CN113975223A - 一种鼻腔清洗液 - Google Patents
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Abstract
本发明涉及一种鼻腔清洗液，属于鼻腔清洗液技术领域。包括1.0‑1.3质量份的电解质、0.1‑0.2质量份的缓冲体系、0.001‑0.002质量份的抗病毒天然产物、0.001‑0.002质量份的稳定剂以及97‑100质量份的纯净水；所述稳定剂用于防止抗病毒天然产物发生氧化；所述抗病毒天然产物用于抑制新型冠状病毒的S蛋白与人体肺部细胞表面的血管紧张素转换酶结合。
Description
技术领域
本发明涉及鼻腔清洗液技术领域，更具体地，涉及一种鼻腔清洗液。
背景技术
新冠病毒是通过呼吸道传播的疾病，随着新冠病毒的爆发，口罩等防护工具的需求量上升。通过口罩抑制病毒的传播是预防病毒感染的有效方法，通过鼻腔清洗给药也能有效预防病毒的侵入。然而，由于鼻腔环境比较脆弱敏感，在洗鼻时加入抗病毒成分需要考虑处方的刺激性，目前通过使用抗病毒成分清洗鼻腔以预防病毒侵入的产品还有待开发。
发明内容
本发明的目的在于提供一种鼻腔清洗液，本发明提供的鼻腔清洗液中含有抗病毒天然产物。
根据本发明的第一方面，提供了一种鼻腔清洗液，包括1.0-1.3质量份的电解质、0.1-0.2质量份的缓冲体系、0.001-0.002质量份的抗病毒天然产物、0.001-0.002质量份的稳定剂以及97-100质量份的纯净水；
所述稳定剂用于防止抗病毒天然产物发生氧化；所述抗病毒天然产物用于抑制新型冠状病毒的S蛋白与人体肺部细胞表面的血管紧张素转换酶结合。
优选地，所述抗病毒天然产物为姜黄素或姜黄素衍生物。
优选地，所述姜黄素衍生物为去甲氧基姜黄素或双去甲氧基姜黄素。
优选地，所述鼻腔清洗液中抗病毒天然产物的浓度为30μM-60μM。
优选地，所述稳定剂为L-半胱氨酸。
优选地，所述电解质为氯化钠；所述缓冲体系为柠檬酸与柠檬酸钠，或者是柠檬酸与碳酸氢钠，或者是柠檬酸、柠檬酸钠与碳酸氢钠。
根据本发明的另一方面，提供了一种药物组合物鼻腔清洗液的应用，所述药物组合物包括1.0-1.3质量份的电解质、0.1-0.2质量份的缓冲体系、 0.001-0.002质量份的抗病毒天然产物、0.001-0.002质量份的稳定剂以及 97-100质量份的纯净水；
所述稳定剂用于防止抗病毒天然产物发生氧化；所述抗病毒天然产物用于抑制新型冠状病毒的S蛋白与人体肺部细胞表面的血管紧张素转换酶结合。
优选地，所述抗病毒天然产物为姜黄素或姜黄素衍生物；
优选地，所述姜黄素衍生物为去甲氧基姜黄素或双去甲氧基姜黄素。
优选地，所述药物组合物中抗病毒天然产物的浓度为30μM-60μM。
优选地，所述稳定剂为L-半胱氨酸；所述电解质为氯化钠；所述缓冲体系为柠檬酸与柠檬酸钠，或者是柠檬酸与碳酸氢钠，或者是柠檬酸、柠檬酸钠与碳酸氢钠。
总体而言，通过本发明所构思的以上技术方案与现有技术相比，主要具备以下的技术优点：
(1)抗病毒药物可以通过体内给药，然而药效取决于药物的吸收、分布情况，最终药物不一定能起到治疗或预防作用。对于通过呼吸系统传播的病毒，鼻腔清洗剂具有更好的治疗或预防效果，药物活性成分能直接作用于呼吸系统引入的病毒，不受药物吸收和分布影响。姜黄素类化合物具有较好的生物活性，然而其生物利用度极低，限制了其体内应用。本研究发现，姜黄素及其衍生物在较低的浓度下即可抑制新型冠状病毒的S蛋白与人体肺部细胞表面的血管紧张素转换酶的结合，从而起到阻止病毒入侵和传播的作用。本发明通过鼻腔洗剂给药的方式避免了姜黄素类化合物生物利用度低的缺点。
(2)本发明纯天然成分温和无刺激和毒性，有利于鼻腔环境的恢复和自愈。
(3)由于鼻腔清洗剂中的活性成分能在呼吸系统中与病毒发生作用，使之无法再与人体细胞表面的受体结合。
附图说明
