Combination of obiscetrapib and SGLT2 inhibitors

Abstract

Provided herein is a pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. Also provided is a dosage form comprising said pharmaceutical composition. In some embodiments, the dosage form is a solid dosage form, such as a tablet. Also provided is a process for preparing a fixed dose formulation of obicetrapib and an SGTL2 inhibitor, as well as a method for using said fixed dose formulation in the treatment of metabolic disorders (e.g., type 2 diabetes). Also provided is a method for treating or preventing metabolic disorders in a subject having or at risk of developing 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.

Description

[Technical field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent No. 63 / 295,276, filed December 30, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0002] 2. Introduction Type 2 diabetes is an increasingly prevalent disease. Due to the high frequency of complications, type 2 diabetes results in a significant reduction in life expectancy. Type 2 diabetes also causes significant morbidity. Due to diabetes-related microvascular complications, type 2 diabetes is now the most frequent cause of adult-onset vision loss, renal failure, and amputation in industrialized countries. Furthermore, the presence of type 2 diabetes is associated with a two- to five-fold increase in cardiovascular disease risk.

[0003] It is now widely accepted that glycemic control makes a difference for patients with type II diabetes. The goal of diabetes treatment today is to achieve and maintain blood glucose as close to normal as possible to prevent long-term micro- and macrovascular complications associated with elevated glucose in the blood. Oral therapeutic options for the treatment of type II diabetes include sulfonylureas, biguanides (metformin), thiazolidinediones, and compounds known as α-glucosidase inhibitors. Active agents from each class are generally administered to patients alone. However, when monotherapy becomes insufficient, combination therapy is feasible, despite the known side effect of weight gain associated with sulfonylurea and thiazolidinone therapy.

[0004] After a long disease duration, most type 2 diabetes patients eventually fail oral treatment and become insulin dependent, requiring daily injections and multiple daily glucose measurements.

[0005] Therefore, there is a need for alternative therapies that can better treat type 2 diabetes and slow the progression to insulin dependence in type 2 diabetes and similar metabolic disorders. Summary of the Invention

[0006] 3. Overview of the Invention 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 said pharmaceutical composition is also provided. In some embodiments, the dosage form is a solid dosage form, such as a tablet. A process for preparing a fixed dose formulation of obicetrapib and an SGTL2 inhibitor, as well as a method for using said fixed dose formulation in the treatment of metabolic disorders (e.g., type 2 diabetes) are also provided. A method for treating or preventing metabolic disorders in a subject having or at risk of developing a metabolic disorder is also provided, 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. Also provided is a method of treating or preventing a metabolic disorder in a subject having or at risk of developing a metabolic disorder, the method comprising administering a therapeutically effective amount of obicetrapib, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharma- ceutically acceptable salt thereof.

[0007] The first aspect of the present disclosure is a) a therapeutically effective amount of obiscetrapib, or a pharma- ceutically acceptable salt thereof; b) a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition includes

[0008] A second aspect of the present disclosure includes a pharmaceutical dosage form comprising a pharmaceutical composition comprising obiscetrapib and an SGLT2 inhibitor (e.g., as described herein).

[0009] A third aspect of the present disclosure includes a method of treating or preventing a metabolic disorder, the method comprising administering to a subject having or at risk of developing a metabolic disorder a pharmaceutical composition comprising a therapeutically effective amount of obiscetrapib and an SGLT2 inhibitor (e.g., as described herein).

[0010] A fourth aspect of the present disclosure includes a method of treating or preventing a metabolic disorder in a subject having or at risk of developing a metabolic disorder, comprising administering a therapeutically effective amount of obicetrapib, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharma- ceutically acceptable salt thereof.

[0011] 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 OF THE PREFERRED EMBODIMENTS

[0012] 4. Detailed Description of the Invention As summarized above, in one aspect, the present disclosure provides a pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. A pharmaceutical dosage form comprising said pharmaceutical composition is also provided. In some embodiments, the dosage form is a solid dosage form, such as a tablet. A process for preparing a fixed dose combination formulation of obicetrapib and an SGTL2 inhibitor, as well as a method for using said fixed dose combination formulation in the treatment of metabolic disorders (e.g., type 2 diabetes) are also provided. A method for treating or preventing metabolic disorders in a subject having or at risk of developing a metabolic disorder is also provided, 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.

[0013] The pharmaceutical composition of the present disclosure is described in more detail below. Obicetrapib active compound is described, and SGLT2 inhibitor is described. Also described are pharmaceutical compositions comprising Obicetrapib and SGLT2 inhibitor, pharmaceutical dosage forms comprising Obicetrapib and SGLT2 inhibitor, and preparation processes of fixed dose formulations thereof. Also described are methods in which the pharmaceutical composition of the present disclosure is used.

[0014] Pharmaceutical Compositions As summarized above, the present disclosure provides a pharmaceutical composition comprising obiscetrapib, or a pharma- ceutically acceptable salt thereof, and an SGTL2 inhibitor, or a pharma- ceutically acceptable salt thereof.

[0015] 4.1.1. Ovicetrapib Compounds The pharmaceutical compositions disclosed herein include obiscetrapib, or a pharma- ceutically acceptable salt thereof. More specifically, obiscetrapib, 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 cholesteryl ester transfer protein (CETP) inhibitor of formula (I), where Et represents an ethyl group: [ka]

[0016] Compared with other known CETP inhibitors, only relatively low doses of the compound of formula (I) are required to achieve almost complete CETP inhibition.Typically, it has been shown that repeated daily doses (once a day) of as low as 2.5 mg of the compound of formula (I) are sufficient to achieve almost complete CETP inhibition.These are significantly lower doses than those that must be 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.

[0017] Inhibition of CETP can lower LDL-C and increase high-density lipoprotein cholesterol (HDLC) levels. CETP is a plasma protein secreted primarily by the liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (apo B)-containing particles (mainly LDL and very low-density lipoprotein VLDL) in exchange for triglycerides, thereby decreasing the cholesterol content in HDL in favor of the cholesterol content in (V)LDL. It is therefore hypothesized that CETP inhibition retains cholesteryl esters in HDL-C and decreases the cholesterol content of the atherogenic apo B fraction.

[0018] In some embodiments, obiscetrapib is in the form of a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" includes any salt that retains the activity of the active agent(s) and is acceptable for pharmaceutical use. A pharmaceutically acceptable salt also refers to any salt that may form in vivo as a result of administration of an acid or an acid that is converted into a salt, another salt, or a prodrug. The pharmaceutically acceptable salt of the disclosed compound may be prepared by methods well known to those skilled in the art.

[0019] 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 salts and magnesium salts; salts with zinc or aluminum; salts with organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucosamine, triethanolamine or dehydroabietylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; salts with organic acids 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.

[0020] Additionally, pharma- ceutically acceptable salts of compound (I) may include, for example, quaternary salts formed between a compound of formula (I) and an alkyl halide or a phenylalkyl halide.

[0021] Additionally, the compositions may include obiscetrapib in the form of a solvate, e.g., with a pharma- ceutically 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.

[0022] In one embodiment, obistrapib is a calcium salt.

[0023] Ovicetrapib has been previously described (see, e.g., WO 2005 / 095409A2). It can be prepared by the methods described therein (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.

[0024] Obicettrapib is present in the pharmaceutical composition in a therapeutically effective amount. With respect to obistrapib, "therapeutically effective amount" refers to an amount effective to lower low-density lipoprotein-cholesterol (LDL-C). Without intending to be bound by theory, it is believed that lower LDL-C reduces lipotoxicity to pancreatic beta cells. In some embodiments, a "therapeutically effective amount" of obistrapib is an amount that, when administered to an individual in one or more doses in combination therapy (e.g., with an SGLT2 inhibitor as described herein), is effective to lower LDL-C in a subject by about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 80%, at least about 90%, or at least about 95%, compared to the LDL-C level in the individual in the absence or prior to combination treatment.

[0025] In some embodiments, the pharmaceutical composition comprises from about 1% w / w to about 25% w / w of obiscetrapib, or a salt, solvate or hydrate thereof. In further embodiments, the composition comprises from about 1% w / w to about 20% w / w, or from about 1% w / w to about 15% w / w, or from about 1% w / w to about 10% w / w, or from about 5% w / w to about 15% w / w, or from about 5% w / w to about 12% w / w of obiscetrapib, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, or about 15% w / w of obistrapib, or a salt, solvate, or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises about 5% w / w of obistrapib, or a salt, solvate, or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises about 10% w / w of obistrapib, or a salt, solvate, or hydrate thereof.

[0026] In some embodiments, the pharmaceutical composition comprises 1% w / w to 25% w / w of obiscetrapib, or a salt, solvate or hydrate thereof. In further embodiments, the composition comprises 1% w / w to 20% w / w, or 1% w / w to 15% w / w, or 1% w / w to 10% w / w, or 5% w / w to 15% w / w, or 5% w / w to 12% w / w of obiscetrapib, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w or 15% w / w of obistrapib, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises 5% w / w of obistrapib, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises 10% w / w of obistrapib, or a salt, solvate or hydrate thereof.

[0027] SGLT2 inhibitors The pharmaceutical compositions disclosed herein also include an SGTL2 inhibitor, or a pharma- ceutically acceptable salt thereof.

[0028] The term "SGLT2 inhibitor" refers to compounds that exhibit an inhibitory effect on the sodium-glucose transporter 2 (SGLT2), in particular human SGLT2, in particular glucopyranosyl derivatives, i.e. compounds having a glucopyranosyl moiety. In some embodiments, the activity of an SGLT2 inhibitor is measured by an inhibition assay, e.g., measuring the activity level of the enzyme in either a cell-free system or in cells following treatment with the compound of interest, as compared to a control, as determined by IC 50 Value or EC 50 In one embodiment, the SGLT2 inhibitor has an IC of 10 μM or less, e.g., 3 μM or less, 1 μM or less, 500 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 30 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even less. 50 Value (or EC 50 The inhibitory effect on human SGLT2 can be determined by methods known in the literature, in particular by the methods described in WO 2005 / 092877 or WO 2007 / 093610 (pages 23 / 24), which are incorporated herein by reference in their entirety. The term "SGLT2 inhibitor" also includes any pharma- ceutically acceptable salts thereof, hydrates and solvates thereof, including the respective crystalline forms.

