Obicipib and SGLT2 inhibitor combinations

Abstract

The invention provides a pharmaceutical composition, which comprises obicterapib or a pharmaceutically acceptable salt of the obicterapib, and an SGTL2 inhibitor or a pharmaceutically acceptable salt of the SGTL2 inhibitor. The invention also provides a dosage form containing the components. In some embodiments, the dosage form is a solid dosage form, such as a tablet. The present invention also provides methods of preparing a fixed dose of formulations of obicterapib and SGTL2 inhibitors, as well as methods of using the formulations in the treatment of metabolic disorders, such as type 2 diabetes mellitus. The invention also provides a method of treating or preventing a metabolic disorder in a subject suffering from or likely to suffer from a metabolic disorder, comprising: administering a therapeutically effective amount of obicterapib or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of at least one SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent No. 63 / 295,276, filed on December 30, 2021, the disclosure of which is incorporated herein by reference in its entirety. Background Art

[0003] Type 2 diabetes is an increasingly prevalent disease. Due to the high frequency of complications, type 2 diabetes leads to a significant reduction in life expectancy. Type 2 diabetes also leads to serious morbidity. Due to diabetes-related microvascular complications, type 2 diabetes is currently the most common cause of adult-onset blindness, renal failure and amputation in the industrial world. In addition, the presence of type 2 diabetes is associated with a 2- to 5-fold increased risk of cardiovascular disease.

[0004] It is now widely accepted that glycemic control makes a difference in patients with type 2 diabetes. The goal of today's diabetes treatment is to achieve and maintain blood glucose levels as close to normal as possible to prevent long-term microvascular and macrovascular complications associated with elevated glucose in the blood. Oral therapeutic options for the treatment of type 2 diabetes include the following compounds: sulfonylureas, biguanides (metformin), thiazolidinediones, and alpha-glucosidase inhibitors. Active drugs from each class are usually administered to patients alone. However, despite the known side effects of weight gain associated with sulfonylurea and thiazolidinone treatment, combination therapy is feasible once monotherapy becomes inadequate.

[0005] After a long course of disease, most people with type 2 diabetes eventually fail oral therapy and become insulin dependent, requiring daily injections and multiple daily blood sugar measurements.

[0006] Therefore, there is a need for alternative therapies that can better treat type 2 diabetes and delay the progression of type 2 diabetes and similar metabolic diseases to insulin dependence. Summary of the invention

[0007] The present disclosure provides a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt thereof, and an SGTL2 inhibitor or a pharmaceutically acceptable salt thereof. A pharmaceutical dosage form comprising the above-mentioned ingredients is also provided. In some embodiments, the dosage form is a solid dosage form, such as a tablet. The present invention also provides a method for preparing a fixed dose of obicetrapib and a SGTL2 inhibitor formulation, and a method for using the formulation to treat metabolic disorders (e.g., type 2 diabetes). The present invention also provides a method for treating or preventing metabolic disorders in a subject suffering from or likely to suffer from a metabolic disorder, comprising: administering a pharmaceutical composition or pharmaceutical dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof and an SGTL2 inhibitor or a pharmaceutically acceptable salt thereof. The present invention also provides a method for treating or preventing metabolic disorders in a subject suffering from or likely to suffer from a metabolic disorder, comprising: administering a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of at least one SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

[0008] A first aspect of the present disclosure includes a pharmaceutical composition comprising:

[0009] a) a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt thereof; and

[0010] b) a therapeutically effective amount of at least one SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

[0011] A second aspect of the present disclosure includes a pharmaceutical dosage form comprising a pharmaceutical composition comprising obicetrapib and an SGLT2 inhibitor (eg, as described herein).

[0012] A third aspect of the present disclosure includes a method of treating or preventing a metabolic disorder comprising administering to a subject having or at risk of having a metabolic disorder a therapeutically effective amount of a pharmaceutical composition comprising obicetrapib and an SGLT2 inhibitor (eg, as described herein).

[0013] A fourth aspect of the present disclosure includes a method for treating or preventing a metabolic disorder in a subject suffering from or at risk of suffering from a metabolic disorder, comprising: administering a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of at least one SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

[0014] In certain embodiments, the metabolic disorder is type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, or metabolic syndrome. DETAILED DESCRIPTION

[0015] As outlined above, in one aspect, the present disclosure provides a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt thereof and an SGTL2 inhibitor or a pharmaceutically acceptable salt thereof. A pharmaceutical dosage form comprising the above-mentioned ingredients is also provided. In some embodiments, the dosage form is a solid dosage form, such as a tablet. The present invention also provides a method for preparing a fixed-dose combination of obicetrapib and an SGTL2 inhibitor formulation, and a method for using the formulation to treat a metabolic disorder (e.g., type 2 diabetes). The present invention also provides a method for treating or preventing a metabolic disorder in a subject suffering from or likely to suffer from a metabolic disorder, comprising: administering a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of at least one SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

[0016] The pharmaceutical compositions of the present disclosure are described in more detail below. Obicetrapib active compounds and SGLT2 inhibitors are described. Pharmaceutical compositions comprising obcetrapib and SGLT2 inhibitors, pharmaceutical dosage forms comprising obcetrapib and SGLT2 inhibitors, and methods of fixed dose formulation thereof are also described. Methods of using the pharmaceutical compositions of the present disclosure are also described.

[0017] 4.1. Pharmaceutical Composition

[0018] As summarized above, the present disclosure provides a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt thereof and an SGTL2 inhibitor or a pharmaceutically acceptable salt thereof.

[0019] 4.1.1. Obicetrapib Compounds

[0020] The pharmaceutical composition disclosed herein includes obicetrapib or a pharmaceutically acceptable salt thereof. More specifically, obicetrapib or (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is a cholesterol ester transfer protein (CETP) inhibitor of formula (I), wherein Et represents an ethyl group:

[0021]

[0022] Compared to other known CETP inhibitors, only relatively low doses of the compound of formula (I) are required to achieve near-complete CETP inhibition. Typically, repeated daily doses (once a day) of as low as 2.5 mg of the compound of formula (I) have been shown to be sufficient to achieve near-complete CETP inhibition. These doses are much lower than those used for other CETP inhibitors. In addition, clinical studies have also shown that the compound of formula (I) is well tolerated and does not cause serious side effects.

[0023] Inhibition of CETP reduces LDL-C and increases high-density lipoprotein cholesterol (HDLC) levels. CETP is a plasma protein secreted primarily by the liver and adipose tissue. CETP mediates the transfer of cholesterol esters from HDL to apolipoprotein B (Apo B)-containing particles (primarily LDL and very low-density lipoprotein VLDL) in exchange for triglycerides, thereby reducing the cholesterol content of HDL and increasing the cholesterol content of (V)LDL. Therefore, it is hypothesized that inhibition of CETP would retain cholesterol esters in HDL-C and reduce the cholesterol content of the atherogenic Apo B fraction.

[0024] In certain embodiments, obicetrapib is in the form of a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salts" include any salts that retain the activity of the active drug and can be used for pharmaceutical purposes. A pharmaceutically acceptable salt also refers to any salt that can be formed in vivo by administering an acid, another salt, or a prodrug that is converted to an acid or salt. Pharmaceutically acceptable salts of the disclosed compounds can be prepared by methods well known to those skilled in the art.

[0025] Pharmaceutically acceptable salts of compound (I) may include, for example, alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc or aluminum salts; organic base salts, such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, triethanolamine or dehydroabietinamine; inorganic acid salts, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; organic acid salts, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid; or salts derived from acidic amino acids (such as aspartic acid or glutamic acid).

[0026] In addition, the pharmaceutically acceptable salt of compound (I) may include, for example, a quaternary salt formed between the compound of formula (I) and an alkyl halide or a phenylalkyl halide.

[0027] Additionally, the composition may comprise obicetrapib in the form of a solvate comprising a pharmaceutically acceptable solvent such as water ("hydrate"), ethanol, etc. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this disclosure.

[0028] In certain embodiments, obicetrapib is a calcium salt.

[0029] Obcetrapib has been previously described (see, e.g., WO 2005 / 095409A2). It can be prepared by the methods described therein (see, e.g., WO 2005 / 095409A2 and U.S. Pat. Nos. 7,872,126 and 8,158,640, Examples 1 and 177-180), or by the methods described in WO 2007 / 116922A1 and U.S. Pat. No. 8,084,611, or by the methods described in WO 2016 / 024858 and U.S. Pat. No. 10,112,904, the disclosures of each of which are incorporated herein by reference in their entirety.

[0030] Obcetrapib is present in a pharmaceutical composition in a therapeutically effective amount. For obicetrapib, a "therapeutically effective amount" refers to an amount that effectively reduces low-density lipoprotein-cholesterol (LDL-C). Without being bound by theory, it is believed that low LDL-C reduces lipotoxicity to pancreatic beta cells. In some embodiments, a "therapeutically effective amount" of obicetrapib is an amount that, when administered to an individual at one or more doses, is effective in reducing LDL-C 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% in a subject in a combination therapy (e.g., in combination with an SGLT2 inhibitor as described herein) compared to an individual's LDL-C level before or without combination therapy.

[0031] In some embodiments, the pharmaceutical composition comprises about 1% to about 25% w / w of obicetrapib or a salt, solvate or hydrate thereof. In other embodiments, the composition comprises about 1% to about 20% w / w, or about 1% to about 15% w / w, or about 1% to about 10% w / w, or about 5% to about 15% w / w, or about 5% to about 12% w / w of obicetrapib or a salt, solvate or hydrate thereof. In other embodiments, the pharmaceutical composition comprises about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, or about 15% w / w of obicetrapib or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 5% w / w of obicetrapib, or a salt, solvate, or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 10% w / w of obicetrapib, or a salt, solvate, or hydrate thereof.

[0032] In some embodiments, the pharmaceutical composition comprises 1% to 25% w / w of obicetrapib or a salt, solvate or hydrate thereof. In other embodiments, the composition comprises 1% to 20% w / w, or 1% to 15% w / w, or 1% to 10% w / w, or 5% to 15% w / w, or 5% to 12% w / w of obicetrapib or a salt, solvate or hydrate thereof. In other embodiments, the pharmaceutical composition comprises 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, or 15% w / w of obicetrapib or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 5% w / w of obicetrapib, or a salt, solvate, or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 10% w / w of obicetrapib, or a salt, solvate, or hydrate thereof.

[0033] SGLT2 inhibitors

[0034] The pharmaceutical compositions disclosed herein also include an SGTL2 inhibitor or a pharmaceutically acceptable salt thereof.

[0035] The term "SGLT2 inhibitor" refers to a compound that has an inhibitory effect on sodium-glucose transporter 2 (SGLT2), in particular human SGLT2, in particular a pyranosyl-glucopyranosyl-derivative, i.e. a compound having a pyranosyl glucopyranosyl moiety. In some embodiments, the activity of the SGLT2 inhibitor is determined by an inhibition assay, for example, by measuring the IC 50 or EC 50 In some embodiments, the IC value of an SGLT2 inhibitor is used to determine the activity level of an enzyme in a cell-free system or in cells treated with a test compound relative to a control. 50 Value (or EC 50 The inhibitory effect of human SGLT2 can be determined by methods known in the literature, particularly in the methods described in application WO 2005 / 092877 or WO 2007 / 093610 (page 23 / 24), which are incorporated herein by reference in their entirety. The term "SGLT2 inhibitor" also includes any pharmaceutically acceptable salts, hydrates and solvates thereof, including their respective crystalline forms.

[0036] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertogliflozin, empagliflozin, bepagliflozin, togliflozin, ipagliptin, lupagliflozin, repagliflozin, repagliflozin etabonate, sergliflozin, sergliflozin etabonate, atigliflozin, and sogliflozin.

