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WO2024226537A1 - Combinaison d'inhibiteur de sglt2 et d'obicetrapib amorphe - Google Patents

Combinaison d'inhibiteur de sglt2 et d'obicetrapib amorphe Download PDF

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Publication number
WO2024226537A1
WO2024226537A1 PCT/US2024/025881 US2024025881W WO2024226537A1 WO 2024226537 A1 WO2024226537 A1 WO 2024226537A1 US 2024025881 W US2024025881 W US 2024025881W WO 2024226537 A1 WO2024226537 A1 WO 2024226537A1
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WIPO (PCT)
Prior art keywords
obicetrapib
amorphous
pharmaceutical composition
sglt2 inhibitor
composition according
Prior art date
Application number
PCT/US2024/025881
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English (en)
Inventor
Michael Harvey DAVIDSON
Marc DITMARSCH
Johannes Jacob Pieter KASTELEIN
Sheng CUI
Andreas René RÖTHELI
Christopher J. BORTHS
Muneki Kishida
Original Assignee
Newamsterdam Pharma B.V.
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Publication of WO2024226537A1 publication Critical patent/WO2024226537A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • Type 2 diabetes is an increasingly prevalent disease. Due to a high frequency of complications, type 2 diabetes leads to a significant reduction of life expectancy. Type 2 diabetes also causes significant morbidity. Because of diabetes-associated microvascular complications, type 2 diabetes is currently the most frequent cause of adult-onset loss of vision, renal failure, and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a two- to five-fold increase in cardiovascular disease risk. [0003] It is now widely accepted that glycemic control makes a difference in type II diabetes patients. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications associated with elevated glucose in the blood.
  • Oral therapeutic options for the treatment of type II diabetes mellitus include compounds known as sulfonylureas, biguanides (metformin), thiazolidinediones (TZDs), and alpha-glucosidase inhibitors.
  • the active agents from each class are generally administered to patients alone. However, once monotherapy becomes inadequate, combination therapy is feasible, despite the known side effect of weight gain associated with sulfonylurea and thiazolidinedione therapies.
  • the present disclosure provides a pharmaceutical composition comprising amorphous obicetrapib, or the calcium salt thereof, and an SGTL2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • pharmaceutical dosage forms including the same.
  • the dosage form is a solid dosage form, such as a tablet.
  • processes for the preparation of (i) amorphous obicetrapib and calcium salts thereof, and (ii) fixed dose combination formulations of amorphous obicetrapib or calcium salt thereof and an SGTL2 inhibitor, or pharmaceutically acceptable salt thereof.
  • a metabolic disorder e.g., type 2 diabetes
  • cardio-metabolic disorder e.g., type 2 diabetes
  • methods for treating or preventing a metabolic disorder or cardiometabolic disorder in a subject who has or is at risk of developing a metabolic or cardiometabolic disorder comprising administering a therapeutically effective amount of
  • a first aspect of this disclosure includes a pharmaceutical composition
  • a pharmaceutical composition comprising: a) a therapeutically effective amount of amorphous obicetrapib, or the calcium salt thereof; and b) a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • a second aspect of this disclosure includes a pharmaceutical composition
  • a pharmaceutical composition comprising: a) a therapeutically effective amount of amorphous obicetrapib hemicalcium, or a pharmaceutically acceptable salt thereof; and b) a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • a third aspect of this disclosure includes a pharmaceutical dosage form including a pharmaceutical composition comprising amorphous calcium salt of obicetrapib or amorphous obicetrapib hemicalcium, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof (e.g., as described herein).
  • a fourth aspect of this disclosure includes a method of treating or preventing a metabolic disorder, comprising administering to a subject having or at risk of developing a metabolic disorder a therapeutically effective amount of a pharmaceutical composition comprising amorphous calcium salt of obicetrapib or amorphous obicetrapib hemicalcium, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof (e.g., as described herein).
  • a fifth aspect of this disclosure includes a method of treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder, comprising: administering a therapeutically effective amount of amorphous calcium salt of obicetrapib or amorphous obicetrapib hemicalcium, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the metabolic disorder is type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, or metabolic syndrome.
  • ITT impaired glucose tolerance
  • IGF impaired fasting blood glucose
  • hyperglycemia postprandial hyperglycemia
  • obesity or metabolic syndrome.
  • FIGS. 1A-B are x-ray diffraction patterns.
  • FIG. 1A is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.
  • FIG. IB is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.
  • FIG. 2 is an x-ray powder diffraction pattern of crystalline obicetrapib hemi calcium.
  • FIGS. 3A-B are polarized light micrographs.
  • FIG. 3A is a polarized light micrograph of amorphous obicetrapib hemicalcium.
  • FIG. 3B is a polarized light micrograph of crystalline obicetrapib hemicalcium.
  • FIG. 4 is a thermogravimetric analysis plot of amorphous obicetrapib hemi calcium.
  • FIGS. 5A-B are modulated differential scanning calorimetry thermogram plots.
  • FIG. 5A is a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium.
  • FIG. 5B is a modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obicetrapib hemicalcium.
  • FIGS. 6A-C are solid-state 13 C-NMR spectrums.
  • FIG. 6A is a solid-state 13 C- NMR spectrum of amorphous and crystalline obicetrapib hemicalcium.
  • FIG. 6B is a solid- state 13 C-NMR spectrum of crystalline obicetrapib hemicalcium.
  • FIG. 6C is a solid-state 13 C-NMR spectrum of amorphous obicetrapib hemicalcium.
  • FIGS. 7A-7B are x-ray powder diffraction patterns.
  • FIG. 7A-7B are x-ray powder diffraction patterns.
  • FIG. 7A is an x-ray powder diffraction pattern of crystalline HC1 obicetrapib and at least partially desolvated crystalline HC1 obicetrapib.
  • FIG. 7B is an x-ray powder diffraction pattern of crystalline HC1 obicetrapib.
  • FIGS. 8A-8B are displays of constructed genetic scores.
  • FIG 8A is a genetic score mimicking CETP inhibition.
  • FIG. 8B is a genetic score mimicking effect of SGLT2 inhibition on glycated hemoglobin levels.
  • FIGS. 9A-9B are forest plots.
  • FIG. 9A is a forest plot displaying SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on diabetes incidence relative to control.
  • FIG 9B is a forest plot displaying SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on diabetes incidence relative to each other.
  • FIGS. 10A-10B are forest plots.
  • FIG. 10A is a forest plot displaying the effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control.
  • FIG. 10B is a forest plot displaying the effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to each other.
  • FIGS. 11A-11D are forest plots displaying the effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels or diabetes relative to control or each other without inclusion of SBP and BMI covariates in the discovery cohort.
  • FIG. 11A displays the according effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control.
  • FIG. 11A displays the according effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control.
  • FIG. 11B displays the according effect of SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to SGLT2 inhibition monotherapy, SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to CETP inhibition monotherapy and CETP inhibition monotherapy relative to SGLT2 inhibition monotherapy.
  • FIG. 11C displays the according effect of SGLT2 inhibition monotherapy relative to control, CETP inhibition monotherapy on diabetes relative to control, and SGLT2 inhibition and CETP inhibition combination therapy relative to control.
  • 11D displays the according effect of SGLT2 inhibition and CETP inhibition combination therapy on diabetes relative to SGLT2 inhibition monotherapy, SGLT2 inhibition and CETP inhibition combination therapy relative to CETP inhibition monotherapy, and SGLT2 inhibition monotherapy relative to CETP inhibition monotherapy.
  • FIGS. 12A-12D are forest plots displaying the effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control or each other in the replication cohort.
  • FIG. 12A displays the according effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control.
  • FIG. 12A displays the according effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control.
  • FIG. 12B displays the according effect of SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to SGLT2 inhibition monotherapy, of SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to CETP inhibition monotherapy, and CETP inhibition monotherapy relative to SGLT2 inhibition monotherapy.
  • FIG. 12C displays the according effect of SGLT2 inhibition monotherapy relative to control, CETP inhibition monotherapy on diabetes relative to control, and SGLT2 inhibition and CETP inhibition combination therapy relative to control.
  • 12D displays the according effect of SGLT2 inhibition and CETP inhibition combination therapy on diabetes relative to SGLT2 inhibition monotherapy, SGLT2 inhibition and CETP inhibition combination therapy relative to CETP inhibition monotherapy, and SGLT2 inhibition monotherapy relative to CETP inhibition monotherapy.
  • FIG. 13 is forest plot displaying CETP genetic score regressed against relevant biomarkers.
  • FIG. 14 is a forest plot displaying SGLT2 genetic score regressed against relevant biomarkers.
  • the present disclosure provides a pharmaceutical composition comprising amorphous obicetrapib or the calcium salt thereof and an SGTL2 inhibitor or a pharmaceutically acceptable salt thereof.
  • pharmaceutical dosage forms including the same.
  • the dosage form is a solid dosage form, such as a tablet.
  • processes for the preparation of (i) amorphous obicetrapib and calcium salts thereof, and (ii) fixed dose combination formulations of amorphous obicetrapib or calcium salt thereof and an SGTL2 inhibitor.
  • a metabolic disorder e.g., type 2 diabetes
  • cardio-metabolic disorder e.g., type 2 diabetes
  • methods for treating or preventing a metabolic disorder or cardiometabolic disorder in a subject who has or is at risk of developing a metabolic or cardiometabolic disorder comprising administering a therapeutically effective amount of
  • compositions of this disclosure are described in greater detail below.
  • the obicetrapib active compound is described, and SGLT2 inhibitors are described.
  • pharmaceutical compositions including amorphous obicetrapib or calcium salt thereof and a SGTL2 inhibitor or pharmaceutically acceptable salt thereof, pharmaceutical dosage forms comprising amorphous obicetrapib or amorphous obicetrapib calcium, and SGLT2 inhibitors or pharmaceutically acceptable salts thereof, and processes for the preparation of fixed dose formulations of the same. Methods in which the pharmaceutical compositions of this disclosure find use are also described.
  • this disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous obicetrapib, or a calcium salt thereof, and an SGTL2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • compositions disclosed herein include amorphous obicetrapib, or the calcium salt thereof. Crystalline obicetrapib has previously been described (see, for example, in U.S. Patent No. 7,872,126 and WO 2005/095409A2).
  • Obicetrapib, or (2R,4S)-4- ⁇ [3,5-bis(trifhroromethyl)benzyl]-[5-(3- carboxypropoxy)pyrimidin-2- yl]amino ⁇ -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester, is a cholesteryl ester transfer protein (CETP) inhibitor of formula (I), wherein Et represents an ethyl group:
  • Inhibiting CETP can reduce low-density lipoprotein cholesterol (LDL-C) and elevates high-density lipoprotein cholesterol (HDL-C) levels.
  • CETP is a plasma protein secreted primarily by liver and adipose tissue.
  • CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (Apo B)-containing particles (mainly low-density lipoprotein (LDL) and very low-density lipoprotein VLDL) in exchange for triglycerides, thereby decreasing the cholesterol content in HDL in favor of that in (V)LDL.
  • Apo B apolipoprotein B
  • the pharmaceutical compositions comprise amorphous obicetrapib calcium salt.
  • the pharmaceutical composition comprises amorphous obicetrapib hemicalcium.
  • the compositions can comprise amorphous obicetrapib or calcium salt thereof in the form of a solvate comprising a pharmaceutically acceptable solvent, such as water (‘hydrate’), ethanol, and the like.
  • a pharmaceutically acceptable solvent such as water (‘hydrate’), ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present disclosure.
  • Amorphous obicetrapib or calcium salt thereof is present in the pharmaceutical composition in a therapeutically effective amount.
  • a “therapeutically effective amount” of obicetrapib is an amount that, when administered to an individual in one or more doses, in combination therapy (e.g., as described herein with an SGLT2 inhibitor), is effective to ameliorate or improve a symptom of a metabolic or cardiometabolic disorder. This can include for example, lessening in severity or progression, or to cure.
  • a “therapeutically effective amount” of obicetrapib is an amount that when administered to an individual in one or more doses, in combination therapy (e.g., as described herein with an SGLT2 inhibitor), is effective to reduce the symptoms in the subject 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 measured levels, assessed, quantified or qualified symptoms in the individual in the absence of, or before, treatment with the combination.
  • the pharmaceutical composition comprises from about 1% to about 25% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In further embodiments, the composition comprises from about 1% to about 20% w/w, or from about 1% to about 15% w/w, or from about 1% to about 10% w/w, or from about 5% to about 15% w/w, or from about 5% to about 12% w/w of amorphous obicetrapib or calcium salt, solvate or hydrate thereof.
  • 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 amorphous obicetrapib, or calcium salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises about 5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises from 1% to 25% w/w of amorphous obicetrapib or calcium salt, solvate or hydrate thereof. In further embodiments, the composition comprises from 1% to 20% w/w, or from 1% to 15% w/w, or from 1% to 10% w/w, or from 5% to 15% w/w, or from 5% to 12% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • 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 amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises 5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the amorphous obicetrapib hemicalcium of the present disclosure is different from and can be distinguished from the crystalline obicetrapib hemicalcium disclosed in U.S. Patent Number 7,872, 126.
  • a common technique used to distinguish crystalline from amorphous materials is x-ray powder diffraction. However, this technique has limitations, especially when the crystalline material is disordered.
  • x-ray powder diffraction patterns of two different lots of amorphous obicetrapib hemicalcium are provided in FIGs. 1 A and IB. These patterns have the familiar “halo” features that are associated with amorphous materials.
  • the x-ray powder diffraction pattern from FIG. IB has peaks at about 3.4°20, about 7.O°20, and about 9.2°29.
  • the x-ray powder diffraction patterns of either FIG. 1 A or FIG. IB may be used to characterize amorphous obicetrapib hemicalcium, provided, however, that occasionally a sharp higher angle peak is found, such as at about 31.7°20 (such as in FIG. IB), and that peak, when present, is due to sodium chloride.
  • the x-ray powder pattern of crystalline obicetrapib hemicalcium is shown in FIG. 2. It too exhibits halo-like behavior which may be indicative of disorder.
  • Operations 11 and 11 A described in Section 4.1.1.2 below set forth various procedures on how to take x-ray powder diffraction of samples.
  • the procedure of Operation 11 was generally used to collect the data set forth in FIGs 1 and 2; Operation 11 A was generally used for FIG. IB.
  • PLM polarized light microscopy
  • a material is viewed through polarized light, and by viewing the material through cross-polarizers, one can differentiate between materials that are anisotropic (e.g., crystals) or isotropic (e.g., amorphous compounds).
  • Anisotropic materials when exposed to polarized light through cross polarizers, exhibit birefringence which manifests itself by exhibiting color change through cross polarizers.
  • Isotropic materials do not show birefringence and exhibit no color change when exposed to polarized light.
  • FIG. 3 A amorphous obicetrapib hemicalcium was analyzed by polarized light microscopy as set forth in Operation 10.
  • FIG. 3 A shows, the materials under study do not birefringe, indicating that the material is amorphous.
  • FIG. 3B is a polarized light micrograph of crystalline obicetrapib hemicalcium.
  • the compounds shown in FIG. 3B are multi-colored which indicates crystallinity.
  • the crystals in FIG. 3B are larger than the particles provided in the amorphous obicetrapib hemicalcium polarized light micrograph of FIG. 3 A. Accordingly, PLM and/or the lack of birefringence can be used to characterize amorphous obicetrapib hemicalcium.
  • mDSC modulated differential scanning calorimetry
  • mDSC thermogram one can measure a glass transition temperature which can be used to characterize an amorphous material.
  • FIG. 5A the mDSC thermogram of amorphous obicetrapib hemicalcium was measured using a sample holder which is open allowing for volatile gases to escape during a measurement. In this FIG.
  • the opening was done by piercing a lid on the pan so as to create a pinhole.
  • a glass transition temperature of about 110°C was recorded for this sample.
  • the term “about” generally refers to a variability of plus or minus 1°C.
  • crystalline obicetrapib calcium has a higher glass transition temperature under the same conditions, and three measurements in FIG. 5B indicate a range between about 118°C and about 125.5°C.
  • the glass transition temperature of amorphous obicetrapib hemicalcium has been measured to be between about 109°C and 112°C when measured with a pinhole.
  • the glass transition temperature of amorphous obicetrapib hemicalcium may also be measured using mDSC with a closed pan.
  • the type of sample preparation may affect the measured glass transition temperature.
  • the glass transition temperature decreases to temperatures of less than about 100°C and in particular between about 70°C and about 92°C depending on humidity.
  • FIG. 4 is a thermogravimetric analysis thermogram of amorphous obicetrapib hemicalcium showing a weight loss of less than 1% when heated to about 200°C. Such weight losses may be, for example, between about 0.8% and about 0.95% including between about 0.84% and about 0.92%. In FIG. 4, the weight loss was determined to be about 0.85%. This particular material was found to have a water content of about 1.5%.
  • the water content of may be higher and include a range from about 0% to about 5% water by weight, including up to about 4% by weight, up to about 3% by weight, and between about 0.5% and 1.5% by weight.
  • FIG. 6A shows a solid-state 13 C-NMR spectrum of both crystalline and amorphous obicetrapib hemicalcium with FIGs 6A and 6B showing the crystalline and amorphous obicetrapib hemicalcium separately. There are at least two differences in the spectra.
  • the crystalline phase has a peak at about 22.1 ppm not present in the amorphous phase.
  • a peak at about 29.5 ppm in the crystalline phase is pronounced while not nearly so in the amorphous phase.
  • the absence of a solid-state 13 C-NMR peak at about 22.1 ppm and/or the absence of a pronounced peak at about 29.5 ppm may be used to characterize amorphous obicetrapib hemicalcium.
  • a solid-state 13 C-NMR spectrum substantially the same as that of FIG. 6C may be used to characterize amorphous obicetrapib hemicalcium.
  • substantially pure amorphous obicetrapib hemicalcium prior to admixture with an SGLT2i.
  • the chemical purity of substantially pure amorphous obicetrapib hemicalcium is 99.9% or greater.
  • a method of preparing an amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium, wherein the method comprises: treating obicetrapib with an acid to form a salt, solvate, or composition; isolating the resulting salt, solvate or composition; and treating that salt, solvate, or composition with a calcium source to create an amorphous obicetrapib calcium salt, such as amorphous obicetrapib hemicalcium.
  • the resulting salt can then be isolated.
  • Examples of calcium sources include calcium salts such as halogenated calcium salts and soluble calcium salts.
  • the calcium source is calcium chloride.
  • An amorphous salt of obicetrapib calcium such as amorphous obicetrapib hemicalcium has been found to occur when there is an intermediate salt, solvate or composition (such composition comprising the corresponding acid used to make a salt). Treating obicetrapib directly with a calcium base such as calcium hydroxide has not been found to be a viable way of making an amorphous salt of obicetrapib calcium due to either low solubility, the weakness of the bases available or both.
  • an intermediate salt such as a sodium salt
  • an additional salt or salt-type exchange such as with the use of a composition or solvate rather than an actual salt
  • the use of the salt, solvate, or composition enables the production of a highly pure amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium.
  • Exemplary salts that may be made as an intermediate include those from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), a sulfate (e.g., methyl sulfate), a halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, prop
  • the intermediate when the intermediate is a solvate or a composition, then the corresponding acids may be used or present.
  • the intermediate when a solvate, the intermediate may further include a solvent such as an organic solvent or water, in which case the solvate would be a hydrate.
  • a solvent such as an organic solvent or water, in which case the solvate would be a hydrate.
  • organic solvent is CPME (cyclopentyl methyl ether).
  • the intermediate is a solvate of an acid.
  • the intermediate is a solvate of an acid and an organic solvent.
  • the intermediate is a solvate comprising an acid and a solvent.
  • the acid is hydrochloric acid and a solvent is CPME.
  • the disclosure includes methods for preparing amorphous obicetrapib calcium salts, such as amorphous obicetrapib hemicalcium.
  • the disclosure further includes amorphous obicetrapib calcium salts, including amorphous obicetrapib hemicalcium, so prepared.
  • an intermediate referred to herein as crystalline HC1 obicetrapib is used in the processes for preparing amorphous obicetrapib calcium, such as amorphous obicetrapib hemicalcium.
  • amorphous obicetrapib hemicalcium is prepared via a chemical synthesis where an intermediate is used denoted by Formula (IH):
  • y varies such that the mass percent of HC1 varies from 0.01% to 8% by weight and is believed to further include an associated organic solvent such as by way of a solvate. In some embodiments, y varies from 0.002 to 1.5. In some embodiments, y varies from 0.3 to 1. In some embodiments, of Formula (IH), as a solvate, is isolated in its crystalline form. In many embodiments, the solvent is CPME. Other solvents which may form solvates include toluene and heptane.
  • Crystalline HC1 obicetrapib as prepared is crystalline.
  • the term crystalline HC1 obicetrapib means crystalline HC1 obicetrapib.
  • the term crystalline HC1 obicetrapib may include CPME as a solvate when CPME is used in the preparation crystalline HC1 obicetrapib.
  • the solvate is of an organic solvent and in many embodiments, that solvent is CPME.
  • the disclosure provides for compositions comprising crystalline HC1 obicetrapib.
  • Formula (IH) is a solvate and not a hydrochloride salt of obicetrapib. It has been found that when CPME is used to deliver HC1 in the reaction to create Formula (IH), the chloride content of Formula (IH) ranges between about 2.5% and 3.0% by weight which is below what one would expect for a neutral salt - namely about 4.7% by weight. In addition, in many embodiments, when CPME is so used, it is found in the material when crystallized.
