WO2022071578A1 - ミネラルコルチコイド受容体拮抗剤と、ｓｇｌｔ２阻害剤の組み合わせ医薬 - Google Patents

ミネラルコルチコイド受容体拮抗剤と、ｓｇｌｔ２阻害剤の組み合わせ医薬 Download PDF

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WO2022071578A1
WO2022071578A1 PCT/JP2021/036423 JP2021036423W WO2022071578A1 WO 2022071578 A1 WO2022071578 A1 WO 2022071578A1 JP 2021036423 W JP2021036423 W JP 2021036423W WO 2022071578 A1 WO2022071578 A1 WO 2022071578A1
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esaxerenone
diabetes
medicine
pharmaceutically acceptable
acceptable salt
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French (fr)
Japanese (ja)
Inventor
智子 松田
大志 吉田
恭行 奥田
貴文 中津
知子 田中
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a combination drug of esaxerenone or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor.
  • SGLT2 inhibitors reabsorb sugar from raw urine by inhibiting the sodium-dependent glucose transporter 2 (hereinafter referred to as SGLT2) present in the proximal tubule of the kidney. It is known to lower the blood glucose level by suppressing glucose and increasing glucose excretion to the outside of the body. Glyfrosin, Luceo glyfrosin and the like are on the market.
  • Esaxerenone which is the active ingredient of the present invention, or a pharmaceutically acceptable salt thereof is a mineral corticoid receptor (aldosterone receptor) antagonist and is disclosed in Patent Document 1 and Patent Document 2.
  • Mineral corticoid receptors are known to play an important role in controlling electrolyte balance and blood pressure in the body, and some mineral corticoid receptor antagonists are marketed as therapeutic agents for hypertension and the like. ..
  • An object of the present invention is to provide a highly safe drug. More specifically, hypertension, heart disease, angina, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerular nephritis, nephrosclerosis, cerebrovascular disease, Cerebral infarction, cerebral bleeding, vascular disorders (arteriosclerosis, post-PTCA re-stenosis, peripheral circulatory disorders), type 1 diabetes, type 2 diabetes, abnormal glucose tolerance, fasting abnormal blood glucose, hyperglycemia, postprandial hyperglycemia, hyper Safe medications for the prevention and / or treatment of body weight, obesity, metabolic syndrome, pregnancy diabetes, newly developed diabetes mellitus (NODAT) and related complications (particularly hypertension, type 2 diabetes, diabetes)
  • the purpose is to provide a drug for the treatment of diabetic nephropathy or hypertension with diabetes).
  • the present invention relates to the following (1) to (16).
  • the drug according to any one of (1) to (7) which is a drug for preventing or treating hypertension.
  • the drug according to any one of (1) to (7) which is a drug for preventing or treating type 2 diabetes.
  • the drug according to any one of (1) to (7) which is a drug for the prevention or treatment of diabetic nephropathy.
  • the drug according to any one of (1) to (7) which is a drug for preventing or treating hypertension associated with diabetes.
  • Hyperglycemia heart disease, angina, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerular nephritis, nephrosclerosis, cerebrovascular disease, cerebral infarction, Cerebral bleeding, vascular disorders (arteriosclerosis, post-PTCA re-stenosis, peripheral circulatory disorders), type 1 diabetes, type 2 diabetes, abnormal glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity , Metabolic Syndrome, Pregnancy Diabetes, Post-Transplant Diabetes (NODAT) and One or More Diseases Selected from the Group Consisting With It, (i) Esakiselenone or Pharmaceutically Acceptable A therapeutic method comprising a salt and (ii) one or more SGLT2 inhibitors, which are administered in combination.
  • a therapeutic method comprising and being administered in combination of these components.
  • the SGLT2 inhibitor is at least one selected from canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, cergliflozin and luseogliflozin. be.
  • the combination drug of esakiselenone or a pharmaceutically acceptable salt thereof of the present invention and one or more SGLT2 inhibitors has an excellent antihypertensive effect and exhibits high safety. Therefore, the drug [preferably hypertension] , Heart disease, angina, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerular nephritis, nephrosclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disorder ( Arteriosclerosis, post-PTCA re-stenosis, peripheral circulatory disorder), type 1 diabetes, type 2 diabetes, abnormal glucose tolerance, abnormal fasting blood glucose, hypertension, postprandial hypertension, overweight, obesity, metabolic syndrome, pregnancy Prevention or treatment (particularly therapeutic agents) of one or more diseases selected from the group consisting of diabetes, newly developed diabetes (NODAT) after transplantation and related complications, and more preferably hypertension and type 2 diabetes.
