WO2021174406A1 - 白头翁皂苷b4在治疗口腔溃疡中的医药用途 - Google Patents

白头翁皂苷b4在治疗口腔溃疡中的医药用途 Download PDF

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WO2021174406A1
WO2021174406A1 PCT/CN2020/077522 CN2020077522W WO2021174406A1 WO 2021174406 A1 WO2021174406 A1 WO 2021174406A1 CN 2020077522 W CN2020077522 W CN 2020077522W WO 2021174406 A1 WO2021174406 A1 WO 2021174406A1
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pulsatilla
oral
saponins
preparation
application
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PCT/CN2020/077522
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French (fr)
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刘琦
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刘琦
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Priority to EP20923234.7A priority Critical patent/EP4115888A4/en
Priority to AU2020433267A priority patent/AU2020433267A1/en
Priority to CA3170423A priority patent/CA3170423A1/en
Priority to PCT/CN2020/077522 priority patent/WO2021174406A1/zh
Priority to US17/905,712 priority patent/US20230102973A1/en
Priority to JP2022552785A priority patent/JP7462783B2/ja
Publication of WO2021174406A1 publication Critical patent/WO2021174406A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

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  • the invention belongs to the field of medicine, and specifically relates to a new medical use of Pulsatilla saponin B4.
  • Oral ulcers are a common type of oral mucosal diseases.
  • the localized tissue defects of the oral mucosal epithelium and the exposure of connective tissues are seen during the onset. Because of the nerves and blood vessels in it, the pain is abnormal after the ulcers are formed.
  • 20% of the population in my country has oral ulcers at least once. Any group may have oral ulcers regardless of age or gender.
  • the disease has seriously affected people’s diet, speech, and reduced The quality of life in real life.
  • recurrent oral ulcers are the most common, accounting for more than 90% of oral ulcers. They often recover from time to time and recur.
  • the course of the disease is generally 7-10 days, and the intermittent period ranges from 10 days to several months.
  • oral ulcers The etiology of oral ulcers is more complicated, and it is often a manifestation of local diseases and systemic diseases in the oral cavity.
  • a large number of studies have shown that the occurrence of oral ulcers is related to the following factors: genetics, immune disorders, trauma, viral or bacterial infections, autoimmunity, gastrointestinal diseases, anemia, endocrine disorders, nutritional deficiencies, and mental stress.
  • oral ulcers are one of the common adverse reactions in patients with malignant tumors during chemotherapy.
  • the chemotherapy drugs most likely to cause oral ulcers are methotrexate, fluorouracil, etoposide and doxorubicin.
  • Clinical treatment includes systemic treatment and local treatment.
  • systemic treatment includes glucocorticoid drugs, antimetabolites, vitamins and trace elements, antiviral drugs, estrogen, etc.; there are also many local treatment methods and drugs, the main role is to reduce inflammation, relieve pain, and promote healing.
  • Commonly used drugs include anti-inflammatory drugs, analgesics, local anesthetics and hormones (locally blocked). But regardless of systemic treatment or local treatment, the effect is not significant.
  • glucocorticoid drugs are not only not conducive to the healing of ulcers, but will increase the degree of ulcers. Therefore, it is of great significance to find new drugs with definite curative effects.
  • Pulsatilla saponins B4 belongs to the lupine type pentacyclic triterpene saponins, and the structural formula is shown in 1.
  • Pulsatilla saponins B4 has strong activity, and there have been many reports in the prior art.
  • Pulsatilla saponins B4 is used as an immunomodulator to treat acute inflammation, which includes acute kidney injury, acute liver injury and acute lung injury caused by overexpression of inflammatory factors (CN105213410A, published on January 6, 2016) .
  • Pulsatilla saponin B4 is used as an EV71 virus inhibitor for hand, foot and mouth disease (CN105535004A, published on May 4, 2016).
  • Liu Qi filed a Chinese invention patent application entitled "Pulsatilla saponins B4 for anti-acute gouty arthritis" on October 18, 2018 (application number CN201811214694.3). But so far, no report on the therapeutic effect of Pulsatilla saponins B4 on oral ulcers has been seen.