[0037] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertogliflozin, empagliflozin, bepagliflozin, togliflozin, ipagliptin, lupagliflozin, repagliflozin ectoate, sergliflozin ectoate, and sogliflozin.

[0038] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertogliflozin, and empagliflozin.

[0039] In some embodiments, the SGLT2 inhibitor is empagliflozin.

[0040] In some embodiments, the SGLT2 inhibitor is dapagliflozin.

[0041] In some embodiments, the SGLT2 inhibitor is canagliflozin.

[0042] In some embodiments, the SGLT2 inhibitor is etoglipizine.

[0043] In certain embodiments, the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of formula (II):

[0044]

[0045] or a hydrate, solvate or pharmaceutically acceptable salt thereof,

[0046] in:

[0047] R 1 is a halogen (e.g. chlorine), (C 1-3 )alkyl or cyano;

[0048] Each R 2 are independently H, (C 1-3 ) alkyl, (C 1-3 ) alkoxy or hydroxy;

[0049] R 3 Yes (C 1-3 ) alkyl, cycloalkyl, alkynyl, (C 1-3 )alkoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and

[0050] n is 0 to 3.

[0051] In certain embodiments, the SGLT2 inhibitor is a prodrug of any of the foregoing SGLT2 inhibitors.

[0052] In certain embodiments, the SGLT2 inhibitor of formula (II) and methods for synthesizing the same 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 in their entirety.

[0053] In some embodiments of Formula (II), R 1 is methyl. In some cases, R 1 is halogen. In some cases, halogen is chlorine. In some other cases, R 1 It's cyano.

[0054] In some embodiments of Formula (II), each R 2 is H. In certain embodiments, n is 1, and R 2 In certain embodiments, n is 1, and R 2In certain embodiments, n is 1, and R 2 It is hydroxyl.

[0055] In certain embodiments of Formula (II), R 3 is ethyl, cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 3 is cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 3 is ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

[0056] In some cases, the SGLT2 inhibitor is selected from any one of the following compounds:

[0057]

[0058]

[0059]

[0060] It should be understood that the definition of the above-listed SGLT2 inhibitors (including pyranose glucopyranosyl-substituted benzene derivatives of formula (II)) also includes hydrates, solvates, polymorphs and prodrugs thereof. The term "empagliflozin" used herein refers to empagliflozin, including hydrates, solvates and crystalline forms thereof. In one embodiment, the SGLT2 inhibitor is a crystalline form as described in international patent application WO 2006 / 117360, which is incorporated herein by reference in its entirety. In certain embodiments, the SGLT2 inhibitor is a crystalline form as described in international patent application WO 2006 / 117359, which is incorporated herein by reference in its entirety. In certain embodiments, the SGLT2 inhibitor is a crystalline form as described in international patent application WO 2008 / 049923, which is incorporated herein by reference in its entirety. These crystalline forms have good solubility properties, which can make the SGLT2 inhibitor have good bioavailability. In addition, the crystalline form is physicochemically stable, thus providing good shelf life stability of the pharmaceutical composition.

[0061] The term "dapagliflozin" as used herein refers to dapagliflozin, including hydrates, solvates and crystalline forms thereof. For example, the compound and its synthesis method are described in WO 03 / 099836. For example, hydrates, solvates and crystalline forms are described in patent applications WO 2008 / 116179 and WO2008 / 002824.

[0062] The term "canagliflozin" as used herein refers to canagliflozin, including its hydrates, solvates and crystalline forms. For example, the compound and its synthesis method are described in WO 2005 / 012326 and WO 2009 / 035969. For example, certain hydrates, solvates and crystalline forms are described in patent application WO 2008 / 069327.

[0063] The term "atigliflozin" as used herein refers to atigliflozin, including its hydrates, solvates and crystalline forms. For example, the compound and its synthesis method are described in WO 2004 / 007517.

[0064] The term "ipagliflozin" as used herein refers to ipagliflozin, including its hydrates, solvates and crystalline forms. For example, the compound and its synthesis method are described in WO 2004 / 080990, WO 2005 / 012326 and WO 2007 / 114475.

[0065] The term "topagliflozin" as used herein refers to topagliflozin, including its hydrates, solvates and crystalline forms. For example, the compound and its synthesis method are described in WO 2007 / 140191 and WO 2008 / 013280.

[0066] The term "regagliflozin" as used herein refers to repagliflozin and prodrugs of repagliflozin, in particular repagliflozin etabonate, including hydrates, solvates and crystalline forms thereof. For example, the synthesis methods thereof are described in patent applications EP 1213296 and EP 1354888.

[0067] The term "sergliflozin" as used herein refers to sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates, solvates and crystalline forms thereof. For example, the methods for its manufacture are described in patent applications EP 1344780 and EP 1489089.

[0068] The disclosure of each of the foregoing documents cited above in relation to specific SGLT2 inhibitors is hereby incorporated by reference in its entirety.

[0069] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an SGLT2 inhibitor (e.g., as described herein). With respect to an SGLT2 inhibitor, a "therapeutically effective amount" refers to an amount that effectively inhibits SGLT2 and / or reduces glucose reabsorption. Without being bound by theory, it is believed that reducing glucose absorption can reduce blood sugar levels, thereby reducing the glucose toxicity of pancreatic beta cells. In some embodiments, a "therapeutically effective amount" of an SGLT2 inhibitor is when applied to an individual at one or more doses, in a combination therapy (e.g., as described herein in combination with obicetrapib), compared to the glucose reabsorption level of an individual without a combination therapy, or compared to the glucose level of an experimenter before or after the combination therapy, effectively reducing glucose reabsorption in an experimenter 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%.

[0070] In some embodiments, the pharmaceutical composition comprises about 1% to about 75% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In other embodiments, the pharmaceutical composition comprises about 1% to about 50% w / w, or about 1% to about 40% w / w, about 1% to about 30% w / w, about 1% to about 20%, about 1% to 10%, or about 5% to about 15% w / w, or about 10% to about 25% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In other embodiments, 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 an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical composition comprises about 5% w / w of an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical composition comprises about 10% w / w of an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical composition comprises about 15% w / w of an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical composition comprises about 25% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 50% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 75% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof.

[0071] In some embodiments, the pharmaceutical composition comprises 1% to 75% w / w of an SGLT2 inhibitor or its salt, solvate or hydrate. In other embodiments, the pharmaceutical composition comprises 1% to 50% w / w, or 1% to 40% w / w, 1% to 30% w / w, 1% to 20%, 1% to 10%, or 5% to 15% w / w, or 10% to 25% w / w of an SGLT2 inhibitor or its salt, solvate or hydrate. In other embodiments, 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 an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical composition comprises 5% w / w of an SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 10% w / w of an SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 15% w / w of an SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 25% w / w of an SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 50% w / w of an SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 75% w / w of an SGLT2 inhibitor, or a salt, solvate or hydrate thereof.

[0072] 4.1.3. Additional Active Drugs

[0073] The pharmaceutical compositions disclosed herein may optionally include one or more additional active drugs. In some embodiments, at least one of the one or more additional active drugs is an antidiabetic drug. In certain embodiments, at least one of the one or more additional active drugs is an antidiabetic drug selected from biguanides, thiazolidinediones, sulfonylureas, glinides, alpha-glucosidase inhibitors, insulin, DPP-4 inhibitors and amylin analogs, including pharmaceutically acceptable salts of the foregoing drugs.

[0074] In some embodiments, the combination of obcetrapib, a SGLT2 inhibitor, and one or more additional active drugs according to the present disclosure may allow for a reduction in the dosage of obcetrapib or SGLT2.

[0075] Reducing the dosage may benefit patients who may suffer side effects from treatment with higher dosages of one or more active ingredients. Therefore, pharmaceutical compositions and methods according to the present disclosure may exhibit fewer side effects relative to corresponding monotherapy with any active drug (e.g., obicetrapib or SGLT2 inhibitors), thereby making treatment more tolerable and improving individual compliance with treatment.

[0076] In certain embodiments, the additional active drug is a biguanide. Examples of biguanides include metformin, phenformin and buformin. In some cases, the additional active drug is metformin. The term "metformin" used herein refers to metformin or a pharmaceutically acceptable salt thereof, such as hydrochloride, metformin (2:1) fumarate and metformin (2:1) succinate, hydrobromide, p-chlorophenoxyacetate or pamoate, and other known monocarboxylic acids and dicarboxylic acids. In one embodiment, the metformin used herein is a hydrochloride metformin salt.

[0077] In certain embodiments, the pharmaceutical composition comprises 1 to 50% w / w of a metformin hydrochloride salt, e.g., 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 a metformin hydrochloride salt.

[0078] In certain embodiments, the additional active drug is a DPP-4 inhibitor. Examples of DPP-4 inhibitors are linagliptin, sitagliptin, vildagliptin, saxagliptin, denagliptin, alogliptin, canagliflozin, megliptin, dulagliptin, including pharmaceutically acceptable salts, hydrates and solvates thereof. In certain embodiments, the DPP-4 inhibitor is linagliptin.

[0079] In certain embodiments, the pharmaceutical composition comprises 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 its salt, solvate or hydrate. In some cases, the pharmaceutical composition comprises 2.5% w / w of linagliptin or its salt, solvate or hydrate. In some cases, the pharmaceutical composition comprises 5% w / w of linagliptin or its salt, solvate or hydrate.

[0080] In certain embodiments, the additional active drug is a thiazolidinedione. The example of thiazolidinedione (TZD) includes pioglitazone and rosiglitazone. The term "pioglitazone" used herein refers to pioglitazone, including its enantiomers, its mixtures and its racemates, or its pharmaceutically acceptable salts, such as hydrochloride. The term "rosiglitazone" used herein refers to rosiglitazone, including its enantiomers, its mixtures and its racemates, or its pharmaceutically acceptable salts, such as maleate.

[0081] In certain embodiments, other active drugs are sulfonylureas. Examples of sulfonylurea drugs are glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride, glyburide, glisoxepide and gliclazide. In some cases, sulfonylureas are selected from tolbutamide, gliquidone, glibenclamide, glipizide and glimepiride. In some cases, sulfonylureas are selected from glibenclamide, glipizide and glimepiride. Each term of the group "glibenclamide", "glimepiride", "gliquidone", "glibornuride", "gliclazide", "gliclazide", "tolbutamide" and "glipizide" used herein refers to each active drug or its pharmaceutically acceptable salt.

[0082] In certain embodiments, the additional active drug is a meglitinide. Examples of meglitinides are nateglinide, repaglinide and mitiglinide. The term "nateglinide" used herein refers to nateglinide, including its enantiomers, its mixtures and its racemates or its pharmaceutically acceptable salts and esters. The term "repaglinide" used herein refers to repaglinide, including its enantiomers, its mixtures and its racemates or its pharmaceutically acceptable salts and esters.

[0083] In certain embodiments, the additional active drug is an inhibitor of alpha-glucosidase. Examples of alpha-glucosidase inhibitors are acarbose, voglibose, and miglitol. As used herein, each term of the group "acarbose," "voglibose," and "miglitol" refers to the respective active drug or a pharmaceutically acceptable salt thereof.

[0084] In certain embodiments, the additional active drug is an amylin analog. An example of an amylin analog is pramlintide, including pharmaceutically acceptable salts, hydrates and solvates thereof. For example, pramlintide acetate, sold under the trade name Symlin.

[0085] Therefore, according to another embodiment, the pharmaceutical composition disclosed herein includes a combination of obicetrapib, an SGLT2 inhibitor and one or more other antidiabetic drugs. In certain embodiments, the other antidiabetic drug is metformin, linagliptin or a combination thereof.

