CN108348440A - 包含hlps的口腔护理产品和方法 - Google Patents
包含hlps的口腔护理产品和方法 Download PDFInfo
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- CN108348440A CN108348440A CN201680062530.6A CN201680062530A CN108348440A CN 108348440 A CN108348440 A CN 108348440A CN 201680062530 A CN201680062530 A CN 201680062530A CN 108348440 A CN108348440 A CN 108348440A
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- fluoride
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/20—Halogens; Compounds thereof
- A61K8/21—Fluorides; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/99—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from microorganisms other than algae or fungi, e.g. protozoa or bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Chemical & Material Sciences (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Cosmetics (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本文提供了包含疏水蛋白样蛋白质(HLPs)的口腔护理组合物,其可用于修复或抑制牙齿侵蚀、促进牙齿再矿化和/或增强氟化物的抗龋洞效应的方法。
Description
背景
牙釉质是覆盖牙冠的钙化材料的薄而坚硬的层。牙釉质的主要矿物成分是羟基磷灰石,它是磷酸钙的结晶形式。牙釉质的化学侵蚀可能来自牙齿暴露于酸性食物和饮品以及由胃逆流引起的胃酸。由于牙本质小管的暴露增加,牙釉质的侵蚀可导致牙齿敏感性增加,并且牙本质可见度的增加也导致出现更多黄牙。唾液膜(沉积在牙齿上的唾液糖蛋白薄层)是保护牙齿免受侵蚀性挑战的必要条件之一。因此,罹患口腔干燥症的人更容易受到酸蚀损伤。
为帮助防止釉质侵蚀而开发的现有方法包括将游离氟化物源加入到口腔护理组合物中。氟化物通过形成氟磷灰石而减少对釉质的伤害,氟磷灰石在低于羟基磷灰石的pH下溶解,因此更耐酸性损伤。类似地,亚锡盐也已被掺入洁齿剂制剂中,通过形成更耐酸的矿物质层以保护釉质表面。也描述了用于涂覆和保护釉质表面的聚合物。
当含有致龋菌的菌斑代谢碳水化合物时,口腔中也会产生酸。由于斑块形成控制质子和矿物质通过釉质扩散的动力学的屏障,斑块的酸引起龋损。将氟离子掺入洁齿剂制剂中是减轻菌斑酸影响的最常见方法。氟化物降低去矿化速率并增强再矿化。已经开发了几种方法来稳定磷酸钙盐或控制菌斑pH以增强再矿化。
尽管已经开发了减轻牙齿上的非细菌和细菌产生的酸的作用的方法,但仍然需要提供改良的口腔护理组合物,其能够有效地修复由酸侵蚀和细菌酸所影响的釉质。
WO2011/157497公开了一种可泡沫化的口腔护理组合物,其包含少于1.5%的阴离子表面活性剂(基于组合物总重量计的阴离子表面活性剂总重)、摩擦清洁剂和疏水蛋白。
简述
发明人出乎意料地发现疏水蛋白样蛋白质(Hydrophobin-like Proteins)(HLP)有效修复或减轻牙齿侵蚀的影响,促进牙齿再矿化,并增强氟化物的抗龋洞效应。
例如,在一项实施方案中,制备HLP用于含有合适的口腔可接受的载体成分的制剂,所述制备通过在缓冲液中稀释,例如磷酸盐缓冲液如Na2HPO4缓冲液(1.5mM)和CaCl2(2.5mM),以提供具有约中性或弱碱性pH的缓冲溶液,例如pH 7-8,例如约pH 7.5,将该溶液过滤并离心,得到包含HLP的滤液。可将杀生物剂(例如0.1%的西吡氯铵)和氟化物加入到滤液中。然后可以将HLP与口腔可接受的载体(例如牙膏或漱口剂基质)的组分组合,以提供用于修复或减轻牙齿侵蚀的影响、促进牙齿再矿化和增强氟化物的抗龋洞效应的口腔护理组合物。
本文涉及口腔护理组合物(组合物1),例如洁齿剂,包含:
a)HLP;
b)口腔可接受的载体,
其中所述HLP以所述组合物总重量的0.01重量%至3重量%的量存在于所述组合物中。例如,本文提供了:
1.1.组合物1,其中HLP具有SEQ ID NO:22的多肽序列。
1.2.任何上述组合物,其包含氟化物。
1.3.任何上述组合物,其中所述HLP已例如使用磷酸盐缓冲液中和至约中性或弱碱性pH,例如pH7-8。
1.4.任何上述组合物,其中所述HLP以有效浓度例如0.1%滤液重量包含杀生物剂如西吡氯铵(CPC)。
1.5.任何上述组合物,其中所述HLP以组合物总重量的0.1重量%至3重量%的量存在于所述组合物中,例如0.2重量%至2重量%,例如约0.2重量%、约1重量%、约1.5重量%、约2重量%。
1.6.任何上述组合物,其中所述组合物包含有效量的氟化物。
1.7.任何上述组合物,其包含100ppm-2500ppm的氟化物的量,例如250ppm-750ppm,如约500ppm氟化物。
1.8.任何上述组合物,其包含口腔可接受的锌盐或氧化物,例如选自氧化锌、柠檬酸锌、乳酸锌、磷酸锌、乙酸锌、氯化锌、与氨基酸形成的锌复合物,以及任何前述的混合物,例如其中锌的量按锌离子重量计为0.1重量%至3重量%,例如约1至约2重量%。
1.9.任何上述组合物,其包含口腔可接受的亚锡盐,例如SnF2或SnCl2。
1.10.任何上述组合物,其中所述组合物为选自漱口水、牙膏、牙胶、牙粉、非研磨性凝胶、摩丝、泡沫、口腔喷雾剂和片剂的形式,例如洁齿剂,如牙膏或漱口水。
1.11.任何上述组合物,其中所述组合物还包含一种或多种选自以下的试剂:摩擦剂、pH调节剂、表面活性剂、泡沫调节剂、增稠剂、粘度调节剂、湿润剂、防牙石或牙垢控制剂、甜味剂、调味剂和着色剂。
1.12.任何上述组合物,其中所述组合物是牙膏。
1.13.任何上述组合物,其包含一种或多种可溶性磷酸盐,例如其中“可溶性磷酸盐”是指口腔可接受的磷酸盐,其在25℃下在水中的溶解度为至少1g/100ml;例如其中所述一种或多种可溶性磷酸盐是焦磷酸和/或聚磷酸的钠盐和/或钾盐,例如三聚磷酸盐;例如其中所述一种或多种可溶性磷酸盐包括焦磷酸四钠(TSPP)、三聚磷酸钠(STPP)或TSPP与STPP的组合;例如,其中所述一种或多种可溶性磷酸盐以组合物的重量计为1-20%、例如2-8%、例如约5%的量存在。
