Combination of an SGLT2 inhibitor and a mineralocorticoid receptor modulator for use in the treatment of cardio-renal diseases

Abstract

1. A pharmaceutical composition comprising: (a) one or more first pellets, the first pellets comprising (i) a first core and (ii) a first coating on the first core, the first coating comprising a mineralocorticoid receptor (MR) modulator and a first binding agent; and (b) one or more second pellets, the second pellets comprising (i) a second core and (ii) a second coating on the second core, the second coating comprising an SGLT2 inhibitor, the SGLT2 inhibitor comprising about 5% to about 20% by weight of the second pellet, wherein the SGLT2 inhibitor comprises about 20% to about 50% by weight of the mineralocorticoid receptor (MR) modulator and about 1% to about 10% by weight of the SGLT2 inhibitor, for use in treating chronic kidney disease or heart failure.

Description

[Technical Field]

[0001] The present disclosure provides a pharmaceutical composition comprising: (a) one or more first pellets, the first pellet comprising (i) a first core and (ii) a first coating on the first core, the first coating comprising a mineralocorticoid receptor (MR) modulator and a first binding agent; and (b) one or more second pellets, the second pellet comprising (i) a second core and (ii) a second coating on the second core, the second coating comprising an SGLT2 inhibitor, the SGLT2 inhibitor comprising about 5% to about 20% by weight of the second pellet, the composition comprising about 20% to about 50% by weight of the mineralocorticoid receptor (MR) modulator and about 1% to about 10% by weight of the SGLT2 inhibitor. The disclosure further provides an oral dosage form comprising the pharmaceutical composition. Also provided is a method of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. The present disclosure also relates to a pharmaceutical composition for treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising an MR modulator and an SGLT2 inhibitor. [Background technology]

[0002] Chronic heart failure (HF) is a leading cause of death, hospitalization, and suboptimal quality of life (QOL). Even with the best available treatments, the 5-year survival rate for HF patients is lower than that for most cancers. Furthermore, the prevalence of chronic HF continues to increase worldwide. An estimated 38,000,000 people are affected worldwide, with over 1 million hospitalizations annually in both the United States and Europe. Approximately 20% to 67% of patients with HF also have chronic kidney disease (CKD), which confers a 25% to 35% increased risk of mortality compared with patients with HF alone. See, e.g., Braunwald et al., Lancet 385(9970):812-24, 2015; Ambrosy et al., Curr Heart Fail Rep. 11(4):416-427, 2014; Sarraf et al., Clin J Am Soc Nephrol. 4(12):2013-26, 2009; and Ather et al., J Am Coll Cardiol. 59(11):998-1005(2012). Summary of the Invention

[0003] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) one or more first pellets, the first pellet comprising (i) a first core and (ii) a first coating on the first core, the first coating comprising a mineralocorticoid receptor (MR) modulator and a first binding agent; and (b) one or more second pellets, the second pellet comprising (i) a second core and (ii) a second coating on the second core, the second coating comprising an SGLT2 inhibitor, wherein the SGLT2 inhibitor comprises about 5% to about 20% by weight of the second pellet, wherein the SGLT2 inhibitor comprises about 20% to about 50% by weight of the mineralocorticoid receptor (MR) modulator and about 1% to about 10% by weight of the SGLT2 inhibitor.

[0004] In some embodiments, the MR modulating agent comprises a compound of formula I:

[0005] [ka]

[0006] In some embodiments, the composition comprises about 20% to about 50% by weight of the MR modulator, hi some embodiments, the composition comprises about 25% or about 45% by weight of the MR modulator.

[0007] In some embodiments, the first binder may be selected from, by way of non-limiting example, povidone, polyethylene glycol, polyethylene oxide, hydroxypropyl methylcellulose (e.g., hypromellose), methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, starch (e.g., corn, potato, and rice), pregelatinized starch, and combinations thereof.

[0008] In some embodiments, the first binder comprises povidone. In some embodiments, the composition comprises about 1% to about 10% by weight of povidone. In some embodiments, the composition comprises about 4% to about 5% by weight of povidone. In some embodiments, the composition comprises about 6% to about 7% by weight of povidone.

[0009] In some embodiments, the first binder comprises povidone and hypromellose. In some embodiments, the composition comprises about 4% to about 6% by weight of povidone. In some embodiments, the composition comprises about 0.5% to about 3% by weight of hypromellose. In some embodiments, the composition comprises about 5% by weight of povidone and about 1% by weight of hypromellose.

[0010] In some embodiments, the first coating may further comprise a first lubricant. The first lubricant may be selected from, by way of non-limiting example, sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate, stearyl alcohol, talc, silica, or a combination thereof. In some embodiments, the first lubricant comprises sodium stearyl fumarate. In some embodiments, the first lubricant comprises 0% to about 0.5% by weight of the composition. In some embodiments, the first core comprises microcrystalline cellulose. In some embodiments, the first core comprises about 10% to about 30% by weight of the composition.

[0011] In some embodiments, the at least one SGLT2 inhibitor is selected from compounds of formula II.

[0012] [ka]

[0013] In some embodiments, at least one SGLT2 inhibitor selected from the compounds of Formula II is in the form of a pharmaceutically acceptable solvate, mixed solvate, or complex. In some embodiments, at least one compound is in the form of a non-crystalline solid (e.g., amorphous form). In some embodiments, at least one compound is in the form of a crystalline solid.

[0014] In some embodiments, at least one compound is in the form of an (S)-propylene glycol ((S)-PG) solvate, having the structure shown below.

[0015] [ka]

[0016] In some embodiments, at least one compound is in the form of a crystalline S-PG solvate. Methods for preparing (S)-PG solvates of dapagliflozin, including crystalline S-PG solvates, are provided in U.S. Patent No. 7,919,598.

[0017] In some embodiments, the composition comprises about 1% to about 10% by weight of the SGLT2 inhibitor, hi some embodiments, the composition comprises about 2.5% to about 4% of the SGLT2 inhibitor.

[0018] In some embodiments, the SGLT2 inhibitor is about 5% to about 20% by weight of the second pellet. In some embodiments, the SGLT2 inhibitor is about 5% to about 15% by weight of the second pellet. In some embodiments, the SGLT2 inhibitor is about 10% to about 15% by weight of the second pellet. In some embodiments, the SGLT2 inhibitor is about 12% to about 14% by weight of the second pellet.

[0019] In some embodiments, the second coating further comprises a second binder, an anti-adherent agent, and optionally a second lubricant. In some embodiments, the second binder may be selected from, for example, povidone (polyvinylpyrrolidone PVP), polyethylene glycol (PEG), polyethylene oxide (PEO), xanthan gum, cellulose derivatives such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), gelatin, starch (e.g., corn, potato, or rice), pregelatinized starch, and related materials, or combinations thereof. In at least one embodiment, the second binder comprises hydroxypropylcellulose. In some embodiments, the second binder comprises about 0.1% to about 5% by weight of the composition. In some embodiments, the anti-adherent agent comprises talc. In some embodiments, the anti-adherent agent comprises about 1% to about 20% by weight of the composition. In some embodiments, the second lubricant comprises sodium stearyl fumarate. In some embodiments, the second lubricant is from 0% to about 1% by weight of the composition. In some embodiments, the second core comprises a sugar, a starch, or a combination thereof. In some embodiments, the second core is from about 10% to about 40% by weight of the composition.

[0020] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule, wherein the ingredients in the capsule can have different or the same weight percentages as in the pharmaceutical composition. In at least one embodiment, the weight percentages in the pharmaceutical composition are different from the weight percentages in the entire capsule. In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule, comprising: (a) one or more first pellets comprising: (i) a first core comprising a microcrystalline cellulose core, the first core being about 5% to about 25% by weight of the capsule; (ii) a first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 constitutes about 10% to about 45% by weight of the capsule; (B) povidone that constitutes about 1% to about 10% by weight of the capsule; and (C) sodium stearyl fumarate, in an amount of about 0.01% to about 1% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: (i) a second core comprising sugar spheres, wherein the sugar spheres are about 5% to about 30% by weight of the capsule; (ii) a second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin propanediol, wherein the dapagliflozin propanediol is about 1% to about 10% by weight of the capsule and about 5% to about 20% by weight of a second pellet; (B) hydroxypropyl cellulose that is about 0.1% to about 1% by weight of the capsule; (C) talc that is about 1% to about 15% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.01% to about 0.1% by weight of the capsule; a second coating comprising: and a second pellet comprising:

[0021] In some embodiments, the present disclosure provides a capsule comprising about 50 mg to about 150 mg of AZD9977. In some embodiments, the present disclosure provides a capsule comprising about 1 mg to about 15 mg of dapagliflozin propanediol.

[0022] In some embodiments, the present disclosure provides a capsule comprising about 10 mg to about 50 mg of AZD9977. In some embodiments, the present disclosure provides a capsule comprising about 10 mg to about 45 mg of AZD9977. In some embodiments, the present disclosure provides a capsule comprising about 10 mg to about 40 mg of AZD9977. In some embodiments, the present disclosure provides a capsule comprising about 1 mg to about 15 mg of dapagliflozin propanediol. In some embodiments, the present disclosure provides a capsule comprising about 5 mg to about 10 mg of dapagliflozin propanediol.

[0023] In some embodiments, the present disclosure provides an oral dosage form comprising the pharmaceutical composition described herein. In some embodiments, the oral dosage form is a capsule. In some embodiments, the pharmaceutical composition in the dosage form comprises about 50 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 150 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 10 mg of dapagliflozin propanediol.

[0024] In some embodiments, the present disclosure provides an oral dosage form comprising a pharmaceutical composition described herein. In some embodiments, the oral dosage form is a capsule. In some embodiments, the pharmaceutical composition in the dosage form comprises about 10 mg to about 50 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 10 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 15 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 20 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 25 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 30 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 35 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 40 mg of AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 45 mg of AZD9977. In some embodiments, the pharmaceutical composition in dosage form comprises about 50 mg of AZD9977. In some embodiments, the pharmaceutical composition in dosage form comprises about 10 mg of dapagliflozin propanediol.

[0025] In some embodiments, at least 75-85% of the MR modulator is released from the pharmaceutical compositions or oral dosage forms described herein within a time range of about 15-30 minutes. In other embodiments, at least 75-85% of the SGLT2 inhibitor is released from the pharmaceutical compositions or oral dosage forms described herein within a time range of about 15-30 minutes. Dissolution profiles can be tested using dissolution techniques known to those skilled in the art (e.g., methods such as USP 1 at 100 rpm or USP 2 at 70 rpm).

[0026] In some embodiments, the present disclosure provides a method of treating heart failure in a subject in need thereof, the method comprising administering a pharmaceutical composition or oral dosage form described herein. Also disclosed is a method of treating chronic kidney disease in a subject in need thereof, the method comprising administering a pharmaceutical composition or oral dosage form described herein.

[0027] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering a pharmaceutical composition or oral dosage form described herein.

[0028] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering a pharmaceutical composition or oral dosage form described herein, wherein the method does not result in a clinically significant increase in associated hyperkalemia in the subject.

[0029] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering a pharmaceutical composition or oral dosage form described herein, wherein there is no clinically significant increase in associated hypotension in the subject.

[0030] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering a pharmaceutical composition or oral dosage form described herein, wherein the method does not result in a clinically significant increase in the risk of associated acute kidney injury in the subject.

[0031] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering a pharmaceutical composition or oral dosage form described herein, wherein the method does not result in a clinically significant increase in the risk of associated gynecomastia in the subject.

[0032] In some embodiments, a daily dose of about 50 mg or about 150 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, administration is once daily. In some embodiments, the pharmaceutical composition or oral dosage form is administered to the subject in a fasting state. In some embodiments, the subject's AUC last and AUC inf is the AUC of subjects administered separate dosage forms of an MR modulator and an SGLT2 inhibitor last and AUC inf It is within 10% of the

[0033] In some embodiments, a daily dose of the MR modulator ranging from about 15 mg to about 40 mg and a daily dose of the SGLT2 inhibitor of about 10 mg are administered. In some embodiments, administration is once daily. In some embodiments, the pharmaceutical composition or oral dosage form is administered to a subject in a fasting state. In some embodiments, the subject's AUC last and AUC inf is the AUC of subjects administered separate dosage forms of an MR modulator and an SGLT2 inhibitor last and AUC inf It is within 10% of the

[0034] In some embodiments, a daily dose of AZD9977 ranging from about 15 mg to about 40 mg and a daily dose of the SGLT2 inhibitor of about 10 mg are administered. In some embodiments, administration is once daily. In some embodiments, the pharmaceutical composition or oral dosage form is administered to a subject in a fasting state. In some embodiments, the subject's AUC last and AUC inf is the AUC of subjects administered separate dosage forms of an MR modulator and an SGLT2 inhibitor last and AUC inf It is within 10% of the [Brief explanation of the drawings]

[0035] The following drawings form part of the present specification and are included to further demonstrate illustrative embodiments of certain aspects of the present disclosure. [Figure 1A]

[0023] Figure 1A shows the results of in vitro dissolution testing of fixed-dose combination (FDC) capsules comprising AZD9977 and dapagliflozin, as described in embodiments herein. Figure 1A shows the in vitro dissolution profile of dapagliflozin tested at 100 rpm in USP Apparatus 1. Figure 1B shows the in vitro dissolution profile of AZD9977 tested at 100 rpm in USP Apparatus 2. Figure 1C shows the in vitro dissolution profile of AZD9977 tested at 100 rpm in USP Apparatus 1. [Figure 1B]

[0023] Figure 1A shows the results of in vitro dissolution testing of fixed-dose combination (FDC) capsules comprising AZD9977 and dapagliflozin, as described in embodiments herein. Figure 1A shows the in vitro dissolution profile of dapagliflozin tested at 100 rpm in USP Apparatus 1. Figure 1B shows the in vitro dissolution profile of AZD9977 tested at 100 rpm in USP Apparatus 2. Figure 1C shows the in vitro dissolution profile of AZD9977 tested at 100 rpm in USP Apparatus 1. [Figure 1C]

[0023] Figure 1A shows the results of in vitro dissolution testing of fixed-dose combination (FDC) capsules comprising AZD9977 and dapagliflozin, as described in embodiments herein. Figure 1A shows the in vitro dissolution profile of dapagliflozin tested at 100 rpm in USP Apparatus 1. Figure 1B shows the in vitro dissolution profile of AZD9977 tested at 100 rpm in USP Apparatus 2. Figure 1C shows the in vitro dissolution profile of AZD9977 tested at 100 rpm in USP Apparatus 1. [Figure 2A]

[0023] Figure 2 shows exemplary pharmaceutical compositions and their components described in embodiments herein. Figure 2A shows single-active dosage forms and pellets of AZD9977 and dapagliflozin. Figure 2B shows a schematic diagram of a clinical trial to evaluate the bioavailability of FDC capsules compared to single-active dosage forms, as described in Example 3. [Figure 2B]

