WO2022051316A1 - Combinaisons à dose fixe de chs-131 et d'un inhibiteur de sglt-2 - Google Patents

Combinaisons à dose fixe de chs-131 et d'un inhibiteur de sglt-2 Download PDF

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WO2022051316A1
WO2022051316A1 PCT/US2021/048587 US2021048587W WO2022051316A1 WO 2022051316 A1 WO2022051316 A1 WO 2022051316A1 US 2021048587 W US2021048587 W US 2021048587W WO 2022051316 A1 WO2022051316 A1 WO 2022051316A1
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solvate
pharmaceutically acceptable
composition
acceptable salt
sglt
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PCT/US2021/048587
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Charles M. Cook
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Coherus Biosciences, Inc.
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Definitions

  • the present disclosure in some embodiments relates to fixed dose combination formulations comprising a PPARy inhibitor that is the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, that are used for treating PPARy-mediated diseases or disorders.
  • the peroxisome proliferator-activated receptors are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily.
  • the PPARs were originally identified as orphan receptors, without known ligands, but were named for their ability to mediate the pleiotropic effects of fatty acid peroxisome proliferators.
  • These receptors function as ligand- regulated transcription factors that control the expression of target genes by binding to their responsive DNA sequence as heterodimers with the retinoid X receptor (“RXR”).
  • RXR retinoid X receptor
  • the target genes encode enzymes involved in lipid metabolism and differentiation of adipocytes. Accordingly, the discovery of transcription factors involved in controlling lipid metabolism has provided insight into regulation of energy homeostasis in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes and dyslipidemia.
  • Peroxisome proliferator-activated receptor y (“PPARy”) is one member of the nuclear receptor superfamily of ligand-activated transcription factors and has been shown to be expressed in an adipose tissue-specific manner. Its expression is induced early during the course of differentiation of several preadipocyte cell lines. Additional research has now demonstrated that PPARy plays a pivotal role in the adipogenic signaling cascade. PPARy also regulates the ob/leptin gene which is involved in regulating energy homeostasis and adipocyte differentiation, which has been shown to be a critical step to be targeted for anti-obesity and diabetic conditions.
  • the compound of Formula (I): is a selective peroxisome proliferator-activated receptor (PPAR) y modulator.
  • the compound of Formula (I) is under development as a treatment for NASH.
  • Renal filtration and reuptake of glucose contributes, among other mechanisms, to the steady state plasma glucose concentration and can therefore serve as an antidiabetic target.
  • Reuptake of filtered glucose across epithelial cells of the kidney proceeds via sodium-dependent glucose cotransporters (SGLTs) located in the brush-border membranes in the tubuli along the sodium gradient.
  • SGLTs sodium-dependent glucose cotransporters
  • SGLT-2 is exclusively expressed in the kidney, whereas SGLT-1 is expressed additionally in other tissues like intestine, colon, skeletal and cardiac muscle.
  • SGLT-3 has been found to be a glucose sensor in interstitial cells of the intestine without any transport function.
  • SGLT2 inhibitors are being used to treat or improve glycemic control in patients with type 2 diabetes by inducing urinary sugar excretion. See, e.g., WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940.
  • the compound of Formula (I) and the SGLT-2 inhibitor each have the desired pharmacokinetic characteristics (e.g. absorption, bioavailability, Cmax, Tmax, AUC, half-life) even though each drug product in the composition has different properties (e.g. solubility, permeability, total dose, dose proportionality).
  • the compound of Formula (I) is poorly soluble (less than 2 pg dissolves in 1 mL of water at pH 1 and less than 0.1 pg dissolves in 1 mL of water at pH 3 to 8).
  • many SGLT-2 inhibitors are highly soluble.
  • the compound of Formula (I) has high permeability while many SGLT-2 inhibitors are categorized as having low permeability.
  • the total dose of the compound of Formula (I) is relatively low (e.g. 1 to 10 mg) which poses challenges in creating a formulation with even distribution to achieve a desired dissolution profile and pharmacokinetic characteristics for that drug product. These characteristics present challenges in identifying suitable excipients for a fixed dose composition and the manufacturing techniques that will result in a stable drug product.
  • compositions comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients.
  • Some embodiments provide a process for preparing a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, comprising: (a) mixing the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, with one or more excipients to form a first blend;
  • step (c) milling the dry granules obtained in step (b);
  • step (d) mixing the milled dry granules obtained in step (c) with one or more excipients to form a second blend;
  • step (g) forming dry granules comprising the third blend, or optionally mixing a granulating solution with the third blend obtained in step (f) to form wet granules, then drying the wet granules to form dry granules;
  • step (h) milling the dry granules obtained in step (g);
  • step (i) mixing the milled dry granules obtained in step (h) with one or more excipients to form a fourth blend;
  • step (j) applying the fourth blend obtained in step (i) to the surface of the tablet core, forming the outer layer.
  • Some embodiments provide a process for preparing a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, comprising:
  • step (c) milling the dry granules obtained in step (b); (d) mixing the milled dry granules obtained in step (c) with one or more excipients to form a second blend;
  • step (h) milling the dry granules obtained in step (g);
  • step (i) mixing the milled dry granules obtained in step (h) with one or more excipients to form a fourth blend;
  • step (j) applying the fourth blend obtained in step (i) to the surface of the tablet core, forming the outer layer;
  • Some embodiments provide a process for preparing, a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, comprising:
  • step (b) forming dry granules comprising the first blend, or optionally mixing a granulating solution with the first blend obtained in step (a) to form wet granules and drying the wet granules to obtain dry granules;
  • step (c) milling the dry granules obtained in step (b);
  • step (d) mixing the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, with one or more excipients to form a second blend; (e) forming dry granules comprising the second blend, or optionally mixing a granulating solution with the second blend obtained in step (d) to form wet granules, then drying the wet granules to form dry granules;
  • step (f) milling the dry granules obtained in step (e);
  • Some embodiments provide a process for preparing a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, comprising:
  • step (c) optionally milling the dry granules obtained in step (b);
  • step (d) compressing the dry granules from step (b) or step (c) to form the tablet core;
  • Some embodiments provide a process for preparing, a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, comprising: (a) mixing the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, with one or more excipients to form a first blend;
  • step (c) optionally milling the dry granules obtained in step (b);
  • step (d) mixing the dry granules obtained in step (b) or step (c) with one or more excipients to form a second blend;
  • Some embodiments provide a process for preparing, a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, comprising:
  • step (b) forming dry granules comprising the first blend, or optionally mixing a granulating solution with the first blend obtained in step (a) to form wet granules;
  • step (c) drying the wet granules obtained in step (b) to form dry granules
  • step (d) milling the dry granules obtained in step (c);
  • step (e) mixing the milled dry granules obtained in step (d) with one or more excipients to form a second blend;
  • step (g) forming dry granules comprising the third blend, or optionally mixing a granulating solution to the third blend obtained in step (f), and mixing the solution and third blend to form wet granules, then drying the wet granules to form dry granules; (h) milling the dry granules obtained in step (g);
  • step (i) mixing the milled dry granules obtained in step (h) with one or more excipients to form a fourth blend;
  • step (k) filling a capsule with the mixture obtained in step (j).
  • Some embodiments provide a process for preparing, a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, comprising:
  • step (c) milling the dry granules obtained in step (b);
  • step (d) mixing the milled dry granules obtained in step (c) with one or more excipients to form a second blend;
  • step (g) forming dry granules comprising the third blend, or optionally mixing a granulating solution with the third blend obtained in step (f) to form wet granules, then drying the wet granules to form dry granules;
  • step (h) milling the dry granules obtained in step (g);
  • step (i) mixing the milled dry granules obtained in step (h) with one or more excipients to form a capsule fill;
  • Some embodiments provide a method of treating a PPARy-mediated disease or disorder, comprising administering a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, to a subject in need thereof.
  • the PPARy-mediated disease or disorder is type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or a combination of any of the foregoing.
  • administering refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian.
  • the preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.
  • CHS- 131 refers to a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is a selective peroxisome proliferator-activated receptor (PPAR) y modulator.
  • PPAR peroxisome proliferator-activated receptor
  • the compound of Formula (I) can be prepared, for example, by the methods described in U.S. Patent No. 6,583,157 or US Patent No. 6,200,995, each of which is incorporated by reference in its entirety herein.
  • different salts e.g., besylate, tosylate HC1, or HBr salts, and/or polymorphs of the compound of Formula (I) are used within the methods and compositions described herein.
  • Salts and polymorphs of the compound of Formula (I), such as those provided herein, can be prepared according to the methods described in U.S. Patent. Nos. 6,583,157 and 7,223,761, the contents of each of which are incorporated by reference in their entireties.
  • SGLT-2 inhibitor refers to a compound that inhibits the Sodium Glucose Co-Transporter-2 (SGLT-2).
  • SGLT-2 inhibitors disrupt reabsorption of glucose by the kidneys and thus exert a glucose-lowering effect.
  • SLGT-2 inhibitors By enhancing glucosuria, independently of insulin, SLGT-2 inhibitors have been shown to treat type 2 diabetes and improve cardiovascular outcomes. See, Wright, 2001, Am J Physiol Renal Physiol 280:F10; and Scheen, 2018, Circ Res 122: 1439.