1.14.任何上述组合物,其中氟化物由选自以下的盐提供:氟化亚锡、氟化钠、氟化钾、单氟磷酸钠、氟硅酸钠、氟硅酸铵、氟化胺(例如N'-十八烷基三亚甲基二胺-N,N,N'-三(2-乙醇)-二氢氟酸盐)、氟化铵、氟化钛、六氟硫酸盐及其组合。
1.15.任何上述组合物,其为包含保湿剂例如选自甘油、山梨醇、丙二醇、聚乙二醇、木糖醇及其混合物的洁齿剂,例如包含按所述组合物重量计至少30%、例如40-50%的甘油。
1.16.任何上述组合物,其为包含一种或多种例如选自阴离子、阳离子、两性离子和非离子表面活性剂及其混合物的表面活性剂的洁齿剂,例如其中洁齿剂基质包含阴离子表面活性剂,例如选自月桂基硫酸钠、月桂基醚硫酸钠及其混合物的表面活性剂,例如其量为所述组合物重量的约0.3%至约4.5%重量、例如1-2%月桂基硫酸钠(SLS)。
1.17.任何上述组合物,其为包含两性离子表面活性剂例如甜菜碱表面活性剂、例如椰油酰胺基丙基甜菜碱的洁齿剂,例如其量为所述组合物重量的约0.1%至约4.5%重量、例如0.5-2%的椰油酰胺基丙基甜菜碱。
1.18.任何上述组合物,其为包含粘度调节量的一种或多种多糖胶质例如黄原胶或角叉菜胶、硅石增稠剂及其组合的洁齿剂。
1.19.任何上述组合物,其是包含胶质条或碎片的洁齿剂。
1.20.任何上述组合物,其包含调味剂、香料和/或着色剂。
1.21.任何上述组合物,其是包含有效量的一种或多种抗菌剂的洁齿剂,例如包含选自以下的抗菌剂:卤代二苯醚(例如三氯生)、草本提取物和精油(例如迷迭香提取物、茶提取物、木兰提取物、麝香草酚、薄荷醇、桉叶醇、香叶醇、香芹酚、柠檬醛、桧木醇、儿茶酚、水杨酸甲酯、表没食子儿茶素没食子酸酯、表没食子儿茶素、没食子酸、牙刷树(miswak)提取物、沙棘提取物)、双胍(bisguanide)防腐剂(例如氯己定、阿来西定或奥替尼啶)、季铵化合物(例如西吡氯铵(CPC)、苯扎氯铵、十四烷基氯化吡啶(TPC)、N-十四烷基-4-乙基吡啶鎓氯化物(TDEPC))、酚类防腐剂、海克替啶、奥替尼啶、血根碱、聚维酮碘、地莫匹醇、Salifluor、金属离子(例如锌盐如柠檬酸锌、亚锡盐、铜盐、铁盐)、血根碱、蜂胶和氧化剂(例如过氧化氢、缓冲的过氧硼酸钠盐或过氧碳酸钠盐)、苯二甲酸及其盐、单过氧苯二甲酸(monoperthalic acid)及其盐和酯、抗坏血酸硬脂酸酯、油酰肌氨酸、烷基硫酸盐、磺基琥珀酸二辛酯、水杨酰苯胺、度米芬、地莫匹醇、辛哌醇及其它哌啶子基衍生物、烟酸制剂、亚氯酸盐;以及任何上述的混合物;例如包含三氯生或西吡氯铵。
1.22.任何上述组合物,其是包含增白剂的洁齿剂,所述增白剂例如选自过氧化物、金属亚氯酸盐、过硼酸盐、过碳酸盐、过氧酸、次氯酸盐及其组合;例如过氧化氢或过氧化氢源,例如脲过氧化物或过氧化物盐或复合物(例如过氧磷酸盐、过氧碳酸盐、过硼酸盐、过氧硅酸盐或过硫酸盐;例如过氧磷酸钙、过硼酸钠、碳酸钠过氧化物、过氧磷酸钠和过硫酸钾)。
1.23.任何上述组合物,其是包含干扰或防止细菌附着的试剂例如对羟基苯甲酸乙酯或壳聚糖的洁齿剂。
1.24.任何上述组合物,其是包含可溶性钙盐的洁齿剂,所述可溶性钙盐例如选自硫酸钙、氯化钙、硝酸钙、乙酸钙、乳酸钙及其组合。
1.25.任何上述组合物,其是包含生理上或口腔可接受的钾盐例如硝酸钾或氯化钾的洁齿剂,所述钾盐的量为有效降低牙本质敏感性的量。
1.26.任何上述组合物,其是包含阴离子聚合物的洁齿剂,所述阴离子聚合物例如合成的阴离子聚合物型聚羧酸盐,例如其中所述阴离子聚合物选自马来酸酐或马来酸与另一种可聚合的烯属不饱和单体的1:4至4:1共聚物;例如,其中阴离子聚合物是甲基乙烯基醚/马来酸酐(PVM/MA)共聚物,其具有约30,000至约1,000,000、例如约300,000至约800,000的平均分子量(M.W.),例如其中阴离子聚合物为组合物重量的约1-5%、例如约2%。
1.27.任何上述组合物,其是包含口气清新剂、香料或调味剂的洁齿剂。
1.28.任何上述组合物,其中所述组合物的pH约为中性,例如约pH 7。
1.29.任何上述组合物,其用于减少和抑制酸侵蚀、清洁牙齿、减少细菌产生的生物膜和斑块、减少牙龈炎、抑制蛀牙和龋洞形成,并减少牙本质过敏。
1.30.任何上述组合物,其用于减少、抑制或修复牙釉质侵蚀。
1.31.任何上述组合物,其用于促进牙釉质的再矿化。
1.32.任何上述组合物,其用于增强氟化物的抗龋洞效应。
组合物1的一项具体的新实施方案是包含以下成分的洁齿剂:
a)HLP;例如包含至少20.0%的干物质、至少2.5%的总氮、4.0-5.0的pH值以及1.0%或更低的灰分含量;其中部分水解的小麦蛋白已被中和至约中性或微碱性pH;
b)任选的有效量的氟化物;
c)口腔可接受的载体,
例如其中HLP的量是0.1重量%至2重量,且
例如其中氟化物是以100ppm至1000ppm,例如约500ppm的量存在。
在一个方面,本公开物提供了组合物1中的任何一种,其用于修复或抑制或保护或防止牙齿侵蚀、促进再矿化、和/或增强氟化物的抗龋洞效应;例如用于根据方法1等的以下方法中的任何一种。
另一方面,本公开物提供了修复或抑制牙齿侵蚀、促进牙齿再矿化和/或增强氟化物的抗龋洞效应的方法(方法1),其包括向牙齿施用组合物,例如组合物1等中的任何一种,例如口腔护理组合物,所述组合物包含:
a)HLP
b)口腔可接受的载体,
其中所述HLP以所述组合物总重量的0.01重量%至3重量%的量存在于所述组合物中。例如,本公开物提供:
1.1.方法1,其中HLP具有SEQ ID NO:22的多肽序列。
1.2.任何上述方法,其中HLP包含氟化物。
1.3.任何上述方法,其中所述HLP以有效浓度例如0.1%滤液重量包含杀生物剂如西吡氯铵(CPC)。
1.4.任何上述方法,其中所述HLP以组合物总重量的0.1重量%至3重量%的量存在于所述组合物中,例如0.2重量%至2重量%,例如约0.2重量%、约1重量%、约1.5重量%或约2重量%。
1.5.任何上述组合物,其中所述组合物包含有效量的氟化物。
1.6.任何上述方法,其中氟化物的量是100ppm-1000ppm,例如约500ppm氟化物。
1.7.任何上述方法,其中所述组合物为选自漱口水、牙膏、牙胶、牙粉、非研磨性凝胶、摩丝、泡沫、口腔喷雾剂和片剂的形式。
1.8.任何上述方法,其中所述组合物还包含一种或多种选自以下的试剂:摩擦剂、pH调节剂、表面活性剂、泡沫调节剂、增稠剂、粘度调节剂、湿润剂、防牙石或牙垢控制剂、甜味剂、调味剂和着色剂。
1.9.任何上述方法,其中所述组合物是洁齿剂,例如牙膏。