[0086] 4.1.4. Excipients

[0087] The pharmaceutical composition provided according to the present disclosure can be orally administered. Therefore, in certain embodiments, the present disclosure provides a pharmaceutical composition, which includes obicetrapib and SGLT2 inhibitors as described herein, and one or more pharmaceutically acceptable excipients or carriers, including but not limited to inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, surfactants, disintegrants, lubricants, adhesives, glidants, adjuvants and combinations thereof. This composition is prepared in a manner well known in the pharmaceutical field (see, for example, Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978-0128200070); and Modern Pharmaceutics, Marcel Dekker, Inc., 4th Ed. (GS Banker & C.T. Rhodes, Eds.)).

[0088] The pharmaceutical composition can be administered orally in a fixed dose combination. It can be administered by capsules, tablets, etc. In one embodiment, obicetrapib and SGLT2 inhibitors are combined in tablet form. In another embodiment, the tablet is a compressed tablet. When preparing a pharmaceutical composition comprising a solid as described herein, the active ingredient is usually diluted by an excipient and / or wrapped in a carrier, which can be in the form of a capsule, tablet, pouch or other container. When an excipient is used as a diluent, it can be in the form of a solid, semisolid or liquid material (as described above), as a carrier, carrier or medium for the active ingredient.

[0089] The pharmaceutical composition can be formulated into a quick-release or sustained-release formulation. A "slow-release formulation" is a formulation designed to slowly release a therapeutic drug in the body over a long period of time, while a "quick-release formulation" is a formulation designed to quickly release a therapeutic drug in the body over a short period of time. In some cases, a quick-release formulation can be coated so that the therapeutic drug is only released when it reaches a desired target in the body (e.g., stomach). In a specific embodiment, the pharmaceutical composition is formulated into a sustained-release formulation.

[0090] The pharmaceutical composition can also include pharmaceutical excipients, such as diluents, adhesives, fillers, glidants, disintegrants, lubricants, solubilizers and combinations thereof. Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated into tablets, the tablets can be uncoated, or can be coated by known techniques (including microencapsulation) to delay decomposition and absorption in the gastrointestinal tract, thereby providing a longer sustained effect. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, can be used alone or together with wax.

[0091] In some embodiments, the pharmaceutical composition comprises a diluent selected from dicalcium phosphate, cellulose, microcrystalline cellulose, compressible sugar, calcium hydrogen phosphate dihydrate, lactose, lactose monohydrate, mannitol, tricalcium phosphate, and combinations thereof. In some cases, the diluent comprises microcrystalline cellulose. In some cases, the diluent comprises mannitol. In some cases, the diluent comprises anhydrous lactose or lactose monohydrate.

[0092] In some embodiments, the pharmaceutical composition comprises a controlled release matrix. In some cases, the diluent is polyethylene oxide and hypromellose.

[0093] In other embodiments, the pharmaceutical composition comprises an amount of about 1 to about 100% w / w, or about 1 to about 80% w / w, or about 1% to about 75% w / w, or about 5 to about 75% w / w, or about 10 to about 70% w / w, or about 15 to about 70% w / w of microcrystalline cellulose. In a specific embodiment, 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. In another specific embodiment, the amount of microcrystalline cellulose is about 60% w / w. In another specific embodiment, the amount of microcrystalline cellulose is about 65% w / w.

[0094] In other embodiments, the pharmaceutical composition comprises an amount of 1 to 100% w / w, or 1 to 80% w / w, or 1 to 75% w / w, or 5 to 75% w / w, or 10 to 70% w / w, or 15 to 70% w / w of microcrystalline cellulose. In a specific embodiment, 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. In another specific embodiment, the amount of microcrystalline cellulose is 60% w / w. In another specific embodiment, the amount of microcrystalline cellulose is 65% w / w.

[0095] In further embodiments, the pharmaceutical composition comprises mannitol in an amount of about 1 to about 40% w / w, or about 1 to about 35% w / w, or about 1% to about 25% w / w, or about 5 to about 35% w / w, or about 10 to about 30% w / w, or about 15 to about 25% w / w. In a specific embodiment, 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. In another specific embodiment, the amount of microcrystalline cellulose is about 20% w / w.

[0096] In further embodiments, the pharmaceutical composition comprises mannitol in an amount of 1 to 40% w / w, or 1 to 35% w / w, or 1 to 25% w / w, or 5 to 35% w / w, or 10 to 30% w / w, or 15 to 25% w / w. In a specific embodiment, mannitol is present in an amount of 5%, or 20%, or 15%, or 30%, or 22%, or 23%, or 24%, or 25% w / w. In another specific embodiment, the amount of microcrystalline cellulose is 20% w / w.

[0097] In some embodiments, the pharmaceutical composition comprises a disintegrant selected from croscarmellose sodium, crospovidone, modified corn starch, pregelatinized starch, sodium starch glycolate, and combinations thereof.

[0098] In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 1 to about 20% w / w, or about 1 to about 15% w / w, or about 1 to about 10% w / w, or about 1 to about 8% w / w, or about 2 to about 8% w / w. In a specific embodiment, 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. In another specific embodiment, the amount of croscarmellose sodium is about 5% w / w.

[0099] In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate in an amount of 1 to 20% w / w, or 1 to 15% w / w, or 1 to 10% w / w, or 1 to 8% w / w, or 2 to 8% w / w. In a specific embodiment, croscarmellose sodium is present in an amount of 1%, or 3%, or 4%, or 5%, or 6%, or 7%, or 10%. In another specific embodiment, the amount of croscarmellose sodium is 5% w / w.

[0100] In some embodiments, the pharmaceutical composition comprises a glidant selected from colloidal silicon dioxide, talc, and combinations thereof.

[0101] In other embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.1 to about 5% w / w, or about 0.1 to about 4.5% w / w, or about 0.1 to about 4% w / w, or about 0.5 to about 5.0% w / w, or about 0.5 to about 3% w / w, or about 0.5 to about 2% w / w, or about 0.5 to about 1.5% w / w. In a specific embodiment, 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. In another specific embodiment, colloidal silicon dioxide is present in an amount of about 1% w / w.

[0102] In other embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of 0.1 to 5% w / w, or 0.1 to 4.5% w / w, or 0.1 to 4% w / w, or 0.5 to 5.0% w / w, or 0.5 to 3% w / w, or 0.5 to 2% w / w, or 0.5 to 1.5% w / w. In a specific embodiment, 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. In another specific embodiment, colloidal silicon dioxide is present in an amount of 1% w / w.

[0103] In some embodiments, 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.

[0104] In other embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.1 to about 3% w / w, or about 0.1 to about 2.5% w / w, or about 0.5 to about 3% w / w, or about 0.5 to about 2.5% w / w, or about 0.5 to about 2% w / w, or about 1 to about 3% w / w, or about 1 to about 2% w / w. In a specific embodiment, 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. In another specific embodiment, magnesium stearate is present in an amount of about 1% w / w.

[0105] In other embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of 0.1 to 3% w / w, or 0.1 to 2.5% w / w, or 0.5 to 3% w / w, or 0.5 to 2.5% w / w, or 0.5 to 2% w / w, or 1 to 3% w / w, or 1 to 2% w / w. In a specific embodiment, 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. In another specific embodiment, magnesium stearate is present in an amount of 1% w / w.

[0106] In one embodiment, the pharmaceutical composition comprises a) about 1 to about 10% w / w of obicetrapib or a salt, solvate or hydrate thereof, and b) about 5 to about 20% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a related embodiment, the composition comprises a) about 5% w / w of obicetrapib or a salt, solvate or hydrate thereof, and b) about 5-20% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In another embodiment, the composition comprises a) about 10% w / w of obicetrapib or a salt, solvate or hydrate thereof, and b) about 5-25% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a further related embodiment, 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. In another embodiment, the composition comprises a) about 10% w / w obicetrapib, or a salt, solvate or hydrate thereof, and b) about 5-25% w / w of an 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.

[0107] In one embodiment, the pharmaceutical composition comprises a) 1 to 10% w / w of obicetrapib or a salt, solvate or hydrate thereof, and b) 5 to 20% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a related embodiment, the composition comprises a) 5% w / w of obicetrapib or a salt, solvate or hydrate thereof, and b) 5-20% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In another embodiment, the composition comprises a) 10% w / w of obicetrapib or a salt, solvate or hydrate thereof, and b) 5-25% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a further related embodiment, 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. In another embodiment, the composition comprises a) 10% w / w obicetrapib or a salt, solvate or hydrate thereof, and b) 5-25% w / w of an 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) 1-10% 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.

[0108] In certain embodiments, the pharmaceutical composition comprises:

[0109] Amount (% by weight) Obicetrapib 1-10 SGTL2 inhibitors 4-75 One or more diluents 5-85 One or more disintegrants 1-15 One or more additional additives Until 100%

[0110] In certain embodiments, the pharmaceutical composition comprises:

[0111] Amount (% by weight) Obicetrapib 3-10 SGTL2 inhibitors 7-20 One or more diluents 65-85 One or more disintegrants 1-5 One or more additional additives Until 100%

[0112] In certain embodiments, the SGLT2 inhibitor is empagliflozin in an amount of 7-9% w / w or 18-20% w / w; and the amount of obicetrapib is 3.5-5% w / w or 7-10% w / w.

[0113] In certain embodiments, the pharmaceutical composition comprises:

[0114] Amount (% by weight) Obicetrapib 4-10 SGTL2 inhibitors 4-10 One or more diluents 65-85 One or more disintegrants 1-5 One or more additional additives Until 100%

[0115] In certain embodiments, the SGLT2 inhibitor is dapagliflozin in an amount of 4-5% w / w or 8-10% w / w; and the amount of obicetrapib is 4-5% w / w or 8-10% w / w.

[0116] In certain embodiments, the pharmaceutical composition comprises:

[0117] Amount (% by weight) Obicetrapib 4-10 SGTL2 inhibitors 4-15 One or more diluents 70-85 One or more disintegrants 1-5 One or more additional additives Until 100%

[0118] In certain embodiments, the SGLT2 inhibitor is etoglipizine, which is used in an amount of 4-5% w / w or 11-13% w / w; and the amount of obicetrapib is 4-5% w / w or 8-10% w / w.

[0119] In certain embodiments, the pharmaceutical composition comprises:

[0120]

[0121]

[0122] In certain embodiments, the SGLT2 inhibitor is canagliflozin in an amount of 45-50% w / w or 70-75% w / w; and the amount of obicetrapib is 1-3% w / w or 3-5% w / w.

[0123] The pharmaceutical compositions described herein can be formulated with obicetrapib and the SGLT2 inhibitor as the two sole pharmaceutically active ingredients in the composition, or can be combined with other active ingredients (eg, as described herein).

[0124] In certain embodiments, 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 formulations and dry powder inhalers.

[0125] In the compositions provided herein, the obicetrapib and SGLT2 inhibitors described herein can be mixed with suitable pharmaceutical carriers. The concentration of each active ingredient in the composition can be, for example, an amount effective to deliver treatment, prevention or improvement of the diseases or conditions described herein or their symptoms after administration.

[0126] In certain embodiments, the pharmaceutical compositions provided herein are formulated for single-dose administration. To formulate the composition, the weight fraction of each active substance is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration to alleviate, prevent the condition being treated or improve one or more symptoms.

