WO2024041746A1 - Fixed dose combination composition of obicetrapib and ezetimibe - Google Patents

Fixed dose combination composition of obicetrapib and ezetimibe Download PDF

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Publication number
WO2024041746A1
WO2024041746A1 PCT/EP2022/075957 EP2022075957W WO2024041746A1 WO 2024041746 A1 WO2024041746 A1 WO 2024041746A1 EP 2022075957 W EP2022075957 W EP 2022075957W WO 2024041746 A1 WO2024041746 A1 WO 2024041746A1
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Prior art keywords
ezetimibe
obicetrapib
pharmaceutical composition
anyone
composition according
Prior art date
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PCT/EP2022/075957
Other languages
French (fr)
Inventor
Joanne Lesley CRAIG
Sheng CUI
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Newamsterdam Pharma B.V.
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Priority to PCT/EP2023/073000 priority Critical patent/WO2024042061A1/en
Publication of WO2024041746A1 publication Critical patent/WO2024041746A1/en

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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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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 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
  • LDL low- density lipoprotein
  • VLDL very-low-density lipoprotein
  • HDL high-density lipoprotein
  • CAIs Cholesterol Absorption Inhibitors
  • 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).
  • the IUPAC name of ezetimibe is (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4- hydroxyphenyl)azetidin-2-one.
  • Ezetimibe is 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.
  • Another therapeutic agent is an inhibitor of the Cholesteryl Ester Transfer Protein (CETP).
  • CETP is a plasma protein secreted primarily by liver and adipose tissue.
  • CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (ApoB)-containing particles (mainly LDL and VLDL) in exchange for triglycerides (TG), thereby decreasing the cholesterol content in HDL in favor of that in (V)LDL.
  • CETP inhibition has been hypothesized to retain cholesteryl esters in HDL-C and decrease the cholesterol content of the atherogenic ApoB fraction.
  • clinical development of CETP inhibitors has not been straightforward, and multiple CETP inhibitors have been dropped at various stages of clinical development.
  • Obicetrapib also known as TA-8995
  • Combination therapy requires co-administration of multiple pills as per the exact instructions of the physician prescribing such therapy to a patient.
  • 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.
  • Preparing a fixed dose combination of different drugs in a single pharmaceutical dosage form is often challenging because of multiple factors such as physicochemical incompatibility of the active pharmaceutical ingredients (APIs), for example API-API- interactions; excipient-excipient interactions and drug-excipient interactions.
  • 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.
  • 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.
  • PEG polyethylene glycol
  • ezetimibe is an inherently non-compressible and poorly flowable API (see for example EP 2168573 A1), thereby preparing tablet formulations of ezetimibe quite challenging.
  • Obicetrapib also has poor water solubility at physiological pH range and exerts a negative effect on the dissolution of ezetimibe (unpublished data).
  • 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, 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 ⁇ 0.5oC.
  • 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%-110% 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 alone
  • 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 0-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 0-t) and/or Cmax, respectively, of 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 eze
  • 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. It has even more surprisingly been found that 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.
  • 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.
  • 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
  • Both obicetrapib and ezetimibe may also be used as different salt forms, solvates or co-crystals. They may also be formulated as pro-drugs.
  • the term “apolipoprotein” as used herein has its conventional meaning and refers to proteins that bind lipids to form lipoproteins.
  • the term “apolipoprotein B” (ApoB) as used herein has its conventional meaning and refers to the protein encoded by the ApoB gene.
  • pharmaceutical 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.
  • solvate 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.
  • Well known solvent molecules include water, alcohols, nitriles and polar organic solvents.
  • subject as used herein refers to humans suffering from or at risk for a certain disease or disorder.
  • 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-cholesterol level above 70 mg/dL, such as above 2.6 mmol/l [100,54 mg/dL]), such that the subject is at an increased risk of suffering a cardiovascular event, compared to those with lower levels.
  • treatment as used herein 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.
  • cardiac 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).
  • hypercholesterolemia 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 as used herein 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 as used herein 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 term ‘fixed dose combination’ as used herein 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.
  • the term ‘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.
  • 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 about 75%-125%, preferably about 80%-125%, and more preferably about 90%-110% 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 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 or co-cry
  • 90% confidence interval for the geometric mean of area under the curve (AUC 0- ⁇ and/or AUC 0-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 0- ⁇ and/or AUC 0-t) and/or Cmax, respectively, of 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, or as a fixed-
  • 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 ⁇ 0.5oC.
  • 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 ⁇ 0.5oC.
  • Ezetimibe is inherently a poorly/non-compressible API (see for example EP 2168573 A1) 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.
  • 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.
  • 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 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. In another preferred embodiment, 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. In a preferred embodiment, ezetimibe is present in one of the two layers and obicetrapib in the other layer of bilayer tablet. In another embodiment, the two component system is capsule formulation. In a preferred embodiment, 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.
  • the 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.
  • the term “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.
  • the pharmaceutical composition comprises ezetimibe as ezetimibe hydrate, preferably ezetimibe monohydrate.
  • 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, HCl, 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 .
  • 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.
  • 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 Dv10, Dv50 and Dv90 (also referred as X10, X50 and X90).
  • the composition comprises micronized ezetimibe having a Dv90 not more than 10 ⁇ m, preferably in the range of 4-10 ⁇ m, more preferably not more than 8.5 ⁇ m; Dv50 not more than 4 ⁇ m, preferably in the range of about 1-4 ⁇ m more, more preferably not more than 3.8 ⁇ m, and Dv10 not more than 1 ⁇ m.
  • the composition comprises micronized obicetrapib having a Dv90 not more than 14 ⁇ m, preferably in the range of about 5-14 ⁇ m; Dv50 not more than 5 ⁇ m, preferably in the range of about 3-5 ⁇ m; and Dv10 not more than 3 ⁇ m.
  • 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 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.
  • Pharmaceutical 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 1%(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 1%(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 40oC 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 40oC 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 25oC 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.
  • 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 1%-2% w/w magnesium stearate; iii. optionally, a glidant, preferably colloidal silicon dioxide or talk or both, more preferably about 1%-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 1%-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.
  • 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 1%-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.
  • 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.
  • a glidant preferably colloidal silicon dioxide or talc or both, more preferably about 1-2% colloidal silicon dioxide or talc or both ;
  • one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w/w microcrystalline cellulose and about 1% to about 20% mannitol.
  • 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.
  • 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 heterozygous 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).
  • 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.
  • 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).
  • 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).
  • 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/m2.
  • 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).
  • 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 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 formulations were prepared at a high level of lactose and a lower impeller speed (as per processing condition 2).
  • the composition and method of the addition of the excipients was amended as detailed in Table 1.
  • 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. Preparation of the final blend and tableting The final blends were prepared by weighing accurately the required amount of extra- granular excipients.
  • 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 EK0 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. These tablets were tested for appearance, assay and impurities content, discriminating dissolution, ezetimibe USP tablet dissolution method, content uniformity, water content by KF and XRPD.
  • Table 1 Composition (% w/w) of granule and tablet of small scale 10 mg ezetimibe and 5 mg obicetrapib trials C ) O P Avicel PH 101 N/A 3.000 N/A 3.000 N/A N/A N/A N/A Formulation prototype 1 2 3 4 C ) T Results: Small-scale trials to develop 10 mg ezetimibe, 5 mg obicetrapib tablets The manufactures of the granule for the small-scale batches were conducted successfully.
  • 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).
  • Table 2 LOD of 10 mg ezetimibe, 5 mg obicetrapib small-scale trials 1 2 4 1 1 2 n o i t i dno c % Granules characterization Chemical characterization analysis The granules were tested for homogeneity of both obicetrapib and ezetimibe, results are reported in Table 3. Both APIs were homogenously dispersed in the granule with maximum RSD % values obtained for batch A4459/01/03, nonetheless within the typical acceptable range for granule homogeneity.
  • Table 3 Granule uniformity of 500 g batch scale prototypes c a cl ) S . S 9 S .
  • Dissolution results in USP ezetimibe method pH 4.5 were consistent with what observed in pH 6.8.
  • A4459/07/02 (4 % Binder) and A4459/08/02 (1 % binder) a significant improvement was observed in dissolution characterization which shows for prototype 4 a profile consistent with the reference commercial ezetimibe tablet.
  • Dissolution profiles are presented in Figure 3, Figure 4 and Figure 5. Assay, content uniformity and impurities profile showed no significant differences across the four formulations for both obicetrapib and ezetimibe.
  • Pr im we Table 8: Impurities profile of small scale 10mg ezetimibe and 5mg obicetrapib B l riti % A4 % La 24 P co 1 im sp m m A4 % La 24 P co 2 im sp min wet massing 40°C/75 % RH 4 N D N D 008 006 016 031 023 009 032 B l riti % A4 % La 49 P co 1 im sp m m A4 % La 49 P co im sp m m
  • Table 9 Results of the dissolution characterization of small scale 10mg ezetimibe and 5mg obicetrapib stress stability M n P T c T O i b 5 A ( M 1 A ( M 1 A (Min – – – (31 – 3 – – – 35) 41) 8) (63 – 72) Max) 36) 76) 70) 56) Manufacturing lot A4459/05/05 A4459/05/
  • XRPD data are summarized in Table 10.
  • Table 1 XRPD data summary of small scale 10mg ezetimibe and 5mg obicetrapib tablets stress stability Sample Batch ID XRPD P t t 1 diti 1 T bl t A4459/05/05 I i i l OBI + EZE A h d + ll EZE H d P P P
  • Example 2 Fixed dose combination for 10 mg ezetimibe and 10 mg obicetrapib tablets (small scale batch ⁇ 500 g) The details of the prototype formulations manufactured in this set of experiments are summarised in Table 11 and Table 12. A key amendment in the formulation composition was the increment of dose strength of obicetrapib (free acid) from 5.0 mg to 10.0 mg.
  • 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.
  • Preparation of the final blend, tableting and coating 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 0 t O Av 5 P 0 K Ko M T 5 Av 7 P 8 K Ligamed MF- N/A 0.500 N/A 0.500 0.500 N/A 0.500 N/A N/A N/A 0.500 Opadry N/A N/A N/A N/A 3.000 N/A N/A N/A N/A N/A N/A N/A 0 * in the water for granulation; ** Lower quantity added due to an issue with the equipment
  • Table 12 Composition (%w/w) of granule and tablet of 10 mg ezetimibe and 10 mg obicetrapib Prototype C (2% O Av P K )* Ko )* M T Av P K Li 0 * Water does
  • the granules presented a PSD similar to that of batch A4459/08/01 (prototype 4) and showed a relatively large quantity of fine particles (Figure 18).
  • the tablet batches presented comparable time of disintegration and higher hardness and lower friability values for similar compression forces.
  • the tablets did not present any critical defects (e.g., capping, lamination).
  • the coated tablets presented a smooth and white surface without any visual cosmetic defects upon close inspection.
  • Table 13 Granule uniformity of 10 mg ezetimibe and 10 mg (free acid) obicetrapib de l t t t i r b c aim) laim m) laim m) laim m) laim m) laim m) laim ) laim ) ) ) ) ) ) )
  • Table 14 XRPD data summary 10 mg ezetimibe and 10 mg (free acid) obicetrapib development prototypes Sample Batch ID XRPD P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P Table 15: Results of the dissolution characterization of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) M 8 n P e T D o O pi 5 A ) ( M 1 A ) ( M 1 A ( M 3 A ( M 4 A ( M 6 A ( M 7 A (Min – 107 108) 107) 103) 104) 103) Max) ) Manufacturing lot A4459/14 A4459/14 A4459/14 A4459/14 A4459/14 A4459/16 A4459/18 A4459/18 A4459/18 A4459/18 A4459/18 A4459/18 A4459/18 A4459/18 A4459/18 A4459/18 A44
  • Table 18 Results for assay, water content and visual appearance of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) prototype C 200 and prototype C scale-up stress stability P N P 2 B A P sc B A With dessiccant . . .
  • Table 19 Results for impurities profile of small scale 10mg ezetimibe and 10 mg obicetra ib (free acid) rotot e C 200 and rotot e C scale-u stress stabilit B ie ) P 2 B A 3 40°C/75%R 0.08 0.06 0.16 0.31 0.05 0.52 0.08 0.65 H exposed 4 weeks - 40°C/75%R 0.06 0.05 0.17 0.28 0.04 N.D 0.05 0.05 P sc B A 2 N. D.
