CN116731905B - 一种益生菌组合物及其应用 - Google Patents
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Abstract
本发明属于生物医药领域，具体涉及益生菌组合物及其治疗/预防化疗相关皮肤黏膜损伤的应用。所述益生菌组合物包括鼠李糖乳杆菌R7970，乳双歧杆菌Probio‑M8，植物乳杆菌LP‑807。本发明将益生菌组合物用于预防性减轻化疗相关皮肤黏膜损伤，通过将化疗大鼠预防性给予益生菌后，大鼠皮肤黏膜损伤的发病率明显下降，对化疗产生的皮肤黏膜损伤的防治具有良好的预防效果。本发明通过将益生菌组合物作为预防/治疗化疗相关手足综合征的药物组合物，提供了一种简单、依从性好、特异性高且疗效确切的预防/治疗化疗相关副作用的方法。
Description
技术领域
本发明属于生物医药领域，具体涉及益生菌组合物及其治疗/预防化疗相关皮肤黏膜损伤的应用。
背景技术
化疗是一种常用的肿瘤治疗方法。虽然其治疗效果良好，但是其对皮肤、粘膜产生较大程度的损伤，严重影响了病人的生活质量和对化疗的耐受能力。
化疗引起的皮肤和粘膜的损伤机制复杂，至今仍不清楚；可能机制包括：1)化疗药物由外泌腺(如汗腺，皮脂腺)清除，化疗药物在外泌腺周边富集引起损伤，加上手足等部位容易被摩擦，导致局部易损伤；2)化疗药物损伤皮肤和粘膜深部的血管或影响了其代谢酶；3)由于化疗药物的毒性作用，继发性引起自由基产生、DNA损伤和局部炎症；4)个体的基因易感因素。这明显不同于放射性口腔黏膜炎。后者主要由于电离辐射损伤细胞DNA链及染色体断裂，导致细胞周期中断及细胞凋亡。
由于化疗引起的皮肤和粘膜的损伤机制复杂，目前的防治方法包括口服维生素B6，涂抹抗氧化乳膏，佩戴小一码手套，进行冰敷、漱口，或者采用食物疗法等方式。但上述防治方法因患者依从性差或者疗效差而无法达到预期目标；因此，化疗相关皮肤黏膜损伤的防治仍是临床的棘手问题。
发明内容
为解决上述技术问题，本发明是基于临床实验中化疗患者在服用益生菌后进行研究，发现益生菌与化疗后重度口腔溃疡的发生率、严重手足综合征的发生率呈负相关。将益生菌用于大鼠皮肤黏膜的保护实验，检测用药后大鼠皮肤黏膜损伤的发病率，发现益生菌针对于化疗引起的皮肤黏膜损伤具有良好的防治作用。
基于此，本发明的目的在于提供益生菌组合物在制备减轻化疗相关皮肤黏膜损伤药物中的应用。
在一个实施例中，本发明提供一种益生菌组合物，所述组合物包括鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳杆菌LP-807；优选地，所述鼠李糖乳杆菌R7970保藏编号为CGMCC No.22244，所述乳双歧杆菌Probio-M8保藏编号为CGMCC No.18610，所述植物乳杆菌LP-807保藏编号为CGMCCNo.24952。
在一个实施例中，所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳杆菌LP-807的含量比例为1～100:1～100:1～100。
在一个实施例中，所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳杆菌LP-807的含量比例为1～10:1～10:1～10。
在一个实施例中，所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳杆菌LP-807的含量比例为1～5:1～5:1～5。
在一个实施例中，所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳杆菌LP-807的含量比例为3:4:3。
在一个实施例中，所述组合物还包括药学上可接受的载体、赋形剂、稀释剂、辅剂和媒介物中的至少一种。
在一个实施例中，本发明提供一种药物制剂，所述药物制剂包括所述的益生菌组合物。
在一个实施例中，所述药物制剂包括固体剂型、半固体剂型、液体剂型或气体剂型。
在一个实施例中，所述药物制剂包括散剂、片剂、丸剂、膜剂、颗粒剂、胶囊剂、软膏剂、栓剂、糊剂、溶液剂、乳剂、混悬剂、注射剂、喷雾剂、气雾剂。