图1为竞争ELISA的标准曲线，横坐标为吸光度值，纵坐标为抑制剂的浓度。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。此外，下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
下面对本发明实施例提供的一种鼻腔清洗液进行具体说明。
本发明实施例提供一种鼻腔清洗液，包括以下重量份的组分：氯化钠 1.3份、缓冲体系0.1份、抗病毒天然产物0.002份、稳定剂0.002份以及纯净水97份。
本发明实施例提供一种鼻腔清洗液，包括以下重量份的组分：氯化钠 1.3份、缓冲盐0.1份、抗病毒天然化合物0.002份、稳定剂0.002份以及纯净水97份。氯化钠的作用是使清洗液的渗透压与生理条件(0.9％氯化钠) 接近，从而达到温和无刺激的效果，优选地，选择1.3份的电解质溶解于 97份水中。缓冲盐的作用是使清洗液的pH与生理条件(中性pH)接近，从而达到温和无刺激的效果，为了得到稳定的缓冲溶液，优选地，选择0.1 份的缓冲盐溶解于97份水中。考虑到其水溶，选择0.002份的抗病毒天然化合物。由于姜黄素类化合物含有酚羟基，在储存过程中容易被氧化，因此加入微量的抗氧化剂L-半胱氨酸。由于所有成分均为纯天然化合物，没有毒性，对儿童和老人没有刺激性和副作用，适用人群广泛。
在一些实施方式中，该鼻腔清洗液包括以下重量份的组分：氯化钠1.3 份、缓冲体系0.1份、抗病毒天然化合物0.002份、稳定剂0.002份以及纯净水97份。
在一些实施方式中，缓冲体系包为拧檬酸与柠檬酸钠，或者是柠檬酸与碳酸氢钠，或者是柠檬酸、柠檬酸钠与碳酸氢钠。
在一些实施方式中，抗病毒天然化合物包括姜黄素、去甲氧基姜黄素、双去甲氧基姜黄素。
上述的姜黄素(Curcumin)、去甲氧基姜黄素(Demethoxycurcumin)、双去甲氧基姜黄素(Bisdemethoxycurcumin)的结构式如下所示：
结构式1、2和3分别是姜黄素、去甲氧基姜黄素和双去甲氧基姜黄素的结构式，这几种化合物为姜黄的主要成分，具有抗冠状病毒的活性，可食用，无毒副作用。因此，我们选择姜黄素、去甲氧基姜黄素、双去甲氧基姜黄作为抗病毒成分。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
用纯净水和各种原料按以下重量比加入容器：纯净水400克，氯化钠 5.64克，碳酸氢钠0.27克，柠檬酸钠0.12克，柠檬酸0.04克，姜黄素0.008 克、L-半胱氨酸0.008克，然后混匀充分溶解，调整溶液pH为7.0，配制 400毫升鼻腔清洗液。姜黄素的浓度换算为54μM。
实施例2
用纯净水和各种原料按以下重量比加入容器：纯净水400克，氯化钠 5.64克，碳酸氢钠0.27克，柠檬酸钠0.12克，柠檬酸0.04克，去甲氧基姜黄素0.008克，L-半胱氨酸0.008克，然后混匀充分溶解，调整溶液pH为 7.0，配制400毫升鼻腔清洗液。姜黄素的浓度换算为59μM。
实施例3
用纯净水和各种原料按以下重量比加入容器：纯净水400克，氯化钠 5.64克，碳酸氢钠0.27克，柠檬酸钠0.12克，柠檬酸0.04克，双去甲氧基姜黄素0.008克，L-半胱氨酸0.008克，然后混匀充分溶解，调整溶液pH 为7.0，配制400毫升鼻腔清洗液。姜黄素的浓度换算为65μM。
实施例4
本实施例通过竞争ELISA实验证明姜黄素、去甲氧基姜黄素或双去甲氧基姜黄素水溶液能有效抑制病毒S蛋白与受体的结合，阻断病毒传播。用DMSO配制三种化合物的母液，浓度为3mM，用于竞争ELISA实验。
实验方法如下所述：