[0023] Figure 2 shows exemplary pharmaceutical compositions and their components described in embodiments herein. Figure 2A shows single-active dosage forms and pellets of AZD9977 and dapagliflozin. Figure 2B shows a schematic diagram of a clinical trial to evaluate the bioavailability of FDC capsules compared to single-active dosage forms, as described in Example 3. [Figure 3A] Figures 3A and 3B show mean plasma AZD9977 concentration versus time curves for subjects in the clinical trial described in Example 3. Figure 3A shows the results on a linear scale. Figure 3B shows the results on a semi-logarithmic scale. [Figure 3B] Figures 3A and 3B show mean plasma AZD9977 concentration versus time curves for subjects in the clinical trial described in Example 3. Figure 3A shows the results on a linear scale. Figure 3B shows the results on a semi-logarithmic scale. [Figure 4A] 1 shows a statistical comparison of pharmacokinetic parameters of AZD9977 in Group 1 (fasted) of the clinical trial described in Example 3. [Figure 4B] 1 shows a statistical comparison of pharmacokinetic parameters of AZD9977 in Group 1 (fed / fasted) of the clinical trial described in Example 3. [Figure 5A] 1 shows a statistical comparison of pharmacokinetic parameters of AZD9977 in Group 2 of the clinical trial described in Example 3. [Figure 5B] 1 shows a statistical comparison of pharmacokinetic parameters of AZD9977 for the same variant of AZD9977 provided in different capsules under fasting conditions across groups of the clinical trial described in Example 3. [Figure 6A] 6A and 6B show geometric mean plasma dapagliflozin concentration versus time curves for subjects in the clinical trial described in Example 3. Figure 6A shows the results on a linear scale. Figure 6B shows the results on a semi-logarithmic scale. [Figure 6B] 6A and 6B show geometric mean plasma dapagliflozin concentration versus time curves for subjects in the clinical trial described in Example 3. Figure 6A shows the results on a linear scale. Figure 6B shows the results on a semi-logarithmic scale. [Figure 7A] 1 shows a statistical comparison of pharmacokinetic parameters of dapagliflozin in Group 1 (fasting) of the clinical trial described in Example 3. [Figure 7B] 1 shows a statistical comparison of pharmacokinetic parameters of dapagliflozin in Group 1 (fed / fasted) of the clinical trial described in Example 3. [Figure 8A] 1 shows a statistical comparison of pharmacokinetic parameters of dapagliflozin in Group 2 of the clinical trial described in Example 3. [Figure 8B] 1 shows a statistical comparison of the pharmacokinetic parameters of dapagliflozin for the same variant of AZD9977 provided in different capsules under fasting conditions across arms of the clinical trial described in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0036] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0037] As used herein, "about" can mean plus or minus 10% of the value provided. When ranges are provided, they are inclusive of the limits. "About" can additionally or alternatively mean either within 10% of the stated value, or within 5% of the stated value, or in some cases within 2.5% of the stated value, or "about" can mean rounded to the nearest significant figure.

[0038] As used herein, "between" refers to a range that includes both ends of the range. For example, a number between x and y explicitly includes the numbers x and y, as well as any number that falls within x and y.

[0039] The mineralocorticoid receptor (MR) is a ligand-activated transcription factor belonging to the oxysteroid nuclear hormone receptor class. MR activation by aldosterone in renal tubules and epithelial cells plays a central role in blood pressure regulation. MR activation in non-epithelial tissues promotes target organ dysfunction by stimulating inflammation, oxidative stress, and fibrosis. Furthermore, pathological activation of MR leads to an increased risk of cardiovascular events. See, for example, Bamberg et al., PLoS One 13(2):e0193380, 2018. As used herein, "MR modulator" refers to a compound that can reduce MR activation, for example, by blocking and / or preventing MR binding to agonists. In some embodiments, the MR modulator of the pharmaceutical compositions described herein comprises an MR antagonist. Non-limiting examples of MR antagonists include spironolactone, eplerenone, canrenone, progesterone, drospirenone, gestodene, and benidipine. In some embodiments, the MR antagonist antagonizes MR in epithelial and non-epithelial tissues. In some embodiments, the MR modulator of the pharmaceutical compositions described herein comprises a selective MR modulator. In some embodiments, the selective MR modulator can antagonize MR in non-epithelial cells but does not substantially affect MR activation in epithelial cells. Non-limiting examples of selective MR modulators include finerenone and AZD9977. AZD9977 or valsinrenone is further described, for example, in WO 2016 / 001631 and is a compound of Formula I:

[0040] [ka]

[0041] Sodium-glucose cotransporter-2 (SGLT2) is the main cotransporter involved in glucose reabsorption in the kidney. As used herein, "SGLT2 inhibitors" (also called gliolidine or fluozin) inhibit SGLT2 activity. In some embodiments, SGLT2 inhibitors inhibit glucose reabsorption in the kidney, thereby lowering blood glucose. SGLT2 inhibitors can slow the progression of kidney disease, reduce HF, and lower the risk of kidney failure and death in subjects with CKD and kidney disease and type 2 diabetes. For example, "SGLT2 inhibitors" are listed in the National Kidney Foundation (<kidney.org / atoz / content / SGLT2-inhibitors> (Accessed June 2022). In some embodiments, the SGLT2 inhibitor of the pharmaceutical compositions described herein comprises canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, or a combination thereof. In some embodiments, the SGLT2 inhibitor comprises a solvated form of canagliflozin, dapagliflozin, empagliflozin, and / or ertugliflozin. In some embodiments, the SGLT2 inhibitor is in a non-crystalline form (e.g., an amorphous form) or a crystalline form. In some embodiments, the SGLT2 inhibitor comprises dapagliflozin propanediol. In some embodiments, "dapagliflozin propanediol" refers to a solvated form of dapagliflozin comprising dapagliflozin, S-(+)-1,2-propanediol, and water in a 1:1:1 ratio. In some embodiments, the theoretical amount of dapagliflozin as the unsolvated form is about 81.29% (w / w) of dapagliflozin propanediol.

[0042] In some embodiments, the present disclosure provides a combination of an MR modulator and an SGLT2 inhibitor in a single dosage form, also referred to as a "fixed-dose combination" or FDC formulation, that is useful for the treatment of HF and / or CKD. In some embodiments, an FDC formulation comprising an MR modulator and an SGLT2 inhibitor provides a greater therapeutic benefit compared to each active ingredient alone. In some embodiments, administration of an FDC formulation comprising an MR modulator and an SGLT2 inhibitor provides a greater therapeutic benefit compared to co-administration of the MR modulator and the SGLT2 inhibitor in separate dosage forms containing a single active ingredient.

[0043] Challenges in developing FDC formulations include, for example, ensuring that the active ingredients in the FDC formulation are physicochemically compatible, preventing undesirable mechanical powder flow and compaction properties of multi-active ingredient blends, and providing a reasonable dosage form size.

[0044] In some embodiments, the FDC formulations provided herein contain two active ingredients that belong to different categories according to the Biopharmaceutics Classification System (BCS), e.g., AZD9977 and dapagliflozin. AZD9977 is a Class 4 drug, characterized by low solubility and low permeability. Dapagliflozin is a BCS Class 3 drug, characterized by high solubility, rapid dissolution, and low permeability. Thus, a particular challenge in developing FDC formulations containing AZD9977 and dapagliflozin is ensuring that the active ingredients have comparable in vitro dissolution and in vivo bioavailability compared to that observed for single-active ingredient formulations. Additionally, while a high drug load of AZD9977 (e.g., about 50 to about 200 mg, or about 120 to about 180 mg in the dosage form, or about 140 to about 160 mg, or about 50 mg or 150 mg in the dosage form) is desired, dosage form size should be maintained at a size that does not interfere with patient compliance. In some embodiments, the FDC formulation is provided in a size 0, size 1, e.g., size 1E hard gelatin capsule.

[0045] To address this issue, a composition is provided herein that includes a first active ingredient, e.g., an MR modulator, in a first pellet and a second active ingredient, e.g., an SGLT2 inhibitor, in a second pellet. In some embodiments, the first and second pellets, each containing the first and second active ingredients, e.g., an MR modulator and an SGLT2 inhibitor, respectively, each include a core and a coating coated on the core. By adjusting the amount and type of components in each coating according to the physicochemical properties, e.g., the solubility, reactivity, and / or stability, of the active ingredients therein, a desired drug loading and dissolution profile for each active ingredient was achieved.

[0046] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) one or more first pellets, the first pellet comprising (i) a first core and (ii) a first coating on the first core, the first coating comprising a mineralocorticoid receptor (MR) modulator and a first binder comprising povidone; and (b) one or more second pellets, the second pellet comprising (i) a second core and (ii) a second coating on the second core, the second coating comprising an SGLT2 inhibitor, the SGLT2 inhibitor comprising about 5% to about 20% by weight of the second pellet, the composition comprising about 20% to about 50% by weight of the mineralocorticoid receptor (MR) modulator and about 1% to about 10% by weight of the SGLT2 inhibitor. In some embodiments, the disclosure provides an oral dosage form comprising the pharmaceutical composition described herein. In some embodiments, the oral dosage form is a capsule, caplet, or tablet. In some embodiments, the oral dosage form is a capsule. In some embodiments, the capsule is a size 000, 00, 00EL, 0, 1, 2, or 3 gelatin capsule. In some embodiments, the capsule is a size 0 gelatin capsule. In some embodiments, the capsule is a size 1 gelatin capsule, such as a 1E gelatin capsule.

[0047] First pellet In some embodiments, the first pellet of the composition comprises a first core and a first coating on the first core. In some embodiments, the first coating comprises an MR modifier and a first binder. In some embodiments, the first coating comprises an MR modifier, a first binder, and a lubricant.

[0048] In some embodiments, the first coating comprises an MR modulating agent. Exemplary MR modulating agents are provided herein. In some embodiments, the MR modulating agent comprises an MR antagonist, a selective MR modulating agent, or a combination thereof. In some embodiments, the MR modulating agent comprises spironolactone, eplerenone, canrenone, progesterone, drospirenone, gestodene, benidipine, finerenone, AZD9977, or a combination thereof. In some embodiments, the MR modulating agent comprises AZD9977 (valcinrenone).

[0049] In some embodiments, the MR modulator is about 20% to about 60% by weight, or about 25% to about 55% by weight, or about 20% to about 50% by weight, or about 30% to about 50% by weight, or about 35% to about 48% by weight, or about 40% to about 45% by weight of the composition. In some embodiments, the MR modulator is about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% by weight of the composition.

[0050] In some embodiments, the MR modulator comprises AZD9977. In some embodiments, the composition comprises about 20% to about 60% by weight of AZD9977. In some embodiments, the composition comprises about 25% to about 55% by weight of AZD9977. In some embodiments, the composition comprises about 20% to about 50% by weight of AZD9977. In some embodiments, the composition comprises about 25% to about 45% by weight of AZD9977. In some embodiments, the composition comprises about 40% to about 45% by weight of AZD9977. In some embodiments, the composition comprises about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% by weight of AZD9977. In some embodiments, the composition comprises about 28% by weight of AZD9977. In some embodiments, the composition comprises about 43% by weight of AZD9977.

[0051] In some embodiments, the first coating comprises a first binder. As used herein, "binder" refers to an excipient that holds together the components of the composition, such as powders, granules, and other dry ingredients. Non-limiting examples of binders that can be used in the compositions described herein include gelatin; cellulose and its derivatives, such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose (also referred to herein as "hypromellose" or "HPMC"), hydroxypropylcellulose, hydroxyethylcellulose, croscarmellose sodium; polyvinylpyrrolidone (also referred to herein as "povidone" or "PVP"); starch (e.g., corn, potato, and rice); sugars and their derivatives, such as pregelatinized starch, sucrose, and lactose; sugar alcohols, such as mannitol; sweeteners, such as isomalt; and polyethylene glycol (PEG), polyethylene oxide (PEO), and combinations thereof.

[0052] In some embodiments, the first binder is present in an amount of about 1% to about 20% by weight, or about 2% to about 15% by weight, or about 3% to about 10% by weight, or about 4% to about 8% by weight, or about 6% to about 7% by weight of the composition. In some embodiments, the first binder is present in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight of the composition. In some embodiments, the first binder is present in an amount of about 4.2%, about 6%, about 6.32%, or about 6.5% by weight of the composition. In some embodiments, the first binder comprises povidone, hypromellose, or a combination thereof.

[0053] In some embodiments, the first binder comprises povidone. In some embodiments, the composition comprises about 1% to about 20% by weight of povidone. In some embodiments, the composition comprises about 2% to about 15% by weight of povidone. In some embodiments, the composition comprises about 3% to about 10% by weight of povidone. In some embodiments, the composition comprises about 4% to about 8% by weight of povidone. In some embodiments, the composition comprises about 6% to about 7% by weight of povidone. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight of povidone. In some embodiments, the composition comprises about 6.0%, about 6.1%, about 6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%, or about 7% by weight of povidone. In some embodiments, the composition comprises about 4.2% by weight of povidone. In some embodiments, the composition comprises about 6.5% by weight of povidone.

[0054] In some embodiments, the first binder comprises povidone and hypromellose. In some embodiments, the composition comprises about 1% to about 10% by weight of povidone, or about 2% to about 8% by weight of povidone, or about 3% to about 7% by weight of povidone, or about 4% to about 6% by weight of povidone. In some embodiments, the composition comprises about 4.50%, about 4.55%, about 4.60%, about 4.65%, about 4.70%, about 4.75%, about 4.80%, about 4.85%, about 4.90%, about 4.95%, about 5.00%, about 5.05%, about 5.10%, about 5.15%, about 5.20%, about 5.25%, about 5.30%, about 5.35%, about 5.40%, about 5.45%, or about 5.50% povidone. In some embodiments, the composition comprises from about 0.1% to about 5% by weight of hypromellose, or from about 0.5% to about 3% by weight of hypromellose, or from about 0.7% to about 2% by weight of hypromellose, or from about 0.8% to about 1% by weight of hypromellose.

[0055] In some embodiments, the composition comprises about 1% to about 10% by weight of povidone, or about 2% to about 8% by weight of povidone, or about 3% to about 7% by weight of povidone, or about 5% by weight of povidone and about 1% by weight of hypromellose. In some embodiments, the composition comprises about 5% by weight of povidone and about 0.1% to about 10% by weight of hypromellose, or about 0.5% to about 3% by weight of hypromellose, or about 0.7% to about 2% by weight of hypromellose, or about 0.8% to about 1% by weight of hypromellose. In some embodiments, the composition comprises about 5% by weight of povidone and about 1% by weight of hypromellose. In some embodiments, the composition comprises about 5.35% by weight of povidone and about 0.97% by weight of hypromellose. In some embodiments, the composition comprises about 4.7% povidone and about 0.85% hypromellose.

[0056] In some embodiments, the first coating further comprises a first lubricant, a solvent, or a combination thereof. In some embodiments, the solvent comprises water. In some embodiments, the solvent is present before the first coating is applied to the first core and is removed (e.g., evaporated) when the first coating is applied to the first core. As used herein, a "lubricant" is a pharmaceutical excipient that can reduce friction between other ingredients and inhibit particle aggregation. Non-limiting examples of lubricants include sodium stearyl fumarate, hydroxypropyl cellulose, hydrogenated vegetable oil, silicon dioxide, stearic acid, magnesium stearate, calcium stearate, stearyl alcohol, talc, silica, glyceride esters such as glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate, and sugar esters such as sorbitan monostearate and sucrose monopalmitate, and combinations thereof.

[0057] In some embodiments, the first lubricant comprises sodium stearyl fumarate. In some embodiments, the first lubricant comprises 0% to about 1%, or about 0.01% to about 0.8%, or about 0.01% to about 0.5%, or about 0.1% to about 0.4%, or about 0.3% to about 0.35% by weight of the composition. In some embodiments, the composition comprises about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, or about 0.5% by weight of sodium stearyl fumarate. In some embodiments, the composition comprises about 0.1% by weight of sodium stearyl fumarate. In some embodiments, the composition comprises about 0.15% by weight of sodium stearyl fumarate.

