Fixed dose combination composition of obicetromibe and ezetimibe

Abstract

This document provides pharmaceutical compositions comprising: obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe; a surfactant; and optionally one or more other pharmaceutically acceptable excipients. Pharmaceutical dosage forms are also provided, including methods for preparing such pharmaceutical compositions, and methods for using such pharmaceutical compositions in the treatment of a subject, including in treatment requiring lowering LDL cholesterol and / or raising HDL cholesterol.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions comprising obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; surfactants and optionally one or more other pharmaceutically acceptable excipients, and their use in the preparation of pharmaceuticals and in the treatment of subjects requiring such treatment (including such treatment requiring lowering LDL cholesterol), or patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients diagnosed with atherosclerotic cardiovascular disease (ASCVD). Background Technology

[0002] Despite advances in treatment, cardiovascular disease (CVD) remains a leading cause of death worldwide, claiming more than 17 million lives annually. For many years, abnormal cholesterol levels have been known to be associated with an increased risk of CVD, such as cardiomyopathy, atherosclerosis, and myocardial infarction. Specifically, individuals with high levels of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol combined with low levels of high-density lipoprotein (HDL) cholesterol have been observed to have the highest risk of cardiovascular disease.

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

[0004] One class of alternative treatment agents is cholesterol absorption inhibitor (CAI). CAI prevents the small intestine from absorbing cholesterol by blocking the uptake of micellar cholesterol, thereby reducing cholesterol esters in chylomicrons and chylomicron residues. CAI reduces the amount of cholesterol circulating back to the liver, thereby increasing the activity of hepatic LDL receptors and increasing the clearance of LDL cholesterol particles from the bloodstream.

[0005] A known example of a CAI is ezetimibe, formerly known as the Schering-Plough compound "Sch-58235" and marketed under various brand names such as Ezetrol and Zetia (Merck Sharp & Dohme / Merck). The IUPAC name for ezetimibe is (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azacyclobutane-2-one. Ezetimibe is frequently administered as a monotherapy or in combination with other treatments. Typically, ezetimibe is available in tablet form containing 10 mg for oral administration.

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

[0007] Despite evidence supporting the potential of CETP inhibition in reducing cardiovascular morbidity, clinical development of CETP inhibitors has not been easy, and many have been abandoned at various stages of clinical development. Orbisetropip (also known as TA-8995) is currently undergoing clinical evaluation.

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

[0009] In some embodiments, the inventors have found that treatment with a combination of obisetropeptide and ezetimibe results in a significant improvement in lipid profiles. Therefore, in general, aspects of the present invention provide a treatment method that includes the simultaneous administration of obisetropeptide and ezetimibe.

[0010] Combination therapy requires the combined administration of multiple pills according to the exact instructions of the physician prescribing such treatment. Because each drug in a combination therapy may have its own set of instructions, maintaining adherence to these instructions over extended periods can be cumbersome, especially for chronic conditions such as those requiring lipid-lowering therapy, and is further complicated for both the patient and their caregiver. This difficulty often leads to non-compliance, impairing efficacy, increasing the risk of adverse reactions, and in many cases, developing resistance or altered sensitivity to target receptors / proteins.

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

[0012] Ezetimibe is a nearly insoluble drug with low solubility across the entire physiological pH range. It is also incompatible with many commonly used excipients and presents stability issues; for example, the presence of polyethylene glycol (PEG) in the coating layer can increase the tetrahydropyran impurities in ezetimibe. Furthermore, ezetimibe is an inherently incompressible and poorly flowing API (see, for example, EP 2168573 A1), making the preparation of ezetimibe tablet formulations quite challenging.

[0013] Obisetropip also exhibits poor water solubility within the physiological pH range and negatively impacts the solubility of ezetimibe (unpublished data). To the applicant's knowledge, no fixed-dose combination of ezetimibe and obisetropip has been found in the art that meets the following criteria: (i) it remains stable over a long period without significantly increasing the level of harmful impurities; (ii) there are no significant API-API interactions, API-excipient interactions, or excipient-excipient interactions that would render such a composition unsuitable for human use; (iii) it consistently provides the desired solubility profiles for each of the two components throughout its shelf life, comparable to or better than a formulation with a single drug; (iv) it is easy to formulate and does not challenge the processability of the components during formulation and scale-up manufacturing; (v) When administered as two separate formulations of each drug, the desired bioavailability is achieved after oral administration to humans, and the two active ingredients are bioequivalent at the same dose, and (vi) improved patient compliance is provided, thereby demonstrating equivalent or superior therapeutic effects over a long period without the side effects of taking multiple pills of a single drug formulation, such as poor patient compliance leading to receptor / protein resistance or hypersensitivity due to long-term and irregular exposure of the receptor / protein to the drug and its metabolites at sub-therapeutic or toxic levels.

[0014] The inventors of this invention have discovered that treatment with the combination of obisetropeptide and ezetimibe resulted in significant improvements in lipid profiles even in subjects who did not adequately respond to (high-intensity) statin therapy (e.g., hypo-responders to high-intensity statins, HIS). More specifically, as described in the experimental section of this document, it has now been demonstrated in a phase 2b clinical trial (“ROSE2”; NCT05266586) that the combination of obisetropeptide (10 mg) and ezetimibe (10 mg) was well-tolerated and reduced the median LDL-C by 59%, clearly demonstrating a supra-additive effect. In particular, patients treated with obisetropeptide experienced a 39% reduction in median LDL-C, meaning that the additional use of ezetimibe on top of obisetropeptide resulted in an additional / incremental reduction of approximately 32% in median LDL-C. This significantly exceeded the LDL-C reductions normally achieved with ezetimibe: ezetimibe monotherapy typically reduces LDL-C levels by 15% to 22% (in patients with hyperlipidemia), while when used in combination with statins, ezetimibe typically results in an incremental reduction of 15% to 20% in LDL-C levels (see, for example, Catapano et al., European Heart Journal (2016) 37, 2999-3058). Significant increases in ApoB and Lp(a) levels were also demonstrated in the trial.

[0015] Therefore, one aspect of the present invention relates to a fixed-dose pharmaceutical composition comprising: obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof; and a pharmaceutically acceptable excipient, the fixed-dose pharmaceutical composition being, for example, a two-component composition wherein one of the components comprises ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof and the other component comprises obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0016] The examples relate to fixed-dose pharmaceutical compositions comprising obisetroprine calcium, as used herein, which is obisetroprine hemicalcium, and which may further comprise amorphous obisetroprine hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and pharmaceutically acceptable excipients, wherein when the pharmaceutical composition is dissolved in a 500 ml solution at about 75 rpm in a USP Type II device at 37 ± 0.5°C, at least about 60%, typically at least about 70%, and more typically at least about 80% of ezetimibe dissolves within about 30 minutes, the solution containing 0.45% SLS in 0.05 M pH 4.5 sodium acetate buffer.

[0017] The embodiments relate to fixed-dose pharmaceutical compositions comprising obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and a pharmaceutically acceptable excipient, wherein the 90% confidence intervals of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of obisetropip after oral administration of the composition to a subject are respectively the area under the curve (AUC 0-∞ and / or AUC 0-t) of obisetropip obtained after oral administration of a reference pharmaceutical composition to similar subjects. The reference composition comprises an equivalent dose of obisetropeptide or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and wherein the reference composition is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0018] Another embodiment relates to a fixed-dose pharmaceutical composition comprising obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and a pharmaceutically acceptable excipient, wherein, after oral administration of the composition to a subject, the 90% confidence intervals of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of ezetimibe and / or ezetimibe are respectively 75%–125%, typically 80%–125%, and more typically 90%–125% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of ezetimibe and / or ezetimibe after oral administration of the reference pharmaceutical composition to similar subjects. Within the range of 110%, wherein the reference comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and wherein the reference composition is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0019] Surprisingly, it was found that the fixed-dose pharmaceutical composition of ezetimibe and obisetropeptide remained stable over a long period without significantly increasing the level of harmful impurities or forming a large number of new impurities. It was also surprisingly found that the fixed-dose pharmaceutical composition of ezetimibe and obisetropeptide did not exhibit any significant API-API interactions, drug-excipient interactions, and / or excipient-excipient interactions that could render the formulation unsuitable for use.

[0020] Even more surprisingly, the pharmaceutical composition consistently provides the same solubility profiles for ezetimibe and obisetropip throughout its entire shelf life, equivalent to the solubility achieved by formulations containing only the single drug. Because the stable composition provides the desired solubility profile with a single pill, it surprisingly overcomes the problems associated with the co-administration of multiple pills containing single-drug formulations, such as poor patient compliance, suboptimal therapeutic effects, and an increased risk of undesirable side effects (e.g., receptor resistance or hypersensitivity). This makes the fixed-dose composition particularly relevant for the chronic treatment of patients requiring lipid-lowering therapy, thus making such a therapy suitable.

[0021] The second aspect relates to a fixed-dose pharmaceutical composition comprising obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof; and a pharmaceutically acceptable excipient, said fixed-dose pharmaceutical composition for lowering LDL cholesterol in patients who require lowering LDL cholesterol and / or raising HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0022] The present invention also provides a method of treating a subject in need, the method comprising concomitant treatment of the subject generally in the form of a fixed-dose pharmaceutical composition as defined herein, using obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof and ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0023] More particularly, the present invention relates to the following aspects.

[0024] One aspect of the invention relates to a method for the preventive and / or therapeutic treatment of a subject suffering from CVD, particularly ASCVD, or at risk of developing CVD, particularly ASCVD, the method comprising concomitant treatment of the subject with obisetropeptide or a pharmaceutically acceptable salt, solvate, or cocrystal thereof and ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof. In a typical embodiment of the invention, the method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0025] Another aspect of the invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and / or obisetropeptide or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, for use in methods of prophylactic and / or therapeutic treatment of a subject suffering from or at risk of CVD, particularly ASCVD, wherein the method comprises concomitant treatment of the subject with ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof and obisetropeptide or a pharmaceutically acceptable salt, solvate, or cocrystal thereof. In a typical embodiment of the invention, the pharmaceutical composition is a fixed-dose pharmaceutical composition as defined herein.

[0026] Another aspect of the invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and / or obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, for use in a method of prophylactic treatment and / or therapeutic treatment of a subject suffering from or at risk of suffering from a group of diseases or disorders selected from the following: treatment of resistant progressive coronary artery disease, progressive kidney disease, peripheral artery disease, and complete statin intolerance, wherein the method comprises concomitant treatment of the subject with ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof and obisetropip or a calcium salt thereof. In a typical embodiment of the invention, the pharmaceutical composition is a fixed-dose pharmaceutical composition as defined herein.

[0027] Another aspect of the invention relates to a method for synergistically reducing LDL-C plasma levels in a subject of need, the method comprising concomitant treatment of the subject with ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof and obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof. In a typical embodiment of the invention, the method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0028] Another aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof and / or obisetropeptide or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, for use in a method of synergistically lowering LDL-C plasma levels in a subject in need, said method comprising concurrent administration of ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof and / or obisetropeptide or a pharmaceutically acceptable salt, solvate, or cocrystal thereof. In a typical embodiment of the invention, said method comprises administration of a fixed dose of the pharmaceutical composition as defined herein.

[0029] Another aspect of the invention relates to a method for synergistically slowing the development and / or progression of CVD (more particularly ASCVD) and / or synergistically reducing the risk and / or occurrence of CVD-related events (especially ASCVD-related events) in subjects of need, said method comprising the concomitant administration of ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and obisetripip or a calcium salt thereof. In a typical embodiment of the invention, said method comprises the administration of a fixed-dose pharmaceutical composition as defined herein.

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

[0031] Another aspect of the invention relates to a method for enhancing, and typically synergistically enhancing, the LDL-C-lowering effect of obisetropip or its pharmaceutically acceptable salts, solvates, or cocrystals in subjects in need, said method comprising concomitant treatment of the subject with ezetimibe or its pharmaceutically acceptable salts, solvates, or cocrystals. In a typical embodiment of the invention, the method comprises administering a fixed-dose pharmaceutical composition as defined herein.

[0032] Another aspect of the invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, for use in a method of enhancing, and typically synergistically enhancing, the LDL-C-lowering effect of obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof in a subject in need, said method comprising concurrent administration of ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof. In a typical embodiment of the invention, the method comprises administration of a fixed dose of the pharmaceutical composition as defined herein.

[0033] Another aspect of the invention relates to a method for enhancing, and typically synergistically enhancing, the therapeutic efficacy of obisetropip or its pharmaceutically acceptable salts, solvates, or cocrystals in subjects of need, particularly in the treatment and / or prevention of CVD, more particularly ASCVD, said method comprising the concomitant administration of ezetimibe or its pharmaceutically acceptable salts, solvates, or cocrystals. In a typical embodiment of the invention, the method comprises the administration of a fixed-dose pharmaceutical composition as defined herein.

[0034] Another aspect of the invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, for use in a method of enhancing, and typically synergistically enhancing, the therapeutic efficacy of obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof in a subject of need, particularly in the treatment and / or prevention of CVD, more particularly ASCVD, said method comprising concurrent administration of ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof. In a typical embodiment of the invention, the method comprises administration of a fixed dose of the pharmaceutical composition as defined herein.

[0035] Another aspect of the invention relates to the use of obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and / or ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof in the preparation of a pharmaceutical agent for any of the methods previously defined. In a typical embodiment of the invention, the pharmaceutical agent is a fixed-dose pharmaceutical composition as defined herein.

[0036] Other aspects of the invention relate to a kit comprising: a package containing multiple drug unit dosage forms, including pharmaceutically acceptable salts, hydrates, or solvates, such as fixed-dose pharmaceutical compositions as defined herein; and a leaflet containing printed instructions for use, the kit being designed for repeated self-administration of the unit dosage forms to treat and / or prevent CVD, particularly ASCVD, by combining obisetropeptide treatment with ezetimibe treatment.

[0037] In this respect, obisetropip can be delivered in a pharmaceutical composition containing said obisetropip, a surfactant, and optionally one or more pharmaceutically acceptable excipients.

[0038] Another aspect of the invention relates to pharmaceutical compositions comprising obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, calcium obisetropip, as used herein, which is obisetropip hemicalcium, and in many embodiments, the calcium obisetropip may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; a surfactant; and optionally one or more pharmaceutically acceptable excipients.

[0039] The present invention also provides a method of treating a subject in need, the method comprising concomitant treatment of the subject with: obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof; and surfactants and optionally one or more other pharmaceutically acceptable excipients.

[0040] One aspect of the invention relates to a method for the preventive and / or therapeutic treatment of a subject suffering from CVD, particularly ASCVD, or at risk of developing CVD, particularly ASCVD, the method comprising concomitant treatment of the subject with: obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and a surfactant and optionally one or more other pharmaceutically acceptable excipients.

[0041] Another aspect of the invention relates to obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof (including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, which may be amorphous obisetropip hemicalcium) and ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and the use of compositions comprising surfactants and optionally one or more pharmaceutically acceptable excipients in the manufacture of a medicament for use in treating human diseases affected by CETP inhibition.

[0042] Other aspects of the invention relate to a kit comprising a package containing multiple pharmaceutical unit dosage forms comprising obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; a surfactant and optionally one or more other pharmaceutically acceptable excipients; and a printed instruction manual containing instructions for repeated self-administration of the unit dosage form for the treatment and / or prevention of a human condition or disease that is improved or treated by CETP inhibition. Other aspects of the invention relate to the use of obisetropip or its pharmaceutically acceptable salts, solvates or cocrystals (including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments may be amorphous obisetropip hemicalcium) for the following purposes: for use in patients who require lowering LDL cholesterol and / or raising HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients diagnosed with atherosclerotic cardiovascular disease (ASCVD) to lower LDL cholesterol.

[0043] Other aspects of the invention relate to the use of obisetropip or its pharmaceutically acceptable salts, solvates, or cocrystals (including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, which may be amorphous obisetropip hemicalcium) for the following purposes: for use in treating subjects with hyperlipidemia or mixed dyslipidemia (or mild dyslipidemia) and / or for lowering LDL cholesterol and / or raising HDL cholesterol in subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH), and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD), and / or for treating subjects who require additional lowering of LDL cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy to treat adults with heterozygous familial hypercholesterolemia (HeFH) or diagnosed with atherosclerotic cardiovascular (CV) disease (ASCVD). In this respect, obisetropip can be delivered in a pharmaceutical composition containing said obisetropip, a surfactant, and optionally one or more pharmaceutically acceptable excipients.

[0044] Another aspect of the invention relates to the use of obisetropip or its pharmaceutically acceptable salts, solvates, or eutectics (including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, which may be amorphous obisetropip hemicalcium) for the following purpose: reducing the risk of cardiovascular events. In such an aspect, obisetropip can be delivered in a pharmaceutical composition containing said obisetropip, a surfactant, and optionally one or more pharmaceutically acceptable excipients.

[0045] It should be understood that, unless otherwise expressly stated, such aspects of the invention relate to the same compositions, the same treatment methods, the same subjects, etc. Specific details and exemplary embodiments of the above methods, as well as the compositions and pharmaceutical kits used therein, will become apparent to those skilled in the art based on the following detailed description and the appended experimental section. Attached Figure Description

[0046] These and other features, aspects, and advantages of the invention will be better understood with reference to the following description and accompanying drawings, in which: Figure 1 This is an X-ray powder diffraction pattern of amorphous obesetropi hemicalcium.

[0047] Figure 2 This is an X-ray powder diffraction pattern of amorphous obesetropi hemicalcium.

[0048] Figure 3 This is an X-ray powder diffraction pattern of crystalline obesetropi hemicalcium.

[0049] Figure 4 This is a polarized light micrograph of amorphous obesetropi hemicalcium.

[0050] Figure 5 This is a polarized light photomicrograph of crystalline ocbisetropi hemicalcium.

[0051] Figure 6 This is a modulated differential scanning calorimetry (DSC) thermogram of amorphous obesetropi hemicalcium (with pinholes).

[0052] Figure 7 This is a modulated differential scanning calorimetry (DSC) thermogram of crystalline ocbisetripi hemicalcium (with pinholes).

[0053] Figure 8 This is a thermogravimetric analysis diagram of amorphous obesetropi hemicalcium.

[0054] Figure 9 It is a solid form of both amorphous and crystalline obisetropeptide hemicalcium. 13 C-NMR spectrum.

[0055] Figure 10It is the solid form of crystalline ocbisetropi hemicalcium. 13 C-NMR spectrum.

[0056] Figure 11 It is a solid form of amorphous obesetropi hemicalcium. 13 C-NMR spectrum.

[0057] Figure 12 This is an X-ray powder diffraction pattern of crystalline HCl oxetine.

[0058] Figure 13 The images show X-ray powder diffraction patterns of crystalline HCl obisetrop (Figure 2) and at least partially desolvated crystalline HCl obisetrop (Figure 1).

[0059] Figure 14 Cumulative undersize of small-scale FDC1 compositions.

[0060] Figure 15 Cumulative undersize of small-scale FDC2 compositions.

[0061] Figure 16 Magnify the cumulative undersize curve of the batch.

[0062] Figure 17 Dissolution curves of octostrip from FDC1 particles in a scaled-up batch.

[0063] Figure 18 Ezetimibe dissolution curves from FDC1 particles in a scaled-up batch.

[0064] Figure 19 Ezetimibe dissolution curves from the final blend of FDC2 from the scaled-up batch.

[0065] Figure 20 Cumulative undersize curve for technical batches.

[0066] Figure 21 Dissolution curves of octocerpti in FDC1 and FDC2 technology batches.

[0067] Figure 22 Dissolution curves of octocerpti in FDC1 and FDC2 technology batches.

[0068] Figure 23 Particle size distribution (PSD) data of particles from technical batches.

[0069] Figure 24 Flowchart used to manufacture FDC-1.

[0070] Figure 25 Flowchart used to manufacture FDC-2. Detailed Implementation

[0071] This invention provides pharmaceutical compositions comprising or consisting of: obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; and ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; a surfactant; and optionally one or more other pharmaceutically acceptable excipients. Pharmaceutical dosage forms comprising the pharmaceutical compositions, including tablets, are also provided.

[0072] Also provided are methods for preparing (i) formulations comprising: obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and surfactants and optionally one or more other pharmaceutically acceptable excipients thereof.

[0073] Also provided is a method of using a pharmaceutical composition comprising: obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and a surfactant and optionally one or more other pharmaceutically acceptable excipients for treating a condition or disease, wherein inhibition of CETP improves such a condition or treats such a disease or both.

[0074] In some embodiments, the dosage form is a solid dosage form, such as a tablet. Methods for preparing the following are also provided: (i) obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof and its calcium salt, and fixed-dose combinations of obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof and its calcium salt; and (ii) ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof.It also provides (a) the following methods of use: a pharmaceutical composition of a fixed-dose combination of obisetropip or its pharmaceutically acceptable salts, solvates or cocrystals or calcium salts and ezetimibe or its pharmaceutically acceptable salts, solvates or cocrystals, for the treatment or prevention of hyperlipidemia or mixed dyslipidemia, or a medicine for the preparation of such pharmaceutical composition for the treatment or prevention of hyperlipidemia or mixed dyslipidemia; (b) The following are methods of use: A pharmaceutical composition of a fixed-dose combination of ocbistrip or its pharmaceutically acceptable salts, solvates or cocrystals or calcium salts, and ezetimibe or its pharmaceutically acceptable salts, solvates or cocrystals, for lowering LDL cholesterol in subjects requiring lowering LDL cholesterol and / or raising HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH) and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD); or a medicine prepared for lowering LDL cholesterol in subjects requiring lowering LDL cholesterol and / or raising HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH) and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD); (c) The following is the intended use of a pharmaceutical composition comprising a fixed-dose combination of ocbistrip or a pharmaceutically acceptable salt, solvate or cocrystal thereof or its calcium salt, and ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, for use in subjects requiring lower LDL cholesterol and / or raising HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH) and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD), or a drug prepared for use in subjects requiring lower LDL cholesterol and / or raising HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH) and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD); (d) Methods for treating subjects requiring lower LDL cholesterol and / or elevated HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH), and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD), wherein the method comprises administering to the patient in need a therapeutically effective dose of a pharmaceutical composition, namely obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof or a calcium salt thereof, and ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and (e) methods for treating subjects with hyperlipidemia or mixed dyslipidemia, wherein the method comprises administering to the patient in need a pharmaceutical composition, namely obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof or a calcium salt thereof, and ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, in a fixed-dose combination.

[0075] In one embodiment, after oral administration of the fixed-dose pharmaceutical composition to a subject, the 90% confidence intervals of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of obisetrop or its pharmaceutically acceptable salts, solvates, or cocrystals thereof were respectively obtained from the area under the curve (AUC 0-∞ and / or AUC 0-t) of obisetrop or its pharmaceutically acceptable salts, solvates, or cocrystals thereof after oral administration of the reference pharmaceutical composition to similar subjects. The reference composition comprises an equivalent dose of obisetropeptide or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0076] In another embodiment, after oral administration of the fixed pharmaceutical composition to a subject, the 90% confidence intervals of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of ezetimibe and / or ezetimibe glucoside are approximately 75%–125%, typically approximately 80%–125%, and more typically approximately 90%–125% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of ezetimibe and / or ezetimibe glucoside, respectively, obtained after oral administration of the reference pharmaceutical composition to similar subjects. Within the range of 110%, wherein the reference comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and wherein the reference composition is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof or its calcium salt, or in a fixed dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0077] Ezetimibe is practically insoluble in water and exhibits poor solubility across the entire physiological pH range. Achieving the desired solubility and thus bioavailability of ezetimibe under in vivo conditions is extremely challenging. This problem is further exacerbated by the reduction in the rate and total amount of soluble ezetimibe by obisetropeptide or its pharmaceutically acceptable salts, solvates, or cocrystallizations (unpublished data). Surprisingly, it has been found that when the pharmaceutical composition is dissolved in a 500 ml solution at 37 ± 0.5°C and a rotation speed of about 75 rpm in a USP Type II device, at least about 60%, typically at least about 70%, and more typically at least about 80% of the ezetimibe from a fixed dose of the pharmaceutical composition dissolves in about 30 minutes in a solution containing 0.45% SLS in 0.05 M sodium acetate buffer at pH 4.5. In a typical embodiment, it was surprisingly found that when the pharmaceutical composition was dissolved in a 500 ml solution at 37 ± 0.5°C and a rotation speed of about 75 rpm in a USP Type II device, at least about 60%, typically at least about 70%, and more typically at least about 80% of the ezetimibe from the fixed-dose pharmaceutical composition dissolved in about 20 minutes, the solution containing 0.45% SLS in 0.05 M pH 4.5 sodium acetate buffer.

[0078] Furthermore, it was surprisingly found that when the pharmaceutical composition was dissolved in 1000 ml of solution at 37 ± 0.5°C and a rotation speed of about 75 rpm in a USP Type II device, at least about 70%, usually at least about 80%, more usually at least about 85%, and even more usually at least about 90% of obisetropeptide or its pharmaceutically acceptable salts, solvates or cocrystals from the fixed-dose pharmaceutical composition dissolved within about 30 minutes in a solution containing a phosphate buffer solution at pH 6.8 + 0.2% w / v polysorbate 80. In a typical embodiment, it was surprisingly found that when the pharmaceutical composition was dissolved in 1000 ml of solution at about 75 rpm in a USP Type II device at 37 ± 0.5°C, at least about 70%, typically at least about 80%, and more typically at least about 85% of obisetropeptide or its pharmaceutically acceptable salts, solvates, or cocrystals from a fixed dose of the pharmaceutical composition dissolved within about 15 minutes, in a solution containing a phosphate buffer solution at pH 6.8 + 0.2% w / v polysorbate 80.

[0079] Ezetimibe is inherently a poorly compressible / incompressible API (see, for example, EP 2168573 A1) and has poor flowability. Therefore, it is extremely challenging for formulation scientists to prepare an ezetimibe tablet formulation that not only meets requirements for hardness, disintegration time, brittleness, shape, and size, but also provides the desired stability and solubility. Surprisingly, it has been found that compositions not only meet the required specifications for solubility and stability for the claimed use, but also conform to the standards for processability parameters (i.e., flowability, compressibility, disintegration time, brittleness, hardness, shape, and size).

[0080] In many embodiments of the invention, including many preferred embodiments, obisetropip is used in the form of amorphous obisetropip hemicalcium. Such preferred embodiments herein are used, for example, in pharmaceutical compositions of the invention, such as unit dosage forms (which may be in tablet form), methods of treatment, manufacturing methods, and kits.

[0081] Obis(trapeptide) or (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is a cholesterol ester transfer protein (CETP) inhibitor having formula (I), where Et represents an ethyl group:

[0082] In some embodiments, the pharmaceutical composition comprises a calcium salt of obisetropeptide, such as amorphous obisetropeptide hemicalcium. In a particular embodiment, the pharmaceutical composition comprises amorphous obisetropeptide hemicalcium. Furthermore, the composition may comprise obisetropeptide or its calcium salt in solvated form, the solvation comprising a pharmaceutically acceptable solvent, such as water (“hydrate”), ethanol, etc. Generally, for the purposes of this invention, the solvated form is considered equivalent to the non-solvated form.

[0083] Ombisetropip or its calcium salt (e.g., amorphous obisetropip hemicalcium) is present in the pharmaceutical composition in a therapeutically effective amount. In some embodiments, a “therapeutically effective amount” of obisetropip is an amount that effectively reduces or improves symptoms of metabolic or cardiovascular metabolic disorders when administered to an individual in combination therapy (e.g., as described herein in examples of pharmaceutical compositions containing ezetimibe) at one or more doses. This may include, for example, reduction in severity or progression, or cure. In some embodiments, a “therapeuticly effective amount” of obisetropip is an amount that, when administered to an individual in combination therapy (e.g., as described herein in examples of pharmaceutical compositions containing ezetimibe) at one or more doses, effectively reduces a subject’s symptoms by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 80%, at least about 90%, or at least about 95% compared to levels of assessed / quantitative / qualitative symptoms measured in an individual not receiving combination therapy or before receiving combination therapy.

[0084] In some embodiments, the pharmaceutical composition comprises about 1% to about 25% w / w obisetropip or its calcium salt (e.g., amorphous obisetropip hemicalcium) or a solvate or hydrate. In further embodiments, the composition comprises about 1% to about 20% w / w, or about 1% to about 15% w / w, or about 1% to about 10% w / w, or about 5% to about 15% w / w, or about 5% to about 12% w / w obisetropip or its calcium salt (e.g., amorphous obisetropip hemicalcium) or a solvate or hydrate. In further embodiments, the pharmaceutical composition comprises about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, or about 15% w / w of obisetropeptide or its calcium salt (e.g., amorphous obisetropeptide hemicalcium) or a solvate or hydrate. In specific embodiments, the pharmaceutical composition comprises about 5% w / w of obisetropeptide or its calcium salt (e.g., amorphous obisetropeptide hemicalcium) or a solvate or hydrate. In specific embodiments, the pharmaceutical composition comprises about 10% w / w of obisetropeptide or its calcium salt (e.g., amorphous obisetropeptide hemicalcium) or a solvate or hydrate.