  • SGLT2 inhibitors include a class of drugs known as gliflozins.
  • SGLT-2 inhibitor is not limited to compounds that only inhibit SGLT-2, thus includes compounds that have other activities in addition to SGLT-2 inhibition.
  • SGLT-2 inhibitors include, but are not limited to, bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATROTM), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin, serfliflozin, licofliglozin, sotagliflozin (ZYNQUISTATM), and tofogliflozin.
  • amorphous refers to a solid material having no long range order in the position of its molecules.
  • the molecules in an amorphous solid are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order.
  • Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points.
  • an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.
  • substantially amorphous refers to a solid material having little or no long range order in the position of its molecules.
  • substantially amorphous materials have less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity).
  • substantially amorphous includes the descriptor, ‘amorphous’, which refers to materials having no (0%) crystallinity (e.g., no detectable crystallinity under standard XRPD conditions).
  • excipient refers to an inactive substance that serves as the vehicle or medium for an active substance.
  • Excipients include, but are not limited to fillers (e.g., lactose, microcrystalline cellulose, dextrose, sucrose, mannitol, sorbitol, starch, dibasic calcium carbonate, and magnesium stearate), disintegrants (e.g., starch, microcrystalline cellulose, sodium starch glycolate, crosscarmellose sodium, crospovidone, gums, and alginates), lubricants (magnesium or calcium stearate, PEG 4000, and PEG 6000), granulating agents (starch, pregelatinized starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methyl cellulose, and acacia), and glidants (colloidal silicon dioxide, talc, and magnesium carbonate).
  • fillers e.g., lactose, microcrystalline cellulose, dextrose, sucrose,
  • Granulating solution refers to a solvent, such as a volatile solvent, or a solution that wets a blend, which upon agitation forms wet granules.
  • Granulating solutions include, for example, solvents such as water, ethanol, and isopropanol, or combinations thereof, as well as solutions of one or more excipients in water, ethanol, isopropanol, or combinations thereof, for example, a solution of povidone in water.
  • tablette core refers to the innermost portion of a tablet that contains drug substance, i.e., the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof and/or the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the term “outer layer” refers to the outermost portion of a tablet that contains drug substance, i.e., the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof and/or the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the outer layer is in contact with a coating and/or seal.
  • intermediate layer refers to a separating layer in contact with both the tablet core and the outer layer.
  • exemplary intermediate layers include, but are not limited to carbopols, hydroxypropylmethylcellulose, and other polymers.
  • solvate means a physical association of a compound with one or more solvent molecules.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
  • Exemplary solvates include, but are not limited to hydrates, ethanolates, propylene glycol hydrates, and hemihydrates.
  • the phrase “pharmaceutically acceptable salt or solvate,” refers to salts of a compound, solvates of a compound, as well as salts of solvates of a compound.
  • a pharmaceutically acceptable salt or solvate of the compound of Formula (I) includes the besylate salt of Formula (I), the hydrate of Formula (I), and the Formula (I) besylate hydrate.
  • fixed combination and “fixed dose combination,” used interchangeably herein, refer to a single composition or single dosage form comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • a non-fixed combination or non-fixed dose combination refer to combination therapy where each active agent is formulated as a separate composition or dosage form, such that they may be administered concurrently or sequentially with variable intervening time limits.
  • a “therapeutically effective amount” of a compound as provided herein is an amount that is sufficient to achieve the desired therapeutic effect and can vary according to the nature and severity of the disease condition, and the potency of the compound.
  • a therapeutic effect is the relief, to some extent, of one or more of the symptoms of the disease, and can include curing a disease. “Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease can exist even after a cure is obtained (such as, e.g., extensive tissue damage).
  • a “therapeutically effective amount” of a compound as provided herein refers to an amount of the compound that is effective as a monotherapy.
  • the amount of each compound as provided herein is a therapeutically effective amount. In such embodiments, the amount of each compound is effective in treating a PPARy-mediated disease or disorder.
  • the amounts of the two compounds as provided herein together are effective in treating a PPARy-mediated disease or disorder (e.g., the amounts of the compound of Formula (I) and an SGLT-2 inhibitor together are effective in treating a PPARy-mediated disease or disorder).
  • the amount of each agent is also referred to as a “jointly therapeutically effective amount.”
  • the amounts of the two compounds as provided herein together are effective in treating a PPARy-mediated disease or disorder (e.g., the amounts of the compound of Formula (I) and an SGLT-2 inhibitor together are effective in treating a PPARy-mediated disease or disorder).
  • the amount of each agent is also referred to as a “jointly therapeutically effective amount.”
  • the term “synergy” or “synergistic” is used herein to mean that the effect of the combination of the two or more therapeutic agents of the combination therapy is greater than the sum of the effect of each agent when administered alone.
  • a “synergistic amount” or “synergistically effective amount” is an amount of the combination of the two combination partners that results in a synergistic effect, as “synergistic” is defined herein. Determining a synergistic interaction between two or more combination partners, the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the combination partners over different w/w (weight per weight) ratio ranges and doses to patients in need of treatment.
  • synergy in in vitro models or in vivo models can be predictive of the effect in humans and other species and in vitro models or in vivo models exist to measure a synergistic effect and the results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and the absolute doses and plasma concentrations required in humans and other species by the application of pharmacokinetic/pharmacodynamic methods.
  • exemplary synergistic effects includes, but are not limited to, enhanced therapeutic efficacy, decreased dosage at equal or increased level of efficacy, reduced or delayed development of drug resistance, reduction of unwanted drug effects (e.g.
  • synergistic effects can include, but are not limited to reducing the risk of developing end-stage kidney disease (ESRD), reducing serum creatinine, reducing cardiovascular death and hospitalization for heart failure, reducing cardiovascular death and hospitalization for heart failure in subject with cardiovascular disease or multiple cardiac risk factors, reducing weight gain, improved cardiovascular function, and reducing diabetic nephropathy with albuminuria.
  • ESRD end-stage kidney disease
  • reducing serum creatinine reducing cardiovascular death and hospitalization for heart failure
  • reducing cardiovascular death and hospitalization for heart failure in subject with cardiovascular disease or multiple cardiac risk factors reducing weight gain, improved cardiovascular function, and reducing diabetic nephropathy with albuminuria.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • subject refers to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired, for example, a human.
  • a “PPARy-mediated disease or disorder” is a condition that results, directly or indirectly, from dysregulation of PPARy, for example, protein expression above or below normal levels, or protein activity above or below normal levels.
  • PPARy-mediated diseases or disorders include, but are not limited to diabetes (including type 1 diabetes and type 2 diabetes), hypercholesterolemia, hyperlipidemia, rheumatoid arthritis, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), chronic kidney disease (CKD), or pulmonary arterial hypertension (PAH).
  • the subject has NAFLD with attendant liver fibrosis.
  • the subject has NASH with attendant liver fibrosis.
  • the subject has NAFLD and type 2 diabetes. In some embodiments, the subject has NASH and type 2 diabetes. In some embodiments, the subject has type 2 diabetes and cardiovascular disease. In some embodiments, the subject has NAFLD and cardiovascular disease. In some embodiments, the subject has NASH and cardiovascular disease. In some embodiments, the subject has type 2 diabetes, cardiovascular disease, and NAFLD. In some embodiments, the subject has type 2 diabetes, cardiovascular disease, and NASH.
  • compositions comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients.
  • the compound of Formula (I) is provided in the form of a free base.
  • the compound of Formula (I) is provided as a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts include 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid (besylate), benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-l,2-disulfonic acid, ethanesulf
  • the compound of Formula (I) is in the form of a besylate salt. In some embodiments, the compound of Formula (I) is in the form of an HC1 salt. In some embodiments, the compound of Formula (I) is in the form of an HBr salt. In some embodiments, the compound of Formula (I) is in the form of a tosylate salt.
  • the SGLT-2 inhibitor is empagliflozin, canagliflozin, or dapagliflozin, or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • the SGLT-2 inhibitor is canagliflozin hemihydrate. In some embodiments, the SGLT-2 inhibitor is empagliflozin. In some embodiments, the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate.
  • the SGLT-2 inhibitor is a free base. In some embodiments, the SGLT-2 inhibitor is a pharmaceutically acceptable salt. In some embodiments, the SGLT-2 inhibitor is a pharmaceutically acceptable solvate. In some embodiments, the SGLT-2 inhibitor is a pharmaceutically acceptable salt of a pharmaceutically acceptable solvate. In some embodiments, the SGLT-2 inhibitor is a pharmaceutically acceptable solvate of a free base.
  • the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is present in an amount from about 5 mg to about 300 mg. In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount from about 5 mg to about 200 mg. In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount from about 5 mg to about 100 mg. In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount from about 5 mg to about 50 mg.
  • the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is present in an amount from about 5 mg to about 25 mg. In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount from about 5 mg to about 20 mg. In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount from about 5 mg to about 15 mg. In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount from about 5 mg to about 10 mg. In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount of about 5 mg, about 10 mg, or about 25 mg.
