CN108883127A - 用于预防和治疗***病的包含乳酸菌的组合物及其用途 - Google Patents
用于预防和治疗***病的包含乳酸菌的组合物及其用途 Download PDFInfo
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- CN108883127A CN108883127A CN201780017531.3A CN201780017531A CN108883127A CN 108883127 A CN108883127 A CN 108883127A CN 201780017531 A CN201780017531 A CN 201780017531A CN 108883127 A CN108883127 A CN 108883127A
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- lactobacillus
- bifidobacterium
- bacterium
- salt
- lactic acid
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Abstract
本发明涉及一种用于治疗或预防***病的组合物,所述组合物包含盐、糖和乳酸菌的本发明组合作为活性成分。本发明的组合物经由多种实验显示出有效的抗菌活性,例如:(1)通过测定pH和乳酸水平变化而进行的引起***病的细菌的生长的间接抑制活性测试(实验实施例1);(2)通过测定测试样品的易感性而进行的引起***病的细菌的生长的直接抑制活性测试(实验实施例2);(3)简单临床测试,并最终确认了该组合在测试中显示出有效的抗菌活性。因此,本发明的组合能够以药物组合物、健康功能食品、食品添加剂、局部用组合物和洗涤剂组合物的形式用于减轻、治疗或预防***病。
Description
技术领域
本发明涉及一种用于预防和治疗***病的组合物及其用途,所述组合物包含盐、糖和乳酸菌作为活性成分。
背景技术
***炎是一种尤其是在怀孕期间在***中发生的病症,其引起***分泌物、炎症和刺激性以及外阴或***瘙痒。三种最常见的***感染和疾病也是***炎最常见的原因。这三种常见的***感染包括:细菌性***病、***酵母感染和滴虫病。
人类***定居着各种微生物、酵母和细菌(germ),例如大约超过104个/mL(***液)的乳杆菌属菌(Lactobacillus spp)(例如卷曲乳杆菌(Lactobacillus crispatus)和詹氏乳杆菌(Lactobacillus jensenii)),其提供pH 4.5-5.1范围内的弱酸性环境以防止微生物感染;人类***还是一个高度多功能的器官,其可深度影响女性及其新生儿的健康。已经报道了在***生境(vaginal niche)中有许多重要的病原体,例如淋病奈瑟氏菌(Neiserria gonorrhea)、脲原体属菌(Ureaplasma species)、生殖支原体(Mycoplasmagenitalium)、链球菌属菌(Streptococcus species)、大肠杆菌(Esherichia coli)、沙眼衣原体(Chlamydia trachomatis)和***毛滴虫(Trichomonas vaginalis)等。
特别地,细菌性***病(BV,最普遍且最有害的***病)使具有BV的女性产生恶臭的***分泌物或局部刺激性,并且细菌性***病与几种更严重的负面结果有关,包括早产、***和HIV感染的获得。具有细菌性***病(BV)病情的女性失去了许多乳杆菌属菌(除了惰性乳杆菌(L.iners))并获得了多种厌氧和兼性细菌。来自具有BV的女性的***液的革兰氏染色显示失去革兰氏阳性杆菌并且它们被革兰氏阴性和革兰氏染色不定球菌和杆菌代替。来自具有BV的受试者的***液的培养典型地产生***加德纳氏菌(Gardnerellavaginalis)和其它细菌的混合物,所述其它细菌可以包括消化链球菌属(Peptostreptococcus)、动弯杆菌属(Mobiluncus)、拟杆菌属(Bacterioides)、普氏菌属(Prevotella)、卟啉单胞菌属(Porphyromonas)、动弯杆菌属和支原体属菌(Mycoplasmaspecies)(Sujatha srinivasan和David N.Fedricks,Review Article,The HumanVaginal Bacterial Biota and Bacterial Vaginosis,InterdisciplinaryPerspectives on Infectious Diseases,Vol.,2008,文章ID 750479,p1-3)。
乳酸菌常见于人类或动物肠道、发酵食品等,被报道为可用作益生菌剂的代表性细菌,并被FDA(食品和药品管理局)认可为安全细菌(Orrhge,K.等,2000,Bifidobateriaand lactobacilli in human health,Drug Experimental Clinical Research.,26,pp95-111)。粘附至肠上皮细胞并寄生的乳酸菌改善了肠道菌群环境并为宿主动物提供了各种有利优势,例如肠道菌群的稳定化、通过抑制肠有害细菌粘附来减少物质分解、有害疾病的预防、免疫激活活性、抗癌活性、降胆固醇活性等。据报道,来自各种腐败微生物和病原微生物的乳酸菌生长抑制活性归因于其代谢物释放抗菌因子的代谢特性,所述抗菌因子例如有机酸、过氧化氢、罗氏菌素(reuterin)、二乙酰、乙醛、细菌素等(Fuller,K.,1989,Probiotics in man and animals,J.Appl.Bacteriol.,66,pp365-378;韩国专利公开No.10-2015-0075447A)。
迄今为止已经研究开发了治疗***炎的有效疗法,例如口服给予广谱抗生素(例如甲硝唑)。然而该疗法显示出许多缺点,例如长期给药情况中的抗生素耐受、全身毒性和可能的***中正常菌群的摧毁,其引起继发并发症,例如乳杆菌属菌数量减少、***pH升高和厌氧微生物增殖等。
因此,迄今为止,需要开发显示出长期治疗活性和安全性并且几乎没有不良反应的新型治疗组合物来治疗***病。
迄今为止,本发明人发现,包含盐和糖的组合作为活性成分的组合物显示出有效的抗菌活性和抗增殖活性(韩国专利注册No.10-1133723 B1/PCT/WO2011/049327 A1);及对***松弛综合征或***干燥疾病的有效治疗效果(韩国专利注册No.10-1470282 B1/PCT/WO2015/050324 A1)。
然而,在任何以上引用文献(通过引用将其公开内容并入本文)中均没有报道或公开盐、糖和乳酸菌的组合对于***病的治疗效果。
为了研究盐、糖和乳酸菌的组合对***病的抑制作用,本发明的发明人进行了以下测试:(1)通过测定pH和乳酸水平变化而进行的引起***病的细菌的生长的间接抑制活性测试(实验实施例1);(2)通过测定测试样品的易感性而进行的引起***病的细菌的生长的直接抑制活性测试(实验实施例2);(3)简单临床测试,并通过确认该组合在测试中显示出有效的抗菌活性而最终完成了本发明。
本发明的这些目的和其它目的将通过下文提供的本发明的详细公开内容而变得明显。
发明内容
技术问题
因此,本发明的另一目的是提供一种用于治疗或预防***病的药物组合物,所述药物组合物包含盐、糖和乳酸菌的组合作为活性成分。
本发明的另一目的是提供盐、糖和乳酸菌的组合在制备用于在哺乳动物中治疗或预防***病的药物中的用途。
本发明的另一目的是提供一种在哺乳动物中治疗或预防***病的方法,其中,所述方法包括向所述哺乳动物给予有效量的盐、糖和乳酸菌的组合及其药学上可接受的载体。
本发明的另一目的是提供一种用于减轻或预防***病的健康功能食品,所述健康功能食品包含盐、糖和乳酸菌的组合作为活性成分。
本发明的另一目的是提供一种用于减轻或预防***病的保健食品,所述保健食品包含盐、糖和乳酸菌的组合作为活性成分。
本发明的另一目的是提供一种用于减轻或预防***病的食品添加剂,所述食品添加剂包含盐、糖和乳酸菌的组合作为活性成分。
本发明的另一目的是提供一种用于治疗或预防***病的局部用组合物,所述局部用组合物包含盐、糖和乳酸菌的组合作为活性成分。
本发明的另一目的是提供一种用于减轻或预防***病的洗涤剂组合物,所述洗涤剂组合物包含盐、糖和乳酸菌的组合作为活性成分。
解决技术问题的技术方案
在本发明的一个实施方式中,本发明提供了一种用于治疗和预防***病的药物组合物,所述药物组合物包含盐、糖和乳酸菌的组合作为活性成分。
本发明提供了一种用于治疗和预防***病的药物组合物,所述药物组合物包含盐、糖和乳酸菌的组合作为活性成分以及药学上可接受的载体或赋形剂。
另外,本发明提供了盐、糖和乳酸菌的组合在制备用于在哺乳动物中治疗或预防***病的药物中的用途。
另外,本发明提供了一种在哺乳动物中治疗或预防***病的方法,其中,所述方法包括向所述哺乳动物给予有效量的盐、糖和乳酸菌的组合及其药学上可接受的载体。
本文所定义的术语“盐”包括精制盐(refined salt)、加工盐(processed salt)(例如熔盐(melted salt))或非精制盐(例如海盐、岩盐)等;优选精制盐(例如氯化钠)或熔盐(例如竹盐);更优选通过将非精制盐在200℃-2000℃、优选800℃-1200℃的温度下熔融2小时至7天、优选12小时至48小时的时间段而制备的熔盐。
本文所定义的术语“糖”包括本领域中已知为有用益生元的糖类化合物,优选单糖、二糖、寡糖、多糖等;更优选包括戊糖(例如木糖、***糖等)、己糖(例如葡萄糖、甘露糖、果糖、半乳糖等)的单糖;二糖,例如乳果糖、乳糖醇、蔗糖、乳糖、麦芽糖、海藻糖等;寡糖,例如果寡糖、棉子糖、水苏糖、麦芽糖糊精等;多糖,例如直链淀粉、纤维素、果胶等;更优选选自于葡萄糖、果糖、半乳糖、乳果糖、乳糖醇、蔗糖、乳糖或果寡糖中的糖类。
