WO2019153325A1 - 青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用及药物组合物 - Google Patents

青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用及药物组合物 Download PDF

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WO2019153325A1
WO2019153325A1 PCT/CN2018/076433 CN2018076433W WO2019153325A1 WO 2019153325 A1 WO2019153325 A1 WO 2019153325A1 CN 2018076433 W CN2018076433 W CN 2018076433W WO 2019153325 A1 WO2019153325 A1 WO 2019153325A1
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diabetes
type
pharmaceutical composition
artemisinin derivative
artemether
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French (fr)
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孙惠力
韩鹏勋
李顺民
易铁钢
邵牧民
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深圳市中医院
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

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  • the present invention belongs to the field of biomedicine, and more particularly to the use and pharmaceutical composition of an artemisinin derivative for the preparation of a medicament for preventing and treating type 2 diabetes and its complications.
  • Diabetes is a chronic non-communicable disease with a high prevalence of human health. It is characterized by elevated blood sugar and can cause chronic damage to various tissues, especially the kidneys, heart, eyes, blood vessels and nerves. In China, with the increase in the prevalence of type 2 diabetes, diabetic nephropathy has gradually replaced glomerulonephritis as the first cause of chronic kidney disease.
  • Artemisinin (Q) is a sesquiterpene lactone drug with a peroxy group extracted from the plant Artemisia annua L., and its common derivatives are dihydroartemisinin (DI) and artesunate. (Artesunate, ART), artemether (J), Arteether, Artemisone, and the like. Artemisinin derivatives are a kind of drugs that can effectively treat malaria. In recent years, studies have shown that these drugs can effectively inhibit tumor development, and also show obvious curative effect in the treatment of systemic lupus erythematosus. The use of artemisinin derivatives in type 2 diabetes and its complications has not yet been discovered.
  • the object of the present invention is to provide an application and a pharmaceutical composition of an artemisinin derivative for the preparation of a medicament for preventing and treating type 2 diabetes and its complications.
  • the present invention proposes the following technical solution: the application of an artemisinin derivative in the preparation of a medicament for preventing and treating type 2 diabetes and its complications.
  • the artemisinin derivative is used to increase the respiratory quotient of type 2 diabetes and promote glucose oxidation of the metabolic substrate.
  • the artemisinin derivative is used to reduce fasting blood glucose in type 2 diabetes and to improve diabetic polydipsia and polyuria symptoms.
  • the artemisinin derivative is used to reduce excretion of urinary albumin in type 2 diabetes and to protect kidney target organs.
  • the medicament is an oral administration dosage form, an injection administration dosage form, a mucosal administration dosage form, or a transdermal administration dosage form.
  • the drug is a tablet, capsule, granule, oral solution, patch, or gel.
  • the artemisinin derivative comprises artemether.
  • the present invention also provides the following technical solution: a pharmaceutical composition for preventing and treating type 2 diabetes and its complications, wherein the active ingredient of the pharmaceutical composition is an artemisinin derivative.
  • the artemisinin derivative comprises artemether.
  • the pharmaceutical composition is a tablet, capsule, granule, oral solution, patch, or gel.
  • the present invention has the following beneficial effects: the present invention aims to investigate the protective effect of artemether on type 2 diabetes mellitus and its complications and the mechanism of action of artemether, and the results show that artemether can significantly increase type 2 diabetic mice.
  • the respiratory quotient promotes glucose oxidation of the metabolic substrate, reduces fasting blood glucose in type 2 diabetic mice, improves polydipsia, polyuria symptoms in type 2 diabetic mice, and reduces renal urinary albumin excretion rate.
