CN103687604A - 用于治疗与致病生物膜相关之病症的材料和方法 - Google Patents
用于治疗与致病生物膜相关之病症的材料和方法 Download PDFInfo
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Abstract
本发明提供了使用容易获得的、无毒的天然物质有效地支持先天免疫和/或驱散致病生物膜、同时支持正常的微生物稳态之恢复的材料和方法。在一个实施方案中,本发明提供了抗生物膜组合物,其包含一种或更多种益生生物、抗微生物蜂蜜和其他成分如益生元化合物、其他蜂巢产品、绿茶衍生物、其他植物衍生物和维生素D3。
Description
相关申请的交叉引用
本申请要求于2011年3月1日提交的、序列号为61/447,735的美国临时申请的优先权,该申请通过引用整体并入本文。
背景技术
在适者生存的世界中,细菌具有出色的适应环境并响应它们所处的环境而进化的能力。某些微生物已通过它们与宿主的共生关系进化出决定性的生存优势。作为在它们的人宿主内或人宿主上方便地生长“生态位(niche)”的交换,这些细菌赋予某些重要的生存优势,例如在这些“友好”细菌茁壮成长的表面上直接抑制病原体定殖。通常情况下,人免疫系统会击退这些作为敌意侵略者的完全相同的细菌。但是通过在它们的人宿主上赋予某些健康益处,这些“益生(probiotic)”细菌在微生物与人之间创造出有益地协同、进化上有利从而在进化上保守的关系。
益生生物赋予的益处之一是刺激宿主的先天免疫系统(innate immunesystem)。作为针对所有感染的主要且首要的防御者,先天免疫系统应答的完整性、效率和迅速对于宿主的生存至关重要。未破坏且顺利运行的先天免疫系统通过限制宿主病原体定殖来保护宿主及其益生生物。虽然对宿主有益,但是这样的保护对于益生生物而言也是利己的,因为直接抑制病原体生长也相反地促进健康、有益生物在这些相同表面上的生长。因此,这些益处虽然同时保护了宿主本身,但是最重要的是保护了赋予该优势的微生物群(microbiota)。然而,大多数微生物不是益生的,但最好不致病,而最坏可能会致命。
百年历史的病菌学说(germ theory)—导致感染只需要一种自由漂浮的(free-floating)“病菌”或微生物—直接决定了后来病原体及其所导致感染的研究的方向。抗生素,治疗感染的主要工具,基于微生物杀灭在自由漂浮(浮游)状态下研究的作为单个细胞起作用的微生物的效率。以传统的最低抑制浓度(Minimum Inhibitory Concentration,MIC)测定来进行抗生素效力的定量。然而,传统的微生物学已经错了。相反,大多数人感染现在被认为是由于整个微生物菌落协调的全体行为。这些菌落由一起工作以分泌被称为生物膜的细胞外基质的微生物构成,所述生物膜包围整个菌落并保护整个菌落不受抗生素之害并免受完整的免疫系统的攻击。
当自由漂浮的浮游细菌锚定至生物表面或诸如留置的(indwelling)医疗器械的惰性表面时,开始形成生物膜。附着的细菌繁殖,并由单层状态发展成小菌落(microcolony)然后发展成临界量(critical mass),在该临界量下发生细菌串话(crosstalk),引发导致生物膜表型的被称为细胞密度感受(quorum sensing)的现象。细胞密度感受打开非固着细菌(non-sessilebacteria)中未表达或产生的生物膜产生基因。细菌集体应答以表达生物膜表型的特异性因子,这导致分泌由生物膜所决定的胞外多糖(exopolysaccharide,EPS)基质。该生物膜表型形态学上的特征为微生物塔(microbial tower)的形成,所述微生物塔由中间具有水通道的包埋的活菌层构成。在正确的环境条件下,自该生物膜释放出自由漂浮的细菌,并在其他表面继续该循环。
世界上大约80%的微生物生物质处于生物膜状态,并且国家卫生研究院估计75%以上的发生在人体内的微生物感染由生物膜的形成和存留引起。这样的感染包括龋齿、牙周炎、肌肉骨骼感染、骨髓炎、细菌性前列腺炎、心内膜炎、慢性支气管炎和其他慢性下呼吸道炎症疾病、囊性纤维化肺炎(cysticfibrosis pneumonia)、中耳炎、慢性扁桃体炎、增殖腺炎(adenoiditis)和设备感染(device infection)。
尽管似乎看起来生物膜是“仅仅另一种类型的感染”,致病生物膜的行为完全不同于自由漂浮、不产生生物膜之形式的相同细菌。由于完全不同的基因组表达,生物膜相关的感染具有与浮游类型的感染不同的临床病程和抗生素应答。此外,治疗与浮游感染“相同”之生物膜相关感染产生抗生素抗性的“超级病菌(superbug)”,因为由该菌落产生的EPS基质给予该菌落1000倍的抗生素抗性,如果是自由流动的形式,该抗生素通常会杀死这些微生物。
由于抗生素未能铲除这些EPS保护的微生物群落,抗生素的使用实际上使该问题复杂化,因为抗生素选择并保持越来越抵抗抗生素的细菌。这些“超级病菌”包括耐甲氧西林金黄色葡萄球菌(methicillin resistantStaphylococcus aureus,MRSA),其为世界上医院感染(nosocomial infection)的主要原因,并且是目前大多数社区中分布广泛的一种细菌。尽管全球都在无意中产生“超级病菌”,用于治疗致病生物膜相关感染的现代药物却很少。另外,解决该问题的方案不仅仅是开发其他新的抗生素,因为为了避免抗生素抗性的“超级病菌”的长期存在,这样的治疗方法必须具有广谱以及抗生物膜活性。这在真实患者中一次又一次地反映出来,对于他们来说,甚至在MIC测试中被“证明”有效的反复、长期抗生素疗程也通常不成功。
攻击、溶解或以其他方式削弱该生物膜基质、中断维持细菌群落的群体机制(quorum mechanism)以及上调局部宿主先天免疫可治愈以其他方式会变成不可治愈的慢性感染或慢性生物膜相关炎性疾病的疾病。在抗击生物膜诱导的慢性炎症(特别是与“超级病菌”有关的那些)中穿透或驱散该细菌生物膜“装甲(armor)”是至关重要的。
体外抗生素效力测试结果可明显低估了致病生物膜在体内对抗所测试和假定的有效抗生素方面赋予的保护。由于生物膜的保护性能,基于这些结果的抗生素选择可能不相关、令人误解且甚至在临床上有害。的确,甚至在MIC研究中被证明有效的重复、长期抗生素疗程经常在罹患生物膜相关炎性状态的患者中不成功。
生物膜状态下的细菌不仅顽强地抵抗抗生素,它们还抵抗其他抗细菌剂和杀微生物剂(biocide),例如醇、酸和碘溶液。事实上,目前的“抗菌剂(antiseptic)”(例如流行的手部“消毒剂(sanitizer)”)可能是部分问题所在,因为使用这样的杀微生物剂可能实际上提高病理性生物膜在相关表面(例如医疗卫生工作者的手)上的流行率。因此,开发诱导生物膜解离和/或预防生物膜分泌的非抗生素方法是研究越来越多的领域。
然而,并非所有的生物膜都是致病的。胃肠益生菌分泌的生物膜保护黏膜表面免受由形成致病生物膜之生物引起的肠感染。另外,诸如某些乳杆菌属(Lactobacillus)细菌和大肠杆菌(E.coli)的协同益生菌给予宿主其他益处,例如正常的肠蠕动、毒素清除和诸如维生素B12的营养物的高效吸收。此外,从进化的观点看,人体需要益生微生物的定殖以有利于生存。这种互相依赖例示了人宿主与其有益微生物群之间的协同关系。
人宿主将炎性反应作为对病原体入侵和伴随的生物膜形成的正常应答。如果这样的炎性反应持续,对最初正常的免疫应答的这种不适当的过度刺激可导致对人宿主自身的损伤并导致疾病。然而,不同于它们的致病对应物,益生生物维持健康和平衡的免疫应答。换句话说,益生菌维持宿主炎性反应和抗炎反应之间的稳态。
炎症是复杂的现象,涉及白血细胞的募集,流体自毛细血管的漏出以及杀灭入侵微生物所需的化学介质和氧化剂的释放。维持稳态是重要的,因为由宿主产生的炎症可引起对宿主自身的损伤。如果不“关闭”,一旦发生病原体的根除,这些非常相同的过程会引起局部组织损伤、身体伤害并随后引起疾病。
益生生物上调身体对病原体的免疫监视,但是还下调炎性信号。益生菌的这种恒定的平衡作用有助于维持免疫刺激与免疫过度刺激之间微妙而关键的稳态。破坏这种稳态可引起某些具有常见共同慢性炎性状态(如迈博姆腺(meibomian gland)功能障碍和慢性鼻窦炎)的共同的人疾病。
生物膜在所有的医药领域中具有广泛的临床相关性。已知细菌生物膜(例如通常与假单胞菌属(Pseudomonas)细菌和葡萄球菌属(Staphylococcus)细菌相关的那些)是难治性感染以及慢性轻度炎症的诱因。它们由集体分泌并形成细胞外基质材料之保护层的细菌生物菌落组成。细菌生物膜中的该细菌菌落似乎对宿主的天然防御以及抗生素治疗非常抵抗。生物膜几乎定殖于这些菌落可黏附其上的人体内或人体上的任何表面。它们通常定殖于诸如导尿管、经皮静脉导管(transcutaneous intravenous line)和人工心瓣膜的生物材料。
干眼(dry eye)是仅在美国就影响超过1千万人的医学病症。它可能是最常见的眼科病症。它在一般的眼科实践中的频率可高至50%。它源于眼泪的产生和/或组成的缺陷,所述眼泪由眼部的泪腺和附器分泌腺产生的。眼睛依赖于恒定的眼泪流来润滑眼睛表面,维持视力和眼睛的整体舒适度。眼泪由水、油、黏液、抗体和其他蛋白质构成。这些通常都由位于眼睛周围的泪腺和眼睑的迈博姆腺所分泌。当眼泪的量存在不平衡和/或眼泪成分的组成和/或量出现异常时,人可能出现许多不同的干眼症状-视力模糊、眼刺激、发红、发痒、疼痛和眼部的“异物”感。
绝大多数的干眼病症是由于迈博姆腺功能障碍,其与眼玫瑰痤疮(rosacea)、睑炎和眼部变态反应相关。干眼综合征的影响包括对生活质量的显著负面影响、角膜损伤、持续的眼部和眼周炎症以及甚至感染。干眼综合征的共同症状包括干、刮擦感、沙粒感或含沙感、异物感、疼痛或痛苦、刺痛、灼烧、眼睛疲劳、发痒、眨眼频率加快、畏光、视力模糊、发红、排出黏液、对佩戴隐形眼镜的不耐受以及甚至过度流泪。这些症状可能是由许多病症引起的,包括狼疮、类风湿性关节炎、舍格伦综合征(Sjogren’ssyndrome)、正常衰老、隐形眼镜的使用、诸如LASIK的任何角膜手术、糖尿病、任何原因的迈博姆腺功能障碍、解剖异常、长时间使用计算机、和药物,以及其他常见眼部表面病症,如变应性结膜炎。发现在干眼患者的眼部表面上白细胞和细胞因子介质提高,表明有持续的炎症。
通常推荐眼睑和眼部卫生方法以稀释并除去被认为影响慢性眼部和眼周炎症的局部刺激物和炎性化学物质。最常见的推荐包括稀释的婴儿香波眼睑洗涤液(dilute baby shampoo lid scrubs)以及其他非处方洗涤剂。然而,这些产品的抗菌性均不足以在临床相关的暴露次数内杀灭眼睑细菌。
尽管干眼综合征具有很多诱因,干眼综合征与诱因无关的共同病理是由于眼泪的质或量的改变引起的眼部表面上的异常改变。泪液由3层组成-亲水黏液层、含水层和脂质层。紧邻角膜的黏液层由结膜杯状细胞产生并被角膜表面糖蛋白吸收。虽然眼泪产生的量可能正常,黏蛋白本身的缺陷或功能障碍可能导致角膜表面不良的润湿和/或糖化,并因此导致干眼综合征共有的干燥和上皮损伤。形成大部分眼泪容积的含水层由泪腺分泌且邻近黏液层。该含水组分的高容积和可扩散性将营养物和氧递送至角膜,所述角膜本身不以别的方式接受大量的血液和营养物流。最后一层是由眼睑的迈博姆腺、蔡斯腺(Zeiss gland)和莫尔腺(Moll gland)分泌的脂质层。该层中的脂质通过降低含水流体的表面张力、允许泪液在眼部表面的高效扩散并减缓眼泪含水层的蒸发而发挥表面活性剂和润滑剂的作用。因为泪腺和迈博姆腺具有雄激素受体,低雄激素状态可引起该脂质层的异常,加速眼泪蒸发并导致干眼。
干眼综合征还可通过最受影响的泪液的组分来表征。因此,干眼综合征可以分为润滑剂缺乏型干眼、含水泪液缺乏型干眼和蒸发型干眼。润滑剂缺乏型干眼涉及眼泪黏蛋白层的异常。黏蛋白层可以被许多病症破坏,包括变应性结膜炎、直接化学刺激(例如滴眼液中的防腐剂)、挥发性黏膜刺激物、病毒感染、热损伤和营养/代谢病症(如维生素缺乏症和蛋白质营养不良)。