  • 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 tablets were tested for content uniformity, XRPD, dissolution and water content by KF. All the intermediates of production and the final drug product were stored as described in the previous sections.
  • Table 22 Composition (% w/w) of granule and tablet for the FDC1 composition 4 Ligamed MF-2-V N/A 0.500 N/A 0.500 N/A 0.500 Composition #1 Composition #2 Composition #3 4 * powder Results
  • 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).
  • the tablet friability, time of disintegration, thickness and hardness were found to be similar among these tablet batches.
  • Granules chemical characterization The granules were tested for homogeneity, and obicetrapib and ezetimibe were found to be homogeneously dispersed.
  • Physical properties characterization XRPD data of the Blend/granules prototypes FDC1 approach are summarized in Table 23. Eze hydrate appears only in the wet granules samples. All the three prototypes present similar flowability. Tablets chemical characterization Results of the chemical characterization of the FDC 1 tablets are reported in Table 24. The results of the analytical characterization did not show any significant differences between the three compositions.
  • Physical properties characterization XRPD data of the Tablets from FDC1 compositions are summarized in Table 25. There is no presence of Eze hydrate in all samples.
  • Table 23 XRPD data summary of granules from FDC1 compositions Sample Batch ID XRPD Prototype 1 Blend before granulation A4459/20/02 OBI + EZE Anhydrous P P P P P P P P P P P Table 24: Results of the chemical characterization of FDC1 compositions Manufacturing lot number A4459/23/02 A4459/23/03 A4459/23/04 P T A O E I I F M T E E T U O : E : D 5 ( 1 ( 1 ( 3 ( 4 ( 6 ( 7 ( D 1 ( 3 ( 4 ( 6 ( 7 (M in Max) (107 – 111) (107 – 108) (107 – 109) Water content KF 4.6 % w/w 4.6 % w/w 4.6 % w/w Table 25: XRPD data summary of granules of FDC1 compositions Sample Batch ID XRPD Com iti n 1 T bl t A4459/23/02 OBI + EZE Anh dr C C EXAMP
  • 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.
  • a single punch compression machine EK0
  • 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).
  • Table 32 Results for assay, water content and visual appearance of prototype 2 FDC2 str P (% Claim) (% Claim) (% w/w) Initial 102.7 96.4 4.1 White round tablet Prototype 2 BN 2 weeks - 40°C/75%RH A4459/28/02 exposed 101.2 95.8 4.6 White round tablets
  • Table 33 Results for impurities profile of prototype 2 FDC2 stress stability Obicetrapib related impurities Ezetimibe related impurities B ti ) P 2 A 0 N.D.
  • 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.
  • the lubricant (MgSt) was added to the bin and mixed.
  • a single punch compression machine was used for the generation of a compression profile and the manufacture of a small batch of tablets.
  • 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 co C , O A P Kollidone 30 1.154 0.652 1.5 1.5 Glycolys 4.615 2.608 6 6 Kolliphor SLS 1.154 0.652 1.5 1.5 Purified Water* 30 N/A N/A N/A T E A P G A L O T ** EXAMPLE 6 Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib as a bilayer tablet by individual granulation of obicetrapib and ezetimib followed by compression (FDC4) Prototype compositions were prepared as summarised in Table 36.
  • the method of granulation of ezetimibe was same as described above for FDC1 and of obicetrapib was same as described above for FDC3.
  • the method of high shear granulation, granule drying, and milling was same described in the previous section for FDC1.
  • the granules were then fed via two hoppers into the compression machine. The first granule was used to fill the die followed by a light compression. 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. All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed.
  • Table 36 Composition (% w/w) of the granule, tablet and coated tablet of the FDC4 co C - Ezetimibe N/A N/A N/A 7.692 10 10 Obicetrapib 7.89 10.26 10.26 N/A N/A N/A Avicel PH 23.614 30.7 30.7 23.614 30.7 101 P 2 K G K S P W T G G A L M In B T O A *pu r e water s a granuat ng agent an oes not eature n any o t e na ormuatons EXAMPLE 7 Scale-up of FDC1 and FDC2 compositions High shear granulation, drying, final blend, tableting and coating 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.
  • the FDC2 blend was tested for content uniformity. For the generation of a compression profile and for the tableting exercise the use of rotary press machines was assessed.
  • 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 the tableting exercise.
  • the tablets were tested for content uniformity (stratified samples: 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, assay and impurities, and water content by KF. All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed. Table 37: Composition (% w/w) of granule, tablet and coated tablet of FDC1 and FDC2 scale-up trials P L Total Tablet N/A 100.000 103.000 N/A 100.000 103.000 * Water does not appear in the final product. The excipient used in the granulation were added as a dry powder Results The high shear granulation of the scale-up batches was conducted successfully. The granules presented similar values of PSD by sieve analysis and a large quantity of fines (Figure 37).
  • Granules chemical characterization The granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe and were found to be homogeneously dispersed. Dissolution of both obicetrapib and ezetimibe and impurities profile of ezetimibe, results reported in Table 38, Figure 38, Figure 39 and Figure 40. Tablets chemical characterization Chemical characterization of the scale up batches uncoated tablets results are reported in Table 39.Dissolution results on uncoated tablets at different compression forces are reported in Table 40, Table 41, Table 42 and Table 43. Results for coated tablets are reported in Table 42. Physical properties characterization XRPD data of the Granules/Tablets from Scale up batches are summarized in Table 43.
  • Table 38 Granule and final blend impurities profile and dissolution result for scale up batches M P T I I E E T D 5 ( 1 ( 1 ( 3 ( 4 ( 6 ( 7 (Min Max) (94 – 99) Dissolution Ezetimibe Manufacturing lot number A4459/29/01 A4459/29/05 15 min Average Dissolution method based on 89 90 ( 3 ( 4 ( 6 ( 7 ( Table 39: Results of the analytical characterization of scale up batches - Uncoated Manufacturing lot number A4459/29/02 A4459/29/05 P T U O E W
  • Table 40 Ezetimibe dissolution results for scale-up batch A4459/29/02 (FDC1) at different compression forces 70 106.6 106.5 107.9 108.4 106.8 108.6 107.4 0.9
  • Table 41 Obicetrapib dissolution results for scale-up batch A4459/29/02 (FDC1) at different compression forces Tablet at 4,5KN Ti i l 1 l
  • 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.
  • Final Blend and tableting The method of preparation of the final blend was described in the previous section (scale-up batches).
  • the FDC2 blend was tested for content uniformity.
  • a rotary press machine was used for manufacture 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.
  • Coating 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. All the intermediates of production and the final drug product were stored in the stability chambers with following packaging: ⁇ 60mL High Density Polyethylene (HDPE) induction sealed and closed with child resistant cap.
  • the fill count for tablets is 20; ⁇ 60mL High Density Polyethylene (HDPE) induction sealed with 2g of desiccant canister and closed with child resistant cap.
  • the fill count for tablets is 20.
  • Table 49 Composition (% w/w) of the granule, tablet and coated tablet of the FDC1 and FDC2 technical batches e t ) 0 6 8 P 6 0 P L Opadry AMB II N/A N/A N/A 3.000 6.90 N/A N/A N/A 3.000 4.50 230.0 103.00 150.0 103.00 Total Tablet N/A 100.000 236.90 N/A 100.000 154.50
  • Results of FDC1 and FDC2 compositions 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 ⁇ m was ca. 70 % - 73 %) ( Figure 45). No relevant differences were observed in comparison to the scale-up batches. In comparison to the FDC2 scale-up batch (batch A4459/29/06), the FDC2 technical batch presented harder tablets for similar levels of compression force albeit, the time of disintegration between these batches was very similar for a given value of tablet hardness.
  • Granules chemical characterization The granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe, and were found to be homogeneously dispersed.
  • Table 50 Results of the analytical characterization of technical batches - Coated Manufacturing lot number A4459/31/02 A4459/31/01 Prototype FDC 1 (intra-Intra) FDC 2 (intra-Extra) T A A O E I I I F M T I I E E T U O E D 1 ( 3 ( 4 ( 6 ( 7 ( D 1 ( 3 ( 4 ( 6 ( 7 ( W ater content KF 4.0 % w/w 3.7 % w/w Table 51: XRPD data summary of granules/tablets from technical batches S F t F F F FDC1 (INTRA- INTRA) Tablet coated A4459/31/02 OBI + EZE Anhydrous Ta G ranules FDC2 A4459/30/01 38.70 87.20 184.73 1.67 Granules FDC1 A4459/30/02 34.17 82.42 275.71 2.92 Table 53: Long-term and accelerated storage stability results for FDC2 technical batch no.
  • Treatment Tl (1 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
  • 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 administration The subjects received Treatment Tl, Treatment T2, or Treatment R according to a three treatment, three-period, six-sequence randomization schedule (Table 57) under direct observation following an overnight fast of at least 10 hours.
  • Treatment T1 1 x obicetrapib, 10 mg and ezetimibe, 10 mg FDC Tablet (Formulation #1)
  • 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 Table 57 S 1 2 3 4 5 6 R T1 T2
  • Each dose was administered with 240 mL of room temperature water. Subjects were instructed to swallow the tablet(s) whole without chewing or biting.
  • Sample Collection, Handling and Bioanalytical Plans Sample Size 4 mL collections (K2EDTA vacutainers) for analysis of obicetrapib 4 mL collections (K2EDTA vacutainers) for analysis of ezetimibe and ezetimibe glucuronide Collection Times Pre-dose samples were collected within 60 minutes before dosing. All times are relative to the dosing minute.
  • obicetrapib Pre-dose (0-hour) and at 0.50,1.0,1.5,2.0,2.5,3.0,3.5,4.0,4.5,5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0*, 96.0*, 144.0*, 192.0*, 240.0* and 336.0* hours post-dose (*return sample)
  • 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 number of collections per period/per subject 49
  • 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.
  • 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. Pharmacokinetic analysis For all treatments, the following pharmacokinetic parameters were calculated for obicetrapib, ezetimibe and its metabohte, ezetimibe glucuronide. Primary PK parameters Cmax: Maximum measured plasma concentration.
  • AUC 0-t Area under the plasma concentration versus time curve from time zero to the last measurable plasma concentration, as calculated by linear trapezoidal method.
  • ⁇ 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 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.
  • R2 Rsquared
  • ⁇ 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.
  • An evaluable ⁇ z was considered not reliable and not reportable if the resulting apparent first- order terminal half-life (t1/2,) value was longer than the time interval over which ⁇ z was estimated.
  • 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 Tl 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 Tl versus R and Treatment Tl was excluded from ANOVA for comparison of Treatments T2 versus R.
  • API Active Pharmaceutical Ingredient °C degree Celsius
  • Compaction compressibility 100 x (TBD-IBD) / TBD)
  • CFM cubic feet per minute CoA Certificate of analysis

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Abstract

The present disclosure relates to stable pharmaceutical compositions comprising fixed dose combination of obicetrapib and ezetimibe, or their salts, solvates or derivatives thereof. The disclosure further describes the use of such compositions for preparation of medicaments and method of treatment of subjects requiring reduction in LDL-cholesterol or those suffering from hyperlipidemia or mixed dyslipidemia.