  • crystalline HC1 obicetrapib When CPME is used in the reaction to deliver dry HC1 and is thus found in the crystallized material, the resulting crystalline Formula (IH) material is referred to as crystalline HC1 obicetrapib, those x-ray powder diffraction pattern is seen in Figure 7A. It is therefore believed that crystalline HC1 obicetrapib is a solvate of CPME and HC1 together with obicetrapib. Solvates, as opposed to salts, can have a variable composition which help explains the variable amount of HC1 seen in crystalline HC1 obicetrapib.
  • amorphous obicetrapib hemicalcium has a chemical purity which is routinely 99.9% pure or greater.
  • Chemical purity is the quantitative representation of whether other chemical entities other than the compound being measured are present.
  • a chemical purity of 99.9% amorphous obicetrapib hemicalcium means that not more than 0.1% of the compounds in a sample of amorphous obicetrapib hemicalcium are other entities.
  • Physical purity refers to the amount of other solid forms of the same compound are present which, in the case of amorphous obicetrapib calcium, the other solid form being crystalline obicetrapib hemicalcium.
  • HC1 obicetrapib as used herein, is not limited to crystalline HC1 obicetrapib. Indeed, upon desolvation, crystalline HC1 obicetrapib may become amorphous.
  • pattern 2 reflects crystalline HC1 obicetrapib subject to a mild drying treatment whereby surface solvent was removed and it can be seen that this compound is crystalline.
  • the sample whose x-ray powder diffraction was measured in pattern 1 was subject to a stronger drying treatment at 48 hours at 55°C at a pressure of 2mbar. As is apparent, this drying changed the material from crystalline to amorphous, likely due to a desolvation of CPME and at least some HC1.
  • NMR spectroscopy for example, was used to show the presence of CPME in the top pattern, but was substantially absent in the lower, amorphous pattern.
  • the amorphous pattern therefore, represents HC1 obicetrapib which is not crystalline obicetrapib. It may be obicetrapib, but is believed to have HC1 associated with the obicetrapib as a solvate and thus is HC1 obicetrapib, but with a lower chloride content than typically found in the ranges found for crystalline HC1 obicetrapib. In some embodiments, that chloride content is less than 0.1% by weight such as between about 0.01% and 0.1% by weight.
  • Crystalline HC1 obicetrapib may be characterized by an x-ray powder diffraction pattern comprising a peak at about 9.8°29.
  • crystalline HC1 obicetrapib may be characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 8.1°20, about 9.8°29, about 13.8°29, about 16.7°29, or about 19.5°29.
  • Table A provides illustrative peaks which may be present in crystalline HC1 obicetrapib.
  • crystalline HC1 obicetrapib may be characterized by an x-ray powder diffraction pattern substantially the same as that in Figure 7B.
  • the amorphous obicetrapib hemicalcium of the present disclosure is prepared by a method that comprises: i. treating obicetrapib with HC1 to obtain crystalline HC1 obicetrapib; ii. isolating crystalline HC1 obicetrapib; iii. preparing an amorphous calcium salt of obicetrapib from the crystalline HC1 obicetrapib isolated in step (ii); and iv. isolating an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemi calcium.
  • the amorphous calcium salt of obicetrapib is in the form of amorphous obicetrapib hemicalcium (see, e.g., Scheme 1, Compound 3).
  • step (iii) includes the following steps:
  • step (iii- 1 ) converting crystalline HC1 obicetrapib of step (ii) to provide obicetrapib in an organic solvent
  • amorphous obicetrapib hemicalcium is isolated with a purity of 95% or more, such as a purity of 95.5% or more, 96% or more, 96.5% or more, 97% or more, 97.5% or more, 98% or more, 98.5% or more, 99% or more, 99.1% or more, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more.
  • amorphous obicetrapib hemicalcium is subjected to a milling process.
  • the milling process is adapted (e.g., parameters such as feed rate, venturi pressure and mill pressure are adapted) to allow production of micronized amorphous obicetrapib hemicalcium.
  • obicetrapib (i.e., starting material in step (i) above) is prepared by a method that comprises: (a) preparing a compound of Formula (IVA), by coupling a compound of Formula (IIA) or a salt thereof, with a compound of Formula (IIIA);
  • the reactions in steps (a)-(d) of the subject method are performed in a solvent, and intermediate compounds of Formulae (IVA), (VA) and (VIIIA) do not need to be isolated from their respective solvents if they are to be processed further to end products.
  • the intermediate compound of Formula (VIA) may be isolated from the solvent as a salt in solid form, such that it can be washed to remove impurities. This isolation step ensures sufficient purity of downstream products.
  • the subject process does not need to comprise purification steps using chromatography, such as column chromatography to achieve the chemical purity levels described herein.
  • the amorphous obicetrapib hemicalcium is prepared by the method set out in Scheme 1.
  • amorphous obicetrapib hemicalcium (compound 3) was prepared in six chemical steps and three isolations from the mesylate salt of (2R,4S)-4- amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A), t-butyl-4-(2- chloropyrimidin-5-yloxy)-butyrate (compound IB), and 3,5-bis(trifluoromethyl)benzyl bromide (compound IE).
  • Compound 1A was coupled with compound IB through a palladium-catalyzed reaction to produce a solution of (2R,4S)-4-[5-(3-t- butoxy carbonylpropoxy )pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline (compound 1C), which was not isolated but directly reacted with excess ethyl chloroformate in the presence of pyridine to produce (2R,4S)-4-[5-(3-t- butoxy carbonylpropoxy )pyrimidin-2 -yl)]amino-2-ethyl-6-tri fluoromethyl-3, 4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester, which was isolated as a crystalline mesylate salt (compound ID).
  • the crystalline mesylate salt, compound ID was alkylated with 3,5 bis(trifluoromethyl)benzyl bromide (compound IE) under strongly basic conditions to produce a solution of (2R,4S)-4- ⁇ [3,5-bis(trifluoromethyl)benzyl]-[5-(3-t- butoxy carbonylpropoxy) pyrimidin-2-yl]amino ⁇ -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (compound IF) in toluene.
  • the bottom aqueous phase was drained, and an aqueous solution of sodium chloride (310 L, 5.0 vol.) was added. The reaction mixture was then stirred at 20°C for 30 minutes. The stirring was once again halted and the reaction mixture was allowed to split 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. The stirring was once again halted and the recti on mixture was allowed to split into two phases. The bottom aqueous phase was separated. The resulting organic solution was then distilled under vacuum at an internal temperature of 65°C or less. Distillation was continued until a final visual volume of 4.0 volumes (250 L) was reached.
  • reaction vessel B a second reaction vessel
  • (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 of reaction vessel B was transferred to vessel A.
  • K3PO4 85 kg, 400 mol, 2.20 equiv. was further added to vessel A and the resulting reaction mixture was heated to an internal temperature of 72°C and stirred for at least 2 hours.
  • the internal temperature of the reaction mixture was then increased linearly to 20°C over the course of 3.5 hours.
  • the mixture was then distilled under vacuum at an internal temperature of 60°C or less. Distillation was continued until approximately 2.50 volumes by visual observation (155 L).
  • 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 less until roughly 2.50 volumes remained by visual observation (155 L).
  • isopropyl acetate (471 L, 6.6 vol.) IM hydrochloric acid (307 L, 5.0 vol.), and 26% aqueous sodium chloride (63 L, 1.2 vol.) were added to the reaction vessel.
  • the resulting mixture was stirred for 30 minutes, then separated into two phases.
  • the bottom aqueous phase was separated, and saturated aqueous sodium bicarbonate solution (132 L, 2.3 vol.) was added.
  • the resulting mixture was stirred for 30 minutes, then separated into two phases.
  • Tetrabutylammonium hydrogensulfate (3.5 kg, 0.16 equiv.) and sodium tert-pentoxide (34.5 kg, 4.8 equiv.) were then added and the resulting reaction mixture was stirred for 10 minutes and degassed with nitrogen.
  • 3,5- bis(trifluoromethyl)benzyl bromide (Compound IE) (28 kg, 1.41 equiv.) was then added to the reaction mixture and stirring was continued for 6.5 hours at 5°C.
  • the reaction mixture was then treated with IN acetic acid solution (320 kg) and allowed to stir for approximately 30 minutes at 20°C. After which time, the stirring was stopped and the mixture was allowed to separate into two phases.
  • the lower aqueous phase was then further treated with water (90 kg, 1.89 wt.), ⁇ -heptane (95 kg, 2.00 wt.), acetonitrile (38 kg, 0.80 wt.) and toluene (42 kg, 0.88 wt.) and once again agitated 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 agitated for an additional 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 tribasic dihydrate (34 kg, 0.72 wt.) and water (205 kg, 4.32 wt.). The resulting mixture was vigorously agitated for 30 minutes and then allowed to separate into two phases before discarding the lower aqueous phase. The remaining organic phase was treated once again with water (240 kg, 5.05 wt.) and agitated for 30 minutes before allowing to separate into two phases and discharging the lower aqueous phase. The organic phase was then concentrated to approximately 3 volumes (approximately 149 L) in-vacuo maintaining an internal temperature of 50°C or less.
  • reaction mixture was diluted with cyclopentyl methyl ether (CPME, 250 kg, 5.26 wt.) and agitated.
  • CPME cyclopentyl methyl ether
  • the solution was then concentrated to approximately 3 volumes (approximately 165 L) in-vacuo maintaining an internal temperature of 50°C or less.
  • seed crystal slurry An aliquot of the reaction mixture was removed, cooled to 11 °C at a linear cooling rate until a slurry formed containing crystals of compound 2 in CPME///-heptane (referred to herein as “seed crystal slurry”).
  • the opaque reaction mixture was then cooled to 11°C over the course of 12 hours at a linear cooling rate.
  • the reaction mixture was then filtered under vacuum at 11°C to collect the solid wet HC1 intermediate (compound 2).
  • a seed crystal slurry of compound 2 (291 g, 0.87 weight percent) in CPME/zz-heptane was then added at 50°C and this temperature was held for 105 minutes.
  • the opaque reaction slurry was then cooled to 11°C over 12 hours at a linear cooling rate.
  • the slurry was then filtered under vacuum at 9°C using a filter dryer.
  • 20 vol.% of CPME in //-heptane (57.4 kg CPME, 180 kg //-heptane) was then added to the reaction vessel and cooled to 11°C.
  • Half the mixture was then poured through the filter dryer as a chromatography wash. The second half was passed through the filter dryer as a slurry wash.
  • Deionized water (245 kg, 7.00 wt.) was added, the reaction mixture was stirred at 23°C for 35 minutes, then the stirring was 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 further 3 times.
  • the organic phase was then concentrated under reduced pressure to approximately 71 L (approximately 2 vol.) maintaining an internal temperature of 55°C or less.
  • Ethanol 115 kg, 3.29 wt.