[0127] In the pharmaceutical compositions provided herein, the concentrations of obcetrapib and the SGLT2 inhibitor will depend on, for example, the physicochemical properties of the compounds, the dosing schedule and the dosage, and other factors known to those skilled in the art. For example, if the composition comprises a salt of obcetrapib, the molecular weight difference between the free base and the salt form needs to be taken into account to adjust the dosage of the salt and / or the amount added to the pharmaceutical composition (i.e., the pharmaceutical dosage form). For example, when expressing the dosage in the label and / or product information of an authorized drug (which includes a salt form of an active compound that can also be used in the free base form), it is common practice to specify that the dosage of the free base is equal to the dosage of the salt used.

[0128] The pharmaceutical compositions described herein are administered to subjects, such as humans or animals (e.g., mammals), in unit dosage forms (e.g., sterile parenteral (e.g., intravenous) solutions or suspensions containing an appropriate amount of a compound or a pharmaceutically acceptable derivative thereof). Also provided are pharmaceutical compositions for administration to humans and animals in unit dosage forms, including oral or nasal solutions or suspensions and oil-water emulsions containing an appropriate amount of a conjugate or a pharmaceutically acceptable derivative thereof. In certain embodiments, the conjugate is formulated and administered in unit dosage forms or multiple dosage forms. The unit dosage form used herein refers to physically discontinuous units suitable for human or animal (e.g., mammal) subjects and individually packaged, as known in the art. Each unit dose contains a predetermined amount of obicetrapib and an SGLT2 inhibitor sufficient to produce the desired therapeutic effect, as well as a desired pharmaceutical carrier, carrier, or diluent. Examples of unit dosage forms include ampoules and syringes and individually packaged tablets. Unit dosage forms can be administered in fractions or multiples thereof. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, administered in isolated unit dosage forms. Examples of multiple dosage forms include vials, capsule bottles, or bottles. Thus, in certain aspects, a multiple dosage form is a multiple of unit doses that are not isolated in packaging.

[0129] In certain embodiments, obicetrapib and SGLT2 inhibitors described herein are in liquid pharmaceutical preparations. Liquid pharmaceutically administrable preparations can be prepared, for example, by dissolving, dispersing or otherwise mixing active compounds and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, dextrose aqueous solution, glycerol, ethylene glycol, etc.), thereby forming a solution or suspension. In certain embodiments, provided herein is a pharmaceutical composition to be administered that may also include a small amount of nontoxic auxiliary substances, such as wetting agents, emulsifiers, solubilizing agents, and pH buffers, etc.

[0130] Actual methods for preparing such dosage forms are known or apparent to those skilled in the art; for example, see, for example, Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13:978-0128200070). Dosage forms or compositions comprising obicetrapib and an SGLT2 inhibitor within the scope disclosed herein, with the remainder consisting of a non-toxic carrier, can be prepared.

[0131] In certain embodiments, parenteral administration is characterized by injection, and subcutaneous injection, intramuscular injection or intravenous injection are also considered here. Injections can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for solutions or suspensions in liquids before injection, or as emulsions. Injections, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. Other routes of administration may include enteral administration, intracerebral administration, intranasal administration, intraarterial administration, intracardiac administration, intraosseous infusion, intrathecal administration and intraperitoneal administration.

[0132] Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products (e.g., freeze-dried powders) ready for mixing with solvents before use (including hypodermic tablets), sterile suspensions ready for injection, sterile dry insoluble products ready for combination with a carrier before use, and sterile emulsions. The solution may be aqueous or non-aqueous.

[0133] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS) and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol and polypropylene glycol and mixtures thereof.

[0134] Pharmaceutically acceptable carriers for parenteral formulations include aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, sequestering or chelating agents, and other pharmaceutically acceptable substances.

[0135] Pharmaceutical carriers also include ethanol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[0136] In certain embodiments, intravenous or intraarterial infusion of a sterile aqueous solution containing the combination described herein is an effective mode of administration. Another embodiment is the injection of a sterile aqueous or oily solution or suspension containing the conjugate described herein when necessary to produce the desired pharmacological effect.

[0137] In certain embodiments, the pharmaceutical formulations are freeze-dried powders that can be reconstituted and administered as solutions, emulsions, and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0138] The lyophilized powder is prepared by dissolving the compound provided herein in a suitable solvent. In some embodiments, the freeze-dried powder is sterile. Suitable solvents may include excipients that improve the stability of the powder or other pharmaceutical ingredients of the powder or reconstituted solution prepared from the powder. Available excipients include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose or other suitable agents. Suitable solvents may also include buffers, such as citrate, sodium phosphate or potassium phosphate or other buffers known to those skilled in the art, in certain embodiments, about neutral pH. The solution is then sterile filtered and then freeze-dried under standard conditions known to those skilled in the art, providing an example of a preparation. In certain embodiments, the resulting solution will be distributed into vials for freeze drying. Freeze-dried powders can be stored under appropriate conditions, for example, at about 4 ° C to room temperature.

[0139] Reconstitution of the lyophilized powder with water for injection provides a formulation for parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier.

[0140] In certain embodiments, the pharmaceutical compositions are formulated as solid dosage forms, such as tablets or capsules (eg, as described below).

[0141] 4.2. Dosage Form

[0142] As described above, the present disclosure provides pharmaceutical dosage forms comprising pharmaceutical compositions described herein. The present disclosure provides tablets, pills, etc. comprising pharmaceutical compositions or dosage forms described herein. Tablets or pills of the present disclosure may be coated to provide dosage forms with the advantage of prolonged action or to protect them from the acidic conditions of the stomach. Tablets may also be formulated into immediate release formulations in the aforementioned manner. In certain embodiments, tablets include film coatings. Film coatings may be used to limit photolytic degradation. Suitable film coatings are selected by conventional screening of commercially available preparations. In one embodiment, the film coating is a coating based on hydroxypropyl methylcellulose. In certain embodiments, the coating accounts for 2-5% of the total weight of the tablet composition and includes a film former, a plasticizer, a glidant, and optionally one or more dyes. In some cases, the coating accounts for 3% of the total tablet composition. Exemplary film coating compositions may include hydroxypropyl methylcellulose (HPMC), lactose monohydrate, titanium dioxide, and triglyceride 1,2,3-triacetoxypropane (triacetin). In some cases, the film coating composition may include hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide, and optionally iron oxides, including red iron oxide and / or yellow iron oxide.

[0143] Tablets can be formulated as monolayer or bilayer tablets. Typically, monolayer tablets contain the active ingredients (i.e., obicetrapib and the SGLT2 inhibitor) mixed together in a single uniform layer. To prepare monolayer tablets, exemplary methods include direct compression, wet granulation, and dry granulation. The direct compression process uses two main process steps: mixing the active ingredients with excipients and compressing the finished tablets.

[0144] In one embodiment, the present disclosure provides a wet granulation method for preparing a pharmaceutical dosage form of the present invention, wherein the method comprises the following steps:

[0145] (1) premixing the active ingredient and most of the excipients including a binder in a mixer to obtain a premix;

[0146] (2) granulating the premix of step (1) by adding a granulating liquid (e.g., purified water);

[0147] (3) drying the granules of step (2) in a fluidized bed dryer or drying oven;

[0148] (4) optionally dry screening the dried particles of step (3);

[0149] (5) mixing the dried granules of step (4) with the remaining excipients (e.g., glidants and lubricants) in a mixer to obtain a final mixture;

[0150] (6) compressing the final mixture of step (5) into tablets on a suitable tablet press to produce tablet cores;

[0151] (7) Optionally, the tablet cores of step (6) are film-coated with a non-functional coating.

[0152] In certain embodiments, the present invention provides pharmaceutical dosage forms obtainable by a wet granulation process (eg, as described herein).

[0153] In another embodiment, the present disclosure provides a direct compression process for preparing the pharmaceutical dosage form of the present invention, wherein the process comprises the following steps:

[0154] (1) premixing the active ingredient and most of the excipients in a mixer to obtain a premix;

[0155] (2) optionally dry sieving the premix through a screen to separate sticky particles and improve content uniformity;

[0156] (3) mixing the premix of step (1) or (2) in a mixer, optionally by adding the remaining excipients to the mixture and continuing to mix;

[0157] (4) compressing the final mixture of step (3) into tablets on a suitable tablet press to produce tablet cores;

[0158] (5) Optionally, the tablet cores of step (4) are film-coated with a non-functional coating.

[0159] In certain embodiments, the present invention provides pharmaceutical dosage forms obtainable by a direct compression process (eg, as described herein).

[0160] In another embodiment, the present disclosure provides a dry granulation method for preparing the pharmaceutical dosage form of the present invention, wherein the method comprises the following steps:

[0161] (1) Mixing the active ingredient with all or part of the excipients in a mixer;

[0162] (2) compacting the mixture of step (1) on a suitable roller compactor;

[0163] (3) reducing the ribbons obtained in step (2) into particles, preferably small particles, by appropriate grinding or sieving steps;

[0164] (4) optionally mixing the granules of step (3) with the remaining excipients in a mixer to obtain a final mixture;

[0165] (5) compressing the granules of step (3) or the final mixture of step (4) into tablets on a suitable tablet press to produce tablet cores;

[0166] (6) Optionally, the tablet cores of step (5) are film-coated with a non-functional coating.

[0167] In certain embodiments, the present invention provides pharmaceutical dosage forms obtainable by a dry granulation method (eg, as described herein).

[0168] Bilayer tablets include active ingredients (i.e., obcetrapib and SGLT2 inhibitors) in separate layers, and can be prepared by preparing a mixture comprising excipients and an active ingredient (i.e., obcetrapib) and preparing a separate mixture comprising a second active ingredient (i.e., SGLT2 inhibitor) and an excipient. Then a mixture can be pre-compressed, and then the second mixture can be added to the top of the first pre-compressed mixture. The resulting tablet comprises two independent layers, and each layer comprises different active ingredients.

[0169] In certain embodiments, a pharmaceutical dosage form comprises a therapeutically effective amount of obcetrapib (eg, as described herein for obcetrapib).

[0170] In certain embodiments, the pharmaceutical dosage form comprises about 1% to about 25% w / w of obicetrapib or a salt, solvate or hydrate thereof. In other embodiments, the pharmaceutical dosage form comprises about 1% to about 20% w / w, or about 1% to about 15% w / w, or about 1% to about 10% w / w, or about 5% to about 15% w / w, or about 5% to about 12% w / w of obicetrapib or a salt, solvate or hydrate thereof. In other embodiments, 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 obicetrapib. In a specific embodiment, the pharmaceutical dosage form comprises about 3-5% w / w of obicetrapib, or a salt, solvate, or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 7-10% w / w of obicetrapib, or a salt, solvate, or hydrate thereof.

[0171] In certain embodiments, the pharmaceutical dosage form comprises 1% to 25% w / w of obicetrapib, or a salt, solvate, or hydrate thereof. In other embodiments, the pharmaceutical dosage form comprises 1% to 20% w / w, or 1% to 15% w / w, or 1% to 10% w / w, or 5% to 15% w / w, or 5% to 12% w / w of obicetrapib, or a salt, solvate, or hydrate thereof. In other embodiments, 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 obicetrapib, or a salt, solvate, or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 3-5% w / w of obicetrapib, or a salt, solvate, or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 7-10% w / w of obicetrapib, or a salt, solvate, or hydrate thereof.

