WO2023193538A1 - 一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用 - Google Patents

一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用 Download PDF

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WO2023193538A1
WO2023193538A1 PCT/CN2023/078182 CN2023078182W WO2023193538A1 WO 2023193538 A1 WO2023193538 A1 WO 2023193538A1 CN 2023078182 W CN2023078182 W CN 2023078182W WO 2023193538 A1 WO2023193538 A1 WO 2023193538A1
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pit
parts
optionally
fissure sealant
fissure
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PCT/CN2023/078182
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English (en)
French (fr)
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杨鹏
胡博文
郭晓贺
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陕西师范大学
美釉(西安)生物技术有限公司
优尼柯(天津)健康管理有限责任公司
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Publication of WO2023193538A1 publication Critical patent/WO2023193538A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/20—Protective coatings for natural or artificial teeth, e.g. sealings, dye coatings or varnish
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
    • A61K6/69—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/70—Preparations for dentistry comprising inorganic additives

Definitions

  • the present application relates to the technical field of biomaterials, and in particular to a pit and fissure sealant used to penetrate and seal pits and fissures on the occlusal surface of teeth and its application.
  • dental caries is one of the top ten most common diseases in the world, affecting 60% to 90% of school-age children, nearly 91% of adults suffer from dental caries, and the incidence of dental caries in the elderly can reach 98%.
  • tooth decay begins in early childhood and continues throughout life.
  • Studies have shown that although the occlusal surface accounts for less than 15% of the total tooth surface, more than 50% of caries occur in the pits and fissures of the occlusal surface of the teeth.
  • Pit and fissures are deep depressions located on the occlusal surface of teeth, with different shapes, of which I-type, IK-type, and inverted Y-type account for more than 50%.
  • the method for preparing an ideal remineralization coating in tooth pits and fissures should have the characteristics of rapidity, good wettability, strong stability, safety and easy operation.
  • the design and preparation of new surface coating technologies are of great significance, especially in the prevention of pit and fissure caries.
  • the purpose of this application is to provide a pit and fissure sealant for penetrating and sealing pits and fissures on the occlusal surface of teeth and its application.
  • This application utilizes the carboxyl groups on the protein and the hydroxyl groups on the polyethylene glycol, and under the dual effects of the disulfide bond reducing agent or oxidizing agent and the oral environment, it can deeply seal pits and fissures and maintain long-term curative effect.
  • the pit and fissure sealant of the present application has certain antibacterial and antifouling properties and can reduce the adhesion and aggregation of bacteria. It has the characteristics of fast speed, good wettability, strong stability, safety and easy operation.
  • this application provides a pit and fissure sealant for penetrating into the pits and fissures of the occlusal surface of teeth, including the following parts by weight of raw materials: 1 to 15 parts of polyethylene glycol, 1 to 20 parts of protein, and disulfide bonds 1 to 10 parts of reducing agent or disulfide bond oxidizing agent, 1 to 3 parts of calcium chloride, and 2 to 20 parts of pH adjuster.
  • the pit and fissure sealant includes the following raw materials in parts by weight: 2 to 8 parts by weight of polyethylene glycol, 4 to 10 parts of protein, 1 to 6 parts of disulfide bond reducing agent or disulfide bond oxidizing agent, and 1 to 2 parts of calcium chloride. and 5 to 10 parts of pH adjuster.
  • the pit and fissure sealant includes the following raw materials in parts by weight: 2 to 5 parts of polyethylene glycol, 4 to 6 parts of protein, 1 to 3 parts of disulfide bond reducing agent or disulfide bond oxidizing agent, and 1 to 2 parts of calcium chloride. and 6 to 10 parts of pH adjuster.
  • the pit and fissure sealant includes the following raw materials in parts by weight: 2.6 to 4.8 parts of polyethylene glycol, 5 to 5.5 parts of protein, 1 to 2 parts of disulfide bond reducing agent or disulfide bond oxidizing agent, and 1 to 1.5 parts of calcium chloride. and 6 to 8 parts of pH adjuster.
  • the pit and fissure sealant includes the following raw materials by weight: 2.6 to 4.8 parts of polyethylene glycol, 5.2 parts of protein, 1.2 parts of disulfide bond reducing agent or disulfide bond oxidizing agent, 1 part of calcium chloride and 6 parts of pH adjuster ⁇ 8 servings.
  • the protein is selected from the group consisting of lysozyme, albumin, ⁇ -lactoprotein, insulin, trypsin, chymotrypsin, myoglobin, hemoglobin, ⁇ -lactoglobulin, thyroglobulin, transferrin and lactoferrin any one or more of them.
  • the above proteins are all suitable for modification with strong reducing agents or strong oxidants, and the resulting ⁇ -sheet structure is used to endow the protein with self-assembly ability.
  • the lysozyme includes one or more of egg white lysozyme, plant lysozyme, animal lysozyme, microbial lysozyme and genetically engineered recombinant lysozyme.
  • albumin includes human-derived albumin and/or animal-derived albumin.
  • the ⁇ -milk protein includes human-derived ⁇ -milk protein and/or animal-derived ⁇ -milk protein.
  • the trypsin includes animal-derived trypsin, human-derived trypsin and/or genetically recombinant insulin.
  • the molecular weight of the polyethylene glycol is 200-5000, optionally 200-4000, optionally 800 ⁇ 4000, optionally 800 ⁇ 2000; optionally, polyethylene glycol is selected from one or more of PEG-800, PEG-2000 and PEG-4000; optionally, the polyethylene glycol The alcohol is selected from PEG-2000.