  • the 14% wt. NaOH solution (15.8 kg, 1.13 eq.) was then added to the reaction vessel containing compound 1 in ethanol maintaining a reaction temperature of 20°C.
  • the reaction mixture was stirred at 20°C for 5 hours to achieve full conversion.
  • Solution B was then cooled to 9°C with agitation.
  • Solution A (see above) was then added via a filter to Solution B over 90 minutes, maintaining a temperature of 10°C.
  • the Solution A vessel was then rinsed forward to solution B with additional ethanol (50 kg, 1.43 wt. relative to compound 1).
  • the resulting slurry was stirred for 1 hour at 9°C.
  • the solids were then collected by filtration and rinsed with deionized water (2 x 175 kg, 5 wt. relative to compound 1).
  • Venturi pressure 100 PSI / 6.9 bar
  • XRPD was performed with Panalytical X’Pert 3 Powder diffractometer using an incident beam of Cu radiation produced using an Empyran tube, fine focused source, on a silicon zero-background holder.
  • a silicon standard NIST SRM 640d
  • Approximately 5 to 10 mg of sample was placed on a silicon zero-background holder and flattened manually using an aluminum spatula to minimize difference in the overall sample height. The holder was then loaded on the instrument for analysis.
  • the XRPD parameters used are listed immediately in Table B below.
  • a PANalytical x-ray powder diffractometer was used with the following measurement conditions, with data acquisition by DataViewer and data evaluation by X’Pert
  • Diffraction patterns were measured using a Thermo Fisher Scientific ARL Equinox 1000 powder diffractometer.
  • the diffractometer is equipped with a copper source and a germanium (111) monochromator providing monochromatic Cu Kai radiation, and a position sensitive gas-ionization detector.
  • Samples were measured in reflection mode using an Al sample holder without any further preparation (i.e., grinding).
  • the detector measures over the entire angle range from approx. 2°29 to 120° 29 simultaneously; in the case of HCl obicetrapib, discernible signals useful for phase identification are seen up to approx. 45°29.
  • the temperature in the diffractometer is typically around 30 °C during measurements.
  • compositions disclosed herein also include a SGTL2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • SGLT2 inhibitor refers to a compound, in particular to a glucopyranosyl-derivative, i.e. compound having a glucopyranosyl-moiety, which shows an inhibitory effect on the sodium-glucose transporter 2 (SGLT2), in particular the human SGLT2.
  • the activity of the SGLT2 inhibitor is determined by an inhibition assay, e.g., by an assay that determines the level of activity of the enzyme either in a cell-free system or in a cell after treatment with a subject compound, relative to a control, by measuring the ICso or ECso value, respectively.
  • the SGLT2 inhibitor has an ICso value (or ECso value) of 19 pM or less, such as 3 pM or less, 1 pM or less, 599 nM or less, 399 nM or less, 299nM or less, 199 nM or less, 59 nM or less, 39 nM or less, 1 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even lower.
  • the inhibitory effect on human SGLT2 can be determined by methods known in the literature, in particular as described in the application WO 2995/992877 or WO 2997/993619 (pages 23/24), which are incorporated herein by reference in their entirety.
  • the term “SGLT2 inhibitor” also comprises any pharmaceutically acceptable salts thereof, hydrates and solvates thereof, including the respective crystalline forms.
  • the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin, remogliflozin etabonate, sergliflozin, sergliflozin etabonate, atigliflozin, and sotagliflozin.
  • the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, and sotagliflozin.
  • the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, and empagliflozin.
  • the SGLT2 inhibitor is empagliflozin.
  • the SGLT2 inhibitor is dapagliflozin.
  • the SGLT2 inhibitor is canagliflozin.
  • the SGLT2 inhibitor is ertugliflozin.
  • the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (II): or a hydrate, solvent, or pharmaceutically acceptable salt thereof, wherein:
  • R 1 is halogen (e.g., chloro), (Ci-3)alkyl, or cyano; each R 2 is independently H, (Ci-3)alkyl, (Ci-3)alkoxy or hydroxy;
  • R 3 is (Ci-3)alkyl, cycloalkyl, alkynyl, (Ci-3)alkoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and n is 0 to 3.
  • the SGLT2 inhibitor is a prodrug of any of the beforementioned SGLT2 inhibitors.
  • the SGLT2 inhibitor of formula (II) and methods of their synthesis are described, for example, in the following international patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO 2008/055870, the disclosures of which are incorporated herein by reference.
  • R 1 is methyl. In some cases, R 1 is halogen. In certain cases, the halogen is chloride. In some other cases, R 1 is cyano.
  • each R 2 is H. In certain some embodiments, n is 1 and R 2 is methyl. In certain embodiments, n is 1 and R 2 is methoxy. In certain embodiments, n is i and R 2 is hydroxy.
  • R 3 is ethyl, cyclopropyl, ethynyl, (R)- tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. In some cases, R 3 is cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. In certain cases, R 3 is ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.
  • the SGLT2 inhibitor is selected from any one of the following compounds: [0105] It is to be understood that the definitions of the above listed SGLT2 inhibitors, including the glucopyranosyl-substituted benzene derivatives of the formula (II), also comprise their hydrates, solvates, polymorphic forms thereof.
  • the term “empagliflozin” as used herein refers to empagliflozin, including hydrates, solvates, and crystalline forms thereof.
  • the SGLT2 inhibitor is in the crystalline form as described in the international patent application WO 2006/117360, which hereby is incorporated herein in its entirety.
  • the SGLT2 inhibitor is in the crystalline form as described in the international patent application WO 2006/117359, which hereby is incorporated herein in its entirety. In certain some embodiments, the SGLT2 inhibitor is in the crystalline form as described in the international patent application WO 2008/049923, which hereby is incorporated herein in its entirety. These crystalline forms possess good solubility properties which can enable good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline forms are physico-chemically stable and thus provide a good shelf-life stability of the pharmaceutical composition.
  • the term “dapagliflozin” as used herein refers to dapagliflozin, including hydrates, solvates, and crystalline forms thereof.
  • the compound and methods of its synthesis are described in WO 03/099836 for example. Hydrates, solvates and crystalline forms are described in the patent applications WO 2008/116179 and WO 2008/002824, for example.
  • canagliflozin refers to canagliflozin, including hydrates, solvates, and crystalline forms thereof.
  • the compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969, for example. Certain hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327, for example.
  • atigliflozin refers to atigliflozin, including hydrates, solvates, and crystalline forms thereof.
  • the compound and methods of its synthesis are described in WO 2004/007517, for example.
  • ipragliflozin refers to ipragliflozin, including hydrates, solvates, and crystalline forms thereof.
  • the compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475, for example.
  • tofogliflozin refers to tofogliflozin, including hydrates, solvates, and crystalline forms thereof.
  • the compound and methods of its synthesis are described in WO 2007/140191 and WO 2008/013280, for example.
  • remogliflozin refers to remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates, solvates, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888, for example.
  • sergliflozin refers to sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates, solvates, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089, for example.
  • the pharmaceutical composition comprises a therapeutically effective amount of a SGLT2 inhibitor (e.g., as described herein).
  • a “therapeutically effective amount” refers to an amount effective to inhibit SGLT2, and/or lower glucose reabsorption.
  • a “therapeutically effective amount” of an SGLT2 inhibitor is an amount that, when administered to an individual in one or more doses, in combination therapy (e.g., as described herein with obicetrapib), is effective to lower glucose reabsorption in the subject by 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 glucose reabsorption level in the individual in the absence of treatment with the combination, or alternatively, compared to the glucose level in the subject before or after treatment with the combination.
  • combination therapy e.g., as described herein with obicetrapib
  • the pharmaceutical composition comprises from about 1% to about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises from about 1% to about 50% w/w, or from about 1% to about 40% w/w, about 1% to about 30% w/w, about 1% to about 20%, about 1% to 10%, or from about 5% to about 15% w/w, or from about 10% to about 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises about 5% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises about 10% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 15% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 50% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises from 1% to 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises from 1% to 50% w/w, or from 1% to 40% w/w, 1% to 30% w/w, 1% to 20%, 1% to 10%, or from 5% to 15% w/w, or from 10% to 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises 5% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises 10% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 15% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 50% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical compositions disclosed herein may optionally include one or more additional active agents.
  • at least one of the one or more additional active agents is an antidiabetic agent.
  • at least of the one or more additional actives is an antidiabetic agent selected from biguanides, thiazolidinediones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, insulin, glucagon- like peptide-1 (GLP-1) agonist, dipeptidyl peptidase-4 (DPP -4) inhibitors and amylin analogs, including pharmaceutically acceptable salts of the beforementioned agents.
  • GLP-1 glucagon- like peptide-1
  • DPP -4 dipeptidyl peptidase-4
  • amylin analogs including pharmaceutically acceptable salts of the beforementioned agents.
  • the combination of obicetrapib, a SGLT2 inhibitor, and one or more additional active agents according to the present disclosure can allow for a reduction
  • a dose reduction can be beneficial for patients who otherwise would potentially suffer from side effects in a therapy using a higher dose of one or more of the active ingredients.
  • the pharmaceutical composition and methods according to the present disclosure can exhibit fewer side effects to a corresponding monotherapy with any of the active agents (e.g., obicetrapib or the SGLT2 inhibitor), thereby making the therapy more tolerable and improving an individual’s compliance with the treatment.
  • the additional active agent is a biguanide.
  • biguanides include metformin, phenformin and buformin.
  • the additional active agent is metformin.
  • metformin refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2: 1) fumarate salt, and the metformin (2: 1) succinate salt, the hydrobromide salt, the p- chlorophenoxy acetate or the embonate, and other known metformin salts of mono and dibasic carboxylic acids. It one embodiment, the metformin employed herein is the metformin hydrochloride salt.
  • the pharmaceutical composition comprises from 1 to 50 % w/w of metformin hydrochloride salt, such as 1 to 45% w/w, 1 to 40% w/w, 1 to 35% w/w, 1 to 30% w/w, 1 to 25% w/w, 1 to 20% w/w, 1 to 15% w/w, 1 to 10% w/w, or 1 to 5% w/w of metformin hydrochloride salt.
  • metformin hydrochloride salt such as 1 to 45% w/w, 1 to 40% w/w, 1 to 35% w/w, 1 to 30% w/w, 1 to 25% w/w, 1 to 20% w/w, 1 to 15% w/w, 1 to 10% w/w, or 1 to 5% w/w of metformin hydrochloride salt.
  • the additional active agent is a DPP-4 inhibitor.
  • DPP -4 inhibitors examples include linagliptin, sitagliptin, vildagliptin, saxagliptin, denagliptin, alogliptin, carmegliptin, melogliptin, dutogliptin, including pharmaceutically acceptable salts, hydrates and solvates thereof.
  • the DPP-4 inhibitor is linagliptin.