[0029] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin, remogliflozin etabonate, sergliflozin, sergliflozin etabonate, atigliflozin, and sotagliflozin.

[0030] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, and sotagliflozin.

[0031] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, and empagliflozin.

[0032] In some embodiments, the SGLT2 inhibitor is empagliflozin.

[0033] In some embodiments, the SGLT2 inhibitor is dapagliflozin.

[0034] In some embodiments, the SGLT2 inhibitor is canagliflozin.

[0035] In some embodiments, the SGLT2 inhibitor is ertugliflozin.

[0036] In one embodiment, the SGLT2 inhibitor has formula (II): [ka] Glucopyranosyl-substituted benzene derivatives of [In the formula, R 1 is halogen (e.g., chloro), (C 1~3 ) alkyl, or cyano; Each R 2 are independently H, (C 1~3 ) alkyl, (C 1~3 ) alkoxy or hydroxy; R 3 is (C 1~3 ) alkyl, cycloalkyl, alkynyl, (C 1~3) alkoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; n is 0 to 3], or a hydrate, solvent, or pharma- ceutically acceptable salt thereof.

[0037] In one embodiment, the SGLT2 inhibitor is a prodrug of any of the above SGLT2 inhibitors.

[0038] In an embodiment, the SGLT2 inhibitors of formula (II) and methods for their synthesis are described, for example, in the following international patent applications: WO2005 / 092877, WO2006 / 117360, WO2006 / 117359, WO2006 / 120208, WO2006 / 064033, WO2007 / 031548, WO2007 / 093610, WO2008 / 020011, WO2008 / 055870, the disclosures of which are incorporated herein by reference.

[0039] In some embodiments of Formula (II), R 1 is methyl. In some cases, R 1 is a halogen. In some cases, the halogen is chloride. In some other cases, R 1 is cyano.

[0040] In some embodiments of Formula (II), each R 2 is H. In certain embodiments, n is 1 and R 2 is methyl. In one embodiment, n is 1 and R 2 In one embodiment, n is 1 and R 2 is hydroxy.

[0041] In certain embodiments of Formula (II), R 3 is ethyl, cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. In some cases, R 3is cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 3 is ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

[0042] In certain instances, the SGLT2 inhibitor is selected from any one of the following compounds: [ka] [ka] [ka]

[0043] It should be understood that the above definition of SGLT2 inhibitors including glucopyranosyl-substituted benzene derivatives of formula (II) also includes their hydrates, solvates, polymorphic forms, and their prodrugs. The term "empagliflozin" as used herein refers to empagliflozin, including its hydrates, solvates, and crystalline forms. In one embodiment, the SGLT2 inhibitor is a crystalline form described in International Patent Application WO2006 / 117360, which is incorporated herein in its entirety. In certain embodiments, the SGLT2 inhibitor is a crystalline form described in International Patent Application WO2006 / 117359, which is incorporated herein in its entirety. In certain embodiments, the SGLT2 inhibitor is a crystalline form described in International Patent Application WO2008 / 049923, which is incorporated herein in its entirety. These crystalline forms have good dissolution properties that may allow good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline forms are physicochemically stable, thus providing good shelf-life stability of the pharmaceutical composition.

[0044] The term "dapagliflozin" as used herein refers to dapagliflozin, including its hydrates, solvates and crystalline forms.The compound and its synthesis method are described, for example, in WO 03 / 099836.The hydrates, solvates and crystalline forms are described, for example, in patent applications WO2008 / 116179 and WO2008 / 002824.

[0045] The term "canagliflozin" as used herein refers to canagliflozin, including its hydrate, solvate and crystalline forms.The compound and its synthesis method are described, for example, in WO2005 / 012326 and WO2009 / 035969.Some hydrates, solvates and crystalline forms are described, for example, in patent application WO2008 / 069327.

[0046] The term "atigliflozin" as used herein refers to atigliflozin, including its hydrates, solvates, and crystalline forms. The compound and its synthesis method are described, for example, in WO 2004 / 007517.

[0047] The term "ipragliflozin" as used herein refers to ipragliflozin, including its hydrates, solvates, and crystalline forms. The compound and its synthesis method are described, for example, in WO 2004 / 080990, WO 2005 / 012326, and WO 2007 / 114475.

[0048] The term "tofogliflozin" as used herein refers to tofogliflozin, including its hydrates, solvates, and crystalline forms. The compound and its synthesis method are described, for example, in WO 2007 / 140191 and WO 2008 / 013280.

[0049] The term "remogliflozin" as used herein refers to remogliflozin, including its hydrates, solvates and crystalline forms, and the prodrugs of remogliflozin, particularly remogliflozin etabonate. Its synthesis method is described, for example, in patent applications EP1213296 and EP1354888.

[0050] The term "sergliflozin" as used herein refers to sergliflozin and prodrugs of sergliflozin, including its hydrates, solvates and crystalline forms, in particular sergliflozin etabonate, the preparation of which is described, for example, in patent applications EP1344780 and EP1489089.

[0051] The disclosure of each of the above references cited above with respect to specific SGLT2 inhibitors is specifically incorporated herein by reference in its entirety.

[0052] 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 effective to inhibit SGLT2 and / or reduce glucose reabsorption. Without intending to be bound by theory, it is believed that reducing glucose absorption reduces blood glucose levels and reduces glucose toxicity in pancreatic beta cells. In some embodiments, a "therapeutically effective amount" of an SGLT2 inhibitor is an amount that, when administered to an individual in combination therapy (e.g., with obiscetrapib as described herein) in one or more doses, is effective to reduce glucose reabsorption in a subject by about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 80%, at least about 90%, or at least about 95%, compared to the glucose reabsorption level in the individual in the absence of treatment with the combination, or alternatively, compared to the glucose level in the subject before or after treatment with the combination.

[0053] In some embodiments, the pharmaceutical composition comprises from about 1% w / w to about 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises from about 1% w / w to about 50% w / w, or from about 1% w / w to about 40% w / w, from about 1% w / w to about 30% w / w, from about 1% to about 20%, from about 1% to 10%, or from about 5% w / w to about 15% w / w, or from about 10% w / w to about 25% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further 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 the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises about 5% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises about 10% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises about 15% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises about 25% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises about 50% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises about 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.

[0054] In some embodiments the pharmaceutical composition comprises 1% w / w to 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments the pharmaceutical composition comprises 1% w / w to 50% w / w, or 1% w / w to 40% w / w, 1% w / w to 30% w / w, 1% to 20%, 1% to 10%, or 5% w / w to 15% w / w, or 10% w / w to 25% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further 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 the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises 5% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises 10% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises 15% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises 25% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises 50% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical composition comprises 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.

[0055] 4.1.3. Additional activators The pharmaceutical compositions disclosed herein may optionally contain one or more additional active agents.In some embodiments, at least one of the one or more additional active agents is an antidiabetic agent.In some embodiments, at least one of the one or more additional active agents is an antidiabetic agent selected from biguanides, thiazolidindione, sulfonylurea, glinide, inhibitors of α-glucosidase, insulin, DPP-4 inhibitors and amylin analogs (including pharmaceutically acceptable salts of said agents).

[0056] In some embodiments, the combination of obiscetrapib, an SGLT2 inhibitor, and one or more additional active agents according to the present disclosure may allow for a reduction in the dose of either obiscetrapib or SGLT2.

[0057] A reduction in dose may be beneficial for patients who would otherwise potentially suffer from side effects in treatments using higher doses of one or more active ingredients. Thus, the pharmaceutical compositions and methods according to the present disclosure may exhibit fewer side effects relative to the corresponding monotherapy with either of the active agents (e.g., obiscetrapib or SGLT2 inhibitors), thereby making the treatment more tolerable and improving individual compliance with the treatment.

[0058] In some embodiments, the additional active agent is a biguanide. Examples of biguanides include metformin, phenformin and buformin. In some cases, the additional active agent is metformin. The term "metformin" used herein refers to metformin or its pharma- ceutically acceptable salts, such as hydrochloride, metformin (2:1) fumarate and metformin (2:1) succinate, hydrobromide, p-chlorophenoxyacetate or embonate, and other known metformin salts of monobasic and dibasic carboxylic acids. In one embodiment, metformin used herein is metformin hydrochloride.

[0059] In certain embodiments, the pharmaceutical composition comprises 1-50% w / w metformin hydrochloride, for example 1-45% w / w, 1-40% w / w, 1-35% w / w, 1-30% w / w, 1-25% w / w, 1-20% w / w, 1-15% w / w, 1-10% w / w, or 1-5% w / w metformin hydrochloride.

[0060] In some embodiments, the additional active agent is a DPP-4 inhibitor.Examples of DPP-4 inhibitors are linagliptin, sitagliptin, vildagliptin, saxagliptin, denagliptin, alogliptin, carmegliptin, melogliptin, dutogliptin (including their pharmaceutically acceptable salts, hydrates and solvates).In some embodiments, the DPP-4 inhibitor is linagliptin.

[0061] In certain embodiments, the pharmaceutical composition comprises 1-10% w / w linagliptin, e.g., 1-9% w / w, 1-8% w / w, 1-7% w / w, 1-6% w / w, 1-5% w / w, 2-5% w / w, 2-4% w / w of linagliptin, or a salt, solvate or hydrate thereof. In some cases, the pharmaceutical composition comprises 2.5% w / w of linagliptin, or a salt, solvate or hydrate thereof. In some cases, the pharmaceutical composition comprises 5% w / w of linagliptin, or a salt, solvate or hydrate thereof.

[0062] In some embodiments, the additional active agent is a thiazolidinedione. Examples of thiazolidinediones (TZDs) include pioglitazone and rosiglitazone. The term "pioglitazone" as used herein refers to pioglitazone, including its enantiomers, mixtures thereof and its racemates, or its pharmaceutically acceptable salts, such as hydrochloride. The term "rosiglitazone" as used herein refers to rosiglitazone, including its enantiomers, mixtures thereof and its racemates, or its pharmaceutically acceptable salts, such as maleate.

