CN115702000A - 用于预防或治疗代谢性疾病或肌肉疾病的包含乳杆菌衍生性囊泡的组合物 - Google Patents
用于预防或治疗代谢性疾病或肌肉疾病的包含乳杆菌衍生性囊泡的组合物 Download PDFInfo
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- CN115702000A CN115702000A CN202180043338.3A CN202180043338A CN115702000A CN 115702000 A CN115702000 A CN 115702000A CN 202180043338 A CN202180043338 A CN 202180043338A CN 115702000 A CN115702000 A CN 115702000A
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- A23V2400/175—Rhamnosus
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Abstract
本发明涉及一种用于预防或治疗代谢性疾病或肌肉疾病的组合物,该组合物包含衍生自乳杆菌属的细菌的囊泡。发明人证实了,当将衍生自乳杆菌属的细菌的囊泡施用到具有由高脂肪引起的代谢性疾病的动物模型中时,囊泡有效地抑制了由高脂肪饮食引起的代谢性疾病,并通过激活肌细胞中的AMPK信号来增加针对代谢压力的稳态,因此,根据本发明的衍生自乳杆菌属的细菌的囊泡可以有效地用于开发用于预防、改善症状或治疗诸如肥胖之类的代谢性疾病和肌肉疾病的药品或保健功能食品。
Description
技术领域
本发明涉及一种用于预防、改善或治疗代谢性疾病或肌肉疾病的组合物,该组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分,以及类似物。
本申请要求分别于2020年6月16日和2021年6月8日在韩国知识产权局提交的韩国专利申请号10-2020-0072685和10-2021-0073948的优先权和权益,并且这些申请的说明书和附图中公开的所有内容被并入本申请中。
背景技术
代谢性疾病是由于体内的代谢紊乱而发生的疾病。一般地,代谢性疾病是由碳水化合物、脂质、蛋白质、维生素、电解质和水的不平衡引起的,包括例如肥胖症、糖尿病、高脂血症、动脉硬化、脂肪肝和高血压。其中,与肥胖症有关的2型糖尿病是一种主要发生在成年期的糖尿病,其特征在于对胰岛素的抵抗。当胰岛素受体本身减少或其敏感性降低,或引起细胞内糖原合成的次级信使出现问题时,对胰岛素的敏感性就会降低。因此,2型糖尿病被称为非胰岛素依赖型糖尿病,占糖尿病的85%至90%。
乳杆菌属的细菌被称为分泌乳酸的代表性好细菌。在乳杆菌物种中,副干酪乳杆菌是杆菌纲的革兰氏阳性物种,其在厌氧环境以及有氧环境中生长良好并被称为妇女阴道中的共生细菌。细菌将通常被称为纳米囊泡的细胞外囊泡(EV)作为具有双膜结构的蛋白脂分泌到细胞外环境中,用于蛋白质、脂质或基因的细胞内交换。除了细菌衍生的蛋白质和核酸之外,衍生自革兰氏阳性细菌(例如副干酪乳杆菌)的囊泡还包括肽聚糖和脂蝶酸,它们是细菌细胞壁的组成成分。
然而,从乳杆菌属或副干酪乳杆菌的细菌中分泌的囊泡还没有被用于预防或治疗代谢性疾病,如肥胖症、代谢综合征、高胰岛素血症、高脂血症、高甘油三酯血症、高胆固醇血症、血脂异常、糖尿病、糖尿病肾病、脂肪肝、非酒精性脂肪性肝炎和动脉硬化。
发明内容
[技术问题]
由于认真进行了一项研究以评估衍生自诸如副干酪乳杆菌和鼠李糖乳杆菌等乳杆菌属的细菌的囊泡是否对代谢性疾病有治疗效果,发明人观察到,将衍生自乳杆菌属的细菌的囊泡施用到由高脂肪饮食引起的肥胖症和糖尿病的动物模型中有效抑制肥胖症和糖尿病,基于此,完成了本发明。
因此,本发明涉及提供一种用于预防、缓解或治疗代谢性疾病的组合物,该组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
此外,本发明还涉及提供一种用于预防、缓解或治疗肌肉疾病的组合物,该组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
此外,本发明还涉及提供一种用于改善肌肉功能的食品组合物,所述食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
此外,本发明还涉及提供一种用于增强运动表现能力的食品组合物,所述食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
然而,本发明要实现的技术问题并不限于上述问题,其他未提及的问题可由本领域技术人员从以下描述中清楚地了解。
[技术方案]
为了实现上述本发明的目的,本发明提供了一种用于预防或治疗代谢性疾病的药物组合物,该药物组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
此外,本发明还提供了一种用于预防或缓解代谢性疾病的食品组合物,该食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
