Drug for improving fluid retention in acute heart failure

Abstract

To provide a therapeutic drug for improving fluid retention in acute heart failure.SOLUTION: The present invention pertains to a drug for improving fluid retention in acute heart failure, the drug containing an SGLT2 inhibitor.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a novel use of an SGLT2 inhibitor. [Background technology]

[0002] SGLT2 inhibitors, such as canagliflozin, are used as antidiabetic drugs. SGLT2 inhibitors are also known to have the effect of improving fluid retention in chronic heart failure one month or later after the onset of heart failure (Non-Patent Document 1), and are known to have the effect of reducing re-hospitalization in chronic heart failure.

[0003] 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 reduce the patient's quality of life. Diuretics are generally chosen as drugs to improve dyspnea and fluid retention, but they often do not provide sufficient effects. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Yoshihiro Seo, et al., Effects and Safety of Sodium Glucose Cotransporter 2 Inhibitors in Diabetes Patients With Drug-Refractory Advanced Heart Failure., Circ J 2018; 82: 1959 - 1962 Summary of the Invention [Problem to be solved by the invention]

[0005] The treatment objectives are different between chronic and acute heart failure. In other words, in the acute phase, treatment to improve symptoms is prioritized, whereas in the chronic phase, treatment to improve clinical endpoints such as suppressing re-hospitalization and total mortality is continued. Therefore, drugs that are effective in treating chronic heart failure do not necessarily show visible effects in treating acute heart failure. In order to improve patients' QOL and improve respiratory and circulatory dynamics, therapeutic drugs that improve fluid retention in the acute phase from immediately after the onset of heart failure are needed. An object of the present invention is to provide a therapeutic agent that improves fluid retention in acute heart failure. [Means for solving the problem]

[0006] Means for Solving the Problems The present inventors have conducted intensive research in light of the above problems and have found that a sodium-glucose cotransporter 2 (hereinafter referred to as "SGLT2") inhibitor, which is known as a therapeutic drug for diabetes, can be effective in improving fluid retention in acute heart failure, thereby completing the present invention.

[0007] That is, the gist of the present invention is as follows. [1] A drug that contains an SGLT2 inhibitor and improves fluid retention in patients with acute heart failure. [2] The drug for improving fluid retention according to [1] above, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin, and pharma- ceutically acceptable salts thereof. [3] SGLT2 inhibitors are used to improve fluid retention in patients with acute heart failure. [4] The SGLT2 inhibitor according to [3] above, which is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin and pharma- ceutically acceptable salts thereof. [5] A method for treating acute rheumatoid arthritis, comprising administering an effective amount of an SGLT2 inhibitor to a patient in need thereof. A method for improving fluid retention in patients with heart failure. [6] The method for improving fluid retention according to [5] above, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin, and pharma- ceutically acceptable salts thereof. [7] Use of SGLT2 inhibitors in the manufacture of drugs to improve fluid retention in acute heart failure. [8] The use according to [7] above, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin, and pharma- ceutically acceptable salts thereof. Effect of the Invention

[0008] According to the present invention, fluid retention in acute heart failure can be improved. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows the urinary volume (mL / day) before administration of canagliflozin (Baseline), and 1 and 7 days after administration. [Diagram 2] Figure 2 shows (a) cardiothoracic ratio, (b) the presence or absence of pulmonary congestion, and (c) the presence or absence of pleural effusion, evaluated using chest X-rays on the day before and 7 days after the start of canagliflozin administration. The white bars in the figure show the results on the day before the start of administration, and the black bars show the results 7 days after. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The drug for ameliorating fluid retention for acute heart failure of the present invention contains an SGLT2 inhibitor. The SGLT2 inhibitor can also be used in combination with a diuretic or other drug. The present invention will now be described.

[0011] (SGLT2 inhibitors) The SGLT2 inhibitor used in the present invention includes drugs that inhibit the reabsorption of sugar by SGLT2. More specific examples of the SGLT2 inhibitor include low molecular weight compounds, SGLT2 expression inhibitors, and SGLT2 specific binding substances.

