51 XRPD data summary of granules/tablets from technical batches
  • Table 52 PSD data summary of granules from technical batches
  • Table 53 Long-term and accelerated storage stability results for FDC2 technical batch no. A4459/31/01 (without desiccant)
  • Table 54 Long-term and accelerated storage stability results for FDC1 technical batch no. A4459/31/02 (without desiccant) Table 54(contd.)
  • Table 55 Long-term and accelerated storage condition results for FDC2 technical batch no. A4459/31/01 (with desiccant) Table 55(contd.)
  • Table 55 (contd.) Table 56: Long-term and accelerated storage condition results for FDC1 technical batch no. A4459/31/02 (with desiccant)
  • Treatment T1 l x obicetrapib, 10 mg and ezetimibe, 10 mg FDC1 tablet [Formulation #1]
  • Treatment T2 lx obicetrapib, 10 mg and ezetimibe, 10 mg FDC2 tablet [Formulation #2]
  • Treatment R (1 X obicetrapib tablet, 10 mg co-administered with 1 x ZETIA® (ezetimibe) tablet, 10 mg
  • Blood samples were collected at pre-dose and at intervals over 336 hours after dosing in each study period. Subjects were confined at the clinical facility from at least 10 horns before dosing until 24 hours after dosing in each study period and returned to the clinical facility for the 48-, 72-, 96-, 144-, 192-, 240-, and 336-hour post-dose blood sample collections. The interval between doses were at least 49 days.
  • the plasma concentrations of obicetrapib, ezetimibe and its metabolite, ezetimibe glucuronide were measured by fully validated analytical methods. Statistical analysis using average bioequivalence methodology were performed to evaluate the bioavailability of each of the test formulations relative to that of the coadministration of the reference products.
  • the subject population included 36 healthy, non-tobacco-, non-nicotine-using, adult male and female subjects.
  • Treatment T2 1 x obicetrapib, 10 mg and ezetimibe, 10 mg FDC Tablet (Formulation #2)
  • Treatment R 1 X obicetrapib Tablet, 10 mg co-administered with 1 X ZETIA® (ezetimibe) Tablet, 10 mg
  • Each dose was administered with 240 mL of room temperature water. Subjects were instructed to swallow the tablet(s) whole without chewing or biting.
  • Pre-dose samples were collected within 60 minutes before dosing. All times are relative to the dosing minute.
  • ezetimibe and ezetimibe glucuronide Pre-dose (0-hour) and at 0.25, 0.50, 0.75,1.0, 1.333, 1.667, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0* and 96.0* hours post-dose (*return sample)
  • Total blood volume per subject The total volume of blood collected for pharmacokinetic sampling was approximately 588 mL.
  • Sample Processing for analysis of obicetrapib Blood samples were collected in room temperature 4 mL K2EDTA vacutainers. After collection, the samples were mixed by gently inverting the tube several (i.e., 8-10) times and placed in an ice/water bath. The samples were then placed in the centrifuge and spin at 3000 rpm for 10 minutes at 4°C. The resulting plasma was separated into two aliquots (at least 1.0 mL in Aliquot 1 and remainder in aliquot 2) and transferred into polypropylene sample storage tubes and stored at -70°C ( ⁇ 10°C) until ready for shipment to the bioanalytical laboratory. The plasma aliquots were placed in the freezer within 30 minutes after sample collection. After collection until placement in the freezer, blood/plasma samples were kept cooled in an ice/water bath.
  • Sample Processing for analysis of ezetimibe and ezetimibe glucuronide Blood samples were collected in room temperature 4 mL K2EDT A vacutainers. After collection, the samples were mixed gently by inverting the tube several (at least 8) times and placed in an ice/water bath. The samples were then placed in the centrifuge and spin at 3000 rpm for 10 minutes at 4°C. The resulting plasma was separated into two aliquots (at least 1.0 mL in Aliquot 1 and remainder in Aliquot 2) and transferred into polypropylene sample storage tubes (e.g., Sarstedt #60.546) and stored at -70°C (or colder) until ready for shipment to the bioanalytical laboratory. After collection until placement in the freezer, blood/plasma samples were kept cooled in an ice/water bath.
  • polypropylene sample storage tubes e.g., Sarstedt #60.546
  • PK parameters Maximum measured plasma concentration.
  • AUC0-t Area under the plasma concentration versus time curve from time zero to the last measurable plasma concentration, as calculated by linear trapezoidal method.
  • Secondary PK parameters Tmax Time of the maximum measured plasma concentration.
