Combination of SGLT2 inhibitor and mineralocorticoid receptor modulator for treatment of heart and kidney diseases

Abstract

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

[0002] Chronic heart failure (HF) is a leading cause of death, hospitalization, and poor quality of life. Even with the best treatment, the 5-year survival rate for patients with HF is worse than for most cancers. In addition, the prevalence of chronic HF continues to rise worldwide. An estimated 38 million people are affected worldwide, with more than one million hospitalizations each year in the United States and Europe. Approximately 20% to 67% of patients with HF also have chronic kidney disease (CKD), which results in a 25% to 35% increased risk of mortality compared to 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 comprising (i) a first core, and (ii) a first coating on the first core, wherein the first coating comprises a mineralocorticoid receptor (MR) modulator and a first binder; and (b) one or more second pellets comprising (i) a second core, and (ii) a second coating on the second core, wherein the second coating comprises an SGLT2 inhibitor, wherein the SGLT2 inhibitor is about 5 weight % to about 20 weight % of the second pellet, wherein the composition comprises about 20 weight % to about 50 weight % of the mineralocorticoid receptor (MR) modulator; and about 1 weight % to about 10 weight % of the SGLT2 inhibitor.

[0004] In some embodiments, the MR modulator comprises a compound of Formula I:

[0005]

[0006] In some embodiments, the composition comprises from about 20 wt% to about 50 wt% of the MR modifier. In some embodiments, the composition comprises about 25 wt% or about 45 wt% of the MR modifier.

[0007] In some embodiments, as non-limiting examples, the first binder can be selected from 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 binding agent comprises povidone. In some embodiments, the composition comprises about 1 wt % to about 10 wt % of povidone. In some embodiments, the composition comprises about 4 wt % to about 5 wt % of povidone. In some embodiments, the composition comprises about 6 wt % to about 7 wt % of povidone.

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

[0010] In some embodiments, the first coating may further include a first lubricant. As a non-limiting example, the first lubricant may be selected from sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate, stearyl alcohol, talc, silicon dioxide or a combination thereof. In some embodiments, the first lubricant includes sodium stearyl fumarate. In some embodiments, the first lubricant is 0 wt % to about 0.5 wt % of the composition. In some embodiments, the first core includes microcrystalline cellulose. In some embodiments, the first core is about 10 wt % to about 30 wt % of the composition.

[0011] In some embodiments, the at least one SGLT2 inhibitor is selected from a compound of Formula II:

[0012]

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

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

[0015]

[0016] In some embodiments, the 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 US Pat. No. 7,919,598.

[0017] In some embodiments, the composition comprises from about 1% to about 10% by weight of the SGLT2 inhibitor. In some embodiments, the composition comprises from 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 also includes a second binding agent, an anti-adhesive agent and optionally a second lubricant. In some embodiments, the second binding agent can be selected from, for example, polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyethylene oxide (PEO), xanthan gum, cellulose derivatives (such as methylcellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC)), gelatin, starch (such as corn, potato or rice), pregelatinized starch and related materials or a combination thereof. In at least one embodiment, the second binding agent includes hydroxypropyl cellulose. In some embodiments, the second binding agent is about 0.1% by weight to about 5% by weight of a composition. In some embodiments, the anti-adhesive agent includes talc. In some embodiments, the anti-adhesive agent is about 1% by weight to about 20% by weight of a composition. In some embodiments, the second lubricant includes sodium stearyl fumarate. In some embodiments, the second lubricant is 0% by weight to about 1% by weight of a composition. In some embodiments, the second core includes sugar, 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 components in the capsule may 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, wherein the first core is about 5 weight % to about 25 weight % of the capsule; (ii) a first coating comprising (A) an MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 10 weight % to about 45 weight % of the capsule; (B) povidone, wherein the povidone is about 1 weight % to about 10 weight % of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01 weight % to about 1 weight % of the capsule; and (b) one or more first Two pellets, which include: (i) a second core, which includes sugar spheres, wherein the sugar spheres are about 5 weight % to about 30 weight % of the capsule; (ii) a second coating, which includes (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 1 weight % to about 10 weight % of the capsule and about 5 weight % to about 20 weight % of the second pellet; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.1 weight % to about 1 weight % of the capsule; (C) talc, wherein the talc is about 1 weight % to about 15 weight % of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01 weight % to about 0.1 weight % of the capsule.

[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 propylene glycol.

[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 propylene glycol. In some embodiments, the present disclosure provides a capsule comprising about 5 mg to about 10 mg of dapagliflozin propylene glycol.

[0023] 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 50 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 150 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 10 mg dapagliflozin propylene glycol.

[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 AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 10 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 15 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 20 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 25 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 30 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 35 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 40 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 45 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 50 mg AZD9977. In some embodiments, the pharmaceutical composition in the dosage form comprises about 10 mg dapagliflozin propylene glycol.

[0025] In some embodiments, at least 75%-85% of the MR modulator is released from the pharmaceutical composition or oral dosage form described herein within a time range of about 15 minutes to 30 minutes. In other embodiments, at least 75%-85% of the SGLT2 inhibitor is released from the pharmaceutical composition or oral dosage form described herein within a time range of about 15 minutes to 30 minutes. The dissolution profile can be tested using dissolution techniques known to those skilled in the art, for example, 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, comprising administering a pharmaceutical composition or oral dosage form as described herein. Also disclosed is a method of treating chronic kidney disease in a subject in need thereof, comprising administering a pharmaceutical composition or oral dosage form as described herein.

[0027] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof, comprising administering the 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 without an associated clinically significant increase in hyperkalemia in the subject, comprising administering a pharmaceutical composition or oral dosage form described herein.

[0029] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof without an associated clinically significant increase in hypotension in the subject, comprising administering a pharmaceutical composition or oral dosage form described herein.

[0030] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof without an associated clinically significant increase in the subject's risk of acute kidney injury, comprising administering a pharmaceutical composition or oral dosage form described herein.

[0031] Also disclosed are methods of treating heart failure and / or chronic kidney disease in a subject in need thereof without an associated clinically significant increase in the subject's risk of gynoid breast development, comprising administering a pharmaceutical composition or oral dosage form described herein.

[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 a day. In some embodiments, the pharmaceutical composition or oral dosage form is administered to a subject in a fasting state. In some embodiments, after administration, the subject's AUC last and AUC inf AUC in subjects taking separate dosage forms of MR modulators and SGLT2 inhibitors last and AUC inf within 10% of.

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

[0034] In some embodiments, a daily dose of AZD9977 in the range of about 15 mg to about 40 mg and a daily dose of the SGLT2 inhibitor of about 10 mg is administered. In some embodiments, administration is once a day. In some embodiments, the pharmaceutical composition or oral dosage form is administered to a subject in a fasting state. In some embodiments, after administration, the subject's AUC last and AUC inf AUC in subjects taking separate dosage forms of MR modulators and SGLT2 inhibitors last and AUC inf within 10% of. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The following drawings form part of this specification and are included to further demonstrate exemplary embodiments of certain aspects of the present disclosure.

[0036] Figures 1A to 1C Shown are the results of an in vitro dissolution study of fixed dose combination (FDC) capsules comprising AZD9977 and dapagliflozin as described in the embodiments herein. Figure 1A Shown is the in vitro dissolution profile of dapagliflozin tested in USP Apparatus 1 at 100 rpm. Figure 1B Shown is the in vitro dissolution profile of AZD9977 tested in USP Apparatus 2 at 100 rpm. Figure 1C Shown is the in vitro dissolution profile of AZD9977 tested in USP Apparatus 1 at 100 rpm.

[0037] Figure 2A and Figure 2B Exemplary pharmaceutical compositions and components thereof as described in the embodiments herein are shown. Figure 2A Single active dosage forms and pellets of AZD9977 and dapagliflozin are shown. Figure 2B A schematic diagram of the clinical study evaluating the bioavailability of FDC capsules compared to single active dosage forms as described in Example 3 is shown.

[0038] Figure 3A and Figure 3B The mean plasma AZD9977 concentration versus time curve for subjects in the clinical study described in Example 3 is shown. Figure 3A Display results on a linear scale; Figure 3B Results are presented on a semi-logarithmic scale.

[0039] Figure 4A Statistical comparison of the pharmacokinetic parameters of AZD9977 in Group 1 (fasted) of the clinical study described in Example 3 is shown.

[0040] Figure 4BStatistical comparison of the pharmacokinetic parameters of AZD9977 in Group 1 (fed / fasted) of the clinical study described in Example 3 is shown.

[0041] Figure 5A Statistical comparison of the pharmacokinetic parameters of AZD9977 in Group 2 of the clinical study described in Example 3 is shown.

[0042] Figure 5B Statistical comparison of the pharmacokinetic parameters of AZD9977 for the same AZD9977 variants provided in different capsules under fasting conditions for each group of the clinical study described in Example 3 is shown.

[0043] Fig. 6A and Figure 6B Shown is a curve of geometric mean plasma dapagliflozin concentration versus time for subjects in the clinical study described in Example 3. Fig. 6A Display results on a linear scale; Figure 6B Results are presented on a semi-logarithmic scale.

[0044] Fig. 7A Statistical comparison of the pharmacokinetic parameters of dapagliflozin in Group 1 (fasting) of the clinical study described in Example 3 is shown.

[0045] Figure 7B Statistical comparison of the pharmacokinetic parameters of dapagliflozin in Group 1 (fed / fasted) of the clinical study described in Example 3 is shown.

[0046] Fig. 8A Statistical comparison of the pharmacokinetic parameters of dapagliflozin in Group 2 of the clinical study described in Example 3 is shown.

[0047] Figure 8B Statistical comparison of the pharmacokinetic parameters of dapagliflozin for the same dapagliflozin variants provided in different capsules under fasting conditions for each group of the clinical study described in Example 3 is shown. DETAILED DESCRIPTION

[0048] 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. In addition, unless otherwise required by context, singular terms shall include plural terms and plural terms shall include the singular.

[0049] As used herein, "about" may refer to plus or minus 10% of the value provided. Where ranges are provided, they include the boundary values. "About" may additionally or alternatively mean within 10% of the value, or within 5% of the value, or in some cases within 2.5% of the value; alternatively, "about" may mean rounded to the nearest significant figure.

[0050] As used herein, "between" is a range that includes the endpoints of the range. For example, numbers between x and y specifically include the numbers x and y and any number that falls within x and y.

[0051] The mineralocorticoid receptor (MR) is a ligand-activated transcriptional binding factor that belongs to the class of oxysteroid nuclear hormone receptors. MR activation of aldosterone in renal tubules and epithelial cells plays a key role in blood pressure control. MR activation in non-epithelial tissues promotes target organ dysfunction by stimulating inflammation, oxidative stress, and fibrosis. In addition, pathological activation of MR leads to an increased risk of cardiovascular events. See, e.g., 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 from binding to an agonist. In some embodiments, the MR modulator of the pharmaceutical composition described herein includes a MR antagonist. Non-limiting examples of MR antagonists include spironolactone, eplerenone, canrenone, progesterone, drospirenone, gestodene, and benidipine. In some embodiments, MR antagonists antagonize MR in epithelial and non-epithelial tissues. In some embodiments, the MR modulator of the pharmaceutical composition described herein comprises a selective MR modulator. In some embodiments, the selective MR modulator is capable of antagonizing 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 balcinrenone is further described, for example, in WO 2016 / 001631 and is a compound of Formula I:

[0052]

[0053] Sodium-glucose cotransporter-2 (SGLT2) is the major cotransporter involved in the reabsorption of sugar in the kidney. As used herein, "SGLT2 inhibitors" (also known as gliflozin or flozin) inhibit SGLT2 activity. In some embodiments, SGLT2 inhibitors inhibit the reabsorption of glucose in the kidney and thus lower blood sugar. SGLT2 inhibitors can slow the progression of kidney disease, reduce HF, and reduce the risk of kidney failure and death in subjects with CKD and those with kidney disease and type 2 diabetes. See, for example, "SGLT2 Inhibitors," National Kidney Foundation (<kidney.org / atoz / content / sglt2-inhibitors> ; accessed in June 2022). In some embodiments, the SGLT2 inhibitor of the pharmaceutical composition described herein includes canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, or a combination thereof. In some embodiments, the SGLT2 inhibitor includes a solvate 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 includes dapagliflozin propylene glycol. In some embodiments, "dapagliflozin propylene glycol" refers to a solvate form of dapagliflozin, which comprises dapagliflozin, (S)-(+)-1,2-propylene glycol, and water in a 1:1:1 ratio. In some embodiments, the theoretical amount of dapagliflozin in a non-solvated form is about 81.29% (w / w) of dapagliflozin propylene glycol.

[0054] In some embodiments, the present disclosure provides a combination of a MR modulator and a SGLT2 inhibitor in a single dosage form, also referred to as a "fixed dose combination" or FDC formulation, which can be used to treat HF ​​and / or CKD. In some embodiments, the FDC formulation comprising a MR modulator and a SGLT2 inhibitor provides a greater therapeutic benefit than each active ingredient alone. In some embodiments, administration of a FDC formulation comprising a MR modulator and a SGLT2 inhibitor provides a greater therapeutic benefit than co-administering the MR modulator and the SGLT2 inhibitor in separate dosage forms containing a single active ingredient.

[0055] 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 compression characteristics of multi-active ingredient blends; and providing a reasonable dosage form size.

[0056] In some embodiments, the FDC formulations provided herein include two active ingredients belonging to different categories according to the Biopharmaceutical Classification System (BCS), such as 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. Therefore, a special challenge in developing FDC formulations comprising AZD9977 and dapagliflozin is to ensure that the active ingredient has an in vitro dissolution and in vivo bioavailability comparable to those observed for single active ingredient formulations. In addition, a high drug loading of AZD9977 is required (e.g., about 50 mg to about 200 mg or about 120 mg to about 180 mg in a dosage form, or about 140 mg to about 160 mg or about 50 mg or 150 mg in a dosage form), but the dosage form size should be maintained in a size that does not hinder patient compliance. In some embodiments, the FDC formulation is provided in a hard gelatin capsule, e.g., size 0, size 1 (such as size IE).

