WO2021049612A1 - Drug for improving fluid retention in acute heart failure - Google Patents

Drug for improving fluid retention in acute heart failure Download PDF

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WO2021049612A1
WO2021049612A1 PCT/JP2020/034463 JP2020034463W WO2021049612A1 WO 2021049612 A1 WO2021049612 A1 WO 2021049612A1 JP 2020034463 W JP2020034463 W JP 2020034463W WO 2021049612 A1 WO2021049612 A1 WO 2021049612A1
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heart failure
fluid retention
sglt2
acute heart
drug
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PCT/JP2020/034463
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French (fr)
Japanese (ja)
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弘一郎 絹川
秀司 城宝
昌樹 中垣内
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国立大学法人富山大学
田辺三菱製薬株式会社
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Priority to JP2021545615A priority Critical patent/JPWO2021049612A1/ja
Publication of WO2021049612A1 publication Critical patent/WO2021049612A1/en

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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
    • A61K31/38—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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to novel uses of SGLT2 inhibitors.
  • SGLT2 inhibitors represented by canagliflozin are used as antidiabetic agents.
  • SGLT2 inhibitors are known to have the effect of improving fluid retention in chronic heart failure one month after the onset of heart failure (Non-Patent Document 1), and are readmitted for chronic heart failure. Is known to have the effect of reducing.
  • dyspnea due to pulmonary congestion and fluid retention such as pleural effusion are considered to be the biggest factors that lower the patient's QOL.
  • a diuretic is generally selected, but in many cases, a sufficient effect cannot be obtained.
  • the purpose of treatment is different between chronic heart failure and acute heart failure. That is, in the acute phase, treatment for improvement of symptoms is prioritized, while in the chronic phase, in addition to this, treatment aimed at improving clinical endpoints such as readmission and suppression of total mortality is continued. .. Therefore, drugs that are effective in treating chronic heart failure do not always have a visible effect in the treatment of acute heart failure. In order to improve the QOL of patients and improve respiratory and circulatory dynamics, therapeutic agents that improve fluid retention in the acute phase immediately after an attack of heart failure are required. An object of the present invention is to provide a therapeutic agent for improving fluid retention in acute heart failure.
  • sodium-dependent glucose cotransporter 2 sodium-glucose co-transporter 2, hereinafter referred to as "SGLT2"
  • SGLT2 sodium-dependent glucose co-transporter 2
  • the drug can have the effect of improving fluid retention in acute heart failure, and have completed the present invention.
  • the gist of the present invention is as follows.
  • a fluid retention improving drug for acute heart failure containing an SGLT2 inhibitor.
  • SGLT2 inhibitors are canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remoglyflozin etabonate, ertzgliflozin, sotagliflozin and pharmaceutically acceptable of these.
  • the body fluid retention improving agent according to the above [1] which is at least one selected from the group consisting of salts.
  • SGLT2 inhibitors are canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remoglyflozin etabonate, ertzgliflozin, sotagliflozin and pharmaceutically acceptable of these.
  • a method for improving fluid retention in a patient with acute heart failure which comprises a step of administering an effective amount of an SGLT2 inhibitor to a patient in need thereof.
  • SGLT2 inhibitors are canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remoglyflozin etabonate, ertzgliflozin, sotagliflozin and pharmaceutically acceptable of these.
  • SGLT2 inhibitors are canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remoglyflozin etabonate, ertzgliflozin, sotagliflozin and pharmaceutically acceptable of these.
  • fluid retention in acute heart failure can be improved.
  • FIG. 1 shows the urine volume (mL / day) before administration of canagliflozin (Baseline), 1 day after administration, and 7 days after administration.
  • FIG. 2 is a diagram showing (a) cardiothoracic ratio, (b) presence or absence of pulmonary congestion, and (c) presence or absence of pleural effusion on the day before and 7 days after the start of canagliflozin administration evaluated using chest X-ray.
  • the white bar in the figure shows the result on the day before the start of administration, and the black bar shows the result on the day after 7 days.
  • the fluid retention improving agent for acute heart failure of the present invention contains an SGLT2 inhibitor.
  • SGLT2 inhibitors can also be used in combination with diuretics and other drugs.
  • the present invention will be described.
  • SGLT2 inhibitor examples of the SGLT2 inhibitor used in the present invention include drugs that inhibit the reabsorption of sugar by SGLT2. More specific SGLT2 inhibitors include low molecular weight compounds, SGLT2 expression inhibitors, SGLT2-specific binding substances and the like.
  • Examples of the low molecular weight compound which is an SGLT2 inhibitor include canagliflozin [(1S) -1,5-Anhydro-1-C (-3 ⁇ [5- (4-fluorophenyl) thiophen-2-yl] methyl ⁇ .
  • salts of low molecular weight compounds that are SGLT2 inhibitors include, for example, salts with alkali metals such as lithium, sodium and potassium; salts with Group 2 metals such as calcium and magnesium; zinc or aluminum. Salts with; salts with amines such as ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N-methyl-glucosamine, triethanolamine, dehydroabiethylamine Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitrate, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid , Salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic
  • pharmaceutically acceptable salts of low molecular weight compounds that are SGLT2 inhibitors include intramolecular salts of the low molecular weight compounds, hydrates, and L-proline, (2S) -propane-1,2-. Solvates such as diols are also included.
  • SGLT2 expression inhibitor examples include siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, and low molecular weight compounds. By administering these expression inhibitors, the expression of SGLT2 can be inhibited.
  • SiRNA small interfering RNA
  • RISC RNA-induced silencing complex
  • sense strand and antisense strand oligonucleotides are synthesized by a DNA / RNA automatic synthesizer, respectively, and denatured in an appropriate annealing buffer at 90 to 95 ° C. for about 1 minute, and then 30 to 70 ° C. It can be prepared by annealing in 1 to 8 hours.
  • ShRNA short hairpin RNA
  • the shRNA may be introduced into cells by a vector and expressed by the U6 promoter or the H1 promoter, or an oligonucleotide having an shRNA sequence may be synthesized by a DNA / RNA automatic synthesizer and self-annealed by the same method as siRNA. May be prepared by.
  • the hairpin structure of the shRNA introduced into the cell is cleaved into siRNA and binds to RNA-induced silencing complex (RISC). This complex binds to and cleaves mRNA that has a sequence complementary to siRNA. This suppresses gene expression in a sequence-specific manner.
  • RISC RNA-induced silencing complex
  • MiRNA is a functional nucleic acid that is encoded on the genome and finally becomes a microRNA of about 20 bases through a multi-step production process.
  • MiRNAs are classified as functional ncRNAs (non-coding RNAs, non-coding RNAs: a general term for RNAs that are not translated into proteins), and play an important role in life phenomena by regulating the expression of other genes. There is.
  • the expression of SGLT2 can be inhibited by administering a miRNA having a specific base sequence to a living body.
  • Ribozyme is an RNA with catalytic activity. Although some ribozymes have various activities, research on ribozymes as an enzyme that cleaves RNA has made it possible to design ribozymes for the purpose of site-specific cleavage of RNA.
  • the ribozyme may have a size of 400 nucleotides or more, such as Group I intron type or M1RNA contained in RNase P, or may be a ribozyme having a size of about 40 nucleotides, which is called a hammer head type or a hairpin type.
  • Antisense nucleic acid is a nucleic acid complementary to the target sequence. Antisense nucleic acids inhibit transcription initiation by triple-strand formation, transcription inhibition by hybrid formation with a site where an open loop structure is locally formed by RNA polymerase, and transcription inhibition by hybrid formation with RNA whose synthesis is progressing.
