CN115942945A - 含源自副干酪乳杆菌的细胞外囊泡的预防或治疗眼病的组合物 - Google Patents
含源自副干酪乳杆菌的细胞外囊泡的预防或治疗眼病的组合物 Download PDFInfo
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Abstract
本发明涉及源自副干酪乳杆菌的细胞外囊泡及其用途,更特别地,涉及一种用于减轻、预防和治疗眼病的组合物,该组合物包含源自副干酪乳杆菌的细胞外囊泡作为活性成分,能够有效抑制由氧化应激介导的细胞衰老引起的眼病的发生。
Description
技术领域
本发明涉及源自副干酪乳杆菌的细胞外囊泡及其用途,更特别地,涉及用于预防或治疗眼病的组合物,该组合物包含源自副干酪乳杆菌的细胞外囊泡作为活性成分。
本申请要求分别于2021年6月3日和2021年10月1日在韩国知识产权局提交的韩国专利申请号10-2021-0072078和10-2021-0130843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
自从21世纪开始以来,过去被认为是流行病的急性传染病已变得不那么重要,而伴随着人类与微生物群系之间的不和谐导致的免疫功能障碍的慢性病已经作为决定生活质量和人类寿命的主要疾病而改变了疾病模式。癌症、心血管疾病、慢性肺病、代谢疾病和神经精神疾病作为21世纪以各种压力引起的免疫和代谢功能异常为特征的顽固性慢性病,是决定人类寿命和生活质量并成为公共卫生问题的重大疾病。
免疫是针对生物、化学、生理和精神压力的细胞防御机制,并通过先天免疫和适应性免疫发生。新陈代谢是制造身体所需的能量以产生各种执行细胞功能的物质,并将由线粒体中产生的ATP在内质网(ER)中产生的蛋白质和脂质提供给需要的区域。细胞从生成的那一刻起就面临着各种压力,并且生物、化学、物理和精神压力在细胞中诱发ER应激,并且当ER应激维持时,细胞死亡或转化为癌细胞。因此,最近发现许多目前存在问题的顽固性疾病是由于重复性ER应激导致的免疫和代谢功能异常引起的。
同时,眼睛的视网膜是属于中枢神经系统的器官,而成熟的视网膜细胞在正常情况下不会像神经元细胞那样分裂。因此,当视网膜细胞的功能下降时,容易出现视觉功能异常,并且老化迅速进行。视网膜细胞功能恶化的最大原因是氧化应激,这是因为构成眼睛的组织,包括视网膜、视神经、感光细胞和晶状体,在日常生活中不断暴露于光和UV等氧化应激。由于这种氧化应激,随着构成细胞的DNA、蛋白质和脂质发生改变并诱导细胞死亡,发生眼部老化,并且严重的是发生年龄相关性眼病,例如地图状萎缩、糖尿病性视网膜病变、白内障、青光眼和干眼症。
此外,当视觉相关细胞不能适当地抵御蓝光和UV等环境压力时,会发生眼睛炎症,并且由于反复的压力会发生慢性炎症性眼病。最近,为了治疗或预防这些慢性炎症性眼病,对炎症细胞因子TNF-α的抑制剂的兴趣正在增加,TNF-α是已知的炎症性疾病的主要介质。
已知人体内共存的微生物数量达到100万亿,比人体细胞多10倍左右,微生物的基因数量比人的基因数量多100倍。微生物群或微生物组是指微生物群落,包括存在于给定栖息地的细菌、古细菌和真核生物。
共存于我们体内的细菌和存在于周围环境中的细菌分泌纳米尺寸的囊泡,以与其他细胞交换诸如基因、低分子化合物和蛋白质之类的信息。黏膜形成物理防御膜,200纳米(nm)或更大尺寸的粒子不能通过所述黏膜,使得共存于黏膜中的细菌不能通过黏膜,但源自细菌的细胞外囊泡具有大约20至200纳米的尺寸,因此相对自由地经由黏膜穿过上皮细胞被我们身体吸收。如上所述,虽然源自细菌的细胞外囊泡是由细菌分泌的,但它们在成分、体内吸收率和副作用风险方面与细菌不同,因此,源自细菌的细胞外囊泡的使用完全不同于活细胞或具有显著效果。
