CN104936576B - 包含amadori化合物的口腔护理组合物 - Google Patents
包含amadori化合物的口腔护理组合物 Download PDFInfo
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- CN104936576B CN104936576B CN201280077781.3A CN201280077781A CN104936576B CN 104936576 B CN104936576 B CN 104936576B CN 201280077781 A CN201280077781 A CN 201280077781A CN 104936576 B CN104936576 B CN 104936576B
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
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Landscapes
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及抑制微生物生物膜形成和/或降解微生物生物膜的口腔护理组合物和方法。本文公开包含具有葡萄糖部分和氨基酸部分的Amadori化合物的口腔护理组合物。Amadori化合物具有在哺乳动物受试者的口腔中抑制口腔微生物生物膜形成和/或降解口腔微生物生物膜的用途。
Description
发明背景
生物膜是结构化的微生物群,所述微生物被包封在自身产生的聚合的细胞外基质内。生物膜通常粘附在活的或惰性的表面。在人或动物体内,生物膜可在任何内表面或外表面上形成。已发现生物膜参与体内广泛种类的微生物感染并引起许多病症包括尿道感染、中耳感染,和特别是口腔疾病。
牙菌斑生物膜是在牙齿表面形成的软沉淀物,并提供牙结石或牙垢形成的场所。因此,牙菌斑生物膜参与牙龈炎、牙周炎、龋齿和其它形式的牙周疾病的发生。牙菌斑生物膜坚固地粘附于牙齿表面,并且甚至通过严格的刷牙方案也几乎不能除去。而且,牙菌斑生物膜在其被除去后迅速地在牙齿表面上重新形成。
已知葡萄糖可通过由几种口腔细菌成分例如变异链球菌(S. mutans)生成的酶的作用在口腔中被代谢。葡萄糖可通过酶的作用在口腔中聚合成葡聚糖,而这样的聚合可引起生物膜在牙齿表面上形成,其随后可在牙齿表面上形成口腔牙菌斑。
存在提供可减少或预防生物膜形成、因此减少口腔牙菌斑形成的口腔护理组合物的持续需求。
因此需要提供用于有效地抑制生物膜形成和/或降解生物膜的口腔护理组合物的改进的作用剂。
发明概述
本发明通过给予口腔Amadori产物满足本领域减少或预防生物膜形成的需求。
Amadori化合物(也称为Amadori产物)经由熟知的Amadori重排反应形成,凭此反应,醛糖经由酸或碱异构化,然后与胺反应,经Schiff碱中间体重排后形成Amadori化合物(见M. Amadori,Atti Accad. Naz. Lincei 2(6),337 (1925);The Merck Index (第14版),pg. ONR-3,(2006))。以下的反应流程显示己糖和氨之间的反应形成Amadori化合物。
醛糖与氨基酸反应的Amadori重排也称为Maillard反应。
虽然制备Amadori化合物(产物)的方法是本领域熟知的,但它们的使用在本领域却知之甚少。Amadori化合物本身被认为没有益处,但作为形成晚期糖基化最终产物(AGE)的中间体化合物起作用,其中Amadori化合物被氧化。这些AGE通常在食品工业中具有作为调味料的益处。一个这样的实例是Amadori化合物的高温分解,产生有焦糖气味的化合物。Mills等,"在加工食品中作为非易失性的风味前体的Amadori化合物(Amadori Compoundsas Nonvolatile Flavor Precursors in Processed Foods)",Agric. Food Chem.,vol.17,no. 4,第723-727页(1969年7月-8月)。
然而,已经令人惊讶地发现,Amadori化合物以它们自身的能力可用作减少或抑制生物膜形成的作用剂。
在第一方面,本发明提供一种包含Amadori化合物的口腔护理组合物。
任选地,Amadori化合物通过酮糖与氨基酸反应形成。
任选地,Amadori化合物通过葡萄糖与氨基酸反应形成,其中氨基酸选自丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸。
在第二方面,本发明提供在哺乳动物受试者的口腔中治疗或预防牙菌斑的组合物。
在第三方面,本发明提供一种包含具有葡萄糖部分和氨基酸部分的Amadori化合物的口腔护理组合物,用于抑制口腔微生物生物膜形成和/或降解口腔微生物生物膜。
在第四方面,本发明提供一种在哺乳动物受试者的口腔中抑制口腔微生物生物膜形成和/或降解口腔微生物生物膜的方法,其包括给予受试者包含具有葡萄糖部分和氨基酸部分的Amadori化合物的组合物。
在第五方面,本发明提供Amadori化合物在口腔护理组合物中的用途,其用于在哺乳动物受试者的口腔中抑制口腔微生物生物膜形成和/或降解口腔微生物生物膜。本发明基于本发明人的这样的发现,即Amadori化合物显示良好的口腔保健益处,且尤其可以口腔护理组合物提供减少的生物膜和牙菌斑形成。
