CN1777581A - 糖尿病治疗剂 - Google Patents
糖尿病治疗剂 Download PDFInfo
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- CN1777581A CN1777581A CNA2004800106886A CN200480010688A CN1777581A CN 1777581 A CN1777581 A CN 1777581A CN A2004800106886 A CNA2004800106886 A CN A2004800106886A CN 200480010688 A CN200480010688 A CN 200480010688A CN 1777581 A CN1777581 A CN 1777581A
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Abstract
本发明的课题在于提供糖尿病治疗剂、胰岛素耐受性改善剂、或用于糖尿病治疗的或用于改善胰岛素耐受性的食品饮料、食品饮料添加剂、饲料或饲料添加剂。为解决该课题,本发明提供了作为有效成分含有羟脯氨酸、羟脯氨酸衍生物或其在药理学上允许的盐的糖尿病治疗剂以及胰岛素耐受性改善剂、用于糖尿病治疗或者用于胰岛素耐受性改善的食品饮料、食品饮料添加剂、饲料和饲料添加剂。
Description
技术领域
本发明涉及糖尿病治疗剂、胰岛素耐受性改善剂、用于糖尿病治疗或者胰岛素耐受性改善的食品饮料、食品饮料添加剂、饲料和饲料添加剂。
背景技术
到目前为止,已知有如磺脲或磺酰胺这样的促进胰岛素分泌的糖尿病治疗剂、噻唑烷(thiazolidine)或双胍剂这样的改善胰岛素耐受性的糖尿病治疗剂、α-葡萄糖苷酶抑制剂这样的改善饭后血糖的糖尿病治疗剂等。在糖尿病的治疗中单独或组合使用这些治疗剂。
羟脯氨酸作为胶原中的主要构成氨基酸广泛存在于自然界中。除了它的N-乙酰基化物用作消炎药物之外,还被用作碳青霉烯类抗生素物质或降血压药物、抗哮喘药物、末梢循环改善药物、阻止血液凝固药物等多种药物的合成原料,从该物质还具有保湿的功能特性考虑,还用于化妆品(バイオサイエンスとインダストリ一,1998年,第56卷,第1号,p.11-16)。此外,还用作果汁饮料或清凉饮料水、普通食品的味感调整或风味改善的食品添加剂,也可以用作香料的原料(第7版,食品添加剂法定解释说明书,广川书店,1998年,p.D-1114-1115)。
已知羟脯氨酸具有抑制肌肤老化作用和改善肤质作用(国际公开第00/51561号小册子、特开2002-80321号公报)、消炎作用、抗风湿作用、镇痛作用和创伤治愈作用(特开平8-337526号公报)等药理作用,不过没有关于糖尿病治疗作用以及胰岛素耐受性改善作用的报告。
此外,虽然已知单羟基化的氨基酸具有类胰岛素和/或胰岛素敏感性促进作用(特表2003-508435号公报),不过一直没有示出与羟脯氨酸和羟脯氨酸衍生物的有效性相关的数据。
发明内容
本发明的目的是提供糖尿病治疗剂、胰岛素耐受性改善剂、用于糖尿病治疗或胰岛素耐受性改善的食品饮料、食品饮料添加剂、饲料或饲料添加剂
本发明涉及下述(1)~(14):
(1)一种糖尿病治疗剂,其中含有通式(I)所表示的羟脯氨酸或羟脯氨酸衍生物[以下称为化合物(I)]或它们的在药理学上允许的盐作为有效成分;
通式(I)
[式中,R1表示氢或酰基,R2表示氢、或饱和或不饱和的烃基,R3以及R4之一表示氢,另一方表示OR5(式中,R5表示氢或酰基)]。
(2)一种用于治疗糖尿病的食品饮料或食品饮料添加剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
(3)一种用于治疗糖尿病的饲料或饲料添加剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
(4)一种胰岛素耐受性改善剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
(5)一种用于改善胰岛素耐受性的食品饮料或食品饮料添加剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