[0012] (Low molecular compound) Examples of low molecular weight compounds that are SGLT2 inhibitors 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-fluorophenyl}-D-glucitol], and dapagliflozin [(1S)-1,5-anhydro-1-C-{4-c hloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol], luseogliflozin [(2S,3R,4R,5S,6R)-2-{5-[(4-Ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl}-6-(hydroxymethyl)thiane-3,4,5-triol], tofogliflozin [(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], sergliflozin etabonate [2-(4-Methoxybenzyl)phenyl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside], remogliflozin etabonate [5-Methyl-1-(propan-2-yl)-4-[[4-[(propan-2-yl)oxy]phenyl]methyl]-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside], ertugliflozin [(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], sotagliflozin [Methyl (5S)-5-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-thio-β-L-xylopyranoside] and pharma- ceutical acceptable salts thereof. These compounds can be produced by any known production method or a modified version of the known method.

[0013] Examples of pharma- ceutically acceptable salts of low molecular weight compounds that are SGLT2 inhibitors include salts with alkali metals such as lithium, sodium, and potassium; salts with group 2 metals such as calcium and magnesium; salts with zinc or aluminum; salts with amines such as ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris(hydroxymethyl)aminomethane, N-methyl-glucosamine, triethanolamine, and dehydroabietylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid; and salts with acidic amino acids such as aspartic acid and glutamic acid.

[0014] Furthermore, pharma- ceutically acceptable salts of low molecular weight compounds that are SGLT2 inhibitors also include internal salts, hydrates, and solvates of the low molecular weight compounds, such as L-proline and (2S)-propane-1,2-diol.

[0015] (SGLT2 expression inhibitor) Examples of SGLT2 expression inhibitors include siRNA, shRNA, miRNA, ribozymes, antisense nucleic acids, small molecule compounds, etc. By administering these expression inhibitors, the expression of SGLT2 can be inhibited.

[0016] siRNA (small interfering RNA) is a small double-stranded RNA of 21 to 23 base pairs that is used for gene silencing by RNA interference. When siRNA is introduced into cells, it binds to the RNA-induced silencing complex (RISC). This complex binds to and cleaves mRNA with a sequence complementary to the siRNA, thereby suppressing gene expression in a sequence-specific manner.

[0017] siRNA can be prepared by synthesizing sense and antisense oligonucleotides using an automatic DNA / RNA synthesizer, denaturing them in an appropriate annealing buffer at 90 to 95°C for about 1 minute, and then annealing them at 30 to 70°C for about 1 to 8 hours.

[0018] shRNA (short hairpin RNA) is a hairpin-shaped RNA sequence used for gene silencing by RNA interference. shRNA may be introduced into cells by a vector and expressed by the U6 promoter or H1 promoter, or it may be prepared by synthesizing an oligonucleotide having an shRNA sequence using an automatic DNA / RNA synthesizer and allowing it to self-anneal in the same manner as siRNA. The hairpin structure of the shRNA introduced into the cell is cleaved into siRNA and binds to the RNA-induced silencing complex (RISC). This complex binds to and cleaves mRNA with a sequence complementary to the siRNA, thereby suppressing gene expression in a sequence-specific manner.

[0019] miRNA (microRNA) is a functional nucleic acid that is encoded on the genome and undergoes a multi-step production process to ultimately become a small RNA of approximately 20 bases. miRNA is classified as a functional ncRNA (non-coding RNA: a general term for RNA that is not translated into protein) and plays an important role in life phenomena by regulating the expression of other genes. By administering miRNA with a specific base sequence to the living body, it is possible to inhibit the expression of SGLT2.

[0020] Ribozymes are RNAs with catalytic activity. Ribozymes have various activities, but research on ribozymes as enzymes that cleave RNA has made it possible to design ribozymes for site-specific cleavage of RNA. Ribozymes may be of 400 nucleotides or more in size, such as group I intron type and M1RNA contained in RNaseP, or may be of about 40 nucleotides in size, such as hammerhead type and hairpin type.

