CN112022843A - D-亮氨酸和氯己定组合物的应用 - Google Patents
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Abstract
本发明属于医药卫生技术领域,涉及D‑亮氨酸和氯己定组合物的应用,尤其涉及D‑亮氨酸和氯己定组合物在制备预防或治疗龋病药物中的应用。本发明通过实验研究证明D‑亮氨酸增强氯己定对致龋变形链球菌的杀菌作用的机制为D‑亮氨酸将生物膜状态的变形链球菌转变为分散状态的浮游变形链球菌,使变形链球菌更易杀灭,从而增强氯己定对变形链球菌的杀灭作用,通过在口腔杀菌剂氯己定中添加绿色化合物D‑亮氨酸,制备D‑亮氨酸和氯己定组合物,杀灭致龋变形链球菌生物膜,大大降低氯己定的使用浓度,降低氯己定临床应用的不良反应,达到同等的杀菌效果,具有临床转化前景。
Description
技术领域
本发明属于医药卫生技术领域,涉及D-亮氨酸和氯己定组合物的应用,尤其涉及D-亮氨酸和氯己定组合物在制备预防或治疗龋病药物中的应用。
背景技术
龋齿是口腔的第一大疾病,变形链球菌被认为是该病的主要致病微生物,它主要通过在牙齿表面形成牙菌斑生物膜而导致龋齿,严重时可发展为牙髓病和根尖周病。龋病只有在牙菌斑生物膜存在的情况下才会发生和发展,因此有效清除和控制牙菌斑生物膜是防治龋病的关键。在临床中,减少变形链球菌数量方法包括机械清除和漱口水。在正畸治疗过程中,变形链球菌生物膜容易在托槽周围积聚,正畸治疗过程往往较长,增加了龋齿发生的风险,由于托槽的存在,机械清除方法不能完全去除附着在牙表面的生物膜和细菌。因此,刷牙后经常需要使用漱口水。在各种漱口水中,最持久使用减少变形链球菌的是氯己定漱口水,高浓度氯己定是保证其杀菌活性的重要因素。然而,副作用是明显的,随着浓度的增加,现象越明显,风险越高。染色是最常见的,此外,也经常观察到牙石形成和味觉改变,与此同时,有人觉得味道是不可接受的。如果能降低浓度,这些现象就能减少甚至消除。然而,目前并未发现有关于D-亮氨酸和氯己定组合物在抑制致龋变形链球菌方面的相关技术的报道。
发明内容
针对现有技术存在的问题,本发明的目的在于提供D-亮氨酸和氯己定组合物在制备预防或治疗龋病药物中的应用。
为了实现上述目的,本发明提供以下技术方案。
D-亮氨酸和氯己定组合物在制备预防或治疗龋病药物中的应用。
进一步地,所述预防或治疗龋病药物中氯己定和D-亮氨酸体积比为1:100。
进一步地,所述预防或治疗龋病药物中氯己定浓度小于1ppm。
进一步地,所述预防或治疗龋病药物中D-亮氨酸的浓度小于100ppm。
进一步地,D-亮氨酸增强氯己定对致龋变形链球菌的杀菌作用。
进一步地,所述药物的剂型为任何药物治疗学上可接受的剂型。
进一步地,所述药物的剂量为任何药物治疗学上可接受的剂量。
一种预防或治疗龋病药物,包括D-亮氨酸和氯己定组合物以及药物上可接受的载体。
与现有技术比,本发明具有以下有益效果。
本发明通过实验研究证明D-亮氨酸增强氯己定对致龋变形链球菌的杀菌作用的机制为D-亮氨酸将生物膜状态的变形链球菌转变为分散状态的浮游变形链球菌,使变形链球菌更易杀灭,从而增强氯己定对变形链球菌的杀灭作用,该作用机制在口腔领域氯己定的应用中尚未见报道。
本发明通过在口腔杀菌剂氯己定中添加绿色化合物D-亮氨酸,制备D-亮氨酸和氯己定组合物,杀灭致龋变形链球菌生物膜,大大降低氯己定的使用浓度,降低氯己定临床应用的不良反应,达到同等的杀菌效果,具有临床转化前景。
说明书附图
图1是平板计数实验结果。
图2是细菌黏附实验结果。
图3是生物膜裂解实验结果。
