A combination drug of a mineralocorticoid receptor antagonist and an SGLT2 inhibitor.

Abstract

A combinational medicine of: esaxerenone or a pharmaceutically acceptable salt thereof; and a SGLT2 inhibitor.

Description

Technical Field

[0001] The present invention relates to a combination medicine of esaxerenone or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor.

Background Art

[0002] SGLT2 inhibitors inhibit sodium-dependent glucose cotransporter 2 (hereinafter referred to as SGLT2) present in the proximal renal tubule of the kidney, suppress the reabsorption of sugar from the primary urine, and increase the excretion of sugar to the outside of the body, thereby reducing blood glucose levels. As antidiabetic drugs, for example, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, sergliflozin, and luseogliflozin are sold.

[0003] Esaxerenone or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, is a mineralocorticoid receptor (aldosterone receptor) antagonist and is disclosed in Patent Document 1 and Patent Document 2. The mineralocorticoid receptor is known to play an important role in the control of the body's electrolyte balance and blood pressure, and some mineralocorticoid receptor antagonists are sold as therapeutic drugs for hypertension and the like.

[0004] So far, nothing is known about the efficacy and safety when esaxerenone and an SGLT2 inhibitor are used in combination. ​​​​​​​​​​​​​​​​ [Overview of the project] [Problems that the invention aims to solve]

[0006] The object of the present invention is to provide a highly safe pharmaceutical product. More specifically, the object is to provide a highly safe pharmaceutical product for the prevention and / or treatment of hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerulonephritis, nephrosclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disorders (arteriosclerosis, restenosis after PTCA, peripheral circulatory disorders), type 1 diabetes, type 2 diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, new-onset diabetes mellitus after transplantation (NODAT), and related complications (particularly a pharmaceutical product for the treatment of hypertension, type 2 diabetes, diabetic nephropathy, or hypertension complicated by diabetes). [Means for solving the problem]

[0007] The inventors of this invention conducted intensive research to solve the above problems and found that combining esaxerenone or a pharmaceutically acceptable salt thereof with an SGLT2 inhibitor is extremely effective in preventing and / or treating the above-mentioned disease. This invention was completed based on the above findings.

[0008] In other words, the present invention relates to the following (1) to (16). (1) A pharmaceutical product characterized by containing (i) esaxerenone or a pharmaceutically acceptable salt thereof, and (ii) one or more SGLT2 inhibitors, and administered in combination with these components. (2) A pharmaceutical product containing esaxerenone or a pharmaceutically acceptable salt thereof, which is administered simultaneously with or at different times to a pharmaceutical product containing one or more SGLT2 inhibitors. (3) A pharmaceutical product containing one or more SGLT2 inhibitors, which is administered simultaneously with or at different times to a pharmaceutical product containing esaxerenone or a pharmaceutically acceptable salt thereof. (4) The pharmaceutical product according to (1), characterized in that (i) esaxerenone or a pharmaceutically acceptable salt thereof and (ii) one or more SGLT2 inhibitors are each contained as active ingredients in different formulations and administered simultaneously or at different times. (5) The pharmaceutical product according to (1), characterized in that (i) esaxerenone or a pharmaceutically acceptable salt thereof and (ii) one or more SGLT2 inhibitors are contained in a single formulation. (6) The pharmaceutical product according to (1), characterized in that (i) esaxerenone or a pharmaceutically acceptable salt thereof, and (ii) one or more SGLT2 inhibitors are included in the kit formulation. (7) The pharmaceutical product according to any one of (1) to (6), wherein the SGLT2 inhibitor is one or more selected from canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, cergliflozin, and luseogliflozin. (8) A pharmaceutical product according to any one of (1) to (7) for the prevention or treatment of one or more diseases selected from the group consisting of hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerulonephritis, nephrosclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disorders (arteriosclerosis, restenosis after PTCA, peripheral circulatory disorders), type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes mellitus, new-onset diabetes mellitus after transplantation (NODAT), and related complications. (9) A medicine for the prevention or treatment of hypertension, as described in any one of (1) to (7). (10) A medicine described in any one of (1) to (7) for the prevention or treatment of type 2 diabetes. (11) A medicine described in any one of (1) to (7) for the prevention or treatment of diabetic nephropathy. (12) A medicine described in any one of (1) to (7) for the prevention or treatment of hypertension complicated with diabetes. (13) A pharmaceutical product according to any one of the forms of a pharmaceutical composition (1) to (12). (14) A method for treating one or more diseases selected from the group consisting of hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerulonephritis, nephrosclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disorders (arteriosclerosis, restenosis after PTCA, peripheral circulatory disorders), type 1 diabetes, type 2 diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, new-onset diabetes mellitus after transplantation (NODAT), and related complications, characterized in that the method comprises (i) esaxerenone or a pharmaceutically acceptable salt thereof, and (ii) one or more SGLT2 inhibitors, and these components are administered in combination. (15) A method for treating one or more diseases selected from hypertension and diabetic nephropathy, characterized in that the method comprises (i) esaxerenone or a pharmaceutically acceptable salt thereof and (ii) one or more SGLT2 inhibitors, and these components are administered in combination. (16) The treatment method described in (14), wherein the SGLT2 inhibitor is one or more selected from canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, cergliflozin, and luseogliflozin. [Effects of the Invention]