  • Tmax is defined as the first time point with this value.
  • ⁇ z Apparent first-order terminal disposition rate constant. This parameter was calculated from the negative of the slope of the dataset with the best-fit least-squares linear regression analysis of the terminal in-linear concentration-time data. The number of data points (3 or more) in the terminal phase (not including Cmax) was included in the final regression analysis for an evaluable ⁇ z was determined from the dataset that has the highest adjusted Rsquared (R2) value of 0.7 or more. ⁇ z was considered non-evaluable if (1) the last three terminal points were used to determine ⁇ z and either the middle or the last point was higher than the preceding point or (2) the resulting adjusted R2 value was less than 0.7.
  • t1/2 The first-order terminal disposition half-life was calculated as ln(2)/ ⁇ z Data set for analysis and statistical methods Linear and semi-logarithmic graphs of the concentration-time profiles for each subject were provided, using the actual times of sample collections. Actual sample collection time were used for calculating the pharmacokinetic parameters. Plasma concentration data from all evaluable subjects with no significant protocol deviation(s) were used for estimation of Cmax and/or AUCs from at least two periods of the study, one of which includes Treatment R. PK parameters from any subject who experienced emesis within two times the median Tmax of obicetrapib or ezetimibe, respectively, calculated from the observed data of the specific treatment arm were excluded from the statistical analysis for the respective analyte.
  • Analyses of Variance was performed on In-transformed AUCo-t, AUCo- ⁇ , and Cmax using an analysis of variance model (ANOVA).
  • the ANOVA was conducted separately for Treatment T1 versus Treatment R analysis and for Treatment T2 versus Treatment R analysis, using an incomplete block design.
  • Treatment T2 was excluded from ANOVA for comparison of Treatments T1 versus R and Treatment T1 was excluded from ANOVA for comparison of Treatments T2 versus R.
  • Confidence intervals (90%) on the geometric mean ratios for AUCo-t, AUCo-co and Cmax for obicetrapib, ezetimibe and ezetimibe glucoronide were found to be within a range of 75%-125%, preferably 80%-125%, and more preferably 90%-110% of AUCo-t, AUCo-co and Cmax of obicetrapib, ezetimibe and ezetimibe glucoronide, respectively.
  • the test formulations #1 and #2 were found to be bioequivalent with reference treatment arm (R). The adverse events observed with T1 or T2 arm of the treatment were statistically not significantly different from the R arm.
  • Dyslipidemias are disorders of lipoprotein metabolism, including lipoprotein overproduction or deficiency, which may be manifested by elevation of the levels of the serum total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-C) and triglyceride (TG) concentrations, and a decrease in the levels of high-density lipoprotein (HDL) cholesterol (HDL-C) concentration.
  • LDL low-density lipoprotein
  • TG triglyceride
  • HDL high-density lipoprotein
  • Dyslipidemia itself does not generally cause any symptoms, but it can lead to symptomatic vascular disease including coronary artery disease and peripheral arterial disease. It is acknowledged that while there are a number of genetic and lifestyle factors which contribute to the development of vascular disease, dyslipidemia is 1 of the most prominent risk factors and normalization of the lipid profile has been a major target in cardiovascular (CV) protection strategies.
  • CV cardiovascular
  • Statins are generally the drug of first choice in treating dyslipidemia. Statins are considered as the most potent, most effective, and best tolerated drugs for reducing LDL-C levels. Many patients, despite treatment with high-intensity statin therapy, do not achieve acceptable levels of LDL-C with statins alone.
  • Cholesteryl ester transfer protein is a plasma glycoprotein produced in the liver and adipose tissue. It circulates in the blood, bound primarily to HDL-C, and is involved in the transfer of cholesteryl esters and TG between lipoproteins. In particular, it mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (ApoB)-containing particles, eg, very low- density lipoprotein and LDL-C, in exchange for TG. As a result, cholesteryl ester from HDL can be taken up by the liver through scavenger receptor class B type 1; this action also leads to decreased HDL-C and ultimately to increased LDL-C.
  • ApoB apolipoprotein B
  • CETP- inhibiting therapies were originally developed based on the premise that increasing HDL-C levels would prevent CV events. However, clinical study results and Mendelian randomization data have revealed that these effects are caused by changes in the concentration of ApoB- containing particles (including LDL particles) rather than changes in the HDL-C levels. Therefore, the LDL-C and ApoB-lowering effects, which arise from CETP inhibition and occur through upregulation of the LDL receptor, will benefit patients with elevated LDL-C and increased CV risk.