  • the pharmaceutical composition comprises from 1 to 10 % w/w of linagliptin, such as 1 to 9% w/w, 1 to 8% w/w, 1 to 7% w/w, 1 to 6% w/w, 1 to 5% w/w, 2 to 5% w/w, 2 to 4% w/w, of linagliptin, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises 2.5% w/w of linagliptin, or a salt, solvate or hydrate thereof.
  • the pharmaceutical composition comprises 5% w/w of linagliptin, or a salt, solvate or hydrate thereof.
  • the additional active agent is a GLP-1 agonist.
  • GLP-1 agonists are semaglutide, exenatide, dulaglutide, liraglutide, lixisenatide or tirzepatide, including pharmaceutically acceptable salts, hydrates and solvates thereof.
  • the GLP-1 agonist is liraglutide.
  • the GLP-1 agonist is semaglutide.
  • the GLP-1 agonist is dulaglutide.
  • the additional active agent is a thiazolidinedione.
  • thiazolidinediones includes pioglitazone and rosiglitazone.
  • the term "pioglitazone” as employed herein refers to pioglitazone, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salt thereof such as the hydrochloride salt.
  • the term "rosiglitazone” as employed herein refers to rosiglitazone, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salt thereof such as the maleate salt.
  • the additional active agent is a sulfonylurea.
  • sulfonylureas are glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibomuride, glyburide, glisoxepide and gliclazide.
  • the sulfonylurea is selected from tolbutamide, gliquidone, glibenclamide, glipizide and glimepiride.
  • the sulfonylurea is selected from glibenclamide, glipizide and glimepiride.
  • glibenclamide refers to the respective active drug or a pharmaceutically acceptable salt thereof.
  • the additional active agent is a glinide.
  • glinides are nateglinide, repaglinide and mitiglinide.
  • nateglinide refers to nateglinide, including its enantiomers, mixtures thereof and its racemate, or pharmaceutically acceptable salts and esters thereof.
  • repaglinide refers to repaglinide, including its enantiomers, mixtures thereof and its racemate, or pharmaceutically acceptable salts and esters thereof.
  • the additional active agent is an inhibitor of alphaglucosidase.
  • inhibitors of alpha- glucosidase are acarbose, voglibose and miglitol.
  • acarbose voglibose
  • miglitol miglitol
  • the additional active is an amylin analog.
  • An example of an amylin analog is pramlintide, including pharmaceutically acceptable salts, hydrates and solvates thereof.
  • pramlintide acetate is marketed under the tradename Symlin.
  • the pharmaceutical compositions disclosed herein include a combination of obicetrapib, an SGLT2 inhibitor and one or more further antidiabetic agents.
  • the further antidiabetic agent is metformin, linagliptin, or a combination thereof. 5.1.4. Excipients
  • the pharmaceutical compositions that comprise amorphous obicetrapib or calcium salt thereof and an SGLT2 inhibitor or pharmaceutically acceptable salt thereof further comprise one or more pharmaceutically acceptable excipients or carriers including but not limited to, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, surfactants, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof.
  • pharmaceutically acceptable excipients or carriers including but not limited to, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, surfactants, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof.
  • compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington: The Science and Practice of Pharmacy (23rd Edition, ISBN-13: 978- 0128200070); and Modern Pharmaceutics, Marcel Dekker, Inc., 4th Ed. (G. S. Banker & C. T. Rhodes, Eds.).
  • the pharmaceutical compositions provided in accordance with the present disclosure are administered orally and the pharmaceutical composition is formulated for oral delivery.
  • the pharmaceutical composition may be in the form of an oral unit dosage form. Administration may be via capsule, tablet, or the like.
  • the amorphous obicetrapib or calcium salt thereof and the SGLT2 inhibitor or pharmaceutically acceptable salt thereof combination is in the form of a tablet.
  • the tablet is a compressed tablet.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, tablet, sachet, or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • the pharmaceutical composition may be formulated for immediate release or sustained release.
  • a “sustained release formulation” is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time
  • an “immediate release formulation” is a formulation which is designed to quickly release a therapeutic agent in the body over a shortened period of time.
  • the immediate release formulation may be coated such that the therapeutic agent is only released once it reached the desired target in the body (e.g. the stomach).
  • the pharmaceutical composition is formulated for immediate release.
  • the pharmaceutical composition may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described herein.
  • the tablet When the pharmaceutical composition is formulated into a tablet, the tablet may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • the pharmaceutical composition comprises a diluent selected from the group consisting of dicalcium phosphate, cellulose, microcrystalline cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate, mannitol, tribasic calcium phosphate, and combinations thereof.
  • the diluent comprises microcrystalline cellulose.
  • the diluent comprises mannitol.
  • the diluent comprises lactose anhydrous or lactose monohydrate.
  • the pharmaceutical composition comprises a controlled release matrix.
  • the diluent is polyethylene oxide and hypromellose.
  • the pharmaceutical composition comprises microcrystalline cellulose in an amount from about 1 to about 100% w/w, or from about 1 to about 80% w/w, or from about 1% to about 75% w/w, or from about 5 to about 75% w/w, or from about 10 to about 70% w/w, or from about 15 to about 70% w/w.
  • the microcrystalline cellulose is present in an amount of about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75% w/w.
  • the microcrystalline cellulose is in an amount of about 60% w/w.
  • the microcrystalline cellulose is in an amount of about 65% w/w.
  • the pharmaceutical composition comprises microcrystalline cellulose in an amount from 1 to 100% vi/vi, or from 1 to 80% w/w, or from 1% to 75% w/w, or from 5 to 75% w/w, or from 10 to 70% w/w, or from 15 to 70% w/w.
  • the microcrystalline cellulose is present in an amount of 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75% w/w.
  • the microcrystalline cellulose is in an amount of 60% w/w.
  • the microcrystalline cellulose is in an amount of 65% w/w.
  • the pharmaceutical composition comprises mannitol in an amount from about 1 to about 40% w/w, or from about 1 to about 35% w/w, or from about 1% to about 25% w/w, or from about 5 to about 35% w/w, or from about 10 to about 30% w/w, or from about 15 to about 25% w/w.
  • the mannitol is present in an amount of about 5%, or about 20%, or about 15%, or about 30%, or about 22%, or about 23%, or about 24%, or about 25% w/w.
  • the microcrystalline cellulose is in an amount of about 20% w/w.
  • the pharmaceutical composition comprises mannitol in an amount from 1 to 40% w/w, or from 1 to 35% w/w, or from 1% to 25% w/w, or from 5 to 35% w/w, or from 10 to 30% w/w, or from 15 to 25% w/w.
  • the mannitol is present in an amount of 5%, or 20%, or 15%, or 30%, or 22%, or 23%, or 24%, or 25% w/w.
  • the microcrystalline cellulose is in an amount of 20% w/w.
  • the pharmaceutical composition comprises a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, modified corn starch, pregelatinized starch, sodium starch glycolate, and combinations thereof.
  • the pharmaceutical composition comprises sodium starch glycolate in an amount from about 1 to about 20% w/w, or from about 1 to about 15% w/w, or from about 1 to about 10% w/w, or from about 1 to about 8% w/w, or from about 2 to about 8% w/w.
  • the croscarmellose sodium is present in an amount of about 1%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 10% w/w.
  • the croscarmellose sodium is in an amount of about 5% w/w.
  • the pharmaceutical composition comprises sodium starch glycolate in an amount from 1 to 20% w/w, or from 1 to 15% w/w, or from 1 to 10% w/w, or from 1 to 8% w/w, or from 2 to 8% w/w.
  • the croscarmellose sodium is present in an amount of 1%, or 3%, or 4%, or 5%, or 6%, or 7%, or 10% w/w.
  • the croscarmellose sodium is in an amount of 5% w/w.
  • the pharmaceutical composition comprises a glidant selected from the group consisting of colloidal silicon dioxide, talc, and combinations thereof.
  • the pharmaceutical composition comprises colloidal silicon dioxide in an amount from about 0.1 to about 5% w/w, or from about 0.1 to about 4.5% w/w, or from about 0.1 to about 4% w/w, or from about 0.5 to about 5.0% w/w, or from about 0.5 to about 3% w/w, or from about 0.5 to about 2% w/w, or from about 0.5 to about 1.5% w/w.
  • the colloidal silicon dioxide is present in an amount of about 0.1% w/w, 0.5% w/w, 0.75% w/w, 0.95% w/w, 1.0% w/w, or 1.2% w/w.
  • the colloidal silicon dioxide is present in an amount of about 1% w/w.
  • the pharmaceutical composition comprises colloidal silicon dioxide in an amount from 0.1 to 5% vi/vi, or from 0.1 to 4.5% vi/vi, or from 0.1 to 4% w/w, or from 0.5 to 5.0% w/w, or from 0.5 to 3% w/w, or from 0.5 to 2% w/w, or from 0.5 to 1.5% w/w.
  • the colloidal silicon dioxide is present in an amount of 0.1% w/w, 0.5% w/w, 0.75% w/w, 0.95% w/w, 1.0% w/w, or 1.2% w/w.
  • the colloidal silicon dioxide is present in an amount of 1% w/w.
  • the pharmaceutical composition comprises a lubricant selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, and combinations thereof.
  • the pharmaceutical composition comprises magnesium stearate in an amount from about 0.1 to about 3% w/w, or from about 0.1 to about 2.5% w/w, or from about 0.5 to about 3% w/w, or from about 0.5 to about 2.5% w/w, or from about 0.5 to about 2% w/w, or from about 1 to about 3% w/w, or from about 1 to about 2% w/w.
  • the magnesium stearate is present in an amount of about 0.1%, or about 0.5, or about 0.7%, or about 0.9%, or about 1.0%, or about 1.2% w/w.
  • the magnesium stearate is in an amount of about 1% w/w.
  • the pharmaceutical composition comprises magnesium stearate in an amount from 0.1 to 3% w/w, or from 0.1 to 2.5% w/w, or from 0.5 to 3% w/w, or from 0.5 to 2.5% vi/vi, or from 0.5 to 2% w/w, or from 1 to 3% w/w, or from 1 to 2% w/w.
  • the magnesium stearate is present in an amount of 0.1%, or 0.5, or 0.7%, or 0.9%, or 1.0%, or 1.2% w/w.
  • the magnesium stearate is in an amount of 1% w/w.
  • the pharmaceutical composition comprises a) about 1 to about 10% w/w of amorphous obicetrapib, or calcium salt, solvate or hydrate thereof, and b) about 5 to about 20% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the composition comprises a) about 5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) about 5-20% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the composition comprises a) about 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) about 5-25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the composition further comprises a) about 40 to about 65% w/w microcrystalline cellulose, b) about 5 to about 23% w/w mannitol, c) about 1 to about 10% w/w sodium starch glycolate, d) about 0.5 to about 3% w/w colloidal silicon dioxide, and e) about 0.1 to about 3% w/w magnesium stearate.