  • the vertical axis shows the proportion of patients with a serum potassium level of 6.0 mEq / L or higher or ⁇ 5.5 mEq / L or higher twice in a row
  • the horizontal axis shows the comparison of placebo and esaxerenone from the left, and the SGLT2 inhibitor in placebo administration.
  • a comparison of the presence or absence of concomitant use and a comparison of the concomitant use of SGLT2 inhibitor in esaxerenone administration are shown.
  • the vertical axis shows the amount of change in blood pressure
  • the horizontal axis shows the week. It is a figure which showed the ratio of the case where the serum potassium level ⁇ 5.5mEq / L was observed in the hypertensive patient with type 2 diabetes who had overt albuminuria.
  • the vertical axis shows the proportion of patients with serum potassium levels of 5.5 mEq / L or higher
  • the horizontal axis shows the overall proportion from the left, and a comparison of the presence or absence of SGLT2 inhibitor in the administration of esaxerenone.
  • the pharmaceutical product of the present invention is characterized in that esaxerenone or a pharmaceutically acceptable salt thereof is combined with one or more SGLT2 inhibitors as an active ingredient.
  • Esakiselenone the active ingredient of the present invention, or a pharmaceutically acceptable salt thereof is known and has a chemical name of (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, which has the following structure (I).
  • esaxerenone in the present invention, esaxerenone, a pharmaceutically acceptable salt, a hydrate or a solvate thereof can also be used.
  • pure forms of atropisomers or any mixture of atropisomers can also be used.
  • the SGLT2 inhibitors that are the active ingredients of the present invention include, for example, canagliflozin, Dapagliflozin, Ipragliflozin, Tofogliflozin, Empagliflozin and luseogliflozin. ) Etc. can be mentioned.
  • SGLT2 inhibitor may be referred to as SGLT2i.
  • canagliflozin is a chemical name, (1S) -1,5-anhydro-1-C-(3- ⁇ [5- (4-fluorophenyl) thiophen-2-yl] methyl ⁇ -4. -Methylphenyl) -D-glucitol, which is marketed in Japan as a therapeutic agent for type 2 diabetes as a product "Canagliflozin hydrate” containing canagliflozin hydrate as an active ingredient.
  • Canagliflozin in the present invention also includes canagliflozin, pharmaceutically acceptable salts and hydrates thereof.
  • dapagliflozin is the chemical name, (1S) -1,5-anhydro-1-C- ⁇ 4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl ⁇ -D-glucitol. It is marketed in Japan as a therapeutic agent for type 1 and type 2 diabetes as a product "Fosiga (registered trademark)" containing dapagliflozin propylene glycol hydrate as an active ingredient. Dapagliflozin in the present invention also includes dapagliflozin, pharmaceutically acceptable salts and hydrates thereof.
  • ipragliflozin is the chemical name, (1S) -1,5-anhydro-1-C- ⁇ 3-[(1-benzothiophen-2-yl) methyl] -4-fluorophenyl ⁇ -. It is D-glycitol and is marketed in Japan as a therapeutic agent for type 1 and type 2 diabetes as a product "Sugra (registered trademark)" containing ipragliflozin L-proline as an active ingredient.
  • the ipragliflozin in the present invention also includes ipragliflozin, pharmaceutically acceptable cocrystals and hydrates thereof.
  • tofogliflozin is a 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 with tofogliflozin hydrate as the active ingredient It is marketed as a type 2 diabetes treatment drug in Japan as products "Develza (registered trademark)" and "Apleway (registered trademark)".
  • the tofogliflozin in the present invention also includes tofogliflozin and its hydrate.
  • "empagliflozin” is a chemical name, (1S) -1,5-anhydro-1-C- ⁇ 4-chloro-3-[(4- ⁇ [(3S) -oxolan-3-yl]].
  • Oxy ⁇ phenyl) methyl] phenyl ⁇ -D-glucitol which is marketed in Japan as a therapeutic drug for type 2 diabetes as "Jadians (registered trademark)", a product containing empagliflozin as an active ingredient.
  • the empagliflozin in the present invention also includes empagliflozin and its hydrate.