  • Obicetrapib (TA-8995) is a selective CETP inhibitor. Inhibition of CETP by obicetrapib blocks the transfer of cholesteryl ester from non-atherogenic HDL particles to particles in lipoprotein fractions (including LDL) that cause atherosclerosis and reduces the concentration of cholesterol in LDL, as well as other atherogenic lipoproteins. Obicetrapib also has several additional compound-specific activities that are hypothesized to be beneficial in patients.
  • obicetrapib treatment not only reduced the number of ApoB-containing particles that constitute LDL-C, it also increased apolipoprotein E (ApoE), which led to the removal of cholesterol via the liver and also reduced lipoprotein (a) (Lp[a]).5
  • obicetrapib not only potently increases HDL-C and the concentration of apolipoprotein Al (ApoAl)-containing lipoproteins but has been demonstrated to be a potent inducer of cholesterol efflux, which is the main driver of reverse cholesterol transport. This effect is considered important because it is expected to reduce established atheroma burden.
  • the first patient study conducted was a Phase 2 clinical study (TA-8995-03) in Denmark and The Netherlands where the aim was to evaluate the optimal dose of obicetrapib alone and in combination with statins in patients with mild dyslipidemia.
  • obicetrapib 10 mg resulted in an additional 50.3% reduction in LDL-C.
  • a second patient study (TA-8995-06) showed a statistically significant reduction in Lp(a) levels following 12 weeks of obicetrapib treatment.
  • TA-8995-303 Two Phase 2 studies of obicetrapib (TA-8995-303 and TA-8995-201) are currently nearing completion.
  • the first study, TA-8995-303 is evaluating the LDL-lowering effects of obicetrapib 5 mg in combination with ezetimibe 10 mg in participants with mild dyslipidemia.
  • the second study, TA-8995-201 is evaluating the LDL-lowering effects of obicetrapib (both 5 mg and 10 mg) as an adjunct to high intensity statin therapy in participants with dyslipidemia who are on high-intensity statins.
  • TA-8995-301 Two Phase 3 studies of obicetrapib 10 mg investigating the treatment of elevated LDL-C levels in participants with established atherosclerotic CV disease (ASCVD), as well as heterozygous familial hypercholesterolemia, are currently in development.
  • One study (TA-8995-301) will include participants on maximally tolerated lipid- lowering therapy, including maximally tolerated doses of statins with an LDL-C inclusion criterion of >100 mg/dL.
  • the other study (TA-8995-302) will also include participants who are on maximally tolerated lipid-lowering therapy, including maximally tolerated doses of statins with an LDL-C inclusion criterion of >70 mg/dL and ⁇ 100 mg/dL.
  • these 2 pivotal studies will evaluate the effects of obicetrapib 10 mg in populations requiring further LDL-C reduction across a range of baseline LDL-C values relevant to contemporary clinical practice.
  • a third Phase 3 study (TA-8995-304) will investigate the effect of obicetrapib 10 mg on clinical outcomes (ie, major adverse CV events, including CV death, non-fatal myocardial infarction, non-fatal stroke, or non-elective coronary revascularization).
  • Statins are considered as first-line therapy for reducing LDL-C levels. However, despite lipid lowering therapy with statins, many patients are unable to achieve acceptable levels of LDL-C.
  • PCSK9 inhibitors are one alternative to statins.
  • these therapies including high costs, limited long-term outcome data relative to statins, and muscle-related events.
  • PCSK9 inhibitors are injectable, this poses a less attractive option for patients who prefer oral medications.
  • Obicetrapib an oral CETP inhibitor
  • ezetimibe an oral cholesterol absorption inhibitor
  • Ezetimibe selectively inhibits intestinal cholesterol absorption.
  • Ezetimibe used as monotherapy for patients with hypercholesterolemia significantly reduces serum LDL-C levels, as evidenced by a meta-analysis of 8 randomized, double-blind, placebo-controlled studies, with a statistically significant mean reduction in LDL-C of 18.58% compared with placebo.
  • Ezetimibe in combination with statin therapy further reduces LDL-C levels.
  • obicetrapib In clinical studies in healthy volunteers, obicetrapib was generally well tolerated in single doses up to 150 mg and multiple doses up to 25 mg/day for 21 days. In clinical studies in patients, obicetrapib was also well tolerated after daily dosing of 10 mg for 12 weeks, both alone and in combination with 2 different statins. Near maximal effects were observed with the 10 mg obicetrapib dose. At this dose level, CETP activity and concentrations were reduced, HDL-C levels were increased, and LDL-C levels were decreased. There were no dose-related adverse events (AEs) identified and no clinically significant changes in vital signs, electrocardiograms (ECGs), or hematology or biochemistry parameters in any clinical studies.