  • the composition comprises a) about 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) about 5-25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof, c) about 40 to about 65% w/w microcrystalline cellulose, d) about 5 to about 23% w/w mannitol, e) about 1 to about 10% w/w sodium starch glycolate, f) about 0.5 to about 3% w/w colloidal silicon dioxide, and g) about 0.1 to about 3% w/w magnesium stearate.
  • the pharmaceutical composition comprises a) 1 to 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) 5 to 20% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the composition comprises a) 5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) 5-20% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the composition comprises a) 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) 5-25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the composition further comprises a) 40 to 65% w/w microcrystalline cellulose, b) 5 to 23% w/w mannitol, c) 1 to 10% w/w sodium starch glycolate, d) 0.5 to 3% w/w colloidal silicon dioxide, and e) 0.1 to 3% w/w magnesium stearate.
  • the composition comprises a) 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) 5-25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof, c) 40 to 65% w/w microcrystalline cellulose, d) 5 to 23% w/w mannitol, e) 1 to 10% w/w sodium starch glycolate, f) 0.5 to 3% w/w colloidal silicon dioxide, and g) 0.1 to 3% w/w magnesium stearate.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the SGLT2 inhibitor is empagliflozin, in an amount of 7- 9% w/w, or 18-20% w/w; and the obicetrapib is in an amount of 3.5-5% w/w, or 7-10% w/w.
  • the pharmaceutical composition comprises:
  • the SGLT2 inhibitor is dapagliflozin, in an amount of 4- 5% w/w, or 8-10% w/w; and the obicetrapib is in an amount of 4-5% w/w, or 8-10% w/w.
  • the pharmaceutical composition comprises:
  • the SGLT2 inhibitor is ertugliflozin, in an amount of 4- 5% w/w, or 11-13% w/w; and the obicetrapib is in an amount of 4-5% w/w, or 8-10% w/w.
  • the pharmaceutical composition comprises:
  • the SGLT2 inhibitor is canagliflozin, in an amount of 45-50% w/w, or 70-75% w/w; and the obicetrapib is in an amount of 1-3% w/w, or 3-5% w/w.
  • compositions described herein can be formulated with amorphous obicetrapib or calcium salt thereof and an SGLT2 inhibitor or pharmaceutically acceptable salt thereof as the two sole pharmaceutically active ingredients in the composition or can be combined with other active ingredients (e.g., as described herein).
  • the pharmaceutical composition is formulated into one or more suitable pharmaceutical preparations, such as solutions, suspensions, powders, sustained release formulations or elixirs in sterile solutions or suspensions for parenteral administration, or as transdermal patch preparation and dry powder inhalers.
  • suitable pharmaceutical preparations such as solutions, suspensions, powders, sustained release formulations or elixirs in sterile solutions or suspensions for parenteral administration, or as transdermal patch preparation and dry powder inhalers.
  • obicetrapib and the SGLT2 inhibitor described herein may be mixed with a suitable pharmaceutical carrier.
  • the concentration of the each active in the compositions can, for example, be effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates a condition or disorder described herein or a symptom thereof.
  • the pharmaceutical compositions provided herein are formulated for single dosage administration.
  • the weight fraction of each active is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.
  • Concentrations of the amorphous obicetrapib and SGLT2 inhibitor in a pharmaceutical composition provided herein will depend on, e.g., the physicochemical characteristics of the compounds, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, if the composition comprises a salt of obicetrapib the amount of said salt to be administered and/or to be incorporated into a pharmaceutical composition (i.e., pharmaceutical dosage form) needs to be adjusted to take account of the molecular weight difference between the free base and salt form.
  • compositions described herein are provided for administration to a subject, for example, humans or animals (e.g., mammals) in unit dosage forms, such as sterile parenteral (e.g., intravenous) solutions or suspensions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
  • Pharmaceutical compositions are also provided for administration to humans and animals in unit dosage form, including oral or nasal solutions or suspensions and oil-water emulsions containing suitable quantities of a conjugate or pharmaceutically acceptable derivatives thereof.
  • the conjugate is, in certain embodiments, formulated and administered in unit-dosage forms or multiple-dosage forms.
  • Unit-dose forms as used herein refers to physically discrete units suitable for human or animal (e.g., mammal) subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of obicetrapib and SGLT2 inhibitor sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged tablets. Unit-dose forms can be administered in fractions or multiples thereof.
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of capsules or bottles. Hence, in specific aspects, multiple dose form is a multiple of unit-doses which are not segregated in packaging.
  • the obicetrapib and SGLT2 inhibitor described herein are in a liquid pharmaceutical formulation.
  • Liquid pharmaceutically administrable formulations can, for example, be prepared by dissolving, dispersing, or otherwise mixing the active compounds and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, and the like, to thereby form a solution or suspension.
  • a pharmaceutical composition provided herein to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, and pH buffering agents and the like.
  • the pharmaceutical composition is formulated as a solid dosage form, such as a tablet or a capsule (e.g., as described herein below).
  • this disclosure provides a pharmaceutical unit dosage form comprising the pharmaceutical composition described herein.
  • the disclosure provides for tablets, pills, and the like, comprising the pharmaceutical compositions or dosage forms described herein.
  • the tablets or pills of the present disclosure may be coated to provide a dosage form affording the advantage of prolonged action or to protect from the acid conditions of the stomach.
  • the tablets may also be formulated for immediate release as previously described.
  • the tablet comprises a film coating.
  • a film coating may be useful for limiting photolytic degradation. Suitable film coatings are selected by routine screening of commercially available preparations.
  • the film coating is a hypromellose-based coating.
  • the coating represents 2- 5% by weight of the total tablet composition and comprises a film-forming agent, a plasticizer, a glidant and optionally one or more pigments. In certain cases, the coating represents 3% of the total tablet composition.
  • An exemplary film coating composition may comprise hydroxypropyl methylcellulose (HPMC), lactose monohydrate, titanium dioxide, and triglyceride 1,2,3-triacetoxypropane (triacetin). In certain cases, the film coating composition may comprise hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and optionally iron oxide, including iron oxide red and/or yellow.
  • the tablets may be formulated into a monolayer or bilayer tablet.
  • monolayer tablets comprise the active ingredients (i.e., obicetrapib and the SGLT2 inhibitor) co-mixed in a single uniform layer.
  • exemplary methods include direct compression, wet granulation and dry granulation.
  • the direct compression tablet process uses two primary process steps: blending the active ingredients with the excipients and compressing the finished tablet.
  • the present disclosure provides a wet granulation process for making the subject pharmaceutical dosage form, wherein said process comprises the steps of:
  • step (1) (2) granulating the pre-mixture of step (1) by adding the granulation liquid, e.g., purified water;
  • the granulation liquid e.g., purified water
  • step (3) drying the granules of step (2) in a fluidized bed dryer or a drying oven;
  • step (3) optionally dry sieving of the dried granules of step (3);
  • step (4) mixing the dried granules of step (4) with the remaining excipients like glidant and lubricant in a mixer to obtain the final mixture;
  • step (6) tableting the final mixture of step (5) by compressing it on a suitable tablet press to produce tablets cores;
  • step (6) optionally film-coating of the tablet cores of step (6) with a non-functional coat.
  • the present invention provides a pharmaceutical dosage form (e.g., as described herein) obtainable by a wet granulation process.
  • the present disclosure provides a direct compression process for making the subject pharmaceutical dosage form, wherein said process comprises the steps of:
  • step (3) mixing the pre-mixture of step (1) or (2) in a mixer, optionally by adding remaining excipients to the mixture and continuing mixing;
  • step (3) tableting the final mixture of step (3) by compressing it on a suitable tablet press to produce the tablet cores;
  • step (4) optionally film-coating of the tablet cores of step (4) with a non-functional coat.
  • the present invention provides a pharmaceutical dosage form obtainable (e.g., as described herein) by a direct compression process.
  • the present disclosure provides a dry granulation process for making the subject pharmaceutical dosage form, wherein said process comprises the steps of:
  • step (3) reducing the ribbons obtained during step (2) to granules, preferably small granules, by suitable milling or sieving steps;
  • step (3) optionally mixing the granules of step (3) with the remaining excipients in a mixer to obtain the final mixture;
  • step (3) tableting the granules of step (3) or the final mixture of step (4) by compressing it on a suitable tablet press to produce the tablet cores;
  • step (6) optionally film-coating of the tablet cores of step (5) with a non-functional coat.
  • the present invention provides a pharmaceutical dosage form (e.g., as described herein) obtainable by a dry granulation process.
  • Bilayer tablets comprise the active ingredients (i.e., obicetrapib and the SGLT2 inhibitor) in separate layers and can be made by making a blend comprising excipients and one active ingredient (i.e., obicetrapib), and making a separate blend comprising the second active ingredient (i.e., the SGLT2 inhibitor) and excipients. One blend may then be precompressed, and the second blend may then be added on top of the first pre-compressed blends. The resulting tablet comprises two separate layers, each layer comprising a different active ingredient.
  • the pharmaceutical dosage form comprises the obicetrapib in a therapeutically effective amount (e.g., as described herein for obicetrapib).
  • the pharmaceutical dosage form comprises from about 1% to about 25% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises from about 1% to about 20% w/w, or from about 1% to about 15% w/w, or from about 1% to about 10% w/w, or from about 5% to about 15% w/w, or from about 5% to about 12% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form 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 amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises about 3-5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 7-10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises from 1% to 25% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises from 1% to 20% w/w, or from 1% to 15% w/w, or from 1% to 10% w/w, or from 5% to 15% w/w, or from 5% to 12% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form 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 amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises 3-5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises 7-10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises from about 1 mg to about 25 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of obicetrapib in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises from about 1 mg to about 20 mg of amorphous obicetrapib, or from about 1 mg to about 15 mg of amorphous obicetrapib, or from about 1 mg to about 10 mg of amorphous obicetrapib, or from about 5 mg to about 15 mg of amorphous obicetrapib, or from about 5 mg to about 12 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose.
  • the pharmaceutical dosage form comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of obicetrapib in an equivalent dose.
  • the pharmaceutical dosage form comprises about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose.
  • the pharmaceutical dosage form comprises about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In another embodiment, the pharmaceutical dosage form comprises 5 mg of obicetrapib as the amorphous calcium salt. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of obicetrapib as the amorphous calcium salt.
  • the pharmaceutical dosage form comprises from 1 mg to 25 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises from 1 mg to 20 mg, or from 1 mg to 15 mg, or from 1 mg to 10 mg, or from 5 mg to 15 mg, or from 5 mg to 12 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose.
  • the pharmaceutical dosage form comprises 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose.
  • the pharmaceutical dosage form comprises 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose.
  • the pharmaceutical dosage form comprises 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In another embodiment, the pharmaceutical dosage form comprises 5 mg of obicetrapib as the amorphous calcium salt. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of obicetrapib as the amorphous calcium salt.