(6)一种用于改善胰岛素耐受性的饲料或饲料添加剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
(7)糖尿病治疗方法,其特征是,给予化合物(I)或其在药理学上允许的盐。
(8)胰岛素耐受性改善方法,其特征是,给予化合物(I)或其在药理学上允许的盐。
(9)化合物(I)或其在药理学上允许的盐在糖尿病治疗剂的制造中的应用。
(10)化合物(I)或其在药理学上允许的盐在用于糖尿病治疗的食品饮料或食品饮料添加剂的制造中的应用。
(11)化合物(I)或其在药理学上允许的盐在用于糖尿病治疗的饲料或饲料添加剂的制造中的应用。
(12)化合物(I)或其在药理学上允许的盐在胰岛素耐受性改善剂的制造中的应用。
(13)化合物(I)或其在药理学上允许的盐在用于改善胰岛素耐受性的食品饮料或食品饮料添加剂的制造中的应用。
(14)化合物(I)或其在药理学上允许的盐在用于改善胰岛素耐受性的饲料或饲料添加剂的制造中的应用。
具体实施方式
在化合物(I)的各个基团的定义中,作为酰基,例如:碳原子数2~23的直链或分支状的酰基,更具体可列举:乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、己酰基、庚酰基、辛酰基、癸酰基、二十烷酰基、三十烷酰基等,其中,优选乙酰基、丙酰基。
作为饱和或不饱和的烃基,例如:碳原子数1~30的直链或分支状的饱和或不饱和的烃基,更具体可列举:甲基、乙基、丙基、异丙基、丁基、t-丁基、异丁基、3-甲基-1-丁基、2-甲基-1-丁基、戊基、己基、辛基、2-乙基己基、十二烷基、十四烷基、十六烷基、十八酰基、油醇、二十烷酰基、植基、二十二烷基、蜂花基(メリツシル)、三十烷基等,其中,优选碳原子数1~20的直链或分支状的饱和或不饱和的烃基,具体可列举:甲基、乙基、丙基、异丙基、丁基、t-丁基、异丁基、3-甲基-1-丁基、2-甲基-1-丁基、戊基、己基、辛基、2-乙基己基、十二烷基、十六烷基、十八酰基、油醇、二十烷基、植基等。
化合物(I)中,R1和R2为氢,R3和R4之一为氢,另一方为OH的化合物是羟脯氨酸。羟脯氨酸作为胶原中的主要构成氨基酸成分以及弹性蛋白的构成氨基酸广泛存在于自然界中。因为有D型或L型,羟基的位置可以在3位或4位,以及其立体构象有顺式和反式之分,所以天然存在的羟脯氨酸已知有8种立体结构。具体可列举:顺式-4-羟基-L-脯氨酸、顺式-4-羟基-D-脯氨酸、顺式-3-羟基-L-脯氨酸、顺式-3-羟基-D-脯氨酸、反式-4-羟基-L-脯氨酸、反式-4-羟基-D-脯氨酸、反式-3-羟基-L-脯氨酸和反式-3-羟基-D-脯氨酸等。
在本发明中,可以使用任何一种羟脯氨酸,优选使用反式-4-羟基-L-脯氨酸。
可以按照常规方法,酸水解来自猪或牛等动物的胶原,纯化获取羟脯氨酸,优选用微生物制造的羟脯氨酸。
作为微生物,可以使用选自属于淀粉霉(
Amycolatopsis)属、指孢囊菌(
Dactylosporangium)属和链霉菌(
Streptomyces)属的微生物或已导入来自上述微生物的脯氨酸3位水解酶或脯氨酸4位水解酶基因的微生物。可以按照Molecular Cloning,A Laboratory Manual,Second Edition,Cold Spring Harbor Laboratory Press(1989),Current Protocols in Molecular Biology,John Wiley & Sons(1987-1997)等中记载的方法,向微生物中导入来自属于淀粉霉属、指孢囊菌属和链霉菌属的微生物的脯氨酸3位水解酶或脯氨酸4位水解酶基因。
例如,可以用从属于淀粉霉属或指孢囊菌属的微生物中分离出的脯氨酸4位水解酶(特开平7-313179号公报)制造反式-4-羟基-L-脯氨酸,或者也可以用从属于链霉菌属的微生物中分离的脯氨酸3位水解酶(特开平7-322885号公报)制造顺式-3-羟基-L-脯氨酸(Bioindustrial,14,31(1997))。
可以按照例如:国际公开第00/51561号小册子等中记载的公知方法,从R1或R5为氢的化合物出发,制造R1或R5为酰基的化合物。
可以按照例如:特开第2000-355531号公报等中记载的公知方法,从R2为氢的化合物出发,制造R2为饱和或不饱和烃基的化合物。
