WO2017015777A1 - 表没食子儿茶素没食子酸酯、其类似物和它们的转化产物及其各自可药用盐的应用 - Google Patents

表没食子儿茶素没食子酸酯、其类似物和它们的转化产物及其各自可药用盐的应用 Download PDF

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WO2017015777A1
WO2017015777A1 PCT/CN2015/000538 CN2015000538W WO2017015777A1 WO 2017015777 A1 WO2017015777 A1 WO 2017015777A1 CN 2015000538 W CN2015000538 W CN 2015000538W WO 2017015777 A1 WO2017015777 A1 WO 2017015777A1
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epigallocatechin gallate
gallate
drug
combination
digestive tract
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PCT/CN2015/000538
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English (en)
French (fr)
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盛军
郝淑美
王宣军
黄业伟
朱强强
卢浩
李彤
黄艳萍
王腾飞
张昕
山云
陈际名
刘提提
丁仕华
龚婉莹
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云南农业大学
云南大叶帝红生物科技有限公司
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Priority to PCT/CN2015/000538 priority Critical patent/WO2017015777A1/zh
Publication of WO2017015777A1 publication Critical patent/WO2017015777A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention is in the field of medicine, and in particular relates to the use of epigallocatechin gallate, analogs thereof and their conversion products and their respective pharmaceutically acceptable salts.
  • Broad-spectrum killing chemicals have different mechanisms for killing tumor cells, but their selectivity is based on the difference in the proliferation rate of tumor cells and normal cells, and the inhibition and killing of tumor cells with rapid proliferative ability is achieved.
  • these drugs also have significant inhibition and killing effects on normal proliferating cells in the body, such as glandular cells and gastrointestinal cells, which are characterized by severe reproductive toxicity and gastrointestinal toxicity.
  • the human digestive tract also known as the inner epidermis, is directly exposed to the outside world. While having a barrier function similar to that of the skin, the digestive tract is also responsible for the vital digestion and absorption functions, which determine the characteristics of the digestive tract, especially the small intestinal mucosa: thin, only one layer of cells, which is beneficial for absorption. It is very easy to cause damage due to contact with the outside world.
  • the body's solution is a rapid renewal of the mucosa of the digestive tract, constantly replacing the damaged tissue with a new mucosa. Studies have shown that human digestive tract mucosa is renewed every 3-5 days, and this renewal growth rate is faster than many tumors, which is why broad-spectrum anti-inflammatory chemotherapy drugs generally have severe gastrointestinal toxicity.
  • One of the objects of the present invention is to provide an epirubic catechin gallate, an analog thereof, and a conversion product thereof, and their respective pharmaceutically acceptable salts, in view of the deficiencies of the prior art.
  • the present invention provides epigallocatechin gallate (EGCG), epigallocatechin gallate analogs and their conversion products and their respective pharmaceutically acceptable salts in the preparation of a protective digestive tract drug and a pharmaceutical combination application.
  • EGCG epigallocatechin gallate
  • epigallocatechin gallate analogs and their conversion products and their respective pharmaceutically acceptable salts in the preparation of a protective digestive tract drug and a pharmaceutical combination application.
  • the epigallocatechin gallate analog comprises, but is not limited to, gallocatechin gallate Ester (GCG) and epicatechin gallate (ECG);
  • the conversion products of the epigallocatechin gallate and epigallocatechin gallate analogs include, but are not limited to, their glycosidation products, One or several combinations of esterification products and acetylation products.
  • the combination of the digestive tract drug and the drug is a drug and a drug combination for treating gastrointestinal damage in tumor chemotherapy.
  • the pharmaceutical and pharmaceutical combination includes, but is not limited to, tablets, powders, pills, emulsions, patches, extracts, capsules, injections, and oral solutions.
  • the present invention further provides a pharmaceutical and pharmaceutical combination for treating gastrointestinal damage in tumor chemotherapy, comprising epigallocatechin gallate, epigallocatechin gallate analog and their One or more of the transformation products and their respective pharmaceutically acceptable salts.
  • the epigallocatechin gallate analog comprises, but is not limited to, gallocatechin gallate (GCG) and epicatechin gallate (ECG); said epigallocatechin gallate
  • GCG gallocatechin gallate
  • ECG epicatechin gallate
  • the conversion products of the ester and epigallocatechin gallate analogs include, but are not limited to, one or a combination of their glycosidation products, esterification products, and acetylation products.