Description

FIXED DOSE COMBINATION COMPOSITION OF OBICETRAPIB AND EZETIMIBE TECHNICAL FIELD The present disclosure relates to 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).. BACKGROUND Despite advances in treatment, cardiovascular disease (CVD) is still a leading cause of death globally, with over 17 million deaths annually. For many years it has been known that abnormal cholesterol levels have been associated with increased risk of cardiovascular disease (CVD), such as cardiomyopathy, atherosclerosis and myocardial infarction. In particular, individuals presenting with high levels of low- density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol combined with low levels of high-density lipoprotein (HDL) cholesterol were observed to be at the highest risk of developing a cardiovascular disease. The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve target blood lipid levels with statin therapy or have partial or complete intolerance to them. To reduce the risk of a recurrent non-fatal or fatal cardiovascular disease, such patients are advised to take combinations of alternative lipid lowering agents. One class of alternative therapeutic agents is Cholesterol Absorption Inhibitors (CAIs). 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). The IUPAC name of ezetimibe is (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4- hydroxyphenyl)azetidin-2-one. Ezetimibe is administered frequently either as a mono- therapy, or in an add-on combination therapy. Typically, the ezetimibe dosage form is a tablet comprising 10 mg ezetimibe, for oral administration. Another therapeutic agent is an inhibitor of the Cholesteryl Ester Transfer Protein (CETP). CETP is a plasma protein secreted primarily by liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (ApoB)-containing particles (mainly LDL and VLDL) in exchange for triglycerides (TG), thereby decreasing the cholesterol content in HDL in favor of that in (V)LDL. Hence, CETP inhibition has been hypothesized to retain cholesteryl esters in HDL-C and decrease the cholesterol content of the atherogenic ApoB fraction. Despite the evidence supporting the potential of CETP inhibition in reducing cardiovascular morbidity, clinical development of CETP inhibitors has not been straightforward, and multiple CETP inhibitors have been dropped at various stages of clinical development. Obicetrapib (also known as TA-8995) is currently under clinical evaluation. 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. Preparing a fixed dose combination of different drugs in a single pharmaceutical dosage form is often challenging because of multiple factors such as physicochemical incompatibility of the active pharmaceutical ingredients (APIs), for example API-API- interactions; excipient-excipient interactions and drug-excipient interactions. 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. As compared to preparing a stable formulation of a single API, 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 A1), thereby preparing tablet formulations of ezetimibe quite challenging. Obicetrapib also has poor water solubility at physiological pH range and exerts a negative effect on the dissolution of ezetimibe (unpublished data). To the best of applicant’s knowledge 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 (vi) which provides an improved patient compliance, thereby demonstrating equivalent or superior therapeutic outcomes in long term without the adverse effects of taking multiple pills of single drug formulations, such as poor patient compliance resulting into development of resistance or hypersensitivity of the receptors/proteins due to chronic and irregular exposure of the receptors/proteins with sub-therapeutic or toxic levels of such drugs and their metabolites. Hence, a continuing need remains for the fixed dose combination formulation of ezetimibe and obicetrapib that fulfills all the criteria as mentioned above for use in the treatment of subjects suffering from hyperlipidemia or mixed dyslipidemia and to reduce the risk for cardiovascular events. SUMMARY A first aspect relates to a fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, 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 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 ± 0.5ºC. An embodiment relates to a fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, 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%-110% 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 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 or co-crystal thereof. Another embodiment relates to a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, 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 0-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 0-t) and/or Cmax, respectively, of 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, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. It has surprisingly been found that 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. It has even more surprisingly been found that 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 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). DEFINITIONS Obicetrapib, also referred to as “TA-8995”, has the following chemical name and chemical structure:
Figure imgf000007_0001
O O {4-[(2-{[3,5-bis(trifluoromethyl)benzyl] [(2R,4S)-1-(ethoxycarbonyl)-2-ethyl- 6- (trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]amino}pyrimidin-5-yl)oxy]butanoic acid} Ezetimibe, also referred to as "Sch-58235”, has the following chemical name and chemical structure: (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4- hydroxyphenyl)azetidin-2-one. Both obicetrapib and ezetimibe may also be used as different salt forms, solvates or co-crystals. They may also be formulated as pro-drugs. The term “apolipoprotein” as used herein has its conventional meaning and refers to proteins that bind lipids to form lipoproteins. The term “apolipoprotein B” (ApoB) as used herein has its conventional meaning and refers to the protein encoded by the ApoB gene. The term ‘pharmaceutical composition’ as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable. The term ‘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. The term “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. The term ‘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. The term ‘salt’ as used herein has its conventional meaning and includes the acid addition and base salts of a pharmaceutically active compound. The term “solvate” 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. Well known solvent molecules include water, alcohols, nitriles and polar organic solvents. The term “subject” as used herein refers to humans suffering from or at risk for a certain disease or disorder. The 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-cholesterol level above 70 mg/dL, such as above 2.6 mmol/l [100,54 mg/dL]), such that the subject is at an increased risk of suffering a cardiovascular event, compared to those with lower levels. The term ‘treatment’ as used herein has its conventional meaning and refers to curative, palliative and prophylactic treatment. The term ‘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. The term “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). The term “hypercholesterolemia” as used herein has its conventional meaning and refers to the condition in which high levels of cholesterol are present in the blood. The term “hyperlipidaemia” as used herein has its conventional meaning and refers to the condition in which there are high amounts of lipids found in the blood. The term “mixed dyslipidaemia” as used herein 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. The term “statin intolerant” as used herein 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. The term ‘cholesterol absorption inhibitor’ (CAI) as used herein has its conventional meaning and refers to compounds which are used to lower LDL-C by blocking enteric and biliary absorption of cholesterol. A known cholesterol absorption inhibitor is ezetimibe. The term “cholesteryl ester transfer protein inhibitor” (CETP inhibitor) as used herein has its conventional meaning and refers to a class of compounds that inhibits the CETP receptor in mammals. A known CETP inhibitor is obicetrapib. The term ‘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 term ‘fixed dose combination’ as used herein 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. The term ‘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. BRIEF DESCRIPTION OF THE DRAWINGS 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 3 Comparison of dissolution profile by discriminatory dissolution method - ezetimibe at pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 4Comparison 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 5 Comparison of dissolution profile of ezetimibe by discriminatory dissolution – pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 6 Comparison of obicetrapib dissolution profile of the stress stability study for batch a4459/05/05 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 7 Comparison of obicetrapib dissolution profile of the stress stability study for batch a4459/05/06 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 8 Comparison of obicetrapib dissolution profile of the stress stability study for batch a4459/05/07 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 9 Comparison of obicetrapib dissolution profile of the stress stability study for batch a4459/05/08 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 10 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459/05/05 -ph6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 11 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459/05/06 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 12 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459/05/07 – pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 13 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459/05/08 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 14 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459/05/05 -pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 15 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459/05/06 -pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 16 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459/05/07 pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib Figure 17 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459/05/08 -pH 4.5 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 ezetimib and 10 mg obicetrapib fixed composition Figure 19 Obicetrapib dissolution profiles for small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition Figure 20 Ezetimibe dissolution profiles (50 rpm) for small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition Figure 21 Ezetimibe dissolution profiles (75 rpm) for small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition Figure 22 Obicetrapib prototype C 200 BN A4459/19/03 stress stability dissolution results for small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition Figure 23 Obicetrapib prototype C scale up BN A4459/19/02 stress stability dissolution results for small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition Figure 24 Ezetimibe prototype C scale up BN A4459/19/02 stress stability dissolution results for small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition Figure 25 Ezetimibe prototype C scale up BN A4459/19/02 stress stability dissolution results for small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition Figure 26 Cumulative undersize for small scale FDC1 compositions Figure 27 Obicetrapib dissolution profiles for FDC1prototypes Figure 28 Ezetimibe dissolution profiles for FDC1 prototypes Figure 29 Cumulative undersize for small scale FDC2 compositions Figure 30 Obicetrapib dissolution profiles for small scale FDC2 compositions Figure 31 Ezetimibe dissolution profiles for small scale FDC2 compositions Figure 32 Obicetrapib dissolution profiles for small scale FDC2 coated tablets by discriminating method Figure 33 Obicetrapib dissolution profiles for small scale FDC2 coated tablets by QC method Figure 34 Ezetimibe dissolution profiles for small scale FDC2 coated tablets by QC method Figure 35 Obicetrapib dissolution profiles for small scale prototype 2 of FDC2 coated tablets from stress stability Figure 36 Ezetimibe dissolution profile for prototype 2 of FDC2 coated tablets from stress stability Figure 37 Cumulative undersize curve for scale-up batches Figure 38 Obicetrapib dissolution profile for FDC1 granule from scale up batch Figure 39 Ezetimibe dissolution profile for FDC1 granule from scale up batch Figure 40 Ezetimibe dissolution profile for FDC2 final blend from scale up batch Figure 41 Obicetrapib dissolution profile for uncoated tablets of FDC1 scale up batch at different compression forces Figure 42 Ezetimibe dissolution profiles for uncoated tablets of FDC1 scale up batch at different compression forces Figure 43 Obicetrapib dissolution profile for uncoated tablets of FDC2 scale up batch at different compression forces Figure 44 Ezetimibe dissolution profiles for uncoated tablets of FDC2 scale up batch at different compression forces Figure 45 Cumulative undersize curve for technical batches Figure 46 Obicetrapib dissolution profiles for FDC1 and FDC 2 technical batches Figure 47 Obicetrapib dissolution profiles for FDC1 and FDC 2 technical batches Figure 48 Particle size distribution (PSD) data of granules from technical batches DETAILED DESCRIPTION A first aspect relates to a fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients. In one of the embodiments, upon oral administration of the said fixed dose pharmaceutical 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 about 75%-125%, preferably about 80%-125%, and more preferably about 90%-110% 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 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 or co-crystal thereof. In another embodiment, upon oral administration of the said fixed pharmaceutical composition to a subject, 90% confidence interval for the geometric mean of area under the curve (AUC 0-∞ and/or AUC 0-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 0-∞ and/or AUC 0-t) and/or Cmax, respectively, of 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, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. 