[0085] In some embodiments, the pharmaceutical composition comprises 1% to 25% w / w obisetropip or its calcium salt (e.g., amorphous obisetropip hemicalcium) or a solvate or hydrate. In further embodiments, the composition comprises 1% to 20% w / w, or 1% to 15% w / w, or 1% to 10% w / w, or 5% to 15% w / w, or 5% to 12% w / w obisetropip or its calcium salt (e.g., amorphous obisetropip hemicalcium) or a solvate or hydrate. In further embodiments, the pharmaceutical composition comprises 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, or 15% w / w of obisetropeptide or its calcium salt (e.g., amorphous obisetropeptide hemicalcium) or a solvate or hydrate. In a particular embodiment, the pharmaceutical composition comprises 5% w / w of obisetropeptide or its calcium salt (e.g., amorphous obisetropeptide hemicalcium) or a solvate or hydrate. In a particular embodiment, the pharmaceutical composition comprises 10% w / w of obisetropeptide or its calcium salt (e.g., amorphous obisetropeptide hemicalcium) or a solvate or hydrate.

[0086] The amorphous obisetrapil hemicalcium of this invention differs from and can be distinguished from the crystalline obisetrapil hemicalcium disclosed in U.S. Patent No. 7,872,126. A common technique for distinguishing crystalline and amorphous materials is X-ray powder diffraction. However, this technique has limitations, especially when the crystalline material is disordered. In the case of amorphous obisetrapil hemicalcium, in... Figure 1 and Figure 2 The paper presents X-ray powder diffraction patterns of amorphous obbis-trappi hemicalcium from two different lots. These patterns exhibit the familiar "halo" characteristic associated with amorphous materials. Figure 2 The X-ray powder diffraction pattern in the image shows peaks at approximately 3.4°2θ, approximately 7.0°2θ, and approximately 9.2°2θ. Figure 1 or Figure 2 X-ray powder diffraction patterns can be used to characterize amorphous obbis-trapeptide hemicalcium; however, if sharper, higher-angle peaks are occasionally found, such as at approximately 31.7°2θ (e.g., at...),... Figure 2 In the middle), the peak (if present) is caused by sodium chloride. X-ray powder illustration of crystalline ocbisetripi hemicalcium is shown in [image / image / description]. Figure 3 It also exhibits halo-like behavior, which may indicate disorder.

[0087] Operations 11 and 11A described below illustrate various procedures for performing X-ray powder diffraction on a sample. The procedure in Operation 11 is typically used for collecting... Figure 1 and Figure 3 The data described herein; Operation 11A is typically used for Figure 2 .

[0088] Another technique used to distinguish between crystalline and amorphous materials is polarized light microscopy (“PLM”). In PLM, materials are observed using polarized light, and by observing the materials via a cross-polarizer, anisotropic materials (e.g., crystals) or isotropic materials (e.g., amorphous compounds) can be distinguished. When anisotropic materials are exposed to polarized light passing through a cross-polarizer, they exhibit birefringence, as evidenced by the color change observed when the light passes through the cross-polarizer. On the other hand, isotropic materials do not exhibit birefringence and do not show a color change when exposed to polarized light.

[0089] exist Figure 4 In this study, as described in Operation 10, amorphous obesetrapi hemicalcium was analyzed by polarized light microscopy. Figure 4 As shown, the studied material does not exhibit birefringence, indicating that the material is amorphous. In contrast, Figure 5 This is a polarized light photomicrograph of crystalline ocbisetripi hemicalcium. It is noteworthy that... Figure 5 The compound shown is multicolored, which indicates crystallinity. Furthermore, Figure 5 The crystals in Figure 5 The amorphous obbis-tropi hemicalcium is shown to have large particles in polarized light micrographs. Therefore, PLM and / or lack of birefringence can be used to characterize amorphous obbis-tropi hemicalcium.

[0090] Further techniques can be used to distinguish amorphous obisetrapeptide hemicalcium from crystalline obisetrapeptide hemicalcium, and therefore other techniques can be used to characterize amorphous obisetrapeptide hemicalcium. One such technique is modulated differential scanning calorimetry, also known as "mDSC". In an mDSC thermogram, the glass transition temperature can be measured, which can be used to characterize amorphous materials. Figure 6 In this study, an open sample holder was used to measure the mDSC thermogram of amorphous obbis-tropi hemicalcium, allowing volatile gases to escape during the measurement. Figure 6 In this case, the opening is created by piercing the lid of the pan to produce a pinhole. The glass transition temperature of this sample is recorded as approximately 110°C. Regarding thermal measurements, the term "approximately" usually refers to a variability of ±1°C. In contrast, crystalline ocbisetripi calcium has a higher glass transition temperature under the same conditions, and Figure 7 Three measurements showed a range between approximately 118°C and approximately 125.5°C. When measured with a pinhole, the glass transition temperature of amorphous obesetrapi hemicalcium was found to be between approximately 109°C and 112°C.

[0091] For example, the glass transition temperature of amorphous obbis-trapeptide hemicalcium can also be measured using mDSC with a closed disk. The type of sample preparation can affect the measured glass transition temperature. In such cases, the glass transition temperature decreases to below about 100°C, and particularly falls between about 70°C and about 92°C, depending on humidity.

[0092] Other thermal techniques can also be used to analyze and characterize amorphous obesetropi calcium, such as thermogravimetric analysis (TGA). Figure 8 The thermogravimetric analysis (TGA) spectral of amorphous obisetropi hemicalcium shows a weight loss of less than 1% when heated to approximately 200°C. Such a weight loss can be, for example, between approximately 0.8% and approximately 0.95% (including between approximately 0.84% ​​and approximately 0.92%). Figure 8 In the study, the weight loss was determined to be approximately 0.85%. The water content of this particular material was found to be approximately 1.5%. In some embodiments, the water content may be higher and includes a range from approximately 0% by weight to approximately 5% by weight, including up to approximately 4% by weight, up to approximately 3% by weight, and between approximately 0.5% by weight and 1.5% by weight.

[0093] solid state 13 C-NMR spectroscopy is another technique that can be used to characterize amorphous materials. Figure 9 The solid states of both crystalline and amorphous obisetropeptide hemicalcium are shown. 13 C-NMR spectrum, in which Figure 10 and Figure 11 Crystalline and amorphous ocbisetrip hemicalcium are shown separately. At least two differences are observed in the spectra. The crystalline phase exhibits a peak at approximately 22.1 ppm, which is absent in the amorphous phase. Furthermore, a peak at approximately 29.5 ppm is prominent in the crystalline phase, but not so prominent in the amorphous phase. Therefore, no solid phase is present at approximately 22.1 ppm. 13 C-NMR peaks and / or the absence of a significant peak at approximately 29.5 ppm can be used to characterize amorphous obisetropic hemicalcium. Additionally, [the following can be used] with [other methods]. Figure 4 The solids shown are essentially the same 13 C-NMR spectroscopy was used to characterize amorphous obesetropi hemicalcium.

[0094] In some embodiments of the invention, substantially pure amorphous obisetropeptide hemicalcium is provided prior to mixing with SGLT2i. In these and other embodiments, the substantially pure amorphous obisetropeptide hemicalcium has a chemical purity of 99.9% or higher.

[0095] In many aspects of the invention, a method for preparing amorphous calcium salts of obisetrop, such as amorphous obisetrop hemicalcium, is provided, wherein the method comprises: treating obisetrop with an acid to form a salt, solvate, or composition; separating the resulting salt, solvate, or composition; and treating the salt, solvate, or composition with a calcium source to generate an amorphous calcium salt of obisetrop, such as amorphous obisetrop hemicalcium. The resulting salt can then be separated.

[0096] Examples of calcium sources include calcium salts, such as calcium halides and soluble calcium salts. In many embodiments, the calcium source is calcium chloride.

[0097] It has been found that amorphous salts of obisetropip, such as amorphous obisetropip hemicalcium, can be prepared in the presence of an intermediate salt, solvate, or composition (such a composition including the corresponding acid used to prepare the salt). Direct treatment of obisetropip with a calcium base (e.g., calcium hydroxide) has not been found to be a feasible method for preparing amorphous salts of obisetropip due to low solubility, the weakness of the available base, or both. Instead, it has been found that preparing amorphous calcium by preparing an intermediate salt (e.g., a sodium salt) is feasible. However, even when using a sodium salt, for the purposes of purity and yield, it is preferable to utilize an additional salt or salt-type exchange associated with the sodium salt of obisetropip (e.g., using a composition or solvate instead of the actual salt). In particular, the use of a salt, solvate, or composition enables the production of amorphous calcium salts of obisetropip with high purity, such as amorphous obisetropip hemicalcium.

[0098] Exemplary salts that can be prepared as intermediates include those derived from: sulfonates (e.g., benzenesulfonates, toluenesulfonates, naphthalenesulfonates, camphorsulfonates, ethanesulfonates, edisylate, or methanesulfonates), sulfates (e.g., methyl sulfates), halogens (e.g., chlorides, iodides, or bromides), acetates, aspartates, benzoates, bicarbonates, bitartrates, carbonates, citrates, decanoates, fumarates, glucohepanoates, glucuronides, glutamates, glycolates, hexanoates, hydroxynaphthoates, hydroxyethyl sulfonates, lactates, lactobionates, malates, maleates, mandelates, mucates, nitrates, octanoates, oleates, dihydroxynaphthyl salts, pantothenates, phosphates, polygalacturonic acids, propionates, salicylates, stearates, succinates, tartrates, or teoclates. When the intermediate is a solvate or composition, the corresponding acid may be used or present. Furthermore, when the intermediate is a solvate, it may further comprise a solvent (e.g., an organic solvent) or water, in which case the solvate will be a hydrate. One such organic solvent is cyclopentyl methyl ether (CPME).

[0099] In some embodiments, the intermediate is a solvation of an acid. In these and other embodiments, the intermediate is a solvation of an acid and an organic solvent. In some specific embodiments, the intermediate is a solvation comprising an acid and a solvent. In some of these embodiments, the acid is hydrochloric acid and the solvent is CPME.

[0100] In many aspects, the invention includes a method for preparing calcium obisetropike salts, such as amorphous obisetropike hemicalcium. The invention further includes the preparation of calcium obisetropike salts, including amorphous obisetropike hemicalcium. In one such preparation, an intermediate referred to herein as crystalline HCl obisetropike is used in the preparation of amorphous obisetropike hemicalcium.

[0101] In many aspects of the invention, amorphous obisetropicillin hemicalcium is prepared by chemical synthesis, wherein an intermediate represented by formula (IH) is used: (IH).

[0102] The variation of y causes the mass percentage of HCl to vary from 0.01 wt% to 8 wt%, and is believed to include, for example, the associated organic solvent in the form of a solvate. In some embodiments, y varies from 0.002 to 1.5. In some embodiments, y varies from 0.3 to 1. In some embodiments, the solvate of formula (IH) is isolated in its crystalline form. In many embodiments, the solvent is CPME. Other solvents that can form the solvate include toluene and heptane.

[0103] The prepared crystalline HCl obisetropeptide is crystalline. Therefore, unless otherwise stated herein, the term crystalline HCl obisetropeptide means crystalline HCl obisetropeptide. Furthermore, when CPME is used to prepare crystalline HCl obisetropeptide, the term crystalline HCl obisetropeptide may include CPME as a solvation. In formula (IH), the solvation is a solvation of an organic solvent, and in many embodiments, the solvent is CPME. In some embodiments, the present invention provides compositions comprising crystalline HCl obisetropeptide.

[0104] Unbound by theory, it is believed that formula (IH) is a solvate rather than the hydrochloride of obisetripeptide. It has been found that when CPME is used in the reaction producing formula (IH) to deliver HCl, the chloride content of formula (IH) ranges from about 2.5% to 3.0% by weight, which is lower than the expected 4.7% by weight for a neutral salt. Furthermore, in many embodiments, when CPME is used in this way, it is found in the material during crystallization. When CPME is used in the reaction to deliver dry HCl and is thus found in the crystalline material, the resulting crystalline formula (IH) material is referred to as crystalline HCl obisetripeptide, and these X-ray powder diffraction patterns are... Figure 12As can be seen in the image. Therefore, it is believed that crystalline HCl obisetropip is a solvate of CPME and HCl along with obisetropip. Unlike salts, solvates can have variable compositions, which helps to explain the variable HCl present in crystalline HCl obisetropip. An advantage of using crystalline HCl obisetropip as an intermediate is that the resulting amorphous obisetropip hemicalcium typically has a chemical purity of 99.9% or higher. Chemical purity is a quantitative expression of the presence of other chemical entities besides the compound being tested. For example, amorphous obisetropip hemicalcium with a chemical purity of 99.9% means that no more than 0.1% of the compound in the sample of amorphous obisetropip hemicalcium is another entity. Physical purity refers to the amount of other solid forms of the same compound present; in the case of amorphous obisetropip calcium, the other solid form is crystalline obisetropip hemicalcium. The invention described herein provides amorphous ocbisetropile hemicalcium that is physically pure, meaning that the amorphous ocbisetropile hemicalcium contains no or substantially no crystalline ocbisetropile hemicalcium. Unless otherwise stated herein, the purity measurements provided herein are measurements of chemical purity.

[0105] As used herein, HCl obisetropip is not limited to crystalline HCl obisetropip. In fact, crystalline HCl obisetropip may become amorphous after desolvation.

[0106] Under stress, crystalline HCl obisetroprine loses its crystallinity. Figure 13 In Figure 2, spectral 2 reflects crystalline HCl obisetropip after a mild drying process that removes the surface solvent, and the compound is crystalline. In contrast, the sample whose X-ray powder diffraction was measured in Figure 1 underwent a more intense drying process for 48 hours at 55°C and 2 mbar. It is evident that this drying likely caused the material to change from crystalline to amorphous due to the desolvation of CPME and at least some of the HCl. For example, NMR spectroscopy shows the presence of CPME in the top spectrum, but its substantial absence in the lower amorphous spectrum. Therefore, the amorphous spectrum represents HCl obisetropip that is not crystalline obisetropip. It may be obisetropip, but is believed to have HCl bound to obisetropip as a solvator, and is therefore HCl obisetropip, but with a lower chloride content than is typically found in the range of crystalline HCl obisetropip. In some embodiments, the chloride content is less than 0.1% by weight, for example, between about 0.01% by weight and 0.1% by weight.

[0107] Crystalline HCl obisetropeptide can be characterized by an X-ray powder diffraction pattern containing a peak at approximately 9.8°2θ. In some embodiments, crystalline HCl obisetropeptide can be characterized by an X-ray powder diffraction pattern containing one or more peaks at approximately 8.1°2θ, approximately 9.8°2θ, approximately 13.8°2θ, approximately 16.7°2θ, or approximately 19.5°2θ. Table 1 provides exemplary peaks that may be present in crystalline HCl obisetropeptide ... Figure 12 The essentially identical X-ray powder diffraction patterns are used for characterization.

[0108] Table 1

[0109] In some embodiments, the amorphous obisetropi hemicalcium of the present invention is prepared by a method comprising the following steps: i. Using HCl to treat obisetropip to obtain crystalline HCl obisetropip; ii. Separate the crystalline HCl oxetine; iii. Preparation of amorphous calcium salts of obisetropeptide from the crystalline HCl obisetropeptide separated in step (ii); and iv. Separation of amorphous calcium salts of obisetrop, such as amorphous obisetrop hemicalcium.

[0110] In some embodiments of the method for separating the amorphous calcium salt of obisetrop, according to step (iv), the amorphous calcium salt of obisetrop is in the form of amorphous obisetrop hemicalcium (see, for example, Scheme 1, Compound 3).

[0111] In some embodiments of the method for preparing amorphous obisetropic hemicalcium, step (iii) includes the following steps: (iii-1) The crystalline HCl ocbisetrapip from step (ii) is converted to provide ocbisetrapip in an organic solvent; (iii-2) Treating obisetropeptide in an organic solvent with an aqueous sodium hydroxide solution to form a sodium salt of obisetropeptide; and (iii-3) The sodium salt of obisetrop is treated with aqueous calcium chloride to form amorphous obisetrop hemicalcium; The compounds in steps (iii-1) and (iii-2) were not isolated.

[0112] In some embodiments of step (iv), amorphous obesetropic hemicalcium with a purity of 95% or higher, such as 95.5% or higher, 96% or higher, 96.5% or higher, 97% or higher, 97.5% or higher, 98% or higher, 98.5% or higher, 99% or higher, 99.1% or higher, 99.2% or higher, 99.3% or higher, 99.4% or higher, 99.5% or higher, 99.6% or higher, 99.7% or higher, 99.8% or higher, or 99.9% or higher, is isolated.

[0113] In some embodiments, the amorphous obbis-trapey hemicalcium is ground. In some embodiments, the grinding process is adapted (e.g., parameters such as feed rate, venturi pressure, and grinding pressure are adapted) to enable the production of micronized amorphous obbis-trapey hemicalcium.

[0114] In some embodiments, obisetrop (i.e., the starting material in step (i) above) is prepared by a method comprising the following: (a) Preparation of compounds of formula (IVA) by coupling a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA):

[0115] Where X 1 It is a leaving group, and Y 1 It is a protecting group; (b) Preparation of carbamates of formula (VA) from compounds of formula (IVA), and separation as solid salts of formula (VIA):

[0116] Where Y 1 It is a protecting group, A n- It is an anion, where n is an integer from 1 to 3; (c) Optionally, the compound of formula (VIA) is desalted and alkylated using the compound of formula (VIIA) to provide the compound of formula (VIIIA):

[0117] Among them, X 2 It is a leaving group, Y 1 It is a protecting group; and (d) Converting the compound of formula (VIIIA) to oxextrapire, wherein reaction steps (a)-(d) are carried out in an organic solvent, optionally without separating compounds (IVA), (VA) and (VIIIA) from the organic solvent, and wherein the process does not require the inclusion of chromatography.

[0118] The reactions in steps (a)-(d) of the main method are carried out in a solvent, and if the intermediate compounds of formulas (IVA), (VA), and (VIIIA) are to be further processed into the final product, it is not necessary to separate the intermediate compounds of formulas (IVA), (VA), and (VIIIA) from their respective solvents. This means that the reaction steps ( x )and( x Any solvent exchange between +1) is achieved through evaporation in step ( x At least a portion of the solvent used in step () is gradually added. x The process involves using a solvent of formula (VIA) such that the compound remains in solution during solvent exchange. The intermediate compound of formula (VIA) can be separated from the solvent as a salt in solid form, allowing the intermediate compound of formula (VIA) to be washed to remove impurities. This separation step ensures sufficient purity for the downstream product. The main process does not require purification steps using chromatographic methods (e.g., column chromatography) to achieve the chemical purity levels described herein.

[0119] In some embodiments, amorphous obesetropi hemicalcium is prepared by the method listed in Scheme 1.

[0120]

[0121] Option 1 Referring to Scheme 1, amorphous obisetropicol (compound 3) was prepared by six chemical steps and three separations of methanesulfonates from (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A), tert-butyl-4-(2-chloropyrimidin-5-yloxy)-butyrate (compound 1B) and 3,5-bis(trifluoromethyl)benzyl bromide (compound 1E). Compound 1A was coupled to compound 1B via a palladium-catalyzed reaction to produce a solution of (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C). Instead of separating the solution, it was reacted directly with excess ethyl chloroformate in the presence of pyridine to produce ethyl (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate, which was then separated into crystalline methanesulfonate (compound 1D). Under strongly alkaline conditions, crystalline methanesulfonate, namely compound 1D, was alkylated with 3,5-bis(trifluoromethyl)benzyl bromide (compound 1E) to produce a solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (compound 1F) in toluene. Then, compound 1F was subjected to acidic cleavage of tert-butyl ester to produce a solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (compound 1). Compound 1 was then converted to Compound 2 (a solvate of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (Compound 2)). Finally, Compound 2 was converted to an amorphous calcium salt (Compound 3) and ground to the target particle size. Compound 2 is crystalline HCl obisetropeptide, and Compound 3 is amorphous obisetropeptide hemicalcium.

[0122] Each step in the preparation of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1), intermediate HCl intermediate (compound 2), and the corresponding amorphous calcium salt (compound 3) will be described in more detail in operations 1 to 9 below.

[0123] The operations described in this section are provided by way of illustration and not limitation. The operations represent only a few examples, and it should be understood that the following operations are illustrative and not limiting. Unless otherwise stated, all substituents are as previously defined. Reagents and starting materials are readily available to those skilled in the art. Specific synthetic steps of each described route may be combined in different ways, or combined with steps from different schemes, to prepare the compounds described herein.

[0124] Operation 1 - Preparation of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound) 1A Free Base)

[0125] (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A) (62 kg, 182 mol, 1.00 equivalent) was added together with toluene (375 L) into a reaction vessel equipped with a reflux condenser. The resulting slurry was stirred at 52°C, and 1 M aqueous sodium hydroxide solution (322 L, 5.2 vol.) was added. The reaction mixture was stirred until all solids dissolved, and then cooled to 20°C. Stirring was stopped, and the reaction mixture was allowed to separate into two phases. The bottom aqueous phase was drained, and an aqueous sodium chloride solution (310 L, 5.0 vol.) was added. The reaction mixture was then stirred at 20°C for 30 minutes. Stirring was stopped again, and the reaction mixture was allowed to separate into two phases. The bottom aqueous phase was drained, and deionized water (310 L, 5.0 vol.) was added. The reaction mixture was then stirred at 20°C for 30 minutes. Stirring was stopped again, and the reaction mixture was allowed to separate into two phases. The bottom aqueous phase was separated. The resulting organic solution was then vacuum distilled at an internal temperature of 65°C or lower. Distillation was continued until a final visual volume of 4.0 volumes (250 L) was reached. The reaction vessel was then cooled to 20°C to provide a solution of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A-free base) in toluene with a small amount of water present. Compound 1A-free base was not separated and was used directly for operation 2.

[0126] Operation 2 - Preparation of (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl 6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C)

[0127] Additional toluene (107 L, 1.5 vol.) was added to a reaction vessel (“Vessel A”) containing (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A-free base) in toluene from the previous step, wherein water <1000 ppm. Then, tert-butyl-4-(2-chloropyrimidin-5-yloxy)-butyrate (compound 1B) (54.6 kg, 200 mol, 1.10 equivalents) was reacted with tert-butanol (… t(-BuOH) (122 L, 1.55 vol.) was added together to container A. The reaction mixture was stirred and nitrogen was purged. Simultaneously, palladium acetate (410 g, 1.8 mol, 1 mol%) was added to a second reaction vessel (“Vessel B”) under nitrogen. (S)-BINAP (2.48 kg, 4.0 mol, 2.2 mol%) and toluene (107 L, 1.5 vol.) were further added to vessel B, and the resulting mixture was stirred to form a red / orange Pd-BINAP solution. The orange / red Pd-BINAP solution in reaction vessel B was transferred to container A. K3PO4 (85 kg, 400 mol, 2.20 equivalent) was further added to container A, and the resulting reaction mixture was heated to an internal temperature of 72°C and stirred for at least 2 hours. The mixture was then cooled to 20°C, deionized water (124 L) was carefully added, and the mixture was stirred for 30 minutes. Stirring was then stopped, and the layers were allowed to separate into two phases. The bottom aqueous phase was separated, and 1M HCl aqueous solution (123 L) was added while stirring. After 30 minutes, stirring was stopped again, and the layers were allowed to separate into two phases. The bottom aqueous phase was separated, and sodium chloride aqueous solution (326 kg, 5.26 vol.) was added while stirring. After 30 minutes, stirring was stopped again, and the layers were allowed to separate into two phases. The bottom aqueous phase was separated, and deionized water (248 L, 4.0 vol.) was added while stirring. After 30 minutes, stirring was stopped again, and the layers were allowed to separate into two phases. The bottom aqueous phase was separated. The resulting reaction mixture was then treated with ethylenediamine (1.60 kg, 0.15 equivalents) and stirred at 20°C for 80 minutes. The reaction mixture was then filtered through a charcoal cartridge, and the filtrate was returned to a clean container. The mixture was then distilled under partial vacuum at an internal temperature of 60°C or lower. Distillation continued until approximately 2.50 volumes remained visually in the reactor (155 L), then acetonitrile (394 L, 5.0 vol.) was added. The mixture was then vacuum distilled at an internal temperature of 60°C or lower. Distillation continued until approximately 2.50 volumes remained visually in the reactor (155 L), and the contents were then cooled to 20°C. Acetonitrile (394 L, 5.0 vol., until approximately 11 volumes (approximately 620 L)) was then added to the reaction vessel to obtain (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) dissolved in acetonitrile. Compound 1C was not isolated but used directly in operation 3.

[0128] Operation 3 - Preparation of crystalline methanesulfonate form of (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidine] [Pyridine-2-yl]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1D)

[0129] (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) was cooled to an internal temperature <10°C in acetonitrile (approximately 620 L) and pyridine (72 L, 900 mol, 4.9 equivalents) was added. Ethyl chloroformate (136 L, 1428 mol, 7.84 equivalents) was then added via a feed funnel while maintaining the internal temperature of the reactor contents at <10°C. The internal temperature of the reaction mixture was then linearly increased to 20°C over a 3.5-hour process. The mixture was then vacuum distilled at an internal temperature of 60°C or lower. Distillation continued until approximately 2.50 volumes (155 L) were visually present. Isopropyl acetate (471 L, 6.6 vol.) was then added to the reaction vessel, and distillation was continued under vacuum at an internal temperature of 60°C or lower until approximately 2.50 volumes (155 L) remained visually. Isopropyl acetate (471 L, 6.6 vol.), 1M hydrochloric acid (307 L, 5.0 vol.), and a 26% aqueous sodium chloride solution (63 L, 1.2 vol.) were then added to the reaction vessel. The resulting mixture was stirred for 30 minutes and then separated into two phases. The bottom aqueous phase was separated, and a saturated aqueous sodium bicarbonate solution (132 L, 2.3 vol.) was added. The resulting mixture was stirred for 30 minutes and then separated into two phases. The bottom aqueous phase was separated, and the remaining mixture was distilled under vacuum and at 60°C or lower to a total volume of approximately 4.0 L (250 L), thereby obtaining (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (corresponding to the free base of compound 1D) in isopropyl acetate based on solution weight.

[0130] Additional isopropyl acetate (86 L, 1.4 vol.) and methyl tert-butyl ether (MTBE, 593 L, 9.6 vol.) were added to the isopropyl acetate (the free base of the corresponding compound 1D), and the jacket temperature was set to 20°C. Then, methanesulfonic acid (MsOH, 17.6 kg, based on a mmol equivalent of the free base of the corresponding compound 1D) was added to the reaction mixture over 60 minutes. The resulting slurry was then stirred for 8 hours. The slurry was then vacuum filtered at 20°C. The solid filter cake was then washed with 75 / 25 v / v isopropyl acetate (78 L, 1.1 vol.) and methyl tert-butyl ether solution (236 L, 2.8 vol.) and then dried under vacuum at 20°C to obtain isolated (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (compound 1D) in crystalline methanesulfonate form with a yield of 74% based on the molar number of compound 1A. The purity of the obtained crystalline compound 1D was >99%.

[0131] Operation 4 - Preparation of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tert-butoxycarbonylpropoxy] Ethyl pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (compound 1F)

[0132] (2R,4S)-4-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (compound 1D) (42 kg) and toluene (465 kg, 12.7 vol.) were added to a reaction vessel at 5°C. Tetrabutylammonium bisulfate (3.5 kg, 0.16 equivalents) and sodium tert-amyloxide (34.5 kg, 4.8 equivalents) were then added, and the resulting reaction mixture was stirred for 10 minutes and degassed with nitrogen. 3,5-bis(trifluoromethyl)benzyl bromide (compound 1E) (28 kg, 1.41 equivalents) was then added to the reaction mixture, and stirring was continued at 5°C for 6.5 hours. The reaction mixture was then treated with 1 N acetic acid solution (320 kg), allowing stirring at 20°C for approximately 30 minutes. Stirring was then stopped, and the mixture was allowed to separate into two phases. The lower aqueous phase was discarded, and the reaction mixture was concentrated under vacuum at an internal temperature of 60°C or lower until approximately 3.3 volumes (137 L) remained, thereby yielding 36.8 wt% (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylic acid ethyl ester (compound 1F) in toluene at a yield of 97% based on the molar number of compound 1D.