  • the present invention provides a new medical use of Pulsatilla saponin B4, namely the application of Pulsatilla saponin B4 in the treatment of oral ulcers, especially oral ulcers caused by chemotherapy.
  • Pulsatilla saponins B4 in the preparation of medicines for treating oral ulcers.
  • the present invention provides the application of Pulsatilla saponin B4 in the preparation of a medicine for treating recurrent oral ulcers.
  • the present invention also provides the application of Pulsatilla saponin B4 in the preparation of a medicine for treating oral ulcers caused by chemotherapy.
  • Pulsatilla saponins B4 as the sole active ingredient in the preparation of the above-mentioned drugs.
  • Pulsatilla saponins B4 and other active ingredients in the preparation of the above-mentioned drugs wherein the other active ingredients are selected from rifampicin, flumethasone, metronidazole, zinc sulfate, montmorillonite, chlorhexidine, chitosan
  • the other active ingredients are selected from rifampicin, flumethasone, metronidazole, zinc sulfate, montmorillonite, chlorhexidine, chitosan
  • the other active ingredients are selected from rifampicin, flumethasone, metronidazole, zinc sulfate, montmorillonite, chlorhexidine, chitosan
  • the other active ingredients are selected from rifampicin, flumethasone, metronidazole, zinc sulfate, montmorillonite, chlorhexidine, chitosan
  • the drug is selected from one or more of oral preparations and non-oral preparations.
  • the non-oral preparation is selected from one or more of injections, rectal administration preparations, oral mucosal patches, and oral membranes.
  • the injection is selected from one or more of subcutaneous injection, intramuscular injection and intravenous injection.
  • the formulation for rectal administration is selected from one or more of rectal suppositories, rectal gels, and rectal infusions.
  • the pharmaceutically acceptable excipients of the present invention include but are not limited to (1) diluents, such as starch, powdered sugar, dextrin, lactose, pregelatinized starch, microcrystalline fibers, inorganic calcium salts (such as calcium sulfate, phosphoric acid) Hydrogen calcium, medicinal calcium carbonate, etc.), mannitol, etc., vegetable oil, polyethylene glycol, cocoa butter, semi-synthetic or fully synthetic fatty acid glycerides, glycerin gelatin, etc.; (2) Adhesives, such as distilled water, ethanol, Starch slurry, povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose, hypromellose, etc.; (3) disintegrant, such as dry starch, carboxymethyl Sodium starch base, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked
  • the object of the application is a mammal, preferably a human.
  • Pulsatilla saponin B4 For human subjects, the dosage of Pulsatilla saponin B4 is usually 50-300 mg per person per day for adults (body weight is 70kg); preferably, for adults with body weight 70kg, Pulsatilla saponin B4 is administered once or several times a day. -300mg/person.
  • Pulsatilla saponin B4 suppository homemade, each weighing 0.14g; based on the content of Pulsatilla saponin B4, there are 14mg/capsule, 7mg/capsule, 3.5mg/capsule, batch number: 20190523;
  • Blank suppository self-made, prepared in parallel with the above-mentioned Pulsatilla saponin B4 suppository, batch number: 20190523-k;
  • Tin powder Jiangsu Seventy Seven Natural Pharmaceutical Co., Ltd., 190102;
  • Dexamethasone Henan Runhong Pharmaceutical Co., Ltd., Zhunzi H41020330.
  • the preparation method of the pulsatilla saponin B4 suppository is:
  • Pulsatilla saponins B4 Pass the Pulsatilla saponins B4 through a 100-mesh sieve and set aside; then weigh the base mixed fatty acid glyceride 36# and mixed fatty acid glyceride 38#, melt them in a 60°C water bath, stir evenly, and then slowly add B4, while adding While stirring, until B4 is evenly dispersed in the matrix, pour it into the suppository mold, let it cool, and take it out.
