CN112996532A - 一种选择性抑制痤疮丙酸杆菌细菌生长的抗微生物组合物 - Google Patents
一种选择性抑制痤疮丙酸杆菌细菌生长的抗微生物组合物 Download PDFInfo
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- CN112996532A CN112996532A CN201980074139.1A CN201980074139A CN112996532A CN 112996532 A CN112996532 A CN 112996532A CN 201980074139 A CN201980074139 A CN 201980074139A CN 112996532 A CN112996532 A CN 112996532A
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- propionibacterium acnes
- endolysin
- thymol
- skin
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Abstract
本发明涉及一种通过选择性抑制痤疮丙酸杆菌细菌来预防或治疗痤疮的方法和组合物。该方法包含用痤疮丙酸杆菌噬菌体来源的内溶素和编码其的核酸分子与选择性精油组合来治疗皮肤。
Description
技术领域
本发明涉及一种通过选择性抑制痤疮丙酸杆菌(P.acnes)细菌来预防或治疗痤疮的方法和组合物。该方法包含用内溶素(endolysin)与精油化合物组合治疗皮肤。
背景技术
痤疮，也称为寻常痤疮(Acne vulgaris)，是一种常见的皮肤症状，几乎所有的青少年和成人在其人生的某个阶段都会受到影响。其病因复杂，涉及异常角质化，皮脂生成过多，雄激素功能，细菌生长和免疫超敏反应。虽然上述过程中的一个或多个与痤疮相关，但是导致痤疮损害形成的事件的一种触发因素和确切顺序尚未被完全了解。与痤疮有关的其它因素是自由基的存在以及随后导致细胞损伤的氧化应激。已观察到痤疮通常发生在富含皮脂腺的区域，如面部、颈部和背部。
细菌痤疮丙酸杆菌(Propionibacterium acnes)也与痤疮的发生有关。其为驻留在人面部皮肤表面的重要细菌和优势细菌之一。痤疮丙酸杆菌是一种兼性厌氧、生长缓慢的棒状革兰氏阳性菌。其存在于皮脂腺中，且其构成皮肤共生微生物群的重要部分。痤疮丙酸杆菌利用皮脂和来自周围皮肤组织的副产物作为能量和营养源。这导致一些脂肪酸释放，其可以刺激卵泡壁并引起炎症，从而导致痤疮或寻常痤疮。寻常痤疮是一种毛囊皮脂腺的慢性炎性病症。几乎所有的青少年在其人生的某个阶段会受到影响，其中15-20％患有中度至重度形式的痤疮。
痤疮已经以多种方式治疗。大多数治疗需要数周至数月才能观察到明显变化。具有抗菌作用的过氧化苯甲酰已用于轻度粉刺病例。在非常严重的痤疮病例中，已使用了抗生素如四环素、红霉素和克林霉素。抗生素被认为通过几种机制起作用，最重要的是减少了毛囊中和周围的细菌数量。它们还被认为可减少由皮脂中的白血细胞产生的刺激性化学物质，从而减少炎症反应。然而，抗生素和其他种类的常规抗微生物治疗的缺点是它们是广谱的，及有助于杀死或抑制皮肤上的大部分细菌。
如上所述，大部分治疗涉及使用合成化学品。许多人不喜欢使用合成化学品，因为他们认为其对人体有害。一些人认为合成化学品会引起副作用。因此，越来越多的人喜欢使用“天然的”材料，例如基于草药来源的活性物质。此外，近来，基于微生物或生物技术来源的活性物质也被认为是比目前使用的纯合成方法更“天然”的。
皮肤是人体的最大器官，被多种微生物定殖。大多数微生物被认为是有益的或机会性的潜在病原体。DNA测序和计算生物学的最新进展正在帮助我们以更高的分辨率鉴定和了解这些微生物对皮肤的有益作用。
皮肤微生物与人类宿主之间的相互作用可以分为三类：1.共生(一方受益，且另一方无害)，2.互惠共生(两方都受益)，3.寄生(一种有机体受益，而另一方受到损害)。通常与疾病相关的微生物主要称为共生体(commensals)。越来越多的证据表明，皮肤上的共生生物可有助于免疫系统对抗病原体并维持微生物群系的内稳态。一个实例为表皮葡萄球菌(Staphylococcus epidermidis)(一种革兰氏阳性凝固酶阴性葡萄球菌)，其在痤疮抑制中起重要作用。表皮葡萄球菌介导甘油的发酵，甘油抑制痤疮丙酸杆菌的过度生长，从而导致痤疮抑制。
因此，使用杀死或抑制皮肤上的所有微生物的广谱抗生素功能的方法在医疗保健从业者中发现越来越不被接受。选择性杀死或抑制皮肤上微生物的方法日益受到医疗保健从业者的青睐。此外，在处理痤疮丙酸杆菌的抗生素抗性菌株中使用抗生素是无效的。
因此，需要找到以选择性方式治疗诸如痤疮的问题的新方法。因此，本发明人开始致力于提供解决痤疮问题的“天然”解决方案。他们采用测试杀死或选择性抑制痤疮丙酸杆菌而非其他生物体如表皮葡萄球菌、大肠杆菌(E.coli)和金黄色葡萄球菌(S.aureus)的生长的新活性物质的方法，并对其进行了实验。他们最终找到了一种痤疮丙酸杆菌噬菌体来源的内溶素与一种精油化合物的组合，该组合被发现可以协同相互作用以选择性抑制痤疮丙酸杆菌的生长。