本发明的进一步的实施方案将从详细的描述和实施例而变得显而易见。
发明详述
应该理解,详细的描述和具体的实施例,虽然指明了本发明的实施方案,但仅仅是意欲为了举例说明的目的,并不意欲限制本发明的范围。
如贯穿本文所用的,范围被用作描述在该范围内的每一个和所有值的速记。可选择在该范围内的任何值作为该范围的端值。
如本文所用的,词语"优选的和"优选地"指在某些情况下提供一定益处的本发明的实施方案。然而,在相同或其它情况下,其它实施方案也可以是优选的。此外,一个或多个优选的实施方案的描述并不意味着其它实施方案不是有用的,且不打算将其它实施方案从本发明的范围内排除。
如本文所用的术语"约",当应用于本发明的组合物和方法的参数值时,表示所述值的计算或测量允许一定的轻微的不精确性,其对组合物或方法的化学或物理属性没有实质影响。如果因为某些理由,由"约"提供的不精确性在本领域中不能用普通的意义另外被理解,那么如本文所用的"约"表示该值至多5%的可能变化。
如在本文所指的,所有的组成百分比均以总组合物的重量计,除非另外指明。
在一些实施方案中,本发明提供一种包含含有葡萄糖部分和氨基酸部分的Amadori化合物的口腔护理组合物。在特定的实施方案中,组合物用于在哺乳动物受试者的口腔中治疗或预防牙菌斑。在特定的实施方案中,Amadori化合物在组合物中是口腔微生物生物膜的减少或预防剂。在特定的实施方案中,口腔护理组合物包含具有葡萄糖部分和氨基酸部分的Amadori化合物,其用于抑制口腔微生物生物膜形成和/或降解口腔微生物生物膜。
Amadori化合物
在第一方面,本发明提供一种包含Amadori化合物的口腔护理组合物。
任选地,Amadori化合物通过醛糖与胺化合物的反应形成。
任选地,Amadori化合物通过戊糖或己糖与氨基酸化合物的反应形成。
任选地,Amadori化合物通过葡萄糖与氨基酸的反应形成,其中氨基酸选自丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸。由D-葡萄糖与氨基酸反应形成的Amadori化合物的开链和环形式仅为了示例性目的在下文示出;L-形式的葡萄糖也被认为是在本发明的范围内。
得自D-葡萄糖和氨基酸的反应产物的Amadori化合物
R是丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸的侧链。对于脯氨酸,R侧链和氮形成吡咯烷环。
在本申请中描述的Amadori化合物的以上结构还意欲涵盖其盐形式和荷电形式。此外,虽然以上Amadori化合物描述了D-葡萄糖,得自L-葡萄糖的Amadori化合物也被认为是本发明的部分。
由葡萄糖和甘氨酸的反应形成的Amadori化合物还可表示为N-(1-脱氧-果糖-1-基)甘氨酸。类似地,葡萄糖与其它天然存在的氨基酸的反应可表示为:
N-(1-脱氧-果糖-1-基)丙氨酸;
N-(1-脱氧-果糖-1-基)精氨酸;
N-(1-脱氧-果糖-1-基)天冬酰胺;
N-(1-脱氧-果糖-1-基)天冬氨酸;
N-(1-脱氧-果糖-1-基)半胱氨酸;
N-(1-脱氧-果糖-1-基)谷氨酰胺;
N-(1-脱氧-果糖-1-基)谷氨酸;
N-(1-脱氧-果糖-1-基)甘氨酸;
N-(1-脱氧-果糖-1-基)组氨酸;
N-(1-脱氧-果糖-1-基)异亮氨酸;
N-(1-脱氧-果糖-1-基)亮氨酸;
N-(1-脱氧-果糖-1-基)赖氨酸;
N-(1-脱氧-果糖-1-基)甲硫氨酸;
N-(1-脱氧-果糖-1-基)苯丙氨酸;
N-(1-脱氧-果糖-1-基)丝氨酸;
N-(1-脱氧-果糖-1-基)苏氨酸;
N-(1-脱氧-果糖-1-基)色氨酸;
N-(1-脱氧-果糖-1-基)酪氨酸;和
N-(1-脱氧-果糖-1-基)缬氨酸。
D-和L-形式两者以及开链和要求保护
任选地,氨基酸选自甘氨酸、赖氨酸、谷氨酸和精氨酸。更任选地,氨基酸部分是甘氨酸或谷氨酸。还更任选地,氨基酸部分是甘氨酸。
任选地,Amadori化合物以基于组合物总重量的约0.005 wt %-约10 wt %、更任选地基于组合物总重量的约0.1 wt %-约7.5 wt %、还更任选地基于组合物总重量的约1 wt%-约5 wt %的浓度存在于组合物中。
在本发明的一个实施方案中,氨基酸可选自甘氨酸、赖氨酸、谷氨酸和精氨酸(N-(1-脱氧-果糖-1-基)甘氨酸;N-(1-脱氧-果糖-1-基)赖氨酸;N-(1-脱氧-果糖-1-基)谷氨酸;N-(1-脱氧-果糖-1-基)精氨酸)。
在一些实施方案中,氨基酸部分是甘氨酸或谷氨酸,优选甘氨酸。
生物膜
本发明的上下文中使用的术语"生物膜"意指被包封在自身产生的聚合的细胞外基质内的任何微生物群。生物膜可粘附在活的或惰性的表面。例如,在口腔中,生物膜可以牙菌斑的形式粘附于牙齿。
生物膜可由一种或多种不同类型的微生物包括例如细菌、古细菌、原虫、真菌和藻类形成。生物膜优选由细菌形成。在一个实施方案中,生物膜由单一种类的细菌形成。在另一个实施方案中,生物膜由多个种类的细菌形成。生物膜可由一种或多种选自粘性放线菌(Actinomyces viscosus)、干酪乳杆菌(Lactobacillus casei)、口腔链球菌(Streptococcus oralis)、具核梭杆菌(Fusobacterium nucleatum)、小韦荣氏球菌(Veillonella parvula)和牙龈卟啉单胞菌(Porphyromonas gingivalis)的细菌形成。