  • the disulfide bond reducing agent is selected from tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP ⁇ HCL), ⁇ -thioethanol ( ⁇ -ME), dithiothreitol (DTT), Any one or more of thioglycolic acid and reduced glutathione (GSH); optionally, the disulfide bond reducing agent is tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP ⁇ HCL) .
  • the concentration in the pit and fissure sealant emulsion (dip coating mixture) is 0.002-20 mg/mL, preferably 0.1-10 mg/mL.
  • the disulfide bond oxidizing agent is selected from the group consisting of trivalent cobalt salt, potassium permanganate, chlorate, concentrated sulfuric acid, nitric acid, hydrochloric acid, hydroiodic acid, hydrobromic acid, perchloric acid, fluorine gas, ozone, chlorine gas, hydrogen peroxide, One or more of periodic acid and sodium ferrate; optionally, the disulfide bond oxidizing agent is selected from potassium permanganate, chlorate, hydrochloric acid, hydroiodic acid, fluorine gas, ozone, chlorine gas, hydrogen peroxide , one or more of periodic acid and sodium ferrate; optionally, the disulfide bond oxidizing agent is selected from one or more of hydrochloric acid, hydriodic acid, hydrogen peroxide, periodic acid and sodium ferrate. .
  • the mass fraction in the pit and fissure sealant emulsion (dip coating mixture) is 0.01 to 50%, preferably 1 to 30%.
  • reducing agents and oxidizing agents are all suitable for the reaction system in the embodiments of the present application, which can transform the protein from an ⁇ -helical structure to a ⁇ -sheet structure and impart self-assembly properties to the protein.
  • the dosage of reducing agent and oxidizing agent should not be too large or too small.
  • the pH adjuster is selected from any one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium benzoate, and sodium citrate, optionally selected from One or both of sodium carbonate and sodium bicarbonate.
  • water is also included for preparing a pit and fissure sealant emulsion of 1 to 400 mg/mL.
  • the concentration of the pit and fissure sealant is 1 to 400 mg/mL, optionally 2 to 40 mg/mL, optionally 6 to 40 mg/mL, optionally 6 to 10 mg/mL, optionally 6 ⁇ 8mg/mL, optionally 6mg/mL.
  • a third aspect provides a pit and fissure sealant for penetrating into and sealing pits and fissures on the occlusal surface of teeth as described in the first aspect or an application of the pit and fissure sealant as described in the second aspect, characterized in that the usage method is: The fissure sealant is applied under pressure and penetrates into the tooth fissures.
  • the pit and fissure sealant of the present application can be physically mixed with protein and polyethylene glycol in one pot, which is simple to prepare, has mild reaction conditions, and has good controllability.
  • the main component is protein, which is non-toxic and non-irritating. It has good biocompatibility and can be stored stably after being prepared in large quantities for easy subsequent use.
  • this application can form a nanometer-thick Lyso-PEG protein coating in pits and fissures, inducing enamel remineralization in the oral saliva environment, starting from the bottom Start to seal the pits and fissures in situ.
  • the new layer formed by this application has certain antibacterial and antifouling properties, which can reduce the adhesion and aggregation of bacteria and inhibit the formation of plaque biofilm.
  • the remineralized layer has a certain tendency and has a dense structure, which can resist the influence of force during chewing. It has clinical application prospects. Widely used and ideal for use.
  • Figure 1 is a laser confocal three-dimensional imaging image of blank pits and fissures and deep film formation in pits and fissures coated with emulsion prepared using the pit and fissure sealant of Example 1; where a is a blank untreated pit and fissure, and b is the coating implementation Example 1 Pit and fissures made of emulsion made from pit and fissure sealant.
  • Figure 2 is a scanning electron microscope image of in vitro testing of pit and fissure sealant-induced mineralization performance.
  • a1 is a blank untreated picture of pits and fissures after mineralization
  • a2 is a blank untreated magnified picture of pits and fissures after mineralization
  • b1 is a blank untreated cross-sectional view of pits and fissures after mineralization
  • b2 is a blank untreated picture.
  • k is a cross-sectional view of pits and fissures after mineralization in artificial saliva with the emulsion prepared by applying the pit and fissure sealant of Comparative Example 1
  • l is the pit and fissure sealing after applying Comparative Example 1
  • the surface mineralization spectrum of the new layer after the emulsion was prepared.
  • Figure 3 is a scanning electron microscope image of the in vitro test of the pit and fissure sealant-induced mineralization performance of the comparative example, where a is a picture of a blank untreated pit and fissure after mineralization, and b is a cross-sectional view of a blank untreated pit and fissure after mineralization.
  • c is the surface mineralization energy spectrum of the blank untreated group;
  • d is the pit and fissure diagram after mineralization in artificial saliva with the emulsion prepared by applying the pit and fissure sealant of Comparative Example 1;
  • e is the pit and fissure diagram of the pit coated with Comparative Example 1
  • Cross-sectional view of pits and fissures after the emulsion made of fissure sealant is mineralized in artificial saliva.
  • Diagram of pits and fissures after the emulsion made of the pit and fissure sealant of Comparative Example 2 is mineralized in artificial saliva.
  • h is a cross-sectional view of pits and fissures after the emulsion made of the pit and fissure sealant of Comparative Example 2 is mineralized in artificial saliva.
  • Figure 4 is an XRD test of the structure of the new layer after coating the pit and fissure sealant, where a is the blank pit and fissure, and b is the new layer after coating the emulsion prepared by the pit and fissure sealant in Example 1.
  • Figure 5 is a scanning electron microscope result of in vitro testing of the antibacterial properties of the new layer induced by the sealant, where a is the bacterial adhesion result on the blank untreated enamel surface, and b is the emulsion induced by the pit and fissure sealant in Example 1 Bacterial adhesion results on the newly formed layer.