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). It has surprisingly been found that from the fixed dose pharmaceutical composition 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 ± 0.5ºC. In a preferred embodiment, it is surprisingly found that from the fixed dose pharmaceutical composition 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 ± 0.5ºC. It was further surprisingly found that from the fixed dose pharmaceutical composition at least about 70%, preferably at least about 80%, more preferably at least about 85%, and even more preferably at least about 90% of obicetrapib is dissolved within about 30 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 ± 0.5ºC. In a preferred embodiment, it is surprisingly found that from the fixed dose pharmaceutical composition 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 ± 0.5ºC. Ezetimibe is inherently a poorly/non-compressible API (see for example EP 2168573 A1) along with poor flowability. It is therefore very challenging for the formulation scientists to prepare a tablet formulation that not only satisfies the requirements with respect to hardness, disintegration time, friability, shape and size, but also provides the desired stability and dissolution, of ezetimibe. It has been surprisingly found that the composition not only meets the required specifications for dissolution and stability for being suitable to the claimed uses, but also qualifies the criteria’s of the processability parameters, namely flowability, compressibility, disintegration time, friability, hardness, shape and size. 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. In a preferred embodiment, 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. Wherever 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. Whenever a salt, solvate or co-crystal of ezetimibe or obicetrapib is used, for the purpose the said dose shall mean a dose equivalent to the weight of ezetimibe or obicetrapib in its free form, respectively. In certain embodiments, 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. In one embodiment, the solid oral dosage form is provided as a dual component pharmaceutical composition. In a preferred embodiment, one of the components of the dual component pharmaceutical composition comprises ezetimibe and another component comprises obicetrapib. In another preferred embodiment, only one of the components of the dual component pharmaceutical composition comprises both ezetimibe and obicetrapib. In certain embodiments, the two component composition is a bilayer tablet formulation. In a preferred embodiment, ezetimibe is present in one of the two layers and obicetrapib in the other layer of bilayer tablet. In another embodiment, the two component system is capsule formulation. In a preferred embodiment, the capsule may have two types of granules wherein one granule type comprises ezetimibe and another granule type comprises obicetrapib. In yet another preferred embodiment, 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. In a certain embodiments, 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 . In another embodiment, the fixed dose pharmaceutical composition is a compressed tablet formulation comprising an extragranular component and an intragranular component. In a preferred embodiment, the intragranular component comprises ezetimibe and extragranular component comprises obicetrapib. In a more preferred embodiment, the intragranular component comprises both ezetimibe and obicetrapib. In another embodiment, the intragranular component comprises obicetrapib and the extragranular component comprises ezetimibe. In yet another embodiment, the extragranular component comprises both ezetimibe and obicetrapib. The 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. In another embodiment, 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. The term “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. The term “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. Optionally, 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. In a preferred embodiment, the composition is obtained by wet granulation followed by compression of the granules in a tablet formulation or filling such granules in a capsule. In one embodiment, 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. In a preferred embodiment, 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. Further, “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. In one embodiment, salts include, but are not limited to, hydrochloride, phosphate, sulfate, mesylate, esylate and besylate salt forms. In one of the preferred embodiments, 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. The term "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. In one of the embodiments, 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. Of the interactions listed above, hydrogen-bonding is the dominant interaction in the formation of the co- crystal, whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other. In another embodiment 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, HCl, 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. 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. In one of the embodiments, 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. Preferably, 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 Dv10, Dv50 and Dv90 (also referred as X10, 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, and Dv10 means 10% of the particles by volume are below this size & 90% above. In one of the preferred embodiments , the composition comprises micronized ezetimibe having a Dv90 not more than 10µm, preferably in the range of 4-10µm, more preferably not more than 8.5 µm; Dv50 not more than 4 µm, preferably in the range of about 1-4 µm more, more preferably not more than 3.8µm, and Dv10 not more than 1µm. In another preferred embodiment , the composition comprises micronized obicetrapib having a Dv90 not more than 14 µm, preferably in the range of about 5-14 µm; Dv50 not more than 5µm, preferably in the range of about 3-5µm; and Dv10 not more than 3µm. 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. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. See “The Handbook of Pharmaceutical Excipients”, 9th edition, Rowe et al., Eds., American Pharmaceuticals Association (2020); and “Remington: The Science and Practice of Pharmacy”, 22nd edition, Gennaro, Ed., Lippincott Williams & Wilkins (2013). 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. In a preferred embodiment, 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. In a preferred embodiment, one or more surfactants are selected from dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, Polysorbate 40 or polysorbate 80 or sodium lauryl sulphate. In a more preferred embodiment 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. In one of the embodiments, the composition comprises a binder : surfactant ratio in the range of about 0.05:5.0 to about 5.0: 0.05, preferably 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. Such ratios of 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. In a preferred embodiment, the disintegrant is croscarmellose sodium or sodium starch glycolate. In a more preferred embodiment 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. In a preferred embodiment, the diluent selected from Lactose such as lactose monohydrate, microcrystalline cellulose and mannitol, or a mixture thereof. In a more preferred embodiment, intragranular component comprises microcrystalline cellulose and lactose monohydrate as diluent. In another preferred embodiment, 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. Examples of 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. Alternatively, commercially available coating compositions comprising film forming polymers marketed under various trade names, such as Opadry®, may be used for coating. Examples of 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. In a preferred embodiment , the film coating is a primary alcohol free coating. Preferably, 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. The term 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. Typically 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. Pharmaceutical 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. In an embodiment , 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 1%(w/w), and even more preferably not more than about 0.5%(w/w) of total related substances of ezetimibe. In a preferred embodiment, 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). In another embodiment , 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 1%(w/w), and even more preferably not more than about 0.5%(w/w) of total related substances of obicetrapib. It has surprisingly been found 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 40ºC temperature and 75% relative humidity. In a preferred embodiment, the composition remains stable at least up to 3 months, preferably at least upto 6 months under stability conditions of 40ºC temperature and 75% relative humidity. In another preferred embodiment, the composition remains stable for at least up to 3 months, 6 months or 12 months under stability conditions of 25ºC temperature and 60% relative humidity. In yet another preferred embodiment, the composition remains stable for at least up to 6 months, 12 months, 18 months or 24 months at room temperature. In one of the preferred embodiments, 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 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; iv. 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; v. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. 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 1%-2% w/w magnesium stearate; iii. optionally, a glidant, preferably colloidal silicon dioxide or talk or both, more preferably about 1%-2% w/w colloidal silicon dioxide or talk or both; iv. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w/w microcrystalline cellulose and about 1% to about 20% mannitol. c. Optionally, 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. In another preferred embodiment, 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. 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 1%-2% w/w colloidal silicon dioxide or talk or both; v. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w/w microcrystalline cellulose and about 1% to about 20% mannitol. c. Optionally, 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. In yet another preferred embodiment, 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. 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. optionally, a glidant, preferably colloidal silicon dioxide or talc or both, more preferably about 1-2% colloidal silicon dioxide or talc or both ; v. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w/w microcrystalline cellulose and about 1% to about 20% mannitol. c. Optionally, 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 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). A second aspect relates to the use 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 for preparation of a medicament for treatment of subjects requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol. In one of the embodiments, the said subjects are suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD). In one embodiment, the said subjects are partially or completely intolerant to statins. In one embodiment, 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 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. In one of the embodiments, 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). In one embodiment, 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). In one embodiment, 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. if 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%-110% 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 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 or co-crystal thereof. 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. if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and/or AUC 0-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 0-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 composition 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, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In one of the embodiments for the use according to the above aspects, 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-∞. In one embodiment, 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/m2. In another embodiment, the subject is human requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol. In a preferred embodiment, the is human is suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD). In one embodiment, the said human is partially or completely intolerant to statins. Preferably 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. For the use of a pharmaceutical composition or a method of treatment according to the other aspects , 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. It has been surprisingly found that 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 fixed dose combination pharmaceutical composition of obicetrapib and ezetimibe will now be illustrated further by means of the following non-limiting examples. EXAMPLES Analytical and physical characterization methods: The methods used throughout the study are summarised in Table A. The specific parameters and conditions for analytical and physical assessments used for each non- limiting example is described in relevant section of such example. Tabl A T X P T K
Figure imgf000032_0001
Discriminating Dissolution discriminating dissolution method for obicetrapib at ph 6.8 and 50 rpm paddle speed. Content Uniformity determination of content uniformity of obicetrapib and ezetimibe by hplc-UV. A s o A i s V
Figure imgf000033_0001
XRPD The XRPD analyses were run in transmission mode on an X'pert Pro / Empyrean X- Ray Diffractometer (PANalytical) equipped with an X’Celerator detector using a standard XRPD Aptuit method. The data were evaluated using the Highscore Plus software. The instrumental parameters used are listed in table B below. Table B d
Figure imgf000033_0002
e e a o vo age cu e v Particle size distribution (PSD) The 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. Tabl C
Figure imgf000033_0003
Start 0.000s opt. concentration ≥1.0% Stop after 5.000s opt. concentration ≤1.0% Trigger timeout 20 s
Figure imgf000034_0001
Discriminating dissolution method pH 6.8 (obicetrapib) Table D I t t l P t V l Di
Figure imgf000034_0002
Discriminating Dissolution method pH 4.5 (ezetimibe) Table E Di
Figure imgf000034_0003
Detection HPLC-UV QC Dissolution method pH 6.8 (obicetrapib) T
Figure imgf000034_0004
Dissolution medium Phosphate buffer solution pH 6.8 + 0.2 %w/v of Polysorbate 80 Dissolution medium volume [mL] 1000 Di
Figure imgf000035_0001
QC Dissolution method pH 4.5 (ezetimibe) Table G Di
Figure imgf000035_0002
Assay and Impurities/Related Substances (obicetrapib) Table H I C M G C A D D I D r D R
Figure imgf000035_0003
un Time [min] 30 (5 minutes next injection delay) Typical Retention Time [min] 16.7 Assay and Impurities/Related Substances (ezetimibe) Table I Intrumental Parameters Value Column Kinetex PFP F5 150mm x 46mm ( article size: 50 m) M G C A D D I D id D R T
Figure imgf000036_0001