[0009] The combination pharmaceutical product of esaxerenone or a pharmaceutically acceptable salt thereof of the present invention and one or more SGLT2 inhibitors has excellent blood pressure lowering effects and exhibits high safety, and is therefore useful as a pharmaceutical product [preferably for the prevention or treatment (especially as a therapeutic agent) of one or more diseases selected from the group consisting of hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerulonephritis, nephrosclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disorders (arteriosclerosis, restenosis after PTCA, peripheral circulatory disorders), type 1 diabetes, type 2 diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, new-onset diabetes mellitus after transplantation (NODAT) and related complications, and more preferably as a preventive or therapeutic agent (especially as a therapeutic agent) of hypertension, type 2 diabetes, diabetic nephropathy, or hypertension complicated by diabetes]. [Brief explanation of the drawing]

[0010] [Figure 1] This figure shows the proportion of patients with type 2 diabetes and hypertension who had microalbuminuria and a serum potassium level of ≥5.5 mEq / L. The vertical axis shows the proportion of patients with a serum potassium level of 5.5 mEq / L or higher, and the horizontal axis, from left to right, shows the overall comparison between placebo and esaxerenone, the comparison of placebo administration with and without concomitant SGLT2 inhibitors, and the comparison of esaxerenone administration with and without concomitant SGLT2 inhibitors. [Figure 2] This figure shows the proportion of patients with type 2 diabetes and hypertension who had microalbuminuria and serum potassium levels of ≥6.0 mEq / L or ≥5.5 mEq / L for two consecutive measurements. The vertical axis shows the proportion of patients with serum potassium levels of ≥6.0 mEq / L or ≥5.5 mEq / L for two consecutive measurements, and the horizontal axis shows, from left to right, a comparison between placebo and esaxerenone overall, a comparison of placebo administration with and without concomitant SGLT2 inhibitor use, and a comparison of esaxerenone administration with and without concomitant SGLT2 inhibitor use. [Figure 3] This figure shows the percentage reduction in UACR in hypertensive patients with type 2 diabetes and microalbuminuria, depending on whether or not they were concomitantly treated with an SGLT2 inhibitor. The vertical axis shows the percentage reduction in UACR, and the horizontal axis shows the number of weeks. [Figure 4] This figure shows the change in systolic blood pressure in patients with type 2 diabetes and hypertension who had microalbuminuria, with or without concomitant use of SGLT2 inhibitors. The vertical axis shows the change in blood pressure, and the horizontal axis shows the number of weeks. [Figure 5] This figure shows the change in diastolic blood pressure in hypertensive patients with type 2 diabetes and microalbuminuria, with and without concomitant use of SGLT2 inhibitors. The vertical axis shows the change in blood pressure, and the horizontal axis shows the number of weeks. [Figure 6]This is a figure showing the proportion of cases with serum potassium level ≥ 5.5 mEq / L in patients with type 2 diabetes complicated with hypertension who had overt albuminuria. The vertical axis shows the proportion of patients with serum potassium level ≥ 5.5 mEq / L, and the horizontal axis shows the overall proportion from the left and the comparison of the presence or absence of concomitant use of SGLT2 inhibitor in esaxerenone administration. [Figure 7] This is a figure showing the proportion of cases with serum potassium level ≥ 6.0 mEq / L or ≥ 5.5 mEq / L for two consecutive times in patients with type 2 diabetes complicated with hypertension who had overt albuminuria. The vertical axis shows the proportion of patients with serum potassium level ≥ 6.0 mEq / L or ≥ 5.5 mEq / L for two consecutive times, and the horizontal axis shows the overall proportion from the left and the comparison of the presence or absence of concomitant use of SGLT2 inhibitor in esaxerenone administration. [Figure 8] This is a figure showing the reduction rate of UACR according to the presence or absence of concomitant use of SGLT2 inhibitor in patients with type 2 diabetes complicated with hypertension who had overt albuminuria. The vertical axis shows the reduction rate of UACR, and the horizontal axis shows the week. [Figure 9] This is a figure showing the change amount of blood pressure according to the presence or absence of concomitant use of SGLT2 inhibitor in patients with type 2 diabetes complicated with hypertension who had overt albuminuria. The vertical axis shows the change amount of blood pressure, and the horizontal axis shows the week.