  • Figure 6 is the results of laser confocal microscopy staining of dead/living bacteria on the blank dental piece (a) and the new layer dental piece (b) treated with the emulsion prepared by pit and fissure sealant in Example 1, wherein, SYTO 9, PI , Merge represents different bacterial stains.
  • Figure 7 is a scanning electron microscope picture of the induced mineralization performance of the sealant tested in animal experiments, where a is a blank tooth cross section, b is an enlarged view of the blank tooth cross section, c is the mineralization energy spectrum of the blank tooth surface, and d is coating example 1
  • the tooth cross section of the emulsion prepared by the pit and fissure sealant e is an enlarged view of the tooth section coated with the emulsion prepared by the pit and fissure sealant of Example 1 (the white arrow is the boundary of the new layer), f is the pit and fissure sealant of Example 1
  • any one or more of PEG (200-5000) can be used to replace polyethylene glycol-2000 in the above-mentioned embodiments 1-8, and this solution is within the protection scope of this application.
  • Albumin human origin, animal origin
  • ⁇ -lactoprotein human origin, animal origin
  • insulin animal origin, human origin, genetic recombinant insulin, etc.
  • trypsin chymotrypsin, etc.
  • the solutions of the lysozyme in Examples 1 to 8 are all within the protection scope of the present application.
  • the preparation method of the graft coupling chemical synthesis of the above-mentioned PEGylated lysozyme is as follows: 10g polyethylene glycol-2000, 5g N, N-succinimide carbonate are dissolved in 30 mL chloroform, and 0.61g triethylamine is added , reacted at room temperature for 8 hours under magnetic stirring. After the reaction was terminated, glacial ether was used to precipitate to obtain succinimide-terminated polyethylene glycol.
  • the lysozyme in the above embodiments and comparative examples is egg white lysozyme, and other types of lysozyme can also achieve the purpose of this application.
  • the inventor added 60 mg of the sealant prepared in Example 1 to 10 mL of deionized water, and gently shook it until the raw materials were fully dissolved, to obtain a 6 mg/mL pit and fissure sealant emulsion with a pH of 7.2. Then various performance tests were conducted on the pit and fissure sealant emulsion.
  • the specific experiments are as follows:
  • the enamel block and enamel sheet coated with the pit and fissure sealant emulsion in Test Example 1 were placed in a centrifuge tube (15 mL centrifuge tube) containing 10 mL of artificial saliva, and cultured at 37°C for 24 hours, every 12 The artificial saliva was replaced every hour, and was taken out after 7 days to observe the sealing conditions in the pits and fissures. A blank pit and fissure without pit and fissure sealant was used as a control experiment.
  • the inventor further compared the effect of pit and fissure sealants obtained in Example 8 and Comparative Example 1 (Lyso-PEG obtained by chemical grafting method) according to the above method by inducing mineralization and blocking pits and fissures (see Figure 2). It can be seen from the figure that the pit and fissure sealing effect (20 ⁇ m) of the pit and fissure sealant obtained by physically mixing polyethylene glycol and protein in one pot and the sealing effect of the pit and fissure sealant of Comparative Example 1 obtained by the complex chemical graft coupling method The effect (22 ⁇ m) is similar. Therefore, the pit and fissure sealant prepared by one-pot physical mixing can avoid complex chemical grafting and coupling reactions, achieve the same pit and fissure sealing effect, and is easy to prepare.
  • the dental plaques coated with pit and fissure sealant emulsion in Test Example 2 and placed in artificial saliva for 7 days were placed in a 24-well plate, and 1 mL of Streptococcus mutans suspension containing culture medium (10 8 /mL) was added. Incubate at 37°C for 24 hours, rinse with deionized water and observe bacterial adhesion and aggregation under a scanning electron microscope. And use unprocessed tooth slices as As a blank control group.
  • the dental piece coated with the sealant emulsion obtained according to the method of Test Example 1 was fixed inside the oral cavity of a mouse (8 weeks old, weighing 200-300 grams), and was taken out for observation after 14 days. A blank control dental film without pit and fissure sealant was used as a control experiment.
  • the section of the blank tooth fragment shows no mineralization layer, and an obvious new layer can be seen on the section of the tooth fragment after sealant treatment.
  • Animal experiments also prove that the pit and fissure sealant of the present application can induce its own mineralization to form a new layer, thereby achieving a sealing effect.
  • Volunteers with good oral hygiene were selected as subjects, and healthy caries-free mandibular second molar occlusal surface pits and fissures were selected as experimental subjects. After brushing and cleaning the tooth surface in the morning and evening, sealant was applied to the occlusal surface pits and fissures under pressure. 5 minutes, twice a day, repeated for 14 days, and then use the QLF instrument to detect the changes in the demineralization area and lesion depth in the pits and fissures before and after use.
  • This application provides a pit and fissure sealant for penetrating into and sealing pits and fissures on the occlusal surface of teeth and its application.
  • Pit and fissure sealing The agent includes the following raw materials by weight: 1 to 15 parts of polyethylene glycol, 1 to 20 parts of protein, 1 to 10 parts of disulfide bond reducing agent or disulfide bond oxidizing agent, 1 to 3 parts of calcium chloride, and 2 pH regulators ⁇ 20 servings.
  • the pit and fissure sealant of the present application can be physically mixed with protein and polyethylene glycol in one pot, and has simple preparation, mild reaction conditions, and good controllability.