  • “luseogliflozin” is a chemical name, (2S, 3R, 4R, 5S, 6R) -2- ⁇ 5-[(4-ethoxyphenyl) methyl] -2-methoxy-4-methylphenyl ⁇ -. 6- (Hydroxymethyl) thian-3,4,5-triol, which is marketed in Japan as a type 2 diabetes treatment drug as "Lusefi (registered trademark)", a product containing luseogliflozin hydrate as an active ingredient. ..
  • the luseogliflozin in the present invention also includes luseogliflozin and its hydrate.
  • "simultaneously" administration is not particularly limited as long as it can be administered at substantially the same time, but it is preferably administered as a single composition.
  • administered at different times is not particularly limited as long as it is an administration form that can be administered separately at different times, but for example, esaxerenone or a pharmaceutically acceptable salt thereof is first administered. Then, after a predetermined time, SGLT2 inhibitors are administered simultaneously (or sequentially after a predetermined time), or SGLT2 inhibitors or diuretics are first administered, and then after a predetermined time, It means to administer esaxerenone or a pharmaceutically acceptable salt thereof in the same manner as described above.
  • the present invention is more excellent in that esaxerenone or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor act to prevent the hypotensive effect from being impaired and side effects are reduced. Can produce the same effect.
  • the pharmaceutical agents of the present invention include hyperglycemia, heart disease, angina, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerular nephritis, renal sclerosis.
  • Esaxerenone or a pharmaceutically acceptable salt thereof of the present invention and an SGLT2 inhibitor show superior effects when they are used in combination as compared with the case where they are administered as a single agent.
  • Diabetic nephropathy depends on the severity of stage 1 (early nephropathy), 2nd stage (early nephropathy), 3rd stage (overt nephropathy), 4th stage (renal failure stage), and It is classified into the 5th stage (diabetes treatment stage). Microalbuminuria is detected in the second stage, and overt albuminuria is detected in the third and subsequent stages. In addition, diabetic nephropathy may be accompanied by hypertension. The present invention can be used regardless of the severity of the disease.
  • Esaxerenone which is the active ingredient of the pharmaceutical composition of the present invention, or a pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor are each individually in a separate unit administration form or mixed in a physical unit administration form. Can be prepared in.
  • the present invention is provided as a pharmaceutical composition containing esaxerenone or a pharmaceutically acceptable salt thereof and one or more SGLT2 inhibitors as active ingredients, respectively, and the pharmaceutical composition is one or more pharmaceutical compositions. It may contain an additive for use.
  • esaxelenone which is an active ingredient of the pharmaceutical composition of the present invention, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor are used.
  • additives such as excipients, suppositories, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, etc., each of itself or as appropriate and pharmacologically acceptable. It can be administered orally by the manufactured tablets, capsules, granules, powders or syrups, or parenterally by injections or suppositories. Since esaxerenone or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor contained in the drug of the present invention are generally orally administered drugs, the drug of the present invention is orally administered. It is desirable to administer.
  • Excipients used include, for example, sugar derivatives such as lactose, sucrose, grape sugar, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch or dextrin; crystalline cellulose and the like.
  • the "lubricating agent" used includes, for example, stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate; waxes such as talc, colloidal silica, bead wax or gay wax; boric acid, adipine. Acids, sulfates such as sodium sulfate; lauryl sulfates such as glycol, fumaric acid, stearyl sodium fumarate, sodium benzoate, D, L-leucine, sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid anhydride or silicic acid. Silica acids such as hydrates; or the above starch derivatives can be mentioned.
  • binder examples include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, or a compound similar to the above-mentioned excipient.
  • the "disintegrant" used may be, for example, a cellulose derivative such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose (carmellose), carboxymethyl cellulose calcium, croscarmellose sodium or internally cross-linked sodium carboxymethyl cellulose; cross-linked polyvinylpyrrolidone; or. , Corn starch, pregelatinized starch, sodium starch glycolate, carboxymethyl starch or chemically modified starch / cellulose such as sodium carboxymethyl starch.
  • a cellulose derivative such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose (carmellose), carboxymethyl cellulose calcium, croscarmellose sodium or internally cross-linked sodium carboxymethyl cellulose; cross-linked polyvinylpyrrolidone; or.
  • Corn starch pregelatinized starch, sodium starch glycolate, carboxymethyl starch or chemically modified starch / cellulose such as sodium carboxymethyl starch.
