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WO2024185663A1 - Composition pour protéger le myocarde ou pour promouvoir la différenciation du myocarde - Google Patents

Composition pour protéger le myocarde ou pour promouvoir la différenciation du myocarde Download PDF

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Publication number
WO2024185663A1
WO2024185663A1 PCT/JP2024/007671 JP2024007671W WO2024185663A1 WO 2024185663 A1 WO2024185663 A1 WO 2024185663A1 JP 2024007671 W JP2024007671 W JP 2024007671W WO 2024185663 A1 WO2024185663 A1 WO 2024185663A1
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Prior art keywords
composition
poria
myocardial
herbal medicines
tang
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PCT/JP2024/007671
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English (en)
Japanese (ja)
Inventor
秀章 田頭
朋大 沼田
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Akita University NUC
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Akita University NUC
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Priority to JP2025505281A priority Critical patent/JPWO2024185663A1/ja
Publication of WO2024185663A1 publication Critical patent/WO2024185663A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This application relates to a composition for protecting myocardium or promoting myocardial differentiation.
  • the three leading causes of death in Japan are malignant tumors, cerebral infarction, and heart disease.
  • the number of patients with chronic heart failure is estimated to exceed one million, and this number is increasing with the aging population.
  • Cardiac hypertrophy is classified into two types: physiological cardiac hypertrophy caused by exercise or pregnancy, and pathological cardiac hypertrophy caused by high blood pressure or ischemia. In both cases, hypertrophy is induced by stress, but only pathological cardiac hypertrophy leads to a decline in cardiac function over time and progresses to heart failure.
  • the prognosis for patients with heart failure is poor, and there is a need for the development of better treatments to improve quality of life and reduce medical costs.
  • heart disease once heart disease has developed, it is impossible to cure it completely with current medical technology, so prevention is important.
  • drugs prescribed to prevent heart disease hypertension drugs, diabetes drugs
  • Non-Patent Document 1 reports that Pachymic Acid, one of the components of Poria cocos, is effective against doxorubicin-induced myocardial damage. However, this does not indicate a direct effect of Poria cocos on the myocardium.
  • the main objective of this disclosure is to provide a new active ingredient for heart disease.
  • This disclosure includes at least the following embodiments [1] to [5].
  • a composition for protecting myocardium or promoting myocardial differentiation comprising Poria cocos as an active ingredient.
  • the composition comprises one or more Poria-containing herbal medicines; The composition described in [1], wherein the one or more Poria-containing herbal medicines bring the Poria into the composition.
  • the composition includes Jumihetokuto, Hachimijiogan, Saikokaryukotsuoyaito, Hankakobokuto, Goreisan, Kohankakabukureito, Tokishakuyakusan, Kamishoyosan, and Katsura.
  • composition described in [1] for use in treating, alleviating, or preventing heart disease.
  • Poria cocos has myocardial protective effects and myocardial differentiation promoting effects.
  • the myocardial protective effects and myocardial differentiation promoting effects are effective for heart disease. Therefore, according to the present disclosure, it is possible to provide a new active ingredient for heart disease.
  • Poria cocoon 20 ⁇ g/mL
  • Ang II-induced cardiomyocyte hypertrophy and mitochondrial morphology and dysfunction were improved (cardiomyocyte staining with Mitotracker and ATP measurement).
  • the present disclosure provides a composition for myocardial protection or myocardial differentiation promotion, which contains Poria cocos as an active ingredient.
  • the composition of the present disclosure may be used solely for myocardial protection, or solely for myocardial differentiation promotion.
  • Poria is a common herbal ingredient contained in various herbal medicines.
  • Poria is contained in herbal medicines such as Hachimijiogan, Tokishakuyakusan, Keipibukuryogan, and Kamikihito.
  • herbal medicines containing Poria directly exhibit a myocardial protective effect via myocardial mitochondrial quality control. They have also identified Poria as the active ingredient.