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  • Health & Medical Sciences (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
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Abstract

本申请提供了一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用，窝沟封闭剂包括如下重量份的原料：聚乙二醇1～15份、蛋白质1～20份、二硫键还原剂或二硫键氧化剂1～10份、氯化钙1～3份、pH调节剂2～20份。本申请的窝沟封闭剂可以通过将蛋白质和聚乙二醇一锅法物理混合，制备简单、反应条件温和、可控性好。

Description

一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用
交叉引用
本申请要求在中国专利局提交的、申请号为202210358705.5、申请日为2022年04月07日、申请名称为“一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用”的中国专利申请的优先权，该申请的全部内容通过引用结合在本申请中。
技术领域
本申请涉及生物材料技术领域，尤其涉及一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用。
背景技术
根据世界卫生组织的数据，龋齿是世界上最常见的十大疾病之一，影响60％至90％的学龄儿童，近91％的成年人患有龋齿，老年人龋齿发病率可达98％。对许多人来说，龋齿始于幼儿期，并持续终生。研究显示，虽然咬合面只占牙齿所有牙面不到15％，但超过50％的龋病发生在牙齿咬合面的窝沟点隙处。窝沟是位于牙齿咬合面的深凹陷，形态各异，其中I型、IK型、倒Y型占50％以上。由于其特殊的形态，这些形态在正常的口腔护理中，很难达到彻底的清洁，从而为菌斑生物膜和致龋基质提供了停滞位点，致龋基质会随着时间的推移产生酸，导致脱矿，最终导致龋病。目前来看，临床上常用的聚合树脂类窝沟封闭剂仅采用机械的封堵作用封闭窝沟，但由于材料本身与牙釉质结构的差异，微渗漏、边缘不密合和高脱落率是现有窝沟封闭剂的主要弊端。因此深入封堵窝沟深处结构且保证材料与窝沟处釉质结构的高度适配是预防窝沟龋发生的重要手段。
为了达到深入封闭窝沟深处的目的，促进窝沟深处釉质原位再矿化有望达到这一目的。在牙齿咬合面窝沟处，特别是窝沟底最深处形成能促进再矿化的活性涂层则是最关键的技术难题。目前为止，只有为数不多的工作包括矿化液直接诱导、细胞外基质蛋白/多肽诱导、水凝胶驱动、前体组装等实现过釉质再矿化。但是这些方法都有很多缺陷限制其在实际治疗中的应用，其中包括极端的反应条件，生物毒性及安全性考虑，材料的粒径较大浸润性能较差，材料难以批量合成制备等。因此，在牙齿窝沟内制备理想的再矿化涂层的方法应该具备快速、浸润性好、稳定性强、安全易操作等特点。综上所述，设计制备新型的表面涂层技术，特别是在预防窝沟龋上具有重要的意义。
发明内容
发明目的
为克服上述不足，本申请的目的在于提供一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用。
本申请利用蛋白质上的羧基与聚乙二醇上的羟基，在二硫键还原剂或氧化剂和口腔环境的双重作用下，能够深入封闭窝沟并能长期保持疗效。另外本申请的窝沟封闭剂具有一定的抗菌抗污性能，可以减少细菌的粘附和聚集。并具备快速、浸润性好、稳定性强、安全易操作等特点。
解决方案
为实现本申请目的，本申请采用的技术方案如下：
第一方面，本申请提供了一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂，包括如下重量份的原料：聚乙二醇1～15份、蛋白质1～20份、二硫键还原剂或二硫键氧化剂1～10份、氯化钙1～3份、pH调节剂2～20份。
进一步地，窝沟封闭剂包括如下重量份的原料：聚乙二醇2～8份、蛋白质4～10份、二硫键还原剂或二硫键氧化剂1～6份、氯化钙1～2份和pH调节剂5～10份。
进一步地，窝沟封闭剂包括如下重量份的原料：聚乙二醇2～5份、蛋白质4～6份、二硫键还原剂或二硫键氧化剂1～3份、氯化钙1～2份和pH调节剂6～10份。
进一步地，窝沟封闭剂包括如下重量份的原料：聚乙二醇2.6～4.8份、蛋白质5～5.5份、二硫键还原剂或二硫键氧化剂1～2份、氯化钙1～1.5份和pH调节剂6～8份。
进一步地，窝沟封闭剂包括如下重量份的原料：聚乙二醇2.6～4.8份、蛋白质5.2份、二硫键还原剂或二硫键氧化剂1.2份、氯化钙1份和pH调节剂6～8份。
进一步地，所述蛋白质选自溶菌酶、白蛋白、ɑ-乳蛋白、胰岛素、胰蛋白酶、糜蛋白酶、肌红蛋白、血红蛋白、β-乳糖球蛋白、甲状腺球蛋白、转铁蛋白和乳铁蛋白中的任意一种或多种。采用以上几种蛋白均适用于强还原剂或强氧化剂进行改性，利用产生的β折叠结构赋予蛋白自组装能力。
进一步地，所述溶菌酶包括蛋清溶菌酶、植物溶菌酶、动物溶菌酶、微生物溶菌酶和基因工程重组溶菌酶中的一种或几种。
进一步地，所述白蛋白包括人源性白蛋白和/或动物源性白蛋白。