1.10.任何上述方法,其中所述组合物是选自上文所述的组合物1等的任何一种。
1.11.任何上述方法,其是用于减少、抑制或修复牙齿侵蚀、例如釉质侵蚀的方法,例如其中将组合物施用于已被鉴定为患有牙齿侵蚀或具有牙齿侵蚀升高风险的患者的牙齿。
1.12.任何上述方法,其是用于促进牙齿再矿化、例如釉质的再矿化的方法,例如其中将组合物施用于已被鉴定为具有去矿化的患者的牙齿。
1.13.任何上述方法,其是用于增强氟化物的抗龋洞效应的方法,例如其中将组合物施用于患者的牙齿,所述患者已经被鉴定为具有蛀牙早期迹象例如早期釉质龋洞,或者被鉴定为具有活动中的侵蚀或蛀牙风险增加。
1.14. 1.15所述的方法,其中所述组合物包含有效量的氟化物和/或其中所述方法还包括施用口腔护理产品,所述口腔护理产品包含有效量的氟化物口腔清洗剂或含有有效量的氟化物的牙膏。
在另一个实施方案中,本公开物提供了HLP在制备口腔护理组合物中的用途,所述组合物例如根据组合物1等中的任一项,用于例如方法1等中的任何一种的修复或抑制牙齿侵蚀、促进再矿化和/或增强氟化物的抗龋洞效应。
另一方面,本公开物提供了制备口腔护理产品的方法(方法2),所述产品为例如用于修复或抑制牙齿侵蚀、促进牙齿再矿化和/或增强氟化物的抗龋洞作用的口腔护理产品,例如根据组合物1等任一项的产品,所述方法包括:
a)通过用缓冲水溶液例如磷酸盐缓冲溶液稀释来中和HLP以获得具有大约中性或弱碱性pH例如pH 7-8的溶液;
b)过滤并离心a)的溶液产物以获得包含HLP的滤液;
c)向b)的滤液产物中加入氟化物(例如以口腔可接受的含氟盐如氟化钠或单氟磷酸钠的形式),并任选地加入杀生物剂(例如西吡氯铵,其有效量为例如滤液重量的0.01-1%,例如约0.1%);
d)将c)的产物与口腔可接受的载体组分混合以获得包含HLP的口腔护理组合物,所述HLP的量为组合物总重量的0.01重量%至3重量%。
例如,本公开物提供了包含HLP的口腔护理组合物,例如根据组合物1等中任一种的组合物,其中所述口腔护理组合物通过方法2等的方法获得或可通过方法2等的方法获得。
根据下文提供的详细描述,本发明的其它应用领域将变得很明显。应该理解,详细描述和具体实例虽然说明了本发明的优选实施方案,但仅用于说明的目的,并不意图限制本发明的范围。
详细描述
优选实施方案的以下描述在本质上仅仅是示例性的,不以任何方式限制本发明、其应用或用途。
如全文所用,范围用作描述在该范围内的各个和每个值的简写。范围内的任何值都可以选择作为范围的终点。此外,本文引用的所有参考文献均通过引用整体并入。如果本公开物中的定义和引用的参考文献中的定义有冲突,则以本公开物为准。
除非另有说明,否则此处和说明书其它地方表达的所有百分比和量应理解为指重量百分比。给出的量是基于物质的有效重量。
疏水蛋白样蛋白质(HLP)
本发明的疏水蛋白样蛋白质(HLP)是来自某些生物体例如真菌和细菌的蛋白质,其具有真实的疏水蛋白序列(=疏水蛋白(Hydrophobin))或者具有与真实的疏水蛋白相关的多肽序列,所述多肽序列能够具有疏水蛋白样性质,例如下文所述的改变接触角。
疏水蛋白(Hydrophobin)是约100个氨基酸的小蛋白质,其对于丝状真菌是特征性的并且不在其他生物体中发生。最近,在天蓝色链霉菌(Streptomyces coelicolor)中发现了疏水蛋白样蛋白质,其被称为“Chaplins”并且同样具有高度表面活性性质。Chaplins可在水-空气界面组装以产生淀粉状蛋白样原纤维(Classen等人2003Genes Dev 1714-1726;Elliot等2003,Genes Dev.17,1727-1740)。
疏水蛋白在各种真菌结构例如气生菌丝、孢子、子实体表面上以不溶于水的形式分布。疏水蛋白的基因是从子囊菌、半知菌和担子菌中分离出来的。一些真菌包含多于一个疏水蛋白基因,例如裂褶菌(Schizophyllum commune)、灰盖鬼伞(Coprinus cinereus)、构巢曲霉(Aspergillus nidulans)。显然,各种疏水蛋白参与真菌发育的不同阶段。所述疏水蛋白可能负责不同功能(van Wetter等人,2000,Mol.Microbiol.,36,201-210;Kershaw等人,1998,Fungal Genet.Biol,1998,23,18-33)。
疏水蛋白除了降低水的表面张力用于产生气生菌丝以外,所描述的生物学功能还有孢子的疏水化(等,1999,Curr.Biol.,19,1985-88;Bell等1992,Genes Dev.,6,2382-2394)。此外,疏水蛋白用于垫衬地衣子实体中的气体通道,并且用作通过真菌病原体鉴定植物表面的***中的组分(Lugones等1999,Mycol.Res.103,635-640;Hamer和Talbot1998,Curr.Opinion Microbiol.,第1卷,693-697)。
互补实验已经证明疏水蛋白可以在单一类别内在一定程度上被功能性地替代。先前公开的疏水蛋白使用常规蛋白质-化学纯化和分离方法可仅以中等的产率和纯度制备。迄今为止,借助基因方法提供大量疏水蛋白的尝试也未成功。
HLP也涉及通式(I)的多肽:
Xn-C1-X1-50-C2-X0-5-C3-X1-100-C4-X1-100-C5-X1-50-C6-X0-5-C7-X1-50-C8-Xm (I)
其中X可以是20种天然存在的氨基酸(Phe、Leu、Ser、Tyr、Cys、Trp、Pro、His、Gln、Arg、Ile、Met、Thr、Asn、Lys、Val、Ala、Asp、Glu、Gly)中任何一种,并且X的下标表示氨基酸的数目,其中下标n和m是0至500之间的数,优选15-300,并且C是半胱氨酸,条件是至少一个缩写为Xn或Xm的肽序列是长度为至少20个氨基酸的肽序列,其在天然条件下不与疏水蛋白连接,该多肽在涂布玻璃表面后改变接触角至少20°。
由C1至C8指定的半胱氨酸可以是还原形式或在本发明的蛋白质中彼此形成二硫键。特别优选分子内形成C-C桥,特别是具有至少一个,优选2个,特别优选3个,非常特别优选4个分子内二硫键的那些,所述分子内二硫键选自下组:C1与C2;C3与C4、C5与C6、C7与C8。如果半胱氨酸也用于由X指定的位置,则通式中各个半胱氨酸位置的编号可以相应地改变。
特别有利的多肽是通式(II)的那些:
Xn-C1-X3-25-C2-X0-2-C3-X5-50-C4-X2-35-C5-X2-15-C6-X0-2-C7-X3-35-C8-Xm (II)