  • the "embroidery” used may be, for example, colloidal clay such as bentonite or bee gum; 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 can be mentioned.
  • the "stabilizers" used include, for example, parahydroxybenzoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalconium chloride, phenol or cresol. Phenols such as: thimerosal; dehydroacetic acid; or sorbic acid can be mentioned.
  • sweeteners such as saccharin sodium or aspartame
  • acidulants such as citric acid, malic acid or tartaric acid
  • fragrances such as menthol, lemon or orange. can.
  • the "diluting agent” used includes, for example, lactose, mannitol, glucose, sculose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone. , Magnesium aluminometasilicate or a mixture thereof, which are usually used as a diluent can be mentioned.
  • the doses of esaxerenone and SGLT2 inhibitor which are the active ingredients of the pharmaceutical composition of the present invention, may change depending on various conditions such as the activity of each drug, the patient's symptoms, age, and body weight.
  • the dose varies depending on the symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg and the upper limit is 1000 mg, respectively, and in the case of parenteral administration, the lower limit is 0.01 mg and the upper limit is 100 mg.
  • the package inserts for esaxerenone, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin and luseogliflozin are incorporated herein by reference in their entirety.
  • Esaxerenone is preferably administered at 2.5 mg or 5 mg once a day.
  • a suitable dosage form of esaxerenone is a tablet or an orally disintegrating tablet (OD tablet).
  • the SGLT2 inhibitor When the SGLT2 inhibitor is canagliflozin, it is preferable to administer 100 mg once a day.
  • the preferred dosage form of canagliflozin is tablets or OD tablets.
  • the SGLT2 inhibitor When the SGLT2 inhibitor is dapagliflozin, it is preferable to administer 5 mg or 10 mg once a day.
  • the preferred dosage form of dapagliflozin is tablets or OD tablets.
  • the SGLT2 inhibitor If the SGLT2 inhibitor is ipragliflozin, it is preferred to administer 25 mg, 50 mg or 100 mg once daily.
  • the preferred dosage form of ipragliflozin is tablets or OD tablets.
  • the SGLT2 inhibitor When the SGLT2 inhibitor is tofogliflozin, it is preferable to administer 20 mg once a day.
  • the preferred dosage form of tofogliflozin is tablets or OD tablets. 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 tablets or OD tablets. 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 OD tablets.
  • the ratio of the dose of esaxerenone, which is the active ingredient of the pharmaceutical composition of the present invention, to the SGLT2 inhibitor can also vary significantly, but the weight ratio is 1: 1 to 10000 to 10000: 1 to 10000. It can be in the range, preferably 1: 1 to 1000 to 1000: 1 to 1000, and more preferably 1: 1 to 100 to 100: 1 to 100.
  • the preferred dose ratio is the weight ratio of esaxerenone: canagliflozin, which ranges from 1:20 to 40.
  • the preferred dose ratio is the weight ratio of esaxerenone: dapagliflozin, which ranges from 1: 2 to 4.
  • the preferred dose ratio is the weight ratio of esaxerenone: ipragliflozin, which ranges from 1:10 to 40.
  • the preferred dose ratio is the weight ratio of esaxerenone: tofogliflozin, which ranges from 1: 4 to 8.
  • the preferred dose ratio is the weight ratio of esaxerenone: empagliflozin, which ranges from 1: 4 to 10.
  • the preferred dose ratio is the weight ratio of esaxerenone: luseogliflozin, which ranges from 2: 1 to 1: 2.
  • the administration period of esaxerenone and the SGLT2 inhibitor is not particularly limited, but it is preferable to continue the administration for 2 weeks or more, and it is more preferable to continue the administration for 4 weeks or more. In another embodiment, the administration is preferably continued for 8 weeks or longer, and more preferably 20 weeks or longer.
  • the suitable dosage form is tablets or OD tablets.
  • Urine albumin-to-creatinine ratio UACR
  • Angiotensin II receptor blocker ARB
  • Angiotensin converting enzyme ACE Creatinine: Cr
  • Example 1 Administration of esaxerenone to hypertensive patients with type 2 diabetes who have microalbuminuria
  • esaxerenone was administered to hypertensive patients with type 2 diabetes who had microalbuminuria, and an SGLT2 inhibitor was used in combination.
  • Various analyzes were performed on the effects of the presence or absence of esaxerenone on the efficacy and safety of esaxerenone.