[0058] In some embodiments, the composition comprises a first pellet, the first pellet having a first coating comprising: about 20 wt% to about 50 wt% of an MR regulator; about 1% by weight to about 10% by weight of a first binder; optionally, about 0.01% to about 0.5% by weight of a first lubricant; All weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0059] In some embodiments, the first coating described herein is coated on the first core. In some embodiments, the first core is pharmaceutically inactive, i.e., does not substantially react with any other components in the composition described herein. In some embodiments, the first core can be selected from, for example, microcrystalline cellulose, sucrose, isomalt, calcium phosphate (e.g., anhydrous calcium hydrogen phosphate), tartaric acid, silica, xylitol, mannitol, lactose, calcium carbonate, starch, silicon dioxide, non-pareil core, or a combination thereof.

[0060] In some embodiments, the first core comprises about 10% to about 50% by weight, or about 10% to about 40% by weight, or about 10% to about 30% by weight, or about 15% to about 30% by weight, or about 15% to about 25% by weight, or about 20% to about 24% by weight of the composition. In some embodiments, the first core comprises about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% by weight of the composition. In some embodiments, the first core comprises microcrystalline cellulose. In some embodiments, the composition comprises about 14.4%, about 21.1%, or about 22.3% by weight of microcrystalline cellulose.

[0061] In some embodiments, the composition comprises a first pellet comprising: a first coating, about 20% to about 60% by weight, or about 25% to about 55% by weight, or about 30% to about 50% by weight, or about 35% to about 48% by weight, or about 40% to about 45% by weight of an MR regulator; about 1% to about 20% by weight, or about 2% to about 15% by weight, or about 3% to about 10% by weight, or about 4% to about 8% by weight, or about 6% to about 7% by weight of povidone; a first coating optionally comprising about 0.01% to about 0.5%, or about 0.08% to about 0.5%, or about 0.1% to about 0.5%, or about 0.2% to about 0.4%, or about 0.3% to about 0.35% by weight of sodium stearyl fumarate; A first core, a first core comprising about 10% to about 50% by weight, or about 12% to about 40% by weight, or about 15% to about 30% by weight, or about 15% to about 25% by weight, or about 20% to about 24% by weight, or about 21% by weight, or about 23% by weight of microcrystalline cellulose; wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0062] In some embodiments, the composition comprises a first pellet comprising: a first coating, Approximately 20 to 30% by weight of an MR regulator; a first coating comprising about 4-5% by weight of povidone; a first core comprising about 10-15% by weight of microcrystalline cellulose; wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0063] In some embodiments, the composition comprises a first pellet comprising: a first coating, Approximately 40-45 wt. % of an MR modifier; a first coating comprising about 6-7% by weight of povidone; a first core comprising about 20-25% by weight of microcrystalline cellulose; wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0064] In some embodiments, the composition comprises a first pellet comprising: a first coating, about 20% to about 60% by weight, or about 25% to about 55% by weight, or about 30% to about 50% by weight, or about 35% to about 48% by weight, or about 40% to about 45% by weight of an MR regulator; a first coating comprising about 1% to about 10%, or about 2% to about 8%, or about 3% to about 7%, or about 4% to about 6% by weight of povidone; A first core, a first core comprising about 10% to about 50% by weight, or about 12% to about 40% by weight, or about 15% to about 30% by weight, or about 15% to about 25% by weight, or about 20% to about 24% by weight, or about 21% by weight, or about 23% by weight of microcrystalline cellulose; wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0065] In some embodiments, the composition comprises a first pellet comprising: a first coating, about 28 wt. % of an MR modifier; a first coating comprising about 4.2% by weight of povidone; a first core comprising about 14.4% by weight of microcrystalline cellulose; wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0066] In some embodiments, the composition comprises a first pellet comprising: a first coating, about 43 wt. % of an MR modifier; a first coating comprising about 6.5% by weight of povidone; a first core comprising about 22.3% by weight of microcrystalline cellulose; wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0067] Second pellet In some embodiments, a second pellet of the composition comprises a second core and a second coating on the second core. In some embodiments, the second coating comprises an SGLT2 inhibitor and a second binder. In some embodiments, the second coating comprises an SGLT2 inhibitor, a second binder, an anti-adherent agent, and optionally a second lubricant.

[0068] In some embodiments, the second coating comprises an SGLT2 inhibitor. Exemplary SGLT2 inhibitors are provided herein. In some embodiments, the SGLT2 inhibitor comprises canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, or a combination thereof. In some embodiments, the SGLT2 inhibitor comprises dapagliflozin or a solvate thereof. Dapagliflozin solvates are further described herein. In some embodiments, the SGLT2 inhibitor comprises dapagliflozin propanediol.

[0069] In some embodiments, the SGLT2 inhibitor is about 1% to about 10% by weight, or about 2% to about 8% by weight, or about 2.5% to about 7.5% by weight, or about 3% to about 7% by weight of the composition. In some embodiments, the SGLT2 inhibitor is about 2% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, about 2.5% by weight, about 2.5% by weight, about 2.6% by weight, about 2.7% by weight, about 2.8% by weight, about 2.9% by weight, about 3% by weight, about 3.1% by weight, about 3.2% by weight, about 3.3% by weight, about 3.4% by weight, about 3.5% by weight, about 3.6% by weight, about 3.7% by weight, about 3.8% by weight, about 3.9% by weight, about 4% by weight, about 4.1% by weight, about 4.2% by weight, or about 4. 3% by weight, about 4.4% by weight, about 4.5% by weight, about 4.6% by weight, about 4.7% by weight, about 4.8% by weight, about 4.9% by weight, about 5% by weight, about 5.1% by weight, about 5.2% by weight, about 5.3% by weight, about 5.4% by weight, about 5.5% by weight, about 5.6% by weight, about 5.7% by weight, about 5.8% by weight, about 5.9% by weight, about 6% by weight, about 6.1% by weight, about 6.2% by weight, about 6.3% by weight, about 6.4% by weight, about 6.5% by weight, about 6.6% by weight, about 6.7% by weight, about 6.8% by weight, about 6.9% by weight, or about 7% by weight.

[0070] In some embodiments, the SGLT2 inhibitor comprises dapagliflozin or a solvate thereof. In some embodiments, the SGLT2 inhibitor comprises dapagliflozin propanediol. In some embodiments, the composition comprises about 1% to about 10% by weight of dapagliflozin or a solvate thereof. In some embodiments, the composition comprises about 2% to about 8% by weight of dapagliflozin or a solvate thereof. In some embodiments, the composition comprises about 2.5% to about 4.5% by weight of dapagliflozin or a solvate thereof. In some embodiments, the composition comprises about 3% to about 4% by weight of dapagliflozin or a solvate thereof. In some embodiments, the composition comprises about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, or about 5% by weight of dapagliflozin or a solvate thereof. In some embodiments, the composition comprises about 3.6% by weight of dapagliflozin propanediol.In some embodiments, the composition comprises about 6.9% by weight of dapagliflozin propanediol.

[0071] In some embodiments, the second coating further comprises a second binder, an anti-adherent, and a second lubricant. As used herein, a "lubricant" is a pharmaceutical excipient that can reduce friction between other ingredients and inhibit particle aggregation. Non-limiting examples of lubricants include sodium stearyl fumarate, hydroxypropyl cellulose, hydrogenated vegetable oil, silicon dioxide, stearic acid, magnesium stearate, calcium stearate, stearyl alcohol, talc, silica, glyceride esters such as glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate, and sugar esters such as sorbitan monostearate and sucrose monopalmitate, and combinations thereof.

[0072] In some embodiments, the second coating comprises a second binder. Exemplary binders are further described herein. In some embodiments, the second binder comprises about 0.05% to about 10% by weight of the composition. In some embodiments, the second binder comprises about 0.1% to about 5% by weight of the composition. In some embodiments, the second binder comprises about 0.2% to about 0.8% by weight of the composition. In some embodiments, the second binder comprises about 0.4% to about 0.5% by weight of the composition. In some embodiments, the second binder comprises about 0.4%, about 0.41%, about 0.42%, about 0.43%, about 0.44%, about 0.45%, about 0.46%, about 0.47%, about 0.48%, about 0.49%, or about 0.5% by weight of the composition. In some embodiments, the second binder comprises hydroxypropyl cellulose. In some embodiments, the composition comprises about 0.5% hydroxypropyl cellulose, hi some embodiments, the composition comprises about 1% hydroxypropyl cellulose.

[0073] In some embodiments, the second coating comprises an anti-adherent. As used herein, an "anti-adherent" is an excipient that prevents particles from agglomerating, for example, by absorbing moisture. Non-limiting examples of anti-adherent agents include tricalcium phosphate, magnesium trisilicate, calcium carbonate, magnesium carbonate, talc (also known as cosmetic powder or hydrated magnesium silicate), powdered cellulose, sodium bicarbonate, sodium silicate, calcium silicate, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, colloidal silica, and polydimethylsiloxane, and combinations thereof.

[0074] In some embodiments, the anti-blocking agent comprises talc. In some embodiments, the anti-blocking agent is present in an amount of about 1% to about 20%, about 1% to about 15%, about 1% to about 12%, about 3% to about 10%, or about 7% to about 9% by weight of the composition. In some embodiments, the anti-blocking agent is present in an amount of about 7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, or about 9% by weight of the composition. In some embodiments, the composition comprises about 7.8% talc by weight. In some embodiments, the anti-blocking agent is about 14%, about 14.1%, about 14.2%, about 14.3%, about 14.4%, about 14.5%, about 14.6%, about 14.7%, about 14.8%, about 14.9%, about 15%, about 15.1%, about 15.2%, about 15.3%, about 15.4%, about 15.5%, about 15.6%, about 15.7%, about 15.8%, about 15.9%, or about 16% by weight of the composition. In some embodiments, the composition comprises about 15.1% talc.

[0075] In some embodiments, the second coating may include a second lubricant, a solvent, or a combination thereof. In some embodiments, the solvent includes water. In some embodiments, the solvent is present before the second coating is coated onto the second core and is removed (e.g., evaporated) when the second coating is coated onto the second core. Exemplary lubricants are further described herein. In some embodiments, the second lubricant is present in an amount of 0% to about 1%, or about 0.05% to about 0.5%, or about 0.08% to about 0.3%, or about 0.1% to about 0.2% by weight of the composition. In some embodiments, the second lubricant is about 0.1%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, or about 0.2% by weight of the composition. In some embodiments, the second lubricant comprises sodium stearyl fumarate. In some embodiments, the composition comprises about 0.1% by weight of sodium stearyl fumarate. In some embodiments, the composition comprises about 0.6% by weight of sodium stearyl fumarate.

[0076] In some embodiments, the composition is a second pellet, the second coating comprising: about 1% by weight to about 30% by weight of an SGLT2 inhibitor; about 0.1 wt % to about 5 wt % of a second binder; about 1% by weight to about 20% by weight of an anti-blocking agent; optionally, about 0.01% to about 1% by weight of a second lubricant; and a second pellet comprising a second coating comprising:

[0077] In some embodiments, the composition is a second pellet, the second coating comprising: about 1% to about 30% by weight of an SGLT2 inhibitor, which is about 10% to about 15% by weight, or about 12% to about 14% by weight of the second pellet; about 0.5% by weight to about 1% by weight of a second binder; about 5% to about 15% by weight of an anti-blocking agent; optionally, about 0.05% to about 0.1% by weight of a second lubricant; and wherein all weights are by weight of the composition. In some embodiments, the SGLT2 inhibitor is dapagliflozin propanediol.

[0078] In some embodiments, a second coating described herein is coated onto the second core. In some embodiments, the second core is pharmaceutically inactive as described herein. In some embodiments, the second core comprises microcrystalline cellulose, sucrose, isomalt, calcium phosphate (e.g., anhydrous calcium hydrogen phosphate), tartaric acid, silica, xylitol, mannitol, lactose, calcium carbonate, starch, silicon dioxide, or a combination thereof. In some embodiments, the second core is a sugar core. Sugar cores, also known as "neutral pellets," "nonpareil cores," "sugar spheres," or "sugar beads," comprise a combination of sugar, such as sucrose and starch. Exemplary sugar cores include, but are not limited to, those commercially available under the trade names SUGLETS®, SANAQ®, and VIVAPHARM® Sugar Spheres.

[0079] In some embodiments, the second core is about 5% to about 40% by weight of the composition, or about 10% to about 40% by weight, or about 10% to about 30% by weight, or about 10% to about 22% by weight, or about 10% to about 15% by weight, or about 11% to about 13% by weight, or about 20% to about 25% by weight, or about 21% to about 23% by weight. In some embodiments, the secondary core comprises about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of the composition. In some embodiments, the secondary core comprises about 15.8% by weight of the composition. In some embodiments, the secondary core comprises about 30.6% by weight of the composition. In some embodiments, the secondary core comprises a sugar, a starch, or a combination thereof. In some embodiments, the secondary core is a sugar core.

[0080] In some embodiments, the composition is a second pellet comprising: a second coating, about 1% to about 10% by weight, or about 2% to about 5% by weight, or about 2.5% to about 4.5% by weight, or about 3% to about 4% by weight of an SGLT2 inhibitor, which is about 6% to about 15% by weight of the second pellet; about 0.1% to about 5% by weight, or about 0.1% to about 2.5% by weight, or about 0.25% to about 1.5% by weight, or about 0.5% to about 1% by weight of hydroxypropyl cellulose; about 1% to about 20% by weight, about 1% to about 17.5% by weight, about 5% to about 15% by weight, about 7% to about 10% by weight, or about 7% to about 9% by weight of talc; optionally, a second coating comprising about 0.01% to about 1%, or about 0.05% to about 1%, or about 0.06% to about 0.5%, or about 0.06% to about 0.1% by weight of sodium stearyl fumarate; a second core, a second core comprising about 5% to about 40% by weight, or about 10% to about 40% by weight, or about 15% to about 30% by weight of a sugar core; and a second pellet comprising:

[0081] In some embodiments, the composition is a second pellet comprising: a second coating, about 3.6% by weight of an SGLT2 inhibitor, which is about 5% to about 15% by weight of the second pellet; about 0.5% by weight of hydroxypropyl cellulose; about 7.8% by weight of talc; optionally, a second coating comprising about 0.06% sodium stearyl fumarate; a second core comprising about 15.8% by weight of a sugar core; and a second pellet comprising:

[0082] In some embodiments, the composition is a second pellet comprising: a second coating, about 6.9% by weight of an SGLT2 inhibitor, which is about 5% to about 15% by weight of the second pellet; about 1% by weight of hydroxypropyl cellulose; About 15% by weight of talc; optionally, a second coating comprising about 0.1% sodium stearyl fumarate; a second core comprising about 30.5% by weight of a sugar core; and a second pellet comprising:

[0083] combination drug In some embodiments, the composition comprising the first and second pellets described herein is contained in a single dosage form. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule or a tablet.

[0084] In some embodiments, the MR modulator of the pharmaceutical composition described herein comprises AZD9977 and the SGLT2 inhibitor of the pharmaceutical composition comprises dapagliflozin or a solvate thereof. In some embodiments, AZD9977 is comprised in a first pellet described herein and dapagliflozin or a solvate thereof is comprised in a second pellet described herein.