在一个实施例中，本发明提供一种食品，所述食品包括所述的益生菌组合物。
在一个实施例中，所述食品包括饮料、奶制品、口香糖以及任何事宜方便人们食用的固体、液体形式的其它食品；优选地，所述奶制品包括酸奶。
在一个实施例中，本发明提供一种护肤品，所述护肤品包括所述的益生菌组合物。
在一个实施例中，本发明提供所述的益生菌组合物、所述的药物制剂、所述的食品或所述的护肤品在制备治疗和/或预防化疗相关皮肤黏膜损伤的药物中的应用；所述治疗和/或预防化疗相关皮肤黏膜损伤包括减轻化疗相关皮肤黏膜损伤。
在一个实施例中，所述化疗相关皮肤黏膜损伤包括化疗引起的口腔黏膜炎、手足综合征。
有益效果
本发明将益生菌组合物用于预防性减轻化疗相关皮肤黏膜损伤，通过将化疗大鼠预防性给予益生菌后，大鼠皮肤黏膜损伤的发病率明显下降，对化疗产生的皮肤黏膜损伤的防治具有良好的预防效果。本发明通过将益生菌组合物作为预防/治疗化疗相关手足综合征的药物组合物，提供了一种简单、依从性好、特异性高且疗效确切的预防/治疗化疗相关副作用的方法。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明动物实验中分别给与益生菌(Probiotics)和安慰剂(Placebo)后的大鼠皮肤黏膜损伤的情况。A)大鼠皮肤黏膜损伤发病率图，B)皮肤黏膜损伤代表图；
图2为本发明临床实验中分别给与益生菌(Probiotics)和安慰剂(Placebo)后的化疗患者口腔溃疡代表图；
图3为本发明临床实验中分别给与益生菌(Probiotics)和安慰剂(Placebo)后的化疗患者手足综合征代表图。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚，下面将结合附图及具体实施例进行详细描述，但本发明的保护范围并不限于以下具体实施例。
除非另有定义，下文中所使用的所有专业术语与本领域技术人员通常理解含义相同。本文中所使用的专业术语只是为了描述具体实施例的目的，并不是旨在限制本发明的保护范围。
除非另有特别说明，本发明中用到的各种原材料、试剂、仪器和设备等均可通过市场购买得到或者可通过现有方法制备得到。
实施例1
将SD大鼠(8-9周龄，200-250g)随机分为化疗+益生菌1组(Chemo+Probiotics1)、化疗+益生菌2组(Chemo+Probiotics2)、化疗+安慰剂组(Chemo+placebo)、正常对照组(Control)。化疗+益生菌组(指益生菌1组和2组)中大鼠尾静脉注射化疗药物阿霉素(2mg/kg，每周一次，连续注射四周)，将益生菌1组中的益生菌条包(一天两次，1活性微生物组条包/只大鼠，合计每次100亿菌/只大鼠)，益生菌2组中的益生菌条包(一天两次，1活性微生物组条包/只大鼠，合计每次100亿菌/只大鼠)给大鼠口服喂养，化疗+安慰剂组大鼠尾静脉注射化疗药物阿霉素(2mg/kg，每周一次，连续注射四周)，将安慰剂条包一天两次，1安慰剂条包/只鼠给大鼠喂养。正常对照组注射生理盐水。
其中，益生菌1组菌株为鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8和植物乳杆菌LP-807，每天每只老鼠中，鼠李糖乳杆菌R7970的使用量为30亿CFU，乳双歧杆菌Probio-M8的使用量为40亿CFU，植物乳杆菌LP-807的使用量为30亿CFU；所述鼠李糖乳杆菌R7970保藏编号为CGMCCNo.22244，所述乳双歧杆菌Probio-M8保藏编号为CGMCC No.18610，所述植物乳杆菌LP-807保藏编号为CGMCC No.24952。
益生菌2组菌株为婴儿双歧杆菌BI-G201，嗜酸乳杆菌LA-G80，两歧双歧杆菌BB-G90，乳双歧杆菌BL-G101(上述菌株来自润盈生物工程(上海)有限公司)，每天每只老鼠中，婴儿双歧杆菌BI-G201，嗜酸乳杆菌LA-G80，两歧双歧杆菌BB-G90以及乳双歧杆菌BL-G101的使用量均为25亿CFU。
结果分析：
如图1所示，
化疗+益生菌组皮肤黏膜损伤发病率明显低于化疗+安慰剂组，这表明，益生菌对化疗产生的皮肤黏膜损伤具有积极的效果。同时，益生菌1组皮肤黏膜损伤发病率明显低于益生菌2组。