进一步地，所述ɑ-乳蛋白包括人源性ɑ-乳蛋白和/或动物源性ɑ-乳蛋白。
进一步地，所述胰蛋白酶包括动物源性胰蛋白酶、人源性胰蛋白酶和/或基因重组胰岛素。
进一步地，所述聚乙二醇的分子量为200～5000，可选地为200～4000，可选地为 800～4000，可选地为800～2000；可选地，聚乙二醇选自PEG-800、PEG-2000和PEG-4000中的一种或几种；可选地，所述聚乙二醇选自PEG-2000。
进一步地，所述二硫键还原剂选自三(2-羧乙基)膦酸盐酸(TCEP·HCL)、β-硫基乙醇(β-ME)、二硫苏糖醇(DTT)、巯基乙酸、还原型谷胱甘肽(GSH)中的任意一种或多种；可选地，所述二硫键还原剂为三(2-羧乙基)膦酸盐酸(TCEP·HCL)。在窝沟封闭剂乳液(浸涂混合液)中的浓度为0.002-20mg/mL，优选为0.1-10mg/mL。
所述二硫键氧化剂选自三价钴盐、高锰酸钾、氯酸盐、浓硫酸、硝酸、盐酸、氢碘酸、氢溴酸、高氯酸、氟气、臭氧、氯气、双氧水、高碘酸和高铁酸钠中的一种或多种；可选地，所述二硫键氧化剂选自高锰酸钾、氯酸盐、盐酸、氢碘酸、氟气、臭氧、氯气、双氧水、高碘酸和高铁酸钠中的一种或多种；可选地，所述二硫键氧化剂选自盐酸、氢碘酸、双氧水、高碘酸和高铁酸钠中的一种或多种。在窝沟封闭剂乳液(浸涂混合液)中的质量分数为0.01～50％，优选为1～30％。
以上几种还原剂、氧化剂均适用于本申请实施例中的反应体系，能够使蛋白由α螺旋结构向β折叠结构转变，赋予蛋白自组装性能。同样，还原剂、氧化剂的用量不宜过大或过小。
进一步地，所述pH调节剂选自碳酸钠、碳酸氢钠、碳酸钾、磷酸氢二钾、磷酸氢二钠、苯甲酸钠、柠檬酸钠中的任意一种或多种，可选地选自碳酸钠、碳酸氢钠中的一种或两种。
进一步地，还包括水，用于配制1～400mg/mL的窝沟封闭剂乳液。
第二方面，提供一种窝沟封闭剂的乳液，包括水和上述第一方面所述的用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂，可选地，乳液的pH为7～7.5。
进一步地，窝沟封闭剂的浓度为1～400mg/mL，可选地为2～40mg/mL，可选地为6～40mg/mL，可选地为6～10mg/mL，可选地为6～8mg/mL，可选地为6mg/mL。
第三方面，提供一种上述第一方面所述的用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂或上述第二方面所述的窝沟封闭剂的应用，其特征在于，使用方式为将窝沟封闭剂加压涂覆并渗透至牙齿窝沟处。
本申请经过体外实验，动物实验及体内预试验证明，该窝沟封闭剂乳液可以深入涂覆并渗透至窝沟内部。唾液中的钙离子可以与窝沟封闭剂乳液中的蛋白质表面基团结合，随着蛋白质附着在牙釉质的表面成膜，诱导牙釉质再矿化形成新生层，达到封闭窝沟的效果，新生层的厚度可随治疗时间的增加而增加，一周即可达20μm。另外诱导形成的新生层，由于其结构的特异性及封堵作用，可以有效的减少细菌的粘附和聚集，防止生 物膜的形成，从而预防龋齿发生。
有益效果
(1)本申请的窝沟封闭剂可以通过将蛋白质和聚乙二醇一锅法物理混合，制备简单、反应条件温和、可控性好。主要成分为蛋白质，无毒无刺激性，具有良好的生物相容性，大量配制后可稳定保存，便于后续使用。
(2)本申请窝沟封闭剂使用方法简便，采用简单的涂抹或浸泡的方法即可达到稳定的Lyso-PEG蛋白膜覆盖效果。
(3)与传统的窝沟封闭剂的机械封堵效果不同，本申请可在窝沟内形成纳米级别厚度的Lyso-PEG蛋白质涂层，在口腔唾液环境下诱导牙釉质再矿化，从底部开始原位封闭窝沟。
(4)本申请形成的新生层具有一定的抗菌抗污性能，可以减少细菌的粘附和聚集，抑制菌斑生物膜的形成。本申请的窝沟封闭剂形成的新生层与天然牙釉质之间没有明显分界，结合紧密，再矿化层有一定的趋向且结构致密，可以抵抗咀嚼过程中的受力等影响，临床应用前景广泛，使用效果理想。
附图说明
一个或多个实施例通过与之对应的附图中的图片进行示例性说明，这些示例性说明并不构成对实施例的限定。在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
图1为空白窝沟和使用实施例1窝沟封闭剂所制乳液涂覆的窝沟深部成膜的激光共聚焦三维成像图；其中，a是空白未处理的窝沟，b是涂覆实施例1窝沟封闭剂所制乳液的窝沟。
图2是体外测试窝沟封闭剂诱导矿化性能的扫描电镜图像。其中，a1是空白未处理的窝沟矿化后的图，a2空白未处理的窝沟矿化后的放大图，b1是空白未处理的窝沟矿化后的断面图，b2是空白未处理的窝沟矿化后的断面放大图，c是空白未处理组的表面矿化物能谱；d是涂覆实施例1的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟图，e是涂覆实施例1的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟断面图，f是涂覆实施例1的窝沟封闭剂所制乳液后新生层的表面矿化物能谱；g是涂覆实施例8的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟图，h是涂覆实施例8的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟断面图，i是涂覆实施例8的窝沟封闭剂所制乳液后新生层的表面矿化物能谱；j是涂覆对比例1的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟图，k是涂覆对比例1的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟断面图，l是涂覆对比例1的窝沟封闭剂所制乳液后新生层的表面矿化物能谱。
