WO2022158591A1 - 肥大型心筋症治療剤 - Google Patents

肥大型心筋症治療剤 Download PDF

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WO2022158591A1
WO2022158591A1 PCT/JP2022/002413 JP2022002413W WO2022158591A1 WO 2022158591 A1 WO2022158591 A1 WO 2022158591A1 JP 2022002413 W JP2022002413 W JP 2022002413W WO 2022158591 A1 WO2022158591 A1 WO 2022158591A1
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aminolevulinic acid
hypertrophic cardiomyopathy
ester
salt
left ventricular
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English (en)
French (fr)
Japanese (ja)
Inventor
康司 岡崎
敦子 岡崎
治 美野輪
秀雄 早乙女
由紀子 八塚
勝晴 土田
紀子 市野
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Juntendo Educational Foundation
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Juntendo Educational Foundation
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Priority to JP2022576771A priority Critical patent/JPWO2022158591A1/ja
Priority to EP22742710.1A priority patent/EP4309651A4/en
Priority to CN202280011367.6A priority patent/CN116829138A/zh
Priority to US18/262,840 priority patent/US20240082189A1/en
Publication of WO2022158591A1 publication Critical patent/WO2022158591A1/ja
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the present invention relates to a therapeutic agent for hypertrophic cardiomyopathy.
  • Hypertrophic cardiomyopathy is defined as "a group of diseases characterized by (1) hypertrophy of the left ventricular or right ventricular myocardium and (2) decreased left ventricular diastolic function due to cardiac hypertrophy", and is designated as an intractable disease. It is a disease (designated intractable disease 58) (Non-Patent Document 1). Hypertrophic cardiomyopathy is classified into obstructive cardiomyopathy that causes left ventricular outflow tract obstruction and non-obstructive cardiomyopathy that does not cause left ventricular outflow tract obstruction. Many have an autosomal dominant family history.
  • Non-Patent Document 1 a maximum left ventricular wall thickness of 15 mm or greater (13 mm or greater if there is a family history of hypertrophic cardiomyopathy) on echocardiography or cardiac MRI.
  • hypertrophic cardiomyopathy the left ventricular filling pressure increases even in the early stages when the left ventricular systolic function is normal and the left ventricular diameter is normal (or shrinking), and the left ventricular relaxation and extensibility are impaired.
  • 5-aminolevulinic acid is a starting material in the porphyrin synthesis pathway, and as a photosensitizer, it is used for photodynamic therapy (treatment of actinic keratosis, acne, skin cancer, etc.), photodynamic diagnosis ( Intraoperative diagnosis of brain tumors, transurethral resection of bladder tumors, etc.) and is also used as a plant growth promoter.
  • photodynamic therapy treatment of actinic keratosis, acne, skin cancer, etc.
  • photodynamic diagnosis Intraoperative diagnosis of brain tumors, transurethral resection of bladder tumors, etc.
  • 5-aminolevulinic acid can be used in combination with an iron compound as a hair restorer (Patent Document 1), enzyme-enhanced therapy for mitochondrial diseases (Non-Patent Document 2), and the like.
  • 5-aminolevulinic acid has been reported to have the effect of increasing the amount of succinyl-CoA in myocardial cells in an animal model of acute
  • An object of the present invention is to provide a new therapeutic agent for hypertrophic cardiomyopathy.
  • the present inventors have used iPS cell-derived cardiomyocytes from patients with hypertrophic cardiomyopathy to search for drugs that affect the rate of myocardial relaxation, which is an index of left ventricular diastolic function.
  • the present invention was completed based on the discovery that it exhibits a relaxation rate improving action and further improves left ventricular diastolic function.
  • the present invention provides the following inventions [1] to [24].
  • a therapeutic agent for hypertrophic cardiomyopathy comprising 5-aminolevulinic acid, its ester, or a salt thereof as an active ingredient.