[0057] To address such challenges, a composition is provided herein that includes a first active ingredient in a first pellet, such as an MR modulator; and a second active ingredient in a second pellet, such as an SGLT2 inhibitor. In some embodiments, the first pellet and the second pellet, which respectively include the first active ingredient and the second active ingredient (e.g., an MR modulator and an SGLT2 inhibitor), each include a core and a coating coated on the core. The desired drug loading and dissolution profile of each active ingredient is achieved 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 ingredient therein).

[0058] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) one or more first pellets comprising (i) a first core, and (ii) a first coating on the first core, wherein the first coating comprises a mineralocorticoid receptor (MR) modulator and a first binder comprising povidone; and (b) one or more second pellets comprising (i) a second core, and (ii) a second coating on the second core, wherein the second coating comprises an SGLT2 inhibitor, wherein the SGLT2 inhibitor is about 5% to about 20% by weight of the second pellet; wherein the composition 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. 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, a caplet, or a tablet. In some embodiments, the oral dosage form is a capsule. In some embodiments, the capsule is a gelatin capsule No. 000, No. 00, No. 00EL, No. 0, No. 1, No. 2, or No. 3. 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 size 1E gelatin capsule.

[0059] First Pellets

[0060] 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 a MR modifier and a first binder. In some embodiments, the first coating comprises a MR modifier, a first binder, and a lubricant.

[0061] In some embodiments, the first coating comprises a MR modulator. Exemplary MR modulators are provided herein. In some embodiments, the MR modulator comprises a MR antagonist, a selective MR modulator, or a combination thereof. In some embodiments, the MR modulator comprises spironolactone, eplerenone, canrenone, progesterone, drospirenone, gestodene, benidipine, finerenone, AZD9977, or a combination thereof. In some embodiments, the MR modulator comprises AZD9977 (balcinrenone).

[0062] In some embodiments, the MR modulator is about 20% to about 60% by weight of the composition, 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. 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.

[0063] In some embodiments, the MR modulator comprises AZD9977. In some embodiments, the composition comprises from about 20 wt % to about 60 wt % AZD9977. In some embodiments, the composition comprises from about 25 wt % to about 55 wt % AZD9977. In some embodiments, the composition comprises from about 20 wt % to about 50 wt % AZD9977. In some embodiments, the composition comprises from about 25 wt % to about 45 wt % AZD9977. In some embodiments, the composition comprises from about 40 wt % to about 45 wt % 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.

[0064] In some embodiments, the first coating comprises a first binder. As used herein, a "binder" refers to an excipient that holds the components of the composition (e.g., powders, granules, and other dry ingredients) together. 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, hydroxypropyl methylcellulose (also referred to herein as "hydroxypropyl methylcellulose" or "HPMC"), hydroxypropyl cellulose, hydroxyethyl cellulose, cross-linked sodium carboxymethyl cellulose; polyvinyl pyrrolidone (also referred to herein as "povidone" or "PVP"); starch (e.g., corn, potato, and rice); pregelatinized starch, sugars, such as sucrose, lactose, and derivatives thereof; sugar alcohols, such as mannitol; sweeteners, such as isomalt; and polyethylene glycol (PEG), polyethylene oxide (PEO), and combinations thereof.

[0065] In some embodiments, the first binder is about 1% to about 20% by weight of the composition, 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. In some embodiments, the first binder is about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of the composition. In some embodiments, the first binder is about 4.2% by weight, about 6% by weight, about 6.32% by weight, or about 6.5% by weight of the composition. In some embodiments, the first binder includes povidone, hypromellose, or a combination thereof.

[0066] In some embodiments, the first binding agent includes povidone. In some embodiments, the composition includes about 1% by weight to about 20% by weight of povidone. In some embodiments, the composition includes about 2% by weight to about 15% by weight of povidone. In some embodiments, the composition includes about 3% by weight to about 10% by weight of povidone. In some embodiments, the composition includes about 4% by weight to about 8% by weight of povidone. In some embodiments, the composition includes about 6% by weight to about 7% by weight of povidone. In some embodiments, the composition includes about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% by weight or about 10% by weight of povidone. In some embodiments, the composition comprises about 6.0 wt %, about 6.1 wt %, about 6.2 wt %, about 6.3 wt %, about 6.4 wt %, about 6.5 wt %, about 6.6 wt %, about 6.7 wt %, about 6.8 wt %, about 6.9 wt % or about 7 wt % of povidone. In some embodiments, the composition comprises about 4.2 wt % of povidone. In some embodiments, the composition comprises about 6.5 wt % of povidone.

[0067] In some embodiments, the first binder comprises povidone and hypromellose.In some embodiments, the composition comprises about 1 wt % to about 10 wt % of povidone, or about 2 wt % to about 8 wt % of povidone, or about 3 wt % to about 7 wt % of povidone, or about 4 wt % to about 6 wt % 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% by weight of povidone. In some embodiments, the composition comprises about 0.1% to about 5% 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.

[0068] 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% of povidone and about 1% of hypromellose. In some embodiments, the composition comprises about 5.35% of povidone and about 0.97% of hypromellose. In some embodiments, the composition comprises about 4.7% of povidone and about 0.85% of hypromellose.

[0069] In some embodiments, the first coating also includes a first lubricant, a solvent, or a combination thereof. In some embodiments, the solvent includes water. In some embodiments, the solvent exists 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, "lubricant" is a pharmaceutical excipient that can reduce friction between other components 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, silicon dioxide, glycerides (such as monostearate, tribehenate and dibehenate) and sugar esters (such as monostearate sorbitan ester and sucrose monopalmitate), and combinations thereof.

[0070] In some embodiments, the first lubricant includes sodium stearyl fumarate.In some embodiments, the first lubricant is 0 wt % to about 1 wt % of the composition, or about 0.01 wt % to about 0.8 wt %, or about 0.01 wt % to about 0.5 wt %, or about 0.1 wt % to about 0.4 wt %, or about 0.3 wt % to about 0.35 wt %.In some embodiments, the composition includes about 0.1 wt %, about 0.15 wt %, about 0.2 wt %, about 0.25 wt %, about 0.3 wt %, about 0.35 wt %, about 0.4 wt %, about 0.45 wt %, about 0.5 wt % of sodium stearyl fumarate.In some embodiments, the composition includes about 0.1 wt % of sodium stearyl fumarate.In some embodiments, the composition includes about 0.15 wt % of sodium stearyl fumarate.

[0071] In some embodiments, the composition comprises a first pellet, wherein the first pellet comprises a first coating comprising:

[0072] from about 20 wt % to about 50 wt % of an MR modifier;

[0073] From about 1 wt % to about 10 wt % of a first binder; and

[0074] Optionally, from about 0.01 wt % to about 0.5 wt % of a first lubricant,

[0075] wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0076] In some embodiments, the first coating described herein is applied to the first core. In some embodiments, the first core is pharmaceutically inert, i.e., substantially does not react with any other component 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, silicon dioxide, xylitol, mannitol, lactose, calcium carbonate, starch, silicon dioxide, non-pareil core, or a combination thereof.

[0077] In some embodiments, the first core is about 10% to about 50% by weight of the composition, 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. In some embodiments, the first core is about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, 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% by weight, about 21.1% by weight, or about 22.3% by weight of microcrystalline cellulose.

[0078] In some embodiments, the composition comprises a first pellet comprising:

[0079] A first coating comprising:

[0080] From about 20% to about 60% by weight, or from about 25% to about 55% by weight, or about

[0081] 30 wt % to about 50 wt %, or about 35 wt % to about 48 wt %, or about 40 wt %

[0082] to about 45 wt % MR modifier;

[0083] From about 1 wt % to about 20 wt %, or from about 2 wt % to about 15 wt %, or from about 3

[0084] % to about 10% by weight, or about 4% to about 8% by weight, or about 6% to about

[0085] 7% by weight of povidone;

[0086] Optionally, from about 0.01 wt % to about 0.5 wt %, or from about 0.08 wt % to about 0.5

[0087] %, or about 0.1 wt % to about 0.5 wt %, or about 0.2 wt % to about 0.4 wt %, or about 0.3 wt % to about 0.35 wt % sodium stearyl fumarate; and

[0088] The first core comprises:

[0089] About 10% to about 50% by weight, or about 12% to about 40% by weight, or about

[0090] 15 wt % to about 30 wt %, or about 15 wt % to about 25 wt %, or about 20 wt %

[0091] to about 24%, or about 21%, or about 23% by weight of microcrystalline cellulose,

[0092] wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0093] In some embodiments, the composition comprises a first pellet comprising:

[0094] A first coating comprising

[0095] about 20 wt % to 30 wt % of an MR modifier;

[0096] about 4% to 5% by weight of povidone; and

[0097] a first core comprising about 10% to 15% by weight of microcrystalline cellulose,

[0098] wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0099] In some embodiments, the composition comprises a first pellet comprising:

[0100] A first coating comprising

[0101] about 40 wt % to 45 wt % of an MR modifier;

[0102] about 6 to 7 weight percent povidone; and

[0103] a first core comprising about 20% to 25% by weight of microcrystalline cellulose,

[0104] wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0105] In some embodiments, the composition comprises a first pellet comprising:

[0106] A first coating comprising:

[0107] about 20 wt % to about 60 wt %, or about 25 wt % to about 55 wt %, or about 30 wt % to about 50 wt %, or about 35 wt % to about 48 wt %, or about 40 wt % to about 45 wt % of an MR modifier;

[0108] about 1 wt % to about 10 wt %, or about 2 wt % to about 8 wt %, or about 3 wt % to about 7 wt %, or about 4 wt % to about 6 wt % of povidone; and

[0109] The first core comprises:

[0110] about 10% to about 50%, or about 12% to about 40%, or about 15% to about 30%, or about 15% to about 25%, or about 20% to about 24%, or about 21%, or about 23% by weight of microcrystalline cellulose,

[0111] wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0112] In some embodiments, the composition comprises a first pellet comprising:

[0113] A first coating comprising

[0114] about 28 wt % MR modifier;

[0115] about 4.2% by weight of povidone; and

[0116] a first core comprising about 14.4% by weight microcrystalline cellulose,

[0117] wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0118] In some embodiments, the composition comprises a first pellet comprising:

[0119] A first coating comprising

[0120] about 43 wt % MR modifier;

[0121] about 6.5% by weight of povidone; and

[0122] a first core comprising about 22.3% by weight of microcrystalline cellulose,

[0123] wherein all weights are by weight of the composition. In some embodiments, the MR modulator comprises AZD9977.

[0124] Second pellet

[0125] In some embodiments, the 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, and optionally a second lubricant.

[0126] 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, ergliflozin 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 propylene glycol.

[0127] In some embodiments, the SGLT2 inhibitor is about 1% to about 10% by weight of the composition, 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. In some embodiments, the SGLT2 inhibitor is 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%, 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%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 5. %, about 4.4 wt %, about 4.5 wt %, about 4.6 wt %, about 4.7 wt %, about 4.8 wt %, about 4.9 wt %, about 5 wt %, about 5.1 wt %, about 5.2 wt %, about 5.3 wt %, about 5.4 wt %, about 5.5 wt %, about 5.6 wt %, about 5.7 wt %, about 5.8 wt %, about 5.9 wt %, about 6 wt %, about 6.1 wt %, about 6.2 wt %, about 6.3 wt %, about 6.4 wt %, about 6.5 wt %, about 6.6 wt %, about 6.7 wt %, about 6.8 wt %, about 6.9 wt % or about 7 wt %.

[0128] In some embodiments, the SGLT2 inhibitor includes dapagliflozin or a solvate thereof. In some embodiments, the SGLT2 inhibitor includes dapagliflozin propylene glycol. In some embodiments, the composition comprises about 1% by weight to about 10% by weight of dapagliflozin or a solvate thereof. In some embodiments, the composition comprises about 2% by weight to about 8% by weight of dapagliflozin or a solvate thereof. In some embodiments, the composition comprises about 2.5% by weight to about 4.5% by weight of dapagliflozin or a solvate thereof. In some embodiments, the composition comprises about 3% by weight 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 propylene glycol. In some embodiments, the composition comprises about 6.9% by weight of dapagliflozin propylene glycol.

[0129] In some embodiments, the second coating further comprises a second binder, an anti-adhesive agent, and a second lubricant. As used herein, a "lubricant" is a pharmaceutical excipient that can reduce friction between other components 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, silicon dioxide, glycerides (such as glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate) and sugar esters (such as sorbitan monostearate and sucrose monopalmitate), and combinations thereof.

[0130] In some embodiments, the second coating comprises a second binding agent.Exemplary binding agents are further described herein.In some embodiments, the second binding agent is about 0.05% by weight to about 10% by weight of the composition.In some embodiments, the second binding agent is about 0.1% by weight to about 5% by weight of the composition.In some embodiments, the second binding agent is about 0.2% by weight to about 0.8% by weight of the composition.In some embodiments, the second binding agent is about 0.4% by weight to about 0.5% by weight of the composition.In some embodiments, the second binding agent is about 0.4% by weight, about 0.41% by weight, about 0.42% by weight, about 0.43% by weight, about 0.44% by weight, about 0.45% by weight, about 0.46% by weight, about 0.47% by weight, about 0.48% by weight, about 0.49% by weight or about 0.5% by weight of the composition.In some embodiments, the second binding agent includes hydroxypropyl cellulose.In some embodiments, the composition includes about 0.5% hydroxypropyl cellulose. In some embodiments, the composition comprises about 1% hydroxypropyl cellulose.