[0063] In some embodiments, the additional active agent is a sulfonylurea. Examples of sulfonylureas are glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride, glyburide, glisoxepide and gliclazide. In some cases, the sulfonylurea is selected from tolbutamide, gliquidone, glibenclamide, glipizide and glimepiride. In some cases, the sulfonylurea is selected from glibenclamide, glipizide and glimepiride. As used herein, each term in the group "glibenclamide", "glimepiride", "gliquidone", "glibornuride", "gliclazide", "glisoxepide", "tolbutamide" and "glipizide" refers to the respective active drug or its pharmaceutically acceptable salt.

[0064] In some embodiments, the additional active agent is a glinide.Examples of glinide are nateglinide, repaglinide and mitiglinide.The term "nateglinide" as used herein refers to nateglinide, including the enantiomers of nateglinide, mixtures thereof and racemates thereof, or pharmaceutically acceptable salts and esters thereof.The term "repaglinide" as used herein refers to repaglinide, including the enantiomers of repaglinide, mixtures thereof and racemates thereof, or pharmaceutically acceptable salts and esters thereof.

[0065] In some embodiments, the additional active agent is an inhibitor of α-glucosidase. Examples of inhibitors of α-glucosidase are acarbose, voglibose and miglitol. Each term of the group "acarbose", "voglibose" and "miglitol" as used herein refers to the respective active drug or its pharma- ceutically acceptable salt.

[0066] In some embodiments, the additional active substance is an amylin analogue.The example of an amylin analogue is pramlintide, including its pharmaceutically acceptable salt, hydrate and solvate.For example, pramlintide acetate is commercially available under the trade name Symlin.

[0067] Thus, according to further embodiments, the pharmaceutical compositions disclosed herein comprise a combination of obiscetrapib, an SGLT2 inhibitor, and one or more additional antidiabetic agents, hi certain embodiments, the additional antidiabetic agents are metformin, linagliptin, or a combination thereof.

[0068] Excipients The pharmaceutical compositions provided according to the present disclosure can be administered orally. Thus, in an embodiment, the present disclosure provides pharmaceutical compositions comprising obiscetrapib and an SGLT2 inhibitor as described herein, and one or more pharma- ceutically 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, binders, glidants, adjuvants, and combinations thereof. Such compositions are prepared by methods well known in the pharmaceutical arts (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. (Edited by G.S. Banker & C.T. Rhodes).

[0069] The pharmaceutical composition may be administered in a fixed dose combination by oral administration. Administration may be via capsule, tablet, etc. In one embodiment, the combination of obiscetrapib and SGLT2 inhibitor is in the form of a tablet. In a further embodiment, the tablet is a compressed tablet. When making pharmaceutical compositions containing solids as described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier, which may be in the form of a capsule, tablet, sachet, or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient.

[0070] The pharmaceutical composition may be formulated for immediate release or sustained release. A "sustained release formulation" is a formulation designed to slowly release a therapeutic agent into the body over an extended period of time, and an "immediate release formulation" is a formulation designed to rapidly release a therapeutic agent into the body over a short period of time. In some cases, an immediate release formulation may be coated so that the therapeutic agent is released only when it reaches the desired target in the body (e.g., the stomach). In certain embodiments, the pharmaceutical composition is formulated for immediate release.

[0071] The pharmaceutical composition may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof.Some examples of suitable excipients are described herein.When the pharmaceutical composition is formulated into a tablet, the tablet may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0072] In some embodiments, the pharmaceutical composition comprises a diluent selected from the group consisting of dicalcium phosphate, cellulose, microcrystalline cellulose, compressible sugar, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate, mannitol, tribasic calcium 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.

[0073] In some embodiments, the pharmaceutical composition comprises a controlled release matrix. In some cases, the diluent is polyethylene oxide and hypromellose.

[0074] In further embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount of from about 1% w / w to about 100% w / w, or from about 1% w / w to about 80% w / w, or from about 1% w / w to about 75% w / w, or from about 5% w / w to about 75% w / w, or from about 10% w / w to about 70% w / w, or from about 15% w / w to about 70% w / w. In certain embodiments, the microcrystalline cellulose is present in an amount of about 5% w / w, or about 10% w / w, or about 15% w / w, or about 20% w / w, or about 25% w / w, or about 30% w / w, or about 35% w / w, or about 40% w / w, or about 45% w / w, or about 50% w / w, or about 55% w / w, or about 60% w / w, or about 65% w / w, or about 70% w / w, or about 75% w / w. In further particular embodiments, the microcrystalline cellulose is in an amount of about 60% w / w. In further particular embodiments, the microcrystalline cellulose is in an amount of about 65% w / w.

[0075] In further embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount between 1% w / w and 100% w / w, or between 1% w / w and 80% w / w, or between 1% w / w and 75% w / w, or between 5% w / w and 75% w / w, or between 10% w / w and 70% w / w, or between 15% w / w and 70% w / w. In certain embodiments, the microcrystalline cellulose is present in an amount of 5% w / w, or 10% w / w, or 15% w / w, or 20% w / w, or 25% w / w, or 30% w / w, or 35% w / w, or 40% w / w, or 45% w / w, or 50% w / w, or 55% w / w, or 60% w / w, or 65% w / w, or 70% w / w, or 75% w / w. In a further particular embodiment, the microcrystalline cellulose is in an amount of 60% w / w.In a further particular embodiment, the microcrystalline cellulose is in an amount of 65% w / w.

[0076] In still further embodiments, the pharmaceutical composition comprises mannitol in an amount of about 1% w / w to about 40% w / w, or about 1% w / w to about 35% w / w, or about 1% w / w to about 25% w / w, or about 5% w / w to about 35% w / w, or about 10% w / w to about 30% w / w, or about 15% w / w to about 25% w / w. In certain embodiments, mannitol is present in an amount of about 5% w / w, or about 20% w / w, or about 15% w / w, or about 30% w / w, or about 22% w / w, or about 23% w / w, or about 24% w / w, or about 25% w / w. In further particular embodiments, the microcrystalline cellulose is in an amount of about 20% w / w.

[0077] In still further embodiments, the pharmaceutical composition comprises mannitol in an amount of 1% w / w to 40% w / w, or 1% w / w to 35% w / w, or 1% w / w to 25% w / w, or 5% w / w to 35% w / w, or 10% w / w to 30% w / w, or 15% w / w to 25% w / w. In particular embodiments, mannitol is present in an amount of 5% w / w, or 20% w / w, or 15% w / w, or 30% w / w, or 22% w / w, or 23% w / w, or 24% w / w, or 25% w / w. In further particular embodiments, microcrystalline cellulose is in an amount of 20% w / w.

[0078] In some embodiments, the pharmaceutical composition comprises a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, modified corn starch, pregelatinized starch, sodium starch glycolate, and combinations thereof.

[0079] In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 1% w / w to about 20% w / w, or about 1% w / w to about 15% w / w, or about 1% w / w to about 10% w / w, or about 1% w / w to about 8% w / w, or about 2% w / w to about 8% w / w. In certain embodiments, croscarmellose sodium is present in an amount of about 1% w / w, or about 3% w / w, or about 4% w / w, or about 5% w / w, or about 6% w / w, or about 7% w / w, or about 10% w / w. In further particular embodiments, croscarmellose sodium is in an amount of about 5% w / w.

[0080] In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate in an amount between 1% w / w and 20% w / w, or between 1% w / w and 15% w / w, or between 1% w / w and 10% w / w, or between 1% w / w and 8% w / w, or between 2% w / w and 8% w / w. In certain embodiments, croscarmellose sodium is present in an amount of 1% w / w, or 3% w / w, or 4% w / w, or 5% w / w, or 6% w / w, or 7% w / w, or 10% w / w. In further particular embodiments, croscarmellose sodium is in an amount of 5% w / w.

[0081] In some embodiments, the pharmaceutical composition comprises a glidant selected from the group consisting of colloidal silicon dioxide, talc, and combinations thereof.

[0082] In further embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.1% w / w to about 5% w / w, or about 0.1% w / w to about 4.5% w / w, or about 0.1% w / w to about 4% w / w, or about 0.5% w / w to about 5.0% w / w, or about 0.5% w / w to about 3% w / w, or about 0.5% w / w to about 2% w / w, or about 0.5% w / w to about 1.5% w / w. In certain embodiments, the colloidal silicon dioxide is present in an amount of about 0.1% w / w, 0.5% w / w, 0.75% w / w, 0.95% w / w, 1.0% w / w, or 1.2% w / w. In further particular embodiments, the colloidal silicon dioxide is present in an amount of about 1% w / w.

[0083] In further embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of 0.1% w / w to 5% w / w, or 0.1% w / w to 4.5% w / w, or 0.1% w / w to 4% w / w, or 0.5% w / w to 5.0% w / w, or 0.5% w / w to 3% w / w, or 0.5% w / w to 2% w / w, or 0.5% w / w to 1.5% w / w. In certain embodiments, the colloidal silicon dioxide is present in an amount of 0.1% w / w, 0.5% w / w, 0.75% w / w, 0.95% w / w, 1.0% w / w, or 1.2% w / w. In further particular embodiments, the colloidal silicon dioxide is present in an amount of 1% w / w.

[0084] 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.

[0085] In further embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.1% w / w to about 3% w / w, or about 0.1% w / w to about 2.5% w / w, or about 0.5% w / w to about 3% w / w, or about 0.5% w / w to about 2.5% w / w, or about 0.5% w / w to about 2% w / w, or about 1% w / w to about 3% w / w, or about 1% w / w to about 2% w / w. In certain embodiments, the magnesium stearate is present in an amount of about 0.1% w / w, or about 0.5% w / w, or about 0.7% w / w, or about 0.9% w / w, or about 1.0% w / w, or about 1.2% w / w. In further particular embodiments, the magnesium stearate is in an amount of about 1% w / w.