  • the artemone is prepared into an oral administration form, an injection administration form, a mucosal administration form or a transdermal administration form using an existing preparation process, or a tablet, a capsule, a granule, an oral solution, a patch Or a gelling agent for the prevention and treatment of type 2 diabetes and its complications, especially diabetic nephropathy.
  • Figure 1 shows the effect of artemether on the respiratory quotient of type 2 diabetic db/db mice after 3 weeks of treatment. Compared with the WT group, *P ⁇ 0.05; compared with the db/db group, ### P ⁇ 0.001;
  • Figure 2 shows the effect of artemether on fasting blood glucose in type 2 diabetic db/db mice.
  • Group compared with WT *** P ⁇ 0.001; Compared with db / db group, # P ⁇ 0.05, ### P ⁇ 0.001;
  • Figure 3 shows the effect of artemether on the urine volume of type 2 diabetes db/db mice (after 2 weeks of artemether treatment), water intake, and food intake (after 3 weeks of artemether treatment).
  • WT group ***P ⁇ 0.001; compared with the db/db group, ### P ⁇ 0.001;
  • Figure 4 shows the effect of artemether on renal urinary albumin excretion rate in type 2 diabetic db/db mice.
  • Group compared with WT *** P ⁇ 0.001; Compared with db / db group, # P ⁇ 0.01;
  • the main blood sugar utilization disorder of diabetes leads to hyperglycemia, which causes damage to various target organs, serious complications, high disability and high mortality.
  • the current pathogenesis is not completely clear.
  • the present invention aims to observe the preventive and therapeutic effects of artemisinin derivatives such as artemether on type 2 diabetes and its complications.
  • the present invention provides the following technical solutions:
  • mice 5 week old male db/db mice and normal control wild type (WT) mice were purchased from Nanjing University-Nanjing Biomedical Research Institute. Animal experiments were carried out in strict accordance with animal ethics guidelines and regulations, and were kept at the Animal Center of Peking University Shenzhen graduate School. The experimental animals were controlled to freely ingest and drink at a constant room temperature of 23 ⁇ 1 ° C, 12 hours light and 12 hours dark cycle. Two weeks later (7 weeks old mice), db/db mice were randomly assigned to db/db group and db/db+artemether group, 6 rats in each group, and 6 wild type mice were selected as normal controls.
  • WT normal control wild type mice
  • the group ie, the WT group in the chart of the present invention
  • the WT group and the db/db group mice were fed with conventional food
  • the db/db+artemether group was fed with artemether-added food.
  • Artemether was purchased from Chengdu Kangbang Biotechnology Co., Ltd. and added to the food of mice at a standard ratio of 0.67 g/kg.
  • Urine volume and urinary albumin determination After 2 weeks of drug intervention (mouse 9 weeks old), each group of mice was given 24-hour urine using metabolic cage (Tecniplast Spa, Buguggiate, Italy), and urine volume was recorded. Value. The 24-hour urinary albumin excretion rate was determined using a urinary albumin ELISA kit (Bethyl Laboratories, Montgomery, TX, U.S.).
  • Measurement data are expressed as mean ⁇ standard deviation. Statistical differences between the two groups of samples were analyzed by independent sample t-test. Comparisons between groups of samples were analyzed by one-way analysis of variance, and statistical analysis was performed using SPSS16.0 statistical software. A statistical difference was considered to be significant at P ⁇ 0.05.
  • 1, artemether can significantly increase the respiratory quotient of type 2 diabetes db / db mice.
  • artemether can significantly reduce the fasting blood glucose of type 2 diabetes db / db mice.
  • artemether significantly improved the symptoms of polydipsia and polyuria in type 2 diabetes db/db mice.
  • artemether can significantly reduce the urinary albumin excretion rate of db / db mice 24h.
  • artemether as an anti-malarial drug can significantly increase the respiratory quotient of type 2 diabetes db/db mice, promote glucose oxidation, lower blood sugar, improve diabetes symptoms, and reduce urinary albumin excretion rate.
  • artemisinin derivatives with artemether as an example have obvious preventive and therapeutic effects on type 2 diabetes and its complications.