[0131] In some embodiments, the second coating comprises an anti-adherent. As used herein, an "anti-adherent" is an excipient that prevents particles from aggregating (e.g., by absorbing moisture). Non-limiting examples of anti-adherents include tricalcium phosphate, magnesium trisilicate, calcium carbonate, magnesium carbonate, talc (also known as talcum powder or hydrated magnesium silicate), powdered cellulose, sodium bicarbonate, sodium silicate, calcium silicate, sodium aluminosilicate, potassium aluminosilicate, calcium aluminosilicate, bentonite, aluminum silicate, colloidal silicon dioxide, and polydimethylsiloxane, and combinations thereof.

[0132] In some embodiments, the antitackifier includes talcum.In some embodiments, the antitackifier is about 1 wt % to about 20 wt %, about 1 wt % to about 15 wt %, about 1 wt % to about 12 wt %, about 3 wt % to about 10 wt % or about 7 wt % to about 9 wt % of the composition.In some embodiments, the antitackifier is about 7 wt %, about 7.1 wt %, about 7.2 wt %, about 7.3 wt %, about 7.4 wt %, about 7.5 wt %, about 7.6 wt %, about 7.7 wt %, about 7.8 wt %, about 7.9 wt %, about 8 wt %, about 8.1 wt %, about 8.2 wt %, about 8.3 wt %, about 8.4 wt %, about 8.5 wt %, about 8.6 wt %, about 8.7 wt %, about 8.8 wt %, about 8.9 wt % or about 9 wt % of the composition.In some embodiments, the composition comprises about 7.8 wt % of talcum. In some embodiments, the anti-adhesive 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.

[0133] 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 exists before the second coating is applied to the second core, and is removed (e.g., evaporated) when the second coating is applied to the second core. Exemplary lubricants are further described herein. In some embodiments, the second lubricant is 0 wt % to about 1 wt % of the composition, or about 0.05 wt % to about 0.5 wt %, or about 0.08 wt % to about 0.3 wt %, or about 0.1 wt % to about 0.2 wt %. In some embodiments, the second lubricant is about 0.1 wt %, about 0.11 wt %, about 0.12 wt %, about 0.13 wt %, about 0.14 wt %, about 0.15 wt %, about 0.16 wt %, about 0.17 wt %, about 0.18 wt %, about 0.19 wt % or about 0.2 wt % 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.

[0134] In some embodiments, the composition comprises a second pellet, wherein the second pellet comprises a second coating comprising:

[0135] about 1 wt % to about 30 wt % of an SGLT2 inhibitor;

[0136] about 0.1 wt % to about 5 wt % of a second binder;

[0137] From about 1 wt % to about 20 wt % of a detackifier; and

[0138] Optionally, from about 0.01 wt % to about 1 wt % of a second lubricant,

[0139] wherein all weights are by weight of the composition. In some embodiments, the SGLT2 inhibitor is dapagliflozin propylene glycol.

[0140] In some embodiments, the composition comprises a second pellet, wherein the second pellet comprises a second coating comprising:

[0141] From about 1 wt % to about 30 wt % of an SGLT2 inhibitor, wherein the SGLT2 inhibitor is from about 10 wt % to about 15 wt % or from about 12 wt % to about 14 wt % of the second pellet.

[0142] quantity%;

[0143] about 0.5 wt % to about 1 wt % of a second binder;

[0144] from about 5 wt % to about 15 wt % of a detackifier; and

[0145] Optionally, from about 0.05 wt % to about 0.1 wt % of a second lubricant,

[0146] wherein all weights are by weight of the composition. In some embodiments, the SGLT2 inhibitor is dapagliflozin propylene glycol.

[0147] In some embodiments, the second coating described herein is applied to the second core. In some embodiments, the second core is pharmaceutically inert as described herein. In some embodiments, the second core comprises microcrystalline cellulose, sucrose, isomalt, calcium phosphate (e.g., anhydrous calcium hydrogen phosphate), tartaric acid, silicon dioxide, xylitol, mannitol, lactose, calcium carbonate, starch, silicon dioxide, or a combination thereof. In some embodiments, the second core is a sugar core. Sugar cores are also referred to as "neutral pellets," "double-core-free," "sugar balls," or "sugar beads," and include a combination of sugar (e.g., sucrose) and starch. Exemplary sugar cores include, but are not limited to, those sold under the trade name and The ones that sugar balls sell.

[0148] In some embodiments, the second core is about 5% to about 40% by weight, 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 of the composition. In some embodiments, the second core is about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight of the composition. In some embodiments, the second core is about 15.8% by weight of the composition. In some embodiments, the second core is about 30.6% by weight of the composition. In some embodiments, the second core comprises sugar, starch, or a combination thereof. In some embodiments, the second core is a sugar core.

[0149] In some embodiments, the composition comprises a second pellet comprising:

[0150] A second coating comprising:

[0151] From about 1 wt % to about 10 wt %, or from about 2 wt % to about 5 wt %, or about 2.5

[0152] % to about 4.5 wt%, or about 3 wt% to about 4 wt% of an SGLT2 inhibitor, wherein the SGLT2 inhibitor is about 6 wt% to about 15 wt% of the second pellet;

[0153] about 0.1% to about 5%, or about 0.1% to about 2.5%, or about 0.25% to about 1.5%, or about 0.5% to about 1% hydroxypropyl cellulose;

[0156] about 1 wt % to about 20 wt %, about 1 wt % to about 17.5 wt %, about 5 wt % to about 15 wt %, about 7 wt % to about 10 wt %, or about 7 wt % to about 9 wt % talc; and

[0157] Optionally, from about 0.01 wt % to about 1 wt %, or from about 0.05 wt % to about 1 wt %, or from about 0.06 wt % to about 0.5 wt %, or from about 0.06 wt % to about 0.1 wt % sodium stearyl fumarate; and

[0158] The second core comprises:

[0159] 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,

[0161] wherein all weights are by weight of the composition. In some embodiments, the SGLT2 inhibitor comprises dapagliflozin.

[0162] In some embodiments, the composition comprises a second pellet comprising:

[0163] A second coating comprising:

[0164] about 3.6 wt % of an SGLT2 inhibitor, wherein the SGLT2 inhibitor is about 5 wt % to about 15 wt % of the second pellet;

[0165] about 0.5% by weight hydroxypropyl cellulose;

[0166] about 7.8 wt % talc; and

[0167] Optionally, about 0.06% sodium stearyl fumarate; and

[0168] a second core comprising about 15.8% by weight of a sugar core,

[0169] wherein all weights are by weight of the composition. In some embodiments, the SGLT2 inhibitor comprises dapagliflozin.

[0170] In some embodiments, the composition comprises a second pellet comprising:

[0171] A second coating comprising:

[0172] about 6.9 wt % of an SGLT2 inhibitor, wherein the SGLT2 inhibitor is about 5 wt % to about 15 wt % of the second pellet;

[0173] about 1% by weight hydroxypropyl cellulose;

[0174] about 15 wt % talc; and

[0175] Optionally, about 0.1% sodium stearyl fumarate; and

[0176] a second core comprising about 30.5% by weight of a sugar core,

[0177] wherein all weights are by weight of the composition. In some embodiments, the SGLT2 inhibitor comprises dapagliflozin.

[0178] combination

[0179] In some embodiments, the composition comprising the first pellet and the second pellet as 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.

[0180] 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, the AZD9977 is contained in a first pellet as described herein, and dapagliflozin or a solvate thereof is contained in a second pellet as described herein.

[0181] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising:

[0182] (a) one or more first pellets comprising:

[0183] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 5% to about 25% by weight of the capsule;

[0184] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 10 wt % to about 45 wt % of the capsule; (B) povidone, wherein the povidone is about 1 wt % to about 10 wt % of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01 wt % to about 1 wt % of the capsule; and

[0185] (b) one or more second pellets comprising:

[0186] i. a second core comprising sugar spheres, wherein the sugar spheres are from about 5% to about 30% by weight of the capsule;

[0187] ii. a second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 1 wt % to about 10 wt % of the capsule; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.1 wt % to about 1 wt % of the capsule; (C) talc, wherein the talc is about 1 wt % to about 15 wt % of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01 wt % to about 0.1 wt % of the capsule.

[0188] In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0189] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising:

[0190] (a) one or more first pellets comprising:

[0191] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 5% to about 20% by weight of the capsule;

[0192] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 15 wt % to about 40 wt % of the capsule; (B) povidone, wherein the povidone is about 2 wt % to about 6 wt % of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.02 wt % to about 0.4 wt % of the capsule; and

[0193] (b) one or more second pellets comprising:

[0194] i. a second core comprising sugar spheres, wherein the sugar spheres are from about 10% to about 22% by weight of the capsule;

[0195] ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin, and wherein the dapagliflozin is about 2% to about 5% by weight of the capsule; (B) hydroxypropylcellulose, wherein the hydroxypropylcellulose is about 0.4% to about 0.6% by weight of the capsule; (C) talc, wherein the talc is about 5% to about 12% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.02% to about 0.08% by weight of the capsule. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0196] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising:

[0197] (a) one or more first pellets comprising:

[0198] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 18% by weight of the capsule;

[0199] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 35% by weight of the capsule; (B) povidone, wherein the povidone is about 5.3% by weight of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.12% by weight of the capsule; and

[0200] (b) one or more second pellets comprising:

[0201] i. a second core comprising sugar spheres, wherein the sugar spheres are about 12.8% by weight of the capsule;

[0202] ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin, and wherein the dapagliflozin is about 2.9% by weight of the capsule; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.38% by weight of the capsule; (C)

[0203] Talc, wherein the talc is about 6.3% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.04% by weight of the capsule. In some embodiments, the composition is included in an oral dosage form. In some embodiments,

[0204] The oral dosage form is a capsule.

[0205] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising:

[0206] (a) one or more first pellets comprising:

[0207] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 9.9% by weight of the capsule;

[0208] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 19.2% by weight of the capsule; (B)

[0209] povidone, wherein the povidone 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; and

[0210] (b) one or more second pellets comprising:

[0211] i. a second core comprising sugar spheres, wherein the sugar spheres are about 21% by weight of the capsule;

[0212] ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin, and wherein the dapagliflozin is about 4.7% by weight of the capsule; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.63% by weight of the capsule; (C)

[0213] Talc, wherein the talc is about 10.4% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.07% by weight of the capsule. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0214] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising:

[0215] (a) one or more first pellets comprising:

[0216] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 5% to about 25% by weight of the capsule;

[0217] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 10 wt % to about 45 wt % of the capsule, (B) povidone, wherein the povidone is about 2 wt % to about 8 wt % of the capsule; (C) hypromellose, wherein the hypromellose is about 0.5 wt % to about 3 wt % of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01 wt % to about 0.5 wt % of the capsule; and

[0218] (b) one or more second pellets comprising:

[0219] i. a second core comprising sugar spheres, wherein the second core is from about 5% to about 30% by weight of the capsule;

[0220] ii. a second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 1 wt % to about 10 wt % of the capsule and about 5 wt % to about 20 wt % of the second pellet, (B)

[0221] Hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.1% to about 1% by weight of the capsule; (C) talc, wherein the talc is about 1% to about 15% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01% to about 1% by weight of the capsule. In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0222] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a capsule comprising:

[0223] (a) one or more first pellets comprising:

[0224] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 23.9% by weight of the capsule;

[0225] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 45.3% by weight of the capsule, and (B)

[0226] povidone, wherein the povidone is about 5.35% by weight of the capsule; (C) hypromellose, wherein the hypromellose is about 0.97% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.34% by weight of the capsule;

[0227] as well as

[0228] (b) one or more second pellets comprising:

[0229] i. a second core comprising sugar spheres, wherein the second core is about 11.7% by weight of the capsule;

[0230] ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 3.7% by weight of the capsule and about 13.2% by weight of the second pellet; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.48% by weight of the capsule; (C) talc, wherein the talc is about 8.2% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.11% by weight of the capsule. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0231] In some embodiments, the MR modulator of the pharmaceutical composition described herein is AZD9977. In some embodiments, the pharmaceutical composition comprises from about 10 mg to about 200 mg AZD9977. In some embodiments, the pharmaceutical composition comprises from about 15 mg to about 100 mg AZD9977. In some embodiments, the pharmaceutical composition comprises from about 15 mg to about 40 mg AZD9977. In some embodiments, the pharmaceutical composition comprises from about 50 mg to about 180 mg AZD9977. In some embodiments, the pharmaceutical composition comprises from about 50 mg to about 150 mg AZD9977. In some embodiments, the pharmaceutical composition comprises about 50 mg AZD9977. In some embodiments, the pharmaceutical composition comprises about 150 mg AZD9977.

[0232] In some embodiments, the SGLT2 inhibitor of the pharmaceutical composition described herein is dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 5 mg to about 20 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 8 mg to about 18 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 15 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 10 mg dapagliflozin propylene glycol.

[0233] In some embodiments, the pharmaceutical compositions described herein contain about 5 mg to about 20 mg of dapagliflozin active equivalents. As used herein, "active equivalent" refers to an equivalent amount of active ingredient dapagliflozin provided by a compound (e.g., a salt or solvate of the active ingredient). As used herein, dapagliflozin propylene glycol provides about 81.29% w / w dapagliflozin active equivalents. In some embodiments, 12 mg of dapagliflozin propylene glycol provides an active equivalent of 10 mg of dapagliflozin.

[0234] In some embodiments, the pharmaceutical composition comprises about 7 mg to about 17 mg of dapagliflozin active equivalent. In some embodiments, the pharmaceutical composition comprises about 8 mg to about 12 mg of dapagliflozin active equivalent. In some embodiments, the pharmaceutical composition comprises about 10 mg of dapagliflozin active equivalent.