  • Glacial acetic acid (Xilong Science Co., Ltd., batch number 180510), chloral hydrate (Tianjin Damao Chemical Reagent Factory, batch number: 20180518), isoflurane (Shenzhen Reward Life Technology Co., Ltd., 217180501)
  • the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate solution. After anesthesia, a 3mm*3mm filter paper impregnated with 100% glacial acetic acid was used to close the right buccal mucosa of the rat for 45s. After 45s of cauterization, a round or elliptical white damage to the buccal mucosa in this area can be seen, indicating the success of the model. .
  • All successfully modeled animals were randomly divided into six groups according to the ulcer area: 114 in the model group, 212 in the Xileisan (15mg/kg) group, 313 in the dexamethasone (0.3mg/kg) group, 4 Pulsatilla saponin B4 high-dose (about 60mg/kg*3, namely 14mg/grain, 1 capsule/time, 3 times/d) group of 14 rats, 5Pulsatilla saponin B4 medium-dose group (about 30mg/kg*3, ie 7mg/ Capsules, 1 capsule/time, 3 times/d) 14 capsules, 6Pulsatilla saponin B4 low dose (approximately 15mg/kg*3, ie 3.5mg/ capsule, 1 capsule/time, 3 times/d) 14 capsules; another set 6 in the normal group.
  • Xileisan group was administered locally for ulcers, once a day; dexamethasone group was administered by intraperitoneal injection, once a day; Pulsatilla saponin B4 was administered rectal Medicine, 3 times/d, blank suppository was given to the model group, 3 times/d.
  • Pulsatilla saponins B4 suppository can significantly reduce the ulcer diameter of rat oral ulcers caused by acetic acid, which is statistically different compared with the model group (p ⁇ 0.05). Its effect of promoting ulcer healing is equivalent to that of dexamethasone and better than tin powder.
  • Pulsatilla saponin B4 Rectal administration of Pulsatilla saponin B4 has a good therapeutic effect on oral ulcers in rats caused by acetic acid. The effect in promoting ulcer healing is equivalent to that of dexamethasone, which is significantly better than Xi Lei powder. At the same time, Pulsatilla saponin B4 can improve body weight, The overall condition of oral ulcer rats reflected by food intake is stronger than that of dexamethasone.
  • Oral ulcer is a common adverse reaction of cancer patients after radiotherapy and chemotherapy.
  • This experiment intends to use the chemotherapeutic drug paclitaxel-induced oral ulcer model in rats.
  • the therapeutic effect of Pulsatilla saponins B4 on oral ulcers is evaluated.
  • Pulsatilla saponin B4 suppository self-made, the preparation method is the same as that of study example 1, each weighs 0.15g; each contains 14mg pulsatilla saponin B4, batch number: 20190523.
  • Dexamethasone Henan Runhong Pharmaceutical Co., Ltd., Zhunzi H41020330.
  • the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate solution. After anesthesia, 6mg/ml paclitaxel injection was injected into the right buccal mucosa of rats to establish a model of oral ulcers caused by chemotherapeutics.
  • All successfully modeled animals were randomly divided into a model group of 7 animals, a Pulsatilla saponin B4 suppository high-dose (about 60mg/kg*2) group of 7 animals, and a normal group of 6 animals.
  • the B4 group was given rectal administration, 1 capsule/time, 2 times/d, for 5 consecutive days; the dexamethasone group was given intraperitoneal injection, 1 time/d, for 5 consecutive days, and the model group was given a blank suppository.
  • * means p ⁇ 0.05 compared with the model group.
  • Pulsatilla saponin B4 has a good therapeutic effect on paclitaxel-induced oral ulcers in rats, can significantly shorten the healing time of ulcers, and can improve the overall condition of the rats (the food intake is increased compared with the model group).
  • the above-mentioned studies suggest that Pulsatilla saponins B4 can be used to treat oral ulcers caused by chemotherapy drugs in tumor patients, which helps to reduce the suffering of patients, improve the quality of life of patients, and enable the smooth completion of chemotherapy.