[0086] In further embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of 0.1% w / w to 3% w / w, or 0.1% w / w to 2.5% w / w, or 0.5% w / w to 3% w / w, or 0.5% w / w to 2.5% w / w, or 0.5% w / w to 2% w / w, or 1% w / w to 3% w / w, or 1% w / w to 2% w / w. In particular embodiments, the magnesium stearate is present in an amount of 0.1% w / w, or 0.5% w / w, or 0.7% w / w, or 0.9% w / w, or 1.0% w / w, or 1.2% w / w. In further particular embodiments, the magnesium stearate is in an amount of 1% w / w.

[0087] In one embodiment, the pharmaceutical composition comprises a) about 1% w / w to about 10% w / w of obiscetrapib, or a salt, solvate or hydrate thereof, and b) about 5% w / w to about 20% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a related embodiment, the composition comprises a) about 5% w / w of obiscetrapib, or a salt, solvate or hydrate thereof, and b) about 5% w / w to 20% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In another embodiment, the composition comprises a) about 10% w / w of obiscetrapib, or a salt, solvate or hydrate thereof, and b) about 5% w / w to 25% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In still further related embodiments, the composition further comprises a) from about 40% w / w to about 65% w / w microcrystalline cellulose, b) from about 5% w / w to about 23% w / w mannitol, c) from about 1% w / w to about 10% w / w sodium starch glycolate, d) from about 0.5% w / w to about 3% w / w colloidal silicon dioxide, and e) from about 0.1% w / w to about 3% w / w magnesium stearate. In another embodiment, the composition comprises a) about 10% w / w of obicetrapib, or a salt, solvate or hydrate thereof; b) about 5% w / w to 25% w / w of an SGLT2 inhibitor, or a salt, solvate or hydrate thereof; c) about 40% w / w to about 65% w / w of microcrystalline cellulose; d) about 5% w / w to about 23% w / w of mannitol; e) about 1% w / w to about 10% w / w of sodium starch glycolate; f) about 0.5% w / w to about 3% w / w of colloidal silicon dioxide; and g) about 0.1% w / w to about 3% w / w of magnesium stearate.

[0088] In one embodiment, the pharmaceutical composition comprises a) 1% w / w to 10% w / w of obiscetrapib, or a salt, solvate or hydrate thereof, and b) 5% w / w to 20% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a related embodiment, the composition comprises a) 5% w / w of obiscetrapib, or a salt, solvate or hydrate thereof, and b) 5% w / w to 20% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In another embodiment, the composition comprises a) 10% w / w of obiscetrapib, or a salt, solvate or hydrate thereof, and b) 5% w / w to 25% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In still further related embodiments, the composition further comprises a) between 40% w / w and 65% w / w of microcrystalline cellulose, b) between 5% w / w and 23% w / w of mannitol, c) between 1% w / w and 10% w / w of sodium starch glycolate, d) between 0.5% w / w and 3% w / w of colloidal silicon dioxide, and e) between 0.1% w / w and 3% w / w of magnesium stearate. In another embodiment, the composition comprises a) 10% w / w of obiscetrapib, or a salt, solvate or hydrate thereof; b) 5% w / w to 25% w / w of an SGLT2 inhibitor, or a salt, solvate or hydrate thereof; c) 40% w / w to 65% w / w of microcrystalline cellulose; d) 5% w / w to 23% w / w of mannitol; e) 1% w / w to 10% w / w of sodium starch glycolate; f) 0.5% w / w to 3% w / w of colloidal silicon dioxide; and g) 0.1% w / w to 3% w / w of magnesium stearate.

[0089] In certain embodiments, the pharmaceutical composition comprises: [Table 18]

[0090] In certain embodiments, the pharmaceutical composition comprises: [Table 19]

[0091] In certain embodiments, the SGLT2 inhibitor is empagliflozin in an amount of 7% w / w to 9% w / w or 18% w / w to 20% w / w and obicetrapib is in an amount of 3.5% w / w to 5% w / w, or 7% w / w to 10% w / w.

[0092] In certain embodiments, the pharmaceutical composition comprises: [Table 20]

[0093] In one embodiment, the SGLT2 inhibitor is dapagliflozin in an amount of 4% w / w to 5% w / w or 8% w / w to 10% w / w and obicetrapib is in an amount of 4% w / w to 5% w / w, or 8% w / w to 10% w / w.

[0094] In certain embodiments, the pharmaceutical composition comprises: [Table 21]

[0095] In one embodiment, the SGLT2 inhibitor is ertugliflozin in an amount of 4% w / w to 5% w / w or 11% w / w to 13% w / w and obicetrapib is in an amount of 4% w / w to 5% w / w or 8% w / w to 10% w / w.

[0096] In certain embodiments, the pharmaceutical composition comprises: [Table 22]

[0097] In certain embodiments, the SGLT2 inhibitor is canagliflozin in an amount of 45% w / w to 50% w / w or 70% w / w to 75% w / w and obicetrapib is in an amount of 1% w / w to 3% w / w, or 3% w / w to 5% w / w.

[0098] The pharmaceutical compositions described herein can be formulated with obiscetrapib and an SGLT2 inhibitor as the only two active pharmaceutical ingredients in the composition, or can be combined with other active ingredients (e.g., as described herein).

[0099] In certain embodiments, the pharmaceutical compositions are 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.

[0100] In the compositions provided herein, the obiscetrapib and SGLT2 inhibitors described herein can be mixed with a suitable pharmaceutical carrier. The concentration of each active agent in the composition can be, for example, effective for delivery of an amount that, upon administration, treats, prevents, or ameliorates a condition or disorder described herein or a symptom thereof.

[0101] In some 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 the selected carrier at effective concentration so that the treated condition is alleviated or prevented, or one or more symptoms are improved.

[0102] The concentration of obistrapib and SGLT2 inhibitor in the pharmaceutical composition provided herein depends, for example, on the physicochemical properties of the compounds, the administration schedule, and the amount administered, as well as other factors known to those skilled in the art. For example, if the composition contains a salt of obistrapib, the amount of said salt administered and / or incorporated into the pharmaceutical composition (i.e., pharmaceutical dosage form) must be adjusted to take into account the difference in molecular weight between the free base form and the salt form. For example, when expressing dose amounts in the label and / or product information of an approved pharmaceutical product that contains a salt form of an active compound that can also be used in free base form, it is common practice to specify the dose of the free base to which the dose of the salt used is equivalent.

[0103] The pharmaceutical compositions described herein are provided for administration to a subject, such as a human or animal (e.g., a mammal), in a unit dosage form, such as a sterile parenteral (e.g., intravenous) solution or suspension containing an appropriate amount of the compound or a pharma- ceutically acceptable derivative thereof. 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 the conjugate or a pharma-ceutically acceptable derivative thereof, are also provided. The conjugate is, in some embodiments, formulated and administered in unit dosage form or multiple dosage form. Unit dosage form, as used herein, refers to a physically discrete unit suitable for a human or animal (e.g., mammal) subject, packaged individually as known in the art. Each unit dosage contains a predetermined amount of obiscetrapib and an SGLT2 inhibitor sufficient to produce the desired therapeutic effect, in association with the necessary pharmaceutical carrier, vehicle, 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. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container that is administered in a separate unit dosage form.Examples of multiple dose forms include vials, capsule bottles or bottles.Thus, in certain embodiments, a multiple dose form is a plurality of unit doses that are not separated in packaging.

[0104] In some embodiments, the obiscetrapib and SGLT2 inhibitors described herein are liquid pharmaceutical formulations. Liquid pharma-ceutically administrable formulations can be prepared, for example, by dissolving, dispersing or otherwise mixing the active compound and any pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, etc., thereby forming a solution or suspension. In some embodiments, the pharmaceutical compositions provided herein to be administered can also contain small amounts of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, and pH buffering agents.

[0105] The actual method of preparing such dosage forms is known or obvious to those skilled in the art.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 can be prepared that contain obiscetrapib and SGLT2 inhibitors within the range disclosed herein, with the remainder being composed of non-toxic carriers.

[0106] Parenteral administration is characterized in some embodiments by injection, either subcutaneously, intramuscularly or intravenously, and is also contemplated herein.Injections can be prepared in conventional form, as liquid solutions or suspensions, as solid forms suitable for liquid solutions or suspensions 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 can include enteral administration, intracerebral administration, nasal administration, intraarterial administration, intracardiac administration, intraosseous injection, intrathecal administration, and intraperitoneal administration.

[0107] Preparations for parenteral administration include sterile liquid preparations ready for injection, sterile dry soluble products ready for combination with a solvent immediately prior to use, including subcutaneous tablets, such as lyophilized powders, sterile suspensions ready for injection, sterile dry insoluble products ready for combination with a vehicle immediately prior to use, and sterile emulsions. Liquid preparations can be either aqueous or non-aqueous.

[0108] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), as well as solutions containing thickening agents and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0109] Pharmaceutically acceptable carriers used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetic agents, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharma- ceutically acceptable substances.

[0110] Pharmaceutical carriers include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[0111] In certain embodiments, intravenous or intraarterial infusion of a sterile aqueous solution containing the combinations described herein is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the conjugates described herein, injected as needed to produce the desired pharmacological effect.

[0112] In certain embodiments, the pharmaceutical formulations are lyophilized powders, which can be reconstituted for administration as solutions, emulsions, and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0113] The lyophilized powder is prepared by dissolving a compound provided herein in a suitable solvent. In some embodiments, the lyophilized powder is sterile. The suitable solvent may contain excipients that improve the stability or other pharmacological components of the powder or reconstituted liquid prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The suitable solvent may also contain a buffer such as citrate, sodium or potassium phosphate, or other such buffers known to those of skill in the art at about neutral pH in some embodiments. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides an example of a formulation. In some embodiments, the resulting solution is apportioned into vials for lyophilization. The lyophilized powder may be stored under appropriate conditions, for example, at about 4° C. to room temperature.

[0114] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier.

[0115] In certain embodiments, the pharmaceutical compositions are formulated as a solid dosage form, such as a tablet or capsule (eg, as described herein below).