[0235] In some embodiments, the pharmaceutical compositions described herein comprise from about 50 mg to about 200 mg AZD9977; and from about 5 mg to about 20 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 50 mg to about 180 mg AZD9977; and from about 8 mg to about 18 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 50 mg to about 150 mg AZD9977; and from about 10 mg to about 15 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 50 mg to about 150 mg AZD9977; and from about 10 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 150 mg AZD9977; and from about 10 mg dapagliflozin propylene glycol. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0236] In some embodiments, the pharmaceutical compositions described herein comprise from about 10 mg to about 50 mg AZD9977; and from about 5 mg to about 20 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 15 mg to about 45 mg AZD9977; and from about 8 mg to about 18 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 15 mg to about 50 mg AZD9977; and from about 10 mg to about 15 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 15 mg to about 10 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 20 mg AZD9977; and from about 10 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical compositions comprise from about 25 mg AZD9977; and from about 10 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 30 mg AZD9977; and about 10 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 35 mg AZD9977; and about 10 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 40 mg AZD9977; and about 10 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 45 mg AZD9977; and about 10 mg dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises about 50 mg AZD9977; and about 10 mg dapagliflozin propylene glycol. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0237] Release curve

[0238] In some embodiments, the pharmaceutical compositions described herein advantageously provide comparable release profiles for both MR modulators (e.g., AZD9977) and SGLT2 inhibitors (e.g., dapagliflozin or a solvate thereof). As described herein, due to its low solubility and low permeability, AZD9977 is a BCS Class 4 drug, while dapagliflozin is a BCS Class 3 drug, i.e., it has high solubility, rapid dissolution, and low permeability. It was unexpectedly found that by including the two active ingredients in separate pellets containing different excipients (e.g., cores, binders, lubricants, and / or anti-adherents as described herein), the two active ingredients can be included in a single dosage form (e.g., a capsule or tablet as described herein), with comparable release profiles for the two active ingredients. The advantages of combining the two active ingredients in a single dosage form are further described herein.

[0239] In some embodiments, the pharmaceutical compositions or oral dosage forms described herein release substantially the same amount of MR modulator and SGLT2 inhibitor. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin propylene glycol.

[0240] In some embodiments, at least 75%-85% of the MR modulator is released from the pharmaceutical composition or oral dosage form described herein within a time range of about 15 minutes to 30 minutes. In other embodiments, at least 75%-85% of the SGLT2 inhibitor is released from the pharmaceutical composition or oral dosage form described herein within a time range of about 15 minutes to 30 minutes. The dissolution profile can be tested using dissolution techniques known to those skilled in the art, for example, methods such as USP 1 at 100 rpm or USP 2 at 70 rpm.

[0241] In some embodiments, the pharmaceutical compositions or oral dosage forms described herein release at least 80% of the MR modulator contained therein within 60 minutes. When tested using USP 2 at 100 rpm. In some embodiments, the pharmaceutical compositions or oral dosage forms described herein release at least 80% of the MR modulator contained therein within 30 minutes when tested using USP 2 at 100 rpm. In some embodiments, the MR modulator is AZD9977.

[0242] In some embodiments, when tested at 100 rpm using USP 1, the pharmaceutical composition or oral dosage form described herein releases at least 80% of the SGLT2 inhibitor contained therein within 60 minutes. In some embodiments, when tested at 100 rpm using USP 1, the pharmaceutical composition or oral dosage form described herein releases at least 80% of the SGLT2 inhibitor contained therein within 30 minutes. In some embodiments, the SGLT2 inhibitor is dapagliflozin propylene glycol.

[0243] method

[0244] In some embodiments, the present disclosure provides a method for treating heart failure in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form as described herein. In some embodiments, the composition comprises 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 propylene glycol.

[0245] In some embodiments, the present disclosure provides a fixed dose combination of a MR modulator and a SGLT2 inhibitor for use in treating heart failure in a subject in need of such treatment, wherein the use comprises administering a pharmaceutical composition comprising a MR modulator and a 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 propylene glycol.

[0246] In some embodiments, the present disclosure provides a method for treating chronic kidney disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or oral dosage form as described herein. In some embodiments, the composition comprises 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 propylene glycol.

[0247] In some embodiments, the present disclosure provides a fixed dose combination of a MR modulator and a SGLT2 inhibitor for use in treating chronic kidney disease in a subject in need of such treatment, wherein the use comprises administering a pharmaceutical composition comprising a MR modulator and a 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 propylene glycol.

[0248] In some embodiments, the present disclosure provides a method for 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 as described herein. In some embodiments, the composition comprises 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 propylene glycol.

[0249] In some embodiments, the present disclosure provides a fixed dose combination of a MR modulator and a SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need of such treatment, wherein the use comprises administering a pharmaceutical composition comprising a MR modulator and a 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 propylene glycol.

[0250] 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, wherein the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, e.g., dapagliflozin propylene glycol.

[0251] In some embodiments, the present disclosure provides a fixed dose combination of a MR modulator and a SGLT2 inhibitor for use in treating heart failure and / or chronic kidney disease in a subject in need of such treatment, wherein the use comprises administering a pharmaceutical composition comprising 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof (e.g. dapagliflozin propylene glycol).

[0252] In some embodiments, the present disclosure provides a method for treating heart failure and / or chronic kidney disease in a subject with hyperkalemia (i.e., having a serum potassium value greater than or equal to 5.5 mmol / L) in need, comprising administering a pharmaceutical composition or oral dosage form as described herein to the subject. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0253] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for the treatment of heart failure and / or chronic kidney disease in a subject with hyperkalemia (i.e., a serum potassium value greater than or equal to 5.5 mmol / L) in need, wherein 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, such as dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0254] In some embodiments, the present disclosure provides a method for treating heart failure and / or chronic kidney disease in a subject at risk of hyperkalemia in need, comprising administering a pharmaceutical composition or oral dosage form as described herein to the subject. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol. As used herein, subjects at risk of hyperkalemia include subjects with impaired renal function, or subjects currently prescribed at least one RAASi, or subjects with T2D, or subjects with at least one previous episode of hyperkalemia, or subjects with a history of adverse reactions to MRA. RAASi drugs may include angiotensin receptor blockers, angiotensin converting enzyme inhibitors, and direct renin inhibitors well known in the art. In some embodiments, following administration of a pharmaceutical composition comprising 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof (eg dapagliflozin propylene glycol), the subject maintains a serum potassium value below 5.5 mmol / L.

[0255] In some embodiments, the present disclosure provides a fixed dose combination of an MR modulator and an SGLT2 inhibitor for the treatment of heart failure and / or chronic kidney disease in a subject at risk of hyperkalemia in need thereof, wherein 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, such as dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0256] In some embodiments, the present disclosure provides a method for treating heart failure and / or chronic kidney disease in a subject with recent worsening of heart failure in need (i.e., stable in a hospital setting or the subject has been hospitalized or received acute HF treatment in an emergency room due to heart failure in the previous 6 months), comprising administering to the subject a pharmaceutical composition or oral dosage form as described herein. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0257] In some embodiments, the present disclosure provides a fixed dose combination of an MR modulator and an SGLT2 inhibitor for the treatment of heart failure and / or chronic kidney disease in a subject with recent worsening of heart failure in need thereof, wherein the use comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0258] In some embodiments, the present disclosure provides a method for treating a subject in need thereof (i.e., the subject has a flow rate of greater than or equal to 20 ml / min to less than or equal to 60 ml / min / 1.73 m 2 A method for treating heart failure and / or impaired renal function in a subject with an eGFR range of ≥50%, comprising administering to the subject a pharmaceutical composition or oral dosage form as described herein. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0259] In some embodiments, the present disclosure provides a fixed dose combination of a MR modulator and a SGLT2 inhibitor for treating heart failure and / or impaired renal function in a subject in need thereof, wherein the use comprises administering to the subject a pharmaceutical composition comprising a MR modulator and a 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0260] In some embodiments, the present disclosure provides a method for treating heart failure and / or chronic kidney disease in a subject who is intolerant to mineralocorticoid receptor antagonists (MRA) or is considered by a physician to be unsuitable for MRA therapy, comprising administering a pharmaceutical composition or oral dosage form as described herein to the subject. In some embodiments, the composition comprises an MR regulator and an SGLT2 inhibitor as described herein. In some embodiments, the MR regulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol. Common MRAs are known in the art and include, but are not limited to, spironolactone, eplerenone, canrenone, progesterone, drospirenone, gestodene and benidipine.

[0261] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for the treatment of heart failure and / or chronic kidney disease in subjects who are intolerant to mineralocorticoid receptor antagonists (MRAs) or who are considered by physicians to be unsuitable for MRA therapy, wherein 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, such as dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0262] In some embodiments, the present disclosure provides a method for reducing the risk of cardiovascular (CV) death and / or heart failure (HF) events in a subject in need thereof, comprising administering a pharmaceutical composition or oral dosage form as described herein to the subject. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol. As used herein, HF events include worsening HF events with hospitalization and / or non-hospitalization due to HF (see, e.g., Abraham, WT et al., JACC: Heart Failure, 8: 961-972 (2020)), for example, unplanned outpatient medical contacts associated with changes in HF therapy, such as:

[0263] a. The patient presents with documented new or worsening symptoms due to the onset of HF,

[0264] b. The patient has objective evidence of new or worsening HF, i.e. physical examination findings and / or laboratory findings,

[0265] c. The patient is receiving at least one treatment specifically for HF, and

[0266] d. Patients have symptomatic improvement and objective signs of HF that respond to therapy.

[0267] In at least one embodiment, the patient experiences one or more HF symptoms selected from the group consisting of dyspnea, decreased exercise tolerance, fatigue, and / or worsening end-organ perfusion or other symptoms of volume overload. In some embodiments of the HF event without hospitalization, the patient receives initiation or intensification of HF-specific therapy. In some embodiments of the HF event without hospitalization, the patient requires a significant increase in oral diuretic therapy, initiation of intravenous diuretics or vasoactive therapy, or mechanical fluid removal.

[0268] In some embodiments, the present disclosure provides a fixed-dose combination of a MR modulator and a SGLT2 inhibitor for reducing the risk of cardiovascular (CV) death and / or heart failure (HF) events in a subject in need thereof, wherein the use comprises administering to the subject a pharmaceutical composition comprising a MR modulator and a 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0269] In some embodiments, the present disclosure provides a method for treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the method does not result in the associated risk of hyperkalemia, the method comprising administering to the subject a pharmaceutical composition or oral dosage form as described herein. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0270] In some embodiments, the present disclosure provides a fixed dose combination of an MR modulator and an SGLT2 inhibitor for treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the use does not result in the associated risk of hyperkalemia, wherein 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, such as dapagliflozin propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0271] In some embodiments, the present disclosure provides a method for treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the method further reduces the subject's UACR, the method comprising administering a pharmaceutical composition or oral dosage form as described herein to the subject. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol. In some embodiments, the reduction in UACR can be a reduction of greater than 30% compared to the baseline UACR, or, for example, a reduction of up to 25%-30% compared to the baseline UACR, for example, a reduction of up to 30% compared to the baseline UACR, for example, a reduction of up to 25% compared to the baseline UACR, for example, a reduction of up to 20% compared to the baseline UACR, for example, a reduction of up to 15% compared to the baseline UACR, for example, a reduction of up to 10% compared to the baseline UACR. In other embodiments, the reduction in UACR can be assessed by subjects transitioning from a higher UACR category to a lower UACR category, such as subjects transitioning from category A3 (UACR>300 mg / g) to category A2 (UACR 30-299 mg / g) or category A1 (UACR<30 mg / g).

[0272] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the use further reduces the subject's UACR, and wherein 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0273] In some embodiments, the present disclosure provides a method for treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the method does not result in the associated risk of hypotension, the method comprising administering to the subject a pharmaceutical composition or oral dosage form as described herein. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0274] In some embodiments, the present disclosure provides a fixed-dose combination of an MR modulator and an SGLT2 inhibitor for the treatment of heart failure and / or chronic kidney disease in a subject in need thereof, wherein the use does not result in the associated risk of hypotension, and wherein 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0275] In some embodiments, the present disclosure provides a method for treating heart failure and / or chronic kidney disease in a subject in need thereof, wherein the method does not result in the associated risk of acute kidney injury, the method comprising administering a pharmaceutical composition or oral dosage form as described herein to the subject. In some embodiments, the composition comprises 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol. As used herein, acute kidney injury may be defined as an increase in serum creatinine reported by the investigator to be greater than or equal to 2 times the baseline known or presumed to have occurred within the past 7 days, and / or a period of up to 28 days requiring the use of temporary renal replacement therapy.

[0276] In some embodiments, the present disclosure provides a fixed dose combination of an MR modulator and an SGLT2 inhibitor for the treatment of heart failure and / or chronic kidney disease in a subject in need thereof, wherein the use does not result in the associated risk of acute kidney injury, and wherein 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 propylene glycol. In some embodiments, the pharmaceutical composition comprises 10 mg to 50 mg AZD9977 and 10 mg dapagliflozin or a solvate thereof, such as dapagliflozin propylene glycol.

[0277] In any of the above embodiments, the subject may have New York Heart Association (NYHA) heart failure classification II to IV. In at least one embodiment, the subject has NYHA heart failure classification II. In at least one embodiment, the subject has NYHA heart failure classification III or IV.

[0278] In any of the above embodiments, the subject suffering from heart failure may include a subject having a left ventricular ejection fraction (LVEF) greater than 50% (i.e., a subject with heart failure with preserved ejection fraction (HFpEF)), or a subject having 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 a moderate ejection fraction (HFmrEF)), or a subject having an LVEF less than 40% (i.e., a subject with heart failure with reduced ejection fraction (HFrEF)).

[0279] In any of the above embodiments, subjects with chronic kidney disease may include subjects who exhibit renal impairment (e.g., proteinuria measurable by UACR, such as subjects falling into UACR categories A2-A3) and / or an estimated eGFR<60 mL / min / 1.73 m2 for at least three months.