其中X可以是20种天然存在的氨基酸(Phe、Leu、Ser、Tyr、Cys、Trp、Pro、His、Gln、Arg、Ile、Met、Thr、Asn、Lys、Val、Ala、Asp、Glu、Gly)中任何一种,并且X的下标表示氨基酸的数目,其中下标n和m为2至300之间的数,C为半胱氨酸,条件是至少一个缩写为Xn或Xm的肽序列为长度至少35个氨基酸的肽序列,其在天然条件下不与疏水蛋白连接,该多肽在涂布玻璃表面后改变接触角至少20°。非常特别有利的多肽是通式(III)的那些:
Xn-C1-X5-9-C2-C3-X11-39-C4-X2-23-C5-X5-9-C6-C7-X6-18-C8-Xm (III)
其中X可以是20种天然存在的氨基酸(Phe、Leu、Ser、Tyr、Cys、Trp、Pro、His、Gln、Arg、Ile、Met、Thr、Asn、Lys、Val、Ala、Asp、Glu、Gly)中任何一种,并且X的下标表示氨基酸的数目,其中下标n和m为0至200之间的数值,C为半胱氨酸,条件是至少一个缩写为Xn或Xm的肽序列为长度至少40个氨基酸的肽序列,其在天然条件下不与疏水蛋白连接,该多肽在涂布玻璃表面后改变接触角至少20°。
所述发明的优选实施方案是具有通式结构式(I)、(II)或(III)的多肽,该结构式包含至少一种I类疏水蛋白,优选至少一种dewA、rodA、hypA、hypB、sc3、basf1、basf2、疏水蛋白或其部分或衍生物。所述疏水蛋白以下面列出的序列在结构上表征。可以有多个、优选2或3个结构相同或不同的疏水蛋白彼此连接并且与相应的合适的在天然条件下不与疏水蛋白的肽序列连接。
本发明特别优选的实施方案是具有SEQ ID NO:20、22、24所述的多肽序列的新蛋白质,以及编码它们的核酸序列,特别是SEQ ID NO:19、21、23所定义的序列。特别优选的实施方案还有这些蛋白质:其从SEQ ID NO:20、22、24所述多肽序列开始,全部氨基酸的至少1个到至多10个、优选5个、特别优选5%被取代、***或缺失,并且仍然具有起始蛋白质的生物学性质的至少50%。此处的蛋白质生物学性质是指接触角的改变,如实施例1所述。
这些HLP及其制备公开于例如EP1848733,其引入本文作为参考。
这些蛋白质在至少一个缩写为Xn或Xm的位置上具有包含至少20、优选至少35、特别优选至少50、特别是至少100个氨基酸的多肽序列(下文称为融合伴侣),其在天然条件下不与疏水蛋白连接。这旨在表达这样的事实,即本发明的蛋白质由疏水蛋白部分和融合伴侣部分组成,它们在自然界中不以这种形式一起出现。
融合伴侣部分可以选自多种蛋白质。也可以将多个融合伴侣连接至一个疏水蛋白部分,例如在疏水蛋白部分的氨基末端(Xn)和羧基末端(Xm)处。然而,也可以将例如两个融合伴侣连接至本发明蛋白质的单个位置(Xn或Xm)。
特别优选的融合伴侣是这样的多肽序列,其能够使本发明的蛋白质涂覆玻璃表面并造成蛋白质处理后的玻璃表面对去污剂处理具有抵抗力,在实验部分(实施例10)对此有详细描述(例如,1%SDS/80℃/10min)。
特别合适的融合伴侣是在微生物中天然存在的多肽,特别是在大肠杆菌或枯草芽孢杆菌中。此类融合伴侣的实例是序列yaad(SEQ ID NO:15和16)、yaae(SEQ ID NO:17和18)以及硫氧还蛋白。非常有用的还有所述序列的片段或衍生物,其仅包含所述序列的一部分、优选70-99%、特别优选80-98%,或者其中单个氨基酸或核苷酸与所述序列相比已被改变。例如,其它氨基酸、特别是两个其它氨基酸,优选氨基酸Arg、Ser,可以连接到yaad和yaae序列的C末端。与天然存在的序列相比,可以优选将其它氨基酸,例如SEQ ID NO:17和18中的氨基酸2号(Gly)***yaae序列中。
此外,也可在两个融合伴侣的连结点***额外的氨基酸,所述氨基酸是在核酸水平新产生的限制性内切核酸酶识别位点或使其失活的结果。
本发明蛋白质的多肽序列还可以通过例如糖基化、乙酰化或者通过化学交联例如用戊二醛进行修饰。
当所述表面用所述蛋白质涂覆时,本发明蛋白质的一个性质是表面性质的变化。所述表面性质的变化可以通过实验在用本发明的蛋白质涂覆表面之前和之后测量水滴的接触角并且测定两次测量的差异来确定。
测量接触角的确切实验条件在实施例1的实验部分中提供。在这些条件下,本发明的蛋白质具有增加接触角至少20°、优选25°、特别优选30°的性质。
以前公开的疏水蛋白的疏水蛋白部分中的极性和非极性氨基酸的位置是保守的,导致特征性的疏水性图。生物物理性质和疏水性的差异导致以前公开的疏水蛋白分为I和II两类(Wessels等人,1994,Ann.Rev.Phytopathol.,32,413-437)。
I类疏水蛋白的组装膜高度不溶(甚至对于1%SDS在升高的温度下也如此),并且可以仅通过浓三氟乙酸(TFA)或甲酸再解离。相反,II类疏水蛋白的组装形式不太稳定。即使60%浓度的乙醇或1%SDS(室温下)也可以再次溶解。
氨基酸序列的比较表明,在II类疏水蛋白中,半胱氨酸C3和C4之间的区域长度明显短于I类疏水蛋白。
此外,II类疏水蛋白具有比I类更多的带电氨基酸。
本发明还涉及制备本发明蛋白质的方法。这些蛋白质可以通过肽合成的已知方法化学制造,例如根据Merrifield的固相合成法。
然而,特别有用的是基因方法,其中分别编码融合伴侣和疏水蛋白部分的两个核酸序列、特别是DNA序列以这样的方式组合,使得组合的核酸序列的基因表达在宿主生物体中产生所需的蛋白质。
此处合适的宿主生物体(生产性生物)可以是原核生物(包括古细菌)或真核生物,特别是包括盐杆菌(halobacteria)和甲烷球菌(methanococci)的细菌、真菌、昆虫细胞、植物细胞和哺乳动物细胞,特别优选大肠杆菌、枯草芽孢杆菌、巨大芽孢杆菌、米曲霉(Aspergillus oryzea)、构巢曲霉、黑曲霉、巴斯德毕赤酵母、假单胞菌物种、乳杆菌、多形汉逊酵母、里氏木霉(Trichoderma reesei)、SF9(或相关细胞)等。
本发明还涉及表达构建体,其包含在调控核酸序列的遗传控制下编码本发明多肽的核酸序列,还涉及包含至少一种所述表达构建体的载体。
优选这类本发明构建体,其包含在具体编码序列5'上游的启动子和在3'下游的终止子序列,以及在合适时还有其它常规调控元件,在每种情况下可操作地连接到所述编码序列。
“可操作的连接”指启动子、编码序列、终止子和在合适时的其它调控元件以这样的方式顺序排列,即每个调控元件能够根据其与表达编码序列相关的预期用途来实现其功能。
可操作的连接的序列实例是靶向序列和增强子、多腺苷酸化信号等。其它调控元件包含可选择的标记物、扩增信号、复制起点等。合适的调控序列的实例描述在Goeddel,Gene Expression Technology:Methods in Enzymology 185,Academic Press,SanDiego,CA(1990)中。
除了这些调控序列之外,这些序列的天然调控可能仍然存在于实际结构基因的上游,并且在合适时已经被遗传修饰以使天然调控被关闭且基因的表达已经增加。