  • the myocardial protective effect can prevent the onset of myocardial hypertrophy and heart failure, and is also thought to be effective against heart disease.
  • Poria cocos has the effect of promoting myocardial differentiation. This effect of promoting myocardial differentiation can be used not only to prevent heart disease, but also in regenerative treatment of failing myocardium. It can also be used to rapidly create myocardial sheets using pluripotent stem cells such as iPS cells.
  • Non-Patent Document 1 reports on the myocardial protective effect of a herbal medicine containing Poria cocoon, but does not report on the direct myocardial protective effect mentioned above. Furthermore, the myocardial differentiation promoting effect of Poria cocoon has never been reported for existing herbal medicines or herbal drug ingredients. Therefore, this disclosure provides a new active ingredient for heart disease. It also provides a new use for compositions using Poria cocoon for heart disease.
  • the composition disclosed herein can be used as a treatment or palliative for any cardiac disease, such as myocardial hypertrophy or heart failure.
  • Poria cocos is also an ingredient of herbal medicines and is extremely safe, making it applicable as a preventive drug for cardiac disease. It can also be used as a regenerative treatment for failing cardiac muscle. In addition, it can be used to rapidly prepare myocardial sheets.
  • the active ingredient Poria cocoon may be present as Poria cocoon itself, as a Poria cocoon extract, or as a combination of both.
  • the Poria cocoon extract can be obtained by a known method such as extracting Poria cocoon with water as a raw material.
  • Poria cocos is known to contain the following ingredients: Lecithin, Pachyman, Dehydroeburicoic acid, Eburicoic acid, Pachymic acid, Poricoic acid BM, Poricoic acid E, Poricoic acid F, Tumulosic acid, 25-Hydroxy-3-epidehydrotumulosic acid, 3-Epidehydropachymic acid, 3-Epidehydrotumulosic acid, 3-O-Acetyl-16 ⁇ -hydroxytrametenolic acid, 3- ⁇ -Hydroxylanosta-7,9,(11),24-trien-21-oic acid, Ergosterol, Histidine, Adenine, and Choline. Therefore, the composition of the present disclosure that contains Poria cocos as an active ingredient contains these ingredients, and contains all of the ingredients contained in Poria cocos or all of the ingredients contained in a Poria cocos extract.
  • composition disclosed herein is administered alone, preferably in the form of a formulation containing pharma- ceutical acceptable additives, to healthy individuals wishing to prevent heart disease, or to patients with or at risk of heart disease.
  • the composition may be administered orally, by injection, or by local administration such as inhalation.
  • the composition is dissolved in a culture medium before use.
  • Poria cocoon may be provided in the composition of the present disclosure from a herbal medicine containing Poria cocoon. That is, the composition of the present disclosure may include a herbal medicine containing Poria cocoon. In other words, Poria cocoon, which is an active ingredient in the composition of the present disclosure, may be present in the composition as one component of a herbal medicine containing Poria cocoon. In one embodiment, a formulation including the composition of the present disclosure may be administered to a patient as a herbal medicine containing Poria cocoon.
  • Examples of Chinese herbal medicines containing Bukurei include Jumihetokuto, Hachimijiogan, Saikokaryukotsuoyaito, Hankakobokuto, Goreisan, Kohankakabukureito, Tokishakuyakusan, Kamishoyosan, Keishibukuregan, Shinbuto, Hanka Hakushutenmato, Reigaijukanto, Ireito, Rikkunshito, Tsuritosan, Juzentaihoto, Sokeikakketsuto, Yokukansan, Gorinsan, Gosekisan, Kishoto, Sansoun, Fukureitan, Shikunshito, Nichento, Examples include Yokukansan Ka Chinpi Hange, Rokumi Gan, Erjutsu Tang, Seihai Tang, Chikuru Ondan Tang, Jiin Shiho Tang, Chaiboku Tang, Sanzao Ren Tang, Gosha Jinki Gan, Ninj
  • formulation ingredients may be used as appropriate.
  • Specific known formulation additives may be selected as appropriate according to the route of administration and the use of the formulation from among the ingredients listed in, for example, (1) Pharmaceutical Additives Handbook, Maruzen Co., Ltd. (1989), (2) Pharmaceutical Additives Dictionary, 1st Edition, Yakuji Nippo Co., Ltd. (1994), (3) Pharmaceutical Additives Dictionary Supplement, 1st Edition, Yakuji Nippo Co., Ltd. (1995), and (4) Pharmacology, Revised 5th Edition, Nanzando Co., Ltd. (1997).