[0133] Operation 5 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl] ethyl amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (compound 1)

[0134] A solution of 37 wt.% of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tert-butoxycarbonylpropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylate (compound 1F) in toluene (128.4 kg of 37 wt.% solution, equivalent to 47.5 kg of compound 1F) was diluted to 32 wt.% and then mixed with acetic acid (253 kg, 5.33 wt.) and 6 M HCl (109.9 kg, 2.32 wt., prepared in situ using 66.1 kg concentrated HCl and 43.8 kg water). The resulting reaction mixture was vigorously stirred and heated to 48°C for 3 hours. The reaction mixture was then cooled to 21°C, and then n-heptane (159.8 kg, 3.36 wt.), acetonitrile (73.8 kg, 1.55 wt.), and water (170 kg, 3.58 wt.) were added. The resulting mixture was stirred for 34 minutes and then allowed to separate into two phases. The lower aqueous phase was then further treated with water (90 kg, 1.89 wt.), n-heptane (95 kg, 2.00 wt.), acetonitrile (38 kg, 0.80 wt.), and toluene (42 kg, 0.88 wt.), and stirred again for 20 minutes before separating the organic phase and discharging the lower aqueous phase. The combined organic phases were then treated with water (240 kg, 5.05 wt.) and stirred again for 30 minutes before separating into two phases. The lower aqueous phase was discarded, and the upper organic phase was treated with 5% w / w sodium citrate trihydrate (34 kg, 0.72 wt.) and water (205 kg, 4.32 wt.). The resulting mixture was vigorously stirred for 30 minutes and then separated into two phases before discarding the lower aqueous phase. The remaining organic phase was again treated with water (240 kg, 5.05 wt.) and stirred for 30 minutes before separating into two phases and removing the lower aqueous phase. The organic phase was then concentrated under vacuum to approximately 3 volumes (approximately 149 L) while maintaining an internal temperature of 50°C or lower. The reaction mixture was diluted with cyclopentyl methyl ether (CPME, 250 kg, 5.26 wt.) and stirred. The solution was then concentrated under vacuum to approximately 3 volumes (approximately 165 L) while maintaining an internal temperature of 50°C or lower.CPME (250 kg, 5.26 wt.) was then added, and the mixture was vacuum concentrated to approximately 2.5 volumes (about 124 L) while maintaining an internal temperature of 50°C or lower, thereby obtaining a solution of 33.7 wt% (compound 1, free base form) of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (CMPE) with 1 wt% toluene and less than 1 wt% n-heptane in cyclopentylmethyl ether (CMPE).

[0135] Operation 6 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl] ethyl amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate hydrochloride (compound 2)

[0136] A solution of 33.7 wt% (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (Compound 1, free base form, 115.6 kg, 59.2 mol) in cyclopentylmethyl ether (CPME) was added under nitrogen atmosphere to a clean reaction vessel with a jacket temperature of 22°C. After dilution with CPME (27.8 kg / 0.58 wt.), n-heptane (54.8 kg, 1.15 wt.) was added, and the internal reaction temperature was raised to 39°C. Then, while maintaining the internal reaction temperature at 39°C, 3.0 M HCl was added at a constant rate to CPME (17.6 kg, 0.37 wt.). After the HCl addition was complete, the internal temperature was raised to 52°C. Then, while maintaining the internal reaction temperature at 51°C, additional n-heptane (133.2 kg, 2.80 wt.) was added at a constant rate. The reaction mixture was heated to 55°C and then cooled to 49°C. Aliquots of the reaction mixture were removed and cooled to 11°C at a linear cooling rate until a slurry containing crystals of compound 2 in CPME / n-heptane (referred to herein as the “seed slurry”) was formed. Compound 2 (169 g, 0.43 wt%) in the seed slurry in CPME / n-heptane was then added at 49°C, and this temperature was maintained for 105 minutes. The opaque reaction mixture was then cooled to 11°C at a linear cooling rate over a 12-hour process. The reaction mixture was then vacuum filtered at 11°C to collect a solid wet HCl intermediate (compound 2). A mixture of CPME and n-heptane (56.6 kg CPME, 179 kg n-heptane) was then added to the reaction vessel and cooled to 11°C. Half of the mixture was then decanted through a filter dryer as a chromatographic wash. The other half was passed through a filter as a slurry wash. Compound 2 was not removed from the filter dryer but was further purified by recrystallization according to the following procedure.

[0137] Compound 2 in cyclopentylmethyl ether (CPME) (77.6 kg) was added to a filter dryer containing Compound 2 and heated to 25°C. The dissolved Compound 2 was then transferred under nitrogen to a reaction vessel with the reactor jacket temperature set to 25°C, and the internal temperature was raised to 38°C. 3.1 M HCl was added to CPME (6.4 kg) to obtain a total HCl equivalent of 1.07 wt% based on the determination of Compound 1 in the crude Compound 2 and the determination of HCl in the crude Compound 2. Then, n-heptane (139.4 kg) was added, and the internal reaction temperature was raised to 51°C. Then, a seed slurry of Compound 2 (291 g, 0.87 wt%) in CPME / n-heptane was added at 50°C, and this temperature was maintained for 105 minutes. The opaque reaction slurry was then cooled to 11°C at a linear cooling rate over 12 hours. The slurry was then vacuum filtered at 9°C using a filter dryer. Then, 20 vol.% CPME (57.4 kg CPME, 180 kg n-heptane) in n-heptane was added to the reaction vessel, and the mixture was cooled to 11°C. Half of the mixture was then decanted through a filter dryer for chromatographic washing. The other half was washed as a slurry through a filter dryer. The wet filter cake was then vacuum dried in multiple steps at jacket temperatures of 25°C, 35°C, 46°C, and 54°C to provide compound 2 with a purity of 99.6 area % in 64% yield (from compound 1F) and residual solvent of 0.3% w CPME and <0.1% w n-heptane.

[0138] Operation 7 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl] ethyl amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (compound 3)

[0139] In an inert reactor, (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hydrochloride (compound 2, 35.0 kg, 48.4 mol) was added to isopropyl acetate (IPAC, 214 kg, 6.11 wt.) and stirred at 22°C to achieve dissolution. Deionized water (245 kg, 7.00 wt.) was added, and the reaction mixture was stirred at 23°C for 35 min. Stirring was then stopped, the phases were separated, and the lower aqueous phase was removed. The process of adding deionized water (245 kg, 7 wt.), stirring, and removing the lower aqueous phase was repeated three times. The organic phase was then concentrated under reduced pressure to approximately 71 L (approximately 2 vol.) while maintaining an internal temperature of 55°C or lower. Ethanol (115 kg, 3.29 wt.) was then added, and the reaction mixture was concentrated under reduced pressure to approximately 78 L (approximately 2 vol.) while maintaining an internal temperature of 55°C or lower. This process of adding ethanol (115 kg, 3.29 wt.) and concentrating was repeated at least twice. The reaction mixture was then cooled to 25°C and subjected to charcoal treatment in a cylinder. The vessel was then rinsed with ethanol (100 kg, 2.86 wt.) and concentrated under vacuum to 147 L (approximately 3.8 vol.) at 55°C or lower. Subsequently, 35 L of EtOH (1.0 vol.) was added, providing (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1) in ethanol as a free base. A 14 wt.% NaOH solution (15.8 kg, 1.13 equivalents) was then added to the reaction vessel containing compound 1 in ethanol while maintaining the reaction temperature at 20°C. The reaction mixture was stirred at 20°C for 5 hours to achieve complete conversion.

[0140] 34% wt. of calcium chloride (aqueous solution) (10.8 kg) was added to an inert reactor. Then deionized water (336 L, 9.61 wt. relative to compound 1) and ethyl acetate (15 kg, 0.43 wt. relative to compound 1) were added, and the mixture was stirred for 30 minutes to provide "solution B".

[0141] Solution B was then cooled to 9°C while stirring. Solution A (see above) was then added to solution B via a filter over 90 minutes while maintaining the temperature at 10°C. The container of solution A was then rinsed forward into solution B with additional ethanol (50 kg, 1.43 wt. relative to compound 1). The resulting slurry was stirred at 9°C for 1 hour. The solid was then collected by filtration and rinsed with deionized water (2 × 175 kg, 5 wt. relative to compound 1). The solid was then vacuum dried at 50°C for 21 hours to obtain 27.6 kg of amorphous obisetropicillin hemicalcium (compound 3) with <1 wt% water (77% yield based on the molar amount of compound 2). Compound 3 was further processed as described below in operation 8.

[0142] Operation 8 - Reprocessing of Compound 3 Compound 3 (27.6 kg) was dissolved in ethanol (55.2 kg, 2 wt. relative to compound 3) at 45°C to 48°C, and then cooled to 11°C. The solution was filtered into a pre-cooled (approximately 10°C) mixture of aqueous CaCl2 solution (8.2 kg, 33 to 35% by weight, 0.3 wt.), water (262 kg, 9.5 wt.), and ethyl acetate (12.6 kg, 0.46 wt.). The resulting suspension was filtered and washed with water (2 x 5 wt., 138 kg / washing step), and the solid was vacuum dried for 23 hours while maintaining an internal temperature of 45°C or lower to obtain 24.8 kg (91% yield) of amorphous calcium salt of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 3) with <1 wt% water and a purity of 97.5 wt. and >99.9 area %.

[0143] Step 9 - Grinding the reprocessed compound 3 Compound 3 was jet-milled using an 8-inch spiral mill. The feed rate, venturi pressure, and mill pressure were adjusted within the ranges listed below to produce micronized Compound 3 that met the particle size acceptance criteria (D90 = 6 µm to 15 µm).

[0144] Feed rate: 17 kg / h to 20 kg / h Grinding pressure: 20 PSI / 1.4 bar Venturi pressure: 100 PSI / 6.9 bar Process gas: Nitrogen Analysis: Mastersizer 3000.

[0145] Operation 10 - Polarized Light Microscopy (PLM) Polarized light photomicrographs were taken at room temperature using a Nikon DS-Fi2 upright microscope. The sample (2 mg) was mounted on a glass slide and covered with a drop of silicone oil. A coverslip was placed on top of the sample for analysis. No light protection was applied to the sample.

[0146] Operation 11 - Powder X-ray Diffraction (XRPD) A Cu radiation incident beam generated using a finely focused Empyran tube source was applied to a silicon zero-background holder using Panalytical X'Pert. 3 XRPD was performed using a powder diffractometer. Prior to analysis, a silicon standard (NIST SRM 640d) was analyzed to verify that the Si 111 peak position was consistent with the NIST-certified position. Approximately 5 to 10 mg of sample was placed on a silicon zero-background support and manually flattened using an aluminum spatula to minimize variations in the overall sample height. The support was then mounted on the instrument for analysis. The XRPD parameters used are listed in Table 2 below.

[0147]

[0148] Operation 11A - Figure 2 Measurements were performed using a PANalytical X-ray powder diffractometer under the following conditions. Data were acquired using a DataViewer and evaluated using X'Pert High Score Plus:

[0149] Operation 11B - X-ray powder diffraction method for crystallizing HCl oxetine ( Figure 12 and Figure 13 ) The diffraction pattern was measured using a Thermo Fisher Scientific ARL Equinox 1000 powder diffractometer. The diffractometer is equipped with a copper source providing monochromatic Cu Kα1 radiation and a germanium (111) monochromator, as well as a position-sensitive gas ionization detector.

[0150] The sample was measured in reflectance mode using an Al sample holder without any further preparation (i.e., grinding). The detector simultaneously measured the entire angular range from approximately 2°2θ to 120°2θ; in the case of HCl obisetrop, identifiable signals for phase identification were visible up to approximately 45°2θ. During measurements, the diffractometer temperature was typically around 30°C.

[0151] Fixed-dose pharmaceutical compositions may comprise a combination of 1 to 10 mg obisetropeptide or its calcium salt, solvate, or hydrate, and 5 to 20 mg ezetimibe. In a typical embodiment, the composition comprises 5 mg obisetropeptide or its calcium salt, solvate, or hydrate, and 10 mg ezetimibe or its pharmaceutically acceptable salt, solvate, or cocrystal. In a further typical embodiment, the composition comprises obisetropeptide or its calcium salt, solvate, or hydrate, and 10 mg ezetimibe or its pharmaceutically acceptable salt, solvate, or cocrystal.

[0152] In a typical embodiment, the pharmaceutical composition is provided in a unit dosage form comprising 5 mg obisetropeptide and 10 mg ezetimibe. In a more typical embodiment, the composition is provided in a unit dosage form comprising 10 mg obisetropeptide and 10 mg ezetimibe.

[0153] Whenever the dosage of obisetrip or ezetimibe is mentioned in this invention in mg and / or relative amounts (by weight), it refers to obisetrip or ezetimibe in its free form. Whenever ezetimibe or a salt, solvate, or eutectic of calcium obisetrip is used, for this purpose, the dosage should refer to a dose equivalent to the weight of ezetimibe or obisetrip in its free form, respectively.

[0154] In some embodiments, the pharmaceutical composition is provided in a solid oral dosage form selected from capsules, mini tablets, tablets, granules, beads, pellets, tablets, capsules, pills, etc., or in a liquid oral dosage form that can be used in the preparation of a pharmaceutical product, including but not limited to beverages, solutions, suspensions, syrups, drinks, and emulsions.

[0155] In one embodiment, the solid oral dosage form is provided as a two-component pharmaceutical composition. In a typical embodiment, one component of the two-component pharmaceutical composition comprises ezetimibe, and the other component comprises obisetropeptide. In another typical embodiment, only one component of the two-component pharmaceutical composition comprises both ezetimibe and obisetropeptide.

[0156] In some embodiments, the two-component composition is a bilayer tablet formulation. In a typical embodiment, ezetimibe is present in one of the two layers of the bilayer tablet, while obisetrop is present in the other layer.

[0157] In another embodiment, the two-component system is a capsule formulation. In a typical embodiment, the capsule may have two types of particles, one containing ezetimibe and the other containing obisetrip. In yet another typical embodiment, the capsule may contain two different types of blends or mini-tablets, each containing either ezetimibe or obisetrip, and optionally, such blends or mini-tablets may be filled into the two separate components of the capsule. In some embodiments, each blend or mini-tablet is filled into a smaller capsule, or such blends are compressed into tablet / capsule-type tablets / mini-tablets, and then these tablets / capsule-type tablets / mini-tablets are filled into a capsule formulation.

[0158] In another embodiment, the fixed-dose pharmaceutical composition is a compressed tablet formulation comprising an extragranular component and an intragranular component. In a typical embodiment, the intragranular component comprises ezetimibe, while the extragranular component comprises obisetripip. In a more typical embodiment, the intragranular component comprises both ezetimibe and obisetripip. In another embodiment, the intragranular component comprises obisetripip, while the extragranular component comprises ezetimibe. In yet another embodiment, the extragranular component comprises both ezetimibe and obisetripip.

[0159] In many of these and other embodiments, the obisetrop is amorphous obisetrop hemicalcium.

[0160] The intraparticle components and extraparticle components are present in a ratio of about 1:99 to about 99:1, typically about 3:97 to about 97:3, and more typically about 5:95 to about 95:5. In another embodiment, the intraparticle components and extraparticle components are present in a ratio of about 10:90 to about 90:10, typically about 20:80 to about 80:20 or about 30:70 to about 70:30, and even more typically about 40:60 to about 60:40 or about 50:50.

[0161] The term "within particles" refers to particles within or present in the particles of a composition, i.e., particles containing a first group of pharmaceutically acceptable excipients (including, but not limited to, binders, disintegrants, diluents, glidants, and solvents) and optionally containing one or more pharmaceutically acceptable active ingredients (in this case, ezetimibe and / or obisetrop)

[0162] The term "extragranular" refers to the addition of pharmaceutically acceptable components to the material after granulation; that is, the extragranular portion includes a second group of pharmaceutically acceptable excipients (including, but not limited to, disintegrants, diluents, lubricants, glidants, etc.). Optionally, the extragranular component may contain one or more pharmaceutically acceptable active ingredients (in this case, ezetimibe and / or obisetrop).

[0163] The pharmaceutical composition can be obtained by known conventional methods such as dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, and hot melt extrusion. In a typical embodiment, the composition is obtained by wet granulation followed by compression of the granules into tablets or by filling such granules into capsules.

[0164] In one embodiment, the pharmaceutical composition comprises ezetimibe in the form of anhydrous ezetimibe. In another embodiment, the pharmaceutical composition comprises ezetimibe in the form of ezetimibe hydrate (in some embodiments, ezetimibe monohydrate). In yet another embodiment, the pharmaceutical composition comprises a mixture of anhydrous ezetimibe and ezetimibe hydrate (in some embodiments, ezetimibe monohydrate). The molar ratio of anhydrous ezetimibe to ezetimibe hydrate (in some embodiments, ezetimibe monohydrate) in the pharmaceutical composition may be 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, or 99.05:0.05. The ratios are within the ranges of 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 typical embodiments, the composition is substantially free of ezetimibe hydrate, and approximately 100% of the ezetimibe is in the form of anhydrous ezetimibe. In another typical embodiment, approximately 99.5% of the ezetimibe is present as anhydrous ezetimibe, while approximately 0.5% is present as ezetimibe hydrate (in some embodiments, ezetimibe monohydrate). In a more typical embodiment, the composition is substantially free of anhydrous ezetimibe, and approximately 100% of the ezetimibe is in the form of ezetimibe hydrate (in some embodiments, ezetimibe monohydrate).

[0165] Ezetimibe may exist in the form of its pharmaceutically acceptable salts, solvates, or cocrystals. Obistrapeptide may exist in the form of calcium salts or solvates. Solvates include, but are not limited to, hydrates. Furthermore, "salt" refers to a compound prepared by reacting an organic acid or basic drug with a pharmaceutically acceptable mineral acid or base, or an organic acid or base; as used herein, "salt" includes hydrates and solvates of salts. Exemplary pharmaceutically acceptable mineral acids or bases, or organic acids or bases, are listed in Tables 1 through 8 of the Handbook of Pharmaceutical Salts edited by PH Stahl and CG Wermuth (VHCA, Zurich, 2002, pp. 334–345). Pharmaceutically acceptable salts of ocbistrapeptide or ezetimibe can be readily prepared by properly mixing a solution of such a compound with the desired acid or base. The salt can precipitate from the solution and be collected by filtration, or it can be recovered by evaporating the solvent. In one embodiment, the salt includes, but is not limited to, hydrochloride, phosphate, sulfate, mesylate salt, esylate salt, and besylate salt forms. In one typical embodiment, the composition comprises obisetropip in the form of an alkali metal or alkaline earth metal salt, and in some embodiments comprises sodium obisetropip, potassium obisetropip, or calcium obisetropip, and in some embodiments comprises calcium obisetropip salt. The term “co-crystal” as used herein refers to a crystalline material consisting of two or more distinct solids at room temperature, each solid having distinct physical properties (e.g., structure, melting point, and heat of fusion), except where, specifically, the active pharmaceutical ingredient may be liquid at room temperature. The co-crystal may comprise a co-crystal former H-bonded to ezetimibe. The co-crystal former may be H-bonded directly to the active pharmaceutical ingredient or H-bonded to another molecule that is bound to ezetimibe. A solvate of an active compound that does not further include a cocrystal form is not a cocrystal. A cocrystal can also be a cocrystal between a cocrystal form and a salt of ezetimibe. Other modes of molecular recognition may also be present, including pi-stacking, guest-host complexation, and van der Waals interaction. Of the interactions listed above, hydrogen bonding is the dominant interaction in the formation of a cocrystal, thereby forming a non-covalent bond between a hydrogen bond donor in one part and a hydrogen bond acceptor in the other. In another embodiment, the cocrystal comprises two cocrystal forms.Eutectic formations include, but are not limited to: free acids, free bases, or zwitterions; salts, inorganic base addition salts (e.g., sodium, potassium, lithium, calcium, magnesium, ammonium, aluminum salts) or organic base addition salts, or inorganic acid addition salts (e.g., HBr addition salts, HCl addition salts, sulfuric acid addition salts, nitric acid addition salts, or phosphate addition salts), or organic acid addition salts (e.g., acetic acid addition salts, propionic acid addition salts, pyruvic acid addition salts, malonic acid addition salts). Addition salts of succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, stearic acid, or lactic acid; anhydrous forms or hydrates (or more particularly, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, pentahydrates) or salts; or solvates or salts in free form. For this purpose, the ratio of active ingredient to cocrystal form can be stoichiometric or non-stoichiometric. For example, ratios of 1:1, 1:1.5, 1:2, and 2:1 of the active ingredient (including its salts or solvates).

[0166] In one embodiment, the fixed-dose pharmaceutical composition comprises ezetimibe or obisetropeptide, or both, as a micronized API. The particle size distribution of this micronized API can be determined by those skilled in the art using methods well-known in the art. These methods include, but are not limited to, laser diffraction (LD), dynamic light scattering (DLS), dynamic image analysis (DIA), or sieve analysis. Typically, the method employed is laser diffraction dry powder dispersion, which provides the particle size distribution by measuring the angular change in the intensity of light scattered as a laser beam passes through a dispersed particulate sample. Larger particles scatter light at a smaller angle relative to the laser beam, while smaller particles scatter light at a larger angle. The angular scattering intensity data is then analyzed to calculate the particle size, which generates a cumulative undersize discrete distribution curve, which gives the volumetric particle size distribution. The particle size obtained by this method is typically recorded as the volume equivalent sphere diameter (Dv). The most common percentiles reported are Dv10, Dv50, and Dv90 (also known as X10, X50, and X90). Dv90 means that 90% of the particles by volume are smaller than a specific size and 10% of the particles by volume are larger than a specific size; Dv50 means that 50% of the particles by volume are smaller than a specific size and 50% of the particles by volume are larger than a specific size; and Dv10 means that 10% of the particles by volume are smaller than this size and 90% of the particles by volume are larger than this size. In many of these and other embodiments, the obisetropeptide of the embodiment is amorphous obisetropeptide hemicalcium.

[0167] In one of the exemplary embodiments, the composition comprises micronized ezetimibe having a Dv90 of not more than 10 µm, in some embodiments in the range of 4-10 µm, and in some embodiments not more than 8.5 µm; a Dv50 of not more than 4 µm, in some embodiments in the range of about 1-4 µm, and in some embodiments not more than 3.8 µm; and a Dv10 of not more than 1 µm. In many of these exemplary embodiments, the obisetropip is amorphous obisetropip hemicalcium.

[0168] Figure 24 The method for preparing coated tablets of obisetropine and ezetimibe using FDC1 is described, and Figure 25This paper describes a method for preparing coated tablets of obisetropeptide and ezetimibe using the FDC2 method. In each case, tablet granules are prepared by wet granulation and then compressed into tablets containing an extragranular component. Examples of excipients used for both the granulation and extragranular processes, as well as the coating, are provided in the figures. In both processes, the surfactant sodium lauryl sulfate is present in the granules. In FDC1, obisetropeptide (which is obisetropeptide calcium in the tablet) is present in the granules containing sodium lauryl sulfate, while in FDC2, obisetropeptide (which is obisetropeptide calcium in the tablet) is present in the extragranular portion. The applicant has observed, as described in Example 6, that obisetropeptide granules have increased bioavailability when combined with a surfactant, as seen from the measurements in Tables 45 and 46, and then when no surfactant is present, for example in FDC2 where no surfactant is present in the extragranular portion of the tablet containing obisetropeptide.

[0169] Figure 24 The same method can also be used to produce tablets of obisetropeptide and ezetimibe, in addition to FDC-1 formulations.

[0170] In many embodiments of the invention, the pharmaceutical composition comprises micronized amorphous ocbisetropre hemicalcium. The particle size distribution of the micronized amorphous ocbisetropre hemicalcium can be determined by those skilled in the art using methods 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. Typically, the method employed is laser diffraction dry powder dispersion, which provides the particle size distribution by measuring the angular variation in the intensity of light scattered as a laser beam passes through a dispersed particulate sample. Larger particles scatter light at a smaller angle relative to the laser beam, while smaller particles scatter light at a larger angle. The angular scattering intensity data is then analyzed to calculate the particle size, which generates a cumulative undersize discrete distribution curve, which gives the volumetric particle size distribution. The particle size obtained according to this method is typically recorded as the volume equivalent sphere diameter (Dv). The most commonly reported percentiles are Dv10, Dv50, and Dv90 (also known as X). 10 X 50 and X 90Dv90 means that 90% of the particles by volume are smaller than a certain size and 10% of the particles by volume are larger than a certain size; Dv50 means that 50% of the particles by volume are smaller than a certain size and 50% of the particles by volume are larger than a certain size; and Dv10 means that 10% of the particles by volume are smaller than this size and 90% of the particles by volume are larger than this size.

[0171] In many embodiments, the composition comprises micronized amorphous obesetrapi hemicalcium having a Dv90 of not more than 14 µm, in some embodiments in the range of about 5-14 µm; a Dv50 of not more than 5 µm, in some embodiments in the range of about 3-5 µm; and a Dv10 of not more than 3 µm.

[0172] As used herein, the term "surfactant" is a compound containing both lipophilic and hydrophilic segments that, when added to water or a solvent, reduce the surface tension of the system. Surfactants can be anionic, cationic, neutral, zwitterionic, or amphoteric. The term "hydrophilicity / lipophilicity balance index" or "HLB" is a numerical index of a given surfactant structure that indicates the balance between its hydrophilic and lipophilic properties. Surfactants with a high HLB are characterized as being more hydrophilic and less lipophilic compared to surfactants with a low HLB.

[0173] Examples of anionic surfactants include carboxylates, such as alkyl carboxylates-fatty acid salts; carboxylate fluorosurfactants; sulfates, such as alkyl sulfates (e.g., sodium lauryl sulfate), alkyl ether sulfates (e.g., sodium laureth sulfate); branched alkyl sulfates; sulfonates such as docusate (e.g., sodium dioctyl sulfosuccinate); alkylbenzene sulfonates; and phosphates such as alkyl aryl ether phosphates and alkyl ether phosphates.

[0174] Examples of cationic surfactants include quaternary ammonium salts and pyridinium salts.

[0175] Examples of nonionic surfactants include fatty alcohol ethers and polyol esters, such as polyoxyethylene esters, poloxamer, glycols, and glycerol esters, as well as sorbitol derivatives. Also included are fatty acid esters of sorbitol (commonly known as Span) and their ethoxylated derivatives (commonly known as Tween). Specific examples include Span 8 (sorbitol trioleate), Span 20 (sorbitol monolaurate), Span 40 (sorbitol monopalmitate), Span 60 (sorbitol monostearate), Span 65 (sorbitol tristearate), and Span 80 (sorbitol monooleate), as well as Tween 20 (polyoxyethylene (20) sorbitol monolaurate), Tween 40 (polyoxyethylene (20) sorbitol monopalmitate), Tween 60 (polyoxyethylene (20) sorbitol monostearate), Tween 65 (polyoxyethylene (20) sorbitol tristearate), Tween 80 (polyoxyethylene (20) sorbitol monooleate), and Tween 85 (polyoxyethylene (20) sorbitol trioleate). Polysorbate 20 or polysorbate 80 are also nonionic surfactants. Another example of a nonionic surfactant is poloxamer, a hydrophilic synthetic block copolymer of poly(oxyethylene). Examples of zwitterionic and / or zwitterionic surfactants include lauryl betaine, lauroyl sarcosinate, lauryl sulfobetaine, laurylamidopropyl betaine (also known as cocamidopropyl betaine), and lauryl dimethylamine oxide.

[0176] In many embodiments, the surfactant in the compositions of the present invention is sodium lauryl sulfate.

[0177] In many embodiments, the surfactant is a salt, an organosulfur compound, or both. In these and other embodiments, the surfactant contains an alkyl chain and may be monosubstituted, for example, monosubstituted with a sulfur moiety. In many embodiments, the sulfur moiety is a sulfate ion.

[0178] In many embodiments, the surfactant is selected from lauric acid or its salts, palmitic acid or its salts, stearic acid or its salts and oleic acid or its salts, polyethylene glycol glycerol esters, polyoxyethylene monoesters, polyoxyethylene ethyl ethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oil, polyethylene glycol having a molecular weight in the range of about 2,000 to 10,000, propylene glycol octanoate, glyceryl oleate and octanoate, esters of glycerol and fatty acids. In many embodiments, one or more surfactants are selected from sodium dioctyl sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, polysorbate 40, or polysorbate 80, or sodium lauryl sulfate. In many embodiments, the surfactant is sodium lauryl sulfate, such as Kolliphor SLS. The surfactant used in the composition is typically a surfactant having an HLB value selected from the following: at least about 15, at least about 20, at least about 30, or at least about 40. In many embodiments, the HLB is between 15 and 50 and includes 15 and 50, or between 30 and 45 and includes 30 and 45, or between 35 and 45 and includes 35 and 45, or between 40 and 45 and includes 40 and 45. In many embodiments, the HLB is 40, which is the HLB of sodium lauryl sulfate. In many embodiments, the HBL value is higher than 40.