另外,定义的基团在实施方法的条件下发生变化或不适合实施方法时,可以用有机合成化学中常用的导入和去除保护基团的方法(Protective Groups in Organic Synthesis,T.W.Greene著,JohnWiley & Sons Inc.(1981))等得到目的化合物。
可以用结晶、层析等常用的纯化方法纯化得到的化合物。
作为化合物(I)的药理学上允许的盐,可举出钠盐、钾盐等的碱金属盐,镁盐、钙盐等的碱土金属盐,铵、四甲基铵等的铵盐,吗啉、哌啶等加成的有机胺加成盐等。
本发明的糖尿病治疗剂或者胰岛素耐受性改善剂是作为有效成分含有单独或混合化合物(I)或其盐的、或与任意其他用于治疗的有效成分的混合物的制剂。
可将有效成分与药理学上允许的一种或一种以上的载体一起混合,按照在制剂学技术领域公知的任意方法制造该制剂。
希望制剂的给予方式使用在治疗时最能发挥效果的方式,可列举:口服给药,或例如:经脉内、腹膜内以及皮下给药等非口服给药,但优选口服给药。
作为给药的剂型可以采用,例如:片剂、散剂、颗粒剂、丸剂、悬浊剂、乳剂、浸出剂、煎剂、胶囊、糖浆、液体制剂、酏剂、提取剂、酊剂、流体提取剂等口服剂,注射剂、点滴剂、膏剂、栓剂等非口服剂中的任何一种,优选作为口服剂使用。
制备口服剂时,可以使用赋形剂、粘合剂、崩解剂、润滑剂、分散剂、悬浊剂、乳化剂、稀释剂、缓冲剂、抗氧化剂、细菌抑制剂等添加剂。
可以添加下述物质制造适于口服给药的制剂,例如:糖浆这种液体制剂可以添加水、蔗糖、山梨糖醇、果糖等糖类;聚乙二醇、丙二醇等二醇类;芝麻油、橄榄油、大豆油等油类;P-羟基苯甲酸酯类等防腐剂;对羟基苯甲酸甲酯等对羟基苯甲酸衍生物、苯甲酸钠等保存剂;草莓香料、薄荷香料类等,进行制剂。
还有,可以添加下述物质适于口服给药制剂,例如:片剂、散剂以及颗粒剂等,可以添加乳糖、白糖、葡萄糖、蔗糖、甘露糖醇、山梨糖醇等糖类;马铃薯、小麦、玉米等淀粉;碳酸钙、硫酸钙、碳酸氢钠、氯化钠等无机物;结晶纤维素、甘草粉末、龙胆粉末等植物粉末等赋形剂;淀粉、琼脂、明胶、结晶纤维素、羧甲基纤维素钠、羧甲基纤维素钙、碳酸钙、碳酸氢钠、藻酸钠等崩解剂;硬脂酸镁、滑石、加氢植物油、聚乙二醇、硅油等润滑剂;聚乙烯醇、羟丙基纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素、明胶、淀粉糊***等粘合剂;脂肪酸酯等表面活性剂;甘油等塑型剂等,进行制剂。
可以使用含有下述物质的载体制备适于非口服给药的制剂,例如:优选含有与接收制剂者的血液等张力的化合物(I)或其盐的灭菌的水性制剂。例如:注射剂时,使用盐溶液、葡萄糖溶液或盐溶液和葡萄糖溶液的混合物组成的载体等制备注射用溶液。
还有,在这些非口服制剂中,可以添加口服制剂中列举的稀释剂、防腐剂、香料类、赋形剂、崩解剂、润滑剂、粘合剂、表面活性剂、塑型剂等中的一种或多种上述辅助成分。
本发明的制剂的给药剂量和给药次数,根据给药方式、患者的年龄、体重、治疗对应症状的性质或严重程度而有所不同,通常,成人每天给药1次至数次,给予5mg~5000mg、优选50mg~5000mg的化合物(I)或其盐。
给药周期没有特别的限定,通常为1天~1年,优选2周~3个月。
另外,本发明的制剂不仅可以用于人,也可以用于人以外的动物(下面,略称为非人动物)。
作为非人动物可列举:哺乳类、鸟类、爬虫类、两栖类、鱼类等人以外的动物。
对非人动物的给药时的给药剂量,根据动物的年龄、种类、症状的性质或严重程度而有所不同,通常每1kg体重每天给药一次到数次,给予0.5mg~500mg、优选5mg~500mg的化合物(I)或其盐。
给药周期没有特别的限定,通常为1天~1年,优选2周~3个月。
用与本发明的制剂同样的方法,制备作为有效成分含有化合物(I)或其盐的食品饮料添加剂。
根据需要,混合或溶解其他食品饮料添加剂加工、制造成如:粉末、颗粒、散丸、片剂、各种液体制剂的形式的本发明的食品饮料添加剂。
除了在食品饮料中添加化合物(I)或其盐、或本发明的食品饮料添加剂之外,可按照一般的食品饮料的制造方法加工、制造本发明的食品饮料。