[0280] In some embodiments, 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 daily dose of MR modulator is administered. In some embodiments, 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 daily dose of SGLT2 inhibitor is administered. In some embodiments, about 10 mg to about 200 mg daily dose of MR modulator and about 5 mg to about 20 mg daily dose of SGLT2 inhibitor are administered. In some embodiments, about 50 mg to about 180 mg daily dose of MR modulator and about 7 mg to about 17 mg daily dose of SGLT2 inhibitor are administered. In some embodiments, about 50 mg to about 150 mg daily dose of MR modulator and about 8 mg to about 12 mg daily dose of SGLT2 inhibitor are administered. In some embodiments, about 15 mg daily dose of MR modulator and about 10 mg daily dose of SGLT2 inhibitor are administered. In some embodiments, about 20 mg of a daily dose of MR modulator and about 10 mg of a daily dose of SGLT2 inhibitor are administered. In some embodiments, about 25 mg of a daily dose of MR modulator and about 10 mg of a daily dose of SGLT2 inhibitor are administered. In some embodiments, about 30 mg of a daily dose of MR modulator and about 10 mg of a daily dose of SGLT2 inhibitor are administered. In some embodiments, about 35 mg of a daily dose of MR modulator and about 10 mg of a daily dose of SGLT2 inhibitor are administered. In some embodiments, about 40 mg of a daily dose of MR modulator and about 10 mg of a daily dose of SGLT2 inhibitor are administered. In some embodiments, about 50 mg of a daily dose of MR modulator and about 10 mg of a daily dose of SGLT2 inhibitor are administered. In some embodiments, about 150 mg of a daily dose of MR modulator and about 10 mg of a daily dose of SGLT2 inhibitor are administered. In some embodiments, the MR modulator is AZD9977. In some embodiments, the SGLT2 inhibitor is dapagliflozin.

[0281] In some embodiments, the pharmaceutical composition comprises: about 10 mg to about 200 mg AZD9977; and about 5 mg to about 20 mg dapagliflozin active equivalent. In some embodiments, the pharmaceutical composition comprises: about 20 mg to about 180 mg AZD9977; and about 7 mg to about 17 mg dapagliflozin active equivalent. In some embodiments, the pharmaceutical composition comprises: about 50 mg to about 160 mg AZD9977; and about 8 mg to about 12 mg dapagliflozin active equivalent. In some embodiments, the pharmaceutical composition comprises: about 150 mg AZD9977; and about 10 mg dapagliflozin active equivalent. In some embodiments, the pharmaceutical composition comprises: about 50 mg AZD9977; and about 10 mg dapagliflozin active equivalent. In some embodiments, a daily dose of about 15 mg AZD9977 and a daily dose of about 10 mg dapagliflozin are administered. In some embodiments, about 20 mg daily dose of AZD9977 and about 10 mg daily dose of dapagliflozin are administered. In some embodiments, about 25 mg daily dose of AZD9977 and about 10 mg daily dose of dapagliflozin are administered. In some embodiments, about 30 mg daily dose of AZD9977 and about 10 mg daily dose of dapagliflozin are administered. In some embodiments, about 35 mg daily dose of AZD9977 and about 10 mg daily dose of dapagliflozin are administered. In some embodiments, about 40 mg daily dose of AZD9977 and about 10 mg daily dose of dapagliflozin are administered. In some embodiments, dapagliflozin is in the form of dapagliflozin propylene glycol. The composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0282] In some embodiments, the method comprises administering a pharmaceutical composition comprising:

[0283] (a) one or more first pellets comprising:

[0284] i. a first core comprising a microcrystalline cellulose core, wherein the first core is from about 10% to about 30% by weight of the composition, optionally from about 10% to about 25% by weight;

[0285] ii. A first coating comprising

[0286] (A) from about 20% to about 50%, by weight of the composition, of a MR modulator, wherein the MR modulator is AZD9977;

[0287] (B) from about 1% to about 10%, optionally from about 4% to about 8%, by weight of the composition, of povidone; and

[0288] (C) from about 0.01% to about 0.5%, optionally from about 0.2% to about 0.4%, by weight of the composition, of sodium stearyl fumarate; and

[0289] (b) one or more second pellets comprising:

[0290] i. a second core comprising sugar spheres, wherein the sugar spheres are from about 10% to about 40% by weight of the composition, optionally from about 15% to about 35% by weight;

[0291] ii. A second coating comprising

[0292] (A) from about 1% to about 10%, optionally from about 3% to about 7%, by weight of the composition, of a SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin, and wherein the SGLT2 is from about 5% to about 20%, optionally from about 5% to about 15%, by weight of the second pellet;

[0293] (B) from about 0.1% to about 5%, optionally from about 0.4% to about 1%, by weight of the composition, of hydroxypropyl cellulose;

[0294] (C) from about 1% to about 20%, optionally from about 7% to about 16%, by weight of the composition, of talc; and

[0295] (D) from about 0.01% to about 1%, optionally from about 0.05% to about 0.2%, by weight of the composition, of sodium stearyl fumarate.

[0296] In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0297] In some embodiments, a method of treating heart failure and / or chronic kidney disease comprises administering a pharmaceutical composition comprising:

[0298] (a) one or more first pellets comprising:

[0299] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 20.7% by weight of the composition;

[0300] ii. A first coating comprising

[0301] (A) about 40%, by weight of the composition, of a MR modulator, wherein the MR modulator is AZD9977;

[0302] (B) about 6% by weight of the composition of povidone; and

[0303] (C) about 0.1%, by weight of the composition, of sodium stearyl fumarate; and

[0304] (b) one or more second pellets comprising:

[0305] i. a second core comprising sugar spheres, wherein the sugar spheres are about 21.9% by weight of the composition;

[0306] ii. A second coating comprising

[0307] (A) about 3.3% by weight of the composition of a SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the SGLT2 is about 12.8% by weight of the second pellet;

[0308] (B) about 0.43%, by weight of the composition, of hydroxypropyl cellulose;

[0309] (C) about 7.2%, by weight of the composition, of talc; and

[0310] (D) about 0.15%, by weight of the composition, of sodium stearyl fumarate.

[0311] In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0312] In some embodiments, a method of treating heart failure and / or chronic kidney disease comprises administering a pharmaceutical composition in the form of a capsule comprising:

[0313] (a) one or more first pellets comprising:

[0314] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 5% to about 25% by weight of the capsule;

[0315] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 10 wt % to about 45 wt % of the capsule; (B) povidone, wherein the povidone is about 1 wt % to about 10 wt % of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01 wt % to about 1 wt % of the capsule; and

[0316] (b) one or more second pellets comprising:

[0317] i. a second core comprising sugar spheres, wherein the sugar spheres are from about 5% to about 30% by weight of the capsule;

[0318] ii. a second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 1 wt % to about 10 wt % of the capsule; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.1 wt % to about 1 wt % of the capsule; (C) talc, wherein the talc is about 1 wt % to about 15 wt % of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01 wt % to about 0.1 wt % of the capsule.

[0319] In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0320] In some embodiments, a method of treating heart failure and / or chronic kidney disease comprises administering a pharmaceutical composition in the form of a capsule comprising:

[0321] (a) one or more first pellets comprising:

[0322] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 5% to about 20% by weight of the capsule;

[0323] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 15 wt % to about 40 wt % of the capsule; (B) povidone, wherein the povidone is about 2 wt % to about 6 wt % of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.02 wt % to about 0.4 wt % of the capsule; and

[0324] (b) one or more second pellets comprising:

[0325] i. a second core comprising sugar spheres, wherein the sugar spheres are from about 10% to about 22% by weight of the capsule;

[0326] ii. a second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin, and wherein the dapagliflozin is about 2% to about 5% by weight of the capsule;

[0327] (B) Hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.4% by weight of the capsule

[0328] (C) talc, wherein the talc is about 5% to about 12% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.02% to about 0.08% by weight of the capsule. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0329] In some embodiments, a method of treating heart failure and / or chronic kidney disease comprises administering a pharmaceutical composition in the form of a capsule comprising:

[0330] (a) one or more first pellets comprising:

[0331] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 18% by weight of the capsule;

[0332] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 35% by weight of the capsule; (B) povidone, wherein the povidone is about 5.3% by weight of the capsule; and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.12% by weight of the capsule; and

[0333] (b) one or more second pellets comprising:

[0334] i. a second core comprising sugar spheres, wherein the sugar spheres are about 12.8% by weight of the capsule;

[0335] ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin, and wherein the dapagliflozin is about 2.9% by weight of the capsule; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.38% by weight of the capsule; (C)

[0336] Talc, wherein the talc is about 6.3% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.04% by weight of the capsule. In some embodiments, the composition is included in an oral dosage form. In some embodiments,

[0337] The oral dosage form is a capsule.

[0338] In some embodiments, a method of treating heart failure and / or chronic kidney disease comprises administering a pharmaceutical composition in the form of a capsule comprising:

[0339] (a) one or more first pellets comprising:

[0340] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 9.9% by weight of the capsule;

[0341] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 19.2% by weight of the capsule; (B)

[0342] povidone, wherein the povidone 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; and

[0343] (b) one or more second pellets comprising:

[0344] i. a second core comprising sugar spheres, wherein the sugar spheres are about 21% by weight of the capsule;

[0345] ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin, and wherein the dapagliflozin is about 4.7% by weight of the capsule; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.63% by weight of the capsule; (C)

[0346] Talc, wherein the talc is about 10.4% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.07% by weight of the capsule. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0347] In some embodiments, a method of treating heart failure and / or chronic kidney disease comprises administering a pharmaceutical composition in the form of a capsule comprising:

[0348] (a) one or more first pellets comprising:

[0349] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 5% to about 25% by weight of the capsule;

[0350] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 10 wt % to about 45 wt % of the capsule, (B) povidone, wherein the povidone is about 2 wt % to about 8 wt % of the capsule; (C) hypromellose, wherein the hypromellose is about 0.5 wt % to about 3 wt % of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01 wt % to about 0.5 wt % of the capsule; and

[0351] (b) one or more second pellets comprising:

[0352] i. a second core comprising sugar spheres, wherein the second core is from about 5% to about 30% by weight of the capsule;

[0353] ii. a second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 1 wt % to about 10 wt % of the capsule and about 5 wt % to about 20 wt % of the second pellet, (B)

[0354] Hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.1% to about 1% by weight of the capsule; (C) talc, wherein the talc is about 1% to about 15% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.01% to about 1% by weight of the capsule. In some embodiments, the composition is included in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0355] In some embodiments, a method of treating heart failure and / or chronic kidney disease comprises administering a pharmaceutical composition in the form of a capsule comprising:

[0356] (a) one or more first pellets comprising:

[0357] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 23.9% by weight of the capsule;

[0358] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 45.3% by weight of the capsule, and (B)

[0359] povidone, wherein the povidone is about 5.35% by weight of the capsule; (C) hypromellose, wherein the hypromellose is about 0.97% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.34% by weight of the capsule;

[0360] as well as

[0361] (b) one or more second pellets comprising:

[0362] i. a second core comprising sugar spheres, wherein the second core is about 11.7% by weight of the capsule;

[0363] ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 3.7% by weight of the capsule and about 13.2% by weight of the second pellet; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.48% by weight of the capsule; (C) talc, wherein the talc is about 8.2% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.11% by weight of the capsule. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0364] In some embodiments, a method of treating heart failure and / or chronic kidney disease comprises administering a pharmaceutical composition in the form of a capsule comprising:

[0365] (a) one or more first pellets comprising:

[0366] i. a first core comprising a microcrystalline cellulose core, wherein the first core is about 56.2% by weight of the capsule;

[0367] ii. a first coating comprising (A) a MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 11.2% by weight of the capsule, and (B)

[0368] Hypromellose, wherein the hypromellose is about 0.22% by weight of the capsule;

[0369] and (C) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.37% by weight of the capsule; and

[0370] (b) one or more second pellets comprising:

[0371] i. a second core comprising sugar spheres, wherein the second core is about 26.3% by weight of the capsule;

[0372] ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 2.8% by weight of the capsule and about 10.7% by weight of the second pellet; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.37% by weight of the capsule; (C) talc, wherein the talc is about 6.2% by weight of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.34% by weight of the capsule. In some embodiments, the composition is contained in an oral dosage form. In some embodiments, the oral dosage form is a capsule.

[0373] In some embodiments, the method includes once daily administration of a pharmaceutical composition or oral dosage form as described herein. In some embodiments, the method includes 2 times a day, 3 times a day, 4 times a day, 5 times a day, 6 times a day or more frequently administering a pharmaceutical composition or oral dosage form as described herein. It will be understood by those of ordinary skill in the art that if the pharmaceutical composition is administered more than once a day, the amount 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, in order to achieve a daily dose of about 50 mg or about 150 mg MR modulator and about 10 mg SGLT2 inhibitor, the composition or oral dosage form administered twice a day should include 22.5 mg or 75 mg MR modulator and 5 mg SGLT2 inhibitor.

[0374] In some embodiments, pharmaceutical composition or oral dosage form is applied to a subject in need under fasting state. As defined by the U.S. Food and Drug Administration, the treatment under "fasting state" is carried out when fasting lasts for at least 10 hours, such as fasting overnight, and until at least 4 hours after administration, just eat. On the contrary, the treatment under "fed state" starts with the same overnight 10-hour fasting, but the subject eats within 30 minutes before administration, and there is no additional food at least 4 hours after administration. See, for example, U.S. Food and Drug Administration (USFood and Drug Administration), Center for Drug Evaluation and Research (CDER) (Center for Drug Evaluation and Research (CDER)), "Guidance for Industry-Food-Effect Bioavailability and Fed Bioequivalence Studies", December 2002.

[0375] In some embodiments, when administered in the fasting state, 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 to an MR modulator and an SGLT2 inhibitor administered in separate dosage forms. Methods for evaluating bioequivalence are known to those of ordinary skill in the art. See, e.g., U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), "Guidance for Industry-Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs—General Considerations-Draft Guidance," March 2014.