  • SiRNA, shRNA, miRNA, ribozyme and antisense nucleic acids may contain various chemical modifications in order to improve stability and activity.
  • the phosphate residue may be replaced with a chemically modified phosphate residue such as phosphorothioate (PS), methylphosphonate, or phosphorodithionate.
  • PS phosphorothioate
  • methylphosphonate methylphosphonate
  • phosphorodithionate phosphorodithionate
  • at least a part thereof may be composed of nucleic acid analogs such as peptide nucleic acid (PNA).
  • PNA peptide nucleic acid
  • SGLT2 specific binding substance examples include those that specifically bind to SGLT2 and inhibit the function of SGLT2, and examples thereof include antibodies, antibody fragments, and aptamers.
  • Antibodies can be produced, for example, by immunizing an animal such as a mouse with an SGLT2 protein or a fragment thereof as an antigen. Alternatively, the antibody can be made, for example, by screening a phage library. Examples of the antibody fragment include Fv, Fab, scFv and the like. The antibody is preferably a monoclonal antibody. Moreover, the antibody may be a commercially available antibody. Aptamers are substances that have the ability to specifically bind to a target substance.
  • nucleic acid aptamers examples include nucleic acid aptamers and peptide aptamers.
  • Nucleic acid aptamers having a specific binding ability to a target peptide can be selected by, for example, the systematic evolution of ligand by exponential evolution (SFLEX) method.
  • SFLEX systematic evolution of ligand by exponential evolution
  • the peptide aptamer having a specific binding ability to the target peptide can be selected by, for example, the Two-hybrid method using yeast.
  • Acute heart failure is specifically defined in the "Acute / Chronic Heart Failure Medical Care Guidelines (2017 revised edition)" prepared by the Japanese Cardiovascular Society, but in the present invention, as a patient with acute heart failure, it is the first attack of heart failure. Includes any seizures caused by an acute exacerbation of chronic heart failure.
  • the target patient in the present invention is a patient who has been switched from treatment by intravenous injection to treatment by an oral drug in acute heart failure and whose respiratory and circulatory dynamics are stable and can be ingested orally. is there.
  • the patient to whom the SGLT2 inhibitor is administered may be complicated with diabetes, but is not limited thereto.
  • the degree of fluid retention can be determined by the cardiothoracic ratio using chest X-rays, the degree of pulmonary congestion and pleural effusion, and the degree of edema. In particular, it is useful to determine the degree of fluid retention based on the degree of pulmonary congestion for the evaluation of respiratory failure. In parallel with the improvement of pulmonary congestion, it is also useful to determine the degree of improvement of the patient's own dyspnea using, for example, the seven point Likert scale. The Seven Point Lycat Scale scores how patients feel when asked by their doctor about dyspnea (significantly worse, moderately worse, mildly worse, no change, mild improvement, moderate improvement, marked improvement). ).
  • the present invention provides a pharmaceutical composition for improving fluid retention in acute heart failure, which contains an SGLT2 inhibitor and a pharmaceutically acceptable carrier. By administering the pharmaceutical composition of this embodiment, fluid retention in acute heart failure can be improved.
  • composition of this embodiment may be formulated into a dosage form used orally or a dosage form used parenterally.
  • Dosage forms used orally include, for example, tablets, capsules, elixirs, microcapsules and the like.
  • Dosage forms used parenterally include, for example, injections, ointments, patches and the like.
  • the pharmaceutically acceptable carrier can be used without particular limitation as long as it is usually used for producing a pharmaceutical composition.
  • Specific examples include, for example, binders such as gelatin, cornstarch, traganth gum, and gum arabic; excipients such as starch and crystalline cellulose; swelling agents such as alginic acid; solvents for injections such as water, ethanol, and glycerin. ; Adhesives such as rubber-based adhesives and silicone-based adhesives can be mentioned.
  • the pharmaceutical composition may contain additives.
  • Additives include lubricants such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin and martitol; flavors such as peppermint and red mono oil; stabilizers such as benzyl alcohol and phenol; phosphoric acid. Buffers such as salts and sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; preservatives and the like.
  • the pharmaceutical composition can be formulated by appropriately combining SGLT2 inhibitors, pharmaceutically acceptable carriers and optionally additives and mixing them in the generally accepted unit dose form required for pharmaceutical practice. ..
  • Targets to which SGLT2 inhibitors are administered include, but are not limited to, for example, humans, monkeys, dogs, cows, horses, ovis aries, pigs, rabbits, mice, rats, guinea pigs, hamsters, and their cells. Can be mentioned. Among them, mammals or mammalian cells are preferable, and humans or human cells are particularly preferable.
  • an SGLT2 inhibitor varies depending on the specific target to be administered, the target's symptoms, body weight, age, gender, etc., and cannot be unconditionally determined.
  • An SGLT2 inhibitor having a body weight of about 0.1 mg / kg to about 100 mg / kg per unit form may be administered.
  • about 0.01 mg to about 50 mg of SGLT2 inhibitor may be administered per unit form of administration.
  • the daily dose of the SGLT2 inhibitor may be an amount effective for improving body fluid retention, and it depends on the specific target to be administered, the target's symptom, body weight, age, gender, etc., and cannot be unconditionally determined.
  • an SGLT2 inhibitor having a body weight of about 0.1 mg / kg to about 100 mg / kg per day may be administered once or twice to three times a day.
  • the SGLT2 inhibitor according to the present invention may be used in combination with at least one selected from the group consisting of a fluid retention improving agent other than the SGLT2 inhibitor and a therapeutic agent for other diseases.
  • the SGLT2 inhibitor and the other drug may be the same preparation or may be different preparations.
  • each preparation may be administered by the same administration route or may be administered by different administration routes.
  • the route of administration includes, for example, oral or injection.
  • each preparation may be administered simultaneously, sequentially, or separately after a certain period of time or period.
  • the SGLT2 inhibitor and the other agent may be a kit containing them.
  • Example 1 Examination of the effect of canagliflozin on decompensated heart failure patients
  • Initial treatment was performed on 34 patients with type 2 diabetes who were hospitalized during the decompensated period of heart failure, and after the condition became stable, 100 mg / day canagliflozin was administered. He was treated for a day.
  • the dose of furosemide was appropriately adjusted during the administration period of canagliflozin.
  • the body weight was significantly reduced (the average body weight before the start of administration was 58.7 ⁇ 14.4 kg, but after 7 days it was 57.2 ⁇ 14.4 kg. P ⁇ 0.001).
  • Urine volume increased after 1 day, but returned to normal after 7 days, as shown in FIG.
  • the present invention provides a novel drug that can be effectively and safely used for improving fluid retention in acute heart failure.

Abstract

The present invention pertains to a drug for improving fluid retention in acute heart failure, the drug containing an SGLT2 inhibitor.

Description

急性心不全における体液貯留改善薬Fluid retention improving drug in acute heart failure
　本発明は、ＳＧＬＴ２阻害薬の新規な用途に関する。 The present invention relates to novel uses of SGLT2 inhibitors.
　カナグリフロジンに代表されるＳＧＬＴ２阻害薬は、糖尿病治療薬として利用されている。また、ＳＧＬＴ２阻害薬には、心不全発症後１か月以降の慢性期の心不全において、体液貯留を改善させる効果のあることが知られており（非特許文献１）、慢性期の心不全において再入院を減少させる効果があることが知られている。 SGLT2 inhibitors represented by canagliflozin are used as antidiabetic agents. In addition, SGLT2 inhibitors are known to have the effect of improving fluid retention in chronic heart failure one month after the onset of heart failure (Non-Patent Document 1), and are readmitted for chronic heart failure. Is known to have the effect of reducing.
