WO2020077819A1 - 白头翁皂苷b4抗急性痛风性关节炎的医药用途 - Google Patents

白头翁皂苷b4抗急性痛风性关节炎的医药用途 Download PDF

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WO2020077819A1
WO2020077819A1 PCT/CN2018/122655 CN2018122655W WO2020077819A1 WO 2020077819 A1 WO2020077819 A1 WO 2020077819A1 CN 2018122655 W CN2018122655 W CN 2018122655W WO 2020077819 A1 WO2020077819 A1 WO 2020077819A1
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injection
gouty arthritis
need
use according
pulsatilla saponin
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PCT/CN2018/122655
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French (fr)
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刘琦
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刘琦
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Priority to JP2021521151A priority Critical patent/JP7335954B2/ja
Priority to AU2018446089A priority patent/AU2018446089B2/en
Priority to EP18937215.4A priority patent/EP3868383A4/en
Priority to US17/286,803 priority patent/US20210338700A1/en
Priority to CA3116793A priority patent/CA3116793C/en
Publication of WO2020077819A1 publication Critical patent/WO2020077819A1/zh

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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions

  • the invention belongs to the field of medicine, and specifically relates to the new medical application of Pulsatilla saponin B4.
  • Gout is a group of diseases caused by long-term purine metabolism disorder and increased blood uric acid causing tissue damage.
  • Acute gouty arthritis is a characteristic symptom of gout. It is a characteristic acute inflammatory reaction caused by urate crystals depositing on joints (especially ankle and foot joints) and surrounding connective tissues. It often occurs suddenly at night, and the patient can wake up due to pain and cannot sleep through the night. Acute gouty arthritis often recurs. Over time, it can develop into polyarthritis, or migratory arthritis. The affected joints are red, swollen, hot, painful, and have limited activity, which seriously affects the patient's quality of life.
  • gout In China, with the continuous improvement of people's living standards and the high intake of high purine, high protein, and high fat, gout not only increases rapidly, but also gradually reduces the age of the sick, and there are teenagers with gout. It is predicted that gout will become a metabolic disease second only to diabetes in China in the next 10 years.
  • non-steroidal anti-inflammatory drugs such as diclofenac sodium, etc.
  • colchicine a non-steroidal anti-inflammatory drug
  • glucocorticoids a drug that has achieved certain clinical effects, the accompanying side effects and adverse reactions are inevitable, such as the gastrointestinal reactions of traditional non-steroidal anti-inflammatory drugs, the cardiovascular system of COX-2 inhibitors Adverse reactions, myelosuppression of colchicine, liver injury, allergies and neurotoxicity, glucocorticoid "withdrawal". Therefore, the exploration of new drugs for the treatment of acute gouty arthritis has become a hot topic in the medical community.
  • Pulsatilla is the dried root of Pulsatilla (Pulsatilla chinensis (Bge.) Regel) in the Ranunculaceae Pulsatilla, which was originally published in the Shennong Materia Medica. Its sexual taste is bitter and cold, with the functions of clearing away heat and detoxification, cooling blood to stop dysentery, dryness and killing insects. It is used to treat heat and blood dysentery, warm malaria and cold fever, epistaxis, blood hemorrhoids. After modern pharmacological studies, it has been found that Pulsatilla has more diverse activities, such as broad-spectrum antibacterial activity, anti-tumor, anti-inflammatory, and enhancing the body's immune function.