图3是体外测试对比例窝沟封闭剂诱导矿化性能的扫描电镜图像，其中a是空白未处理的窝沟矿化后的图，b是空白未处理的窝沟矿化后的断面图，c是是空白未处理组的表面矿化能谱；d是涂覆对比例1的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟图，e是涂覆对比例1的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟断面图，f是涂覆对比例1的窝沟封闭剂所制乳液后新生层的表面矿化物能谱；g是涂覆对比例2的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟图，h是涂覆对比例2的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟断面图，i是涂覆对比例2的窝沟封闭剂所制乳液后新生层的表面矿化物能谱；j是涂覆对比例3的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟图，k是涂覆对比例3的窝沟封闭剂所制乳液在人工唾液内矿化后的窝沟断面图，l是涂覆对比例3得到的窝沟封闭剂后新生层的表面矿化物能谱。
图4是XRD测试涂覆窝沟封闭剂涂覆后的新生层结构，其中a是空白窝沟，b是涂覆实施例1窝沟封闭剂所制乳液后的新生层。
图5是体外测试封闭剂诱导形成的新生层的抗菌性能的扫描电镜结果，其中a是空白未作处理的牙釉质表面的细菌粘附结果，b是实施例1窝沟封闭剂所制乳液诱导形成的新生层上的细菌粘附结果。
图6是实施例1窝沟封闭剂所制乳液处理后的空白牙片(a)和新生层牙片(b)的死/活菌染色激光共聚焦显微镜的结果图，其中，SYTO 9、PI、Merge代表不同的细菌染色剂。
图7是动物实验测试封闭剂的诱导矿化性能扫描电镜图，其中a是空白牙断面，b是空白牙断面放大图，c是空白牙表面的矿化物能谱，d是涂覆实施例1窝沟封闭剂所制乳液的牙断面，e是涂覆实施例1窝沟封闭剂所制乳液的牙断面放大图(白色箭头处为新生层界限)，f是涂覆实施例1窝沟封闭剂所制乳液的牙表面的矿化物能谱。
具体实施方式
为使本申请实施例的目的、技术方案和优点更加清楚，下面将对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
另外，为了更好的说明本申请，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本申请同样可以实施。在一些实施例中，对于本领域技术人员熟知的原料、元件、方法、手段等未作详细描述，以便于凸显本申请的主旨。
除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换 如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。
实施例1
将48mg聚乙二醇-2000、52mg溶菌酶、12mg三(2-羧乙基)膦酸盐酸、10mg氯化钙、60mg碳酸氢钠均匀混合，得到窝沟封闭剂。
实施例2
将50mg聚乙二醇-2000、64mg溶菌酶、15mg三(2-羧乙基)膦酸盐酸、15mg氯化钙、70mg碳酸氢钠均匀混合，得到窝沟封闭剂。
实施例3
将60mg聚乙二醇-2000、74mg溶菌酶、20mg三(2-羧乙基)膦酸盐酸、10mg氯化钙、80mg碳酸钠均匀混合，得到窝沟封闭剂。
实施例4
将100mg聚乙二醇-2000、120mg溶菌酶、60mg三(2-羧乙基)膦酸盐酸、20mg氯化钙、20mg碳酸氢钠均匀混合，得到窝沟封闭剂。
实施例5
将100mg聚乙二醇-2000、118mg溶菌酶、60mg三(2-羧乙基)膦酸盐酸、30mg氯化钙、100mg碳酸氢钠均匀混合，得到窝沟封闭剂。
实施例6
将150mg聚乙二醇-2000、180mg溶菌酶、100mg三(2-羧乙基)膦酸盐酸、20mg氯化钙、100mg碳酸氢钠均匀混合，得到窝沟封闭剂。
实施例7
将200mg聚乙二醇-2000、220mg溶菌酶、100mg三(2-羧乙基)膦酸盐酸、10mg氯化钙、200mg碳酸氢钠均匀混合，得到窝沟封闭剂。
实施例8
将26mg聚乙二醇-2000、52mg溶菌酶、12mg三(2-羧乙基)膦酸盐酸、10mg氯化钙、60mg碳酸氢钠均匀混合，得到窝沟封闭剂。
本申请中也可以用PEG(200～5000)中的任意一种或多种替换上述实施例1～8中的聚乙二醇-2000，该方案均在本申请的保护范围内。
本申请也可用白蛋白(人源性、动物源性)、ɑ-乳蛋白(人源性、动物源性)、胰岛素(动物源性、人源性、基因重组胰岛素等)、胰蛋白酶、糜蛋白酶、肌红蛋白、血红蛋白、β-乳糖球蛋白、甲状腺球蛋白、转铁蛋白、乳铁蛋白中的任意一种或多种替换上 述实施例1～8中的溶菌酶，该方案均在本申请的保护范围内。
对比例1