局部分泌的源自细菌的细胞外囊泡通过黏膜的上皮细胞被吸收以诱导局部炎症反应,并且已通过上皮细胞的囊泡被全身吸收以分布到相应器官,并调节所分布器官中的免疫和炎症反应。例如,源自大肠杆菌等病原细菌的囊泡是一种模拟病毒的病原纳米颗粒,会局部引起结肠炎或食物中毒,并且当吸收到血管中时,通过血管内皮炎症反应促进全身炎症反应和血液凝固。另一方面,源自有益细菌的囊泡可以通过调节由病原囊泡引起的免疫和代谢功能异常来控制疾病。
乳酸菌包括大量将碳水化合物转化为乳酸的细菌,已知会发酵酸奶、乳酸菌饮料和泡菜等食物,以保护身体免受存在于消化器官(例如肠道)中的其他病原微生物(肠道细菌)或存在于阴道中的其他病原微生物的侵害,并帮助维持体内平衡。在乳酸菌中,副干酪乳杆菌是不形成孢子的好氧乳酸菌,并且已知可作为人体胃肠道和女性阴道的共生细菌以保护人体免受病原细菌的侵害。
然而,没有源自副干酪乳杆菌的细胞外囊泡应用于治疗与年龄或炎症相关的眼病的报告案例。
发明内容
【技术问题】
为了解决上述现有技术中的问题,本发明旨在提供一种用于预防或治疗眼病的药物组合物,其包含源自副干酪乳杆菌的细胞外囊泡作为活性成分。
此外,本发明的另一目的是提供一种用于预防或减轻眼病的食品组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
此外,本发明的又一目的是提供一种用于预防或治疗眼病的准药物组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
此外,本发明的另一个目的是提供一种用于预防或治疗眼病的可吸入组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
此外,本发明的再一个目的是提供一种用于药物递送以治疗眼病的组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
然而,本发明要解决的技术问题不限于上述问题,并且本领域技术人员根据以下描述可以清楚地理解未提及的其他问题。
【技术方案】
本发明提供一种用于预防或治疗眼病的药物组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
此外,本发明提供一种用于预防或减轻眼病的食品组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
此外,本发明提供一种用于预防或减轻眼病的准药物组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
此外,本发明提供一种用于预防或减轻眼病的可吸入组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
此外,本发明提供一种用于药物递送以治疗眼病的组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
在本发明的一个实施方案中,眼病可以是年龄相关性眼病,但本发明不限于此。
在本发明的另一个实施方案中,眼病可以是炎症性眼病,但本发明不限于此。
在本发明的又一个实施方案中,眼病可以是选自由以下组成的组的一种或多种疾病:Leber先天性黑朦(LCA)、斯特格病(Stargardt’s disease)、Usher综合征、脉络膜功能不全、Rod-Cone或Cone-Rod营养障碍性疾病、纤毛病、线粒体功能障碍、进行性视网膜萎缩、退行性视网膜疾病、年龄相关性黄斑变性(AMD)、湿性AMD、干性AMD、地图状萎缩、家族性或获得性黄斑病变、视网膜光感受器疾病、视网膜色素上皮相关疾病、糖尿病性视网膜病变、囊性黄斑水肿、视网膜脱离、外伤性视网膜损伤、医源性视网膜损伤、黄斑裂孔、黄斑毛细血管扩张症、神经节细胞疾病、视神经细胞疾病、青光眼、白内障、视神经病变、缺血性视网膜疾病、早产儿视网膜病变、视网膜血管阻塞、家族性大动脉瘤、视网膜血管疾病、眼血管疾病、由青光眼和缺血性视神经病变引的视网膜神经细胞变性,但本发明不限于此。
在本发明的又一个实施方案中,炎症性眼病可以是选自由以下组成的组的一种或多种疾病:色素性视网膜炎(RP)、结膜炎、巩膜炎、角膜炎、虹膜炎、葡萄膜炎、脉络膜视网膜炎、脉络膜炎和视网膜炎,但是本发明不限于此。