用于口腔护理组合物的任选的作用剂
依据本发明的组合物还可包含一种或多种另外的作用剂,所述作用剂有效地预防或治疗口腔的硬或软组织的病症或疾病,预防或治疗生理型疾病或病症,或其提供美容益处。
另外的作用剂典型地选自抗微生物剂(其不是Amadori化合物)、抗-牙菌斑剂、增白剂、清洁剂、矫味剂、甜味剂、粘附剂、表面活性剂、泡沫调节剂、研磨剂、pH调节剂、保湿剂、口感剂、着色剂、研磨剂、牙垢控制(抗牙结石)剂、氟离子源、唾液刺激剂、抗-敏感剂、抗氧化剂、营养素、酶及其组合。应该理解,虽然以上各类材料的每一种的一般属性可以是不同的,但可有一些共同的属性,并且任何给定的材料可能起着两种或更多种所述种类的材料的多重作用。优选地,选择与组合物的其它成分相容的载体。
在一些实施方案中,本发明的组合物任选地包含抗微生物(如,抗细菌)剂。抗微生物剂可选自三氯生、西吡氯铵、木兰提取物、厚朴酚、和厚朴酚、丁基厚朴酚、丙基和厚朴酚、氯化锌、乳酸锌、柠檬酸锌、氟化亚锡和氯化亚锡。有用的抗菌剂的其它示例性列表在美国专利号5,776,435 (Gaffar等)中提供,其内容通过引用结合到本文中。
一种或多种抗微生物剂任选地以有效抑制和/或降解口腔中的生物膜的量存在。优选地,抗微生物剂以适合预防或治疗由生物膜形成引起的病症的量存在,例如病症选自牙菌斑、龋齿、牙周病、牙龈炎或口臭。
典型地,抗微生物剂各自以基于组合物总重量的约0.001 wt %-约10 wt %、例如约0.1 wt %-约3 wt %的浓度存在于组合物中。
本文的那些有用的调味料包括可有效提高组合物的味道的任何材料或材料的混合物。可使用任何口腔可接受的天然或合成的调味料,例如调味油、调味醛、酯、醇、类似的材料及其组合。调味料包括香草醛、鼠尾草、牛至、欧芹油、留兰香油、肉桂油、冬青油(水杨酸甲酯)、薄荷油、丁香油、月桂油、茴香油、桉树油、柑橘油、果油和精油(包括从柠檬、橘子、酸橙、葡萄柚、杏、香蕉、葡萄、苹果、草莓、樱桃、菠萝等衍生的那些)、豆和坚果衍生的风味(如咖啡、可可、可乐、花生、杏仁等)、吸附和包封的调味料,及其混合物。在本文的调味料中还包括提供香味和/或其它在口中的感官作用,包括凉或热作用的成分。这样的成分包括薄荷醇、乙酸薄荷酯、乳酸薄荷酯、樟脑、桉树油、桉油精、茴香脑、丁香酚、桂皮、覆盆子酮(oxanone)、α-紫罗兰酮、丙烯基乙基愈创木酚(propenyl guaiethol)、百里酚、芳樟醇、苯甲醛、肉桂醛、N-乙基-p-薄荷烷-3-甲酰胺、N,2,3-三甲基-2-异丙基丁酰胺、3-1-薄荷氧基-丙烷-1,2-二醇、肉桂醛甘油缩醛(CGA)、薄荷酮甘油缩醛(MGA)及其混合物。一种或多种调味料任选地以约0.01 wt %-约5 wt %的总量存在,任选地在不同的实施方案中以约0.05-约2 wt %、约0.1 wt %-约2.5 wt %和约0.1-约0.5 wt %的总量存在。
本文的那些有用的甜味剂包括葡萄糖、聚葡萄糖、蔗糖、麦芽糖、糊精、干转化糖、甘露糖、木糖、核糖、果糖(fructose)、果糖(levulose)、半乳糖、玉米糖浆、部分水解淀粉、氢化淀粉水解物、山梨醇、甘露醇、木糖醇、麦芽糖醇、异麦芽酮糖醇(isomalt)、阿斯巴坦、纽甜、糖精及其盐、三氯蔗糖、二肽基强甜味剂、环己基氨基磺酸盐、双氢查耳酮及其混合物。
口感剂包括在组合物的使用期间赋予所需质地或其它感觉的材料。
本文的那些有用的着色剂包括色素、染料、色淀和赋予特定的光泽和反射的作用剂如珠光剂。在不同的实施方案中,着色剂可有效在牙齿表面提供白色或浅色涂层,用作已被组合物有效地接触的牙齿表面位置的指示剂,和/或改变组合物的外观,特别是颜色和/或不透明性,以增进对消费者的吸引力。可以使用任何口腔可接受的着色剂,包括FD&C染料和色素、滑石、云母、碳酸镁、碳酸钙、硅酸镁、硅酸铝镁、二氧化硅、二氧化钛、氧化锌、红色、黄色、棕色和黑色的铁氧化物、亚铁氰化铁铵、锰紫、群青(ultramarine)、钛云母(titaniated mica)、氯氧化铋及其混合物。一种或多种着色剂任选地以约0.001 wt %-约20 wt %、例如约0.01 wt %-约10 wt %或约0.1 wt %-约5 wt %的总量存在。
本发明的组合物还可包含用作例如抛光剂的任选的研磨剂。一些实施方案提供包含基于组合物总重量的约5-约15 wt %研磨剂的口腔护理组合物。
当研磨剂存在时,平均粒径通常为约0.1-约30微米,例如约1-约20或约5-15微米。
可以使用任何口腔可接受的研磨剂,但应该选择研磨剂的类型、细度(粒度)和量,以使牙齿釉质在正常使用组合物时不被过度磨损。合适的任选的研磨剂包括二氧化硅(例如以沉淀二氧化硅或作为与氧化铝混合的形式存在)、不溶性磷酸盐、碳酸钙及其混合物。用作研磨剂的不溶性磷酸盐有正磷酸盐、聚偏磷酸盐和焦磷酸盐。示例性实例为正磷酸二钙二水合物、焦磷酸钙、焦磷酸钙、磷酸三钙、聚偏磷酸钙和不溶性聚偏磷酸钠。