  • AEs dose-related adverse events
  • obicetrapib has the ability to inhibit CETP, decrease LDL-C levels, increase HDL-C levels, and importantly, reduce the number of atherogenic ApoB-containing particles in a way that is useful in the treatment of dyslipidemia.
  • obicetrapib has no adverse effect on critical physiological systems (eg, central nervous system, respiratory system, gastric emptying, urinary tract, and steroidal hormonal production [including aldosterone levels]) at doses up to 300 mg/kg in rats.
  • critical physiological systems eg, central nervous system, respiratory system, gastric emptying, urinary tract, and steroidal hormonal production [including aldosterone levels]
  • obicetrapib was also well tolerated after daily dosing of 10 mg for 12 weeks, both alone and in combination with 2 different statins. There were no dose- related AEs identified and no clinically significant changes in vital signs, ECGs, or hematology or biochemistry parameters in any clinical studies.
  • the primary objective of this study is to evaluate the effect of obicetrapib 10 mg + ezetimibe 10 mg combination therapy compared with placebo, when used as an adjunct to high- intensity statin therapy, on LDL-C at Day 84.
  • the secondary objectives of this study include the following, in hierarchical order:
  • the exploratory objectives of this study include the following:
  • This study will be a placebo-controlled, double-blind, randomized, Phase 2 study to evaluate the efficacy, safety, and tolerability of obicetrapib 10 mg, both in combination with ezetimibe 10 mg and as monotherapy, as an adjunct to high-intensity statin therapy. This study will take place at approximately 20 sites in the United States. 3.1.1 Screening Period
  • ICF informed consent form
  • Combination therapy Obicetrapib 10 mg + ezetimibe 10 mg (administered as one 10 mg obicetrapib tablet and one 10 mg ezetimibe capsule);
  • Obicetrapib monotherapy Obicetrapib 10 mg (administered as one 10 mg obicetrapib tablet and 1 placebo capsule); or
  • Placebo administered as 1 placebo tablet and 1 placebo capsule.
  • the assigned study drugs will be administered by the participants orally with water, once daily on Day 1 to Day 84 at approximately the same time each morning. Participants will return to the site on Day 28 ( ⁇ 2 days), Day 84 ( ⁇ 2 days), and Day 112 ( ⁇ 2 days) for efficacy, safety, and pharmacokinetic (PK) assessments. Participants, Investigators, the Clinical Research Organization (CRO), and the Sponsor will be blinded to all lipid results from Day 1 (Visit 2) for the first participant until all enrolled participants complete the Day 84 (End of Treatment) visit or are withdrawn from the study, in order to protect blinding to treatment assignment.
  • CRO Clinical Research Organization
  • the Investigator In cases of COVID-19 limitations, it is the Investigator’s responsibility to assure the safety of participants. If necessary, the Sponsor will implement and document mitigation strategies.
  • the study visit(s) can be conducted in-clinic or virtually. If conducted virtually, the visit will include alternative methods for safety, efficacy, and distribution/collection of study drug, including but not limited to phone/video contact, alternative location for biologic sample collection, alternative secure delivery of study drug, home health care (if available), and a secured way of transferring participant data from and to home health services and the site.
  • the Sponsor will document the changes made, communicate recommendations about such changes in a timely fashion to minimize or prevent disruptions to the study, and support sites in implementing these changes. Documentation of these cases and the site’s management of participants should be recorded in the Investigator study files. In the absence of a COVID-19 impact, it is expected that Investigators and participants follow the protocol requirements as set forth.
  • the indication for this study is dyslipidemia.

Abstract

La présente divulgation concerne des compositions pharmaceutiques stables comprenant une combinaison de dose fixe d'obicetrapib et d'ézétimibe, ou leurs sels, solvates ou dérivés. La divulgation concerne en outre l'utilisation d'ézétimibe et d'obicetrapib, par exemple sous la forme de telles combinaisons de doses fixes, pour la préparation de médicaments et un procédé de traitement de sujets nécessitant une réduction du cholestérol LDL ou de ceux souffrant d'hyperlipidémie ou de dyslipidémie mixte.
PCT/EP2023/073000 2022-08-22 2023-08-22 Polythérapie d'obicetrapib et d'ézétimibe et compositions pharmaceutiques à dose fixe WO2024042061A1 (fr)

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US202363483574P 2023-02-07 2023-02-07
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