  • Pulsatilla has rich triterpenoid saponins.
  • Pulsatilla saponin B4 belongs to the lupin type pentacyclic triterpene saponin, and its structural formula is shown in 1.
  • Pulsatilla saponin B4 has strong activity.
  • the Chinese invention patent application of publication number CN105213410A (Publication Date: January 6, 2016) discloses the application of Pulsatilla saponin B4 as an immunomodulator in the treatment of acute inflammation drugs. Including acute kidney injury, acute liver injury and acute lung injury due to overexpression of inflammatory factors.
  • Another example is the Chinese invention patent application with publication number CN105535004A (publication date May 4, 2016), which discloses the application of the compound as an EV71 virus inhibitor in the preparation of anti-hand-foot-mouth disease drugs. But so far, no report of Pulsatilla saponin B4 for the treatment of acute gouty arthritis.
  • the present invention provides a new medical application of Pulsatilla saponin B4 in the treatment of acute gouty arthritis.
  • Pulsatilla saponin B4 in preparing medicine for treating acute gouty arthritis.
  • the present invention provides the use of Pulsatilla saponin B4 as the only active ingredient in the preparation of a medicament for treating acute gouty arthritis.
  • the present invention provides the use of Pulsatilla saponin B4 together with other active ingredients in the preparation of a medicament for treating acute gouty arthritis; wherein the other active ingredients are selected from non-steroidal anti-inflammatory drugs, autumn One or more of narcisine and glucocorticoid.
  • non-steroidal anti-inflammatory drugs include but are not limited to ibuprofen, indomethacin, nimesulide, naproxen, naproxen, diclofenac sodium, loxoprofen sodium, rofecoxib, celec Xibu and Etocoxi etc.
  • the glucocorticoids include but are not limited to prednisone, prednisone, betamethasone, beclomethasone propionate, depot, prednisolone, hydrocortisone, dexamethasone, and the like.
  • the non-oral preparation is selected from one or more of injections, rectal preparations, and pulmonary administration preparations; more preferably, one or more of injections and rectal preparations.
  • the formulation for rectal administration is selected from rectal suppositories and / rectal infusions.
  • the pharmaceutically acceptable auxiliary materials of the present invention include, but are not limited to (1) diluents, such as starch, powdered sugar, dextrin, lactose, pregelatinized starch, microcrystalline fiber, inorganic calcium salts (such as calcium sulfate, phosphoric acid Calcium hydrogen, medicinal calcium carbonate, etc.), mannitol, vegetable oil, polyethylene glycol, cocoa butter, semi-synthetic or fully synthetic fatty acid glycerides, glycerin gelatin, etc .; (2) binders, such as distilled water, ethanol, Starch slurry, povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose, hypromellose, etc .; (3) disintegrants, such as dry starch, carboxymethyl Sodium starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, crospovidone, etc
  • the method for treating acute gouty arthritis includes the step of administering Pulsatilla saponin B4 to patients in need by subcutaneous injection, intramuscular injection or intravenous injection.
  • the patient in need is a mammal in need, more preferably a human in need.
  • Pulsatilla saponin B4 can significantly relieve joint swelling caused by acute gouty arthritis. Therefore, Pulsatilla saponin B4 injection is expected to provide new options for clinical treatment of acute gouty arthritis.