实施例2
共纳入6名术后需要进行计划接受含有多柔比星脂质体注射液方案化疗的女性乳腺癌患者，连续接受至少4个周期的治疗。随机将其分为两组(每组3人)，一组口服活性微生物A(正方形组活性微生物条包)，另一组口服活性微生物组B(长方形组活性微生物条包)，每日早晚各一次，对其口腔黏膜炎及手足综合征的发生率及其严重程度进行记录。
其中，微生物A组(正方形组)菌株组成为婴儿双歧杆菌BI-G201，嗜酸乳杆菌LA-G80，两歧双歧杆菌BB-G90，乳双歧杆菌BL-G101(上述菌株来自润盈生物工程(上海)有限公司)，每次每个人婴儿双歧杆菌BI-G201，嗜酸乳杆菌LA-G80，两歧双歧杆菌BB-G90以及乳双歧杆菌BL-G101的使用量均为25亿CFU。
微生物B组(长方形组)菌株组成为鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8和植物乳杆菌LP-807；每次每个人鼠李糖乳杆菌R7970的使用量为30亿CFU，乳双歧杆菌Probio-M8的使用量为40亿CFU，植物乳杆菌LP-807的使用量为30亿CFU。所述鼠李糖乳杆菌R7970保藏编号为CGMCC No.22244，所述乳双歧杆菌Probio-M8保藏编号为CGMCCNo.18610，所述植物乳杆菌LP-807保藏编号为CGMCC No.24952。
结果分析：
如表1，口服活性微生物组B(长方形组)口腔黏膜炎(OM)和手足综合征(HFS)的发病率上明显低于口服微生物组A(正方形组)。且该结果与实施例1的动物实验结果一致，证明不同微生物配方，不同微生物菌株在化疗引起的口腔黏膜损伤和手足综合征方面效果差异甚大。
表1
实施例3
将临床化疗患者随机分为安慰剂组或益生菌组，益生菌组患者在整个化疗过程中(自第一次化疗开始时至最后一次化疗结束后)予以补充益生菌配方；安慰剂组的患者在整个化疗过程中(自第一次化疗开始时至最后一次化疗结束后)予以补充安慰剂(所使用的安慰剂条包含有益生菌条包中除益生菌以外的全部辅料，且在形状、大小和气味上均与益生菌条包相同)。每个周期根据世界卫生组织(WHO)制定的标准对其皮肤粘膜损伤的发生及严重程度进行分级和记录。其中，益生菌组配方的菌株组成为鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8和植物乳杆菌LP-807；所述鼠李糖乳杆菌R7970保藏编号为CGMCC No.22244，所述乳双歧杆菌Probio-M8保藏编号为CGMCC No.18610，所述植物乳杆菌LP-807保藏编号为CGMCC No.24952。
所述试验具体步骤如下：
对115名女性I-III期乳腺癌患者进行系统筛选和沟通，在征得患者和家属同意后，纳入实验，随机分为安慰剂组或益生菌组。
益生菌组：对益生菌组的患者在整个化疗过程中(自第一次化疗开始时至最后一次化疗结束后)予以补充益生菌，具体方法为口服活性微生物组条包，每天两次，于餐后半小时后以温水送服。每次鼠李糖乳杆菌R7970的使用量为30亿CFU，乳双歧杆菌Probio-M8的使用量为40亿CFU，植物乳杆菌LP-807的使用量为30亿CFU。所述鼠李糖乳杆菌R7970保藏编号为CGMCC No.22244，所述乳双歧杆菌Probio-M8保藏编号为CGMCC No.18610，所述植物乳杆菌LP-807保藏编号为CGMCC No.24952。
安慰剂组：对安慰剂组的患者在整个化疗过程中(自第一次化疗开始时至最后一次化疗结束后)予以补充安慰剂条包，所使用的安慰剂条包含有益生菌组条包中除益生菌以外的全部辅料，且在形状、大小和气味上均与益生菌条包相同，具体方法亦为口服安慰剂条包，每天两次，每天两次，于餐后半小时后以温水送服。对上述安慰剂组和益生菌组化疗后乳腺癌患者各组的口腔溃疡和手足并发症的发生率和严重程度评估。
化疗引起的口腔黏膜炎用WHO标准分Ⅰ～Ⅳ四个等级：Ⅰ级：口腔黏膜起红斑和疼痛；Ⅱ级：口腔黏膜红斑、溃疡，但能固体饮食；Ⅲ级：口腔黏膜溃疡，需要流食；Ⅳ级：严重溃疡无法饮食，需肠外或肠内营养支持。