此外,本发明的食品饮料可采用如下方法进行制造。如:流动层制粒、搅拌制粒、挤压制粒、转动制粒、气流制粒、压缩成型制粒、分解破碎制粒、喷雾制粒、喷射制粒等制粒方法;盘式包覆、流动层包覆、干法包覆等包覆方法;粉状干燥、过剩水蒸汽法、发泡法、微波加热法等膨化方法;挤压制粒机或挤塑机等挤压方法进行制造。
作为本发明的食品饮料可以是下述任何一种形式,例如:果汁类、清凉饮料水、茶类、乳酸菌饮料、发酵乳、冷点、黄油、奶酪、酸乳、加工乳、脱脂乳等乳制品;火腿、香肠、汉堡等畜肉制品;鱼糕、鱼卷、油炸鱼丸等鱼肉制品;蛋卷、鸡蛋豆腐等鸡蛋制品;饼干、果冻、口香糖、糖果、零食点心等点心类;面包类、面类、腌制物类、熏制品、晾干物、煮制物、盐制保藏品、汤类、调味料等。
还有,本发明的食品饮料还可以是下述形式,例如:粉末状食品、片层状食品、瓶装食品、罐装食品、袋装食品、胶囊粒状食品、片剂状食品、流动食品、饮料剂等。
本发明的食品饮料可以用作具有糖尿病治疗作用的健康饮料食品或功能性饮料食品。
在本发明的食品饮料或食品饮料添加剂中还可以添加用于一般食品饮料的添加剂,例如:食品添加剂手册(日本食品添加剂协会,平成9年1月6日发行)中记载的甜味剂、着色剂、保存剂、增粘稳定剂、防氧化剂、发色剂、漂白剂、防霉菌剂、胶基质、苦味剂、酶、光泽剂、酸味剂、调味剂、乳化剂、强化剂、制造用剂、香料、香辛料提取物等。
可根据食品饮料的种类、期望摄取该食品饮料产生的效果等适当选择向本发明的食品饮料中加入的化合物(I)或其盐、或食品饮料添加剂的添加量。通常添加使之含有0.1重量%~100重量%、优选1.0重量%~100重量%的化合物(I)或其盐。
根据摄取方式、摄取者的年龄、体重等差异,通常成人每天,一次或数次口服给予,即摄取本发明的食品饮料,其中含5mg~5000mg、优选50mg~5000mg的化合物(I)或其盐。
摄取周期没有特别限制,通常为1天~1年,优选2周~3个月。
用与本发明的食品饮料添加剂相同的方法,制备作为效成分含有化合物(I)或其盐的饲料添加剂。根据需要,混合或溶解其他饲料添加剂,加工、制造成例如:粉末、颗粒、散丸、片剂、各种液体制剂形式的本发明的饲料添加剂。
除了在非人动物用的饲料中添加化合物(I)或其盐、或本发明的饲料添加剂之外,可以用一般的饲料制造方法加工、制造本发明的饲料。
作为非人动物用的饲料,可以是哺乳类、鸟类、爬虫类、两栖类或鱼类等任何一种非人动物用的饲料,可列举:狗、猫、鼠等宠物用的饲料,牛、猪等家畜用的饲料,鸡、七面鸟等家禽用的饲料,鲷鱼、鲥鱼等养殖鱼用的饲料等。
作为添加化合物(I)或其盐、或本发明的饲料添加剂的饲料,可列举:谷物类、糠类、植物油残渣类、动物饲料原料、其他的饲料原料、纯化品等。
谷物类可列举:高梁、小麦、大麦、燕麦、黑麦、黑米、荞麦、谷子、黍、稗子、玉米、大豆等。
糠类可列举:米糠、脱脂米糠、麸皮、粉末、小麦胚芽、麦糠、片、玉米糠、玉米胚芽等。
植物油残渣类可列举:大豆油残渣、黄豆粉、亚麻籽油残渣、棉籽油残渣、花生油残渣、红花油残渣、椰子油残渣、棕榈油残渣、芝麻油残渣、向日葵油残渣、菜籽油残渣、木棉油残渣、芥末油残渣等。
动物饲料原料可列举:鱼粉(北洋粉、输入粉、ホ一ルミ一ル、沿岸粉)、鱼汁、肉粉、肉骨粉、血粉、分解毛、骨粉、家畜用处理副产品、羽毛粉、蚕蛹、脱脂乳粉、酪蛋白、干燥乳清等。
其他的饲料原料可列举:植物茎叶类(紫苜蓿、ヘイキユ一ブ、紫苜蓿叶子粉、刺槐粉末等)、玉米加工工业副产品(玉米粉、玉米饲料、玉米渣(ステ一プリカ一)等)、淀粉加工品(淀粉等)、砂糖、发酵工业产品(酵母、啤酒残渣、麦芽根、酒糟、酱油残渣等)、农业制造副产品(柑桔加工残渣、豆腐残渣、咖啡残渣、可可残渣等)、蕃薯树、蚕豆、银菊粉、海藻、磷虾类、蓝藻类、绿藻、矿物等。
纯化品可列举:蛋白质(酪蛋白、白蛋白等)、氨基酸、糖类(淀粉、纤维素、蔗糖、葡萄糖等)、矿物质、维生素等。
本发明的饲料可采用如下方法进行制造。如:流动层制粒、搅拌制粒、挤压制粒、转动制粒、气流制粒、压缩成形制粒、分解破碎制粒、喷雾制粒、喷射制粒等制粒方法;盘式包覆、流动层包覆、干法包覆等包覆方法;粉状干燥、过剩水蒸汽法、发泡法、微波加热法等膨化方法;挤压制粒机或挤塑机等挤压方法进行制造。
本发明的饲料可用作抗糖尿病或改善胰岛素耐受性的饲料。
根据饲料的种类、期望摄取该饲料得到的效果适当选择向本发明的饲料中添加的化合物(I)或其盐、或饲料添加剂的量,通常添加使之含有0.1重量%~100重量%、优选1.0重量%~100重量的化合物(I)或其盐。