作为本发明的一种示例性实施方案,乳杆菌属的细菌可以是副干酪乳杆菌或鼠李糖乳杆菌,但不限于此。
作为本发明的另一个示例性实施方案,食品组合物可以是保健功能食品组合物,但不限于此。
作为本发明的另一个示例性实施方案,代谢性疾病可以是选自由以下项组成的群组的一种或多种疾病:肥胖症、代谢综合征、高胰岛素血症、高脂血症、高甘油三酯血症、高胆固醇血症、血脂异常、糖尿病、糖尿病肾病、糖尿病视网膜病变、脂肪肝、非酒精性脂肪性肝炎和动脉硬化。
作为本发明的另一个示例性实施方案,囊泡可以具有10至1000nm的平均直径。
作为本发明的另一个示例性实施方案,囊泡可以从乳杆菌属细菌的培养液中分离出来。
作为本发明的另一个示例性实施方案,囊泡可以使用从通过添加乳杆菌属细菌制备的食物中分离出的囊泡获得。
作为本发明的另一个示例性实施方案,囊泡可以由乳杆菌属细菌天然或人工分泌。
此外,本发明还提供了一种用于预防或治疗代谢性疾病的方法,该方法包含向个体施用该组合物。
此外,本发明还提供了包含衍生自乳杆菌属细菌的囊泡作为活性成分的组合物用于预防或治疗代谢性疾病的用途。
此外,本发明还提供了衍生自乳杆菌属细菌的囊泡用于制备预防或治疗代谢性疾病的药物的用途。
此外,本发明还提供了一种用于预防或治疗肌肉疾病的药物组合物,该药物组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
此外,本发明还提供了一种用于改善肌肉功能的食品组合物,该食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
此外,本发明还提供了一种用于增强运动表现能力的食品组合物,该食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
作为本发明的一种示例性实施方案,乳杆菌属细菌可以是副干酪乳杆菌或鼠李糖乳杆菌。
作为本发明的另一个示例性实施方案,肌肉疾病可以是选自由以下项组成的群组的一种或多种:萎缩症、肌肉萎缩症、肌肉营养不良、肌无力症、恶病质和肌肉疏松症。
此外,本发明还提供了一种用于预防或治疗肌肉疾病的方法,该方法包含将该组合物施用于个体。
此外,本发明还提供了包含衍生自乳杆菌属细菌的囊泡作为活性成分的组合物用于预防或治疗肌肉疾病的用途。
此外,本发明还提供了衍生自乳杆菌属细菌的囊泡用于制备预防或治疗肌肉疾病的药物的用途。
此外,本发明还提供了一种用于改善肌肉功能或增强运动表现能力的方法,该方法包含向个体施用包含衍生自乳杆菌属细菌的囊泡作为活性成分的组合物。
此外,本发明还提供了包含衍生自乳杆菌属细菌的囊泡作为活性成分的组合物用于改善肌肉功能或增强运动表现能力的用途。
此外,本发明还提供了衍生自乳杆菌属细菌的囊泡用于制备改善肌肉功能或增强运动表现能力的药物的用途。
[有利效果]
发明人证实,当将衍生自乳杆菌属细菌的囊泡施用于高脂肪西式饮食诱导的代谢性疾病的动物模型中时,囊泡不仅降低了体重和饭量,而且有效地抑制了由西式饮食引起的代谢紊乱,并通过激活肌细胞中的AMPK信号增加了针对代谢压力的稳态,并且根据本发明的衍生自乳杆菌属细菌的囊泡能够有效地用于开发用于预防、改善症状或治疗代谢性疾病和肌肉疾病(如肥胖症)、代谢综合征、高胰岛素血症、高脂血症、高甘油三酯血症、高胆固醇血症、血脂异常、糖尿病、糖尿病肾病、糖尿病视网膜病变、脂肪肝、非酒精性脂肪性肝炎和动脉硬化的药物或保健功能食品。
附图说明
图1是通过SDS-PAGE和银染色方法分析从副干酪乳杆菌培养物中分离出的囊泡中所含的蛋白质模式的图。
图2是评价将副干酪乳杆菌囊泡用荧光标记并口服施用后囊泡的分布模式的图。
图3是对具有由高脂肪饮食诱导的代谢性疾病的小鼠模型口服施用副干酪乳杆菌衍生性囊泡后,确认治疗代谢性疾病的效果的实验方案。
图4是将副干酪乳杆菌衍生性囊泡直接口服施用到具有由高脂肪饮食诱导的代谢性疾病的小鼠模型中后,观察体重变化的结果。
图5是在将不同浓度的副干酪乳杆菌衍生性囊泡(MDH-001)口服施用到具有由高脂肪饮食诱导的代谢性疾病的小鼠模型中后,评估治疗代谢性疾病效果的浓度依赖性的实验方案。
图6是在直接将各种浓度的副干酪乳杆菌衍生性囊泡口服施用到具有由高脂肪饮食诱导的代谢性疾病的小鼠模型中后,评估体重变化和食物摄入量的结果。
图7是在将二甲双胍、大肠杆菌衍生性囊泡(EcEV)或副干酪乳杆菌衍生性囊泡(L-EV)施用到肌细胞中后评估GLUT4转运体(一种葡萄糖受体)的表达程度的结果。
图8是在胰岛素、二甲双胍、大肠杆菌衍生性囊泡(EcEV)或副干酪乳杆菌衍生性囊泡(L-EV)施用到肌细胞中后评估肌细胞中的葡萄糖摄入程度的结果。
图9是在用胰岛素、二甲双胍、各种浓度的副干酪乳杆菌衍生性囊泡(L.paracaseiEV)处理肌细胞后1小时评估AMPK激活的结果。
图10是在用胰岛素、二甲双胍、各种浓度的鼠李糖乳杆菌衍生性囊泡(L.rhamnosus EV)处理肌细胞后1小时评估AMPK激活的结果。
具体实施方式
发明人证实,在具有由高脂肪饮食诱导的代谢性疾病的小鼠模型中,当口服施用衍生自乳杆菌属细菌的囊泡时,食物摄入量减少,并且以剂量依赖的方式抑制了体重增加。
在本发明的另一个实施方案中,在具有由高脂肪饮食诱导的代谢性疾病的小鼠模型中,证实了当口服施用衍生自乳杆菌属细菌的囊泡时,空腹血糖水平得到抑制。