本发明的组合物任选地包含牙垢控制(抗牙结石)剂。本文的那些有用的牙垢控制剂包括任何这些作用剂的盐,例如它们的碱金属盐和铵盐:磷酸盐和多磷酸盐(例如焦磷酸盐)、聚氨基丙烷磺酸(AMPS)、聚烯烃磺酸盐、聚烯烃磷酸盐、二膦酸盐如氮杂环烷烃-2,2-二膦酸盐(例如,氮杂环庚烷-2,2-二膦酸)、N-甲基氮杂环戊烷-2,3-二膦酸、乙烷-1-羟基-1,1-二膦酸(EHDP)和乙烷-1-氨基-1,1-二膦酸盐、膦酰基链烷羧酸。有用的无机磷酸盐和多磷酸盐包括磷酸二氢钠、磷酸氢二钠和磷酸三钠、三聚磷酸钠、四聚磷酸盐、焦磷酸一钠、焦磷酸二钠、焦磷酸三钠和焦磷酸四钠、三偏磷酸钠、六偏磷酸钠及其混合物。其它有用的牙垢控制剂包括聚羧酸酯聚合物和聚乙烯甲基醚/马来酸酐(PVM/MA)共聚物,如GANTREZ®。
氟化物盐和氟离子源,例如,为可溶性的氟化物盐,是本领域已知的并可掺入到本发明的组合物中。代表性的氟离子源包括,但不限于:氟化亚锡、氟化钠、氟化钾、一氟磷酸钾、一氟磷酸钠、一氟磷酸铵、氟硅酸钠、氟硅酸铵、氟化胺如奥拉氟(olaflur) (N'-十八烷基三亚甲基二胺-N,N,N'-三(2-乙醇)-二氢氟化物)、氟化铵及其组合。在某些实施方案中,氟离子源包括氟化亚锡、氟化钠、氟化胺、一氟磷酸钠及其混合物。在某些实施方案中,本发明的口腔护理组合物还可包含氟离子源或提供氟的成分,其量足以供应约50-约5000 ppm氟离子,例如,约100-约1000、约200-约500、或约250 ppm氟离子。氟离子源可以约0.001 wt%-约10 wt %,例如约0.003 wt %-约5 wt %、0.01 wt %-约1 wt、或约0.05 wt %的水平加入到本发明的组合物中。然而,将要理解的是,提供适当水平的氟离子的氟化物盐的重量将明显地基于所述盐中抗衡离子的重量而变化,本领域技术人员可容易地确定这样的量。优选的氟化物盐可以是氟化钠。
本发明的组合物任选地包含可用于例如缓解干口症的唾液刺激剂。可使用任何口腔可接受的唾液刺激剂,包括但不限于食物酸如柠檬酸、乳酸、苹果酸、琥珀酸酸、抗坏血酸、己二酸、富马酸和酒石酸及其混合物。一种或多种唾液刺激剂任选地以唾液刺激有效的总量存在。
本发明的组合物任选地加入一种或多种抗敏感剂,例如,钾盐如硝酸钾、碳酸氢钾、氯化钾、柠檬酸钾和草酸钾;辣椒素;丁香酚;锶盐;锌盐;氯化物盐及其组合。这样的作用剂可以有效量,例如,根据所选择的作用剂以基于组合物总重量的约1 wt %-约20 wt %重量加入。本发明的组合物当应用于牙齿时,也可用来通过堵塞牙本质小管治疗超敏反应。
本发明的组合物还可包含牙齿增白或牙齿漂白组合物,其是本领域已知的。合适的增白和漂白组合物包括过氧化物、金属亚氯酸盐、过硫酸盐。过氧化物包括氢过氧化物、过氧化氢、碱金属和碱土金属的过氧化物、有机过氧化合物、过氧酸及其混合物。碱金属和碱土金属的过氧化物包括过氧化锂、过氧化钾、过氧化钠、过氧化镁、过氧化钙、过氧化物钡及其混合物。其它过氧化物包括过硼酸盐、过氧化脲及其混合物。合适的金属亚氯酸盐可包括亚氯酸钙、亚氯酸钡、亚氯酸镁、亚氯酸锂、亚氯酸钠和亚氯酸钾。这样的作用剂可以有效量加入,例如,根据所选择的作用以基于组合物总重量的约1 wt %-约20 wt %重量加入。
在一些实施方案中,本发明的组合物还包含抗氧化剂。可使用任何口腔可接受的抗氧化剂,包括丁羟回醚(BHA)、丁羟甲苯(BHT)、维生素A、类胡萝卜素、维生素E、类黄酮、多酚、抗坏血酸、草药抗氧化剂、叶绿素、褪黑激素及其混合物。
在一些实施方案中,本发明的组合物还包含营养素。合适的营养素包括维生素、矿物质、氨基酸及其混合物。维生素包括维生素C和D、硫胺、核黄素、泛酸钙、烟酸、叶酸、烟酰胺、吡哆醇、氰钴维生素、对-氨基苯甲酸、生物类黄酮及其混合物。营养补充剂包括氨基酸(如L-色氨酸、L-赖氨酸、甲硫氨酸、苏氨酸、左肉毒碱和L-肉毒碱)、亲脂物质(如胆碱、肌醇、甜菜碱和亚油酸)及其混合物。
本发明的组合物可包含表面活性的作用剂(表面活性剂)。合适的表面活性剂包括但不限于以下的水溶性盐:C8-20烷基硫酸盐、C8-20脂肪酸的磺化单甘油酯、肌氨酸盐、牛磺酸盐、十二烷基硫酸钠、椰油酰基单甘酯磺酸钠、十二烷基肌氨酸钠、十二烷基羟乙基磺酸钠(sodium lauryl isoethionate)、月桂醇聚醚羧酸钠和十二烷基苯磺酸钠、和椰油酰胺丙基甜菜碱。
用于本发明的实践的酶描述于美国专利号7,939,306中,该专利通过引用结合到本文中。这些酶包括蛋白酶类中的蛋白物质,其分解或水解蛋白(蛋白酶)。这些蛋白水解酶从天然来源或通过具有氮源和碳源的微生物的作用而获得。用于本发明的实践的蛋白水解酶的实例包括木瓜蛋白酶、菠萝蛋白酶、胰凝乳蛋白酶、无花果蛋白酶和alcalase。
从木瓜树的乳白色乳胶获得的木瓜蛋白酶是优选用于本发明的实践的蛋白水解酶,并以约0.1-约10%重量和优选约0.5-约5%重量的量掺入本发明的口腔护理组合物中,这样的木瓜蛋白酶具有150-300 MCU/毫克的活性,如通过比德尔索亚组的乳凝块测定试验(Milk Clot Assay Test of the Biddle Sawyer Group) (见J. Biol. Chem.,vol. 121,737-745页)所测定的。
可与蛋白酶木瓜蛋白酶组合配制的另外的酶是葡糖淀粉酶。葡糖淀粉酶是一种经发酵培养的黑曲霉源的糖化葡糖淀粉酶。这种酶可水解葡萄糖基低聚糖的α-D-1,6-糖苷分支点和α-1,4-糖苷键二者。本发明的产物包含约0.001-2%的糖酶且优选地为约0.01-0.55%重量。依据本发明的有用的另外糖酶是葡糖淀粉酶、α和β-淀粉酶、葡聚糖酶(dextranase)和变聚糖酶(mutanase)。