含水泪液缺乏型干眼是由于泪腺分泌的含水层的功能或量的异常引起的。泪液缺乏可以由许多全身病症引起,如舍格伦综合征、舍格伦病(Sjogren’sdisease)、狼疮、类风湿性关节炎和糖尿病以及与泪腺萎缩相关的正常衰老过程。其他诱因包括眼部化学刺激物、泪腺损伤、病毒感染、绝经期和药物如利尿药、抗组胺药、口服避孕药或激素治疗、降压药、抗抑郁药和全身性血管收缩剂。
蒸发型干眼是由于脂质层的异常。由于脂质层不能充当有效的表面活性剂和润滑剂(emollient),它引起泪液层的过度蒸发。最常见的是,蒸发型干眼是由于迈博姆腺功能障碍、环境条件(空气传播的刺激物、低环境湿度、高环境温度)和使用计算机,所述使用计算机显著降低正常的眨眼频率,引起泪液自角膜表面更迅速的蒸发。
除了泪液层的异常,干眼还有其他诱因。这些诱因包括解剖学(如格雷夫斯病(Grave’s disease)中见到的眼表面的过度暴露,与正常衰老相关的眼睑的外翻)和神经的诱因。眼部表面的神经刺激通常引起对泪腺的直接反馈,然后泪腺在应答中适当地调整分泌。这种神经反馈被影响眼部感官的周围神经损伤、脑血管意外或者更常见的LASIK角膜手术所抑制。眼部和眼眶手术可能仅仅由于仪器对组织的物理作用和手术创伤而引起干眼综合征。此外,诸如亚油酸的必需脂肪酸(EFA)的异常比例和/或量以及ω-3和ω-6EFA之间的不平衡可引起眼部表面炎症和干眼。长时间使用隐形眼镜可由于机械干扰营养物和氧的正常分布以及通常发生于隐形眼镜本身的物质的慢性沉积而引起干眼。这些微凝结物(microconcretion)成为假单胞菌和葡萄球菌的细菌生长和致病生物膜产生的场所(nidus)以及对角膜上皮的持续的微创伤的原因。
无论眼部表面失调的具体原因如何,眼部表面的慢性炎症是最终结果。先天免疫系统似乎是该过程的主要发起者。在任何原因的干眼综合征中,均出现诸如结膜CD4 T细胞和角膜CD11b+单核细胞之免疫细胞的低水平、持续的眼部表面和眼部周围浸润。由眼部表面干燥诱导的局部组织应激诱导分泌诸如IL-1、TNF-α和IL-6的炎性细胞因子。这些物质激活附近的抗原呈递细胞(antigen presenting cell,APC),所述抗原呈递细胞继而引起产生IL-17的Th17细胞和产生IFN-γ的Th1细胞的膨胀。复杂的细胞因子IL-17和IFN-γ通过提高白细胞至眼部表面的迁移而使炎性反应持续。随着时间的延长,这种低水平的炎症可使得眼睛更易遭受细菌、病毒和其他感染。
虽然普通人群中慢性干眼综合征的高频率建立了持续的需求,目前却没有针对该病症的特别有效的治疗。非处方治疗提供短暂的症状缓解,且未能解决眼部炎症的潜在问题。的确,使用这些产品经常加重干眼本身。由于长期暴露于这些化学物质引起的角膜损伤,人工泪液中的眼用防腐剂经常使干眼综合征恶化。过度使用“使发红消退(get the red out)”的局部血管收缩剂也可能加速角膜炎症。在处方药分类中,在过去的十年里,只有一种不属于人工泪液之类别的新产品曾在美国被批准用于治疗干眼-即Restasis(环孢素)。局部环孢素非常昂贵,并且具有显著的副作用谱,并且具有仅为15%的较差临床应答率。因此,缓解眼睛的干燥、刺激和/或发炎的症状目前限于补充眼液(即使用人工泪液),使用泪点塞(punctal plug)以降低进入鼻泪管的泪液损失的手术治疗,使用有潜在危险的药物或治疗性眼用装置如“湿度室眼镜(moisture chamber spectacles)”和治疗用隐形眼镜。然而,这些方法成本高、不灵便,可进一步使眼部病理学持续,而且仅部分地有效。
目前的药物开发集中于几种新的药品。有一些证据表明局部激素治疗可以帮助缓解慢性干眼。在酝酿中的还有修饰的环孢素、局部甾体和非甾体抗炎剂、口服a-3腺苷受体激动剂、被称为消退素(resolvin)的合成抗炎分子、抗LFA-1化合物、促炎白介素拮抗剂、免疫抑制性单克隆抗体、局部抗生素、化学促分泌素(secretagogue)和含有透明质酸的人工泪液溶液。然而,除了最后一种,所有这些都是昂贵的药品,而且透明质酸滴剂发挥类似于已上市的人工泪液的作用。二级治疗已经包括局部抗生素治疗以解决与干眼相关的常见的轻度感染。尽管干眼的频率不高,但普遍接受的治疗仍然不够,如该领域中当前广泛的研究和持续的药物开发所证明的那样。当前的研究努力集中于开发合成的免疫调节药物—没有新的非处方眼用抗炎化合物存在或已知处于计划中。
乳杆菌属(Lactobacillus)细菌提取物之前已用于化妆品应用(US专利申请号11/70/810,L’Oreal专利,WO9907332,JP 3112983,JP 2002037739)。然而乳杆菌属以前尚未用于治疗干眼。蜂蜜也已用于化妆品应用以治疗慢性皮肤炎症和/或感染。然而,蜂蜜以前尚未用于治疗干眼。
在本发明之前,治疗慢性鼻窦炎通常包括长期且重复的抗生素、鼻内及全身皮脂类固醇和甚至耳鼻喉科外科手术。然而,即使慢性鼻窦炎越来越被认为是生物膜相关疾病,也还没有针对该病症的生物膜组分本身的治疗。在本发明中提出的用于干眼综合征的相同种类的溶液还可应用于治疗慢性鼻窦炎或缓解其症状。
与慢性鼻窦炎类似,慢性牙周炎在普通人群中也很普遍。伴随着基因和环境因素,牙菌斑生物膜是慢性牙周疾病的发展所必需的。即使此时没有足够的证据建立因果关系,许多研究已经表明口腔疾病与心脏疾病中动脉粥样化形成之间明确的平行关系。不过,治疗口腔疾病导致如诸如hsCRP的炎性标志物所反映出的全身炎性负荷的降低和内皮功能的提高。然而,目前可用于慢性牙龈和牙周疾病的仅有的治疗是清创术和全身应用或龈下施用的抗生素。然而,如上所述,抗生素对致病生物膜的效果通常较差。
其他普遍的慢性炎性疾病涉及呼吸道。这些病症包括变应性鼻结膜炎、慢性支气管炎和哮喘。已经清楚地确定诸如囊性纤维化和曲霉病的较不常见的病症涉及诸如假单胞菌和曲霉属真菌生物膜的生物膜,引起显著的发病率和死亡率。所有这些病症的治疗包括类固醇和全身性抗生素和抗真菌剂。具体地,有时候大环内酯类抗生素是具有免疫调节特性的抗生素,可以有益于患有与慢性炎症相关的呼吸道疾病,这部分地因为它们可以降低生物膜形成。然而,此时除了抗微生物剂或类固醇,没有其他的非侵入性治疗选择。
目前的抗生素明确且反复地表明确实无法治疗生物膜相关的感染。此外,本身没有公知的或被证实的抗生物膜治疗。治疗致病生物膜形成的假定的继发感染的尝试包括反复的长期抗生素治疗,物理地除去生物膜(即手术或清创术)和局部灭菌剂,如基于醇的泡沫或用于手部清洁的凝胶。这些治疗不仅不能恢复正常的生理学,它们还破坏先天免疫的稳态-抗生素培育越来越有抗性的“超级病菌”,手术或清创术引起解剖学上的伤口,所述伤口创造了另一个潜在的感染部位,并且局部消毒剂可以通过根除正常的共生体和病原体而支持致病生物膜的发展和生长。
有可能目前的抗感染剂无法治疗世界上的许多感染,因为这样的治疗无法治疗生物膜组分,并且事实上,可能甚至引起提高的致病生物膜生长和恶化的感染。此外,生物膜本身的形成和附着可以产生使得该特定病原体引起感染的机会窗(windows of opportunity)。为了有效,必须使治疗靶向病原体生物膜破坏,必须支持而不是妨碍正常的先天免疫,而且应当中断负责维持致病生物膜的细胞密度感受机制。
在眼领域中,如果能够使用安全、廉价和局部施用的化合物而不是抗生素、合成免疫调节剂或全身递送的化合物直接在眼部表面上引起抗炎和/或抗生物膜效果,则会非常有用。可进一步限制或甚至避免使用大多数滴眼剂中存在的化学防腐剂也会非常有用,因为这些化学物质本身可恶化眼部表面炎症。
目前,没有可用于在具有干眼综合征、干眼和/或慢性发炎的、发红的或受刺激的眼的症状的个体眼部表面上引发抗炎和抗生物膜效果的方法或治疗。此外,亟需可潜在地治愈抗生素抗性的“超级病菌”感染而不保持抗生素抗性的全球问题的非抗生素、非侵入性抗生物膜治疗。另外,诸如抗生素或手术治疗的当前治疗具有明显的相关副作用、成本和治疗失败以及对包括“未涉及”区域在内的身体其余部分的影响。
还会期望直接施用于致病生物膜感染的区域的治疗,包括诸如人黏膜以及角质化和非角质化的上皮的表面。这样的局部施用技术会避开全身毒性,因为它们明显地通过局部(皮肤药物、鼻喷雾剂、口腔吸入器或喷雾器、滴眼液、口服含片等)递送体系来施用。还期望治疗会是廉价且安全的,例如,期望治疗由天然的、通常被认为安全的(generally regarded as safe,GRAS)衍生物/非药物成分构成。最后,如果可将抗生物膜化合物施用至惰性表面(即医院设备、飞机盘桌(tray table)、学校课桌)以在整体上限制医院/临床环境以及社区中致病生物膜的扩散/存在会是有用的。
发明概述
本发明提供了使用容易获得的、无毒的天然物质有效地支持先天免疫和/或驱散致病生物膜、同时支持正常的微生物稳态之恢复的材料和方法。
可通过直接施用将本发明的组合物递送至受影响组织,显著提高效力和安全性。由于直接将该组合物施用至受致病生物膜影响的区域,包括诸如人黏膜以及角质化和非角质化的上皮的表面,它直接解决了目前对于非侵入性抗生物膜治疗的需求。
这样的局部导引治疗的实例包括皮肤药物、鼻喷雾剂和鼻洗液、滴耳剂、口腔吸入器或喷雾器、滴眼液、隐形眼睛、隐形眼镜溶液、口服含片、洁齿剂(dentifrice)(例如漱口剂、牙膏、牙线(floss)、牙周治疗等)。在每种实例中,经由载剂施用本发明的组合物,基于解剖学施用的区域,所述载剂的组成在生理学上是适当的。
基于所涉及的解剖学区域,本发明还可以使用分两步或更多步的施用方法,例如局部施用第一组合物以减少病理性生物膜,然后施用第二组合物以促进正常共生细菌的稳态的恢复。
本发明的组合物还可以施用至惰性表面(例如医院设备、飞机盘桌、学校课桌)以在整体上限制环境以及社区中致病生物膜的扩散/存在。
本发明的另一优势在于其组分的已确立的安全性。本文所述的组合物由已经各自被确定为安全的组分构成。在优选的一些实施方案中,本发明的组合物包含天然的、通常被认为安全(GRAS)的成分的混合物。
本发明的另一优势在于其与抗生素组合的潜力。由于本发明具有抗生物膜作用,它使得潜在的生物膜相关的感染容易受通常在生物膜治疗中无效的抗生素的影响。本发明还允许以较低的量使用抗生素,从而降低毒性以及治疗花费,因为本发明使潜在的病原微生物对抗生素的抗微生物机制“敏感”。
本发明组合物的许多但非全部的实施方案共有的一些成分包括单独使用或者与活的或死的益生微生物或其他微生物(包括细菌、真菌和诸如钝顶节旋藻(螺旋藻)(Arthrospira(Spirulina)platensis)的蓝细菌)组合使用的微生物代谢物、细胞和/或非细胞级分、以及药用级蜂蜜。可以在某些实施方案中使用的其他成分包括但不限于诸如松胶(larch gum)或阿拉伯胶的益生元(prebiotic)化合物,诸如蜂王浆(royal jelly)、蜂粮(bee bread)和蜂胶(propolis)的其他蜂巢产品,诸如茶素没食子酸酯(epigallocatechin gallate,EGCG)和L-茶氨酸(L-theanine)的绿茶衍生物,来自例如土木香(Inulahelenium)、互叶白千层(Melaleuca alternifolia)和麦卢卡树(Leptospermumscoparium)的其他植物衍生物,以及水溶性和水不溶性的维生素D3。
有利地,在优选的实施方案中,本发明组合物的成分相互合作以抑制生物膜相关的感染,同时通过促使致病生物膜消散以及提高正常的局部先天免疫应答而改善相关的慢性炎症病症。
在眼部及附件组织施用的领域中,本发明组合物可用于治疗潜在的与干眼综合征相关的炎性过程。眼部表面上或附近的致病生物膜的后遗症可引起慢性眼部轻度炎性病症,包括干眼综合征。本发明提供了用于治疗干眼综合征的症状和诱因的组合物。具体地,这些组合物抑制致病生物膜生长并在眼部/附件表面上产生整体的抗炎作用。