  • Placebo tablets which are pale yellowish white film-coated tablets containing lactose hydrate as the main component, were orally administered once daily for 52 weeks, in principle after breakfast. (Confirmation of the effect of reducing the expression rate in cases with increased serum potassium level) The percentage of subjects who developed the following events from the start of administration of the investigational drug to the end of administration was calculated for each administration 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 twice in a row. rice field.
  • the sample collection period during the study period is 2 weeks for the observation period, 2 to 52 weeks for the treatment period, at the time of discontinuation, 2 weeks after the investigational drug dose increase, and 4 weeks after the end / discontinuation of the treatment period, and the serum potassium level is 5.5 mEq / L. If the above values were shown, remeasurement was performed by centralized measurement within 3 days in principle. (Test results) It was found that in hypertensive patients with type 2 diabetes who had microalbuminuria, the combined use of SGLT2 inhibitor at the time of administration of esaxerenone increased the rate of suppression of the increase in serum potassium level as compared with the group without the combined use. The results are shown in FIGS. 1 and 2.
  • FIG. 1 and 2 The results are shown in FIGS. 1 and 2.
  • FIG. 1 shows the proportion of cases in which a serum potassium level of ⁇ 5.5 mEq / L was observed
  • FIG. 2 shows a serum potassium level of ⁇ 6.0 mEq / L or ⁇ 5.5 mEq / L twice in a row. The percentage of cases was shown.
  • Tables 1 and 2 show the proportion of cases with a serum potassium level of ⁇ 5.5 mEq / L classified by type of SGLT2 inhibitor, and Table 2 shows a serum potassium level of ⁇ 6.0 mEq / L or ⁇ for two consecutive times. The proportion of cases with 5.5 mEq / L was classified according to the type of SGLT2 inhibitor.
  • Sample collection method and measurement method The clinical trial site conducted refrigerated storage of the first urine collected from the subjects in the early morning of the day of the visit, and measured the sample at a centralized measurement institution.
  • the sample collection period during the study period was the start date of the observation period, 2 weeks, 3 weeks *, the treatment period of 4 weeks, 8 to 52 weeks, the time of discontinuation (if possible), and the end / discontinuation of the treatment period 4 weeks.
  • the UACR was calculated using the following formula.
  • UACR (urinary albumin concentration ( ⁇ g / mL) / urinary creatinine concentration (mg / dL)) x 100, which was performed only when the criteria were not met at the 2nd week of the observation period.
  • Analytical method Summary statistics of measured values at each time point and changes from baseline were calculated for each treatment group according to the presence or absence of SGLT2 inhibitor concomitant use. In addition, using the log conversion value of UACR, the analysis of covariance using the change from the baseline of the log conversion value as the result variable, the administration group as the factor, and the baseline value (the log conversion value of UACR) as the covariance.
  • Analytical method Summary statistics of measured values at each time point and changes from baseline were calculated for each treatment group according to the presence or absence of SGLT2 inhibitor concomitant use. In addition, using the ANCOVA model with the administration group as a factor and the baseline value as a covariant, the amount of change was calculated for each administration group. (Test results) It was found that the antihypertensive effect of esaxerenone in hypertensive patients with type 2 diabetes having microalbuminuria was not affected by the concomitant use of SGLT2 inhibitor and showed an excellent antihypertensive effect. The results are shown in FIGS. 4 and 5. FIG. 4 shows the amount of change in systolic blood pressure, and FIG. 5 shows the amount of change in diastolic blood pressure.
  • Example 2 Administration of esaxerenone to hypertensive patients with type 2 diabetes having overt albuminuria
  • An SGLT2 inhibitor was conducted in a clinical study to administer esaxerenone to hypertensive patients with type 2 diabetes who had overt albuminuria.
  • Various analyzes were conducted on the effects of the combined use of esaxerenone on the efficacy and safety of esaxerenone.
  • ⁇ 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 twice in a row. rice field.
  • the sample collection period during the study period is 2 weeks during the observation period, 2 to 28 weeks during the treatment period, at the time of discontinuation, 2 weeks after the investigational drug dose increase, and 4 weeks after the end / discontinuation of the treatment period, and the serum potassium level is 5.5 mEq / L. If the above values were shown, remeasurement was performed by centralized measurement within 3 days in principle.