本文所定义的术语“乳酸菌”包括本领域中任何通常已知的或可获得的作为益生菌的乳酸菌,优选地,所述乳酸菌为来自诸如国际保藏机构(International depositoryauthority,IDA)的国际认可的保藏机构的任何常规可获得的作为益生菌的乳酸菌,如韩国的韩国典型培养物保藏中心(Korean Collection for Type Cultures,KCTC)、韩国微生物培养中心(Korean Culture Center of Microorganisms,KCCM)或韩国农业培养物保藏中心(Korean Agricultural Culture Collection,KACC);美国的农业研究菌种保藏中心(Agricultural Research Service Culture Collection,NRRL)或美国典型培养物保藏中心(American Type Culture Collection,ATCC)、Provasoli-Guillard海洋藻类和微生物群国家中心(Provasoli-Guillard National Center for Marine Algae andMicrobiota,NCMA);英国的藻类和原生动物培养物保藏中心(Culture Collection ofAlgae and protozoa,CCAP)、欧洲细胞培养物保藏中心(European Collection of CellCultures,ECACC)、国际真菌研究所(International Mycological Institute,IMI)、国家典型培养物保藏中心(National Collection of Type Culture,NCTC)、国家酵母培养物保藏中心(National Collection of Yeast Cultures,NCYC)、国家工业、食品和海洋细菌保藏中心(National Colections of Industria,Food and marine Bacteria,NCIMB)或国家生物学标准和对照研究所(National Institute for Biological Standards andControls,NIBSC);法国的国家微生物培养物保藏中心(Collection Nationale DeCultures de Micro-organisms,CNCM);德国的莱布尼茨研究所DSMZ-德国微生物和细胞培养物保藏中心(Lebniz-Institu DSMZ-Deutsche Sammlung von Mikroorganismen undZellkulturen GmbH,DSMZ);日本的国际专利生物保藏单位(International patentorganism Depository,IPOD)、国家技术与评估研究所-专利微生物保藏中心(NationalInstitute of Technology and Evaluation,Patent Microorganism Depository,NPMD);中国的中国培养物保藏中心(China Center for Culture Collection,CCTCC)、中国普通微生物菌种保藏管理中心(China General Microbiological Culture CollectionCenter,CGMCC)等;具体地,所述乳酸菌为属于如下属中的任何乳酸菌:乳杆菌属菌(Lactobacillus spp.)、双歧杆菌属菌(Bifidobacterium spp.)、芽孢杆菌属菌(Bacillusspp.)、链球菌属菌(Streptococcus spp.)、肠球菌属菌(Enterococcus spp.)、酵母属菌(Saccharomyces spp.)、明串珠菌属菌(Leuconostoc spp.)等;更具体地,所述乳酸菌为选自于由如下乳酸菌所组成的组中的任何乳酸菌:乳杆菌属菌,例如植物乳杆菌(lactobacillus plantarum)、戊糖乳杆菌(lactobacillus pentosus)、干酪乳杆菌(lactobacillus casei)、干酪乳杆菌副干酪亚种(lactobacillus caseissp.paracasei)、鼠李糖乳杆菌(lactobacillus rhamnosus)、嗜酸乳杆菌(lactobacillusacidophilus)、德氏乳杆菌(lactobacillus delbrueckii)、德氏乳杆菌保加利亚亚种(lactobacillus delbrueckii,ssp.bulgaricus)、德氏乳杆菌德氏亚种(lactobacillusdelbrueckii,ssp.delbrueckii)、发酵乳杆菌(lactobacillus fermentum)、加氏乳杆菌(lactobacillus gasseri)、罗伊氏乳杆菌(lactobacillus reuteri)、短乳杆菌(lactobacillus brevis)、纤维二糖乳杆菌(lactobacillus cellobiosus)、卷曲乳杆菌(lactobacillus crispatusi)、乳杆菌GG(lactobacillus GG)、约氏乳杆菌(lactobacillus johnsonii)、乳酸乳杆菌(lactobacillus lactis)、唾液乳杆菌(lactobacillus salivarius)等;双歧杆菌属菌,例如长双歧杆菌(Bifidobacteriumlongum)、两歧双歧杆菌(Bifidobacterium bifidum)、短双歧杆菌(Bifidobacteriumbreve)、动物双歧杆菌乳酸亚种(Bifidobacterium animalis ssp,lactis)、青春双歧杆菌(Bifidobacterium adolescentis)、假链状双歧杆菌(Bifidobacteriumpseudocatenulatum)、链状双歧杆菌(Bifidobacterium catenulatum)、婴儿双歧杆菌(Bifidobacterium infantis)、嗜热双歧杆菌(Bifidobacterium thermophilum)等;芽孢杆菌属菌,例如toyoi蜡状芽孢杆菌(Bacillus cereus toyoi)、蜡状芽孢杆菌(Bacilluscereus)等;链球菌属菌,例如嗜热链球菌(Streptococcus thermophiles)、乳脂链球菌(Streptococcus cremoris)、婴儿链球菌(Streptococcus infantarius)、中间型链球菌(Streptococcus intermedius)、乳酸链球菌(Streptococcus lactis)、唾液链球菌嗜热亚种(Streptococcus salivarius subsp.Thermophiles)等;肠球菌属菌,例如粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcus faecium)等;酵母属菌,例如酿酒酵母(Saccharomyces cerevisiae)、布拉酵母(Saccharomyces boulardii)等;明串珠菌属菌,例如柠檬明串珠菌(Leuconostoc citreum)、肠膜明串珠菌(Leuconostocmesenteroides)等;更具体地,乳杆菌属菌,例如植物乳杆菌、戊糖乳杆菌、干酪乳杆菌、干酪乳杆菌副干酪亚种、鼠李糖乳杆菌或嗜酸乳杆菌;双歧杆菌属菌,例如长双歧杆菌、两歧双歧杆菌或短双歧杆菌;芽孢杆菌属菌,例如toyoi蜡状芽孢杆菌或蜡状芽孢杆菌;链球菌属菌,例如嗜热链球菌、乳脂链球菌、婴儿链球菌、中间型链球菌或乳酸链球菌。
本文所定义的术语“盐、糖和乳酸菌的组合”包括具有如下混合比例的盐、糖和乳酸菌的组合:1:(100-0.01):(100-0.01)重量份(w/w)、优选1:(50-0.5):(50-0.5)重量份(w/w)、更优选1:(30-0.3):(30-0.3)重量份(w/w)、更加优选1:(10-0.1):(10-0.1)重量份(w/w)、最优选1:(5-1):(5-1)重量份(w/w)。
本发明的组合物可进一步包含另外的抗生素、染料和香料等,基于组合物的总重量,所述另外的抗生素、染料和香料等的量为上述组合物的约0.1wt%-20wt%。
在下文中对本发明进行详细描述。
可通过下述程序详细地制备含有盐、糖和乳酸菌的组合的本发明的组合物。
例如,本发明的清洗组合可通过以下方式进行制备:在步骤1,制备精制盐、加工盐(如熔盐)或非精制盐(如海盐、岩盐等),优选精制盐或加工盐,所述精制盐或加工盐通过在200℃-2000℃、优选800℃-1200℃的温度下熔融非精制盐2小时至7天、优选12小时至48小时的时间段以获得熔盐来制备;将该熔盐与糖化合物(例如单糖、二糖、寡糖、多糖等)和乳酸菌(属于乳杆菌属菌、双歧杆菌属菌、芽孢杆菌属菌、链球菌属菌、肠球菌属菌、酵母属菌、明串珠菌属菌等)以1:(100-0.01):(100-0.01)重量份(w/w)、优选1:(50-0.5):(50-0.5)重量份(w/w)、更优选1:(30-0.3):(30-0.3)重量份(w/w)、更加优选1:(10-0.1):(10-0.1)重量份(w/w)、最优选1:(5-1):(5-1)重量份(w/w)的混合比例进行混合,以获得本发明的组合;以及将该组合溶于根据需要具有适量的另外的添加剂(例如另外的抗生素、染料、香料等)的适量的药学上可接受的载体或赋形剂、营养学上(sitologically)可接受的添加剂或局部可接受的载体(例如蒸馏水、缓冲液或等渗溶液),以获得本发明的组合物。