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Abstract

本发明公开了青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用，和含有青蒿素衍生物的药物组合物。经实验表明青蒿素衍生物例如蒿甲醚可增加2型糖尿病的呼吸商，促进代谢底物葡萄糖氧化，降低2型糖尿病血糖，改善多饮、多尿症状，减少尿蛋白排泄的作用。

Description

青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用及药物组合物 技术领域
本发明属于生物医药领域，更具体的说，涉及青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用及药物组合物。
背景技术
糖尿病是一类严重威胁人类健康具有很高患病率的慢性非传染性疾病，以血糖升高为特征，可导致各种组织，特别是肾脏、心脏、眼睛、血管、神经等慢性损害。在中国，随着2型糖尿病患病率的增加，糖尿病肾病也逐渐取代肾小球肾炎成为慢性肾脏病的首位致病因素。
青蒿素(artemisinin,Q)是从植物青蒿中提取的有过氧基团的倍半萜内酯药物，其常见的衍生物有双氢青蒿素(Dihydroartemisinin，DI)、青蒿琥酯(Artesunate，ART)、蒿甲醚(artemether，J)、蒿乙醚(Arteether)、青蒿酮(Artemisone)等。青蒿素衍生物是一类能有效治疗疟疾的药物，近年研究显示该类药物能有效的抑制肿瘤发展，在系统性红斑狼疮的治疗中也显示出了明显的疗效。目前尚未发现青蒿素衍生物在2型糖尿病及其并发症中的应用。
发明内容
本发明的目的在于提供青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用及药物组合物。
本发明为了达到上述目的，提出如下技术方案：青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用。
在其中一些实施例中，所述青蒿素衍生物用于增加2型糖尿病的呼吸商，促进代谢底物葡萄糖氧化。
在其中一些实施例中，所述青蒿素衍生物用于降低2型糖尿病的空腹血糖，改善糖尿病多饮、多尿症状。
在其中一些实施例中，所述青蒿素衍生物用于降低2型糖尿病尿白蛋白的排泄，保护肾脏靶器官。
在其中一些实施例中，所述药物为口服给药剂型、注射给药剂型、粘膜给药剂型或者经皮给药剂型。
在其中一些实施例中，所述药物为片剂、胶囊剂、颗粒剂、口服液、贴剂或者凝胶剂。
在其中一些实施例中，所述青蒿素衍生物包括蒿甲醚。
本发明为了达到上述目的，还提出如下技术方案：一种用于预防和治疗2型糖尿病及其并发症的药物组合物，所述药物组合物的有效成分为青蒿素衍生物。
在其中一些实施例中，所述青蒿素衍生物包括蒿甲醚。
在其中一些实施例中，所述药物组合物为片剂、胶囊剂、颗粒剂、口服液、贴剂或者凝胶剂。
实施本发明，具有如下有益效果：本发明旨在探讨蒿甲醚对2型糖尿病及其并发症的保护作用及蒿甲醚的作用机制，结果显示：蒿甲醚可明显增加2型糖尿病小鼠的呼吸商，促进代谢底物葡萄糖氧化，降低2型糖尿病小鼠的空腹血糖，改善2型糖尿病小鼠多饮、多尿症状，并减少肾脏尿白蛋白的排泄率。使用现有的制备工艺将蒿甲醚制成口服给药剂型、注射给药剂型、粘膜给药剂型或者经皮给药剂型的药物，或者片剂、胶囊剂、颗粒剂、口服液、贴剂或者凝胶剂的药物，可以用于预防和治疗2型糖尿病及其并发症尤其是糖尿病肾病。
附图说明
下面将结合附图及实施例对本发明作进一步说明，附图中：
图1为蒿甲醚治疗3周后对2型糖尿病db/db小鼠呼吸商的影响结果。与WT组比较，*P<0.05；与db/db组比较， ###P<0.001；
图2为蒿甲醚对2型糖尿病db/db小鼠空腹血糖的影响结果。与WT组比较，***P<0.001；与db/db组比较， #P<0.05， ###P<0.001；
图3为蒿甲醚对2型糖尿病db/db小鼠尿量(蒿甲醚治疗2周后)、饮水量、进食量(蒿甲醚治疗3周后)的影响结果。与WT组比较，***P<0.001；与db/db组比较， ###P<0.001；
图4为蒿甲醚对2型糖尿病db/db小鼠肾脏尿白蛋白排泄率的影响结果。与WT组比较，***P<0.001；与db/db组比较， #P<0.01；