  • the SGLT-2 inhibitor is canagliflozin. In some embodiments, the canagliflozin is present in an amount of about 100 mg or about 300 mg. In some embodiments, the canagliflozin is present in an amount of about 100 mg or about 300 mg of canagliflozin hemihydrate. In some other embodiments, the SGLT-2 inhibitor is dapagliflozin. In still other embodiments, the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate. In some embodiments, the dapagliflozin is present in an amount of about 5 mg or about 10 mg.
  • the dapagliflozin is present in an amount of about 5 mg or about 10 mg of dapagliflozin propylene glycol hydrate.
  • the SGLT-2 inhibitor is empagliflozin.
  • the empagliflozin is present in an amount of about 10 mg or about 25 mg.
  • the dose is a therapeutically effective amount.
  • the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is present in an amount from about 0.1 mg to about 10 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is present in an amount from about 0.5 mg to about 5 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is present in an amount from about 1 mg to about 3 mg. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is present in an amount of 1.5 mg or 3 mg.
  • the amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is present in an amount from about 0.5 to about 4 milligrams (mg). For example, from about 0.5 to about 3.5 mg, about 1 to about 3 mg, or about 1.5 to about 2.5 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is administered at a dose from about 0.5 to about 1.5 mg, about 1 to about 2 mg, about 1.5 to about 2.5 mg, about 2 to about 3 mg, or about any value in between. In some embodiments, the dose is a therapeutically effective amount.
  • the composition is formulated for administration twice a day or daily. In some embodiments, the composition is formulated for administration daily.
  • the composition comprises particles comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the particles are in the form of a powder.
  • the particles comprise the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and one or more excipients.
  • the particles consist essentially of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the particles are micronized. In some embodiments, 90% of the mass of the micronized particles have a size (d90) of about 2 ⁇ m to about 10 ⁇ m, or any value in between.
  • the size of the micronized particles is determined by direct imaging, laser diffraction, or a combination thereof.
  • Direct imaging provides the volume distribution of particles, removing the grouping of particle sizes which is characteristic of sieve analyses by determining the full range of particle sizes in the sample and hence drawing the true volumetric distribution.
  • particles are illuminated and imaged from the same side.
  • Direct imaging of particles also allows morphology information to be measured as well as size distribution data, for example, aspect ratio of particles (maximum and minimum diameter measurements), surface quality, and roughness.
  • Laser diffraction relies on detectors that measure the light-scattering effect caused by the interaction of a laser beam with particles. Similar to sieve analysis particle characteristics other than size cannot be measured.
  • the composition comprises granules comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the composition comprises grains comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the composition comprises particles comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the particles are in the form of a powder.
  • the particles comprise the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and one or more excipients.
  • the particles consist essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the particles are micronized.
  • 90% of the mass of the micronized particles have a size (d90) of less than or equal to about 250 ⁇ m. In some embodiments, 90% of the mass of the micronized particles have a size (d90) of about 2 ⁇ m to about 10 ⁇ m, or any value in between.
  • 50% of the mass of the micronized particles have a size (d50) of less than or equal to about 100 ⁇ m. In some embodiments, 50% of the mass of the micronized particles have a size (d50) of less than or equal to about 100 ⁇ m.
  • the size of the micronized particles is determined by direct imaging, laser diffraction, or a combination thereof. In some embodiments, the size of the micronized particles is determined by direct imaging, laser diffraction, or a combination thereof.
  • the composition comprises granules comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition comprises grains comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is in the form of a tablet. In some embodiments, the composition is in the form of a capsule. In some embodiments, the capsule is a gelatin capsule or a hydroxypropylmethylcellulose (HPMC) capsule.
  • HPMC hydroxypropylmethylcellulose
  • the tablet comprises a tablet core and an outer layer; wherein the tablet core comprises the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof; and wherein the outer layer comprises the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the tablet core contacts the outer layer.
  • the composition further comprises an intermediate layer between the tablet core and the outer layer and contacting the tablet core and outer layer.
  • the intermediate layer comprises one or more excipients.
  • the intermediate layer comprises one excipient.
  • Exemplary intermediate layers include, but are not limited to carbopols, hydroxypropylmethylcellulose, and other polymers.
  • the dissolution rate of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is about the same in a composition with an intermediate layer as in a reference composition lacking the intermediate layer.
  • the dissolution rate of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is about the same in a composition with an intermediate layer as in a reference composition lacking the intermediate layer.
  • the composition further comprises an immediate release coating around the outer layer.
  • exemplary immediate release coatings include, but are not limited to film coatings.
  • the outer layer consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the outer layer comprises the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and one or more excipients. In some embodiments, the outer layer comprises granules comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the tablet core further comprises one or more excipients.
  • the one or more excipients are selected from Acrylates Copolymer, Adipic Acid, Agar, Alginic Acid, Alkyl Aryl Sodium Sulfonate, Allantoin, Aluminum Acetate, Aluminum Hydroxide, Aluminum Monostearate, Aluminum Oxide, Aluminum Polyester, Aluminum Silicate, Aluminum Silicate Pentahydrate, Aluminum Starch Octenyl succinate, Aluminum Stearate, Aluminum Sulfate Anhydrous, Aminobenzoate Sodium, Ammonio Methacrylate Copolymer, Ammonio Methacrylate Copolymer Type A, Ammonio Methacrylate Copolymer Type B, Ammonium Acetate, Ammonium Calcium Alginate, Ammonium Chloride, Ammonium Lauryl Sulfate, Ammonium Phosphate Dibasic, Ammonium Sulfate, Anhydrous Citric Acid, Anhydrous Dextrose, Anhydrous Dibasic Calcium Phos
  • the one or more excipients are selected from crospovidone, croscarmellose sodium, sodium starch glycolate, povidone, colloidal silicon dioxide, silicon dioxide, colloidal anhydrous silica, hydroxypropylcellulose, sodium stearoyl fumarate, maize starch, lactose monohydrate, anhydrous lactose, dextrose, sucrose, sorbitol, calcium carbonate, calcium stearate, PEG, microcrystalline cellulose, pregelatinized starch, talc, magnesium carbonate, mannitol, hydroxypropylmethylcellulose, and magnesium stearate.
  • the tablet core comprises granules comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the capsule comprises a tablet core and capsule fill.
  • the tablet core comprises the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof; and wherein the capsule fill comprises the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the tablet core further comprises one or more excipients; and wherein the capsule fill further comprises one or more excipients.
  • the composition further comprises an outer layer comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and an intermediate layer between the tablet core and the outer layer and contacting the tablet core and outer layer.
  • the composition further comprises an outer layer comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof wherein the tablet core is in contact with the outer layer.
  • the outer layer consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the outer layer comprises the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and one or more excipients, as described herein.
  • the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate, and the one or more excipients are crospovidone, silicon dioxide, microcrystalline cellulose, lactose, and magnesium stearate.
  • the SGLT-2 inhibitor is canagliflozin hemihydrate, and the one or more excipients are croscarmellose sodium, microcrystalline cellulose, lactose, hydroxypropylcellulose, and magnesium stearate.
  • the SGLT-2 inhibitor is empagliflozin, and the one or more excipients are croscarmellose sodium, microcrystalline cellulose, colloidal anhydrous silica, lactose, hydroxypropylcellulose, and magnesium stearate.
  • the outer layer comprises granules comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the outer layer comprises granules comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and one or more excipients, as described herein.
  • the tablet core comprises granules comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the granules are coated with a layer comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the granules further comprise one or more excipients, as described herein.
  • the granules consisting essentially of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the layer comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof further comprises one or more excipients.
  • the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate, and the one or more excipients are crospovidone, silicon dioxide, microcrystalline cellulose, lactose, and magnesium stearate. In some embodiments, the SGLT-2 inhibitor is canagliflozin hemihydrate, and the one or more excipients are croscarmellose sodium, microcrystalline cellulose, lactose, hydroxypropylcellulose, and magnesium stearate.
  • the SGLT-2 inhibitor is empagliflozin, and the one or more excipients are croscarmellose sodium, microcrystalline cellulose, colloidal anhydrous silica, lactose, hydroxypropylcellulose, and magnesium stearate.
  • the layer comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the composition comprises (i) granules comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and (ii) granules comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the composition comprises (i) granules comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and (ii) the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, in powder form.
  • the granules comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof further comprise one or more excipients.
  • the granules comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof consist essentially of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the granules comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof further comprise one or more excipients.
  • the granules comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof consist essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • (i) and (ii) are blended.
  • the particles comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof have a mean diameter from about 100 nm to about 2 ⁇ m, or any value in between, for example, about 100 nm to about 500 nm, about 250 nm to about 750 nm, about 500 nm to about 1 ⁇ m, about 750 nm to about 1.25 ⁇ m, about 1 ⁇ m to about 1.5 ⁇ m, about 1.25 ⁇ m to about 1.75 ⁇ m, about 1.5 ⁇ m to about 2 ⁇ m, or any value in between.