因此,在本发明的另一个实施方式中,本发明提供了用于制备本发明的清洗组合的方法,该方法包括以下步骤:在步骤1,制备精制盐、加工盐(如熔盐)或非精制盐(如海盐、岩盐等),优选精制盐或加工盐,所述精制盐或加工盐通过在200℃-2000℃、优选800℃-1200℃的温度下熔融非精制盐2小时至7天、优选12小时至48小时的时间段以获得熔盐来制备;在步骤2,将该盐与糖化合物(例如单糖、二糖、寡糖、多糖等)和乳酸菌(属于乳杆菌属菌、双歧杆菌属菌、芽孢杆菌属菌、链球菌属菌、肠球菌属菌、酵母属菌、明串珠菌属菌等)以1:(100-0.01):(100-0.01)重量份(w/w)、优选1:(50-0.5):(50-0.5)重量份(w/w)、更优选1:(30-0.3):(30-0.3)重量份(w/w)、更加优选1:(10-0.1):(10-0.1)重量份(w/w)、最优选1:(5-1):(5-1)重量份(w/w)的混合比例进行混合,以获得本发明的组合;以及在步骤3,将该组合溶于根据需要具有适量的另外的添加剂(例如另外的抗生素、染料、香料等)的适量的蒸馏水、缓冲液或等渗溶液,以获得本发明的清洗组合物。
本文所定义的术语“***病”包括选自细菌性***病、真菌性***炎或滴虫性***炎中的***病,优选由如下引起的***病:***加德纳氏菌、脆弱拟杆菌(Bacterioidfragilis)、***毛滴虫、白色念珠菌(Candida albicans)、无乳链球菌(Streptococcusagalactiae)、金黄色葡萄球菌(Streptococcus aureus)、金黄色酿脓葡萄球菌(Staphylococcus aureus)、淋病奈瑟氏菌、大肠杆菌、阴沟肠杆菌(Enterobactercloacae)、铜绿假单胞菌(Pseudomonas aeruginosa)或鼠伤寒沙门氏菌(Salmonellatyphimurium)等。
本发明的组合物可进一步包含另外的抗生素、染料和香料等,基于组合物的总重量,所述另外的抗生素、染料和香料等的量为上述组合物的约0.1wt%-20wt%。
已证明了包含通过上述方法制备的盐、糖和乳酸菌的组合的本发明的组合物经由多种实验显示出有效的抗菌活性,例如:(1)通过测定pH和乳酸水平变化而进行的引起***病的细菌的生长的间接抑制活性测试(实验实施例1);(2)通过测定测试样品的易感性而进行的引起***病的细菌的生长的直接抑制活性测试(实验实施例2);(3)简单临床测试,并最终确认了该组合在测试中显示出有效的抗菌活性。
因此,本发明的用于治疗或预防***病的组合物包含通过上述方法制备的盐、糖和乳酸菌的组合以及药学上可接受的载体。
另外,本发明提供了通过上述方法制备的盐、糖和乳酸菌的组合在制备用于在哺乳动物中治疗或预防***病的药物中的用途。
另外,本发明提供了一种在哺乳动物中治疗或预防***病的方法,其中,该方法包括向所述哺乳动物给予有效量的通过上述方法制备的盐、糖和乳酸菌的组合及其药学上可接受的载体。
本文所定义的术语“预防”是指对易于受困于疾病的哺乳动物中的此类疾病的抑制;本文所使用的术语“治疗”是指:(a)抑制疾病或病症发展、(b)减轻疾病或病症或(c)消除疾病或病症。
本文所定义的术语“药学上可接受的载体或赋形剂”包括用于组成药物的非活性成分、药物添加剂。它们包括染料、香料、粘合剂、软化剂(emollients)、填充剂、润滑剂、防腐剂以及许多其它种类。常见的赋形剂包括玉米淀粉、乳糖、滑石、硬脂酸镁、蔗糖、明胶、硬脂酸钙、二氧化硅、虫胶和釉料(glaze),其在本领域中是熟知的(参见食品和药品管理局主页或药物信息在线)或在先文献(例如Rowe,Raymond C等,Handbook of PharmaceuticalExcipients,Pharmaceutical Press,第7版,2012)。
基于组合物的总重量,本发明的用于治疗和预防***病的组合物可包含0.1wt%-99wt%、优选0.1wt%-50wt%的上述组合。
根据本发明的组合物可作为包含药学上可接受的载体、佐剂或稀释剂(例如乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、***树胶、海藻酸盐/酯、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、聚乙烯吡咯烷酮、水、甲基羟基苯甲酸酯、丙基羟基苯甲酸酯、滑石、硬脂酸镁和矿物油)的药物组合物提供。制剂可另外含有填充剂、抗凝集剂(anti-agglutinating agents)、润滑剂、保湿剂、调味剂、乳化剂、防腐剂等。可通过采用本领域中熟知的任何程序对本发明的组合物进行配制,从而在将该组合物给予患者后提供活性成分的快速释放、缓释或延迟释放。
例如,可将本发明的组合物溶于油、丙二醇或通常用于生产注射剂的其它溶剂中。载体的合适实例包括生理盐水、聚乙二醇、乙醇、植物油、肉豆蔻酸异丙酯等,但不限于此。对于局部给予,可将本发明的提取物配制为软膏剂和霜剂的形式。
可将含有本发明组合物的药物制剂制备为任何形式,例如口服剂型(散剂、片剂、胶囊剂、软胶囊剂、水性药物、糖浆剂、酏剂、丸剂、散剂、囊剂(sachet)、颗粒剂)或局部用制品(霜剂、软膏剂、洗剂、凝胶剂、香膏剂(balm)、贴剂、糊剂、喷雾溶液剂、气雾剂等)或可注射制品(溶液剂、混悬剂、乳剂)。
处于药物剂型形式的本发明组合物能够以它们药学上可接受的盐的形式使用,并且还可单独使用或以适当的联合使用以及与其它药学活性化合物组合使用。
本发明组合的期望剂量根据受试者的状况和体重、严重程度、药物形式、给予途径和给予周期而变化,并且可由本领域技术人员进行选择。然而,为了获得期望效果,通常推荐按照重量/天计以0.0001mg/kg-1000mg/kg、优选0.001mg/kg-100mg/kg的量给予本发明的组合。该剂量可每天单次给予或分数次给予。
可经由多种途径将本发明的药物组合物给予受试动物,例如哺乳动物(大鼠、小鼠、家畜或人)。所有的给予模式均在考虑之列,例如可进行口服给予、直肠给予,或者通过静脉内注射、肌肉内注射、皮下注射、皮内注射、鞘内注射、硬膜外注射或脑室内注射给予。
本发明的组合物还可在各种健康功能食品和保健食品的制备中用作主要成分或添加剂和助剂。
因此,本发明的另一目的是提供一种用于预防或减轻***病的健康功能食品,所述健康功能食品包含盐、糖和乳酸菌。
本文所定义的术语“健康功能食品”是指具有增强的功能(如物理功能或生理功能)的功能食品,该食品通过将本发明的组合物添加到常规食品中来预防或改善人或哺乳动物中的目标疾病。
本发明的另一目的是提供一种用于预防或减轻***病的保健食品,所述保健食品包含盐、糖和乳酸菌以及营养学上可接受的添加剂。
本文所定义的术语“保健食品”是指含有本发明的组合的食品,其中本发明的组合作为少量的添加剂形式或作为总量的散剂、颗粒剂、胶囊剂、丸剂、片剂等形式未显示出特定的预期效果但显示出总的预期效果。
本文所定义的术语“营养学上可接受的添加剂”包括其预期用途导致或可被合理预期直接或间接地导致该物质成为任何食品的组分或者影响任何食品的特性的任意物质,并且可根据其来源分为三组,即:(1)化学合成添加剂,例如酮、甘氨酸、柠檬酸钾、烟酸等;(2)天然添加剂,例如柿子染料、甘草提取物、结晶纤维素、gua dum等;(3)与其混合的添加剂(the mixed additive therewith),例如L-谷氨酸钠、防腐剂、焦油染料等或者根据其在食品中的功能而分的各种类型,例如稠化剂、熟化剂、漂白剂、螯合剂(sequestrant)、湿润剂、防结块剂、澄清剂、固化剂、乳化剂、稳定剂、增稠剂、碱和酸、发泡剂、营养素、着色剂、调味剂、甜味剂、防腐剂、抗氧化剂等,其是本领域或现有文献中熟知的(参见GSFA在线的主页中的“Codex General Standard for Food Additives”(GSFA,Codex STAN 192-1995))。
如果将物质添加到食品中以在该食品中用于特定目的,则将该物质称为直接添加剂;而间接食品添加剂则是由于食品的包装、储存或其它处理而以痕量成为食品的一部分的添加剂。
本文所公开的术语“保健食品或健康功能食品”可被囊括在食品、健康饮料、膳食补充剂等中,并且可配制成药学上给药形式的剂型,例如散剂、颗粒剂、片剂、混悬剂、乳剂、糖浆剂、咀嚼片剂、胶囊剂、饮料等;或食品形式,例如面包、米糕(rice cake)、干果、糖果、巧克力、口香糖、冰淇淋、奶(例如低脂奶、乳糖水解奶、山羊奶、加工奶)、乳制品(例如发酵乳、黄油、浓缩乳、奶油、乳脂肪(butter oil)、天然奶酪、加工奶酪、奶粉、乳清等)、加工肉制品(例如汉堡包、火腿、香肠、培根等)、加工蛋制品、鱼肉制品(例如鱼饼等)、面条产品(例如方便面、干面条、湿面条、油炸面条、非油炸面条、糊化(gelatinized)干面条、熟面条、冷冻面条、意大利面等)、茶产品(例如茶包、浸出茶(leached tea)等)、健康饮品(例如水果饮品、蔬菜饮品、碳酸软饮品、豆乳饮品、乳酸饮料混合饮料等)、调味食品(例如酱油、豆酱、红辣椒酱、豆豉(chunjang)(一种通过焦糖着色的发酵大豆产品)、清麴酱(cheonggukjang)(通过枯草芽孢杆菌(B.subtillis)天然发酵的大豆)、混合酱、醋、酱汁、番茄酱、咖喱、调料等)、人造奶油、起酥油、披萨等,以用于预防或改善目标疾病,但本文并不打算仅限于此。
另外,可将上述组合添加到食品或饮料中以用于预防和改善目标病症。对于功能健康食品组合物而言,在作为功能健康食品或保健食品的食品或饮料中,上述组合的量通常可为食品总重量的约0.01w/w%-100w/w%。特别地,尽管本发明的组合在功能健康食品、保健食品或特殊营养食品中的优选量可根据每种食品的预期目的而变化,但是通常优选将其作为添加剂以如下量来使用:基于100%比例的食品组合物,本发明组合的量在食品(例如面条等)中为约0.01%-5%,在保健食品中为40%-100%。