  • the pharmaceutical and pharmaceutical combination includes, but is not limited to, tablets, powders, pills, emulsions, patches, extracts, capsules, injections, and oral solutions.
  • the invention also provides a method of treating or preventing gastrointestinal damage in a mammal, the method comprising administering to a mammal in need of such treatment an effective amount of epigallocatechin gallate, epigallocatechin gallate One or more of the analogs and their conversion products and their respective pharmaceutically acceptable salts.
  • the epigallocatechin gallate analog comprises, but is not limited to, gallocatechin gallate (GCG) and epicatechin gallate (ECG); said epigallocatechin gallate
  • GCG gallocatechin gallate
  • ECG epicatechin gallate
  • the conversion products of the ester and epigallocatechin gallate analogs include, but are not limited to, one or a combination of their glycosidation products, esterification products, and acetylation products.
  • the digestive tract injury is a digestive tract injury caused by tumor chemotherapy or a similar gastrointestinal injury caused by other pathologies.
  • the present invention has the beneficial effects of the epigallocatechin gallate (EGCG), the epigallocatechin gallate analog and the conversion products thereof and the respective pharmaceutically acceptable salts thereof for preparing a medicament for protecting the digestive tract
  • EGCG epigallocatechin gallate
  • Cisplatin injury was induced by cisplatin/5-fluorouracil (tail vein injection), and EGCG treatment group (adding EGCG) In the feed, the digestive tract of the mice was significantly improved.
  • Fig. 1 is a view showing a normal mouse jejunum villus in the application example 1 of the EGGG of the present invention for preparing a medicament for protecting a digestive tract and a drug.
  • Figure 2 shows the application of EGGG of the present invention in the preparation of a protective digestive tract drug and a drug combination.
  • Fig. 3 is a view showing the jejunum villi of the 0.01% EGCG-treated group of the EGGG of the present invention in the preparation of a protective digestive tract drug and a drug combination in Example 1.
  • Fig. 4 is a view showing the jejunum villi of a 0.1% EGCG-treated group of the EGGG of the present invention in the preparation of a protective digestive tract drug and a drug combination in Example 1.
  • Fig. 5 is a view showing a normal mouse jejunum villus in the application example 2 of the EGGG of the present invention for preparing a protective digestive tract drug and a drug combination.
  • Fig. 6 is a view showing the jejunum villi of a mouse medicinal drug (5-fluorouracil)-injured in the preparation of a protective digestive tract drug and a drug combination according to the present invention.
  • Fig. 7 is a view showing the jejunum villi of the 0.01% EGCG-treated group of the EGGG of the present invention in the preparation of a protective digestive tract drug and a drug combination in Example 2.
  • Fig. 8 is a view showing the jejunum villi of a 0.1% EGCG-treated group of the EGGG of the present invention in the preparation of a protective digestive tract drug and a drug combination in Example 2.
  • the present invention provides epigallocatechin gallate (EGCG), epigallocatechin gallate analogs and their conversion products and their respective pharmaceutically acceptable salts in the preparation of a protective digestive tract drug and a pharmaceutical combination application.
  • EGCG epigallocatechin gallate
  • epigallocatechin gallate analogs and their conversion products and their respective pharmaceutically acceptable salts in the preparation of a protective digestive tract drug and a pharmaceutical combination application.
  • the epigallocatechin gallate analog includes, but is not limited to, gallocatechin gallate (GCG) and epicatechin gallate (ECG); the epigallocatechin gallate and the table
  • the conversion products of the gallocatechin gallate analogs include, but are not limited to, one or several combinations of their glycosidation products, esterification products, and acetylation products.
  • the combination of the digestive tract drug and the drug is a drug and a drug combination for treating gastrointestinal damage in tumor chemotherapy.
  • the pharmaceutical and pharmaceutical combinations include, but are not limited to, tablets, powders, pills, emulsions, patches, extracts, capsules, injections, and oral solutions.
  • the present invention further provides a pharmaceutical and pharmaceutical combination for treating gastrointestinal damage in tumor chemotherapy, comprising epigallocatechin gallate, epigallocatechin gallate analog and their One or more of the transformation products and their respective pharmaceutically acceptable salts.
  • the epigallocatechin gallate analog includes, but is not limited to, gallocatechin gallate (GCG) and epicatechin gallate (ECG); the epigallocatechin gallate and the table
  • the conversion products of the gallocatechin gallate analogs include, but are not limited to, one or several combinations of their glycosidation products, esterification products, and acetylation products.