优选的核酸构建体还有利地包含一个或多个已经提到的增强子序列,其与启动子功能性连接并且能够使得核酸序列的表达增加。其它有利的序列例如其它调控元件或终止子也可以***DNA序列的3'末端。
本发明的核酸可以以一个或多个拷贝存在于构建体中。在合适时,该构建体可以包含其它标记物,例如抗生素抗性或补充营养缺陷型的基因,用于选择构建体。
对于本发明方法有利的调节序列的实例存在于启动子如cos、tac、trp、tet、trp-tet、Ipp、lac、Ipp-lac、lacIq-T7、T5、T3、gal、trc、ara、rhaP(rhaPBAD)SP6、λ-PR或λ-P启动子,它们有利地用于革兰氏阴性菌。在革兰氏阳性菌启动子amy和SP02中、在酵母或真菌启动子ADC1、MFα、AC、P-60、CYC1、GAPDH、TEF、rp28、ADH中还存在有利的调节序列的其它实例。也可使用人工启动子进行调控。
为了在宿主生物体中表达,有利地将核酸构建体***载体中,例如质粒或噬菌体,其使基因能够在宿主中最佳表达。除了质粒和噬菌体之外,载体还指技术人员已知的任何其它载体,即例如病毒如SV40、CMV、杆状病毒和腺病毒、转座子、IS元件、噬粒、粘粒以及直链或环状DNA以及农杆菌***。
这些载体可以在宿主生物体中自主复制或者可以在染色体中复制。这些载体构成本发明的另一个实施方案。适合的质粒实例是大肠杆菌中的pLG338、pACYC184、pBR322、pUC18、pUC19、pKC30、pRep4、pHS1、pKK223-3、pDHE19.2、pHS2、pPLc236、pMBL24、pLG200、pUR290、pIN-III”3-B1、tgt11或pBdCl,链霉菌中的pIJ101、pIJ364、pIJ702或pIJ361,芽孢杆菌中的pUB110、pC194或pBD214,棒杆菌中的pSA77或pAJ667,真菌中的pALS1、pIL2或pBB116,酵母中的2α、pAG-1、YEp6、YEp13或pEMBLYe23,或植物中的pLGV23、pGHIac+、pBIN19、pAK2004或pDH51。所述质粒是可能的质粒的一小部分。其它质粒对技术人员来说是熟知的并可在例如“克隆载体”书中找到(Pouwels P.H.等人编辑,Elsevier,Amsterdam-New York-Oxford,1985,ISBN 0 444 904018)。
有利地是,为了表达存在的其它基因,核酸构建体另外还包含用于增加表达的3'-和/或5'-末端调控序列,其根据宿主生物体和所选基因的最佳表达进行选择。
这些调控序列旨在使基因和蛋白质表达能够特异性表达。根据宿主生物体,这可能意味着,例如该基因仅在诱导后才表达或过表达,或者其立即表达和/或过表达。
就此而言,调控序列或因子可以优选地对引入的基因的基因表达具有有益影响并由此增加基因表达。因此,通过使用强转录信号如启动子和/或增强子可以有利地在转录水平上增强调控元件。然而,除此之外,例如也可以通过改善mRNA稳定性来增强翻译。
在载体的另一个实施方案中,包含本发明的核酸构建体或本发明的核酸的载体还可以有利地以直链DNA的形式引入微生物中并通过异源或同源重组的方式整合到宿主的基因组中。所述直链DNA可以由直链化载体如质粒组成,或者仅由本发明的核酸构建体或核酸组成。
为了实现生物体中异源基因的最佳表达,根据生物体中所用的特定密码子选择来修饰核酸序列是有利的。密码子选择可以根据计算机分析所述生物体的其它已知的基因来容易地确定。
本发明的表达盒是通过将合适的启动子与合适的编码核苷酸序列和终止子信号或聚腺苷酸化信号融合来制备。为此目的,使用文献中所描述的熟悉的重组和克隆技术,例如T.Maniatis,E.F.Fritsch和J.Sambrook,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,Cold Spring Harbor,NY(1989)以及T.J.Silhavy,M.L.Berman和L.W.Enquist,Experiments with Gene Fusions,Cold Spring HarborLaboratory,Cold Spring Harbor,NY(1984)以及Ausubel,F.M.等人,Current Protocolsin Molecular Biology,Greene Publishing Assoc.和Wiley Interscience(1987)中所述。
为了在合适的宿主生物体中表达,有利地将重组核酸构建体或基因构建体***到宿主特异性载体中,其使得基因能够在宿主中最佳表达。载体对于本领域技术人员是熟知的并且可以在例如“克隆载体”中找到(Pouwels P.H.等人编辑,Elsevier,Amsterdam-NewYork-Oxford,1985)。
本发明的载体可以用于制备重组微生物,其例如用至少一种本发明的载体转化并且可以用于制备本发明的多肽。有利地,将本发明的上述重组构建体引入合适的宿主***中并在合适的宿主***中表达。在此优选使用本领域技术人员已知的常规克隆和转染方法,例如共沉淀、原生质体融合、电穿孔、逆转录病毒转染等,以便在特定表达***中表达所述核酸。合适的***如以下文献中所述,例如Current Protocols in Molecular Biology,F.Ausubel等人编辑,Wiley Interscience,New York 1997,或Sambrook等人MolecularCloning:A Laboratory Manual,第2版,Cold Spring Harbor Laboratory,Cold SpringHarbor Laboratory Press,Cold Spring Harbor,NY,1989。
根据本发明也可以制备同源重组微生物。为此目的,制备包含至少一部分本发明基因或编码序列的载体,在合适时,引入至少一个氨基酸缺失、添加或取代以修饰,例如功能性地破坏本发明的序列(敲除载体)。所引入的序列可以是例如同样来自相关微生物的同源物或来源于哺乳动物、酵母或昆虫来源。或者,可以将用于同源重组的载体设计使其内源基因突变或在同源重组过程中以某种其它方式被修饰,但仍编码功能性蛋白质(例如,上游调节区可能已经以修饰内源蛋白质表达的方式被修饰)。本发明基因的修饰片段位于同源重组载体中。用于同源重组的合适载体的构建例如在Thomas,K.R.和Capecchi,M.R.(1987)Cell 51:503中所述。
任何原核生物或真核生物原则上都适合用作本发明核酸或核酸构建体的重组宿主生物体。有利使用的宿主生物体是微生物,如细菌、真菌或酵母。有利地使用革兰氏阳性或革兰氏阴性菌,优选以下菌科:肠杆菌科、假单胞菌科、根瘤菌科、链霉菌科或诺卡尔菌科,特别优选以下菌属:埃希氏菌属、假单胞菌属、链霉菌属、诺卡尔菌属、伯克霍尔德氏菌属、沙门氏菌属、农杆菌属或红球菌属。