Mode for Carrying Out the Invention

[0011] The medicament of the present invention is characterized in that it combines esaxerenone or a pharmaceutically acceptable salt thereof and one or more SGLT2 inhibitors as active ingredients.

[0012] Esaxerenone or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, is known, and its chemical name is (5P)-1-(2-hydroxyethyl)-N-[4-(methanesulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide or (S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, and it has the following structure (I).

[0013] [Chemical formula]

[0014] In Japan, a product named "Minemblo (registered trademark)" containing esaxerenone as an active ingredient is sold as a therapeutic agent for hypertension. In the present invention, esaxerenone may be esaxerenone, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. Further, a pure form of an atropisomer or any mixture of atropisomers can also be used.

[0015] Examples of the SGLT2 inhibitor which is an active ingredient of the present invention include canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, luseogliflozin and the like. In this specification, the SGLT2 inhibitor may be referred to as SGLT2i.

[0016] In the present invention, "canagliflozin" has the chemical name (1S)-1,5-anhydro-1-C-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-D-glucitol, and a product named "Canaglu (registered trademark)" containing canagliflozin hydrate as an active ingredient is sold as a therapeutic agent for type 2 diabetes in Japan. Canagliflozin in the present invention also includes canagliflozin, pharmaceutically acceptable salts and hydrates thereof.

[0017] In the present invention, "dapagliflozin" has the chemical name (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol, and is sold in Japan as a treatment for type 1 and type 2 diabetes under the product name "Forxiga®," which contains dapagliflozin propylene glycol hydrate as the active ingredient. In the present invention, dapagliflozin also includes dapagliflozin, pharmaceutically acceptable salts, and their hydrates.

[0018] In the present invention, "ipragliflozin" has the chemical name (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glycitol, and is sold in Japan as a treatment for type 1 and type 2 diabetes under the product name "Suglat®," which contains ipragliflozin L-proline as the active ingredient. In the present invention, ipragliflozin also includes ipragliflozin, pharmaceutically acceptable cocrystals, and their hydrates.

[0019] In the present invention, "tofogliflozin" has the chemical name (1S,3'R,4S',5'S,6'R)-6-[(4-ethylphenyl)methyl]-6'-(hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]-3',4',5'-triol, and products containing tofogliflozin hydrate as the active ingredient, "Deberza®" and "Apluway®," are sold in Japan as treatments for type 2 diabetes. In the present invention, tofogliflozin also includes tofogliflozin and its hydrate.

[0020] In the present invention, "empagliflozin" has the chemical name (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxyphenyl)methyl]phenyl}-D-glucitol, and is sold in Japan as a treatment for type 2 diabetes under the product name "Jardiance®," which contains empagliflozin as the active ingredient. The empagliflozin in the present invention also includes empagliflozin and its hydrate.

[0021] In this invention, "luseogliflozin" has the chemical name (2S,3R,4R,5S,6R)-2-{5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl}-6-(hydroxymethyl)thian-3,4,5-triol, and is sold in Japan as a treatment for type 2 diabetes under the product name "Lusefi®," which contains luseogliflozin hydrate as the active ingredient. In this invention, luseogliflozin also includes luseogliflozin and its hydrate.

[0022] In the present invention, "simultaneous administration" is not particularly limited as long as it is an administration form that can be administered at approximately the same time, but it is preferable to administer it as a single composition.

[0023] In the present invention, "administering at different times" is not particularly limited as long as it is an administration method that can be administered separately at different times. For example, it means administering esaxerenone or a pharmaceutically acceptable salt thereof first, and then simultaneously administering an SGLT2 inhibitor (or administering them sequentially after a predetermined time) after a predetermined time, or administering an SGLT2 inhibitor or a diuretic first, and then administering esaxerenone or a pharmaceutically acceptable salt thereof after a predetermined time in the same manner as described above.

[0024] As specifically shown in the examples herein, the present invention enables the action of esaxerenone or a pharmaceutically acceptable salt thereof with an SGLT2 inhibitor to produce a superior effect with reduced side effects without impairing the antihypertensive effect. Based on the above action, the pharmaceuticals of the present invention can be used for the prevention or treatment (especially treatment) of hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerulonephritis, nephrosclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disorders (arteriosclerosis, restenosis after PTCA, peripheral circulatory disorders), type 1 diabetes, type 2 diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, new-onset diabetes mellitus after transplantation (NODAT), and related complications. Furthermore, when esaxerenone or a pharmaceutically acceptable salt thereof of the present invention is used in combination with an SGLT2 inhibitor, it exhibits superior efficacy compared to when each is administered as a single agent.