在本发明的又一个实施方案中,当将衍生自乳杆菌属细菌的囊泡施用到肌细胞中时,证实了GLUT4(胰岛素抵抗的指标)的表达以及肌细胞中的葡萄糖摄入通过囊泡增加。
在本发明的另一个实施方案中,证实了当将衍生自乳杆菌属细菌的囊泡施用到肌细胞中时,囊泡增加胰岛素抵抗的机制与AMPK激活相关联。
因此,本发明提供了一种用于预防、缓解或治疗代谢性疾病或肌肉疾病的药物组合物,该药物组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
在本发明中,乳杆菌属细菌可以是乳杆菌副干酪乳杆菌或鼠李糖乳杆菌,但不限于此。
如本文所用,术语“囊泡”是指由各种细菌分泌的纳米级膜形成的结构,并且在本发明中,该术语统称为由乳杆菌属细菌自然分泌,或人工生产的膜形成的所有结构。可以通过使用选自由以下项组成的群组的一种或多种方法从包括乳杆菌属细菌的细菌细胞的培养液中分离出囊泡:离心、超高速离心、高压处理、挤出、超声处理、细胞裂解、均质化、冻融、电穿孔、机械降解、化学处理、通过过滤器过滤、凝胶过滤色谱法、自由流动电泳和毛细管电泳。此外,还可以进一步包括用于去除杂质和浓缩所获囊泡的洗涤等过程。
本发明的囊泡可以从乳杆菌属细菌的培养液或通过添加乳杆菌属细菌制备的食品中分离出来,并且囊泡可以由乳杆菌属细菌天然或人工分泌,但不限于此。
用于从本发明的乳杆菌属细菌的培养液或发酵食品中分离囊泡的方法没有特别限制,只要包括囊泡即可。例如,可以使用诸如离心、超高速离心、通过过滤器过滤、凝胶过滤色谱法、自由流动电泳或毛细管电泳及其组合之类的方法来分离囊泡,并且另外,可以进一步包括诸如洗涤以去除杂质并浓缩获得的囊泡之类的过程。
在本发明中,通过该方法分离的囊泡可以具有10至1000nm,10至900nm,10至800nm,10至700nm,10至600nm,10至500nm,10至400nm,10至300nm,10至200nm,20至1000nm,20至900nm,20至800nm,20至700nm,20至600nm,20至500nm,20至400nm,20至300nm,20至200nm,30至1000nm,30至900nm,30至800nm,30至700nm,30至600nm,30至500nm,30至400nm,30至300nm,30至200nm,40至1000nm,40至900nm,40至800nm,40至700nm,40至600nm,40至500nm,40至400nm,40至300nm,40至200nm,20至180nm,30至180nm,40至180nm,20至170nm,20至160nm,40至160nm,45至155nm,或50至150nm的平均直径,但是平均直径不限于此。
本文所用的术语“代谢性疾病”涵盖由于体内代谢紊乱而发生的疾病。一般地,代谢性疾病是由碳水化合物、脂质、蛋白质、维生素、电解质和水的不平衡引起的,包括例如肥胖症、代谢综合征、高胰岛素血症、高脂血症、高甘油三酯血症、高胆固醇血症、血脂异常、糖尿病、糖尿病肾病、糖尿病视网膜病、脂肪肝、非酒精性脂肪性肝炎和动脉硬化。
本文所用的术语“肌肉疾病”可指由肌肉耗损或退化引起的疾病,但本发明不限于此。在本发明中,肌肉疾病可以是选自由以下项组成的群组中的一种或多种:萎缩症、肌肉萎缩症、肌肉营养不良、肌无力症、恶病质和肌肉疏松症,但本发明不限于此。肌肉耗损和退化是由遗传因素、后天因素、衰老等引起的。本发明的组合物具有促进肌肉增加的效果,而肌肉的类型不受限制。肌肉增加是指肌肉性能的改善,特别是在身体成分方面的改善,并且肌肉质量(muscle mass)可以通过体育锻炼增加,通过将具有肌肉增加效果的材料施用到体内的方法改善耐力。
本发明组合物中的囊泡的量可以根据疾病的症状、症状的进展程度、患者的状况等进行适当调整,其范围可从例如相对于该组合物的总重量的0.0001wt%至99.9wt%或0.001wt%至50wt%,但本发明不限于此。量比率是基于从中去除了溶剂的干燥产物的量的值。
根据本发明的药物组合物可以进一步包括通常用于制备药物组合物的合适的载体、赋形剂和稀释剂。赋形剂可以为例如选自由以下组成的组的一种或多种:稀释剂、粘合剂、崩解剂、润滑剂、吸附剂、湿润剂、膜包衣材料和控释添加剂。
根据本发明的药物组合物可以根据常用方法配制成以下形式来使用,该形式例如:粉剂、颗粒剂、缓释型颗粒剂、肠溶颗粒剂、液体剂、滴眼剂、酏剂、乳剂、混悬剂、醑剂、锭剂、芳香水剂、柠檬水剂、片剂、缓释型片剂、肠溶片、舌下片、硬胶囊、软胶囊、缓释型胶囊、肠溶胶囊、丸剂、酊剂、软提取物、干提取物、液体提取物、注射剂、胶囊、灌流剂或外用制剂,例如膏药、洗剂、糊剂、喷雾剂、吸入剂、贴剂、无菌注射液或气雾剂。外用制剂可具有诸如霜剂、凝胶剂、贴剂、喷雾剂、软膏剂、硬膏剂、洗剂、搽剂、糊剂或泥罨剂等制剂。
作为可包含在根据本发明的药物组合物中的载体、赋形剂和稀释剂,可使用乳糖、右旋糖、蔗糖、低聚糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。
对于制剂,使用常用的稀释剂或赋形剂,例如填充剂、增稠剂、粘合剂、润湿剂、崩解剂和表面活性剂。