在本发明的又一个实施方案中,炎症性眼病可以由IL-6介导,但本发明不限于此。
在本发明的又一个实施方案中,眼病可以是由免疫功能障碍或代谢功能障碍引起的眼病,但本发明不限于此。
在本发明的又一个实施方案中,眼病可以是由氧化应激引起的眼病,但本发明不限于此。
在本发明的又一个实施方案中,囊泡的平均直径可以为10至300nm,但本发明不限于此。
在本发明的又一个实施方案中,囊泡可以由副干酪乳杆菌天然或人工分泌,但本发明不限于此。
在本发明的又一个实施方案中,囊泡可以从副干酪乳杆菌培养液或通过添加副干酪乳杆菌制备的食物中分离,但本发明不限于此。
此外,本发明提供一种用于预防或治疗眼病的方法,该方法包括向受试者施用包含源自副干酪乳杆菌的囊泡的组合物。
此外,本发明提供了包含源自副干酪乳杆菌的囊泡的组合物用于预防或治疗眼病的用途。
此外,本发明提供了源自副干酪乳杆菌的囊泡在制备用于预防或治疗眼病的药物中的用途。
此外,本发明提供了源自副干酪乳杆菌的囊泡在制备用于预防或减轻眼病的食品中的用途。
另外,本发明提供了源自副干酪乳杆菌的囊泡在制备用于预防或减轻眼病的准药物中的用途。
此外,本发明提供了一种用于递送药物以治疗眼病的方法,该方法包括向受试者施用包含源自副干酪乳杆菌的囊泡的组合物。
另外,本发明提供了包含源自副干酪乳杆菌的囊泡的组合物用于递送药物以治疗眼病的用途。
此外,本发明提供源自副干酪乳杆菌的囊泡在制备用于治疗眼病的药物递送剂中的用途。
【优势效果】
经证实,根据本发明的源自副干酪乳杆菌的细胞外囊泡被吸收到体内后,通过血脑屏障(BBB)分布到中枢神经系统,并且在被吸收入细胞后,有效抑制难治性炎症性疾病的主要介质IL-6的分泌,激活AMPK信号传导以增强代谢功能,并且有效抑制由细胞衰老和炎症引起的眼病的发生。另外,由于证实了当将囊泡施用于患有由氧化应激引起的眼病的兔模型时,显著抑制了由氧化应激引起的视网膜变性的发生,因此根据本发明的源自副干酪乳杆菌的细胞外囊泡可有望广泛用作用于减轻、预防或治疗眼病的药物。
附图说明
图1是本发明一实施方案的源自副干酪乳杆菌的细胞外囊泡的口服给药后的分布模式的分析结果。
图2是本发明一实施方案的源自副干酪乳杆菌的细胞外囊泡在口服给药后在中枢神经系统中的分布模式的分析结果。
图3是评价根据本发明一实施方案的源自副干酪乳杆菌的细胞外囊泡对LPS对炎性细胞因子分泌的影响的抑制作用以及囊泡在源自副干酪乳杆菌的细胞外囊泡(MDH-001:副干酪乳杆菌EV)的热处理、酸处理或胆汁处理中的治疗效果的图。
图4显示了评价根据本发明一实施方案的源自副干酪乳杆菌的细胞外囊泡对代谢功能障碍的治疗效果,以及通过用二甲双胍(作为对照药物)和源自副干酪乳杆菌的细胞外囊泡(MDH-001:副干酪乳杆菌EV)处理细胞来评价对AMPK信号传导(其是代谢功能的关键信号通路)的影响的结果。
图5显示了根据本发明一实施方案通过源自副干酪乳杆菌的细胞外囊泡的口服给药来确认对眼病的功效的动物模型试验和评价方法。
图6是显示通过将源自副干酪乳杆菌的细胞外囊泡口服给药到患有眼病的兔模型中以确定对眼病的功效,通过测量处理组与对照相比的视网膜变性区域而获得的结果的图。G1:未处理的阴性对照,G2:疾病诱导的阳性对照,G3:低剂量囊泡处理组,G4:高剂量囊泡处理组。
图7是在将源自副干酪乳杆菌的细胞外囊泡口服给药到患有由氧化应激引起的眼病的兔模型中以确定对年龄相关性眼病的疗效后用眼底照相机(日本拓普康TRC-50IX)拍摄的一组眼底照片。G1:未处理的阴性对照,G2:疾病诱导的阳性对照,G3:低剂量囊泡处理组,G4:高剂量囊泡处理组。
图8是示出本发明一实施方案的源自副干酪乳杆菌的细胞外囊泡对眼病的作用机制的图。
具体实施方式
本发明涉及源自副干酪乳杆菌的细胞外囊泡及其用途。
本发明人分离了源自副干酪乳杆菌的囊泡。
发明人证实,源自副干酪乳杆菌的细胞外囊泡在口服给药后很好地递送至多个器官,并通过血脑屏障(BBB)迁移和分布在包括视网膜在内的中枢神经系统中(见实施例2).