让非人动物摄取本发明的饲料时,根据摄取形式、摄取动物的种类、该动物的年龄、体重等而有所不同,通常每1kg体重每天,一次或数次口服给予,即摄取0.5mg~500mg、优选5mg~500mg的化合物(I)或其盐。
摄取周期没有特别限制,通常为1天~1年,优选2周~3个月。
用上述方法,通过给予人或非人动物化合物(I)或其盐可以治疗糖尿病或改善胰岛素耐受性。
本发明的最佳实施方式
实施例1
将15只II型糖尿病动物模型KK-Ay/Ta Jcl小鼠(日本CREA社、雄性、6周龄)按照每组5只分成3组,定为第1组~第3组。
让第1组~第3组的小鼠自由摄食、饮水。让第1组的小鼠摄取市售的饲料CE-2(日本CREA社制)。让第2组的小鼠摄取添加1重量%的反式-4-羟基-L-脯氨酸(协和发酵工业社制造,以下略称为羟脯氨酸)的CE-2。让第3组小鼠摄取添加1重量%的反式-N-乙酰-4-羟基-L-脯氨酸(协和发酵工业社制造,以下略称为N-乙酰羟脯氨酸)的CE-2。
在实验开始当天和第17天后从尾静脉采血,用MEDISAFE leaderGR-101(THERMO公司制)测定未禁食时的血糖值,在实验开始17天后到18天之间的18个小时的禁食期间,从下大静脉采取全血,得到血清。用小鼠胰岛素酶免试剂盒(SHIBAYAGI公司制)测定该血清中的胰岛素值。数值用平均值±标准误差(n=5)表示,通过t检验计算统计学的可信度(p值)。并且,第1组~第3组在实验期间的摄食量无有意义性差别。
从实验开始当天到17天后的未禁食时的血糖值测定结果如表1所示。
表1
血糖值(mg/dl) | ||
实验开始当天 | 实验开始17天后 | |
第1组第2组第3组 | 241.3±14.1243.0±12.2241.0±15.5 | 485.2±27.2260.4±10.8*226.2±12.9* |
*:相对第1组,p<0.0005
从表1可知,在实验开始17天后,与同一天的第1组的血糖值相比,第2组和第3组的血糖值有意义地表现出低值,而且,这两组从实验开始当天起均抑制了高血糖症状的发展。通过该结果可以确定羟脯氨酸和N-乙酰羟脯氨酸具有抗糖尿病作用。
血清胰岛素值的测定结果如表2所示。
表2
血清胰岛素值(ng/dl) | |
第1组第2组第3组 | 1.11±0.081.01±0.080.69±0.06* |
*:相对第1组,p<0.005
从表2可知,与第1组的血清胰岛素值相比,第3组的血清胰岛素值有意义地表现出低值,其高胰岛素血症得到改善。此外,认为第2组的血清胰岛素值和第1组的血清胰岛素值相比,无有意义性差异。
通过表1和表2的结果可以确定羟脯氨酸和N-乙酰羟脯氨酸通过改善胰岛素耐受性,表现出抗糖尿病作用。
实施例2
将15只II型糖尿病动物模型KK-Ay/Ta Jcl小鼠(日本CREA社、雄性、6周龄)按照每组5只分成3组,定为第1组~第3组。
让第1组~第3组的小鼠自由摄食、饮水。让第1组的小鼠摄取市售的饲料CE-2(日本CREA社制造)。让第2组的小鼠摄取添加1重量%的反式-4-羟基-L-脯氨酸乙酯(三洋化学研究所社制造,以下略称为羟脯氨酸乙酯)的CE-2。让第3组小鼠摄取添加1重量%的反式-N,O-二乙酰-4-羟基-L-脯氨酸油烯酯(日本化学社制造,以下略称为二乙酰羟脯氨酸油烯酯)的CE-2。
在实验开始当天和第10天后从尾静脉采血,用MEDISAFE leaderGR-101测定未禁食时的血糖值,在实验开始10天后到11天之间的18个小时的禁食期间,从下大静脉采取全血,得到血清。用小鼠胰岛素酶免试剂盒测定该血清中的胰岛素值。数值用平均值±标准误差(n=5)表示,通过t检验计算统计学的可信度(p值)。并且,第1组~第3组在实验期间的摄食量无有意义性差别。
从实验开始当天到10天后的未禁食时的血糖值测定结果如表3所示。
表3
血糖值(mg/dl) | ||
实验开始当天 | 实验开始10天后 | |
第1组第2组第3组 | 252.0±31.6253.0±9.5241.0±11.9 | 350.4±30.7217.2±11.3*215.2±20.3* |
*:相对第1组,p<0.005