  • the additives may be any formulation components that can be used to form an oral preparation and that can achieve the objectives of the present disclosure, but typically, known formulation components such as excipients, binders, disintegrants, lubricants, and coating agents are selected.
  • Specific oral preparations include tablets, capsules, granules, fine granules, powders, and syrups.
  • the oral preparations also include preparations (e.g., immediate release preparations, sustained release preparations) that use known formulation components to control the release of pharmaceutical compounds contained as active ingredients in the body.
  • enteric preparations also include enteric preparations, and in some cases enteric preparations are preferable.
  • enteric preparations include coated preparations and matrix preparations that use enteric coating agents such as cellulose phthalate, hydroxypropylmethylcellulose phthalate, and methyl methacrylate-methacrylic acid copolymers, as described below, as well as capsule preparations that contain such enteric coating agents in the shell.
  • Specific formulation ingredients used in the oral preparations include, but are not limited to, the following. 1) Examples of excipients: lactose, starch (including corn starch), crystalline cellulose, microcrystalline cellulose, crystalline cellulose-sodium caromellose, dextrin, sucrose, glucose, mannitol, calcium carbonate, calcium phosphate, calcium sulfate, calcium silicate, crospovidone, dried yeast, and soybean oil unsaponifiables.
  • excipients lactose, starch (including corn starch), crystalline cellulose, microcrystalline cellulose, crystalline cellulose-sodium caromellose, dextrin, sucrose, glucose, mannitol, calcium carbonate, calcium phosphate, calcium sulfate, calcium silicate, crospovidone, dried yeast, and soybean oil unsaponifiables.
  • binders hydroxypropyl cellulose (HPC), starch (including corn starch), gelatin, gum arabic, methylcellulose (MC), carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP), ethyl cellulose (EC), glucose and sucrose.
  • disintegrants starch (including corn starch), agar, gelatin, CMC-Na, CMC-Ca, crystalline cellulose, crystalline cellulose-caromellose sodium, low-substituted HPC, crospovidone, calcium carbonate, sodium bicarbonate.
  • lubricants magnesium stearate, hydrogenated vegetable oil, talc, macrogol, and light anhydrous silicic acid.
  • Examples of coating agents sucrose, HPC, shellac, gelatin, glycerin, sorbitol, EC, HPC, hydroxypropyl methylcellulose (HPMC), PVP, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid copolymer, titanium oxide.
  • the additives used are formulation components capable of forming an aqueous or non-aqueous injection, and generally include known formulation components such as solubilizers, solubilizers, suspending agents, buffers, stabilizers, and preservatives, but may also include known formulation components that form a powder injection to be dissolved or suspended at the time of administration.
  • dissolving agents for the above-mentioned injections include water for injection, physiological saline, Ringer's solution, vegetable oils (e.g., olive oil, sesame oil, soybean oil), ethanol, propylene glycol, polyethylene glycol, glycerin, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.
  • formulation components such as the solubilizing agent, suspending agent, buffer, stabilizer, and preservative of the above-mentioned injection include polyoxyethylene hydrogenated castor oil, ethylenediamine, benzyl alcohol, polysorbate 80, carmellose sodium, sodium hydroxide, sodium citrate, sodium acetate, potassium dihydrogen phosphate, sodium hydrogen sulfite, ascorbic acid, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, etc.
  • formulation components constituting the above-mentioned powder injection include glucose, sorbitol, etc.
  • Aerosols may be generated in any form, including a type in which the active pharmaceutical ingredient and a propellant such as a fluorocarbon alternative are filled in the same sealed container and sprayed, or a nebulizer or atomizer type that uses compressed gas such as carbon dioxide or nitrogen filled in a container separate from the active pharmaceutical ingredient.
  • formulation components such as propellants, solubilizers, stabilizers, buffers, suspending agents, emulsifiers, and preservatives of the above aerosol agents include chlorine-free fluorohydrocarbons [e.g., 1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227)], alcohol, propylene glycol, polyethylene glycol, polysorbate 80, glycerin, egg yolk lecithin, soybean lecithin, ⁇ -tocopherol, ascorbic acid, benzalkonium chloride, chlorobutanol, etc.
  • chlorine-free fluorohydrocarbons e.g., 1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227)