将SARS-CoV-2S protein RBD用包被液稀释200倍，每孔加入100μL 到96孔板中，4℃过夜包被。将96孔板里的包被液倒掉，重复洗板3次，并拍干。用300μL封闭液在37℃封闭1.5小时，洗板。将生物素标记Human ACE2(人血管紧张素转化酶2)蛋白用稀释液稀释到1μg/mL，每孔加入 50μL。再将SARS-CoV-2Inhibitor从100μg/mL稀释到40μg/mL后，按照等体积往下稀释，一共稀释7个点，最后一个孔加入稀释液，作为标准曲线，每孔加入50μL。对于姜黄素及其衍生物，用稀释液稀释100倍后，每孔加入50μL，37℃反应1小时。洗板，加入Streptavidin-HRP，用稀释液将Streptavidin-HRP稀释100倍，即0.5μg/mL，每孔加入100μL，37℃避光反应1小时，洗板。每孔加入100μL TMB，37℃避光反应20min进行显色。每孔加入50μL终止液终止反应，用酶标仪设置波长450nm，读取吸光度值。
竞争ELISA的标准曲线(图1)表明，随着抑制剂(中和抗体)浓度的增加，最终孔板的吸光度值降低，因此竞争法ELISA可以用于测试化合物抑制病毒S蛋白与受体结合的活性。此外，使用SARS-CoV-2抑制剂筛选试剂盒对于多个血液来源的抗体候选物进行中和筛选，筛选出多株具有中和能力的抗体候选物，经P3实验室验证可以有效中和新冠病毒对于Vero 细胞的感染，因此SARS-CoV-2抑制剂筛选试剂盒和新冠病毒中和实验两者之间具有很好的相关性。姜黄素、去甲氧基姜黄素及双去甲氧基姜黄素的抑制活性数据(表1)表明，测试的化合物在30μM浓度下能有效抑制病毒与受体的结合，阻断病毒传播。
表1姜黄素、去甲氧基姜黄素及双去甲氧基姜黄素的抑制活性
实施例5
用纯净水和化合物按以下重量比加入容器：纯净水400克，双去甲氧基姜黄素0.008克，混匀充分溶解，口服给药。由于姜黄素类化合物口服生物利用度很差，到达肺部的药物量很少，无法有效抑制病毒感染。
本领域的技术人员容易理解，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种鼻腔清洗液，其特征在于，包括1.0-1.3质量份的电解质、0.1-0.2质量份的缓冲体系、0.001-0.002质量份的抗病毒天然产物、0.001-0.002质量份的稳定剂以及97-100质量份的纯净水；
所述稳定剂用于防止抗病毒天然产物发生氧化；所述抗病毒天然产物用于抑制新型冠状病毒的S蛋白与人体肺部细胞表面的血管紧张素转换酶结合。
2.如权利要求1所述的鼻腔清洗液，其特征在于，所述抗病毒天然产物为姜黄素或姜黄素衍生物。
3.如权利要求2所述的鼻腔清洗液，其特征在于，所述姜黄素衍生物为去甲氧基姜黄素或双去甲氧基姜黄素。
4.如权利要求1-3任一所述的鼻腔清洗液，其特征在于，所述鼻腔清洗液中抗病毒天然产物的浓度为30μM-60μM。
5.如权利要求1-3任一所述的鼻腔清洗液，其特征在于，所述稳定剂为L-半胱氨酸。
6.如权利要求1-3任一所述的鼻腔清洗液，其特征在于，所述电解质为氯化钠；所述缓冲体系为柠檬酸与柠檬酸钠，或者是柠檬酸与碳酸氢钠，或者是柠檬酸、柠檬酸钠与碳酸氢钠。
7.一种药物组合物用于制备鼻腔清洗液的应用，其特征在于，所述药物组合物包括1.0-1.3质量份的电解质、0.1-0.2质量份的缓冲体系、0.001-0.002质量份的抗病毒天然产物、0.001-0.002质量份的稳定剂以及97-100质量份的纯净水；
所述稳定剂用于防止抗病毒天然产物发生氧化；所述抗病毒天然产物用于抑制新型冠状病毒的S蛋白与人体肺部细胞表面的血管紧张素转换酶结合。
8.如权利要求7所述的应用，其特征在于，所述抗病毒天然产物为姜黄素或姜黄素衍生物；
优选地，所述姜黄素衍生物为去甲氧基姜黄素或双去甲氧基姜黄素。
9.如权利要求7或8所述的应用，其特征在于，所述药物组合物中抗病毒天然产物的浓度为30μM-60μM。
10.如权利要求7或8所述的应用，其特征在于，所述稳定剂为L-半胱氨酸；所述电解质为氯化钠；所述缓冲体系为柠檬酸与柠檬酸钠，或者是柠檬酸与碳酸氢钠，或者是柠檬酸、柠檬酸钠与碳酸氢钠。
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