Example 1 Fixed dose combination tablet of 10 mg ezetimibe, 5 mg obicetrapib (small scale batch ~500 g) High shear granulation and fluid bed drying Four prototype formulations were assessed. 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). In the preliminary four trials (granule batches A4459/05/01, A4459/05/02, A4459/05/03 and A4459/05/04) the quantity of the plastic filler and the brittle filler was assessed at high or low level and two high shear granulation processing conditions were tested. In the last two trials (granule batches A4459/07/01 and A4459/08/01) the formulations were prepared at a high level of lactose and a lower impeller speed (as per processing condition 2). The composition and method of the addition of the excipients was amended as detailed in Table 1. 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. Preparation of the final blend and tableting 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. For the compression, a single punch compression machine (specifically, the EK0 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. These tablets were tested for appearance, assay and impurities content, discriminating dissolution, ezetimibe USP tablet dissolution method, content uniformity, water content by KF and XRPD. All the intermediates of production and the uncoated tablets were stored in double LDPE bags closed with a cable tie and transferred into a sealed aluminium bag with silica. Table 1: Composition (% w/w) of granule and tablet of small scale 10 mg ezetimibe and 5 mg obicetrapib trials C ) O P
Figure imgf000037_0001
Avicel PH 101 N/A 3.000 N/A 3.000 N/A N/A N/A N/A Formulation prototype 1 2 3 4 C ) T
Figure imgf000038_0001
Results: Small-scale trials to develop 10 mg ezetimibe, 5 mg obicetrapib tablets The manufactures of the granule for the small-scale batches were conducted successfully. During granulation the energy consumption increased upon addition of the granulation solution and, after drying, the LOD of the granule was lower than the initial LOD (Table 2). The granules A4459/05/01 and A4459/05/02 presented coarser particles in comparison to granule batches A4459/05/03 and A4459/05/04. This was linked to a higher level of lactose in the formulation rather than to the parameters of granulation (process condition 1 vs process condition 2). As the quantity of the binder and water for granulation was reduced and the level of surfactant increased, the granule batches A4459/07/01 and A4459/08/01 (that were manufactured with a higher level of lactose), presented particles with a larger portion of fines in comparison to batches A4459/05/01 and A4459/05/02 (Figure 1 and Figure 2). Briefly, the tablets with higher content of microcrystalline cellulose (batches A4459/05/07 and A4459/05/08) showed faster disintegration time, lower friability and higher hardness values than those containing a higher quantity of lactose (batches A4459/05/05 and A4459/05/06). Overall, these tablet batches presented a suitable appearance. The tablet batches A4459/07/02 and A4459/08/02 (containing high level of lactose) presented faster time of disintegration and suitable dissolution profile of both drug substances. However, 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 A4459/05/05 and A4459/05/06). Table 2: LOD of 10 mg ezetimibe, 5 mg obicetrapib small-scale trials 1 2 4 1 1 2 n oi t idno c %
Figure imgf000039_0001
Granules characterization Chemical characterization analysis The granules were tested for homogeneity of both obicetrapib and ezetimibe, results are reported in Table 3. Both APIs were homogenously dispersed in the granule with maximum RSD % values obtained for batch A4459/05/03, nonetheless within the typical acceptable range for granule homogeneity. Table 3: Granule uniformity of 500 g batch scale prototypes c a cl ) S . S 9 S . S 2 S 3 S 6 5
Figure imgf000039_0002
% 0.82 0.66 0.40 0.55 1.32 0.99 0.53 0.31 1.6 1.7 1.4 1.4 Physical properties characterization As reported in Table 4, a small amount of ezetimibe (EZE) hydrate was found in all the wet granules samples. However, during the drying process the formed EZE hydrate converts back to EZE anhydrous with exception of batch 05/01 in which small trace of the hydrate polymorphic form appears to be still present. Table 4. XRPD data summary small scale 10mg ezetimibe and 5mg obicetrapib blends and wet and dry granules Sample Batch ID XRPD e
Figure imgf000040_0001
Tablets characterization Chemical characterization analysis 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 dissolution profiles for Obicetrapib showed for Prototypes A4459/05/08, A4459/05/06 and A4459/05/07 a similar trend in dissolution with Prototype A4459/05/08 (high amount of Avicel & low impeller speed) dissolving rapidly in the range 5-15 minutes. Prototype A4459/05/05 (high Lactose & high impeller speed) dissolved significantly slower. Dissolution results in USP ezetimibe method pH 4.5 were consistent with what observed in pH 6.8. For prototypes 3 and 4 batches A4459/07/02 (4 % Binder) and A4459/08/02 (1 % binder) a significant improvement was observed in dissolution characterization which shows for prototype 4 a profile consistent with the reference commercial ezetimibe tablet. Dissolution profiles are presented in Figure 3, Figure 4 and Figure 5. Assay, content uniformity and impurities profile showed no significant differences across the four formulations for both obicetrapib and ezetimibe. Table 5: Results of the analytical characterization of small scale 10mg ezetimibe and 5mg obicetrapib Manufacturing lot number A4459/05/0 A4459/05/0 A4459/05/0 A4459/05/0 A4459/07/0 A4459/08/0 5 6 7 8 2 2 P 4 c 2 M T A A O ( E ( I I ( I % F M F T o 0 E n E te a T o 0 U d O .6 E D O 5 ( 1 ( 1 ( ) 3 ( ) 4 ( ) 6 ( ) 7 ( ) D E
Figure imgf000041_0001
5 min Average pH 6.80.2 2 7 6 15 (Min Max) %w/v of (2 – 2) (5 – 9) (5 – 7) (12 – 17) - - Manufacturing lot number A4459/05/0 A4459/05/0 A4459/05/0 A4459/05/0 A4459/07/0 A4459/08/0 5 6 7 8 2 2 1 ( 1 ( 3 ( 4 ( 6 ( 7 ( D E 1 ( 3 ( 4 ( 6 ( 7 ( ) W
Figure imgf000042_0001
Stress Stability Prototypes 1 and 2 with different process conditions were evaluated in a stress stability study with the following design Table 6: Stress stability study design
Figure imgf000042_0002
Key: T= Tested for appearance, assay & related substances, discriminating dissolution, water content by KF, and form check by XRPD (T)= Optional testing Results are reported in Table 7, Table 8 and Table 9. Table 7: Result for Appearance, assay and water content of small scale 10mg ez r entBa w)
Figure imgf000042_0003
A4459/05/05 Initial White round tablets 100.2 101.4 4.99 MCC : Lactose = 24.9: 60°C/75% RH 49.9 P k d 2 weeks Off-white round t bl t 99.3 101.7 5.25 Pr hig mi A4 M 49. Pr lo mi A4 M 24. Pr hig mi A4 M 24. Pr im we
Figure imgf000043_0001
Table 8: Impurities profile of small scale 10mg ezetimibe and 5mg obicetrapib B l riti % A4 % La 24 P co 1 im sp m m A4 % La 24 P co 2 im sp
Figure imgf000043_0002
min wet massing 40°C/75 % RH 4 N D N D 008 006 016 031 023 009 032 B l riti % A4 % La 49 P co 1 im sp m m A4 % La 49 P co im sp m m
Figure imgf000044_0001
Table 9: Results of the dissolution characterization of small scale 10mg ezetimibe and 5mg obicetrapib stress stability M n P T c T O ib 5 A ( M 1 A ( M 1 A
Figure imgf000044_0002
(Min – – – (31 – 3 – – – 35) 41) 8) (63 – 72) Max) 36) 76) 70) 56) Manufacturing lot A4459/05/05 A4459/05/06 number P 3 A ( ) M 4 A ( ) M 6 A ( ) M 7 A ( ) M T c T E 5 A ( M 1 A ( M 1 A ( M 3 A ( M 4 A ( M 6 A ( M 7 A ( M P R E 1 A ( M 3 A
Figure imgf000045_0001
(Min speed and 19) 18) 2 (19 – 21) (40 – 42) Max) 500 mL 4) 41) 35) 40) Manufacturing lot A4459/05/05 A4459/05/06 number P 4 A ( M 6 A ( M 7 A ( M
Figure imgf000046_0001
Table 09 (cont.): Results of the dissolution characterization of small scale 10mg ezetimibe and 5mg obicetrapib stress stability Manufacturing lot A4459/05/07 A4459/05/08 n P T c T O ib 5 A ( M 1 A ( M 1 A ( M 3 A ( ) M 4 A ( ) M 6 A ( ) M 7 A ( ) M T c T
Figure imgf000046_0002
lt lt Ezetimibe (n=6) (n=3) (n=3) (n=3) (n=6) (n=3) (n=3) (n=3) Manufacturing lot A4459/05/07 A4459/05/08 number P 5 A ( M 1 A ( M 1 A ( M 3 A ( M 4 A ( M 6 A ( M 7 A ( M P R E 1 A ( M 3 A ( M 4 A ( M 6 A ( M 7 A (
Figure imgf000047_0001
Max) ) ) ) ) ) ) Physical properties characterization With exception of prototype tablet A4459/05/05 in which the small presence of EZE hydrate is observed in the initial time point sample and in all the samples placed on stability, for the other tablets prototypes a small amount of the EZE hydrate form appears at the 3WK and 4WK time points. XRPD data are summarized in Table 10. Table 1: XRPD data summary of small scale 10mg ezetimibe and 5mg obicetrapib tablets stress stability Sample Batch ID XRPD P t t 1 diti 1 T bl t A4459/05/05 I i i l OBI + EZE A h d + ll EZE H d P P P
Figure imgf000048_0001
Example 2 Fixed dose combination for 10 mg ezetimibe and 10 mg obicetrapib tablets (small scale batch ~500 g) The details of the prototype formulations manufactured in this set of experiments are summarised in Table 11 and Table 12. A key amendment in the formulation composition was the increment of dose strength of obicetrapib (free acid) from 5.0 mg to 10.0 mg. High shear granulation and fluid bed drying These trials were executed as small-scale batches (500 g batch size) according to process condition 2. However, batch A4459/16/02 (known as “prototype C scale-up”) was executed at 2 Kg batch size scale. 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. Preparation of the final blend, tableting and coating 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. All the intermediates of production and the final drug product were stored in double LDPE bags closed with cable ties and transferred into a thermosealed aluminium bag containing silica. Table 11: Composition (%w/w) of granule and tablet of small scale 10 mg ezetimibe 10 mg obicetrapib 0 t O Av 5 P 0 K Ko M T 5 Av 7 P 8 K
Figure imgf000049_0001
Ligamed MF- N/A 0.500 N/A 0.500 0.500 N/A 0.500 N/A N/A N/A 0.500 Opadry N/A N/A N/A N/A 3.000 N/A N/A N/A N/A N/A N/A 0 * in
Figure imgf000050_0001
the water for granulation; ** Lower quantity added due to an issue with the equipment Table 12 Composition (%w/w) of granule and tablet of 10 mg ezetimibe and 10 mg obicetrapib Prototype C (2% O Av P K )* Ko )* M T Av P K Li
Figure imgf000050_0002
0 * Water does not appear in the tablet; in = material added as a dry powder, out = material solubilised in the water for granulation Results: These granulation trials were conducted successfully. Overall, the granules presented a PSD similar to that of batch A4459/08/01 (prototype 4) and showed a relatively large quantity of fine particles (Figure 18). In comparison to batch A4459/08/02 (prototype 4, condition 2), the tablet batches presented comparable time of disintegration and higher hardness and lower friability values for similar compression forces. The tablets did not present any critical defects (e.g., capping, lamination). The coated tablets presented a smooth and white surface without any visual cosmetic defects upon close inspection. Granules characterization Chemical characterization analysis The granules were tested for homogeneity of both obicetrapib and ezetimibe, results are reported in Table 13. Analysis were performed on n=6 except for scale up batch performed with n=10. Physical properties characterization XRPD data of the development prototypes are summarized in Table 14. 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. Tablets characterization Chemical characterization Analysis Results for the characterization of the small scale batches are reported in Table 15. Prototypes were tested for dissolution. The dissolution results for obicetrapib showed similar profiles for all the prototypes tested with small differences deemed to be analytical variability. For ezetimibe most promising results were obtained for prototypes D and C which obtained promising results with prototypes C meeting the USP specification of Q=80+5 at 30 minutes, on three vessel. This most promising prototypes were also characterized with USP dissolution method conditions for ezetimibe at the higher paddle speed of 75 rpm. This was due since it was highlighted that the USP method, developed for a lighter tablet comparing to the developed fixed dose combination, appeared to be overdiscriminating for tablets with target weight up to 200 mg. The results showed profiles consistent with that currently commercialized formulation. Physical properties characterization All the tablets of small scale prototypes produced presented small amount of EZE hydrate with exception of the Prototype C and C scale up 200mg batches as reported in Table 16. Table 13: Granule uniformity of 10 mg ezetimibe and 10 mg (free acid) obicetrapib de l t t t i r b
Figure imgf000051_0001
c aim) laim m) laim m) laim m) laim m) laim m) laim ) ) ) ) ) ) Sam 105.6 100. 101.2 97.8 104.0 99.1 102.3 102. #1 1 98.4 106.6 1 103.6 98.6 S 0 S 5 S . S 3 S . S S S S 4 R
Figure imgf000052_0001
Table 14: XRPD data summary 10 mg ezetimibe and 10 mg (free acid) obicetrapib development prototypes Sample Batch ID XRPD P P P P P P P P P P P P P P P P P P
Figure imgf000053_0001
Table 15: Results of the dissolution characterization of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) M 8 n P e T D o O pi 5 A ) ( M 1 A ) ( M 1 A ( M 3 A ( M 4 A ( M 6 A ( M 7 A
Figure imgf000053_0002
(Min – 107 108) 107) 103) 104) 103) Max) ) Manufacturing lot A4459/14 A4459/14 A4459/14 A4459/14 A4459/16 A4459/18 A4459/18 A4459/18 number /01 /04 /02 /03 /03 /03 /01 /02 D o E e 1 A ( ) M 3 A ( ) M 4 A ( ) M 6 A ( ) M 7 A ( M D o E e 1 A ( ) M 3 A ( 3) M 4 A ( M 6 A ( M 7 A ( M
Figure imgf000054_0001
ax) Table 16: XRPD data summary of small scale tablets prototype batches S T T T T T T T
Figure imgf000054_0002
Tablet Prototype D A4459/18/02 OBI + EZE Anhydrous +small EZE Hydrate Stress Stability Based on the process tableting parameters and dissolution data, the following tablet prototypes were selected to assess the feasibility of the coating process: A4459/16/03 (150 mg/tab, prototype C scale-up) A4459/18/03 (200 mg /tab prototype C scale-up/200mg), and subsequently set down for stability a stress stability study with the following design. Results are reported in Table 17 and Table 18. Table 17: Stress stability study design Storage Conditions Time (weeks) Ke
Figure imgf000055_0001
y T= Tested for appearance, assay & related substances, Content Uniformity (only at initial) discriminating dissolution, water content by KF, and form check by XRPD (T)= Optional testing Table 18: Results for assay, water content and visual appearance of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) prototype C 200 and prototype C scale-up stress stability P N P 2 B A P sc B A
Figure imgf000055_0002
With dessiccant . . . Table 19: Results for impurities profile of small scale 10mg ezetimibe and 10 mg obicetra ib (free acid) rotot e C 200 and rotot e C scale-u stress stabilit B ie ) P 2 B A
Figure imgf000055_0003
3 40°C/75%R 0.08 0.06 0.16 0.31 0.05 0.52 0.08 0.65 H exposed 4 weeks - 40°C/75%R 0.06 0.05 0.17 0.28 0.04 N.D 0.05 0.05 P sc B A 2 N.