[0085] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets, i. a first core comprising a microcrystalline cellulose core, the first core comprising about 5% to about 25% by weight of the capsule; ii. a first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 constitutes about 10% to about 45% by weight of the capsule; (B) povidone that constitutes about 1% to about 10% by weight of the capsule; and (C) sodium stearyl fumarate, in an amount of about 0.01% to about 1% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets, i. a second core comprising sugar spheres, wherein the sugar spheres comprise about 5% to about 30% by weight of the capsule; ii. a second coating, (A) an SGLT2 inhibitor that is dapagliflozin propanediol, wherein the dapagliflozin propanediol is about 1% to about 10% by weight of the capsule; (B) hydroxypropyl cellulose that is about 0.1% to about 1% by weight of the capsule; (C) talc that is about 1% to about 15% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.01% to about 0.1% by weight of the capsule; a second coating comprising: and a second pellet comprising: In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0086] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets, i. a first core comprising a microcrystalline cellulose core, the first core being about 5% to about 20% by weight of the capsule; ii. a first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 constitutes about 15% to about 40% by weight of the capsule; (B) povidone that constitutes about 2% to about 6% by weight of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.02% to about 0.4% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets, i. a second core comprising sugar spheres, wherein the sugar spheres comprise about 10% to about 22% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin, wherein the dapagliflozin constitutes about 2% to about 5% by weight of the capsule; (B) hydroxypropyl cellulose that constitutes about 0.4% to about 0.6% by weight of the capsule; (C) talc that constitutes about 5% to about 12% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.02% to about 0.08% by weight of the capsule; a second coating comprising: and a second pellet comprising: In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0087] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets, i. a first core comprising a microcrystalline cellulose core, the first core being about 18% by weight of the capsule; ii. A first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 is about 35% by weight of the capsule; (B) povidone that is about 5.3% by weight of the capsule; and (C) sodium stearyl fumarate, in an amount of about 0.12% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets, i. a second core comprising sugar spheres, wherein the sugar spheres are about 12.8% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin, wherein the dapagliflozin is about 2.9% by weight of the capsule; (B) hydroxypropyl cellulose that is about 0.38% by weight of the capsule; (C) talc that is about 6.3% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.04% by weight of the capsule; a second coating comprising: and a second pellet comprising: In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0088] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets, i. a first core comprising a microcrystalline cellulose core, the first core being about 9.9% by weight of the capsule; ii. a first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 is about 19.2% by weight of the capsule; (B) povidone that is about 2.9% by weight of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.06% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets, i. a second core comprising sugar spheres, wherein the sugar spheres constitute about 21% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin, wherein the dapagliflozin is about 4.7% by weight of the capsule; (B) hydroxypropyl cellulose that is about 0.63% by weight of the capsule; (C) talc that is about 10.4% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.07% by weight of the capsule; a second coating comprising: and a second pellet comprising: In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0089] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets, i. a first core comprising a microcrystalline cellulose core, the first core comprising about 5% to about 25% by weight of the capsule; ii. A first coating comprising: (A) An MR regulator which is AZD9977, wherein the AZD9977 accounts for about 10% to about 45% by weight of the capsule; (B) povidone, which is about 2% to about 8% by weight of the capsule; (C) hypromellose, which is about 0.5% to about 3% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.01% to about 0.5% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets, i. a second core comprising sugar spheres, the second core comprising about 5% to about 30% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor which is dapagliflozin propanediol, wherein the dapagliflozin propanediol accounts for about 1% by weight to about 10% by weight of the capsule and about 5% by weight to about 20% by weight of the second pellet; (B) hydroxypropyl cellulose, which is about 0.1% to about 1% by weight of the capsule; (C) talc, which is about 1% to about 15% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.01% to about 0.1% by weight of the capsule; a second coating comprising: and a second pellet comprising: In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0090] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets, i. a first core comprising a microcrystalline cellulose core, the first core being about 23.9% by weight of the capsule; ii. a first coating comprising: (A) an MR modulator which is AZD9977, wherein the AZD9977 is about 45.3% by weight of the capsule; (B) povidone, in an amount of about 5.35% by weight of the capsule; (C) hypromellose, in an amount of about 0.97% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.34% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets, i. a second core comprising sugar spheres, the second core being about 11.7% by weight of the capsule; ii. (A) an SGLT2 inhibitor that is dapagliflozin propanediol, wherein the dapagliflozin propanediol is about 3.7% by weight of the capsule and about 13.2% by weight of a second pellet; (B) hydroxypropyl cellulose that is about 0.48% by weight of the capsule; (C) talc that is about 8.2% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.11% by weight of the capsule; a second coating comprising: and a second pellet comprising: In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0091] In some embodiments, the MR modulator of the pharmaceutical compositions described herein is AZD9977. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 200 mg of AZD9977. In some embodiments, the pharmaceutical composition comprises about 15 mg to about 100 mg of AZD9977. In some embodiments, the pharmaceutical composition comprises about 15 mg to about 40 mg of AZD9977. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 180 mg of AZD9977. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 150 mg of AZD9977. In some embodiments, the pharmaceutical composition comprises about 50 mg of AZD9977. In some embodiments, the pharmaceutical composition comprises about 150 mg of AZD9977.

[0092] In some embodiments, the SGLT2 inhibitor in the pharmaceutical compositions described herein is dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 5 mg to about 20 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 8 mg to about 18 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 15 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 10 mg of dapagliflozin propanediol.

[0093] In some embodiments, the pharmaceutical compositions described herein contain about 5 mg to about 20 mg of active equivalents of dapagliflozin. As used herein, "active equivalent" refers to the amount of the active ingredient, dapagliflozin, provided by a compound, e.g., a salt or solvate of the active ingredient. As used herein, dapagliflozin propanediol provides about 81.29% w / w active equivalent of dapagliflozin. In some embodiments, 12 mg of dapagliflozin propanediol provides the active equivalent of 10 mg of dapagliflozin.

[0094] In some embodiments, the pharmaceutical composition comprises an active equivalent amount of dapagliflozin of about 7 mg to about 17 mg. In some embodiments, the pharmaceutical composition comprises an active equivalent amount of dapagliflozin of about 8 mg to about 12 mg. In some embodiments, the pharmaceutical composition comprises an active equivalent amount of dapagliflozin of about 10 mg.

[0095] In some embodiments, the pharmaceutical compositions described herein comprise about 50 mg to about 200 mg of AZD9977 and about 5 mg to about 20 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions comprise about 50 mg to about 180 mg of AZD9977 and about 8 mg to about 18 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions comprise about 50 mg to about 150 mg of AZD9977 and about 10 mg to about 15 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions comprise about 50 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions comprise about 150 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the compositions are included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0096] In some embodiments, the pharmaceutical compositions described herein contain about 10 mg to about 50 mg of AZD9977 and about 5 mg to about 20 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions contain about 15 mg to about 45 mg of AZD9977 and about 8 mg to about 18 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions contain about 15 mg to about 50 mg of AZD9977 and about 10 mg to about 15 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions contain about 15 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions contain about 20 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical compositions contain about 25 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 30 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 35 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 40 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 45 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises about 50 mg of AZD9977 and about 10 mg of dapagliflozin propanediol. In some embodiments, the composition is comprised in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0097] Release Profile In some embodiments, the pharmaceutical compositions described herein advantageously provide equivalent release profiles for both the MR modulator, e.g., AZD9977, and the SGLT2 inhibitor, e.g., dapagliflozin or a solvate thereof. As described herein, AZD9977 is a BCS Class 4 drug due to its low solubility and low permeability, while dapagliflozin is a BCS Class 3 drug, i.e., a drug with high solubility, rapid dissolution, and low permeability. It has unexpectedly been discovered that by including the two active ingredients in separate pellets containing distinct excipients (e.g., a core, binder, lubricant, and / or anti-adherent agent described herein), the two active ingredients can be included in a single dosage form, such as a capsule or tablet described herein, with equivalent release profiles for both active ingredients. The advantages of combining two active ingredients in a single dosage form are further described herein.

[0098] In some embodiments, the pharmaceutical compositions or oral dosage forms described herein release substantially equal amounts of the MR modulator and the SGLT2 inhibitor. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin propanediol.

[0099] In some embodiments, at least 75-85% of the MR modulator is released from the pharmaceutical compositions or oral dosage forms described herein within a time range of about 15-30 minutes. In other embodiments, at least 75-85% of the SGLT2 inhibitor is released from the pharmaceutical compositions or oral dosage forms described herein within a time range of about 15-30 minutes. Dissolution profiles can be tested using dissolution techniques known to those skilled in the art, such as USP 1 at 100 rpm or USP 2 at 70 rpm.

[0100] In some embodiments, the pharmaceutical compositions or oral dosage forms described herein release at least 80% of the MR modifier contained therein within 60 minutes when tested at 100 rpm using USP 2. In some embodiments, the pharmaceutical compositions or oral dosage forms described herein release at least 80% of the MR modifier contained therein within 30 minutes when tested at 100 rpm using USP 2. In some embodiments, the MR modifier is AZD9977.

[0101] In some embodiments, the pharmaceutical compositions or oral dosage forms described herein release at least 80% of the SGLT2 inhibitor contained therein within 60 minutes when tested at 100 rpm using USP 1. In some embodiments, the pharmaceutical compositions or oral dosage forms described herein release at least 80% of the SGLT2 inhibitor contained therein within 30 minutes when tested at 100 rpm using USP 1. In some embodiments, the SGLT2 inhibitor is dapagliflozin propanediol.

[0102] method In some embodiments, the present disclosure provides a method of treating heart failure in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0103] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure in a subject in need thereof, the use comprising administering a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0104] In some embodiments, the present disclosure provides a method of treating chronic kidney disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0105] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating chronic kidney disease in a subject in need thereof, the use comprising administering a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0106] In some embodiments, the present disclosure provides a method of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0107] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need thereof, the use comprising administering a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0108] In some embodiments, the disclosure provides a method of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein, wherein the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0109] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need thereof, the use comprising administering a pharmaceutical composition comprising 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0110] In some embodiments, the present disclosure provides methods of treating heart failure and / or chronic kidney disease in a subject with hyperkalemia (i.e., having a serum potassium level of 5.5 mmol / L or greater), comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0111] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject with hyperkalemia (i.e., a serum potassium level of 5.5 mmol / L or greater), the use comprising administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0112] In some embodiments, the present disclosure provides a method of treating heart failure and / or chronic kidney disease in a subject at risk for hyperkalemia in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. As used herein, a subject at risk for hyperkalemia includes a subject with impaired renal function, or a subject currently prescribed at least one RAASi, or a subject with T2D, or a subject who has had at least one previous hyperkalemia episode, or a subject with a history of an adverse reaction to an MRA. RAASi drugs may include angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and direct renin inhibitors known in the art. In some embodiments, a subject maintains a serum potassium level of less than 5.5 mmol / L after administration of a pharmaceutical composition comprising 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0113] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject at risk for hyperkalemia and in need of such treatment, the use comprising administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0114] In some embodiments, the present disclosure provides methods of treating heart failure and / or chronic kidney disease in a subject in need thereof who has a recent worsening of heart failure (i.e., either stable in a hospital setting, or the subject is hospitalized or has received acute HF treatment in an emergency facility for heart failure within the past six months), comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0115] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need of treatment for heart failure and / or chronic kidney disease who has a recent worsening of heart failure, the use comprising administering a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0116] In some embodiments, the present disclosure provides a method for treating heart failure and / or renal dysfunction in subjects in need of treatment (i.e., greater than 20 ml / min to 60 ml / min / 1.73 m 2 The present invention provides a method of doing so in a subject having an eGFR in the range of up to 100 mg / kg, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0117] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or renal dysfunction in a subject in need thereof, the use comprising administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0118] In some embodiments, the present disclosure provides a method of treating heart failure and / or chronic kidney disease in a subject in need thereof who is intolerant to mineralocorticoid receptor antagonists (MRAs) or who is deemed by a physician to be unsuitable for MRA therapy, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. Common MRAs are known in the art; non-limiting examples include spironolactone, eplerenone, canrenone, progesterone, drospirenone, gestodene, and benidipine.

[0119] In some embodiments, the present disclosure provides a fixed-dose combination of a mineralocorticoid receptor antagonist (MR) modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need of such treatment who is intolerant to MRAs or who a physician deems unsuitable for MRA therapy, the use comprising administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0120] In some embodiments, the present disclosure provides a method of reducing the risk of cardiovascular (CV) death and / or heart failure (HF) events in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. As used herein, an HF event includes hospitalization for HF and / or a worsening HF event without hospitalization (see, e.g., Abraham, WT et al., JACC:Heart Failure, 8:961-972 (2020)), e.g., an unscheduled outpatient medical visit associated with a change in HF treatment, such as: a. The patient had documented new or worsening symptoms due to HF at the time of presentation; b. The patient had objective evidence, i.e., physical exam and / or laboratory findings of new or worsening HF; c. The patient has received at least one treatment specific for HF; and d. Patients had symptomatic improvement and objective signs of HF in response to treatment.

[0121] In at least one embodiment, the patient experiences one or more symptoms of HF selected from the group consisting of dyspnea, decreased exercise tolerance, fatigue, and / or other symptoms of impaired end-organ perfusion or volume overload. In some embodiments where a HF event without hospitalization is required, the patient undergoes initiation or intensification of HF-specific therapy. In some embodiments where the HF event does not require hospitalization, the patient requires initiation of oral diuretic therapy, intravenous diuretics or vasoactive therapy, or a significant increase in mechanical fluid removal.

[0122] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in reducing the risk of cardiovascular (CV) death and / or heart failure (HF) events in a subject in need thereof, the use comprising administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0123] In some embodiments, the present disclosure provides a method of treating heart failure and / or chronic kidney disease in a subject in need thereof, the method not resulting in the associated risk of hyperkalemia, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0124] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the use does not result in an associated risk of hyperkalemia, and the use comprises administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0125] In some embodiments, the present disclosure provides a method of treating heart failure and / or chronic kidney disease in a subject in need thereof, further reducing UACR in the subject, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the decrease in UACR can be a decrease of more than 30% compared to baseline UACR, or, for example, a decrease of up to 25% to 30% compared to baseline UACR, for example, a decrease of up to 30% compared to baseline UACR, for example, a decrease of up to 25% compared to baseline UACR, for example, a decrease of up to 20% compared to baseline UACR, for example, a decrease of up to 15% compared to baseline UACR, for example, a decrease of up to 10% compared to baseline UACR. In other embodiments, a decrease in UACR can be assessed by a subject moving from a higher UACR category to a lower UACR category, such as a subject moving from the A3 category (UACR > 300 mg / g) to the A2 category (UACR 30-299 mg / g) or the A1 category (UACR < 30 mg / g).

[0126] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the use further reduces UACR in the subject, and the treatment comprises administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, such as dapagliflozin propanediol.

[0127] In some embodiments, the present disclosure provides a method of treating heart failure and / or chronic kidney disease in a subject in need thereof, without the associated risk of hypotension, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0128] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the use does not result in an associated risk of hypotension, and the treatment comprises administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0129] In some embodiments, the present disclosure provides a method of treating heart failure and / or chronic kidney disease in a subject in need thereof, the method not posing an associated risk of acute kidney injury, comprising administering to the subject a pharmaceutical composition or oral dosage form described herein. In some embodiments, the composition comprises an MR modulator and an SGLT2 inhibitor described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. As used herein, acute kidney injury may be defined as either an examiner-reported increase in serum creatinine of more than two-fold the baseline value, perceived or estimated to have occurred within the past seven days, and / or requiring the use of temporary renal replacement therapy for up to 28 days.