根据宿主生物体,本发明方法中使用的生物体以本领域技术人员已知的方式生长或培养。微生物通常在液体培养基中生长,所述液体培养基包含通常为糖形式的碳源、通常以有机氮源如酵母提取物或盐如硫酸铵形式的氮源、微量元素如铁、锰、镁盐以及合适的话还包含维生素,在0-100℃、优选10-60℃的温度下生长,同时用氧气充气。营养液的pH可以在此处保持或不保持在固定值,即在生长期间调节。生长可能会按批次、半批次或连续发生。营养素可在发酵开始时首先引入或随后半连续或连续进料。酶可以使用实施例中描述的方法从生物体中分离或将其以粗提物用于反应。
本发明还涉及重组生产本发明的多肽或其功能性的生物活性片段的方法,所述方法包括培养产生多肽的微生物,在合适时诱导所述多肽的表达并从培养物中分离它们。以此方式,多肽也可在需要时以工业规模生产。重组微生物可以通过已知方法培养和发酵。例如,细菌可以在TB培养基或LB培养基中并且在20至40℃的温度和6至9的pH下繁殖。合适的培养条件详细描述于例如T.Maniatis,E.F.Fritsch和J.Sambrook,Molecular Cloning:ALaboratory Manual,Cold Spring Harbor Laboratory,Cold Spring Harbor,NY(1989)。
如果多肽不分泌到培养基中,则将细胞破碎并通过已知的分离蛋白质的方法从裂解物中分离产物。细胞可以任选地通过高频超声波,高压例如在法国压力室中,通过渗透压裂解,通过洗涤剂作用,水解酶或有机溶剂的作用,通过使用匀浆器或所列出的这几种方法的组合进行破碎。
多肽可以通过已知的色谱方法例如分子筛色谱(凝胶过滤)如Q-琼脂糖色谱、离子交换色谱和疏水色谱,以及还可通过其它常规方法如超滤、结晶、盐析、透析和天然凝胶电泳进行纯化。合适的方法例如Cooper,F.G.,Biochemische Arbeitsmethoden[原标题:Thetools of biochemistry],Verlag Water de Gruyter,Berlin,New York或Scopes,R.,Protein Purification,Springer Verlag,New York,Heidelberg,Berlin中所述。
为了分离重组蛋白质,使用将cDNA延伸特定核苷酸序列并由此编码例如帮助纯化的改变的多肽或融合蛋白的载体***或寡核苷酸可能是有利的。这种合适的修饰的实例是充当锚的“标签”,例如已知为六个组氨酸锚的修饰,或可被抗体识别为抗原的表位(例如Harlow,E.和Lane,D.,1988,Antibodies:A Laboratory Manual.Cold Spring Harbor(N.Y.)Press中所述)。其它合适的标签是例如HA、钙调蛋白-BD、GST、MBD;壳多糖-DB、抗生蛋白链菌素-BD-Avi标签、Flag标签、T7等。这些锚可以用于将蛋白质附着到固体支持物例如聚合物基质上,所述基质例如可能已经被引入到色谱柱或微量滴定板或任何其它支持物上。相应的纯化方案可以从商业的亲和标签供应商处获得。
在一些实施方案中,HLP以组合物总重量的0.01重量%至3重量%的量存在于组合物中。在一些实施方案中,HLP以组合物总重量的0.1重量%至3重量%、或0.1重量%至2重量%、或0.1重量%至1重量%的量存在于组合物中。在其它实施方案中,HLP以组合物总重量的0.05重量%至1重量%、或0.1重量%至0.5的量存在于组合物中。在其它的实施方案中,HLP以组合物总重量的0.5重量%至3重量%、或0.5重量%至2重量%、或0.5重量%至1重量%的量存在于组合物中。在其它的实施方案中,HLP以组合物总重量的1重量%至3重量%、或重量%至2重量%的量存在于组合物中。
口腔可接受的载体和任选的成分
如本文所用的表述“口腔可接受的载体”表示以预期的量和浓度用于口腔使用是安全和可接受的材料制成的载体,例如在常规牙膏和漱口水中可发现的材料。这样的材料包括水或其它可含有保湿剂例如甘油、山梨醇、木糖醇等的溶剂。在某些方面,术语“口腔可接受的载体”包括口腔护理组合物的除HLP和氟化物之外的所有组分。在其它方面,该术语是指用于将HLP和/或任何其它功能性成分递送至口腔的惰性或无活性的成分。
用于本发明的口腔可接受的载体包括用于制备漱口水或口腔清洗剂、牙膏、牙胶、牙粉、锭剂、口香糖、珠、可食用条、片剂等的常规和已知载体。应当选择载体以便彼此相容并与组合物的其它成分相容。
提供以下非限制性实例。在牙膏组合物中,载体通常是提供组合物重量的主要部分的水/湿润剂体系。或者,牙膏组合物的载体组分可包含水、一种或多种湿润剂以及除水解小麦蛋白或水解大米蛋白之外的其它功能组分。在漱口剂和口腔清洗剂制剂中,载体通常是水解小麦蛋白或水解大米蛋白溶解或分散于其中的水/醇液体混合物。在可溶性锭剂中,载体通常包含在口腔中缓慢溶解的固体基质材料。在口香糖中,载体通常包含胶质基,而在可食用条中,载体通常包含一种或多种成膜聚合物。
本文提供的口腔护理组合物可进一步包含一种或多种其他成分,其选自摩擦剂、pH调节剂、表面活性剂、泡沫调节剂、增稠剂、粘度调节剂、湿润剂、防牙石或牙垢控制剂、甜味剂、调味剂、着色剂和防腐剂。这些成分也可以被视为载体材料。下面提供非限制性的实例。
在一个实施方案中,本发明的组合物包含至少一种摩擦剂,可用作例如抛光剂。可以使用任何口腔可接受的摩擦剂,但应选择摩擦剂的类型、细度(粒度)和量以使得在正常使用组合物时牙齿釉质不会过度磨损。合适的摩擦剂包括但不限于硅石,例如以硅胶、水合二氧化硅或沉淀二氧化硅的形式,氧化铝、不溶性磷酸盐、碳酸钙、树脂摩擦剂如脲-甲醛缩合产物等。可用作摩擦剂的不溶性磷酸盐是正磷酸盐、聚偏磷酸盐和焦磷酸盐。说明性实例是二水合正磷酸二钙、焦磷酸钙、β-焦磷酸钙、磷酸三钙、聚偏磷酸钙和不溶性聚偏磷酸钠。在本发明的口腔护理组合物中,任选存在以组合物总重量的1重量%至5重量%的量的一种或多种摩擦剂。摩擦剂(如果存在的话)的平均粒度通常为0.1至30μm,并且优选5至15μm。
在另一个实施方案中,本发明的口腔护理组合物包含至少一种碳酸氢盐,用于例如由于泡腾和释放二氧化碳而赋予牙齿和牙龈“清洁感”。可以使用任何口腔可接受的碳酸氢盐,包括但不限于碱金属碳酸氢盐如碳酸氢钠和碳酸氢钾、碳酸氢铵等。一种或多种碳酸氢盐任选地以组合物的1重量%至10重量%的总量存在。