[0376] In some embodiments, as measured by AUC last and AUC inf The pharmaceutical compositions or oral dosage forms described herein are bioequivalent to separate dosage forms of the MR modulator and the SGLT2 inhibitor as measured by one or both of AUC last ” refers to the time from the time of administration to the last measurable (positive) concentration (T last As used herein, "AUC inf ” refers to the area under the drug concentration curve extrapolated to infinity from the time of dosing and is a theoretical measure of the total exposure of the drug in the body from administration to complete elimination.

[0377] In some embodiments, the AUC of a subject after administration of a pharmaceutical composition or oral dosage form as described herein is last and AUC inf AUC in subjects taking separate dosage forms of MR modulators and SGLT2 inhibitors last and AUC inf In some embodiments, the AUC of a subject after administration of a pharmaceutical composition or oral dosage form as described herein is within about 1% to about 20%. last and AUC inf AUC in subjects taking separate dosage forms of MR modulators and SGLT2 inhibitors last and AUC inf In some embodiments, the AUC of a subject after administration of a pharmaceutical composition or oral dosage form as described herein is within about 5% to about 15%. last and AUC infAUC in subjects taking separate dosage forms of MR modulators and SGLT2 inhibitors last and AUC inf In some embodiments, after administration of a pharmaceutical composition or oral dosage form as described herein, the AUC last and AUC inf AUC in subjects taking separate dosage forms of MR modulators and SGLT2 inhibitors last and AUC inf In some embodiments, the AUC of a subject after administration of a pharmaceutical composition or oral dosage form as described herein is within 10%, 8%, 5 or 2%. last and AUC inf AUC in subjects taking separate dosage forms of MR modulators and SGLT2 inhibitors last and AUC inf Basically the same.

[0378] In some embodiments, the subject in need is diagnosed with chronic heart failure (HF), chronic kidney disease (CKD), or both. In some embodiments, the subject in need is diagnosed with chronic HF and is at an elevated risk of developing CKD; or is diagnosed with CKD and is at an elevated 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 participating in a clinical trial of a pharmaceutical composition or oral dosage form described herein.

[0379] In some embodiments, the present disclosure provides a method of preparing a capsule comprising a pharmaceutical composition described herein, comprising:

[0380] (1) forming a first pellet, which comprises:

[0381] a) combining a first binder with water to form a first binder / water solution;

[0382] b) adding a MR modifier to a first binder / water solution to form a first suspension;

[0383] c) optionally, sieving the first suspension through a 200 μm-300 μm sieve;

[0384] d) coating the first core with the sieved first suspension to form a first coated core;

[0385] e) mixing the first coated core with a first lubricant to form a first pellet;

[0386] (2) forming a second pellet, which comprises:

[0387] a) combining a second binder with water to form a second binder / water solution;

[0388] b) adding the SGLT2 inhibitor and the anti-adherent agent to the second binder / water solution to form a second suspension;

[0389] c) coating the second core with the second suspension to form a second coated core;

[0390] d) mixing the second coated core with a second lubricant to form second pellets;

[0391] (3) Combining the first pellet and the second pellet in a capsule.

[0392] Components of the method are further described herein. In some embodiments, the first binder comprises povidone or povidone and hydroxypropyl methylcellulose; the MR modulator comprises AZD9977; the first core comprises microcrystalline cellulose; and the first lubricant comprises sodium stearyl fumarate. In some embodiments, the second binder comprises hydroxypropyl cellulose; the SGLT2 inhibitor comprises dapagliflozin propylene glycol; the anti-adherent comprises talc; the second core comprises sugar spheres; and the second lubricant comprises sodium stearyl fumarate. In some embodiments, the first pellet comprises at least two first binders, wherein steps (1) (a) to (1) (d) are repeated for each first binder, thereby coating the first core with at least two layers comprising each first binder and the MR modulator. In some embodiments, the coating comprises spray coating. The spray coating method is known to those of ordinary skill in the art.

[0393] In some embodiments, the present disclosure provides a method of preparing a capsule comprising a pharmaceutical composition described herein, comprising:

[0394] (1) forming a first pellet, which comprises:

[0395] a) combining povidone with water to form a povidone / water solution;

[0396] b) adding AZD9977 to the povidone / water solution to form a first suspension, wherein

[0397] The first suspension comprises about 20% w / w to about 30% w / w AZD9977;

[0398] c) sieving or wet-milling the first suspension through a 200 μm-300 μm sieve;

[0399] d) coating the microcrystalline cellulose core with the sieved first suspension to form a first coated core;

[0400] e) mixing the first coated core with sodium stearyl fumarate to form a first pellet;

[0401] (2) forming a second pellet, which comprises:

[0402] a) combining hydroxypropyl cellulose with water to form an HPC / water solution;

[0403] b) adding dapagliflozin propylene glycol and talc to the HPC / water solution to form a second suspension, wherein the second suspension comprises about 10% to about 15% dapagliflozin propylene glycol;

[0404] c) coating the sugar sphere core with the second suspension to form a second coated core;

[0405] d) mixing the second coated core with sodium stearyl fumarate to form a second pellet;

[0406] (3) Combining the first pellet and the second pellet in a capsule.

[0407] In some embodiments, the present disclosure provides a method of preparing a capsule comprising a pharmaceutical composition described herein, comprising:

[0408] (1) forming a first pellet, which comprises:

[0409] a) combining hypromellose with water to form a hypromellose / water solution;

[0410] b) adding AZD9977 to the hypromellose / water solution to form a suspension, wherein the suspension comprises about 20% w / w to about 30% w / w AZD9977;

[0411] c) sieving the suspension of (b) through a 200 μm-300 μm sieve;

[0412] d) coating the microcrystalline cellulose core with the sieved suspension of (c) to form a first coated core comprising a first layer;

[0413] e) combining povidone with water to form a povidone / water solution;

[0414] f) adding AZD9977 to the povidone / water solution to form a suspension, wherein the suspension comprises from about 20% w / w to about 30% w / w AZD9977;

[0415] g) sieving the suspension of (f) through a 200 μm-300 μm sieve;

[0416] h) coating the first coated core comprising the first layer with the sieved suspension of (g) to form a first coated core comprising the first layer and the second layer;

[0417] g) mixing a first core including a first layer and a second layer with sodium stearyl fumarate to form a first pellet;

[0418] (2) forming a second pellet, which comprises:

[0419] a) combining hydroxypropyl cellulose with water to form an HPC / water solution;

[0420] b) adding dapagliflozin propylene glycol and talc to the HPC / water solution to form a second suspension;

[0421] c) coating the sugar sphere core with the second suspension to form a second coated core;

[0422] d) mixing the second coated core with sodium stearyl fumarate to form a second pellet;

[0423] (3) Combining the first pellet and the second pellet in a capsule.

[0424] 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 and in any order.

[0425] All publications, patents, and patent applications cited herein are incorporated by reference in their entirety.

[0426] The specific examples included herein are for illustrative purposes only and should not be considered as limitations of the present disclosure. In addition, the compositions, systems and methods provided herein have been described with respect to some of their embodiments, and many details have been elaborated for illustrative purposes. It will be apparent to those skilled in the art that the present disclosure allows additional embodiments, and without departing from the basic principles of the present disclosure, some details described herein may be changed. Any activating agent and reagent used in the following examples are commercially available, or according to the description provided herein, can be prepared by those skilled in the art according to standard literature procedures.

[0427] Example

[0428] Example 1. Preparation of AZD9977+dapagliflozin capsules

[0429] Immediate-release (IR) dapagliflozin pellets :

[0430] Preparation of dapagliflozin spray coating suspension (D1 suspension) for low drug load pellets. 7.5 g hydroxypropylcellulose (HPC) SSL (Nisso Soda) was added to 1312.8 g purified water and stirred for about 2 hours (until a clear solution). 123.8 g talc and 56.25 g 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 RT.

[0431] 85mg / g dapagliflozin IR pellets (D1) were spray coated. 300g of Wu Shuang core ( JRSPharma) was 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 load of 83.5 mg / g.

[0432] Preparation of dapagliflozin spray coating suspension (D2 suspension) for high drug load pellets. 5.0 g HPCSSL (Nisso Soda) was added to 875.7 g purified water and stirred for about 2 hours (until a clear solution). 82.5 g talc and 37.5 g 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 RT.

[0433] 130mg / g dapagliflozin IR pellets (D2) were spray coated. 100g of Wu Shuang core ( JRSPharma) was loaded into a Wurster fluid bed spray coater (Graniten Engineering). Under the conditions summarized in Table 1, the cores were coated with 847.7 g of the dapagliflozin coating suspension to produce 174 g of dapagliflozin IR pellets with a drug load of 131.5 mg / g.

[0434] Preparation of dapagliflozin spray coating suspension (D3 suspension) for dapagliflozin pellets. 0.9 kg HPCSSL (Nisso Soda) was added to 67.5 kg purified water and stirred for about 1 hour (until a clear solution). 14.85 kg talc and 6.75 kg dapagliflozin (Dottikon) were added to the HPC SSL / water solution to produce a 25% (w / w) dapagliflozin coating suspension, which was stirred overnight at RT.

[0435] 105mg / g dapagliflozin IR pellets (D3) were spray coated. 30kg of Wu Shuang core ( JRS Pharma) was loaded into a Wurster fluidized bed spray coater (GPCG30, Glatt). Under the conditions summarized in Table 1, the cores were coated with 90 kg of the dapagliflozin coating suspension to produce 49.5 kg of dapagliflozin IR pellets with a drug load of 107 mg / g.

[0436] Immediate release (IR) AZD9977 pellets :

[0437] 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 about 1 hour (until a clear solution). 400 g of AZD9977 (STAWuXi) was added to the PVP K30 / water solution to produce a 23% (w / w) AZD9977 coating suspension, which was stirred overnight at RT. The suspension was sieved through a 250 μm sieve before use in the coating step.

[0438] 600mg / g AZD9977 IR pellets (A1) were spray coated. 170g of microcrystalline cellulose (MCC) core ( 100, JRS Pharma) was 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 load of 598 mg / g.

[0439] Preparation of AZD9977 spray coating suspension (A2a suspension - layer 1). 12 g of hydroxypropylmethylcellulose (HPMC) 6 cps (Dow Chem) was added to 468 g of purified water and stirred for about 1 hour (until a clear solution). 120 g of AZD9977 (STA WuXi) was added to the HPMC / water solution to produce a 22% (w / w) AZD9977 coating suspension A2a, which was stirred overnight at RT. The suspension was sieved through 250 μm before use in the coating step.

[0440] 320mg / g AZD9977 IR pellets (A2a-first layer) were spray coated. 200g MCC cores ( 100, JRS Pharma) was 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 AZD9977IR pellets A2a with a drug load of 323 mg / g.

[0441] Preparation of AZD9977 spray coating suspension (A2 suspension - layer 2). 45 g PVP K30 (BASF) was added to 1155 g purified water and stirred for about 30 minutes (until a clear solution). 300 g AZD9977 (STA WuXi) was added to the PVP K30 / water solution to produce a 23% (w / w) AZD9977 suspension, which was stirred overnight at RT. The suspension was sieved through 250 μm before use in the coating step.

[0442] Spray coating of 600 mg / g AZD9977 IR pellets (A2 - second 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 summarised in Table 1 to produce 547 g of AZD9977 IR pellets A2 with a drug load of 605 mg / g.

[0443] Preparation of AZD9977 spray coating suspension (A3 suspension). 1.0 kg hydroxypropylmethylcellulose (HPMC) 6 cps (Dow Chem) was added to 39 kg purified water and stirred for at least 0.5 hours (until a clear solution). 10 kg AZD9977 (STA WuXi) was added to the HPMC / water solution to produce a 22% (w / w) AZD9977 coating suspension, which was stirred overnight at RT.

[0444] Spray coating of 200 mg / g AZD9977 IR pellets (A3-second layer) 39 kg of microcrystalline cellulose (MCC) core ( 200, JRS Pharma) was loaded into a Wurster fluid bed spray coater (GPCG30). The cores were coated with 50 kg of AZD9977 coating suspension under the conditions outlined in the table below to produce 49.0 kg of AZD9977 IR pellets with a drug load of 202 mg / g.

[0445] Table 1. Spray coating process parameters .

[0446]

[0447] Fill D1, D2, D3, A1, A2, A3 pellets into capsules

[0448] lubricating :

[0449] A1: 518g of AZD9977 pellets A1 were mixed with 2.34g of sodium stearyl fumarate in a Turbula T2F mixer for 10 minutes / 23rpm to produce 520.6g of lubricated AZD9977 pellets.

[0450] A2: 543g of AZD9977 pellets A2 were mixed with 2.45g of sodium stearyl fumarate in a Turbula T2F mixer for 10 minutes / 23 rpm to produce 544.7g of lubricated AZD9977 pellets.

[0451] D1: 388.5 g of dapagliflozin pellets D1 were mixed with 1.76 g of sodium stearyl fumarate in a Turbula T2F mixer for 10 min / 23 rpm to produce 390.3 g of lubricated dapagliflozin DL low pellets.

[0452] D2: 167.3 g of dapagliflozin pellets D2 were mixed with 0.76 g of sodium stearyl fumarate in a Turbula T2F mixer for 10 min / 23 rpm to produce 168.1 g of lubricated dapagliflozin DL High pellets.

[0453] D3: 167.3 g of dapagliflozin pellets D3 were mixed with 0.76 g of sodium stearyl fumarate in a Turbula T2F mixer for 10 min / 23 rpm to produce 168.1 g of lubricated dapagliflozin DL pellets.

[0454] FDC capsules (also shown in Figure 2A middle):

[0455] Capsule 1 ("FDC1"): 150 mg AZD9977 pellets A1 and 10 mg dapagliflozin D1 were administered. 250 g of lubricated AZD9977 pellets A1 and 124 g of dapagliflozin pellets D1 were filled into 1000 white, size 0 gelatin capsules (Capsugel) using a JuBo capsule filler, with an average fill weight of 250 mg AZD9977 pellets and 124 mg dapagliflozin pellets per capsule.