  • alcohol propylene glycol
  • polyethylene glycol polyethylene glycol
  • polysorbate 80
  • nebulizer or atomizer type water for injection, purified water, etc. can be used as a formulation ingredient.
  • inhalants in addition to the spray, nebulizer, and atomizer types using the above-mentioned propellants, it is also possible to use powder forms.
  • powder inhalants can take the same form as existing powder inhalants [e.g., Intal (registered trademark) capsules and their administration device Spinhaler (registered trademark); for administering sodium cromoglycate].
  • composition of the present disclosure can be administered locally in the form of ointments, patches, external liquid preparations, eye drops, nasal drops, suppositories, etc., in addition to the above-mentioned inhalants, and these locally administered preparations can use formulation ingredients listed in the above-mentioned Pharmaceutical Additives Handbook and Pharmaceutical Additives Encyclopedia, etc., as appropriate.
  • a manufacturing method known per se for example, a manufacturing method described in the 15th Edition of the Japanese Pharmacopoeia (JP XV) or a manufacturing method with appropriate modifications thereto, can be used.
  • composition of the present disclosure is administered to mammals, particularly humans, and the dosage, converted into the amount of Poria cocos, the active ingredient, is usually about 0.1 to 1,000 mg (per day) and preferably about 0.1 to 500 mg (per day) when used as an oral agent.
  • the dosage converted into the amount of Poria cocos, the active ingredient, is usually about 0.1 to 1,000 mg (per day) and preferably about 0.1 to 500 mg (per day) when used as an oral agent.
  • it is usually about 0.01 to 200 mg (per day) and preferably about 0.05 to 100 mg (per day).
  • topical agent it is usually about 0.01 to 200 mg (per day) and preferably about 0.05 to 100 mg (per day).
  • the route and optimal amount are determined taking into consideration the patient's condition (general condition, symptoms, presence or absence of complications, etc.), age, sex, weight, etc.
  • Cardiomyocytes were harvested from 1-3 day old neonatal Wistar rats using Pierce Cardiomyocyte Isolation Kit (Thermo Fisher Scientific, MA). Then, 100 nM Ang II was treated and cultured for 48 hours to induce pathological cardiomyocyte hypertrophy.
  • various test groups were treated with various herbal medicines or Poria cocos during Ang II treatment, the solvent group was treated with Ang II and DMSO, and the control group was treated with only DMSO (final DMSO concentration: 0.1%).
  • the cardiomyocytes were washed with PBS (pH 7.4) 48 hours after treatment with Ang II and various herbal medicines or Poria cocos, and then fixed with 4% formalaldehyde. After fixation, the cells were stained with Rhodamine-phalloidin reagent (ab235138, Abcam, UK) according to the Abcam protocol. After mounting, fluorescent images were obtained with a Fluorescence Microscope BZ-X800 (Keyence, Japan), and the cell area was measured with Image J. The number of cells measured was 100 or more for each group.
  • CMXRos MitoTracker Red CMXRos (M7512, Invitrogen, CA) according to the protocol of Invitrogen. After encapsulation, images were obtained using a confocal laser microscope (LSM980, Carl Zeiss Microscopy), and the mitochondrial length was measured using Image J. The number of cells measured was 5 or more for each group.
  • ⁇ Measurement of intracellular ATP amount> The amount of ATP in the cardiomyocytes was measured using an ATP assay kit (Wako, Japan) according to the protocol of Wako Co., Ltd. Luminescence was measured using Lumitester C-110 (Kikkoman Biochemifa, Japan).
  • Real-time PCR was then performed using a LightCycler® 480 real-time PCR system (Roche Diagnostics Ltd., Switzerland).
  • Various primers were used according to previously published literature (see Non-Patent Document 2 for Nkx2.5, Non-Patent Document 3 for TBX5, and Non-Patent Document 4 for HAND1).
  • Hachimijiogan, Tokishakuyakusan, Keipibukuryogan, Mokubokito, Shakuyakukanzoto and Kamikihito have a small cell surface area and were found to inhibit myocardial cell hypertrophy.
  • Hachimijiogan, Tokishakuyakusan, Keipibukuryogan and Kamikihito contain Fuling as a herbal ingredient. Therefore, of these Kampo medicines, Tokishakuyakusan, Keipibukuryogan and Kamikihito were selected as hit Kampo medicines and the following test was carried out.
  • the Poria cocos treatment group had a smaller cell surface area and suppressed myocardial cell hypertrophy.
  • the Poria cocos treatment group suppressed mitochondrial fragmentation and had sufficient ATP production.