Figure imgf000056_0001
D. = Not Detected Table 20: Results of the dissolution characterization of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) prototype C 200 and prototype C scale-up stress stability M n P d T O ib 5 A ( M 1 A ( M 1 A ( M 3 A ) ( M 4 A ) ( M 6 A ) ( M 7 A ) (M
Figure imgf000056_0002
in – 106) Max) 107) Manufacturing lot Prototype C Prototype C scale up BN A4459/19/02 number 200 BN A4459/19/03 P R E 1 A ( M 3 A ( M 4 A ( M 6 A ( M 7 A ( M E 1 A ( M 3 A ( M 4 A ( M 6 A ( M 7 A ( ) M
Figure imgf000057_0001
ax) 103) Physical properties characterization XRPD data of samples placed on stress stability are summarized in Table 21. Both prototype tablets present ezetimibe hydrate when exposed at 40°C/75%RH condition at 2WK, however once packaged the polymorphic conversion does not happen up to 4WK storage. Table 21 XRPD data summary of prototype C 200 and scale up placed on stress stability Sample Batch ID XRPD Tablet Prototype C scale up Initial A4459/19/02 OBI + EZE Anhydrous 2 4 4 4 T 2 4 4 4
Figure imgf000058_0001
EXAMPLE 3 Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by co-granulation of drug substances/active ingredients (FDC1) (small scale batch ~ 500 g) High shear granulation, drying, preparation of final blend and tableting Three compositions (Composition 1 batch A4459/20/02, Composition 2 batch A4459/20/03 and Composition 3 batch A4459/20/04) were prepared as summarised in Table 22. 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 tablets were tested for content uniformity, XRPD, dissolution and water content by KF. All the intermediates of production and the final drug product were stored as described in the previous sections. Table 22: Composition (% w/w) of granule and tablet for the FDC1 composition 4
Figure imgf000058_0002
Ligamed MF-2-V N/A 0.500 N/A 0.500 N/A 0.500 Composition #1 Composition #2 Composition #3 4 *
Figure imgf000059_0001
powder Results 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. In general, 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). The tablet friability, time of disintegration, thickness and hardness were found to be similar among these tablet batches. Granules chemical characterization The granules were tested for homogeneity, and obicetrapib and ezetimibe were found to be homogeneously dispersed. Physical properties characterization XRPD data of the Blend/granules prototypes FDC1 approach are summarized in Table 23. Eze hydrate appears only in the wet granules samples. All the three prototypes present similar flowability. Tablets chemical characterization Results of the chemical characterization of the FDC 1 tablets are reported in Table 24. The results of the analytical characterization did not show any significant differences between the three compositions. Physical properties characterization XRPD data of the Tablets from FDC1 compositions are summarized in Table 25. There is no presence of Eze hydrate in all samples. Table 23: XRPD data summary of granules from FDC1 compositions Sample Batch ID XRPD Prototype 1 Blend before granulation A4459/20/02 OBI + EZE Anhydrous P P P P P P P P
Figure imgf000060_0001
Table 24: Results of the chemical characterization of FDC1 compositions Manufacturing lot number A4459/23/02 A4459/23/03 A4459/23/04 P T A O E I I F M T E E T U O : E : D 5 ( 1 ( 1 ( 3 ( 4 ( 6 ( 7 ( D 1 ( 3 ( 4 ( 6 ( 7 (M
Figure imgf000060_0002
in Max) (107 – 111) (107 – 108) (107 – 109) Water content KF 4.6 % w/w 4.6 % w/w 4.6 % w/w Table 25: XRPD data summary of granules of FDC1 compositions Sample Batch ID XRPD Com iti n 1 T bl t A4459/23/02 OBI + EZE Anh dr C C
Figure imgf000061_0001
EXAMPLE 4 Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by granulation of ezetimibe and addition of obicetrapib in the extra-granule (FDC2) High shear granulation and drying Three 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. Preparation of final blend, tableting and coating The components of the extra-granular formulation are listed below: - Obicetrapib - Plastic filler (Avicel PH 200) - Brittle filler (Pearlitol 200 SD) - Disintegrant (Glycolys) - Glydant (Aerosil 200) - Lubricant (Ligamed MF-2-V) 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. For the generation of a compression profile and the manufacture of a small batch of tablets, a single punch compression machine (EK0) equipped with an 9.0 mm round punch (R=11) was used. 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. All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed. Table 26: Composition (% w/w) of granule, tablet and coated tablet of FDC2 compositions Prototype 1 Prototype 2 Prototype 3 A le te , ) 8 47 P 14 2 8 2 A 21 1 57 P 1 0 0 L 0 O 0
Figure imgf000062_0001
00 0 *Water does not appear in the final product. All excipients for granulation added as a dry powder Results 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. Granules chemical characterization A4459/20/01 blend was tested for homogeneity of both obicetrapib and ezetimibe, and was found to be homogeneously dispersed. Results for other two granules were not collected. Tablets chemical characterization Chemical characterization of the protoype 1 of FDC 2 tablets results are reported in Table 27 and Table 28. The results of the analytical characterization did not show any significant differences between the three prototypes of FDC2. Physical Properties characterization 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 M P T A O E I I F M T 0. E E a T 0. U O .2 - E D 5 ( 1 ( 1 ( 3 ( 4 ( 6 ( 7 ( D
Figure imgf000063_0001
15 min Average based on USP method 68 (Min Max) conditions at pH 4.5, 50 (61 – 71) - - Manufacturing lot number A4459/23/01 A4459/26/01 A4459/26/02 30 min Average rpm paddle speed and 76 ( 4 ( 6 ( 7 ( D 1 ( 3 ( 4 ( 6 ( 7 ( W
Figure imgf000064_0001
Table 28: Results of the analytical characterization of FDC2- Coated M P d T A O E I I F M T E E T U O : E : D 5 ( 1 ( 1 ( 3 ( 4 ( 6 ( 7 ( D 1 (
Figure imgf000064_0002
. 30 min Average 80, 75 rpm paddle 95 95 95 (Min Max) (94 – 96) (94 – 97) (92 – 97) Manufacturing lot number A4459/27/01 A4459/27/02 A4459/27/03 45 min Average speed and 1000 mL 96 96 96 ( 6 ( 7 ( D 1 ( 3 ( 4 ( 6 ( 7 ( W
Figure imgf000065_0001
Table 29: XRPD data summary of granules from FDC2 compositions Sa l B t h ID XRPD P P P
Figure imgf000065_0002
Table 30: XRPD data summary of tablets from FDC2 compositions S P P P
Figure imgf000065_0003
Stress Stability Prototype 2 coated tablet was selected for the stress stability study with the following design Table 31: Stress stability study design
Figure imgf000065_0004
40 C/75%RH closed Accelerated (T) - (T) Key: T= Tested for appearance, assay & related substances, discriminating dissolution, water content by KF, and form check by XRPD (T)= Optional testing Results are reported in Table 66, Table 67 and Table 68. Table 32: Results for assay, water content and visual appearance of prototype 2 FDC2 str P
Figure imgf000065_0005
(% Claim) (% Claim) (% w/w) Initial 102.7 96.4 4.1 White round tablet Prototype 2 BN 2 weeks - 40°C/75%RH A4459/28/02 exposed 101.2 95.8 4.6 White round tablets
Figure imgf000066_0001
Table 33: Results for impurities profile of prototype 2 FDC2 stress stability Obicetrapib related impurities Ezetimibe related impurities B ti ) P 2 A 0
Figure imgf000066_0002
N.D. = Not Detected Table 34: Results of the dissolution characterization of prototype 2 FDC2 stress stability M T T O 5 A ( 1 A ( 1 A ( 3 A ( 4 A ( 6 A ( 7 A ( T E 1 A ( 3 A ( 4 A ( 6
Figure imgf000066_0003
Average (Min Max) (92 – 101) (86 – 91) (90 – 101) (88 – 102) Manufacturing lot number Prototype 2 BN A4459/28/02 70 min 103 A (
Figure imgf000067_0001
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. For the generation of a compression profile and the manufacture of a small batch of tablets, a single punch compression machine was used. 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. All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed. Table 35: Composition (% w/w) of the granule, tablet and coated tablet of the FDC3 co C , O A P
Figure imgf000067_0002
Kollidone 30 1.154 0.652 1.5 1.5 Glycolys 4.615 2.608 6 6 Kolliphor SLS 1.154 0.652 1.5 1.5 Purified Water* 30 N/A N/A N/A T E A P G A L O T **
Figure imgf000068_0001
EXAMPLE 6 Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib as a bilayer tablet by individual granulation of obicetrapib and ezetimib followed by compression (FDC4) Prototype compositions were prepared as summarised in Table 36. The method of granulation of ezetimibe was same as described above for FDC1 and of obicetrapib was same as described above for FDC3. The method of high shear granulation, granule drying, and milling was same described in the previous section for FDC1. The granules were then fed via two hoppers into the compression machine. The first granule was used to fill the die followed by a light compression. 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. All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed. Table 36: Composition (% w/w) of the granule, tablet and coated tablet of the FDC4 co C -
Figure imgf000068_0002
Ezetimibe N/A N/A N/A 7.692 10 10 Obicetrapib 7.89 10.26 10.26 N/A N/A N/A Avicel PH 23.614 30.7 30.7 23.614 30.7 30.7 101 P 2 K G K S P W T G G A L M In B T O A *pu
Figure imgf000069_0001
r e water s a granuat ng agent an oes not eature n any o t e na ormuatons EXAMPLE 7 Scale-up of FDC1 and FDC2 compositions High shear granulation, drying, final blend, tableting and coating 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. For the generation of a compression profile and for the tableting exercise the use of rotary press machines was assessed. 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 the tableting exercise. The tablets were tested for content uniformity (stratified samples: 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, assay and impurities, and water content by KF. All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed. Table 37: Composition (% w/w) of granule, tablet and coated tablet of FDC1 and FDC2 scale-up trials P L
Figure imgf000070_0001
Total Tablet N/A 100.000 103.000 N/A 100.000 103.000 * Water does not appear in the final product. The excipient used in the granulation were added as a dry powder Results The high shear granulation of the scale-up batches was conducted successfully. The granules presented similar values of PSD by sieve analysis and a large quantity of fines (Figure 37). These PSD values were comparable to those found in the previous trials (e.g. batch A4459/16/02 as a reference for the FDC1 scale-up batch and batch A4459/25/01 as a reference for the FDC2 scale-up batch). Despite this similarity of PSD data, the flowability of the scale- up batches improved in comparison to that of the reference batches according to the value of the Hauser ratio. These tablets presented disintegration time shorter than 5 mins and friability lower than 0.2%. The coating process was performed without any critical issues and the appearance of the coated tablets for both formulation approaches was suitable since the surface of the tablets was smooth. Granules chemical characterization The granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe and were found to be homogeneously dispersed. Dissolution of both obicetrapib and ezetimibe and impurities profile of ezetimibe, results reported in Table 38, Figure 38, Figure 39 and Figure 40. Tablets chemical characterization Chemical characterization of the scale up batches uncoated tablets results are reported in Table 39.Dissolution results on uncoated tablets at different compression forces are reported in Table 40, Table 41, Table 42 and Table 43. Results for coated tablets are reported in Table 42. Physical properties characterization XRPD data of the Granules/Tablets from Scale up batches are summarized in Table 43. All the batches tested showed the absence of EZE hydrate. Table 38: Granule and final blend impurities profile and dissolution result for scale up batches M P T I I E E T D 5 ( 1 ( 1 ( 3 ( 4 ( 6 ( 7
Figure imgf000071_0001
(Min Max) (94 – 99) Dissolution Ezetimibe Manufacturing lot number A4459/29/01 A4459/29/05 15 min Average Dissolution method based on 89 90 ( 3 ( 4 ( 6 ( 7 (
Figure imgf000072_0001
Table 39: Results of the analytical characterization of scale up batches - Uncoated Manufacturing lot number A4459/29/02 A4459/29/05 P T U O E W
Figure imgf000072_0002
Table 40: Ezetimibe dissolution results for scale-up batch A4459/29/02 (FDC1) at different compression forces
Figure imgf000072_0003
70 106.6 106.5 107.9 108.4 106.8 108.6 107.4 0.9 Table 41: Obicetrapib dissolution results for scale-up batch A4459/29/02 (FDC1) at different compression forces Tablet at 4,5KN Ti i l 1 l 2 l l 4 l l M R l R D
Figure imgf000073_0001
Table 42: Ezetimibe dissolution results for scale-up batch A4459/29/05 (FDC2) at different compression forces
Figure imgf000073_0002
. . . . . . . . 70 102.7 102.6 102.9 104.0 104.8 102.2 103.2 1.0 Table 43: Obicetrapib dissolution results for scale-up batch A4459/29/05 (FDC2) at dif
Figure imgf000073_0003
5 57.7 60.1 64.5 64.5 65.1 74.2 64.3 8.8 10 78.4 77.5 80.1 78.4 79.2 88.2 80.3 4.9 15 83.7 82.0 83.3 81.9 82.7 90.6 84.0 3.9 30 867 844 863 835 856 927 865 38
Figure imgf000074_0001
Table 44: Results of the analytical characterization of scale up batches 10mg ezetimibe0 mg obicetrapib - Coated M P T A A O E I I F M T I E E T D 5 ( 1 ( 1 ( 3 ( 4 ( 6 ( 7 ( D 1 ( 3 ( 4 (
Figure imgf000074_0002
60 min Average volume 104 99 (Min Max) (103 – 106) (94 – 102) Manufacturing lot number A4459/29/03 A4459/29/06 70 min Average 106 104 ( W
Figure imgf000075_0001
Table 45: XRPD data summary of granules/tablets from scale up batch Sample Batch ID XRPD F F F F
Figure imgf000075_0002