如果本发明的健康饮料组合物以所示比例包含上述组合作为必需组分,则对其它液体组分没有特别限制,其中,如同常规饮料一样,其它组分可以是各种祛臭剂或天然碳水化合物等。上述天然碳水化合物的实例是:单糖,例如葡萄糖、果糖等;二糖,例如麦芽糖、蔗糖等;常规糖,例如糊精、环糊精;以及糖醇,例如木糖醇和赤藓糖醇等。作为除上述成分以外的其它祛臭剂,可有利地使用天然祛臭剂(例如taumatin、甜叶菊提取物(例如levaudioside A、甘草甜素等))以及合成祛臭剂(例如糖精、阿斯巴甜等)。在100mL本发明饮料组合物的比例内,上述天然碳水化合物的量的范围通常为约1g-20g、优选5g-12g。
除上述组成之外的其它组分是各种营养素、维生素、矿物质或电解质、合成调味剂、着色剂和改良剂(在奶酪、巧克力等情况中)、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体粘合剂、pH控制剂、稳定剂、防腐剂、甘油、醇、碳酸饮料中使用的碳化剂等。除上述组分之外的其它组分可以是用于制备天然果汁、果汁饮料和蔬菜饮料的果汁,其中,所述组分可单独使用或组合使用。组分的比例不是很重要,但相对于每100w/w%的本发明组合物,其范围通常为约0w/w%-20w/w%。其中包含上述提取物或化合物的可添加食品的实例是各种食品、饮料、口香糖、维生素复合物、健康改善食品等。
本发明的组合没有毒性和副作用,因此它们可安全使用。
本发明的另一目的是提供一种用于治疗或预防***病的局部用组合物,所述局部用组合物包含盐、糖和乳酸菌的组合作为活性成分。
本发明的局部用组合物根据使用方法可另外含有常规载体、佐剂或稀释剂。优选根据用法和应用方法将所述载体作为合适的物质使用,但是并不限于此。合适的稀释剂列于Remington’s Pharmaceutical Science(Mack Publishing co,Easton PA)的书面文本中。
在下文中,以下配制方法和赋形剂仅为示例性的,并不以任何方式限制本发明。
根据本发明的组合物可作为包含药学上可接受的载体、佐剂或稀释剂(例如乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、***树胶、海藻酸盐/酯、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、聚乙烯吡咯烷酮、水、甲基羟基苯甲酸酯、丙基羟基苯甲酸酯、滑石、硬脂酸镁和矿物油)的本发明局部用组合物提供。制剂可另外含有填充剂、抗凝集剂、润滑剂、保湿剂、调味剂、乳化剂、防腐剂等。可通过采用本领域中熟知的任何程序对本发明的组合物进行配制,从而在将该组合物给予患者后提供活性成分的快速释放、缓释或延迟释放。
例如,可将本发明的局部用组合物溶于蒸馏水、pH缓冲液、油、丙二醇或本领域常用的其它溶剂。载体的合适实例包括生理盐水、聚乙二醇、乙醇、植物油、肉豆蔻酸异丙酯等,但不限于此。对于局部给予,可将本发明的化合物配制为软膏剂和霜剂的形式。
可加入溶解助剂、乳化剂、pH控制剂等,将本发明的组合物制成任何形式,例如:局部用制品,例如水溶液、非水溶剂、混悬剂、乳剂、冻干制品、栓剂制品、清洗液、凝胶剂、胶质体(jelly)、泡沫剂、霜剂、软膏剂、洗剂、香膏剂、贴剂、糊剂、喷雾溶液剂、气雾剂等;或***制品,例如***片剂、***霜剂、***软膏剂、敷料溶液(dressing solution)、喷雾制品、***胶囊剂、***膜剂、***海绵剂(vaginal sponge);用于卫生用品(例如卫生棉条、卫生巾、尿布、内裤等)的涂抹制品(spreading preparation)或喷雾制品,优选***片剂组合物或清洗液组合物。
上述非水溶剂和混悬剂可包括丙二醇、聚乙二醇、植物油(如橄榄油)、油酸乙酯等。
上述栓剂制品可包含witepsol、聚乙二醇(macrogol)、Tween 61、kakao黄油、月桂酸、甘油明胶(glycerol gelatin)等。
因此,本发明提供了一种用于治疗或预防***病的清洗液溶液组合物或***片剂组合物,所述清洗液溶液组合物或***片剂组合物包含盐、糖和乳酸菌的组合以及药学上可接受的载体。
处于药物剂型形式的本发明局部用组合物能够以它们药学上可接受的盐的形式使用,并且还可单独使用或以适当的联合使用以及与其它药学活性化合物(例如本领域熟知的来源于植物、动物或矿物的抗菌化合物或提取物)组合使用。
本发明组合的期望剂量根据受试者的状况和体重、严重程度、药物形式、给予途径和给予周期而变化,并且可由本领域技术人员进行选择。然而,为了获得期望效果,通常推荐按照重量/天计以0.001mg/kg-1000mg/kg、优选0.01mg/kg-100mg/kg的量给予本发明的组合。该剂量可每天单次给予或分数次给予。就组合物而言,基于组合物的总重量,本发明的组合应当以0.01wt%-99.99wt%、优选0.1wt%-99wt%、更优选1wt%-20wt%、最优选5wt%-10wt%的量存在。
可经由多种途径将本发明的组合物给予受试动物,例如哺乳动物(大鼠、小鼠、家畜或人)。所有的给予模式均在考虑之列,例如可进行外部给予、局部给予、口服给予、直肠给予,或者通过静脉内注射、肌肉内注射、皮下注射、皮内注射、鞘内注射、硬膜外注射或脑室内注射给予,优选外部给予或局部给予。
本发明的另一目的是提供一种用于减轻或预防***病的洗涤剂组合物,所述洗涤剂组合物包含盐、糖和乳酸菌的组合作为活性成分。
任何传统的清洗成分都可用作本发明组合物的一部分。给出的水平是重量百分比并且是指总组合物(在包封组合物的实施方式的情况下不包括水溶性膜)。洗涤剂组合物可为有助洗剂(built)或无助洗剂(unbuilt),并且包含一种或多种洗涤剂活性组分,该活性组分可选自漂白剂、漂白活化剂、漂白催化剂、表面活性剂、碱源、酶、聚合物分散剂、抗腐蚀剂(例如硅酸钠)和护理剂。高度优选的洗涤剂组分包括助洗剂(builder)化合物、碱源、抗再沉积剂、磺化聚合物、酶和额外的漂白剂。
可加入溶解助剂、乳化剂、pH控制剂等,将本发明的洗涤剂组合物制成任何形式,例如:局部用制品,例如水溶液、非水溶剂、混悬剂、乳剂、冻干制品、栓剂制品、清洗液、凝胶剂、胶质体、泡沫剂、霜剂、软膏剂、洗剂、香膏剂、贴剂、糊剂、喷雾溶液剂、气雾剂等;或***制品,例如***片剂、***霜剂、***软膏剂、敷料溶液、喷雾制品、***胶囊剂、***膜剂、***海绵剂;用于卫生用品(例如卫生棉条、卫生巾、尿布、内裤等)的涂抹制品或喷雾制品,优选***片剂组合物或清洗液组合物。
适用于本文的助洗剂包括:形成水溶性硬离子络合物的助洗剂(螯合助洗剂),例如柠檬酸盐和多磷酸盐(例如三聚磷酸钠、六水合三聚磷酸钠、三聚磷酸钾、三聚磷酸钠和三聚磷酸钾的混合盐);以及形成硬沉淀物的助洗剂(沉淀助洗剂),例如碳酸盐(例如碳酸钠)。
单位剂量形式的产品包括片剂、胶囊剂、囊剂、袋剂(pouches)等。
对于本领域技术人员显而易见的是,在不脱离本发明的精神或范围的情况下,可对本发明的组合物、用途和制品进行各种修改和变化。
有益效果
如本发明所述,包含通过上述方法制备的盐、糖和乳酸菌的组合的本发明组合物经由多种实验显示出有效的抗菌活性,例如:(1)通过测定pH和乳酸水平变化而进行的引起***病的细菌的生长的间接抑制活性测试(实验实施例1);(2)通过测定测试样品的易感性而进行的引起***病的细菌的生长的直接抑制活性测试(实验实施例2);(3)简单临床测试,并最终确认了该组合在测试中显示出有效的抗菌活性。因此,本发明的组合能够以药物组合物、健康功能食品、食品添加剂、局部用组合物和洗涤剂组合物的形式用于减轻、治疗或预防***病。
具体实施方式
对于本领域技术人员显而易见的是,在不脱离本发明的精神或范围的情况下,可以对本发明的组合物、用途和制品进行各种修改和变化。
通过以下实施例更具体地解释本发明。然而,应该理解的是,本发明不以任何方式限于这些实施例。
实施例
以下参考实施例、实施例和实验实施例旨在进一步说明本发明,而不限制其范围。
实施例1.本发明的组合的制备
1-1.盐的制备
1-1-1.熔盐的制备
通过使用加热器(MS-E104,TOPS Co.Ltd.)在850℃-1000℃下将900mg非精制盐(Shinan salt coop,88-6,Dongniseonchakjang-gil,Sangtaedong-ri,Sinui-myeon,Sinan-gun,Jeollanam-do,韩国,58857)熔融24小时来获得400mg熔盐(下文表示为“MS”)。
1-1-2.精制盐的制备
400mg精制盐(NaCl,F.W.58.44)(下文表示为“RS”)购自公司(SPPO-91701,DuksanPure Chemicals,Co.,Ltd,53,Siwon-ro,133beon-gil,Danwon-gu,Ansan-si,Gyeonggi-do,韩国)。
1-1-3.非精制盐的制备
400mg非精制盐(天然盐)(下文表示为“US”)购自公司(Shinan salt coop,88-6,Dongniseonchakjang-gil,Sangtaedong-ri,Sinui-myeon,Sinan-gun,Jeollanam-do,韩国,58857)。
1-2.糖的制备
1-2-1.葡萄糖的制备
800mg葡萄糖(D(+)-葡萄糖)(下文表示为“GL”)购自公司(Cat.No.jb01,J.T.Baker Chemical Company)。
1-2-2.果寡糖的制备
800mg果寡糖(源自菊苣)(下文表示为“FO”)购自公司(Cat.No.F8052050g,Sigma-Aldrich Co.LLC)。
1-2-3.乳果糖的制备