将50mg通过接枝偶联化学合成方法得到的聚乙二醇(PEG-2000)化溶菌酶、12mg三(2-羧乙基)膦酸盐酸、10mg氯化钙、60mg碳酸氢钠均匀混合，得到对比例1的窝沟封闭剂。
取60mg上述对比例1的窝沟封闭剂加入到10mL去离子水，得到6mg/mL的对比例1的窝沟封闭剂乳液，其pH为7.2。
上述聚乙二醇化溶菌酶的接枝偶联化学合成制备方法为：10g聚乙二醇-2000、5gN,N-琥珀酰亚胺碳酸酯溶于30mL三氯甲烷中，加入0.61g三乙胺，磁力搅拌下室温反应8小时。反应终止后用冰乙醚沉淀得到琥珀酰亚胺封端的聚乙二醇。称取1g琥珀酰亚胺封端的聚乙二醇与0.14g溶菌酶溶解到20mL pH7.5的三(2-羧乙基)膦的三羟甲基氨基甲烷缓冲液中，室温搅拌反应8小时后，透析、冻干，得到聚乙二醇化溶菌酶。
对比例2
将8mg聚乙二醇-2000、52mg溶菌酶、12mg三(2-羧乙基)膦酸盐酸、10mg氯化钙、60mg碳酸氢钠均匀混合，得到对比例2的窝沟封闭剂。
取60mg上述对比例2的窝沟封闭剂加入到10mL去离子水，得到6mg/mL的对比例2的窝沟封闭剂乳液，其pH为7.2。
对比例3
将2mg聚乙二醇-2000、52mg溶菌酶、12mg三(2-羧乙基)膦酸盐酸、10mg氯化钙、60mg碳酸氢钠均匀混合，得到对比例3的窝沟封闭剂。
取60mg上述对比例3的窝沟封闭剂加入到10mL去离子水，得到6mg/mL的对比例3的窝沟封闭剂乳液，其pH为7.2。
上述实施例和对比例中的溶菌酶为蛋清溶菌酶，其它类型的溶菌酶也能达到本申请的目的。
为了证明本申请的有益效果，发明人将60mg实施例1制备的封闭剂加入10mL去离子水中，轻轻摇晃至原料充分溶解，得到6mg/mL的窝沟封闭剂乳液，其pH为7.2。然后对该窝沟封闭剂乳液进行各种性能测试，具体实验如下：
试验例1
窝沟封闭剂的涂覆性能验证
收集健康无龋且无明显磨耗的新鲜离体磨牙样品，清洗干净后，慢速切片机去除牙根，制备5×5×1mm的牙釉质片样本和保留沟窝的牙釉质块样本，牙片用砂纸梯度打磨 抛光，制备的保留窝沟的牙釉质块用超声清洗，确保窝沟内的菌斑完全清洗干净后备用作为体外实验样本。
将上述体外实验样本浸泡在窝沟封闭剂乳液中，在室温下放置5分钟后取出。由于窝沟封闭剂可以和荧光染料硫磺素T(ThT)特异性结合的特点，利用激光共聚焦显微镜三维成像表征，结果如图1，结果证明该窝沟封闭剂可以深入涂覆在窝沟的底部，形成稳定的膜结构覆盖。
试验例2
封闭剂诱导矿化封堵窝沟的性能验证
将试验例1中的涂覆窝沟封闭剂乳液的牙釉质块及牙釉质片分别放置在含有10mL人工唾液的离心管(15mL离心管)内，在37℃的环境下培养24小时，每12小时更换一次人工唾液，7天后取出观察窝沟内的封闭状况，并以未涂覆窝沟封闭剂的空白牙窝沟作为对照实验。
从图2的扫描电镜结果显示，涂覆窝沟封闭及的牙釉质块窝沟底部可见新生的矿化晶体紧密排列，封闭深度可达20μm。元素能谱分析和XRD结果(图4)证明再矿化的晶体为羟基磷灰石。而空白未处理的对照实验中窝沟内未见新生矿化物。以上测试证明，本申请窝沟封闭剂可以涂覆并渗透至窝沟底部，吸附唾液中的矿物离子，诱导自发的矿化过程，封堵窝沟。
发明人按照上述方法还进一步比较了实施例8和对比例1(化学接枝法方法得到Lyso-PEG)得到的窝沟封闭剂诱导矿化封堵窝沟的效果(见图2)。由图可知，一锅法物理混合聚乙二醇和蛋白质得到的窝沟封闭剂的窝沟封闭效果(20μm)和通过复杂化学接枝偶联的方法得到的对比例1的窝沟封闭剂的封闭效果(22μm)类似。因此一锅法物理混合制备的窝沟封闭剂可以避免复杂的化学接枝偶联反应，并达到同样的窝沟封闭效果，制备简便。
另外，为了验证聚乙二醇含量对窝沟封闭效果的影响，发明人同时又进行了对比例2和对比例3的试验，结果见图3，结果显示聚乙二醇的含量较低时制得的窝沟封闭剂对窝沟封闭效果不明显。
试验例3
窝沟封闭剂诱导形成新生层的抗菌性能验证
将试验例2涂覆窝沟封闭剂乳液并置于人工唾液内7天处理的牙片放置在24孔板内，加入1mL含培养基的变形链球菌悬浊液(108个/mL)，在37℃的环境下培养24小时，用去离子水冲洗后扫描电镜下观察细菌的粘附和聚集情况。并以未作处理的牙片作 为空白对照组。
从图5扫描电镜结果可以看出，未处理的牙片上有大量的细菌粘附。接近形成菌斑样结构，而涂覆封闭剂后有新生层的牙片上的细菌粘附数量明显减少。另外从激光共聚焦显微镜结果(见图6)也可以看出，经过死/活细菌染色剂染色的空白牙片上，活菌明显多于死菌，而涂覆封闭剂后形成的新生层牙片上活菌数明显减少。
试验例4
动物实验测试封闭剂性能
将按试验例1的方法得到的涂覆封闭剂乳液的牙片固定在小鼠口腔内部(8周大，体重200～300克)，14天后取出观察。并以未涂窝沟封闭剂的空白对照牙片作为对照实验。
从图7可以看出，空白牙片断面显示没有矿化层生成，在封闭剂处理后的牙片断面上可见明显的新生层。动物实验也同样证明，本申请的窝沟封闭剂可以诱导自身矿化形成新生层，从而达到封闭效果。
试验例5
临床预试验测试封闭剂的性能。
选取口腔卫生良好的志愿者作为受试者，选择健康无龋的下颌第二磨牙咬合面窝沟作为实验对象，早晚刷牙清洁牙面后，加压涂覆封闭剂于咬合面窝沟处，每次5分钟，每日两次，重复14天后，利用QLF仪器检测使用前后窝沟处的脱矿面积及病变深度的变化。