  • An agent for improving left ventricular diastolic function in hypertrophic cardiomyopathy comprising 5-aminolevulinic acid, its ester, or a salt thereof as an active ingredient.
  • a myocardial relaxation rate improving agent for hypertrophic cardiomyopathy comprising 5-aminolevulinic acid, an ester thereof, or a salt thereof as an active ingredient.
  • a therapeutic agent for hypertrophic cardiomyopathy containing 5-aminolevulinic acid, its ester or salt thereof and an iron compound.
  • a myocardial relaxation rate improving agent for hypertrophic cardiomyopathy containing 5-aminolevulinic acid, its ester or salt thereof and an iron compound.
  • a myocardial relaxation rate improving agent for hypertrophic cardiomyopathy which is 5-aminolevulinic acid, an ester thereof, or a salt thereof.
  • a myocardial relaxation rate improving agent for hypertrophic cardiomyopathy which is 5-aminolevulinic acid, an ester thereof, or a salt thereof.
  • 5-aminolevulinic acid, its ester, or a salt thereof which is used for treating hypertrophic cardiomyopathy.
  • 5-aminolevulinic acid, an ester thereof, or a salt thereof which is used for improving left ventricular diastolic function in hypertrophic cardiomyopathy.
  • a combination of 5-aminolevulinic acid, an ester thereof or a salt thereof and an iron compound for use in treating hypertrophic cardiomyopathy [17] A combination of 5-aminolevulinic acid, an ester thereof, or a salt thereof and an iron compound, which is used for improving left ventricular diastolic function in hypertrophic cardiomyopathy. [18] A combination of 5-aminolevulinic acid, an ester thereof or a salt thereof and an iron compound for improving the rate of myocardial relaxation in hypertrophic cardiomyopathy. [19] A method for treating hypertrophic cardiomyopathy, which comprises administering an effective amount of 5-aminolevulinic acid, an ester thereof, or a salt thereof.
  • a method for improving left ventricular diastolic function in hypertrophic cardiomyopathy which comprises administering an effective amount of 5-aminolevulinic acid, its ester, or a salt thereof.
  • a method for improving the rate of myocardial relaxation in hypertrophic cardiomyopathy which comprises administering an effective amount of 5-aminolevulinic acid, an ester thereof, or a salt thereof.
  • a method for treating hypertrophic cardiomyopathy which comprises administering 5-aminolevulinic acid, its ester, or a salt thereof in combination with an iron compound.
  • a method for improving left ventricular diastolic function in hypertrophic cardiomyopathy which comprises administering 5-aminolevulinic acid, an ester thereof, or a salt thereof and an iron compound in combination.
  • a method for improving the rate of myocardial relaxation in hypertrophic cardiomyopathy which comprises administering 5-aminolevulinic acid, an ester thereof, or a salt thereof and an iron compound in combination.
  • 5-aminolevulinic acid improves the rate of myocardial relaxation, which is an index of left ventricular diastolic function in hypertrophic cardiomyopathy, and improves essential left ventricular diastolic function symptoms in hypertrophic cardiomyopathy. It becomes possible to treat hypertrophic cardiomyopathy.
  • Fig. 2 shows the rate of myocardial relaxation in iPS cell-derived cardiomyocytes from patients with hypertrophic cardiomyopathy and the effect of 5-aminolevulinic acid on the rate of relaxation.
  • Fig. 2 shows myocardial relaxation rate in normal controls (normal cardiomyocytes) and the effect of 5-aminolevulinic acid on the relaxation rate.
  • Fig. 2 shows a comparison of relaxation rates in iPS cell-derived cardiomyocytes from patients with hypertrophic cardiomyopathy and normal cardiomyocytes.
  • the active ingredient of the therapeutic agent for hypertrophic cardiomyopathy of the present invention is 5-aminolevulinic acid, its ester or salt thereof.
  • 5-Aminolevulinic acid, esters thereof, and salts thereof (hereinafter collectively referred to as 5-aminolevulinic acids) are known, for example, as described in Patent Document 1.