具体实施方式
下面将结合附图对本发明的实施例进行具体描述。
糖尿病主要血糖利用障碍导致高血糖，进而引起各种靶器官的损害，并发症严重，致残和致死率高，目前发病机制尚不完全明确。
本发明旨在观察青蒿素衍生物例如蒿甲醚对2型糖尿病及其并发症的防治作用。
本发明为了达到上述目的，提供如下技术方案：
1、研究蒿甲醚治疗对2型糖尿病小鼠呼吸商的影响；
2、研究蒿甲醚治疗对2型糖尿病小鼠空腹血糖的影响；
3、研究蒿甲醚治疗对2型糖尿病小鼠多饮、多尿症状的影响；
4、研究蒿甲醚治疗对2型糖尿病小鼠尿白蛋白排泄率的影响。
一、实验方法
1、动物模型：5周龄雄性db/db小鼠和正常对照野生型(wild type，WT)小鼠购买于南京大学-南京生物医药研究院。动物实验严格按照动物伦理相关准则和条例进行，饲养于北京大学深圳研究生院动物中心。实验动物受控在恒定室温23±1℃，12小时光照和12小时黑暗循环的条件下，同时自由摄食和饮水。2周后(小鼠7周龄)，将db/db实验小鼠随机分配为db/db组和db/db+蒿甲醚组，每组6只，另外选取6只野生型小鼠作为正常对照组(即本发明图表中WT组)，其中WT组和db/db组小鼠喂养常规食物，db/db+蒿甲醚组喂养添加蒿甲醚的食物。蒿甲醚购买于成都康邦生物科技有限公司，以 0.67g/kg标准比例添加到小鼠的食物中。
2、呼吸商、饮水量、进食量测定：药物干预3周后(小鼠10周龄)，将各组小鼠放于动物能量监测系统(Comprehensive laboratory animal monitoring system,CLAMS,Columbus Instruments,Columbus,OH,U.S.)记录24小时(7a.m.至次日7a.m.)能量代谢状态，呼吸商以VCO 2/VO 2表示，也即是呼出CO 2体积与消耗O 2体积的比值。同时记录饮水量和进食量。
3、空腹血糖测定：药物开始干预后，每2周测定各组小鼠空腹血糖，将每组小鼠禁食不禁水(9a.m.至3p.m.)后使用血糖仪(Roche,Basel,Switzerland)测定血糖数值，共计监测四周。
4、尿量及尿白蛋白测定：药物干预2周后(小鼠9周龄)，将各组小鼠使用代谢笼(Tecniplast S.p.a,Buguggiate,Italy)留取24小时尿液，并记录尿量数值。使用尿白蛋白ELISA试剂盒(Bethyl Laboratories,Montgomery,TX,U.S.)测定24h尿白蛋白排泄率。
5、统计分析
计量资料使用均数±标准差表示。两组样本间的统计差异采用独立样本t检验进行分析，多组样本之间的比较使用单因素方差分析，统计分析采用SPSS16.0统计软件处理。P<0.05时视为在统计学上差异具有显著性。
二、结果
1、蒿甲醚可显著增加2型糖尿病db/db小鼠的呼吸商。
如图1所示，蒿甲醚药物干预3周后(即小鼠10周龄时)，db/db组小鼠呼吸商明显降低，经蒿甲醚干预3周后db/db+蒿甲醚组呼吸商较db/db组明显升高。
2、蒿甲醚可明显降低2型糖尿病db/db小鼠的空腹血糖。
如图2所示，db/db小鼠空腹血糖逐渐升高，在治疗0周、2周、4周时显著高于WT组，蒿甲醚治疗2周和4周后可明显降低db/db小鼠空腹血糖。
3、蒿甲醚明显改善2型糖尿病db/db小鼠多饮、多尿的症状。
如图3所示，蒿甲醚治疗2周后，db/db小鼠的尿量明显减少，多尿症状 显著改善。蒿甲醚治疗3周后，db/db小鼠饮水量明显减少，多饮症状明显改善。蒿甲醚治疗后，db/db小鼠的进食量虽有所减少，但统计学并未有显著性意义。
4、蒿甲醚可明显减少db/db小鼠24h尿白蛋白排泄率。
如图4所示，蒿甲醚治疗2周后，db/db小鼠的肾脏尿白蛋白排泄率明显下降，表明其有明显的肾保护作用。
上述实验结果表明，蒿甲醚作为一种抗疟疾药，可显著增加2型糖尿病db/db小鼠的呼吸商，促进葡萄糖氧化，降低血糖，改善糖尿病症状，降低尿白蛋白排泄率。综上，以蒿甲醚为例的青蒿素衍生物对2型糖尿病及其并发症具有明显的防治作用。
上面结合附图对本发明的实施例进行了描述，但是本发明并不局限于上述的具体实施方式，上述的具体实施方式仅仅是示意性的，而不是限制性的，本领域的普通技术人员在本发明的启示下，在不脱离本发明宗旨和权利要求所保护的范围情况下，还可做出很多形式，这些均属于本发明的保护范围之内。