[0025] Diabetic nephropathy is classified into five stages based on its severity: Stage 1 (pre-nephropathy), Stage 2 (early nephropathy), Stage 3 (overt nephropathy), Stage 4 (renal failure), and Stage 5 (dialysis treatment). Microalbuminuria is detected in Stage 2, and overt albuminuria is detected from Stage 3 onward. Diabetic nephropathy may also be accompanied by hypertension. This invention can be used regardless of the severity of the disease.

[0026] The present invention provides a method for preventing or treating a disease (particularly a treatment method) by administering an effective amount of esaxerenone or a pharmaceutically acceptable salt thereof and one or more SGLT2 inhibitors to a warm-blooded animal (particularly a human) for the production of the above-mentioned pharmaceutical.

[0027] The active ingredient of the pharmaceutical composition of the present invention, esaxerenone or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor can each be prepared individually in separate unit dosage forms, or mixed together to form a single physical unit dosage form.

[0028] The present invention provides a pharmaceutical composition containing esaxerenone or a pharmaceutically acceptable salt thereof and one or more SGLT2 inhibitors as active ingredients, and this pharmaceutical composition may contain one or more pharmaceutical additives.

[0029] When the pharmaceutical composition of the present invention is used as a preventive or therapeutic agent for the above-mentioned diseases, the active ingredients of the pharmaceutical composition of the present invention, esaxerenone or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor, can be administered orally or parenterally by injection or suppository, etc., in the form of tablets, capsules, granules, powders, or syrups, etc., manufactured according to well-known methods using each of these ingredients alone or with appropriate pharmaceutically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, and other additives. Since esaxerenone or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor contained in the pharmaceutical of the present invention are generally administered orally, it is desirable that the pharmaceutical of the present invention be administered orally.

[0030] Examples of "excipients" used include sugar derivatives such as lactose, sucrose, glucose, mannitol, or sorbitol; starch derivatives such as corn starch, potato starch, α-starch, or dextrin; cellulose derivatives such as crystalline cellulose; organic excipients such as gum arabic, dextran, or pullulan; or silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, or magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or inorganic excipients such as sulfates such as calcium sulfate.

[0031] Examples of "lubricants" used include metal stearates such as stearic acid, calcium stearate, or magnesium stearate; waxes such as talc, colloidal silica, beeswax, or gynesia wax; sulfates such as boric acid, adipic acid, or sodium sulfate; lauryl sulfates such as glycol, fumaric acid, sodium stearyl fumarate, sodium benzoate, D,L-leucine, sodium lauryl sulfate, or magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or the starch derivatives mentioned above.

[0032] Examples of "binders" that can be used include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, macrogol, or compounds similar to those used as excipients.

[0033] Examples of "disintegrants" used include cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose (carmellose), calcium carboxymethylcellulose, croscarmellose sodium, or internally cross-linked sodium carboxymethylcellulose; cross-linked polyvinylpyrrolidone; or chemically modified starches and celluloses such as corn starch, pregelatinized starch, sodium starch glycolate, carboxymethyl starch, or sodium carboxymethyl starch.

[0034] Examples of emulsifiers used include colloidal clays such as bentonite or beegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; or nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, or sucrose fatty acid esters.

[0035] Examples of "stabilizers" used include parahydroxybenzoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol; phenols such as benzalkonium chloride, phenol, or cresol; thimerosal; dehydroacetic acid; or sorbic acid.

[0036] Examples of "flavoring and odor-correcting agents" used include sweeteners such as sodium saccharin or aspartame; acidulants such as citric acid, malic acid, or tartaric acid; or flavorings such as menthol, lemon, or orange.

[0037] Examples of diluents used include those commonly used as diluents, such as lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminometasilicate, or mixtures thereof.

[0038] The dosage of esaxerenone and SGLT2 inhibitors, which are the active ingredients of the pharmaceutical composition of the present invention, may vary depending on various conditions such as the activity of each drug, the patient's symptoms, age, and weight. Although the dosage varies depending on the symptoms and age, for oral administration, a minimum of 0.1 mg and a maximum of 1000 mg per dose may be used for each drug, and for parenteral administration, a minimum of 0.01 mg and a maximum of 100 mg per dose may be used for adults, administered 1 to 6 times per day, simultaneously or separately at different times, depending on the symptoms. It is preferable to follow the dosage and administration instructions described in the package insert for each drug. The package inserts for esaxerenone, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, and luseogliflozin are incorporated herein by reference in their entirety.