  • FIGS. 6 and 7 show the proportion of cases in which a serum potassium level of ⁇ 5.5 mEq / L was observed, and FIG. 7 shows a serum potassium level of ⁇ 6.0 mEq / L or ⁇ 5.5 mEq / L twice in a row. The percentage of cases was shown.
  • Tables 3 and 4 show the proportion of cases with a serum potassium level of ⁇ 5.5 mEq / L classified by type of SGLT2 inhibitor
  • Table 4 shows a serum potassium level of ⁇ 6.0 mEq / L or ⁇ for two consecutive times. The proportion of cases with 5.5 mEq / L was classified according to the type of SGLT2 inhibitor.
  • Sample collection method and measurement method The medical institution conducting the clinical trial stored the first urine collected from the subjects in the early morning of the day of the visit in a refrigerator, and the centralized measurement institution measured the submitted sample.
  • the sample collection period during the study period was the start date of the observation period, 2 weeks, 3 weeks *, the treatment period of 4 weeks, 8 to 28 weeks, the time of discontinuation (if possible), and the end / discontinuation of the treatment period 4 weeks.
  • the UACR was calculated using the following formula.
  • UACR (mg / g ⁇ Cr) (urinary albumin concentration ( ⁇ g / mL) / urinary creatinine concentration (mg / dL)) x 100, which was performed only when the criteria were not met at the 2nd week of the observation period.
  • Analytical method Summary statistics of measured values at each time point and changes from baseline were calculated for each treatment group according to the presence or absence of SGLT2 inhibitor concomitant use. (Test results) It was found that the UACR-reducing effect of esaxerenone was not affected by the concomitant use of SGLT2 inhibitors in patients with hypertension with type 2 diabetes who had overt albuminuria, and showed an excellent UACR-reducing effect.
  • Sample collection method and measurement method Blood pressure values were measured at the clinical trial site for 5 minutes or more in a sitting position, and then blood pressure measurement was repeated with the same arm at intervals of 1 to 2 minutes, for a total of 3 times.
  • the measurement period during the study period was the start date of the observation period, 2 weeks, the treatment period 2 to 28 weeks, the time of discontinuation, the dose increase 2 weeks later, and the end of the treatment period 4 weeks later.
  • Analytical method Summary statistics of measured values at each time point and changes from baseline were calculated for each treatment group according to the presence or absence of SGLT2 inhibitor concomitant use. (Test results) It was found that the antihypertensive effect of esaxerenone was not affected by the concomitant use of SGLT2 inhibitor and showed an excellent antihypertensive effect. The results are shown in FIG. (Formulation example)
  • the powder of the above prescription is mixed and tableted with a tableting machine to make one tablet of 300 mg.
  • This tablet can be sugar-coated as needed.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024047574A1 (en) * 2022-09-01 2024-03-07 Astrazeneca Ab Combination of sglt2 inhibitors and mineralcorticoid receptor modulators for use in treatment of cardiorenal diseases
WO2024164183A1 (zh) * 2023-02-08 2024-08-15 华东理工大学 一种sglt2抑制剂与薄荷醇的组合及其治疗心脏疾病的用途

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2015012205A1 (ja) * 2013-07-23 2015-01-29 第一三共株式会社 高血圧症の予防又は治療のための医薬
WO2017164208A1 (ja) * 2016-03-24 2017-09-28 第一三共株式会社 腎疾患の治療のための医薬

Patent Citations (2)

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WO2015012205A1 (ja) * 2013-07-23 2015-01-29 第一三共株式会社 高血圧症の予防又は治療のための医薬
WO2017164208A1 (ja) * 2016-03-24 2017-09-28 第一三共株式会社 腎疾患の治療のための医薬

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ZOU HONGHONG, ZHOU BAOQIN, XU GAOSI: "SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease", CARDIOVASCULAR DIABETOLOGY, vol. 16, no. 1, 1 December 2017 (2017-12-01), pages 65, XP055820525, DOI: 10.1186/s12933-017-0547-1 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024047574A1 (en) * 2022-09-01 2024-03-07 Astrazeneca Ab Combination of sglt2 inhibitors and mineralcorticoid receptor modulators for use in treatment of cardiorenal diseases
WO2024164183A1 (zh) * 2023-02-08 2024-08-15 华东理工大学 一种sglt2抑制剂与薄荷醇的组合及其治疗心脏疾病的用途

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