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Abstract

涉及白头翁皂苷B4的医药用途。具体地，提供白头翁皂苷B4在制备治疗口腔溃疡的药物中的应用；尤其是白头翁皂苷B4在制备治疗复发性口腔溃疡的药物以及制备治疗化疗所致口腔溃疡的药物中的应用。

Description

白头翁皂苷B4在治疗口腔溃疡中的医药用途 技术领域
本发明属于医药领域，具体涉及白头翁皂苷B4的新的医药用途。
背景技术
口腔溃疡是口腔粘膜疾病中较常见的一种,发作时见口腔黏膜上皮的局限性组织缺损、结缔组织暴露，因其内含有神经血管，溃疡形成后疼痛异常。通过相关流行病学的调查，我国有百分之二十的人群至少出现口腔溃疡一次，不论年龄、性别，任何群体都有可能发生口腔溃疡，该疾病严重影响了人们的饮食、言语，降低了现实生活中的生活质量。临床上，又以复发性口腔溃疡最为常见，占口腔溃疡的90％以上，时发时愈，反复发作，病程一般为7-10天，间歇期从10天到数月不等。口腔溃疡病因较为复杂，往往是局部疾病和全身疾病在口腔的表征，病因有些明确，有些还不甚明了。但是大量研究已表明，口腔溃疡发生与下列因素相关：遗传、免疫失调、创伤、病毒或细菌感染、自身免疫、胃肠道疾病、贫血、内分泌失调、营养缺乏以及精神紧张。
此外，口腔溃疡是恶性肿瘤患者在化疗过程中常见的不良反应之一。国内文献报道，恶性肿瘤患者化疗后口腔溃疡发生率为66％～75％，国外文献报道其发生率为40％～90％(孙晶晶，等.恶性肿瘤患者化疗所致口腔溃疡防治现状[J].齐鲁护理杂志，2013年，第19卷第21期：57-58)，严重影响患者进食,造成营养缺乏,水电解质紊乱,阻碍患者接受进一步治疗,甚至发生败血症,导致患者死亡。最易导致口腔溃疡的化疗药物是甲氨蝶呤、氟尿嘧啶、依托泊苷和阿霉素。
由于病因和发病机制尚不完全明确，该疾病的治疗还没有特别有效的方法，临床治疗包括全身治疗和局部治疗。其中，全身治疗有糖皮质激素类药物、抗代谢类药物、维生素和微量元素、抗病毒药物、雌激素等；局部治疗的方法和药物也较多，主要作用是消炎、止痛，并促进愈合，常用的药物包括消炎类药物，止痛类药物，局麻药和激素(局部封闭)。但不管全身治疗还是局部治疗，疗效均不显著。此外，对于化疗引起的口腔溃疡，糖皮质激素类药物不仅不利于溃疡的愈合，反而会加重溃疡程度。因此，寻找新的疗效确切的药物具有重要的意义。
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 PCTCN2020077522-appb-000001
白头翁皂苷B4具有较强的活性，现有技术中已多有报道。如，白头翁皂苷B4作为免疫调节剂应用于治疗急性炎症，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(CN105213410A，公开日2016年1月6日)。又如，白头翁皂苷B4作为EV71病毒抑制剂应用于手足口病(CN105535004A，公开日2016年5月4日)。还比如刘琦在2018年10月18日提出了名称为“白头翁皂苷B4抗急性痛风性关节炎的医药用途”的中国发明专利申请(申请号CN201811214694.3)。但迄今为止，尚未见到白头翁皂苷B4对于口腔溃疡的治疗作用的报道。
发明内容
针对现有技术的不足，本发明提供白头翁皂苷B4新的医药用途，即白头翁皂苷B4在治疗口腔溃疡，尤其是化疗所致口腔溃疡中的应用。
为了实现上述发明目的，本发明采用了如下的技术方案：
白头翁皂苷B4在制备治疗口腔溃疡的药物中的应用。
作为一种优选的实施方案，本发明提供白头翁皂苷B4在制备治疗复发性口腔溃疡的药物中的应用。
作为另一种优选的实施方案，本发明还提供白头翁皂苷B4在制备治疗化疗所致口腔溃疡的药物中的应用。
优选地，白头翁皂苷B4作为唯一活性成分在制备上述药物中的应用。