  • the relaxation rate improving action of 5-aminolevulinic acids on hypertrophic cardiomyopathy is not known at all.
  • Examples of 5-aminolevulinic acid esters include straight-chain, branched-chain or cyclic C 1-24 groups optionally having substituents such as hydroxy group, alkoxy group, phenyl group, benzyl group and hydroxymethyl group.
  • Alkyl esters of Specific examples of 5-aminolevulinic acid esters include 5-aminolevulinic acid methyl ester, 5-aminolevulinic acid ethyl ester, 5-aminolevulinic acid isopropyl ester, 5-aminolevulinic acid hexyl ester, 5-aminolevulinic acid cyclohexyl ester, and 5-aminolevulinic acid.
  • heptyl ester 5-aminolevulinic acid octyl ester, 5-aminolevulinic acid nonyl ester, 5-aminolevulinic acid dodecyl ester, 5-aminolevulinic acid hexadecyl ester, 5-aminolevulinic acid benzyl ester, 5-aminolevulinic acid phenethyl ester, 5-aminolevulinic acid phenylpropyl ester, 5-aminolevulinic acid hydroxyethyl ester, 5-aminolevulinic acid ethoxyethyl ester and the like.
  • Salt forms of 5-aminolevulinic acid or esters thereof include inorganic acid salts such as phosphate, hydrochloride, nitrate, sulfate; acetate, propionate, butyrate, valerate, citrate, Organic acid salts such as fumarate, maleate, malate, succinate, oxalate, lactate, tartrate, glycolate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts and the like.
  • inorganic acid salts such as phosphate, hydrochloride, nitrate, sulfate; acetate, propionate, butyrate, valerate, citrate, Organic acid salts such as fumarate, maleate, malate, succinate, oxalate, lactate, tartrate, glycolate
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts and the like alkaline earth metal salts and the like.
  • 5-Aminolevulinic acids have the effect of significantly improving the myocardial relaxation rate, which is an index of left ventricular diastolic function, using cardiomyocytes derived from iPS cells of patients with hypertrophic cardiomyopathy, as shown in the Examples below.
  • 5-aminolevulinic acid improves the rate of myocardial relaxation by improving the function of Ca 2+ uptake into the sarcoplasmic reticulum.
  • 5-aminolevulinic acid improves left ventricular diastolic function in vivo.
  • 5-aminolevulinic acids are useful as agents for improving the rate of myocardial relaxation in hypertrophic cardiomyopathy, agents for improving left ventricular diastolic function in hypertrophic cardiomyopathy, and agents for treating hypertrophic cardiomyopathy.
  • 5-Aminolevulinic acids can be used alone as a therapeutic agent for hypertrophic cardiomyopathy, but from the viewpoint of supplementing iron compounds present in the body and further enhancing the action and effect, 5-aminolevulinic acids and iron compounds are used. It is preferable to use them in combination.
  • iron compounds include iron complexes and iron salts.
  • iron complexes include heme iron, dextran iron, ferric sodium diethylenetriaminepentaacetate, ferric ammonium diethylenetriaminepentaacetate, ferric sodium ethylenediaminetetraacetate, ferric ammonium ethylenediaminetetraacetate, triethylenetetraamine ferric, ferric sodium dicarboxymethylglutamate, and the like. are mentioned.
  • iron salt examples include one or more selected from organic acid iron salts and inorganic acid iron salts.
  • specific examples of iron salts include ferrous citrate, sodium iron citrate, ammonium iron citrate, iron acetate, iron oxalate, ferrous succinate, sodium iron citrate succinate, ferrous pyrophosphate, Ferric pyrophosphate, iron lactate, ferrous gluconate, ferrous formate, ferric formate, potassium ferric ammonium oxalate, ferrous sulfate, ferric sulfate, ferric ammonium sulfate, ferric carbonate iron, ferrous chloride, ferric chloride and the like.