  • the pharmaceutical and pharmaceutical combinations include, but are not limited to, tablets, powders, pills, emulsions, patches, extracts, capsules, injections, and oral solutions.
  • the present invention also provides a method of treating or preventing gastrointestinal damage in a mammal, the method comprising the need for such treatment
  • the treated mammal takes one or more of an effective amount of epigallocatechin gallate, epigallocatechin gallate analog, and their conversion products, and their respective pharmaceutically acceptable salts.
  • the epigallocatechin gallate analog includes, but is not limited to, gallocatechin gallate (GCG) and epicatechin gallate (ECG); the epigallocatechin gallate and the table
  • the conversion products of the gallocatechin gallate analogs include, but are not limited to, one or several combinations of their glycosidation products, esterification products, and acetylation products.
  • the digestive tract injury is a digestive tract injury caused by tumor chemotherapy or a similar gastrointestinal injury caused by other pathologies.
  • the present invention utilizes BALB/C mice (male, 10 weeks old, 20 ⁇ 2 g) and cisplatin (tail vein injection, 5 mg/Kg) to establish a small amount of chemotherapy drugs.
  • Mouse digestive tract injury model The mice were divided into 4 groups, and the mice were grouped and treated as shown in Table 1.
  • FIG. 1 shows normal mouse jejunum villi.
  • Figure 2 shows jejunum villi in mice damaged by chemotherapeutic drugs (cisplatin);
  • Figure 3 shows jejunum villi in 0.01% EGCG-treated mice;
  • Figure 4 shows jejunum villi in 0.1% EGCG-treated mice.
  • the present invention utilizes BALB/C mice (male, 10 weeks old, 20 ⁇ 2 g) and 5-fluorouracil (tail vein injection, 80 mg/Kg) to establish a mouse model of digestive tract injury caused by chemotherapeutic drugs.
  • the mice were divided into 4 groups, and the mice were grouped and processed as shown in Table 2.
  • Fig. 5 shows normal mouse jejunum villi.
  • Figure 6 is a chemotherapy drug (5-fluorourine) Pyrimidine) injured jejunum villi;
  • Figure 7 is the jejunum villi of 0.01% EGCG treated group;
  • Figure 8 is the jejunum villi of 0.1% EGCG treated group.
  • epigallocatechin gallate EGCG