　急性心不全発症後において、肺うっ血による呼吸困難や胸水などの体液貯留は、患者のＱＯＬを低下させる最大の要因として考えられている。呼吸困難や体液貯留を改善する薬剤としては、一般的には、利尿薬が選択されるが十分な効果が得られない場合も多い。 After the onset of acute heart failure, dyspnea due to pulmonary congestion and fluid retention such as pleural effusion are considered to be the biggest factors that lower the patient's QOL. As a drug for improving dyspnea and fluid retention, a diuretic is generally selected, but in many cases, a sufficient effect cannot be obtained.
　慢性期の心不全と急性期の心不全では治療目的が異なる。すなわち、急性期では、症状の改善に対する治療が優先されるのに対し、慢性期には、これに加えて再入院や総死亡の抑制など臨床エンドポイントの改善を目的とした治療が継続される。したがって、慢性心不全の治療に有効とされている薬剤が、急性心不全の治療に目に見える効果を示すとは限らない。患者のＱＯＬを向上させ、呼吸・循環動態を改善するために、心不全の発作直後から急性期における体液貯留を改善する治療薬が求められている。
　本発明は急性心不全における体液貯留を改善する治療薬を提供することを目的とする。 The purpose of treatment is different between chronic heart failure and acute heart failure. That is, in the acute phase, treatment for improvement of symptoms is prioritized, while in the chronic phase, in addition to this, treatment aimed at improving clinical endpoints such as readmission and suppression of total mortality is continued. .. Therefore, drugs that are effective in treating chronic heart failure do not always have a visible effect in the treatment of acute heart failure. In order to improve the QOL of patients and improve respiratory and circulatory dynamics, therapeutic agents that improve fluid retention in the acute phase immediately after an attack of heart failure are required.
An object of the present invention is to provide a therapeutic agent for improving fluid retention in acute heart failure.
　本発明者は、上記課題に鑑み鋭意検討を重ねたところ、糖尿病治療薬として知られているナトリウム依存性グルコース共輸送体２（ｓｏｄｉｕｍ－ｇｌｕｃｏｓｅ　ｃｏ－ｔｒａｎｓｐｏｒｔｅｒ　２、以下、「ＳＧＬＴ２」という。）阻害薬が、急性心不全における体液貯留を改善する効果を奏しうることを見出し、本発明を完成するに至った。 As a result of diligent studies in view of the above problems, the present inventor has inhibited sodium-dependent glucose cotransporter 2 (sodium-glucose co-transporter 2, hereinafter referred to as "SGLT2"), which is known as a therapeutic agent for diabetes. We have found that the drug can have the effect of improving fluid retention in acute heart failure, and have completed the present invention.
　すなわち、本発明の要旨は、以下のとおりである。
［１］　ＳＧＬＴ２阻害薬を含有する、急性心不全の体液貯留改善薬。
［２］　ＳＧＬＴ２阻害薬が、カナグリフロジン、イプラグリフロジン、ルセオグリフロジン、トホグリフロジン、セルグリフロジンエタボナート、レモグリフロジンエタボナート、エルツグリフロジン、ソタグリフロジン及びこれらの薬学的に許容される塩からなる群より選ばれる少なくとも１つである、上記［１］記載の体液貯留改善薬。
［３］　急性心不全の体液貯留改善薬として使用される、ＳＧＬＴ２阻害薬。
［４］　ＳＧＬＴ２阻害薬が、カナグリフロジン、イプラグリフロジン、ルセオグリフロジン、トホグリフロジン、セルグリフロジンエタボナート、レモグリフロジンエタボナート、エルツグリフロジン、ソタグリフロジン及びこれらの薬学的に許容される塩からなる群より選ばれる少なくとも１つである、上記［３］記載のＳＧＬＴ２阻害薬。
［５］　有効量のＳＧＬＴ２阻害薬をそれを必要とする患者に投与する工程を含む、急性心不全患者における体液貯留改善方法。
［６］　ＳＧＬＴ２阻害薬が、カナグリフロジン、イプラグリフロジン、ルセオグリフロジン、トホグリフロジン、セルグリフロジンエタボナート、レモグリフロジンエタボナート、エルツグリフロジン、ソタグリフロジン及びこれらの薬学的に許容される塩からなる群より選ばれる少なくとも１つである、上記［５］記載の体液貯留改善方法。
［７］　急性心不全の体液貯留改善薬の製造における、ＳＧＬＴ２阻害薬の使用。
［８］　ＳＧＬＴ２阻害薬が、カナグリフロジン、イプラグリフロジン、ルセオグリフロジン、トホグリフロジン、セルグリフロジンエタボナート、レモグリフロジンエタボナート、エルツグリフロジン、ソタグリフロジン及びこれらの薬学的に許容される塩からなる群より選ばれる少なくとも１つである、上記［７］記載の使用。 That is, the gist of the present invention is as follows.
[1] A fluid retention improving drug for acute heart failure containing an SGLT2 inhibitor.
[2] SGLT2 inhibitors are canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remoglyflozin etabonate, ertzgliflozin, sotagliflozin and pharmaceutically acceptable of these. The body fluid retention improving agent according to the above [1], which is at least one selected from the group consisting of salts.
[3] An SGLT2 inhibitor used as a fluid retention improving drug for acute heart failure.
[4] SGLT2 inhibitors are canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remoglyflozin etabonate, ertzgliflozin, sotagliflozin and pharmaceutically acceptable of these. The SGLT2 inhibitor according to the above [3], which is at least one selected from the group consisting of salts.
[5] A method for improving fluid retention in a patient with acute heart failure, which comprises a step of administering an effective amount of an SGLT2 inhibitor to a patient in need thereof.
[6] SGLT2 inhibitors are canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remoglyflozin etabonate, ertzgliflozin, sotagliflozin and pharmaceutically acceptable of these. The method for improving body fluid retention according to the above [5], which is at least one selected from the group consisting of salts.
[7] Use of SGLT2 inhibitors in the manufacture of fluid retention improving agents for acute heart failure.
[8] SGLT2 inhibitors are canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remoglyflozin etabonate, ertzgliflozin, sotagliflozin and pharmaceutically acceptable of these. The use according to [7] above, which is at least one selected from the group consisting of salts.
　本発明によれば、急性心不全における体液貯留を改善することができる。 According to the present invention, fluid retention in acute heart failure can be improved.
図１は、カナグリフロジン投与前（Ｂａｓｅｌｉｎｅ）、投与１日後及び７日後の尿量（ｍＬ／ｄａｙ）を示す。FIG. 1 shows the urine volume (mL / day) before administration of canagliflozin (Baseline), 1 day after administration, and 7 days after administration. 図２は、胸部Ｘ線を用いて評価したカナグリフロジン投与開始前日と７日後の（ａ）心胸郭比、（ｂ）肺うっ血の有無、（ｃ）胸水の有無を示す図である。図中の白色バーは投与開始前日の結果を示し、黒色バーは７日後の結果を示す。FIG. 2 is a diagram showing (a) cardiothoracic ratio, (b) presence or absence of pulmonary congestion, and (c) presence or absence of pleural effusion on the day before and 7 days after the start of canagliflozin administration evaluated using chest X-ray. The white bar in the figure shows the result on the day before the start of administration, and the black bar shows the result on the day after 7 days.
　本発明の急性心不全の体液貯留改善薬は、ＳＧＬＴ２阻害薬を含有する。また、ＳＧＬＴ２阻害薬は、利尿薬やその他薬剤を併用して使用することもできる。
　以下、本発明について説明する。 The fluid retention improving agent for acute heart failure of the present invention contains an SGLT2 inhibitor. In addition, SGLT2 inhibitors can also be used in combination with diuretics and other drugs.