  • the content of the iron compound is not particularly limited, but is preferably 0.01 part by mass to 1 part by mass, more preferably 0.05 part by mass to 1 part by mass, and 0.1 More preferably 1 part by mass to 1 part by mass.
  • the administration route of the therapeutic agent of the present invention can be selected from systemic administration, local administration, oral route, and parenteral route, depending on the disease, symptoms, etc., and depending on the administration method and route, suitable agents Oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or injections (e.g., intravenous injection, intramuscular injection, etc.), suppositories, transdermal agents, intranasal agents, Parenteral administration in forms such as inhalants can be selected.
  • Therapeutic agents for oral administration according to the present invention include solid formulations such as tablets, capsules, powders, and granules. Such formulations are produced by conventional methods by mixing excipients, lubricants, disintegrants, solubilizers and the like with the active ingredient.
  • Excipients include, for example, milk sugar (lactose), cellulose, mannitol, glucose and the like.
  • Lubricants can be, for example, magnesium stearate.
  • Disintegrants include, for example, carboxymethyl starch sodium, polyvinylpyrrolidone, croscarmellose sodium and the like. Tablets or pills may optionally be coated with sugar or gastric or enteric coatings.
  • a therapeutic agent for oral administration may be a liquid preparation such as a pharmacologically acceptable extract, emulsion, solution, suspension, syrup, spirit, or elixir.
  • a liquid preparation such as a pharmacologically acceptable extract, emulsion, solution, suspension, syrup, spirit, or elixir.
  • Such formulations contain commonly used inert solvents (e.g., purified water, ethanol, etc.), as well as solubilizers, wetting agents, suspending agents, sweetening agents, flavoring agents, flavoring agents, Buffers (eg, sodium citrate, etc.), stabilizers or preservatives may be included.
  • Therapeutic agents for parenteral administration include injections such as sterile aqueous or non-aqueous solutions, suspensions, or emulsions, ointments and lotions, sublingual agents for oral administration, oral patches, and intranasal agents. Aerosols or suppositories for administration are included. In the case of an injection, it can be administered by usual intravenous administration, intraarterial administration, subcutaneous, intradermal, intramuscular injection, or the like.
  • Aqueous solvents for injection include, for example, distilled water and physiological saline.
  • Non-aqueous solvents for injections include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (pharmacopoeial name). These formulations may further contain tonicity agents (e.g., sodium chloride, glucose, etc.), preservatives, wetting agents, emulsifiers, dispersing agents, stabilizers, pH adjusters (e.g., sodium citrate, sodium acetate, phosphoric acid, etc.). sodium, etc.), buffering agents, local anesthetics (eg, procaine hydrochloride, lidocaine hydrochloride, etc.) or solubilizing agents. These formulations may be sterilized by, for example, filtration through a bacteria-retaining filter, formulation with sterilizing agents, or irradiation.
  • tonicity agents e.g., sodium chloride, glucose, etc.
  • preservatives e.g., wetting agents, emulsifiers
  • the dosage of the therapeutic agent of the present invention varies depending on the route of administration, symptoms, age, etc., it is generally preferable that the amount of 5-aminolevulinic acid for adults is 10 mg to 1 g per day.
  • Example 1 Hypertrophic Cardiomyopathy Patient iPS Cell-Derived Cardiomyocytes Cardiomyocytes differentiated from hypertrophic cardiomyopathy patient-derived iPS cells were purchased, seeded, cultured, and then 5-aminolevulinic acid/sodium ferrous citrate (ALA/ SFC) was administered. 4M Mycell Cardiomyocytes (MYH7 R403Q) (C1081, cat# 556-3478I) (Cellular Dynamics) was used as cardiomyocytes. As a control, cardiomyocytes derived from iPS cells derived from normal subjects (Cell Cardiomyocytes (Control) (C1056, cat #551-33491) (Cellular Dynamics) were used.