可用于本发明的实践的其它酶包括其它糖酶例如α-淀粉酶、β-淀粉酶、葡聚糖酶和变聚糖酶和脂肪酶例如植物脂肪酶、胃脂肪酶、胰脂肪酶、果胶酶、鞣酸酶、溶菌酶和丝氨酸蛋白酶。
脂肪酶从选择的黑曲霉菌株获得,显示随机裂解脂肪和油的1,3位。当用橄榄油测试时,所述酶在pH 5.0-7.0具有最大的脂肪分解活性。脂肪酶可以约0.010-约5.0%重量和优选地约0.02-约0.10%重量的浓度包括在洁齿剂组合物中。
鞣酸酶的存在可进一步有助于促进外源性染色的分解。鞣酸酶已从黑曲霉和蒜曲霉(Aspergillus allianceus)纯化并用于鞣酸的水解,鞣酸已知使牙齿表面变色。
本发明可包含的其它合适的酶包括来自蛋清的溶菌酶,其含有具有14,600道尔顿分子量的、经4个二硫键交联的单多肽链。通过促进裂解N-乙酰基murarnic酸的1号碳和N-乙酰基-D-葡糖胺的4号碳之间的糖苷键(其经体内聚合形成细胞壁多糖)的细菌细胞壁的水解,所述酶可显示抗菌特性。此外,果胶酶(该酶存在于大多数植物中)促进多糖果胶水解成糖和半乳糖醛酸。
在不同的实施方案中,依据本发明的口腔组合物不是意图吞咽的,而是保留在口腔中足够实现预定的用途的时间。在其它便携式实施方案(例如锭剂、薄荷糖、珠粒、包药干糊片(wafer)、为口腔应用从小型便携式喷雾器配制的液体、为口腔应用从小型便携式液滴产生瓶配制的液体,或柔性软片)中,口腔组合物是意欲吞咽的,任选地在口腔中保留足够实现预定的用途的时间后。
依据本发明的组合物优选地包含在产品例如洁齿剂、漱口剂、口腔清洗剂、牙膏、凝胶、牙用霜剂、口香糖或便携式剂量制品例如,但不限于,锭剂、薄荷糖、珠粒、包药干糊片、为口腔应用从小型便携式喷雾器(喷雾瓶)配制的液体、为口腔应用在小型便携式液滴产生瓶中配制的液体,或柔性软片("口香糖")中的口腔可接受的载体。如果用于动物或宠物,兽用糊剂、可咀嚼剂或动物犒赏食品也可用作口腔可接受的载体。
如在本文所用的,"口腔可接受的载体"指对用于本发明的组合物为安全的、与合理的利益/风险比相称的材料或材料的组合。
在一些实施方案中,本发明还提供包含如上定义的口腔护理组合物的便携式剂量制品,其中便携式剂量制品选自锭剂、薄荷糖、珠粒、包药干糊片、含有在为口腔应用作为喷雾剂配制的液体中的所述混合物的小型便携式喷雾器、含有在为口腔应用作为滴剂配制的液体中的所述混合物的小型便携式瓶、和柔性软片。
优选地,因此,用于本发明的特定材料和组合物是药学上或美容上可接受的,临床上有效的和/或临床上灵验的。如在本文所用的,这样的"药学上可接受的"或"美容上可接受的"、"临床上有效的"和/或"临床上灵验的"组分是适用于人和/或动物的组分,其以提供所需治疗、预防、感官、装饰或美容的益处、而没有过度的不良副作用(例如毒性、刺激性和过敏反应)、与合理的利益/风险比相称的适宜量(临床上有效量)提供。
组合物中的所有成分,除了它们的主要功能外,还可具有其它功能,并可对组合物的整体性质包括稳定性、有效性、一致性、口感、味道、气味等作出贡献。
使用方法
依据本发明的组合物可给予或应用于人或其它哺乳动物受试者。所述组合物可适合给予或应用于人或哺乳动物受试者的口腔。典型地,所述组合物用于抑制微生物生物膜形成和/或降解微生物生物膜。
在一些实施方案中,本发明提供在哺乳动物受试者的口腔中抑制口腔微生物生物膜形成和/或降解口腔微生物生物膜的方法,其包括给予受试者包含Amadori化合物的组合物。
在一些实施方案中,所述方法包括治疗或预防哺乳动物受试者的口腔中的牙菌斑。
在一些实施方案中,本发明提供Amadori化合物在口腔护理组合物中的用途,其用于在哺乳动物受试者的口腔中抑制口腔微生物生物膜形成和/或降解口腔微生物生物膜。
在一些实施方案中,本发明还提供用于预防或治疗口腔的疾病状况的如上定义的组合物。典型地,疾病状况由生物膜形成所引起。疾病状况可选自牙菌斑、龋齿、牙周病、牙龈炎和口臭。
因此,本发明提供用作药物的如上定义的组合物,并且特别是用于抑制微生物生物膜形成和/或降解微生物生物膜。
包含依据本发明的组合物的药物可给予患者。碳水化合物抗代谢物可以有效地抑制生物膜形成和/或降解生物膜,而不与其它口腔护理活性成分不相容或使其它口腔护理活性成分不稳定,且不使其它所需的另外的口腔护理成分失活,同时易于体内传递。
本发明以以下非-限制性实施例举例说明。
实施例
实施例1
在该实施例中,由葡萄糖与甘氨酸的反应制备Amadori化合物(N-(1-脱氧-果糖-1-基)甘氨酸)
将50克D-葡萄糖(278 mmol)、8克焦亚硫酸钠(Na2S2O5, 42 mmol)和7.5 mL去离子(DI)水的混合物加热至95℃。然后将5克甘氨酸(66 mmol)加入到该混合物中并将得到的混合物于95℃加热1小时。将橙-棕色反应混合物用EtOH稀释至最终体积360 mL,其含61 wt%EtOH。以相同的方式制备另外两批反应混合物。