Hereinafter, the present invention will be described.
（ＳＧＬＴ２阻害薬）
　本発明で用いられるＳＧＬＴ２阻害薬としては、ＳＧＬＴ２による糖の再吸収を阻害する薬物が挙げられる。より具体的なＳＧＬＴ２阻害薬としては、低分子化合物、ＳＧＬＴ２発現阻害薬、ＳＧＬＴ２特異的結合物質などが挙げられる。 (SGLT2 inhibitor)
Examples of the SGLT2 inhibitor used in the present invention include drugs that inhibit the reabsorption of sugar by SGLT2. More specific SGLT2 inhibitors include low molecular weight compounds, SGLT2 expression inhibitors, SGLT2-specific binding substances and the like.
（低分子化合物）
　ＳＧＬＴ２阻害薬である低分子化合物としては、例えば、カナグリフロジン［（１Ｓ）－１，５－Ａｎｈｙｄｒｏ－１－Ｃ（－３｛［５－（４－ｆｌｕｏｒｏｐｈｅｎｙｌ）ｔｈｉｏｐｈｅｎ－２－ｙｌ］ｍｅｔｈｙｌ｝－４－ｍｅｔｈｙｌｐｈｅｎｙｌ）－Ｄ－ｇｌｕｃｉｔｏｌ］、エンパグリフロジン［（１Ｓ）－１，５－Ａｎｈｙｄｒｏ－１－Ｃ－｛４－ｃｈｌｏｒｏ－３－［（４－｛［（３Ｓ）－ｏｘｏｌａｎ－３－ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）ｍｅｔｈｙｌ］ｐｈｅｎｙｌ｝－Ｄ－ｇｌｕｃｉｔｏｌ］、イプラグリフロジン［（１Ｓ）－１，５－Ａｎｈｙｄｒｏ－１－Ｃ－｛３－［（１－ｂｅｎｚｏｔｈｉｏｐｈｅｎ－２－ｙｌ）ｍｅｔｈｙｌ］－４－ｆｌｕｏｒｏｐｈｅｎｙｌ｝－Ｄ－ｇｌｕｃｉｔｏｌ］、ダパグリフロジン［（１Ｓ）－１，５－Ａｎｈｙｄｒｏ－１－Ｃ－｛４－ｃｈｌｏｒｏ－３－［（４－ｅｔｈｏｘｙｐｈｅｎｙｌ）ｍｅｔｈｙｌ］ｐｈｅｎｙｌ｝－Ｄ－ｇｌｕｃｉｔｏｌ］、ルセオグリフロジン［（２Ｓ，３Ｒ，４Ｒ，５Ｓ，６Ｒ）－２－｛５－［（４－Ｅｔｈｏｘｙｐｈｅｎｙｌ）ｍｅｔｈｙｌ］－２－ｍｅｔｈｏｘｙ－４－ｍｅｔｈｙｌｐｈｅｎｙｌ｝－６－（ｈｙｄｒｏｘｙｍｅｔｈｙｌ）ｔｈｉａｎｅ－３，４，５－ｔｒｉｏｌ］、トホグリフロジン［（１Ｓ，３’Ｒ，４’Ｓ，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］、セルグリフロジンエタボナート［２－（４－Ｍｅｔｈｏｘｙｂｅｎｚｙｌ）ｐｈｅｎｙｌ　６－Ｏ－（ｅｔｈｏｘｙｃａｒｂｏｎｙｌ）－β－Ｄ－ｇｌｕｃｏｐｙｒａｎｏｓｉｄｅ］、レモグリフロジンエタボナート［５－Ｍｅｔｈｙｌ－１－（ｐｒｏｐａｎ－２－ｙｌ）－４－［［４－［（ｐｒｏｐａｎ－２－ｙｌ）ｏｘｙ］ｐｈｅｎｙｌ］ｍｅｔｈｙｌ］－１Ｈ－ｐｙｒａｚｏｌ－３－ｙｌ　６－Ｏ－（ｅｔｈｏｘｙｃａｒｂｏｎｙｌ）－β－Ｄ－ｇｌｕｃｏｐｙｒａｎｏｓｉｄｅ］、エルツグリフロジン［（１Ｓ，２Ｓ，３Ｓ，４Ｒ，５Ｓ）－５－［４－Ｃｈｌｏｒｏ－３－［（４－ｅｔｈｏｘｙｐｈｅｎｙｌ）ｍｅｔｈｙｌ］ｐｈｅｎｙｌ］－１－（ｈｙｄｒｏｘｙｍｅｔｈｙｌ）－６，８－ｄｉｏｘａｂｉｃｙｃｌｏ［３．２．１］ｏｃｔａｎｅ－２，３，４－ｔｒｉｏｌ］、ソタグリフロジン［Ｍｅｔｈｙｌ　（５Ｓ）－５－Ｃ－［４－ｃｈｌｏｒｏ－３－［（４－ｅｔｈｏｘｙｐｈｅｎｙｌ）ｍｅｔｈｙｌ］ｐｈｅｎｙｌ］－１－ｔｈｉｏ－β－Ｌ－ｘｙｌｏｐｙｒａｎｏｓｉｄｅ］、及びこれらの薬学的に許容される塩が挙げられる。これらの化合物は、公知の製造方法又は当該方法に改変を施した任意の製造方法により、製造することができる。 (Low molecular weight compound)
Examples of the low molecular weight compound which is an SGLT2 inhibitor include canagliflozin [(1S) -1,5-Anhydro-1-C (-3 {[5- (4-fluorophenyl) thiophen-2-yl] methyl}. -4-methylphenyl) -D-glucitol], empagliflozin [(1S) -1,5-Anhydro-1-C- {4-chloro-3-[(4-{[(3S) -oxolan-3-] yl] oxy} phenyl) methyl] phenyl} -D-glucitol], ipragliflozin [(1S) -1,5-Anhydro-1-C- {3-[(1-benzothiophen-2-yl) methyl]- 4-fluoropheneyl} -D-glucitol], dapagliflozin [(1S) -1,5-Anhydro-1-C- {4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl} -D-glucitol], Ruse Ogliflozin [(2S, 3R, 4R, 5S, 6R) -2- {5-[(4-Ethoxyphenyl) methyl] -2-methoxy-4-methylphenyl} -6- (hydroxymethyl) thiane-3,4,5 -Triol], tohogliflozin [(1S, 3'R, 4'S, 5'S, 6'R) -6-[(4-Ethylphenyl) methyl] -6'-(hydroxymethyl) -3', 4', 5', 6'-tellahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4', 5'-triol], cergliflozin etabonate [2- (4-Methylbenzyl) phenyl 6-O- (ethoxycarbonyl) -β-D-glucopylanoside], lemoglyflozin etabonate [5-Methyl-1- (propan-2-yl) -4-[[4-[(propan-2-yl)] ) Oxy] phenyl] methyl] -1H-pyrazol-3-yl 6-O- (ethoxycarbonyl) -β-D-glucopylanoside], Erzglyfrosin [(1S, 2S, 3S, 4R, 5S) -5- [4 -Chloro-3-[(4-ethoxyphenyl) methyl] phenyl] -1- (hydroxymethyl) -6,8-dioxab iciclo [3.2.1] octane-2,3,4-triol], sotagliflozin [Methyl (5S) -5-C- [4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl] -1- thio-β-L-xylopyranoside], and pharmaceutically acceptable salts thereof. These compounds can be produced by a known production method or an arbitrary production method obtained by modifying the method.