或者，白头翁皂苷B4和其它活性成分一起在制备上述药物中的应用；其中，其它活性成分选自利福平、氟美松、甲硝唑、硫酸锌、蒙脱石、氯己定、壳聚糖、硫糖铝、聚肌胞、左旋咪唑、维生素C、B族维生素、粒-巨噬细胞集落刺激因子、重组人表皮生长因子、重组人角质细胞生长因子等中的一种或多种。
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、口腔黏膜贴剂、口腔膜剂中的一种或多种。
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、直肠凝胶剂、直肠灌注剂中的一种或多种。
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。
优选的，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的给药量，通常为成人(体重按70kg计)每天50-300mg/人；优选地，体重按照70kg计的成人，白头翁皂苷B4每天一次或数次共给予50-300mg/人。
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药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
研究例1 白头翁皂苷B4对醋酸致大鼠口腔溃疡的作用
1.实验目的
通过建立醋酸致大鼠口腔溃疡模型，通过观察大鼠造模后摄食量，溃疡直径变化，溃疡愈合时间等，评价白头翁皂苷B4对口腔溃疡的治疗作用。
2.实验材料
2.1实验动物：SFP级SD大鼠，雄性，200-220g，购于湖南斯莱克实验动物有限公司，合格证号：No.43004700060832，许可证号：SCXK(湘) 2016-0002。
2.2受试药物：
白头翁皂苷B4栓剂：自制，每粒重0.14g；以白头翁皂苷B4含量计，分别有14mg/粒，7mg/粒，3.5mg/粒三种规格，批号：20190523；
空白栓剂：自制，与上述白头翁皂苷B4栓剂平行制备，批号：20190523-k；
锡类散：江苏七O七天然制药有限公司，190102；
地塞米松：河南润弘制药股份有限公司，国药准字H41020330。
所述白头翁皂苷B4栓剂的制备方法为：
将白头翁皂苷B4过100目筛，备用；再称取基质混合脂肪酸甘油酯36#和混合脂肪酸甘油酯38#，将其置于60℃水浴中熔融，搅拌均匀，再缓缓加入B4，边加边搅拌，直至B4均匀分散在基质中，灌入栓模中，放冷，取出，即得。
2.3实验试剂：
冰醋酸(西陇科学股份有限公司，批号180510)，水合氯醛(天津市大茂化学试剂厂，批号：20180518)，异氟烷(深圳市瑞沃德生命科技有限公司，217180501)
2.4实验仪器：麻醉机(瑞沃德，R580)，游标卡尺(Mitutoyo,CD-6”CSX)。
3.实验方法
3.1醋酸致口腔溃疡大鼠模型建立
大鼠经腹腔注射10％水合氯醛溶液行麻醉。麻醉后，用浸有100％冰醋酸的3mm*3mm滤纸片，紧贴大鼠右侧颊黏膜45s，烧灼45s后，可见该区域颊黏膜出现圆形或椭圆形的白色损害，显示造模成功。
3.2实验分组
所有造模成功的动物，根据溃疡面积随机分为六组：①模型组14只，②锡类散(15mg/kg)组12只，③地塞米松(0.3mg/kg)组13只，④白头翁皂苷B4高剂量(约60mg/kg*3，即14mg/粒，1粒/次，3次/d)组14只，⑤白头翁皂苷B4中剂量组(约30mg/kg*3，即7mg/粒，1粒/次，3次/d)14只，⑥白头翁皂苷B4低剂量(约15mg/kg*3，即3.5mg/粒，1粒/次，3次/d)14只；另设正常组6只。
3.3给药
造模24h后，开始给药，连续3天，其中：锡类散组溃疡局部给药，1次/d；地塞米松组腹腔注射给药，1次/d；白头翁皂苷B4各组直肠给药，3次/d，模型组给予空白栓剂，3次/d。
3.4观察指标