[0179] The surfactant is typically present in an amount of about 0.2% to 10%, about 0.5% to about 5%, about 0.5% to about 2%, or about 0.5% to about 1%, typically about 1.0 ± 0.5%, based on the weight of the granular composition in one embodiment and on the weight of the total tablets in another embodiment.

[0180] The pharmaceutical composition may further optionally comprise one or more additional pharmaceutically acceptable excipients. Excipients include, but are not limited to, one or more binders, surfactants, disintegrants, flow aids, lubricants, diluents, chelating agents, desiccants, or absorbents. When another surfactant is used, it may be a different surfactant than previously used. Techniques and excipients for formulating oral dosage forms are disclosed by citing the following references, all of which are incorporated herein by reference. See “ The Handbook of Pharmaceutical Excipients"Handbook of Pharmaceutical Excipients", 9th edition, Rowe et al., eds., American Pharmaceutical Association (2020); and "Remington: The Science and Practice of Pharmacy", 22nd edition, edited by Gennaro, Lippincott Williams & Wilkins (2013).

[0181] In some embodiments, one or more adhesives used in the pharmaceutical composition are selected from: cellulose derivatives, such as methylcellulose and carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and hydroxyethylcellulose; gelatin, glucose, sucrose, lactose, dextrose, xylitol, sorbitol, maltitol, polymethyl methacrylate, polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone, starch paste, pregelatinized starch, tragacanth gum, alginate and salts of alginate such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, and bentonite. In some embodiments, the adhesive is polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone, such as copolyvinylpyrrolidone or Colidon 30.

[0182] The binder may typically be present in amounts of about 0.2% to about 10%, about 0.5% to about 5%, about 0.5% to about 2%, or about 0.5% to about 1%, in some embodiments about 1.0 ± 0.5% by weight of the granular composition, and in other embodiments by weight of the total tablets.

[0183] In one embodiment, the composition comprises a binder:surfactant ratio in the range of about 0.05:5.0 to about 5.0:0.05, in some embodiments about 0.5:4.5 to about 4.5:0.5, in some embodiments about 1:4 to about 4:1, about 1:2 to about 2:1, and in some embodiments about 1:1. Such a binder:surfactant ratio can be used in particulate compositions (e.g., in-part or out-of-part compositions) or in the total composition of tablets.

[0184] The pharmaceutical composition may further comprise one or more disintegrants selected from: crospyropyrrolidone, crospycarboxymethyl cellulose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, alginate, sodium alginate, microcrystalline cellulose, sodium carboxyacetic acid starch, or pregelatinized starch. In many embodiments, the disintegrant is crospycarboxymethyl cellulose sodium or sodium carboxyacetic acid starch.

[0185] The disintegrant may be present in an amount of about 0.5% to about 10%, about 1% to about 8%, about 2% to about 5%, about 2% to about 3%, about 4% to about 5%, or about 7% to about 8% in some embodiments, based on the weight of the granular composition and in another embodiment, based on the weight of the total tablets.

[0186] One or more diluents used in a pharmaceutical composition may be selected from the group consisting of: inorganic phosphates, such as dicalcium phosphate; or sugars or sugar analogs and derivatives thereof, particularly lactose (e.g., lactose monohydrate or anhydrous lactose), dextrose, sorbitol, mannitol, sucrose, maltodextrin, isomaltose; or cellulose, such as microcrystalline cellulose or powdered cellulose. In typical embodiments, the diluent is selected from lactose (e.g., lactose monohydrate), microcrystalline cellulose, and mannitol, or mixtures thereof. In more typical embodiments, the intragranule component comprises microcrystalline cellulose and lactose monohydrate as diluents. In another typical embodiment, microcrystalline cellulose and mannitol are present as diluents in the extragranule component. The diluent may be present in an amount of about 10% to about 95% by weight of the granule composition in one embodiment and in another embodiment by weight of the total tablets, typically about 40% to about 90%, more typically about 60% to about 85%, or even more typically about 70% to about 85%.

[0187] The pharmaceutical composition may optionally be film-coated using techniques well-known in the art, such as spraying or dip-coating in a conventional coating pan or fluidized bed processor. Alternatively, a hot-melt technique may be used to perform the coating. Film coating comprises a film-forming polymer, one or more pharmaceutically acceptable excipients, and a pharmaceutically acceptable solvent. Examples of film-forming agents include, but are not limited to: cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and ethylcellulose; polyvinyl alcohol; waxes; fatty substances; or mixtures thereof. Alternatively, coating may be performed using commercially available coating compositions comprising film-forming polymers marketed under various trademarks (e.g., Opadry®).

[0188] Examples of solvents used to prepare the coating solution are selected from methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, chloroform, dichloromethane, water, or mixtures thereof. In typical embodiments, the film coating is a primary alcohol-free coating. In some embodiments, the primary alcohol-free coating is a coating made using water.

[0189] In some embodiments, the flow aid present in the pharmaceutical dosage form is selected from silica, talc, magnesium stearate, etc. Typical flow aids are silica (e.g., Aerosil®) or magnesium stearate (e.g., Ligamed MF 2V) or mixtures thereof. The flow aid is typically present in some embodiments in an amount of about 0.1% to 10%, about 0.1% to about 5%, or about 1% to about 2% based on the weight of the granular composition and in another embodiment based on the weight of the total tablets.

[0190] In some embodiments, the lubricant present in the pharmaceutical composition is selected from fatty acids or fatty acid derivatives, such as alkali metal and alkaline earth metal salts of stearic acid, alkali metal and alkaline earth metal salts of lauric acid, and / or alkali metal and alkaline earth metal salts of palmitic acid. A typical lubricant is magnesium stearate, and this lubricant may generally be present in an amount of about 0.1% to 10%, about 0.1% to about 5%, or about 1% to about 2% based on the weight of the granular composition in one embodiment and on the weight of the total tablets in another embodiment.

[0191] Stability is an essential quality attribute of pharmaceutical formulations, determining the shelf life of a composition during which it remains suitable for its intended use from both therapeutic and safety perspectives. The term "stability" in pharmaceutical compositions refers to the maintenance of one or more parameters controlling the physical and chemical integrity of the active pharmaceutical ingredient (API) within pharmaceutically acceptable ranges during the product's shelf life. Typically, one or more such parameters are selected from: identification of the active ingredient in the composition by methods such as HPLC and / or ultraviolet (UV) spectroscopy; the visual appearance of the composition; the assay percentage of the active ingredient in the composition; the individual and / or total percentages of related substances and / or impurities in the composition; the uniformity of the composition relative to the active ingredient; the dissolution rate; and microbial limits.

[0192] Pharmaceutical compositions often lose their efficacy and / or safety over time due to the loss or degradation of the active ingredient or its conversion into impurities commonly referred to as related substances. Stable, fixed-dose pharmaceutical compositions retain at least up to about 90% (w / w) of the claimed potency of ezetimibe and obisetropeptide.

[0193] Ezetimibe is known to cause stability issues related to its formulation due to interactions with excipients and / or combination drug partners. Surprisingly, it has been found that fixed-dose pharmaceutical compositions effectively control the levels of individual and total relevant substances of ezetimibe during preparation and storage. In the examples, stable fixed-dose pharmaceutical compositions have individual relevant substances of ezetimibe not exceeding about 5% (w / w), typically not exceeding about 2% (w / w), more typically not exceeding about 1% (w / w), and even more typically not exceeding about 0.2% (w / w); and total relevant substances of ezetimibe not exceeding about 5% (w / w), typically not exceeding about 2% (w / w), more typically not exceeding about 1% (w / w), and even more typically not exceeding about 0.5% (w / w). In a typical embodiment, the fixed-dose pharmaceutical composition comprises ezetimibe and obisetropip, wherein the ezetimibe tetrahydropyran analog impurity is not more than about 2% (w / w), typically not more than about 0.5% (w / w), more typically not more than about 0.3% (w / w), and even more typically not more than about 0.2% (w / w).

[0194] In another embodiment, the stable fixed-dose pharmaceutical composition has no more than about 5% (w / w), usually no more than about 2% (w / w), more usually no more than about 0.5% (w / w), even more usually no more than about 0.3% (w / w), and most usually no more than about 0.2% (w / w) of any unspecified individual obisetropeptide-related substances; and no more than about 5% (w / w), usually no more than about 2% (w / w), more usually no more than about 1% (w / w), and even more usually no more than about 0.5% (w / w) of total obisetropeptide-related substances.

[0195] Surprisingly, it has been found that the pharmaceutical composition remains stable at 40°C and 75% relative humidity for at least one month, typically at least three months, and more typically at least six months. In typical embodiments, the composition remains stable at 40°C and 75% relative humidity for at least three months, and in some embodiments at least six months. In another typical embodiment, the composition remains stable at 25°C and 60% relative humidity for at least three, six, or twelve months. In yet another typical embodiment, the composition remains stable at room temperature for at least six, twelve, eighteen, or twenty-four months.

[0196] In one of the typical embodiments, the pharmaceutical composition is a tablet formulation comprising or consisting of the following: Intraparticle components, including: Calcium obisetropeptide is equivalent to 10 mg of obisetropeptide free acid; Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe monohydrate equivalent to 10 mg of ezetimibe; The binder and surfactant are in a 1:1 ratio, typically each comprising approximately 1 + 0.5% w / w of the particle components; typically, the binder is 1 + 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 + 0.5% w / w of sodium lauryl sulfate. The disintegrant is selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more typically sodium carboxyacetate starch; typically the disintegrant accounts for about 2% w / w to 8% w / w of the granule components, preferably 3% w / w to 6% w / w, and more typically about 4.5 + 0.5% w / w. One or more diluents selected from disaccharides, typically lactose or sucrose, more typically anhydrous lactose or lactose monohydrate, and even more typically lactose monohydrate; polysaccharides, typically cellulose, more typically microcrystalline cellulose; and sugar alcohols, typically sorbitol, xylitol, or mannitol.

[0197] In such compositions, they further comprise an extraparticle component comprising: a disintegrant selected from croscarmellose sodium, pregelatinized starch, or sodium carboxyacetate starch, more typically sodium carboxyacetate starch, and even more typically about 4%-6% w / w of sodium carboxyacetate starch; optionally a lubricant, typically magnesium stearate, more typically about 1%-2% w / w of magnesium stearate; and optionally a flow aid, typically colloidal silica or talc, or both colloidal silica and talc, more typically about 1%-2%. w / w colloidal silica or talc or both colloidal silica and talc; optionally one or more diluents selected from disaccharides, typically lactose or sucrose, more typically anhydrous lactose or lactose monohydrate, even more typically lactose monohydrate; polysaccharides, typically cellulose, more typically microcrystalline cellulose; sugar alcohols, typically sorbitol, xylitol or mannitol; more typically mannitol or microcrystalline cellulose, even more typically about 20% w / w to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol.

[0198] Optionally, the composition comprises a film coating, which typically does not contain primary alcohols, and more typically does not contain polyethylene glycol.

[0199] In yet another typical embodiment, the pharmaceutical composition is a tablet formulation comprising or consisting of: an intragranular component comprising: Calcium obisetropeptide is equivalent to 10 mg of obisetropeptide free acid; The binder and surfactant are in a 1:1 ratio, typically the binder and surfactant each comprising approximately 1 + 0.5% w / w of the particle components; more typically the binder is 1 + 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 + 0.5% w / w of sodium lauryl sulfate. The disintegrant is selected from croscarmellose sodium, pregelatinized starch, or sodium carboxyacetate starch, more typically sodium carboxyacetate starch; typically the disintegrant constitutes about 2% w / w to 8% w / w of the granule components, preferably 3% w / w to 6% w / w, and more typically about 4.5 ± 0.5% w / w; and One or more diluents selected from disaccharides, typically lactose or sucrose, more typically anhydrous lactose or lactose monohydrate, and even more typically lactose monohydrate; polysaccharides, typically cellulose, more typically microcrystalline cellulose; and sugar alcohols, typically sorbitol, xylitol, or mannitol.

[0200] In such compositions, they further comprise an extraparticle component, which includes: Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe; The disintegrant is selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more commonly sodium carboxyacetate starch; even more commonly about 4%-6% w / w sodium carboxyacetate starch; Optional lubricant, typically magnesium stearate, more often about 1-2% w / w magnesium stearate; Optional flow aids, typically colloidal silica or talc, or both colloidal silica and talc, more typically about 1-2% colloidal silica or talc, or both colloidal silica and talc; and Optionally, one or more diluents selected from disaccharides, typically lactose or sucrose, more typically anhydrous lactose or lactose monohydrate, even more typically lactose monohydrate; polysaccharides, typically cellulose, more typically microcrystalline cellulose; sugar alcohols, typically sorbitol, xylitol or mannitol; more typically mannitol and microcrystalline cellulose, even more typically about 20% w / w to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol.

[0201] Optionally, the composition comprises a film coating, which typically does not contain primary alcohols, and more typically does not contain polyethylene glycol.

[0202] On the other hand, there are pharmaceutical compositions comprising obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous obisetropip hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof; and surfactants and optionally one or more other pharmaceutically acceptable excipients, for use in subjects requiring additional low-density lipoprotein cholesterol reduction as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or confirmed atherosclerotic cardiovascular (CV) disease (ASCVD).

[0203] The second aspect relates to the use of a pharmaceutical composition for the preparation of a medicament for treating subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, the pharmaceutical composition comprising amorphous octocerpicaspirin hemicalcium, ezetimibe, and a surfactant, and optionally one or more other pharmaceutically acceptable excipients.

[0204] In many embodiments, the subject has or has hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH), or is diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0205] In many embodiments, the subject is partially or completely intolerant to statins.

[0206] In many embodiments, the pharmaceutical compositions of the present invention are used to treat subjects who require lowering LDL cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or a confirmed atherosclerotic cardiovascular (CV) disease (ASCVD).

[0207] The third aspect relates to a method of treating a subject who requires lowering LDL cholesterol and / or raising HDL cholesterol, wherein the method comprises administering to the subject a therapeutically effective dose of a pharmaceutical composition comprising amorphous octoceryl trapezil hemicalcium and a surfactant, and optionally one or more other pharmaceutically acceptable excipients.

[0208] In many embodiments of the present invention, the method is used to treat subjects who have or have hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH), or are diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0209] In many embodiments, the pharmaceutical composition of the present invention is administered orally to the subject. In one embodiment, the subject is required to additionally lower LDL 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 diagnosed with atherosclerotic cardiovascular (CV) disease (ASCVD).

[0210] In one embodiment, the subject is partially or completely intolerant to statins.

[0211] The fourth aspect relates to a fixed-dose combination pharmaceutical composition of obisetropeptide and ezetimibe, wherein the pharmaceutical composition is suitable for the use according to the second aspect or the treatment method according to the third aspect in the following cases: a. The fixed-dose pharmaceutical composition is administered orally to the subject; b. Measure the concentration of obisetropeptide in the blood of the subject at one or more time points after administration to provide a set of obisetropeptide concentration / time data points, thereby providing the area under the curve (AUC); and c. The 90% confidence intervals of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of obisetropeptide are respectively within the range of 75%-125%, typically 80%-125%, and more typically 90%-110% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of obisetropeptide obtained after oral administration of a reference pharmaceutical composition to similar subjects, wherein the reference composition comprises an equivalent dose of obisetropeptide or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and wherein the reference composition is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof. In many of these and other embodiments of this fourth aspect, the obisetropeptide of the embodiment is amorphous obisetropeptide hemicalcium.

[0212] The fifth aspect relates to a fixed-dose combination pharmaceutical composition of obisetropeptide and ezetimibe, wherein the pharmaceutical composition is suitable for the use described in the second aspect or the treatment method described in the third aspect in the following cases: The fixed-dose pharmaceutical composition is administered orally to a subject, and ezetimibe and / or ezetimibe glucoside in the subject's blood are measured at one or more time points after administration to provide a set of concentration / time data points for ezetimibe and / or ezetimibe glucoside, thereby providing the area under the curve (AUC) for ezetimibe and / or ezetimibe glucoside, respectively; and The 90% confidence intervals of the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of ezetimibe and / or ezetimibe glucoside are respectively within the range of 75%-125%, typically 80%-125%, and more typically 90%-110% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax of ezetimibe and / or ezetimibe glucoside obtained after oral administration of the reference pharmaceutical composition to similar subjects, wherein the reference composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and wherein the reference composition is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising obisetropip or its calcium salt, or in a fixed-dose combination with ezetimibe or its pharmaceutically acceptable salt, solvate, or cocrystal thereof.

[0213] In one embodiment of the use according to the above aspects, t in AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC 0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0-336) or AUC 0-∞, typically 48 hours (AUC 0-48), and more typically 72 hours (AUC 0-72) or AUC 0-∞.

[0214] In some embodiments, the subjects are healthy human subjects, typically adult men or women who do not use tobacco or nicotine, more typically aged 18-65, and optionally, the persons have a body mass index of 18.5 to 29.9 kg / m2.

[0215] In many of these and other embodiments of this fifth aspect, the obisetrop is amorphous obisetrop hemicalcium.

[0216] In these and other embodiments, the subjects are individuals who need to lower LDL cholesterol and / or raise HDL cholesterol. In many such embodiments, the human subjects have or have hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH), or are diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0217] In some embodiments, the human subject has an LDL-cholesterol level ≥ 70 mg / Dl, and optionally, the human subject is not adequately controlled by their current lipid-lowering therapy. For the use or treatment of the pharmaceutical composition according to other aspects, the composition may be administered to the subject in need to deliver a total daily oral dose of 5 mg obisetropeptide and 10 mg ezetimibe, 10 mg obisetropeptide and 10 mg ezetimibe, or 20 mg obisetropeptide and 20 mg ezetimibe; in some embodiments, the composition may be administered to the subject to deliver a daily oral dose of 10 mg obisetropeptide and 10 mg ezetimibe.

[0218] Surprisingly, it has been found that the dissolution profiles of ezetimibe from the fixed-dose combination are not worse than, and sometimes even better than, those of the commercially available ezetimibe formulation (Zetia®) discussed in detail in the Examples section. It has also been surprisingly found that the fixed-dose combination compositions disclosed herein are bioequivalent to combinations of monotherapy drugs co-administered in human subjects. The confidence intervals (90%) for the geometric mean ratios of AUC 0-t, AUC 0-∞, and Cmax of obisetropeptide, ezetimibe, and ezetimibe glucoside from the two representative compositions FDC1 and FDC2 are found to be in the range of 75%–125% of the AUC 0-t, AUC 0-∞, and Cmax of obisetropeptide, ezetimibe, and ezetimibe glucoside obtained from co-administration of monotherapy formulations of ezetimibe and obisetropeptide at the same dose, 80%–125% in some examples, and 90%–110% in some examples. In many of these and other embodiments, the obisetrop is amorphous obisetrop hemicalcium.

[0219] As described in previous sections of this document, the present invention provides methods for curative and / or preventative treatment of subjects in need. More particularly, the present invention provides methods for treating and / or preventing cardiovascular disease, particularly atherosclerotic cardiovascular disease, in such subjects using compositions as defined herein. The present invention further provides methods for treating and / or preventing one or more symptoms associated with (atherosclerotic) cardiovascular disease in such subjects using compositions as defined herein. The present invention further provides methods for treating and / or preventing one or more symptoms associated with and / or caused by (atherosclerotic) cardiovascular disease in such subjects using compositions as defined herein. The present invention further provides methods for treating and / or preventing one or more causative factors (e.g., elevated LDL-C levels and / or elevated ApoB levels) associated with (atherosclerotic) cardiovascular disease in such subjects using compositions as defined herein. The present invention further provides methods for reducing and / or improving resistance or low responsiveness to statin therapy, particularly high-intensity statin therapy, in such subjects using compositions as defined herein.

[0220] The term "treatment" (e.g., "method of treating a disease...") used in conjunction with a specific disease or symptom refers to curing, alleviating, or eliminating the disease and / or accompanying symptoms, reducing the severity of the disease, stabilizing the state of the disease (i.e., preventing it from worsening), delaying or slowing the progression of the disease, improving the disease state, or prolonging survival (compared to expected survival without treatment). The term "preventing" as used herein refers to reducing the risk of a subject developing the disease and / or accompanying symptoms, or delaying the onset of the disease in a subject. The term "treatment" (e.g., "method of treating a subject") used with respect to a patient or subject generally refers to the administration of a therapeutic compound to the patient or subject for any therapeutic and / or preventative purpose.

[0221] The term “cardiovascular disease” as used in this article has its traditional meaning and refers to a disease or condition in which the cardiovascular system of the subject is impaired. Examples of cardiovascular diseases include thromboembolic diseases (e.g., arterial thromboembolic disease, venous thromboembolic disease, or ventricular thromboembolic disease); atherosclerosis; hypertensive heart disease; coronary artery disease; carotid artery disease; stroke; peripheral artery disease involving atherosclerosis; restenosis; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (first or recurrent); acute myocardial infarction. (infarction, AMI); myocardial infarction; ischemic heart disease; myocardial ischemia; ischemia; sudden ischemic death; transient ischemic attack; stroke; peripheral occlusive artery disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary artery thrombosis; cerebral artery thrombosis, cerebral embolism; renal embolism; pulmonary embolism; etc.

[0222] As used herein, the term "atherosclerotic cardiovascular disease" refers to a specific subset of cardiovascular diseases that include atherosclerosis as a component or precursor of a particular type of cardiovascular disease. Atherosclerosis is a chronic inflammatory response that occurs in the walls of arteries associated with preserved LDL-C. It involves the formation of atherosclerotic plaques, which can lead to narrowing ("stenosis") of the arteries and can ultimately result in partial or complete closure of the arterial opening and / or plaque rupture. Therefore, atherosclerotic disease or disorder includes the consequences of atherosclerotic plaque formation and rupture, including but not limited to arterial stenosis or narrowing, heart failure, aneurysm formation including aortic aneurysms, aortic dissection, and ischemic events (e.g., myocardial infarction and stroke).

[0223] In particularly typical embodiments, atherosclerotic cardiovascular diseases and / or pathologies associated with atherosclerotic cardiovascular diseases that can be advantageously treated and / or prevented according to the invention are selected from the group consisting of: arteriosclerosis, peripheral vascular disease, hyperlipidemia, mixed dyslipidemia, β-lipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina pectoris, ischemia, myocardial ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, and stroke.

[0224] As will be apparent from the teachings of this invention, the methods of this invention are effective and / or intended to reduce and / or normalize LDL-C plasma levels. Specifically, the methods are effective and / or intended to reduce LDL-C plasma levels by at least 5% from baseline, where baseline is defined as the start of treatment with obisetropeptide and ezetimibe, and more typically by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%. In further embodiments, the methods are effective and / or intended to reduce LDL-C plasma levels by at least 5 mg / dL from baseline, where baseline is defined as the start of treatment with obisetropeptide and ezetimibe, and more typically by at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 25 mg / dL, at least 30 mg / dL, at least 35 mg / dL, or at least 40 mg / dL. In further embodiments, the method is effective and / or intended to reduce LDL-C plasma levels to levels below 85 mg / dL, and in some embodiments below 80 mg / dL, below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 55 mg / dL, or below 50 mg / dL.

[0225] As will be apparent from the teachings of this invention, the administration of ezetimibe (or a pharmaceutically acceptable salt, solvate, or cocrystal thereof) in addition to obisetropip (or its calcium salt or solvate) significantly enhances LDL-C reduction, particularly through additive or synergistic enhancement. More specifically, to enhance the LDL-C-reducing effect of obisetropip as defined herein, the method of administering ezetimibe (or its pharmaceutically acceptable salt, solvate, or cocrystal thereof) of this invention effectively and / or aims to further reduce LDL-C plasma levels by at least 20%, more typically by at least 22.5%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, or at least 30%, compared to methods based on the use of obisetropip alone or its calcium salt or solvate (or at least without the use of ezetimibe). In further embodiments, these methods are effective and / or designed to further reduce LDL-C plasma levels by at least 20 mg / dL, more typically by at least 22.5 mg / dL, at least 25 mg / dL, at least 27.5 mg / dL, at least 30 mg / dL, at least 32.5 mg / dL, or at least 35 mg / dL, compared to methods based on the use of obisetropip or its calcium salt (or at least without ezetimibe).

[0226] In a typical embodiment of the invention, the method is effective and / or intended to reduce and / or normalize ApoB plasma levels. More specifically, the method is effective and / or intended to reduce ApoB plasma levels by at least 5% from baseline, where baseline is defined as the start of treatment with obisetropeptide and ezetimibe, and more typically by at least 10%, at least 15%, at least 20%, at least 22.5%, at least 25%, or at least 27.5%. In a further embodiment, the method is effective and / or intended to reduce ApoB plasma levels by at least 5 mg / dL from baseline, where baseline is defined as the start of treatment with obisetropeptide and ezetimibe, and more typically by at least 5 mg / dL, at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 22.5 mg / dL, at least 25 mg / dL, or at least 27.5 mg / dL. In further embodiments, the method is effective and / or intended to reduce ApoB plasma levels to levels below 80 mg / dL, and in some embodiments below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 57.5 mg / dL, or below 55 mg / dL.

[0227] In a typical embodiment of the invention, the method is effective and / or intended to reduce and / or normalize Lp(a) plasma levels. More specifically, the method is effective and / or intended to reduce Lp(a) plasma levels by at least 5% from baseline, where the baseline is defined as the beginning of treatment with obisetropeptide and ezetimibe, and more typically by at least 7.5%, at least 10%, at least 12.5%, at least 15%, at least 17.5%, or at least 20%. In a further embodiment, the method is effective and / or intended to reduce Lp(a) plasma levels by at least 5 nmol / L from baseline, where the baseline is defined as the beginning of treatment with obisetropeptide and ezetimibe, and more typically by at least 10 nmol / L, at least 15 nmol / L, at least 20 nmol / L, at least 25 nmol / L, at least 30 nmol / L, at least 35 nmol / L, or at least 40 nmol / L. In further embodiments, the method is effective and / or intended to reduce Lp(a) plasma levels to levels below 110 nmol / L, and in some embodiments below 105 nmol / L, below 100 nmol / L, below 95 nmol / L, below 90 nmol / L, below 85 nmol / L, or below 80 nmol / L.

[0228] In some embodiments of the invention, the method is effective and / or designed to reduce and / or improve resistance or low responsiveness to statin therapy, particularly high-intensity statin therapy. High-intensity statin therapy is a term conventionally used in the art to refer to a regimen based on the highest permissible dose of a statin that has the highest efficacy in lowering LDL-C, particularly regimens that typically show an LDL-C reduction of ≥ 50% in normally responsive subjects. Currently, only rosuvastatin at 20 mg or 40 mg daily and atorvastatin at 40 mg or 80 mg daily meet the criteria among the statins used in clinical practice. In the context of this invention, low responsiveness to HIS therapy means that a subject receiving HIS therapy fails to achieve a 35% reduction in LDL-C. In some embodiments, it means that a subject receiving HIS therapy fails to achieve a 30% reduction in LDL-C, a 25% reduction in LDL-C, a 20% reduction in LDL-C, a 15% reduction in LDL-C, or a 10% reduction in LDL-C. Mitigating and / or improving low responsiveness to HIS therapy means reducing the difference between the subject's response (LDL-C reduction) and the (average) response of a normally responding subject. In further embodiments of the invention, the method is effective and / or intended to normalize the response to statin therapy.

[0229] As previously described herein, the methods of the present invention are intended to treat and / or prevent CVD, particularly ASCVD, in subjects who have or are at risk of developing CVD, particularly ASCVD.

[0230] The term “subject” refers to a living organism, typically a mammal, and particularly a human subject, that has or is susceptible to a disease or condition that can be treated with the compositions provided herein.

[0231] In a particularly typical embodiment of the invention, the subject is a subject diagnosed with CVD, particularly ASCVD.

[0232] In a further typical embodiment of the invention, the subject is a subject who is considered to have a risk of CVD, particularly ASCVD (typically with a higher-than-average risk), which may be determined, for example, by a healthcare professional.

[0233] In a typical embodiment of the invention, the subject is a subject suffering from one or more conditions known to be causally and / or epidemiologically associated with the occurrence of (AS)CVD, such as diabetes, hypertension, hypercholesterolemia, including overweight / obesity, metabolic syndrome, etc. In a further typical embodiment of the invention, the subject is a subject who is genetically predisposed to (AS)CVD. In a further typical embodiment of the invention, the subject is a subject who is susceptible to (AS)CVD due to lifestyle / habitual factors (e.g., unhealthy diet, lack of exercise, alcohol consumption, smoking).