[0130] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the use does not result in an associated risk of acute kidney injury, and the treatment comprises administering to the subject a pharmaceutical composition comprising an MR modulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg of AZD9977 and 10 mg of dapagliflozin or a solvate thereof, e.g., dapagliflozin propanediol.

[0131] In any of the above embodiments, the subject can have New York Heart Association (NYHA) heart failure class II-IV. In at least one embodiment, the subject has NYHA heart failure class II. In at least one embodiment, the subject has NYHA heart failure class III or IV.

[0132] In any of the above embodiments, the subject with heart failure may include a subject with a left ventricular ejection fraction (LVEF) greater than 50% (i.e., a subject with heart failure with preserved ejection fraction (HFpEF)), or a subject with an LVEF ranging from greater than or equal to 40% to less than or equal to 50% (i.e., a subject with heart failure with mid-range ejection fraction (HFmReF)), or a subject with an LVEF less than 40% (i.e., a subject with heart failure with reduced ejection fraction (HfREF)).

[0133] In any of the above embodiments, subjects with chronic kidney disease can include subjects exhibiting kidney damage (e.g., proteinuria that can be measured by UACR, e.g., subjects classified as UACR category A2-A3) and / or an estimated eGFR<60 ml / min / 1.73 m2 sustained for at least 3 months.

[0134] In some embodiments, a daily dose of about 10 mg to about 200 mg, or about 15 mg to about 40 mg, or about 20 mg to about 180 mg, or about 50 mg to about 160 mg, or about 150 mg of the MR modulator is administered. In some embodiments, a daily dose of about 5 mg to about 20 mg, or about 7 mg to about 17 mg, or about 8 mg to about 12 mg, or about 10 mg of the SGLT2 inhibitor is administered. In some embodiments, a daily dose of about 10 mg to about 200 mg of the MR modulator and a daily dose of about 5 mg to about 20 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 50 mg to about 180 mg of the MR modulator and a daily dose of about 7 mg to about 17 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 50 mg to about 150 mg of the MR modulator and a daily dose of about 8 mg to about 12 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 15 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 20 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 25 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 30 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 35 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 40 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 50 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, a daily dose of about 150 mg of the MR modulator and a daily dose of about 10 mg of the SGLT2 inhibitor are administered. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin.

[0135] In some embodiments, the pharmaceutical composition comprises about 10 mg to about 200 mg of AZD9977 and about 5 mg to about 20 mg of active equivalent of dapagliflozin. In some embodiments, the pharmaceutical composition comprises about 20 mg to about 180 mg of AZD9977 and about 7 mg to about 17 mg of active equivalent of dapagliflozin. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 160 mg of AZD9977 and about 8 mg to about 12 mg of active equivalent of dapagliflozin. In some embodiments, the pharmaceutical composition comprises about 150 mg of AZD9977 and about 10 mg of active equivalent of dapagliflozin. In some embodiments, the pharmaceutical composition comprises about 50 mg of AZD9977 and about 10 mg of active equivalent of dapagliflozin. In some embodiments, a daily dose of about 15 mg of AZD9977 and a daily dose of about 10 mg of dapagliflozin is administered. In some embodiments, a daily dose of about 20 mg of AZD 9977 and a daily dose of about 10 mg of dapagliflozin are administered. In some embodiments, a daily dose of about 25 mg of AZD 9977 and a daily dose of about 10 mg of dapagliflozin are administered. In some embodiments, a daily dose of about 30 mg of AZD 9977 and a daily dose of about 10 mg of dapagliflozin are administered. In some embodiments, a daily dose of about 35 mg of AZD 9977 and a daily dose of about 10 mg of dapagliflozin are administered. In some embodiments, a daily dose of about 40 mg of AZD 9977 and a daily dose of about 10 mg of dapagliflozin are administered. In some embodiments, the dapagliflozin is in the form of dapagliflozin propanediol, and the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0136] In some embodiments, the method comprises providing a pharmaceutical composition comprising: (a) one or more first pellets, i. a first core comprising a microcrystalline cellulose core, the first core being from about 10% to about 30% by weight of the composition, optionally from about 10% to about 25% by weight; ii. A first coating comprising: (A) about 20% to about 50% by weight of the composition of an MR modulator that is AZD9977; (B) about 1% to about 10%, optionally about 4% to about 8%, by weight of the composition, of povidone, and (C) sodium stearyl fumarate, from about 0.01% to about 0.5%, optionally from about 0.2% to about 0.4%, by weight of the composition; a first coating comprising: a first pellet comprising: (b) one or more second pellets, i. a second core comprising sugar spheres, wherein the sugar spheres comprise from about 10% to about 40% by weight of the composition, optionally from about 15% to about 35% by weight; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin, which is about 1% to about 10% by weight of the composition, optionally about 3% to about 7% by weight, and the SGLT2 is about 5% to about 20% by weight of the second pellet, optionally about 5% to about 15% by weight; (B) from about 0.1% to about 5%, optionally from about 0.4% to about 1%, by weight of the composition, of hydroxypropyl cellulose; (C) talc, from about 1% to about 20%, optionally from about 7% to about 16%, by weight of the composition; and (D) sodium stearyl fumarate, from about 0.01% to about 1%, optionally from about 0.05% to about 0.2%, by weight of the composition; a second coating comprising: and a second pellet comprising:

[0137] In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0138] In some embodiments, the method of treating heart failure and / or chronic kidney disease includes a pharmaceutical composition comprising: (a) one or more first pellets comprising: i. a first core comprising a microcrystalline cellulose core, the first core being about 20.7% by weight of the composition; ii. a first coating comprising: (A) an MR modulator which is AZD9977, and which is about 40% by weight of the composition; (B) about 6% by weight of the composition of povidone, and (C) about 0.1% by weight of the composition of sodium stearyl fumarate; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: i. a second core comprising sugar spheres, wherein the sugar spheres constitute about 21.9% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor which is dapagliflozin propanediol and is about 3.3% by weight of the composition and the SGLT2 is about 12.8% by weight of the second pellet; (B) about 0.43% by weight of the composition of hydroxypropyl cellulose; (C) talc, in an amount of about 7.2% by weight of the composition; and (D) about 0.15% by weight of the composition of sodium stearyl fumarate; a second coating comprising: and a second pellet comprising:

[0139] In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0140] In some embodiments, the method of treating heart failure and / or chronic kidney disease includes providing a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets comprising: i. a first core comprising a microcrystalline cellulose core, the first core comprising about 5% to about 25% by weight of the capsule; ii. a first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 constitutes about 10% to about 45% by weight of the capsule; (B) povidone that constitutes about 1% to about 10% by weight of the capsule; and (C) sodium stearyl fumarate, in an amount of about 0.01% to about 1% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: i. a second core comprising sugar spheres, wherein the sugar spheres comprise about 5% to about 30% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin propanediol, wherein the dapagliflozin propanediol is about 1% to about 10% by weight of the capsule; (B) hydroxypropyl cellulose that is about 0.1% to about 1% by weight of the capsule; (C) talc that is about 1% to about 15% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.01% to about 0.1% by weight of the capsule; a second coating comprising: and a second pellet comprising: (I) a pharmaceutical composition comprising: (I) a first pellet comprising: (I) a second pellet ...

[0141] In some embodiments, the method of treating heart failure and / or chronic kidney disease includes providing a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets comprising: i. a first core comprising a microcrystalline cellulose core, the first core being about 5% to about 20% by weight of the capsule; ii. A first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 constitutes about 15% to about 40% by weight of the capsule; (B) povidone that constitutes about 2% to about 6% by weight of the capsule; and (C) sodium stearyl fumarate, in an amount of about 0.02% to about 0.4% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: i. a second core comprising sugar spheres, wherein the sugar spheres comprise about 10% to about 22% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin, wherein the dapagliflozin is about 2% to about 5% by weight of the capsule; (B) hydroxypropyl cellulose that is about 0.4% to about 0.6% by weight of the capsule; (C) talc that is about 5% to about 12% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.02% to about 0.08% by weight of the capsule; a second coating comprising: and a second pellet comprising: (I) a pharmaceutical composition comprising: (I) a first pellet comprising: (I) a second pellet ...

[0142] In some embodiments, the method of treating heart failure and / or chronic kidney disease includes providing a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets comprising: i. a first core comprising a microcrystalline cellulose core, the first core being about 18% by weight of the capsule; ii. A first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 is about 35% of the capsule; (B) povidone that is about 5.3% by weight of the capsule; and (C) sodium stearyl fumarate, in an amount of about 0.12% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: i. a second core comprising sugar spheres, wherein the sugar spheres are about 12.8% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin, wherein the dapagliflozin is about 2.9% by weight of the capsule; (B) hydroxypropyl cellulose that is about 0.38% by weight of the capsule; (C) talc that is about 6.3% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.04% by weight of the capsule; a second coating comprising: and a second pellet comprising: (I) a pharmaceutical composition comprising: (I) a first pellet comprising: (I) a second pellet ...

[0143] In some embodiments, the method of treating heart failure and / or chronic kidney disease includes providing a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets comprising: i. a first core comprising a microcrystalline cellulose core, the first core being about 9.9% by weight of the capsule; ii. a first coating comprising: (A) an MR modulator that is AZD9977, wherein the AZD9977 is about 19.2% by weight of the capsule; (B) povidone that is about 2.9% by weight of the capsule; and (C) sodium stearyl fumarate, in an amount of about 0.06% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: i. a second core comprising sugar spheres, wherein the sugar spheres constitute about 21% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin, wherein the dapagliflozin is about 4.7% by weight of the capsule; (B) hydroxypropyl cellulose that is about 0.63% by weight of the capsule; (C) talc that is about 10.4% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.07% by weight of the capsule; a second coating comprising: and a second pellet comprising: (I) a pharmaceutical composition comprising: (I) a first pellet comprising: (I) a second pellet ...

[0144] In some embodiments, the method of treating heart failure and / or chronic kidney disease includes providing a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets comprising: i. a first core comprising a microcrystalline cellulose core, the first core comprising about 5% to about 25% by weight of the capsule; ii. a first coating comprising: (A) An MR regulator which is AZD9977, wherein the AZD9977 accounts for about 10% to about 45% by weight of the capsule; (B) povidone, which is about 2% to about 8% by weight of the capsule; (C) hypromellose, wherein the hypromellose is about 0.5% to about 3% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.01% to about 0.5% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: i. a second core comprising sugar spheres, the second core comprising about 5% to about 30% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor which is dapagliflozin propanediol, wherein the dapagliflozin propanediol accounts for about 1% by weight to about 10% by weight of the capsule and about 5% by weight to about 20% by weight of the second pellet; (B) hydroxypropyl cellulose, which is about 0.1% to about 1% by weight of the capsule; (C) talc, which is about 1% to about 15% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.01% to about 1% by weight of the capsule; a second coating comprising: and a second pellet comprising: (I) a pharmaceutical composition comprising: (I) a first pellet comprising: (I) a second pellet ...

[0145] In some embodiments, the method of treating heart failure and / or chronic kidney disease includes providing a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets comprising: i. a first core comprising a microcrystalline cellulose core, the first core being about 23.9% by weight of the capsule; ii. a first coating comprising: (A) an MR modulator which is AZD9977, wherein the AZD9977 is about 45.3% by weight of the capsule; (B) povidone, in an amount of about 5.35% by weight of the capsule; (C) hypromellose, in an amount of about 0.97% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.34% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: i. a second core comprising sugar spheres, the second core being about 11.7% by weight of the capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin propanediol, wherein the dapagliflozin propanediol is about 3.7% by weight of the capsule and about 13.2% by weight of the second pellets; (B) hydroxypropyl cellulose that is about 0.48% by weight of the capsule; (C) talc that is about 8.2% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.11% by weight of the capsule; a second coating comprising: and a second pellet comprising: (I) a pharmaceutical composition comprising: (I) a first pellet comprising: (I) a second pellet ...

[0146] In some embodiments, the method of treating heart failure and / or chronic kidney disease includes providing a pharmaceutical composition in the form of a capsule comprising: (a) one or more first pellets comprising: i. a first core comprising a microcrystalline cellulose core, the first core being about 56.2% by weight of the capsule; ii. a first coating comprising: (A) an MR modulator which is AZD9977, wherein the AZD9977 is about 11.2% by weight of the capsule; (B) hypromellose, in an amount of about 0.22% by weight of the capsule; and (C) sodium stearyl fumarate, in an amount of about 0.37% by weight of the capsule; a first coating comprising: a first pellet comprising: (b) one or more second pellets comprising: i. a second core comprising sugar spheres, said second core being about 26.3% by weight of said capsule; ii. A second coating comprising: (A) an SGLT2 inhibitor that is dapagliflozin propanediol, wherein the dapagliflozin propanediol is about 2.8% by weight of the capsule and about 10.7% by weight of the second pellets; (B) hydroxypropyl cellulose that is about 0.37% by weight of the capsule; (C) talc that is about 6.2% by weight of the capsule; and (D) sodium stearyl fumarate, in an amount of about 0.34% by weight of the capsule; a second coating comprising: and a second pellet comprising: (I) a pharmaceutical composition comprising: (I) a first pellet comprising: (I) a second pellet ...

[0147] In some embodiments, the method comprises administering a pharmaceutical composition or oral dosage form described herein once daily. In some embodiments, the method comprises administering a pharmaceutical composition or oral dosage form described herein twice daily, three times daily, four times daily, five times daily, six times daily, or more frequently. One skilled in the art will understand that if the pharmaceutical composition is administered more than twice daily, the amounts of the MR modulator (e.g., AZD9977) and the SGLT2 inhibitor (e.g., dapagliflozin) in the pharmaceutical composition should be adjusted accordingly to maintain the desired daily dose. For example, to achieve a daily dose of about 50 mg or about 150 mg of the MR modulator and about 10 mg of the SGLT2 inhibitor, a composition or oral dosage form for twice-daily administration should contain 22.5 mg or 75 mg of the MR modulator and 5 mg of the SGLT2 inhibitor.

[0148] In some embodiments, the pharmaceutical composition or oral dosage form is administered to a subject in need thereof in a fasted state. As defined by the US Food and Drug Administration, treatment in a "fasted state" is performed when there is a fast lasting at least 10 hours, for example, an overnight fast, and no food is taken until at least 4 hours after drug administration. In contrast, treatment in a "fed state" is performed starting from the same overnight 10-hour fast, but the subject eats a meal within 30 minutes before drug administration and does not take additional food for at least 4 hours after drug administration. See, for example, US Food and Drug Administration, Center for Drug Evaluation and Research (CDER), "Guidance for Industry-Food-Effect Bioavailability and Fed Bioequivalence Studies," December 2002.

[0149] In some embodiments, a pharmaceutical composition or oral dosage form comprising an MR modulator (e.g., AZD9977) and an SGLT2 inhibitor (e.g., dapagliflozin or a solvate thereof) provides bioequivalence, when administered in the fasted state, to the MR modulator and the SGLT2 inhibitor administered in separate dosage forms. Methods for assessing bioequivalence are known to those of skill in the art. See, e.g., US Food and Drug Administration, Center for Drug Evaluation and Research (CDER), "Guidance for Industry - Bioavailability and Bioequivalence Studies Submitted in NDA or IND General Considerations - Draft Guidance," March 2014.