[0039] Esaxerenone is preferably administered once daily at a dose of 2.5 mg or 5 mg. The preferred dosage forms of esaxerenone are tablets or orally disintegrating tablets (OD tablets).

[0040] If the SGLT2 inhibitor is canagliflozin, it is preferable to administer 100 mg once daily. The preferred dosage form of canagliflozin is a tablet or an orally disintegrating tablet. If the SGLT2 inhibitor is dapagliflozin, it is preferable to administer 5 mg or 10 mg once daily. The preferred dosage form of dapagliflozin is a tablet or an orally disintegrating tablet. If the SGLT2 inhibitor is ipragliflozin, it is preferable to administer 25 mg, 50 mg, or 100 mg once daily. The preferred dosage form of ipragliflozin is a tablet or an orally disintegrating tablet. If the SGLT2 inhibitor is tofogliflozin, it is preferable to administer 20 mg once daily. The preferred dosage form of tofogliflozin is a tablet or an orally disintegrating tablet. If the SGLT2 inhibitor is empagliflozin, it is preferable to administer 10 mg or 25 mg once daily. The preferred dosage form of empagliflozin is a tablet or an orally disintegrating tablet. If the SGLT2 inhibitor is luseogliflozin, it is preferable to administer 2.5 mg or 5 mg once daily. The preferred dosage form of luseogliflozin is tablets or orally disintegrating tablets.

[0041] Furthermore, the ratio of esaxerenone, the active ingredient of the pharmaceutical composition of the present invention, to the dosage of the SGLT2 inhibitor can also vary considerably, but may be within the range of 1:1 to 10000 to 10000:1 to 10000 by weight, preferably 1:1 to 1000 to 1000:1 to 1000, and even more preferably 1:1 to 100 to 100:1 to 100.

[0042] When esaxerenone is used as an SGLT2 inhibitor and canagliflozin is used, the preferred dosage ratio is esaxerenone:canagliflozin in the range of 1:20 to 40 by weight. When esaxerenone is used as an SGLT2 inhibitor and dapagliflozin is used, the preferred dosage ratio is esaxerenone:dapagliflozin in the range of 1:2 to 4 by weight. When esaxerenone is used as an SGLT2 inhibitor and ipragliflozin is used, the preferred dosage ratio is esaxerenone:ipragliflozin in the range of 1:10 to 40 by weight. When esaxerenone is used as an SGLT2 inhibitor and tofogliflozin is used, the preferred dosage ratio is esaxerenone:tofogliflozin in the range of 1:4 to 8 by weight. When esaxerenone is used as the SGLT2 inhibitor empagliflozin, the preferred dosage ratio is esaxerenone:empagliflozin by weight in the range of 1:4 to 10. When esaxerenone is used as the SGLT2 inhibitor luseogliflozin, the preferred dosage ratio is esaxerenone:luseogliflozin by weight in the range of 2:1 to 1:2.

[0043] The duration of administration of esaxerenone and the SGLT2 inhibitor is not particularly limited, but it is preferable to continue administration for at least two weeks, and more preferably for at least four weeks. In another embodiment, it is preferable to continue administration for at least eight weeks, and more preferably for at least twenty weeks.

[0044] When esaxerenone and an SGLT2 inhibitor are combined into a drug, the preferred dosage form is a tablet or an orally disintegrating tablet. [Examples]

[0045] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0046] The abbreviations used in the following examples have the following meanings. Urinary albumin-to-creatinine ratio (UACR): Angiotensin II receptor blockers (ARBs) Angiotensin-converting enzyme (ACE): Creatinine: Cr Estimated Glomerular Filtration Rate (eGFR)

[0047] (Example 1) Administration of esaxerenone to a patient with hypertension complicated by type 2 diabetes and presenting with microalbuminuria A clinical trial was conducted in which esaxerenone was administered to hypertensive patients with type 2 diabetes who had microalbuminuria. Various analyses were performed to determine the effects of concomitant use of SGLT2 inhibitors on the efficacy and safety of esaxerenone. (Patients eligible for clinical trials) 1) Patients who are 20 years of age or older at the time of obtaining consent 2) Patients diagnosed with type 2 diabetes 3) Patients whose clinical laboratory values ​​(intensive measurements) measured during the observation period fall into the following categories. i) UACR measured in the first morning urine sample is between 45 mg / g·Cr and 300 mg / g·Cr for two or more measurements. ii) eGFRcreat of 30 mL / min / 1.73 m 2 That's all. 4) Patients with hypertension who have been taking one ARB or ACE inhibitor without any changes in dosage or administration for at least 12 weeks prior to the start of investigational drug administration. (Clinical trial design) This was a multicenter, placebo-controlled, randomized, double-blind, parallel-group comparative study to investigate the superiority of esaxerenone over placebo in improving UACR (ultraacinergic accelerometer) during 52 weeks of administration in hypertensive patients with type 2 diabetes and microalbuminuria who were receiving ARBs or ACE inhibitors, and to examine the safety of long-term administration of esaxerenone. Various effects were analyzed with and without concomitant use of SGLT2 inhibitors. (Dosage form, dosage, route of administration) Dosage and Administration of Investigational Drug: Esaxerenone tablets 1.25 mg or 2.5 mg were administered orally once daily for 52 weeks, generally after breakfast. The initial dose was 1.25 mg of esaxerenone, and the dose was increased to 2.5 mg based on serum potassium levels.