作为根据本发明的片剂、粉剂、颗粒剂、胶囊剂、丸剂和锭剂的添加剂,可使用赋形剂,例如玉米淀粉、马铃薯淀粉、小麦淀粉、乳糖、白糖、葡萄糖、果糖、D-甘露醇、沉淀的碳酸钙、合成硅酸铝、磷酸氢钙、硫酸钙、氯化钠、碳酸氢钠、纯化羊毛脂、微晶纤维素、糊精、海藻酸钠、甲基纤维素、羧甲基纤维素钠、高岭土、尿素、胶体硅胶、羟丙基淀粉、羟丙基甲基纤维素(HPMC)1928、HPMC 2208、HPMC 2906、HPMC 2910、丙二醇、酪蛋白、乳酸钙和以及粘合剂,例如明胶、阿拉伯胶、乙醇、琼脂粉、醋酸邻苯二甲酸纤维素、羧甲基纤维素、羧甲基纤维素钙、葡萄糖、纯净水、酪蛋白酸钠、甘油、硬脂酸、羧甲基纤维素钠、甲基纤维素钠、甲基纤维素、微晶纤维素、糊精、羟纤维素、羟丙基淀粉、羟甲基纤维素、纯化虫胶、淀粉、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯醇和聚乙烯吡咯烷酮;并且可使用崩解剂,例如羟丙基甲基纤维素、玉米淀粉、琼脂粉、甲基纤维素、膨润土、羟丙基淀粉、羧甲基纤维素钠、海藻酸钠、羧甲基纤维素钙、柠檬酸钙、十二烷基硫酸钠、硅酸酐、1-羟丙基纤维素、葡聚糖、离子交换树脂、聚乙酸乙烯酯、经甲醛处理的酪蛋白和明胶、海藻酸、直链淀粉、瓜尔胶、碳酸氢钠、聚乙烯吡咯烷酮、磷酸钙、凝胶淀粉、阿拉伯胶、支链淀粉、果胶、多聚磷酸钠、乙基纤维素、白糖、硅酸铝镁、二山梨糖醇溶液和轻质无水硅酸;以及润滑剂,例如硬脂酸钙、硬脂酸镁、硬脂酸、氢化植物油、滑石粉、石松粉、高岭土、凡士林、硬脂酸钠、可可脂、水杨酸钠、水杨酸镁、聚乙二醇(PEG)4000、PEG 6000、液体石蜡、氢化大豆油(Lubri蜡)、硬脂酸铝、硬脂酸锌、十二烷基硫酸钠、氧化镁、聚乙二醇(Macrogol)、合成硅酸铝、硅酸酐、高级脂肪酸、高级醇、硅油、石蜡油、聚乙二醇脂肪酸醚、淀粉、氯化钠、乙酸钠、油酸钠、dl-亮氨酸和轻质无水硅酸。
作为根据本发明的液体的添加剂,可使用水、稀盐酸、稀硫酸、柠檬酸钠、单硬脂酸蔗糖、聚氧乙烯山梨糖醇脂肪酸酯(双酯)、聚氧乙烯单烷基醚、羊毛脂醚、羊毛脂酯、乙酸、盐酸、氨水、碳酸铵、氢氧化钾、氢氧化钠、醇溶谷蛋白、聚乙烯基吡咯烷酮、乙基纤维素和羧甲基纤维素钠。
在根据本发明的糖浆中,可使用白糖溶液、其他糖或甜味剂等,并且根据需要,可使用香料、着色剂、防腐剂、稳定剂、悬浮剂、乳化剂、增粘剂等。
在根据本发明的乳液中,可使用纯净水,并且根据需要可使用乳化剂、防腐剂、稳定剂、香料等。
在根据本发明的悬浮液中,可使用悬浮剂,例如阿拉伯胶、黄蓍胶、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、微晶纤维素、海藻酸钠、羟丙基甲基纤维素(HPMC)1828、HPMC2906、HPMC 2910等,并且根据需要,可使用表面活性剂、防腐剂、稳定剂、着色剂和香料。
根据本发明的注射剂可以包括:溶剂,例如注射用蒸馏水、0.9%氯化钠溶液、林格氏溶液、葡萄糖溶液、葡萄糖+氯化钠溶液、PEG、乳酸林格氏溶液、乙醇、丙二醇、非挥发性油-芝麻油、棉籽油、花生油、豆油、玉米油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苯酯;助溶剂,例如苯甲酸钠、水杨酸钠、乙酸钠、尿素、氨基甲酸酯、单乙基乙酰胺、苯基丁氮酮、丙二醇、吐温系列、烟酸酰胺、六胺和二甲基乙酰胺;缓冲剂,例如弱酸及其盐(乙酸和乙酸钠)、弱碱及其盐(氨和乙酸铵)、有机化合物、蛋白质、白蛋白、蛋白胨和树胶;等渗剂,例如氯化钠;稳定剂,例如亚硫酸氢钠(NaHSO3)二氧化碳气体、焦亚硫酸钠(Na2S2O5)、亚硫酸钠(Na2SO3)、氮气(N2)、乙二胺四乙酸;硫酸化剂,例如0.1%亚硫酸氢钠、甲醛合次硫酸氢钠、硫脲、乙二胺四乙酸二钠、丙酮合亚硫酸氢钠等;镇痛剂,例如苯甲醇、氯丁醇、盐酸普鲁卡因、葡萄糖和葡萄糖酸钙;以及悬浮剂,例如CMC钠、海藻酸钠、吐温80和单硬脂酸铝。
在根据本发明的栓剂中,可使用基质,例如可可脂、羊毛脂、Witepsol、聚乙二醇、甘油明胶、甲基纤维素、羧甲基纤维素、硬脂酸和油酸的混合物、Subanal、棉籽油、花生油、棕榈油、可可脂+胆固醇、卵磷脂、lanette蜡、单硬脂酸甘油酯、吐温或span、imhausen、monolan(单硬脂酸丙二醇酯)、甘油、Adeps solidus、buytyrum Tego-G、cebes Pharma 16、hexalide base 95、cotomar、Hydrokote SP、S-70-XXA、S-70-XX75(S-70-XX95)、Hydrokote25、Hydrokote 711、idropostal、massa estrarium(A,AS,B,C,D,E,I,T),masa-MF,masupol,masupol-15,neosuppostal-N,paramount-B,supposiro OSI,OSIX,A,B,C,D,H,L,栓剂基质IV型AB,B,A,BC,BBG,E,BGF,C,D,299,suppostal N,Es,Wecoby W,R,S,M,Fs以及tegester甘油三酯物质(TG-95,MA,57)。
用于口服给药的固体制剂包括片剂、丸剂、粉剂、颗粒剂、胶囊剂等,并且此类固体制剂通过将组合物与至少一种赋形剂,例如淀粉、碳酸钙、蔗糖、乳糖、明胶等混合来制备。除了简单的赋形剂外,还使用诸如硬脂酸镁和滑石粉之类的润滑剂。