[0172] In some embodiments, the pharmaceutical dosage form comprises about 1 mg to about 25 mg of obicetrapib, or an equivalent amount of a salt, solvate, or hydrate thereof. In other embodiments, the pharmaceutical dosage form comprises about 1 mg to about 20 mg of obcetrapib, or about 1 mg to about 15 mg of obcetrapib, or about 1 mg to about 10 mg of obcetrapib, or about 5 mg to about 15 mg of obcetrapib, or about 5 mg to about 12 mg of obcetrapib, or an equivalent amount of a salt, solvate, or hydrate of obcetrapib. In other embodiments, 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 obcetrapib, or an equivalent amount of a salt, solvate, or hydrate of obcetrapib. In a specific embodiment, the pharmaceutical dosage form comprises about 5 mg of obcetrapib or an equivalent dose of a salt, solvate, or hydrate of obcetrapib. In a specific embodiment, the pharmaceutical dosage form comprises about 10 mg of obcetrapib or an equivalent dose of a salt, solvate, or hydrate of obcetrapib. In another embodiment, the pharmaceutical dosage form comprises 5 mg of obicetrapib as a calcium salt. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of obicetrapib as a calcium salt.

[0173] In some embodiments, the pharmaceutical dosage form comprises 1 mg to 25 mg of obcetrapib or an equivalent dose of a salt, solvate or hydrate of obcetrapib. In other embodiments, the pharmaceutical dosage form comprises 1 mg to 20 mg of obcetrapib, or 1 mg to 15 mg of obcetrapib, or 1 mg to 10 mg of obcetrapib, or 5 mg to 15 mg of obcetrapib, or 5 mg to 12 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib. In other embodiments, 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 obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib. In a specific embodiment, the pharmaceutical dosage form comprises 5 mg of obcetrapib or an equivalent dose of a salt, solvate, or hydrate of obcetrapib. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of obcetrapib or an equivalent dose of a salt, solvate, or hydrate of obcetrapib. In another embodiment, the pharmaceutical dosage form comprises 5 mg of obicetrapib as a calcium salt. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of obicetrapib as a calcium salt.

[0174] In certain embodiments, the pharmaceutical dosage form comprises a therapeutically effective amount of a SGLT2 inhibitor (eg, as described herein for the subject SGLT2 inhibitor).

[0175] In some embodiments, the pharmaceutical dosage form comprises about 1% to about 75% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In other embodiments, the pharmaceutical dosage form comprises about 1% to about 40% w / w, or about 1% to about 30% w / w, about 1% to about 20% w / w, about 1% to about 10%, or about 5% to about 15% w / w, or about 10% to about 25% w / w, or about 45% to about 75% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In other embodiments, 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 an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises about 5% w / w of an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises about 10% w / w of an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises about 15% w / w of an SGLT2 inhibitor or its salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises about 25% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 50% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 75% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof.

[0176] In some embodiments, the pharmaceutical dosage form comprises 1% to 75% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In other embodiments, the pharmaceutical dosage form comprises 1% to 40% w / w, or 1% to 30% w / w, 1% to 20% w / w, 1% to 10%, or 5% to 15% w / w, or 10% to 25% w / w, or 45% to 75% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In other embodiments, 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 an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 5% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 10% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 15% w / w of an SGLT2 inhibitor or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 25% w / w of an 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.

[0177] In some embodiments, the pharmaceutical dosage form includes about 1mg to about 300mg of the SGLT2 inhibitor or the salt, solvate or hydrate of the SGLT2 inhibitor of the same dose. In other embodiments, the pharmaceutical dosage form includes about 5mg to about 100mg of the SGLT2 inhibitor, or about 5mg to about 50mg of the SGLT2 inhibitor, or about 10mg to about 25mg of the SGLT2 inhibitor, or about 5mg to about 15mg of the SGLT2 inhibitor, or about 5mg to about 10mg of the SGLT2 inhibitor, or the salt, solvate or hydrate of the SGLT2 inhibitor of the same dose. In other embodiments, the pharmaceutical composition includes about 100mg, about 300mg, about 150mg to 250mg or about 100mg to 200mg of the SGLT2 inhibitor, or the salt, solvate or hydrate of the SGLT2 inhibitor of the same dose. In certain embodiments, the pharmaceutical dosage form comprises about 5mg, about 7mg, about 8mg, about 10mg, about 12mg, about 15mg, about 18mg, about 20mg, about 22mg, about 25mg, about 30mg, about 40mg or about 50mg of an SGLT2 inhibitor or an equivalent dose of an SGLT2 inhibitor salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises about 5mg of an SGLT2 inhibitor or an equivalent dose of an SGLT2 inhibitor salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises about 10mg of an SGLT2 inhibitor or an equivalent dose of an SGLT2 inhibitor salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises about 15mg of an SGLT2 inhibitor or an equivalent dose of an SGLT2 inhibitor salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises about 25mg of an SGLT2 inhibitor or an equivalent dose of an SGLT2 inhibitor salt, solvate or hydrate. In a specific embodiment, the pharmaceutical dosage form comprises a salt, solvate or hydrate of the SGLT2 inhibitor of about 100mg or an equal dose of the SGLT2 inhibitor. In a specific embodiment, the pharmaceutical dosage form comprises a salt, solvate or hydrate of the SGLT2 inhibitor of about 300mg or an equal dose of the SGLT2 inhibitor. In certain embodiments, any of the above amounts are the free free alkali form of the SGLT2 inhibitor, or a salt, solvate or hydrate of the SGLT2 inhibitor of an equal dose. In certain embodiments, the amount is the salt form of the SGLT2 inhibitor, or a salt, solvate or hydrate of the SGLT2 inhibitor of an equal dose.

[0178] In some embodiments, pharmaceutical dosage form includes 1mg to 300mg of SGLT2 inhibitor or a salt, solvate or hydrate of the SGLT2 inhibitor of equal dose. In other embodiments, pharmaceutical dosage form includes 5mg to 100mg of SGLT2 inhibitor, or 5mg to 50mg of SGLT2 inhibitor, or 10mg to 25mg of SGLT2 inhibitor, or 5mg to 15mg of SGLT2 inhibitor, or 5mg to 10mg of SGLT2 inhibitor, or a salt, solvate or hydrate of the SGLT2 inhibitor of equal dose. In other embodiments, pharmaceutical composition includes 100mg, 300mg, 150mg to 250mg or 100mg to 200mg of SGLT2 inhibitor, or a salt, solvate or hydrate of the SGLT2 inhibitor of equal dose. In certain embodiments, the pharmaceutical dosage form comprises 5mg, 7mg, 8mg, 10mg, 12mg, 15mg, 18mg, 20mg, 22mg, 25mg, 30mg, 40mg or 50mg of a SGLT2 inhibitor or a salt, solvate or hydrate of an SGLT2 inhibitor of equal dose. In a specific embodiment, the pharmaceutical dosage form comprises 5mg of a SGLT2 inhibitor or a salt, solvate or hydrate of an SGLT2 inhibitor of equal dose. In a specific embodiment, the pharmaceutical dosage form comprises 10mg of a SGLT2 inhibitor or a salt, solvate or hydrate of an SGLT2 inhibitor of equal dose. In a specific embodiment, the pharmaceutical dosage form comprises 15mg of a SGLT2 inhibitor or a salt, solvate or hydrate of an SGLT2 inhibitor of equal dose. In a specific embodiment, the pharmaceutical dosage form comprises 25mg of a SGLT2 inhibitor or a salt, solvate or hydrate of an SGLT2 inhibitor of equal dose. In a specific embodiment, the pharmaceutical dosage form comprises a salt, solvate or hydrate of the SGLT2 inhibitor of 100mg or an equal dose of the SGLT2 inhibitor. In a specific embodiment, the pharmaceutical dosage form comprises a salt, solvate or hydrate of the SGLT2 inhibitor of 300mg or an equal dose of the SGLT2 inhibitor. In certain embodiments, any of the above amounts are the free alkali form of the SGLT2 inhibitor, or a salt, solvate or hydrate of the SGLT2 inhibitor of an equal dose. In certain embodiments, the amount is the salt form of the SGLT2 inhibitor, or a salt, solvate or hydrate of the SGLT2 inhibitor of an equal dose.

[0179] In one embodiment, the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate, or hydrate of obcetrapib, and b) about 10 mg to about 25 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) about 5 mg of obcetrapib, or an equivalent dose of a salt, solvate, or hydrate of obcetrapib, and b) about 10 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) about 5 mg of obcetrapib, or an equivalent dose of a salt, solvate, or hydrate of obcetrapib, and b) about 25 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of an SGLT2 inhibitor. In another embodiment, the tablet comprises a) about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 10 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 25 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is empagliflozin.

[0180] In one embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 10 mg to 25 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 10 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 25 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In another embodiment, the tablet comprises a) 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 10 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 25 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is empagliflozin.

[0181] In another embodiment, the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 5 mg to about 15 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) about 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 5 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) about 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 15 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In another embodiment, the tablet comprises a) about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 5 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In another embodiment, the tablet comprises a) about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 15 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is ertogliflozin.

[0182] In another embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 5 mg to 15 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 5 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 15 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In another embodiment, the tablet comprises a) 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 5 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In another embodiment, the tablet comprises a) 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 15 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is ertogliflozin.

[0183] In another embodiment, the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 5 mg to about 10 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is dapagliflozin.

[0184] In another embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 5 mg to 10 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is dapagliflozin.

[0185] In another embodiment, the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 100 mg to about 300 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) about 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 100 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) about 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 300 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 100 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In another embodiment, the tablet comprises a) about 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) about 300 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is canagliflozin.

[0186] In another embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 100 mg to 300 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 100 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) 5 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 300 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In a related embodiment, the dosage form comprises a) 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 100 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In another embodiment, the tablet comprises a) 10 mg of obcetrapib, or an equivalent dose of a salt, solvate or hydrate of obcetrapib, and b) 300 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is canagliflozin.

[0187] As used herein, the term "equivalent dose" refers to an amount of a given compound that is "equivalent" to a specific amount of a reference compound (e.g., a free base form of the compound). For example, if a dosage form contains a salt of obcetrapib, the amount of salt added to the pharmaceutical dosage form needs to be adjusted to take into account the difference in molecular weight between obcetrapib as a free base form and a salt form.

[0188] In certain embodiments, the pharmaceutical dosage form comprises one or more additional active compounds (e.g., as described herein). In certain embodiments, the pharmaceutical dosage form further comprises a therapeutically effective amount of metformin (e.g., metformin hydrochloride). In certain embodiments, the pharmaceutical dosage form comprises 500 mg to 1000 mg of metformin, e.g., 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).

[0189] In certain embodiments, the pharmaceutical form further comprises a therapeutically effective amount of linagliptin. In certain embodiments, the pharmaceutical dosage form comprises 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 an equivalent dose of a salt, solvate or hydrate of linagliptin. In some cases, the pharmaceutical composition comprises 2.5 mg of linagliptin or an equivalent dose of a salt, solvate or hydrate of linagliptin. In some cases, the pharmaceutical composition comprises 5 mg of linagliptin, or an equivalent dose of a salt, solvate or hydrate of linagliptin.

[0190] In certain embodiments, 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 form comprises microcrystalline cellulose, mannitol, or a combination of the two.

[0191] In certain embodiments, the pharmaceutical dosage form comprises microcrystalline cellulose in an amount of 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 mg to 65 mg. In a specific embodiment, the amount of microcrystalline cellulose is about 60 mg. In another specific embodiment, the amount of microcrystalline cellulose is about 65 mg.

[0192] In certain embodiments, the pharmaceutical dosage form comprises an amount of 40 mg to 80 mg of microcrystalline cellulose, such as 45 mg to 75 mg, 45 mg to 70 mg, 45 mg to 65 mg, or 50 mg to 65 mg. In a specific embodiment, the amount of microcrystalline cellulose is 60 mg. In another specific embodiment, the amount of microcrystalline cellulose is 65 mg.

[0193] In certain embodiments, the pharmaceutical dosage form comprises mannitol in an amount of 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. In a specific embodiment, the amount of microcrystalline cellulose is about 23 mg.