名称为“抗痤疮的治疗(Treatments for resistant acne)”的US2016346294(Vyome Biosciences)总体上涉及用于治疗一般细菌感染并且更具体地治疗具有抗生素抗性病原体的细菌感染的新分子、组合物和制剂。其中例举的是头状葡萄球菌(S.capitis)(未具体提及亚种)，其被认为是病原体，而非抗微生物剂。
EP23488316B1(Unilever，2013)公开了一种包含麝香草酚和萜品醇的组合对表面进行消毒的方法以及一种包含其的洗去组合物。
上述两个出版物没有教导痤疮丙酸杆菌噬菌体来源的内溶素与精油化合物的组合可以用于选择性抑制痤疮丙酸杆菌的生长。
本发明的一个目的为提供对痤疮丙酸杆菌的选择性杀死或抑制以治疗痤疮。
本发明的另一个目的为提供通过更天然或基于天然的活性物质治疗痤疮的解决方案。
发明内容
根据本发明的第一方面，提供了一种用于选择性抑制痤疮丙酸杆菌细菌的生长的抗微生物组合物，其包含
(i)痤疮丙酸杆菌噬菌体来源的内溶素或编码其的核酸分子；和
(ii)具有以下结构的通式1的精油化合物
其中R1为H、OH或OR，其中R为具有1至5个碳原子的烷基链；
R2为C1至C6直链烷基；或C3至C6支链烷基；或C5至C6环烷基或杂环烷基；或C6芳基。
根据本发明的另一方面，提供了一种控制或根除来自皮肤的痤疮丙酸杆菌的方法，其包含将本发明的组合物施用于所需的皮肤表面上的步骤。
具体实施方式
通过阅读以下详细描述和所附权利要求书，这些和其它方面、特征和优点对于本领域的普通技术人员将变得显而易见。为了避免疑问，本发明的一个方面的任何特征可用于本发明的任何其它方面。词语“包含”旨在表示“包括”但不一定“由…组成(consistingof)”或“由…构成(composed of)”。换言之，所列出的步骤或选项不必是穷举的。应注意，在以下描述中给出的实施例旨在阐明本发明，而不旨在将本发明限于这些实施例本身。类似地，除非另外指明，否则所有百分比均为重量/重量百分比。
除了在操作和对比实施例中，或在另外明确指示的情况下，本说明书中指示材料的量或反应条件、材料的物理特性和/或用途的所有数字应理解为由词语“约”修饰。除非另外指明，否则以格式“x至y”表示的数值范围应理解为包括x和y。当对于特定特征以“x至y”的格式描述多个优选范围时，应当理解，组合不同端点的所有范围也是预期的。
根据本发明的组合物可以是用于清洁或消毒哺乳动物(特别是人类)的表面区域例如皮肤和/或毛发的免洗型(leave-on format)或洗去型(wash-off format)形式。这种组合物包括应用于人体的还用于改善外观、清洁度、气味控制或总体美观的任何产品。本发明的组合物可为液体、乳液(lotion)、霜剂、泡沫或凝胶或化妆水(toner)的形式，或与用具一起施用或经由面膜、垫或贴片施用。如本文所用的“皮肤”是指包括面部和身体(例如，颈部、胸部、背部、臂部、腋下、手部、腿部、臀部和头皮)上的皮肤。其尤其可用于治疗面部或形成痤疮的身体的任何其它部位的痤疮。
根据本发明的组合物包含痤疮丙酸杆菌噬菌体来源的内溶素和编码其的核酸分子。尤其优选的组合物包含痤疮丙酸杆菌噬菌体来源的内溶素。
痤疮丙酸杆菌(P.acnes)是指痤疮丙酸杆菌(Propionibacterium acnes)，也称为痤疮丙酸杆菌(Cutibacterium acnes)。
本发明人研究了用于抑制痤疮丙酸杆菌的各种方法，并为此目的实现了细菌噬菌体和细菌噬菌体来源的酶的应用。一组噬菌体来源的酶是称为内溶素的肽聚糖(PG)水解酶。内溶素是由双链DNA噬菌体编码的新型胞壁水解酶(muralytic hydrolase)，其降解细菌细胞壁的PG层，从而使子代噬菌体在感染周期的后期逃逸。当外部暴露于PG时，纯化的内溶素可引起“从外部裂解”。基于其抗微生物特性(当外部添加时具有特别的底物特异性和高活性)，来自感染革兰氏阳性病原体的噬菌体的内溶素是本发明人的动机和假设，作为本发明的组合物的一个要素。
因此，有用的是所含的内溶素为重组形式的痤疮丙酸杆菌噬菌体內溶素。该内溶素优选是从丙酸杆菌噬菌体29399B_C(GenBank：JX262225.1)的内溶素基因序列(基因ID：NC_018851；855个核苷酸碱基对长，284个氨基酸，蛋白质ID：97935.1)克隆的，其经密码子优化以在大肠杆菌中表达并克隆至可商购的pET303/CT-His表达载体中。
特别有用的内溶素的核苷酸序列如以下列出的序列ID SEQ ID1所示：
ATGCGTTATATTCCGGCAGCACATCATTCAGCAGGTAGCAATCATCCGGTTAATCGTGTTGTTATTCATGCAACCTGTCCGGATGTTGGTTTTCCGAGCGCAAGCCGTAAAGGTCGTGCAGTTAGCACCGCAAACTATTTTGCAAGCCCGAGCAGCGGTGGTAGCGCACATTATGTTTGTGATATTGGTGAAACCGTTCAGTGTCTGAGCGAAGGCACCATTGGTTGGCATGCACCGCCTAATCCGCATAGCCTGGGTATTGAAATTTGTGCAGATGGTGGTAGCCATGCAAGCTTTCGTGTTCCGGGTCATGCATATACCCGTGAACAGTGGCTGGATCCGCGTGTTTGGCCTGCAGTTGAAAAAGCAGCAATTCTGTGTCGTCGTCTGTGCGATAAATACAATGTTCCGAAACGTAAACTGAGCGCAGCAGATCTGAAAGCAGGTCGTCGTGGTGTTTGTGGTCATGTTGATGTTACCGATGCATGGCATCAGAGCGATCATGATGATCCGGGTCCGTGGTTTCCGTGGGATCGTTTTATGGCAGTTGTTAATGGTCATAACGAAAGCGGTGAACTGACCGTTGCAGATGTTAAAGCACTGCATGATCAGATTAAACAGCTGAGCGCACAGCTGGCAGGTAGCGTTAATAAACTGCATCATGATGTTGGTGTTGTTCAGGTTCAGAATGGTGATCTGGGTAAACGTGTTGATGCACTGAGCTGGGTTAAAAATCCGGTTACCGGTAAACTGTGGCGTACCAAAGATGCACTGTGGTCAGTTTGGTATTATGTTCTGGAATGTCGTAGCCGTATTGATCGTCTGGAAAGCGCAGTTAATGGTCTGAAAAAACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAA。
一个特别优选的方面涉及其中终止密码子从基因的3'端去除以容纳6X组氨酸标签的內溶素。
具有C端组氨酸标签(x6)的内溶素的多肽序列
MRYIPAAHHSAGSNHPVNRVVIHATCPDVGFPSASRKGRAVSTANYFASPSSGGSAHYVCDIGETVQCLSEGTIGWHAPPNPHSLGIEICADGGSHASFRVPGHAYTREQWLDPRVWPAVEKAAILCRRLCDKYNVPKRKLSAADLKAGRRGVCGHVDVTDAWHQSDHDDPGPWFPWDRFMAVVNGHNESGELTVADVKALHDQIKQLSAQLAGSVNKLHHDVGVVQVQNGDLGKRVDALSWVKNPVTGKLWRTKDALWSVWYYVLECRSRIDRLESAVNGLKKLEHHHHHH。
用于可选地包括在本发明的组合物中的内溶素的核酸分子也可能包含该内溶素的片段、变体和融合物，其能够特异性结合和/或裂解痤疮丙酸杆菌的细胞。
本发明的组合物包括具有以下结构的通式的精油化合物
其中R1为H、OH或OR，其中R为具有1至5个碳原子的烷基链；
R2为C1至C6直链烷基；或C3至C6支链烷基；或C5至C6环烷基或杂环烷基；或C6芳基。
用于本发明组合物中的根据式2的化合物的最优选的精油化合物选自：麝香草酚、香芹酚、(E)-2(丙-1-烯基)苯酚、2-丙基苯酚、4-戊基苯酚、4-仲丁基苯酚、2-苄基苯酚或丁香酚或其组合。
这些化合物的结构如下所示：
麝香草酚的结构如下所示：
麝香草酚
香芹酚
(E)-2(丙-1-烯基)苯酚
2-丙基苯酚
4-戊基苯酚
4-仲丁基苯酚
2-苄基苯酚
丁香酚
上述精油化合物中，麝香草酚、香芹酚、4-戊基苯酚或4-仲丁基苯酚更优选用于本发明的组合物中。最优选的精油化合物为麝香草酚。
按组合物的重量计，精油化合物优选以0.001％至1％，优选0.005％至1％，更优选0.005％至0.5％包括在组合物中。
进一步更优选地，在本发明的组合物中包括萜烯基的其他精油化合物。最优选的萜烯基化合物为萜品醇。萜品醇优选选自：α-萜品醇、β-萜品醇、γ-萜品醇或其混合物。特别优选的是萜品醇为α-萜品醇。萜品醇可以纯化形式加入抗微生物组合物中。
萜品醇化合物的结构如下：
按组合物的重量计，该抗微生物组合物优选包含0.01％至1％的萜品醇，更优选0.05％至0.5％的萜品醇。
根据本发明的一个特别优选的方面，该组合物包含麝香草酚和萜品醇的混合物。
不希望受理论的束缚，本发明人认为，精油与内溶素的组合协同地靶向对细菌防御至关重要的两种不同的底物。他们认为，对于革兰氏阳性菌如痤疮丙酸杆菌，内溶素会干扰细菌的最外层包衣(即细胞壁)，从而为麝香草酚提供快速通路以靶向细菌内细胞膜中的脂质部分。这一起解释了痤疮丙酸杆菌的快速和特异性裂解。
本发明的组合物优选包括表面施用可接受的载体。优选的表面施用可接受的载体可包含无水性基质、凝胶、乳液、霜剂或乳剂。
本发明的组合物优选为洗去组合物，并且这通过包括以重量计1％至80％的表面活性剂来实现。通常，该表面活性剂可选自众所周知的教科书(如“Surface ActiveAgents”第1卷，Schwartz&Perry,Interscience 1949，第2卷，Schwartz,Perry&Berch,Interscience1958和/或“McCutcheon's Emulsifiers and Detergents”现行版，Manufacturing Confectioners Company出版或“enside Taschenbuch”，H.Stache,第二版,Carl Hauser Verlag,1981)中所述的表面活性剂。可以使用任何类型的表面活性剂，即阴离子、阳离子、非离子、两性离子或两性表面活性剂。
特别优选的表面活性剂为肥皂。肥皂是用于本发明组合物的个人洗涤应用的合适表面活性剂。肥皂优选为C8-C24肥皂，更优选为C10-C20肥皂，且最优选为C12-C16肥皂。肥皂可以具有或可以不具有一个或多个碳-碳双键或三键。肥皂的阳离子可以为碱金属、碱土金属或铵。优选地，肥皂的阳离子选自钠、钾或铵。更优选地，肥皂的阳离子为钠或钾。