800mg乳果糖(下文表示为“LS”)购自公司(Cat.No.,126-03732,Wako PureChemical Industries)。
1-2-4.果糖的制备
800mg果糖(下文表示为“FS”)购自公司(Cat.No.,64505-0410,Junsei ChemicalCo.Ltd)。
1-2-5.乳糖醇的制备
800mg乳糖醇(下文表示为“LT”)购自公司(Cat.No.,sc488686,Santa CruzBiotechnology,Inc)。
1-3.乳酸菌的制备和培养
1-3-1.乳酸菌的制备
表1中列出的各种乳酸菌分配(apportioned)自KCTC(韩国典型培养物保藏中心,韩国)并用于以下实验中。
[表1]
乳酸菌
1-3-2.细菌的培养
(1)实验中使用了如下细菌:兼性厌氧和微需氧细菌,即嗜酸乳杆菌(KCTCNo.3164)、链球菌属菌(KCTC No.5644)、长双歧杆菌长亚种(KCTC No.3128)等;以及需氧细菌,即蜡状芽孢杆菌(KCTC No.13123)等。
(2)除了上述乳酸菌之外,实验中还使用了引起***病的细菌,即脆弱拟杆菌(KCTC No.5013)和***加德纳氏菌(KCTC No.5097)。
(3)将引起***病的细菌(即脆弱拟杆菌(KCTC No.5013)和***加德纳氏菌(KCTCNo.5097))接种到补充有5%绵羊血的Casmans培养基(12g胰蛋白胨、5g肉蛋白胨、5g氯化钠、3g酵母提取物、3g牛肉提取物、1g淀粉酪蛋白、0.5g D-葡萄糖、0.05g烟酰胺、0.005g对氨基苯甲酸、1L蒸馏水、pH 7.3)中,并通过使用GasPakTM EZ Pouch***(BD,Cat.No.26083,USA)在37℃下以150rpm的速度进行振荡孵育。
(4)将兼性厌氧和微需氧细菌(即嗜酸乳杆菌(KCTC No.3164)、链球菌属菌(KCTCNo.5644)、长双歧杆菌长亚种(KCTC No.3128)等)以及需氧细菌(即蜡状芽孢杆菌(KCTCNo.13123)等)接种到MRS培养基(10g蛋白酶蛋白胨、10g牛肉提取物、5g酵母提取物、20g D-葡萄糖、1mL Tween 80、2g K2HPO4、5g乙酸钠、2g柠檬酸氢二铵、0.2g MgSO4·7H2O、0.2gMnSO4·H2O、1L蒸馏水、pH 6.2-6.5)中,并在37℃下以150rpm的速度进行振荡孵育。
1-4.本发明组合的制备
将上述步骤中制备的50mg熔盐与上述步骤中制备的5mg干燥葡萄糖和1mg干燥嗜酸乳杆菌充分混合在一起,得到本发明的组合(下文表示为“CL1”)。
将该组合保持在-75℃的冰箱中,并在使用前通过溶解在蒸馏水中用于以下实验。
根据与上述类似的方法制备表2中列出的本发明的其它组合。
[表2]
组合
实施例2.本发明的***片剂组合物的制备
通过使用制片装置(KT2000,Kumsungkigong)将实施例1中制备的组合(包含400mg熔盐、800mg葡萄糖和40mg干燥嗜酸乳杆菌)与2mg硬脂酸镁混合,以配制成本发明的***片剂组合物组合(下文表示为“SGL2”)。
实施例3.本发明的***清洗溶液组合物的制备
通过在搅拌下与表3中所示的以下成分(下文表示为“SGL3”)混合48小时来制备包含实施例1中制备的组合(包含400mg精制盐、800mg葡萄糖和40mg干燥长双歧杆菌长亚种)的***清洗溶液组合物。
[表3]
SGL4溶液(100mL)
实验实施例1.对引起***病的菌株的生长的抑制作用
为了间接地测定实施例1中制备的本发明的组合对引起***病的菌株的生长的抑制作用,根据文献(Choi,J.G.等,Antibacterial activity of Ecklonia cava againstmethicillin-resistant Staphylococcus aureus and Salmonella spp.,FoodbornePathog.Dis.,2010(Apr.):7(4),pp435-441)中公开的程序进行以下测试。
1-1.测试菌株
根据引用文献(D.D.Charles等,identification of haemophilus vaginalis,1960,Journal of bacteriology p277,R.P.Morgan等,Amniotic fluid andmaternalrace influence responsiveness of fetal membranes to bacteria,Journalof reproductive immunology,96(2012)68-78),将引起***病的细菌(即脆弱拟杆菌(KCTC No.5013)和***加德纳氏菌(KCTC No.5097))接种到补充有5%FBS(胎牛血清)的Casmans培养基(12g胰蛋白胨、5g肉蛋白胨、5g氯化钠、3g酵母提取物、3g牛肉提取物、1g淀粉酪蛋白、0.5g D-葡萄糖、0.05g烟酰胺、0.005g对氨基苯甲酸、1L蒸馏水、pH 7.3、5%FBS)中,并通过使用GasPakTM EZ Pouch***(带指示器的Anaerobic Gas Generation Pouch***,BD,Cat.No.26083,USA)在37℃下以150rpm的速度进行振荡孵育。
1-2.实验材料
将表2中所示的本发明的组合用作测试样品,乳酸购自公司(Cat.No.252476,ACS试剂,85%-90%,处于水中的L-乳酸,Sigma-Aldrich Co.LLC)。
1-3.实验目的
本实验的目的是测定与仅用引起***病的菌株处理的对照组相比,用实施例1中制备的测试样品处理的测试组中的OD(光密度)、pH和乳酸水平的变化。
1-4.实验程序
1-4-1.对照组
将实施例1中制备的测试样品加入引起***病的菌株(即脆弱拟杆菌(KCTCNo.5013)和***加德纳氏菌(KCTC No.5097))的培养基中。将预培养的引起***病的菌株(吸光度:OD660=1.0A,1/100v/v)再次接种到含有FBS的Casman培养基中,并在37℃下以150rpm的速度进行振荡孵育12小时。用实施例1中制备的测试样品处理对照组。
1-4-2.比较组
仅将表1中所示的各种乳酸菌加入到引起***病的菌株(即脆弱拟杆菌(KCTCNo.5013)和***加德纳氏菌(KCTC No.5097))的培养基中。将预培养的引起***病的菌株(吸光度:OD660=1.0A,1/100v/v)再次接种到含有FBS的Casman培养基中,并在37℃下以150rpm的速度进行振荡孵育12小时。仅用乳酸菌处理比较组。
1-4-3.测试样品组
将1mg乳酸菌和实施例1中制备的测试样品的组合加入引起***病的菌株(即脆弱拟杆菌(KCTC No.5013)和***加德纳氏菌(KCTC No.5097))的培养管中,并在37℃下以150rpm的速度进行振荡孵育18小时。用1mg乳酸菌和实施例1中制备的测试样品处理测试样品组。
1-4-4.pH值的测定
按照如下方式对对照组和测试样品组中pH值的变化进行测定。
通过使用装置(pH计,SevenEasy,Mettler Toledo,Swiss)测定对照组和测试样品组中的细胞培养液的pH。
1-4-5.乳酸水平的测定
按照如下方式使用分析试剂盒(D-/L-乳酸(快速)分析试剂盒,megazyme,Cat.No.K-DLATE)对对照组和测试样品组中的乳酸水平进行测定。
将1.5mL蒸馏水、0.1mL测试样品和0.02mL缓冲溶液(缓冲液;加上D-谷氨酸和叠氮化钠(0.02%w/v)、0.1mL NAD、DGP(D-谷氨酸-丙酮酸转氨酶混悬液))倒入比色皿中并一起混合3分钟。通过使用分光光度计(Spectronic Genesys 2,Thermo,USA)测定吸光度A1值(波长:340nm),并将0.02mL D-LDL(D-乳酸脱氢酶混悬液,D-/L-乳酸试剂盒,Megazyme,Ireland)加入溶液中一起混合5分钟。
通过使用分光光度计(Spectronic Genesys 2,Thermo,USA)测定吸光度A2值(波长:340nm)。
最后,将0.02mL D-LDL(D-乳酸脱氢酶混悬液,D-/L-乳酸试剂盒,Megazyme,Ireland)加入溶液中一起混合10分钟,并通过使用分光光度计(Spectronic Genesys 2,Thermo,USA)测定吸光度A3值(波长:340nm)。
通过使用软件(Mega-CalcTM,Megazyme,IDA Business Park,Bray,Co.Wicklow,A98YV29,Ireland)和所得吸光度值A1-A3确定对照组和测试样品组中的乳酸水平。
1-5.测试结果
与仅用引起***病的菌株处理的对照组相比,用实施例1中制备的测试样品处理的测试组中的OD(光密度)、pH和乳酸水平的变化的测试结果示于表4、表5(***加德纳氏菌菌株)和表6、表7(脆弱拟杆菌菌株)中。
1-5-1.***加德纳氏菌菌株(见表4、表5)
在以***加德纳氏菌菌株处理的实验的情况下,用本发明的组合处理的测试组显示出酸性环境(即pH范围为4.0-4.9),在***中提供了***加德纳氏菌菌株生长的抑制环境,而未用本发明的组合处理的对照组显示pH范围为5.19-5.52。
对于在***中具有有害细菌生长抑制活性的乳酸的水平而言,用本发明的组合处理的测试组中的乳酸水平范围为0.970mg/mL-1.712mg/mL,与仅用乳酸菌处理的比较组相比,在***中提供了更有效的***加德纳氏菌菌株生长抑制活性,而未用本发明的组合处理的对照组显示乳酸水平范围为0.711mg/mL-0.765mg/mL。
1-5-2.脆弱拟杆菌菌株(见表6、表7)
在以脆弱拟杆菌菌株处理的实验的情况下,用本发明的组合处理的测试组显示出酸性环境(即pH范围为4.4-4.9),在***中提供了脆弱拟杆菌菌株生长的抑制环境,而未用本发明的组合处理的对照组显示pH范围为5.21-5.62。