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Abstract

L'invention concerne un nouveau principe actif contre les maladies cardiaques.　Plus spécifiquement, l'invention concerne une composition pour protéger le myocarde ou pour promouvoir la différenciation du myocarde, laquelle composition contient Poria Cocos Wolf en tant que principe actif.
PCT/JP2024/007671 2023-03-03 2024-03-01 Composition pour protéger le myocarde ou pour promouvoir la différenciation du myocarde Pending WO2024185663A1 (fr)

Priority Applications (1)

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JP2025505281A JPWO2024185663A1 (fr) 2023-03-03 2024-03-01

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JP2023-032884 2023-03-03
JP2023032884 2023-03-03

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020160059A1 (en) * 2000-09-13 2002-10-31 Wei Xiao Cinnamomi and poria composition, method to prepare same and uses thereof
CN110604782A (zh) * 2019-09-17 2019-12-24 江苏医盟健康科技有限公司 一种治疗心脏病的药物及其制备方法
CN114887024A (zh) * 2022-05-05 2022-08-12 南京晓庄学院 一种治疗冠心病的中药组合物及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020160059A1 (en) * 2000-09-13 2002-10-31 Wei Xiao Cinnamomi and poria composition, method to prepare same and uses thereof
CN110604782A (zh) * 2019-09-17 2019-12-24 江苏医盟健康科技有限公司 一种治疗心脏病的药物及其制备方法
CN114887024A (zh) * 2022-05-05 2022-08-12 南京晓庄学院 一种治疗冠心病的中药组合物及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI FANG-FANG, YUAN YUAN, LIU YUAN, WU QING-QING, JIAO RONG, YANG ZHENG, ZHOU MENG-QIAO, TANG QI-ZHU: "Pachymic acid protects H9c2 cardiomyocytes from lipopolysaccharide-induced inflammation and apoptosis by inhibiting the extracellular signal-regulated kinase 1/2 and p38 pathways", MOLECULAR MEDICINE REPORTS, SPANDIDOS PUBLICATIONS, GR, vol. 12, no. 2, 1 August 2015 (2015-08-01), GR , pages 2807 - 2813, XP093208162, ISSN: 1791-2997, DOI: 10.3892/mmr.2015.3712 *
YOUNIS NAHLA N., SALAMA ALAA, SHAHEEN MOHAMED A., EISSA RANA G.: "Pachymic Acid Attenuated Doxorubicin-Induced Heart Failure by Suppressing miR-24 and Preserving Cardiac Junctophilin-2 in Rats", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL (MDPI), BASEL, CH, vol. 22, no. 19, 2 October 2021 (2021-10-02), Basel, CH , pages 10710, XP093208151, ISSN: 1422-0067, DOI: 10.3390/ijms221910710 *

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