Claims (10)

  1. 青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述青蒿素衍生物用于增加2型糖尿病的呼吸商，促进代谢底物葡萄糖氧化。
  3. 根据权利要求1所述的应用，其特征在于，所述青蒿素衍生物用于降低2型糖尿病的空腹血糖，改善糖尿病多饮、多尿症状。
  4. 根据权利要求1所述的应用，其特征在于，所述青蒿素衍生物用于降低2型糖尿病尿白蛋白的排泄，保护肾脏靶器官。
  5. 根据权利要求1所述的应用，其特征在于，所述药物为口服给药剂型、注射给药剂型、粘膜给药剂型或者经皮给药剂型。
  6. 根据权利要求1所述的应用，其特征在于，所述药物为片剂、胶囊剂、颗粒剂、口服液、贴剂或者凝胶剂。
  7. 根据权利要求1所述的应用，其特征在于，所述青蒿素衍生物包括蒿甲醚。
  8. 一种用于预防和治疗2型糖尿病及其并发症的药物组合物，其特征在于，所述药物组合物的有效成分为青蒿素衍生物。
  9. 根据权利要求7所述的药物组合物，其特征在于，所述青蒿素衍生物包括蒿甲醚。
  10. 根据权利要求7所述的药物组合物，其特征在于，所述药物组合物为片剂、胶囊剂、颗粒剂、口服液、贴剂或者凝胶剂。
PCT/CN2018/076433 2018-02-12 2018-02-12 青蒿素衍生物在制备预防和治疗2型糖尿病及其并发症药物中的应用及药物组合物 WO2019153325A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106459079A (zh) * 2014-04-11 2017-02-22 分子医学研究中心责任有限公司 青蒿素化合物及桥蛋白激动剂的医疗用途
CN107349198A (zh) * 2016-05-10 2017-11-17 复旦大学 蒿甲醚在制备促进脂肪分解和改善糖代谢制剂中的用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106459079A (zh) * 2014-04-11 2017-02-22 分子医学研究中心责任有限公司 青蒿素化合物及桥蛋白激动剂的医疗用途
CN107349198A (zh) * 2016-05-10 2017-11-17 复旦大学 蒿甲醚在制备促进脂肪分解和改善糖代谢制剂中的用途

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