此外,本发明人证实,源自副干酪乳杆菌的细胞外囊泡抑制了响应于LPS引起的炎症的IL-6分泌,并且这种抑制作用通过对囊泡的热处理、酸处理和胆汁处理得以维持(见实施例3)。
此外,本发明人证实,由于源自副干酪乳杆菌的细胞外囊泡通过激活AMPK信号传导(其是调节代谢紊乱的关键信号因子)诱导自噬,因此可以通过增加代谢功能的稳态来治疗由代谢紊乱引起的眼病(见实施例4)。
此外,本发明人证实,通过将源自副干酪乳杆菌的细胞外囊泡口服给药至患有由氧化应激引起的黄斑变性的兔模型,显著减少了由视网膜色素上皮细胞层的变性引起的黄斑变性(见实施例5)。
因此,本发明提供了一种用于预防、减轻或治疗眼病的组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。该组合物包括药物组合物、食品组合物和准药物组合物。
在下文中,将详细描述本发明的源自副干酪乳杆菌的细胞外囊泡在预防、减轻或治疗眼病中的用途。
如本文所用,术语囊泡或细胞外囊泡是指由各种细菌分泌的纳米级膜形成的结构,并且包括例如源自革兰氏阴性菌(如大肠杆菌)的细胞外囊泡,其具有内毒素(脂多糖)、有毒蛋白质以及细菌DNA和RNA两者;或源自革兰氏阳性菌(如微球菌)的细胞外囊泡,其具有外膜囊泡(OMV)、蛋白质和核酸以及细菌细胞壁的成分,例如肽聚糖和脂磷壁酸。
在本说明书中,囊泡涵盖由副干酪乳杆菌天然分泌的或由人工产生的膜形成的所有结构。
囊泡可以通过在副干酪乳杆菌培养期间的热处理或高压灭菌,或使用选自由以下组成的组的针对细胞培养物的一种或多种方法来分离:离心、超速离心、高压灭菌、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、用过滤器过滤、凝胶过滤色谱法、预流动电泳和毛细管电泳。此外,为了分离,可以进一步对获得的囊泡进行洗涤以去除杂质并浓缩。
用于从本发明的副干酪乳杆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之类的方法及其组合的方法来分离囊泡,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。
本文所用的术语“眼病”是指与眼部相关的疾病。
本文所用的术语“年龄相关性眼病”是这样一个概念,其不仅包括由随老化而生物功能退化引起的眼病,而且还包括表现出与因生物功能退化的速度比实际年龄要快而主要发生在老年人中的疾病症状相似的症状的眼病。在本发明中,年龄相关性眼病可以包括由AMPK介导的眼病和由氧化应激引起的眼病。年龄相关性眼病可以包含,例如选自由以下组成的组的一种或多种:Leber先天性黑朦(LCA)、斯特格病、Usher综合征、脉络膜功能不全、Rod-Cone或Cone-Rod营养障碍性疾病、纤毛病、线粒体功能障碍、进行性视网膜萎缩、退行性视网膜疾病、年龄相关性黄斑变性(AMD)、湿性AMD、干性AMD、地图状萎缩、家族性或获得性黄斑病变、视网膜光感受器疾病、视网膜色素上皮相关疾病、糖尿病性视网膜病变、囊性黄斑水肿、视网膜脱离、外伤性视网膜损伤、医源性视网膜损伤、黄斑裂孔、黄斑毛细血管扩张症、神经节细胞疾病、视神经细胞疾病、青光眼、白内障、视神经病变、缺血性视网膜疾病、早产儿视网膜病变、视网膜血管阻塞、家族性大动脉瘤、视网膜血管疾病、眼血管疾病、由青光眼和缺血性视神经病变引起的视网膜神经细胞变性,但本发明不限于此。
本文所用的术语“炎症性眼病”是包括由炎症性致病因子引起的眼部炎症引起的所有眼病的概念,并且在本发明中,炎症性眼病可以包括由IL-6介导的眼病或由氧化应激引起的眼病。炎症性眼病可以包括例如色素性视网膜炎(RP)、结膜炎、巩膜炎、角膜炎、虹膜炎、葡萄膜炎、脉络膜视网膜炎、脉络膜炎和视网膜炎,但本发明不限于此。
本文所用的“视网膜地图状萎缩”是这样一种疾病,其中由于年龄相关性黄斑变性和血液供应不良导致视网膜和脉络膜毛细血管因玻璃疣钙化而萎缩,玻璃疣是视网膜色素上皮细胞中积聚的废物,并且萎缩区域扩大为地图形状并扩散到中心区域,从而导致视力丧失。