这样的眼部及附近表面的局部治疗改善了眼部-附件区域病原体与有益微生物群落之间的稳态。对病原体与非病原体或甚至有益生物之间的再平衡或对其进行的调整改善了眼睛的慢性发干、刺激、发红或发炎的症状。这样的改善可由本发明的实施方案引起,其包含局部施用的活的或死的微生物和/或它们的提取物以及具有抗生物膜作用的药用级蜂蜜的混合物。另外,可以根据本发明使用诸如L-茶氨酸、维生素D3、益生元多糖和海洋生物螺旋藻的其他化合物治疗与病理性生物膜相关的病症。
本发明部分地基于对慢性眼部炎性状态(具体地为干眼综合征)中生物膜的角色的认识。眼部和附件微生物组的功能是“加强”局部先天免疫系统并保护定殖表面。共生的微生物群落与眼部黏膜和免疫上皮细胞之间的串话有助于维持眼部表面稳态和眼部表面健康。定殖于眼部表面的共生体包括诸如葡萄球菌属(Staphylococci)细菌、棒状杆菌属(Corynebacterium)细菌、链球菌属(Streptococcus)细菌和丙酸杆菌属(Proprionibacterium)细菌的多种微生物。该微生物组(microbiome)保持相对稳定,除非被打破。然而,有许多常见情形可能影响健康的眼部和眼周微生物组平衡一抗生素和其他药物、隐形眼镜、睑炎、迈博姆腺功能障碍、眼玫瑰痤疮或眼部慢性刺激和/或眼部干燥的其他诱因。当正常的眼部和眼周微生物群被任何数量的可能的常见诱因干扰时,产生眼部表面刺激、炎症和不适感。
施用本文所述的局部施用的混合物引起眼部表面和周围区域的炎症的降低。由于干眼疾病的许多不相干诱因与慢性炎症的相同的免疫发病机理合并,本发明可被一般大众用于眼睛慢性发干、发红、刺激和/或发炎的症状改善。
除了治疗干眼之外,本发明的组合物可用于预防和/或破坏存在于多种其他慢性炎性状态中、与多种其他慢性炎性状态相关或引起多种其他慢性炎性状态的病理性生物膜和/或慢性感染,所述多种其他慢性炎性状态例如慢性鼻窦炎,慢性牙周炎,慢性支气管炎和包括曲霉病、囊性纤维化和哮喘在内的其他呼吸道炎症状态,诸如“游泳者耳病(swimmer’s ear)”、外耳炎和慢性耳炎的炎性耳部病症,以及诸如特应性皮炎和湿疹的炎性皮肤病症。这些病症的病理生理学可能涉及通过致病物种和致病生物膜形成而破坏正常的共生菌群。本发明改善与这些病症和潜在的炎性状态相关的症状。
发明详述
本发明提供了使用容易获得的、无毒的天然物质有效地支持先天免疫和/或驱散致病生物膜、同时支持正常的微生物稳态之恢复的材料和方法。
本发明的许多但非全部的实施方案共有的要素包括一种或更多种益生生物(例如嗜酸乳杆菌(Lactobacillus acidophilus)、酿酒酵母(Saccharomycescerevisiae)或大肠杆菌的生物)、其一部分和/或其代谢物与具有抗生物膜作用的抗微生物蜂蜜的组合,所述抗微生物蜂蜜例如麦芦卡蜂蜜(Medi-Honey,Comvita,新西兰,或通过验证15kGy保健品用辐照灭菌剂量的ISO11137-2a 2006,Food Technology Service Incorporated,Mulberry,Florida灭菌的麦芦卡蜂蜜)。
可以在其他但不一定所有的实施方案中使用的其他要素包括诸如松胶或阿拉伯胶的益生元化合物,诸如蜂王浆、蜂粮和蜂胶的其他蜂巢产品,诸如茶素没食子酸酯(EGCG)和L-茶氨酸的绿茶衍生物,来自例如土木香和麦卢卡树的其他植物衍生物,以及维生素D3。
本发明最一般的形式提供了包含活性组分之混合物的组合物,可以将所述组合物本身添加至适合于施用部位的任何载剂。
本发明的该具体实施方案与在其施用中所用的载剂或载体无关。例如,这样的实施方案可以被用作“成分”,可以将其添加至其他已存在的或目前尚未开发的产品。本发明的这种“成分”形式的一种配方包含药用级蜂蜜和益生生物,例如:
配方1:100B CFU冻干的*嗜热链球菌(S.thermophilus)+100μL蜂蜜=1B CFU/ml 100%蜂蜜
配方2:250μL 100B CFU/ml*嗜热链球菌+500μL蜂蜜=25B CFU/ml75%蜂蜜
配方3:500μL 100B CFU/ml*嗜热链球菌+500μL蜂蜜=50B CFU/ml50%蜂蜜
配方4:750μL 100B CFU/ml*嗜热链球菌+250μL蜂蜜=75B CFU/ml33%蜂蜜
配方5:900μL 100B CFU/ml*嗜热链球菌+100μL蜂蜜=90B CFU/ml10%蜂蜜
*特定菌株嗜热链球菌ATCC BAA-250;然而,可以替换为其他菌株。
在添加益生菌之前,可以将诸如Medi-Honey(Comvita Inc.,新西兰)的经γ辐照的蜂蜜或经滤过灭菌的蜂蜜不经稀释地使用,或在无菌的生理盐水溶液中稀释至不同的终浓度。可以使用诸如冷冻干燥的嗜热链球菌(NCFB2393或LMG 183ll或ATCC BAA-250)的生物并将其添加至100%蜂蜜或蜂蜜-上述盐溶液以获得终浓度为1000亿CFU/ml的混合物。
本发明的这种“成分”形式的另一种配方包含来源丰富的源自益生生物的1mg或更多的生物表面活性剂。收率随着生物菌株类型和培养条件而变化。可以将这种生物表面活性剂级分稀释在标准的PBS溶液中以改变生物表面活性剂浓度。例如:
配方6:1000μg**嗜热链球菌生物表面活性剂在1000μL***PBS中,用于1mg/ml稀释
配方7:500μg**嗜热链球菌生物表面活性剂在1000μL***PBS中,用于0.5mg/ml稀释
配方8:500μg**嗜热链球菌生物表面活性剂在250μL***PBS中,用于2mg/ml稀释
配方9:500μg**嗜热链球菌生物表面活性剂在100μL***PBS中,用于5mg/ml稀释
配方10:10mg**嗜热链球菌生物表面活性剂在1mL***PBS中,用于10mg/ml稀释
*生物表面活性剂分离方法的实施方案在下文中描述。
**特定菌株嗜热链球菌ATCC BAA-250;然而,可以替换为其他菌株。
***可以用诸如Medi-Honey的蜂蜜或具有抗生物膜特征的蜂蜜代替无菌的标准PBS溶液。每一种这样的溶液可以根据需要进一步稀释。
可以将本发明的组合物直接施用至所涉及的区域,如人黏膜、角质化或非角质化的上皮表面。这种技术降低或消除全身毒性,因为施用是局部进行的(皮肤药物、鼻喷雾剂、口腔吸入器或喷雾器、滴眼液、口服含片等)。
此外,基于所涉及的解剖学区域,本发明可以使用分两步或更多步的施用方法,即,局部施用第一制剂以减少病理性生物膜,然后施用第二制剂以辅助恢复正常的共生细菌稳态。
本发明的多种实施方案包括眼部滴剂、凝胶、软膏、乳膏或适于向施用区域递送活性化合物的其他载剂、眼周洗剂、凝胶、软膏、乳膏或适于向施用区域递送的其他载剂、鼻内含水或非含水喷雾剂、鼻腔盐水冲洗剂(nasalsaline rinse)、皮肤皂、洗剂、乳膏、润肤剂和溶液(如用于隐形眼镜清洗及维护的溶液)或喷雾剂。
可以通过使用Calgary Biofilm Device(FDA Class I批准的用于生物膜接种的装置)(US专利号6599714,通过引用并入本文)进行MBEC(最低生物膜清除浓度)程序或者用于评价抗生物膜效力的其他手段评价本发明的成分、提取物和/或混合物的抗生物膜效力。这可以包括下文详细描述的方法。可采用的其他抗微生物测试包括:琼脂或纸片扩散技术(disk-diffusiontechnique)、Kirby-Bauer测试和最低抑制浓度(MIC)。这些技术是本领域技术人员公知的,在此将不详细叙述。试验方案可以见于John Lammert的“Techniques in Microbiology”,Pearson Education,2007和George A.Wistreich的“Microbiology Laboratory Fundamentals and Applications”,Pearson Education,2003,其通过引用整体并入本文。
目前的高通量抗生物膜效力测试基本上限于一种测试,即MBEC测试(见上文,U.S.专利号6,599,714)。该具体测试具有许多限制,包括不可再用性和测试板的费用以及缺乏围绕每一单独的桩(生物膜应在其上生长)的有效剪切力。没有足够的剪切力,不能刺激发生强的生物膜形成并且不可能接近真正的体内生物膜条件。
然而,微生物的生物膜可以在旋转管反应器体系中在诸如球(sphere)的相对无孔的介质上生长。这种无孔的介质可以以无菌的5mm玻璃球为代表。反应器容器可以是无菌的50ml管状聚苯乙烯Falcon管或放置在摇床上的类似的柱。该管或柱可以具有防水的顶部,使得机械旋转器上的旋转不引起容器内容物的溢出(即通过螺旋盖、橡胶塞或软木塞保护内容物)。可以通过具有开放网格(open mesh)的可热压塑料塞将球固定在管或柱的一端。每一管或柱含有足够的开放空间,使得当将该装置机械地旋转时,产生冲洗作用以向黏附至球表面的细胞生物提供剪切力而不在封闭体系内的介质上产生真空或静电效应。经由过滤泵循环的诸如管入口和管出口的装置允许使用无菌的镊子或类似装置对单独的球进行介质替换和防腐剂去除。循环生物生长介质可以通过膜过滤灭菌。可以通过多种显微染色技术进行在球上生长的足够的生物膜形成的阳性测定。
已在球上生长的生物膜可以针对放置在细菌敏感性孔中的一系列抗微生物剂进行测试。使用孔板或类似的装置创建小的标准的琼脂菌苔(agarlawn)。该技术是本领域技术人员公知的,在此不详细叙述。试验方案可见于John Lammert的“Techniques in Microbiology”,Pearson Education,2007和George A.Wistreich的“Microbiology Laboratory Fundamentals andApplications”,Pearson Education,2003,其通过引用整体并入本文。制备琼脂,将其高压灭菌并等分后装入消毒容器中,与不同浓度的测试抗微生物剂混合并冷却。琼脂固化后,从琼脂菌苔中打出圆形孔,其尺寸等于生物膜球的尺寸。然后将球放在所述孔中。
将含有所述孔和被生物膜包被之球的板盖上盖并在湿润恒温器中在适合于所研究的特定生物的条件下孵育。抗生物膜效力的程度通过直接观察特定孔周围的细菌生长来判断,即,生长的直径越小,该特定化合物的抗生物膜效力越大。或者,可以通过由转化混合在琼脂介质中的某些着色剂以增强生物膜生长的可视化产生的颜色改变来测量抗生物膜效力的程度。
可通过进行用于相同抗微生物化合物和所测试的微生物的最低抑制浓度(MIC)测试将抗生物膜效力(生物膜抑制浓度或BIC)与浮游效力(planktonic efficacy)直接比较。此外,可使用类似于麦芦卡因子(Molan,Peter,“Method for the assay of antibacterial activity of honey(蜂蜜的抗菌活性的测试方法)”,2005,通过引用并入本文)的分类体系测量抗生物膜效力,除此之外,在这种情况下,所测量的是完全生物膜生长抑制的尺寸(生物膜抑制浓度,或BIC),而不是诸如蜂蜜的混合物的抗微生物物质的杀灭直径(“抑制带”)。该方法将用于开发包括蜂蜜在内的个体化合物对一系列细菌的BIC标准,以及化合物在一起的复合物对细菌组的BIC标准,所述细菌组例如革兰氏阴性细菌、对甲氧西林敏感的和耐甲氧西林的葡萄球菌等。
在本发明的另一高通量变化形式中,可以将如上所述的被生物膜包被的球直接放入96孔板中并用一系列抗微生物化合物和/或浓度进行处理。可以通过超声处理从这些球中除去生物膜,并通过平板接种和分光光度法对所得上清液进行解释,其方法类似于MBEC法(见前述引用)中所述的方法。
在培养用于本发明的任何生物期间,可以使或不使培养物生长至最大平台生长期(此时可以以最大生物膜产生来收获它们)。
在某些实施方案中,生物的细胞或非细胞级分或提取物或者它们的细胞外环境(例如生物膜衍生物本身)可具有可能甚至比该级分本身的来源更有效的特定抗生物膜和/或抗炎效力。
本发明的生物膜抑制组合物
可以以多种形式制备本发明的成分,所述形式包括但不限于粉末、悬浮液和溶液。此外,可作为冻干粉末或培养物上清液和/或如果适当的话以浓缩形式制备诸如益生菌的多种成分。