对于在***中具有有害细菌生长抑制活性的乳酸的水平而言,用本发明的组合处理的测试组中的乳酸水平范围为0.4420mg/mL-1.049mg/mL,与仅用乳酸菌处理的比较组相比,在***中提供了更有效的脆弱拟杆菌菌株生长抑制活性,而未用本发明的组合处理的对照组显示乳酸水平为0.000mg/mL。
因此,证实了本发明的组合通过提供必需的营养素来促进乳酸菌的生长,从而刺激了维持***酸性环境的乳酸的生产。
[表4]
乳酸水平和pH的变化(***加德纳氏菌菌株)
[表5]
乳酸水平和pH的变化(***加德纳氏菌菌株)
[表6]
乳酸水平和pH的变化(脆弱拟杆菌菌株)
[表7]
乳酸水平和pH的变化(脆弱拟杆菌菌株)
实验实施例2.对引起***病的菌株的生长的直接抑制作用
为了确认实施例1中制备的本发明的组合对引起***病的菌株的生长的直接抑制作用,按照如下方式进行如下测试。
2-1.初步测试的目的
通过使用乳酸菌和引起***病的菌株的各种抗性抗生素来测定实验中使用的乳酸菌和引起***病的菌株的易感性,并且可定量且直接地测定本发明的组合对引起***病的菌株的抑制活性或促进作用。
本实验中使用了各种浓度的各种抗生素,即50μg/mL氨苄青霉素(Cat.No.AM0510,Georgia Chem.,美国)、50μg/mL卡那霉素(Cat.No.KA2003,Georgia Chem.,美国)、34μg/mL氯霉素(Art.3886.2,德国)、15μg/mL四环素(Art.Nr.HP63.1,德国)、50μg/mL链霉素(Cat.No.S1027,Biosesang,韩国)、20μg/mL庆大霉素(Cat.No.GS3007,Georgia Chem.,美国)和25μg/mL利福平(Cat.No.R3501,Sigma-Alrich,美国)。
2-2.对引起***病的菌株的易感性的初步测试
2-2-1.实验程序
将引起***病的菌株(即脆弱拟杆菌(KCTC No.5013)和***加德纳氏菌(KCTCNo.5097))接种到补充有5%绵羊血和1.5%琼脂的Casmans培养基中,并在厌氧条件下通过使用GasPakTM EZ Gas Generation Pouch***(BD,Cat.No.26083,美国)进行振荡孵育36小时。
在孵育后,将菌落通过铂圈收集并接种到补充有5%FBS(胎牛血清)的Casmans培养基(12g胰蛋白胨、5g肉蛋白胨、5g氯化钠、3g酵母提取物、3g牛肉提取物、1g淀粉酪蛋白、0.5g D-葡萄糖、0.05g烟酰胺、0.005g对氨基苯甲酸、1L蒸馏水、pH 7.3、5%FBS)中。根据引用文献(Treatment of Gardnella vaginalis infection.,JI.Adinma等,J.Obstetricsand Gynaecology,17(6),pp.573-575,1997;Treatment of urinary tract infection byGardnella vaginalis;a composition of oral metronidazole versus ampicillin,AG.PA.等,Rev Latioam Microbiol.2001,43(2):pp65-69;Antimicrobialsusceptibilities of Gardnella vaginalis.,Kharsany AB.等,antimicrobial agentsand chemotherapy,1993,pp2733-2735.;Susceptibilities of Bacteroides fragilisto six antibiotics determined by standardized antimicrobial discsusceptibility testing.,Sutter VL.等,antimicrobial agents and chemotherapy,1973,pp188-193),通过使用GasPakTM EZ Pouch***(带指示器的Anaerobic GasGeneration Pouch***,BD,Cat.No.26083,USA)在37℃下以150rpm的速度进行振荡孵育24小时。
2-2-2.测试结果
结果,表8中示出了各种抗生素针对引起***病的细菌的抗生素易感性。
[表8]
各种抗生素针对引起***病的细菌的抗生素易感性
2-3.对乳酸菌菌株的易感性的初步测试
2-2-1.实验程序
为了测定生产大量乳酸的乳酸菌菌株(即嗜酸乳杆菌(KCTC No.3164)、长双歧杆菌长亚种(KCTC No.3128)等)的抗生素抗性,将细菌接种到MRS培养基(10g蛋白酶蛋白胨、10g牛肉提取物、5g酵母提取物、20g D-葡萄糖、1mL Tween 80、2g K2HPO4、5g乙酸钠、2g柠檬酸氢二铵、0.2g MgSO4·7H2O、0.2g MnSO4·H2O、1L蒸馏水、pH 6.2-6.5)中,并在37℃下以150rpm的速度进行振荡孵育。
对于厌氧孵育,根据引用文献(Antibiotic susceptibility of members of thelactobacillus acidophilus group using broth microdilution and molecularidentification of their resistance determinants,M.Sigrids等,InternationalJournal of Food Microbiology 144(2010),pp81-87;Antibiotic sensitivity of acidstressed probiotic Lactobacillus acidophilus ncdc 291,NNK,GS.,The internetJournal of microbiology,第9卷,(2010);Antimicrobial susceptibility ofbifidobactria.,F.CM.等,Journal of antimicrobial Chemotherapy(2005)55,pp.38-44),通过使用GasPakTM EZ Pouch***(具有指示器的Anaerobic Gas Generation Pouch***,BD,Cat.No.26083,美国)在37℃下以150rpm的速度将培养基进行振荡孵育24小时。
2-2-2.测试结果
结果,表9中示出了各种抗生素针对乳酸菌菌株的抗生素易感性。
[表9]
各种抗生素针对乳酸菌菌株的抗生素易感性
2-3.对抗生素易感性的主要实验
2-3-1.实验程序
为了测定引起***病的菌株(即脆弱拟杆菌(KCTC No.5013)和***加德纳氏菌(KCTC No.5097))以及生产大量乳酸的各种乳酸菌菌株(即嗜酸乳杆菌(KCTC No.3164)、长双歧杆菌长亚种(KCTC No.3128)等)的抗生素抗性,进行以下实验。
通过将50μg/mL氨苄青霉素处理至用脆弱拟杆菌和各种乳杆菌菌株同时处理的组来测定脆弱拟杆菌的生长速率,导致各种乳杆菌菌株生长的抑制。
通过将50μg/mL氨苄青霉素处理至用脆弱拟杆菌和各种双歧杆菌菌株同时处理的组来测定脆弱拟杆菌的生长速率,导致各种双歧杆菌菌株生长的抑制。
通过将20μg/mL氨苄青霉素处理至用***加德纳氏菌和各种乳杆菌菌株同时处理的组来测定***加德纳氏菌的生长速率,导致各种乳杆菌菌株生长的抑制。
通过将20μg/mL氨苄青霉素处理至用脆弱拟杆菌和各种双歧杆菌菌株同时处理的组来测定***加德纳氏菌的生长速率,导致各种双歧杆菌菌株生长的抑制。
基于初步测试的测试结果将测试组分为5组,即:(a)用精制盐和葡萄糖(1:1,w/w)的组合处理的组I,例如CL1、CF1、CB1、CS1;(b)用熔盐和果寡糖(1:2,w/w)的组合处理的组II,例如CL2、CF2、CB2、CS2;(c)用非精制盐和乳果糖(1:5,w/w)的组合处理的组III,如CL3、CF3、CB3、CS3;(d)用精制盐和果糖(2:1,w/w)的组合处理的组IV,如CL4、CF4、CB4、CS4;以及(e)用熔盐和乳糖醇(5:1,w/w)的组合处理的组V,如CL5、CF5、CB5、CS5。将稀释的测试样品再次接种到包含50μg/mL氨苄青霉素或20μg庆大霉素的选定培养基中。将20μl预孵育培养基(处于液体培养基中)稀释至1,000μl补充有5%FBS(胎牛血清)的Casmans培养基(12g胰蛋白胨、5g肉蛋白胨、5g氯化钠、3g酵母提取物、3g牛肉提取物、1g淀粉酪蛋白、0.5g D-葡萄糖、0.05g烟酰胺、0.005g对氨基苯甲酸、1L蒸馏水、pH 7.3、5%FBS)中,并收集20μl培养基以再次接种到包含选定抗生素并补充有5%FBS的3mL Casmans培养基中。通过使用GasPakTMEZ Pouch***(具有指示器的Anaerobic Gas Generation Pouch***,BD,Cat.No.26083,美国)在37℃下以150rpm的速度将含有琼脂的固体培养基和液体培养基两者进行振荡孵育24小时。
通过使用分光光度计(Spectronic genesis 2,Thermo,美国,600nm波长下的O.D.值)测定在液体培养基中培养的细菌的生长速率,并通过计算菌落数量测定其在固体培养基中的生长速率。
2-3-2.测试结果
从示出了脆弱拟杆菌在选定培养基(Casmans培养基:MRS培养基(v/v),含有50μg/mL氨苄青霉素)中的测试结果的表10可以看出,证实了在与各种乳杆菌菌株一起培养的组I、组III和组V中的脆弱拟杆菌的生长被抑制,O.D(光密度)值和菌落计数的测试结果示于表10。
[表10]