从表3可知,在实验开始10天后,与同一天的第1组的血糖值相比,第2组和第3组的血糖值有意义地表现出低值,而且即使与实验开始当天的血糖值相比,也分别表现出低值。通过该结果可以确定羟脯氨酸乙酯和二乙酰羟脯氨酸油烯酯具有抗糖尿病作用。
血清胰岛素值的测定结果如表4所示。
表4
血清胰岛素值(ng/dl) | |
第1组第2组第3组 | 0.63±0.020.52±0.100.64±0.12 |
从表4可知,与第1组的血清胰岛素值相比,第2组和第3组的血清胰岛素值无有意义性差别。
通过表3和表4的结果可以确定羟脯氨酸乙酯和二乙酰羟脯氨酸油烯酯通过改善胰岛素耐受性,表现出抗糖尿病作用。
实施例3
将16只II型糖尿病动物模型KK-Ay/Ta Jcl小鼠(日本CREA社、雄性、6周龄)按照每组8只分成2组,定为第1组和第2组。
在18个小时的禁食之后,向第1组的小鼠经口给予生理盐水,按照1g/kg体重(以下称为“B.W.”)向第2组的小鼠经口给予20%(w/v)N-乙酰羟脯氨酸的水溶液(溶解在生理盐水中)。1个小时后,按照2g/kg体重B.W.向第1组以及第2组的小鼠经口给予40%(w/v)的葡萄糖水溶液,使之负荷糖。在给予葡萄糖水溶液前60分(-60分钟)、给予时(0分钟)、给予后30分钟和给予后120分钟时从尾静脉采血,用MEDISAFE leader GR-101测定血糖值。数值用平均值±标准误差(n=8)表示,通过t检验计算统计学的可信度(p值)。
血糖值的测定结果如表5所示。
表5
血糖值(mg/dl) | ||||
-60分钟 | 0分钟 | 30分钟 | 120分钟 | |
第1组第2组 | 160.2±12.6159.4±5.6 | 179.7±12.6179.9±11.6 | 490.4±21.2407.1±17.1* | 270.9±37.6210.4±14.4 |
*:相对第1组,p<0.05
从表5可知,在给予葡萄糖水溶液30分钟和120分钟时,与第1组的血糖值相比,第2组的血糖值表现出低值,在第2组,抑制了糖负荷造成的血糖值上升。通过该结果可以确定N-乙酰羟脯氨酸具有抗糖尿病作用。
实施例4
将12只II型糖尿病动物模型GK/Jcl大鼠(日本CREA社、雄性、9周龄)按照每组6只分成2组,定为第1组和第2组。
按照5ml/kg B.W.向第1组的大鼠经口给予溶剂(0.5%(w/v)甲基纤维素#400)。按照1000mg/kg B.W.向第2组的大鼠经口给予用上述溶剂溶解的200mg/ml的羟脯氨酸溶液。在给予溶剂或羟脯氨酸溶液时(0分钟)、给予后30分钟、60分钟、以及120分钟时从尾静脉采血,用MEDISAFE leader GR-101测定血糖值。数值用平均值±标准误差(n=6)表示,通过t检验计算统计学的可信度(p值)。
血糖值的测定结果如表6所示。
表6
血糖值(mg/dl) | ||||
0分钟 | 30分钟 | 60分钟 | 120分钟 | |
第1组第2组 | 189.7±8.4189.2±8.4 | 249.5±9.3220.3±13.8 | 249.5±11.6189.5±10.9** | 186.3±9.1156.0±6.8* |
*:相对第1组,p<0.05;**:相对第1组,p<0.01
从表6可知,在给予后60分钟和120分钟时,与第1组的血糖值相比,第2组的血糖值有意义地表现出低值。通过该结果可以确定羟脯氨酸具有抗糖尿病作用。
实施例5
将18只II型糖尿病动物模型GK/Jcl大鼠(日本CREA社、雄性、9周龄)按照每组6只分成3组,定为第1组~第3组。
在18个小时的禁食之后,按照5ml/kg B.W.向第1组大鼠经口给予溶剂(0.5%(w/v)甲基纤维素#400)。按照300mg/kg B.W.向第2组大鼠经口给予用上述溶剂溶解的60mg/ml的羟脯氨酸溶液。按照1000mg/kg B.W.向第3组的大鼠经口给予用上述溶剂溶解的200mg/ml的羟脯氨酸溶液。经口给予30分钟后,按照2g/kg体重B.W.向第1组~第3组的大鼠经口给予20%(w/v)的葡萄糖水溶液,使之负荷糖。在给予葡萄糖水溶液前30分(-30分钟)、给予时(0分钟)、给予后30分钟、60分钟和120分钟时从尾静脉采血,用MEIDISAFE leaderGR-101测定血糖值。
数值用平均值±标准误差(n=6)表示,通过一元方差分析和Dunnett检验计算第1组和第2组、与第1组和第3组间的统计学的可信度(p值)。