在某些实施方案中,治疗组合物包含至少一种益生生物,其浓度为(BCFU/组合物重量)至少约0.001B CFU/g、0.005B CFU/g、0.01B CFU/g、0.05B CFU/g、0.1B CFU/g、0.5B CFU/g、1B CFU/g、5B CFU/g、10B CFU/g、50B CFU/g、100B CFU/g或500B CFU/g。
在某些实施方案中,治疗组合物包含至少一种益生生物,其浓度为(BCFU/组合物重量)不大于约0.05B CFU/g、0.1B CFU/g、0.5B CFU/g、1BCFU/g、5B CFU/g、10B CFU/g、50B CFU/g、100B CFU/g、500B CFU/g或1000B CFU/g。
在某些实施方案中,治疗组合物包含益生微生物,其浓度范围为(B CFU/组合物重量)约0.001B CFU/g至100B CFU/g、0.1B CFU/g至90B CFU/g、5B CFU/g至80B CFU/g、10B CFU/g至70B CFU/g或30B CFU/g至50BCFU/g。
在某些实施方案中,治疗组合物包含以下浓度(成分重量/组合物重量)的成分:至少约1μg/g、5μg/g、10μg/g、20μg/g、50μg/g、0.1mg/g、0.5mg/g、1mg/g、5mg/g、10mg/g、50mg/g、100mg/g或500mg/g,其中所述成分选自微生物提取物、化学取代基(chemical substituent)、细胞或非细胞组分和/或益生微生物的代谢物、蜂蜜、蜂巢产品、生物表面活性剂、益生元、植物提取物和维生素D。
在某些实施方案中,治疗组合物包含以下浓度(成分重量/组合物重量)的成分:不大于约10μg/g、50μg/g、0.1mg/g、0.5mg/g、1mg/g、10mg/g、50mg/g、100mg/g或500mg/g,其中所述成分选自微生物的提取物、化学取代基、细胞或非细胞组分和/或益生微生物的代谢物、蜂蜜、生物表面活性剂、益生元、植物提取物和维生素D。
在某些实施方案中,所述成分选自益生微生物、化学取代基、细胞或非细胞组分和/或益生微生物的代谢物。
在一个实施方案中,治疗组合物的pH为5.0以上、5.5以上、6.0以上、6.3以上、6.5以上、6.7以上或7.0以上。在一个实施方案中,治疗组合物的pH为9.0以下、8.5以下、8.0以下、7.7以下、7.5以下、7.3以下或7.0以下。
确认生物膜抑制活性
有利地,本发明的某些组合物可预防或抑制致病生物膜的形成。此外,本发明的某些组合物可降低、控制或清除已存在的致病生物膜。
本发明的组合物可通过多种机制预防或抑制致病生物膜的形成,和/或降低、控制或清除已存在的致病生物膜,所述机制包括预防、抑制和/或破坏生物膜或病原微生物向生物或非生物表面的沉积、黏附和/或锚定;预防、抑制和/或破坏诸如胞外多糖(EPS)基质的细胞外因子的分泌和/或释放;和/或预防、抑制和/或破坏细胞密度感受机制。
在一个实施方案中,本发明提供了用于选择本发明的组合物的一种或更多种成分的方法,其中所述成分通过预防和/或抑制目的病原微生物形成生物膜,其中该方法包括以下步骤:
a)提供候选成分或候选成分的混合物,其中所述候选成分选自微生物、微生物的提取物、化学取代基、细胞或非细胞组分、微生物的代谢物、蜂蜜、蜂巢产品、生物表面活性剂、益生元、植物提取物和维生素D;
b)将所述候选成分与目的病原微生物相接触;以及
c)如果所述成分通过预防或抑制目的病原微生物形成生物膜,则选择该候选成分。
在测试用于预防生物膜的一个实施方案中,所述目的病原微生物处于浮游状态。
在另一个实施方案中,在一系列浓度和/或pH下孵育一种或更多种候选成分与目的病原微生物以确定预防或抑制生物膜形成的最佳浓度和/或pH。
在另一个实施方案中,所述方法包括确定本发明的所选择的成分、所选择的成分的混合物、和/或组合物的最低生物膜抑制浓度。
在一个实施方案中,所述候选成分选自益生微生物、益生微生物的提取物、化学取代基、细胞或非细胞组分、以及益生微生物的代谢物。
在一个实施方案中,所述益生微生物选自气球菌属(Aerococcus)、大肠杆菌、芽孢杆菌属(Bacillus)、肠球菌属(Enterococcus)、梭杆菌属(Fusobacterium)、乳球菌属(Lactococcus)、明串珠菌属(Leuconostoc)、蜜蜂球菌属(Melissacoccus)、微球菌属(Micrococcus)、酒球菌属(Oenococcus)、芽孢乳杆菌属(Sorolactobacillus)、链球菌属、葡萄球菌属、酵母属(Saccharomyces)、片球菌属(Pediococcus)、消化链球菌属(Peptostreptococcus)、丙酸杆菌属(Proprionebacterium)和魏斯氏菌属(Weissella)。在另一个实施方案中,所述微生物选自表1。
在优选的一些实施方案中,病原微生物或生物膜选自耐甲氧西林金黄色葡萄球菌(MRSA)、金黄色葡萄球菌、表皮葡萄球菌(S.epidermidis)、铜绿假单胞菌(Pseudomonas aeruginosa)、假单胞菌属(Pseudomonas)、流感嗜血杆菌(Haemophilus influenza)、棒状杆菌属(Corynebacterium)、念珠菌属(Candida)或曲霉属(Aspergillus)。
与生物膜感染相关疾病的诊断和治疗
在一个实施方案中,本发明提供了预防和/或治疗由生物膜引起或与生物膜相关的疾病的方法。在一个实施方案中,该方法包括对需要这样的治疗的个体施用有效量的本发明的组合物。
本文所用的术语“治疗(treatment)”或其任何语法变体(例如治疗(treat)、治疗(treating)和治疗(treatment)等)包括但不限于缓解或减轻疾病或病症的症状,减轻、压制、抑制、减小或影响病症的进展、严重程度和/或范围。
本文所用的术语“预防(prevention)”或其任何语法变体(例如预防(prevent)、预防(preventing)和预防(prevention)等)包括但不限于推迟症状的发作,预防疾病的复发,延长症状发作之间的潜伏期,或其组合。本文所用的预防不要求完全无症状。
本文所用的术语“有效量”是指可预防、缓解和/或治疗与生物膜相关的病理病症。
在一个实施方案中,“有此治疗需要的个体”是指经诊断患有与生物膜相关的病理病症的个体。在一个具体的实施方案中,本发明包括诊断个体是否具有生物膜感染,其中然后向该经诊断患有生物膜感染的个体施用本发明的组合物。
可通过例如美国专利申请公开No.2010/0285496中描述的临床技术来实现生物膜感染的诊断。可通过诸如X-射线和CT扫描的成像技术来确定致病生物膜感染的位置。
在一个实施方案中,可如下检测生物膜感染:
a)从对象获得生物样品;以及
b)测量一种或更多种生物标志物(例如,蛋白、mRNA)的存在,所述生物标志物由生物膜状态而非自由漂浮(浮游)状态的微生物选择性地表达。
此外,可通过测量与自由漂浮(浮游)状态相比,生物膜状态的微生物以高水平表达的一种或更多种生物标志物的存在来检测生物膜感染。在另一个实施方案中,可通过细菌细胞外多糖(EPS)基质或EPS中含有的化学物质的存在来检测生物膜感染。
另外,可通过例如使用识别由病原微生物释放的抗原或肽的抗体或者使用识别病原微生物之核酸分子的探针来确定形成生物膜的病原微生物。
本文所用的术语“生物样品”包括但不限于含有从对象分离之组织、细胞和/或生物流体的样品。生物样品的实例包括但不限于组织、细胞、活检、血液、淋巴、血清、血浆、尿、唾液和眼泪。在某些具体的实施方案中,生物样品包括眼泪、鼻液(nasal fluid)和唾液。
可通过本领域已知的技术确定可根据本发明使用的生物标志物的存在和/或水平,例如酶联免疫测定(ELISA)、Western印迹、Northern印迹、免疫学测定、免疫荧光和核酸杂交技术。
与生物膜感染相关的疾病
在某些实施方案中,本发明可用于预防、治疗或缓解由生物膜感染引起或与生物膜感染相关的疾病,包括但不限于皮炎、痤疮、慢性支气管炎、囊性纤维化、慢性龈炎、慢性炎性肠疾病、慢性湿疹、慢性无法治愈伤口、慢性膀胱炎和与诸如隐形眼镜的医学设备相关的炎症。本发明人还发现生物膜感染引起诸如以下的疾病或与所述疾病相关:慢性睑炎和眼、眼周和皮肤上皮的其他慢性炎性病症如干眼综合征、迈博姆腺炎(meibomianitis)和玫瑰痤疮。
在一个实施方案中,本发明可用于预防、治疗或缓解涉及生物膜的耳鼻喉科实践(otolaryngology practice)中的病症,包括中耳炎、慢性鼻窦炎、慢性扁桃体炎、腺样体炎以及耳蜗和中耳植入设备故障。尽管需要改进的治疗方法,诸如机械破坏(即,受感染物质的去除或手术切除)或长期抗生素治疗的现有技术的方法仍然是治疗由生物膜引起的慢性炎性状态的中流砥柱。
本发明人发现某些眼和眼周感染由生物膜相关的慢性炎性状态引起。例如,在眼科领域中,在白内障手术后的眼内炎方面,视网膜脱离手术、泪点塞、人工鼻泪管植入后的巩膜扣带术(sclera buckle)方面,在角膜炎相关的软质隐形眼镜方面,已经报道了生物膜的存在。事实上,尽管使用了杀微生物剂,在所有的隐形眼镜病例中接近81%、隐形眼镜中接近50%以及所有的隐形眼镜溶液中接近30%出现微生物污染。与细菌生物膜形成相关的感染倾向于顽固持久,并且最常自生物膜中分离的生物是金黄色葡萄球菌、表皮葡萄球菌和铜绿假单胞菌。与通常在正常眼中发现的革兰氏阳性共生菌相比,干眼的眼部表面以及慢性睑炎和隐形眼镜佩带者的眼睑边缘被显著更多的细菌和显著更多的革兰氏阴性细菌定殖。
在一个实施方案中,本发明可用于预防、治疗或缓解慢性鼻窦炎,其为与致病生物膜形成相关的慢性炎性状态的另一个实例。慢性鼻窦炎的病理生理学可能涉及病原体对正常的共生细菌群的破坏和随后的致病生物膜形成。所引起的一般症状包括流鼻涕(nasal dripping)、窦内压(sinus pressure)、复发性头痛、后鼻滴流(post-nasal drip)和咳嗽。
在某些实施方案中,本发明可用于预防、治疗或缓解由生物膜感染引起或与生物膜感染相关的疾病,其包括但不限于哮喘、曲霉病、“游泳者耳病”、外耳炎、慢性耳炎、特应性皮炎、慢性鼻窦炎、变应性鼻炎、变应性结膜炎、慢性支气管炎、慢性龈炎、慢性鼻窦炎和慢性牙周炎。
治疗组合物和制剂
本发明还提供了治疗或药物组合物,其包含可与可药用载体相组合之形式的本发明成分。在一个实施方案中,本发明的组合物配制成经眼、经眼周、经鼻、经牙或经肺施用。
术语″载体″是指与化合物一起施用的稀释剂、辅料、赋形剂或载剂。这样的药物载体可以是无菌液体,如水和油,包括诸如矿物油的石油,诸如花生油、大豆油和芝麻油的植物油,动物油,或合成来源的油。
适当的药用赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩(chalk)、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂乳粉(dried skim milk)、甘油、丙二醇、水、乙醇等。如果需要,治疗组合物还可以包含少量的润湿剂或乳化剂或pH缓冲剂。这些组合物可采取溶液剂、悬浮剂、乳剂、乳膏剂、洗剂、滴剂、喷雾剂、凝胶剂、油、气雾剂、粉末、软膏剂、缓释制剂等的形式。可将该组合物与传统的黏合剂和诸如甘油三酯的载体一起配制。合适的药用载体的实例描述于E.W. Martin的″Remington′s Pharmaceutical Sciences″中。这样的组合物含有治疗有效量的治疗组合物以及适量的载体以提供适于向患者施用的形式。该制剂应当适合于施用方式。
在某些实施方案中,本发明的组合物包含一种或更多种抗微生物剂、抗细菌剂、抗病毒剂、抗真菌剂或抗酵母剂。
可将本发明的治疗或药物组合物配制成中性形式或盐形式。可药用盐包括与盐酸、磷酸、乙酸、草酸和酒石酸形成的盐,以及与钠、钾、铵、钙和铁的氢氧化物形成的盐等。