与各种乳杆菌菌株一起培养的脆弱拟杆菌的生长的测试结果
从示出了脆弱拟杆菌在选定培养基(Casmans培养基:MRS培养基(v/v),含有50μg/mL氨苄青霉素)中的测试结果的表11可以看出,证实了在与双歧杆菌菌株一起培养的组I、组II、组III、组IV和组V中的脆弱拟杆菌的生长被抑制,O.D(光密度)值和菌落计数的测试结果示于表11。
[表11]
与双歧杆菌菌株一起培养的脆弱拟杆菌的生长的测试结果
从示出了脆弱拟杆菌在选定培养基(Casmans培养基:MRS培养基(v/v),含有50μg/mL氨苄青霉素)中的测试结果的表12可以看出,证实了在与蜡状芽孢杆菌菌株一起培养的组I、组II、组III、组IV和组V中的脆弱拟杆菌的生长被抑制,O.D(光密度)值和菌落计数的测试结果示于表12。
[表12]
与蜡状芽孢杆菌菌株一起培养的脆弱拟杆菌的生长的测试结果
从示出了脆弱拟杆菌在选定培养基(Casmans培养基:MRS培养基(v/v),含有50μg/mL氨苄青霉素)中的测试结果的表13可以看出,证实了在与链球菌菌株一起培养的组I、组II、组III、组IV和组V中的脆弱拟杆菌的生长被抑制,O.D(光密度)值和菌落计数的测试结果示于表13。
[表13]
与链球菌菌株一起培养的脆弱拟杆菌的生长的测试结果
从示出了***加德纳氏菌在选定培养基(Casmans培养基:MRS培养基(v/v),含有20μg/mL庆大霉素)中的测试结果的表14可以看出,证实了在与各种乳杆菌菌株一起培养的组III中的***加德纳氏菌的生长被抑制,O.D(光密度)值和菌落计数的测试结果示于表14。
[表14]
与各种乳杆菌菌株一起培养的***加德纳氏菌的生长的测试结果
从示出了***加德纳氏菌在选定培养基(Casmans培养基:MRS培养基(v/v),含有50μg/mL氨苄青霉素)中的测试结果的表15可以看出,证实了在与各种双歧杆菌菌株一起培养的组I、组II、组III、组IV和组V中的***加德纳氏菌的生长被抑制,O.D(光密度)值和菌落计数的测试结果示于表15。
[表15]
与双歧杆菌菌株一起培养的***加德纳氏菌的生长的测试结果
从示出了***加德纳氏菌在选定培养基(Casmans培养基:MRS培养基(v/v),含有50μg/mL氨苄青霉素)中的测试结果的表16可以看出,证实了在与蜡状芽孢杆菌菌株一起培养的组I、组II、组III、组IV和组V中的***加德纳氏菌的生长被抑制,O.D(光密度)值和菌落计数的测试结果示于表16。
[表16]
与蜡状芽孢杆菌菌株一起培养的***加德纳氏菌的生长的测试结果
从示出了***加德纳氏菌在选定培养基(Casmans培养基:MRS培养基(v/v),含有50μg/mL氨苄青霉素)中的测试结果的表17可以看出,证实了在与链球菌菌株一起培养的组I、组II、组III、组IV和组V中的***加德纳氏菌的生长被抑制,O.D(光密度)值和菌落计数的测试结果示于表17。
[表17]
与链球菌菌株一起培养的***加德纳氏菌的生长的测试结果
因此,通过上述实验证实了与用乳酸菌单独处理以及用盐和糖的组合单独处理相比,本发明的组合显示出对引起***病的细菌更有效的抑制作用。
实验实施例3.简单临床测试(1)
向100名志愿者(由居住在韩国的年龄20-50岁的35名患有***病的患者和65名正常女性组成)外部给予实施例2中制备的1,200mg***片剂组合物(SGL2)5天(每天一次),以进行问卷调查,并调查了如下各种内容的差异:(a)难闻气味的防止作用;(b)新鲜感水平;以及(c)皮肤银屑病的缓解活性。
调查结果分为四组:(1)非常满意;(2)满意;(3)正常;以及(4)不满意,调查结果示于表18。
[表18]
调查结果
结果,从表18可以看出,对于(a)难闻气味的防止作用,在用本发明的组合物处理后,94%的志愿者满意,特别地,79%的志愿者非常满意。
对于(b)新鲜感水平,在用本发明的组合物处理后,86%的志愿者满意,特别地,72%的志愿者非常满意。
对于皮肤银屑病的缓解活性,在用本发明的组合物处理后,85%的志愿者满意,特别地,67%的志愿者非常满意。
因此,已经证明本发明的***片剂组合物具有有效的有利作用,例如:(a)难闻气味的预防作用;(b)新鲜感水平;以及(c)皮肤银屑病的缓解活性等,并且该组合物作为***片剂组合物以用于治疗或预防患者***的***病是有用的。
显而易见的是,由此描述的发明能够以许多方式进行变化。不应认为此类变化脱离了本发明的精神和范围,并且对本领域技术人员而言显而易见的是,所有此类修改均旨在被囊括于所附权利要求书的范围内。
实验实施例4.简单临床测试(2)
向100名志愿者(由居住在韩国的年龄20-50岁的42名患有***病的患者和58名正常女性组成)外部给予实施例3中制备的200mL***清洗组合物(SGL4)5天(每天一次),并通过使用pH计(MP-103,www.yuyuinst.co.kr)测定用本发明的组合物处理之前(A)和之后(B)的pH之间的***pH值差异。
结果,从表19可以看出,在用本发明的组合物处理之前,85%的测试组的***pH达到5.5以上;然而,在用本发明的组合物处理之后,90%的测试组的***pH达到正常pH范围。
[表19]
pH差异
因此,已经证明本发明的清洗组合物(其可以是SGL4)可用于降低患有***碱化的患者的***pH。
显而易见的是,由此描述的发明能够以许多方式进行变化。不应认为此类变化脱离了本发明的精神和范围,并且对本领域技术人员而言显而易见的是,所有此类修改均旨在被囊括于所附权利要求书的范围内。
实验实施例5.大鼠中口服给药的急性毒性测试
通过向6周龄的SPF Sprague-Dawley大鼠给予本发明的组合(SGL2和SGL4)来进行急性毒性测试。
向由2只大鼠组成的各组口服给予250mg/kg、500mg/kg、1000mg/kg、5000mg/kg的本发明的组合,并对大鼠症状观察14天。在给予本发明的组合之后,对所有临床变化(即,死亡率、临床征象、体重变化)进行观察,并进行血液测试(例如血液学测试和血液生物化学测试)。在尸体解剖后观察腹部器官和胸部器官的异常变化。
在任何组或任一性别中,在死亡率、临床征象、体重变化和总体发现(grossfindings)方面均没有显示出任何变化。此外,在用5000mg/kg的本发明组合处理的测试组中未显示任何毒性。
因此,证实了本发明制备的本发明组合是有效且安全的物质,其在口服给药中显示出大于5000mg/kg的LD50。
在下文中,将对配制方法和赋形剂种类进行描述,但是本发明不限于此。代表性的制备实例描述如下。
注射剂的制备
通过常规注射剂制备方法将活性组分溶解、将pH控制至约7.5、然后将所有组分填充入2mL安瓿中并灭菌来制备注射剂制品。
散剂的制备
通过将以上组分混合并填充密封包装来制备散剂制品。
片剂的制备
通过将以上组分混合并进行压片来制备片剂制品。
胶囊剂的制备
通过常规明胶剂制备方法将以上组分混合并填充明胶胶囊来制备片剂制品。
液体剂的制备
通过常规液体剂制备方法将活性组分溶解、然后将所有组分填充入1000mL安瓿中并灭菌来制备液体剂制品。
健康食品的制备
上述维生素和矿物质混合物能够以多种方式进行变化。不应认为此类变化脱离了本发明的精神和范围。
健康饮料的制备
通过常规健康饮料制备方法将活性组分溶解、混合、在85℃下搅拌1小时、过滤、然后将所有组分填充入1000mL安瓿中并灭菌来制备健康饮料制品。
显而易见的是,由此描述的发明能够以许多方式进行变化。不应认为此类变化脱离了本发明的精神和范围,并且对本领域技术人员而言显而易见的是,所有此类修改均旨在被囊括于所附权利要求书的范围内。
工业实用性
如本发明所述,本发明提供了一种用于治疗或预防***病的组合物,所述组合物包含盐、糖和乳酸菌的本发明组合作为活性成分。本发明的组合物经由多种实验显示出有效的抗菌活性,例如:(1)通过测定pH和乳酸水平变化而进行的引起***病的细菌的生长的间接抑制活性测试(实验实施例1);(2)通过测定测试样品的易感性而进行的引起***病的细菌的生长的直接抑制活性测试(实验实施例2);(3)简单临床测试,并最终确认了该组合在测试中显示出有效的抗菌活性。因此,本发明的组合能够以药物组合物、健康功能食品、食品添加剂、局部用组合物和洗涤剂组合物的形式用于减轻、治疗或预防***病。
Claims (17)
1.一种用于治疗和预防***病的药物组合物,所述药物组合物包含盐、糖和乳酸菌的组合作为活性成分。
2.如权利要求1所述的药物组合物,其中,所述盐选自于由精制盐、加工盐和非精制盐所组成的组。
3.如权利要求1所述的药物组合物,其中,所述糖选自于由单糖、二糖、寡糖和多糖所组成的组。
4.如权利要求3所述的药物组合物,其中,所述糖选自于由如下糖所组成的组:
木糖、***糖、葡萄糖、甘露糖、果糖、半乳糖、乳果糖、乳糖醇、蔗糖、乳糖、麦芽糖、海藻糖、果寡糖、棉子糖、水苏糖、麦芽糖糊精、直链淀粉、纤维素和果胶。
5.如权利要求1所述的药物组合物,其中,所述乳酸菌选自于由如下乳酸菌所组成的组:
乳杆菌属菌(Lactobacillus spp.),例如植物乳杆菌(lactobacillus plantarum)、戊糖乳杆菌(lactobacillus pentosus)、干酪乳杆菌(lactobacillus casei)、干酪乳杆菌副干酪亚种(lactobacillus casei ssp.paracasei)、鼠李糖乳杆菌(lactobacillusrhamnosus)、嗜酸乳杆菌(lactobacillus acidophilus)、德氏乳杆菌(lactobacillusdelbrueckii)、德氏乳杆菌保加利亚亚种(lactobacillus delbrueckii,ssp.bulgaricus)、德氏乳杆菌德氏亚种(lactobacillus delbrueckii,ssp.delbrueckii)、发酵乳杆菌(lactobacillus fermentum)、加氏乳杆菌(lactobacillusgasseri)、罗伊氏乳杆菌(lactobacillus reuteri)、短乳杆菌(lactobacillus brevis)、纤维二糖乳杆菌(lactobacillus cellobiosus)、卷曲乳杆菌(lactobacilluscrispatusi)、乳杆菌GG(lactobacillus GG)、约氏乳杆菌(lactobacillus johnsonii)、乳酸乳杆菌(lactobacillus lactis)、唾液乳杆菌(lactobacillus salivarius)等;双歧杆菌属菌(Bifidobacterium spp.),例如长双歧杆菌(Bifidobacterium longum)、两歧双歧杆菌(Bifidobacterium bifidum)、短双歧杆菌(Bifidobacterium breve)、动物双歧杆菌乳酸亚种(Bifidobacterium animalis ssp,lactis)、青春双歧杆菌(Bifidobacteriumadolescentis)、假链状双歧杆菌(Bifidobacterium pseudocatenulatum)、链状双歧杆菌(Bifidobacterium catenulatum)、婴儿双歧杆菌(Bifidobacterium infantis)、嗜热双歧杆菌(Bifidobacterium thermophilum)等;芽孢杆菌属菌(Bacillus spp.),例如toyoi蜡状芽孢杆菌(Bacillus cereus toyoi)、蜡状芽孢杆菌(Bacillus cereus)等;链球菌属菌(Streptococcus spp.),例如嗜热链球菌(Streptococcus thermophiles)、乳脂链球菌(Streptococcus cremoris)、婴儿链球菌(Streptococcus infantarius)、中间型链球菌(Streptococcus intermedius)、乳酸链球菌(Streptococcus lactis)、唾液链球菌嗜热亚种(Streptococcus salivarius subsp.Thermophiles)等;肠球菌属菌(Enterococcusspp.),例如粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcus faecium)等;酵母属菌(Saccharomyces spp.),例如酿酒酵母(Saccharomyces cerevisiae)、布拉酵母(Saccharomyces boulardii)等;明串珠菌属菌(Leuconostoc spp.),例如柠檬明串珠菌(Leuconostoc citreum)、肠膜明串珠菌(Leuconostoc mesenteroides)等。
6.如权利要求5所述的药物组合物,其中,所述乳酸菌选自于由如下乳酸菌所组成的组:
乳杆菌属菌,例如植物乳杆菌、戊糖乳杆菌、干酪乳杆菌、干酪乳杆菌副干酪亚种、鼠李糖乳杆菌、嗜酸乳杆菌、德氏乳杆菌、德氏乳杆菌保加利亚亚种、德氏乳杆菌德氏亚种、发酵乳杆菌、加氏乳杆菌、罗伊氏乳杆菌、短乳杆菌、纤维二糖乳杆菌、卷曲乳杆菌、乳杆菌GG、约氏乳杆菌、乳酸乳杆菌、唾液乳杆菌等;以及双歧杆菌属菌,例如长双歧杆菌、两歧双歧杆菌、短双歧杆菌、动物双歧杆菌乳酸亚种、青春双歧杆菌、假链状双歧杆菌、链状双歧杆菌、婴儿双歧杆菌、嗜热双歧杆菌等。
7.如权利要求1所述的药物组合物,其中,所述盐、糖和乳酸菌的组合为具有1:(100-0.01):(100-0.01)重量份(w/w)的混合比例的盐、糖和乳酸菌的组合。
8.如权利要求7所述的药物组合物,其中,所述***病选自于由细菌性***病、真菌性***炎和滴虫性***炎所组成的组。
9.一种用于减轻和预防***病的健康功能食品,所述健康功能食品包含盐、糖和乳酸菌的组合作为活性成分。
10.如权利要求9所述的健康功能食品,所述健康功能食品处于食品、健康饮料或膳食补充剂的形式。
11.一种用于预防或减轻***病的保健食品,所述保健食品包含盐、糖和乳酸菌的组合以及营养学上可接受的添加剂。
12.盐、糖和乳酸菌的组合在制备用于在哺乳动物中治疗或预防***病的药物中的用途。
13.一种在哺乳动物中治疗或预防***病的方法,其中,所述方法包括向所述哺乳动物给予有效量的盐、糖和乳酸菌的组合及其药学上可接受的载体。
14.一种用于治疗或预防***病的局部用组合物,所述局部用组合物包含盐、糖和乳酸菌的组合作为活性成分。
15.一种用于治疗或预防***病的清洗液溶液组合物或***片剂组合物,所述清洗液溶液组合物或***片剂组合物包含盐、糖和乳酸菌的组合以及药学上可接受的载体。
16.一种用于减轻或预防***病的洗涤剂组合物,所述洗涤剂组合物包含盐、糖和乳酸菌的组合作为活性成分。
17.如权利要求16所述的洗涤剂组合物,所述洗涤剂组合物是如下形式:
局部用制品,例如水溶液、非水溶剂、混悬剂、乳剂、冻干制品、栓剂制品、清洗液、凝胶剂、胶质体、泡沫剂、霜剂、软膏剂、洗剂、香膏剂、贴剂、糊剂、喷雾溶液剂、气雾剂等;或***制品,例如***片剂、***霜剂、***软膏剂、敷料溶液、喷雾制品、***胶囊剂、***膜剂、***海绵剂;用于卫生用品(例如卫生棉条、卫生巾、尿布、内裤等)的涂抹制品或喷雾制品。
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WO2023053073A1 (en) * | 2021-09-30 | 2023-04-06 | Blis Technologies Limited | Probiotic enhancers and uses thereof |
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SE9100364L (sv) * | 1991-02-05 | 1992-08-06 | Bac Dev In Sweden Ab | Tampong eller binda impregnerad med en kultur av levande mjoelksyrabakterier i avsikt att minska risken foer urogenitala infektioner |
US6093394A (en) * | 1997-04-11 | 2000-07-25 | Gynelogix, Inc. | Vaginal lactobacillus medicant |
SI1506781T1 (zh) * | 2003-11-03 | 2005-08-31 | Volkmann Peter Hansen | |
KR101133723B1 (ko) * | 2009-10-19 | 2012-04-09 | 최원석 | 소금 및 당을 유효성분으로 함유하는 질염 예방 및 치료용 조성물 및 이의 용도 |
KR20150075447A (ko) * | 2013-12-26 | 2015-07-06 | (주)정가진면역연구소 | 여성 자궁 질염 예방 및 개선 기능성 조성물 |
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CN112175851A (zh) * | 2019-07-01 | 2021-01-05 | 中国科学院上海有机化学研究所湖州生物制造创新中心 | 乳酸杆菌混合高密度发酵及乳酸杆菌复合菌制剂的制备 |
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CN112806576A (zh) * | 2019-10-29 | 2021-05-18 | 锦乔生物科技有限公司 | 抑制***炎病原菌的组合物、***清洁组合物以及其用途 |
CN112806576B (zh) * | 2019-10-29 | 2024-04-05 | 锦乔生物科技有限公司 | 抑制***炎病原菌的组合物、***清洁组合物以及其用途 |
TWI784210B (zh) * | 2019-11-08 | 2022-11-21 | 豐華生物科技股份有限公司 | 用以抑制***炎病原菌之組合物、***清潔組合物以及其用途 |
TWI819833B (zh) * | 2022-10-04 | 2023-10-21 | 益佳元生物科技股份有限公司 | ***清潔組合物 |
CN116121211A (zh) * | 2022-12-29 | 2023-05-16 | 北京聚益成广科技有限公司 | 一种诱导复合益生菌产抑菌生物酶的培养方法 |
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US20190070229A1 (en) | 2019-03-07 |
RU2018124654A (ru) | 2020-06-10 |
PH12018501603A1 (en) | 2019-05-15 |
KR101784847B1 (ko) | 2017-10-13 |
WO2017196006A1 (en) | 2017-11-16 |
EP3454869A1 (en) | 2019-03-20 |
BR112018070277A2 (pt) | 2019-01-29 |
AU2017264267A1 (en) | 2018-07-12 |
JP2019524636A (ja) | 2019-09-05 |
MX2018010994A (es) | 2019-03-07 |
CA3010577A1 (en) | 2017-11-16 |
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