[0234] According to a typical embodiment of the invention, the subject to be treated has elevated plasma LDL-C levels, typically at least 70 mg / dL, more typically at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL, or at least 100 mg / dL. Furthermore, according to a typical embodiment of the invention, the subject's plasma LDL-C level is at least 125% of the average plasma LDL-C level of healthy subjects, for example at least 150%, at least 175%, or at least 200%. Normal LDL-C (reference) values ​​typically depend on sex and age.

[0235] According to a typical embodiment of the invention, the subject to be treated has elevated ApoB plasma levels, typically at least 70 mg / dL, more typically at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL, or at least 100 mg / dL. Furthermore, according to a typical embodiment of the invention, the subject's ApoB plasma level is at least 125% of the average ApoB plasma level of healthy subjects, for example at least 150%, at least 175%, or at least 200%. Normal ApoB (reference) values ​​typically depend on sex and age.

[0236] According to a typical embodiment of the invention, the subject to be treated has elevated non-HDL-C plasma levels, typically at least 100 mg / dL, more typically at least 105 mg / dL, at least 110 mg / dL, at least 115 mg / dL, at least 120 mg / dL, at least 125 mg / dL, or at least 130 mg / dL. Furthermore, according to a typical embodiment of the invention, the subject's non-HDL-C plasma level is at least 125% of the average non-HDL-C plasma level of healthy subjects, for example at least 150%, at least 175%, or at least 200%. Normal non-HDL-C (reference) values ​​typically depend on sex and age.

[0237] In one embodiment of the invention, the subject is a human male. In another embodiment of the invention, the subject is a human female.

[0238] In a further typical embodiment of the invention, subjects are typically at increased risk based on age (e.g., subjects older than 35, 40, 45, 50, 55, 60, 65, or 70 years of age) in combination with one or more other risk factors defined herein.

[0239] According to certain embodiments of the invention, the subject to be treated exhibits low responsiveness to statin therapy, particularly high-intensity statin therapy (HIS). High-intensity statin therapy is a term conventionally used in the art to refer to a regimen based on the highest permissible dose of statin that has the highest efficacy in lowering LDL-C, particularly regimens that typically show an LDL-C reduction of ≥50% in normally responsive subjects. In current clinical practice, only rosuvastatin 20 mg / day or 40 mg / day and atorvastatin 40 mg / day or 80 mg / day are considered HIS. In a typical embodiment of the invention, the subject is a subject receiving HIS therapy who has failed to achieve a 35% reduction in LDL-C; in some embodiments, it is a subject receiving HIS therapy who has failed to achieve a 30%, 25%, 20%, 15%, or 10% reduction in LDL-C. In a typical embodiment of the invention, the subject’s low responsiveness to statin therapy, particularly HIS therapy, is established after at least one month (continuous) of HIS therapy, and more typically after at least two months, at least three months, at least four months, at least five months, or at least six months.

[0240] All aspects of the invention as defined herein relate to treatment methods including the administration (typically repeated administration) of a composition comprising obisetropeptide or its salts or solvates / hydrates (in some embodiments, any composition as previously defined herein).

[0241] Therefore, in many embodiments of the invention, the method includes administering a pharmaceutical composition comprising obisetropip and ezetimibe, wherein obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof (including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, which may be amorphous obisetropip hemicalcium) such that the dose of obisetropip is at least 1 mg, and in some embodiments at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 11 mg, at least 12 mg, at least 13 mg, at least 14 mg, or at least 15 mg.

[0242] According to various aspects of the invention, the method includes administering obisetropip or its pharmaceutically acceptable salts, solvates or cocrystals (including, for example, calcium obisetropip, as used herein, which is obisetropip hemicalcium, and in many embodiments may be amorphous calcium obisetropip) in doses of 100 mg or less, more typically 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less, or 11 mg of obisetropip.

[0243] According to various aspects of the invention, the method includes administering a pharmaceutical composition comprising obisetropip and ezetimibe, wherein obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof (including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, the obisetropip calcium may be amorphous), such that the dose of obisetropip is in the range of 1-100 mg, 2-50 mg, 3-50 mg, 4-25 mg, 4.5-15 mg, or 5-10 mg.

[0244] In some typical embodiments, the method includes administering obisetropip or its pharmaceutically acceptable salts, solvates or cocrystals (including, for example, calcium obisetropip, as used herein, which is obisetropip hemicalcium, and in many embodiments, may be amorphous obisetropip hemicalcium) at doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg of obisetropip.

[0245] In some particularly typical embodiments, the method includes administering obisetropip or its pharmaceutically acceptable salts, solvates, or cocrystals (including, for example, obisetropip calcium, as used herein, which is obisetropip hemicalcium, and in many embodiments, which may be amorphous obisetropip hemicalcium) at doses of 5, 7.5, 10, 12.5, or 15 mg. The invention includes both administering such doses and the dose itself.

[0246] As will be apparent to those skilled in the art, based on the teachings of this invention, the method of this invention further includes simultaneous treatment with ezetimibe. For this purpose, ezetimibe and obisetrop (or its therapeutically acceptable calcium salt or solvate) may be administered simultaneously or approximately simultaneously, sequentially or simultaneously, or at different times. In typical embodiments of the invention, obisetrop and ezetimibe are administered at equal frequencies and intervals, more typically once daily, or even more typically at the same time of day, in two separate unit dosage forms, sequentially or simultaneously, and in some embodiments in the form of a fixed-dose combination product as defined herein. In typical embodiments, the method of the present invention comprises administering ezetimibe at a daily dose of 1-30 mg, 2-25 mg, 3-20 mg, 4-17.5 mg, or 5-15 mg, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg, most typically about 10 mg; or administering an equivalent dose of a salt, solvate, or eutectic of ezetimibe. In many of these and other embodiments, the obisetrip is amorphous obisetrip hemicalcium.

[0247] In pharmaceutical compositions (e.g., tablets) containing a salt of obisetraprine (e.g., obisetraprine hemicalcium), the amount of salt is adjusted to meet the required dosage of obisetraprine. For example, in an example of a dosage form containing 10 mg of obisetraprine, when obisetraprine calcium is used as obisetraprine hemicalcium, such a dosage form would contain 10.26 mg of obisetraprine calcium (retaining two significant figures). As used herein, obisetraprine calcium contains one calcium cation for each of the two obisetraprine anions. The term "obisetraprine hemicalcium" means one obisetraprine anion for each hemicalcium cation. For example, the two terms are equivalent when calculating the amount of obisetraprine in a dosage form. In many of these and other examples, the obisetraprine calcium of the examples is amorphous obisetraprine hemicalcium.

[0248] In other embodiments, pharmaceutical compositions (including tablets) are provided in which the dose of obisetropeptide is about 8 mg, comprising 8 mg. In such embodiments, when the material in the tablet is obisetropeptide calcium and the dose is 8 mg, the amount of obisetropeptide calcium will be 8.21 mg (retaining two significant figures). In many of these and other embodiments, the obisetropeptide calcium of the embodiment is amorphous obisetropeptide hemicalcium.

[0249] As will be apparent to those skilled in the art, based on the teachings of this invention, in some embodiments the method of this invention further includes simultaneous treatment with an HMG CoA reductase inhibitor, and in some embodiments simultaneous HIS therapy. For this purpose, the HMG CoA reductase inhibitor and obisetropip (or its therapeutically acceptable calcium salt or solvate) may be administered simultaneously or approximately simultaneously, sequentially or simultaneously, or at different times. In typical embodiments of this invention, the frequency and interval of administration of obisetropip and the HMG CoA reductase inhibitor are equal, more typically each administered once daily, or even more typically at the same time of day, in two separate unit dosage forms administered sequentially or simultaneously, or in the form of a fixed-dose combination product. In typical embodiments, the method of the present invention includes administering rosuvastatin at a daily dose of 10-50 mg, 15-45 mg, 17.5-42.5 mg, or 20-40 mg, such as 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 mg, most typically about 20 mg or 40 mg; or administering a salt, solvate, or cocrystal of rosuvastatin at an equivalent dose. In typical embodiments, the method of the present invention comprises administering atorvastatin at a daily dose of 30-90 mg, 35-85 mg, 37.5-82.5 mg, or 40-80 mg, such as 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85 mg, most typically about 40 mg or 80 mg; or administering atorvastatin salts, solvates, or cocrystals at an equivalent dose. In some typical embodiments, the method of the present invention does not include concomitant treatment with an HMG CoA reductase inhibitor.

[0250] In particularly typical embodiments of the invention, the treatment comprises repeated administration of a composition containing amorphous obisetroprene hemicalcium, within the dosage range described herein. In particularly typical embodiments of the invention, the treatment comprises, in some embodiments, repeated administration of the composition at a dosage range previously defined herein at a frequency of at least once every two days or at least once daily. In particularly typical embodiments of the invention, the treatment comprises, in some embodiments, repeated administration of the composition at a dosage range previously defined herein at a frequency of once to four times daily. In particularly typical embodiments of the invention, the method comprises administering the composition, which contains amorphous obisetroprene hemicalcium and a surfactant, and optionally one or more other pharmaceutically acceptable excipients, once or twice daily.

[0251] As will be apparent to those skilled in the art, based on the teachings of this invention, the daily doses shown herein may be included in a single unit dosage form or in multiple unit dosage forms. In the most typical embodiment of the invention, the method comprises administering a composition once daily at the doses listed herein, the composition comprising amorphous obisetroprene hemicalcium and a surfactant, and optionally one or more other pharmaceutically acceptable excipients. However, methods comprising administering two unit dosage forms at certain predetermined times of day, each unit dosage form comprising approximately half of the daily dose as described above, for example, one unit dosage form administered in the morning (e.g., shortly after the subject wakes up) and another unit dosage form administered in the evening (e.g., approximately when the subject eats dinner or goes to sleep). Embodiments in which unit dosage forms are used, comprising a higher amount of the composition than the daily dose indicated herein, these compositions comprising amorphous obisetroprene hemicalcium and a surfactant, and optionally one or more other pharmaceutically acceptable excipients. This may, for example, include the use of extended-release dosage forms that remain in the body and continuously release the active ingredient for a sufficiently long period of time.

[0252] In embodiments, methods and / or compositions according to the invention are provided, wherein such methods and / or uses include administering to a subject at doses and frequencies that effectively reduce a subject's LDL-C plasma levels, ApoB plasma levels, and / or Lp(a) plasma levels, and in some embodiments, repeatedly administering compositions comprising, more generally, reducing one or more of a subject's LDL-C plasma levels, ApoB plasma levels, and / or Lp(a) plasma levels to the ranges described elsewhere herein: amorphous obisetropeptide hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and a surfactant and optionally one or more additional pharmaceutically acceptable excipients. In particularly typical embodiments of the invention, these treatments include repeated administration of compositions comprising amorphous obisetropeptide hemicalcium and a surfactant, and optionally one or more additional pharmaceutically acceptable excipients, according to the above-defined regimens, for periods of at least one month, at least three months, at least four months, at least six months, at least nine months, at least one year, at least two years, at least three years, at least five years, at least ten years, at least 20 years, or at least 30 years. There is no particular upper limit; treatment can continue for the remainder of the subject's life as long as it is deemed beneficial to the subject's overall health and well-being (as determined by a properly qualified healthcare professional).

[0253] Another aspect of the invention relates to a pharmaceutical kit comprising a package containing multiple unit dosage forms and a package insert, wherein the unit dosage forms contain a pharmaceutical composition according to the invention, and wherein the package insert contains printed instructions for use to guide repeated self-administration of the unit dosage forms to achieve any therapeutic purpose as defined herein, such as treatment and / or prevention of any heart disease or functional impairment as defined herein.

[0254] According to embodiments of the invention, a pharmaceutical kit includes a container (e.g., a cardboard box) containing one or more blister packs containing a plurality of solid unit dosage forms as previously defined herein, and in some embodiments, a plurality of tablets as previously defined herein. In particularly typical embodiments of the invention, the pharmaceutical kit contains at least 5, at least 8, at least 10, at least 12, or at least 15 of the said unit dosage forms, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 of the said unit dosage forms. In many embodiments of the invention, the pharmaceutical kit contains only unit dosage forms as defined herein, which contain compositions comprising amorphous obisetroprene hemicalcium and a surfactant, and optionally one or more additional pharmaceutically acceptable excipients. In some embodiments of the invention, the pharmaceutical kit comprises only a plurality of unit dosage forms as defined herein, which contain compositions comprising amorphous obisetroprene hemicalcium and a surfactant, and optionally one or more other pharmaceutically acceptable excipients as the sole active ingredient. In some embodiments of the invention, the pharmaceutical kit typically comprises only a plurality of unit dosage forms containing obisetroprene as the sole active ingredient, as defined herein, and a plurality of (in some embodiments, an equal number) unit dosage forms containing ezetimibe as the sole active ingredient, at dosage levels described elsewhere herein. In one embodiment of the invention, the pharmaceutical kit comprises only a plurality of defined unit dosage forms, each containing obisetroprene and ezetimibe, and more typically comprises a plurality of fixed-dose pharmaceutical compositions as defined herein. In some embodiments, the pharmaceutical kit as defined herein may further comprise, typically at dosage levels described elsewhere herein, a plurality of unit dosage forms containing an HMG CoA reductase inhibitor as the sole active ingredient, and in some embodiments, atorvastatin or rosuvastatin.

[0255] According to the present invention, the pharmaceutical kit includes a package insert containing a patient information package insert, which is typically a printed patient information package insert containing information including descriptions of the form and composition of the unit dosage form contained in the kit, indications of the intended therapeutic indications of the product, instructions on how to use the product, and information and warnings regarding use-related side effects and contraindications. Those skilled in the art will understand that, based on the information provided herein, the package insert as part of the kit according to the present invention will typically contain information regarding therapeutic indications, uses, treatment regimens, etc., as described above with respect to the treatment methods of the present invention. In a particularly typical embodiment of the invention, the package insert contains printed instructions for use for repeated (self-)administration of the unit dosage form to treat and / or prevent CVD, particularly ASCVD.

[0256] Other embodiments include: 1. A fixed-dose pharmaceutical composition, said pharmaceutical composition comprising or consisting of the following: a. Obistrapillin or its pharmaceutically acceptable salts, solvates or cocrystals. b. Ezetimibe or its pharmaceutically acceptable salts, solvates, or cocrystals. c. Surfactants, and d. One or more pharmaceutically acceptable excipients.

[0257] 2. The pharmaceutical composition as described in Example 1, wherein the area under the curve (AUC) of obisetropeptide is [value missing] after oral administration of the composition to a subject. 0-∞ and / or AUC 0-t The 90% confidence intervals of the geometric mean of ) and / or Cmax were respectively the area under the curve (AUC) of obisetropeptide obtained after oral administration of the reference drug composition to similar subjects. 0-∞ and / or AUC 0-t The reference composition comprises an equivalent dose of obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0258] 3. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoside after oral administration of the composition to a subject is [data missing]. 0-∞and / or AUC 0-t The 90% confidence intervals of the geometric mean of ezetimibe and / or Cmax were respectively calculated as the areas under the curves (AUCs) of ezetimibe and / or ezetimibe glucoside obtained after oral administration of the reference drug composition to similar subjects. 0-∞ and / or AUC 0-t The reference composition is in the range of 75%-125%, preferably 80%-125%, and more preferably 90%-110% of Cmax, wherein the reference composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and wherein the reference composition is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising obisetropip or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof.

[0259] 4. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the pharmaceutical composition is intended for use in treating subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, wherein the pharmaceutical composition is considered suitable for the stated use in the following circumstances: a. The fixed-dose pharmaceutical composition is administered orally to the subject; b. Measure the concentration of obisetropeptide in the plasma of the subject at one or more time points after administration to provide a set of obisetropeptide concentration / time data points to provide the area under the curve (AUC); and c. Area under the curve (AUC) of the obese curve 0-∞ and / or AUC 0-t The 90% confidence intervals of the geometric mean of ) and / or Cmax were respectively the area under the curve (AUC) of obisetropeptide obtained after oral administration of the reference drug composition to similar subjects. 0-∞ and / or AUC 0-t The reference composition comprises an equivalent dose of obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0260] 5. The pharmaceutical composition as described in any of the foregoing embodiments, for use in treating subjects requiring lowering LDL cholesterol and / or raising HDL cholesterol, wherein the pharmaceutical composition is considered suitable for the stated use in the following circumstances: a. The fixed-dose pharmaceutical composition is administered orally to the subject; b. Measure the concentrations of ezetimibe and / or ezetimibe glucoside in the plasma of the subject at one or more time points after administration to provide a set of ezetimibe and / or ezetimibe glucoside concentration / time data points, thereby providing the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoside, respectively; and c. Area under the curve (AUC) of ezetimibe and / or ezetimibe glucoside 0-∞ and / or AUC 0-t The 90% confidence intervals of the geometric mean of ezetimibe and / or Cmax were respectively calculated as the areas under the curves (AUCs) of ezetimibe and / or ezetimibe glucoside obtained after oral administration of the reference drug composition to similar subjects. 0-∞ and / or AUC 0-t The reference composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof, or in a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0261] 6. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the use of said composition is for lowering LDL cholesterol and / or raising HDL cholesterol in a person suffering from heterozygous familial hypercholesterolemia (HeFH) and / or diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0262] 7. The pharmaceutical composition as described in any of the foregoing embodiments, wherein t in AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC 0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0-336) or AUC 0-∞, preferably 48 hours (AUC 0-48), and more preferably AUC 0-∞.

[0263] 8. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the subject is a human being, preferably a healthy human being, more preferably a human being who needs to lower LDL cholesterol and / or raise HDL cholesterol, a human being with heterozygous familial hypercholesterolemia (HeFH) and / or a human being diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0264] 9. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the subject is a healthy adult male or female aged 18-65 years who does not use tobacco or nicotine, and optionally, said person has a blood glucose level of 18.5 to 29.9 kg / m³. 2 Body Mass Index (BMI).

[0265] 10. The pharmaceutical composition as described in any of the preceding embodiments, wherein the person requiring lowering LDL cholesterol, and / or the person suffering from heterozygous familial hypercholesterolemia (HeFH), and / or the person diagnosed with atherosclerotic cardiovascular disease (ASCVD) has an LDL-cholesterol level of ≥ 70 mg / dL, and optionally the person is not adequately controlled by their current lipid-lowering therapy.

[0266] 11. The pharmaceutical composition as described in any of the preceding embodiments, wherein when the pharmaceutical composition is dissolved in 500 ml of solution at a rotation speed of about 75 rpm in a USP Type II device at 37 ± 0.5°C, at least about 60%, preferably at least about 70%, and more preferably at least about 80% of ezetimibe dissolves within about 30 minutes, the solution containing 0.45% SLS in 0.05 M sodium acetate buffer at pH 4.5.

[0267] 12. The pharmaceutical composition as described in any of the preceding embodiments, wherein when the pharmaceutical composition is dissolved in 1000 ml of solution in a USP Type II device at a rotation speed of about 75 rpm at 37 ± 0.5°C, at least about 70%, preferably at least about 80%, and more preferably at least about 85% of obisetropeptide dissolves within about 15 minutes, the solution comprising a phosphate buffer solution at pH 6.8 + 0.2% w / v polysorbate 80.

[0268] 13. The pharmaceutical composition as described in any of the preceding embodiments, wherein the composition comprises 1 mg to 20 mg of obisetropeptide and 5 mg to 20 mg of ezetimibe, preferably the composition comprises 5 mg of obisetropeptide and 10 mg of ezetimibe or 10 mg of obisetropeptide and 10 mg of ezetimibe.

[0269] 14. The pharmaceutical composition as described in any of the preceding embodiments, wherein the composition is provided in a unit dosage form comprising 1 mg to 20 mg obisetropeptide and 5 mg to 20 mg ezetimibe, preferably the unit dosage form comprising 5 mg obisetropeptide and 10 mg ezetimibe, or 10 mg obisetropeptide and 10 mg ezetimibe.

[0270] 15. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises no more than about 2% (w / w), preferably no more than about 0.5% (w / w), more preferably no more than about 0.3% (w / w), and even more preferably no more than about 0.2% (w / w) as an impurity of an ezetimibe tetrahydropyran analogue.

[0271] 16. The pharmaceutical composition as described in any of the foregoing embodiments, wherein ezetimibe or obisetropeptide, or both ezetimibe and obisetropeptide, are micronized.

[0272] 17. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises micronized ezetimibe, the micronized ezetimibe having a Dv of not more than 10 µm, preferably in the range of 4-10 µm, and more preferably not more than 8.5 µm. 90 Dv not exceeding 4 µm, preferably in the range of about 1 µm to 4 µm, more preferably not exceeding 3.8 µm. 50 ; and Dv not exceeding 1 µm 10 .

[0273] 18. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises micronized obisetropeptide, the micronized obisetropeptide having a Dv of not more than 14 µm, preferably in the range of about 5-14 µm. 90 Dv not exceeding 5 µm, preferably in the range of about 3-5 µm 50 ; and Dv not exceeding 3 µm 10 .

[0274] 19. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises ezetimibe in the form of anhydrous ezetimibe, ezetimibe monohydrate, or a mixture thereof.

[0275] 20. The pharmaceutical composition as described in any of the preceding embodiments, wherein the composition comprises obisetropip in the form of an alkali metal or alkaline earth metal salt of obisetropip, preferably comprising obisetropip sodium, obisetropip potassium or obisetropip calcium, and more preferably comprising obisetropip calcium salt.

[0276] 21. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition is a two-component composition, and wherein one of the components comprises ezetimibe and the other component comprises obisetropeptide.

[0277] 22. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition is a two-component composition, and wherein one of the two components comprises both ezetimibe and obisetropip.

[0278] 23. The pharmaceutical composition as described in any one of Examples 21-22, wherein the two-component composition is a bilayer tablet formulation, a capsule formulation comprising two types of particles or composed of two types of particles, or a tablet formulation comprising an extragranular component and an intragranular component.

[0279] 24. The pharmaceutical composition as described in Example 22, wherein: a. The intragranular component includes ezetimibe, and the extragranular component includes obisetropine; or The intragranular components include both ezetimibe and obisetrop; and the extragranular components consist only of excipients.

[0280] 25. The pharmaceutical composition as described in Example 22, wherein: a. The intragranular component includes obisetropine, and the extragranular component includes ezetimibe; or b. The external component of the particles includes both ezetimibe and obisetropeptide, and the internal component of the particles includes only excipients.

[0281] 26. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition further comprises one or more binders, wherein preferably the binder:surfactant ratio in the intraparticle component is in the range of about 0.05:5.0 to about 5.0:0.05, preferably about 0.5:4.5 to about 4.5:0.5, more preferably about 1:4 to about 4:1, even more preferably about 1:2 to about 2:1, and most preferably about 1:1.

[0282] 27. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition further comprises one or more binders selected from: cellulose derivatives, preferably selected from methylcellulose and carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and hydroxyethylcellulose; gelatin, glucose, dextran, xylitol, polymethacrylate, polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone, starch paste, sucrose, sorbitol, pregelatinized starch, tragacanth gum, alginate and salts of alginate such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonite, preferably the binder is polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone, more preferably the binder is copovidone, and even more preferably the binder is Colidon 30.

[0283] 28. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the surfactant has an HLB value of at least 15, at least 20, at least 30, or at least 40; preferably, the surfactant is selected from lauric acid or a salt of lauric acid, palmitic acid or a salt of palmitic acid, stearic acid or a salt of stearic acid and oleic acid or a salt of oleic acid, polyethylene glycol glyceride, polyoxyethylene monoester, polyoxyethylene ethyl ethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oil, polyethylene glycol having a molecular weight in the range of about 2,000 to 10,000, propylene glycol octanoate, glyceryl oleate and octanoate, esters of glycerol and fatty acids; more preferably, the surfactant is selected from sodium dioctyl sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, polysorbate 40, or polysorbate 80 or sodium lauryl sulfate; and even more preferably, the surfactant is sodium lauryl sulfate.

[0284] 29. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition further comprises one or more disintegrants selected from crospovidone, crospovidone sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, alginate, sodium alginate, microcrystalline cellulose, sodium carboxyacetate starch, and pregelatinized starch, preferably crospovidone sodium carboxymethyl cellulose or sodium carboxyacetate starch, and more preferably sodium carboxyacetate starch.

[0285] 30. The pharmaceutical composition as described in any of the preceding embodiments, wherein the composition remains stable at 40°C / 75% relative humidity for at least 1 month, preferably at least 3 months and more preferably at least 6 months, or remains stable at 25°C / 60% relative humidity for at least 3 months, preferably at least 6 months and more preferably at least 12 months.

[0286] 31. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition is a tablet formulation comprising or consisting of the following: a. Intraparticle components, including: i. Calcium obisetrop, equivalent to 10 mg of obisetrop free acid; ii. Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe; iii. A binder and surfactant in a 1:1 ratio, preferably the binder and the surfactant each comprising about 1 ± 0.5% w / w of the particle components; more preferably, the binder is 1 ± 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 ± 0.5% w / w of sodium lauryl sulfate. iv. A disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; v. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. Extraparticle components, which include: i. A disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; ii. Optionally, a lubricant, preferably magnesium stearate, iii. Optionally, a flow aid, preferably colloidal silica or talc or both colloidal silica and talc; iv. Optionally one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose; c. Optionally, the pharmaceutical composition includes a film coating, preferably the film coating is free of primary alcohols, and more preferably the film coating is free of polyethylene glycol.

[0287] 32. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises a tablet formulation comprising or consisting of the following: a. Intraparticle components, including: i. Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe; ii. A binder and surfactant in a 1:1 ratio, preferably the binder and the surfactant each comprising about 1 ± 0.5% w / w of the particle components; more preferably, the binder is 1 ± 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 ± 0.5% w / w of sodium lauryl sulfate. iii. A disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. Extraparticle components, which include: i. Calcium obisetrop, equivalent to 10 mg of obisetrop free acid; ii. A disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; iii. Optionally, a lubricant, preferably magnesium stearate, iv. Optionally, a flow aid, preferably colloidal silica or talc or both colloidal silica and talc; v. Optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose; c. Optionally, the pharmaceutical composition includes a film coating, preferably the film coating is free of primary alcohols, and more preferably the film coating is free of polyethylene glycol.

[0288] 33. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises a tablet formulation comprising or consisting of the following: a. Intraparticle components, including: i. Calcium obisetrop, equivalent to 10 mg of obisetrop free acid; ii. A binder and surfactant in a 1:1 ratio, preferably the binder and the surfactant each comprising about 1 ± 0.5% w / w of the particle components; more preferably, the binder is 1 ± 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 ± 0.5% w / w of sodium lauryl sulfate. iii. A disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. Extraparticle components, which include: i. Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe. ii. A disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; iii. Optionally, a lubricant, preferably magnesium stearate, iv. Optionally, a flow aid, preferably colloidal silica or talc or both colloidal silica and talc; v. Optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose; c. Optionally, the pharmaceutical composition includes a film coating, preferably the film coating is free of primary alcohols, and more preferably the film coating is free of polyethylene glycol.

[0289] 34. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the pharmaceutical composition is used in the treatment of subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, preferably subjects who have hyperlipidemia or mixed dyslipidemia.

[0290] 35. The pharmaceutical composition as described in any of the foregoing embodiments, for use in patients who require lowering LDL cholesterol and / or raising HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH), and / or patients diagnosed with atherosclerotic cardiovascular disease (ASCVD) with LDL cholesterol.

[0291] 36. Use of the pharmaceutical composition as described in any of the foregoing embodiments for the preparation of a medicament for treating a subject suffering from hyperlipidemia or mixed dyslipidemia.

[0292] 37. The pharmaceutical composition as described in any of the foregoing embodiments is used to prepare a medicament for reducing LDL cholesterol in subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH), and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0293] 38. Use of the pharmaceutical composition as described in any of the foregoing embodiments for the preparation of a medicament for reducing the risk of cardiovascular events.

[0294] 39. The use as described in any of the foregoing embodiments, wherein the subject has mild dyslipidemia.

[0295] 40. A method of treating a subject who requires lowering LDL cholesterol and / or raising HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH), and / or a subject diagnosed with atherosclerotic cardiovascular disease (ASCVD), wherein the method comprises administering to the patient in need a therapeutically effective dose of a pharmaceutical composition as described in any of the foregoing embodiments.

[0296] 41. A method of treating a subject suffering from hyperlipidemia or mixed dyslipidemia, wherein the method comprises administering to the patient in need a pharmaceutical composition as described in any of the foregoing embodiments.

[0297] 42. The use of the pharmaceutical composition as described in any of the foregoing embodiments for the preparation of a medicament or a treatment method, wherein the subject has an LDL-cholesterol level of ≥ 50 mg / dL, preferably ≥ 70 mg / dL, and optionally, the person is not adequately controlled by their current lipid-lowering therapy.