肥皂可通过脂肪和/或脂肪酸的皂化获得。通常用于肥皂制造的脂肪或油可为诸如牛脂(tallow)、牛脂硬脂(tallow stearines)、棕榈油、棕榈硬脂、大豆油、鱼油、蓖麻油、米糠油、向日葵油、椰子油、巴巴苏油、棕榈仁油等。在上述方法中，脂肪酸衍生自选自椰子、米糠、花生(groundnut)、牛脂、棕榈、棕榈仁、棉籽、大豆、蓖麻等的油/脂肪。
典型的脂肪酸混合物由5％-30％椰子脂肪酸和70％-95％来自硬化米糠油的脂肪酸组成。衍生自其它合适的油/脂肪诸如花生、大豆、牛脂、棕榈、棕榈仁等的脂肪酸也可以其它所需比例使用。最优选的肥皂为月桂酸根肥皂。当存在于本发明的固体形式中时，肥皂的存在量为以组合物重量计的30％至90％，优选50％至85％，更优选55％至75％。当存在于组合物的液体形式中时，肥皂的存在量为以组合物重量计的0.5％至20％，优选1％至10％。
或者，表面活性剂为非离子表面活性剂，诸如C8-C22，优选C8-C16脂肪醇乙氧基化物，包含1-8个的环氧乙烷，该表面活性剂优选选自：伯烷基硫酸盐、仲烷基磺酸盐、烷基苯磺酸盐或乙氧基化烷基硫酸盐。该组合物可进一步包含阴离子表面活性剂，诸如烷基醚硫酸盐，优选具有1至3个环氧乙烷基团的那些，来自天然或合成来源，和/或磺酸。特别优选的是月桂基醚硫酸钠。烷基多葡糖苷也可存在于组合物中，优选碳链长度为C6-C16的那些。在清洁应用的液体形式中合适的表面活性剂浓度通常以组合物重量计大于0.5％但小于10％，优选为1％至5％。在固体组合物中，表面活性剂的存在量为以组合物重量计的5％至40％，优选为10％至30％。
根据组合物的形式，水的存在量可优选地为以组合物重量的10％至90％。在固体组合物中，水的存在量可为10％-30％，而在液体或半固体组合物中，水的存在量可为40％-90％。
本发明的组合物特别适用于其中抗微生物活性物质与表面的接触时间短，即小于5分钟，优选小于2分钟，进一步更优选小于1分钟并且在许多情况下小于15秒的洗去(washoff)方法。
当根据本发明的组合物为免洗组合物时，其优选包含香料(fragrance)、表面活性剂、有机防晒剂、无机防晒剂、润肤剂(emollient)、湿润剂、体质颜料(extender pigment)和防腐剂中的一种或多种。
防晒剂包括阻挡有害紫外光的那些物质。优选的防晒剂为对氨基苯甲酸(PABA)、肉桂酸盐(cinnamate)和水杨酸盐(salicylate)的衍生物。例如，可以使用阿伏苯甲酮(avobenzophenone)(
1789)、甲氧基肉桂酸辛酯和2-羟基-4-甲氧基苯甲酮(也称为氧苯酮)。甲氧基肉桂酸辛酯和2-羟基-4-甲氧基苯甲酮分别以商标
MCX和苯甲酮-3(Benzophenone-3)商购获得。也可使用
(一种亚苄基樟脑衍生物)和甲酚曲唑三硅氧烷(drometrizole trisiloxane)(一种苯并三唑)。进一步的实例包括奥克立林(Octocrylene)、苯基苯并咪唑磺酸(也称为
)、水杨酸乙基己酯、萘甲酸二乙基己酯，bimotrizinole(商标为
S)和双辛酚三唑(bisoctrizole)(
M)。无机防晒剂包括反射或散射太阳光线的氧化物如二氧化钛和氧化锌。组合物中防晒剂的存在量可以根据所需的免受UV辐射的防护程度而变化。优选地，该组合物包含以重量计的0.01％-15％，更优选以防晒剂重量计的0.1％-10％，且最优选0.5-％7.5％。
可以使用的香料类型的示例性实例包括包含萜烯和萜烯衍生物的那些，如Bauer,K.,et al.,Common Fragrance and Flavor Materials,VCH Publishers(1990)中所述的那些。其它实例包括月桂烯、二氢月桂烯醇、柠檬醛、万寿菊酮、顺式-牛龙牛儿酸、香茅酸、其混合物。
载体作为组合物的成分的稀释剂或分散剂。载体可以是水性基的、无水的或乳液，其中通常优选油包水或水包油乳液。如果需要使用水，则水通常构成组合物的余量，其最优选为以组合物重量计的40％至80％。
除了水之外，可以任选地包括有机溶剂作为载体以辅助本发明的组合物中的任何其他载体。实例包括烷醇如乙醇和异丙醇。
其它合适的有机溶剂包括酯油如肉豆蔻酸异丙酯、肉豆蔻酸鲸蜡酯、肉豆蔻酸2-辛基十二烷基酯、鳄梨油、杏仁油、橄榄油和新戊二醇二癸酸酯。通常，这种酯油有助于乳化组合物，并且通常使用有效量以产生稳定的，并且最优选地，油包水乳液。
如果需要，也可以使用润肤剂作为载体。优选醇如1-十六醇(即鲸蜡醇)。其它润肤剂包括硅油和合成酯。适宜使用的硅油包括含有3-9个，优选4-5个硅原子的环状或线性聚二甲基硅氧烷。可用作润肤剂的非挥发性硅油包括聚烷基硅氧烷、聚烷基芳基硅氧烷和聚醚硅氧烷共聚物。非挥发性聚烷基硅氧烷可用聚二甲基硅氧烷。也可以使用硅氧烷弹性体。可任选使用的酯润肤剂为：
(i)具有10至20个碳原子的脂肪酸的烯基或烷基酯。其实例包括新戊酸异花生基酯(isoarachidyl neopentanoate)、异壬酸异壬酯、肉豆蔻酸油酯、硬脂酸油酯和油酸油酯；
(ii)醚酯，诸如乙氧基化脂肪醇的脂肪酸酯；