(1)一般情况观察：造模第2d起每日测量每笼动物摄食量，每2d一次测 量动物体重。
(2)溃疡表面直径测量：造模第2d、4d和第5d，用标尺测量并记录溃疡面直径。
4.实验结果
4.1白头翁皂苷B4栓剂对口腔溃疡大鼠体重的影响：
结果见表1。
表1 B4栓剂对醋酸致口腔溃疡大鼠体重的影响
Figure PCTCN2020077522-appb-000002
Figure PCTCN2020077522-appb-000003
注：*表示与地塞米松组比较，p<0.05。
由表1可见，地塞米松组给药后体重明显下降；除地塞米松组外，其余各给药组动物体重在给药后较模型组有增加趋势；造模第4d(给药3d后)开始，白头翁皂苷B4各剂量组和地塞米松组比较，体重明显升高，差异具有显著性(p<0.05)。
4.2白头翁皂苷B4对醋酸致口腔溃疡大鼠摄食量的影响：
结果见表2。
表2 白头翁皂苷B4栓剂对醋酸致口腔溃疡大鼠摄食量的影响
Figure PCTCN2020077522-appb-000004
Figure PCTCN2020077522-appb-000005
注：*表示与模型组比较，p<0.05。
由表2可见，造模后，与正常组动物相比，各造模组动物摄食量均明显下降，尤其是在造模第3天模型组和各给药组的摄食最少，说明造模第3天 时溃疡最严重，疼痛造成各组动物的摄食量均减少。随后随着溃疡的向愈，疼痛减轻，各组动物摄食量逐渐增加。在溃疡最严重的造模第3天，白头翁皂苷B4各剂量组的摄食量均多于模型组，其中高、中剂量组差异具有统计学意义(p<0.05)；说明白头翁皂苷B4各剂量组的溃疡损伤均较轻。地塞米松组在造模第3天(给药1天后)摄食量较模型组有所增加，但随后摄食量较模型组明显减少，且均少于白头翁皂苷B4各剂量组。
4.3白头翁皂苷B4对醋酸致口腔溃疡大鼠溃疡直径的影响：
结果见表3。
表3 白头翁皂苷B4栓剂对醋酸致口腔溃疡大鼠溃疡直径的影响
Figure PCTCN2020077522-appb-000006
Figure PCTCN2020077522-appb-000007
注：*表示与模型组比较，p<0.05。
表3的数据示出，从造模第4d，第5d开始，白头翁皂苷B4栓剂可以明显减小醋酸致大鼠口腔溃疡的溃疡直径，与模型组比较，具有统计学差异(p<0.05)，其促进溃疡愈合的作用与地塞米松相当，好于锡类散。
5.结论
白头翁皂苷B4直肠给药，对于醋酸所致大鼠口腔溃疡具有很好的治疗作用，在促进溃疡愈合的作用与地塞米松相当，显著好于锡类散；同时，白头翁皂苷B4在改善体重、摄食量等反映的口腔溃疡大鼠的整体状况方面强于地塞米松。
研究例2 白头翁皂苷B4对化疗药物紫杉醇致大鼠口腔溃疡的治疗作用
1.实验目的
口腔溃疡是肿瘤患者放化疗后常见的不良反应。本实验拟用化疗药物紫杉醇致大鼠口腔溃疡模型，通过观察大鼠造模后摄食量，溃疡愈合时间等，评价白头翁皂苷B4对口腔溃疡的治疗作用。
2.实验材料
2.1实验动物：SFP级SD大鼠，雄性，180-200g，购于湖南斯莱克实验动物有限公司，合格证号：No.1107271911003468，许可证号：SCXK(湘) 2016-0002。
2.2受试药物：
白头翁皂苷B4栓剂：自制，制备方法同研究例1；每粒重0.15g；每粒含14mg白头翁皂苷B4，批号：20190523。
同时平行制备空白栓剂。
地塞米松：河南润弘制药股份有限公司，国药准字H41020330。
2.3实验试剂：紫杉醇注射液(北京双鹭药业股份有限公司，批号20190101)，水合氯醛(天津市大茂化学试剂厂，批号20180518)，异氟烷(深圳市瑞沃德生命科技有限公司，217180501)
2.4实验仪器：麻醉机(瑞沃德，R580)，游标卡尺(Mitutoyo,CD-6”CSX)。
3.实验方法
3.1紫杉醇注射液致口腔溃疡大鼠模型建立
大鼠经腹腔注射10％水合氯醛溶液行麻醉。麻醉后，以6mg/ml紫杉醇注射液，大鼠右侧颊黏膜内注射50ul建立化疗药致口腔溃疡模型。