  • the particles comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof have a mean diameter of about 100 nm, about 200 nm, about 300 nm, about 400 nm, about 500 nm, about 600 nm, about 700 nm, about 800 nm, about 900 nm, about 1 ⁇ m, about 1.1 ⁇ m, about 1.2 ⁇ m, about 1.3 ⁇ m, about 1.4 ⁇ m, about 1.5 ⁇ m, about 1.6 ⁇ m, about 1.7 ⁇ m, about 1.8 ⁇ m, about 1.9 ⁇ m, or about 2 ⁇ m.
  • the particles comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof have a mean diameter from about 100 nm to about 1 ⁇ m, or any value in between, for example, about 100 nm, about 200 nm, about 300 nm, about 400 nm, about 500 nm, about 600 nm, about 700 nm, about 800 nm, about 900 nm, or about 1 ⁇ m, or any value in between.
  • the particles comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof have a mean diameter from 100 nm to about 2 ⁇ m, or any value in between, for example, about 100 nm to about 500 nm, about 250 nm to about 750 nm, about 500 nm to about 1 ⁇ m, about 750 nm to about 1.25 ⁇ m, about 1 ⁇ m to about 1.5 ⁇ m, about 1.25 ⁇ m to about 1.75 ⁇ m, about 1.5 ⁇ m to about 2 ⁇ m, or any value in between.
  • the particles comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof have a mean diameter of about 100 nm, about 200 nm, about 300 nm, about 400 nm, about 500 nm, about 600 nm, about 700 nm, about 800 nm, about 900 nm, about 1 ⁇ m, about 1.1 ⁇ m, about 1.2 ⁇ m, about 1.3 ⁇ m, about 1.4 ⁇ m, about 1.5 ⁇ m, about 1.6 ⁇ m, about 1.7 ⁇ m, about 1.8 ⁇ m, about 1.9 ⁇ m, or about 2 ⁇ m.
  • the particles comprising the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof have a mean diameter from about 100 nm to about 1 ⁇ m, or any value in between, for example, about 100 nm, about 200 nm, about 300 nm, about 400 nm, about 500 nm, about 600 nm, about 700 nm, about 800 nm, about 900 nm, or about 1 ⁇ m, or any value in between.
  • the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is present in substantially amorphous form.
  • the substantially amorphous compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is prepared by spray drying, spray drying with one or more excipients, hot-melt extrusion, dissolution followed by lyophilization, evaporation vacuum drying, tray drying, microwave drying or other processes that are known to a skilled person to result in solvent evaporation, thereby resulting in the formation of solid dispersion or dissolution followed by precipitation onto an amorphous substrate.
  • the amorphous substrate is amorphous silica or fumed silica.
  • Hot melt extrusion is the processing of a material above its glass transition temperature (Tg), combining melting and mechanical energy followed by expulsion through an extruder to provide an amorphous material. All components are sheared, heated, plastified, mixed and dispersed, and finally shaped by pressing them through a die opening.
  • the material to be processed e.g., a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and/or an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof
  • an excipients can be optionally mixed with one or more excipients, and heated above the melting point of the compound of mixture while being processed in an extruder, such as a twin-screw extruder.
  • Spray drying is another method for manufacturing amorphous solid materials.
  • Fast solvent evaporation that leads to a rapid transformation of solution to a solid state.
  • a solution or slurry of a compound is formed (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and/or an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof), optionally including one or more excipients, and the solution or slurry is passed through an atomizer or spray nozzle to disperse the liquid into a stream of hot gas (e.g., nitrogen or air) which rapidly evaporates the solvent.
  • a stream of hot gas e.g., nitrogen or air
  • Dissolution followed by precipitation onto an amorphous substrate involves dissolving material (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and/or an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof) in a suitable solvent, and optionally also dissolving one or more excipients in the solvent, to form a solution.
  • the solution may be passed over the amorphous substrate and treated with a hot gas stream (e.g., nitrogen) to aid in solvent removal.
  • a hot gas stream e.g., nitrogen
  • the amorphous substrate is amorphous silica.
  • the amorphous substrate is fumed silica.
  • dissolution e.g., a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and/or an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof
  • a suitable solvent and/or water
  • the process may further comprise further drying using a secondary drying cycle comprising at least one secondary drying stage.
  • the frozen mixtures are exposed to a vacuum sufficient to remove the water or solvent (which may exist in a liquid and/or solid phase) at the average temperature of the primary drying cycle.
  • the primary drying cycle is optionally followed by a secondary drying cycle, during which residual water or solvent is removed. Completion of the lyophilization process yields a stable amorphous solid.
  • the hot drying gas can be passed in as a co-current, same direction as sprayed liquid atomizer, or counter-current, where the hot air flows against the flow from the atomizer. With co- current flow, particles spend less time in the system and the particle separator (typically a cyclone device).
  • the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is present in crystalline form.
  • buffer refers to an aqueous solution that resists a change in pH.
  • Exemplary buffers include, but are not limited to, phosphate, acetate, and citrate.
  • the composition exhibits a dissolution profile in about 900 mL of water, containing about 0.5% sodium dodecyl sulfate (SDS) at about pH 1.5, at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 50 rpm; wherein from about 70 to about 80 wt % of the total amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is released after about 45 minutes. In some embodiments, about 75 wt % of the total amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is released after about 45 minutes.
  • SDS sodium dodecyl sulfate
  • the composition exhibits a dissolution profile in about 900 mL buffer at from about pH 1 to about pH 2 at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 1 (basket) at a speed of about 50 to about 100 rpm; wherein from about 60 to about 80 wt % of the total amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is released after about 45 minutes.
  • the composition exhibits a dissolution profile in about 900 mL buffer at from about pH 1 to about pH 2 at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 50 to about 100 rpm; wherein from about 50 to about 99 wt % of the total amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is released after about 45 minutes.
  • the composition exhibits a dissolution profile in about 900 mL buffer at from about pH 1 to about pH 2 at 37° C. ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 50 to about 100 rpm; wherein from about 60 to about 80 wt % of the total amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is released after about 45 minutes.
  • the composition exhibits a dissolution profile in about 1,000 mL of acetate buffer at about pH 4.5, at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 60 rpm; wherein from about 50 to about 99 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes. In some embodiments, about 75 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes.
  • the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is dapagliflozin propylene glycol hydrate.
  • the composition exhibits a dissolution profile in about 900 mL of 0.05M phosphate buffer at about pH 6.8 at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 75 rpm; wherein from about 50 to about 99 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes.
  • the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes.
  • the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is empagliflozin.
  • the composition exhibits a dissolution profile in about 1,000 mL of water with 0.75% wt sodium lauryl sulfate (SLS) at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 75 rpm; wherein from about 50 to about 99 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 20 minutes. In some embodiments, about 75 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 20 minutes.
  • SLS sodium lauryl sulfate
  • the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is canagliflozin hemihydrate.
  • the composition exhibits a dissolution profile in about 900 mL buffer at from about pH 4 to about pH 7.5 at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 1 (basket) at a speed of about 50 to about 100 rpm; wherein from about 25 to about 99 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes.
  • the composition exhibits a dissolution profile in about 900 mL buffer at from about pH 4 to about pH 7.5 at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 1 (basket) at a speed of about 50 to about 100 rpm; wherein from about 50 to about 99 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes.
  • the composition exhibits a dissolution profile in about 900 mL buffer at from about pH 4 to about pH 7.5 at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 50 to about 100 rpm; wherein from about 25 to about 99 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes.
  • the composition exhibits a dissolution profile in about 900 mL buffer at from about pH 4 to about pH 7.5 at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 50 to about 100 rpm; wherein from about 50 to about 99 wt % of the total amount of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes. In some embodiments, about 50% to about 99 wt %, or any value in between, of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is released after about 45 minutes.
  • about 50% to about 75%, about 60% to about 85%, about 70% to about 95%, or about 80% to about 99%, or any value in between is released after about 45 minutes.
  • about 75 to about 99% of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is released after about 45 minutes, for example, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any value in between.
  • about 25% to about 99 wt %, or any value in between, of the SGLT- 2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes.
  • about 50% to about 99 wt %, or any value in between, of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes.
  • about 50% to about 75%, about 60% to about 85%, about 70% to about 95%, or about 80% to about 99%, or any value in between, is released after about 15 minutes.
  • about 75 to about 99% of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is released after about 15 minutes, for example, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any value in between.
  • the compositions described herein provide a Cmax of the compound of Formula (I) of from about 50 to about 60 ng/mL/mg, when administered to a subject. In some embodiments, the compositions described herein provide a Cmax of the compound of Formula (I) of about 54 ng/mL/mg, when administered to a subject. In some embodiments, the compositions described herein provide a Tmax of the compound of Formula (I) of from about 3 hours to about 6 hours, when administered to a subject, for example, about 3 hours, about 4 hours, about 5 hours, or about 6 hours. In some embodiments, the subject is in a fasted state. In some embodiments, the subject is in a fed state.
  • the he compositions described herein provide a T max of the compound of Formula (I) of from about 3 hours to about 4 hours, when administered to a subject in a fasted state. In some embodiments, the he compositions described herein provide a Tmax of the compound of Formula (I) of from about 4 hours to about 5 hours, when administered to a subject in a fed state. In some embodiments, the compositions described herein provide an AUC of the compound of Formula (I) of from about 700 to about 1,000 ng ⁇ hr/mL/mg, when administered to a subject.