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  • Chemical Kinetics & Catalysis (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
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Abstract

白头翁皂苷B4在制备治疗急性痛风性关节炎的药物中的用途。

Description

白头翁皂苷B4抗急性痛风性关节炎的医药用途
相关申请的交叉引用
本申请要求2018年10月18日递交的申请号为201811214694.3，名称为“白头翁皂苷B4抗急性痛风性关节炎的医药用途”的中国专利申请的权益，在此将其全部内容引入作为参考。
技术领域
本发明属于医药领域，具体涉及白头翁皂苷B4的医药新用途。
背景技术
痛风是长期嘌呤代谢障碍，血尿酸增高引致组织损伤的一组疾病。急性痛风性关节炎，是痛风的特征性症状，是尿酸盐结晶沉着于关节(尤其是踝部与足部关节)及周围结缔组织而引起的特征性急性炎症反应。其常在夜间突发，患者可因疼痛而醒并且彻夜不能入睡。急性痛风性关节炎常反复发作，久之，则可发展为多关节炎，或游走性关节炎，受累关节红、肿、热、痛，活动受限，严重影响患者的生活质量。在中国，随着人们生活水平的不断提高，高嘌呤、高蛋白、高脂肪的大量摄入，痛风不仅发病率迅速增长，甚至患病年龄层逐渐降低，出现十几岁的青少年痛风患者。据预测，今后10年，痛风在中国将成为仅次于糖尿病的代谢性疾病。
目前对于急性痛风性关节炎的治疗，常用药物为非甾体抗炎药物(如双氯芬酸钠等)、秋水仙碱和糖皮质激素。这些药物虽然在临床中都取得了一定的疗效，但伴随而来的副作用和不良反应不可避免，如传统非甾体类抗炎药的胃肠道反应，COX-2抑制剂的心血管系统的不良反应，秋水仙碱的骨髓抑制、肝损伤、过敏和神经毒性，糖皮质激素的“停药反跳”等。因此，探索治疗急性痛风性关节炎的新药成为医学界关注的热点。
中药白头翁，系毛茛科白头翁属植物白头翁(Pulsatilla chinensis(Bge.)Regel)的干燥根，始载于《神农本草经》。其性味苦寒，具有清热解毒、凉血止痢、燥湿杀虫等功效，用于治疗热毒血痢，温疟寒热，鼻衄，血痔。经过现代药理研究发现白头翁具有更多样的活性，如广谱的抗菌活性、抗肿瘤、抗炎、增强机体免疫功能等作用。
白头翁具有丰富的三萜皂苷类成分。白头翁皂苷B4属于羽扇豆烷型的五环三萜皂苷，结构式如1所示。
Figure PCTCN2018122655-appb-000001
白头翁皂苷B4具有较强的活性，如公开号CN105213410A(公开日2016年1月6日)的中国发明专利申请公开了白头翁皂苷B4作为免疫调节剂在治疗急性炎症药物中的应用，所述急性炎症包括由于炎症因子过度表达引起的急性肾损伤、急性肝损伤和急性肺损伤。又如公开号CN105535004A(公开日2016年5月4日)的中国发明专利申请公开了该化合物作为EV71病毒抑制剂在制备抗手足口病药物中的应用。但迄今为止，尚未见到白头翁皂苷B4用于治疗急性痛风性关节炎的报道。
发明内容
针对现有技术的不足，本发明提供白头翁皂苷B4在治疗急性痛风性关节炎的新医药用途。
为了实现上述技术效果，本发明采用了如下的技术方案：
白头翁皂苷B4在制备治疗急性痛风性关节炎的药物中的应用。
作为一种优选地实施方案，本发明提供白头翁皂苷B4作为唯一活性成分在制备治疗急性痛风性关节炎的药物中的应用。
作为另一种优选地实施方案，本发明提供白头翁皂苷B4和其它活性成分一起在制备治疗急性痛风性关节炎的药物中的应用；其中所述其它活性成分选自非甾体抗炎药物、秋水仙碱、糖皮质激素中的一种或多种。
所述非甾体抗炎药物包括但不限于布洛芬、吲哚美辛、尼美舒利、萘普生、萘普酮、双氯芬酸钠、洛索洛芬钠、罗非昔布、塞来昔布和依托考昔等。
所述糖皮质激素包括但不限于泼尼松、甲泼尼松、倍他米松、丙酸倍氯米松、得宝松、泼尼松龙、氢化可的松和地塞米松等。
优选地，所述药物还包括药学上可以接受的辅料。
优选地，所述药物选自口服制剂和非口服制剂中的一种或多种。