[0048] Dosage and administration of the control drug: A placebo tablet, a pale yellowish-white film-coated tablet containing lactose monohydrate as the main ingredient, was administered orally once daily for 52 weeks, generally after breakfast. (Confirmation of the effect of reducing the incidence rate of elevated serum potassium levels) The percentage of subjects who experienced the following events from the start of investigational drug administration to the end of administration was calculated for each treatment group. • Serum potassium level is 5.5 mEq / L or higher • Serum potassium level is 6.0 mEq / L or higher, or 5.5 mEq / L or higher for two consecutive measurements. Measurements were performed using a centralized monitoring system, with blood samples collected and processed at the clinical trial site. Sample collection during the clinical trial period was performed at 2 weeks during the observation phase, 2-52 weeks during the treatment phase, at discontinuation, 2 weeks after increasing the investigational drug dose, and 4 weeks after the end of the treatment phase or discontinuation. If serum potassium levels were 5.5 mEq / L or higher, re-measurement was performed using a centralized monitoring system within 3 days in principle. (Test results) In patients with hypertension complicated by type 2 diabetes and microalbuminuria, we found that co-administration of an SGLT2 inhibitor with esaxerenone increased the rate of suppression of serum potassium elevation compared to the group that did not receive the inhibitor. The results are shown in Figures 1 and 2. Figure 1 shows the percentage of cases with serum potassium levels ≥ 5.5 mEq / L, and Figure 2 shows the percentage of cases with serum potassium levels ≥ 6.0 mEq / L or ≥ 5.5 mEq / L for two consecutive measurements.

[0049] Furthermore, analysis by type of SGLT2 inhibitor revealed that this effect is independent of the type of SGLT2 inhibitor. The results are shown in Tables 1 and 2. Table 1 shows the proportion of cases with serum potassium levels ≥ 5.5 mEq / L, classified by type of SGLT2 inhibitor, and Table 2 shows the proportion of cases with serum potassium levels ≥ 6.0 mEq / L or ≥ 5.5 mEq / L for two consecutive tests, classified by type of SGLT2 inhibitor.

[0050] [Table 1]

[0051] [Table 2]

[0052] (Confirmation of the effect of reducing UACR) Sample Collection and Measurement Method: The clinical trial site refrigerated and stored the first morning urine sample collected from each subject on the day of their visit, and the samples were measured at a centralized testing facility. Sample collection during the trial period was performed at the start of the observation period, at 2 weeks, 3 weeks*, 4 weeks of the treatment period, 8-52 weeks, at discontinuation (if possible), and at the end of the treatment period or 4 weeks after discontinuation. UACR was calculated using the following formula. *: Performed only if the criteria were not met at 2 weeks of the observation period. UACR (mg / g·Cr) = (Urinary albumin concentration (μg / mL) / Urinary creatinine concentration (mg / dL)) × 100 Analysis Method: For each treatment group, summary statistics of measured values ​​and changes from baseline were calculated separately for those receiving concomitant SGLT2 inhibitors. Furthermore, using the logarithmic transformed value of UACR, an analysis of covariance (ANCOVA) model was used, with the change from baseline of the logarithmic transformed value as the outcome variable, the treatment group as the factor, and the baseline value (logarithmic transformed value of UACR) as the covariate. The pre-treatment ratio was then calculated for each treatment group. (Test results) In hypertensive patients with type 2 diabetes and microalbuminuria, we found that esaxerenone showed a superior UACR reduction effect, regardless of whether or not an SGLT2 inhibitor was used concomitantly. The results are shown in Figure 3. (Confirmation of blood pressure-lowering effect) Sample collection and measurement methods: Blood pressure was measured at the clinical trial site by repeatedly measuring blood pressure on the same arm at 1-2 minute intervals after the patient had rested in a seated position for at least 5 minutes, for a total of 3 measurements. Measurements during the clinical trial period were taken at the start of the observation period, at 2 weeks, at 2-52 weeks of the treatment period, at discontinuation, 2 weeks after dose increase, and 4 weeks after the end of the treatment period.