[0194] In an embodiment, the pharmaceutical dosage form comprises 1 mg to 35 mg of mannitol, such as 1 mg to 30 mg, 1 mg to 30 mg, 1 mg to 25 mg or 10 to 25 mg. In a specific embodiment, the amount of microcrystalline cellulose is 23 mg.

[0195] In certain embodiments, the pharmaceutical dosage form comprises one or more disintegrants. In some cases, the disintegrant is sodium starch glycolate. In certain embodiments, the pharmaceutical dosage form comprises sodium starch glycolate in an amount of 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. In a specific embodiment, the amount of sodium starch glycolate is about 5 mg.

[0196] In certain embodiments, the pharmaceutical dosage form comprises sodium starch glycolate in an amount of 1 mg to 15 mg, for example 1 mg to 10 mg, 1 mg to 8 mg, 2 mg to 7 mg or 4 mg to 6 mg. In a specific embodiment, the amount of sodium starch glycolate is 5 mg.

[0197] In certain embodiments, the pharmaceutical dosage form comprises one or more glidants. In some cases, the glidant is colloidal silicon dioxide. In certain embodiments, the pharmaceutical dosage form comprises colloidal silicon dioxide in an amount of 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 mg to 2 mg. In a specific embodiment, the amount of colloidal silicon dioxide is about 1 mg.

[0198] In certain embodiments, the pharmaceutical dosage form comprises colloidal silicon dioxide in an amount of 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 mg to 2 mg. In a specific embodiment, the amount of colloidal silicon dioxide is 1 mg.

[0199] In certain embodiments, the pharmaceutical dosage form comprises one or more lubricants. In some cases, the lubricant is magnesium stearate. In certain embodiments, the pharmaceutical dosage form comprises an amount of about 0.1 mg to 5 mg of magnesium stearate, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 mg to 2 mg. In a specific embodiment, the amount of colloidal silicon dioxide is about 1 mg.

[0200] In certain embodiments, the pharmaceutical dosage form comprises magnesium stearate in an amount of 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 mg to 2 mg. In a specific embodiment, the amount of colloidal silicon dioxide is 1 mg.

[0201] In other embodiments, the pharmaceutical compositions, pharmaceutical dosage forms, or tablets described herein are free of negative drug-drug interactions. In related embodiments, the pharmaceutical compositions, pharmaceutical dosage forms, or tablets are free of negative drug-drug interactions with other antidiabetic drugs. In another embodiment, the pharmaceutical compositions, pharmaceutical dosage forms, or tablets described herein can be administered without regard to food, with or without regard to whether the patient is taking another antidiabetic drug.

[0202] 4.3. Usage

[0203] As described above, also provided herein is a method for treating or preventing a metabolic disorder, the method comprising administering to a subject suffering from or at risk of suffering from a metabolic disorder a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form comprising a pharmaceutical composition, the pharmaceutical composition comprising a combination of obicetrapib and an SGLT2 inhibitor as described herein.

[0204] In another aspect, a method for treating or preventing a metabolic disorder is provided, the method comprising administering to a subject having or at risk of having a metabolic disorder a therapeutically effective amount of obicetrapib and administering to a subject having or at risk of having a metabolic disorder a therapeutically effective amount of an SGLT2 inhibitor.

[0205] Without being limited by any particular theory, administration of a pharmaceutical composition or a dosage form comprising a pharmaceutical composition comprising a combination of obicetrapib and an SGLT2 inhibitor as defined herein, or administration of both obicetrapib and an SGLT2 inhibitor alone, can be used to prevent, slow the development of, delay or treat metabolic disorders, in particular to delay the progression to insulin dependence. This opens up new therapeutic possibilities for the treatment and prevention of type 2 diabetes, obesity, diabetic complications and adjacent disease states.

[0206] Therefore, the present disclosure provides a method for preventing, slowing the development of, delaying or treating a metabolic disorder selected from type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity and metabolic syndrome in a subject in need thereof by administering to the patient a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of the present disclosure, or administering both obicetrapib and an SGLT2 inhibitor alone.

[0207] With respect to diseases or conditions associated with impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and / or metabolic syndrome, pharmaceutical compositions according to the present disclosure, or both obicetrapib and an SGLT2 inhibitor administered alone, may also have valuable disease-modifying properties.

[0208] The present invention also provides a method for preventing, slowing, delaying or reversing the progression of impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and / or the progression from metabolic syndrome to type 2 diabetes in a subject in need thereof by administering to the patient a therapeutically effective amount of the pharmaceutical composition or pharmaceutical dosage form of the present invention, or by administering both obicetrapib and an SGLT2 inhibitor alone.

[0209] Therefore, the pharmaceutical compositions and dosage forms described herein are effective in treating diseases and / or conditions associated with or caused by elevated blood glucose levels.

[0210] In various embodiments, a method is provided for preventing, slowing the development of, delaying or treating a disease or condition selected from diabetic complications (e.g., cataracts) and micro- and macrovascular diseases (e.g., nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, atherosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmia and vascular restenosis) by administering a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of the present disclosure to a patient, or by administering both obicetrapib and an SGLT2 inhibitor alone. Specifically, one or more aspects of diabetic nephropathy, such as hyperperfusion, proteinuria and albuminuria, can be treated, their progression slowed or their onset delayed or prevented. The term "tissue ischemia" specifically includes diabetic macrovascular disease, diabetic microangiopathy, impaired wound healing and diabetic ulcers.

[0211] By administering the pharmaceutical composition according to the present disclosure, or by administering both obicetrapib and an SGLT2 inhibitor separately, and due to the activity of obicetrapib and an SGLT2 inhibitor, excessive blood sugar levels may not be converted into insoluble storage forms, such as fat, but are excreted through the patient's urine, and LDL cholesterol levels are reduced. Therefore, the pharmaceutical compositions and dosage forms described herein do not lead to weight gain, and in some cases may even lead to weight loss.

[0212] Therefore, in some embodiments of the present method, a method is provided for reducing the body weight or preventing weight gain or promoting weight loss in a subject in need thereof by administering to the patient a therapeutically effective amount of a pharmaceutical composition or dosage form of the present disclosure, or by administering both obicetrapib and an SGLT2 inhibitor separately.

[0213] According to the present disclosure, the combination of obicetrapib and SGLT2 inhibitors in the pharmaceutical composition or the pharmacological effects of obicetrapib and SGLT2 inhibitors administered alone are independent of insulin. Therefore, blood sugar control can be improved without increasing the burden on pancreatic β cells, and the health and function of β cells can be improved by reducing lipid-induced toxicity. By administering a pharmaceutical composition according to the present disclosure, or administering obicetrapib and SGLT2 inhibitors alone, β cell degeneration and β cell function decline, such as apoptosis or necrosis of pancreatic β cells, can be delayed or prevented. In addition, the function of pancreatic cells can be improved or restored, and the number and size of pancreatic β cells can be increased. It can be shown that by using a pharmaceutical composition or dosage form according to the present invention for treatment, the differentiation state and proliferation of pancreatic β cells disturbed by hyperglycemia and hyperlipidemia or dyslipidemia can be normalized.

[0214] Therefore, the present invention also provides a method for preventing, slowing, delaying or treating pancreatic β cell degeneration and / or decreased pancreatic β cell function and / or for improving and / or restoring pancreatic β cell function and / or restoring pancreatic insulin secretion function in a subject in need thereof by administering to the patient a therapeutically effective amount of the pharmaceutical composition or pharmaceutical dosage form of the present invention, or by administering both obicetrapib and an SGLT2 inhibitor alone.

[0215] By administering a pharmaceutical composition according to the present disclosure, or administering both obcetrapib and an SGLT2 inhibitor alone, and due to the activity of obcetrapib and an SGLT2 inhibitor, the abnormal accumulation of fat in the liver can be reduced or inhibited. Therefore, according to the present disclosure, there is also provided a method for preventing, slowing down, delaying or treating a disease or condition caused by abnormal accumulation of liver fat in a subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of the present disclosure to the patient, or by administering both obcetrapib and an SGLT2 inhibitor alone. The disease or condition attributed to abnormal accumulation of liver fat is particularly selected from common fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), high nutrition-induced fatty liver, diabetic fatty liver, alcohol-induced fatty liver or toxic fatty liver.

[0216] Therefore, the present invention also provides a method for maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance in a patient in need thereof by administering to the patient a therapeutically effective amount of the pharmaceutical composition or pharmaceutical dosage form of the present disclosure, or by administering both obicetrapib and an SGLT2 inhibitor separately.

[0217] 4.4. Kit

[0218] Also provided herein is a pharmaceutical kit comprising a package containing a plurality of unit dosage forms of the drug (eg, as described herein) and instructions for use.

[0219] According to an embodiment of the present invention, the pharmaceutical kit comprises a container, such as a high-density polyethylene (HDPE) bottle, or a box comprising one or more blister packages, wherein the bottle or blister package may contain a plurality of solid unit dosage forms as described herein. In certain embodiments, the container or package comprises at least 5, at least 8, at least 10, at least 12, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of the at least 15 unit dosage forms.

[0220] According to the present invention, the drug kit comprises instructions (e.g., instructions) inserted into the container or box, typically a patient information leaflet containing printed information, which may include a description of the form and composition of the unit dosage form contained in the kit, an indication of the therapeutic indication for which the product is intended, instructions on how to use the product, and information and warnings about adverse reactions and contraindications associated with use. According to the present disclosure, the instructions typically contain information about therapeutic indications, uses, treatment regimens, etc., as described herein for the treatment methods of the present invention. In some cases, the instructions contain printed instructions for repeated (self-) administration of the drug unit dosage form to treat and / or prevent metabolic disorders, particularly type 2 diabetes.

[0221] 4.5. Definitions

[0222] The terms "subject" and "patient" are used interchangeably. The subject can be a mammal, such as a non-primate (e.g., a cow, pig, horse, cat, dog, sheep, rabbit, rat, mouse, etc.) or a primate (e.g., monkey and human), such as a human. In certain embodiments, the subject is a mammal, such as a human, diagnosed with a disease or disorder described herein. In another embodiment, the subject is a mammal, such as a human, at risk for a disease or disorder described herein. In a specific embodiment, the subject is a human.

[0223] The terms "therapies" and "therapy" are used in their broadest sense in the clinical setting.

[0224] The term "pharmaceutically acceptable" means that the material does not have the properties that would cause a reasonably prudent physician to avoid administering it to a patient, taking into account the disease or condition to be treated and the respective route of administration. For example, it is usually required that such materials are substantially sterile, such as for injections.

[0225] The term "carrier" refers to a glidant, diluent, adjuvant, excipient or carrier administered together with the compound, but is not limited thereto. Examples of carriers are described herein and in Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978-0128200070).

[0226] The term "diluent" refers to a compound used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize the compound. Non-limiting examples of diluents include starch, sugar, 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 dihydrate, mannitol, and tricalcium phosphate.

[0227] The term "binder" used in this application refers to any pharmaceutically acceptable film that can be used to hold the active ingredients and inert ingredients of the carrier together to maintain cohesive and discrete parts. Non-limiting examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone and ethyl cellulose.

[0228] The term "disintegrant" refers to a substance that, when added to a solid dosage form, promotes its disintegration or disintegration after administration and allows the active ingredient to be released as effectively as possible so that it dissolves rapidly. Non-limiting examples of disintegrants include corn starch, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, modified corn starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, pregelatinized starch, and alginic acid.

[0229] The term "lubricant" refers to an excipient added to a powder mixture to prevent the compacted powdered material from sticking to the equipment during tableting or encapsulation. It helps the tablet to be ejected from the die and can improve powder flow. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silicon dioxide, 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 acids.