  • epigallocatechin gallate analogues and their conversion products of the present invention and their respective pharmaceutically acceptable salts for the preparation of a medicament for protecting digestive tract and a combination of drugs
  • the mouse model was used to improve the gastrointestinal tract injury of chemotherapeutic drugs by EGCG.
  • the gastrointestinal damage was induced by cisplatin/5-fluorouracil (tail vein injection), and the EGCG treatment group (adding EGCG to the feed) was used.
  • the digestive tract has been significantly improved.

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Abstract

本发明提供了表没食子儿茶素没食子酸酯（EGCG）、表没食子儿茶素没食子酸酯类似物、它们的转化产物及其可药用盐在制备保护消化道药物中的应用。所述消化道损伤可由治疗肿瘤的化疗药物引起。

Description

表没食子儿茶素没食子酸酯、其类似物和它们的转化产物及其各自可药用盐的应用 技术领域
本发明属于药物领域，具体涉及表没食子儿茶素没食子酸酯、其类似物和它们的转化产物及其各自可药用盐的应用。
背景技术
恶性肿瘤是危害人类身心健康的严重疾病，广谱杀伤性化学药物疗法是治疗恶性肿瘤的主要方法之一，可通过化学药物阻止癌细胞的增殖、浸润、转移，直至杀灭癌细胞，从而提高肿瘤患者生存率。缺点在于其副作用，尤其是严重的消化道损伤，引起胃肠道反应(如恶心、呕吐)等副反应症状，导致病人难以耐受，进而限制了化疗药物的应用剂量和范围，这也是很多在动物实验中表现良好的药物在人群中效果不理想的重要原因。
广谱杀伤性化学药物杀灭肿瘤细胞的机理各异，但其选择性都基于肿瘤细胞和正常细胞增殖速度的差异，实现对具有快速增殖能力的肿瘤细胞的抑制和杀伤。但不可避免的，这些药物对机体内正常的具有快速增殖能力的细胞也具有显著的抑制和杀伤作用，如生殖腺细胞和胃肠道细胞，表现为严重的生殖毒性和消化道毒性。
人类的消化道，由于直接与外界接触，又称为内表皮。在具有与皮肤类似的屏障功能的同时，消化道又担负着至关重要的消化、吸收功能，这决定了消化道，尤其是小肠黏膜的特点：薄，仅有1层细胞，有利于吸收功能，由于与外界接触而非常容易发生损伤。机体的解决方案是消化道黏膜的快速更新，不断用新生黏膜代替破损组织细胞。研究表明，人类的消化道黏膜每3-5天更新1遍，这样的更新生长速度比很多肿瘤的速度都要快，这也是广谱杀伤性化疗药物一般都具有严重消化道毒性的原因。
临床上常用的消化道毒性症状缓解方法是服用止吐药，能够缓解症状，但并未解决消化道损伤的问题。迄今为止，尚缺乏有效的预防或治疗化疗导致的消化道粘膜损伤的方法。茶叶经过长期饮用的验证，表明其具有良好的安全性，对茶叶水提物(即普通茶水的内含物质)的研究发现，其中60％的物质是一种称为表没食子儿茶素没食子酸酯(EGCG)的儿茶素，人们认为EGCG是茶叶的主要生物活性物质，已经将其作为一种保健食品和膳食补充剂在市场上广泛销售，而关于EGCG在肿瘤化疗中保护消化道的应用未见报道。肿瘤化疗中消化道副反应问题的解决，可以大大提高病人对化疗的耐受性，从而提高肿瘤病人对化疗的反应性和治愈率，很可能是肿瘤治疗领域的重大突破。
发明内容
本发明的目的之一是针对现有技术的不足，提供一种表没食子儿茶素没食子酸酯、其类似物和它们的转化产物及其各自可药用盐的应用。
本发明提供一种表没食子儿茶素没食子酸酯(EGCG)、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐在制备保护消化道药物和药物组合中的应用。
进一步的，所述表没食子儿茶素没食子酸酯类似物包含但不限于没食子儿茶素没食子酸 酯(GCG)和表儿茶素没食子酸酯(ECG)；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含但不限于它们的糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
进一步的，所述保护消化道药物和药物组合为治疗肿瘤化疗中消化道损伤的药物和药物组合。
进一步的，所述药物和药物组合包含但不限于片剂、粉剂、丸剂、乳剂、贴剂、浸膏、胶囊、注射液和口服液。
本发明再提供一种用于治疗肿瘤化疗中消化道损伤的药物和药物组合，所述药物和药物组合包含表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐的一种或几种。
进一步的，所述表没食子儿茶素没食子酸酯类似物包含但不限于没食子儿茶素没食子酸酯(GCG)和表儿茶素没食子酸酯(ECG)；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含但不限于它们的糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