　ＳＧＬＴ２阻害薬である低分子化合物の薬学的に許容される塩としては、例えば、リチウム、ナトリウム、カリウムなどのアルカリ金属との塩；カルシウム、マグネシウムなどの第２族金属との塩；亜鉛又はアルミニウムとの塩；アンモニア、コリン、ジエタノールアミン、リジン、エチレンジアミン、ｔ－ブチルアミン、ｔ－オクチルアミン、トリス（ヒドロキシメチル）アミノメタン、Ｎ－メチル－グルコサミン、トリエタノールアミン、デヒドロアビエチルアミンなどのアミンとの塩；塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸などの無機酸との塩；ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマール酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸などの有機酸との塩；アスパラギン酸、グルタミン酸などの酸性アミノ酸との塩などが挙げられる。 Pharmaceutically acceptable salts of low molecular weight compounds that are SGLT2 inhibitors include, for example, salts with alkali metals such as lithium, sodium and potassium; salts with Group 2 metals such as calcium and magnesium; zinc or aluminum. Salts with; salts with amines such as ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N-methyl-glucosamine, triethanolamine, dehydroabiethylamine Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitrate, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid , Salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid; salts with acidic amino acids such as aspartic acid, glutamate and the like.
　更に、ＳＧＬＴ２阻害薬である低分子化合物の薬学的に許容される塩には、当該低分子化合物の分子内塩、水和物、及び、Ｌ－プロリン、（２Ｓ）－プロパン－１，２－ジオールなどの溶媒和物も包含される。 Furthermore, pharmaceutically acceptable salts of low molecular weight compounds that are SGLT2 inhibitors include intramolecular salts of the low molecular weight compounds, hydrates, and L-proline, (2S) -propane-1,2-. Solvates such as diols are also included.
（ＳＧＬＴ２発現阻害薬）
　ＳＧＬＴ２発現阻害薬としては、例えば、ｓｉＲＮＡ、ｓｈＲＮＡ、ｍｉＲＮＡ、リボザイム、アンチセンス核酸、低分子化合物などが挙げられる。これらの発現阻害薬を投与することにより、ＳＧＬＴ２の発現を阻害することができる。 (SGLT2 expression inhibitor)
Examples of SGLT2 expression inhibitors include siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, and low molecular weight compounds. By administering these expression inhibitors, the expression of SGLT2 can be inhibited.
　ｓｉＲＮＡ（ｓｍａｌｌ　ｉｎｔｅｒｆｅｒｉｎｇ　ＲＮＡ）は、ＲＮＡ干渉による遺伝子サイレンシングのために用いられる２１～２３塩基対の低分子２本鎖ＲＮＡである。細胞内に導入されたｓｉＲＮＡは、ＲＮＡ誘導サイレンシング複合体（ＲＩＳＣ）と結合する。この複合体はｓｉＲＮＡと相補的な配列を持つｍＲＮＡに結合し切断する。これにより、配列特異的に遺伝子の発現を抑制する。 SiRNA (small interfering RNA) is a 21-23 base pair low molecular weight double-stranded RNA used for gene silencing by RNA interference. SiRNA introduced into cells binds to RNA-induced silencing complex (RISC). This complex binds to and cleaves mRNA that has a sequence complementary to siRNA. This suppresses gene expression in a sequence-specific manner.
　ｓｉＲＮＡは、センス鎖及びアンチセンス鎖オリゴヌクレオチドをＤＮＡ／ＲＮＡ自動合成機でそれぞれ合成し、例えば、適当なアニーリング緩衝液中、９０～９５℃で約１分程度変性させた後、３０～７０℃で約１～８時間アニーリングさせることにより調製することができる。 For siRNA, sense strand and antisense strand oligonucleotides are synthesized by a DNA / RNA automatic synthesizer, respectively, and denatured in an appropriate annealing buffer at 90 to 95 ° C. for about 1 minute, and then 30 to 70 ° C. It can be prepared by annealing in 1 to 8 hours.
　ｓｈＲＮＡ（ｓｈｏｒｔ　ｈａｉｒｐｉｎ　ＲＮＡ）は、ＲＮＡ干渉による遺伝子サイレンシングのために用いられるヘアピン型のＲＮＡ配列である。ｓｈＲＮＡは、ベクターによって細胞に導入し、Ｕ６プロモーター又はＨ１プロモーターで発現させてもよいし、ｓｈＲＮＡ配列を有するオリゴヌクレオチドをＤＮＡ／ＲＮＡ自動合成機で合成し、ｓｉＲＮＡと同様の方法によりセルフアニーリングさせることによって調製してもよい。細胞内に導入されたｓｈＲＮＡのヘアピン構造は、ｓｉＲＮＡへと切断され、ＲＮＡ誘導サイレンシング複合体（ＲＩＳＣ）と結合する。この複合体はｓｉＲＮＡと相補的な配列を持つｍＲＮＡに結合し切断する。これにより、配列特異的に遺伝子の発現を抑制する。 ShRNA (short hairpin RNA) is a hairpin-type RNA sequence used for gene silencing by RNA interference. The shRNA may be introduced into cells by a vector and expressed by the U6 promoter or the H1 promoter, or an oligonucleotide having an shRNA sequence may be synthesized by a DNA / RNA automatic synthesizer and self-annealed by the same method as siRNA. May be prepared by. The hairpin structure of the shRNA introduced into the cell is cleaved into siRNA and binds to RNA-induced silencing complex (RISC). This complex binds to and cleaves mRNA that has a sequence complementary to siRNA. This suppresses gene expression in a sequence-specific manner.
　ｍｉＲＮＡ（ｍｉｃｒｏＲＮＡ、マイクロＲＮＡ）は、ゲノム上にコードされ、多段階的な生成過程を経て最終的に約２０塩基の微小ＲＮＡとなる機能性核酸である。ｍｉＲＮＡは、機能性のｎｃＲＮＡ（ｎｏｎ－ｃｏｄｉｎｇ　ＲＮＡ、非コードＲＮＡ：タンパク質に翻訳されないＲＮＡの総称）に分類されており、他の遺伝子の発現を調節するという、生命現象において重要な役割を担っている。特定の塩基配列を有するｍｉＲＮＡを生体に投与することにより、ＳＧＬＴ２の発現を阻害することができる。 MiRNA (microRNA, microRNA) is a functional nucleic acid that is encoded on the genome and finally becomes a microRNA of about 20 bases through a multi-step production process. MiRNAs are classified as functional ncRNAs (non-coding RNAs, non-coding RNAs: a general term for RNAs that are not translated into proteins), and play an important role in life phenomena by regulating the expression of other genes. There is. The expression of SGLT2 can be inhibited by administering a miRNA having a specific base sequence to a living body.
　リボザイムは、触媒活性を有するＲＮＡである。リボザイムには種々の活性を有するものがあるが、ＲＮＡを切断する酵素としてのリボザイムの研究により、ＲＮＡの部位特異的な切断を目的とするリボザイムの設計が可能となっている。リボザイムは、グループＩイントロン型、ＲＮａｓｅＰに含まれるＭ１ＲＮＡ等の４００ヌクレオチド以上の大きさのものであってもよく、ハンマーヘッド型、ヘアピン型などと呼ばれる４０ヌクレオチド程度のものであってもよい。 Ribozyme is an RNA with catalytic activity. Although some ribozymes have various activities, research on ribozymes as an enzyme that cleaves RNA has made it possible to design ribozymes for the purpose of site-specific cleavage of RNA. The ribozyme may have a size of 400 nucleotides or more, such as Group I intron type or M1RNA contained in RNase P, or may be a ribozyme having a size of about 40 nucleotides, which is called a hammer head type or a hairpin type.