[0298] 43. Use or treatment of the pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition is administered to the subject in need to deliver a total daily oral dose of 5 mg obisetropeptide and 10 mg ezetimibe, 10 mg obisetropeptide and 10 mg ezetimibe, or 20 mg obisetropeptide and 20 mg ezetimibe, preferably to the subject to deliver a daily oral dose of 10 mg obisetropeptide and 10 mg ezetimibe.

[0299] 44. Use or treatment of the pharmaceutical composition as described in any of the foregoing embodiments, wherein the subject in need is a subject who requires additional reduction of low-density lipoprotein cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy for the treatment of an adult with heterozygous familial hypercholesterolemia (HeFH) or a confirmed atherosclerotic cardiovascular (CV) disease (ASCVD).

[0300] 45. A pharmaceutical composition comprising obisetropeptide and ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and a pharmaceutically acceptable carrier, for use in a subject who requires additional reduction of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of an adult with heterozygous familial hypercholesterolemia (HeFH) or a confirmed atherosclerotic cardiovascular (CV) disease (ASCVD).

[0301] Further embodiments include: 1. A fixed-dose pharmaceutical composition comprising: a. Amorphous obisetrop or its calcium salt; b. Ezetimibe or its pharmaceutically acceptable salts, solvates, or cocrystals; a. c. Surfactants; and d. One or more pharmaceutically acceptable excipients.

[0302] 2. The pharmaceutical composition as described in Example 1, wherein the amorphous obisetrop is amorphous obisetrop hemicalcium.

[0303] 3. The pharmaceutical composition as described in Example 1 or Example 2, wherein the amorphous obisetropip calcium salt substantially does not contain any crystalline salt of obisetropip calcium.

[0304] 4. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous oxisetropeptide calcium has an X-ray powder diffraction pattern substantially the same as that of FIG49 or 50.

[0305] 5. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous ocbisetrop calcium has an X-ray powder diffraction pattern containing one or more X-ray powder diffraction peaks at about 3.4°2θ, about 7.0°2θ, and about 9.2°2θ.

[0306] 6. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous oxetetropsid calcium does not exhibit birefringence.

[0307] 7. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous ocbisetropi calcium has a glass transition temperature between about 107°C and about 112°C.

[0308] 8. The pharmaceutical composition as described in Example 7, wherein the glass transition temperature is measured using modulated differential scanning calorimetry.

[0309] 9. The pharmaceutical composition as described in Example 8, wherein the measurement using modulated differential scanning calorimetry employs an open sample pan.

[0310] 10. The pharmaceutical composition as described in Example 9, wherein the opening is a pinhole.

[0311] 11. The pharmaceutical composition as described in any one of Examples 6 to 10, wherein the glass transition temperature is at a value between about 110°C and about 112°C.

[0312] 12. The pharmaceutical composition as described in any of the preceding embodiments, wherein the amorphous obisetropica calcium has a glass transition temperature of less than about 100°C when measured by differential scanning calorimetry using a closed sample pan.

[0313] 13. The pharmaceutical composition as described in Example 12, wherein the amorphous oxetetropsid calcium has a glass transition temperature between about 70°C and about 92°C when measured by differential scanning calorimetry using a closed sample pan.

[0314] 14. The pharmaceutical composition as described in Example 13, wherein the amorphous octosectrapi calcium has a weight loss of less than about 1% when heated to about 200°C.

[0315] 15. The pharmaceutical composition as described in Example 14, wherein the weight loss of the amorphous octocetropi calcium is between about 0.8% and about 0.95%.

[0316] 16. The pharmaceutical composition as described in Example 15, wherein the weight loss of the amorphous ocbisetroppe calcium is between about 0.84% ​​and about 0.92%.

[0317] 17. The pharmaceutical composition as described in any of the preceding embodiments, wherein the amorphous ocbisetropeptide calcium has a water content of less than about 5%.

[0318] 18. The pharmaceutical composition as described in Example 17, wherein the amorphous ocbisetropeptide calcium water content is less than about 4%.

[0319] 19. The pharmaceutical composition as described in Example 18, wherein the amorphous ocbisetropeptide calcium contains less than about 3% water.

[0320] 20. The pharmaceutical composition as described in Example 19, wherein the water content of the amorphous octostripi calcium is between about 0.5% and about 1.5%.

[0321] 21. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous octosectrapi calcium is in bulk form or in the form of a formulated composition, having a particle size distribution in which about 90% of the particles have a diameter of about 15 micrometers or less.

[0322] 22. The pharmaceutical composition as described in Example 21, wherein about 90% of the amorphous obisetropeptide calcium particles have a diameter between about 6 micrometers and about 15 micrometers.

[0323] 23. The pharmaceutical composition as described in Example 22, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 14 micrometers or less.

[0324] 24. The pharmaceutical composition as described in Example 23, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 13 micrometers or less.

[0325] 25. The pharmaceutical composition as described in Example 24, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 12 micrometers or less.

[0326] 26. The pharmaceutical composition as described in Example 25, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 11 micrometers or less.

[0327] 27. The pharmaceutical composition as described in Example 26, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 10 micrometers or less.

[0328] 28. The pharmaceutical composition as described in Example 27, wherein about 90% or more of these amorphous octosectrapi calcium particles have a diameter of about 9 micrometers or less.

[0329] 29. The pharmaceutical composition as described in Example 28, wherein about 90% or more of these amorphous octosectrapi calcium particles have a diameter of about 8 micrometers or less.

[0330] 30. The pharmaceutical composition as described in Example 29, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 7 micrometers or less.

[0331] 31. The pharmaceutical composition as described in Example 30, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 6 micrometers or less.

[0332] 32. The pharmaceutical composition as described in Example 31, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 5 micrometers or less.

[0333] 33. The pharmaceutical composition as described in Example 32, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 4 micrometers or less.

[0334] 34. The pharmaceutical composition as described in Example 33, wherein about 90% or more of these amorphous obisetropeptide calcium particles have a diameter of about 3 micrometers or less.

[0335] 35. The pharmaceutical composition as described in any of the preceding embodiments, wherein the amorphous octosectrapi calcium is in bulk form or in the form of a formulated composition, having a particle size distribution in which about 50% of the particles have a diameter of about 5 micrometers or less.

[0336] 36. The pharmaceutical composition as described in Example 35, wherein about 50% of these amorphous obisetropeptide calcium particles have a diameter of about 4 micrometers or less.

[0337] 37. The pharmaceutical composition as described in Example 36, wherein about 50% of these amorphous obisetropeptide calcium particles have a diameter of about 3 micrometers or less.

[0338] 38. The pharmaceutical composition as described in any of the preceding embodiments, wherein the amorphous octosectrapi calcium is in bulk form or in the form of a formulated composition, having a particle size distribution in which about 10% of the particles have a diameter of about 2 micrometers or less.

[0339] 39. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous ocbisetropeptide calcium has a chemical purity of at least 98.0%.

[0340] 40. The pharmaceutical composition as described in Example 39, wherein the amorphous ocbisetropike calcium has a chemical purity of at least 99.0%.

[0341] 41. The pharmaceutical composition as described in Example 40, wherein the amorphous ocbisetropeptide calcium has a chemical purity of at least 98.0%.

[0342] 42. The pharmaceutical composition as described in Example 41, wherein the amorphous ocbisetropike calcium has a chemical purity of at least 99.0%.

[0343] 43. The pharmaceutical composition as described in Example 42, wherein the amorphous ocbisetropike calcium has a chemical purity of at least 99.5%.

[0344] 44. The pharmaceutical composition as described in Example 43, wherein the amorphous octosectrapi calcium has a chemical purity of at least 99.6%.

[0345] 45. The pharmaceutical composition as described in Example 44, wherein the amorphous ocbisetropike calcium has a chemical purity of at least 99.7%.

[0346] 46. ​​The pharmaceutical composition as described in Example 45, wherein the amorphous ocbisetropike calcium has a chemical purity of at least 99.8%.

[0347] 47. The pharmaceutical composition as described in Example 46, wherein the amorphous ocbisetropike calcium has a chemical purity of at least 99.9%.

[0348] 48. The pharmaceutical composition as described in any of the preceding embodiments, wherein the amorphous obisetrop calcium has a solid-state 13C-NMR spectrum substantially the same as the solid-state 13C-NMR spectrum of FIG59.

[0349] 49. The pharmaceutical composition as described in any of the preceding embodiments, wherein the amorphous obisetrop calcium has a solid-state 13C-NMR spectrum in which no peak is present at about 22.1 ppm.

[0350] 50. The pharmaceutical composition as described in any of the preceding embodiments, wherein the amorphous obisetrop calcium has a solid-state 13C-NMR spectrum in which no peak is present at about 29.5 ppm.

[0351] 51. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous oxetetol calcium has been ground.

[0352] 52. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous oxetetol calcium has been jet-milled.

[0353] 53. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the amorphous oxetetrol calcium has been spray-dried.

[0354] 54. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the area under the curve (AUC) of obisetropeptide is [value missing] after oral administration of the composition to a subject. 0-∞ and / or AUC 0-tThe 90% confidence intervals of the geometric mean of ) and / or Cmax were respectively the area under the curve (AUC) of obisetropeptide obtained after oral administration of the reference drug composition to similar subjects. 0-∞ and / or AUC 0-t The reference composition comprises an equivalent dose of amorphous octocerci or its calcium salt, and is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising ezetimibe or its pharmaceutically acceptable salt, solvate or cocrystal, or in a fixed dose combination with ezetimibe or its pharmaceutically acceptable salt, solvate or cocrystal.

[0355] 55. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoside after oral administration of the composition to a subject is [data missing]. 0-∞ and / or AUC 0-t The 90% confidence intervals of the geometric mean of ezetimibe and / or Cmax were respectively calculated as the areas under the curves (AUCs) of ezetimibe and / or ezetimibe glucoside obtained after oral administration of the reference drug composition to similar subjects. 0-∞ and / or AUC 0-t The reference composition is in the range of 75%-125%, preferably 80%-125%, and more preferably 90%-110% of Cmax, wherein the reference contains an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and wherein the reference composition is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising amorphous obisetropip or its calcium salt, or in a fixed-dose combination with ezetimibe or its pharmaceutically acceptable salt, solvate, or cocrystal thereof.

[0356] 56. The pharmaceutical composition as described in any of the foregoing embodiments, for use in treating subjects requiring lowering LDL cholesterol and / or raising HDL cholesterol, wherein the pharmaceutical composition is considered suitable for the stated use in the following circumstances: a. The fixed-dose pharmaceutical composition is administered orally to the subject; b. Measure the concentration of obisetropeptide in the plasma of the subject at one or more time points after administration to provide a set of obisetropeptide concentration / time data points to provide the area under the curve (AUC); and c. Area under the curve (AUC) of the obese curve 0-∞ and / or AUC 0-tThe 90% confidence intervals of the geometric mean of ) and / or Cmax were respectively the area under the curve (AUC) of obisetropeptide obtained after oral administration of the reference drug composition to similar subjects. 0-∞ and / or AUC 0-t The reference composition comprises an equivalent dose of amorphous octocerci or its calcium salt, and is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising ezetimibe or its pharmaceutically acceptable salt, solvate or cocrystal, or in a fixed dose combination with ezetimibe or its pharmaceutically acceptable salt, solvate or cocrystal.

[0357] 57. The pharmaceutical composition as described in any of the foregoing embodiments, for use in treating subjects requiring lowering LDL cholesterol and / or raising HDL cholesterol, wherein the pharmaceutical composition is considered suitable for the stated use in the following circumstances: a. The fixed-dose pharmaceutical composition is administered orally to the subject; b. Measure the concentrations of ezetimibe and / or ezetimibe glucoside in the plasma of the subject at one or more time points after administration to provide a set of ezetimibe and / or ezetimibe glucoside concentration / time data points, thereby providing the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoside, respectively; and c. Area under the curve (AUC) of ezetimibe and / or ezetimibe glucoside 0-∞ and / or AUC 0-t The 90% confidence intervals of the geometric mean of ezetimibe and / or Cmax were respectively calculated as the areas under the curves (AUCs) of ezetimibe and / or ezetimibe glucoside obtained after oral administration of the reference drug composition to similar subjects. 0-∞ and / or AUC 0-t The reference composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and is administered alone, or concurrently or sequentially with another pharmaceutical composition comprising amorphous obisetropip or its calcium salt, or in a fixed dose combination with ezetimibe or its pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0358] 58. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the use of said composition is for lowering LDL cholesterol and / or raising HDL cholesterol in a person suffering from heterozygous familial hypercholesterolemia (HeFH) and / or diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0359] 59. The pharmaceutical composition as described in any of the preceding embodiments, wherein t in AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC 0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0-336) or AUC 0-∞, preferably 48 hours (AUC 0-48), and more preferably AUC 0-∞.

[0360] 60. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the subject is a human being, preferably a healthy human being, more preferably a human being who needs to lower LDL cholesterol and / or raise HDL cholesterol, a human being with heterozygous familial hypercholesterolemia (HeFH) and / or a human being diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0361] 61. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the subject is a healthy adult male or female aged 18-65 years who does not use tobacco or nicotine, and optionally, said person has a blood glucose level of 18.5 to 29.9 kg / m³. 2 Body Mass Index (BMI).

[0362] 62. The pharmaceutical composition as described in any of the preceding embodiments, wherein the person requiring lowering LDL cholesterol, and / or the person suffering from heterozygous familial hypercholesterolemia (HeFH), and / or the person diagnosed with atherosclerotic cardiovascular disease (ASCVD) has an LDL-cholesterol level ≥ 70 mg / dL, and optionally the person is not adequately controlled by their current lipid-lowering therapy.

[0363] 63. The pharmaceutical composition as described in any of the preceding embodiments, wherein when the pharmaceutical composition is dissolved in 500 ml of solution at a rotation speed of about 75 rpm in a USP Type II device at 37 ± 0.5°C, at least about 60%, preferably at least about 70%, and more preferably at least about 80% of ezetimibe dissolves within about 30 minutes, the solution containing 0.45% SLS in 0.05 M sodium acetate buffer at pH 4.5.

[0364] 64. The pharmaceutical composition as described in any of the preceding embodiments, wherein when the pharmaceutical composition is dissolved in 1000 ml of solution in a USP Type II device at a rotation speed of about 75 rpm at 37 ± 0.5°C, at least about 70%, preferably at least about 80%, and more preferably at least about 85% of amorphous obisetropeptide dissolves within about 15 minutes, the solution comprising a phosphate buffer solution at pH 6.8 + 0.2% w / v polysorbate 80.

[0365] 65. The pharmaceutical composition as described in any of the preceding embodiments, wherein the composition comprises 1 mg to 20 mg of amorphous octocerpram and 5 mg to 20 mg of ezetimibe, preferably the composition comprises 5 mg of amorphous octocerpram and 10 mg of ezetimibe or 10 mg of amorphous octocerpram and 10 mg of ezetimibe.

[0366] 66. The pharmaceutical composition as described in any of the preceding embodiments, wherein the composition is provided in a unit dosage form comprising 1 mg to 20 mg of amorphous octocerpram and 5 mg to 20 mg of ezetimibe, preferably the unit dosage form comprising 5 mg of amorphous octocerpram and 10 mg of ezetimibe, or 10 mg of amorphous octocerpram and 10 mg of ezetimibe.

[0367] 67. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises no more than about 2% (w / w), preferably no more than about 0.5% (w / w), more preferably no more than about 0.3% (w / w), and even more preferably no more than about 0.2% (w / w) as an impurity of an ezetimibe tetrahydropyran analogue.

[0368] 68. The pharmaceutical composition as described in any of the preceding embodiments, wherein ezetimibe or amorphous octosecropillin, or both ezetimibe and amorphous octosecropillin, are micronized.

[0369] 69. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises micronized ezetimibe, the micronized ezetimibe having a Dv of not more than 10 µm, preferably in the range of 4-10 µm, and more preferably not more than 8.5 µm. 90 Dv not exceeding 4 µm, preferably in the range of about 1 µm to 4 µm, more preferably not exceeding 3.8 µm. 50 ; and Dv not exceeding 1 µm 10 .

[0370] 70. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises micronized amorphous obisetropeptide, the micronized amorphous obisetropeptide having a Dv of not more than 14 µm, preferably in the range of about 5-14 µm. 90 Dv not exceeding 5 µm, preferably in the range of about 3-5 µm 50 ; and Dv not exceeding 3 µm 10 .

[0371] 71. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises ezetimibe in the form of anhydrous ezetimibe, ezetimibe monohydrate, or a mixture thereof.

[0372] 72. The pharmaceutical composition as described in any of the preceding embodiments, wherein the composition comprises amorphous obisetropip in the form of an alkali metal or alkaline earth metal salt of amorphous obisetropip, preferably comprising amorphous obisetropip sodium, amorphous obisetropip potassium or amorphous obisetropip calcium, and more preferably comprising amorphous obisetropip calcium salt.

[0373] 73. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition is a two-component composition, and wherein one of the components comprises ezetimibe and the other component comprises amorphous octosecropeptide.

[0374] 74. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition is a two-component composition, and wherein one of the two components comprises both ezetimibe and amorphous octosecropeptide.

[0375] 75. The pharmaceutical composition of any one of Examples 21-22, wherein the two-component composition is a bilayer tablet formulation, a capsule formulation comprising two types of particles or composed of two types of particles, or a tablet formulation comprising an extragranular component and an intragranular component.

[0376] 76. The pharmaceutical composition as described in Example 22, wherein: a. The intraparticle component contains ezetimibe, and the extraparticle component contains amorphous obesetrapi; or The internal components of the particles include both ezetimibe and amorphous obesetrop; and the external components of the particles consist only of excipients.

[0377] 77. The pharmaceutical composition as described in Example 22, wherein: a. The internal component of the particle contains amorphous obesetropine, and the external component of the particle contains ezetimibe; or b. The external component of the particle contains both ezetimibe and amorphous obesetropeptide, and the internal component of the particle contains only excipients.

[0378] 78. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition further comprises one or more binders, wherein preferably the binder:surfactant ratio in the intraparticle component is in the range of about 0.05:5.0 to about 5.0:0.05, preferably about 0.5:4.5 to about 4.5:0.5, more preferably about 1:4 to about 4:1, even more preferably about 1:2 to about 2:1, and most preferably about 1:1.

[0379] 79. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition further comprises one or more binders selected from: cellulose derivatives, preferably selected from methylcellulose and carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and hydroxyethylcellulose; gelatin, glucose, dextran, xylitol, polymethacrylate, polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone, starch paste, sucrose, sorbitol, pregelatinized starch, tragacanth gum, alginate and salts of alginate such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonite, preferably the binder is polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone, more preferably the binder is copovidone, and even more preferably the binder is Colidon 30.

[0380] 80. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the surfactant has an HLB value of at least 15, at least 20, at least 30, or at least 40; preferably, the surfactant is selected from lauric acid or a salt of lauric acid, palmitic acid or a salt of palmitic acid, stearic acid or a salt of stearic acid and oleic acid or a salt of oleic acid, polyethylene glycol glyceride, polyoxyethylene monoester, polyoxyethylene ethyl ethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oil, polyethylene glycol having a molecular weight in the range of about 2,000 to 10,000, propylene glycol octanoate, glyceryl oleate and octanoate, esters of glycerol and fatty acids; more preferably, the surfactant is selected from sodium dioctyl sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, polysorbate 40, or polysorbate 80 or sodium lauryl sulfate; and even more preferably, the surfactant is sodium lauryl sulfate.

[0381] 81. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition further comprises one or more disintegrants selected from crospovidone, crospovidone sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, alginate, sodium alginate, microcrystalline cellulose, sodium carboxyacetic acid starch, and pregelatinized starch, preferably crospovidone sodium carboxymethyl cellulose or sodium carboxyacetic acid starch, and more preferably sodium carboxyacetic acid starch.

[0382] 82. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition remains stable at 40°C / 75% relative humidity for at least 1 month, preferably at least 3 months and more preferably at least 6 months, or remains stable at 25°C / 60% relative humidity for at least 3 months, preferably at least 6 months and more preferably at least 12 months.

[0383] 83. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition is a tablet formulation comprising or consisting of the following: b. Intraparticle components, including: v. Amorphous ocbisetrop calcium equivalent to 10 mg of ocbisetrop free acid; vi. Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe; vii. A binder and surfactant in a 1:1 ratio, preferably the binder and the surfactant each accounting for about 1 ± 0.5% w / w of the particle components; more preferably, the binder is 1 ± 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 ± 0.5% w / w of sodium lauryl sulfate. viii. A disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; ix. 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; d. Extraparticle components, including: i. A disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; ii. Optionally, a lubricant, preferably magnesium stearate, iii. Optionally, a flow aid, preferably colloidal silica or talc or both colloidal silica and talc; iv. Optionally one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose; e. Optionally, the pharmaceutical composition includes a film coating, preferably the film coating is free of primary alcohols, and more preferably the film coating is free of polyethylene glycol.

[0384] 84. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises a tablet formulation comprising or consisting of the following: d. Intraparticle components, including: i. Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe; ii. A binder and surfactant in a 1:1 ratio, preferably the binder and the surfactant each comprising about 1 ± 0.5% w / w of the particle components; more preferably, the binder is 1 ± 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 ± 0.5% w / w of sodium lauryl sulfate. iii. A disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; e. Extraparticle components, including: vi. Amorphous ocbisetrop calcium equivalent to 10 mg of ocbisetrop free acid; vii. A disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; viii. Optionally, a lubricant, preferably magnesium stearate. ix. Optionally, a flow aid, preferably colloidal silica or talc or both colloidal silica and talc; x. 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; f. Optionally, the pharmaceutical composition includes a film coating, preferably the film coating is free of primary alcohols, and more preferably the film coating is free of polyethylene glycol.

[0385] 85. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the composition comprises a tablet formulation comprising or consisting of the following: d. Intraparticle components, including: v. Amorphous ocbisetrapti calcium equivalent to 10 mg of ocbisetrapti free acid vi. A binder and surfactant in a 1:1 ratio, preferably the binder and the surfactant each accounting for about 1 ± 0.5% w / w of the particle components; more preferably, the binder is 1 ± 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 ± 0.5% w / w of sodium lauryl sulfate. vii. A disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 6% w / w, more preferably about 4.5 ± 0.5% w / w; viii. 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; e. Extraparticle components, including: vi. Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe. vii. A disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; viii. Optionally, a lubricant, preferably magnesium stearate. ix. Optionally, a flow aid, preferably colloidal silica or talc or both colloidal silica and talc; x. 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; f. Optionally, the pharmaceutical composition includes a film coating, preferably the film coating is free of primary alcohols, and more preferably the film coating is free of polyethylene glycol.

[0386] 86. The pharmaceutical composition as described in any of the foregoing embodiments, wherein the pharmaceutical composition is used in the treatment of subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, preferably those subjects who have hyperlipidemia or mixed dyslipidemia.

[0387] 87. The pharmaceutical composition as described in any of the foregoing embodiments, for use in patients who require lowering LDL cholesterol and / or raising HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH), and / or patients diagnosed with atherosclerotic cardiovascular disease (ASCVD) with LDL cholesterol.

[0388] 88. The use of the pharmaceutical composition as described in any of the foregoing embodiments for the preparation of a medicament for treating a subject suffering from hyperlipidemia or mixed dyslipidemia.

[0389] 89. The pharmaceutical composition as described in any of the foregoing embodiments is used to prepare a medicament for reducing LDL cholesterol in subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH), and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD).

[0390] 90. Use of the pharmaceutical composition as described in any of the foregoing embodiments for the preparation of a medicament for reducing the risk of cardiovascular events.

[0391] 91. The use as described in any of the foregoing embodiments, wherein the subject suffers from mild dyslipidemia.

[0392] Disclaimer In many embodiments of the present invention, various pharmaceutical compositions are excluded as described below.

[0393] In some embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of the following: Intraparticle components, including: Calcium obisetropeptide is equivalent to 10 mg of obisetropeptide free acid; Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe monohydrate equivalent to 10 mg of ezetimibe; The binder and surfactant are in a 1:1 ratio, preferably the binder and the surfactant each account for about 1 + 0.5% w / w of the particle components; more preferably, the binder is 1 + 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 + 0.5% w / w of sodium lauryl sulfate. The disintegrant is selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 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; Extra-particulate components, including: The disintegrant is selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch, and even more preferably about 4% w / w to 6% w / w sodium carboxyacetate starch; The lubricant is optionally magnesium stearate, more preferably about 1% w / w to 2% w / w magnesium stearate; Optionally, the flow aid is preferably colloidal silica or talc or both colloidal silica and talc, more preferably about 1% w / w to 2% w / w of colloidal silica or talc or both colloidal silica and talc. Optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohol, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose, even more preferably about 20% w / w to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol; Optionally, the composition comprises a film coating, preferably free of primary alcohols, and more preferably free of polyethylene glycols.

[0394] In some embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of the following: Intraparticle components, including: Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe; The binder and surfactant are in a 1:1 ratio, preferably the binder and the surfactant each account for about 1 + 0.5% w / w of the particle components; more preferably, the binder is 1 + 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 + 0.5% w / w of sodium lauryl sulfate. The disintegrant is selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 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; Extra-particulate components include: Calcium obisetropeptide is equivalent to 10 mg of obisetropeptide free acid; The disintegrant is selected from microcrystalline cellulose, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch, and even more preferably about 4% w / w to 6% w / w sodium carboxyacetate starch; The lubricant is optionally magnesium stearate, more preferably about 1% w / w magnesium stearate; Optionally, the flow aid is preferably colloidal silica or talc or both colloidal silica and talc, more preferably about 1% w / w to 2% w / w of colloidal silica or talc or both colloidal silica and talc. Optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohol, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose, even more preferably about 20% w / w to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol; Optionally, the composition comprises a film coating, preferably free of primary alcohols, and more preferably free of polyethylene glycols.

[0395] In some embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of the following: Intraparticle components, including: Calcium obisetropeptide is equivalent to 10 mg of obisetropeptide free acid; The binder and surfactant are in a 1:1 ratio, preferably the binder and the surfactant each account for about 1 + 0.5% w / w of the particle components; more preferably, the binder is 1 + 0.5% w / w of povidone or polyvinylpyrrolidone, and the surfactant is 1 + 0.5% w / w of sodium lauryl sulfate. The disintegrant is selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; preferably the disintegrant accounts for about 2% w / w to 8% w / w of the component in the particle, more preferably 3% w / w to 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; Extra-particulate components include: Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe. The disintegrant is selected from croscarmellose sodium, pregelatinized starch, or sodium carboxyacetate starch, more preferably sodium carboxyacetate starch; even more preferably about 4% w / w to 6% w / w sodium carboxyacetate starch. The lubricant is optionally magnesium stearate, more preferably magnesium stearate of about 1% w / w to 2% w / w. Optionally, the flow aid is preferably colloidal silica or talc or both colloidal silica and talc, more preferably about 1% to 2% colloidal silica or talc or both colloidal silica and talc. Optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohol, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose, even more preferably about 20% w / w to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol.

[0396] Optionally, the composition comprises a film coating, preferably free of primary alcohols, and more preferably free of polyethylene glycols.

[0397] In some embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of the following: Intraparticle components, including: Calcium obisetropeptide is equivalent to 10 mg of obisetropeptide free acid; Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe monohydrate equivalent to 10 mg of ezetimibe; The ratio of adhesive to surfactant is 1:1; The disintegrant is selected from croscarmellose sodium cellulose, pregelatinized starch and sodium carboxyacetate starch; One or more diluents selected from disaccharides, polysaccharides, and sugar alcohols; and Extra-particulate components, including: The disintegrant is selected from croscarmellose sodium, pregelatinized starch or sodium carboxyacetic acid starch.

[0398] In some embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of the following: Intraparticle components, including: Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe; The ratio of adhesive to surfactant is 1:1; The disintegrant is selected from croscarmellose sodium cellulose, pregelatinized starch and sodium carboxyacetate starch; One or more diluents selected from disaccharides, polysaccharides, and sugar alcohols; and Extra-particulate components include: Calcium obisetropeptide, equivalent to 10 mg of obisetropeptide free acid; and The disintegrant is selected from microcrystalline cellulose, pregelatinized starch and sodium carboxyacetic acid starch.

[0399] In some embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of the following: Intraparticle components, including: Calcium obisetropeptide is equivalent to 10 mg of obisetropeptide free acid; The ratio of adhesive to surfactant is 1:1; The disintegrant is selected from croscarmellose sodium, pregelatinized starch, or sodium carboxyacetate starch; and One or more diluents selected from disaccharides, polysaccharides, and sugar alcohols; and Extra-particulate components include: Anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate, equivalent to 10 mg of ezetimibe; and The disintegrant is selected from croscarmellose sodium, pregelatinized starch and sodium carboxyacetic acid starch.