本文所用的“年龄相关性黄斑变性(AMD)”是视网膜黄斑部(在视力中起着非常重要的作用)因老化而伴随各种变化的疾病。在本发明中,年龄相关性黄斑变性可以包括干性(非渗出性)和湿性(渗出性)类型。“干性AMD”是指视网膜中出现玻璃疣或视网膜色素上皮萎缩等病变的情况,约占AMD的90%。黄斑内的感光细胞逐渐萎缩,视力逐渐下降,它可进展成湿性形式。在“湿性AMD”中,新的脉络膜血管在视网膜下生长,并且由于新血管本身或血管的出血或渗出,很可能发生严重的视力损伤,并在发病后数月至数年内可能因视神经乳头萎缩(disc atrophy)和严重出血而失明。
本文所用的“糖尿病性视网膜病变”是糖尿病中出现的微血管并发症之一,是由高血压引起的视网膜血管渗透性增加等毛细血管的功能和形态变化以及随之而来的多种生化变化、缺血和新生血管形成引起的。在本发明中,糖尿病视网膜病变可以包括非增殖性或增殖性视网膜病变,但本发明不限于此。“非增殖性视网膜病变”是指由于血清渗漏或血管阻塞,视网膜内的小血管被削弱并且营养供应中断的病症。“增殖性视网膜病变”已知会因没有对血液循环不良部位的新血管出血进行适当治疗而在5年内导致失明。
在本发明中,囊泡可以是球状的形式,并且具有以下平均直径:10-300nm、10-200nm、10-190nm、10-180nm、10-170nm、10-160nm、10-150nm、10-140nm、10-130nm、10-120nm、10-110nm、10-100nm、10-90nm、10-80nm、10-70nm、10-60nm、10-50nm、20-200nm、20-180nm、20-160nm、20至140nm、20至120nm、20至100nm,或20至80nm,优选20-200nm,但是不限于此。
本文所用的术语“包含……作为活性成分”是指足以实现源自副干酪乳杆菌的细胞外囊泡的功效或活性的量。
本发明的组合物中囊泡的量可根据疾病的症状、症状的进展程度、患者的病症等进行适当调整,并且范围可以为,例如,相对于组合物的总重量,0.0001wt%至99.9wt%或0.001wt%至50wt%,但本发明不限于此。量比率是基于除去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受试者。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、腹膜内给药、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。
在本发明中,眼部给药可以是选自由结膜内给药、玻璃体内给药、视网膜下给药、脉络膜上给药、结膜下给药和腱下给药组成的组中的一种,但本发明不限于此。
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,本发明提供一种食品组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
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。
此外,本发明可以以包含源自副干酪乳杆菌的囊泡作为活性成分的可吸入组合物的形式提供。
在吸入制剂的情况下,该化合物可以根据本领域已知的方法配制,并且可以通过使用合适的推进剂以气雾剂喷雾的形式从加压包或喷雾器方便地递送,所述推进剂为例如二氯氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体。在加压气雾剂的情况下,剂量单位可通过设置用于输送计量的阀来确定。例如,用于吸入器或吹入器中的明胶胶囊和药筒可被配制成包含化合物和合适的粉末基质(例如乳糖或淀粉)的粉末混合物。
此外,本发明可以提供一种准药物组合物,其包含源自副干酪乳杆菌的细胞外囊泡作为活性成分。
本文所用的术语“准药物”是指在用于诊断、治愈、改善、减轻、治疗或预防人类或动物疾病的产品中表现出比药物更温和的作用的产品。例如,根据药事法(PharmaceuticalAffairs Act),准药物不包括用作药物的产品,而包括用于治疗或预防人类·动物疾病的纺织·橡胶产品、对人体作用较弱或不直接作用于人体的产品,并且不是仪器或机器或类似物,以及用于预防传染病的消毒剂和杀虫剂。