[0456] Capsule 2 ("FDC2"): 150 mg AZD9977 pellets A2 and 10 mg dapagliflozin D2 were administered. 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 filler, with an average fill weight of 250 mg AZD9977 pellets and 80 mg dapagliflozin pellets per capsule.

[0457] Capsule 3 ("FDC3"): 150 mg AZD9977 pellets A1 and 10 mg dapagliflozin D2 were administered. 250 g of lubricated AZD9977 pellets A1 and 80 g of dapagliflozin pellets D2 were filled into 1000 white, size 0 gelatin capsules (Capsugel) using a JuBo capsule filler, with an average fill weight of 250 mg AZD9977 pellets and 80 mg dapagliflozin pellets per capsule.

[0458] Capsule 4 ("FDC4"): 150 mg AZD9977 pellets A2 and 10 mg dapagliflozin D1 were administered. 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 filler, with an average fill weight of 250 mg AZD9977 pellets and 124 mg dapagliflozin pellets per capsule.

[0459] Capsule 5: 40 mg AZD9977 pellets A3 and 10 mg dapagliflozin D3 were administered. 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 filler, with an average fill weight of 200 mg AZD9977 pellets and 93.4 mg dapagliflozin pellets per capsule.

[0460] Example 2. Dissolution study

[0461] The FDC formulations described in Example 1 (Capsules 1-4) were subjected to in vitro dissolution studies.

[0462] The results are shown in Figure 1A (Dapagliflozin, tested in USP Apparatus 1 at 100 rpm), Figure 1B (AZD9977, tested in USP Apparatus 2 at 100 rpm) and Figure 1C (AZD9977, tested in USP Apparatus 1 at 100 rpm). Figure 1A As shown, all four FDC formulations released >80% of dapagliflozin within 30 minutes, as tested in USP Apparatus 1 at 100 rpm. Figure 1B As shown, all four FDC formulations released >80% of AZD9977 within 30 minutes, as tested in USP Apparatus 2 at 100 rpm. Figure 1CAs shown, FDC 1 and FDC 3 containing AZD9977 pellets coated with povidone released >80% of AZD9977 within 30 minutes as tested in USP Apparatus 1 at 100 rpm; and FDC 2 and FDC 4 containing AZD9977 pellets coated with HPMC / povidone released >60% of AZD9977 within 30 minutes as tested in USP Apparatus 1 at 100 rpm.

[0463] Example 3. Clinical study to evaluate the bioavailability of AZD9977 and dapagliflozin FDC capsules

[0464] A randomized, parallel-group, open-label, four / five-period, eight-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 into Figure 2B One of 8 treatment sequences depicted. Treatments are as follows:

[0465] Group 1 :

[0466] Treatment A1 = 150 mg AZD9977 (AZD9977 capsule 50 mg + AZD9977 capsule 100 mg) and 10 mg dapagliflozin tablet, fasting;

[0467] Treatment B = 150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasting;

[0468] Treatment C = 150 mg AZD9977 + 10 mg dapagliflozin capsule 1, taken with food;

[0469] Treatment D = 150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fasting;

[0470] Treatment E = 150 mg AZD9977 + 10 mg dapagliflozin capsule 2, taken with food;

[0471] Group 2 :

[0472] Treatment A2 = 150 mg AZD9977 (AZD9977 capsule 50 mg + AZD9977 capsule 100 mg) and 10 mg dapagliflozin tablet, fasting;

[0473] Treatment F = 150 mg AZD9977 + 10 mg dapagliflozin capsule 3, fasting;

[0474] Treatment G = 150 mg AZD9977 + 10 mg dapagliflozin capsules 4, fasting;

[0475] Treatment H = 10 mg dapagliflozin capsule, fasting.

[0476] Plasma AZD9977 concentrations after single oral administration of different formulations of AZD9977 and dapagliflozin .

[0477] The mean plasma AZD9977 concentration versus time curve is presented in Figure 3A (linear scale) and Figure 3B (semi-logarithmic scale).

[0478] Low to moderate inter-subject variability was observed for AUC across all treatments, with geometric mean coefficients of variation ranging from approximately 20% to 28%. Low to high inter-subject variability was observed for Cmax across all treatments, with geometric mean coefficients of variation ranging from approximately 15% to 50%.

[0479] AZD9977 AUClast and AUCinf were comparable between Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasting) and Reference Treatment A1 (150 mg AZD9977 (AZD9977 capsule 50 mg + AZD9977 capsule 100 mg) and 10 mg dapagliflozin tablet, fasting). Cmax was 14% lower than the reference treatment and C24 values ​​were 49% higher than the reference treatment. Figure 4A .

[0480] AZD9977 AUClast and AUCinf were comparable between Treatment D (150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fasting) and Reference Treatment A1 (150 mg AZD9977 (AZD9977 capsule 50 mg + AZD9977 capsule 100 mg) and 10 mg dapagliflozin tablet, fasting). Cmax may be 7% lower than the reference treatment and C24 values ​​may be 23% higher than the reference treatment. Figure 4A .

[0481] For treatment C (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fed) vs. treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasted), the AZD9977 AUClast and AUCinf in the fed state were 21% and 18% higher than in the fasted state, respectively. The Cmax in the fed state was 56% higher, and the C24 value was 69% lower. See Figure 4B .

[0482] For treatment E (150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fed) vs. treatment D (150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fasted), AUClast and AUCinf in the fed state were comparable to the values ​​in the fasted state. Cmax in the fed state was 31% higher and C24 values ​​were 56% lower. Figure 4B .

[0483] AZD9977 AUClast and AUCinf were comparable between treatment F (150 mg AZD9977 + 10 mg dapagliflozin capsules 3, fasting) and reference treatment A2 (150 mg AZD9977 [AZD9977 capsules 50 mg + AZD9977 capsules 100 mg] and 10 mg dapagliflozin tablets, fasting). Cmax may be 10% lower than the reference treatment and C24 values ​​may be 11% higher than the reference treatment. Figure 5A .

[0484] AZD9977 AUClast and AUCinf were comparable between treatment G (150 mg AZD9977 + 10 mg dapagliflozin capsules 4, fasting) and reference treatment A2 (150 mg AZD9977 [AZD9977 capsules 50 mg + AZD9977 capsules 100 mg] and 10 mg dapagliflozin tablets, fasting). Cmax may be 16% lower than the reference treatment, and C24 values ​​may be 43% higher than the reference treatment. Figure 5A .

[0485] For Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasting) versus Treatment F (150 mg AZD9977 + 10 mg dapagliflozin capsule 3, fasting), AZD9977 variant 1, Treatment B, AZD9977 exposure (AUClast, AUCinf, Cmax and C24) was comparable to Treatment F. Figure 5B .

[0486] For Treatment D (150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fasting) vs. Treatment G (150 mg AZD9977 + 10 mg dapagliflozin capsule 4, fasting), AZD9977 variant 2, Treatment D AZD9977 AUClast and AUCinf were comparable to Treatment G AUClast and AUCinf values. Treatment D Cmax was 11% higher than Treatment G Cmax, and Treatment D C24 value was 29% lower than Treatment G C24 value. See Figure 5B .

[0487] Plasma dapagliflozin concentrations after single oral administration of AZD9977 and different formulations of dapagliflozin .

[0488] The geometric mean plasma dapagliflozin concentration versus time curve is presented in Fig. 6A (linear scale) and Figure 6B (semi-logarithmic scale).

[0489] Low inter-subject variability was observed for AUC across all treatments, with geometric mean coefficients of variation ranging from approximately 10% to 21%. Low to moderate inter-subject variability was observed for Cmax across all treatments, with geometric mean coefficients of variation ranging from approximately 17% to 38%.

[0490] Dapagliflozin AUClast and AUCinf were comparable between Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasting) and Reference Treatment A1 (150 mg AZD9977 (AZD9977 capsule 50 mg + AZD9977 capsule 100 mg) and 10 mg dapagliflozin tablet, fasting). Cmax may be 11% lower than the reference treatment, and C24 values ​​may be 7% higher than the reference treatment. Fig. 7A .

[0491] Dapagliflozin AUClast and AUCinf were comparable between Treatment D (150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fasting) and Reference Treatment A1 (150 mg AZD9977 (AZD9977 capsule 50 mg + AZD9977 capsule 100 mg) and 10 mg dapagliflozin tablet, fasting). Cmax was 9% lower than the reference treatment and C24 value was 11% higher than the reference treatment. Fig. 7A .

[0492] For Treatment C (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fed) vs Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasted), the dapagliflozin AUClast and AUCinf in the fed state were comparable to those observed in the fasted state. Cmax was 34% lower and C24 values ​​were 12% higher in the fed state. Figure 7B .

[0493] For Treatment E (150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fed) vs. Treatment D (150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fasted), the dapagliflozin AUClast and AUCinf in the fed state were comparable to values ​​observed in the fasted state. Cmax in the fed state was 28% lower, and C24 values ​​were comparable to values ​​observed in the fasted state. Figure 7B .

[0494] Dapagliflozin AUClast and AUCinf were comparable between Treatment F (150 mg AZD9977 + 10 mg dapagliflozin capsules 3, fasting) and Reference Treatment A2 (150 mg AZD9977 (AZD9977 capsules 50 mg + AZD9977 capsules 100 mg) and 10 mg dapagliflozin tablets, fasting). Cmax was 22% lower than Treatment A2 Cmax, and C24 values ​​were 7% higher than Treatment A2 C24. Fig. 8A .

[0495] For treatment G (150 mg AZD9977 + 10 mg dapagliflozin capsules 4, fasting) versus reference treatment A2 (150 mg AZD9977 (AZD9977 capsules 50 mg + AZD9977 capsules 100 mg) and 10 mg dapagliflozin tablets, fasting), AUClast and AUCinf may be 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 Fig. 8A .

[0496] For treatment H (10 mg dapagliflozin capsules, fasting) versus reference treatment A2 (150 mg AZD9977 (AZD9977 capsules 50 mg + AZD9977 capsules 100 mg) and 10 mg dapagliflozin tablets, fasting), AUClast was 7% higher and AUCinf was 6% higher than treatment A2 values, respectively. Cmax was 26% lower than treatment A2 Cmax, and C24 value was 15% higher than treatment A2 C24. See Fig. 8A .

[0497] For Treatment B (150 mg AZD9977 + 10 mg dapagliflozin capsule 1, fasting) vs. Treatment G (150 mg AZD9977 + 10 mg dapagliflozin capsule 4, fasting), dapagliflozin variant 1, Treatment B dapagliflozin AUClast and AUCinf were 6% lower than Treatment G AUClast and AUCinf. Treatment B Cmax was 16% lower than Treatment G Cmax, and Treatment B C24 values ​​were comparable to Treatment G C24. See Figure 8B .

[0498] For treatment D (150 mg AZD9977 + 10 mg dapagliflozin capsule 2, fasting) vs. treatment F (150 mg AZD9977 + 10 mg dapagliflozin capsule 3, fasting), dapagliflozin variant 2, dapagliflozin AUClast and AUCinf were comparable. Treatment D Cmax may be 7% higher than treatment F Cmax, and treatment D C24 values ​​may be 8% higher than treatment F C24 values. See Figure 8B .

[0499] Pharmacokinetic conclusion .

[0500] Exposure to AZD9977 and dapagliflozin from all four capsules (treatments B, D, F, G) under fasting conditions 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 observed for the reference treatments.

[0501] The administration of capsule 1 and capsule 2 with food resulted in a slight delay in the tmax of AZD9977. For treatment C (capsule 1, fed), the AUClast, AUCinf and Cmax values ​​of AZD9977 were higher than those observed for treatment B (capsule 1, fasted), with the C24 value being lower in the fed state. For treatment E (capsule 2, fed), the AUClast and AUCinf values ​​of AZD9977 were comparable to those of treatment D (capsule 2, fasted), the Cmax in the fed state may be higher than that in the fasted state, and the C24 value may be lower than that in the fasted state. In summary, the magnitude of the effect of food on the PK of AZD9977 appears to be lower in capsule 2 than in capsule 1.

[0502] For dapagliflozin in Treatment C (Capsule 1, fed) and Treatment E (Capsule 2, fed), the tmax in the fed state was slightly later than the fasted tmax, but the exposure to dapagliflozin in terms of AUClast and AUCinf was comparable between the fed and fasted states. For Treatment C, Cmax was lower than that of Treatment B, and C24 was higher than that of Treatment B. For Treatment E, Cmax was lower than that of Treatment D, and C24 values ​​were comparable.

[0503] Exposure to AZD9977 variant 1 from capsule 1 (treatment B) was comparable to that 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 that from capsule 4 (treatment G) in terms of AUClast and AUCinf. Treatment D Cmax was 11% higher than Treatment G Cmax, and Treatment D C24 values ​​were 29% lower than Treatment G C24 values.

[0504] The exposure to dapagliflozin variant 1 from capsule 1 (treatment B) was 6% lower than that from capsule 4 (treatment G) in terms of AUClast and AUCinf. The Cmax of treatment B was 16% lower than that of treatment G, and the C24 values ​​were comparable.

[0505] The 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. The Cmax and C24 values ​​of treatment D were likely 7%-8% higher than those of treatment F.

[0506] For AZD9977, all capsule formulations had a common trend in the fasting state; AUClast and AUCinf 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 Cmax tended to be lower than the reference treatment, and C24 tended to be higher. Similar trends were observed for dapagliflozin, with the slight exception of treatment G, where AUClast and AUCinf values ​​were slightly higher than the reference treatment, Cmax was comparable to the reference treatment, and C24 tended to be slightly lower.