图4是生物膜活性实验结果。
图5是ATP定量生物荧光实验结果。
图6是D-亮氨酸细胞毒性实验结果。
图7是D-亮氨酸实时细胞定量分析实验结果。
具体实施方式
下面结合具体实施例和附图详细介绍本发明的技术方案和技术效果。未注明具体条件的实验方法,通常按照常规条件,例如教科书和实验指南中所述的条件,或按照制造厂商所建议的条件,为本领域普通技术人员熟知或易于获知,以下实施例仅为本发明的优选实施例,并不限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
实施例D-亮氨酸增强氯己定对致龋变形链球菌的杀菌作用相关实验研究。
一、抗菌实验。
1、抗菌实验分组。
第一组:无处理组(对照组)。
第二组:100ppm D-亮氨酸组。
第三组:1ppm氯己定组。
第四组:1ppm氯己定+100ppm D-亮氨酸组。
第五组:10ppm氯己定组。
2、实验内容。
本研究使用了变形链球菌,实验前,从冷冻甘油中提取细菌,在脑心浸出液肉汤(BHI,pH=7.0)琼脂培养基(AOBOX,中国)中培养,37℃厌氧条件(90%N2,10%CO2)72h。将BHI培养基在121℃下灭菌15min,变形链球菌菌落转移到50ml BHI液体培养基中,在37℃下厌氧培养24h。氯己定和D-亮氨酸购自Sigma-Aldrich公司。分别加入氢氧化钠和醋酸溶液,将氯己定和D-亮氨酸溶液中和至pH=7.0。在蒸馏水中制备100ppm氯己定和1000ppm D-亮氨酸作为储存溶液。使用前,用0.22μm注射器过滤器过滤灭菌。
316L不锈钢(SS)是常用的牙科材料,如正畸托槽。用200、600、800、1000粒度磨砂纸依次抛光顶部暴露表面积为1cm2的316L不锈钢薄片。然后用乙醇和蒸馏水浸泡,超声水洗15min。实验前用紫外光对样品的各面进行15min的灭菌。
所有实验均在厌氧罐中进行,厌氧气体为90%N2和10%CO2。将变形链球菌浓度稀释至最终细菌浓度1×106CFU mL-1。在实验之前,变形链球菌生物膜在316L不锈钢样品表面生长,24h后,长满变形链球菌的样品取出,在磷酸盐缓冲液(PBS、pH=7.0)中冲洗去除松散的表面浮游细菌。然后,将样品浸泡在24孔培养皿中,培养皿中装满2ml灭菌的BHI培养基,分组为不含药物(对照)组,1ppm氯己定组和10ppm氯己定组,100ppm D-亮氨酸组,1ppm氯己定和100ppm D-亮氨酸混合组。
1)平板计数实验。
37℃处理24h后,取出样品,用PBS洗涤以去除浮游细菌。然后将样品转移到含1ml无菌PBS的EP管中,每个涡旋1分钟。将每管100μl悬液涂布在BHI琼脂板上,37℃厌氧培养72h后,取出琼脂板计数菌落。采用最大似然数法(MPN)计算细菌数量。
2)细菌黏附实验。
共培养24h后,PBS冲洗2次。然后在3%(w/v)戊二醛中,4℃条件下浸泡4h,然后在浓度为50%、60%、70%、80%、90%、95%、100%(v/v)的乙醇溶液中依次脱水10min,样品喷金,扫描电镜观察。
3)生物膜裂解实验。
采用激光共聚焦扫描显微镜观察不同处理下生物膜的胞外聚合物物质(EPS)和细菌活力。24小时后用PBS冲洗样品,将浮游细菌洗去。然后用4'6-二氨基-2-苯基吲哚(DAPI),SYPRO Tangerine和Concanavalin A Alexa 633(ConA-Alexa 633)标记生物膜的DNA,多糖和蛋白质。
4)生物膜活性实验。