本发明还提供了成分的修饰,使得其在一旦施用至对象时更为稳定,即,一旦施用,与未修饰的形式相比其有效期更长。这样的修饰是本领域技术人员公知的,例如微胶囊等。
施用方式
在一个实施方案中,本发明的组合物通过局部施用递送至生物表面,包括但不限于眼、牙、牙龈、耳和皮肤;以及非生物表面,如医疗器械,包括但不限于插管、矫形器械、植入物、人工心瓣膜、人工关节、矫形植入物、分流器(shunt)、起搏器和除颤器、气管内导管、血液透析/腹膜透析装置、牙种植体和血管内插管。
本发明的治疗或药物组合物有效地治疗具体疾病、病症或障碍的量将取决于施用途径,疾病、病症或障碍的严重性,并且应当根据医师的判断和每一位患者的情况来决定。通常,剂量为约0.001mg/kg至约3g/kg。这样的单位剂量可以每日施用多于一次,例如每日两次或三次。
可以与载体材料组合以生产单一剂型的活性成分的量会根据病症的类型和待治疗的对象而变化。通常,治疗组合物含有约5%至约95%的活性成分(w/w)。更具体地,治疗组合物含有约20%(w/w)至约80%或约30%至约70%的活性成分(w/w)。
以下是本发明的多种组分的具体描述。
益生菌
益生菌是被证明以某种方式对人体有益的微生物。2001年世界卫生组织的一次关于益生微生物的研讨会将这些生物定义为“当以适当的量摄取时对其宿主的健康具有正面效应的活微生物”(世界卫生组织,Joint FAO/WHOExpert Consultation on Evaluation of Health and Nutritional Properties ofProbiotics in Food Including Powder Milk with Live Lactic Acid Bacteria(包含具有活乳酸菌的乳粉的食物中的益生菌的健康和营养特性评价的联合FAO/WHO专家评议会),2001年10月)。然而,应当注意,可用于本发明的益生生物可以不是活的;而且,它们事实上可以包括通常被认为与人宿主共生或者甚至是人宿主的病原体的微生物或其级分。
可单独使用一种益生菌或可将益生菌组合用于本发明。它们可以以活的或死的形式、作为该微生物的一个或更多个级分、作为该微生物的代谢物、灭活的、半灭活的或其组合的形式用于本发明。还可以使用生物膜细胞外聚合物质(EPS)的级分或生物膜“黏液(slime)”。这些多样的提取物(级分、代谢物)可以是细胞或非细胞的并且可来自细胞内或细胞外来源。例如,可以分离并纯化和/或可以使用可获得的包含在微生物培养物上清液中的诸如生物表面活性剂的代谢物。可以使用表现出生物表面活性剂活性的由非细胞级分构成的提取物。可以10微克/ml至10克/ml的浓度使用这样的提取物。
作为另一个实例,这些提取物可以包括当将益生菌培养成菌落时产生的生物膜的级分。这样的级分可以被分离、浓缩、富集和/或由消耗的介质组成。可以从浮游培养物和/或生物膜反应器中收获它们。可以在生物生长曲线上的任何点收获它们。或者,可以在某些酶、终产物等的某些最大或最小活性期获取它们。
业已证明,益生菌和其他微生物/生物可通过包括但不限于如下的方法培养成菌落:滴流流动/湿-干反应器、高流反应器(high flow reactor)、固定床反应器、膨胀床反应器、流化床反应器、膜反应器和旋转圆盘反应器。参见例如Cheng K等,“Advances in biofilm reactors for production ofvalue-added products”,Appl Microbiol Biotechnol,2010,87:445-456,其通过引用整体并入本文。这样做的具体方法是本领域技术人员公知的并且容易在文献中找到。参见例如Cotter,J等,“Characterization of a modifiedrotating disk reactor for the cultivation of Staphylococcus epidermis biofilm”,Journal of Applied Microbiology,2010,109,2105-2117;Jackson G等,“Growing reproducible biofilm with respect to structure and cell counts”,Journal of Microbiological Methods,2001,October,47(1):1-10;O′Toole,G等,“Initiation of biofilm formation in Pseudomonas fluoroscens WCS365proceeds via multiple,convergent signalling pathways:a genetic analysis”,Molecular Microbiology,l998,28(3),449-446and Wu,J等,“Evaluation ofDifferent Methods for Extracting Extracellular DNA from the BiofilmMatrix”,Applied and Environmental Microbiology,Aug.2009,p.5390-5395;所有参考文献通过引用整体并入本文。
还众所周知的是,生物膜可通过许多不同的方法分级,包括但不限于离心、过滤、加热、共混、超声处理、用络合剂处理、用离子(阳离子)交换树脂和氢氧化钠处理的技术(Nielsen,PH和Jahn,A,Microbial ExtracellularPolymeric Substances(eds Wingender,J.,Neu,T.,Flemming,H.C.),p.49-72,Springer-Heidelberg,1999;Thomas DP等,“Proteomics for the analysis ofthe Candida albicans biofilm lifestyle”,Proteomics,2006,6(21);5795-804,Flemming,H等,“The biofilm matrix”,Nature Reviews in Microbiology,2010,8(9):623-633;所有参考文献通过引用整体并入本文)。
诸如胞外多糖的生物膜的级分可通过使用诸如乙醇的醇或丙酮沉淀来浓缩(Kanmani,P等,“Production and purification of a novelexopolysaccharide from lactic acid bacterium Streptococcus phocae P180 andits functional characteristics activity in vitro”,Bioresource Technology,2011,article in press;Aguilera,A等,“Extraction of extracellular polymericsubstances from extreme acidic microbial biofilm”,Appl MicrobiolBiotechnol,2008,78(6):1079-1088;所有参考文献通过引用整体并入本文)。这样的提取物还可如表6所述以1mg/ml至1000mg/ml的浓度使用。
适合用于本发明的益生菌的具体实例包括非乳酸细菌以及产生乳酸的细菌(lactic acid producing bacteria,LAB)。这些包括拟杆菌属(Bacteroides)、双歧杆菌属(Bifidobacterium)和乳杆菌属(Lactobacillus);以及气球菌属、大肠杆菌、芽胞杆菌属、肠球菌属、梭杆菌属、乳球菌属、明串珠菌属、蜜蜂球菌属、微球菌属、酒球菌属、芽孢乳杆菌属、链球菌属、葡萄球菌属、酵母属、片球菌属细菌、消化链球菌属、丙酸杆菌属和魏斯氏菌属的某些菌株。适合用于本发明的微生物的实例已在别的地方更广泛地列举和描述(见表1)。在一个实例中,例如,可以使用嗜酸乳杆菌(ATCC 4356)的提取物和/或大肠杆菌K12(ATCC 10798)和/或嗜热链球菌(Streptococcus thermophilus)4022(如ATCC 19258)菌株的提取物。
本发明的抗炎活性在1千万至100亿菌落形成单位(CFU)每毫升(mL)(和/或由这些数量的细菌产生的代谢物的量)的浓度下最显著。
表1-示例性益生生物和商业来源
与微生物的培养和分级相关的示例性材料和方法
如已经讨论的那样,本发明使用与细菌和非细菌微生物和生物膜生长和收获有关的多种材料和方法。例如,可以使用Krasowska A等,“Theantagonistic effect of Saccharomyces boulardii on Candida albiCansfilamentation,adhesion and biofilm formation”,FEMS Yeast Res((2009)1312-1321中所述的方案获得酵母属酵母的滤液。然后可以使用上文提及的任何技术将浮游和生物膜细菌和非细菌培养物分级成多种亚区室,如核、亚核、细胞质、裂解物、上清液、消耗的介质、细胞膜、生物表面活性剂、细胞外DNA、细胞外RNA等。
特别地,可使用许多方法获得、分离和富集由微生物产生或得到的生物表面活性剂。这些描述于科学文献中,如Baker SC等,“Enrichment andpurification of lipopeptide biosurfactants”,Adv Exp Med Biol 2010;672:281-288,Rivardo,F等,“Anti-adhesion activity of two biosurfactantsproduced by Bacillus spp.prevents biofilm formation of human bacterialpathogens”,Appl Microbiol Biotechnol(2009)83:541-553,Gudina,E等,“Isolation and functional characterization of a biosurfactant produced byLactobacillusparacasci”,Colloids and Surfaces B:Biointerfaces76(2010)298-304,Gudina E等,“Antimicrobial and antiadhesive properties of abiosurfactant isolated from Lactobacillusparacasei ssp.Paracasei A20”,Letters in Applied Microbiology,50(2010)419-424,Sarachat,T等,“Purification and concentration of a rhamnolipid biosurfactant produced byPseudomonas aeruginosa SP4 using foam fractionation”,BioresourceTechnology 101(2010)324-330 and Rivardo F等,“Synergistic effect oflipopeptide biosurfactant with antibiotics against Escherischia coli CFT073biofilm”,International Journal of Antimicrobial Journal,(2011),未公开文献。所有出版物通过引用整体并入本文。
