CN116531402B - 一种抗炎抗病毒的配方、滴眼液及其应用 - Google Patents
一种抗炎抗病毒的配方、滴眼液及其应用 Download PDFInfo
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- CN116531402B CN116531402B CN202310765441.XA CN202310765441A CN116531402B CN 116531402 B CN116531402 B CN 116531402B CN 202310765441 A CN202310765441 A CN 202310765441A CN 116531402 B CN116531402 B CN 116531402B
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明属于生物医药技术领域，具体涉及一种抗炎抗病毒的配方、滴眼液及其应用，抗炎抗病毒的配方以质量份计，包括以下组分：PDRN0.05‑0.15份；氯霉素0.1‑0.3份；透明质酸0.05‑0.15份；硼砂0.02‑0.05份；琼脂0.01‑0.02份；生理盐水0.1‑1.0份；蒸馏水98‑99份。本发明在配方中加入PDRN，有效的改善了眼表生理状态，在单纯疱疹病毒角膜炎的治疗中起到积极的辅助作用。
Description
技术领域
本发明涉及一种抗炎抗病毒的配方、滴眼液及其应用，属于生物医药技术领域。
背景技术
PDRN(Polydeoxyribonucleic)又称多聚脱氧核糖核苷酸，已研究证实其可通过活化A2嘌呤能受体调节细胞因子和生长因子的表达，进而影响细胞的生长和分化，在缓解炎症、组织再生、创伤修复等方面具有显著效果。随着国际核苷酸类药物研发技术的不断进步，其在核酸药物研发及应用开发方面价值潜力会不断增长。
近年来，核苷类抗病毒药物的研究相当活跃，核苷类抗病毒药物的研究报道大量涌现，第一个核苷药物碘苷(IDU)被用于治疗疱疹性角膜炎获得成功和阿昔洛韦的研制成功引起了人们对核苷类抗病毒药物的广泛关注，抗病毒化学疗法取得了相当大的进展。阿昔洛韦对HSV-1、HSV-2、VZV和EBV有较高的疗效和选择性，是第一个研制成功并上市的无环核苷类抗病毒药物，且对HCMV也有中等活性。目前它的作用机制已经被阐明，主要是病毒DNA链终止剂和病毒DNA聚合酶抑制剂。但目前的核苷药物存在许多缺陷，如生物利用度低、溶解度小等副作用均应改进，因此，抗病毒药物的研究依旧是当务之急。
众所周知，角膜的亲脂性和亲水性区域是药物穿透的最大屏障。在治疗上，基质型单纯疱疹病毒角膜炎中，传统的滴眼液具有眼部局部应用渗透性差、眼表滞留时间短等缺点，导致治疗效果差，不能改善眼表生理状态。
发明内容
本发明针对传统的治疗基质型单纯疱疹病毒角膜炎的滴眼液具有眼部局部应用渗透性差、眼表滞留时间短，导致治疗效果差、不能改善眼表生理状态等缺陷，提供一种抗炎抗病毒的配方、滴眼液及其应用。
本发明解决上述技术问题的技术方案如下：
本发明的目的之一在于提供一种抗炎抗病毒的配方，以质量份计，包括以下组分：
本发明的目的之二在于提供一种抗炎抗病毒的滴眼液，其采用如上所述的抗炎抗病毒的配方制备。
进一步，所述抗炎抗病毒的配方还包括0.03-0.08份防腐剂，所述防腐剂为尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、苯扎氯氨、苯扎溴铵、氯丁醇、苯乙醇、苯甲醇、脱氢醋酸纳、山梨酸和山梨酸纳中的一种或者一种以上的混合物。
进一步，上述滴眼液主要采用如下步骤制备：
1)将透明质酸和PDRN分别进入水中，使其溶解，备用；
2)将琼脂溶于水中，加热至沸腾使其溶解，冷却备用；
3)将硼砂溶于水中，加热至75-85℃使其溶解，然后加入氯霉素、防腐剂和生理盐水，加热溶解，冷却备用；
4)将上述步骤1)、2)、3)制得的物质混合均匀后，加入余量的蒸馏水，除菌过滤，得到抗炎抗病毒的滴眼液。
进一步，所述步骤4)中，采用微孔滤膜进行除菌过滤。
进一步，所述微孔滤膜的孔径为0.15-0.20μm。