(iii)多元醇酯。乙二醇单脂肪酸酯和乙二醇二脂肪酸酯，二乙二醇单脂肪酸酯和二乙二醇二脂肪酸酯，聚乙二醇(200-6000)单脂肪酸酯和聚乙二醇二脂肪酸酯，丙二醇单脂肪酸酯和丙二醇二脂肪酸酯，聚丙二醇2000单油酸酯，聚丙二醇2000单硬脂酸酯，乙氧基化丙二醇单硬脂酸酯，甘油单脂肪酸酯和甘油二脂肪酸酯，聚甘油多脂肪酸酯，乙氧基化甘油单硬脂酸酯，1,3-丁二醇单硬脂酸酯，1,3-丁二醇二硬脂酸酯，聚氧乙烯多元醇脂肪酸酯，山梨聚糖脂肪酸酯，且聚氧乙烯山梨聚糖脂肪酸酯是令人满意的多元醇酯；
(iv)蜡酯，诸如蜂蜡、鲸蜡、硬脂酸硬脂酯和花生醇山嵛酸酯；以及，
(v)甾醇酯，其中胆固醇脂肪酸酯为实例。
润肤剂，当存在时，通常占以组合物重量计的0.1％-50％，该组合物包括其中包含的所有范围。
还可以包括具有10至30个碳原子的脂肪酸作为载体。这种脂肪酸的实例包括壬酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、异硬脂酸、油酸、亚油酸、花生酸、山嵛酸或芥酸及其混合物。
组合物中也可以使用多元醇型湿润剂。湿润剂通常有助于提高润肤剂的功效，减少皮肤表面上的鳞屑，促进去除积累的鳞屑并改善皮肤感觉。典型的多元醇包括甘油、聚亚烷基二醇，更优选亚烷基多元醇及其衍生物，包括丙二醇、二丙二醇、聚丙二醇、聚乙二醇及其衍生物、山梨醇、羟丙基山梨醇、己二醇、1,3-丁二醇、1,2,6-己三醇、乙氧基化甘油、丙氧基化甘油及其混合物。为了获得最佳结果，湿润剂优选为丙二醇或透明质酸钠。可以使用的其它湿润剂包括羟乙基脲。湿润剂的量可以为以重量计的0.2％-25％，且优选以组合物重量计的0.5-15％。
可通过使用矿脂或石蜡来改善保湿。增稠剂也可用作组合物中载体的一部分。典型的增稠剂包括交联的丙烯酸酯(例如
982)、疏水改性的丙烯酸酯(例如
1382)、纤维素衍生物和天然树胶。其中有用的纤维素衍生物为羧甲基纤维素钠、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素和羟甲基纤维素。适宜用于本发明的天然树胶包括瓜耳胶(guar)、黄原胶、菌核(sclerotium)、角叉菜胶、果胶和这些树胶的组合。增稠剂的量可在以组合物重量计的0.001％-5％，最佳为0.01％-0.5％范围内。
还可以存在表面活性剂。当存在时，表面活性剂的总量为以组合物重量计的2％-40％，优选4％-20％，最佳5％-12％。该表面活性剂选自阴离子、非离子、阳离子和两性活性剂。特别优选的非离子表面活性剂为具有每摩尔疏水物与2至100摩尔环氧乙烷或环氧丙烷缩合的C10-20脂肪醇或酸疏水物的那些；乙二醇的单脂肪酸酯和乙二醇的二脂肪酸酯；脂肪酸单甘油酯；山梨聚糖，单C8-C20脂肪酸和二C8-C20脂肪酸；嵌段共聚物(环氧乙烷/环氧丙烷)；和聚氧乙烯山梨聚糖及其组合。烷基多糖苷和糖类脂肪酰胺(例如甲基葡糖酰胺)也是合适的非离子表面活性剂。
优选的阴离子表面活性剂包括肥皂、烷基醚硫酸盐和磺酸盐、烷基硫酸盐和磺酸盐，烷基苯磺酸盐、烷基和二烷基磺基琥珀酸盐、C8-20酰基羟乙基磺酸盐、酰基谷氨酸盐、C8-20烷基醚磷酸盐及其组合。
各种其它成分也可用于组合物中。活性物质被定义为除润肤剂和仅仅改善组合物物理特性的成分以外的皮肤有益剂。虽然不限于这类，但一般实例包括体质颜料诸如滑石和二氧化硅，以及α-羟基酸、β-羟基酸和锌盐。
β-羟基酸包括水杨酸。氧化锌和吡硫锌为有用的锌盐的实例。
需要保护组合物(特别是含水的那些组合物)免受有害微生物的影响。可能需要抗微生物化合物(诸如三氯生)和防腐剂。合适的防腐剂包括对羟基苯甲酸的烷基酯、乙内酰脲衍生物、丙酸盐和各种季铵化合物。特别优选的防腐剂为对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯氧乙醇和苯甲醇。防腐剂为以组合物重量的0.1％-2％。
包装可以为贴片、瓶、管、滚球式涂抹器、推进剂驱动的气雾剂装置、挤压容器或带盖广口瓶。
根据本发明的另一方面，提供了一种控制或根除来自皮肤的痤疮丙酸杆菌的方法，其包含将本发明的组合物施用于所需的皮肤表面上的步骤。该方法优选是非治疗性的。该方法尤其用于减少或消除皮肤上的痤疮。
现在将借助于以下非限制性实施例来说明本发明。
实施例
痤疮丙酸杆菌噬菌体来源的重组内溶素与麝香草酚；以及麝香草酚+萜品醇的组
合的协同作用。
痤疮丙酸杆菌6919菌株(ATCC，USA)通过甘油保存液(Glycerol stock)在厌氧条件下在RCM琼脂上生长。将一环来自甘油保存液的培养物在新鲜制备的RCM琼脂平板上划线，并于37℃厌氧温育4-5天。温育后，从板中取出培养物并重悬于盐水中，然后在4℃以8000rpm离心6分钟。将所获得的沉淀物重悬于10mM HEPES缓冲液(pH7.0)中。在HEPES缓冲液中制备0.5的OD600培养物。将0.5OD调节的培养物的1：10稀释物用于接触杀死测定(contact kill assay)，其相当于106细胞/ml。