  • Cell Cardiomyocytes Control
  • C1056, cat #551-33491 Cellular Dynamics
  • iCell Plating medium M1001, cat #550- 33581 (Cellular Dynamics) was used.
  • iCell Maintenance medium M1003, cat #557-3359I (Cellular Dynamics) was used as a culture medium.
  • the dosages were ALA/SFC 0 ⁇ M/0 ⁇ M, 10 ⁇ M/5 ⁇ M, 30 ⁇ M/1 ⁇ M, and 100 ⁇ M/50 ⁇ M for diseased cardiomyocytes and normal cardiomyocytes, respectively.
  • the drug was dissolved in iCell Maintenance medium (M1003), adjusted to the above concentration, and then administered by replacing the culture medium in each well with these.
  • the relaxation rate measurement was performed three times in total, including before the administration on the 15th day and two more times after the administration as follows.
  • Day 18 Second administration of ALA/SFC
  • Day 20 After the first relaxation rate after administration was measured using SONY SI8000, the third administration of ALA/SFC was carried out on the same day.
  • Day 22 The fourth administration of ALA/SFC was performed.
  • Day 24 The fifth administration of ALA/SFC was performed.
  • Day 26 The second relaxation rate after administration was measured using SONY SI8000.
  • FIG. 1 shows the myocardial relaxation rate in hypertrophic cardiomyopathy patient iPS cell-derived cardiomyocytes and the effect of 5-aminolevulinic acid on the relaxation rate. From FIG. 1, the relaxation rate of hypertrophic cardiomyopathy was 2.3 ⁇ 0.6 ⁇ M ⁇ standard deviation), which was significantly lower than that of normal cardiomyocytes. In contrast to this decrease in relaxation rate, the addition of 5-aminolevulinic acid markedly increased the relaxation rate of hypertrophic cardiomyopathy cardiomyocytes.
  • FIG. 2 also shows the myocardial relaxation rate in normal myocardial cells (normal myocardial control) and the effect of 5-aminolevulinic acid on the relaxation rate. From FIG.
  • the relaxation rate of hypertrophic cardiomyopathy cardiomyocytes was 4.4 ⁇ 0.6 ⁇ M/sec (mean value ⁇ standard deviation). did not increase significantly.
  • a comparison of relaxation rates in both cells is shown in FIG. Therefore, it was found that 5-aminolevulinic acids ameliorate the decrease in myocardial relaxation rate in hypertrophic cardiomyopathy and improve myocardial diastolic function.
  • HCM hypertrophic cardiomyopathy
  • iPS Cell-induced cardiomyocytes as a hypertrophic cardiomyopathy (HCM) model, and cardiomyocytes induced from hypertrophic cardiomyopathy patient-derived iPS Cells (obtained from CDI Co.) were seeded in a 96-well plate under the following conditions. .
  • the cell density was 3 ⁇ 10 4 /well. ⁇ The medium for seeding is CDI co.
  • iPs Cardiomyocyte Plating Medium IPMM; M1001, cat#550-33581) (Cellular Dynamics) was used, and iPs Cardiomyocyte Maintenance Medium (ICMM; M1003, cat#517-3359) was used for long-term culture. microliter/well).
  • a fluorescence waveform was obtained by sequentially digitizing the fluorescence intensity over the entire screen of the obtained image data. Waveform analysis was performed on these numerical data using Webfinder, which is waveform analysis software. Parameters calculated from the waveforms are the line width (sec) at each 10%, 20%, 30%, 50%, 70%, 90% of the height of the waveform (sec), the length of the interval between angular waves (sec) and the fluorescence intensity ( ⁇ F). Results are shown in FIG. As is clear from FIG. 4, the addition of 5-aminolevulinic acid clearly decreased the peak width at 50% of the waveform height, demonstrating that the Ca 2+ uptake function into the sarcoplasmic reticulum was improved.
  • Example 3 The effect of 5-aminolevulinic acid on zebrafish cardiomyopathy model was investigated.