  • the compositions described herein provide an AUC of the compound of Formula (I) of from about 750 to about 900 ng ⁇ hr/mL/mg, when administered to a subject.
  • the compositions described herein provide a Cmax of the compound of Formula (I) of from about 50 to about 60 ng/mL/mg, a T max of the compound of Formula (I) of from about 3 hours to about 6 hours, and an AUC of the compound of Formula (I) of from about 700 to about 1,000 ng ⁇ hr/mL/mg, when administered to a subject.
  • the compositions described herein provide a Cmax of the SGLT-2 inhibitor of from about 5 to about 150 ng/mL/mg, when administered to a subject. In some embodiments, the compositions described herein provide a Cmax of the SGLT-2 inhibitor of about 10 to about 15 ng/mL/mg, when administered to a subject. In some embodiments, the compositions described herein provide a Cmax of empagliflozin of from about 75 to about 125 ng/mL/mg, when administered to a subject. In some embodiments, the compositions described herein provide a Cmax of canagliflozin of from about 5 to about 15 ng/mL/mg, when administered to a subject.
  • the compositions described herein provide a Tmax of the SGLT-2 inhibitor of from about 0.5 hours to about 2.5 hours, when administered to a subject, for example, about 0.5 hours, about 0.75 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, or about 2.5 hours.
  • the subject is in a fasted state.
  • the subject is in a fed state.
  • the compositions described herein provide a Tmax of the SGLT-2 inhibitor of from about 1 to about 2 hours, when administered to a subject.
  • the compositions described herein provide a Tmax of dapagliflozin of about 2 hours, when administered to a subject.
  • compositions described herein provide a Tmax of empagliflozin of about 1 hour, when administered to a subject. In some embodiments, the compositions described herein provide a Tmax of canagliflozin of about 1.5 hours, when administered to a subject.
  • compositions described herein provide an AUC of the SGLT-2 inhibitor of from about 30 to about 80 ng hr/mL/mg, when administered to a subject. In some embodiments, the compositions described herein provide an AUC of the SGLT-2 inhibitor of from about 30 to about 50 ng hr/mL/mg, about 40 to about 60 ng hr/mL/mg, about 50 to about 70 ng hr/mL/mg, or about 60 to about 80 ng hr/mL/mg, when administered to a subject.
  • the compositions described herein provide an AUC of dapagliflozin of from about 35 to about 55 ng hr/mL/mg, when administered to a subject. In some embodiments, the compositions described herein provide an AUC of empagliflozin of from about 30 to about 40 ng hr/mL/mg, when administered to a subject. In some embodiments, the compositions described herein provide an AUC of canagliflozin of from about 60 to about 80 ng hr/mL/mg, when administered to a subject.
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process comprising:
  • step (c) mixing the dry granules obtained in step (b) with one or more excipients to form a second blend;
  • step (g) mixing the dry granules obtained in step (h) with one or more excipients to form a fourth blend
  • step (h) applying the fourth blend obtained in step (i) to the surface of the tablet core, forming the outer layer.
  • the dry granules obtained in steps (b) and/or (f) are milled prior to the mixing with one or more excipients in steps (c) and/or (g).
  • the third blend of step (e) consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • forming dry granules comprises mixing a granulating solution with a blend, as described herein (for example, in step (e)), to form wet granules, and drying the wet granules to form dry granules.
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process comprising:
  • step (c) milling the dry granules obtained in step (b);
  • step (d) mixing the milled dry granules obtained in step (c) with one or more excipients to form a second blend;
  • step (g) forming dry granules comprising the third blend, or optionally mixing a granulating solution with the third blend obtained in step (f) to form wet granules, then drying the wet granules to form dry granules;
  • step (h) milling the dry granules obtained in step (g);
  • step (i) mixing the milled dry granules obtained in step (h) with one or more excipients to form a fourth blend;
  • step (j) applying the fourth blend obtained in step (i) to the surface of the tablet core, forming the outer layer.
  • the third blend of step (f) consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • forming dry granules comprises mixing a granulating solution with a blend, as described herein (for example, in step (b)), to form wet granules, and drying the wet granules to form dry granules.
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process comprising:
  • step (c) milling the dry granules obtained in step (b);
  • step (d) mixing the milled dry granules obtained in step (c) with one or more excipients to form a second blend;
  • step (h) milling the dry granules obtained in step (g);
  • step (i) mixing the milled dry granules obtained in step (h) with one or more excipients to form a fourth blend;
  • step (j) applying the fourth blend obtained in step (i) to the surface of the tablet core, forming the outer layer;
  • the third blend of step (f) consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • forming dry granules comprises mixing a granulating solution with a blend, as described herein (for example, in step (b)), to form wet granules, and drying the wet granules to form dry granules.
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process, comprising:
  • step (e) mixing the milled dry granules obtained in steps (c) and (f) with one or more excipients to form a third blend; and (f) compressing the third blend to form a tablet.
  • the dry granules obtained in steps (b) and/or (d) are milled prior to the mixing with one or more excipients in steps (c) and/or (e).
  • the second blend of step (c) consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • forming dry granules comprises mixing a granulating solution with a blend, as described herein (for example, in step (d)), to form wet granules, and drying the wet granules to form dry granules.
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process, comprising:
  • step (b) forming dry granules comprising the first blend, or optionally mixing a granulating solution with the first blend obtained in step (a) to form wet granules and drying the wet granules to obtain dry granules;
  • step (c) milling the dry granules obtained in step (b);
  • step (e) forming dry granules comprising the second blend, or optionally mixing a granulating solution with the second blend obtained in step (d) to form wet granules, then drying the wet granules to form dry granules;
  • step (f) milling the dry granules obtained in step (e);
  • step (g) mixing the milled dry granules obtained in steps (c) and (f) with one or more excipients to form a third blend; and (h) compressing the third blend to form a tablet.
  • the second blend of step (d) consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • forming dry granules comprises mixing a granulating solution with a blend, as described herein (for example, in step (d)), to form wet granules, and drying the wet granules to form dry granules.
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process, comprising:
  • step (c) optionally milling the dry granules obtained in step (b);
  • step (d) compressing the dry granules from step (b) or step (c) to form the tablet core;
  • forming dry granules comprises mixing a granulating solution with a blend, as described herein (for example, in step (b)), to form wet granules, and drying the wet granules to form dry granules.
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process, comprising:
  • step (c) optionally milling the dry granules obtained in step (b);
  • step (d) mixing the dry granules obtained in step (b) or step (c) with one or more excipients to form a second blend;
  • forming dry granules comprises mixing a granulating solution with a blend, as described herein (for example, in step (b)), to form wet granules, and drying the wet granules to form dry granules.
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process, comprising:
  • step (b) forming dry granules comprising the first blend, or optionally mixing a granulating solution with the first blend obtained in step (a) to form wet granules;
  • step (c) drying the wet granules obtained in step (b) to form dry granules
  • step (d) milling the dry granules obtained in step (c); (e) mixing the milled dry granules obtained in step (d) with one or more excipients to form a second blend;
  • step (g) forming dry granules comprising the third blend, or optionally mixing a granulating solution to the third blend obtained in step (f), and mixing the solution and third blend to form wet granules, then drying the wet granules to form dry granules;
  • step (h) milling the dry granules obtained in step (g);
  • step (i) mixing the milled dry granules obtained in step (h) with one or more excipients to form a fourth blend;
  • step (k) filling a capsule with the mixture obtained in step (j).
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process, comprising:
  • step (c) milling the dry granules obtained in step (b);
  • step (d) mixing the milled dry granules obtained in step (c) with one or more excipients to form a second blend;
  • step (g) forming dry granules comprising the third blend, or optionally mixing a granulating solution with the third blend obtained in step (f) to form wet granules, then drying the wet granules to form dry granules;
  • step (h) milling the dry granules obtained in step (g);
  • step (i) mixing the milled dry granules obtained in step (h) with one or more excipients to form a capsule fill;
  • Some embodiments provide a process for preparing the composition, comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, the process comprising:
  • step (g) optionally applying a film coating to the tablet.
  • the dry granules obtained in steps (b) and/or (d) are milled prior to the mixing in step (e).
  • the second blend of step (c) consists essentially of the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • forming dry granules comprises mixing a granulating solution with a blend, as described herein (for example, in step (b)), to form wet granules, and drying the wet granules to form dry granules.
  • milling further comprises screen sieving.
  • forming dry granules comprises roller compaction.
  • forming wet granules comprises contacting a fluidized bed with a blend, as described herein.
  • the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, of step (a) is present in substantially amorphous form.
  • the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, of step (a) is prepared by spray drying, spray drying with one or more excipients, hot-melt extrusion, or dissolution followed by precipitation onto an amorphous substrate, as described herein.
  • the amorphous substrate is amorphous silica or fumed silica.