用于口服给药的液体制剂的示例包括混悬剂、内服液体、乳剂、糖浆剂等,并且这些液体制剂除了诸如水和液体石蜡之类简单常用稀释剂之外还可以包括各种类型的赋形剂,例如润湿剂、甜味剂、香料、防腐剂等。用于肠胃外给药的制剂包括无菌水溶液、非水溶剂、悬浮液、乳剂、冻干制剂和栓剂。非水溶剂和悬浮液的非限制性示例包括丙二醇、聚乙二醇、植物油(例如橄榄油)以及可注射酯(例如油酸乙酯)。
根据本发明的药物组合物以药学有效量施用。在本发明中,“药学有效量”是指以适用于医学治疗的合理获益/风险比足以治疗疾病的量,有效剂量水平可根据患者的疾病类型、疾病的严重程度、药物的活性、对药物的敏感性、给药时间、给药途径、排泄率、治疗周期、同时使用的药物以及其他医学领域众所周知的因素来确定。
根据本发明的组合物可以单独的治疗剂或与其他治疗剂组合的形式施用,可以与相关领域的治疗剂依次或同时施用,并且可以单剂量或多剂量施用。考虑到所有上述因素,重要的是以可获得最大效果但不具有任何副作用的最小量施用组合物,并且这可由本领域普通技术人员容易地确定。
根据本发明的药物组合物可经由各种途径施用于个体。可预测所有给药方法,并且该药物组合物可经由例如以下方式给药:口服给药、皮下注射、静脉内注射、肌肉注射、鞘内(脊髓周围空间)注射、舌下给药、经由口腔粘膜给药、直肠内插入、阴道内插入、眼内给药、耳内给药、鼻内给药、吸入、经由口或鼻喷雾、透皮给药、经皮给药等。
本发明的药物组合物根据作为活性成分的药物的类型,连同各种相关因素(例如所治疗的疾病、给药途径、患者的年龄、性别和体重,以及疾病的严重程度)来确定。具体地,根据本发明的组合物的有效量可根据患者的年龄、性别和体重而变化,并且一般地,每天或每隔一天给药,也可每天一次到三次给药,0.001至150mg组合物/kg体重,优选地0.01至100mg组合物/kg体重。然而,由于有效量可根据给药途径、肥胖的严重程度、性别、体重、年龄等增加或减少,因此剂量不旨在以任何方式限制本发明的范围。
如本文所用,“受试者”是指需要治疗疾病的受试者,更具体地,是指哺乳动物,例如人或非人灵长类动物、小鼠、大鼠、狗、猫、马和牛,但本发明不限于此。
如本文所用,“施用”是指通过使用任意合适的方法向受试者提供本发明的预定组合物。
如本文所用,术语“预防”意指抑制或延迟目标疾病发作的所有作用。如本文所用,术语“治疗”意指经由施用根据本发明的药物组合物而减轻或有益地改变目标疾病和由此引起的异常代谢症状的所有作用。如本文所用,术语“改善”意指经由施用根据本发明的组合物来降低与目标疾病相关的参数(例如症状)的程度的所有作用。
此外,本发明还提供了一种用于预防或缓解代谢性疾病或肌肉疾病的食品组合物,该食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
此外,本发明还提供了一种用于改善肌肉功能的食品组合物,该食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
此外,本发明还提供了一种用于增强运动表现能力的食品组合物,该食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
肌肉功能的改善是指加强肌肉的内在属性或功能,如增加肌肉质量、提高肌肉力量和恢复肌肉疲劳。
本文使用的“肌肉”涵盖筋、肌肉和肌腱,而“肌肉功能”是指通过肌肉收缩施加力量的能力,包括肌肉力量,即施加最大收缩力以克服阻力的能力;肌肉耐力,即表现肌肉在给定重量下能重复收缩和放松的时间或次数的能力;以及肌肉爆发力,即在短时间段内施加强大力量的能力。这种肌肉功能由肝脏控制,并与肌肉质量成正比。术语“改善肌肉功能”是指更好地增强肌肉功能。
术语“增强运动表现能力”是指增强肌肉功能(如肌肉力量或肌肉耐力)的效果,优选增加肌肉力量或肌肉耐力。相应地,该组合物具有增加运动耐力、加强肌肉力量、增强平衡感和/或增强运动适应性的效果。通过促进能量消耗改善运动表现能力的代表性方法之一是通过增加由线粒体引起的脂肪酸氧化产生ATP能量的方法。AMPK、pAMPK、PPARδ、ERRα、Tfam等是已知的与改善运动表现能力有关的因素。
食品组合物可以为健康功能食品组合物,但不限于此。
根据本发明的囊泡可通过将活性成分原样添加到食品中使用,或可与其他食品或食品成分一起使用,但可根据典型的方法适当使用。活性成分的混合量可根据其使用目的(预防或减轻)适当地确定。一般地,当制备食品或饮料时,本发明的组合物的添加量为基于原料计15wt%或更少,优选地10wt%或更少。然而,就为了健康和卫生目的或为了健康控制目的而长期摄入而言,该量可少于上述范围,并且囊泡在稳定性方面没有问题,因此活性成分可以超过上述范围的量使用。
食物的类型没有特别限制。可向其添加材料的食品的示例包括肉类、香肠、面包、巧克力、糖果、小吃、蜜饯、比萨、方便面、其他面条、口香糖、包括冰淇淋在内的乳制品、各种汤、饮料、茶、酒精饮料、复合维生素等,并且包括所有典型意义上的健康功能性食品。
根据本发明的健康饮料组合物可包含各种调味剂或天然碳水化合物等作为典型饮料中的附加成分。上述天然碳水化合物可以为单糖(例如葡萄糖和果糖),二糖(例如麦芽糖和蔗糖),多糖(例如糊精和环糊精),以及糖醇(例如木糖醇、山梨糖醇和赤藓糖醇)。作为甜味剂,可以使用天然甜味剂(例如索马甜和甜菊提取物)、合成甜味剂(例如糖精、阿斯巴甜),等等。天然碳水化合物的比例通常为每100ml本发明组合物约0.01至0.20g,或约0.04至0.10g。