使用LIVE/DEAD BacLight细菌活力试剂盒对活细菌和死细菌细胞进行区分。处理24h后,生物膜用STYO-9和碘化丙啶(PI)染色。然后,冲洗样品去除多余的染料,并使用CLSM观察。SYTO-9染料在活细菌中显示绿色荧光,PI染料在死细菌中显示红色荧光。
5)ATP定量生物荧光实验。
生物发光法定量生物膜ATP,评价316L不锈钢表面固着细菌总数。处理24小时后,使用UPF10-ATP仪对样品进行分析,该仪器用于测量固着细菌的生物发光量,以相对光单位(RLU)表示。
3、实验结果。
1)平板计数实验。
实验结果如图1所示,平板表面计数:第四组、第五组<第三组<第一组、第二组。
2)细菌黏附实验。
实验结果如图2所示,扫描电镜观察细菌黏附数:第四组、第五组<第三组<第一组、第二组。
3)生物膜裂解实验。
实验结果如图3所示,细菌胞外分泌物:第四组、第五组<第三组<第一组、第二组。
4)生物膜活性实验。
实验结果如图4所示,细菌死亡数量:第四组、第五组>第三组>第一组、第二组5)ATP定量生物荧光实验。
实验结果如图5所示,细菌ATP数量:第四组、第五组<第三组<第一组、第二组。
以上实验结果证实,D-亮氨酸能够增强氯己定对致龋病变形链球菌生物膜的杀灭作用,将氯己定浓度降低为原来的十分之一。
二、细胞实验。
1、细胞实验分组。
第一组:无处理组(对照组)。
第二组:50ppm D-亮氨酸组。
第三组:100ppm D-亮氨酸组。
第四组:200ppm D-亮氨酸组。
第五组:400ppm D-亮氨酸组。
2、实验内容。
1)细胞毒性实验。
使用人胚肾293(HEK293)细胞,借助细胞活力kit-8试剂盒和实时细胞分析研究D-亮氨酸的细胞毒性。首先,在37℃、5%CO2的气体中,将HEK293细胞接种到50ppm、100ppm、200ppm和400ppm的D-亮氨酸中(2000个细胞/孔),共培养24、48、72h后,每孔加入10%CCK8溶液,37℃孵育2h。然后用酶标仪测定450nm处的光密度(OD)值。
2)实时细胞分析实验。
在RTCA实验中,将2000个细胞/孔的HEK293细胞悬浮液和50ppm、100ppm、200ppm和400ppm的D-亮氨酸加入到e-plate中,置于RTCA***中培养72h,结果以细胞指数(cellindex,CI)表示细胞毒性。
3、实验结果。
1)细胞毒性实验。
实验结果如图6所示,D-亮氨酸与细胞共培养后,没有对细胞生长产生明显的影响。
2)实时细胞分析实验。
实验结果如图7所示,随着时间的推移,D-亮氨酸对细胞的增殖曲线没有影响。
以上两部分实验结果表明:D-亮氨酸没有明显细胞毒性。
Claims (8)
1.D-亮氨酸和氯己定组合物在制备预防或治疗龋病药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述预防或治疗龋病药物中氯己定和 D-亮氨酸体积比为1:100。
3.如权利要求1所述的应用,其特征在于,所述预防或治疗龋病药物中氯己定浓度小于1 ppm。
4.如权利要求1所述的应用,其特征在于,所述预防或治疗龋病药物中D-亮氨酸的浓度小于100 ppm。
5.如权利要求1所述的应用,其特征在于,D-亮氨酸增强氯己定对致龋变形链球菌的杀菌作用。
6.如权利要求1所述的应用,其特征在于,所述药物的剂型为任何药物治疗学上可接受的剂型。
7.如权利要求1所述的应用,其特征在于,所述药物的剂量为任何药物治疗学上可接受的剂量。
8.一种预防或治疗龋病药物,其特征在于,包括D-亮氨酸和氯己定组合物以及药物上可接受的载体。
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