[0400] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 7.168% w / w ezetimibe; 3.678% w / w obisetropeptide or a salt thereof; 26.826% w / w microcrystalline cellulose, particularly Avicel PH101; 53.651% w / w lactose monohydrate, particularly Pharmatose 200M; 5.018% w / w polyvinylpyrrolidone, particularly Colicon 30; 3.301% w / w sodium carboxyacetate starch, particularly Glycolys; and 0.358% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0401] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 6.666% w / w ezetimibe; 3.421% w / w obisetropeptide or a salt thereof; 27.948% w / w microcrystalline cellulose, particularly Avicel PH101; 49.895% w / w lactose monohydrate, particularly Pharmatose 200M; 4.667% w / w polyvinylpyrrolidone, particularly Colicon 30; 5.570% w / w sodium carboxyacetate starch, particularly Glycolys; 0.333% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; 0.750% w / w fumed silica, particularly Aerosil 200; and 0.750% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 5 mg.

[0402] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 7.168% w / w ezetimibe; 3.678% w / w obisetropeptide or a salt thereof; 53.651% w / w microcrystalline cellulose, particularly Avicel PH101; 28.826% w / w lactose monohydrate, particularly Pharmatose 200M; 5.018% w / w polyvinylpyrrolidone, particularly Colicon 30; 3.301% w / w sodium carboxyacetate starch, particularly Glycolys; and 0.358% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0403] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 6.666% w / w ezetimibe; 3.421% w / w obisetropeptide or a salt thereof; 52.895% w / w microcrystalline cellulose, particularly Avicel PH101; 24.948% w / w lactose monohydrate, particularly Pharmatose 200M; 4.667% w / w polyvinylpyrrolidone, particularly Colicon 30; 5.570% w / w sodium carboxyacetate starch, particularly Glycolys; 0.333% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; 0.750% w / w fumed silica, particularly Aerosil 200; and 0.750% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 5 mg.

[0404] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 7.017% w / w ezetimibe; 3.601% w / w obisetropeptide or a salt thereof; 20.968% w / w microcrystalline cellulose, particularly Avicel PH101; 57.887% w / w lactose monohydrate, particularly Pharmatose 200M; 4.211% w / w polyvinylpyrrolidone, particularly Colicon 30; 4.211% w / w sodium carboxyacetate starch, particularly Glycolys; and 2.105% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0405] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 6.666% w / w ezetimibe; 3.421% w / w obisetropeptide or a salt thereof; 19.920% w / w microcrystalline cellulose, particularly Avicel PH101; 54.993% w / w lactose monohydrate, particularly Pharmatose 200M; 4.000% w / w polyvinylpyrrolidone, particularly Colicon 30; 8.000% w / w sodium carboxyacetate starch, particularly Glycolys; 2.000% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 1.000% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 5 mg.

[0406] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 7.073% w / w ezetimibe; 3.630% w / w obisetropeptide or a salt thereof; 21.775% w / w microcrystalline cellulose, particularly Avicel PH101; 60.095% w / w lactose monohydrate, particularly Pharmatose 200M; 1.061% w / w polyvinylpyrrolidone, particularly clodin 30; 4.244% w / w sodium carboxyacetate starch, particularly Glycolys; and 2.122% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0407] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 6.666% w / w ezetimibe; 3.421% w / w obisetropeptide or a salt thereof; 20.717% w / w microcrystalline cellulose, particularly Avicel PH101; 57.196% w / w lactose monohydrate, particularly Pharmatose 200M; 1.000% w / w polyvinylpyrrolidone, particularly Colicon 30; 8.000% w / w sodium carboxyacetate starch, particularly Glycolys; 2.000% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 1.000% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 5 mg.

[0408] In some embodiments, the pharmaceutical composition is not a granule, but rather, based on the total dry weight of the granule, the granule comprises the following: 6.981% w / w ezetimibe; 7.162% w / w obisetrop; 20.935% w / w microcrystalline cellulose, particularly Avicel PH101; 57.592% w / w lactose monohydrate, particularly Pharmatose 200M; 1.047% w / w polyvinylpyrrolidone, particularly clodin 30; 4.189% w / w sodium carboxyacetate starch, particularly Glycolys; and 2.094% w / w sodium lauryl sulfate.

[0409] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 6.667% w / w ezetimibe; 6.840% w / w obisetrop; 19.993% w / w microcrystalline cellulose, particularly Avicel PH101; 55.000% w / w lactose monohydrate, particularly Pharmatose 200M; 1.000% w / w polyvinylpyrrolidone, particularly Colicon 30; 8.000% w / w sodium carboxyacetate starch, particularly Glycolys; 2.000% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 0.500% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg, and obisetrop is present in an amount of about 10 mg.

[0410] In some embodiments, the pharmaceutical composition is not a granule, but rather, based on the total dry weight of the granule, the granule comprises the following: 6.981% w / w ezetimibe; 7.162% w / w obisetropeptide; 21.982% w / w microcrystalline cellulose, particularly Avicel PH101; 57.592% w / w lactose monohydrate, particularly Pharmatose 200M; 1.047% w / w polyvinylpyrrolidone, particularly clodin 30; 4.189% w / w sodium carboxyacetate starch, particularly Glycolys; and 1.047% w / w sodium lauryl sulfate.

[0411] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 6.667% w / w ezetimibe; 6.840% w / w obisetropeptide; 20.993% w / w microcrystalline cellulose, particularly Avicel PH101; 55.000% w / w lactose monohydrate, particularly Pharmatose 200M; 1.000% w / w polyvinylpyrrolidone, particularly Colicon 30; 8.000% w / w sodium carboxyacetate starch, particularly Glycolys; 1.000% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 0.500% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0412] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 6.981% w / w ezetimibe; 7.162% w / w obisetrop; 21.982% w / w microcrystalline cellulose, particularly Avicel PH101; 57.592% w / w lactose monohydrate, particularly Pharmatose 200M; 1.047% w / w polyvinylpyrrolidone, particularly clodin 30; 4.189% w / w sodium carboxyacetate starch, particularly Glycolys; and 1.047% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0413] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 6.981% w / w ezetimibe; 7.162% w / w obisetrop; 21.982% w / w microcrystalline cellulose, particularly Avicel PH101; 57.592% w / w lactose monohydrate, particularly Pharmatose 200M; 1.047% w / w polyvinylpyrrolidone, particularly clodin 30; 4.189% w / w sodium carboxyacetate starch, particularly Glycolys; and 1.047% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0414] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 5,000% w / w ezetimibe; 5,130% w / w obisetrop; 25,432% w / w microcrystalline cellulose, particularly Avicel PH101; 51,688% w / w lactose monohydrate, particularly Pharmatose 200M; 3,750% w / w polyvinylpyrrolidone, particularly Colicon 30; 7,000% w / w sodium carboxyacetate starch, particularly Glycolys; 1,500% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 0,500% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg, and obisetrop is present in an amount of about 10 mg.

[0415] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 6.981% w / w ezetimibe; 7.162% w / w obisetrop; 21.982% w / w microcrystalline cellulose, particularly Avicel PH101; 57.592% w / w lactose monohydrate, particularly Pharmatose 200M; 1.047% w / w polyvinylpyrrolidone, particularly clodin 30; 4.189% w / w sodium carboxyacetate starch, particularly Glycolys; and 1.047% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0416] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 6.632% w / w ezetimibe; 6.804% w / w obisetropeptide; 20.883% w / w microcrystalline cellulose, particularly Avicel PH101; 54.712% w / w lactose monohydrate, particularly Pharmatose 200M; 0.995% w / w polyvinylpyrrolidone, particularly Colicon 30; 7.980% w / w sodium carboxyacetate starch, particularly Glycolys; 0.995% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 1.000% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a (coated) tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0417] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 6.981% w / w ezetimibe; 7.162% w / w obisetropeptide; 20.935% w / w microcrystalline cellulose, particularly Avicel PH101; 57.592% w / w lactose monohydrate, particularly Pharmatose 200M; 1.047% w / w polyvinylpyrrolidone, particularly clodin 30; 4.189% w / w sodium carboxyacetate starch, particularly Glycolys; and 2.094% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0418] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 6.667% w / w ezetimibe; 6.840% w / w obisetrop; 19.993% w / w microcrystalline cellulose, particularly Avicel PH101; 55.000% w / w lactose monohydrate, particularly Pharmatose 200M; 1.000% w / w polyvinylpyrrolidone, particularly Colicon 30; 8.000% w / w sodium carboxyacetate starch, particularly Glycolys; 2.000% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 0.500% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg, and obisetrop is present in an amount of about 10 mg.

[0419] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 6.667% w / w ezetimibe; 6.840% w / w obisetrop; 20.993% w / w microcrystalline cellulose, particularly Avicel PH101; 55.000% w / w lactose monohydrate, particularly Pharmatose 200M; 1.000% w / w polyvinylpyrrolidone, particularly Colicon 30; 8.000% w / w sodium carboxyacetate starch, particularly Glycolys; 1.000% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 0.500% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg, and obisetrop is present in an amount of about 10 mg.

[0420] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 5,000% w / w ezetimibe; 7,162% w / w obisetropeptide; 26,182% w / w microcrystalline cellulose, particularly Avicel PH101; 51,688% w / w lactose monohydrate, particularly Pharmatose 200M; 3,750% w / w polyvinylpyrrolidone, particularly Colicon 30; 7,000% w / w sodium carboxyacetate starch, particularly Glycolys; 0,750% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 0,500% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a (coated) tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0421] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 6.981% w / w ezetimibe; 7.162% w / w obisetrop; 21.982% w / w microcrystalline cellulose, particularly Avicel PH101; 57.592% w / w lactose monohydrate, particularly Pharmatose 200M; 1.047% w / w polyvinylpyrrolidone, particularly clodin 30; 4.189% w / w sodium carboxyacetate starch, particularly Glycolys; and 1.047% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0422] In some embodiments, the pharmaceutical composition does not comprise tablets containing: 6.667% w / w ezetimibe; 6.840% w / w obisetrop; 20.993% w / w microcrystalline cellulose, particularly Avicel PH101; 55.000% w / w lactose monohydrate, particularly Pharmatose 200M; 1.000% w / w polyvinylpyrrolidone, particularly Colicon 30; 8.000% w / w sodium carboxyacetate starch, particularly Glycolys; 1.000% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 0.500% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg, and obisetrop is present in an amount of about 10 mg.

[0423] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 4.348% w / w ezetimibe; 4.461% w / w obisetropeptide; 39.321% w / w microcrystalline cellulose, particularly Avicel PH101; 34.914% w / w lactose monohydrate, particularly Pharmatose 200M; 0.652% w / w polyvinylpyrrolidone, particularly clodinafop-methyl 30; 4.782% w / w sodium carboxyacetate starch, particularly Glycolys; 0.652% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; 10.000% (w / w) mannitol, particularly Pearlitol 200 SD; and 0.435% (w / w) fumed silica, particularly Aerosil. 200; and 0.435% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a (coated) tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0424] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 4.348% w / w ezetimibe; 4.461% w / w obisetropeptide; 36.465% w / w microcrystalline cellulose, particularly Avicel PH101; 34.914% w / w lactose monohydrate, particularly Pharmatose 200M; 0.652% w / w polyvinylpyrrolidone, particularly clodinafop-methyl 30; 7.608% w / w sodium carboxyacetate starch, particularly Glycolys; 0.652% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; 8.900% (w / w) mannitol, particularly Pearlitol 200 SD; and 1.000% (w / w) fumed silica, particularly Aerosil. 200; and 1,000% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a (coated) tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0425] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 4.348% w / w ezetimibe; 4.461% w / w obisetropeptide; 36.104% w / w microcrystalline cellulose, particularly Avicel PH101; 34.914% w / w lactose monohydrate, particularly Pharmatose 200M; 0.652% w / w polyvinylpyrrolidone, particularly clodin 30; 7.608% w / w sodium carboxyacetate starch, particularly Glycolys; 0.652% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; 8.761% (w / w) mannitol, particularly Pearlitol 200 SD; and 1.000% (w / w) fumed silica, particularly Aerosil. 200; and 1,500% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a (coated) tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0426] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 7.89% w / w obisetropeptide; 23.614% w / w microcrystalline cellulose, particularly Avicel PH101; 61.573% w / w lactose monohydrate, particularly Pharmatose 200M; 1.154% w / w polyvinylpyrrolidone, particularly Colicon 30; 4.615% w / w sodium carboxyacetate starch, particularly Glycolys; and 1.154% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0427] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 4.438% w / w ezetimibe; 4.46% w / w obisetropeptide; 36.577% w / w microcrystalline cellulose, particularly Avicel PH101; 34.802% w / w lactose (monohydrate), particularly Pharmatose 200M; 0.652% w / w polyvinylpyrrolidone, particularly Colitone 30; 7.608% w / w sodium carboxyacetate starch, particularly Glycolys; 0.652% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; 8.9% (w / w) mannitol, particularly Pearlitol 200 SD; 1% (w / w) fumed silica, particularly Aerosil 200; and 1% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a (coated) tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0428] In some embodiments, the pharmaceutical composition is not a bilayer tablet or a coated bilayer tablet, but rather, based on the total weight of the tablet (excluding any coating), the bilayer tablet or the coated bilayer tablet comprises the following: 10 mg of ezetimibe; 10.26 mg of obisetropeptide; 61.4 mg of microcrystalline cellulose, particularly Avicel PH101; 160.34 mg of lactose (monohydrate), particularly Pharmatose 200M; 3 mg of polyvinylpyrrolidone, particularly Colicon 30; 23 mg of sodium carboxyacetate starch, particularly Glycolys; 3 mg of sodium lauryl sulfate, particularly Kolliphor SLS granules; and 1.4 mg of magnesium stearate, particularly Ligamed MF-2-V.

[0429] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 4.438% w / w ezetimibe; 4.461% w / w obisetropeptide; 36.465% w / w microcrystalline cellulose, particularly Avicel PH101; 34.914% w / w lactose (monohydrate), particularly Pharmatose 200M; 0.652% w / w polyvinylpyrrolidone, particularly clodinafop-methyl 30; 7.608% w / w sodium carboxyacetate starch, particularly Glycolys; 0.652% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; 8.900% (w / w) mannitol, particularly Pearlitol 200 SD; and 1.000% (w / w) fumed silica, particularly Aerosil. 200; and 1% w / w magnesium stearate, particularly Ligamed MF-2-V. More particularly, preferably, the pharmaceutical composition is not a (coated) tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0430] In some embodiments, the pharmaceutical composition is not a particle, but rather, based on the total dry weight of the particle, the particle comprises the following: 7.018% w / w ezetimibe; 7.200% w / w obisetrop; 21.950% w / w microcrystalline cellulose, particularly Avicel PH101; 57.516% w / w lactose monohydrate, particularly Pharmatose 200M; 1.053% w / w polyvinylpyrrolidone, particularly clodin 30; 4.210% w / w sodium carboxyacetate starch, particularly Glycolys; and 1.053% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules.

[0431] In some embodiments, the pharmaceutical composition is not a tablet or a coated tablet, but rather, based on the total weight of the tablet (excluding any coating), the tablet or the coated tablet comprises the following: 6.667% w / w ezetimibe; 6.840% w / w obisetropeptide; 20.853% w / w microcrystalline cellulose, particularly Avicel PH101; 54.640% w / w lactose (monohydrate), particularly Pharmatose 200M; 1.000% w / w polyvinylpyrrolidone, particularly clodin 30; 8.000% w / w sodium carboxyacetate starch, particularly Glycolys; 1.000% w / w sodium lauryl sulfate, particularly Kolliphor SLS granules; and 1.000% w / w magnesium stearate, particularly Ligamed MF-2-V. More specifically, preferably, the pharmaceutical composition is not a (coated) tablet of the composition, wherein ezetimibe is present in an amount of about 10 mg and obisetropeptide is present in an amount of about 10 mg.

[0432] Terms and Definitions Also known as "TA-8995", obisetropeptide has the following chemical name and chemical structure:

[0433] {4-[(2-{[3,5-bis(trifluoromethyl)benzyl] [(2R,4S)-1-(ethoxycarbonyl)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-yl]amino}pyrimidin-5-yl)oxy]butyric acid}.

[0434] Also known as "Sch-58235", ezetimibe has the following chemical name and chemical structure:

[0435] (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)114 ezetimibe-2-one.

[0436] Obistrapillin and ezetimibe can also be used as different salt forms, solvates, or cocrystals. Obistrapillin and ezetimibe can also be formulated as prodrugs.

[0437] The term "as used in this article" apolipoprotein ( apolipoprotein The word "lipoprotein" has its traditional meaning and refers to proteins that bind to lipids to form lipoproteins.

[0438] The term "as used in this article" Apolipoprotein B"(ApoB)" has its traditional meaning and refers to the protein encoded by the ApoB gene.

[0439] The term "as used in this article" Pharmaceutical Composition "It has its traditional meaning and refers to a pharmaceutically acceptable composition."

[0440] The term "as used in this article" Pharmaceutically acceptable "With its traditional meaning, it refers to compounds, materials, compositions and / or dosage forms that are suitable for contact with the tissues of mammals (especially humans) within a reasonable medical judgment, without excessive toxicity, irritation, allergic reactions and other problematic complications, and with a commensurate and reasonable benefit / risk ratio."

[0441] The term "as used in this article" Carrier The term "carrier" has its traditional meaning and refers to a pharmaceutically acceptable diluent, adjuvant, excipient, or vehicle that is administered together with the active ingredient of a drug.

[0442] The term "as used in this article" excipient "(excipient)" has its traditional meaning and refers to a pharmaceutically acceptable ingredient commonly used in pharmaceutical technologies for preparing granular, solid, or liquid oral dosage forms.

[0443] The term "as used in this article" Salt "(salt)" has its traditional meaning and includes acid addition salts and base salts of pharmaceutically active compounds.

[0444] The term "as used in this article" solvates The word "solvate" has its traditional meaning and refers to a compound formed through solvation, such as a combination of solvent molecules and solute molecules or ions. Well-known solvent molecules include water, alcohols, nitriles, and polar organic solvents.

[0445] The term "as used in this article" Subjects "(subject)" refers to a person who has a certain disease or condition or is at risk of developing a certain disease or condition. The term "(subject)" Subjects "and" patient "(patient)" can be used interchangeably in this article.

[0446] the term" Increased risk"(increased risk)" has its traditional meaning and refers to a situation in which a subject, in some embodiments a human subject (male or female), has an increased risk of cardiovascular events based on their risk profile (including LDL-cholesterol levels above 70 mg / Dl, such as above 2.6 mmol / L [100, 54 mg / Dl]) compared to a subject with lower levels.

[0447] The term "as used in this article" treat The word "treatment" has its traditional meaning and refers to curative, palliative, and prophylactic treatment.

[0448] The term "as used in this article" Cardiovascular disease "(cardiovascular disease)" has its traditional meaning and includes the clinical manifestations of arteriosclerosis, peripheral vascular disease, angina pectoris, ischemia, myocardial ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, and stroke.

[0449] The term "as used in this article" Cardiovascular events "(cardiovascular event)" has its traditional meaning and refers to the occurrence of myocardial infarction, stroke, coronary death, or the necessity of coronary revascularization (Ference et al., European Heart J. 38(32):2459-2472, 2017).

[0450] The term "as used in this article" hypercholesterolemia "Hypercholesterolemia" has its traditional meaning and refers to a disease characterized by high levels of cholesterol in the blood.

[0451] The term "as used in this article" hyperlipidemia "Hyperlipidaemia" has its traditional meaning and refers to a disease in which high levels of lipids are found in the blood.

[0452] The term "as used in this article" Mixed dyslipidemia ( mixed "Dyslipidaemia" has its traditional meaning and refers to a disease characterized by elevated levels of LDL cholesterol and triglycerides in the blood, accompanied by low levels of HDL cholesterol.

[0453] The term "as used in this article" Intolerance to statins "Statin intolerant" has its traditional meaning and refers to a subject's inability to tolerate two or more statin drugs, one of which is at a low dose, due to adverse safety effects that are initiated or increased during statin therapy and eliminated or improved upon discontinuation of statin therapy. In this regard, a similar definition approved by the FDA in the Phase III trial of bepidelic acid (Esperion) is also referenced.

[0454] The term "as used in this article" Cholesterol absorption inhibitors "(cholesterol absorption inhibitor, CAI)" has its traditional meaning and refers to compounds that lower LDL-C by blocking the absorption of cholesterol in the intestines and bile ducts. One known cholesterol absorption inhibitor is ezetimibe.

[0455] The term "cholesterol ester transfer protein inhibitor" as used in this article cholesteryl ester transfer protein inhibitor "(CETP inhibitor)" has its traditional meaning and refers to a class of compounds that inhibit CETP receptors in mammals. One known CETP inhibitor is obisetropeptide.

[0456] the term" Unit dosage form "(unit dosage form)" has its traditional meaning and refers to a dosage form that can be effectively administered to a subject (in some embodiments, a human) and is readily disposeable and packaged to remain a physically and chemically stable unit dose containing a therapeutic pharmaceutical preparation (i.e., obisetropip or a combination of therapeutic pharmaceutical preparations (e.g., obisetropip and ezetimibe)).

[0457] As used herein, the term “fixed dose combination” has its conventional meaning and refers to a combination of two or more drugs or active ingredients present in a single dose unit (e.g., a tablet or capsule) and administered in such a defined dose.

[0458] The term “free dose combination” as used in this article has its traditional meaning and refers to a combination of two drugs or active ingredients administered simultaneously as two different dose units.

[0459] The fixed-dose combination pharmaceutical compositions of the present invention containing obisetropeptide (including those containing obisetropeptide calcium) and ezetimibe, and the treatment methods of the present invention using obisetropeptide (including those containing obisetropeptide calcium) and ezetimibe, will be further illustrated by the following non-limiting examples.

[0460] 1. Example Although the invention has been specifically shown and described with reference to exemplary embodiments and various alternative embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the spirit and scope of the invention.

[0461] Table 3 summarizes the methods used throughout the study. The specific parameters and conditions for the analysis and physical evaluation used for each non-restricted instance are described in the relevant sections of this instance.

[0462] Table 3

[0463] XRPD XRPD analysis was performed in transmission mode on an X'pertPro / Empyrean X-ray diffractometer (PANalytical) equipped with an X'Celerator detector using the standard Aptuit method. The data were evaluated using Highscore Plus software. The instrument parameters used are listed in Table 4 below.

[0464] Table 4

[0465] Particle size distribution (PSD) PSD analysis was performed on a new Sympatec Helos laser diffractometer equipped with RODOS / M for dispersion and ASPIROS or VIBRI for sample delivery. Powder dispersion was achieved using compressed air and a spray gun utilizing the Venturi effect. Details of the PSD method are listed in Table 5.

[0466] Table 5

[0467] Differential dissolution method at pH 6.8 (Orbesetide) Table 6

[0468] Differential dissolution method at pH 4.5 (ezetimibe) Table 7

[0469] QC dissolution method at pH 6.8 (Orbesetide) Table 8

[0470] QC dissolution method at pH 4.5 (Ezetimibe) Table 9

[0471] Determination of impurities / related substances (Orbisetrop) Table 10

[0472] Example 1: A fixed-dose combination of 10 mg ezetimibe and 10 mg obisetrapip obtained by co-granulation of the drug substance / active ingredient (FDC1) High-shear granulation, drying, preparation of final blends and tableting Three compositions were prepared as summarized in Table 11 (Composition 1, batch A4459 / 20 / 02; Composition 2, batch A4459 / 20 / 03; and Composition 3, batch A4459 / 20 / 04). The prototype formulation composition selected for these compositions was the prototype formulation composition of "Prototype C" (e.g., particle batch A4459 / 13 / 03). Particle preparation and characterization (LOD and XRPD) were described in the previous section (Small-Scale Manufacturing). Particle content uniformity, LOD, sieve analysis, TBD, and XRPD were tested. As described in the previous example, the manufacture of blends for tableting and compression profiling, as well as small-batch tablets with a weight of 150 mg, was performed. Tablet content uniformity, XRPD, solubility, and water content were tested by KF testing. All intermediates and final pharmaceutical products produced were stored as described in the previous section.

[0473]

[0474] Water will not be present in the final product. All excipients used for granulation are added in dry powder form. result High-shear granulation was successfully performed. The drying step proceeded without any issues, and after 15 minutes of drying, the LOD of the granules was lower than the initial LOD. Generally, despite the increase in impeller speed (composition 1)... Figure 14Regardless of the wet aggregation time (composition 2) or the amount of granulating agent (composition 3), the particles still exhibit a relatively large number of fine particles. These tablet batches were found to have similar tablet brittleness, disintegration time, thickness, and hardness.

[0475] Particle chemical characterization Homogeneity tests were performed on the particles, and it was found that oxetine and ezetimibe were homogeneously dispersed.

[0476] Physical property characterization Table 12 summarizes the XRPD data for the blend / particle prototypes using the FDC1 method. Ezetimibe hydrate was found only in the wet particle samples. All three prototypes exhibited similar flowability.

[0477] Tablet chemical characterization The results of the chemical characterization of the FDC1 tablets are reported in Table 13. The results of the analytical characterization do not show any significant differences between the three compositions.

[0478] Physical property characterization Table 14 summarizes the XRPD data for tablets from the FDC1 composition. Ezetimibe hydrate was absent in all samples.

[0479]

[0480]

[0481]

[0482] Example 2: A fixed-dose combination of 10 mg ezetimibe and 10 mg obisetraprine (FDC2) obtained by granulating ezetimibe and adding obisetraprine to the granules. High-shear granulation and drying Three compositions were prepared as summarized in Table 15. The excipients contained in the granules were the same as those used in the granule manufacturing of the FDC1 method. The formulation composition of these granules reflects that of the FDC1 granule "prototype C". The methods for high-shear granulation, granule drying, and grinding have been described in previous chapters. Granulation uniformity (Izzybaby only), sieve analysis, TBD, and XRPD were tested.

[0483] Preparation of the final blend, tableting and coating The components of the in-vitro granule formulation are listed below: -Obiscop - Plastic filler (Avicel PH 200) - Brittle filler (Pearlitol 200 SD) - Disintegrants (Glycolys) -Glydant (Aerosil 200) - Lubricant (Ligamed MF-2-V) The final blend was prepared by accurately weighing and screening the extra-particle components (excipients and APIs). The excipients and particles were loaded into hoppers of appropriate volume and blended using a Pharmatech mixer. Then, a lubricant (MgSt) was added to the hopper and mixed.

[0484] To generate compression profiles and manufacture small batches of tablets, a single-punch press (EK0) equipped with a 9.0 mm round punch (R = 11) was used. The target tablet weight was 230 mg, and throughout the process, tablet brittleness, disintegration time, hardness, appearance and thickness, as well as individual tablet weight and the weight of ten tablets were monitored.

[0485] The tablet content uniformity (stratified samples: beginning, middle and end of production), XRPD, solubility, and water content were tested using KF testing.

[0486] Tablets were coated using a 20% w / w Opadry AMB II white aqueous suspension to achieve the desired target weight gain (target weight gain 3% w / w, limit 2% w / w to 4% w / w). The coating suspension and coating method were described in previous sections. Coating parameters and tablet weight gain were monitored throughout processing. The XRPD, solubility, appearance, and content uniformity of the coated tablets were tested, and the water content was determined by KF testing.

[0487] All intermediates and final pharmaceutical products produced were stored in double-layered LDPE bags with silica and then transferred to heat-sealed aluminum bags.

[0488]

[0489] Water will not be present in the final product. All excipients used for granulation are added in dry powder form. result High-shear granulation of the FDC2 composition was successfully performed. The drying step proceeded without any issues, and after approximately 16 minutes of drying, the LOD of the granules was lower than the initial LOD. The granules exhibited a relatively large number of fine particles ( Figure 15 The disintegration time and thickness values ​​between FDC2 tablet batches are similar.

[0490] Particle chemical characterization The homogeneity of obisetropine and ezetimibe in the A4459 / 20 / 01 blend was tested and found to be homogeneous dispersion. Results for the other two particle types were not collected.

[0491] Tablet chemical characterization The chemical characterization results of prototype 1 of FDC2 tablets are reported in Tables 16 and 17. The analytical characterization results do not show any significant differences between the three prototypes of FDC2.

[0492] Physical property characterization Table 18 summarizes the XRPD data for blends / particles from the FDC2 compositions. Table 19 summarizes the XRPD data for tablets from the FDC2 method. A small amount of Eze hydrate was present in Prototype 1.

[0493]

[0494]

[0495]

[0496]

[0497] Stress stability The following design was used to conduct stress stability studies on prototype 2 coated tablets.

[0498] key: T = The appearance, measurement, and related substances, as well as the distinguishing solubility, were tested. The water content was tested using KF, and a formal inspection was performed using XRPD. (T) = Optional Test The results are reported in Tables 21-23.