优选地，所述非口服制剂选自注射剂、直肠给药制剂、肺部给药制剂中的一种或多种；更优选为注射剂和直肠给药制剂中的一种或多种。
所述注射剂选自皮下注射剂、肌肉注射剂和静脉注射剂中的一种或多种。
所述直肠给药制剂选自直肠栓剂和/直肠灌注剂。
本发明所述药学上可以接受的辅料，包括但不限于(1)稀释剂，例如淀粉、糖粉、糊精、乳糖、预胶化淀粉、微晶纤维、无机钙盐(如硫酸钙、磷酸氢钙、药用碳酸钙等)、甘露醇等、植物油、聚乙二醇、可可豆脂、半合成或全合成脂肪酸甘油酯、甘油明胶等；(2)粘合剂，例如蒸馏水、乙醇、淀粉浆、聚维酮、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素和乙基纤维素、羟丙甲纤维素等；(3)崩解剂，例如干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、交联聚维酮等；(4)润滑剂，例如硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类、月桂醇硫酸镁等；(5)溶剂，例如注射用水、乙醇等；(6)防腐剂，例如苯甲酸及其盐类、山梨酸及其盐类、尼泊金酯类等。
优选地，所述应用的对象是哺乳动物，优选为人。
以人为施用对象，白头翁皂苷B4的给予量，通常为成人(体重按70kg计)每天0.4-1.6mg/kg体重，更优选地每天一次或数次共给予0.4-1.6mg/kg体重。
本发明还提供一种治疗急性痛风性关节炎的方法，该方法包括向有需要的患者施用白头翁皂苷B4的步骤。
优选地，所述治疗急性痛风性关节炎的方法包括通过皮下注射、肌肉注射或静脉注射向有需要的患者施用白头翁皂苷B4的步骤。
优选地，所述有需要的患者为有需要的哺乳动物，更优选为有需要的人。
优选地，所述治疗急性痛风性关节炎的方法包括向有需要的人每天一次或数次施用白头翁皂苷B4共计0.4-1.6mg/kg体重的步骤。
作为一种优选地实施方式，本发明提供一种治疗急性痛风性关节炎的方法，该方法包括通过皮下注射、肌肉注射或静脉注射向有需要的人每天一次或数次施用白头翁皂苷B4共计0.4-1.6mg/kg体重的步骤。
发明人通过多次动物试验证明，白头翁皂苷B4静脉、皮下或肌肉注射能够明显缓解急性痛风性关节炎所致关节肿胀。因此，白头翁皂苷B4注射液有望为临床治疗急性痛风性关节炎提供新的选择。
实施发明的最佳方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的原料、试剂材料等，如无特殊说明，均为市售购买产品。
实施例1白头翁皂苷B4对尿酸钠致大鼠急性痛风性关节炎效果的初步观察
1.实验材料
1.1实验药物：白头翁皂苷B4注射液(自制，以下简称“B4注射液”)；秋水仙碱，批号：171116，西双版纳版纳药业有限责任公司。
上述B4注射液通过如下方法制备：
取处方量的白头翁皂苷B4原料，精密称定，加入适量的注射用水，在磁力搅拌作用下使白头翁皂苷B4原料溶解完全后，向溶液中加入溶液质量0.10％的活性炭，在100℃水浴条件下加热并搅拌15min，用注射用水稀释至100ml，摇匀，经0.22μm微孔滤膜过滤除去活性炭，精密量取2ml中间体药液装入5ml的安瓿瓶中，在115℃条件下灭菌30min后，即得。
1.2试剂：尿酸钠，Sigma公司，货号：U2875-5G，批号：BCBS7438
1.3动物：SD大鼠，60只，雄性，180～220g，购自湖南斯莱克景达实验动物有限公司，适应性喂养一周后，用于实验。
1.4仪器：足趾容积仪，型号：YLS-7B，淮北正华生物仪器设备有限公司
2.实验方法
2.1尿酸钠(MSU)晶体及混悬液的制备：将5ml 1mol/L的NaOH和800mg尿酸钠加入155ml去热原的灭菌注射用水中并煮沸，使尿酸钠完全溶解，自然降温并搅拌，滴入1mol/L的HCl至pH值7.0，溶液呈乳白色后立即3000r/min离心2min，收集晶体，于烘箱60℃烘干，装于EP管，4℃保存。用前将MSU晶体在121℃高压灭菌30min，分散于PBS配成所需浓度，即得尿酸钠(MSU)混悬液。取少量混悬液涂片，光学镜下可见长梭形晶体。