从图8可以看出，随着时间的延长，脱矿区域白斑面积及脱矿程度明显减少，窝沟病变深度随时间也不断减少。临床预试验结果证明，封闭剂处理后，随时间的延长，脱矿程度明显减低。结果证明，本申请封闭剂可以涂覆并渗透至窝沟底部，形成稳定的膜结构覆盖，并在唾液环境下吸附钙离子磷酸根离子诱导羟基磷灰石晶体的形成，自身矿化实现窝沟的封堵效果，从而减少微渗漏和边缘不密合性，达到减少窝沟龋的效果。
最后应说明的是：以上实施例仅用以说明本申请的技术方案，而非对其限制；尽管参照前述实施例对本申请进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本申请各实施例技术方案的精神和范围。
工业实用性
本申请提供了一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用，窝沟封闭 剂包括如下重量份的原料：聚乙二醇1～15份、蛋白质1～20份、二硫键还原剂或二硫键氧化剂1～10份、氯化钙1～3份、pH调节剂2～20份。本申请的窝沟封闭剂可以通过将蛋白质和聚乙二醇一锅法物理混合，制备简单、反应条件温和、可控性好。

Claims (10)

  1. 一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂，其特征在于，包括如下重量份的原料：
  2. 根据权利要求1所述的窝沟封闭剂，其特征在于，窝沟封闭剂包括如下重量份的原料：聚乙二醇2～8份、蛋白质4～10份、二硫键还原剂或二硫键氧化剂1～6份、氯化钙1～2份和pH调节剂5～10份；
    可选地，窝沟封闭剂包括如下重量份的原料：聚乙二醇2～5份、蛋白质4～6份、二硫键还原剂或二硫键氧化剂1～3份、氯化钙1～2份和pH调节剂6～10份；
    可选地，窝沟封闭剂包括如下重量份的原料：聚乙二醇2.6～4.8份、蛋白质5～5.5份、二硫键还原剂或二硫键氧化剂1～2份、氯化钙1～1.5份和pH调节剂6～8份；
    可选地，窝沟封闭剂包括如下重量份的原料：聚乙二醇2.6～4.8份、蛋白质5.2份、二硫键还原剂或二硫键氧化剂1.2份、氯化钙1份和pH调节剂6～8份。
  3. 根据权利要求1或2所述的窝沟封闭剂，其特征在于，所述蛋白质选自溶菌酶、白蛋白、ɑ-乳蛋白、胰岛素、胰蛋白酶、糜蛋白酶、肌红蛋白、血红蛋白、β-乳糖球蛋白、甲状腺球蛋白、转铁蛋白和乳铁蛋白中的任意一种或多种；
    可选地，所述溶菌酶包括蛋清溶菌酶、植物溶菌酶、动物溶菌酶、微生物溶菌酶和基因工程重组溶菌酶中的一种或几种；
    可选地，所述白蛋白包括人源性白蛋白和/或动物源性白蛋白；
    可选地，所述ɑ-乳蛋白包括人源性ɑ-乳蛋白和/或动物源性ɑ-乳蛋白；
    可选地，所述胰蛋白酶包括动物源性胰蛋白酶、人源性胰蛋白酶和/或基因重组胰岛素。
  4. 根据权利要求1至3任一所述的窝沟封闭剂，其特征在于，所述聚乙二醇的分子量为200～5000，可选地为200～4000，可选地为800～4000，可选地为800～2000；可选地，聚乙二醇选自PEG-800、PEG-2000和PEG-4000中的一种或几种；可选地，所述聚乙二醇选自PEG-2000。
  5. 根据权利要求1至4任一所述的窝沟封闭剂，其特征在于，所述二硫键还原剂选自三(2-羧乙基)膦酸盐酸、β-硫基乙醇、二硫苏糖醇、巯基乙酸、还原型谷胱甘肽中的任意一种或多种；可选地，所述二硫键还原剂为三(2-羧乙基)膦酸盐酸；
    所述二硫键氧化剂选自三价钴盐、高锰酸钾、氯酸盐、浓硫酸、硝酸、盐酸、氢碘酸、氢溴酸、高氯酸、氟气、臭氧、氯气、双氧水、高碘酸和高铁酸钠中的一种或多种；可选地，所述二硫键氧化剂选自高锰酸钾、氯酸盐、盐酸、氢碘酸、氟气、臭氧、氯气、双氧水、高碘酸和高铁酸钠中的一种或多种；可选地，所述二硫键氧化剂选自盐酸、氢碘酸、双氧水、高碘酸和高铁酸钠中的一种或多种。
  6. 根据权利要求1至5任一所述的窝沟封闭剂，其特征在于，所述pH调节剂选自碳酸钠、碳酸氢钠、碳酸钾、磷酸氢二钾、磷酸氢二钠、苯甲酸钠、柠檬酸钠中的任意一种或多种，可选地选自碳酸钠、碳酸氢钠中的一种或两种。
  7. 根据权利要求1至6任一所述的窝沟封闭剂，其特征在于，还包括水，用于配制1～400mg/mL的窝沟封闭剂乳液。
  8. 一种窝沟封闭剂的乳液，其特征在于，包括水和权利要求1至6任一所述的用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂，可选地，乳液的pH为7～7.5。
  9. 根据权利要求8所述的窝沟封闭剂的乳液，其特征在于，窝沟封闭剂的浓度为1～400mg/mL，可选地为2～40mg/mL，可选地为6～40mg/mL，可选地为6～10mg/mL，可选地为6～8mg/mL，可选地为6mg/mL。
  10. 一种权利要求1至6任一所述的用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂或权利要求7至9任一所述的窝沟封闭剂的应用，其特征在于，使用方式为将窝沟封闭剂加压涂覆并渗透至牙齿窝沟处。
PCT/CN2023/078182 2022-04-07 2023-02-24 一种用于渗入封闭牙齿咬合面窝沟的窝沟封闭剂及其应用 WO2023193538A1 (zh)

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