EXAMPLE 8 Technical batches of FDC1 and FDC2 compositions The batch numbers and compositions of the granules, tablets and coated tablets of the technical manufactures of the FDC1 and FDC2 formulations are detailed in Table 49. High shear granulation and drying 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. For both FDC1 and FDC2 compositions, 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) was sprayed and, following spraying, 1 min wet massing was conducted. 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. Final Blend and tableting The method of preparation of the final blend was described in the previous section (scale-up batches). The FDC2 blend was tested for content uniformity. For the generation of a compression profile and for the tableting campaign, a rotary press machine was used. To manufacture 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. Coating 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. All the intermediates of production and the final drug product were stored in the stability chambers with following packaging: ^ 60mL High Density Polyethylene (HDPE) induction sealed and closed with child resistant cap. The fill count for tablets is 20; ^ 60mL High Density Polyethylene (HDPE) induction sealed with 2g of desiccant canister and closed with child resistant cap. The fill count for tablets is 20. Table 49: Composition (% w/w) of the granule, tablet and coated tablet of the FDC1 and FDC2 technical batches e t ) 0 6 8 P 6 0 P L
Figure imgf000076_0001
Opadry AMB II N/A N/A N/A 3.000 6.90 N/A N/A N/A 3.000 4.50 230.0 103.00 150.0 103.00 Total Tablet N/A 100.000 236.90 N/A 100.000 154.50
Figure imgf000077_0001
Results Technical batches of FDC1 and FDC2 compositions 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 µm was ca. 70 % - 73 %) (Figure 45). No relevant differences were observed in comparison to the scale-up batches. In comparison to the FDC2 scale-up batch (batch A4459/29/06), the FDC2 technical batch presented harder tablets for similar levels of compression force albeit, the time of disintegration between these batches was very similar for a given value of tablet hardness. Granules chemical characterization The granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe, and were found to be homogeneously dispersed. Tablets chemical characterization Chemical characterization of the technical batches coated tablets results are reported in Table 50. The tablets showed a suitable level of quality with the % claims within the typical acceptance criterion for clinical phases (i.e. 90.0 – 110.0 %). The results of the content uniformity test met the pharmacopoeia requirement of AV < 15.0. Dissolution met the proposed specification for Q=75% at 45 minutes (Figure 46 and Figure 47). Physical properties characterization XRPD data of the Granules/Tablets from Technical Batches are summarized in Table 51. All the batches tested showed the absence of EZE hydrate with exception of the granules from the FDC2 formulation. However, the hydrate form disappears in the coated tablet. Both batches of Granules show similar flowability. PSD data of granules are reported in Table 52 and in Figure 48. Batches show similar bi-modal curves. Stability studies A summary of physicochemical analysis of technical batches after three months of storage for FDC2 composition is provided in Table 53 (without desiccant) and Table 54 (with desiccant), and for FDC1 composition in Table 55 (without desiccant) and Table 56 (with desiccant). Table 50: Results of the analytical characterization of technical batches - Coated Manufacturing lot number A4459/31/02 A4459/31/01 Prototype FDC 1 (intra-Intra) FDC 2 (intra-Extra) T A A O E I I I F M T I I E E T U O E D 1 ( 3 ( 4 ( 6 ( 7 ( D 1 ( 3 ( 4 ( 6 ( 7 ( W
Figure imgf000078_0001
ater content KF 4.0 % w/w 3.7 % w/w Table 51: XRPD data summary of granules/tablets from technical batches S F t F F
Figure imgf000078_0002
FDC1 (INTRA- INTRA) Tablet coated A4459/31/02 OBI + EZE Anhydrous Ta G
Figure imgf000078_0003
ranules FDC2 A4459/30/01 38.70 87.20 184.73 1.67 Granules FDC1 A4459/30/02 34.17 82.42 275.71 2.92 Table 53: Long-term and accelerated storage stability results for FDC2 technical batch no. A4459/31/01 (without desiccant) Storage Time Appearan./Colo OBICETRAPI DIASTEREOISOME ETHYL FROL MONO- C diti M th APP/1001 B TA8995 R A t ESTER A t BN FREE 3 S n % In 2 R P 3 R P 4 R P Tab
Figure imgf000079_0001
e 53 (Contd.) E 1 S In 2 P 3 P 4 Pa
Figure imgf000079_0002
. . . . . . Tab I S n In 2 R P 3 R P 4 R
Figure imgf000079_0003
. . . . - Packaged Table 53 (contd.) Storage Time Time Time Time Time Time Time Condition (Month point(min) 30 point(min) 30 point(min) 45 point(min) 45 point(min) 60 point(min) 60 P ) S o In 2 R P 3 R P 4 R P Tab
Figure imgf000080_0001
St r Tim Tim Tim Tim Tim Tim Tim B 8 S n lt In 2 R P 3 R P 4 R P
Figure imgf000080_0002
Table 53(contd ) E S t In 2 P 3 P 40
Figure imgf000080_0003
Packaged 3 98 97 - 101 101 101 - 104 105 102 - 107 Ta S S In 2 P 3
Figure imgf000080_0004
Packaged 1 4.2 100 95 – 105 10.22 9.69 – 10.71 Storage Condition Time Water content Strength Strength Strength Strength (Months) UMID/1231 RESR/1001 RESR/1001 RESR/1001 RESR/1001 S 4 P N/
Figure imgf000081_0001
Table 54: Long-term and accelerated storage stability results for FDC1 technical batch no. A4459/31/02 (without desiccant) Storage Time Appearan./Colo OBICETRAP DIASTEREOISOM ETHYL FROL MONO- C E 3 S n In 2 R P 3 R P 4 R P
Figure imgf000081_0002
Table 54(contd.) E 1 S In 2 P 3 P 4 Pa
Figure imgf000081_0003
ckaged 3 0.07 <0.05 0.34 104.3 <0.05 <0.05 Ta I S n In 2 R P 3 R P 4
Figure imgf000081_0004
RH 3 <0.05 0.05 <0.05 0.05 90 89 - 91 Packaged Table 54(contd.) Storage Time Time Time Time Time Time Time Condition (Month point(min) 30 point(min) 30 point(min) 45 point(min) 45 point(min) 60 point(min) 60 P ) S o In 2 R P 3 R P 4 R P Tab
Figure imgf000082_0001
St r Tim Tim Tim Tim Tim Tim Tim B 8 S t n In 2 R P 3 R P 4 R P
Figure imgf000082_0002
Table 54 (contd ) E S lt In 2 P 3 P 4
Figure imgf000082_0003
Packaged 3 102 96 – 107 104 98 – 108 106 102 - 109 Ta S S In 2 P 3
Figure imgf000082_0004
Packaged 1 4.8 65 61 – 69 6.62 6.22 – 7.04 Storage Condition Time Water content Strength Strength Strength Strength (Months) UMID/1231 RESR/1001 RESR/1001 RESR/1001 RESR/1001 S 4 P N/
Figure imgf000083_0001
Table 55: Long-term and accelerated storage condition results for FDC2 technical batch no. A4459/31/01 (with desiccant) Storage Time Appearan./Colo OBICETRAPI DIASTEREOISOME ETHYL FROL MONO- C E 3 S n % In 2 R P 4 R P Tab
Figure imgf000083_0002
le 55(contd.) E 1 S % In 2 P 4 Pa
Figure imgf000083_0003
c age Tab I S n In 2 R P 4 R
Figure imgf000083_0004
Packaged Table 55(contd.) Storage Time Time Time Time Time Time Time Condition (Month point(min) 30 point(min) 45 point(min) 45 point(min) 60 point(min) 60 point(min) 70 P ) S s o In 2 R P 4 R P Ta
Figure imgf000084_0001
Storage Time Time Time Time Time Time Time E S P, 5 In 2 P 4 P
Figure imgf000084_0002
Table 55(contd.) 1 S In 2 P 4 Pa
Figure imgf000084_0003
ckaged Ta S In 2
Figure imgf000084_0004
40ºC/75% RH Packaged 3 114 102 – 127 11.59 10.40 – 12.95 Table 56: Long-term and accelerated storage condition results for FDC1 technical batch no. A4459/31/02 (with desiccant) Storage Time Appearan./Colo OBICETRAPI DIASTEREOISOME ETHYL FROL MONO- Condition (Months ur APP/1001 B (TA-8995) R Amount ESTER Amount BN FREE 3 S n % In 2 R P 4 R P Ta
Figure imgf000085_0001
Storage Time IMP RRT0.93 IMP RRT0.94 Total EZETIMIBE EZETIMIBE EZETIMIBE 1 S % In 2 P 4 P
Figure imgf000085_0002
Table 56(contd.) I S n In 2 R P 4 R Pa
Figure imgf000085_0003
ckaged Tab C 0 P ) S s o In 2 R P 4 RH
Figure imgf000085_0004
Packaged Table 56(contd.) Storage Time Time Time Time Time Time Time Condition (Months) point(min) 70 point(min) point(min) point(min) point(min) point(min) E S P, 5 In 2 P 4 P Ta
Figure imgf000086_0001
Storage Time Time Time Time Time Time Water 1 S In 2 P 4 P Tab
Figure imgf000086_0002
le 56 (contd.) S In 2 4
Figure imgf000086_0003
N/A: Not Applicable EXAMPLE 9 Study to evaluate the comparative bioavailability of two fixed-dose combination formulations of obicetrapib/ezetimibe 10 mg/10 mg (FDC1 and FDC2) with obicetrapib, 10 mg co-administered with ezetimibe, 10 mg in healthy adult subjects under fasted conditions Study design This was an open-label, single-dose, randomized, three-treatment, three-period, six-sequence crossover study comparing the two test products and coadministration of the reference products under fasted conditions. In each of the study periods, the subjects received either Treatment Tl (1 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]), or Treatment R (1 X obicetrapib tablet, 10 mg co-administered with 1 x ZETIA® (ezetimibe) tablet, 10 mg) following an overnight fast of at least 10 hours. The order of administration followed a six sequence randomization schedule. 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. Selection of study population The subject population included 36 healthy, non-tobacco-, non-nicotine-using, adult male and female subjects. Treatment administration The subjects received Treatment Tl, Treatment T2, or Treatment R according to a three treatment, three-period, six-sequence randomization schedule (Table 57) under direct observation following an overnight fast of at least 10 hours. ^ Treatment T1:1 x obicetrapib, 10 mg and ezetimibe, 10 mg FDC Tablet (Formulation #1) ^ 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 Table 57 S 1 2 3 4 5
Figure imgf000087_0001
6 R T1 T2 Each dose was administered with 240 mL of room temperature water. Subjects were instructed to swallow the tablet(s) whole without chewing or biting. Sample Collection, Handling and Bioanalytical Plans Sample Size 4 mL collections (K2EDTA vacutainers) for analysis of obicetrapib 4 mL collections (K2EDTA vacutainers) for analysis of ezetimibe and ezetimibe glucuronide Collection Times Pre-dose samples were collected within 60 minutes before dosing. All times are relative to the dosing minute. For analysis of obicetrapib: Pre-dose (0-hour) and at 0.50,1.0,1.5,2.0,2.5,3.0,3.5,4.0,4.5,5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0*, 96.0*, 144.0*, 192.0*, 240.0* and 336.0* hours post-dose (*return sample) For analysis of 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 number of collections per period/per subject: 49 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. Pharmacokinetic analysis For all treatments, the following pharmacokinetic parameters were calculated for obicetrapib, ezetimibe and its metabohte, ezetimibe glucuronide. Primary PK parameters Cmax: 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. AUC0-∞:Area under the plasma concentration versus time curve from time zero to infinity where AUCo-∞ = AUCo-t + Ct/λz. Ct is the last measurable concentration and λz is the terminal disposition rate constant. Secondary PK parameters Tmax: Time of the maximum measured plasma concentration. If the maximum value occured at more than one time point, Tmax is defined as the first time point with this value. λz: 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 λz was determined from the dataset that has the highest adjusted Rsquared (R2) value of 0.7 or more. λz was considered non-evaluable if (1) the last three terminal points were used to determine λz 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. An evaluable λz was considered not reliable and not reportable if the resulting apparent first- order terminal half-life (t1/2,) value was longer than the time interval over which λz was estimated. If the resulting t1/2, value was longer than the time interval over which λz was determined, an interval that was longer than the estimated t1/2, was explored. The interval with the next highest adjusted R2 value was chosen and the decrease in the adjusted R2 value was assessed to determine if a reliable estimation of the λz was possible. If λz was deemed not reliable then no t1/2, and AUCo-∞ values were reported for that dataset. t1/2: The first-order terminal disposition half-life was calculated as ln(2)/λz 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 Tl 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 Tl versus R and Treatment Tl was excluded from ANOVA for comparison of Treatments T2 versus R. Confidence intervals (90%) on the geometric mean ratios (obtained from logarithmic transformed data) for AUCo-t, AUCo-∞ and Cmax for the comparison of each of the FDC formulations (Tl and T2) to Treatment R was constructed to test two one-sided hypotheses at the a = 0.05 level of significance. Results Confidence intervals (90%) on the geometric mean ratios for AUCo-t, AUCo-∞ and Cmax for obicetrapib, ezetimibe and ezetimibe glucoronide (from T1 and T2 for formulation #1 as well as formulation #2) 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. 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. List of Abbreviations: API Active Pharmaceutical Ingredient °C degree Celsius CC Compaction compressibility (= 100 x (TBD-IBD) / TBD) CFM cubic feet per minute CoA Certificate of analysis DBD Dynamic bulk density (= (TBD - IBD)2 / TBD] + IBD) e.g. for example eze/EZE Ezetimibe FDC1 Formulation development composition 1 FDC2 Formulation development composition 2 g gram H Hausner ratio (= TBD / IBD) HPLC High Performance Liquid Chromatography IBD Initial bulk density (= mass/initial volume) KF Karl Fisher kp Kilopound KN Kilonewton LC Label claim LLS Laser Light Scattering Lt Liter mg milligram min minute mL millilitre mm millimeter N.R Not recorded N.D Not detected Obi/OBI Obicetrapib (Known also as TA-8995) pH -log [H+] or pH = - log a + H PSD Particle Size Distribution RH Relative Humidity (aw * 100) rpm rotation per minute RRT Relative retention time RSD Relative standard deviation sec second SD Standard deviation SLS Kolliphor SLS Fine, EP & USP/NF & JP T Temperature (°C) TBD Tapped bulk density (= mass/tapped volume) vs versus w/w weight/weight XRPD X-Ray Powder Diffraction µm microns Ø diameter % a/a % area of impurity to the total area of peaks not being present in the blank

Claims

CLAIMS 1. A fixed dose pharmaceutical composition comprising or consisting of: a. Obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, b. Ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, c. One or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein 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%-110% 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 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 or co-crystal thereof.