进一步的，所述药物和药物组合包含但不限于片剂、粉剂、丸剂、乳剂、贴剂、浸膏、胶囊、注射液和口服液。
本发明还提供一种治疗或预防哺乳动物消化道损伤的方法，所述方法包含使需要这种治疗的哺乳动物服用有效数量的表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐中的一种或几种。
进一步的，所述表没食子儿茶素没食子酸酯类似物包含但不限于没食子儿茶素没食子酸酯(GCG)和表儿茶素没食子酸酯(ECG)；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含但不限于它们的糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
进一步的，所述消化道损伤为肿瘤化疗所致的消化道损伤或其他病理所致的类似消化道损伤。
本发明的有益效果在于：本发明的表没食子儿茶素没食子酸酯(EGCG)、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐在制备保护消化道药物和药物组合中的应用，利用小鼠模型进行了EGCG改善化疗药物对消化道损伤的试验，使用顺铂/5-氟尿嘧啶(尾静脉注射)造成小鼠消化道损伤，EGCG处理组(将EGCG添加在饲料中)小鼠的消化道得到显著改善。这些数据有力地证明了EGCG具有显著缓解化疗引起的消化道损伤的作用。EGCG作为来源于茶叶的天然产物，可安全、有效地改善或治疗肿瘤化疗中的消化道损伤，对提高化疗效果、改善化疗过程给肿瘤病人造成的痛苦具有非常重要的意义。
附图说明
图1所示为本发明EGGG在制备保护消化道药物和药物组合中的应用实施例1中正常的小鼠空肠绒毛图。
图2所示为本发明EGGG在制备保护消化道药物和药物组合中的应用实施例1中化疗药 物(顺铂)损伤的小鼠空肠绒毛图。
图3所示为本发明EGGG在制备保护消化道药物和药物组合中的应用实施例1中0.01％EGCG处理组小鼠空肠绒毛图。
图4所示为本发明EGGG在制备保护消化道药物和药物组合中的应用实施例1中0.1％EGCG处理组小鼠空肠绒毛图。
图5所示为本发明EGGG在制备保护消化道药物和药物组合中的应用实施例2中正常的小鼠空肠绒毛图。
图6所示为本发明EGGG在制备保护消化道药物和药物组合中的应用实施例2中化疗药物(5-氟尿嘧啶)损伤的小鼠空肠绒毛图。
图7所示为本发明EGGG在制备保护消化道药物和药物组合中的应用实施例2中0.01％EGCG处理组小鼠空肠绒毛图。
图8所示为本发明EGGG在制备保护消化道药物和药物组合中的应用实施例2中0.1％EGCG处理组小鼠空肠绒毛图。
具体实施方式
下文将结合具体附图详细描述本发明具体实施例。应当注意的是，下述实施例中描述的技术特征或者技术特征的组合不应当被认为是孤立的，它们可以被相互组合从而达到更好的技术效果。
本发明提供一种表没食子儿茶素没食子酸酯(EGCG)、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐在制备保护消化道药物和药物组合中的应用。
所述表没食子儿茶素没食子酸酯类似物包含但不限于没食子儿茶素没食子酸酯(GCG)和表儿茶素没食子酸酯(ECG)；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含但不限于它们的糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
所述保护消化道药物和药物组合为治疗肿瘤化疗中消化道损伤的药物和药物组合。
所述药物和药物组合包含但不限于片剂、粉剂、丸剂、乳剂、贴剂、浸膏、胶囊、注射液和口服液。
本发明再提供一种用于治疗肿瘤化疗中消化道损伤的药物和药物组合，所述药物和药物组合包含表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐的一种或几种。
所述表没食子儿茶素没食子酸酯类似物包含但不限于没食子儿茶素没食子酸酯(GCG)和表儿茶素没食子酸酯(ECG)；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含但不限于它们的糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
所述药物和药物组合包含但不限于片剂、粉剂、丸剂、乳剂、贴剂、浸膏、胶囊、注射液和口服液。
本发明还提供一种治疗或预防哺乳动物消化道损伤的方法，所述方法包含使需要这种治 疗的哺乳动物服用有效数量的表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐中的一种或几种。
所述表没食子儿茶素没食子酸酯类似物包含但不限于没食子儿茶素没食子酸酯(GCG)和表儿茶素没食子酸酯(ECG)；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含但不限于它们的糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
所述消化道损伤为肿瘤化疗所致的消化道损伤或其他病理所致的类似消化道损伤。
实施例1
为验证EGCG缓解化疗药物消化道副反应的效应，本发明利用BALB/C小鼠(雄性，10周龄，20±2g)和顺铂(尾静脉注射，5mg/Kg)建立化疗药物导致的小鼠消化道损伤模型。小鼠被分为4组，小鼠分组及处理方法如表1所示。