除上述成分之外,本发明的组合物还可含有各种营养素、维生素、电解质、调味剂、着色剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、酒精、碳酸饮料中使用的碳酸化剂等。此外,本发明的组合物还可含有用于制备天然果汁、果汁饮料和蔬菜饮料的果肉。这些成分可以单独使用或组合使用。这些添加剂的比例不十分重要,但一般被选择在每100重量份本发明组合物0.01至0.20重量份的范围内。
在下文中,将提出有助于理解本发明的优选实施例。然而,提供以下实施例仅是为了更容易理解本发明,并且本发明的内容不受以下实施例的限制。
实施例
实施例1.源自副干酪乳杆菌的囊泡的分离
为了分离衍生自乳杆菌属的代表性细菌的囊泡,如副干酪乳杆菌和鼠李糖乳杆菌衍生性囊泡(胞外囊泡;EV),将乳杆菌菌株接种到MRS(de Man-Rogosa and Sharpe)培养基中,在37℃和200rpm下培养至具有1.0至1.5的吸光度(OD600nm),再接种到Luria Bertani(LB)培养基中并孵育。然后,通过回收包括细菌细胞的培养液并于4℃以10,000g离心20分钟,获得去除了细菌细胞的上清液。又使用0.22μm的过滤器过滤所获得的上清液,并使用100kDa的Pellicon 2盒式滤膜(Merck Millipore)和MasterFlex泵系统(Cole-Parmer)将过滤的上清液浓缩至50mL或更小的体积。通过使用0.22μm的过滤器再次过滤浓缩的上清液,分离出衍生自乳杆菌细菌的囊泡。在下面的实施例中,使用分离的囊泡进行了实验。
实施例2.衍生自副干酪乳杆菌的囊泡的表征
为了确认通过实施例1的方法获得的衍生自副干酪乳杆菌的囊泡(细胞外囊泡;EV)的特征,进行了蛋白质定量、粒度测量以及分布和蛋白质模式分析。
作为使用BCA方法进行蛋白质定量的结果,确认平均蛋白质浓度为3至5mg/mL。此外,为了确认衍生自副干酪乳杆菌的囊泡的大小和分布,使用NS300仪器(MalvernPanalytical)进行了纳米颗粒追踪分析(NTA)。在基于蛋白质浓度将样品的浓度稀释到1mg/mL后,将样品稀释100到2000倍以将‘颗粒/帧’值调整到20至100。
结果,确认细胞外囊泡的大小为50至150nm,每1mL含有1.0E+11颗粒/mL或更多。
此外,为了确认衍生自副干酪乳杆菌的囊泡的蛋白质模式,进行了十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)和银染色。
如图1所示,证实了在五个主要条带(接近130、95、85、70和45kDa)中观察到衍生自副干酪乳杆菌的囊泡。
实施例3.衍生自副干酪乳杆菌的囊泡的药代动力学特征
为了确认药代动力学特性,如口服施用衍生自副干酪乳杆菌的囊泡的全身吸收和分布模式,通过以下方法确认在体内的分布。
将用荧光剂Cy7标记的衍生自副干酪乳杆菌的囊泡口服施用到小鼠中,为了确认0、1、3、6、24、32、48、56和72小时后对不同器官的浸润模式,获取血液、心脏、肺、肝、肾、脾、胃肠道和大脑。使用光学成像设备(Davinch-Invivo Fluoro Chemi(western);Davinch-K)观察所获取的组织的荧光信号。
如图2所示,证实了,在施用衍生自副干酪乳杆菌的囊泡后,囊泡在1小时内被胃吸收,在3小时分布在胃、小肠、大肠和肺中,并且在3小时后也分布在肝脏和大脑中。也就是说,从32到48小时连续观察细胞外囊泡在各种组织中的荧光信号的结果,证实了在口服施用细胞外囊泡的情况下,囊泡分布在包括胃、肠、肺、肝和大脑在内的整个身体,直到48小时。
实施例4.衍生自副干酪乳杆菌的囊泡在具有由高脂肪饮食诱导的代谢性疾病的
小鼠内的肥胖治疗效果
为了确认实施例1中得到的衍生自副干酪乳杆菌的囊泡是否抑制由高脂肪饮食诱导的代谢性疾病,通过以下方法进行了实验。
具体地,根据图3所示的实验方案,制备了喂食普通饮食(RD)的正常小鼠和喂食高脂肪饮食(HFD)达4个月以诱导代谢性疾病的小鼠。将实施例1中获得的衍生自副干酪乳杆菌的囊泡按每只小鼠10μg施用到代谢性疾病模型达3周。这里,阴性对照(NC)被喂食正常饮食,而阳性对照(肥胖)被喂食高脂肪饮食。作为对照药物,衍生自鼠李糖乳杆菌(L.rhamnosus)的囊泡、衍生自乳酸乳杆菌(L.lactis)的囊泡和衍生自奇异变形杆菌(P.mirabilis)的囊泡以与衍生自副干酪乳杆菌的囊泡相同的剂量进行口服施用。此外,在每2天施用囊泡的同时,还测量了体重。
如图4所示,与未施用药物的高脂肪饮食喂养的阳性对照组(肥胖)相比,在施用衍生自副干酪乳杆菌(L.paracasei)的囊泡的组中以及施用衍生自鼠李糖乳杆菌(L.rhamnosus)的囊泡的组中,体重都下降,并且在摄入衍生自副干酪乳杆菌的囊泡的组中,更明显地观察到体重下降。
然而,施用衍生自奇异变形杆菌(P.mirabilis)的囊泡的组显示出与高脂肪饮食喂养的阳性对照相似的体重,与仅喂养高脂肪饮食的组相比,奇异变形杆菌组甚至显示出增加的体重,而施用乳杆菌衍生性囊泡的组显示出轻微的体重下降。
实施例5.衍生自副干酪乳杆菌的囊泡在具有由高脂饮食诱导的代谢性疾病的小