在另一个实施方案中,本发明的口腔护理组合物包含至少一种pH调节剂。这些试剂包括降低pH的酸化剂、提高pH的碱化剂和缓冲剂,以将pH控制在期望的范围内。例如,可以包括一种或多种选自酸化剂、碱化剂和缓冲剂的化合物以提供2-10的pH,或者在各种示例性实施方案中,pH为2-8、3-9、4-8、5-7、6-10或7-9。可以使用任何口腔可接受的pH调节剂,包括但不限于羧酸、磷酸和磺酸、酸式盐(例如柠檬酸单钠、柠檬酸二钠、苹果酸一钠)、碱金属氢氧化物例如氢氧化钠、碳酸盐如碳酸钠、碳酸氢盐、硼酸盐、硅酸盐、磷酸盐(如磷酸一钠、磷酸三钠、焦磷酸盐)、咪唑等。一种或多种pH调节剂任选地以有效维持组合物在口腔可接受的pH范围内的总量存在。
在另一个实施方案中,本发明的组合物包含至少一种表面活性剂,例如用于为组合物和其中所含的组分提供增强的稳定性,帮助通过洗涤剂作用清洁牙齿表面,并且在搅拌时提供泡沫(例如,在用本发明的洁齿剂组合物刷牙期间)。可以使用任何口腔可接受的表面活性剂,包括阴离子、非离子或两性表面活性剂。合适的阴离子表面活性剂包括但不限于C8-20烷基硫酸盐的水溶性盐、C8-20脂肪酸的磺酰化甘油单酯、肌氨酸盐、牛磺酸盐等。合适的非离子表面活性剂包括但不限于泊洛沙姆、聚氧乙烯脱水山梨糖醇酯、脂肪醇乙氧基化物、烷基酚乙氧基化物、叔胺氧化物、叔膦氧化物、二烷基亚砜等。合适的两性表面活性剂包括但不限于具有阴离子基团例如羧酸根、硫酸根、磺酸根、磷酸根或膦酸根的C 8-20脂族仲胺和叔胺的衍生物。一个合适的例子是椰油酰胺基丙基甜菜碱。一种或多种表面活性剂任选地以组合物总重量的0.01重量%至10重量%,例如0.05重量%至5重量%或0.1重量%至2重量%的总量存在。
在另一个实施方案中,本发明的口腔护理组合物包含至少一种泡沫调节剂,其可用于例如增加组合物在搅拌时产生的泡沫的量、厚度或稳定性。可以使用任何口腔可接受的泡沫调节剂,包括但不限于聚乙二醇(PEG)。一种或多种PEG任选地以组合物总重量的0.1重量%至10重量%的总量存在。
在另一个实施方案中,本发明的口腔护理组合物包含至少一种增稠剂,可用于例如赋予组合物所需的稠度和/或口感。可以使用任何口腔可接受的增稠剂,包括但不限于卡波姆(羧基乙烯基聚合物)、角叉菜胶、纤维素聚合物如羟乙基纤维素、羧甲基纤维素(CMC)及其盐、天然树胶如刺梧桐胶、黄原胶、***胶和黄蓍胶、胶体硅酸镁铝、胶体二氧化硅等。一种或多种增稠剂任选以组合物总重量的0.01重量%至15重量%的总量存在。
在另一个实施方案中,本发明的组合物包含至少一种粘度调节剂,其可用于例如抑制成分的沉降或分离或在搅拌液体组合物时促进成分的再分散。可以使用任何口腔可接受的粘度调节剂,包括但不限于矿物油、凡士林、粘土、二氧化硅等。一种或多种粘度调节剂任选以组合物总重量的0.01重量%至10重量%的总量存在。
在另一个实施方案中,本发明的口腔护理组合物包含至少一种湿润剂,其可用于防止牙膏在暴露于空气时硬化。可以使用任何口腔可接受的湿润剂,包括但不限于多元醇如甘油、山梨醇、木糖醇或低分子量PEG。大多数湿润剂也可用作甜味剂。一种或多种湿润剂任选地以组合物总重量的1重量%至50重量%的总量存在。
在另一个实施方案中,本发明的口腔护理组合物包含增强组合物味道的至少一种甜味剂。包括但不限于右旋糖、蔗糖、麦芽糖、糊精、甘露糖、木糖、核糖、果糖、左旋糖、半乳糖、玉米糖浆、部分水解的淀粉、氢化淀粉水解产物、山梨醇、甘露醇、木糖醇、麦芽糖醇、异麦芽糖醇、阿斯巴甜、纽甜、糖精及其盐、基于二肽的强力甜味剂、甜蜜素等。一种或多种甜味剂任选地以组合物总重量的0.005重量%至5重量%的总量存在。
在另一个实施方案中,本发明的口腔护理组合物包含至少一种改善组合物味道的调味剂。可以使用任何口腔可接受的天然或合成调味剂,包括但不限于香草醛、鼠尾草、马郁兰、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、果油和香精等。调味剂还包括在口腔中提供香味和/或其它感官效果的成分,包括冷或热效果。这些成分示例性地包括薄荷醇、乙酸薄荷基酯、乳酸薄荷基酯、樟脑、桉树油、桉叶脑、丁香酚、肉桂、氧杂环己酮(oxanone)、α-紫罗兰酮、麝香草酚、芳樟醇、苯甲醛、肉桂醛、N-乙基对薄荷烷-3-甲酰胺、N,2,3-三甲基-2-异丙基丁酰胺、3-(1-薄荷基氧基)-丙烷-1,2-二醇、肉桂醛甘油缩醛(CGA)、薄荷酮甘油缩醛(MGA)等。一种或多种调味剂任选地以组合物总重量的0.01重量%至5重量%的总量存在。
在另一个实施方案中,本发明的口腔护理组合物包含至少一种着色剂。着色剂可用于许多功能。这些功能包括在牙齿表面上提供白色或浅色涂层,指示已被组合物有效接触的牙齿表面上的位置,和/或改变组合物的外观以增强对消费者的吸引力。可以使用任何口腔可接受的着色剂,包括但不限于滑石、云母、碳酸镁、碳酸钙、硅酸镁、硅酸镁铝、硅石、二氧化钛、氧化锌、氧化铁、亚铁氰化铁铵、锰紫、钛化云母、氯化氧铋等。一种或多种着色剂任选以组合物总重量的0.001重量%至20重量%的总量存在。
在另一个实施方案中,本发明的口腔护理组合物包含防腐剂。防腐剂可以选自对羟基苯甲酸酯、山梨酸钾、苯甲醇、苯氧乙醇、聚氨基丙基双胍、辛酸、苯甲酸钠和西吡氯铵。在一些实施方案中,防腐剂以组合物总重量的约0.001至约1重量%的浓度存在。
在另一个实施方案中,本发明的口腔护理组合物是包含胶质基、香料、甜味剂和HLP的口香糖。胶质基存在量为约4.8%至约90%,风味剂为约0.1%至约10%,甜味剂为约0.1%至约95%,HLP为约0.01%至约0.5%。
以下实施例说明了本发明的组合物及其用途。示例性的组合物是说明性的,并不限制本发明的范围。
实施例
实施例1:接触角的改变
使用HLP的表面的涂覆/评价
玻璃(窗户玻璃,Süddeutsche Glas,Mannheim,德国):
-HLP浓度:100μg/mL
-将玻璃板在50mM乙酸钠pH 4+0.1%吐温20中孵育过夜(温度:80℃)
-涂覆后,用蒸馏水洗涤
-随后,在80℃和1%SDS的蒸馏水溶液中孵育10分钟
-用蒸馏水洗涤。
将样品风干,并测定5μl的一滴水的接触角(以°表示)。
在Dataphysics Contact Angle System OCA 15+、软件SCA 20.2.0.(2002年11月)仪器上测定接触角。根据生产商的说明书进行测定。
未处理的玻璃得到的接触角为30±5°;用SEQ ID NO:20(yaad-dewA-his6)的功能性HLP涂覆后得到的接触角为75±5°。
实施例2:表面粗糙度
将牛牙齿切割、研磨并抛光以获得尺寸约为3mm×3mm×2mm的釉块。釉质的厚度约为1-2mm,牙本质的厚度约为1mm。所有的测量都在釉质表面上进行。