在本发明中,准药物组合物可以配制成眼科组合物,例如,选自由眼用液体、滴眼剂、眼药膏、注射液和洗眼液组成的组的一种或多种,但本发明是不限于此。
此外,本发明提供一种用于递送药物以治疗眼病的组合物,其包含源自副干酪乳杆菌的细胞外囊泡作为活性成分。
本文所用的术语“药物递送”是指将药物装载和递送至根据本发明的组合物以将药物递送至特定器官、组织、细胞或细胞器的任何手段或作用。
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
为了分离源自副干酪乳杆菌的细胞外囊泡(EV),将各种副干酪乳杆菌接种到自制培养基中,于37℃以200rpm培养直至吸光度(OD600nm)变为1.0至1.5,然后重新接种到该培养基中并进行培养。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过滤器再次过滤浓缩的上清液来分离源自副干酪乳杆菌的囊泡(MDH-001)。使用Pierce BCA蛋白质检测试剂盒(Thermo FisherScientific)测量上清液中蛋白质的量。对分离的囊泡进行了以下实验。
实施例2.源自副干酪乳杆菌的囊泡的药代动力学特性的评价
为了研究源自副干酪乳杆菌的囊泡在口服给药期间的药代动力学特性,通过对小鼠口服给药利用荧光染色试剂Cy7-NHS染色的囊泡,测量从给药前立即到给药后72小时在体内和每个器官中表达的荧光。
如图1所示,将用荧光染色的源自副干酪乳杆菌的细胞外囊泡口服给药,并在1小时后观察到荧光信号。可以证实,在3小时时,在胃、小肠、大肠和肺中记录到微弱的信号水平,并在6小时时,在大脑以及胃、小肠、大肠和肺中显示出信号。此类荧光信号在口服给药后6到24小时显示出最强的信号,显示出逐渐减弱的趋势,并在48小时后几乎消失。
此外,如图2所示,观察到,在将源自副干酪乳杆菌的细胞外囊泡口服给药之后,评价在中枢神经系统中的分布模式,在口服给药3小时后它们在中枢神经系统中有分布,在6小时时显示出峰值,在48小时后信号消失。
由该结果可知,源自副干酪乳杆菌的细胞外囊泡在口服给药时,通过粘膜被吸收到体内,分布在各个器官中,特别是,它们通过BBB迁移到包括视网膜在内的中枢神经系统并进行分布。
实施例3:源自副干酪乳杆菌的细胞外囊泡对LPS引起的炎症反应的抗炎作用的评
价
为了证实源自副干酪乳杆菌的细胞外囊泡的抗炎作用,小鼠巨噬细胞(RAW 264.7细胞)用10μg/mL或100μg/mL的源自副干酪乳杆菌的细胞外囊泡进行预处理,并用100ng/mL的LPS作为炎症诱导剂进行处理,接着测量炎症相关标志物IL-6的分泌量。此外,为了评价源自副干酪乳杆菌的细胞外囊泡是否可以口服给药,对囊泡进行热处理、酸处理和胆汁处理,然后测定IL-6的分泌量。
结果,如图3所示,与用LPS 100ng/ml的LPS处理的阳性对照组相比,证实源自副干酪乳杆菌的细胞外囊泡显著降低了IL-6的分泌量。此外,证实了在源自副干酪乳杆菌的细胞外囊泡的热处理、酸处理和胆汁处理中,抑制巨噬细胞分泌IL-6的效果也得以维持。
上述结果显示源自副干酪乳杆菌的细胞外囊泡对热或酸是稳定的,并且当囊泡被口服给药时,可以维持抗炎作用。
实施例4:源自副干酪乳杆菌的细胞外囊泡对AMPK信号传导(调节代谢紊乱的关键
信号传导)激活的影响的评价
AMP激活的蛋白激酶(AMPK)信号传导通过自噬等机制抑制能量消耗中发生的代谢紊乱。在本发明中,用源自副干酪乳杆菌的细胞外囊泡(MDH-001-CM)处理细胞以评价对AMPK激活的影响。将接种了2x106个细胞的DMEM无血清培养基放入60-mm细胞培养皿中并培养2小时。之后,将源自副干酪乳杆菌的细胞外囊泡以0、0.1、1或10μg/mL处理1小时,并用胰岛素(1μM)和二甲双胍(50mM)处理1小时作为比较组。为了进行细胞裂解测定,将经样品处理的培养皿置于冰上,抽吸上清液,并加入各5mL的冷PBS缓冲液来洗涤两次。将10μL蛋白酶/磷酸酶抑制剂加入到1mL裂解缓冲液中并充分混合,在每个皿上滴加100μL细胞裂解缓冲液,并在冰上温育5分钟。用刮刀分离后,将细胞转移到1.5mL微管中,然后在冰上重复涡旋和温育20分钟,每次1分钟。