鼠内的剂量依赖性治疗效果
为了评价根据衍生自副干酪乳杆菌的囊泡的剂量治疗由高脂肪饮食诱导的代谢性疾病的疗效,通过以下方法进行了实验。
如图5所示,制备其中由高脂肪饮食(60%高脂肪饮食;HFD)诱导肥胖症和糖尿病达2周的小鼠模型,以小鼠每重量(g)3、10或30mg/kg的剂量施用实施例1中获得的衍生自副干酪乳杆菌的囊泡(MDH-001)达8周。这里,作为阳性对照,使用了小鼠组,其通过将PBS施用到其中通过高脂肪饮食(60%高脂肪饮食;HFD)诱导肥胖症和糖尿病达2周的鼠模型中制备。在每2天施用囊泡的同时,测量体重。
如图6所示,证实了,施用8周的囊泡剂量越大,减轻体重的效果越明显,在施用30mg/kg的囊泡的小鼠组中,与施用PBS的小鼠组相比,证实体重减轻了约5%至7%。也证实了所施用的囊泡以剂量依赖的方式减少食物摄入量的效果。
从上述结果证实,衍生自副干酪乳杆菌的囊泡以剂量依赖的方式抑制肥胖,并与食物摄入量的减少相关联。
实施例6.衍生自副干酪乳杆菌的囊泡对肌细胞中葡萄糖代谢的影响
为了评估衍生自副干酪乳杆菌的囊泡对肌细胞中葡萄糖转运体4型(GLUT4)表达的影响,用10μg/ml的衍生自副干酪乳杆菌的囊泡(L-EV)在体外处理肌细胞1小时。之后,通过邻苯二胺(OPD)试验评估细胞膜上GLUT4的表达程度。使用来自大肠杆菌的囊泡(EcEV)和二甲双胍作为对照。
结果,如图7所示,证实GLUT4的表达没有通过衍生自大肠杆菌(EcEV)的囊泡增加,但是通过衍生自副干酪乳杆菌和二甲双胍的囊泡却增加。
此外,为了评估衍生自副干酪乳杆菌的囊泡对肌细胞中葡萄糖代谢的影响,用10μg/ml的衍生自副干酪乳杆菌的囊泡在体外处理肌细胞1小时。之后,用放射性同位素确认葡萄糖的摄入。
结果,如图8所示,葡萄糖摄入没有通过衍生自大肠杆菌的囊泡(EcEV)增加,但是通过衍生自副干酪乳杆菌的囊泡(L-EV)和二甲双胍增加。
从上述结果可以看出,衍生自副干酪乳杆菌的囊泡在胰岛素作用的器官(如肌细胞)中抑制了胰岛素抵抗,由此提高了胰岛素反应性。
实施例7.衍生自副干酪乳杆菌的囊泡对肌细胞中AMPK激活的影响
在禁食或锻炼期间,肌细胞中的能量被耗尽,因此ATP产量减少,而AMP产量增加。在此,众所周知,AMPK信号的激活增加细胞中针对代谢压力的稳态。为了评估由衍生自副干酪乳杆菌的囊泡对肥胖和胰岛素抵抗的抑制效果是否与AMPK信号相关联,通过以下方法进行了实验。也就是说,用浓度为0、0.1、1或10μg/ml的衍生自副干酪乳杆菌的囊泡(L-EV)在体外处理肌细胞1小时。之后,通过蛋白免疫印迹法测量AMPK磷酸化(pAMPK)水平,这是一种AMPK信号指标。作为对照药物,使用了胰岛素和二甲双胍。
结果,如图9所示,pAMPK表达被对照药物胰岛素所抑制,而通过二甲双胍增加。此外,当衍生自副干酪乳杆菌的囊泡被处理时,pAMPK表达以囊泡浓度依赖的方式增加。这意味着衍生自副干酪乳杆菌的囊泡对肥胖和胰岛素抵抗的抑制效果与通过代谢压力维持细胞稳态的AMPK信号密切相关。
实施例8.衍生自鼠李糖乳杆菌的囊泡对肌细胞中AMPK激活的影响
为了评估衍生自鼠李糖乳杆菌的囊泡对肥胖和胰岛素抵抗的抑制效果是否与AMPK信号相关联,通过以下方法进行了实验。也就是说,用衍生自鼠李糖乳杆菌的囊泡(L-EV)按0、0.1、1、10μg/ml在体外处理肌细胞达1小时。之后,通过蛋白免疫印迹法测量AMPK磷酸化(pAMPK)的水平,这是AMPK信号指标。使用胰岛素和二甲双胍作为对照药物。
结果,如图10所示,pAMPK表达被对照药物胰岛素所抑制,而通过二甲双胍增加。此外,当衍生自鼠李糖乳杆菌的囊泡被处理时,pAMPK表达以囊泡浓度依赖的方式增加。这意味着衍生自鼠李糖乳杆菌的的囊泡对肥胖和胰岛素抵抗的抑制效果与通过代谢压力维持细胞稳态的AMPK信号密切相关。
提供本发明的上述描述是出于说明的目的,并且本发明所属领域的普通技术人员将理解,在不改变本发明的技术精神或实质特征的情况下,可以容易地将本发明修改为其他特定形式。因此,应当理解,上述实施例仅在所有方面进行了说明,而不是限制性的。
工业适用性
发明人证实,当将衍生自乳杆菌属细菌的囊泡施用于高脂肪西式饮食诱导的代谢性疾病的动物模型中时,不仅能够降低体重和饭量,而且能够有效地抑制由西式饮食引起的代谢紊乱,并通过激活肌细胞中的AMPK信号增加了针对代谢压力的稳态。因此,根据本发明的衍生自乳杆菌属细菌的囊泡能够有效地用于开发用于预防、改善症状或治疗代谢性疾病和肌肉疾病的药物或保健功能食品,并因此具有工业实用性。
Claims (17)
1.一种用于预防或治疗代谢性疾病或肌肉疾病的药物组合物,所述药物组合物包含衍生自乳杆菌属的细菌的囊泡作为活性成分。
2.根据权利要求1所述的药物组合物,其中所述乳杆菌属的所述细菌是副干酪乳杆菌或鼠李糖乳杆菌。
3.根据权利要求1所述的药物组合物,其中所述代谢性疾病选自由以下项组成的群组:肥胖症、代谢综合征、高胰岛素血症、高脂血症、高甘油三酯血症、高胆固醇血症、血脂异常、糖尿病、糖尿病肾病、糖尿病视网膜病变、脂肪肝、非酒精性脂肪性肝炎和动脉硬化。
4.根据权利要求1所述的药物组合物,其中所述肌肉疾病是选自由以下项组成的群组的一种或多种:萎缩症、肌肉萎缩症、肌肉营养不良、肌无力症、恶病质和肌肉疏松症。