[0230] The term "film coating" refers to a thin, uniform film on the surface of a substrate (e.g., a tablet). Film coatings are particularly useful for protecting active ingredients from photolytic degradation. Non-limiting examples of film coatings include polyvinyl alcohol-based, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate film coatings.

[0231] The term "glidant" as used herein is intended to refer to an agent used in tablet and capsule formulations to improve flowability during tablet compression and produce an anti-caking effect. Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0232] The term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to achieve treatment as defined herein when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the patient being treated, the patient's weight and age, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art.

[0233] The term "unit dosage form" or "pharmaceutical dosage form" refers to physically discrete units suitable as unitary dosages for human subjects 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., tablets).

[0234] The terms "treatment" or "treating," when related to a disease or condition, include preventing the occurrence of the disease or condition, inhibiting the disease or condition, eliminating the disease or condition, and / or alleviating one or more symptoms of the disease or condition.

[0235] As used herein, the term "% w / w" refers to the weight of a component based on the total weight of the composition in which it is contained. For example, if component A is present in an amount of 50% w / w in 100 mg of the composition, component A is present in an amount of 50 mg.

[0236] Unless otherwise expressly stated, when a compound can present alternative tautomeric, positional and / or stereoisomeric forms, all alternative isomers should be included in the scope of the claimed subject matter. For example, when a compound is described as a specific optical isomer D- or L-, both optical isomers are included herein. For example, when a compound is described as having one of two tautomeric forms, both tautomeric forms are included herein. Therefore, the compounds provided herein can be enantiomerically pure, or stereoisomerically or diastereoisomerically mixed. The compounds provided herein may contain chiral centers. The chiral center may be (R) or (S) configuration, or a mixture thereof. The chiral centers of the compounds provided herein may be diastereoisomerized in vivo. Therefore, those skilled in the art will recognize that for compounds that diastereoisomerize in vivo, administering the compound in its (R) form is equivalent to administering the compound in its (S) form.

[0237] The present disclosure also includes 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 in the compound according to the present disclosure has been exchanged for another atom having the same atomic number but having an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that may be incorporated into a compound according to the present disclosure are hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, e.g. 2 H (deuterium), 3 H (tritium), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I. Certain isotopic variations of the compounds according to the present disclosure, particularly those into which one or more radioactive isotopes have been incorporated, may be useful, for example, for studying the mechanism of action or the distribution of the active compound in vivo. 3 H. 14 C and / or 18 F isotope-labeled compounds are suitable for this purpose. In addition, because the compound has higher metabolic stability, such as extending the half-life in the body or reducing the required active dose, the introduction of isotopes (such as deuterium) can bring special therapeutic benefits. In some embodiments, the hydrogen atoms of the compounds described herein can be replaced by deuterium atoms. In certain embodiments, unless otherwise stated, "deuteration" applied to chemical groups refers to isotope-enriched deuterium chemical groups, and its deuterium content is significantly higher than its natural abundance. Isotopic variants of compounds according to the present disclosure can be prepared by various methods, including, for example, the methods described below and in the working examples, by using the corresponding isotope modification of specific reagents and / or starting compounds.

[0238] Therefore, any embodiment described herein is meant to include salts, single stereoisomers, mixtures of stereoisomers, and / or isotopic forms of the compounds.

[0239] Unless otherwise specified, the term "about" or "approximately" refers to the acceptable error of a particular value determined by a person of ordinary skill in the art, which depends in part on the measurement or determination of the value. In certain embodiments, the term "about" or "approximately" refers to within 1, 2 or 3 standard deviations. In certain embodiments, the term "about" or "approximately" refers to 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" refers to within the positive or negative 10% range of the value clearly listed, rounded up or down to the nearest integer.

[0240] 5. Examples

[0241] The examples in this section are for illustrative purposes only and are not limiting. The examples represent only some embodiments, and it should be understood that the following examples are illustrative and not limiting. Unless otherwise specified, all substituents are as defined above. Reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps of each of the routes described can be combined in different ways, or combined with steps of different schemes, to prepare the compounds described herein. 5.1. Example 1: 2×2 factorial Mendelian randomization analysis of the effect of combined genetic variation of SGLT2 and CETP on the incidence of diabetes in UKBiobank

[0242] introduce

[0243] A post hoc meta-analysis of data collected from clinical trials of CETP inhibitors showed that CETP inhibitors used alone or in combination with other lipid-lowering drugs were associated with a reduced incidence of diabetes (see, e.g., W. Masson et al., Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk, Diabetes & Metabolism, Volume 44, Issue 6, 2018, Pages 508-513). In the current study described below, a 2×2 factorial Mendelian randomization (MR) design was used to investigate whether the combined use of CETP inhibitors and SGLT2 inhibitors would reduce the incidence of diabetes compared with SGLT2 inhibitor monotherapy in 233,765 individuals from UK Biobank.

[0244] method

[0245] Construction of CETP genetic score:In order to construct a genetic score that simulates the effect of CETP inhibitors, single nucleotide polymorphism (SNP) scores in 4 CETP regions closely related to HDL were constructed. The genetic score uses all available SNPs in the UK Biobank genotyping information, which is 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 simulates a higher degree of drug CETP inhibition.

[0246] Construction of SGLT2 genetic score :To construct a genetic score that mimics the effects of SGLT2 inhibitors, a single nucleotide polymorphism (SNP) score in two SGLT2 regions that are closely associated with SGLT2 expression was constructed. The genetic score uses all available SNPs in the UK Biobank genotyping information, which is included in the Katzmann et al. (Katzmann, JL, Mason, AM, W., Kleber, ME, Niessner, A., Blüher, 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 simulates a higher degree of drug SGLT2 inhibition.

[0247] Include individuals : For the 2 × 2 factorial MR analysis, all individuals with genotyping information (containing all SNPs required to construct the genetic score) and all biomarker values ​​in the UK Biobank were included. In addition, only individuals of UK ancestry were included in the analysis to control for population stratification bias. A total of 233,765 individuals met all inclusion criteria.

[0248] Grouping: Individuals were divided into two groups based on whether their CETP genetic score was above or below the median CETP score. Within each group, individuals were divided into two additional groups based on whether their SGLT2 genetic score was above or below the median SGLT2 genetic score. A total of four subgroups were formed, and the details of each subgroup are shown in Table 1 below.

[0249]

[0250] As used herein, Group 1 is referred to as the “control group,” Group 2 is referred to as the “SGLT2 monotherapy group,” Group 3 is referred to as the “CETP monotherapy group,” and Group 4 is referred to as the “combination therapy group.” This nomenclature is used because that is the treatment approach represented by each group, but note that the changes in HDL and A1C resulting from the genetic score-based groupings are different in magnitude than the actual drug treatments they are designed to help study.

[0251] Statistical analysis : Quantitative characteristics of each group were compared using one-way ANOVA. When ANOVA detected differences between groups, each group was paired compared with every other group using one-way ANOVA to characterize differences between groups. Gender composition was compared using the chi-square test. The incidence of diabetes was compared between groups using logistic regression analysis.

[0252] Results and discussion

[0253] The variance analysis on HDL among the four groups yielded an overall p-value (p<0.00001), indicating that the mean HDL values ​​of the groups were significantly different. We used paired ANOVA to characterize the specific differences between each group. The results are shown in Table 2 below:

[0254]

[0255] If the CETP score worked as expected, it would be expected that there would be a significant difference between the control and the observed CETP monotherapy (Groups 1 and 3; p=0). Significant differences in HDL were observed between Groups 1 and 3 (control vs. CETP inhibitor monotherapy), Groups 1 and 4 (control vs. combination therapy), Groups 2 and 3 (SGLT2 inhibitor monotherapy vs. CETP inhibitor monotherapy), and Groups 2 and 4 (SGLT2 inhibitor monotherapy vs. combination therapy). These results suggest that the separation of HDL between the groups was achieved in a pattern consistent with CETP inhibitor treatment and that the SGLT2 gene score worked as expected. These results also suggest that SGLT2 inhibitors had no effect on HDL levels. The same pattern of statistical significance and opposite direction of effect were observed in ApoB, LDL, and TG, other biomarkers known to be associated with the CETP genetic score (see, e.g., Tables 9-11 under "Other Regression Data" below).

[0256] The ANOVA on glycated hemoglobin between the four groups also yielded an overall p-value (p<0.00001), indicating that there were significant differences between the groups. The results are shown in Table 3 below:

[0257]

[0258]

[0259] If the SGLT2 score worked as expected, a significant difference between the control and the observed SGLT2 monotherapy would be expected (Group 1 and Group 2; p = 0.035). However, significant differences in glycated hemoglobin levels were also observed between Group 1 and Group 3, Group 1 and Group 4, Group 2 and Group 4, and Group 3 and Group 4. The CETP gene score was also associated with glycated hemoglobin, and CETP inhibitor monotherapy resulted in a significant reduction. Notably, glycated hemoglobin levels were significantly reduced between Group 2 and Group 4 (SGLT2 inhibitor monotherapy and combination therapy). These results suggest that combined treatment with SGLT2 and CETP inhibitors may help reduce glycated hemoglobin levels compared with SGLT2 inhibitors alone.

[0260] When the incidence of diabetes among the four groups was compared, it was found that Group 4 (combination treatment) was the only group with a significant reduction in the incidence of diabetes compared to the control (OR = 0.934; p = 0.00222). It was also found that the incidence of diabetes in Group 4 was significantly lower than that in Group 3 (OR = 0.969; p = 0.00745) and Group 2 (OR = 0.957; p = 0.02785). The reduction in the incidence of diabetes in Group 4 compared to all other groups suggests that genetically mediated CETP inhibition and SGLT2 inhibition have a stronger protective effect against the development of diabetes than genetically mediated inhibition of each alone. The following Tables 4-6 summarize these results:

[0261]

[0262]

[0263] The combined observations of HbA1c reduction and reduced diabetes incidence in the combination-therapy group and all other treatment groups suggest that pharmacological interventions targeting both CETP and SGLT2 will achieve greater glycemic control than targeting CETP or SGLT2 alone.

[0264] Other regression data

[0265] The p-values ​​of other regressions are shown in Table 7-11 below:

[0266] Age: p = 0.3485

[0267] Gender: p = 0.922937

[0268] Weight: p = 0.1622; not significant.

[0269]

[0270]

[0271] Sensitivity analysis

[0272] As mentioned above, the SGLT2 score had an effect on glycated hemoglobin as expected, being associated with lower glycated hemoglobin, just as SGLT2 inhibition was associated with lower glycated hemoglobin. However, the SGLT2 score was associated with an improvement in BMI and blood pressure between groups 1 and 2, which is contrary to the observed effect of SGLT2 inhibitors in practice.

[0273] To further investigate this phenomenon, we performed sensitivity analyses using linear regression (for glycated hemoglobin) and logistic regression (for diabetes) and included BMI, blood pressure, weight, age, and sex as covariates to separate the effects of the genetic score independent of these variables. Under this analytical approach, the differences in glycated hemoglobin and diabetes between groups 2 and 4 and groups 3 and 4 were re-evaluated. The results are shown in Tables 12 and 13 below:

[0274]

[0275] In summary, the sensitivity analysis results shown in Tables 12 and 13 are consistent with the above analysis results (eg, described in the Results and Discussion section). The significance of the tests on HbA1c and diabetes incidence was not affected by BMI, BP, weight, age or sex.

[0276] 5.2. Example 2: Preparation of fixed-dose tablets

[0277] The following examples are illustrative procedures of how to prepare and test the obicetrapib and SGLT2 fixed-dose combination tablets described herein.