之后,在4℃下以14,000rpm进行离心10分钟,分别将5μL和70μL裂解的样品上清液转移到两个1.5mL微管中。将转移有5μL上清液的微管储存于-20℃,将16.5μL的5X样品缓冲液放入转移有70μL上清液的微管中并于100℃煮沸5分钟。将煮沸的样品储存于-20℃。为了进行BCA定量分析,在室温下取出加入了5μL裂解的样品上清液的1.5mL微管,与20μL无菌蒸馏水一起涡旋,然后降速(spin down)。通过将2mg/mL牛血清白蛋白(BSA)溶解在无菌蒸馏水中,然后稀释1/2,制备2、1、0.5、0.25、0.125、0.0625、0.03125和0mg/mL的储备液。将每种浓度的BSA以25μL添加到96孔聚苯乙烯板的3个孔中,并将25μL裂解的样品也添加到一个孔中。将8mL的BCA蛋白检测试剂A和160μL的BCA蛋白检测试剂B混合,然后将其200μL放入孔中。在37℃温育箱中反应30分钟后,使用SpectraMax M3酶标仪(美国的Molecular Devices)在562nm处测量吸光度。对于蛋白质印迹,在Tris-甘氨酸SDS-聚丙烯酰胺凝胶电泳期间制备10%凝胶,测量50μg蛋白质/样品并加载。转移至硝酸纤维素膜后,用5%脱脂奶封闭反应,将AMPKα抗体按1:400稀释,将磷酸化AMPKα抗体按1:400稀释,用5%的脱脂奶将β-肌动蛋白抗体按1:1,000稀释,并与膜混合过夜。将所得膜用1X PBST(含0.05%吐温-20的PBS)溶液洗涤3次持续5分钟后,将抗兔IgG和HRP结合抗体以1:1,000稀释,与膜混合1小时。将得到的膜用1X PBST溶液洗涤3次持续5分钟,然后将West-Q化学发光底物试剂盒(West-Q Chemiluminescent Substrate Kit)的溶液A和溶液B以1:1混合的溶液充分喷涂在膜上,接着使用Chemidoc系统检测条带。
结果,如图4所示,证实了磷酸化AMPK的表达依赖于源自副干酪乳杆菌的细胞外囊泡(MDH-001-CM)的处理浓度而增加。可见源自副干酪乳杆菌的细胞外囊泡以剂量依赖性方式激活AMPK信号传导,诱导自噬并抑制代谢功能障碍,从而增加细胞稳态。
实施例5:源自副干酪乳杆菌的细胞外囊泡在患有由氧化应激引起的眼病的兔模
型中的治疗效果的评价
已知氧化应激在诸如年龄相关性变性(AMD)、早产儿视网膜病变、视网膜光损伤、青光眼和病理方面的白内障之类的各种眼病中起着重要作用(Beatty S.,Koh H.,PhilM.,Henson D.,和Boulton M.,“The role of oxidative stress in the pathogenesisof age-related macular degeneration”,Surv.Ophthalmol.,45(2):115-134(2000))。
因此,为了通过氧化应激诱发眼病,将作为氧化应激诱发黄斑变性的材料的碘酸钠(SI)一次静脉内给药至兔子。为了评价源自副干酪乳杆菌的细胞外囊泡的治疗效果,在诱导前3天至诱导后7天每天口服给药一次0.25mg/kg和2.5mg/kg的源自副干酪乳杆菌的细胞外囊泡(MDH-001)。为了进行评价,在最后给药日,即在疾病诱导后的第7天,用眼底照相机(日本拓普康TRC-50IX)拍摄视网膜变性区域,并进行分析(图5)。
结果,如图6所示,在低剂量囊泡(MDH-001)处理组(G3)和高剂量囊泡(MDH-001)处理组(G4)中,与阳性对照(G2)相比,视网膜色素上皮(RPE)的变性区域在统计学上显著减少,从而证实了剂量依赖性。
同时,为了评价源自副干酪乳杆菌的细胞外囊泡对黄斑变性的治疗效果,将散瞳剂(Midriacil 1%滴眼液)滴入兔右眼后,将该动物麻醉,然后用眼底照相机拍摄其眼底。结果示于图7。
如图7所示,在阴性对照(G1)中几乎没有显示黄斑变性,而在诱发疾病的阳性对照(G2)中清楚地显示了黄斑变性。此外,可见在低剂量囊泡处理组(G3)和高剂量囊泡处理组(G4)中,与阳性对照相比,黄斑变性显著减少,而在高剂量囊泡处理组中,更清楚地显示出减少效果。