[0116] 4.2. Pharmaceutical dosage forms As summarized above, the present disclosure provides pharmaceutical dosage forms comprising the pharmaceutical compositions described herein. The present disclosure provides tablets, pills, etc. comprising the pharmaceutical compositions or dosage forms described herein. The tablets or pills of the present disclosure may be coated to provide a dosage form that provides the advantage of long action or to protect against acidic conditions in the stomach. The tablets may also be formulated for immediate release as previously described. In an embodiment, the tablets include a film coating. Film coatings may be useful to limit photolytic degradation. Suitable film coatings are selected by routine screening of commercially available preparations. In one embodiment, the film coating is a hypromellose-based coating. In an embodiment, the coating represents 2-5% by weight of the total tablet composition and includes a film former, a plasticizer, a glidant, and optionally one or more dyes. In some cases, the coating represents 3% of the total tablet composition. An exemplary film coating composition may include hydroxypropyl methylcellulose (HPMC), lactose monohydrate, titanium dioxide, and the 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 oxide, including red and / or yellow iron oxide.

[0117] Tablets can be formulated into single-layer or bilayer tablets. Typically, monolayer tablets contain the active ingredients (i.e., obicetrapib and SGLT2 inhibitor) co-mixed in a single homogenous layer. To make monolayer tablets, exemplary methods include direct compression, wet granulation and dry granulation. The direct compression tablet process uses two main process steps: blending the active ingredient with excipients and compressing the finished tablet.

[0118] In one embodiment, the present disclosure provides a wet granulation process for making the subject pharmaceutical dosage forms, said process comprising the steps of: (1) premixing the active ingredient and the main part of the excipients including the binder in a mixer to obtain a premix; (2) granulating the pre-blend of step (1) by adding a granulation liquid, e.g., purified water; (3) drying the granules of step (2) in a fluid bed dryer or drying oven; (4) optionally, dry sieving the dried granules of step (3); (5) blending the dried granules of step (4) with the remaining excipients such as glidants and lubricants in a mixer to obtain the final blend; (6) compressing the final blend of step (5) in a suitable tablet press to produce tablet cores; (7) Optionally, film coating the tablet cores of step (6) with a non-functional coat.

[0119] In certain embodiments, the present invention provides a pharmaceutical dosage form (eg, as described herein) obtainable by a wet granulation process.

[0120] In another embodiment, the present disclosure provides a direct compression process for making the subject pharmaceutical dosage forms, said process comprising the steps of: (1) premixing the main parts of the active ingredients and excipients in a mixer to obtain a premix; (2) If necessary, dry screening the preliminary mixture through a screen to separate agglomerated particles and improve content uniformity; (3) blending the pre-blend of step (1) or (2) in a mixer by adding remaining excipients to the blend, as needed, and continuing blending; (4) compressing the final blend of step (3) in a suitable tablet press to produce tablet cores; (5) Optionally, film coating the tablet cores of step (4) with a non-functional coat.

[0121] In certain embodiments, the present invention provides a pharmaceutical dosage form (eg, as described herein) obtainable by a direct compression process.

[0122] In another embodiment, the present disclosure provides a dry granulation process for making the subject pharmaceutical dosage forms, said process comprising the steps of: (1) mixing the active ingredient with either all or a portion of the excipients in a mixer; (2) compacting the mixture of step (1) with a suitable roller compactor; (3) reducing the ribbons obtained during step (2) to granules, preferably small granules, by an appropriate grinding or sieving step; (4) Optionally, blending the granules of step (3) with the remaining excipients in a mixer to obtain a final blend; (5) compressing the granules of step (3) or the final blend of step (4) in a suitable tablet press to produce tablet cores; (6) Optionally, film coating the tablet cores of step (5) with a non-functional coat.

[0123] In certain embodiments, the present invention provides a pharmaceutical dosage form (eg, as described herein) obtainable by a dry granulation process.

[0124] A bilayer tablet contains the active ingredients (i.e., obicetrapib and an SGLT2 inhibitor) in separate layers and can be made by making a blend containing excipients and one active ingredient (i.e., obicetrapib) and making a separate blend containing a second active ingredient (i.e., an SGLT2 inhibitor) and excipients. One blend can then be pre-compressed and the second blend can then be added on top of the first pre-compressed blend. The resulting tablet contains two separate layers, each layer containing a different active ingredient.

[0125] In certain embodiments, the pharmaceutical dosage form comprises a therapeutically effective amount of obiscetrapib (eg, as described herein for obiscetrapib).

[0126] In certain embodiments, the pharmaceutical dosage form comprises from about 1% w / w to about 25% w / w of obiscetrapib, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises from about 1% w / w to about 20% w / w, or from about 1% w / w to about 15% w / w, or from about 1% w / w to about 10% w / w, or from about 5% w / w to about 15% w / w, or from about 5% w / w to about 12% w / w of obiscetrapib, or a salt, solvate or hydrate thereof. In further 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 obistrapib, or a salt, solvate, or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises about 3% w / w to 5% w / w of obistrapib, or a salt, solvate, or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises about 7% w / w to 10% w / w of obistrapib, or a salt, solvate, or hydrate thereof.

[0127] In certain embodiments, the pharmaceutical dosage form comprises 1% w / w to 25% w / w of obiscetrapib, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises 1% w / w to 20% w / w, or 1% w / w to 15% w / w, or 1% w / w to 10% w / w, or 5% w / w to 15% w / w, or 5% w / w to 12% w / w of obiscetrapib, or a salt, solvate or hydrate thereof. In further 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 obistrapib, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises 3% w / w to 5% w / w of obistrapib, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises 7% w / w to 10% w / w of obistrapib, or a salt, solvate or hydrate thereof.

[0128] In some embodiments, the pharmaceutical dosage form contains from about 1 mg to about 25 mg of obicetrapib, or an equivalent dosage of a salt, solvate or hydrate of obicetrapib. In further embodiments, the pharmaceutical dosage form contains from about 1 mg to about 20 mg of obicetrapib, or from about 1 mg to about 15 mg of obicetrapib, or from about 1 mg to about 10 mg of obicetrapib, or from about 5 mg to about 15 mg of obicetrapib, or from about 5 mg to about 12 mg of obicetrapib, or an equivalent dosage of a salt, solvate or hydrate of obicetrapib. In further 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 obicetrapib, or an equivalent dose of a salt, solvate, or hydrate of obicetrapib. In certain embodiments, the pharmaceutical dosage form comprises about 5 mg of obicetrapib, or an equivalent dose of a salt, solvate, or hydrate of obicetrapib. In certain embodiments, the pharmaceutical dosage form comprises about 10 mg of obicetrapib, or an equivalent dose of a salt, solvate, or hydrate of obicetrapib. In another embodiment, the pharmaceutical dosage form comprises 5 mg of obicetrapib as the calcium salt. In certain embodiments, the pharmaceutical dosage form comprises 10 mg of obicetrapib as the calcium salt.

[0129] In some embodiments, the pharmaceutical dosage form comprises 1 mg to 25 mg of obicetrapib, or an equivalent dosage of a salt, solvate or hydrate of obicetrapib. In further embodiments, the pharmaceutical dosage form comprises 1 mg to 20 mg of obicetrapib, or 1 mg to 15 mg of obicetrapib, or 1 mg to 10 mg of obicetrapib, or 5 mg to 15 mg of obicetrapib, or 5 mg to 12 mg of obicetrapib, or an equivalent dosage of a salt, solvate or hydrate of obicetrapib. In further 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 obicetrapib, or an equivalent dosage of a salt, solvate or hydrate of obicetrapib. In certain embodiments, the pharmaceutical dosage form comprises 5 mg of obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib. In certain embodiments, the pharmaceutical dosage form comprises 10 mg of obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib. In another embodiment, the pharmaceutical dosage form comprises 5 mg of obicetrapib as a calcium salt. In certain embodiments, the pharmaceutical dosage form comprises 10 mg of obicetrapib as a calcium salt.

[0130] In certain embodiments, the pharmaceutical dosage form comprises a therapeutically effective amount of an SGLT2 inhibitor (e.g., as described herein for the subject SGLT2 inhibitors).

[0131] In some embodiments, the pharmaceutical dosage form comprises from about 1% w / w to about 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises from about 1% w / w to about 40% w / w, or from about 1% w / w to about 30% w / w, from about 1% w / w to about 20% w / w, from about 1% to about 10%, or from about 5% w / w to about 15% w / w, or from about 10% w / w to about 25% w / w, or from about 45% w / w to about 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further 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 the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises about 5% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises about 10% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises about 15% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises about 25% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises about 50% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises about 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.

[0132] In some embodiments the pharmaceutical dosage form comprises 1% w / w to 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments the pharmaceutical dosage form comprises 1% w / w to 40% w / w, or 1% w / w to 30% w / w, 1% w / w to 20% w / w, 1% to 10%, or 5% w / w to 15% w / w, or 10% w / w to 25% w / w, or 45% w / w to 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further 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 the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises 5% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises 10% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises 15% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises 25% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises 50% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In certain embodiments, the pharmaceutical dosage form comprises 75% w / w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.

[0133] In some embodiments, the pharmaceutical dosage form comprises about 1 mg to about 300 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In further embodiments, the pharmaceutical dosage form comprises about 5 mg to about 100 mg of the SGLT2 inhibitor, or about 5 mg to about 50 mg of the SGLT2 inhibitor, or about 10 mg to about 25 mg of the SGLT2 inhibitor, or about 5 mg to about 15 mg of the SGLT2 inhibitor, or about 5 mg to about 10 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In further embodiments, the pharmaceutical composition comprises about 100 mg, about 300 mg, about 150 mg to 250 mg, or about 100 mg to 200 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises about 5 mg, about 7 mg, about 8 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises about 5 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises about 10 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises about 15 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises about 25 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises about 100 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises about 300 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In some embodiments, any of the above amounts are the free base form of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor.In certain embodiments, the amount is a salt form of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor.