  • zebrafish cardiomyopathy model cardiac troponin T knockdown (tnnt2a KD)
  • the target sequence of tnnt2a-MO used to prepare this cardiomyopathy model is 5′-CATGTTTGCTCTGATCTGACACGCA-3′ (SEQ ID NO: 1), and the target sequence of Standard control MO (Control-MO) used as a negative control is 5.
  • a glass needle prepared by processing a glass capillary (GD-1, Narishige) using a puller (PC-100, Narishige) was filled with a working solution of MO, and a DNA injection set (IM-400, 0.2LE-8SBZN , MMO-220C, M-152, GJ-1, IP, Narishige).
  • IM-400, 0.2LE-8SBZN , MMO-220C, M-152, GJ-1, IP, Narishige a DNA injection set
  • RIKEN-WT were naturally mated, fertilized eggs were obtained from the same parent, and approximately 3 nL of working solution was injected per 1-4 cell stage fertilized egg. After microinjection, the fertilized eggs were transferred to a 10 cm petri dish (Aznol sterile petri dish) and grown in an incubator set at 28° C. using standard breeding solution E2 Medium.
  • DAY 3 Under non-anaesthesia, the individual was mounted on a 3 cm glass bottom dish (Greiner) using 1% low-melting point agarose gel, and bright field was observed using a 20x objective lens mounted on an inverted microscope CKX53 (Olympus). Cardiac imaging was performed and movies were acquired.

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PCT/JP2022/002413 2021-01-25 2022-01-24 肥大型心筋症治療剤 Ceased WO2022158591A1 (ja)

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JP2022576771A JPWO2022158591A1 (enExample) 2021-01-25 2022-01-24
EP22742710.1A EP4309651A4 (en) 2021-01-25 2022-01-24 THERAPEUTIC AGENT FOR HYPERTROPHIC CARDIOMYOPATHY
CN202280011367.6A CN116829138A (zh) 2021-01-25 2022-01-24 肥厚型心肌病治疗剂
US18/262,840 US20240082189A1 (en) 2021-01-25 2022-01-24 Therapeutic agent for hypertrophic cardiomyopathy

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WO2005105022A1 (ja) 2004-04-28 2005-11-10 Yoshiyasu Ito 育毛剤
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JP2011016753A (ja) * 2009-07-08 2011-01-27 Sbi Alapromo Co Ltd ５−アミノレブリン酸若しくはその誘導体、又はそれらの塩を有効成分とするがんの予防・改善剤
WO2020059242A1 (ja) 2018-09-20 2020-03-26 国立大学法人北海道大学 心不全の病態の評価方法

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WO2005105022A1 (ja) 2004-04-28 2005-11-10 Yoshiyasu Ito 育毛剤
JP2008255059A (ja) * 2007-04-05 2008-10-23 Cosmo Oil Co Ltd ミトコンドリア障害脳疾患治療剤及び診断剤
JP2011016753A (ja) * 2009-07-08 2011-01-27 Sbi Alapromo Co Ltd ５−アミノレブリン酸若しくはその誘導体、又はそれらの塩を有効成分とするがんの予防・改善剤
WO2020059242A1 (ja) 2018-09-20 2020-03-26 国立大学法人北海道大学 心不全の病態の評価方法

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"Guideline on Diagnosis and Treatment of Cardiomyopathies", 2018, THE JAPANESE CIRCULATION SOCIETY
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ONO, KOH ET AL.: "Chronic Disease Treatment Manual, I. Cardiovascular Disease, 7. Myocardial Disease ", SOGO RINSHO - CLINIC ALL-ROUND, NAGAI SHOTEN, OSAKA,, JP, vol. 46, no. 5, 1 May 1997 (1997-05-01), JP , pages 844 - 849, XP009538406, ISSN: 0371-1900 *
SCIENTIFIC REPORTS, vol. 9, 2019, pages 10549
See also references of EP4309651A4

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