该测定以200μl总体积进行。将14μl纯化的内溶素(终浓度100μg/ml)用于测定。在无水乙醇中新鲜制备10％w/v的精油。接触测定是在10mM HEPES缓冲液(pH 7.0)中进行的。作为对照，将181μl的1：10稀释的0.6OD600调节的培养物与19μl HEPES缓冲液混合至200μl的体积。类似地，对于内溶素和精油，将所需量的蛋白质与痤疮丙酸杆菌培养物混合，用于单独和组合处理。将混合物混合并在37℃在振荡培养箱中温育2小时。温育后，通过在D/E肉汤中连续1：10稀释然后用盐水稀释来中和样品。将100μl各稀释物铺在新鲜RCM琼脂平板上并使其干燥。将板用石蜡膜密封并在厌氧室中于37℃温育4-5天。温育后，对菌落计数并以log CFU/ml估计滴度。相对于对照，计算单独和组合处理的相对log减少，且该数据列于下表中：
上表中的数据显示，在各种浓度范围内，内溶素与麝香草酚以及其与麝香草酚和萜品醇的组合对痤疮丙酸杆菌联合暴露2小时，具有协同抗微生物活性。
序列表
<110> 联合利华知识产权控股有限公司
<120> 一种选择性抑制痤疮丙酸杆菌细菌生长的抗微生物组合物
<130> J2323
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 893
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence of endolysin
<400> 1
atgcgttata ttccggcagc acatcattca gcaggtagca atcatccggt taatcgtgtt 60
gttattcatg caacctgtcc ggatgttggt tttccgagcg caagccgtaa aggtcgtgca 120
gttagcaccg caaactattt tgcaagcccg agcagcggtg gtagcgcaca ttatgtttgt 180
gatattggtg aaaccgttca gtgtctgagc gaaggcacca ttggttggca tgcaccgcct 240
aatccgcata gcctgggtat tgaaatttgt gcagatggtg gtagccatgc aagctttcgt 300
gttccgggtc atgcatatac ccgtgaacag tggctggatc cgcgtgtttg gcctgcagtt 360
gaaaaagcag caattctgtg tcgtcgtctg tgcgataaat acaatgttcc gaaacgtaaa 420
ctgagcgcag cagatctgaa agcaggtcgt cgtggtgttt gtggtcatgt tgatgttacc 480
gatgcatggc atcagagcga tcatgatgat ccgggtccgt ggtttccgtg ggatcgtttt 540
atggcagttg ttaatggtca taacgaaagc ggtgaactga ccgttgcaga tgttaaagca 600
ctgcatgatc agattaaaca gctgagcgca cagctggcag gtagcgttaa taaactgcat 660
catgatgttg gtgttgttca ggttcagaat ggtgatctgg gtaaacgtgt tgatgcactg 720
agctgggtta aaaatccggt taccggtaaa ctgtggcgta ccaaagatgc actgtggtca 780
gtttggtatt atgttctgga atgtcgtagc cgtattgatc gtctggaaag cgcagttaat 840
ggtctgaaaa aactcgagca ccaccaccac caccactgag atccggctgc taa 893
<210> 2
<211> 292
<212> PRT
<213> Artificial Sequence
<220>
<223> Polypeptide sequence of Endolysin with C-terminal Histidine tag
(x6)
<400> 2
Met Arg Tyr Ile Pro Ala Ala His His Ser Ala Gly Ser Asn His Pro
1 5 10 15
Val Asn Arg Val Val Ile His Ala Thr Cys Pro Asp Val Gly Phe Pro
20 25 30
Ser Ala Ser Arg Lys Gly Arg Ala Val Ser Thr Ala Asn Tyr Phe Ala
35 40 45
Ser Pro Ser Ser Gly Gly Ser Ala His Tyr Val Cys Asp Ile Gly Glu
50 55 60
Thr Val Gln Cys Leu Ser Glu Gly Thr Ile Gly Trp His Ala Pro Pro
65 70 75 80
Asn Pro His Ser Leu Gly Ile Glu Ile Cys Ala Asp Gly Gly Ser His
85 90 95
Ala Ser Phe Arg Val Pro Gly His Ala Tyr Thr Arg Glu Gln Trp Leu
100 105 110
Asp Pro Arg Val Trp Pro Ala Val Glu Lys Ala Ala Ile Leu Cys Arg