由以上结果可知,本发明的源自副干酪乳杆菌的细胞外囊泡能够有效地抑制由氧化应激引起的眼病的发生。特别是,证实了不仅通过致病因子抑制炎症介质的分泌,而且通过AMPK信号传导增强对代谢应激的抵抗力,可以有效地调节细胞老化相关性眼病的病因(图8)。
因此,预期本发明的源自副干酪乳杆菌的细胞外囊泡可用于减轻、预防或治疗年龄相关性和炎症性眼病。
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
经证实,根据本发明的源自副干酪乳杆菌的细胞外囊泡被吸收到体内后,通过血脑屏障(BBB)分布在中枢神经系统中,并且在被吸收入细胞后,有效抑制难治性炎症性疾病的主要介质IL-6的分泌,激活AMPK信号传导以增强代谢功能,并且有效抑制由细胞衰老和炎症引起的眼病的发生。另外,由于证实了当将囊泡施用于患有由氧化应激引起的眼病的兔模型时,显著抑制了由氧化应激引起的视网膜变性的发生,因此根据本发明的源自副干酪乳杆菌的细胞外囊泡能够广泛用作用于减轻、预防或治疗眼病的药物并因此具有工业实用性。
Claims (18)
1.一种用于预防或治疗眼病的药物组合物,其包含源自副干酪乳杆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,其中所述眼病是年龄相关性眼病。
3.根据权利要求1所述的药物组合物,其中所述眼病是炎症性眼病。
4.根据权利要求1所述的药物组合物,其中所述眼病是选自由以下组成的组的一种或多种疾病:Leber先天性黑朦症(LCA)、斯特格病、Usher综合征、脉络膜功能不全、Rod-Cone或Cone-Rod营养障碍性疾病、纤毛病、线粒体功能障碍、进行性视网膜萎缩、退行性视网膜疾病、年龄相关性黄斑变性(AMD)、湿性AMD、干性AMD、地图状萎缩、家族性或获得性黄斑病变、视网膜光感受器疾病、视网膜色素上皮相关疾病、糖尿病性视网膜病变、囊性黄斑水肿、视网膜脱离、外伤性视网膜损伤、医源性视网膜损伤、黄斑裂孔、黄斑毛细血管扩张症、神经节细胞疾病、视神经细胞疾病、青光眼、白内障、视神经病变、缺血性视网膜疾病、早产儿视网膜病变、视网膜血管阻塞、家族性大动脉瘤、视网膜血管疾病、眼血管疾病、由青光眼和缺血性视神经病变引的视网膜神经细胞变性。
5.根据权利要求3所述的药物组合物,其中所述炎症性眼病是选自由以下组成的组的一种或多种疾病:色素性视网膜炎(RP)、结膜炎、巩膜炎、角膜炎、虹膜炎、葡萄膜炎、脉络膜视网膜炎、脉络膜炎和视网膜炎。
6.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300nm的平均直径。
7.根据权利要求1所述的药物组合物,其中所述囊泡是由副干酪乳杆菌天然或人工分泌的。
8.根据权利要求1所述的药物组合物,其中所述囊泡是从副干酪乳杆菌培养液或通过添加副干酪乳杆菌制备的食物中分离的。
9.一种用于预防或减轻眼病的食品组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
10.一种用于预防或减轻眼病的准药物组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
11.一种用于预防或减轻眼病的可吸入组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
12.一种用于药物递送以治疗眼病的组合物,其包含源自副干酪乳杆菌的囊泡作为活性成分。
13.一种用于预防或治疗眼病的方法,所述方法包括向受试者施用包含源自副干酪乳杆菌的囊泡的组合物。
14.包含源自副干酪乳杆菌的囊泡的组合物用于预防或治疗眼病的用途。
15.源自副干酪乳杆菌的囊泡在制备用于预防或治疗眼病的药物中的用途。
16.一种用于递送药物以治疗眼病的方法,所述方法包括向受试者施用包含源自副干酪乳杆菌的囊泡的组合物。
17.包含源自副干酪乳杆菌的囊泡的组合物用于递送药物以治疗眼病的用途。
18.源自副干酪乳杆菌的囊泡用于制备用于治疗眼病的药物递送剂的用途。
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