[0507] The administration of capsule 1 and capsule 2 with food causes the tmax of AZD9977 to be slightly delayed. For treatment C (capsule 1, fed), AUClast, AUCinf and Cmax values ​​are significantly higher than those observed for treatment B (capsule 1, fasted), wherein C24 values ​​are significantly lower in the fed state. For treatment E (capsule 2, fed), in terms of AUClast and AUCinf, the effect of comparable exposure to AZD9977 under fasting conditions is less significant, although Cmax appears to be higher and C24 appears to be lower in the fed state. For dapagliflozin in treatment C and treatment E, tmax in the fed state is slightly later than fasting tmax, but the exposure to dapagliflozin in terms of AUClast and AUCinf is comparable between the fed state and the fasted state. The Cmax of dapagliflozin in capsule 1 and capsule 2 is lower in the fed state, and the C24 of capsule 1 is slightly higher, but the C24 of capsule 2 is comparable.

[0508] The effect of food on the pharmacokinetics of AZD9977 and dapagliflozin is unlikely to be clinically relevant and the fixed-dose combination of AZD9977 / dapagliflozin is not expected to be taken without dietary guidance.

[0509] AZD9977 variant 1 was administered as treatment B (capsule 1) and treatment F (capsule 3) in combination with different variants of dapagliflozin. The exposure to AZD9977 variant 1 from capsule 1 was comparable to that from capsule 3 in terms of AUClast, AUCinf, Cmax and C24. AZD9977 variant 2 was administered as treatment D (capsule 2) and treatment G (capsule 4). The exposure to AZD9977 variant 2 from capsule 2 was comparable to that from capsule 4 in terms of AUClast and AUCinf, although the Cmax value of capsule 2 appears to be potentially higher and the C24 of capsule 2 may be lower.

[0510] The same dapagliflozin variant was 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). Capsule 1 may have lower exposure to dapagliflozin variant 1, while capsule 2 may have comparable exposure to dapagliflozin variant 2 with respect to AUClast and AUCinf as capsule 3. For variant 1, the Cmax of treatment B (capsule 1) may be lower than the Cmax observed for treatment G (capsule 4), with C24 comparable to the C24 observed for treatment G (capsule 4). For variant 2, the Cmax and C24 of treatment D (capsule 2) may be higher than the Cmax and C24 observed for treatment F (capsule 3).

[0511] Example 4. Phase 3 formulation of AZD9977 and dapagliflozin capsules

[0512] Immediate release (IR) AZD9977 pellets :

[0513] 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). 34 kg of AZD9977 (STA WuXi) was added to the PVP K30 / water solution to produce a 23% (w / w) AZD9977 coating suspension, which was stirred overnight at RT. The particle size of the suspension was reduced using a co-ball mill.

[0514] 600mg / g AZD9977 IR pellets (A1) were spray coated. 17kg of microcrystalline cellulose (MCC) core ( 100, JRS Pharma) was loaded into a Wurster fluid bed spray coater (GPCG30). The cores were coated with 165 kg of AZD9977 coating suspension under the conditions summarized in Table 2 to produce 54.2 kg of AZD9977 IR pellets with a drug load of 601 mg / g.

[0515] Immediate-release (IR) dapagliflozin pellets :

[0516] Prepare dapagliflozin spray coating suspension. 0.9 kg hydroxypropylcellulose (HPC SSL from Nisso) was added to 67.5 kg purified water and stirred for at least 0.5 hours (until a clear solution). 14.85 kg talc (Imerys) and 6.75 kg dapagliflozin (Dottikon) were added to the HPC solution to produce a 25% (w / w) dapagliflozin coating suspension. The suspension was stirred overnight at RT.

[0517] Spray coating of 105 mg / g dapagliflozin IR pellets. 30 kg of sugar sphere (NP) core ( JRSPharma) was loaded into a Wurster fluid bed spray coater (GPCG30). Under the conditions summarized in Table 2, the cores were coated with 90 kg of the dapagliflozin coating suspension to produce 49.5 kg of dapagliflozin IR pellets with a drug load of 107 mg / g.

[0518] Table 2. Stage 3 spray coating process parameters .

[0519] Process parameters Dapagliflozin pills AZD9977 pellets A1 unit Inlet fluidizing gas temperature 97-99 95-105 [℃] Outlet fluidizing gas temperature 44-63 45-50 [℃] Fluidizing gas flow Approx. 1254 Approx. 1045 <![CDATA[[Nm 3 / h]]]> Amount of water in the fluidizing gas 5.8 6.0 [g / kg] Atomizer flow 70 47-53 <![CDATA[[Nm 3 / h]]]> Atomizer pressure 4 2.5-2.7 [bar] Average spray rate 500 410 [g / min]

[0520] Filling pellets into capsules

[0521] lubricating :

[0522] AZD9977: 49.9 kg AZD9977 pellets were mixed with 0.1 kg sodium stearyl fumarate (SSF PRUV, Moehs) in a 200L double cone mixer for 10 minutes / 15 rpm to produce 50.0 kg lubricated AZD9977 pellets.

[0523] Dapagliflozin: 99.8 kg of dapagliflozin pellets were mixed with 0.2 kg of sodium stearyl fumarate (SSF PRUV, Moehs) in a 200 L double cone mixer for 10 min / 15 rpm to produce 100.0 kg of lubricated dapagliflozin pellets.

[0524] FDC capsules :

[0525] Dosing of 50 mg AZD9977 and 10 mg dapagliflozin. Using an MG Futura encapsulator, 50.0 kg of lubricated AZD9977 pellets and 57.5 kg of lubricated dapagliflozin pellets were filled into 600000 white, size 1EL gelatin capsules (Capsugel) with an average fill weight of 83.4 mg AZD9977 pellets and 95.9 mg dapagliflozin pellets.

[0526] 150 mg AZD9977 and 10 mg dapagliflozin were administered. Using a MG Futura encapsulator, 50.0 kg of lubricated AZD9977 pellets and 19.2 kg of lubricated dapagliflozin pellets were filled into 200000 white, size 1 EL gelatin capsules (Capsugel) with an average fill weight of 250 mg AZD9977 pellets and 95.9 mg dapagliflozin pellets.

Claims

1. A pharmaceutical composition, comprising: (a) one or more first pellets comprising i. The first core, and ii. a first coating on the first core, wherein the first coating comprises a mineralocorticoid receptor (MR) modulator and a first binder; and (b) one or more second pellets comprising i. The second core, and ii. a second coating on the second core, wherein the second coating comprises an SGLT2 inhibitor, wherein the SGLT2 inhibitor is about 5 wt % to about 20 wt % of the second pellet, wherein the composition comprises about 20 wt % to about 50 wt % of the mineralocorticoid receptor (MR) modulator; and about 1 wt % to about 10 wt % of the SGLT2 inhibitor.

2. The pharmaceutical composition according to claim 1, wherein the MR modulator comprises a compound of formula I: (AZD9977 or balcinrenone).

3. The pharmaceutical composition of claim 1 or 2, wherein the composition comprises about 25 wt% to about 45 wt% of the MR modulator.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the composition comprises 25 wt% to about 30 wt% of the MR modulator, or about 40 wt% or about 45 wt% of the MR modulator.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the first binder comprises povidone.

6. The pharmaceutical composition of claim 5, wherein the composition comprises from about 1 wt% to about 10 wt% povidone.

7. The pharmaceutical composition of claim 6, wherein the composition comprises about 4 wt% to about 5 wt% povidone or about 6 wt% to about 7 wt% povidone.

8. The pharmaceutical composition according to any one of claims 1 to 4, wherein the first binder comprises povidone and hypromellose.

9. The pharmaceutical composition of claim 8, wherein the composition comprises about 4% to about 6% by weight of povidone.

10. The pharmaceutical composition of claim 8 or 9, wherein the composition comprises about 0.5% to about 3% by weight of hypromellose.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein the composition comprises about 5% by weight of povidone and about 1% by weight of hypromellose.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the first coating further comprises a first lubricant.

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

14. The pharmaceutical composition of claim 12 or 13, wherein the first lubricant is about 0.01 wt% to about 0.5 wt% of the composition.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the first core comprises microcrystalline cellulose.

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

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the SGLT2 inhibitor comprises dapagliflozin.

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

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the composition comprises from about 2% to about 8% by weight of the SGLT2 inhibitor.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the composition comprises about 2.5% to about 4% of the SGLT2 inhibitor.

21. The pharmaceutical composition of any one of claims 1 to 20, wherein the SGLT2 inhibitor is about 5% to about 15% by weight of the second pellet.

22. The pharmaceutical composition of claim 21, wherein the SGLT2 inhibitor is about 7 wt% to about 13 wt% of the second pellet.

23. The pharmaceutical composition of claim 22, wherein the SGLT2 inhibitor is about 8 wt% to about 12 wt% of the second pellet.

24. The pharmaceutical composition of any one of claims 1 to 20, wherein the SGLT2 inhibitor is about 10% to about 15% by weight of the second pellet.

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

26. The pharmaceutical composition of claim 25, wherein the SGLT2 inhibitor is about 12.8% by weight of the second pellet.

27. The pharmaceutical composition of any one of claims 1 to 26, wherein the second coating further comprises a second binder, an anti-adherent agent, and a second lubricant.

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

29. The pharmaceutical composition of claim 27 or 28, wherein the second binder is about 0.1% to about 5% by weight of the composition.

30. The pharmaceutical composition of any one of claims 27 to 29, wherein the anti-adherent agent comprises talc.

31. The pharmaceutical composition of any one of claims 27 to 30, wherein the anti-adherent agent is about 1% to about 20% by weight of the composition.

32. The pharmaceutical composition of any one of claims 27 to 31, wherein the second lubricant comprises sodium stearyl fumarate.

33. The pharmaceutical composition of any one of claims 27 to 32, wherein the second lubricant is about 0.01% to about 1% by weight of the composition.

34. The pharmaceutical composition of any one of claims 1 to 33, wherein the second core comprises sugar, starch, or a combination thereof.

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

36. 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, wherein the first core is about 5% to about 25% by weight of the capsule; ii. A first coating comprising (A) an MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 10% to about 45% by weight of the capsule; (B) povidone, wherein the povidone is about 1% to about 10% by weight of the capsule; and (C) sodium stearyl fumarate, wherein the Sodium stearyl fumarate is about 0.01% to about 1% by weight of the capsule; as well as (b) one or more second pellets comprising: i. A second core comprising sugar spheres, wherein the sugar spheres are about 5 times the weight of the capsule. % to about 30% by weight; ii. A second coating comprising (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor The agent is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is About 1% to about 10% by weight of the capsule and about 5% by weight of the second pellet to about 20% by weight; (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.1% to about 1% by weight of the capsule; (C) talc, wherein The talc is about 1% to about 15% by weight of the capsule; and (D) stearyl Sodium fumarate, wherein the sodium stearyl fumarate is about 0.01 weight percent of the capsule. The amount is from % to about 1% by weight.

37. 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, wherein the first core is about 5% to about 25% by weight of the capsule; ii. A first coating comprising (A) an MR modulator, wherein the MR modulator is AZD9977, and wherein the AZD9977 is about 15% to about 40% by weight of the capsule, (B) povidone, wherein the povidone is about 2% to about 8% by weight of the capsule; and (C) sodium stearyl fumarate, wherein the Sodium stearyl fumarate is about 0.1% to about 0.5% by weight of the capsule; as well as (b) one or more second pellets comprising: i. a second core comprising sugar spheres, wherein the second core is about 10% to about 25% by weight of the capsule; ii. a second coating comprising: (A) an SGLT2 inhibitor, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol, and wherein the dapagliflozin propylene glycol is about 2 wt % to about 5 wt % of the capsule and about 5 wt % to about 20 wt % of the second pellet, (B) hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is about 0.2 wt % to about 0.8 wt % of the capsule; (C) talc, wherein the talc is about 5 wt % to about 12 wt % of the capsule; and (D) sodium stearyl fumarate, wherein the sodium stearyl fumarate is about 0.03 wt % to about 0.1 wt % of the capsule.

38. A pharmaceutical composition according to claim 36 or 37 wherein the capsule comprises about 50 mg or about 150 mg AZD9977.

39. The pharmaceutical composition according to any one of claims 36 to 38, wherein the capsule comprises about 10 mg of dapagliflozin propylene glycol.

40. An oral dosage form comprising the pharmaceutical composition according to any one of claims 1 to 35.

41. The oral dosage form of claim 40, wherein the oral dosage form is a capsule.

42. An oral dosage form according to claim 40 or 41 wherein the pharmaceutical composition in the dosage form comprises about 50 mg or about 150 mg AZD9977.

43. The oral dosage form according to any one of claims 40 to 42, wherein the pharmaceutical composition in the dosage form comprises about 10 mg of dapagliflozin propylene glycol.

44. The pharmaceutical composition of any one of claims 1 to 39 or the oral dosage form of claims 40 to 43, wherein at least 80% of the MR modulator is released within 30 minutes.

45. The pharmaceutical composition according to any one of claims 1 to 39 or the oral dosage form according to claims 40 to 44, wherein at least 80% of the SGLT2 inhibitor is released within 30 minutes.

46. ​​A method of treating heart failure in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 1 to 39 or an oral dosage form according to any one of claims 40 to 45.

47. The method of claim 46, wherein 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.

48. The method of claim 46 or 47, wherein the administration is once daily.

49. The method of any one of claims 46 to 48, wherein the pharmaceutical composition or oral dosage form is administered to a subject in a fasting state.

50. The method of any one of claims 46 to 49, wherein after said administration said subject's AUC last and AUC inf AUC in subjects administered separate dosage forms of the MR modulator and the SGLT2 inhibitor last and AUC inf within 10% of.

51. A method of treating chronic kidney disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 1 to 39 or an oral dosage form according to any one of claims 40 to 45.

52. The method of claim 51, wherein 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.

53. The method of claim 51 or 52, wherein the administration is once daily.

54. The method of any one of claims 51 to 53, wherein the pharmaceutical composition or oral dosage form is administered to a subject in a fasting state.

55. The method of any one of claims 51 to 54, wherein after said administration said subject's AUC last and AUC inf AUC in subjects administered separate dosage forms of the MR modulator and the SGLT2 inhibitor last and AUC inf within 10% of.

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