此外,可以使用筛选方法来鉴别和评估产生生物表面活性剂的微生物。这些技术容易在文献中找到,如在Burch A等,“Novel High-ThroughputDetection Method To Assess Bacterial Surfactant Production”,Applied andEnvironmental Microbiology,Aug 2010,p.5363-5372和Walter V等,“Screening concepts for the isolation of biosurfactant producingmicro-organisms”,Adv Exp Med Biol 2010;672:1-13中描述的那些。这些出版物通过引用整体并入本文。
蜂蜜和其他蜂巢产品
数百年来用于治疗包括感染在内的多种疾病的蜂蜜已被证明具有抗微生物以及抗炎作用(Viuda-Martos,M,“Functional Properties of honey,propolis and royal jelly”,J Food Sci2008Nov;73(9):R117-24)。这些作用的原因包括被称为甲基丙酮醛(methyl glyoxal,MGO)的多糖,(Adams,C,“Theorigin of methylglyoxal in New Zealand manuka(Leptospermum scoparium)honey”,Carbohydrate Research,2009May26;344(8):1050-1053),过氧化氢活性,低pH,高渗量(osmolarity)和抗微生物肽活性(Kwakman,P,“Howhoney kills bacteria”,FASEB J,2010Jul;24(7):2576-82)。某些蜂蜜已被证实对一些病原体具有抗生物膜作用;但是,没有可商购的基于蜂蜜的适用于治疗、去除或预防与疾病有关的生物膜的产品。
本发明还提供了标准化的药用级蜂蜜的制备和表征的方法以及临床应用。此时本发明的非常普遍的成分包括医用级蜂蜜,如已被灭菌以在伤口上使用的Medi-Honey(Comvita Inc.,新西兰)。由于蜂蜜的抗菌质量(antisepticquality)随着年数、收集的花粉和花蜜、批次(lot)、季节等,每一批次的麦芦卡蜂蜜都具有代表其抗菌效力的量度,该量度被称为“独特的麦芦卡因子(Unique Manuka Factor)”。如上文所讨论的,UMF数字来自于抗菌活性的实验室测试,其中将该蜂蜜与标准参照抗菌剂苯酚进行对比。例如,UMF20+会相当于20%苯酚溶液的抗菌效力。目前没有其他蜂蜜具有以这种方式测量的抗微生物质量。
然而,这种抗菌表征方法具有两个明显的缺点—对于待处理的微生物的抗微生物活性是未知的,并且这种量度只适用于麦芦卡蜂蜜,其他蜂蜜均不适用。所有的蜂蜜都具有抗微生物质量,很可能随类型的不同而变化。如果打算包含蜂蜜作为药物抗微生物装备的一部分,需要像抗生素一样通过标准化的经验证的试验对其进行表征。对于目前的抗生素,这些包括细菌和真菌抑制浓度(MIC)试验,如国家临床标准委员会(National Committee onClinical Standards,NCCLS)参考手册(通过引用并入本文)中记载的。还可以通过某些方法确定蜂蜜对于诸如呼吸道合胞体病毒(Respiratory SyncytialVirus)(RSV)的特定病毒的抗病毒活性,所述方法例如Sudo K,“YM-53403,a unique anti-respiratory syncytial virus agent with a novel mechanism ofaction”,J of Antiviral Research,2005(65):125-131(通过引用并入本文)中描述的方法。其他公认可以使用的可商购的用于抗病毒活性的试验包括OxoidM.I.C.Evaluators(Oxoid Ltd.,United Kingdon)、Etest(BioMerieux,France)和其他类似试验。
特别地,蜂蜜的抗生物膜活性需要通过生物膜抑制浓度(BIC)试验来标准化,这可以通过例如对样品进行最低生物膜清除浓度(Minimum BiofilmElimination Concentration,MBEC)试验方法(参见Ceri等的美国专利6,051,423,其通过引用并入本文)来完成。
如在每一标准NCCLS方案的MIC试验中用抗生素完成的那样,蜂蜜的BIC试验应当针对普通的人病原体来进行,如金黄色葡萄球菌、假单胞菌、耐甲氧西林和对甲氧西林敏感的金黄色葡萄球菌、流感嗜血杆菌、棒状杆菌属、念珠菌属、曲霉属等。本文还描述了使用表征的生物膜球的抗生物膜效力试验的可选方法。由于固有的变化性,来自蜜蜂在觅食中利用的多个单花种来源(麦卢卡、松树、柑橘等)的每一批应当根据所得蜂蜜的抗微生物/抗生物膜活性进行表征。
然后应当将来自单花种蜂蜜的抗微生物/抗生物膜活性与多种抗生素进行比较,即橙花蜂蜜与氨苄青霉素相比在抗金黄色葡萄球菌方面的活性。耐甲氧西林金黄色葡萄球菌的情形中尤其重要。或者,可以通过使用其中只生长一种传粉植物并饲养蜜蜂的封闭温室产生单花种蜂蜜。然后从这些蜂巢收获蜂蜜,确保它们的单花种和一致的性质。
然后会通过低剂量γ辐照或微过滤将用于医疗用途的蜂蜜灭菌以便如本发明上文所述用作用于抗微生物目的的局部等价物。可以10%至90%体积/体积(蜂巢产品/本发明)使用蜂蜜。还可将多种单花种蜂蜜相组合以提供更好、更广谱的覆盖。
对于蜂蜜或蜂巢产品,将样品在无菌的pH中性生理盐水溶液中稀释至0.001%至100%的测试浓度,并代替上文提及的方案中的抗生素使用。
还可以使用除了蜂蜜以外的蜂巢产品。例如,可以使用下文所述的方法制备蜂胶和蜂王浆并以1微克/ml至10mg/ml使用。
在本发明的制备期间,可以使用多种方法处理由益生提取物和蜂蜜(例如,乳杆菌属细菌和麦芦卡蜂蜜)构成的多种样品和/或保持其未被处理。处理可以包括对显示出抗生物膜和抗炎活性的提取物样品进行细胞分级、热处理、超声处理、过滤、酶处理、γ辐照或其他灭菌方法、微粉化、生物表面活性剂分离、结晶和/或冻干。
与蜂蜜和其他蜂巢产品相关的示例性材料和方法
无菌蜂巢产品的多种提取物的制备
在本发明的制备期间,可以使用多种方法处理由诸如蜂蜜、蜂胶、蜂王浆、蜂粮或蜂花粉的蜂巢产品构成的多种样品和/或保持其未被处理。处理可以包括通过化学手段对蛋白质、糖、花粉、多酚或其他成分进行分级,高效液相色谱,物理(滤器)超滤,凝胶电泳,热处理,酶处理,微粉化,超声,结晶,脱水或冻干。
例如,可以如以下文献所述进行分级:Salazar-Olivo,L.A.等,“Screeningof biological activities present in honeybee(Apis mellifera)royal j elly”,Toxicology in Vitro 19(2005)645-651;Mishima S等,“Effects of propolis oncell growth and gene expression in HL-60cells”,J Ethnopharmacol 2005,99:5-11;Nakajima Y等,“Comparison of bee products based on assays ofantioxidant capacities”,BMC Complementary and Alternative Medicine2009,9:4;Santos,F.等,“Antibacterial activity of Brazilian propolis andfractions against oral anaerobe bacteria”,J Ethnopharmacol2002,80:1-7;Maruyama,H等,“Anti-inflammatory effect of bee pollen ethanol extractfrom Cistus sp.of Spanish origin on carrageenan-induced rat hind pawedema”,BMC Complementary and Alternative Medicine 2010,10:30;Yu,F等,“Royal Jelly Proteome Comparison BetweenA.mellifera ligustica and A.cerana cerana”,Journal of Proteome Research2010,9,2207-2215以及Scarselli,R等,“Towards royal jelly proteome”,Proteomics 2005,5,769-776。
生物表面活性剂
生物表面活性剂是由微生物释放的并且通常无毒且可生物降解的化合物。在一个实施方案中,可根据本发明使用的生物表面活性剂由包括不产乳酸的细菌和产乳酸的细菌(LAB)在内的益生菌释放。在一个实施方案中,可根据本发明使用的生物表面活性剂由包括但不限于拟杆菌属、双歧杆菌属和乳杆菌属的益生菌释放。
在另一些实施方案中,生物表面活性剂可由气球菌属、大肠杆菌、芽孢杆菌属、肠球菌、梭杆菌属、乳球菌属、明串珠菌属、蜜蜂球菌属、微球菌属、酒球菌属、芽孢乳杆菌属、链球菌属、葡萄球菌、酵母菌属、片球菌属、消化链球菌属、丙酸杆菌属或魏斯氏菌属的某些菌株释放。在另一个实施方案中,生物表面活性剂可由表1中所列的一种或更多种生物释放。
可根据本发明使用的生物表面活性剂可以是糖脂或脂蛋白。在一个实施方案中,生物表面活性剂可以是糖脂、脂肽、缩肽、磷脂、取代的脂肪酸、脂多糖、细菌表面乳糖(surlactin)、表面活性素(surfactin)、visconsin、刺孢青霉酸(spiculisporic acid)或鼠李糖脂。
益生元
益生元是见于许多植物中的不易消化的纤维性低聚果糖或低聚半乳糖(FOS或GOS),其被大肠代谢形成诸如丁酸的短链脂肪酸。这些脂肪酸在代谢上支持肠中的益生菌落,并且有助于产生有效的局部先天免疫应答。因此,补充益生元可以提高益生补充的效力。这种组合被称为合益素治疗(synbiotictherapy)。
在某些实施方案中,本发明可以10微克/ml至100mg/ml的浓度使用诸如槐豆(角豆树(carob))胶的某些益生元以增强抗生物膜效力。这些包括低聚果糖(FOS)、低聚甘露糖(manno-ologosaccharide)(MOS)、低聚半乳糖(GOS)、阿拉伯半乳聚糖和其他膳食纤维、菊粉、乳果糖、抗性淀粉、异麦芽糖醇(isomalt)、燕麦麸和果胶。可以使用落叶松聚阿拉伯半乳糖(Larcharabinogalactan)并且还被称为AG,Ara-6,阿拉伯半乳聚糖(Arabinogalactan),Arabinogalactin,膳食纤维,落叶松(larch),松胶,落叶松树(larch tree),落叶松属(larix),蒙古落叶松(Mongolian Larch),蒙古落叶松木材(Mongolian Larchwood),可溶性纤维,Stractan,西部落叶松(Western Larch),西部落叶松阿拉伯半乳聚糖(Western LarchArabinogalactan),树胶(Wood Gum),木糖(Wood Sugar),欧洲落叶松(Larixdecidua),欧洲落叶松(Larix europaea),Pinus Larix,粗皮落叶松(Larixoccidentalis),Larix gmelinii var.gmerlinii,落叶松(Larix dahurica)和Abiesgmelinii。还可以使用:魔芋葡甘聚糖(koniac glucomannan),也称为魔芋胶、水解魔芋(hydrolyzed konjac)、水解葡甘露聚糖(hydrolyzedglucomannan)、未水解魔芋(unhydrolyzed konjac)、水解葡甘露聚糖、甘露蜜(Manna)、魔芋(Konjac)、魔芋纤维、蒟蒻(Devil’s Tongue)和魔芋(Elephant-Foot Yam)。还可以使用:可溶性或不溶性β葡聚糖,也称为谷物之麸(bran of cereal grains)、植物纤维素、真菌组分、蘑菇组分、海藻组分、凝胶多糖(curdlan)、昆布多糖(laminarin)、金藻昆布多糖(crysolaminarin)、香菇多糖(lentinan)、多糖-K(Polysaccharide-K)、地衣淀粉(lichenin)、pleuran、黄原胶和酵母聚糖(zymosan)。