  • the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, of step (a) is milled prior to step (a). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, of step (a) is micronized prior to step (a). In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of steps (d), (e), or (f), is present in crystalline form. In some embodiments, the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is milled prior to use in the processes described herein.
  • the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof is micronized prior to use in the processes described herein.
  • micronizing comprises forming particles having a mean diameter of from about 2 ⁇ m to about 10 ⁇ m, or any value in between.
  • Some embodiments provide a method of treating a PPARy-mediated disease or disorder, comprising administering a composition comprising a fixed dose combination of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof; an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof; and one or more excipients, to a subject in need thereof.
  • the PPARy-mediated disease or disorder is type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or a combination of any of the foregoing.
  • the PPARy-mediated disease or disorder is type 2 diabetes and NASH. In some embodiments, the type 2 diabetes and NASH are treated.
  • the NASH is treated.
  • the subject has been previously diagnosed with NASH.
  • the subject has been previously diagnosed with type 2 diabetes.
  • the subject has been previously diagnosed with NASH and type 2 diabetes.
  • the subject has been previously diagnosed with NASH and type 2 diabetes, wherein administration composition described herein treats the NASH.
  • the subject has one or more cardiac risk factors, for example, high blood pressure, high cholesterol, a history (previous or current) of smoking, a family history of cardiovascular disease, obesity, and previous myocardial infarction or stroke.
  • the desired therapeutic effect is the same therapeutic effect observed in monotherapy of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, e.g., any of the beneficial or desired results including clinical results as described herein, for example slowing the symptomatic progression of a PPARy-mediated disease or disorder, or symptoms thereof.
  • the desired therapeutic effect is the same therapeutic effect observed in monotherapy of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, e.g., any of the beneficial or desired results including clinical results as described herein, for example slowing the symptomatic progression of a PPARy-mediated disease or disorder, or symptoms thereof.
  • an unwanted drug effect, side effect, or adverse event is associated with or observed in monotherapy of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof and/or SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • an unwanted drug effect, side effect, or adverse event includes, but is not limited to edema, weight gain, hypertension, cardiovascular disease, and cardiovascular events (e.g. cardiovascular death, nonfatal myocardial infarction and nonfatal stroke).
  • Type 2 diabetes is an increasingly prevalent disease that due to a high frequency of complications leads to a significant reduction of life expectancy. Because of diabetes-associated microvascular complications, type 2 diabetes is currently the most frequent cause of adult-onset loss of vision, renal failure, and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a two to five fold increase in cardiovascular disease risk. After long duration of disease, most patients with type 2 diabetes will eventually fail on oral therapy and become insulin dependent with the necessity for daily injections and multiple daily glucose measurements.
  • the high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycemia-associated complications or chronic damages (including micro- and macrovascular complications such as diabetic nephropathy, retinopathy or neuropathy, and/or cardiovascular complications) in patients with type 2 diabetes.
  • the World Health Organization diagnostic criteria for diabetes are shown below. Table 1. World Health Organization Diabetes Diagnostic Criteria
  • the treatment of diabetes comprises one or more of a reduction in fasting glucose levels, improved glucose tolerance, and a decrease in HbAic.
  • NAFLD is characterized by hepatic steatosis with no secondary causes of hepatic steatosis including excessive alcohol consumption, other known liver diseases, or long-term use of a steatogenic medication (Chalasani et al., Hepatology. 2018, 67(1):328-357, which is hereby incorporated by reference in its entirety).
  • NAFLD can be categorized into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). According to Chalasani et al., NAFL is defined as the presence of ⁇ 5% hepatic steatosis without evidence of hepatocellular injury in the form of hepatocyte ballooning.
  • NASH is defined as the presence of > 5% hepatic steatosis and inflammation with hepatocyte injury (e.g., ballooning), with or without any liver fibrosis. Additionally, NASH is commonly associated with hepatic inflammation and liver fibrosis, which can progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. However, liver fibrosis is not always present in NASH, but the severity of fibrosis can be linked to long-term outcomes.
  • these approaches include determining one or more of hepatic steatosis (e.g., accumulation of fat in the liver); the NAFLD Activity Score (NAS); hepatic inflammation; biomarkers indicative of one or more of liver damage, hepatic inflammation, liver fibrosis, and/or liver cirrhosis (e.g., serum markers and panels); and liver fibrosis and/or cirrhosis.
  • physiological indicators of NAFLD can include liver morphology, liver stiffness, and the size or weight of the subject’s liver.
  • NAFLD in the subject is evidenced by an accumulation of hepatic fat and detection of a biomarker indicative of liver damage.
  • elevated serum ferritin and low titers of serum autoantibodies can be common features of NAFLD.
  • methods to assess NAFLD include magnetic resonance imaging, either by spectroscopy or by proton density fat fraction (MRI-PDFF) to quantify steatosis, transient elastography (FIBROSCAN®), hepatic venous pressure gradient (HPVG), hepatic stiffness measurement with MRE for diagnosing significant liver fibrosis and/or cirrhosis, and assessing histological features of liver biopsy.
  • MRI-PDFF proton density fat fraction
  • HPVG hepatic venous pressure gradient
  • MRE hepatic stiffness measurement with MRE for diagnosing significant liver fibrosis and/or cirrhosis
  • magnetic resonance imaging is used to detect one or more of steatohepatitis (NASH-MRI), liver fibrosis (Fibro-MRI), and steatosis see, for example, U.S. Application Publication Nos. 2016/146715 and 2005/0215882, each of which are incorporated herein by reference in their entireties.
  • NASH-MRI steatohepatitis
  • Fibro-MRI liver fibrosis
  • steatosis see, for example, U.S. Application Publication Nos. 2016/146715 and 2005/0215882, each of which are incorporated herein by reference in their entireties.
  • treatment of NAFLD comprises one or more of a decrease in symptoms; a reduction in the amount of hepatic steatosis; a decrease in the NAS; a decrease in hepatic inflammation; a decrease in the level of biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and/or liver cirrhosis; and a reduction in fibrosis and/or cirrhosis, a lack of further progression of fibrosis and/or cirrhosis, or a slowing of the progression of fibrosis and/or cirrhosis.
  • the severity of NALFD can be assessed using the NAS.
  • treatment of NAFLD can be assessed using the NAS.
  • treatment of NAFLD comprises a reduction in the NAS following administration of one or more compounds described herein.
  • the NAS can be determined as described in Kleiner et al., Hepatology. 2005, 41(6): 1313-1321, which is hereby incorporated by reference in its entirety. See, for example, Table 2 for a simplified NAS scheme adapted from Kleiner.
  • the NAS is determined non-invasively, for example, as described in U.S. Application Publication No. 2018/0140219, which is incorporated by reference herein in its entirety.
  • the presence of hepatic inflammation is determined by one or more methods selected from the group consisting of biomarkers indicative of hepatic inflammation and a liver biopsy sample(s) from the subject.
  • the severity of hepatic inflammation is determined from a liver biopsy sample(s) from the subject. For example, hepatic inflammation in a liver biopsy sample can be assessed as described in Kleiner et al., Hepatology. 2005, 41(6): 1313-1321 and Brunt et al., Am J Gastroenterol 1999, 94:2467-2474, each of which are hereby incorporated by reference in their entireties.
  • treatment of NAFLD comprises treatment of fibrosis and/or cirrhosis, e.g., a decrease in the severity of fibrosis, a lack of further progression of fibrosis and/or cirrhosis, or a slowing of the progression of fibrosis and/or cirrhosis.
  • the presence of fibrosis and/or cirrhosis is determined by one or more methods selected from the group consisting of transient elastography (e.g., FIBROSCAN®), non-invasive markers of hepatic fibrosis, and histological features of a liver biopsy.
  • the severity (e.g., stage) of fibrosis is determined by one or more methods selected from the group consisting of transient elastography (e.g., FIBROSCAN®), a fibrosis-scoring system, biomarkers of hepatic fibrosis (e.g., non-invasive biomarkers), and hepatic venous pressure gradient (HVPG).
  • transient elastography e.g., FIBROSCAN®
  • biomarkers of hepatic fibrosis e.g., non-invasive biomarkers
  • HVPG hepatic venous pressure gradient
  • fibrosis scoring systems include the NAFLD fibrosis scoring system (see, e.g., Angulo, et al., Hepatology . 2007; 45(4):846-54), the fibrosis scoring system in Brunt et al., Am J Gastroenterol .
  • the presence of NAFLD is determined by one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and/or liver cirrhosis or scoring systems thereof.
  • the severity of NAFLD is determined by one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and/or liver cirrhosis or scoring systems thereof.
  • the level of the biomarker can be determined by, for example, measuring, quantifying, and monitoring the expression level of the gene or mRNA encoding the biomarker and/or the peptide or protein of the biomarker.
  • Non-limiting examples of biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and/or liver cirrhosis and/or scoring systems thereof include the aspartate aminotransferase (AST) to platelet ratio index (APRI); the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ratio (AAR); the FIB-4 score, which is based on the APRI, alanine aminotransferase (ALT) levels, and age of the subject (see, e.g., McPherson et al., Gut.