[0134] In some embodiments the pharmaceutical dosage form comprises 1 mg to 300 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In further embodiments the pharmaceutical dosage form comprises 5 mg to 100 mg of the SGLT2 inhibitor, or 5 mg to 50 mg of the SGLT2 inhibitor, or 10 mg to 25 mg of the SGLT2 inhibitor, or 5 mg to 15 mg of the SGLT2 inhibitor, or 5 mg to 10 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In further embodiments the pharmaceutical composition comprises 100 mg, 300 mg, 150 mg to 250 mg, or 100 mg to 200 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises 5 mg, 7 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 30 mg, 40 mg, or 50 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises 5 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises 10 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises 15 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises 25 mg of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate, or hydrate of the SGLT2 inhibitor. In certain embodiments, the pharmaceutical dosage form comprises 100mg of SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor.In certain embodiments, the pharmaceutical dosage form comprises 300mg of SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor.In some embodiments, any of the above amounts are the free base form of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor.In some embodiments, the amount is the salt form of the SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of the SGLT2 inhibitor.

[0135] In one embodiment, the pharmaceutical dosage form comprises: a) about 5 mg to about 10 mg of obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; and b) about 25 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In an embodiment, the SGLT2 inhibitor is empagliflozin.

[0136] In one embodiment, the pharmaceutical dosage form comprises: a) 5 mg to 10 mg of obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; and b) 25 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In an embodiment, the SGLT2 inhibitor is empagliflozin.

[0137] In another embodiment, the pharmaceutical dosage form comprises: a) about 5 mg to about 10 mg of obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; and b) about 15 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In an embodiment, the SGLT2 inhibitor is ertugliflozin.

[0138] In another embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib, 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib, 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib, 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; and b) 15 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In an embodiment, the SGLT2 inhibitor is ertugliflozin.

[0139] In another embodiment, the pharmaceutical dosage form comprises: a) about 5 mg to about 10 mg of obiscetrapib, or an equivalent dose of a salt, solvate or hydrate of obiscetrapib; 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 one embodiment, the SGLT2 inhibitor is dapagliflozin.

[0140] In another embodiment, the pharmaceutical dosage form comprises: a) 5 mg to 10 mg of obiscetrapib, or an equivalent dose of a salt, solvate or hydrate of obiscetrapib; 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 one embodiment, the SGLT2 inhibitor is dapagliflozin.

[0141] In another embodiment, the pharmaceutical dosage form comprises: a) about 5 mg to about 10 mg of obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; and b) about 300 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In an embodiment, the SGLT2 inhibitor is canagliflozin.

[0142] In another embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib, 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib, 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib, 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; 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 obicetrapib, or an equivalent dose of a salt, solvate or hydrate of obicetrapib; and b) 300 mg of an SGLT2 inhibitor, or an equivalent dose of a salt, solvate or hydrate of an SGLT2 inhibitor. In an embodiment, the SGLT2 inhibitor is canagliflozin.

[0143] 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., the free base form of the compound). For example, if a dosage form includes a salt of obistrapib, the amount of salt to be incorporated into the pharmaceutical dosage form must be adjusted to take into account the difference in molecular weight between obistrapib as a free base form and the salt form.

[0144] In some embodiments, the pharmaceutical dosage form comprises one or more additional active compounds (e.g., as described herein). In some embodiments, the pharmaceutical dosage form further comprises a therapeutically effective amount of metformin (e.g., metformin hydrochloride). In some embodiments, the pharmaceutical dosage form comprises 500 mg to 1000 mg of metformin, such as 500 mg to 900 mg, 500 mg to 800 mg, 500 mg to 700 mg, or 500 mg to 600 mg of metformin (e.g., metformin hydrochloride).

[0145] In some embodiments, the pharmaceutical form further comprises a therapeutically effective amount of linagliptin. In some embodiments, the pharmaceutical dosage form comprises 1 mg to 10 mg of linagliptin, e.g., 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.

[0146] In some embodiments, the pharmaceutical dosage form comprises one or more excipients (e.g., as described herein). In some embodiments, the pharmaceutical dosage form comprises one or more diluents. In some embodiments, the pharmaceutical dosage form comprises microcrystalline cellulose, mannitol, or a combination of both.

[0147] In some 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 to 65 mg. In a particular embodiment, the microcrystalline cellulose is in an amount of about 60 mg. In a further particular embodiment, the microcrystalline cellulose is in an amount of about 65 mg.

[0148] In some embodiments, the pharmaceutical dosage form comprises microcrystalline cellulose in an amount of 40 mg to 80 mg, such as 45 mg to 75 mg, 45 mg to 70 mg, 45 mg to 65 mg, or 50 to 65 mg. In a particular embodiment, the microcrystalline cellulose is in an amount of 60 mg. In a further particular embodiment, the microcrystalline cellulose is in an amount of 65 mg.

[0149] 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 certain embodiments, the microcrystalline cellulose is in an amount of about 23 mg.

[0150] In an embodiment, the pharmaceutical dosage form comprises mannitol in an amount of 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 particular embodiment, the microcrystalline cellulose is in an amount of 23 mg.

[0151] In some embodiments, the pharmaceutical dosage form comprises one or more disintegrants. In some cases, the disintegrant is sodium starch glycolate. In some 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 certain embodiments, the sodium starch glycolate is in an amount of about 5 mg.

[0152] In certain embodiments, the pharmaceutical dosage form comprises sodium starch glycolate in an amount of 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 certain embodiments, the sodium starch glycolate is in an amount of 5 mg.

[0153] In some embodiments, the pharmaceutical dosage form comprises one or more glidants. In some cases, the glidant is colloidal silicon dioxide. In some 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 to 2 mg. In certain embodiments, the colloidal silicon dioxide is in an amount of about 1 mg.

[0154] 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 to 2 mg. In certain embodiments, the colloidal silicon dioxide is in an amount of 1 mg.

[0155] In some embodiments, the pharmaceutical dosage form includes one or more lubricants. In some cases, the lubricant is magnesium stearate. In some embodiments, the pharmaceutical dosage form includes magnesium stearate 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 to 2 mg. In certain embodiments, the colloidal silicon dioxide is in an amount of about 1 mg.

[0156] 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 to 2 mg. In certain embodiments, the colloidal silicon dioxide is in an amount of 1 mg.

[0157] In further embodiments, the pharmaceutical compositions, pharmaceutical dosage forms, or tablets described herein do not include negative drug-drug interactions. In related embodiments, the pharmaceutical compositions, pharmaceutical dosage forms, or tablets do not include negative drug-drug interactions with other antidiabetic agents. In further embodiments, the pharmaceutical compositions, pharmaceutical dosage forms, or tablets described herein can be administered without regard to food and regardless of whether the patient is taking another antidiabetic agent.

[0158] 4.3.How to use As summarized above, also provided herein is a method of treating or preventing a metabolic disorder, comprising administering to a subject having or at risk of developing a metabolic disorder a therapeutically effective amount of a pharmaceutical composition, or a pharmaceutical dosage form comprising a pharmaceutical composition comprising a combination of obiscetrapib and an SGLT2 inhibitor as described herein.

[0159] In another aspect, there is provided a method of treating or preventing a metabolic disorder, the method comprising administering to a subject having or at risk of developing a metabolic disorder a therapeutically effective amount of obiscetrapib and administering a therapeutically effective amount of an SGLT2 inhibitor.

[0160] Without being bound to any particular theory, pharmaceutical compositions or dosage forms including a pharmaceutical composition comprising a combination of obiscetrapib and an SGLT2 inhibitor as defined herein, or a pharmaceutical composition or dosage form in which both obiscetrapib and an SGLT2 inhibitor are administered separately, can be used to prevent, delay, slow or treat metabolic disorders, in particular to delay the progression to insulin dependence, which opens new therapeutic possibilities in the treatment and prevention of type 2 diabetes, obesity, diabetic complications and adjacent disease states.

[0161] Thus, the present disclosure provides a method for preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity and metabolic syndrome in a patient 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 by administering both obiscetrapib and an SGLT2 inhibitor separately.

[0162] The pharmaceutical compositions according to the present disclosure, or the separate administration of both obiscetrapib and an SGLT2 inhibitor, may also have beneficial disease-modifying properties with respect to diseases or conditions associated with impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and / or metabolic syndrome.

[0163] Also provided herein is a method for preventing, slowing, delaying or reversing the progression to type 2 diabetes in a patient in need thereof from impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and / or metabolic syndrome by administering to the patient a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of the present disclosure, or by administering both obiscetrapib and an SGLT2 inhibitor separately.

[0164] Thus, the pharmaceutical compositions and dosage forms described herein may be effective in treating conditions and / or diseases associated with or caused by elevated blood glucose levels.

[0165] In various embodiments, a method is provided for preventing, slowing the progression, delaying or treating a condition or disorder selected from the group consisting of diabetic complications such as cataracts, and microvascular and macrovascular diseases such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac rhythm disorders and vascular restenosis, by administering to a patient a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of the present disclosure, or by administering both obiscetrapib and an SGLT2 inhibitor separately. In particular, one or more aspects of diabetic nephropathy such as hyperperfusion, proteinuria and albuminuria can be treated, their progression can be delayed, or their onset can be delayed or prevented. The term "tissue ischemia" includes, in particular, diabetic macroangiopathy, diabetic microangiopathy, wound healing disorders and diabetic ulcers.

[0166] By administering the pharmaceutical composition according to the present disclosure, or by administering both obiscetrapib and an SGLT2 inhibitor separately, and due to the activity of obiscetrapib and an SGLT2 inhibitor, excess blood glucose levels are not converted into insoluble storage forms such as fat, and can be excreted through the patient's urine, lowering LDL cholesterol levels. Thus, the pharmaceutical compositions and dosage forms described herein do not cause weight gain, and in some cases may even result in weight loss.

[0167] Thus, in some embodiments of the subject methods, methods are provided for reducing weight or preventing weight gain or promoting weight loss in a patient 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 by administering both obiscetrapib and an SGLT2 inhibitor separately.