[0499]

[0500]

[0501] ND = Not detected

[0502] Example 3: Scale-up of FDC1 and FDC2 compositions High-shear granulation, drying, final blend, tableting and coating Following the methods detailed in the FDC1 and FDC2 formulation methods above, the API and excipients were accurately dispensed, screened, and added to the granulation bowl. The granulation parameters are the same for both the FDC1 and FDC2 methods. Granulation uniformity (for the FDC1 method only), LOD, sieve analysis, TBD, and XRPD were tested.

[0503] The final blends of the FDC1 and FDC2 compositions were prepared to manufacture tablets with batch numbers and compositions detailed in Table 24. The non-granule components were manually screened and loaded into hoppers of appropriate volume. The granules were mixed with the non-granule materials using a Pharmatech mixer. The content uniformity of the FDC2 blend was then tested.

[0504] The use of a rotary press machine was evaluated to generate compression profiles and conduct tableting drills. During the tableting drills, tablet brittleness, disintegration time, hardness, thickness, and appearance, as well as individual tablet weight and the weight of ten tablets, were monitored. Tablet content uniformity (stratified samples: beginning, middle, and end of production), XRPD, solubility, and water content were tested using a KF test.

[0505] Tablets were coated using a 20% w / w Opadry AMB II white aqueous suspension to achieve the desired target weight gain (target weight gain 3% w / w, limit 2% w / w to 4% w / w). The coating suspension and coating method were described in previous sections. Coating parameters and tablet weight gain were monitored throughout processing. The XRPD, solubility, appearance, determinations, and impurities of the coated tablets were tested, and the water content was determined by KF assay.

[0506] All intermediates and final pharmaceutical products produced were stored in double-layered LDPE bags with silica and then transferred to heat-sealed aluminum bags.

[0507]

[0508] Water will not be present in the final product. Excipients used for granulation are added in dry powder form. result High-shear granulation on a scale-up basis was successfully performed. Sieve analysis revealed that the particles exhibited similar PSD values ​​and contained a large number of fine particles (…). Figure 16These PSD values ​​are comparable to those found in previous trials (e.g., batch A4459 / 16 / 02 as a reference for FDC1 scale-up batch and batch A4459 / 25 / 01 as a reference for FDC2 scale-up batch). Despite this similarity in PSD data, the flowability of the scale-up batches is improved compared to the reference batches, based on the Hauser ratio values. These tablets exhibit disintegration times of less than 5 minutes and brittleness of less than 0.2%. The coating process was performed without any serious problems, and the appearance of the coated tablets from both formulation methods was satisfactory, as the tablet surface was smooth.

[0509] Particle chemical characterization The homogeneity of both obisetropine and ezetimibe in the particles and the final blend was tested, and they were found to be homogeneously dispersed. (See Table 25.) Figure 17 , Figure 18 and Figure 19 The report presents the solubility results of both oxacrylamide and ezetimibe, as well as the impurity profile of ezetimibe.

[0510] Tablet chemical characterization The chemical characterization results of the scaled-up uncoated tablets are reported in Table 26. The dissolution results of the uncoated tablets under different compression forces are reported in Tables 27, 28, 29, and 30. The results for the coated tablets are reported in Table 29.

[0511] Physical property characterization Table 30 summarizes the XRPD data from scaled-up batches of granules / tablets. All tested batches showed the absence of EZE hydrates.

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520] Example 4: Technical batches of FDC1 and FDC2 compositions Table 33 details the batch numbers and composition of granules, tablets, and coated tablets manufactured by the technical manufacturers of FDC1 and FDC2 formulations.

[0521] High-shear granulation and drying The components of FDC1 granules (batch A4459 / 30 / 02) and FDC2 granules (batch A4459 / 30 / 01) were manually screened and added to the granulation bowl. For both FDC1 and FDC2 compositions, the batch size of the granules was 2 kg, and the same granulation processing conditions were used. The physical mixture was blended at 220 rpm for 5 minutes, and a LOD test was performed. Granulator (purified water) was sprayed, and wet agglomeration was performed for 1 minute after spraying. Samples for XRPD and LOD were taken. The granules were then dried using a fluidized bed dryer. The drying step was terminated when the LOD of the granules was equal to or lower than the initial LOD or lower than 3% (w / w). Granulation uniformity (FDC1 only), PSD, LOD, sieve analysis, TBD, and XRPD were tested.

[0522] Final blend and tablet The method for preparing the final blend was described in a previous chapter (scale-up). The content uniformity of the FDC2 blend was tested.

[0523] A rotary press was used to generate compression profiles and perform tableting activities. A 7.0 mm diameter punch was used to manufacture FDC1 tablets (150 mg target tablet weight), while an 8.5 mm diameter punch was used to manufacture FDC2 tablets (230.0 mg tablet weight). During tableting, tablet brittleness, disintegration time, hardness, thickness, and appearance, as well as the weight of a single tablet and the weight of ten tablets, were monitored. Tablet content uniformity (stratified samples: beginning, middle, and end of production), XRPD, solubility, and water content were tested using a KF test.

[0524] Coating A coating suspension with a solids content of 20% (w / w) was prepared by adding the required amount of opadry to water while stirring. The suspension was mixed for at least 45 minutes, and its visual homogeneity was confirmed. The spraying rate of the coating suspension was then measured. The coating suspension was continuously stirred. The weight gain of the tablets was monitored throughout the manufacturing process, and spraying was stopped when the desired target weight gain (3% w / w, 2% w / w to 4% w / w limit) was achieved. The coated tablets were visually inspected, and the XRPD, solubility, appearance, and content uniformity of the coated tablets were tested. The water content was also tested using the KF test.

[0525] All intermediates and final pharmaceutical products produced are stored in stability chambers with the following packaging: • 60 mL high-density polyethylene (HDPE) sensor-sealed and sealed with a child safety cap. The tablet has a fill count of 20. • Use a 2 g desiccant container for a 60 mL high-density polyethylene (HDPE) induction seal and seal with a child safety cap. The tablet fill count is 20.

[0526]

[0527] Results: Technical batches of FDC1 and FDC2 compositions High-shear granulation was successfully performed in the technical batch without any issues during the process. Powder consumption was comparable to that observed in the scale-up batch. The drying process was performed within 45 minutes due to the particle LOD being less than 3%. The particles exhibited similar PSD values, and the amount of fine particles was relatively high (e.g., the amount of particles smaller than 125 µm was approximately 70%–73%). Figure 20 No differences were observed compared to the scaled-up batch.

[0528] Compared to the FDC2 scaled-up batch (batch A4459 / 29 / 06), the FDC2 technology batches offer tablets that are harder despite similar levels of compressive force. For a given tablet hardness value, the disintegration times between these batches are extremely similar.

[0529] Particle chemical characterization The homogeneity of both octosylcholine and ezetimibe in the particles and the final blend was tested, and they were found to be homogeneously dispersed.

[0530] Tablet chemical characterization The chemical characterization results of the technical batch coated tablets are reported in Table 34. The tablets showed an appropriate level of quality, with their claimed percentages within the typical acceptance criteria range for clinical stages (i.e., 90.0% - 110.0%). The results of the content uniformity test met the pharmacopoeia requirement AV < 15.0. Solubility at 45 minutes met the proposed specification of Q = 75% (…). Figure 21 and Figure 22 ).

[0531] Physical property characterization Table 35 summarizes the XRPD data for granules / tablets from technical batches. Except for granules from the FDC2 formulation, all tested batches showed the absence of EZE hydrates. However, the hydrated form disappeared in the coated tablets. The two batches of granules showed similar flowability. See Table 36 and... Figure 23 The report included PSD data for the particles. Batch samples showed similar bimodal curves.

[0532] Stability Study An overview of the physicochemical analysis of the technical batches after three months of storage of the FDC2 composition is provided in Tables 37 (without desiccant) and 38 (with desiccant), and an overview of the physicochemical analysis of the technical batches after three months of storage of the FDC1 composition is provided in Tables 39 (without desiccant) and 40 (with desiccant).

[0533]

[0534]

[0535]

[0536]

[0537] Table 37 (continued)

[0538] Table 37 (continued)

[0539] Table 37 (continued)

[0540] Table 37 (continued)

[0541] Table 37 (continued)

[0542] Table 37 (continued)

[0543] N / A: Not applicable

[0544] Table 38 (continued)

[0545] Table 38 (continued)

[0546] Table 38 (continued)

[0547] Table 38 (continued)

[0548] Table 38 (continued)

[0549] Table 38 (continued)

[0550] N / A: Not applicable

[0551] Table 39 (continued)

[0552] Table 39 (continued)

[0553] Table 39 (continued)

[0554] Table 39 (continued)

[0555] Table 39 (continued)

[0556] Table 39 (continued)

[0557]

[0558] Table 40 (continued)

[0559] Table 40 (continued)

[0560] Table 40 (continued)

[0561] Table 40 (continued)

[0562] Table 40 (continued)

[0563] Table 40 (continued)

[0564] N / A: Not applicable Example 5: A study was conducted to evaluate the comparative bioavailability of two fixed-dose combination formulations of obisetropeptide / ezetimibe 10 mg / 10 mg (fdc1 and fdc2) versus obisetropeptide 10 mg and ezetimibe 10 mg in healthy adult subjects under fasting conditions.

[0565] Research Design This is an open-label, single-dose, randomized, three-treatment, three-cycle, six-sequence crossover study comparing the co-administration of two test products and a reference product under fasting conditions. In each study phase, subjects received one of the following treatments after an overnight fast of at least 10 hours: Treatment T1 (1 x obisetropeptide 10 mg and ezetimibe 10 mg FDC1 tablets [Formulation #1]), Treatment T2 (1 x obisetropeptide 10 mg and ezetimibe 10 mg FDC2 tablets [Formulation #2]), or Treatment R (1 x obisetropeptide tablet 10 mg co-administered with 1 x ZETIA® (ezetimibe) tablet 10 mg). The order of administration followed a six-sequence randomization schedule. Blood samples were collected at intervals exceeding 336 hours before and after the dose in each study cycle. During each study period, subjects were confined to the clinical facility from at least 10 hours before dose administration until 24 hours after dose administration, and returned to the clinical facility for blood sample collection at 48, 72, 96, 144, 192, 240, and 336 hours after dose administration. The interval between doses was at least 49 days.

[0566] Table 41 below lists formulation #1 (also referred to herein as FDC1 and T1) used in this example and Example 6. Similarly, Table 42 below lists formulation #1 (also referred to herein as FDC2 and T2) used in this example and Example 6. The reference formulation of obisetropeptide (Therapeutic R) does not contain sodium lauryl sulfate or any other surfactant. Instead, the excipients in Therapeutic R are microcrystalline cellulose, sodium carboxyacetate starch, colloidal silica, and magnesium stearate in the core. Therapeutic R tablets are coated with hydroxypropyl methylcellulose, lactose monohydrate, titanium dioxide, and triacetylglycerol.

[0567] Table 41: Composition of Obismetrapil 10 mg Ezetimibe 10 mg FDC Tablets (FDC-1)

[0568] Table 42: Composition of Obismetrapil 10 mg Ezetimibe 10 mg FDC Tablets (FDC-2)

[0569] Plasma concentrations of obisetropeptide, ezetimibe, and its metabolite ezetimibe glucoside were measured using fully effective analytical methods. Statistical analysis was performed using the mean bioequivalence method to assess the bioavailability of each test formulation relative to a reference product when administered together.

[0570] Selection of research group The study population consisted of 36 healthy, non-smoking, and nicotine-free adult male and female participants.

[0571] Treatment application Subjects received treatment T1, treatment T2, or treatment R after a randomization schedule of three treatments, three cycles, and six sequences (Table 43) following an overnight fast of at least 10 hours and were directly observed.

[0572] • Treatment for T1: 1 x obisetropeptide 10 mg and ezetimibe 10 mg FDC tablets (Formulation #1) • Treatment of T2: 1 x obisetropeptide 10 mg and ezetimibe 10 mg FDC tablets (Formulation #2) • Treatment R: 1 X obisetropeptide tablets 10 mg and 1 X ZETIA® (ezetimibe) tablets 10 mg are administered simultaneously.

[0573] Each dose is administered with 240 mL of room temperature water. Instruct subjects to swallow the tablet whole without chewing or biting.

[0574] Sample collection, handling and bioanalysis plan Sample size 4 mL of the sample (K2EDTA vacuum blood collection tube) was used for the analysis of obisetropeptide. 4 mL of the sample (K2EDTA vacuum blood collection tube) was used for the analysis of ezetimibe and ezetimibe glucuronide. Collection time Collect samples within 60 minutes prior to the administration of the dose. All times are relative to minutes before administration.

[0575] Analysis of oxextropeptide: before administration (0 hours) and at 0.50 hours, 1.0 hour, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours, 5.0 hours, 6.0 hours, 7.0 hours, 9.0 hours, 12.0 hours, 16.0 hours, 20.0 hours, 24.0 hours, and 48.0 hours after administration. Hours, 72.0 Hours, 96.0 Hours, 144.0 Hours, 192.0 Hours, 240.0 Hours and 336.0 hour ( (Returned Samples) Analysis of ezetimibe and ezetimibe glucoside: before quantitative administration (0 hours) and at 0.25 hours, 0.50 hours, 0.75 hours, 1.0 hour, 1.333 hours, 1.667 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours, 5.0 hours, 6.0 hours, 7.0 hours, 9.0 hours, 12.0 hours, 16.0 hours, 20.0 hours, 24.0 hours, and 48.0 hours after quantitative administration. Hours, 72.0 Hours and 96.0 hour ( (Returned Samples) Total number of collections per cycle / per subject: 49 Total blood volume for each subject: The total volume of blood collected for pharmacokinetic sampling was approximately 588 mL.

[0576] Sample preparation for obisetropeptide analysis: Blood samples were collected in 4 mL K2EDTA vacuum blood collection tubes at room temperature. After collection, the samples were mixed by gently inverting the tube several times (i.e., 8–10 times) and placed in an ice / water bath. The samples were then centrifuged at 3000 rpm for 10 minutes at 4°C. The resulting plasma was aliquoted into two equal aliquots (at least 1.0 mL in aliquot 1 and the remainder in aliquot 2) and transferred to polypropylene sample storage tubes, which were stored at -70°C (± 10°C) until ready for transport to a bioanalytical laboratory. Placing the plasma aliquots in the refrigerator within 30 minutes of collection. The blood / plasma samples were kept chilled in an ice / water bath after collection until placed in the refrigerator.

[0577] Sample preparation for analysis of ezetimibe and ezetimibe glucoside: Collect blood samples in 4 mL K2EDTA vacuum blood collection tubes at room temperature. After collection, gently mix the sample by inverting the tube several times (at least 8 times) and place it in an ice / water bath. Then place the sample in a centrifuge and centrifuge at 3000 rpm for 10 minutes at 4°C. Divide the result...

Claims

1. A pharmaceutical composition comprising: Obistrapillin or its pharmaceutically acceptable salts, solvates or cocrystals; Ezetimibe or its pharmaceutically acceptable salts, solvates or cocrystals; Surfactants; and Optionally, one or more other pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1, wherein the surfactant is a salt, and the obisetropeptide or its pharmaceutically acceptable salt, solvate or eutectic is amorphous obisetropeptide hemicalcium.

3. The pharmaceutical composition of claim 1 or 2, wherein the surfactant is an organosulfur compound.

4. The pharmaceutical composition of claim 1, 2 or 3, wherein the surfactant is a substituted alkyl group.

5. The pharmaceutical composition of claim 4, wherein the surfactant is monosubstituted.

6. The pharmaceutical composition of claim 5, wherein the monosubstituent comprises a sulfur atom.

7. The pharmaceutical composition of claim 6, wherein the monosubstituent is a sulfate group.

8. The pharmaceutical composition of claim 1, wherein the surfactant is an anionic surfactant.

9. The pharmaceutical composition of claim 1, wherein the surfactant is a cationic surfactant.

10. The pharmaceutical composition of claim 1, wherein the surfactant is a nonionic surfactant.

11. The pharmaceutical composition of claim 1, wherein the surfactant is an amphoteric surfactant.

12. The pharmaceutical composition of claim 1 or 8, wherein the surfactant is a carboxylate, sulfate, sulfonate, or phosphate compound.

13. The pharmaceutical composition of claim 1 or 8, wherein the surfactant is a sulfate or sulfonate.

14. The pharmaceutical composition of claim 1 or 8, wherein the surfactant is selected from alkyl carboxylates-fatty acid salts; carboxylate fluorosurfactants; alkyl sulfates-alkyl ether sulfates; branched alkyl sulfates; docusate; alkylbenzene sulfonates; phosphate esters; and alkyl ether phosphates.

15. The pharmaceutical composition of claim 1 or 8, wherein the surfactant is sodium lauryl sulfate, or sodium lauryl ether sulfate, or sodium dioctyl sulfosuccinate, or alkyl aryl ether phosphate and alkyl ether phosphate.

16. The pharmaceutical composition of claim 1, wherein the surfactant is sodium lauryl sulfate.

17. The pharmaceutical composition of claim 1 or 9, wherein the surfactant is a quaternary ammonium salt.

18. The pharmaceutical composition of claim 17, wherein the surfactant is a pyridinium salt.

19. The pharmaceutical composition of claim 1 or 10, wherein the surfactant is a fatty alcohol ether and a polyol ester, a fatty acid ester of sorbitol or its ethoxylated derivative, or a synthetic block copolymer of hydrophilic poly(oxyethylene).

20. The pharmaceutical composition of claim 1 or 10, wherein the surfactant is a polyoxyethylene ester, porrazam, glycol, glycol ester, or sorbitol derivative.

21. The pharmaceutical composition of claim 1 or 10, wherein the surfactant is sorbitol trioleate, sorbitol monolaurate, sorbitol monopalmitate, sorbitol monostearate, sorbitol tristearate, and sorbitol monooleate, as well as polyoxyethylene (20) sorbitol monolaurate, polyoxyethylene (20) sorbitol monopalmitate, polyoxyethylene (20) sorbitol monostearate, polyoxyethylene (20) sorbitol tristearate, polyoxyethylene (20) sorbitol monooleate, polyoxyethylene (20) sorbitol trioleate, polysorbate 20, or polysorbate 80.

22. The pharmaceutical composition of claim 1 or 11, wherein the zwitterionic surfactant is lauryl betaine, lauroyl sarcosinate, lauryl sulfobetaine, laurylamidopropyl betaine, or lauryl dimethylamine oxide.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the surfactant has an HLB content of at least 15.

24. The pharmaceutical composition of claim 23, wherein the surfactant has an HLB of at least 20.

25. The pharmaceutical composition of claim 24, wherein the surfactant has an HLB of at least 30.

26. The pharmaceutical composition of claim 25, wherein the surfactant has an HLB of at least 35.

27. The pharmaceutical composition of claim 23, wherein the surfactant has an HLB value between 15 and 50, including 15 and 50.

28. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB value between 30 and 45, including 30 and 45.

29. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB value between 40 and 45, including 40 and 45.

30. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB concentration between 38 and 42, including 38 and 42.

31. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB between 39 and 41, including 39 and 41.

32. The pharmaceutical composition of claim 27, wherein the surfactant has 38, 39, 40, 41 or 42 HLB.

33. The pharmaceutical composition of claim 27, wherein the surfactant has 40 HLB.

34. The pharmaceutical composition according to any one of claims 1-33, wherein the surfactant is present in the composition at a concentration of about 0.2% to about 10% by weight.

35. The pharmaceutical composition of claim 34, wherein the surfactant is present in the composition at a concentration of about 0.5% to about 5% by weight.

36. The pharmaceutical composition of claim 35, wherein the surfactant is present in the composition at a concentration of about 0.5% to about 2% by weight.

37. The pharmaceutical composition of claim 35, wherein the surfactant is present in the composition at about 0.5% to about 1% by weight.

38. The pharmaceutical composition of claim 35, wherein the surfactant is present in the composition at a concentration of about 0.5% to about 1.5% by weight.

39. The pharmaceutical composition of claims 1 to 38, wherein the composition comprises an inner part and an outer part.

40. The pharmaceutical composition of claim 39, wherein the obisetropeptide or its pharmaceutically acceptable salt, solvate or cocrystal and the surfactant are present in the particulate portion.

41. The pharmaceutical composition according to claims 1-40, wherein the pharmaceutical composition is uncoated.

42. The pharmaceutical composition according to claims 1-40, wherein the pharmaceutical composition is coated.

43. The pharmaceutical composition of claims 1-42, further comprising one or more other pharmaceutically acceptable excipients.

44. The pharmaceutical composition of claim 43, wherein the one or more pharmaceutically acceptable excipients are selected from one or more diluents, binders, disintegrants, second surfactants, and lubricants.

45. The pharmaceutical composition of claim 44, wherein the one or more diluents are inorganic phosphates, sugars, sugar analogs or sugar derivatives.

46. ​​The pharmaceutical composition of claim 44, wherein the one or more diluents are calcium hydrogen phosphate, lactose, lactose monohydrate, anhydrous lactose, dextrose, sorbitol, mannitol, sucrose, maltodextrin, isomaltose, cellulose, microcrystalline cellulose or powdered cellulose.

47. The pharmaceutical composition of claim 45 or claim 46, wherein the one or more diluents are in the granule component.

48. The pharmaceutical composition of claim 45 or claim 46, wherein the diluent is in the extraparticle component.

49. The pharmaceutical composition of any one of claims 44-48, wherein the one or more adhesives are cellulose derivatives.

50. The pharmaceutical composition of claims 44-49, wherein the one or more adhesives are methylcellulose and carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, glucose, sucrose, lactose, dextrose, xylitol, sorbitol, maltitol, polymethyl methacrylate, copolymers of polyvinylpyrrolidone and polyvinylpyrrolidone, starch paste, pregelatinized starch, tragacanth gum, alginate and salts of alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, and bentonite.

51. The pharmaceutical composition according to any one of claims 44-49, wherein the one or more adhesives are sodium alginate, polyvinylpyrrolidone, or a copolymer of polyvinylpyrrolidone.

52. The pharmaceutical composition according to any one of claims 44-49, wherein the one or more adhesives are copolyvinylpyrrolidone or Colidon 30.

53. The pharmaceutical composition according to any one of claims 44-52, wherein the one or more disintegrants are croscarmellose, croscarmellose sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, alginate, sodium alginate, microcrystalline cellulose, sodium carboxyacetic acid starch, or pregelatinized starch.

54. The pharmaceutical composition according to any one of claims 44-52, wherein the one or more disintegrants are croscarmellose sodium or carboxyacetic acid starch sodium.

55. The pharmaceutical composition of claims 44-54, wherein the one or more lubricants are fatty acids or fatty acid derivatives.

56. The pharmaceutical composition according to claims 44-54, wherein the one or more lubricants are alkali metal or alkaline earth metal salts of stearic acid, alkali metal or alkaline earth metal salts of lauric acid, or alkali metal or alkaline earth metal salts of palmitic acid.

57. The pharmaceutical composition of claims 44-54, wherein the one or more lubricants are magnesium stearate. The pharmaceutical composition of any of the preceding claims is intended for use in treating subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, preferably subjects with hyperlipidemia or mixed dyslipidemia.

58. The pharmaceutical composition of any one of claims 1-57, wherein the pharmaceutical composition is used to lower LDL cholesterol in patients who require lowering LDL cholesterol and / or raising HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients diagnosed with atherosclerotic cardiovascular disease (ASCVD).

59. Use of the pharmaceutical composition of any one of claims 1-57 for the preparation of a medicament for treating a subject suffering from hyperlipidemia or mixed dyslipidemia.

60. Use of the pharmaceutical composition of any one of claims 1-57 for the preparation of a medicament for reducing LDL cholesterol in subjects who require lowering LDL cholesterol and / or raising HDL cholesterol, subjects with heterozygous familial hypercholesterolemia (HeFH), and / or subjects diagnosed with atherosclerotic cardiovascular disease (ASCVD).

61. Use of the pharmaceutical composition of any one of claims 1-57 in the preparation of a medicament for reducing the risk of cardiovascular events.

62. The use as described in any one of claims 1-57, wherein the subject suffers from mild dyslipidemia.

63. A method of treating a subject who requires lowering LDL cholesterol and / or raising HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH), and / or a subject diagnosed with atherosclerotic cardiovascular disease (ASCVD), wherein the method comprises administering to the patient in need a therapeutically effective dose of the pharmaceutical composition as described in any one of claims 1-57.

64. A method of treating a subject suffering from hyperlipidemia or mixed dyslipidemia, wherein the method comprises administering to the patient in need the pharmaceutical composition of any one of claims 1-57.

65. The use of the pharmaceutical composition of any one of claims 1-57 for the preparation of a medicament or a treatment method, wherein the subject has an LDL-cholesterol level of >50 mg / dL, preferably >70 mg / dL, and optionally, the person is not adequately controlled by his / her current lipid-lowering therapy.

66. Use or treatment of the pharmaceutical composition of any one of claims 1-57, wherein the subject in need is a subject who requires additional reduction of low-density lipoprotein cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy for the treatment of an adult with heterozygous familial hypercholesterolemia (HeFH) or a confirmed atherosclerotic cardiovascular (CV) disease (ASCVD).

67. A pharmaceutical composition comprising an effective dose of any one of the pharmaceutical compositions of claims 1-57, the pharmaceutical composition being used in treating subjects who require additional reduction of low-density lipoprotein cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy for treating adults with heterozygous familial hypercholesterolemia (HeFH) or a confirmed atherosclerotic cardiovascular (CV) disease (ASCVD).

68. The pharmaceutical composition of any one of claims 1-57, wherein obisetropip or a pharmaceutically acceptable salt, solvate or cocrystal thereof, a surfactant, and optionally one or more other pharmaceutically acceptable excipients are in the granules.

69. The pharmaceutical composition of claim 68, wherein the particles are prepared by wet granulation.

70. A method for preparing pharmaceutical composition particles, the pharmaceutical composition particles comprising obisetropeptide or a pharmaceutically acceptable salt, solvate or cocrystal thereof, a surfactant, and optionally one or more other pharmaceutically acceptable excipients, the method comprising the steps of: (a) Combining ocbisetraprine or its pharmaceutically acceptable salts, solvates or cocrystals, surfactants, binders, and optionally one or more other pharmaceutical excipients to form a solid mixture; (b) combining the solid mixture with water to form a wet mixture; and (c) Granulate the wet mixture into granules.

71. The method of claim 70, further comprising compressing the granules into tablets.

72. The method of claim 71, further comprising mixing the granules with an additional powder and compressing them into tablets.

73. The method of claim 72, wherein the additional powder comprises one or more excipients.

74. The method of claim 73, wherein the additional powder comprises obisetropeptide or a pharmaceutically acceptable salt, solvate, or eutectic thereof.

75. The method of claim 73, wherein the additional powder comprises an active ingredient other than obisetropine.

76. The method of any one of claims 70 to 75, wherein the obisetropip or its pharmaceutically acceptable salt, solvate or eutectic is amorphous obisetropip hemicalcium.

77. The method of any one of claims 70 to 76, further comprising coating the tablets.

78. A pharmaceutical composition granule prepared by the method of claim 70.

79. A pharmaceutical composition tablet prepared by the method according to any one of claims 71 to 78.

80. The pharmaceutical composition of any one of claims 1-57 and 78-70, wherein the obisetropeptide or its pharmaceutically acceptable salt, solvate or cocrystal is the sole active ingredient in the pharmaceutical composition.

81. The method or use as described in any one of claims 58-67 or 71-77, wherein the obisetropeptide or its pharmaceutically acceptable salt, solvate or cocrystal is the sole active ingredient in the pharmaceutical composition.

82. The pharmaceutical composition of claim 82, wherein the obisetropip or its pharmaceutically acceptable salt, solvate or eutectic is amorphous obisetropip hemicalcium.

83. The method of claim 81, wherein the obisetropeptide or its pharmaceutically acceptable salt, solvate or eutectic is amorphous obisetropeptide hemicalcium.

84. The pharmaceutical composition of any one of claims 39-58 or 68-69, wherein the obisetropeptide or its pharmaceutically acceptable salt, solvate or eutectic is amorphous obisetropeptide hemicalcium.

85. The pharmaceutical composition of any one of claims 1-58, 67-69, 78-80, 82 or 84, wherein the amount of obisetropeptide in the pharmaceutical composition is between about 5 mg and 15 mg.

86. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 5 mg.

87. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 6 mg.

88. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 7 mg.

89. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 8 mg.

90. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 9 mg.

91. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 10 mg.

92. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 11 mg.

93. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 12 mg.

94. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 13 mg.

95. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 14 mg.

96. The pharmaceutical composition of claim 85, wherein the amount of obisetropeptide in the pharmaceutical composition is 15 mg.

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