3.2实验分组
所有造模成功的动物，随机分为模型组7只和白头翁皂苷B4栓剂高剂量(约60mg/kg*2)组7只，另设正常组6只。
3.3给药
造模24h后，B4组开始直肠给药，1粒/次，2次/d，连续5d；地塞米松组腹腔注射给药，1次/d，连续5d，模型组给予空白栓剂。
3.4观察指标
(1)一般情况观察：造模当天禁食不禁水12hr，造模第二天给药后开始定量给予饲料，造模第3d开始(给药第2d),每日测量每笼动物摄食量。
(2)溃疡表面直径测量：造模第2d开始，用游标卡尺测量并记录溃疡面直径，连续7d。
4.实验结果
4.1白头翁皂苷B4对紫杉醇致口腔溃疡大鼠摄食量的影响：
结果见表4。
表4 白头翁皂苷B4对紫杉醇致口腔溃疡大鼠摄食量的影响
Figure PCTCN2020077522-appb-000008
Figure PCTCN2020077522-appb-000009
注：*表示与模型组相比，p<0.05。
由表4可见，造模后，与正常组动物相比，各造模组动物摄食量均明显下降，其中在造模第3天摄食最少，然后逐步恢复，至第6天开始基本恢复，摄食量和正常组相当。在此期间，白头翁皂苷B4组摄食量始终高于模型组，且在第3天和第4天差异具有统计学意义(p<0.05)。而阳性药地塞米松组摄食量并没有明显改善。
4.2白头翁皂苷B4对紫杉醇致口腔溃疡大鼠溃疡直径的影响：
实验结果见表5。
表5 白头翁皂苷B4对紫杉醇致口腔溃疡大鼠溃疡直径的影响
Figure PCTCN2020077522-appb-000010
Figure PCTCN2020077522-appb-000011
注：*表示与模型组比较，p<0.05。
表5的实验数据表明，给药后，白头翁皂苷B4栓剂可以明显缩小溃疡面，从造模第3d开始，与模型组相比具有显著性差异(P<0.05)。地塞米松组溃疡直径与模型组比没有明显差异。
5.结论
以上研究结果表明，白头翁皂苷B4对紫杉醇致大鼠口腔溃疡具有很好的治疗作用，能够明显缩短溃疡愈合的时间，且能够改善大鼠的整体状况(摄食量较模型组增加)。通过上述研究提示白头翁皂苷B4能够用于治疗肿瘤患者因为化疗药物引起的口腔溃疡，这有助于减少患者的痛苦，改善患者的生活质量，使化疗能够顺利完成。

Claims (10)

  1. 白头翁皂苷B4在制备治疗口腔溃疡的药物中的应用。
  2. 白头翁皂苷B4在制备治疗复发性口腔溃疡的药物中的应用。
  3. 白头翁皂苷B4在制备治疗化疗所致口腔溃疡的药物中的应用。
  4. 根据权利要求1至3中任一项所述的应用，其特征在于，白头翁皂苷B4作为唯一活性成分在制备所述药物中的应用。
  5. 根据权利要求1至3中任一项所述的应用，其特征在于，白头翁皂苷B4和其它活性成分一起在制备上述药物中的应用；其中，其它活性成分选自利福平、氟美松、甲硝唑、硫酸锌、蒙脱石、氯己定、壳聚糖、硫糖铝、聚肌胞、左旋咪唑、维生素C、B族维生素、粒-巨噬细胞集落刺激因子、重组人表皮生长因子和重组人角质细胞生长因子中的一种或多种。
  6. 根据权利要求1至5中任一项所述的应用，其特征在于，所述药物选自口服制剂和非口服制剂中的一种或多种。
  7. 根据权利要求6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、口腔黏膜贴剂、口腔膜剂中的一种或多种。
  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。
  9. 根据权利要求7所述的应用，其特征在于，所述直肠给药制剂选自直肠栓剂、直肠凝胶剂、直肠灌注剂中的一种或多种。
  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。
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