提供结合树脂的色谱柱(Dowex HCR-W2, 氢形式)。柱具有200克树脂和容纳4 cm内径 x 18 cm长度树脂的柱尺寸,和柱的总长度为60 cm。树脂用800 mL的2 N HCl,接着用450 mL的1 N NaOH、800 mL的1 N HCl和200 mL的DI水预处理。将约700 mL的反应混合物填充到树脂柱中。用400 mL的EtOH (70 vol. %)、500 mL的DI水和1000 mL氨水溶液(0.22 N)进行柱分离。将产生的提取物分为多个连续的100mL流分。每个100 mL流分使用质谱检测得自葡萄糖与甘氨酸的反应的Amadori化合物。用MS检测器以m/z: 238 [M+1]建立质谱。
发现得自葡萄糖与甘氨酸的反应的Amadori化合物存在于流分中,所述流分是应用300mL氨水溶液后洗脱的流分。合并含有得自葡萄糖与甘氨酸的反应的Amadori化合物的流分并冷冻干燥。使产生的粉末溶于MeOH,接着经结晶形成结晶的得自葡萄糖与甘氨酸反应的Amadori化合物。
实施例2
在该实施例中,从葡萄糖与精氨酸的反应制备Amadori化合物(N-(1-脱氧-果糖-1-基)精氨酸)。
将50 g的D-葡萄糖(278 mmol)、8 g焦亚硫酸钠(Na2S2O5, 45 mmol)和7.5 mL DI水的混合物加热至95℃。然后,将11.6 g精氨酸加入到该混合物中并将得到的混合物于95℃加热1小时。将橙-棕色反应混合物用150 mL DI水和220 mL的EtOH稀释至最终体积370mL。
采用如在实施例1中使用的相同树脂柱,以分离出得自葡萄糖与精氨酸的反应的Amadori化合物。用400 mL的2 N HCl,接着用225 mL的1 N NaOH,然后用400 mL 1 N HCl预处理树脂。随后,将200 mL样品溶液填充到树脂柱中。用400 mL的EtOH (70 vol. %)、400mL的DI水和氨水溶液(0.22 N)进行洗脱。使用液相色谱/质谱(LC/MS)检测每个100 mL流分的得自葡萄糖与精氨酸反应的Amadori化合物。合并含有得自葡萄糖与精氨酸反应的Amadori化合物的流分并冷冻干燥。使产生的粉末溶于MeOH,接着经重结晶形成结晶的得自葡萄糖与精氨酸反应的Amadori化合物。
实施例3
在该实施例中,从葡萄糖与赖氨酸的反应制备Amadori化合物(N-(1-脱氧-果糖-1-基)赖氨酸)。
将50 g的D-葡萄糖(278 mmol)、8 g焦亚硫酸钠(Na2S2O5, 45 mmol)和7.5 mL DI水的混合物加热至95℃。然后将12.2 g赖氨酸加入到该混合物中并将得到的混合物于95℃加热1小时。将橙-棕色反应混合物用150 mL DI水和220 mL的EtOH稀释至最终体积370 mL。
采用如在实施例1中使用的相同树脂柱以分离出得自葡萄糖与赖氨酸的反应的Amadori化合物。用400 mL的2 N HCl,接着用225 mL的1 N NaOH,然后用400 mL的1 N HCl预处理树脂。随后,将200 mL样品溶液填充到树脂柱中。用400 mL的EtOH (70 vol. %)、400mL的DI水和氨水溶液(0.22 N)进行柱分离。使用LC/MS检测每个100 mL流分的得自葡萄糖与赖氨酸反应的Amadori化合物。合并含有得自葡萄糖与赖氨酸反应的Amadori化合物的流分并冷冻干燥。使产生的粉末溶于MeOH,接着经重结晶形成结晶的得自葡萄糖与赖氨酸反应的Amadori化合物。
实施例4
在该实施例中,从葡萄糖与谷氨酸的反应制备Amadori化合物(N-(1-脱氧-果糖-1-基)谷氨酸)。
将3.74 g氢氧化钾(67 mmol)在无水甲醇(100 mL)中的溶液加入到9.82 g的L-谷氨酸(67 mmol)中并搅拌直至氨基酸稍稍溶解。加入甲醇(300 mL)和7.2 g的D-葡萄糖(40mmol),并搅拌悬浮液并在回流下于75℃加热1小时。置换经煮沸除掉和收集的甲醇,并将该混合物在回流下于75℃再次加热1小时。对于第二次,置换经煮沸除掉和收集的甲醇。将另外3.7408 g氢氧化钾(67 mmol)加入到该混合物中,然后在回流下于75℃加热1小时。
将产生的橙-棕色反应混合物冷却至室温并在真空下浓缩至100 mL。剩余的氨基酸通过过滤除去并将含有产物的滤液转移至4个离心小瓶中。将丙酮滴加入滤液中,将得到的在过量的丙酮中的黄色沉淀物以9000 rpm离心15 min。除去上清液,加入20 mL甲醇以再次溶解生成的固体沉淀。样品通过从甲醇/丙酮中2次重结晶纯化,形成结晶的得自葡萄糖与谷氨酸反应的Amadori化合物。
实施例5
在该实施例中,研究得自葡萄糖与甘氨酸的反应的Amadori化合物抑制变异链球菌(Streptococcus mutans)的葡萄糖代谢的能力。
葡萄糖通常可通过由可存在于口腔中的几种口腔细菌成分例如变异链球菌(S. mutans)生成的酶在口腔中被代谢。
制备溶于蒸馏水的0.4 wt%葡萄糖的葡萄糖储备液(0.4g/100mL)。将4.0 wt%的得自葡萄糖与甘氨酸反应的Amadori化合物溶于蒸馏水(0.4g/10mL),制备得自葡萄糖与甘氨酸反应的Amadori化合物储备液。
如下制备细菌溶液:将变异链球菌(ATCC # 25175)在TSB培养基中培养过夜,然后使得到的细菌沉淀用磷酸盐缓冲盐水(pH = 7.4) (PBS)再悬浮细菌至OD610=0.8 (具有对于1-cm光通路,在610 nm的0.8光学读数的浓度)。
根据实施例5,使包含1mL细菌溶液、0.5mL的得自葡萄糖与甘氨酸反应的Amadori化合物溶液和0.5mL葡萄糖溶液的试验样品于37℃ (代表正常的人体温)的温度经历培养。