[0168] The pharmacological effects of the combination of obistrapib and an SGLT2 inhibitor in a pharmaceutical composition according to the present disclosure, or by separate administration, are independent of insulin. Thus, improved glycemic control is possible without additional strain on pancreatic beta cells, and improved beta cell health and function is possible by reducing lipid-induced toxicity. Administration of a pharmaceutical composition according to the present disclosure, or separate administration of both obistrapib and an SGLT2 inhibitor, can delay or prevent beta cell degeneration and reduced beta cell functionality, such as apoptosis or necrosis of pancreatic beta cells. Furthermore, the functionality of pancreatic cells can be improved or restored, and the number and size of pancreatic beta cells increased. It can be shown that the differentiation state and hyperplasia of pancreatic beta cells, which are disturbed by hyperglycemia and hyperlipidemia or dyslipidemia, can be normalized by treatment with a pharmaceutical composition or dosage form according to the present disclosure.

[0169] Thus, also provided herein is a method of preventing, slowing down, delaying or treating pancreatic beta cell degeneration and / or the decline in functionality of pancreatic beta cells, and / or improving and / or restoring functionality of pancreatic beta cells and / or restoring functionality of pancreatic insulin secretion in a patient 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 by administering both obiscetrapib and an SGLT2 inhibitor separately.

[0170] Due to administration of the pharmaceutical composition according to the present disclosure, or administration of both obiscetrapib and SGLT2 inhibitor separately, and activity of obiscetrapib and SGLT2 inhibitor, abnormal accumulation of fat in liver can be reduced or inhibited. Therefore, according to the present disclosure, there is also provided a method for preventing, slowing, delaying or treating a disease or condition caused by abnormal accumulation of liver fat in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition or pharmaceutical dosage form of the present disclosure, or by administering both obiscetrapib and SGLT2 inhibitor separately. The disease or condition caused by abnormal accumulation of liver fat is particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fatty liver, diabetic fatty liver, alcohol-induced fatty liver or toxic fatty liver.

[0171] Thus, also provided herein is 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 a pharmaceutical composition or pharmaceutical dosage form of the present disclosure, or by administering both obiscetrapib and an SGLT2 inhibitor separately.

[0172] 4.4.Kit Also provided herein are pharmaceutical kits that include a package containing a plurality of unit pharmaceutical dosage forms (eg, as described herein) and instructions for use.

[0173] In accordance with an embodiment of the present invention, the pharmaceutical kit comprises a container, such as a high density polyethylene (HDPE) bottle, or a box containing one or more blister packs, the bottle or blister pack may contain a plurality of solid unit pharmaceutical dosage forms as described herein. In an embodiment, the container or pack contains at least 5, at least 8, at least 10, at least 12 or at least 15 of said unit pharmaceutical dosage forms, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms.

[0174] According to the present invention, the pharmaceutical kit includes instructions (e.g., leaflets) 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 pharmaceutical dosage form included in the kit, an indication of the therapeutic indication for which the product is intended, an indication on how the product should be used, and information and warnings regarding adverse effects and contraindications associated with use. According to the present disclosure, the leaflet typically includes information regarding the therapeutic indication, use, treatment regimen, etc., as described herein in connection with the treatment method of the present invention. In some cases, the leaflet includes printed instructions for repeated (self) administration of the pharmaceutical unit dosage form to treat and / or prevent metabolic disorders, particularly type 2 diabetes.

[0175] 4.5.Definition The terms "subject" and "patient" are used interchangeably. The subject may be a mammal, such as a non-primate (e.g., cow, pig, horse, cat, dog, goat, rabbit, rat, mouse, etc.) or a primate (e.g., monkey and human), e.g., a human. In some embodiments, the subject is a mammal, e.g., a human, diagnosed with a disease or disorder provided herein. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein. In certain embodiments, the subject is a human.

[0176] The terms "therapies" and "therapy" are used in the broadest sense as understood in the clinical arts.

[0177] The term "pharmaceutical acceptable" indicates that a material does not possess properties that would cause a reasonably prudent medical practitioner to avoid administering the material to a patient, taking into account the disease or condition to be treated and the respective route of administration. For example, such materials are generally required to be essentially sterile, e.g., in the case of injectables.

[0178] The term "carrier" refers to, but is not limited to, a flux enhancer, diluent, adjuvant, excipient, or vehicle with which the compound is administered. 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).

[0179] The term "diluent" refers to a chemical compound used to dilute the compound of interest before delivery. Diluents can also act to stabilize the compound. Non-limiting examples of diluents include starch, sugars, 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, compressed sugar, dehydrated dibasic calcium phosphate, mannitol and tribasic calcium phosphate.

[0180] The term "binder" as used herein refers to any pharma- ceutically acceptable film that can be used to bind the active and inactive components of the carrier together to keep the cohesive and separate parts together. Non-limiting examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, and ethyl cellulose.

[0181] The term "disintegrant" refers to a substance that, when added to a solid formulation, facilitates its breakup or disintegration after administration, allowing the release of the active ingredient as efficiently as possible to allow its rapid dissolution. Non-limiting examples of disintegrants include corn starch, sodium starch glycolate, croscarmellose sodium, modified corn starch, sodium carboxymethyl starch, crospovidone, pregelatinized starch, and alginic acid.

[0182] The term "lubricant" refers to an excipient added to a powder blend to prevent the compressed powder mass from sticking to the equipment during the tableting or encapsulation process. It can aid in the ejection of the tablet from the die and improve powder flow. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fat, 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.

[0183] 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, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate film coatings.

[0184] The term "glidant" as used herein is intended to mean an agent used in tablet and capsule formulations to improve flow characteristics during tablet compression and to provide an anti-caking effect. Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0185] The term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to effect such treatment when administered to a mammal in need of treatment as defined herein. The therapeutically effective amount varies depending on the patient to be treated, the patient's weight and age, the severity of the disease state, the mode of administration, etc., and can be readily determined by one skilled in the art.

[0186] The term "unit dosage form" or "pharmaceutical dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., tablet).

[0187] The term "treatment" or "treating", as it relates to a disease or condition, includes preventing the occurrence of a disease or condition, inhibiting a disease or condition, eliminating a disease or condition, and / or alleviating one or more symptoms of a disease or condition.

[0188] As used herein, the term "% w / w" refers to the weight of a component based on the total weight of the composition containing the component. For example, if component A is present in an amount of 50% w / w in a 100 mg composition, then component A is present in an amount of 50 mg.

[0189] Unless otherwise specified, when a compound can take the form of alternative tautomers, regioisomers and / or stereoisomers, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, when a compound is described as a particular optical isomer D- or L-, both optical isomers are intended to be encompassed herein. For example, when a compound is described as having one of two tautomers, both tautomers are intended to be encompassed herein. Thus, the compounds provided herein may be enantiomerically pure or may be stereoisomeric or diastereomeric mixtures. The compounds provided herein may contain chiral centers. Such chiral centers may be in either the (R) or (S) configuration, or may be mixtures thereof. The chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent to administration of a compound in its (S) form for compounds that undergo epimerization in vivo.

[0190] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether or not they are radioactive. 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 is replaced with another atom having the same atomic number but an atomic mass different from the atomic mass that normally or predominantly occurs in nature. Examples of isotopes that can be incorporated into compounds according to the present disclosure include isotopes of 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 131I. Certain isotopic variations of the compounds according to the present disclosure, particularly those incorporating one or more radioisotopes, may be useful, for example, in studying mechanism of action or distribution of the active compound in the body. 3 H, 14 C and / or 18 Compounds labeled with F isotopes are suitable for this purpose. Furthermore, the incorporation of isotopes, such as deuterium, may provide certain therapeutic benefits as a result of greater metabolic stability of the compound, such as an increased half-life in the body or a reduced active dose required. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. In certain embodiments, "deuteration," as applied to a chemical group, refers to a chemical group that is isotopically enriched with an amount of deuterium substantially greater than its natural abundance, unless otherwise specified. Isotopic variants of compounds according to the present disclosure can be prepared by using the corresponding isotopic modifications of certain reagents and / or starting compounds therein, by a variety of methods, including, for example, those described below and in the working examples.

[0191] Thus, any of the embodiments described herein are meant to include salts, single stereoisomers, mixtures of stereoisomers, and / or isotopic forms of the compounds.

[0192] Unless otherwise specified, the term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. 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 ±10% of the explicitly recited value, rounded either up or down to the nearest integer. EXAMPLES

[0193] 5. Working Example The examples in this section are provided by way of illustration and not limitation. It should be understood that the examples can represent only some embodiments, and that the following examples are illustrative and not limiting. All substituents are as defined above unless otherwise specified. Reagents and starting materials are readily available to one of ordinary skill in the art. Certain synthetic steps for each of the described routes can be prepared in different ways or in combination with steps from different schemes to prepare the compounds described herein.

[0194] 5.1. Example 1: 2x2 factor Mendelian randomization analysis of the combined effect of SGLT2 and CETP genetic variants on diabetes incidence in the UK Biobank Introduction A post-hoc meta-analysis of data collected from clinical trials of CETP inhibitors demonstrated that the use of CETP inhibitors, either alone or in combination with other lipid-lowering drugs, is 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, we investigated whether the combination of a CETP inhibitor with an SGLT2 inhibitor results in a reduced incidence of diabetes when compared with SGLT2 inhibitor monotherapy using a 2 × 2 factor Mendelian randomization (MR) design using 233,765 individuals from the UK Biobank. method

[0195] Construction of CETP gene score: To construct a gene score that mimics the effect of CETP inhibitors, we constructed a score of four single nucleotide polymorphisms (SNPs) in the CETP region that are strongly correlated with HDL. The gene score uses all available SNPs from the UK Biobank genotyping information included in the CETP score described by 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). Higher CETP gene scores mimic a greater degree of pharmaceutical CETP inhibition.

[0196] Construction of SGLT2 Gene Score: To construct a gene score that mimics the effects of SGLT2 inhibitors, we constructed a score of two single nucleotide polymorphisms (SNPs) in the SGLT2 region that strongly correlate with SGLT2 expression. The gene score uses all available SNPs from the UK Biobank genotyping information included in the SGLT2 score described by Katzmann et al. (Katzmann, JL, Mason, AM, Maurz, W., Kleber, ME, Niessner, A., Bluher, M., Speer, T. and Laufs, U. (2021), Genetic Variation in Sodium-glucose Cotransporter 2 and Heart Failure. Clin. Pharmacol. Ther., 110: 149-158). Higher SGLT2 gene scores mimic a greater degree of pharmaceutical SGLT2 inhibition.