植物提取物
已知植物提取物具有抗炎和抗微生物特性。本发明的一些实施方案中使用的植物提取物包括土木香(horseheal)(Inula h elenium,菊科(Asteraceae),土木香(elecampane))、突厥蔷薇(Rosa damascena L.,蔷薇科(Rosaceae))、熏衣草(Lavandula angustifolia L.,唇形科(Labiatae))、春黄菊(Matricariarecutica L.,菊科)、橙(芸香科(Rutaceae))、桉树(蓝桉(Eucalyptus globulus L.),桃金娘科(Myrtaceae))、老鹳草属(汉荭鱼腥草(Geranium robertianum L.),牻牛儿苗科(Geraniaceae))、杜松(juniper)(欧洲刺柏(Juniperus communisL.),柏科(Cupressaceae))、柑橘(甜橙(Citrus sinensis L.),芸香料)、茶树(teatree)(互叶白千层(Melaceuca alternifolia))、麦卢卡树(Leptospermumscoparium)、尼姆树(neem tree)(印度苦楝树(Azadirachta indica,A.Juss))、茶(tea plant)(Camellia sinensis)和迷迭香油(迷迭香(Rosmarinus offcinalisL.),唇形科)。可以使用上述植物的精油或水馏分。例如,可以1%至10%体积/体积(植物提取物体发明)的浓度使用麦卢卡油。可以直接从供应商购买药用级品质的植物材料、馏分和植物油,或者可以根据下述方法产生水蒸馏精油(hydrodistillate essence),其也可以1%至10%体积/体积(植物提取物体发明)的浓度使用。
与植物提取物有关的示例性材料和方法
使用Clevenger型装置或类似技术的植物提取物制备方法
在本发明的制备期间,可以多种方式制备植物提取物,特别是在它们的精油的纯化方面。请参见Clevenger,JF,“Apparatus for the determination ofvolatile oil”,1928;J Am Pharm Assoc,17;346,通过引用整体并入本文。可以使用其他技术,例如在Vian,M等,“Microwave hydrodiffusion and gravity,anew technique for extraction of essential oils”,Journal of Chromatography A,1190(2008),14-17或Farhat,A等,“Eco-friendly and cleaner process forisolation of essential oil using microwave energy-experimental andtheoretical study”,Journal of Chromatography A,1216(2009),5077-5085中描述的那些。
其他植物提取物-茶提取物
本发明还利用茶(Camellia sinensis)衍生物。更具体地,可以使用量均为10微克/ml至10mg/ml的L-茶氨酸和/或绿茶多酚,如表没食子儿茶素没食子酸酯(EGCG)。
已知烷基胺抗原刺激先天免疫应答。最浓的植物来源的烷基胺抗原是绿茶中被称为L-茶氨酸的氨基酸(Bukowski,J等,“Human gamma delta T cellsrecogn ize alkylamines derived from microbes,edible plants andtea:implications for innate immunity”,1999,Immunity,Vol.11,57-65)。L-茶氨酸表示为化学式C2H5NHCOCH2CH2CH(NH2)COOH,D-和或L,D-茶氨酸,2-氨基-4-(乙基氨基甲酰基)丁酸,N-乙基-L-谷氨酰胺,γ-谷氨酰基乙酰胺,N-γ-乙基-L-谷氨酰胺,γ-乙氨基-L-谷氨酸,茶氨酸(Suntheanine),5-N-乙基谷氨酰胺、绿茶或其他茶的提取物,生茶叶或精制茶叶,植物茶或某些其他山茶属植物(即日本山茶(C.japonica)、茶梅(C.sasanqua))或某些种类蘑菇(即褐绒盖牛肝菌(Xerocomus badius))的根或其他组分。
已知某些茶多酚具有抗氧化和抗微生物作用。表没食子儿茶素没食子酸酯(EGCG)是绿茶的主要多酚组分。其他多酚包括表没食子儿茶素、表儿茶素没食子酸酯和表儿茶素。
维生素D
除了其公知的对骨代谢的作用,最近发现维生素D对先天免疫系统有作用。维生素D3在诸如皮肤和眼的身体表面诱导产生诸如杀菌肽(cathelicidin)(LL37)的抗微生物肽(anti-microbial peptide,AMP)。
可以将维生素D3添加至制剂中,作为另外的活性成分。更具体地,可以1微克至1mg/ml的量使用维生素D的活性形式。还更具体地,可以使用目前处于专利保护之中的水溶性形式的维生素D。
其他活的或死的生物
可以使用的其他活的或死的微生物包括可安全地施用于人的那些,包括人共生体,在环境中发现的某些生物(例如海洋生物或嗜极端菌(extremophile)(例如在地热出风口(geothermal vent)或温泉中发现的生物))和/或它们的提取物或代谢物。人共生体是通常定殖于人体而不引起疾病的非致病生物。这些包括原核生物界(Monera)和真菌界(Fungi)的某些成员,包括子囊菌门(Ascomycota)。
还可以使用念珠菌属酵母、酵母属酵母、克鲁维酵母属(Kluyveromyces)酵母、德巴里酵母属(Debaromyces)酵母、接合酵母属(Zygosaccharomyces)酵母和裂殖酵母属(Schizosaccharomyces)酵母以及耶氏酵母属(Yarrowia)酵母、有孢圆酵母属(Torulaspora)、毕赤酵母属(Pichea)酵母以及曲霉属霉菌和青霉菌属(Penicillium)霉菌。还可以使用面包酵母细胞壁,或细胞壁组分(如酵母聚糖(酿酒酵母)),或其他酵母、真菌组分或蘑菇组分。还可以10微克至100mg重量/体积(提取物体发明)使用藻类、真菌和细菌提取物,和/或以1千万至100亿菌落形成单位(CFU)每毫升(mL)(和/或由这些数量的生物产生的代谢物的量)使用活的或死的生物。
与其他活的和死的微生物相关的示例性材料和方法
来自钝顶螺旋藻(Sirulina platensis)的多糖提取物制剂
在本发明的制备期间,可以由其他非细菌生物(包括蓝绿藻钝顶螺旋藻)制备特定的提取物。特别地,可使用Yang,L等,“Inhibitory effects ofpolysaccharhide extract from Spirulina platensis on cornealneovascularization”,Molecular Vision 2009;15:1951-1961或Pugh,N等,“Isolation of three high molecular weight polysaccharide preparations withpotent immunostimulatory activity from Spirulina platensis,Aphanizomenonflos-aqae and Chlorella pyrenoidosa”,Planta Med 67(2001)737-742所述的方法。
以下是说明用于实践本发明方法的实施例。这些实施例不应被视为是限制性的。
实施例1-用于眼部、眼周和鼻窦应用的具体实施方案
施用本发明的组合物的具体部位包括但不限于眼部、鼻部、口腔和皮肤。可根据本发明使用的载体包括但不限于喷雾剂、乳膏剂、软膏剂、洗剂、凝胶剂、滴剂、肥皂或适合于施用部位的任何其他形式。可使用本领域技术人员已知的标准方法制备这些组合物。
本发明的实施方案还可以作为例如清洁剂施用至惰性物体,如气雾剂和非气雾剂喷雾剂、洗涤剂、肥皂等。实施方案可以作为单次使用施用,或者可以在24小时期间内施用一次或更多次。
尽管下述制剂用于举例说明,可以使用其他制剂类型。优选使用无菌技术在生物防护罩(biocontainment hood)下制备制剂以尽可能无菌。制剂1-10可以使用如上所述的配方1-10作为活性组分。然而,也可以如下所述分别添加每一单独的组分。在上述配方中,可用多种生物代替益生嗜热链球菌的任何菌株。
制剂1-用于眼部干燥、刺激之症状缓解的滴眼剂溶液
2ml嗜热链球菌1000亿CFU/1ml无菌PBS
5ml未稀释的麦芦卡蜂蜜
3ml无菌生理盐水溶液
10ml 20B CFU/ml 50%蜂蜜溶液
采用本领域从业者公知的技术将该制剂等分至无菌滴眼剂瓶中并调节至中性pH。每一瓶滴眼剂溶液可以含有选定的制剂体积,例如,含10ml的15ml滴眼剂瓶。可以将滴眼剂瓶在其整个使用寿命期间储存在例如4摄氏度下。
制剂2-用于干眼和眼睑刺激之症状缓解的眼霜(Eye Cream)
500B CFU冷冻干燥的嗜热链球菌
5ml未稀释的蜂蜜
45ml冷乳膏基质
50ml含10B CFU/ml 10%蜂蜜的冷乳膏基质
可以将上述成分混合在本领域从业人员公知的标准冷乳膏中,即由鲸蜡醇酯蜡、白蜡、矿物油、硼酸钠和纯化水的基质构成的一种标准冷乳膏。可以将该制剂储存在含有20ml本发明的无菌罐中。可以将该冷乳膏混合物在其整个使用寿命期间储存在4摄氏度下。
制剂3-用于慢性鼻腔鼻窦充血之症状缓解的鼻用溶液剂
10ml非无菌或无菌的麦芦卡蜂蜜(Medi-Honey,Comvita Inc.,新西兰)
39ml无菌生理盐水溶液至终浓度为20%v/v
1ml 50B CFU/ml PBS冷冻干燥的灭活的嗜热链球菌(ATCC BAA-250)
50ml含1B CFU/ml 20%蜂蜜的生理盐水基质
可以使用或不使用防腐剂和/或抗氧化剂和/或黏度增强剂来制备溶液剂。可以将溶液滤过0.2微米滤器(Millipore)进入15、20或30ml无菌鼻用喷雾瓶中。将该鼻用喷雾瓶在其整个使用寿命期间保持储存在4摄氏度下,或者作为替代地可以在室温下储存最多30天。
制剂4-用于慢性鼻窦充血之症状缓解的鼻用冲洗袋(Nasal IrrigationPacket)
500mg脱水麦芦卡蜂蜜(方法参见上文)。
当在250ml水中重构时1000亿CFU/ml的冷冻干燥的灭活的嗜热链球菌(ATCC BAA-250)(如果需要,使用适当的赋形剂)。
当在250ml水中重构时产生等渗和pH中性溶液的氯化钠和碳酸氢钠的粉状USP级共混物。当消费者将其重构在250ml水中时,一份鼻用冲洗袋的内容物产生含375M CFU/ml的4mg/ml蜂蜜溶液。
可以用容量为250ml的鼻用冲洗瓶包装这种形式的本发明。或者,袋本身可以单独包装。
制剂5-用于慢性鼻腔鼻窦充血之症状缓解的鼻腔冲洗的浓缩液体形式
2.5ml麦芦卡蜂蜜(Medi-Honey,Comvita Inc.,新西兰)
2.0ml中性pH下的无菌生理盐水溶液
0.5ml在无菌PBS中的冷冻干燥的灭活的嗜热链球菌(ATCC BAA-250)
100B CFU/ml
5ml 2B CFU/ml于1%蜂蜜溶液(消费者进行最终的重构)
可以使用或不使用防腐剂和/或抗氧化剂和/或黏度增强剂来制备溶液。可以将溶液滤过0.2微米滤器(Millipore)进入10ml一次性容器中。可以使用或不使用具有适当容量的鼻用冲洗瓶包装溶液以达到适当的渗透性,使得当与250ml水混合时,最终溶液是等渗的。
实施例2-用于皮肤应用的一些具体实施方案
制剂6-用于清洗慢性刺激的干燥和/或正常皮肤的凝胶剂
50ml无菌或非无菌的麦芦卡蜂蜜