　アンチセンス核酸は、標的配列に相補的な核酸である。アンチセンス核酸は、三重鎖形成による転写開始阻害、ＲＮＡポリメラーゼによって局部的に開状ループ構造が形成された部位とのハイブリッド形成による転写抑制、合成の進みつつあるＲＮＡとのハイブリッド形成による転写阻害、イントロンとエクソンとの接合点でのハイブリッド形成によるスプライシング抑制、スプライソソーム形成部位とのハイブリッド形成によるスプライシング抑制、ｍＲＮＡとのハイブリッド形成による核から細胞質への移行抑制、キャッピング部位やポリ（Ａ）付加部位とのハイブリッド形成によるスプライシング抑制、翻訳開始因子結合部位とのハイブリッド形成による翻訳開始抑制、開始コドン近傍のリボソーム結合部位とのハイブリッド形成による翻訳抑制、ｍＲＮＡの翻訳領域やポリソーム結合部位とのハイブリッド形成によるペプチド鎖の伸長阻止、核酸とタンパク質との相互作用部位とのハイブリッド形成による遺伝子発現抑制等により、標的遺伝子の発現を抑制することができる。 Antisense nucleic acid is a nucleic acid complementary to the target sequence. Antisense nucleic acids inhibit transcription initiation by triple-strand formation, transcription inhibition by hybrid formation with a site where an open loop structure is locally formed by RNA polymerase, and transcription inhibition by hybrid formation with RNA whose synthesis is progressing. Suppression of splicing by hybrid formation at the junction of intron and exon, suppression of splicing by hybrid formation with sprisosome formation site, suppression of transcription from nucleus to cytoplasm by hybrid formation with mRNA, capping site and poly (A) addition site Suppressing splicing by hybrid formation with, translation initiation inhibition by hybrid formation with translation initiation factor binding site, translation inhibition by hybrid formation with ribosome binding site near the initiation codon, by hybrid formation with mRNA translation region or polysome binding site The expression of the target gene can be suppressed by inhibiting the elongation of the peptide chain, suppressing the gene expression by hybridizing the interaction site between the nucleic acid and the protein, and the like.
　ｓｉＲＮＡ、ｓｈＲＮＡ、ｍｉＲＮＡ、リボザイム及びアンチセンス核酸は、安定性や活性を向上させるために、種々の化学修飾を含んでいてもよい。例えば、ヌクレアーゼ等の加水分解酵素による分解を防ぐために、リン酸残基を、例えば、ホスホロチオエート（ＰＳ）、メチルホスホネート、ホスホロジチオネート等の化学修飾リン酸残基に置換してもよい。また、少なくとも一部をペプチド核酸（ＰＮＡ）等の核酸類似体により構成してもよい。 SiRNA, shRNA, miRNA, ribozyme and antisense nucleic acids may contain various chemical modifications in order to improve stability and activity. For example, in order to prevent degradation by a hydrolase such as a nuclease, the phosphate residue may be replaced with a chemically modified phosphate residue such as phosphorothioate (PS), methylphosphonate, or phosphorodithionate. Further, at least a part thereof may be composed of nucleic acid analogs such as peptide nucleic acid (PNA).
（ＳＧＬＴ２特異的結合物質）
　ＳＧＬＴ２特異的結合物質としては、ＳＧＬＴ２に特異的に結合してＳＧＬＴ２の機能を阻害するものが挙げられ、例えば、抗体、抗体断片、アプタマーなどが挙げられる。抗体は、例えば、マウス等の動物に、ＳＧＬＴ２タンパク質又はその断片を抗原として免疫することによって作製することができる。或いは、抗体は、例えば、ファージライブラリーのスクリーニングにより作製することができる。抗体断片としては、Ｆｖ、Ｆａｂ、ｓｃＦｖなどが挙げられる。抗体は、モノクローナル抗体であることが好ましい。また、抗体は、市販の抗体であってもよい。アプタマーは、標的物質に対する特異的結合能を有する物質である。アプタマーとしては、核酸アプタマー、ペプチドアプタマーなどが挙げられる。標的ペプチドに特異的結合能を有する核酸アプタマーは、例えば、ｓｙｓｔｅｍａｔｉｃ　ｅｖｏｌｕｔｉｏｎ　ｏｆ　ｌｉｇａｎｄ　ｂｙ　ｅｘｐｏｎｅｎｔｉａｌ　ｅｎｒｉｃｈｍｅｎｔ（ＳＦＬＥＸ）法などにより選別することができる。また、標的ペプチドに特異的結合能を有するペプチドアプタマーは、例えば酵母を用いたＴｗｏ－ｈｙｂｒｉｄ法などにより選別することができる。 (SGLT2 specific binding substance)
Examples of the SGLT2-specific binding substance include those that specifically bind to SGLT2 and inhibit the function of SGLT2, and examples thereof include antibodies, antibody fragments, and aptamers. Antibodies can be produced, for example, by immunizing an animal such as a mouse with an SGLT2 protein or a fragment thereof as an antigen. Alternatively, the antibody can be made, for example, by screening a phage library. Examples of the antibody fragment include Fv, Fab, scFv and the like. The antibody is preferably a monoclonal antibody. Moreover, the antibody may be a commercially available antibody. Aptamers are substances that have the ability to specifically bind to a target substance. Examples of the aptamer include nucleic acid aptamers and peptide aptamers. Nucleic acid aptamers having a specific binding ability to a target peptide can be selected by, for example, the systematic evolution of ligand by exponential evolution (SFLEX) method. Further, the peptide aptamer having a specific binding ability to the target peptide can be selected by, for example, the Two-hybrid method using yeast.
（急性心不全）
　急性心不全については、日本循環器学会作成の「急性・慢性心不全診療ガイドライン（２０１７年改定版）」に具体的な定義があるが、本発明において、急性心不全の患者としては、心不全の初回発作と慢性心不全の急性増悪によって生じる発作のいずれも含む。また、本発明における対象患者は、急性心不全において、静脈内注射による治療から、経口薬による治療に切替えられた患者のうち、呼吸循環動態が安定して、経口摂取可能となった患者が対象である。
　また、本発明において、ＳＧＬＴ２阻害薬を投薬される患者は、糖尿病を合併していてもよいが、それに限定されるものではない。 (Acute heart failure)
Acute heart failure is specifically defined in the "Acute / Chronic Heart Failure Medical Care Guidelines (2017 revised edition)" prepared by the Japanese Cardiovascular Society, but in the present invention, as a patient with acute heart failure, it is the first attack of heart failure. Includes any seizures caused by an acute exacerbation of chronic heart failure. In addition, the target patient in the present invention is a patient who has been switched from treatment by intravenous injection to treatment by an oral drug in acute heart failure and whose respiratory and circulatory dynamics are stable and can be ingested orally. is there.
Further, in the present invention, the patient to whom the SGLT2 inhibitor is administered may be complicated with diabetes, but is not limited thereto.
（体液貯留改善）
　本発明において、体液貯留の程度は、胸部Ｘ線を用いた心胸郭比、肺うっ血及び胸水の程度や浮腫の程度で判定することができる。特に、呼吸不全の評価のため体液貯留の程度は、肺うっ血の程度で判定することが有用である。
　また、肺うっ血の改善と並行して、患者自身の呼吸困難の改善度を、例えば、セブンポイントライカートスケール（seven point Likert scale）を用いて判定することも有用である。セブンポイントライカートスケールは、患者が呼吸困難について担当医師より質問されたときにどう感じたかをスコア（著明に悪化、中等度悪化、軽度悪化、変化なし、軽度改善、中等度改善、著明改善）により表現するものである。 (Improvement of fluid retention)
In the present invention, the degree of fluid retention can be determined by the cardiothoracic ratio using chest X-rays, the degree of pulmonary congestion and pleural effusion, and the degree of edema. In particular, it is useful to determine the degree of fluid retention based on the degree of pulmonary congestion for the evaluation of respiratory failure.