5.根据权利要求1所述的药物组合物,其中所述囊泡具有10至1000nm的平均直径。
6.根据权利要求1所述的药物组合物,其中所述囊泡从所述乳杆菌属的细菌的培养液中分离出来。
7.根据权利要求1所述的药物组合物,其中所述囊泡从通过添加所述乳杆菌属的细菌而制备的食品中分离出来。
8.根据权利要求1所述的药物组合物,其中所述囊泡是由所述乳杆菌属的细菌天然或人工分泌的。
9.一种用于预防或缓解代谢性疾病或肌肉疾病的食品组合物,所述食品组合物包含衍生自乳杆菌属的细菌的囊泡作为活性成分。
10.一种用于改善肌肉功能的食品组合物,所述食品组合物包含衍生自乳杆菌属的细菌的囊泡作为活性成分。
11.一种用于增强运动表现能力的食品组合物,所述食品组合物包含衍生自乳杆菌属细菌的囊泡作为活性成分。
12.一种预防或治疗代谢性疾病或肌肉疾病的方法,所述方法包括向个体施用包含衍生自乳杆菌属的细菌的囊泡作为活性成分的组合物。
13.包含衍生自乳杆菌属的细菌的囊泡作为活性成分的组合物用于预防或治疗代谢性疾病或肌肉疾病的用途。
14.衍生自乳杆菌属的细菌的囊泡用于制备预防或治疗代谢性疾病或肌肉疾病的药物的用途。
15.一种用于改善肌肉功能或增强运动表现能力的方法,所述方法包含向个体施用包含衍生自乳杆菌属的细菌的囊泡作为活性成分的组合物。
16.包含衍生自乳杆菌属的细菌的囊泡作为活性成分的组合物用于改善肌肉功能或增强运动表现能力的用途。
17.衍生自乳杆菌属的细菌的囊泡用于制备改善肌肉功能或提高运动表现能力的药物的用途。
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KR102098069B1 (ko) | 2018-01-26 | 2020-04-07 | 영남대학교 산학협력단 | 내열성 향상을 위한 기능성 물질 캡슐, 이를 이용한 필라멘트 및 이의 제조방법 |
KR102101692B1 (ko) * | 2018-03-05 | 2020-04-20 | 주식회사 엠디헬스케어 | 락토바실러스 속 세균 유래 나노소포 및 이의 용도 |
ES2954685T3 (es) * | 2018-06-01 | 2023-11-23 | Nzym Deutschland Gmbh | Microvesículas derivadas de productos de origen vegetal fermentados, método para su preparación y utilización |
KR20200072685A (ko) | 2018-12-13 | 2020-06-23 | 주식회사 원익아이피에스 | 기판 처리 장치 및 기판 처리 장치의 밸브 상태 감지 방법 |
KR102098067B1 (ko) * | 2018-12-31 | 2020-04-07 | 주식회사 엠디헬스케어 | 락토바실러스 파라카제이 유래 소포 및 이의 용도 |
KR102049700B1 (ko) * | 2019-07-31 | 2019-11-28 | (주) 에이투젠 | 락토바실러스 루테리 atg-f4를 포함하는 근육질환 예방 또는 치료용 조성물 |
KR20210073948A (ko) | 2019-12-11 | 2021-06-21 | 주식회사 웰빙엘에스 | 전통발효식품 유래 미생물로 발효되어 면역증가 활성을 가지며, 저작성이 용이한 노인식용 발효 곤드레 부산물의 제조방법 |
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2020
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- 2021-06-08 KR KR1020210073948A patent/KR102567721B1/ko active IP Right Grant
- 2021-06-14 WO PCT/KR2021/007369 patent/WO2021256793A1/ko unknown
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EP3960192A1 (en) | 2022-03-02 |
EP3960192A4 (en) | 2022-11-02 |
EP4218781A1 (en) | 2023-08-02 |
KR102257130B1 (ko) | 2021-05-28 |
WO2021256665A1 (ko) | 2021-12-23 |
KR20230126681A (ko) | 2023-08-30 |
JP2023527881A (ja) | 2023-06-30 |
KR102567721B1 (ko) | 2023-08-18 |
US20220249581A1 (en) | 2022-08-11 |
KR20210155745A (ko) | 2021-12-23 |
WO2021256793A1 (ko) | 2021-12-23 |
JP7461083B2 (ja) | 2024-04-03 |
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