[0021] Antisense nucleic acid is a nucleic acid complementary to a target sequence. Antisense nucleic acid can inhibit the expression of a target gene by inhibiting transcription initiation by forming a triplex, inhibiting transcription by hybridizing with a site where an open loop structure is formed locally by RNA polymerase, inhibiting transcription by hybridizing with RNA in the process of synthesis, inhibiting splicing by hybridizing with an intron-exon junction, inhibiting splicing by hybridizing with a spliceosome formation site, inhibiting migration from the nucleus to the cytoplasm by hybridizing with mRNA, inhibiting splicing by hybridizing with a capping site or poly(A) addition site, inhibiting translation initiation by hybridizing with a translation initiation factor binding site, inhibiting translation by hybridizing with a ribosome binding site near the initiation codon, preventing peptide chain elongation by hybridizing with the translation region or polysome binding site of mRNA, inhibiting gene expression by hybridizing with a nucleic acid-protein interaction site, etc.

[0022] siRNA, shRNA, miRNA, ribozyme and antisense nucleic acid may contain various chemical modifications to improve stability and activity. For example, to prevent degradation by hydrolases such as nucleases, phosphate residues may be replaced with chemically modified phosphate residues such as phosphorothioate (PS), methylphosphonate, phosphorodithioate, etc. Also, at least a part of them may be composed of a nucleic acid analog such as peptide nucleic acid (PNA).

[0023] (SGLT2 specific binding substance) Examples of SGLT2-specific binding substances include substances that specifically bind to SGLT2 and inhibit the function of SGLT2, such as antibodies, antibody fragments, and aptamers. Antibodies can be produced, for example, by immunizing animals such as mice with the SGLT2 protein or a fragment thereof as an antigen. Alternatively, antibodies can be produced, for example, by screening a phage library. Examples of antibody fragments include Fv, Fab, and scFv. The antibody is preferably a monoclonal antibody. The antibody may also be a commercially available antibody. An aptamer is a substance that has a specific binding ability to a target substance. Examples of aptamers include nucleic acid aptamers and peptide aptamers. Nucleic acid aptamers that have a specific binding ability to a target peptide can be selected, for example, by the systematic evolution of ligand by exponential enrichment (SFLEX) method. In addition, it is possible to select a target peptide by screening a phage library. Peptide aptamers having specific binding ability to tides can be selected, for example, by the two-hybrid method using yeast.

[0024] (Acute heart failure) Acute heart failure is specifically defined in the "Guidelines for the Treatment of Acute and Chronic Heart Failure (2017 revised edition)" prepared by the Japanese Circulation Society, but in the present invention, patients with acute heart failure include both the first attack of heart failure and attacks caused by acute exacerbation of chronic heart failure. In addition, the target patients in the present invention are patients who have been switched from intravenous injection treatment to oral drug treatment for acute heart failure, and whose cardiorespiratory dynamics have stabilized and who are able to take oral medication. In addition, in the present invention, a patient to whom an SGLT2 inhibitor is administered may have diabetes mellitus, but is not limited to this.

[0025] (Improvement of fluid retention) In the present invention, the degree of fluid retention can be determined by the cardiothoracic ratio, the degree of pulmonary congestion and pleural effusion, and the degree of edema using chest X-ray. In particular, for the evaluation of respiratory failure, it is useful to determine the degree of fluid retention based on the degree of pulmonary congestion. In addition, in parallel with the improvement of pulmonary congestion, it is also useful to assess the degree of improvement in the patient's own dyspnea using, for example, the seven-point Likert scale, which expresses how the patient felt when asked about dyspnea by the attending physician with a score (markedly worse, moderately worse, mildly worse, no change, mildly improved, moderately improved, markedly improved).

[0026] Pharmaceutical Composition The present invention provides a pharmaceutical composition for improving fluid retention in acute heart failure, comprising an SGLT2 inhibitor and a pharma- ceutical acceptable carrier. By administering the pharmaceutical composition of this embodiment, fluid retention in acute heart failure can be improved.

[0027] The pharmaceutical composition of this embodiment may be formulated into a dosage form for oral use or a dosage form for parenteral use. For oral use, for example, tablets, capsules, elixirs, microcapsules, etc. For parenteral use, for example, injections, ointments, patches, etc.

[0028] As the pharmaceutically acceptable carrier, any one that is usually used in the manufacture of pharmaceutical compositions can be used without any particular limitation.Specific examples include, for example, binders such as gelatin, cornstarch, gum tragacanth, gum arabic, etc.; excipients such as starch and crystalline cellulose, swelling agents such as alginic acid, solvents for injections such as water, ethanol, and glycerin, and adhesives such as rubber-based adhesives and silicone-based adhesives.