表1小鼠分组及处理
Figure PCTCN2015000538-appb-000001
取注射5天后的小鼠空肠，用福尔马林固定24h，然后进行HE染色，观察小鼠肠道绒毛的损伤情况，结果如图1-4所示，图1为正常的小鼠空肠绒毛；图2为被化疗药物(顺铂)损伤的小鼠空肠绒毛；图3为0.01％EGCG处理组小鼠空肠绒毛；图4为0.1％EGCG处理组小鼠空肠绒毛。
由图1-4可知，与正常组小鼠相比，接受顺铂注射5天后的小鼠空肠绒毛长度约缩短至正常小鼠的三分之一，且小肠隐窝快速增殖细胞群消失。与模型组小鼠相比，口服不同剂量EGCG(在饲料中添加不同比例EGCG)的小鼠肠绒毛长度显著恢复，0.1％EGCG处理组小鼠空肠绒毛的形态和长度显著改善，隐窝快速增殖细胞群显著增加。试验结果有力地证明了EGCG具有显著缓解顺铂引起的肠道损伤的作用。
实施例2
本发明利用BALB/C小鼠(雄性，10周龄，20±2g)和5-氟尿嘧啶(尾静脉注射，80mg/Kg)建立化疗药物导致的小鼠消化道损伤模型。小鼠被分为4组，小鼠分组及处理方法如表2所示。
表2小鼠分组及处理
Figure PCTCN2015000538-appb-000002
取注射7天后的小鼠空肠，用福尔马林固定24h，然后进行HE染色，观察小鼠肠道绒毛的损伤情况，结果如图5-8所示，图5为正常的小鼠空肠绒毛；图6为被化疗药物(5-氟尿 嘧啶)损伤的小鼠空肠绒毛；图7为0.01％EGCG处理组小鼠空肠绒毛；图8为0.1％EGCG处理组小鼠空肠绒毛。
由图5-8可知，与正常组小鼠相比，接受5-氟尿嘧啶注射7天后的小鼠空肠绒毛长度显著缩短，且小肠隐窝快速增殖细胞群基本消失。与模型组小鼠相比，口服不同剂量EGCG(在饲料中添加不同比例EGCG)的小鼠肠绒毛长度得以恢复，0.1％EGCG处理组小鼠空肠绒毛的形态和长度明显改善，隐窝快速增殖细胞群显著增加。试验结果证明了EGCG具有显著缓解5-氟尿嘧啶引起的肠道损伤的作用。
本发明的表没食子儿茶素没食子酸酯(EGCG)、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐在制备保护消化道药物和药物组合中的应用，利用小鼠模型进行了EGCG改善化疗药物对消化道损伤的试验，使用顺铂/5-氟尿嘧啶(尾静脉注射)造成小鼠消化道损伤，EGCG处理组(将EGCG添加在饲料中)小鼠的消化道得到显著改善。这些数据有力地证明了EGCG具有显著缓解化疗药物引起的消化道损伤的作用。EGCG作为来源于茶叶的天然产物，可安全、有效地改善或治疗肿瘤化疗中的消化道损伤，对改善化疗过程给肿瘤病人造成的痛苦具有非常重要的意义。
本文虽然已经给出了本发明的一些实施例，但是本领域的技术人员应当理解，在不脱离本发明精神的情况下，可以对本文的实施例进行改变。上述实施例只是示例性的，不应以本文的实施例作为本发明权利范围的限定。

Claims (10)

  1. 表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐在制备保护消化道药物和药物组合中的应用。
  2. 如权利要求1所述的应用，其特征在于，所述表没食子儿茶素没食子酸酯类似物包含没食子儿茶素没食子酸酯和表儿茶素没食子酸酯；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
  3. 如权利要求1或2任一项所述的应用，其特征在于，所述保护消化道药物和药物组合为治疗肿瘤化疗中消化道损伤的药物和药物组合。
  4. 如权利要求3所述的应用，其特征在于，所述药物和药物组合包含片剂、粉剂、丸剂、乳剂、贴剂、浸膏、胶囊、注射液和口服液。
  5. 一种用于治疗肿瘤化疗中消化道损伤的药物和药物组合，其特征在于，所述药物和药物组合包含表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐中的一种或几种。
  6. 如权利要求5所述的药物和药物组合，其特征在于，所述表没食子儿茶素没食子酸酯类似物包含没食子儿茶素没食子酸酯和表儿茶素没食子酸酯；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
  7. 如权利要求5或6任一项所述的药物和药物组合，其特征在于，所述药物和药物组合包含片剂、粉剂、丸剂、乳剂、贴剂、浸膏、胶囊、注射液和口服液。
  8. 一种治疗或预防哺乳动物消化道损伤的方法，其特征在于，所述方法包含使需要这种治疗的哺乳动物服用有效数量的表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯类似物和它们的转化产物及其各自可药用盐中的一种或几种。
  9. 如权利要求8所述的治疗或预防哺乳动物消化道损伤的方法，其特征在于，所述表没食子儿茶素没食子酸酯类似物包含没食子儿茶素没食子酸酯和表儿茶素没食子酸酯；所述表没食子儿茶素没食子酸酯和表没食子儿茶素没食子酸酯类似物的转化产物包含糖苷化产物、酯化产物和乙酰化产物中的一种或几种组合。
  10. 如权利要求8或9任一项所述的治疗或预防哺乳动物消化道损伤的方法，其特征在于，所述消化道损伤为肿瘤化疗所致的消化道损伤或其他病理所致的类似消化道损伤。
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