[0197] Individuals included: For the 2 × 2 factorial MR analysis, we included all individuals in the UK Biobank with genotyping information, including all SNPs required to construct a genetic score, as well as all biomarker values. Furthermore, to control for population stratification bias, only individuals of British descent were included in the analysis. In total, 233,765 individuals met all inclusion criteria.

[0198] Separation into groups: Individuals were divided into two groups based on whether their CETP gene score was greater than or less than the median CETP score. Then, within each group, individuals were divided into two additional groups based on whether their SGLT2 gene score was greater than or less than the median SGLT2 gene score. A total of four groups were formed, each of which is shown in Table 1 below. [Table 1]

[0199] As used herein, the first group is referred to as the "control group," the second group is referred to as the "SGLT2 monotherapy group," the third group is referred to as the "CETP monotherapy group," and the fourth group is referred to as the "combination therapy group." This nomenclature is adopted because these are the treatments each group represents, but it should be noted that the magnitude of change in HDL and glycated hemoglobin mediated by the separation into groups based on gene scores differs from the actual drug treatments that are intended to support the study.

[0200] Statistical Analysis: Comparisons between quantitative traits in each group were performed using one-way ANOVA. Where ANOVA detected differences between groups, each group was compared pairwise with all other groups using one-way ANOVA to characterize differences between groups. Comparisons of gender composition were performed using chi-square. Comparisons of diabetes incidence rates between groups were performed using logistic regression. Results and Discussion

[0201] ANOVA performed among the four groups for HDL produced an overall p-value (p<0.00001), suggesting that the mean HDL values ​​were significantly different among the groups. We used pairwise ANOVA between each group to characterize the specific differences. The results are shown in Table 2 below: [Table 2]

[0202] If the CETP score worked as intended, one would expect to see significant differences between control and CETP monotherapy, and this was observed (groups 1 and 3; p=0). HDL was observed to be significantly different between groups 1 and 3 (control vs. CETP inhibitor monotherapy), 1 and 4 (control vs. combination therapy), 2 and 3 (SGLT2 inhibitor monotherapy vs. CETP inhibitor monotherapy), and 2 and 4 (SGLT2 inhibitor monotherapy vs. combination therapy). These results indicate that between-group separation of HDL was achieved in a pattern consistent with CETP inhibitor therapy, indicating that the SGLT2 gene score works as intended. These results also suggest that SGLT2 inhibitors do not affect HDL levels. The same pattern of statistical significance and opposite effect direction was observed for apoB, LDL and TG, other biomarkers known to correlate with the CETP gene score (see, for example, Tables 9-11 in "Other Regression Data" below).

[0203] ANOVA performed among the four groups for glycated hemoglobin similarly yielded an overall p-value (p<0.00001), suggesting significant differences among the groups. The results are shown in Table 3 below. [Table 3]

[0204] If the SGLT2 score worked as intended, we would expect to see a significant difference between control and SGLT2 monotherapy, and this was observed (groups 1 and 2; p=0.035). However, significant differences in glycated hemoglobin levels were also observed between groups 1 and 3, 1 and 4, 2 and 4, and 3 and 4. The CETP gene score also correlates with glycated hemoglobin, with CETP inhibitor monotherapy resulting in a significant reduction. Notably, there was a significant reduction in glycated hemoglobin levels between groups 2 and 4 (SGLT2 inhibitor monotherapy and combination therapy). These results indicate that combination therapy with an SGLT2 inhibitor and a CETP inhibitor may be useful in achieving lower glycated hemoglobin levels than an SGLT2 inhibitor alone.

[0205] Comparing the incidence of diabetes among the four groups, group 4 (combination therapy) was found to be the only group with a significantly reduced incidence of diabetes compared to the control (OR=0.934; p=0.00222). Group 4 was also found to have a significantly lower incidence of diabetes than groups 3 (OR=0.969; p=0.00745) and 2 (OR=0.957; p=0.02785). The reduced incidence of diabetes in group 4 compared to all other groups suggests that genetically mediated CETP and SGLT2 inhibition confers greater protection against the development of diabetes than genetically mediated inhibition of each individually. These results are summarized in Tables 4-6 below: [Table 4] [Table 5] [Table 6]

[0206] The combined observations of reductions in glycated hemoglobin and incidence of diabetes between the combination therapy group and all other groups suggest that by targeting CETP and SGLT2 concomitantly with pharmaceutical intervention, increased glycemic control is achieved compared to targeting CETP or SGLT2 individually. Other regression data

[0207] P-values ​​from other regressions performed are shown below and in Tables 7-11:

[0208] Age: p=0.3485

[0209] Gender:p=0.922937

[0210] Body weight: p=0.1622; not significant. [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0211] Sensitivity analysis As shown herein above, the SGLT2 score worked as intended with respect to glycated hemoglobin, correlating with a reduction in glycated hemoglobin in the same way that SGLT2 inhibition correlates with a reduction in glycated hemoglobin. However, the SGLT2 score correlated with an increase in BMI and blood pressure between group 1 and group 2, which is the opposite of the effect that SGLT2 inhibitors have been observed to have in practice.

[0212] To further explore this phenomenon, sensitivity analyses were performed using linear regression (for glycated hemoglobin) and logistic regression (for diabetes), including BMI, blood pressure, weight, age and sex as covariates to isolate the effect of the gene scores independent of these variables. The differences between groups 2 and 4 and groups 3 and 4 were re-evaluated in glycated hemoglobin and diabetes under this analysis method. The results are shown in Tables 12 and 13 below: [Table 12] [Table 13]

[0213] In summary, the results of the sensitivity analyses shown in Tables 12 and 13 are consistent with the results from the analyses shown herein above (e.g., in the Results and Discussion section). The significance of the tests for glycated hemoglobin and incidence of diabetes is not affected by BMI, BP, weight, age, or sex.

[0214] 5.2. Example 2: Preparation of fixed dose tablets The following example is an exemplary procedure of how the obiscetrapib and SGLT2 fixed dose combination tablets described herein can be prepared and tested.

[0215] 5.2.1. Example 2A: Composition Exemplary pharmaceutical dosage forms (e.g., as disclosed herein) are formulated as white, film-coated, round, biconvex tablets with a diameter of 6 mm without identification markings. The tablets can be manufactured in the dosage strengths (doses of obiscetrapib expressed as the calcium salt) shown in Tables 14-17 below.

[0216] A complete description of the ingredients and quantitative composition of the fixed dose tablets containing obicetrapib 5 mg or 10 mg and an SGLT2 inhibitor is provided in Tables 14-17 (amounts expressed as % w / w). [Table 14] [Table 15] [Table 16-1] [Table 16-2] Table 17: Fixed dose formulations of obiscetrapib and canagliflozin Component Amount (%w / w) Amount (%w / w) Amount (%w / w) Amount (%w / w) Obicetrapib [1] Active substance Canagliflozin [2] Microcrystalline Cellulose Diluent Mannitol [Table 17]

[0217] 5.2.1. Example 2B: Preparation The general manufacturing process for the above fixed dose tablets by direct compression is described below: (1) blending obiscetrapib and an SGLT2 inhibitor with microcrystalline cellulose, mannitol, sodium starch glycolate and colloidal silicon dioxide in a mixer to obtain a premix; (2) adding magnesium stearate to the premix from step (1) and continuing mixing; (3) compressing the final blend of step (1) into 6 mm biconvex tablet cores in a suitable tablet press; (4) 6 mm biconvex tablet cores are film-coated with a proprietary aesthetic film coating.

[0218] 6. Equivalents and Incorporation by Reference While the present invention has been particularly shown and described with reference to preferred and various alternative embodiments, it will be understood by those skilled in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention.

[0219] All references, issued patents, and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes.

Claims

1. a) a therapeutically effective amount of obicetrapib, or a pharmaceutically acceptable salt thereof; b) a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof; 10. A pharmaceutical composition comprising:

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

3. 2. The pharmaceutical composition of claim 1, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, and sotagliflozin.

4. 2. The pharmaceutical composition of claim 1, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, and empagliflozin.

5. 4. The pharmaceutical composition of claim 3, wherein the SGLT2 inhibitor is empagliflozin.

6. 4. The pharmaceutical composition of claim 3, wherein the SGLT2 inhibitor is dapagliflozin.

7. 4. The pharmaceutical composition of claim 3, wherein the SGLT2 inhibitor is canagliflozin.

8. 4. The pharmaceutical composition of claim 3, wherein the SGLT2 inhibitor is ertugliflozin.

9. 10. The pharmaceutical composition of claim 1, further comprising one or more additional active agents.

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

11. The pharmaceutical composition of claim 10, wherein the DDP-4 inhibitor is linagliptin.

12. 10. The pharmaceutical composition of claim 1, comprising 1% w / w to 25% w / w of obicetrapib.

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

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

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

16. 2. The pharmaceutical composition of claim 1, comprising 5% w / w to 50% w / w of said SGLT2 inhibitor.

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

18. 10. The pharmaceutical composition of claim 1, further comprising one or more of a diluent, a disintegrant, a glidant, a filler, a lubricant, and any combination thereof.

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

20. 19. The pharmaceutical composition of claim 18, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, modified corn starch, pregelatinized starch, sodium starch glycolate, and combinations thereof.

21. 19. The pharmaceutical composition of claim 18, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, talc, and combinations thereof.

22. 19. The pharmaceutical composition of claim 18, wherein the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, and combinations thereof.

23. 10. The pharmaceutical composition of claim 1, wherein the composition comprises: Table 23

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

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

26. A pharmaceutical dosage form comprising the pharmaceutical composition of claim 1.

27. 1. A pharmaceutical composition or pharmaceutical dosage form for use in treating or preventing a metabolic disorder, said pharmaceutical composition or pharmaceutical dosage form comprising: a) a therapeutically effective amount of obicetrapib, or a pharmaceutically acceptable salt thereof; b) a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof; 1. A pharmaceutical composition or pharmaceutical dosage form comprising:

28. 28. The pharmaceutical composition or pharmaceutical dosage form of claim 27, 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.

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