[0053] Analysis Method: Summary statistics of measured values ​​and changes from baseline were calculated for each treatment group, categorized by whether or not SGLT2 inhibitors were used concomitantly. In addition, the change was calculated for each treatment group using an ANCOVA model with the treatment group as a factor and baseline values ​​as a covariate. (Test results) In patients with hypertension complicated by type 2 diabetes and microalbuminuria, we found that esaxerenone showed excellent antihypertensive effects, regardless of whether or not an SGLT2 inhibitor was used concomitantly. The results are shown in Figures 4 and 5. Figure 4 shows the change in systolic blood pressure, and Figure 5 shows the change in diastolic blood pressure.

[0054] (Example 2) Administration of esaxerenone to a patient with hypertension complicated by type 2 diabetes and overt albuminuria. A clinical trial was conducted in which esaxerenone was administered to hypertensive patients with type 2 diabetes who had overt albuminuria. Various analyses were performed to examine the effects of concomitant use of SGLT2 inhibitors on the efficacy and safety of esaxerenone. (Patients eligible for clinical trials) 1) Patients who are 20 years of age or older at the time of obtaining consent 2) Patients diagnosed with type 2 diabetes 3) Patients whose clinical laboratory values ​​(intensive measurements) measured during the observation period fall into the following categories. i) UACR measured in the first morning urine sample is 300 mg / g Cr or higher but less than 1000 mg / g Cr for two or more measurements. ii) eGFRcreat of 30 mL / min / 1.73 m 2 That's all. 4) Patients with hypertension who have been taking one ARB or ACE inhibitor without any changes in dosage or administration for at least 12 weeks prior to the start of investigational drug administration. (Clinical trial design) This was a multicenter, randomized, single-arm, open-label trial investigating the safety and efficacy of esaxerenone administered for 28 weeks to hypertensive patients with type 2 diabetes and overt albuminuria who were receiving ARBs or ACE inhibitors. Various effects were analyzed with and without concomitant use of SGLT2 inhibitors. (Dosage form, dosage, route of administration) Dosage and Administration of Investigational Drug: Esaxerenone tablets 1.25 mg or 2.5 mg were administered orally once daily for 28 weeks, generally after breakfast. The initial dose was 1.25 mg of esaxerenone, and the dose was increased to 2.5 mg based on serum potassium levels. (Confirmation of the effect of reducing the incidence rate of elevated serum potassium levels) The percentage of subjects who experienced the following events from the start of investigational drug administration to the end of administration was calculated for each treatment group. • Serum potassium level is 5.5 mEq / L or higher • Serum potassium level of 6.0 mEq / L or higher, or 5.5 mEq / L or higher for two consecutive measurements. Measurements were performed using a centralized monitoring system, with blood samples collected and processed at the clinical trial site. Sample collection during the clinical trial period was performed at 2 weeks during the observation phase, 2-28 weeks during the treatment phase, at discontinuation, 2 weeks after increasing the investigational drug dose, and 4 weeks after the end of the treatment phase or discontinuation. If serum potassium levels were 5.5 mEq / L or higher, re-measurement was performed within 3 days using a centralized monitoring system. (Test results) In hypertensive patients with type 2 diabetes and overt albuminuria, we found that concomitant use of an SGLT2 inhibitor in addition to esaxerenone administration tended to reduce the incidence of elevated serum potassium levels compared to the group that did not receive concomitant treatment. The results are shown in Figures 6 and 7. Figure 6 shows the percentage of cases with serum potassium levels ≥ 5.5 mEq / L, and Figure 7 shows the percentage of cases with serum potassium levels ≥ 6.0 mEq / L or ≥ 5.5 mEq / L for two consecutive measurements.

[0055] Furthermore, analysis by type of SGLT2 inhibitor revealed that this effect is independent of the type of SGLT2 inhibitor. The results are shown in Tables 3 and 4. Table 3 shows the proportion of cases with serum potassium levels ≥ 5.5 mEq / L, classified by type of SGLT2 inhibitor, and Table 4 shows the proportion of cases with serum potassium levels ≥ 6.0 mEq / L or ≥ 5.5 mEq / L for two consecutive tests, classified by type of SGLT2 inhibitor.