40ml生理盐水溶液,中性pH,含5%甲基纤维素1500cP,10%v/v
10ml在无菌PBS中的冷冻干燥的灭活的嗜热链球菌(ATCC BAA-250)
100B CFU/ml
100ml 10B CFU/ml于50%蜂蜜溶液中
可以将终产品包装在无菌的手动泵容器中,其中每一泵在每一泵循环中分配5ml本发明。可以将该特定剂型留在所施用的区域而无需清洗。
制剂7-用于清洗慢性刺激的干燥和/或正常皮肤的液体皂
50ml甘油液体皂基质
50ml本发明(即上述制剂5)的浓缩液体形式
100ml 1B CFU/ml于0.5%蜂蜜溶液中
可以将上述成分在轻微的加热和搅拌下混合,并倒入100ml手动泵瓶中,冷却并包装。
制剂8-用于清洗慢性刺激的干燥和/或正常皮肤的沐浴添加剂(BathAdditive)
10克柠檬酸钠
20克碳酸氢钠
10克结晶或脱水的麦芦卡蜂蜜(如上所述)
100B CFU冷冻干燥的灭活的嗜热链球菌(ATCC BAA-250)
5ml熏衣草精油
5ml麦卢卡精油
50克2B CFU/gm 20%蜂蜜混合物
可以用金缕梅(witch hazel)固化,放入50ml的圆顶模具(domed mold)中,使其硬化并将其包装在密封的一次性包装中。
实施例3-用于环境应用的一些具体实施方案
制剂9-用于清洗可能暴露于致病生物膜定殖的无生命表面的环境抗生物膜喷雾剂
80ml含洗涤喷雾剂载剂的稀醇或醋基质
10ml非无菌麦芦卡蜂蜜
10ml 100B CFU/ml PBS冷冻干燥的灭活嗜热链球菌ATCC BAA-250
100ml 100亿CFU/ml10%蜂蜜溶液
可以包装在手压泵室喷雾容器中;每一泵可以分配相当于1ml溶液的气溶胶体积。可以将该特定剂型留在所施用的区域而无需清洗。
实施例4-耳部应用的一些具体实施方案
制剂10-用于耳部慢性刺激、发炎之症状减轻的滴耳剂
3mlγ辐照的无菌麦芦卡蜂蜜(Medi-Honey,Comvita Inc.,新西兰)
6ml无菌甘油
1ml嗜热链球菌1000亿CFU/1ml无菌PBS
10ml 100亿CFU/ml30%蜂蜜溶液
实施例5-呼吸道应用的一些具体实施方案
制剂11-吸入剂溶液
50mg无水柠檬酸
2mlγ辐照的无菌麦芦卡蜂蜜(Medi-Honey,Comvita Inc.,新西兰)
1ml 500亿CFU/ml嗜热链球菌CFU/ml无菌PBS
97ml无菌生理盐水
100ml 5亿CFU/ml嗜热链球菌CFU/ml 2%蜂蜜溶液
实施例6-牙科应用的具体实施方案
制剂12-牙膏
15ml木糖醇
3mg NaCl
38g甘油
2ml百里香酚馏分(即美国薄荷属(Monarda))
20g麦芦卡蜂蜜
1ml嗜热链球菌1000亿CFU/1ml无菌PBS
80ml嗜热链球菌1.25B CFU/1ml
实施例7-牙周应用的一些具体实施方案
制剂13-用于治疗牙周炎的刮除剂(Curettage Agent)
冻干的嗜热链球菌,终浓度为10B CFU/克载剂。
麦芦卡蜂蜜,在120F下脱水,碾成粉末;终浓度为50g/载剂。
可以将聚乳酸(PLA)上的聚酯、聚乙交酯(PGA)、聚已酸内酯(PCL)或其他可生物降解的共聚物用作旨在龈下施用到牙周袋中的这种制剂的递送载剂。
可以修饰上述制剂,使得其可用作牙线的涂层,并入漱口剂(mouthwash)、口香糖(gum)或锭剂(lozenge)中。
可以根据需要将在成分的详细描述中提及的益生元、植物油和其他组分添加至成分的任一制剂中,例如包括但不限于螺旋藻的其他生物、维生素D3、L-茶氨酸和EGCG。
应当理解,本文所述的实施例和实施方案仅用于举例说明的目的,根据它们作出的多种修饰和改变是本领域技术人员容易想到的并且应当包括在本申请的精神和范围以及所附权利要求的范围内。
Claims (41)
1.分离的生物活性组合物,其来自生物膜、已在其中培养生物膜的介质或从患者提取然后作为生物膜来培养的生物样品。
2.分离的生物活性组合物,其来自生物膜、已在其中培养生物膜的介质或从患者提取然后作为生物膜来培养的生物样品,其中所述生物活性是调节所述组合物所施用于之微生物组的能力。
3.根据权利要求1或2所述的组合物,其中所述组合物通过提取来分离。
4.根据权利要求3所述的组合物,其中可通过物理或化学处理来获得所述提取物。
5.根据权利要求4所述的组合物,其中可通过用气泡处理来获得所述提取物。
6.根据权利要求1或2所述的组合物,所述组合物是非细胞的。
7.根据权利要求1或2所述的组合物,其中所述组合物包含生物表面活性剂。
8.根据权利要求1或2所述的组合物,其中所述生物活性是影响生物膜的活性。
9.根据权利要求8所述的组合物,其中所述活性包括选自以下的一种或更多种活性:附着抑制,生长抑制,生物膜基质破坏,预防、抑制和/或破坏细胞外因子的分泌和/或释放,以及预防、抑制和/或破坏细胞密度感受机制。
10.根据权利要求8所述的组合物,其中所述活性包括选自以下的一种或更多种活性:附着促进,生长促进,生物膜基质稳定化或内聚,促进、上调或稳定细胞外因子的分泌和/或释放,以及促进、上调或稳定细胞密度感受机制。
11.根据权利要求1或2所述的组合物,其中所述生物膜来自益生生物。
12.根据权利要求1或2所述的组合物,其在施用于动物时调节免疫系统和/或炎性应答。
13.化妆品或药物组合物,其配制成用于向动物施用,其中所述化妆品或药物组合物包含权利要求1或2所述的分离的生物活性组合物和任何可接受的载体。
14.根据权利要求13所述的组合物,其还包含选自以下的一种或更多种成分:益生菌、抗生素、生物表面活性剂、植物提取物、维生素、益生元和蜂巢产品。
15.根据权利要求13所述的组合物,其为化妆品组合物,其中所述载体适于化妆品用。
16.根据权利要求13所述的组合物,其为药物组合物,其中所述载体适于药用。
17.根据权利要求13所述的组合物,其配制成用于局部施用。
18.根据权利要求17所述的组合物,其配制成用于向选自以下的位置施用:眼、眼周、窦、鼻、牙周、口咽、耳、角质化和非角质化的皮肤表面、下呼吸道、胃肠和泌尿生殖器。
19.根据权利要求13所述的组合物,其配制成通过内镜、舌下滴管、针或注射器技术、直接或间接递送、冲洗、直接或间接施用于相关部位、导管引导的施用或血管内输注来施用。
20.组合物,其配制成用于向无生命表面施用,其中所述配制的组合物包含权利要求1或2所述的分离的生物活性组合物和任何可接受的载体。
21.用于操纵微生物组的方法,其中所述方法包括将所述微生物组、生物膜和/或所述微生物组和/或生物膜的周围环境暴露于权利要求1或2所述的组合物。
22.根据权利要求21所述的方法,其用于操纵人微生物组。
23.根据权利要求21所述的方法,其中所述生物活性组合物从生物膜中分离,所述生物膜得自被操纵的同一微生物组。
24.根据权利要求21所述的方法,其用于治疗动物中的病理病症。
25.根据权利要求24所述的方法,其中所述动物是人。
26.根据权利要求24所述的方法,其中所述病症是急性或慢性炎症。
27.根据权利要求24所述的方法,其中所述病症选自干眼和其他慢性或急性眼部病症,慢性或急性鼻窦炎,慢性或急性鼻炎,慢性或急性牙周炎,慢性或急性支气管炎、囊性纤维化和其他呼吸道炎症状态,包括急性和慢性耳炎和外耳炎在内的炎性耳部病症,炎性皮肤病症,包括胃炎和胃食管反流在内的炎性肠病症,炎性泌尿生殖器病症和炎性心血管病症。
28.根据权利要求24所述的方法,其中通过经由内镜、舌下滴管、针或注射器技术、直接或间接递送、冲洗、直接或间接施用于相关部位、导管引导的施用或血管内输注的施用来治疗所述病理病症。
29.根据权利要求21所述的方法,其用于影响无生命表面上的生物膜的附着抑制,生长抑制,生物膜基质破坏,细胞外因子之分泌和/或释放的预防、抑制和/或破坏,以及细胞密度感受机制的预防、抑制和/或破坏。
30.用于在动物中调节免疫系统和/或炎性应答的方法,其中所述方法包括向有此调节需要的动物施用有效量的权利要求1或2所述的组合物。
31.根据权利要求30所述的方法,其中所述动物是人。
32.用于鉴定生物活性组合物的方法,其中所述方法包括培养生物膜,物理或化学地处理所述生物膜或在其中培养所述生物膜的介质,以产生一种或更多种提取物级分;测试所述级分以鉴定生物活性;以及如果发现级分具有生物活性则选择该级分。
33.根据权利要求32所述的方法,其中所述生物膜是益生生物膜。
34.根据权利要求32所述的方法,其中所述生物膜或介质得自患者。
35.根据权利要求32所述的方法,其中用气泡、溶剂和/或pH调节剂来处理所述生物膜或在其中培养所述生物膜的所述介质。
36.通过权利要求32所述方法选择的级分。
37.根据权利要求32所述方法,其还包括在所选择的级分中鉴定一种或更多种分离的化合物,其中所述化合物是有生物活性的。
38.通过权利要求37所述的方法鉴定的化合物。
39.组合物,其包含权利要求38所述的化合物和任何化妆品和/或药物载体。
40.吸入装置,其包含权利要求1或2所述的组合物。
41.根据权利要求40所述的吸入装置,其中所述组合物配制成包含生物表面活性剂。
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CN113456549B (zh) * | 2021-07-20 | 2023-01-31 | 广东桂格日化有限公司 | 一种驱蚊组合物及含有该组合物的花露水 |
CN113662971A (zh) * | 2021-08-30 | 2021-11-19 | 江西省养蜂研究所(江西省蜂业技术推广站) | 一种天然蜂粮含片及其生产方法 |
CN113662971B (zh) * | 2021-08-30 | 2023-02-24 | 江西省养蜂研究所(江西省蜂业技术推广站) | 一种天然蜂粮含片及其生产方法 |
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CN111518866A (zh) | 2020-08-11 |
JP2014506923A (ja) | 2014-03-20 |
US20240099308A1 (en) | 2024-03-28 |
WO2012118535A1 (en) | 2012-09-07 |
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US20220110330A1 (en) | 2022-04-14 |
US20170281699A1 (en) | 2017-10-05 |
US20200108107A1 (en) | 2020-04-09 |
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US11825848B2 (en) | 2023-11-28 |
JP2021080303A (ja) | 2021-05-27 |
US10004771B2 (en) | 2018-06-26 |
US20140037688A1 (en) | 2014-02-06 |
JP6908568B2 (ja) | 2021-07-28 |
EP2680866A1 (en) | 2014-01-08 |
JP2016222703A (ja) | 2016-12-28 |
US10086025B2 (en) | 2018-10-02 |
US20170216377A1 (en) | 2017-08-03 |
JP6594269B2 (ja) | 2019-10-23 |
JP2019006830A (ja) | 2019-01-17 |
US9717765B2 (en) | 2017-08-01 |
US9504739B2 (en) | 2016-11-29 |
US9713631B2 (en) | 2017-07-25 |
US20170056455A1 (en) | 2017-03-02 |
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