然后,在培养期10分钟后、培养期30分钟后和培养期60分钟后,将200µL试验样品转移到各个HPLC小瓶。使用HPLC小瓶盖密封小瓶。立即将HPLC小瓶置于100℃水浴中约5分钟使酶变性。
使得到的产物经历气相色谱-质谱(GC-MS)测试和分析以确定α-和β-葡萄糖形式存在的量。结果示于表1。在表1中,指明了在MS检测期间,在各自的培养时间,在各个样品中检测的每个各自的α-和β-葡萄糖形式的计量数,计量数表示各种葡萄糖形式存在的量
比较实施例1
在比较实施例1中,在对照样品上重复实施例5的测试,所述对照样品包含1mL细菌溶液、0.5mL葡萄糖溶液和0.5mL去离子水。换言之,比较实施例1没有得自葡萄糖与甘氨酸反应的Amadori化合物。也使对照样品于37℃温度经历培养相同的各个时间段。相应的结果也示于表1中。
从表1可以看出,将实施例5的试验样品与比较实施例1的对照样品进行比较,得自葡萄糖与甘氨酸的反应的Amadori化合物的存在抑制在口腔细菌的存在下的葡萄糖代谢。在实施例5中,当得自葡萄糖与甘氨酸反应的Amadori化合物与葡萄糖和变异链球菌细菌一起存在时,葡萄糖计数是高的,然而在比较实施例1中,当得自葡萄糖与甘氨酸反应的Amadori化合物不与葡萄糖和变异链球菌细菌一起存在时,葡萄糖计数是低的。因此,得自葡萄糖与甘氨酸反应的Amadori化合物抑制葡萄糖代谢。
当变异链球菌于37℃与葡萄糖一起培养时,葡萄糖可被代谢。然而,当得自葡萄糖与甘氨酸反应的Amadori化合物与变异链球菌和葡萄糖共同培养时,表1中的结果表明葡萄糖代谢在从10至60分钟的培养时间段内被显著地抑制,即抑制至少56%。
实施例6
在该实施例中,研究得自葡萄糖与甘氨酸反应的Amadori化合物抑制生物膜形成的能力。
使培养的变异链球菌(ATCC # 25175)细菌的样品在TSB培养基中生长过夜,随后经离心形成沉淀,然后将离心的变异链球菌用含有1%葡萄糖的TSB (胰蛋白酶大豆肉汤)再悬浮并调节至OD610=0.5 (具有对于1-cm光通路,在610 nm的0.5的光学读数的浓度)。将再悬浮的变异链球菌(OD610=0.5)的50微升样品与50微升试验样品共同培养。试验样品含1wt%葡萄糖和2 wt%得自葡萄糖与甘氨酸反应的Amadori化合物。总计100 µL的再悬浮的变异链球菌(OD610=0.5)和试验样品,表示一种澄清的唾液,在96-孔板(该板用澄清的唾液预包被)中共同培养,然后于37℃放置过夜。
共同培养期后,从孔板抽吸上清液液体。将50微升量的结晶紫加入到各孔中并允许染色任何生物膜10分钟的时期。用100 µL的PBS洗涤该孔板。
生物膜的量通过用具有波长590 nm的电磁辐射照射孔板并测量吸光度来测定。结果示于表2。吸光度读数越低,所检测的生物膜的量越少。
比较实施例2
在比较实施例2中,对照样品含有变异链球菌和1 wt%葡萄糖并经如在实施例6中相同的共同培养试验处理和吸光度测量。结果示于表2。
实施例7
在该实施例中,研究得自葡萄糖与精氨酸的反应的Amadori化合物抑制生物膜形成的能力。样品制备和对生物膜的测试与实施例6的相同,但代替1 wt%葡萄糖和2 wt%得自葡萄糖与甘氨酸反应的Amadori化合物,试验样品含有1 wt%葡萄糖和2 wt%得自葡萄糖与精氨酸的反应的Amadori化合物。在相同的共同培养试验后,生物膜的量使用实施例6的试验方法再次测定。吸光度读数结果示于表2。
实施例8
在该实施例中,研究得自葡萄糖与谷氨酸反应的Amadori化合物抑制生物膜形成的能力。
样品制备和对生物膜的测试与实施例6的相同,但代替1 wt% of葡萄糖和2 wt%得自葡萄糖与甘氨酸反应的Amadori化合物,试验样品含有1 wt%和葡萄糖和2 wt%得自葡萄糖与谷氨酸反应的Amadori化合物。
在相同的共同培养试验后,生物膜的量使用实施例6的试验方法再次测定。吸光度读数结果示于表2。
表2显示实施例6表现出低量的生物膜,这通过平均吸光度读数0.2885得到反映。
表2显示实施例7也表现出适当低量的生物膜,这通过平均吸光度读数1.2808得到反映。
表2显示实施例8也表现出低量的生物膜,这通过平均吸光度读数0.5476得到反映。
表2显示比较实施例2表现出高量的生物膜,这通过平均吸光度读数2.0346得到反映。
讨论实施例6-8和比较实施例1的结果,葡萄糖通常可通过由几种口腔细菌成分例如变异链球菌生成的酶的作用在口腔中聚合为葡聚糖。这样的聚合可引起生物膜在牙齿表面上形成,其随后可形成牙菌斑。在实验上,从实施例6-8发现,当葡萄糖与变异链球菌和各个Amadori化合物在包被唾液的96-孔板中共同培养时,与当葡萄糖与变异链球菌但没有任何Amadori化合物在包被唾液的96-孔板中共同培养时相比较,生物膜受到抑制。该实验数据显示,Amadori化合物抑制生物膜形成,并因此减少牙菌斑在牙齿表面上的形成。
生物膜形成结果在不同的Amadori化合物之间是不同的。如在表2中所示的,得自葡萄糖与甘氨酸反应的Amadori化合物和得自葡萄糖与谷氨酸反应的Amadori化合物两者对生物膜形成表现出非常强烈的抑制作用,而得自葡萄糖与精氨酸的反应的Amadori化合物表现出相对弱的抑制作用,但其无论如何强于在得自葡萄糖与精氨酸的反应的Amadori化合物不存在时的抑制作用。本发明人相信,不受任何理论的束缚,氨基酸部分的侧链和电子的电荷可影响形成葡聚糖和因此形成生物膜的酶活性。