115 120 125
Arg Leu Cys Asp Lys Tyr Asn Val Pro Lys Arg Lys Leu Ser Ala Ala
130 135 140
Asp Leu Lys Ala Gly Arg Arg Gly Val Cys Gly His Val Asp Val Thr
145 150 155 160
Asp Ala Trp His Gln Ser Asp His Asp Asp Pro Gly Pro Trp Phe Pro
165 170 175
Trp Asp Arg Phe Met Ala Val Val Asn Gly His Asn Glu Ser Gly Glu
180 185 190
Leu Thr Val Ala Asp Val Lys Ala Leu His Asp Gln Ile Lys Gln Leu
195 200 205
Ser Ala Gln Leu Ala Gly Ser Val Asn Lys Leu His His Asp Val Gly
210 215 220
Val Val Gln Val Gln Asn Gly Asp Leu Gly Lys Arg Val Asp Ala Leu
225 230 235 240
Ser Trp Val Lys Asn Pro Val Thr Gly Lys Leu Trp Arg Thr Lys Asp
245 250 255
Ala Leu Trp Ser Val Trp Tyr Tyr Val Leu Glu Cys Arg Ser Arg Ile
260 265 270
Asp Arg Leu Glu Ser Ala Val Asn Gly Leu Lys Lys Leu Glu His His
275 280 285
His His His His
290
Claims (14)
1.一种用于选择性抑制痤疮丙酸杆菌(P.acnes)细菌生长的抗微生物组合物，其包含
(i)痤疮丙酸杆菌噬菌体来源的内溶素或编码其的核酸分子；和
(ii)具有以下结构的通式1的精油化合物
其中R1为H、OH或OR，其中R为具有1至5个碳原子的烷基链；
R2为C1至C6直链烷基；或C3至C6支链烷基；或C5至C6环烷基或杂环烷基；或C6芳基。
2.权利要求1所要求的组合物，其中所述内溶素为重组形式的痤疮丙酸杆菌噬菌体內溶素。
3.权利要求1或2所要求的组合物，其中所述内溶素是从丙酸杆菌噬菌体29399B_C(GenBank：JX262225.1)的内溶素基因序列(基因ID：NC_018851；855个核苷酸碱基对长，284个氨基酸，蛋白质ID：97935.1)克隆的，其经密码子优化以在大肠杆菌(E.coli)中表达并克隆至可商购的pET303/CT-His表达载体中。
4.权利要求1至3中任一项所要求的组合物，其中将终止密码子从所述基因的3'端去除以容纳6X组氨酸标签。
5.前述权利要求中任一项所要求的组合物，其中内溶素的核苷酸序列为SEQ ID1：ATGCGTTATATTCCGGCAGCACATCATTCAGCAGGTAGCAATCATCCGGTTAATCGTGTTGTTATTCATGCAACCTGTCCGGATGTTGGTTTTCCGAGCGCAAGCCGTAAAGGTCGTGCAGTTAGCACCGCAAACTATTTTGCAAGCCCGAGCAGCGGTGGTAGCGCACATTATGTTTGTGATATTGGTGAAACCGTTCAGTGTCTGAGCGAAGGCACCATTGGTTGGCATGCACCGCCTAATCCGCATAGCCTGGGTATTGAAATTTGTGCAGATGGTGGTAGCCATGCAAGCTTTCGTGTTCCGGGTCATGCATATACCCGTGAACAGTGGCTGGATCCGCGTGTTTGGCCTGCAGTTGAAAAAGCAGCAATTCTGTGTCGTCGTCTGTGCGATAAATACAATGTTCCGAAACGTAAACTGAGCGCAGCAGATCTGAAAGCAGGTCGTCGTGGTGTTTGTGGTCATGTTGATGTTACCGATGCATGGCATCAGAGCGATCATGATGATCCGGGTCCGTGGTTTCCGTGGGATCGTTTTATGGCAGTTGTTAATGGTCATAACGAAAGCGGTGAACTGACCGTTGCAGATGTTAAAGCACTGCATGATCAGATTAAACAGCTGAGCGCACAGCTGGCAGGTAGCGTTAATAAACTGCATCATGATGTTGGTGTTGTTCAGGTTCAGAATGGTGATCTGGGTAAACGTGTTGATGCACTGAGCTGGGTTAAAAATCCGGTTACCGGTAAACTGTGGCGTACCAAAGATGCACTGTGGTCAGTTTGGTATTATGTTCTGGAATGTCGTAGCCGTATTGATCGTCTGGAAAGCGCAGTTAATGGTCTGAAAAAACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAA。
6.前述权利要求中任一项所要求的组合物，其中所述核酸分子包含内溶素的片段、变体和融合物，所述内溶素的片段、变体和融合物能够特异性结合和/或裂解痤疮丙酸杆菌的细胞。