[0150] In some embodiments, the pharmaceutical compositions or oral dosage forms described herein have an AUC last and AUC infAs used herein, "AUC" refers to the bioequivalence of the MR modulator and the SGLT2 inhibitor to separate dosage forms of the MR modulator and the SGLT2 inhibitor when measured by one or both of the AUC last ” is the time from the time of dosing to the time of the last measurable (positive) concentration (T last As used herein, "AUC" refers to the area under the curve of drug concentration up to the inf " refers to the area under the curve of drug concentration from the time of dosing, extrapolated to infinity, and is a theoretical measure of the total exposure of a drug to the body from administration to complete elimination.

[0151] In some embodiments, the AUC of a subject after administration of a pharmaceutical composition or oral dosage form described herein last and AUC inf is the AUC of subjects administered separate dosage forms of an MR modulator and an SGLT2 inhibitor last and AUC inf In some embodiments, the AUC last and AUC inf is the AUC of subjects administered separate dosage forms of an MR modulator and an SGLT2 inhibitor last and AUC inf In some embodiments, the AUC last and AUC inf is the AUC of subjects administered separate dosage forms of an MR modulator and an SGLT2 inhibitor last and AUC inf In some embodiments, the AUC last and AUC inf is the AUC of subjects administered separate dosage forms of an MR modulator and an SGLT2 inhibitor last and AUC inf In some embodiments, the AUC of a subject after administration of a pharmaceutical composition or oral dosage form described herein is within 10%, within 8%, within 5%, or within 2% of last and AUC infis the AUC of subjects administered separate dosage forms of an MR modulator and an SGLT2 inhibitor last and AUC inf is essentially the same as

[0152] In some embodiments, the subject in need thereof has been diagnosed with chronic heart failure (HF), chronic kidney disease (CKD), or both. In some embodiments, the subject in need thereof has been diagnosed with chronic HF and is at high risk of developing CKD, or has been diagnosed with CKD and is at high risk of developing chronic HF. In some embodiments, the subject has a family history of chronic HF, CKD, or both. In some embodiments, the subject is a healthy subject enrolled in a clinical trial of the pharmaceutical compositions or oral dosage forms described herein.

[0153] In some embodiments, the present disclosure provides a method of making a capsule comprising a pharmaceutical composition described herein, comprising: (1) forming a first pellet, comprising: a) combining a first binder with water to form a first binder / aqueous solution; b) adding an MR modifier to the first binder / aqueous solution to form a first suspension; c) optionally sieving the first suspension through a 200-300 μm sieve; d) coating the first cores with the sieved first suspension to form first coated cores; e) mixing the first coated cores with a first lubricant to form first pellets; forming a first pellet, (2) forming a second pellet, comprising: a) combining a second binder with water to form a second binder / aqueous solution; b) adding an SGLT2 inhibitor and an anti-adherent agent to the second binder / aqueous solution to form a second suspension; c) coating a second core with said second suspension to form a second coated core; d) mixing the second coated cores with a second lubricant to form second pellets; forming a second pellet, comprising: (3) combining the first pellet and the second pellet in a capsule; The present invention provides a method comprising:

[0154] Components of this method are further described herein. In some embodiments, the first binder comprises povidone or povidone and hypromellose, the MR modifier comprises AZD9977, the first core comprises microcrystalline cellulose, and / or the first lubricant comprises sodium stearyl fumarate. In some embodiments, the second binder comprises hydroxypropyl cellulose, the SGLT2 inhibitor comprises dapagliflozin propanediol, the anti-adherent agent comprises talc, the second core comprises sugar spheres, and / or the second lubricant comprises sodium stearyl fumarate. In some embodiments, the first pellet comprises at least two first binders, and steps (1)(a)-(1)(d) are repeated for each first binder, thereby coating the first core with at least two layers each comprising a first binder and an MR modifier. In some embodiments, coating comprises spray coating. Spray coating processes are known to those skilled in the art.

[0155] In some embodiments, the present disclosure provides a method of making a capsule comprising a pharmaceutical composition described herein, comprising: (1) forming a first pellet, comprising: a) combining povidone with water to form a povidone / water solution; b) adding AZD9977 to the povidone / water solution to form a first suspension comprising about 20% to about 30% w / w AZD9977; c) sieving or wet-milling the first suspension through a 200-300 μm sieve; d) coating microcrystalline cellulose cores with the sieved first suspension to form first coated cores; e) mixing the first coated cores with sodium stearyl fumarate to form first pellets; forming a first pellet, (2) forming a second pellet, comprising: a) combining hydroxypropyl cellulose with water to form an HPC / water solution; b) adding dapagliflozin propanediol and talc to the HPC / water solution to form a second suspension comprising about 10% to about 15% dapagliflozin propanediol; c) coating sugar sphere cores with said second suspension to form second coated cores; d) mixing the second coated cores with sodium stearyl fumarate to form second pellets; forming a second pellet, comprising: (3) combining the first pellet and the second pellet in a capsule; The present invention provides a method comprising:

[0156] In some embodiments, the present disclosure provides a method of making a capsule comprising a pharmaceutical composition described herein, comprising: (1) forming a first pellet, comprising: a) combining hypromellose with water to form a hypromellose / water solution; b) adding AZD9977 to the hypromellose / water solution to form a suspension containing about 20% to about 30% w / w of AZD9977; c) sieving the suspension of (b) through a 200-300 μm sieve; d) coating a microcrystalline cellulose core with the sieved suspension of (c) to form a first coated core comprising a first layer; e) combining povidone with water to form a povidone / water solution; f) adding AZD9977 to the povidone / water solution to form a suspension containing about 20% to about 30% w / w AZD9977; g) sieving the suspension of (f) through a 200-300 μm sieve; h) coating the first coated core including the first layer with the sieved suspension of (g), thereby forming a first coated core including first and second layers; g) mixing the first core comprising the first and second layers with sodium stearyl fumarate to form a first pellet; forming a first pellet, (2) forming a second pellet, comprising: a) combining hydroxypropyl cellulose with water to form an HPC / water solution; b) adding dapagliflozin propanediol and talc to the HPC / water solution to form a second suspension; c) coating sugar sphere cores with said second suspension to form second coated cores; d) mixing the second coated cores with sodium stearyl fumarate to form second pellets; forming a second pellet, comprising: (3) combining the first pellet and the second pellet in a capsule; The present invention provides a method comprising:

[0157] In some embodiments, steps (1) and (2) of the methods described herein are performed in parallel. In some embodiments, steps (1) and (2) of the methods are performed sequentially, in any order.

[0158] The entire contents of all publications, patents, and patent applications referenced herein are hereby incorporated by reference.

[0159] The specific examples included herein are for illustrative purposes only and should not be construed as limiting the present disclosure. Furthermore, the compositions, systems, and methods provided herein have been described in connection with specific embodiments thereof, and numerous details have been set forth for illustrative purposes. It will be apparent to those skilled in the art that the present disclosure is susceptible to additional embodiments and that some of the details described herein may be modified without departing from the basic principles of the present disclosure. Any active agents and reagents used in the following examples are either commercially available or can be prepared according to standard literature procedures by those skilled in the art with the benefit of the description provided herein. [Example]

[0160] Example 1. Preparation of AZD9977 + Dapagliflozin Capsules Immediate-release (IR) dapagliflozin pellets: Preparation of dapagliflozin spray coating suspension (D1 suspension) for low drug load pellets. 7.5 g of hydroxypropyl cellulose (HPC) SSL (Nisso Soda) was added to 1312.8 g of purified water and stirred for approximately 2 hours (until a clear solution was obtained). 123.8 g of talc and 56.25 g of dapagliflozin (Dottikon) were added to the HPC SSL / water solution to produce a 12.5% ​​(w / w) dapagliflozin coating suspension, which was stirred overnight at room temperature.

[0161] Spray coating of 85 mg / g dapagliflozin IR pellets (D1). 300 g of nonpareil cores (VIVAPHARM®, JRS Pharma) were loaded into a Wurster fluid bed spray coater (Graniten Engineering). The cores were coated with 1207 g of the dapagliflozin coating suspension under the conditions summarized in Table 1 to produce 400 g of dapagliflozin IR pellets with a drug loading of 83.5 mg / g.

[0162] Preparation of dapagliflozin spray coating suspension (D2 suspension) for high drug-loaded pellets. 5.0 g of HPC SSL (Nisso Soda) was added to 875.7 g of purified water and stirred for approximately 2 hours (until a clear solution was obtained). 82.5 g of talc and 37.5 g of dapagliflozin (Dottikon) were added to the HPC SSL / water solution to produce a 12.5% ​​(w / w) dapagliflozin coating suspension, which was stirred overnight at room temperature.

[0163] Spray coating of 130 mg / g dapagliflozin IR pellets (D2). 100 g of nonpareil cores (VIVAPHARM®, JRS Pharma) were loaded into a Wurster fluid bed spray coater (Graniten Engineering). The cores were coated with 847.7 g of the dapagliflozin coating suspension under the conditions summarized in Table 1 to produce 174 g of dapagliflozin IR pellets with a drug loading of 131.5 mg / g.

[0164] Preparation of dapagliflozin spray coating suspension (D3 suspension) for dapa pellets. 0.9 kg of HPC SSL (Nisso Soda) was added to 67.5 kg of purified water and stirred for approximately 1 hour (until a clear solution was obtained). 14.85 kg of talc and 6.75 kg of dapagliflozin (Dottikon) were added to the HPC SSL / water solution to produce a 25% (w / w) dapagliflozin coating suspension, which was stirred overnight at room temperature.

[0165] Spray coating of 105 mg / g dapagliflozin IR pellets (D3). 30 kg of nonpareil cores (VIVAPHARM®, JRS Pharma) were loaded into a Wurster fluid bed spray coater (GPCG30, Glatt). The cores were coated with 90 kg of the dapagliflozin coating suspension under the conditions summarized in Table 1 to produce 49.5 kg of dapagliflozin IR pellets with a drug loading of 107 mg / g.

[0166] Immediate release (IR) AZD9977 pellets: Preparation of AZD9977 spray coating suspension (A1 suspension). 60 g of polyvinylpyrrolidone (povidone; PVP) K30 (BASF) was added to 1540 g of purified water and stirred for approximately 1 hour (until a clear solution was obtained). 400 g of AZD9977 (STA WuXi) was added to the PVPK30 / water solution to produce a 23% (w / w) AZD9977 coating suspension, which was stirred overnight at room temperature. The suspension was passed through a 250 μm sieve before use in the coating step.

[0167] Spray coating of 600 mg / g AZD9977 IR pellets (A1). 170 g of microcrystalline cellulose (MCC) cores (VIVAPUR® 100, JRS Pharma) were loaded into a Wurster fluid-bed spray coater (Graniten Engineering). The cores were coated with 1653 g of AZD9977 coating suspension 1 under the conditions summarized in Table 1 to produce 532 g of AZD9977 IR pellets 1 with a drug loading of 598 mg / g.

[0168] Preparation of AZD9977 spray coating suspension (A2a suspension - Layer 1). 12 g of hydroxypropyl methylcellulose (HPMC) 6 cps (Dow Chem) was added to 468 g of purified water and stirred for approximately 1 hour (until a clear solution was obtained). 120 g of AZD9977 (STA WuXi) was added to the HPMC / water solution to produce 22% (w / w) AZD9977 coating suspension A2a, which was stirred overnight at room temperature. The suspension was sieved through a 250 μm sieve before use in the coating step.

[0169] Spray coating of 320 mg / g AZD9977 IR pellets (A2a—first layer). 200 g of MCC cores (VIVAPUR® 100, JRS Pharma) were loaded into a Wurster fluid-bed spray coater (Graniten Engineering). The cores were coated with 504 g of AZD9977 coating suspension A2a under the conditions summarized in Table 1 to produce 293 g of AZD9977 IR pellets A2a with a drug loading of 323 mg / g.

[0170] Preparation of AZD9977 spray coating suspension (A2 suspension - Layer 2). 45 g of PVP K30 (BASF) was added to 1155 g of purified water and stirred for approximately 30 minutes (until a clear solution was obtained). 300 g of AZD9977 (STA WuXi) was added to the PVP K30 / water solution to produce a 23% (w / w) AZD9977 suspension, which was allowed to stir overnight at room temperature. The suspension was sieved through a 250 μm sieve before use in the coating step.

[0171] Spray coating of 600 mg / g AZD9977 IR pellets (A2 - 2nd layer). 265 g of AZD9977 IR pellets A2a were loaded into a Wurster fluid bed spray coater (Graniten Engineering). The cores were coated with 1266 g of AZD9977 coating suspension A2 under the conditions summarized in Table 1 to produce 547 g of AZD9977 IR pellets A2 with a drug loading of 605 mg / g.

[0172] Preparation of AZD9977 spray coating suspension (A3 suspension): 1.0 kg of hydroxypropyl methylcellulose (HPMC) 6 cps (Dow Chem) was added to 39 kg of purified water and stirred for at least 0.5 hours (until a clear solution was obtained). 10 kg of AZD9977 (STA WuXi) was added to the HPMC / water solution to produce a 22% (w / w) AZD9977 coating suspension, which was stirred overnight at room temperature.

[0173] Spray coating of 200 mg / g AZD9977 IR pellets (A3-2nd layer). 39 kg of microcrystalline cellulose (MCC) cores (VIVAPUR® 200, JRS Pharma) were loaded into a Wurster fluid bed spray coater (GPCG30). The cores were coated with 50 kg of the AZD9977 coating suspension under the conditions summarized in the table below to produce 49.0 kg of AZD9977 IR pellets with a drug loading of 202 mg / g.

[0174] [Table 1]

[0175] Filling D1, D2, D3, A1, A2, A3 pellets into capsules Lubricating: A1: 518g of AZD9977 pellets A1 were mixed with 2.34g of sodium stearyl fumarate in a Turbula T2F blender for 10 minutes at 23 rpm to produce 520.6g of lubricated AZD9977 pellets. A2: 543g of AZD9977 pellets A2 were mixed with 2.45g of sodium stearyl fumarate in a Turbula T2F blender for 10 minutes at 23 rpm to produce 544.7g of lubricated AZD9977 pellets. D1: Approximately 388.5 g of dapagliflozin pellets D1 were mixed with 1.76 g of sodium stearyl fumarate in a Turbula T2F blender for 10 minutes at 23 rpm to produce 390.3 g of lubricated dapagliflozin DL-low pellets. D2: 167.3 g of dapagliflozin pellets D2 were mixed with 0.76 g of sodium stearyl fumarate in a Turbula T2F blender for 10 minutes at 23 rpm to produce 168.1 g of lubricated dapagliflozin DL-high pellets. D3: 167.3 g of dapagliflozin pellets D3 were mixed with 0.76 g of sodium stearyl fumarate in a Turbula T2F blender for 10 minutes at 23 rpm to produce 168.1 g of lubricated dapagliflozin DL pellets.

[0176] FDC capsule (also shown in Figure 2A): Capsule 1 ("FDC1"): Dose 150 mg AZD9977 pellets Al and 10 mg dapagliflozin D1. 250 g of lubricated AZD9977 pellets Al and 124 g of dapagliflozin pellets D1 were filled into 1000 white size 0 gelatin capsules (Capsugel) using a Jubo capsule filling machine at an average fill weight of 250 mg AZD9977 pellets and 124 mg dapagliflozin pellets per capsule.

[0177] Capsule 2 ("FDC2"): Dose 150 mg AZD9977 pellets A2 and 10 mg dapagliflozin D2. 250 g of lubricated AZD9977 pellets A2 and 80 g of dapagliflozin pellets D2 were filled into 1000 white size 0 gelatin capsules (Capsugel) using a Jubo capsule filling machine at an average fill weight of 250 mg AZD9977 pellets and 80 mg dapagliflozin pellets per capsule.