[0056] [Table 3]

[0057] [Table 4]

[0058] (Confirmation of the effect of reducing UACR) Sample Collection and Measurement Methods: The clinical trial site refrigerated and stored the first morning urine sample collected from each subject on the day of their visit, and the central testing facility measured the submitted samples. Sample collection during the trial period was performed at the start of the observation period, at 2 weeks, 3 weeks*, 4 weeks, 8-28 weeks, at discontinuation (if possible), and 4 weeks after the end of the treatment period or discontinuation. UACR was calculated using the following formula. *: Performed only if the criteria were not met at 2 weeks of the observation period. UACR (mg / g·Cr) = (Urinary albumin concentration (μg / mL) / Urinary creatinine concentration (mg / dL)) × 100 Analysis method: Summary statistics of measured values ​​and changes from baseline were calculated for each treatment group, categorized by whether or not SGLT2 inhibitors were used concomitantly. (Test results) In hypertensive patients with type 2 diabetes and overt albuminuria, we found that esaxerenone's effect on reducing uACR was not affected by the presence or absence of concomitant use of SGLT2 inhibitors, and that it showed a superior effect on reducing uACR. The results are shown in Figure 8. (Confirmation of blood pressure-lowering effect) Sample collection and measurement methods: Blood pressure was measured at the clinical trial site by repeatedly measuring blood pressure on the same arm at 1-2 minute intervals after the patient had rested in a seated position for at least 5 minutes, for a total of 3 measurements. Measurements during the clinical trial period were taken on the start of the observation period, at 2 weeks, during the treatment period from 2 to 28 weeks, at discontinuation, 2 weeks after dose increase, and 4 weeks after the end of the treatment period.

[0059] Analysis method: Summary statistics of measured values ​​and changes from baseline were calculated for each treatment group, categorized by whether or not SGLT2 inhibitors were used concomitantly. (Test results) We found that the antihypertensive effect of esaxerenone was not affected by the presence or absence of concomitant use of SGLT2 inhibitors, and that it showed excellent antihypertensive effects. The results are shown in Figure 9. (Example of formulation)

[0060] [Table 5]

[0061] The powders of the above formulation are mixed and compressed into 300 mg tablets using a tablet press. These tablets may be coated with sugar if necessary.

Claims

1. A pharmaceutical product characterized by containing (i) esaxerenone or a pharmaceutically acceptable salt thereof, and (ii) one or more SGLT2 inhibitors, and being administered in combination thereof, The SGLT2 inhibitor is one or more selected from canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, and luseogliflozin. A pharmaceutical product intended for use in patients with hypertension complicated by type 2 diabetes and albuminuria.

2. A pharmaceutical product containing esaxerenone or a pharmaceutically acceptable salt thereof, characterized in that it is administered simultaneously with or at different times to a pharmaceutical product containing one or more SGLT2 inhibitors, The SGLT2 inhibitor is one or more selected from canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, and luseogliflozin. A pharmaceutical product intended for use in patients with hypertension complicated by type 2 diabetes and albuminuria.

3. A pharmaceutical product characterized by containing one or more SGLT2 inhibitors and being administered simultaneously with or at different times to a pharmaceutical product containing esaxerenone or a pharmaceutically acceptable salt thereof, The SGLT2 inhibitor is one or more selected from canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, and luseogliflozin. A pharmaceutical product intended for use in patients with hypertension complicated by type 2 diabetes and albuminuria.

4. The pharmaceutical product according to claim 1, characterized in that (i) esaxerenone or a pharmaceutically acceptable salt thereof and (ii) one or more SGLT2 inhibitors are each contained as active ingredients in different formulations and administered simultaneously or at different times.

5. The pharmaceutical product according to claim 1, characterized in that (i) esaxerenone or a pharmaceutically acceptable salt thereof and (ii) one or more SGLT2 inhibitors are contained in a single formulation.

6. The pharmaceutical product according to claim 1, characterized in that (i) esaxerenone or a pharmaceutically acceptable salt thereof and (ii) one or more SGLT2 inhibitors are included in the kit formulation.

7. The pharmaceutical agent according to any one of claims 1 to 6, wherein the increase in serum potassium levels is suppressed compared to when an SGLT2 inhibitor is not administered.

8. A pharmaceutical product according to any one of claims 1 to 7, which is a pharmaceutical product for the prevention or treatment of hypertension.

9. A pharmaceutical product according to any one of claims 1 to 7, which is a pharmaceutical product for the prevention or treatment of type 2 diabetes.

10. A pharmaceutical product according to any one of claims 1 to 7, which is a pharmaceutical product for the prevention or treatment of diabetic nephropathy.

11. A pharmaceutical product according to any one of claims 1 to 7, which is a pharmaceutical product for the prevention or treatment of hypertension complicated with diabetes.

12. A pharmaceutical composition according to any one of claims 1 to 11.

13. A pharmaceutical product according to any one of claims 1 to 12, for administration to a patient with hypertension complicated by type 2 diabetes having trace or overt albuminuria.

14. The pharmaceutical product according to any one of claims 1 to 13, wherein esaxerenone or a pharmaceutically acceptable salt thereof is esaxerenone.

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