血糖值的测定结果如表7所示。
表7
血糖值(mg/dl) | |||||
-30分钟 | 0分钟 | 30分钟 | 60分钟 | 120分钟 | |
第1组第2组第3组 | 110.3±3.2113.3±2.7112.2±3.3 | 141.0±4.2144.2±7.2137.0±6.6 | 296.8±2.8269.5±15.3226.2±3.0* | 336.7±9.5298.2±7.5*247.3±4.4* | 211.5±3.8207.5±6.3181.2±7.3* |
*:相对第1组,p<0.01
从表7可知,在给予葡萄糖后60分钟时,与第1组的血糖值相比,第2组的血糖值有意义地表现出低值,在第2组抑制了糖负荷造成的血糖值上升。此外,在给予葡萄糖后30分钟、60分钟和120分钟时第3组的血糖值和第1组的比较,有意义地显示出低值,在第3组抑制了糖负荷造成的血糖值上升。通过该结果可以确定羟脯氨酸具有剂量依赖性的抗糖尿病作用。
实施例6
按照每孔1.2×105个C2C12细胞(来自小鼠的横纹肌细胞株,大日本制药公司),接种到12孔板中,使用添加了10%胎牛血清(Invitrogen公司制)的DMEM培养基(Invitrogen公司制),在CO2(5%CO2/95%空气)中,于37℃培养下培养3天。当细胞融合时,更换成添加了2%牛血清(Invitrogen公司制)的DMEM培养基,再培养4天,使之分化成肌肉纤维细胞(肌肉细胞)。再次用添加了2%牛血清(Invitrogen公司制)的DMEM培养基更换,向其中添加牛胰岛素(Invitrogen公司制)使其终浓度为1μg/ml或0.1μg/ml、或使牛胰岛素终浓度为0.1μg/ml以及使反式-4-羟基-L-脯氨酸甲酯(国产化学公司制,以下称为羟基脯氨酸甲酯)终浓度为100μg/ml、或使牛胰岛素终浓度为0.1μg/ml以及使羟基脯氨酸乙酯终浓度为100μg/ml,再培养3天。回收培养上清,用葡萄糖CII检测仪(和光纯药公司制)测定葡萄糖浓度,调查分化后的C2C12细胞的葡萄糖消耗情况。数值用平均值±标准误差(n=3、mg/l)表示,通过t检验计算统计学的可信度(p值)。
添加了胰岛素、羟脯氨酸甲酯以及羟脯氨酸乙酯的浓度、以及培养上清中的葡萄糖浓度如表8所示。
表8
添加物 | 葡萄糖(mg/ml) |
无胰岛素(0.1μg/ml)胰岛素(0.1μg/ml)+羟脯氨酸甲酯(100μg/ml)胰岛素(0.1μg/ml)+羟脯氨酸乙酯(100μg/ml)胰岛素(1μg/ml) | 1859±201260±15*1926±47*2984±29*2942±34*2 |
*1:相对无添加物,p<0.001
*2:相对胰岛素(0.1μg/ml),p<0.005
由表8可知,通过添加0.1μg/ml的胰岛素能够有意义地促进C2C12细胞的葡萄糖消耗,而且,在0.1μg/ml胰岛素和100μg/ml羟脯氨酸甲酯、0.1μg/ml胰岛素和100μg/ml羟脯氨酸乙酯共存时,该消耗有意义地增高至单独使用10倍浓度(1μg/ml)胰岛素所能达到的水平。
由上述结果可知,羟脯氨酸甲酯和羟脯氨酸乙酯能够增强胰岛素对肌肉的作用。
实施例7
向表9记载的配合的组合物中加入水至1000ml,制造用于糖尿病治疗的清凉饮料水(10瓶的量)。
表9
组成 | 含量 |
羟脯氨酸维生素C维生素B1维生素B2维生素B6液体糖柠檬酸香料 | 5g1g5mg10mg25mg150g3g1g |
实施例8
表10记载的配合的组合物用水1000ml提取,制造用于糖尿病治疗的茶饮料1000ml。
表10
组成 | 含量 |
羟脯氨酸茶叶 | 5g15g |
实施例9
按照表11记载的配合,制造用于糖尿病治疗的口香糖(30个的量)。
表11
组成 | 含量 |
羟脯氨酸胶基质砂糖饴糖香料 | 1.5g25g63g10g1g |
实施例10
按照表12记载的配合制造用于糖尿病治疗的糖果(20个的量)。
表12
组成 | 含量 |
羟脯氨酸砂糖饴糖香料 | 1g80g20g0.1g |
实施例11
按照表13记载的处方,用常规方法制造用于糖尿病治疗的片剂(每片200mg)。
表13
组成 | 含量 |