[0178] Capsule 3 ("FDC3"): Dose 150 mg AZD9977 pellets Al and 10 mg dapagliflozin D2. 250 g of lubricated AZD9977 pellets Al and 80 g of dapagliflozin pellets D2 were filled into 1000 white size 0 gelatin capsules (Capsugel) using a Jubo capsule filling machine at an average fill weight of 250 mg AZD9977 pellets and 80 mg dapagliflozin pellets per capsule.

[0179] Capsule 4 ("FDC4"): Dose 150 mg AZD9977 pellets A2 and 10 mg dapagliflozin D1. 250 g of lubricated AZD9977 pellets A2 and 124 g of dapagliflozin pellets D1 were filled into 1000 white size 0 gelatin capsules (Capsugel) using a Jubo capsule filling machine at an average fill weight of 250 mg AZD9977 pellets and 124 mg dapagliflozin pellets per capsule.

[0180] Capsule 5: Dose of 40 mg AZD9977 pellets A3 and 10 mg dapagliflozin D3. 201 g of lubricated AZD9977 pellets A3 and 93.8 g of dapagliflozin pellets D3 were filled into 1000 white size 2 gelatin capsules (Capsugel) using a Jubo capsule filling machine to an average fill weight of 200 mg AZD9977 pellets and 93.4 mg dapagliflozin pellets per capsule.

[0181] Example 2. Dissolution test The FDC formulations (capsules 1 to 4) described in Example 1 were subjected to an in vitro dissolution test.

[0182] The results are shown in Figure 1A (dapagliflozin, tested at 100 rpm in USP Apparatus 1), Figure 1B (AZD9977, tested at 100 rpm in USP Apparatus 2), and Figure 1C (AZD9977, tested at 100 rpm in USP Apparatus 1). As shown in Figure 1A, all four FDC formulations released >80% of dapagliflozin within 30 minutes when tested at 100 rpm in USP Apparatus 1. As shown in Figure 1B, all four FDC formulations released >80% of AZD9977 within 30 minutes when tested at 100 rpm in USP Apparatus 2. As shown in Figure 1C, FDC 1 and FDC 3, containing povidone-coated AZD9977 pellets, released >80% of AZD9977 within 30 minutes when tested in USP Apparatus 1 at 100 rpm; FDC 2 and FDC 4, containing HPMC / povidone-coated AZD9977 pellets, released >60% of AZD9977 within 30 minutes when tested in USP Apparatus 1 at 100 rpm.

[0183] Example 3. Clinical trial to evaluate the bioavailability of AZD9977 and dapagliflozin FDC capsules A randomized, parallel-group, open-label, 4 / 5 period, 8-treatment, single-dose, crossover study was conducted in healthy volunteers to evaluate the bioavailability of AZD9977 and dapagliflozin FDC formulations (capsules 1-4) as described in Example 1. Subjects were randomized to one of eight treatment sequences as shown in Figure 2B. Treatments were as follows: Group 1: Treatment A1 = 150 mg AZD9977 (AZD9977 capsules 50 mg + AZD9977 capsules 100 mg) and 10 mg dapagliflozin tablets, fasting; Treatment B = 150 mg AZD9977 + 1 10 mg dapagliflozin capsule, fasting; Treatment C = 150 mg AZD9977 + 10 mg dapagliflozin capsule, fed; Treatment D = 150 mg AZD9977 + 2 x 10 mg dapagliflozin capsules, fasting; Treatment E = 150 mg AZD9977 + 2 x 10 mg dapagliflozin capsules, fed; Group 2: Treatment A2 = 150 mg AZD9977 (50 mg AZD9977 capsules + 100 mg AZD9977 capsules) and 10 mg dapagliflozin tablets, fasting; Treatment F = 150 mg AZD9977 + 10 mg dapagliflozin capsule 3, fasting; Treatment G = 150 mg AZD9977 + 4 10 mg dapagliflozin capsules, fasting; Treatment H = 10 mg dapagliflozin capsule, fasting.

[0184] Plasma AZD9977 concentrations after single oral administration of different formulations of AZD9977 and dapagliflozin. The mean plasma AZD9977 concentration versus time curves are shown in Figure 3A (linear scale) and Figure 3B (semi-logarithmic scale).

[0185] Low to moderate intersubject variability in AUC was observed across all treatments, with the geometric mean coefficient of variation ranging from approximately 20% to 28%. Low to high intersubject variability in Cmax was observed across all treatments, with the geometric mean coefficient of variation ranging from approximately 15% to 50%.

[0186] AZD9977 AUClast and AUCinf were comparable between Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasted) and the reference, Treatment A1 (150 mg AZD9977 (50 mg AZD9977 capsule + 100 mg AZD9977 capsule) and 10 mg dapagliflozin tablet, fasted). Cmax was sometimes 14% lower than the reference treatment, and C24 values ​​were 49% higher than the reference treatment. See Figure 4A.

[0187] AZD9977 AUClast and AUCinf were comparable between Treatment D (150 mg AZD9977 + 2 10 mg dapagliflozin capsules, fasted) and the reference, Treatment A1 (150 mg AZD9977 (50 mg AZD9977 capsules + 100 mg AZD9977 capsules) and 10 mg dapagliflozin tablets, fasted). Cmax was sometimes 7% lower than the reference treatment, and C24 values ​​were sometimes 23% higher than the reference treatment. See Figure 4A.

[0188] In Treatment C (150 mg AZD9977 + 10 mg dapagliflozin capsule, fed) vs. Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule, fasted), AZD9977 AUClast and AUCinf were 21% and 18% higher, respectively, in the fed state compared to the fasted state. Cmax was 56% higher and C24 values ​​were 69% lower in the fed state. See Figure 4B.

[0189] For Treatment E (150 mg AZD9977 + 2 10 mg dapagliflozin capsules, fed) vs. Treatment D (150 mg AZD9977 + 2 10 mg dapagliflozin capsules, fasted), AUClast and AUCinf in the fed state were comparable to those in the fasted state. Cmax was sometimes 31% higher and C24 values ​​were 56% lower in the fed state. See Figure 4B.

[0190] AZD9977 AUClast and AUCinf were comparable between treatment F (150 mg AZD9977 + 10 mg dapagliflozin capsule 3, fasted) and the reference, treatment A2 (150 mg AZD9977 (50 mg AZD9977 capsule + 100 mg AZD9977 capsule) and 10 mg dapagliflozin tablet, fasted). Cmax was sometimes 10% lower than the reference treatment, and C24 values ​​were sometimes 11% higher than the reference treatment. See Figure 5A.

[0191] AZD9977 AUClast and AUCinf were comparable between Treatment G (150 mg AZD9977 + 4 10 mg dapagliflozin capsules, fasted) and the reference, Treatment A2 (150 mg AZD9977 (50 mg AZD9977 capsules + 100 mg AZD9977 capsules) and 10 mg dapagliflozin tablets, fasted). Cmax was sometimes 16% lower than the reference treatment, and C24 values ​​were sometimes 43% higher than the reference treatment. See Figure 5A.

[0192] For Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasted) vs. Treatment F (150 mg AZD9977 + 3 10 mg dapagliflozin capsules, fasted), AZD9977 variant 1, Treatment B AZD9977 exposure (AUClast, AUCinf, Cmax and C24) was comparable to Treatment F. See Figure 5B.

[0193] For Treatment D (150 mg AZD9977 + 2 10 mg dapagliflozin capsules, fasted) vs. Treatment G (150 mg AZD9977 + 4 10 mg dapagliflozin capsules, fasted), AZD9977 variant 2, Treatment D AZD9977 AUC and AUC were comparable to Treatment G AUC and AUC values. Treatment D C was sometimes 11% higher than Treatment G C, and Treatment D C values ​​were 29% lower than Treatment G C values. See Figure 5B.

[0194] Plasma dapagliflozin concentrations after single oral doses of AZD9977 and different formulations of dapagliflozin. The geometric mean plasma dapagliflozin concentration versus time curves are shown in Figure 6A (linear scale) and Figure 6B (semi-logarithmic scale).

[0195] Low intersubject variability in AUC was observed across all treatments, with the geometric mean coefficient of variation ranging from approximately 10% to 21%. Low to moderate intersubject variability in Cmax was observed across all treatments, with the geometric mean coefficient of variation ranging from approximately 17% to 38%.

[0196] Dapagliflozin AUClast and AUCinf were comparable between Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasted) and the reference, Treatment A1 (150 mg AZD9977 (50 mg AZD9977 capsule + 100 mg AZD9977 capsule) and 10 mg dapagliflozin tablet, fasted). Cmax was sometimes 11% lower than the reference treatment, and C24 values ​​were sometimes 7% higher than the reference treatment. See Figure 7A.

[0197] Dapagliflozin AUClast and AUCinf were comparable between Treatment D (150 mg AZD9977 + 2 10 mg dapagliflozin capsules, fasted) and the reference, Treatment A1 (150 mg AZD9977 (50 mg AZD9977 capsules + 100 mg AZD9977 capsules) and 10 mg dapagliflozin tablets, fasted). Cmax was sometimes 9% lower than the reference treatment, and C24 values ​​were 11% higher than the reference treatment. See Figure 7A.

[0198] In Treatment C (150 mg AZD9977 + 10 mg dapagliflozin capsule, fed) vs. Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule, fasted), dapagliflozin AUClast and AUCinf in the fed state were comparable to those observed in the fasted state. Cmax was 34% lower in the fed state, and C24 values ​​were occasionally 12% higher. See Figure 7B.

[0199] For Treatment E (150 mg AZD9977 + 2 10 mg dapagliflozin capsules, fed) vs. Treatment D (150 mg AZD9977 + 2 10 mg dapagliflozin capsules, fasted), dapagliflozin AUClast and AUCinf in the fed state were comparable to those observed in the fasted state. Cmax was 28% lower in the fed state, and C24 values ​​were comparable to those observed in the fasted state. See Figure 7B.

[0200] Dapagliflozin AUClast and AUCinf were comparable between Treatment F (150 mg AZD9977 + 10 mg dapagliflozin capsule 3, fasted) and the reference, Treatment A2 (150 mg AZD9977 (50 mg AZD9977 capsule + 100 mg AZD9977 capsule) and 10 mg dapagliflozin tablet, fasted). Cmax was 22% lower than Treatment A2 Cmax, and C24 values ​​were 7% higher than Treatment A2 C24. See Figure 8A.

[0201] For Treatment G (150 mg AZD9977 + 10 mg dapagliflozin capsule 4, fasted) vs. reference Treatment A2 (150 mg AZD9977 (50 mg AZD9977 capsules + 100 mg AZD9977 capsules) and 10 mg dapagliflozin tablets, fasted), AUClast and AUCinf were occasionally 8% and 9% higher than Treatment A2 values, respectively. Cmax was comparable to Treatment A2 Cmax, and C24 values ​​were 11% higher than Treatment A2 C24. See Figure 8A.

[0202] For Treatment H (10 mg dapagliflozin capsules, fasted) versus reference Treatment A2 (150 mg AZD9977 (50 mg AZD9977 capsules + 100 mg AZD9977 capsules) and 10 mg dapagliflozin tablets, fasted), AUC was 7% higher than Treatment A2 values ​​and AUC was 6% higher than Treatment A2 values. C was 26% lower than Treatment A2 C, and C values ​​were 15% higher than Treatment A2 C. See Figure 8A.

[0203] For Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasted) vs. Treatment G (150 mg AZD9977 + 4 10 mg dapagliflozin capsules, fasted), dapagliflozin variant 1, Treatment B dapagliflozin AUClast and AUCinf were 6% lower than Treatment G AUClast and AUCinf. Treatment B Cmax was sometimes 16% lower than Treatment G Cmax, and Treatment B C24 values ​​were comparable to Treatment G C24. See Figure 8B.

[0204] Dapagliflozin variant 2, dapagliflozin AUClast, and AUCinf were comparable for Treatment D (150 mg AZD9977 + 2 10 mg dapagliflozin capsules, fasted) versus Treatment F (150 mg AZD9977 + 3 10 mg dapagliflozin capsules, fasted). Treatment D Cmax was occasionally 7% higher than Treatment F Cmax, and Treatment D C24 values ​​were occasionally 8% higher than Treatment F C24 values. See Figure 8B.

[0205] Pharmacokinetic conclusions. Under fasting conditions, exposure to AZD9977 and dapagliflozin from all four capsules (Treatments B, D, F, G) was generally comparable to the respective reference treatments (A1 and A2) in terms of AUClast and AUCinf, however, there was a trend toward lower Cmax and higher C24 than those observed for the reference treatments.

[0206] Administration of Capsules 1 and 2 with food resulted in a slightly delayed t for AZD9977. For Treatment C (Capsule 1, fed), AUC, AUC, and C values ​​for AZD9977 were higher than those observed for Treatment B (Capsule 1, fasted), and C values ​​were lower in the fed state. For Treatment E (Capsule 2, fed), AUC, and AUC values ​​for AZD9977 were similar to Treatment D (Capsule 2, fasted), with C sometimes higher and C values ​​lower in the fed state than in the fasted state. Overall, the magnitude of the effect of food on AZD9977 PK appeared to be less for Capsule 2 than for Capsule 1.

[0207] For dapagliflozin in Treatment C (Capsule 1, fed) and Treatment E (Capsule 2, fed), the fed tmax was slightly later than the fasted tmax, but exposure to dapagliflozin was comparable between the fed and fasted states with respect to AUClast and AUCinf. For Treatment C, Cmax was lower than Treatment B Cmax and C24 was higher than Treatment B C24. For Treatment E, Cmax was lower than Treatment D Cmax and C24 values ​​were comparable.

[0208] Exposure to AZD9977 variant 1 from capsule 1 (treatment B) was comparable to exposure from capsule 3 (treatment F) in terms of AUClast, AUCinf, Cmax, and C24. Exposure to AZD9977 variant 2 from capsule 2 (treatment D) was comparable to exposure from capsule 4 (treatment G) in terms of AUClast and AUCinf. Treatment D Cmax was occasionally 11% higher than Treatment G Cmax, and Treatment D C24 values ​​were 29% lower than Treatment G C24 values.

[0209] Dapagliflozin variant 1 exposure from capsule 1 (treatment B) was 6% less than that from capsule 4 (treatment G) in terms of AUClast and AUCinf. Treatment B Cmax was sometimes 16% lower than Treatment G Cmax, with comparable C24 values.

[0210] Exposure to dapagliflozin variant 2 from capsule 2 (treatment D) was comparable to that from capsule 3 (treatment F) in terms of AUClast and AUCinf. Treatment D Cmax and C24 values ​​were occasionally 7-8% higher than Treatment F values.

[0211] For AZD9977, trends were consistent across all capsule formulations in the fasted state. The AUC and AUC values ​​for capsules (treatments B, C, D, E, F, and G) were generally comparable to those observed for the respective reference treatments (A1 or A2), but C tended to be lower and C tended to be higher than the reference treatments. Similar trends were observed for dapagliflozin, with the minor exception of treatment G, where AUC and AUC values ​​were slightly higher than the reference treatment, C was comparable to the reference treatment, and C tended to be slightly lower.