  • hyaluronic acid pro-inflammatory cytokines
  • a panel of biomarkers consisting of ⁇ 2-macroglobulin, haptoglobin, apolipoprotein Al, bilirubin, gamma glutamyl transpeptidase (GGT) combined with a subject’s age and gender to generate a measure of fibrosis and necroinflammatory activity in the liver (e.g., FIBROTEST®, FIBROSURE®)
  • a panel of biomarkers consisting of bilirubin, gamma-glutamyltransferase, hyaluronic acid, ⁇ 2 -macroglobulin combined with the subject’s age and sex (e.g., HEPASCORE®; see, e.g., Adams et al., Clin Chem.
  • biomarkers consisting of tissue inhibitor of metalloproteinase- 1, hyaluronic acid, and ⁇ 2-macroglobulin
  • a panel of biomarkers consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA)
  • TGF tissue inhibitor of metalloproteinases 1
  • PIIINP amino-terminal propeptide of type III procollagen
  • HA hyaluronic acid
  • ELF Enhanced Liver Fibrosis
  • the presence of fibrosis is determined by one or more of the FIB-4 score, a panel of biomarkers consisting of ⁇ 2-macroglobulin, haptoglobin, apolipoprotein Al, bilirubin, gamma glutamyl transpeptidase (GGT) combined with a subject’s age and gender to generate a measure of fibrosis and necroinflammatory activity in the liver (e.g., FIBROTEST®, FIBROSURE®), a panel of biomarkers consisting of bilirubin, gamma-glutamyltransferase, hyaluronic acid, ⁇ 2- macroglobulin combined with the subject’s age and sex (e.g., HEPASCORE®; see, e.g., Adams et al., Clin Chem.
  • HEPASCORE® see, e.g., Adams et al., Clin Chem.
  • biomarkers consisting of tissue inhibitor of metalloproteinase- 1, hyaluronic acid, and ⁇ 2-macroglobulin
  • FIBROSPECT® tissue inhibitor of metalloproteinases 1
  • PIIINP aminoterminal propeptide of type III procollagen
  • HA hyaluronic acid
  • the level of aspartate aminotransferase does not increase. In some embodiments, the level of aspartate aminotransferase (AST) decreases. In some embodiments, the level of alanine aminotransferase (ALT) does not increase. In some embodiments, the level of alanine aminotransferase (ALT) decreases.
  • the “level” of an enzyme refers to the concentration of the enzyme, e.g., within blood. For example, the level of AST or ALT can be expressed as Units/L.
  • the severity of fibrosis is determined by one or more of the FIB-4 score, a panel of biomarkers consisting of ⁇ 2-macroglobulin, haptoglobin, apolipoprotein Al, bilirubin, gamma glutamyl transpeptidase (GGT) combined with a subject’s age and gender to generate a measure of fibrosis and necroinflammatory activity in the liver (e.g., FIBROTEST®, FIBROSURE®), a panel of biomarkers consisting of bilirubin, gamma-glutamyltransferase, hyaluronic acid, ⁇ 2 -macroglobulin combined with the subject’s age and sex (e.g., HEPASCORE®; see, e.g., Adams et al., Clin Chem.
  • HEPASCORE® see, e.g., Adams et al., Clin Chem.
  • hepatic inflammation is determined by the level of liver inflammation biomarkers, e.g., pro-inflammatory cytokines.
  • biomarkers indicative of liver inflammation include interleukin-(IL) 6, interleukin-(IL) 1 ⁇ , tumor necrosis factor (TNF)- ⁇ , transforming growth factor (TGF)- ⁇ , monocyte chemotactic protein (MCP)-1, C- reactive protein (CRP), PAI-1, and collagen isoforms such as Col1a1, Col1a2, and Col4a1 (see, e.g., Neuman, et al., Can J Gastroenterol Hepatol. 2014 Dec; 28(11): 607–618 and U.S. Patent No. 9,872,844, each of which are incorporated by reference herein in their entireties).
  • Liver inflammation can also be assessed by change of macrophage infiltration, e.g., measuring a change of CD68 expression level.
  • liver inflammation can be determined by measuring or monitoring serum levels or circulating levels of one or more of interleukin-(IL) 6, interleukin-(IL) 1 ⁇ , tumor necrosis factor (TNF)- ⁇ , transforming growth factor (TGF)- ⁇ , monocyte chemotactic protein (MCP)-1, and C-reactive protein
  • the NAFLD is NAFLD with attendant cholestasis. In cholestasis, the release of bile, including bile acids, from the liver is blocked.
  • Bile acids can cause hepatocyte damage (see, e.g., Perez MJ, Briz O. World J Gastroenterol. 2009 Apr 14;15(14):1677-89) likely leading to or increasing the progression of fibrosis (e.g., cirrhosis) and increasing the risk of hepatocellular carcinoma (see, e.g., Sorrentino P et al.. Dig Dis Sci. 2005 Jun;50(6):1130-5 and Satapathy SK and Sanyal AJ. Semin Liver Dis. 2015, 35(3):221-35, each of which are incorporated by reference herein in their entireties).
  • the NAFLD with attendant cholestasis is NASH with attendant cholestasis.
  • the treatment of NAFLD comprises treatment of pruritus. In some embodiments, the treatment of NAFLD with attendant cholestasis comprises treatment of pruritus. In some embodiments, a subject with NAFLD with attendant cholestasis has pruritus. In some embodiments, treatment of NAFLD comprises an increase in adiponectin. It is thought that the compound of Formula (I) may be a selective activator of a highly limited number of PPARy pathways including pathways regulated by adiponectin.
  • Adiponectin is an anti-fibrotic and anti-inflammatory adipokine in the liver (see e.g., Park et al., Curr Pathobiol Rep.2015 Dec 1; 3(4): 243–252.).
  • the level of adiponectin is determined by, for example, an ELISA enzymatic assay. (CRP).
  • treatment of NAFLD comprises a decrease of one or more symptoms associated with NAFLD in the subject. Exemplary symptoms can include one or more of an enlarged liver, fatigue, pain in the upper right abdomen, abdominal swelling, enlarged blood vessels just beneath the skin's surface, enlarged breasts in men, enlarged spleen, red palms, jaundice, and pruritus.
  • the subject is asymptomatic.
  • the treatment of NAFLD comprises a reduction in hepatic steatosis.
  • hepatic steatosis is decreased by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%. 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% following administration of (a) and (b) for a period of time.
  • the treatment of NAFLD is assessed using the NAFLD Activity Score (NAS).
  • treatment of NAFLD comprises a decrease in the NAS.
  • the NAS for a sample from the subject following administration is 7 or less.
  • the NAS for a sample from the subject following administration is 5 or less, 4 or less, 3 or less, or 2 or less.
  • the NAFLD activity score (NAS) for a sample from the subject following administration during the period of time is 7 or less.
  • the NAS for a sample from the subject following administration during the period of time is 5 or less, 4 or less, 3 or less, or 2 or less.
  • the sample from the subject is from a liver biopsy.
  • the treatment of NAFLD can be assessed using the NAFLD Activity Score (NAS).
  • NAS NAFLD Activity Score
  • the NAS for a sample from the subject following administration is reduced by 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more.
  • the NAS for a sample from the subject following administration is reduced by 1, 2, 3, 4, 5, or 6.
  • the NAFLD activity score (NAS) for a sample from the subject following administration during the period of time is reduced by 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more.
  • the NAS for a sample from the subject following administration during the period of time is reduced by 1, 2, 3, 4, 5, or 6.
  • the sample from the subject is from a liver biopsy.
  • the treatment of NAFLD comprises treatment of hepatic inflammation.
  • the severity of the hepatic inflammation is decreased by about 1% to about 50%, about 25% to about 75%, or about 50% to about 100%.
  • the severity of hepatic inflammation is decreased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%.
  • the treatment of NAFLD comprises treatment of fibrosis.
  • the treatment of the NAFLD comprises treatment of cirrhosis (e.g., stage 4 of fibrosis).
  • treatment of fibrosis comprises a decrease in the stage of fibrosis, for example, from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 4 to stage 0, from stage 3 to stage 2, from stage 3 to stage 1, from stage 3 to stage 0, from stage 2 to stage 1, from stage 2 to stage 0, or from stage 1 to stage 0.
  • the adiponectin level in the subject is increased by at least about 30%, at least about 68%, at least about 175%, or at least about 200%. In some embodiments, the increase is by at least about 175%.
  • the level of aspartate aminotransferase (AST) in the subject does not increase. In some embodiments, the level of aspartate aminotransferase (AST) in the subject decreases. In some embodiments, the level of alanine aminotransferase (ALT) in the subject does not increase. In some embodiments, the level of alanine aminotransferase (ALT) in the subject decreases. In some embodiments, the total body weight of the subject does not increase. In some embodiments, the total body weight of the subject decreases. In some embodiments, the body mass index (BMI) of the subject does not increase. In some embodiments, the body mass index (BMI) of the subject decreases. In some embodiments, the waist and hip (WTH) ratio of the subject does not increase. In some embodiments, the waist and hip (WTH) ratio of the subject decreases.
  • a non-invasive liver fibrosis marker does not increase or decreases.
  • the non-invasive liver fibrosis marker is Enhanced Liver Fibrosis (ELF) panel.