3. The pharmaceutical composition according to anyone of the preceding claims, 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 0-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 0-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, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.
4. The pharmaceutical composition according to anyone of the preceding claims for use in treatment of subjects requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol, wherein the pharmaceutical composition is considered to be suitable for said use when: a. the said fixed dose pharmaceutical composition is orally administered to a subject; b. the concentration of obicetrapib in the subject’s plasma 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. if 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%-110% 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 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 or co-crystal thereof.
5. The pharmaceutical composition according to anyone of the preceding claims for use in treatment of subjects requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol, wherein the pharmaceutical composition is considered to be suitable for said use when: a. the said fixed dose pharmaceutical composition is orally administered to a subject; b. the concentration of ezetimibe and/or ezetimibe glucoronide in the subject’s plasma 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, c. if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and/or AUC 0-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 0-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 composition 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, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.
6. The pharmaceutical composition according to anyone of the preceding claims, wherein the use of the said composition is for reduction in LDL cholesterol and/or an increase in HDL cholesterol, a human suffering from heterozygous familial hypercholesterolemia (HeFH) and/or having an established atherosclerotic cardiovascular disease (ASCVD).
7. The pharmaceutical composition according to anyone of the preceding claims, wherein the 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 AUC0-∞.
8. The pharmaceutical composition according to anyone of the preceding claims, wherein the subject is a human, preferably a healthy human, more preferably a human requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol, a human suffering from heterozygous familial hypercholesterolemia (HeFH) and/or having an established atherosclerotic cardiovascular disease (ASCVD).
9. The pharmaceutical composition according to anyone of the preceding claims, wherein the subject is an healthy, non-tobacco, non-nicotine using adult male or female human of 18-65 years of age, and optionally, the said human has a body mass index of 18.5 to 29.9 Kg/m2.
10. The pharmaceutical composition according to anyone of the preceding claims, wherein the human requiring reduction in LDL cholesterol, and/or the human suffering from heterozygous familial hypercholesterolemia (HeFH), and/or the human having an established atherosclerotic cardiovascular disease (ASCVD) has LDL-cholesterol levels >70 mg/dL, and optionally the said humans are not adequately controlled by their current lipid-modifying therapies.
11. The pharmaceutical composition according to anyone of the preceding claims, wherein at least about 60%, preferably at least about 70% and more preferably at least about 80% of ezetimibe is dissolved in 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 ± 0.5ºC.
12. The pharmaceutical composition according to anyone of the preceding claims, wherein at least about 70%, preferably at least about 80% and more preferably at least about 85% of obicetrapib is dissolved in 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 of polysorbate 80 at a rotation speed of about 75 rpm at 37 ± 0.5ºC.
13. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition comprises 1 to 20 mg obicetrapib and 5 to 20 mg ezetimibe, preferably said composition comprises 5 mg obicetrapib and 10 mg ezetimibe or 10 mg obicetrapib and 10 mg ezetimibe.
14. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition is provided as a unit dosage form comprising 1 to 20 mg obicetrapib and 5 to 20 mg ezetimibe, preferably the unit dosage comprises 5 mg obicetrapib and 10 mg ezetimibe, or 10 mg obicetrapib and 10 mg ezetimibe.
15. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition comprises ezetimibe tetrahydropyran analog as an impurity 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).
16. The pharmaceutical composition according to any one of the preceding claims, wherein either ezetimibe or obicetrapib or both are micronized.
17. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition comprises micronized ezetimibe having a Dv90 not more than 10µm, preferably in the range of 4-10µm, more preferably not more than 8.5 µm; Dv50 not more than 4 µm, preferably in the range of about 1-4 µm more, more preferably not more than 3.8µm, and Dv10 not more than 1µm.
18. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition comprises micronized obicetrapib having a Dv90 not more than 14 µm, preferably in the range of about 5-14 µm; Dv50 not more than 5µm, preferably in the range of about 3-5µm; and Dv10 not more than 3µm.
19. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition comprises ezetimibe as anhydrous ezetimibe, ezetimibe monohydrate or a mixture thereof.
20. The pharmaceutical composition according to anyone of the preceding claims, wherein 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.
21. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition is a dual component composition, and wherein one of the components comprises ezetimibe and another component comprises obicetrapib.
22. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition is a dual component composition, and wherein one of the two components comprises both ezetimibe and obicetrapib.
23. The pharmaceutical composition according to anyone of the claims 21-22, wherein the two component composition is a bilayer tablet formulation, a capsule formulation comprising or consisting of two types of granules, or a tablet formulation comprising an extragranular component and an intragranular component.
24. The pharmaceutical composition of claim 22, wherein: a. the intragranular component comprises ezetimibe and extragranular component comprises obicetrapib; or the intragranular component comprises both ezetimibe and obicetrapib; and the extragranular component comprises only excipients.
25. The pharmaceutical composition according to claim 22, wherein: a. the intragranular component comprises obicetrapib and the extragranular component comprises ezetimibe; or b. the extragranular component comprises both ezetimibe and obicetrapib and the intragranular component comprises only excipients.
26. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition further comprises one or more binders and surfactants with a binder : surfactant ratio, preferably the ratio in the intragranular component, 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.
27. The pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises one or more binders selected from cellulose derivatives, preferably selected from methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, sucrose, sorbitol, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites, preferably the binder is polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone, more preferably copovidone, and even more preferably the binder is Kollidon 30.
28. The pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises one or more surfactants having an HLB value of at least 15, at least 20, at least 30 or at least 40; preferably one or more 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; more preferably 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; and even more preferably the surfactant is sodium lauryl sulphate.
29. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition 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, pregelatinized starch, preferably the disintegrant is croscarmellose sodium or sodium starch glycolate, and more preferably the disintegrant is sodium starch glycolate.
30. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition is stable for at least 1 month, preferably at least 3 months and more preferably at least 6 months at 40ºC/75% relative humidity, or for at least 3 months, preferably at least 6 months and more preferably at least 12 months at 25ºC/60% relative humidity.
31. The pharmaceutical composition according to anyone of the preceding claims, wherein the 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 hydrate equivalent to ezetimibe 10 mg; iii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w/wof the granule of intragranular component; more preferably the binder is 1+0.5% w/wpolyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w/w sodium lauryl sulphate; iv. 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; v. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. An extragranular component comprising: i. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; ii. optionally, a lubricant, preferably magnesium stearate, iii. optionally, a glidant, preferably colloidal silicon dioxide or talc or both; iv. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose. c. Optionally, the 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.
32. The pharmaceutical composition according to anyone of the preceding claims, wherein the 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. 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 extragranular component comprising: i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; iii. optionally, a lubricant, preferably magnesium stearate, iv. optionally, a glidant, preferably colloidal silicon dioxide or talc or both; v. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose. c. Optionally, the 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.
33. The pharmaceutical composition according to anyone of the preceding claims, wherein the composition comprises 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. 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 extragranular component comprising: i. Ezetimibe anhydrous or a mixture of Ezetimibe anhydrous and Ezetimibe hydrate equivalent to Ezetimibe 10 mg ii. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; iii. optionally, a lubricant, preferably magnesium stearate, iv. optionally, a glidant, preferably colloidal silicon dioxide or talc or both, v. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose. c. Optionally, the 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.
34. The pharmaceutical composition according to anyone of the preceding claims for use in the treatment of subjects requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol, preferably the subjects suffering from hyperlipidaemia or mixed dyslipidaemia.
35. The pharmaceutical composition according to anyone of the preceding claims 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).
36. Use of a pharmaceutical composition according to anyone of the preceding claims for preparation of a medicament for treatment of subjects suffering from hyperlipidaemia or mixed dyslipidaemia.
37. Use of a pharmaceutical composition according to anyone of the preceding claims for preparation of a medicament for reducing LDL cholesterol in a subject requiring a reduction in LDL cholesterol and/or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and/or a subject with established atherosclerotic cardiovascular disease (ASCVD).
38. Use of a pharmaceutical composition according to anyone of the preceding claims for preparation of a medicament for reducing the risk for cardiovascular events.
39. Use according to anyone of the preceding claims, wherein the subject suffers from mild dyslipidemia.
40. A method of treatment of a subject requiring reduction in LDL cholesterol and/or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and/or subject with established atherosclerotic cardiovascular disease (ASCVD), wherein the method comprises administering a therapeutically effective dose of the pharmaceutical composition of anyone of the preceding claims to a patient in need thereof.
41. A method of treatment of subjects suffering from hyperlipidaemia or mixed dyslipidaemia, wherein the method comprises administering the pharmaceutical composition of anyone of the preceding claims to a patient in need thereof.
42. The use of a pharmaceutical composition for preparation of a medicament or a method of treatment according to anyone of the preceding claims, wherein the subject has LDL- cholesterol levels >50 mg/dL, preferably >70 mg/dL, and optionally, the said humans are not adequately controlled by their current lipid-modifying therapies.
43. The use of a pharmaceutical composition or a method of treatment according to anyone one of the preceding claims, wherein the subject in need thereof is 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.
44. The use of a pharmaceutical composition or a method of treatment according to anyone of the preceding claims, wherein the subject in need thereof is a subject 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 45. 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).
PCT/EP2022/075957 2022-08-22 2022-09-19 Fixed dose combination composition of obicetrapib and ezetimibe WO2024041746A1 (en)

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