本发明人还相信,不受任何理论的束缚,Amadori化合物在化学结构上与葡萄糖类似,其在葡萄糖降解和聚合期间可附着于酶的活性部分。然而,由于Amadori化合物不是葡萄糖,因此它们可有效地抑制葡萄糖降解和聚合酶。
总而言之,实验已经发现,来自葡萄糖与甘氨酸反应的Amadori化合物可显著地抑制葡萄糖降解和生物膜形成。实验已经发现,来自葡萄糖与谷氨酸反应的Amadori化合物也可抑制生物膜形成。实验还发现,在较小程度上,得自葡萄糖与精氨酸的反应的Amadori化合物也可抑制生物膜形成。
因此,本发明人已经发现几种Amadori化合物对口腔护理应用的新用途,例如,已发现代表葡萄糖和选自甘氨酸(最小的氨基酸)、谷氨酸(带负电荷氨基酸)、赖氨酸和精氨酸(带正电荷氨基酸)的氨基酸部分的反应产物的4种Amadori化合物显著地抑制葡萄糖的酸降解和口腔细菌的生物膜形成。
本领域技术人员将意识到,在不背离本发明的精神的情况下,可以对本文描述的实施方案进行各种变化和修饰。意欲使所有这样的变化落入所附权利要求书的范围内。
Claims (15)
1.Amadori化合物在制备用于在哺乳动物受试者的口腔中抑制或减少口腔微生物生物膜形成的口腔护理组合物中的用途,其中Amadori化合物是葡萄糖与氨基酸的反应产物,其中氨基酸选自丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。
2.权利要求1的用途,其中氨基酸选自甘氨酸、赖氨酸、谷氨酸和精氨酸。
3.权利要求1或2的用途,其中Amadori化合物以基于组合物总重量的0.005 wt %-10wt %的浓度存在于组合物中。
4.权利要求1或2的用途,其中Amadori化合物以基于组合物总重量的0.1 wt %-7.5 wt%的浓度存在于组合物中。
5.权利要求1或2的用途,其中Amadori化合物以基于组合物总重量的1 wt %-5 wt %的浓度存在于组合物中。
6.权利要求1或2的用途,其中组合物包含口腔可接受的载体并被配制为洁齿剂、凝胶或锭剂。
7.权利要求6的用途,其中组合物被配制为口腔清洗剂。
8.权利要求6的用途,其中组合物被配制为牙膏、牙用霜剂、漱口剂或口香糖。
9.权利要求1或2的用途,其中组合物还包含不是Amadori化合物的抗微生物剂、抗-牙菌斑剂、增白剂、清洁剂、粘附剂、表面活性剂、泡沫调节剂、研磨剂、pH调节剂、保湿剂、口感剂、着色剂、牙垢控制剂、氟离子源、唾液刺激剂、抗-敏感剂、抗氧化剂、营养素、酶及其组合。
10.权利要求9的用途,其中组合物进一步包含矫味剂。
11.权利要求9的用途,其中组合物进一步包含甜味剂。
12.权利要求9的用途,其中抗微生物剂选自三氯生、西吡氯铵、木兰提取物、厚朴酚、和厚朴酚、丁基厚朴酚、丙基和厚朴酚、氯化锌、乳酸锌、柠檬酸锌、氟化亚锡和氯化亚锡。
13.权利要求9的用途,其中牙垢控制剂是聚羧酸酯聚合物或聚乙烯甲基醚/马来酸酐(PVM/MA)共聚物。
14.权利要求9的用途,其中酶是选自蛋白酶、糖酶、脂肪酶、鞣酸酶、溶菌酶、果胶酶及其组合的一种或多种酶。
15.权利要求14的用途,其中蛋白酶选自木瓜蛋白酶、菠萝蛋白酶、胰凝乳蛋白酶、无花果蛋白酶、alcalase及其组合,和糖酶选自葡糖淀粉酶、α-淀粉酶、β-淀粉酶、葡聚糖酶、变聚糖酶及其组合。
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"Amadori Compounds as Nonvolatile Flavor Precursors in Processed Foods";Frank D.Mills,等;《AGRIC.FOOD CHEM.》;19690831;第17卷(第4期);第723-727页 * |
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Publication number | Publication date |
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MX2015007781A (es) | 2015-09-04 |
CN104936576A (zh) | 2015-09-23 |
WO2014098793A1 (en) | 2014-06-26 |
US9993414B2 (en) | 2018-06-12 |
US20150328120A1 (en) | 2015-11-19 |
AR094040A1 (es) | 2015-07-08 |
AU2012397308B2 (en) | 2016-01-21 |
BR112015014254A2 (pt) | 2017-07-11 |
MX352553B (es) | 2017-11-29 |
AU2012397308A1 (en) | 2015-06-11 |
EP2931241B1 (en) | 2017-02-15 |
TW201436815A (zh) | 2014-10-01 |
EP2931241A1 (en) | 2015-10-21 |
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