在酸蚀刻之前和之后测量釉块的表面粗糙度。通过将釉质块置于1%柠檬酸溶液(pH3.8)中直到表面粗糙度(Sq)达到100-200时完成酸蚀刻。将该Sq值记录为蚀刻的釉质的表面粗糙度。(Sq是在ISO 25178中定义的标准量度,基本上是相对于被测表面的算术平均高度的均方根高度,因此它对应于测量区域内与中心平面相对的所有绝对距离的平均值,如果它较高,则意味着表面上有更明显的峰和谷,即表面更粗糙,如果它较低,则表面更光滑。)使用Na2HPO4缓冲液(1.5mM)和CaCl2(2.5mM)将HLP、例如BioMin 145稀释至最终浓度。中和至pH7.5后,将溶液过滤并离心。随后将酸蚀刻的釉质块与包含浓度为17μM的BioMin145的溶液(每块用2ml溶液)孵育60分钟。
在60分钟孵育期后,将釉块在人工唾液(AS)溶液(0.4g NaCl、0.4g KCl、0.8gCaCl2、0.69g NaH2PO4、1g尿素、1升蒸馏水;pH 7(用1M NaOH调节))中孵育22小时。然后用HLP BioMin 145对釉块进行第二次处理,并再次用人工唾液孵育22小时。然后用去离子(DI)水冲洗并风干釉块,随后测量它们的表面粗糙度。用0.5%PBS处理的釉质块用作实验的阴性对照。结果如表1所示。%修复表示相对于(未处理的)酸蚀刻釉质的表面粗糙度,通过蛋白质处理获得的表面粗糙度(Sq)的减少%。
表1–表面粗糙度实验结果
实验溶液 | 平均再矿化% |
17μM BioMin 145 | 15% |
PBS | -1% |
参见图1:使用粗糙度实验测定的BioMin 145的修复效能
如表1所示,浓度为17μM的BioMin 145有效降低酸蚀刻的釉质块的表面粗糙度。
实施例2-纳米压痕
如实施例1所述制备釉块。酸蚀刻通过将釉块在1%柠檬酸溶液(pH 3.8)中放置15分钟来实现。在蚀刻之前和之后测量500nm深度处的纳米硬度和杨氏模量。将蚀刻的釉块与浓度为20μM的HLP、例如BioMin 145的溶液一起孵育30分钟(2ml溶液/块),随后如实施例1所述与AS溶液温育22-24小时。将HLP和AS孵育步骤再重复两次,然后用去离子水冲洗釉块并风干。在500nm深度测量经处理的釉质块的纳米硬度和杨氏模量以评估HLP的釉质修复效果。使用500ppm氟化物的溶液作为实验的阳性对照。结果如表2和3所示。
表2–水解小麦蛋白的修复效能–纳米硬度
表3–水解小麦蛋白的修复效能–杨氏模量
从表2和3中可以看出,BioMin 145有效修复酸侵蚀的釉质。
实施例3–显微硬度
如实施例1所述制备釉块。显微硬度使用具有努普金刚石压头和50g负荷的Micromet 6020显微硬度测试仪(Buehler,Lake Bluff,IL,USA)测量。选择努氏硬度(KH)至少为300的釉块。通过浸入30%磷酸中15秒来蚀刻釉块。测量釉块的左侧和右侧的KH。随后,用胶带覆盖釉块的右侧,然后用20μM的HLP、例如BioMin 93溶液处理釉块,每次如实施例1中所述中和,两次各30分钟。(釉块右侧上的胶带防止该侧暴露于蛋白质溶液并用作内部对照)。在两次处理之间和第二次处理之后用去离子水以5分钟、500PRM洗涤釉块两次。随后,除去胶带并将釉块在AS溶液(0.2mM MgCl2、1mM CaCl2.H2O、20mM HEPES缓冲液、4mMKH2PO4、16mM KCl、4.5mM NH4Cl、300ppm NaF、0.05重量%NaN3,pH 7(用1M NaOH调节))中孵育7天。在用去离子水清洗釉块并将冲洗后的釉块空气干燥后,再次测量显微硬度。按照((显微硬度修复的-显微硬度蚀刻的)/(显微硬度完整的-显微硬度蚀刻的))*100计算表面显微硬度恢复百分比(SMHL,再矿化%)。表4中显示了显微硬度测定的结果。
表4–显微硬度实验结果
蛋白质 | %再矿化(平均值) |
20μM BioMin 93 | 37% |
对照缓冲液 | 1.67% |
从表4可以看出,BioMin 93有效地使酸蚀刻的釉质块的釉质表面再矿化。请注意,对于所有的显微硬度测试,从结果中减去浸入人工唾液并从人工唾液中得到一些修复的右侧/内部控制侧的再矿化百分比,以使数据呈现出HLP的差别效果。
虽然已经说明和描述了本发明的具体实施方案,但是对于本领域技术人员来说显而易见,可以在不背离如所附权利要求所限定的本发明的范围的情况下进行各种改变和修改。
Claims (17)
1.修复或抑制牙齿侵蚀、促进牙齿再矿化和/或增强氟化物的抗龋洞效应的方法,其包括向牙齿施用口腔护理组合物,所述组合物包含:
a)HLP
b)口腔可接受的载体,
其中HLP以所述组合物总重量的0.01重量%至3重量%的量存在于所述组合物中。
2.根据权利要求1的方法,其中HLP具有SEQ ID NO:1-24所述的多肽序列,或具有以下多肽序列:其从SEQ ID NO:1-24所述多肽序列开始,全部氨基酸的至多5%被取代、***或缺失,并且仍然具有起始蛋白质(SEQ ID NO:1-24)的生物学性质的至少50%。
3.根据上述权利要求任一项的方法,其中HLP已被中和至约中性或弱碱性pH。
4.根据权利要求1的方法,其中所述口腔护理组合物还包含有效量的氟化物。
5.根据上述权利要求任一项的方法,其中HLP以所述组合物总重量的0.1重量%至3重量%的量存在于所述组合物中。
6.根据上述权利要求任一项的方法,其中所述组合物是口腔清洗剂。
7.根据上述权利要求任一项的方法,其中氟化物的量为约500ppm氟化物。
8.根据上述权利要求任一项的方法,其中所述组合物是洁齿剂。
9.根据上述权利要求任一项的方法,其是用于减少、抑制或修复牙齿侵蚀的方法。
10.根据上述权利要求任一项的方法,其是用于促进牙齿再矿化的方法。
11.根据上述权利要求任一项的方法,其是用于增强氟化物的抗龋洞效应的方法。
12.洁齿剂,其包含:
a)HLP,其已被中和为大约中性或弱碱性pH;
b)有效量的氟化物;和
c)口腔可接受的载体。
13.口腔护理组合物,其包含:
a)HLP;
b)任选的有效量的氟化物;
c)口腔可接受的载体,
其中HLP以组合物总重量的0.01重量%至3重量的量存在于组合物中,所述组合物用于修复或抑制牙釉质侵蚀、促进牙釉质再矿化和/或增强氟化物的抗龋洞效应。
14.在口腔护理组合物中的HLP,所述组合物用于修复或抑制牙齿侵蚀、促进牙齿再矿化和/或增强氟化物的抗龋洞效应。
15.制备包含HLP的口腔护理产品的方法,所述方法包括:
a)通过用缓冲水溶液稀释来中和HLP以获得具有大约中性或弱碱性pH的溶液;
b)过滤并离心a)的溶液产物以获得包含HLP的滤液;
c)向b)的滤液产物中加入氟化物和任选的杀生物剂;
d)将c)的产物与口腔可接受的载体组分混合。
16.包含HLP的口腔护理组合物,其中所述口腔护理组合物通过权利要求15的方法获得或可通过权利要求15获得。
17.口香糖组合物,其包含:
a)胶质基;
b)香料;
c)甜味剂,和
d)占口香糖组合物重量约0.01%到约0.5%的HLP。
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