In parallel with the improvement of pulmonary congestion, it is also useful to determine the degree of improvement of the patient's own dyspnea using, for example, the seven point Likert scale. The Seven Point Lycat Scale scores how patients feel when asked by their doctor about dyspnea (significantly worse, moderately worse, mildly worse, no change, mild improvement, moderate improvement, marked improvement). ).
（医薬組成物）
　本発明は、ＳＧＬＴ２阻害薬及び薬学的に許容される担体を含有する、急性心不全における体液貯留改善用医薬組成物を提供する。本実施態様の医薬組成物を投与することによって、急性心不全における体液貯留を改善することができる。 (Pharmaceutical composition)
The present invention provides a pharmaceutical composition for improving fluid retention in acute heart failure, which contains an SGLT2 inhibitor and a pharmaceutically acceptable carrier. By administering the pharmaceutical composition of this embodiment, fluid retention in acute heart failure can be improved.
　本実施態様の医薬組成物は、経口的に使用される剤型又は非経口的に使用される剤型に製剤化されていてもよい。経口的に使用される剤型としては、例えば、錠剤、カプセル剤、エリキシル剤、マイクロカプセル剤などが挙げられる。非経口的に使用される剤型としては、例えば、注射剤、軟膏剤、貼付剤などが挙げられる。 The pharmaceutical composition of this embodiment may be formulated into a dosage form used orally or a dosage form used parenterally. Dosage forms used orally include, for example, tablets, capsules, elixirs, microcapsules and the like. Dosage forms used parenterally include, for example, injections, ointments, patches and the like.
　薬学的に許容される担体としては、医薬組成物の製造に通常用いられるものであれば、特に制限なく用いることができる。具体的な例としては、例えば、ゼラチン、コーンスターチ、トラガントガム、アラビアゴム等の結合剤；デンプン、結晶性セルロース等の賦形剤；アルギン酸等の膨化剤；水、エタノール、グリセリン等の注射剤用溶剤；ゴム系粘着剤、シリコーン系粘着剤等の粘着剤などが挙げられる。 The pharmaceutically acceptable carrier can be used without particular limitation as long as it is usually used for producing a pharmaceutical composition. Specific examples include, for example, binders such as gelatin, cornstarch, traganth gum, and gum arabic; excipients such as starch and crystalline cellulose; swelling agents such as alginic acid; solvents for injections such as water, ethanol, and glycerin. ; Adhesives such as rubber-based adhesives and silicone-based adhesives can be mentioned.
　医薬組成物は添加剤を含んでいてもよい。添加剤としては、ステアリン酸カルシウム、ステアリン酸マグネシウム等の潤滑剤；ショ糖、乳糖、サッカリン、マルチトール等の甘味剤；ペパーミント、アカモノ油等の香味剤；ベンジルアルコール、フェノール等の安定剤；リン酸塩、酢酸ナトリウム等の緩衝剤；安息香酸ベンジル、ベンジルアルコール等の溶解補助剤；酸化防止剤；防腐剤などが挙げられる。 The pharmaceutical composition may contain additives. Additives include lubricants such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin and martitol; flavors such as peppermint and red mono oil; stabilizers such as benzyl alcohol and phenol; phosphoric acid. Buffers such as salts and sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; preservatives and the like.
　医薬組成物は、ＳＧＬＴ２阻害薬、薬学的に許容される担体及び所望により添加剤を適宜組み合わせて、一般に認められた製薬実施に要求される単位用量形態で混和することによって製剤化することができる。 The pharmaceutical composition can be formulated by appropriately combining SGLT2 inhibitors, pharmaceutically acceptable carriers and optionally additives and mixing them in the generally accepted unit dose form required for pharmaceutical practice. ..
　ＳＧＬＴ２阻害薬を投与する対象としては、限定されるものではないが、例えば、ヒト、サル、イヌ、ウシ、ウマ、ヒツジ、ブタ、ウサギ、マウス、ラット、モルモット、ハムスター、及びそれらの細胞などが挙げられる。なかでも、哺乳動物又は哺乳動物細胞が好ましく、ヒト又はヒト細胞が特に好ましい。 Targets to which SGLT2 inhibitors are administered include, but are not limited to, for example, humans, monkeys, dogs, cows, horses, ovis aries, pigs, rabbits, mice, rats, guinea pigs, hamsters, and their cells. Can be mentioned. Among them, mammals or mammalian cells are preferable, and humans or human cells are particularly preferable.
　ＳＧＬＴ２阻害薬の投与量は、投与する具体的な対象、対象の症状、体重、年齢、性別などによって異なり、一概には決定できないが、経口投与の場合には、成人であれば、例えば、投与単位形態あたり約０．１ｍｇ／ｋｇ～約１００ｍｇ／ｋｇ体重のＳＧＬＴ２阻害薬を投与すればよい。また、注射剤の場合には、成人であれば、例えば、投与単位形態あたり約０．０１ｍｇ～約５０ｍｇのＳＧＬＴ２阻害薬を投与すればよい。 The dose of an SGLT2 inhibitor varies depending on the specific target to be administered, the target's symptoms, body weight, age, gender, etc., and cannot be unconditionally determined. An SGLT2 inhibitor having a body weight of about 0.1 mg / kg to about 100 mg / kg per unit form may be administered. In the case of an injection, for adults, for example, about 0.01 mg to about 50 mg of SGLT2 inhibitor may be administered per unit form of administration.
　また、ＳＧＬＴ２阻害薬の１日投与量は体液貯留改善に有効な量であればよく、投与する具体的な対象、対象の症状、体重、年齢、性別などによって異なり、一概には決定できないが、例えば、成人であれば、１日あたり約０．１ｍｇ／ｋｇ～約１００ｍｇ／ｋｇ体重のＳＧＬＴ２阻害薬を１日１回又は２回～３回程度に分けて投与すればよい。 In addition, the daily dose of the SGLT2 inhibitor may be an amount effective for improving body fluid retention, and it depends on the specific target to be administered, the target's symptom, body weight, age, gender, etc., and cannot be unconditionally determined. For example, in the case of an adult, an SGLT2 inhibitor having a body weight of about 0.1 mg / kg to about 100 mg / kg per day may be administered once or twice to three times a day.
　本発明に係るＳＧＬＴ２阻害薬は、ＳＧＬＴ２阻害薬以外の体液貯留改善薬及び他の疾患の治療薬からなる群より選択される少なくとも１つと組合せて、使用してもよい。ＳＧＬＴ２阻害薬と他の薬剤とは、同一の製剤にしてもよいし、別々の製剤にしてもよい。また、各製剤は、同一の投与経路で投与してもよいし、別々の投与経路で投与してもよい。投与経路としては、例えば、経口又は注射が挙げられる。更に、各製剤は、同時に投与してもよいし、逐次的に投与してもよいし、一定の時間ないし期間を空けて別々に投与してもよい。一実施態様において、ＳＧＬＴ２阻害薬と他の薬剤とは、これらを包含するキットとしてもよい。 The SGLT2 inhibitor according to the present invention may be used in combination with at least one selected from the group consisting of a fluid retention improving agent other than the SGLT2 inhibitor and a therapeutic agent for other diseases. The SGLT2 inhibitor and the other drug may be the same preparation or may be different preparations. In addition, each preparation may be administered by the same administration route or may be administered by different administration routes. The route of administration includes, for example, oral or injection. Further, each preparation may be administered simultaneously, sequentially, or separately after a certain period of time or period. In one embodiment, the SGLT2 inhibitor and the other agent may be a kit containing them.