[0029] The pharmaceutical composition may contain additives, such as lubricants such as calcium stearate and magnesium stearate, sweeteners such as sucrose, lactose, saccharin and maltitol, flavorings such as peppermint and saffron oil, stabilizers such as benzyl alcohol and phenol, buffers such as phosphates and sodium acetate, solubilizers such as benzyl benzoate and benzyl alcohol, antioxidants, and preservatives.

[0030] The pharmaceutical composition can be formulated by appropriately combining an SGLT2 inhibitor, a pharma- ceutically acceptable carrier, and optionally an additive, and mixing them in a unit dose form required for generally accepted pharmaceutical practice.

[0031] Subjects to which the SGLT2 inhibitor is administered include, but are not limited to, humans. Examples of such animals include animals such as monkeys, dogs, cows, horses, sheep, pigs, rabbits, mice, rats, guinea pigs, and hamsters, as well as cells thereof. Among these, mammals or mammalian cells are preferred, and humans or human cells are particularly preferred.

[0032] The dosage of the SGLT2 inhibitor varies depending on the specific subject, symptoms, body weight, age, sex, etc., and cannot be determined in general, but in the case of oral administration, for example, about 0.1 mg / kg to about 100 mg / kg body weight of the SGLT2 inhibitor may be administered per dosage unit to an adult. In addition, in the case of injection, for example, about 0.01 mg to about 50 mg of the SGLT2 inhibitor may be administered per dosage unit to an adult.

[0033] Furthermore, the daily dose of the SGLT2 inhibitor may be any amount effective for improving fluid retention, and varies depending on the specific subject to which it is administered, the subject's symptoms, body weight, age, sex, etc., and cannot be determined in general terms. For example, for adults, about 0.1 mg / kg to about 100 mg / kg of body weight of the SGLT2 inhibitor may be administered once a day or in divided doses about two to three times a day.

[0034] The SGLT2 inhibitor according to the present invention may be used in combination with at least one selected from the group consisting of fluid retention improving drugs other than SGLT2 inhibitors and therapeutic drugs for other diseases. The SGLT2 inhibitor and the other drug may be in the same formulation or in separate formulations. In addition, each formulation may be administered by the same administration route or by separate administration routes. Examples of the administration route include oral or injection. Furthermore, each formulation may be administered simultaneously, sequentially, or separately at a certain time or period. In one embodiment, the SGLT2 inhibitor and the other drug may be in a kit containing them. EXAMPLES

[0035] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples.

[0036] Example 1 Efficacy of canagliflozin in patients with decompensated heart failure Thirty-four patients with type 2 diabetes were hospitalized with decompensated heart failure and were administered 100 mg / day of canagliflozin for 7 days after initial treatment and stabilization of their condition. The dose of furosemide was adjusted appropriately during the canagliflozin treatment period. As a result of treatment with canagliflozin for 7 days, body weight was significantly reduced (mean body weight before treatment was started was 58.7 ± 14.4 kg, after 7 days it was 57.2 ± 14.4 kg, P < 0.001). As shown in Figure 1, urine volume increased after 1 day but returned to normal after 7 days. Dyspnea improved in most patients. The cardiothoracic ratio, pulmonary congestion, and pleural effusion were evaluated using chest X-rays the day before and 7 days after the start of canagliflozin administration. As a result, significant improvements were observed in all items, (a) cardiothoracic ratio, (b) pulmonary congestion, and (c) pleural effusion, as shown in Figure 2. The white bars in Figure 2 show the results the day before the start of administration, and the black bars show the results 7 days later.

[0037] From the above, it has been clarified that according to the present invention, administration of an SGLT2 inhibitor can improve fluid retention in the acute phase of heart failure. [Industrial Applicability]

[0038] The present invention provides a novel medicine that is effective and safe to use for improving fluid retention due to acute heart failure.

Claims

1. A drug that contains an SGLT2 inhibitor and improves fluid retention in acute heart failure.

2. The drug for improving body fluid retention according to claim 1, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, sotagliflozin, and pharma- ceutically acceptable salts thereof.

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