2.2分组给药及模型建立：将60只大鼠按体重随机分为6组，每组10只：①模型组，②秋水仙碱组(0.3mg/kg)，③B4皮下注射给药组(5mg/kg*2)，④B4静脉注射给药组(5mg/kg*2)，⑤B4肌肉注射给药高 剂量组(5mg/kg*2)，⑥B4肌肉注射给药低剂量(2.5mg/kg*2)组；另设正常组(5只大鼠)。正常组和模型组注射给与同等体积生理盐水，B4各给药组按相应给药途经给予相应药物，2次/d，每次间隔4hr，连续3d。
造模方法：造模当天，给药组给药1h后开始造模，其中：
①模型组：每只大鼠右侧踝关节背侧注射40mg/mLMSU混悬液，0.2mL/只；
②秋水仙碱组：秋水仙碱组造模当天给药1次，给药后1h每只大鼠右侧踝关节背侧注射40mg/mLMSU混悬液，0.2mL/只；
③～⑥B4各给药组：末次给药后1h后每只大鼠右侧踝关节背侧注射40mg/mLMSU混悬液，0.2mL/只，造模后3h各给药组再给药一次。
2.3关节肿胀度的测定：分别于造模前，造模后2h、4h、6h、8h、12h、24h测定右踝关节的容积，以“造模后关节容积-造模前关节容积”，计算肿胀度。
3.实验结果
见表1。
表1的数据示出：与正常组比较，模型组大鼠造模后2h关节明显肿胀，8h到12h达高峰，24h自发减轻。与模型组比较，各给药组关节肿胀度都有不同程度降低，其中B4皮下注射造模后2-6h，B4肌肉注射组造模后2-4h，静脉注射组造模后4-6h，秋水仙碱组造模后4h，关节肿胀度都明显降低，具有显著性差异。B4各给药组和秋水碱组比较没有显著性差异，说明在试验的给药途径和给药剂量下，B4减轻尿酸钠(MSU)晶体所致大鼠关节急性肿胀的作用与秋水碱相当。
4.实验结论
本次试验结果表明，B4通过皮下注射、肌肉注射和静脉注射，都能够明显缓解急性痛风性关节炎关节肿胀。
实施例2白头翁皂苷B4对尿酸钠致大鼠急性痛风性关节炎效果的再次观察
在实施例1的基础上，减少白头翁皂苷B4的给药剂量，再次考察其改善尿酸钠致大鼠急性痛风性关节炎的关节肿胀的效果。
1.实验材料：同实施例1的“1.”项
2.实验方法
2.1尿酸钠(MSU)晶体及混悬液的制备：同实施例1的“2.1”项。
2.2分组给药及模型建立：
2.2.1分组：将50只大鼠按体重随机分为5组，每组10只：
①模型组，②秋水仙碱组(0.15mg/kg)，③B4皮下注射给药组(2.5mg/kg*2)，④B4肌肉注射给药组(2.5mg/kg*2)，⑤B4静脉注射给药组(2.5mg/kg*2)。
2.2.2给药：模型组注射给与同等体积生理盐水，各给药组(包括B4的各给药组和秋水碱组)都只在造模当天给药，其中秋水碱组给药1次，B4各组连续给药2次，每次间隔时间4h。
2.2.3造模及关节肿胀度测定：给药组第1次给药后1h开始造模，造模方法同实施例1。分别于造模前，造模后2h、4h、6h、8h和12h测定右踝关节的容积，以“造模后关节容积-造模前关节容积”，计算肿胀度。
3.实验结果：
见表2。
表2的数据示出：模型组在造模后8-12h肿胀度达高峰；与模型组比较，各给药组关节肿胀度都有不同程度降低，其中B4皮下注射组在造模后6-12h、B4肌肉注射组在造模后8-12h、B4静脉注射组在造模后8-12h和秋水仙碱组在造模后6-12h，关节肿胀度明显降低，与模型组比较具有显著性差异。B4各给药组和秋水碱组比较没有显著性差异，说明在试验的给药途径和给药剂量下，B4减轻尿酸钠致大鼠急性痛风性关节炎的关节肿胀的作用与秋水碱相当。虽然没有显著性差异，但是B4皮下注射组在造模后2-8h的关节肿胀度都是各组中最小的，B4肌肉注射组在造模后12h的关节肿胀度在各组中最小，显示出一定的作用优势。
4.实验结论：
本次试验结果表明，与实施例1的结果相似，B4注射液具有明显缓解急性痛风性关节炎关节肿胀的作用。
表1 B4对MSU致急性痛风性关节炎大鼠关节肿胀度的影响
Figure PCTCN2018122655-appb-000002
Figure PCTCN2018122655-appb-000003
注：与模型组比较， ΔP＜0.05， ΔΔP＜0.01
表2 B4对MSU致大鼠急性痛风性关节炎关节肿胀度的影响
Figure PCTCN2018122655-appb-000004
Figure PCTCN2018122655-appb-000005
注：与模型组比较， ΔP＜0.05， ΔΔP＜0.01