羟脯氨酸乳糖玉米淀粉合成硅酸铝羧甲基纤维素钙硬脂酸镁 | 50mg90mg30mg12mg15mg3mg |
实施例12
按照表14记载的处方,用常规方法制造用于糖尿病治疗的散剂(每包550mg)。
表14
组成 | 含量 |
羟脯氨酸甲酯乳糖玉米淀粉 | 50mg300mg200mg |
实施例13
按照表15记载的处方,制造用于糖尿病治疗的硬胶囊(每个胶囊160mg)。
表15
组成 | 含量 |
羟脯氨酸甲酯乳糖玉米淀粉羟丙基纤维素 | 50mg60mg30mg20mg |
向50mg羟脯氨酸甲酯中添加60mg乳糖和30mg玉米淀粉,混合,向其中添加含20mg羟丙基纤维素的水溶液,混炼。然后,用挤压造粒机按照常规方法制造颗粒。将该颗粒填充到明胶硬胶囊中,制造硬胶囊。
实施例14
按照表16记载的处方制造用于糖尿病治疗的软胶囊(每个胶囊170mg)。
表16
组成 | 含量 |
二乙酰羟脯氨酸油烯酯大豆油 | 50mg120mg |
向120mg大豆油中添加50mg二乙酰羟脯氨酸油烯酯,混合。然后用旋转模式自动成型机按照常规方法,将其填充到软胶囊中,制造软胶囊。
产业上的可利用性
根据本发明,提供了糖尿病治疗剂、胰岛素耐受性改善剂、用于糖尿病治疗的或用于改善胰岛素耐受性的食品饮料、食品饮料添加剂、饲料或饲料添加剂。
Claims (14)
1.一种糖尿病治疗剂,其中含有通式(I)所表示的羟脯氨酸或羟脯氨酸衍生物[以下称为化合物(I)]或它们的在药理学上允许的盐作为有效成分;
通式(I)
[式中,R1表示氢或酰基,R2表示氢、或饱和或不饱和的烃基,R3以及R4之一表示氢,另一方表示OR5(式中,R5表示氢或酰基)]。
2.一种用于治疗糖尿病的食品饮料或食品饮料添加剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
3.一种用于治疗糖尿病的饲料或饲料添加剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
4.一种胰岛素耐受性改善剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
5.一种用于改善胰岛素耐受性的食品饮料或食品饮料添加剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
6.一种用于改善胰岛素耐受性的饲料或饲料添加剂,其中含有作为有效成分的化合物(I)或其在药理学上允许的盐。
7.糖尿病治疗方法,其特征是,给予化合物(I)或其在药理学上允许的盐。
8.胰岛素耐受性改善方法,其特征是,给予化合物(I)或其在药理学上允许的盐。
9.化合物(I)或其在药理学上允许的盐在糖尿病治疗剂的制造中的应用。
10.化合物(I)或其在药理学上允许的盐在用于糖尿病治疗的食品饮料或食品饮料添加剂的制造中的应用。
11.化合物(I)或其在药理学上允许的盐在用于糖尿病治疗的饲料或饲料添加剂的制造中的应用。
12.化合物(I)或其在药理学上允许的盐在胰岛素耐受性改善剂的制造中的应用。
13.化合物(I)或其在药理学上允许的盐在用于改善胰岛素耐受性的食品饮料或食品饮料添加剂的制造中的应用。
14.化合物(I)或其在药理学上允许的盐在用于改善胰岛素耐受性的饲料或饲料添加剂的制造中的应用。
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WO2006120574A2 (en) * | 2005-02-18 | 2006-11-16 | Innodia Inc. | Analogs of 4-hydroxyisoleucine and uses thereof |
CN101252926A (zh) * | 2005-03-22 | 2008-08-27 | 因诺迪亚有限公司 | 用于预防和治疗肥胖症及相关综合征的化合物与组合物 |
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CN101912600B (zh) * | 2010-01-11 | 2014-01-29 | 杨国汉 | 改善胰岛素在溶液中稳定性的方法 |
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