[0212] Administration of Capsule 1 and Capsule 2 with food resulted in a slightly delayed tmax for AZD9977. For Treatment C (Capsule 1, fed), AUClast, AUCinf, and Cmax values ​​were significantly higher than those observed for Treatment B (Capsule 1, fasted), and C24 values ​​were significantly lower in the fed state. For Treatment E (Capsule 2, fed), the effect of equivalent exposure to AZD9977 in the fasted state was less pronounced with respect to AUClast and AUCinf, but the fed state appeared to result in a higher Cmax and a lower C24. For dapagliflozin in Treatments C and E, the fed state tmax was slightly later than the fasted state, but exposure to dapagliflozin was comparable between the fed and fasted states with respect to AUClast and AUCinf. The Cmax of dapagliflozin was lower in the fed state for both capsule 1 and capsule 2, and C24 was slightly higher for capsule 1 but comparable for capsule 2.

[0213] The effect of food on the pharmacokinetics of AZD9977 and dapagliflozin is unlikely to be clinically relevant, and the AZD9977 / dapagliflozin fixed-dose combination is expected to be taken without dietary advice.

[0214] AZD9977 variant 1 was administered in combination with a different variant of dapagliflozin as treatment B (capsule 1) and treatment F (capsule 3). Exposure to AZD9977 variant 1 from capsule 1 was comparable to exposure from capsule 3 in terms of AUC, AUC, C, and C. AZD9977 variant 2 was administered as treatment D (capsule 2) and treatment G (capsule 4). Exposure to AZD9977 variant 2 from capsule 2 was comparable to exposure from capsule 4 in terms of AUC and AUC, although C values ​​appeared to be higher in some cases for capsule 2 and C was lower in some cases for capsule 2.

[0215] The same dapagliflozin variants were administered in different capsules, with variant 1 administered as treatment B (capsule 1) and treatment G (capsule 4), and variant 2 administered as treatment D (capsule 2) and treatment F (capsule 3). Dapagliflozin exposure to variant 1 was sometimes less than that observed for capsule 1 in terms of AUC and AUC, while dapagliflozin exposure to variant 2 from capsule 2 was comparable to that observed for capsule 3 in terms of AUC and AUC. For variant 1, C for treatment B (capsule 1) was sometimes lower than that observed for treatment G (capsule 4), and C was comparable to that observed for treatment G (capsule 4). For variant 2, C and C for treatment D (capsule 2) were sometimes higher than those observed for treatment F (capsule 3).

[0216] Example 4. Phase 3 formulation of AZD9977 and dapagliflozin capsules Immediate release (IR) AZD9977 pellets: Preparation of AZD9977 spray coating suspension (A1 suspension). 5.1 kg of polyvinylpyrrolidone (povidone; PVP) K30 (BASF) was added to 130.9 kg of purified water and stirred for at least 0.5 hours (until a clear solution was obtained). 34 kg of AZD9977 (STA WuXi) was added to the PVPK 30 / water solution to produce a 23% (w / w) AZD9977 coating suspension, which was stirred overnight at room temperature. The particle size of the suspension was reduced using a Coball mill.

[0217] Spray coating of 600 mg / g AZD9977 IR pellets (A1). 17 kg of microcrystalline cellulose (MCC) cores (VIVAPUR® 100, JRS Pharma) were loaded into a Wurster fluid-bed spray coater (GPCG30). The cores were coated with 165 kg of the AZD9977 coating suspension under the conditions summarized in Table 2 to produce 54.2 kg of AZD9977 IR pellets with a drug loading of 601 mg / g.

[0218] Immediate Release (IR) Dapa Pellets: Preparation of Dapa spray coating suspension. 0.9 kg of hydroxypropyl cellulose (HPC SSL from Nisso) was added to 67.5 kg of purified water and stirred for at least 0.5 hours (until a clear solution was obtained). 14.85 kg of talc (Imerys) and 6.75 kg of dapagliflozin (Dottikon) were added to the HPC solution to produce a 25% (w / w) Dapa coating suspension. The suspension was stirred overnight at room temperature.

[0219] Spray coating of 105 mg / g Dapa IR pellets. 30 kg of sugar sphere (NP) cores (Vivapharm®, JRS Pharma) were loaded into a Wurster fluid-bed spray coater (GPCG30). The cores were coated with 90 kg of the Dapa coating suspension under the conditions summarized in Table 2 to produce 49.5 kg of Dapa IR pellets with a drug loading of 107 mg / g.

[0220] [Table 2]

[0221] Filling the capsules with pellets Lubricating: AZD9977: 49.9 kg of AZD9977 pellets were mixed with 0.1 kg of sodium stearyl fumarate (SSF PRUV, Moehs) in a 200 L double cone blender for 10 minutes at 15 rpm to produce 50.0 kg of lubricated AZD9977 pellets.

[0222] Dapagliflozin: 99.8 kg of dapagliflozin pellets were mixed with 0.2 kg of sodium stearyl fumarate (SSF Purve, Moehs) in a 200 L double cone blender for 10 minutes at 15 rpm to produce 100.0 kg of lubricated dapagliflozin pellets.

[0223] FDC capsules: Dose 50 mg AZD9977 and 10 mg dapagliflozin. 50.0 kg of lubricated AZD9977 pellets and 57.5 kg of lubricated dapagliflozin pellets were filled into 600,000 white size 1 EL gelatin capsules (Capsugel) using an MG Futura encapsulator, at an average fill weight of 83.4 mg AZD9977 pellets and 95.9 mg dapagliflozin pellets.

[0224] Dose 150 mg AZD9977 and 10 mg dapagliflozin. 50.0 kg of lubricated AZD9977 pellets and 19.2 kg of lubricated dapagliflozin pellets were filled into 200,000 white size 1 EL gelatin capsules (Capsugel) using an MG Futura encapsulator, at an average fill weight of 250 mg AZD9977 pellets and 95.9 mg dapagliflozin pellets.

Claims

1. A pharmaceutical composition, (a) One or more first pellets, i. The first core, and ii. A first pellet comprising a first coating on the first core, the first coating comprising a mineralocorticoid receptor (MR) modulator and a first binder, (b) One or more second pellets, i. The second core, and ii. A second pellet comprising a second coating on the second core, the second coating comprising an SGLT2 inhibitor, wherein the SGLT2 inhibitor is present in an amount of about 5% to about 20% by weight of the second pellet, A pharmaceutical composition comprising about 20% to about 50% by weight of the mineralocorticoid receptor (MR) modulator and about 1% to about 10% by weight of the SGLT2 inhibitor.

2. The aforementioned MR modifier is given by formula I: 【Chemistry 1】 The pharmaceutical composition according to claim 1, comprising the compound.

3. The pharmaceutical composition according to claim 1, comprising approximately 25% to approximately 45% by weight of the MR modifier.

4. The pharmaceutical composition according to claim 1, comprising 25% to about 30% by weight of the MR modifier, or about 40% by weight or about 45% by weight of the MR modifier.

5. The pharmaceutical composition according to claim 1, wherein the first binder comprises povidone.

6. The pharmaceutical composition according to claim 5, comprising approximately 1% to approximately 10% by weight of povidone.

7. The pharmaceutical composition according to claim 6, comprising approximately 4% to approximately 5% by weight of povidone or approximately 6% to approximately 7% by weight of povidone.

8. The pharmaceutical composition according to claim 1, wherein the first binder comprises povidone and hypromellose.

9. The pharmaceutical composition according to claim 8, comprising approximately 4% to approximately 6% by weight of povidone.

10. The pharmaceutical composition according to claim 8, comprising approximately 0.5% to approximately 3% by weight of hypromellose.

11. The pharmaceutical composition according to claim 8, comprising about 5% by weight of povidone and about 1% by weight of hypromellose.

12. The pharmaceutical composition according to claim 1, wherein the first coating further comprises a first lubricant.

13. The pharmaceutical composition according to claim 12, wherein the first lubricant comprises sodium stearyl fumarate.

14. The pharmaceutical composition according to claim 12, wherein the first lubricant is present in an amount of about 0.01% to about 0.5% by weight of the composition.

15. The pharmaceutical composition according to claim 1, wherein the first core comprises microcrystalline cellulose.

16. The pharmaceutical composition according to claim 15, wherein the first core is in an amount of about 10% to about 30% by weight of the composition.

17. The pharmaceutical composition according to claim 1, wherein the SGLT2 inhibitor comprises dapagliflozin.

18. The pharmaceutical composition according to claim 17, wherein the SGLT2 inhibitor comprises either amorphous dapagliflozin or crystalline dapagliflozin.

19. The pharmaceutical composition according to claim 1, comprising approximately 2% to approximately 8% by weight of the SGLT2 inhibitor.

20. The pharmaceutical composition according to claim 1, comprising approximately 2.5% to approximately 4% of the SGLT2 inhibitor.

21. The pharmaceutical composition according to claim 1, wherein the SGLT2 inhibitor is present in an amount of about 5% to about 15% by weight of the second pellet.

22. The pharmaceutical composition according to claim 21, wherein the SGLT2 inhibitor is present in an amount of about 7% to about 13% by weight of the second pellet.

23. The pharmaceutical composition according to claim 22, wherein the SGLT2 inhibitor is present in an amount of about 8% to about 12% by weight of the second pellet.

24. The pharmaceutical composition according to claim 1, wherein the SGLT2 inhibitor is present in an amount of about 10% to about 15% by weight of the second pellet.

25. The pharmaceutical composition according to claim 24, wherein the SGLT2 inhibitor is present in an amount of about 12% to about 14% by weight of the second pellet.

26. The pharmaceutical composition according to claim 25, wherein the SGLT2 inhibitor is present in an amount of about 12.8% by weight of the second pellet.

27. The pharmaceutical composition according to claim 1, wherein the second coating further comprises a second binder, an anti-tackifying agent, and a second lubricant.

28. The pharmaceutical composition according to claim 27, wherein the second binder comprises hydroxypropyl cellulose.

29. The pharmaceutical composition according to claim 27, wherein the second binder is in an amount of about 0.1% to about 5% by weight of the composition.

30. The pharmaceutical composition according to claim 27, wherein the anti-tack agent comprises talc.

31. The pharmaceutical composition according to claim 27, wherein the anti-tack agent is present in an amount of about 1% to about 20% by weight of the composition.

32. The pharmaceutical composition according to claim 27, wherein the second lubricant comprises sodium stearyl fumarate.

33. The pharmaceutical composition according to claim 27, wherein the second lubricant is present in an amount of about 0.01% to about 1% by weight of the composition.

34. The pharmaceutical composition according to claim 1, wherein the second core comprises sugar, starch, or a combination thereof.

35. The pharmaceutical composition according to claim 34, wherein the second core is in an amount of about 10% to about 40% by weight of the composition.

36. A pharmaceutical composition in the form of a capsule, (a) One or more first pellets, i. A first core comprising a microcrystalline cellulose core, wherein the first core constitutes about 5% to about 25% by weight of the capsule. ii. The first coating is: (A) an MR modifier which is AZD9977, wherein AZD9977 is present in an amount of about 10% to about 45% by weight of the capsule, (B) povidone present in an amount of about 1% to about 10% by weight of the capsule, and (C) Sodium stearyl fumarate, in an amount of approximately 0.01% to approximately 1% by weight of the capsule. A first coating, including A first pellet containing, (b) One or more second pellets, i. A second core containing sugar globules, wherein the sugar globules constitute about 5% to about 30% by weight of the capsule, ii. The second coating is: (A) an SGLT2 inhibitor which is dapagliflozin propanediol, wherein the dapagliflozin propanediol is in an amount of about 1% to about 10% by weight of the capsule and about 5% to about 20% by weight of the second pellet, (B) hydroxypropyl cellulose in an amount of about 0.1% to about 1% by weight of the capsule, (C) talc in an amount of about 1% to about 15% by weight of the capsule, and (D) Sodium stearyl fumarate, in an amount of about 0.01% to about 1% by weight of the capsule. A second coating, including A pharmaceutical composition comprising a second pellet containing the same substance.

37. A pharmaceutical composition in the form of a capsule, (a) One or more first pellets, i. A first core comprising a microcrystalline cellulose core, wherein the first core constitutes about 5% to about 25% by weight of the capsule. ii. The first coating is: (A) an MR modifier which is AZD9977, wherein AZD9977 is present in an amount of about 15% to about 40% by weight of the capsule, (B) povidone present in an amount of about 2% to about 8% by weight of the capsule, and (C) Sodium stearyl fumarate, in an amount of approximately 0.1% to approximately 0.5% by weight of the capsule. A first coating, including A first pellet containing, (b) One or more second pellets, i. A second core containing sugar globules, comprising about 10% to about 25% by weight of the capsule, ii. The second coating is: (A) an SGLT2 inhibitor which is dapagliflozin propanediol, wherein the dapagliflozin propanediol is in an amount of about 2% to about 5% by weight of the capsule and about 5% to about 20% by weight of the second pellet, (B) hydroxypropyl cellulose in an amount of about 0.2% to about 0.8% by weight of the capsule, (C) talc in an amount of about 5% to about 12% by weight of the capsule, and (D) Sodium stearyl fumarate, in an amount of approximately 0.03% to approximately 0.1% by weight of the capsule. A second coating, including A pharmaceutical composition comprising a second pellet containing the same substance.

38. The pharmaceutical composition according to claim 36, wherein the capsule contains either about 50 mg or about 150 mg of AZD9977.

39. The pharmaceutical composition according to claim 36, wherein the capsule contains about 10 mg of dapagliflozin propanediol.

40. The pharmaceutical composition according to claim 1, in oral dosage form.

41. The pharmaceutical composition according to claim 40, which is a capsule.

42. The pharmaceutical composition according to claim 40, wherein the pharmaceutical composition in the dosage form contains about 50 mg or about 150 mg of AZD9977.

43. The pharmaceutical composition according to claim 40, wherein the pharmaceutical composition in the dosage form contains about 10 mg of dapagliflozin propanediol.

44. The pharmaceutical composition according to claim 1, wherein at least 80% of the MR regulator is released within 30 minutes.

45. The pharmaceutical composition according to claim 1, wherein at least 80% of the SGLT2 inhibitor is released within 30 minutes.

46. A pharmaceutical composition according to any one of claims 1 to 45 for treating heart failure in a person requiring treatment for heart failure.

47. The pharmaceutical composition according to claim 46, wherein a daily dose of approximately 50 mg or approximately 150 mg of the MR regulator and approximately 10 mg of the SGLT2 inhibitor are administered.

48. The pharmaceutical composition according to claim 46, wherein the administration is once a day.

49. The pharmaceutical composition according to claim 46, wherein the pharmaceutical composition is administered to the subject in a fasted state.

50. AUC of TH after the aforementioned administration ｌａｓｔ and AUC ｉｎｆ However, the AUC of the subject who was administered the MR regulator and the SGLT2 inhibitor in separate dosage forms ｌａｓｔ and AUC ｉｎｆ The pharmaceutical composition according to claim 46, wherein the amount is within 10%.

51. A pharmaceutical composition according to any one of claims 1 to 45 for treating chronic kidney disease in a subject requiring treatment for chronic kidney disease.

52. The pharmaceutical composition according to claim 51, wherein a daily dose of approximately 50 mg or approximately 150 mg of the MR regulator and a daily dose of approximately 10 mg of the SGLT2 inhibitor are administered.

53. The pharmaceutical composition according to claim 51, wherein the administration is once a day.

54. The pharmaceutical composition according to claim 51, wherein the pharmaceutical composition is administered to the subject in a fasted state.

55. AUC of TH after the aforementioned administration ｌａｓｔ and AUC ｉｎｆ However, the AUC of the subject who was administered the MR regulator and the SGLT2 inhibitor in separate dosage forms ｌａｓｔ and AUC ｉｎｆ The pharmaceutical composition according to claim 51, wherein the amount is within 10%.

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