Claims (15)

  1. 白头翁皂苷B4在制备治疗急性痛风性关节炎的药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，白头翁皂苷B4作为唯一活性成分在制备治疗急性痛风性关节炎的药物中的应用。
  3. 根据权利要求1所述的应用，其特征在于，白头翁皂苷B4和其它活性成分一起在制备治疗急性痛风性关节炎的药物中的应用；其中所述其它活性成分选自非甾体抗炎药物、秋水仙碱、糖皮质激素中的一种或多种。
  4. 根据权利要求3所述的应用，其特征在于，所述非甾体抗炎药物选自布洛芬、吲哚美辛、尼美舒利、萘普生、萘普酮、双氯芬酸钠、洛索洛芬钠、罗非昔布、塞来昔布和依托考昔中的一种或多种。
  5. 根据权利要求3所述的应用，其特征在于，所述糖皮质激素选自泼尼松、甲泼尼松、倍他米松、丙酸倍氯米松、得宝松、泼尼松龙、氢化可的松和地塞米松中的一种或多种。
  6. 根据权利要求1至5中任一项所述的应用，其特征在于，所述药物还包括药学上可以接受的辅料。
  7. 根据权利要求1至6中任一项所述的应用，其特征在于，所述药物选自口服制剂和非口服制剂中的一种或多种。
  8. 根据权利要求7所述的应用，其特征在于，所述非口服制剂选自注射剂、直肠给药制剂、肺部给药制剂中的一种或多种；更优选为注射剂和直肠给药制剂中的一种或多种。
  9. 根据权利要求8所述的应用，其特征在于，所述注射剂选自皮下注射剂、肌肉注射剂和静脉注射剂中的一种或多种；
    所述直肠给药制剂选自直肠栓剂和/直肠灌注剂。
  10. 根据权利要求1至9中任一项所述的应用，其特征在于，所述应用的对象是哺乳动物，优选为人。
  11. 一种治疗急性痛风性关节炎的方法，该方法包括向有需要的患者施用白头翁皂苷B4的步骤。
  12. 根据权利要求11所述的方法，其特征在于，所述方法包括通过皮下注射、肌肉注射或静脉注射向有需要的患者施用白头翁皂苷B4的步骤。
  13. 根据权利要求11或12所述的方法，其特征在于，所述有需要的患者为有需要的哺乳动物，更优选为有需要的人。
  14. 根据权利要求11至13中任一项所述的方法，其特征在于，所述方法包括向有需要的人每天一次或数次施用白头翁皂苷B4共计0.4-1.6mg/kg体重的步骤。
  15. 根据权利要求11至14中任一项所述的方法，其特征在于，所述方法包括通过皮下注射、肌肉注射或静脉注射向有需要的人每天一次或数次施用白头翁皂苷B4共计0.4-1.6mg/kg体重的步骤。
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JP2023039876A (ja) * 2021-09-09 2023-03-22 ＭｉＺ株式会社 痛風の改善および／または症状の悪化を抑制するのための組成物
JP7414203B2 (ja) 2021-09-09 2024-01-16 ＭｉＺ株式会社 痛風の改善および／または症状の悪化を抑制するのための組成物

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