7.前述权利要求中任一项所要求的组合物，其中所述精油化合物选自：麝香草酚、香芹酚、(E)-2-(丙-1-烯基)苯酚、2-丙基苯酚、4-戊基苯酚、4-仲丁基苯酚、2-苄基苯酚或丁香酚或其组合。
8.权利要求7所要求的组合物，其中所述精油化合物为麝香草酚、香芹酚、4-戊基苯酚或4-仲丁基苯酚，优选为麝香草酚。
9.前述权利要求中任一项所要求的组合物，其中所述组合物还包含萜品醇。
10.权利要求9所要求的组合物，其包含萜品醇与精油化合物麝香草酚的混合物。
11.前述权利要求中任一项所要求的组合物，其还包含表面施用可接受的载体。
12.权利要求11所要求的组合物，其中所述表面施用可接受的载体包含无水性基质、凝胶、乳液、霜剂或乳剂。
13.一种控制或根除来自皮肤的痤疮丙酸杆菌的方法，其包含将前述权利要求中任一项所要求的组合物施用于所需的皮肤表面上的步骤。
14.权利要求13所要求的方法，其用于减少或消除皮肤上的痤疮。
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| EP18207026 | 2018-11-19 | ||
| EP18207026.8 | 2018-11-19 | ||
| PCT/EP2019/080678 WO2020104216A1 (en) | 2018-11-19 | 2019-11-08 | An antimicrobial composition for selectively inhibiting growth of p. acnes bacteria |
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| WO2015117957A1 (en) * | 2014-02-07 | 2015-08-13 | Unilever N.V. | A topical composition |
| WO2018195415A1 (en) * | 2017-04-21 | 2018-10-25 | Phi Therapeutics, Inc. | Compositions comprising propionibacterium acnes bacteriophages for treating acne |
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| BR112016017690A2 (pt) | 2014-01-29 | 2017-08-08 | Vyome Biosciences Pvt Ltd | Tratamentos para acne resistente |
| WO2016130024A1 (en) * | 2015-02-13 | 2016-08-18 | Supreme Biotechnologies Limited | Endolysin expression platform |
| MX2019010822A (es) * | 2017-03-16 | 2019-10-30 | Unilever Nv | Una composicion antimicrobiana que comprende aceite esencial y un lipido antimicrobiano. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015117957A1 (en) * | 2014-02-07 | 2015-08-13 | Unilever N.V. | A topical composition |
| WO2018195415A1 (en) * | 2017-04-21 | 2018-10-25 | Phi Therapeutics, Inc. | Compositions comprising propionibacterium acnes bacteriophages for treating acne |
Non-Patent Citations (1)
| Title |
|---|
| LAURA J. MARINELLI: "Propionibacterium acnes Bacteriophages Display Limited Genetic Diversity and Broad Killing Activity against Bacterial Skin Isolates", 《MBIOLOGY》, vol. 3, no. 5, 25 September 2012 (2012-09-25), XP055362789, DOI: 10.1128/mBio.00279-12 * |
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| MX2021005526A (es) | 2021-06-18 |
| EP3883596A1 (en) | 2021-09-29 |
| US20210386835A1 (en) | 2021-12-16 |
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