[0278] 5.2.1. Example 2A: Composition

[0279] An exemplary pharmaceutical dosage form (e.g., as disclosed herein) is formulated as a 6 mm diameter, white, film-coated, round, biconvex tablet without identifying markings. Tablets can be produced in the dosage strengths (doses of obicetrapib expressed as calcium salt) shown in Tables 14-17 below.

[0280] Tables 14-17 provide a complete description of the ingredients and quantitative composition of fixed-dose tablets comprising 5 mg or 10 mg of obicetrapib and an SGLT2 inhibitor (amounts expressed as % w / w)

[0281]

[0282]

[0283]

[0284] 5.2.1. Example 2B: Preparation

[0285] The general manufacturing process for preparing the above fixed dose tablets by direct compression is described as follows:

[0286] (1) mixing obicetrapib and the SGLT2 inhibitor with microcrystalline cellulose, mannitol, sodium starch glycolate and colloidal silicon dioxide in a mixer to obtain a premix;

[0287] (2) adding magnesium stearate to the premix of step (1) and continuing mixing;

[0288] (3) compressing the final mixture of step (1) into 6 mm biconvex tablet cores on a suitable tablet press;

[0289] (4) Film coat the 6 mm biconvex core tablets with a special aesthetic film coater.

[0290] 6. Equivalents and Incorporation by Reference

[0291] While the present invention has been particularly shown and described with reference to a preferred embodiment and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and details may be made without departing from the spirit and scope of the invention.

[0292] All references, issued patents, and patent applications cited in the text of this specification are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A pharmaceutical composition comprising: a) a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt thereof; and b) a therapeutically effective amount of at least one SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the obicetrapib is a calcium salt.

3. The pharmaceutical composition according to claim 1 or 2, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertogliflozin, empagliflozin, bepagliflozin, togliflozin, ipagliptin, lupagliflozin, repagliflozin etabonate, sergliflozin etabonate and sogliflozin.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertogliflozin and empagliflozin.

5. The pharmaceutical composition according to claim 3 or 4, wherein the SGLT2 inhibitor is empagliflozin.

6. The pharmaceutical composition according to claim 3 or 4, wherein the SGLT2 inhibitor is dapagliflozin.

7. The pharmaceutical composition according to claim 3 or 4, wherein the SGLT2 inhibitor is canagliflozin.

8. The pharmaceutical composition according to claim 3 or 4, wherein the SGLT2 inhibitor is ertogliflozin.

9. A pharmaceutical composition according to any one of claims 1 to 8, further comprising one or more additional active drugs.

10. The pharmaceutical composition according to claim 9, wherein the one or more additional active drugs are selected from metformin and a DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 10, wherein the DPP-4 inhibitor is linagliptin.

12. A pharmaceutical composition according to any one of claims 1 to 11 comprising 1% to 25% w / w of obicetrapib.

13. The pharmaceutical composition according to claim 12, comprising 1% to 10% w / w of obicetrapib.

14. The pharmaceutical composition of claim 13, comprising about 5% w / w obicetrapib.

15. The pharmaceutical composition of claim 13, comprising about 10% w / w obicetrapib.

16. A pharmaceutical composition according to any one of claims 1 to 15 comprising 5% to 50% w / w of the SGLT2 inhibitor.

17. The pharmaceutical composition according to claim 16, comprising 5% to 25% w / w of the SGLT2 inhibitor.

18. The pharmaceutical composition according to any one of claims 1 to 17, further comprising one or more of a diluent, a disintegrant, a glidant, a filler, a lubricant and any combination thereof.

19. The pharmaceutical composition of claim 18, wherein the diluent is selected from the group consisting of dicalcium phosphate, cellulose, microcrystalline cellulose, compressible sugar, dibasic calcium phosphate dihydrate, lactose, lactose monohydrate, anhydrous lactose, mannitol, tricalcium phosphate, and combinations thereof.

20. The pharmaceutical composition according to claim 18 or 19, wherein the disintegrant is selected from the group consisting of cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, modified corn starch, pregelatinized starch, sodium carboxymethyl starch, and combinations thereof.

21. The pharmaceutical composition according to any one of claims 18 to 20, wherein the glidant is selected from colloidal silicon dioxide, talc and combinations thereof.

22. The pharmaceutical composition according to any one of claims 18 to 21, wherein the lubricant is selected from calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, and combinations thereof.

23. A pharmaceutical composition according to any one of claims 1 to 22, wherein the composition comprises:

24. The pharmaceutical composition of claim 23, further comprising one or more lubricants.

25. The pharmaceutical composition according to claim 23 or 24, further comprising one or more glidants.

26. A pharmaceutical dosage form comprising the pharmaceutical composition of any one of claims 1 to 25.

27. The pharmaceutical dosage form according to claim 26, wherein the obicetrapib is present in an amount of 1 to 25 mg.

28. The pharmaceutical dosage form according to claim 27, wherein the obicetrapib is present in an amount of 1 to 10 mg.

29. The pharmaceutical dosage form according to claim 27, wherein the obicetrapib is present in an amount of 5 mg.

30. The pharmaceutical dosage form of claim 27, wherein the obicetrapib is present in an amount of 10 mg.

31. The pharmaceutical dosage form according to any one of claims 26 to 30, wherein the SGLT2 inhibitor is present in an amount of 1 to 300 mg.

32. The pharmaceutical dosage form according to claim 31, wherein the SGLT2 inhibitor is present in an amount of 5 to 100 mg.

33. The pharmaceutical dosage form according to claim 31, wherein the SGLT2 inhibitor is present in an amount of 5 to 50 mg.

34. The pharmaceutical dosage form according to claim 31, wherein the SGLT2 inhibitor is present in an amount of 10 to 25 mg.

35. The pharmaceutical dosage form according to claim 34, wherein the SGLT2 inhibitor is empagliflozin.

36. The pharmaceutical dosage form according to claim 31, wherein the SGLT2 inhibitor is present in an amount of 5 to 15 mg.

37. The pharmaceutical dosage form according to claim 36, wherein the SGLT2 inhibitor is etoglipizide.

38. The pharmaceutical dosage form according to claim 31, wherein the SGLT2 inhibitor is present in an amount of 5 to 10 mg.

39. The pharmaceutical dosage form according to claim 38, wherein the SGLT2 inhibitor is dapagliflozin.

40. The pharmaceutical dosage form according to claim 31, wherein the SGLT2 inhibitor is present in an amount of 100 to 300 mg.

41. The pharmaceutical dosage form according to claim 40, wherein the SGLT2 inhibitor is canagliflozin.

42. The pharmaceutical dosage form of claim 31, wherein the SGLT2 inhibitor is present in an amount of 5 mg.

43. The pharmaceutical dosage form according to claim 31, wherein the SGLT2 inhibitor is present in an amount of 10 mg.

44. The pharmaceutical dosage form of claim 31, wherein the SGLT2 inhibitor is present in an amount of 15 mg.

45. The pharmaceutical dosage form of claim 31, wherein the SGLT2 inhibitor is present in an amount of 25 mg.

46. ​​The pharmaceutical dosage form of claim 31, wherein the SGLT2 inhibitor is present in an amount of 100 mg.

47. The pharmaceutical dosage form of claim 31, wherein the SGLT2 inhibitor is present in an amount of 300 mg.

48. The pharmaceutical dosage form of claim 26, wherein the obicetrapib is present in an amount of 5 to 10 mg; and the SGLT2 inhibitor is empagliflozin, present in an amount of 10 to 25 mg.

49. The pharmaceutical dosage form of claim 26, wherein the obicetrapib is present in an amount of 5 to 10 mg; and the SGLT2 inhibitor is etoglipizine, present in an amount of 5 to 15 mg.

50. The pharmaceutical dosage form of claim 26, wherein the obicetrapib is present in an amount of 5 to 10 mg; and the SGLT2 inhibitor is dapagliflozin, present in an amount of 5 to 10 mg.

51. The pharmaceutical dosage form of claim 26, wherein the obicetrapib is present in an amount of 5 to 10 mg; and the SGLT2 inhibitor is canagliflozin, present in an amount of 100 to 300 mg.

52. The pharmaceutical dosage form according to any one of claims 26 to 51, wherein the dosage form is a solid dosage form.

53. The pharmaceutical dosage form of claim 52, wherein the solid dosage form is a tablet.

54. The pharmaceutical dosage form according to claim 53, further comprising a film coating.

55. A method for treating or preventing a metabolic disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 25 or a pharmaceutical dosage form according to any one of claims 26 to 54 to a subject suffering from or at risk of suffering from a metabolic disorder.

56. The method of claim 55, wherein the metabolic disorder is selected from type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, and metabolic syndrome.

57. A method of treating or preventing a metabolic disorder in a subject having or likely to have a metabolic disorder, comprising: administering a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt thereof; and A therapeutically effective amount of at least one SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

58. The method of claim 57, wherein the metabolic disorder is selected from type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, and metabolic syndrome.

59. The method of claim 57 or 58, wherein the obicetrapib is a calcium salt.

60. The method according to any one of claims 57 to 59, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertogliflozin, empagliflozin, bepagliflozin, togliflozin, ipagliptin, lupagliflozin, repagliflozin etabonate, sergliflozin etabonate and sogliflozin.

61. The method according to any one of claims 57 to 60, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertogliflozin and empagliflozin.

62. The method of claim 60 or 61, wherein the SGLT2 inhibitor is empagliflozin.

63. The method of claim 60 or 61, wherein the SGLT2 inhibitor is dapagliflozin.

64. The method of claim 60 or 61, wherein the SGLT2 inhibitor is canagliflozin.

65. The method of claim 60 or 61, wherein the SGLT2 inhibitor is ertogliflozin.

66. The method of any one of claims 57 to 65, wherein the therapeutically effective amount of obicetrapib is 1 to 25 mg per day.

67. The method of claim 66, wherein the therapeutically effective amount of obicetrapib is 1 to 10 mg per day.

68. The method of claim 66, wherein the therapeutically effective amount of obicetrapib is 5 mg per day.

69. The method of claim 66, wherein the therapeutically effective amount of obicetrapib is 10 mg per day.

70. The method of any one of claims 57 to 61, wherein the therapeutically effective amount of the SGLT2 inhibitor is 1 to 300 mg per day.

71. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 5 to 100 mg per day.

72. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 5 to 50 mg per day.

73. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 10 to 25 mg per day.

74. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 5 to 15 mg per day.

75. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 5 to 10 mg per day.

76. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 100 to 300 mg per day.

77. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 5 mg per day.

78. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 10 mg per day.

79. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 15 mg per day.

80. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 25 mg per day.

81. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 100 mg per day.

82. The method of claim 70, wherein the therapeutically effective amount of the SGLT2 inhibitor is 300 mg per day.

83. The method of claim 57, wherein the therapeutically effective amount of obicetrapib is 5 to 10 mg per day; the therapeutically effective amount of the SGLT2 inhibitor is 10 to 25 mg per day; and the SGLT2 inhibitor is empagliflozin.

84. The method of claim 57, wherein the therapeutically effective amount of obicetrapib is 5 to 10 mg per day; the therapeutically effective amount of the SGLT2 inhibitor is 5 to 15 mg per day; and the SGLT2 inhibitor is etoglipizide.

85. The method of claim 57, wherein the therapeutically effective amount of obicetrapib is 5 to 10 mg per day; the therapeutically effective amount of the SGLT2 inhibitor is 5 to 10 mg per day; and the SGLT2 inhibitor is dapagliflozin.

86. The method of claim 57, wherein the therapeutically effective amount of obicetrapib is 5 to 10 mg per day; the therapeutically effective amount of the SGLT2 inhibitor is 100 to 300 mg per day; and the SGLT2 inhibitor is canagliflozin.

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