  • the pharmaceutical dosage form comprises the SGLT2 inhibitor in a therapeutically effective amount (e.g., as described herein for the subject SGLT2 inhibitors).
  • the pharmaceutical dosage form comprises from about 1% to about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises from about 1% to about 40% w/w, or from about 1% to about 30% w/w, about 1% to about 20% w/w, about 1% to about 10%, or from about 5% to about 15% w/w, or from about 10% to about 25% w/w, or from about 45% to about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, or about 75% w/w, of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises about 5% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises about 10% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 15% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 50% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises from 1% to 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises from 1% to 40% w/w, or from 1% to 30% w/w, 1% to 20% w/w, 1% to 10%, or from 5% to 15% w/w, or from 10% to 25% w/w, or from 45% to 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, or 75% w/w, of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises 5% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises 10% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 15% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 50% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.
  • the pharmaceutical dosage form comprises from about 1 mg to about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises from about 5 mg to about 100 mg of the SGLT2 inhibitor, or from about 5 mg to about 50 mg of the SGLT2 inhibitor, or from about 10 mg to about 25 mg of the SGLT2 inhibitor, or from about 5 mg to about 15 mg of the SGLT2 inhibitor, or from about 5 mg to about 10 mg of SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical composition comprises about 100 mg, about 300 mg, about 150 mg to 250 mg, or about 100 mg to 200 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises about 5 mg, about 7 mg, about 8 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises about 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises about 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, any of the above amounts are of the free base form of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain some embodiments, the amounts are of a salt form of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises from 1 mg to 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises from 5 mg to 100 mg of the SGLT2 inhibitor, or from 5 mg to 50 mg of the SGLT2 inhibitor, or from 10 mg to 25 mg of the SGLT2 inhibitor, or from 5 mg to 15 mg of the SGLT2 inhibitor, or from 5 mg to 10 mg of SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical composition comprises 100 mg, 300 mg, 150 mg to 250 mg, or 100 mg to 200 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises 5 mg, 7 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 30 mg, 40 mg, or 50 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • any of the above amounts are of the free base form of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the amounts are of a salt form of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose and, b) about 10 mg to about 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the tablet comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the SGLT2 inhibitor is empagliflozin.
  • the pharmaceutical dosage form comprises a) 5 mg to 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose and, b) 10 mg to 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the tablet comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the SGLT2 inhibitor is empagliflozin.
  • the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 5 mg to about 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the tablet comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the tablet comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the SGLT2 inhibitor is ertugliflozin.
  • the pharmaceutical dosage form comprises a) 5 mg to 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 5 mg to 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the tablet comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the tablet comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the SGLT2 inhibitor is ertugliflozin.
  • the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 5 mg to about 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the SGLT2 inhibitor is dapagliflozin.
  • the pharmaceutical dosage form comprises a) 5 mg to 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 5 mg to 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the SGLT2 inhibitor is dapagliflozin.
  • the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 100 mg to about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the tablet comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose and b) about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the SGLT2 inhibitor is canagliflozin.
  • the pharmaceutical dosage form comprises a) 5 mg to 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 100 mg to 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the dosage form comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the tablet comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose and b) 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.
  • the SGLT2 inhibitor is canagliflozin.
  • the term “equivalent dose” refers to an amount of a given compound “equivalent” to a specified amount of a reference compound (e.g., a free base form of a compound).
  • a reference compound e.g., a free base form of a compound.
  • the amount of the salt to be incorporated in the pharmaceutical dosage form needs to be adjusted to take account of the molecular weight difference between obicetrapib as the free base form and the salt form.
  • the pharmaceutical dosage form comprises one or more additional active compounds (e.g., as described herein).
  • the pharmaceutical dosage form further comprises a therapeutically effective amount of metformin (e.g., metformin hydrochloride).
  • metformin e.g., metformin hydrochloride
  • the pharmaceutical dosage form comprises from 500 mg to 1000 mg of metformin, such as 500 mg to 900 mg, 500 mg to 800 mg, 500 mg to 700 mg, or 500 mg to 600 mg of metformin (e.g., metformin hydrochloride).
  • the pharmaceutical form further comprises a therapeutically effective amount of linagliptin.
  • the pharmaceutical dosage form comprises from 1 mg to 10 mg of linagliptin, such as 1 mg to 9 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 6 mg, 1 mg to 5 mg, 2 mg to 5 mg, 2 mg to 4 mg, of linagliptin, or a salt, solvate, or hydrate of linagliptin in an equivalent dose.
  • the pharmaceutical composition comprises 2.5 mg of linagliptin, or a salt, solvate, or hydrate of linagliptin in an equivalent dose.
  • the pharmaceutical composition comprises 5 mg of linagliptin, or a salt, solvate, or hydrate of linagliptin in an equivalent dose.
  • the pharmaceutical dosage form comprises one or more excipients (e.g., as described herein). In certain embodiments, the pharmaceutical dosage form comprises one or more diluents. In certain embodiments, the pharmaceutical dosage from comprises microcrystalline cellulose, mannitol, or a combination of both.
  • the pharmaceutical dosage form comprises microcrystalline cellulose in an amount from about 40 mg to 80 mg, such as 45 mg to 75 mg, 45 mg to 70 mg, 45 mg to 65 mg, or 50 to 65 mg.
  • the microcrystalline cellulose is in an amount of about 60 mg. In a further specific embodiment, the microcrystalline cellulose is in an amount of about 65 mg.
  • the pharmaceutical dosage form comprises microcrystalline cellulose in an amount from 40 mg to 80 mg, such as 45 mg to 75 mg, 45 mg to 70 mg, 45 mg to 65 mg, or 50 to 65 mg.
  • the microcrystalline cellulose is in an amount of 60 mg. In a further specific embodiment, the microcrystalline cellulose is in an amount of 65 mg.
  • the pharmaceutical dosage form comprises mannitol in an amount from about 1 mg to 35 mg, such as 1 mg to 30 mg, 1 mg to 30 mg, 1 mg to 25 mg, or 10 to 25 mg.
  • the microcrystalline cellulose is in an amount of about 23 mg.
  • the pharmaceutical dosage form comprises mannitol in an amount from 1 mg to 35 mg, such as 1 mg to 30 mg, 1 mg to 30 mg, 1 mg to 25 mg, or 10 to 25 mg.
  • the microcrystalline cellulose is in an amount of 23 mg.
  • the pharmaceutical dosage form comprises one or more disintegrants.
  • the disintegrant is sodium starch glycolate.
  • the pharmaceutical dosage form comprises sodium starch glycolate in an amount from about 1 mg to 15 mg, such as 1 mg to 10 mg, 1 mg to 8 mg, 2 mg to 7 mg, or 4 to 6 mg.
  • the sodium starch glycolate is in an amount of about 5 mg.
  • the pharmaceutical dosage form comprises sodium starch glycolate in an amount from 1 mg to 15 mg, such as 1 mg to 10 mg, 1 mg to 8 mg, 2 mg to 7 mg, or 4 to 6 mg.
  • the sodium starch glycolate is in an amount of 5 mg.
  • the pharmaceutical dosage form comprises one or more glidants.
  • the glidant is colloidal silicon dioxide.
  • the pharmaceutical dosage form comprises colloidal silicon dioxide in an amount from about 0.1 mg to 5 mg, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 to 2 mg. In a specific embodiment, the colloidal silicon dioxide is in an amount of about 1 mg.
  • the pharmaceutical dosage form comprises colloidal silicon dioxide in an amount from 0.1 mg to 5 mg, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 to 2 mg. In a specific embodiment, the colloidal silicon dioxide is in an amount of 1 mg.
  • the pharmaceutical dosage form comprises one or more lubricants. In certain cases, the lubricant is magnesium stearate. In certain embodiments, the pharmaceutical dosage form comprises magnesium stearate in an amount from about 0.1 mg to 5 mg, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 to 2 mg. In a specific embodiment, the colloidal silicon dioxide is in an amount of about 1 mg.
  • the pharmaceutical dosage form comprises magnesium stearate in an amount from 0.1 mg to 5 mg, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 to 2 mg.
  • the colloidal silicon dioxide is in an amount of 1 mg.
  • the pharmaceutical composition, pharmaceutical dosage form, or tablet as described herein is free of negative drug-drug interactions.
  • the pharmaceutical composition, pharmaceutical dosage form, or tablet is free of negative drug-drug interactions with other antidiabetic agents.
  • the pharmaceutical composition, pharmaceutical dosage form, or tablet as described herein is administrable without regard to food and with or without regard to the patient being on another antidiabetic agent.
  • a metabolic disorder or cardio-metabolic disorder comprising administering to a subject having or at risk of developing a metabolic or cardio-metabolic disorder, a therapeutically effective amount of a pharmaceutical composition, or a pharmaceutical dosage form comprising a pharmaceutical composition, that comprises a combination of amorphous obicetrapib or calcium salt thereof and an SGLT2 inhibitor or pharmaceutically acceptable salt thereof, as described herein.
  • methods for treating or preventing a metabolic disorder or cardio-metabolic disorder, the method comprising administering to a subject having or at risk of developing a metabolic disorder or cardio-metabolic disorder a therapeutically effective amount of amorphous obicetrapib or calcium salt thereof and administering a therapeutically effective amount of an SGLT2 inhibitor or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition or dosage form comprising a pharmaceutical composition comprising a combination of amorphous obicetrapib or calcium salt thereof and a SGLT2 inhibitor or pharmaceutically acceptable salt thereof as defined herein, or separately administering both obicetrapib and an SGLT2 inhibitor, can be used for preventing, slowing progression of, delaying or treating a metabolic disorder, and in particular for delaying progression to insulin-dependence. This opens up new therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus, obesity, complications of diabetes mellitus and of neighboring disease states.
  • a pharmaceutical composition or dosage form comprising a pharmaceutical composition comprising a combination of amorphous obicetrapib or calcium salt thereof and a SGLT2 inhibitor or pharmaceutically acceptable salt thereof as defined herein, or separately administering both obicetrapib and an SGLT2 inhibitor, can be used for improving health outcomes in a subject
  • the present disclosure provides a method for preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity and metabolic syndrome in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or separately administering both obicetrapib and an SGLT2 inhibitor.
  • a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity and metabolic syndrome in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or separately administering both obicetrapib and an
  • the pharmaceutical composition according to the present disclosure may also have valuable disease-modifying properties with respect to diseases or conditions related to impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or metabolic syndrome.
  • ITT impaired glucose tolerance
  • IGF impaired fasting blood glucose
  • metabolic syndrome insulin resistance
  • Also provided herein is a method for preventing, slowing, delaying or reversing progression from impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor.
  • ITT impaired glucose tolerance
  • IGF impaired fasting blood glucose
  • compositions and dosage forms described herein can be effective to treat conditions and/or diseases related to or caused by an increased blood glucose level.
  • complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina
  • tissue ischemia particularly comprises diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing and diabetic ulcer.
  • a method for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight in a patient in need thereof by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor.
  • the pharmacological effect of the combination of obicetrapib and an SGLT2 inhibitor in the pharmaceutical composition, or through separate administration, according to the present disclosure is independent of insulin. Therefore, an improvement of the glycemic control is possible without an additional strain on the pancreatic beta cells, and an improvement in beta cell health and function is possible by reduction of lipid-induced toxicity.
  • beta-cell degeneration and a decline of beta-cell functionality can be delayed or prevented.
  • pancreatic cells can be improved or restored, and the number and size of pancreatic beta cells increased. It may be shown that the differentiation status and hyperplasia of pancreatic beta-cells disturbed by hyperglycemia and hyperlipidemia or dyslipidemia can be normalized by treatment with a pharmaceutical composition or dosage form according to the present disclosure.
  • a method for preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion in a patient in need thereof by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor.
  • a pharmaceutical composition according to the present disclosure or separate administration of both obicetrapib and an SGLT2 inhibitor, and due to the activity of the obicetrapib and SGLT2 inhibitor, an abnormal accumulation of fat in the liver may be reduced or inhibited. Therefore, according to present disclosure, there is also provided a method for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor.
  • liver fat Diseases or conditions which are attributed to an abnormal accumulation of liver fat are particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fatty liver, diabetic fatty liver, alcoholic- induced fatty liver or toxic fatty liver.
  • NAFL non-alcoholic fatty liver
  • NASH non-alcoholic steatohepatitis
  • hyperalimentation-induced fatty liver diabetic fatty liver
  • alcoholic- induced fatty liver or toxic fatty liver.
  • kits for maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor.
  • kits comprising a package containing a plurality of unit pharmaceutical dosage forms (e.g., as described herein) and instructions for use.
  • the pharmaceutical kit comprises a container, such as a high-density polyethylene (HDPE) bottles, or a box including one or more blister packs, wherein the bottles or blister packs can contain a plurality of solid unit pharmaceutical dosage forms as described herein.
  • the container or pack comprises at least 5, at least 8, at least 10, at least 12 of at least 15 of said unit pharmaceutical dosage forms, e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms.
  • the pharmaceutical kit comprises instructions (e.g., a leaflet) inserted into the container or box, typically a patient information leaflet containing printed information, which information may include a description of the form and composition of the unit pharmaceutical dosage forms contained in the kit, an indication of the therapeutic indications for which the product is intended, instructions as to how the product is to be used and information and warnings concerning adverse effects and contraindications associated with the use.
  • the leaflet will usually contain the information concerning the therapeutic indications, uses, treatment regimens, etc. as described herein in relation to the methods of treatment of the present invention.
  • the leaflet contains printed instructions to repeatedly (self-)administer the pharmaceutical unit dosage forms in order to treat and/or prevent a metabolic disorder, in particular type 2 diabetes mellitus.
  • a “subject” can be a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, goats, rabbits, rats, mice, etc.) or a primate (e.g., monkey and human), for example a human.
  • a primate e.g., monkey and human
  • “Patient” refers to a human subject.
  • the subject is a mammal, e.g., a human, diagnosed with a disease or disorder provided herein.
  • the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein.
  • the subject is human.
  • the terms “therapy”, “treat”, and “treating” are used in their broadest sense understood in the clinical arts.
  • the term “pharmaceutically acceptable” indicates that the material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.
  • carrier refers to a glidant, diluent, adjuvant, excipient, or vehicle etc. with which the compound is administered, without limitation. Examples of carriers are described herein and also in Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978-0128200070).
  • diluent refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also serve to stabilize compounds. Nonlimiting examples of diluents include starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate.
  • binder when used herein relates to any pharmaceutically acceptable film which can be used to bind together the active and inert components of the carrier together to maintain cohesive and discrete portions.
  • binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, copovidone, and ethyl cellulose.
  • disintegranf refers to a substance which, upon addition to a solid preparation, facilitates its break-up or disintegration after administration and permits the release of an active ingredient as efficiently as possible to allow for its rapid dissolution.
  • disintegrants include maize starch, sodium starch glycolate, croscarmellose sodium, modified corn starch, sodium carboxymethyl starch, crospovidone, pregelatinized starch, and alginic acid.
  • lubricant refers to an excipient which is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. It aids the ejection of the tablet form the dies, and can improve powder flow.
  • Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc; and solubilizers such as fatty acids including lauric acid, oleic acid, and C8/C10 fatty acid.
  • film coating refers to a thin, uniform, film on the surface of a substrate (e.g. tablet).
  • Film coatings are particularly useful for protecting the active ingredient from photolytic degradation.
  • Non-limiting examples of film coatings include polyvinylalcohol based, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate film coatings.
  • glidanf as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect.
  • glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.
  • an effective amount refers to an amount that is sufficient to effect treatment, as defined herein, when administered to a mammal in need of such treatment.
  • the therapeutically effective amount may vary depending upon the patient being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • unit dosage forms or “pharmaceutical dosage forms” refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet).
  • a suitable pharmaceutical excipient e.g., a tablet
  • % w/w refers to the weight of a component based on the total weight of a composition comprising the component. For example, if component A is present in an amount of 50% w/w in a 100 mg composition, component A is present in an amount of 50 mg.
  • Such chiral centers may be of either the (R) or (5) configurations, or may be a mixture thereof.
  • the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (A) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (5) form.
  • the present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not.
  • An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 C1, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I.
  • Particular isotopic variants of a compound according to the present disclosure especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body.
  • Isotopic variants of the compounds according to the present disclosure can be prepared by various, including, for example, the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
  • any of the embodiments described herein are meant to include a salt, a single stereoisomer, a mixture of stereoisomers and/or an isotopic form of the compounds.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations.
  • the term “about” or “approximately” means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1% or 0.05% of a given value or range. Unless otherwise specified, the term “about” means within plus or minus 10% of a the explicitly recited value, rounded either up or down to the nearest value based on the expressed degree of precision.
  • Example 1 A 2x2 Factorial Mendelian Randomization Analysis of the Effect of Combined SGLT2 and CETP Genetic Variation on Diabetes Incidence in the UK Biobank
  • CETP genetic score To construct a genetic score to mimic the effects of CETP inhibitors, a score of 4 single nucleotide polymorphisms (SNPs) in the CETP region that are strongly correlated with HDL was built. The genetic score uses all available SNPs in the UK Biobank genotyping information that were included in the CETP score described in Ference et al. (Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of Genetic Variants Related to CETP Inhibitors and Statins with Lipoprotein Levels and Cardiovascular Risk. JAMA. 2017;318(10):947-956). A higher CETP genetic score mimics a greater degree of pharmaceutical CETP inhibition (FIG. 8 A).
  • SGLT2 genetic score To construct a genetic score to mimic the effects of SGLT2 inhibitors, a score of 2 single nucleotide polymorphisms (SNPs) in the SGLT2 region that are strongly correlated with SGLT2 expression was built. The genetic score uses all available SNPs in the UK Biobank genotyping information that were included in the SGLT2 score described in Katzmann et al. (Katzmann, J.L., Mason, A.M., Marz, W., Kleber, M.E., Niessner, A., Bluher, M., Speer, T. and Laufs, U. (2021), Genetic Variation in Sodium-glucose Cotransporter 2 and Heart Failure. Clin. Pharmacol. Ther., 110: 149-158). A higher SGLT2 genetic score mimics a greater degree of pharmaceutical SGLT2 inhibition (FIG. 8B).
  • Group 1 was referred to as the “control group”
  • Group 2 was referred to as the “SGLT2 monotherapy group”
  • Group 3 was referred to as the “CETP monotherapy group”
  • Group 4 was referred to as the “combination therapy group.”
  • each genetic score results in glycemic control on diabetes incidence relative to the control group. To do so, we compared the incidence of diabetes between Groups 2, 3, and 4 (monotherapies or combination therapy) with that of Group 1 (control) using logistic regression and include age, sex, SBP, and BMI as covariates. We found that Group 4 (corresponding to combination therapy) was the only group associated with a statistically significant decrease in diabetes incidence relative to control (FIG. 9A).
  • Group 4 was associated with a statistically significant decrease in glycated hemoglobin relative to Group 2 (SGLT2 inhibitor monotherapy) and Group 3 (CETP inhibitor monotherapy), while Groups 2 and 3 were not significantly different from each other with respect to glycated hemoglobin levels (FIG. 10B).
  • BMI, weight, age, sex and blood pressure did not differ significantly between groups.
  • HDL is strongly correlated with diabetes (higher HDL associated with lower diabetes) and also with glycated hemoglobin (high HDL associated with lower glycated hemoglobin in the overall cohort and all groups individually at p ⁇ 2e-16 for all.
  • Exemplary pharmaceutical dosage forms are formulated as a 6 mm diameter, white, film-coated, round, biconvex tablet with no identifying markings. Tablets can be manufactured in the dosage strengths shown in tables 21-24 below (dose of obicetrapib expressed as the calcium salt).
  • amorphous obicetrapib typically amorphous obicetrapib calcium salt, and the SGLT2 inhibitor are blended with microcrystalline cellulose, mannitol, sodium starch glycolate, and colloidal silicon dioxide in a mixer to obtain a pre-mixture;
  • magnesium stearate is added to the pre-mixture of step (1) and mixing continued;
  • step (1) tableting the final mixture of step (1) by compressing it into 6 mm biconvex tablet cores on a suitable tablet press;

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Abstract

L'invention concerne une composition pharmaceutique comprenant un sel de calcium amorphe d'obicetrapib et au moins un inhibiteur de SGLT2, ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également des formes posologiques les comprenant. Dans certains modes de réalisation, la forme posologique est une forme posologique solide, telle qu'un comprimé. L'invention concerne également des méthodes de préparation de formulations à dose fixe de calcium d'obicetrapib amorphe et d'un inhibiteur de SGTL2, et des méthodes d'utilisation de celles-ci dans le traitement d'un trouble métabolique (par exemple, le diabète de type 2) ou une maladie cardiométabolique. L'invention concerne également des méthodes de traitement ou de prévention d'un trouble métabolique ou d'une maladie cardiométabolique chez un sujet qui souffre d'un trouble métabolique ou d'une maladie cardiométabolique, ou qui présente un risque d'en développer un, consistant à : administrer une quantité thérapeutiquement efficace d'obicetrapib, ou d'un sel de qualité pharmaceutique de celui-ci ; et une quantité thérapeutiquement efficace d'au moins un inhibiteur de SGLT2, ou d'un sel de qualité pharmaceutique de celui-ci.
PCT/US2024/025881 2023-04-24 2024-04-23 Combinaison d'inhibiteur de sglt2 et d'obicetrapib amorphe WO2024226537A1 (fr)

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