  • treatment of NAFLD comprises a decrease in the level of one or more biomarkers indicative of one or more of liver damage, inflammation, fibrosis, and/or cirrhosis, e.g., any of the biomarkers as described herein.
  • treatment of NAFLD comprises a decrease in the level of one or more biomarkers indicative of one or more of liver damage, inflammation, fibrosis, and/or cirrhosis by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%.
  • the treatment of NAFLD decreases the level of serum bile acids in the subject. In some embodiments, the treatment of NAFLD comprises treatment of pruritus.
  • the subject has liver fibrosis associated with the NAFLD. In some embodiments, the subject has hepatic cirrhosis (e.g., stage 4 fibrosis) associated with the NAFLD. In some embodiments, the subject has liver fibrosis as a comorbidity. In some embodiments, the subject has hepatic cirrhosis (e.g., stage 4 fibrosis) as a comorbidity. In some embodiments, the subject has liver fibrosis caused by the NAFLD. In some embodiments, the subject has hepatic cirrhosis (e.g., stage 4 fibrosis) caused by the NAFLD.
  • the subject has hepatic cirrhosis (e.g., stage 4 fibrosis) caused by the NAFLD.
  • the NAFLD is simple nonalcoholic fatty liver (NAFL). In some embodiments, the NAFLD is NAFL with attendant liver fibrosis. In some embodiments, the NAFLD is NAFL with attendant liver cirrhosis.
  • the NAFLD is nonalcoholic steatohepatitis (NASH). In some embodiments, the NAFLD is NASH with attendant liver fibrosis. In some embodiments, the NAFLD is NASH with attendant liver cirrhosis.
  • NASH nonalcoholic steatohepatitis
  • the method further comprises performing a liver biopsy to determine the NAFLD activity score of the biopsy sample obtained from the subject.
  • Pulmonary arterial hypertension is a life-threatening disease characterized by a progressive pulmonary vasculopathy leading to right ventricular hypertrophy. Right heart failure occurs if left untreated.
  • the hemodynamic definition of PAH is an average resting pulmonary artery pressure greater than or equal to 25 mmHg in the presence of a pulmonary capillary wedge pressure less than or equal to 15 mmHg.
  • the normal average pulmonary artery pressure is 12- 16 mmHg and normal wedge pressure is 6-12 mmHg . If left untreated, it carries a high rate of mortality.
  • familial or idiopathic IP AH disease is the most common type (-55%), followed by PH secondary to congenital heart disease (-35%) and chronic respiratory disorders (-15%)
  • Pathologies involved in PAH include one or more of vasoconstriction, vascular proliferation and remodeling, thrombosis and inflammation.
  • Features of PAH may include reduction in peripheral PAs vascular pruning, thickening of the pulmonary adventitia, venous hypertrophy, and increased expression of TGF- ⁇ ; matrix proteins such as elastin, fibronectin, and tenascin-C; and glycosaminoglycans.
  • B and T cells may be found in abundance in the perivascular space and may be seen invading the vessel wall.
  • An additional feature that may be observed in severe forms of PAH is a complex vascular lesion known as plexiform lesion.
  • Dysfunctional EPCs which are hyperproliferative with impaired ability to form vascular networks, may also be implicated in the vascular remodeling in PAH.
  • Factors that increase the rapidity of development of pulmonary vascular disease may include increased MPAP, increased pulmonary blood flow, and the presence of hypoxia or hypercapnia.
  • the events that drive heart failure in PAH may include maladaptive RV hypertrophy (RVH) and dilation, capillary rarefication, cardiac fibrosis, in some cases myocardial ischemia/ hypoxia, and ultimately, RV failure.
  • RVH pulmonary vascular disease
  • Cardiovascular remodeling in pulmonary vascular disease (PVD), PAH, and RV failure may relate to increased growth factor-mediated cell proliferation, activation and recruitment of myofibroblasts, DNA damage/resistance to apoptosis, extracellular matrix remodeling and fibrosis, and inflammation and endothelial dysfunction, with a smaller contribution from vasoconstriction.
  • Abnormalities in glucose and lipid metabolism and epigenetic dysregulation [microRNAs (miRNAs) may be observed.
  • Histone deacetylases (HDACs) may be involved in both PAH/PVD and RV failure.
  • the subject that has been identified, selected, or diagnosed as having PAH through the use of histological analysis and/or a regulatory agency-approved, e.g., FDA- approved test or assay for identifying PAH in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • a regulatory agency-approved e.g., FDA- approved test or assay for identifying PAH in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the PAH is selected from idiopathic PAH; familial PAH; PAH associated with a collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAH associated with a congenital heart disease selected from; atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductusarteriosus; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with ingestion of a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant venous or capillary involvement; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hem
  • the PAH is idiopathic PAH. In some embodiments, the PAH is familial PAH. In some embodiments, the PAH is PAH associated with a collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis. In some embodiments, the PAH is PAH associated with a congenital heart disease selected from; atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductusarteriosus. In some embodiments, the PAH is PAH associated with portal hypertension.
  • ASD atrial septic defect
  • VSD ventricular septic defect
  • the PAH is PAH associated with portal hypertension.
  • the PAH is PAH associated with HIV infection. In some embodiments, the PAH is PAH associated with ingestion of a drug or toxin. In some embodiments, the PAH is PAH associated with hereditary hemorrhagic telangiectasia. In some embodiments, the PAH is PAH associated with splenectomy. In some embodiments, the PAH is PAH associated with significant venous or capillary involvement. In some embodiments, the PAH is PAH associated with pulmonary veno-occlusive disease (PVOD). In some embodiments, the PAH is PAH associated with pulmonary capillary hemangiomatosis (PCH).
  • PVOD pulmonary veno-occlusive disease
  • PCH pulmonary capillary hemangiomatosis
  • the treatment of PAH comprises relieving at least to some extent one or more signs or symptoms associated with PAH.
  • the symptoms are one or more of the following: dyspnea, angina, syncope and edema.
  • Example 1 Preparation of a fixed dose combination tablet comprising a tablet core and a coating.
  • 3 mg of the besylate salt of the compound of Formula (I) are mixed with MCC, crosspovidone, colloidal silicon dioxide, lactose monohydrate, povidone and magnesium stearate to form a powder blend.
  • Wet granulation with ethanol provides granules containing the besylate salt of the compound of Formula (I).
  • the granules are then compressed in a tablet core.
  • the tablet core is then coated with a mixture of dapagliflozin propylene glycol hydrate, MCC, crospovidone, silicon dioxide, lactose, and magnesium stearate.
  • APVA coating may be added if desired.
  • Example 2 Preparation of a fixed dose combination tablet.
  • 3 mg of the besylate salt of the compound of Formula (I) are mixed with MCC, crosspovidone, colloidal silicon dioxide, lactose monohydrate, povidone and magnesium stearate to form a powder blend.
  • Wet granulation with ethanol provides granules containing the besylate salt of the compound of Formula (I).
  • 10 mg of dapagliflozin propylene glycol hydrate are wet granulated with ethanol with MCC, crospovidone, silicon dioxide, lactose, and magnesium stearate to provide granules containing the dapagliflozin propylene glycol hydrate.
  • the granules containing the besylate salt of the compound of Formula (I) and the granules containing the dapagliflozin propylene glycol hydrate are then blended with each other and with additional excipients.
  • the resulting blend is compressed in a tablet core.
  • the tablet core is then coated with a mixture of dapagliflozin propylene glycol hydrate, MCC, crospovidone, silicon dioxide, lactose, and magnesium stearate.
  • a PVA coating may be added if desired.
  • Example 3 Dissolution of a fixed dose combination tablet.
  • Tablet (A) is prepared as follows: 3 mg of the besylate salt of the compound of Formula (I) are mixed with MCC, crospovidone, colloidal silicon dioxide, lactose monohydrate, povidone and magnesium stearate to form a powder blend. Wet granulation with ethanol provides granules containing the besylate salt of the compound of Formula (I). The granules are then compressed in a tablet.
  • the dissolution rate of tablet (A) is then determined in about 900 mL of water, containing about 0.5% sodium dodecyl sulfate (SDS) at about pH 1.5, at 37° C ⁇ 0.5° C according to USP 28 ⁇ 711> test method 2 (paddle) at a speed of about 50 rpm.
  • the dissolution rate of tablet (B) is then determined under the same conditions as described above for tablet (A).

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Abstract

L'invention concerne des formulations de combinaisons à dose fixe utiles pour le traitement de maladies ou d'états pathologiques à médiation par PPARγ. L'invention concerne notamment des combinaisons à dose fixe contenant le composé de formule (I), ou son sel ou solvate pharmaceutiquement acceptable, et un inhibiteur de SGLT-2, ou son sel ou solvate pharmaceutiquement acceptable. L'invention concerne également des procédés de fabrication et des procédés d'utilisation de formulations de combinaisons à dose fixe.
PCT/US2021/048587 2020-09-03 2021-09-01 Combinaisons à dose fixe de chs-131 et d'un inhibiteur de sglt-2 WO2022051316A1 (fr)

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