手足综合征用WHO的分级为Ⅰ～Ⅳ四个等级。Ⅰ级：手足感觉迟钝或感觉异常，麻刺感；可见红斑，组织学可见表皮网状组织血管扩张。Ⅱ级：持物或行走时不适，无痛性肿胀或红斑，还可出现红肿；Ⅲ级：掌和跖部痛性红斑和肿胀，甲周红斑和肿胀，可见皮肤皲裂，组织学示表皮见孤立坏死的角质细胞。Ⅳ级：脱屑，溃疡，水疱，剧烈疼痛，组织学示表皮完全坏死。
如表2，表3，图2，图3所示，根据化疗后乳腺癌患者各组的口腔溃疡和手足并发症的发生率和严重程度评估，可知益生菌组能够降低了化疗药物诱导的手足并发症(HFS)和口腔溃疡(OM)的发生率及其严重性。
表2
表3
根据上述研究，将本发明益生菌作为减轻化疗手足综合征及口腔溃疡的药物或食品或护肤品。通过将益生菌组合物作为预防/治疗化疗相关手足综合征的药物组合物或保健食品、护肤品，提供了一种简单、依从性好、特异性高且疗效确切具有协同作用的预防/治疗化疗相关副作用的方法。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原理的前提下，还可以作出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种益生菌组合物在制备治疗和/或预防化疗相关皮肤黏膜损伤的药物中的应用，其特征在于，所述组合物包括鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳酸菌Lp-807；
所述鼠李糖乳杆菌R7970保藏编号为CGMCC No.22244，所述乳双歧杆菌Probio-M8保藏编号为CGMCC No.18610，所述植物乳杆菌LP-807保藏编号为CGMCC No.22907；
所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳酸菌Lp-807的含量比例为1～10:1～10:1～10。
2.根据权利要求1所述的应用，其特征在于，所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳酸菌Lp-807的含量比例为1～5:1～5:1～5。
3.根据权利要求1所述的应用，其特征在于，所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳酸菌Lp-807的含量比例为3:4:3。
4.根据权利要求1所述的应用，其特征在于，所述组合物还包括药学上可接受的载体、赋形剂、稀释剂、辅剂和媒介物中的至少一种。
5.一种药物制剂在制备治疗和/或预防化疗相关皮肤黏膜损伤的药物中的应用，其特征在于，
其特征在于，所述药物制剂包括鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳酸菌Lp-807；
所述鼠李糖乳杆菌R7970保藏编号为CGMCC No.22244，所述乳双歧杆菌Probio-M8保藏编号为CGMCC No.18610，所述植物乳杆菌LP-807保藏编号为CGMCC No.22907；
所述药物制剂中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳酸菌Lp-807的含量比例为1～10:1～10:1～10。
6.根据权利要求5所述的应用，其特征在于，所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳酸菌Lp-807的含量比例为1～5:1～5:1～5。
7.根据权利要求5所述的应用，其特征在于，所述组合物中鼠李糖乳杆菌R7970，乳双歧杆菌Probio-M8，植物乳酸菌Lp-807的含量比例为3:4:3。
8.根据权利要求5-7任一项所述的应用，其特征在于，所述药物制剂包括固体剂型、半固体剂型、液体剂型或气体剂型。
9.根据权利要求8所述的应用，其特征在于，所述药物制剂包括散剂、片剂、丸剂、膜剂、颗粒剂、胶囊剂、软膏剂、栓剂、糊剂、溶液剂、乳剂、混悬剂、喷雾剂、气雾剂。
10.根据权利要求1-7任一项所述的应用，其特征在于，所述化疗相关皮肤黏膜损伤包括化疗引起的口腔黏膜炎、手足综合征。
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