　以下に、実施例を用いて本発明を更に詳細に説明するが、本発明は、これらにより何ら限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
　（実施例１）
　非代償性心不全患者に対するカナグリフロジンの効果検討
　３４例の心不全非代償期で入院した２型糖尿病患者に対し初期治療を行い、病態が安定した後に、１００ｍｇ／日カナグリフロジンを投与し、７日間治療を行った。なお、カナグリフロジン投与期間中、フロセミドの用量は適宜調節した。
　７日間のカナグリフロジン投与による治療の結果、体重は有意に減少した（投与開始前の平均体重は５８．７±１４．４ｋｇであったが、７日後には５７．２±１４．４ｋｇ、Ｐ＜０．００１）。尿量は、図１に示す通り、１日後に増加したが７日後には元に戻った。また呼吸困難感は大部分の患者で改善した。
　カナグリフロジン投与開始前日と７日後に、胸部Ｘ線を用いて、心胸郭比、肺うっ血及び胸水の程度を評価した結果、図２に示す通り、（ａ）心胸郭比、（ｂ）肺うっ血、（ｃ）胸水、いずれの項目でも有意な改善が認められた。尚、図２中の白色バーは投与開始前日の結果を示し、黒色バーは７日後の結果を示している。 (Example 1)
Examination of the effect of canagliflozin on decompensated heart failure patients Initial treatment was performed on 34 patients with type 2 diabetes who were hospitalized during the decompensated period of heart failure, and after the condition became stable, 100 mg / day canagliflozin was administered. He was treated for a day. The dose of furosemide was appropriately adjusted during the administration period of canagliflozin.
As a result of treatment with canagliflozin for 7 days, the body weight was significantly reduced (the average body weight before the start of administration was 58.7 ± 14.4 kg, but after 7 days it was 57.2 ± 14.4 kg. P <0.001). Urine volume increased after 1 day, but returned to normal after 7 days, as shown in FIG. Also, dyspnea improved in most patients.
As a result of evaluating the cardiothoracic ratio, pulmonary congestion and the degree of pleural effusion using chest X-rays on the day before and 7 days after the start of canaglyphrosin administration, as shown in FIG. 2, (a) cardiothoracic ratio and (b) lung. Significant improvement was observed in all items of congestion and (c) pleural effusion. The white bar in FIG. 2 shows the result on the day before the start of administration, and the black bar shows the result on the day after 7 days.
　以上より、本発明によれば、ＳＧＬＴ２阻害薬の投与により、心不全の急性期における体液貯留を改善することができることが明らかになった。 From the above, it was clarified that according to the present invention, administration of an SGLT2 inhibitor can improve fluid retention in the acute phase of heart failure.
　本発明は、急性心不全の体液貯留改善に有効かつ安全に使用可能な新規な医薬を提供するものである。 The present invention provides a novel drug that can be effectively and safely used for improving fluid retention in acute heart failure.

Claims (2)

  1. 　ＳＧＬＴ２阻害薬を含有する、急性心不全の体液貯留改善薬。 A fluid retention improving drug for acute heart failure containing an SGLT2 inhibitor.
  2. 　ＳＧＬＴ２阻害薬が、カナグリフロジン、イプラグリフロジン、ルセオグリフロジン、トホグリフロジン、セルグリフロジンエタボナート、レモグリフロジンエタボナート、エルツグリフロジン、ソタグリフロジン及びこれらの薬学的に許容される塩からなる群より選ばれる少なくとも１つである、請求項１記載の体液貯留改善薬。 SGLT2 inhibitors consist of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, cergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin and pharmaceutically acceptable salts thereof The fluid retention improving agent according to claim 1, which is at least one selected from the group.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017186353A (en) * 2012-08-30 2017-10-12 大正製薬株式会社 Combination of SGLT2 inhibitor and antihypertensive drug
JP2019508453A (en) * 2016-03-16 2019-03-28 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Pharmaceutical composition comprising empagliflozin and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017186353A (en) * 2012-08-30 2017-10-12 大正製薬株式会社 Combination of SGLT2 inhibitor and antihypertensive drug
JP2019508453A (en) * 2016-03-16 2019-03-28 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Pharmaceutical composition comprising empagliflozin and use thereof

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BUTLER JAVED, SAVARESE GIANLUIGI, SATTAR NAVEED, JANUZZI JAMES, VERMA SUBODH, LUND LARS H, FITCHETT DAVID, ZELLER CORDULA, GEORGE : "Empagliflozin is associated with a lower risk of post- acute heart failure rehospitalization and mortality: insights from the empa- reg outcome trial", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 73, no. 9, March 2019 (2019-03-01), pages 663, XP055806058 *
DAMMAN KEVIN, BEUSEKAMP JOOST C., BOORSMA EVA M., SWART HENK P., SMILDE TOM D.J., ELVAN ARIF, ECK J.W. MARTIJN, HEERSPINK HIDDO J.: "Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin onclinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF", EUROPEAN JOURNAL OF HEART FAILURE, vol. 22, no. 4, January 2020 (2020-01-01), pages 713 - 722, XP055806067 *
GROENEWEGEN AMY, RUTTEN FRANS H.: "Sodium-glucose co-transporter 2 inhibitors and acute heart failure", EUROPEAN JOURNAL OF HEART FAILURE, vol. 22, no. 4, April 2020 (2020-04-01), pages 723 - 725, XP055806065 *
NOMOTO, KAZUMIKI,: ""Efficacy of canagliflozin for acute heart failure with Diabetes",", ABSTRACTS OF ANNUAL SCIENTIFIC SESSION OF THE JAPANESE COLLEGE OF CARDIOLOGY : LECTURE ABSTRACTS OF JAPANESE COLLEGE OF CARDIOLOGY, vol. 64, 2016, pages P-481 *
TAKAGI,ATSUTOSHI ET AL.,: ""A case in which an SGLT2 inhibitor was effective in acute heart failure treatment with diabetes".", ABSTRACTS OF ANNUAL SCIENTIFIC SESSION OF THE JAPANESE COLLEGE OF CARDIOLOGY : LECTURE ABSTRACTS OF JAPANESE COLLEGE OF CARDIOLOGY), vol. 64, 2016, pages P-306 *
TAKAHIRO KAMBARA; REI SHIBATA; HIROYUKI OSANAI; YOSHIHITO NAKASHIMA; HIROSHI ASANO; TOYOAKI MUROHARA; MASAYOSHI AJIOKA: "Importance of sodium-glucose cotransporter 2 inhibitor use in diabetic patients with acute heart failure", THERAPEUTIC ADVANCES IN CARDIOVASCULAR DISEASE, vol. 13, December 2019 (2019-12-01), pages 1 - 10, XP055694508 *
YASUYUKI CHIBA MD, KAZUYA YONEZAWA, MASAHUMI HIMENO, MIDORI YUKINO, KYO SHIMAZU, SHOGO IMAGAWA, KAORU KOMURO, NORIKO KIMURA, TEISU: "Left ventricular noncompaction with intractable heart failure responsive to empagliflozin", JOURNAL OF CARDIOLOGY CASES, vol. 18, no. 6, 2018, pages 192 - 196, XP055806060 *

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