本发明的目的之三在于提供一种如上所述的抗炎抗病毒的配方在制备治疗单纯疱疹病毒引起的基质型角膜炎的药物领域的应用。
进一步，所述药物为滴眼液。
本发明的有益效果在于：本发明在配方中加入PDRN，可以有效促进伤口愈合，同时起到抗炎以及抗病毒等作用效果，有效的改善了眼表生理状态，在单纯疱疹病毒角膜炎的治疗中起到积极的辅助作用。
附图说明
图1为PDRN对HSV-1、HSV-2以及HCMV病毒的抑制作用图；
图2为PDRN对病毒gD蛋白的mRNA表达的抑制作用；
图3为PDRN在体内水平上对小鼠组织中病毒载量的影响；
图4为PDRN在体内水平上对小鼠体重的影响；
图5为PDRN在体内水平上对小鼠生存率的影响。
具体实施方式
以下结合附图对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。
如无特别说明，本实施例所采用的试剂或者原料均为市售产品。
本实施例采用的PDRN在三文鱼精巢组织中的提取，传统的PDRN提取工艺多采用对人体有害的有机溶剂，且提取工艺复杂、步骤繁琐，进而导致提取率低、有害残留多。本发明在原有提取工艺的基础上，在降低提取成本的同时减少有害有机溶剂的使用，其纯化方法包括如下步骤：
①鱼精巢预处理：取出在-20℃下冷冻的三文鱼鱼白(即精巢)，在冰上解冻，然后在生理盐水中挑出杂质，蒸馏水洗涤两次，称取精巢20g，溶于120mL生理盐水中，将鱼精巢彻底粉碎，得到混合物。
②鱼精细胞收集：将步骤①中得到的混合物在4℃，3500rpm条件下离心30min，弃掉上清，收集沉淀物。
③酶解鱼精细胞中的鱼精蛋白：在37℃下，将步骤②得到的含鱼精细胞的沉淀物加入0.15M NaCl/0.5mM EDTA的混合盐溶液中搅拌均匀，其中，沉淀物与混合盐的比例为1:5，即沉淀物20g，混合盐溶液100mL；再按照鱼精巢原料质量(即20g)与胰蛋白酶质量比为250:1的比例，即胰蛋白酶80mg，加入至沉淀物与混合盐的反应体系中，并在37℃下搅拌酶解20h。
④SDS(十二烷基硫酸钠)除鱼精蛋白，离心获得含PDRN上清液：继续在上述步骤③的反应体系中加入鱼精巢原料重量8％的SDS、终浓度为1.8M的NaCl溶液，持续搅拌4h后，在6000rpm、室温条件下，离心1h，收集上清液。
⑤无水乙醇沉淀获得PDRN：将上述步骤④得到的上清液加入预先冷却的无水乙醇中搅拌，其中，按照上清液与无水乙醇的体积比为1:2的比例加入，低温下使絮状的DNA析出，将上述DNA取出，采用75％乙醇水溶液洗涤2次，使沉淀泛起，轻缓颠倒数次，4000rpm离心5min，倾去上部液体，残留乙醇用枪头吸除，粉碎沉淀，冷冻干燥机进行干燥。
⑥PDRN溶解：将上述步骤⑤获得的DNA溶解于生理盐水中，溶解度为10mg/mL，4℃下，每隔5min混匀，持续3h，测定DNA纯度。
⑦PDRN破碎：将上述步骤⑥得到的DNA溶液，利用超声波分解仪进行DNA分解，冰浴下，300w分解30min(期间，超声10s停5s)，降低DNA分子量，利用凝胶电泳观察DNA分子量大小。
⑧PDRN干燥：将上述步骤⑦分解后的DNA经过0.2μm的精密滤膜进行过滤，-20℃预冻1h，-80℃预冻至少3h，冷冻干燥机进行干燥以获得最终成品。
对上述提取方法制得的PDRN进行下列实验。
一、PDRN对HSV-1、HSV-2以及HCMV病毒感染的体外抑制活性
非洲绿猴肾细胞Vero细胞培养于MEM培养基，HSV-1F株、HSV-2E和HCMV Towne病毒株购于ATCC(美国)。实验均经过重复验证，与对照组数据的比值表示细胞活性。折线图用GraphPad Prism 8.0.1制作，结果以平均值±SEM表示。
细胞毒性实验：Vero细胞接种于96孔板中，待单层细胞长满，用HSV-1F株、HSV-2E和HCMV Towne病毒株感染细胞24h，吸弃原培养液，将梯度稀释PDRN(终浓度50、100、200、500、800、1000μg/mL；以脂质体体积ul：PDRN质量ug的比例为1:2将lipo2000与PDRN混匀静置5min，以便让PDRN顺利进入细胞)加入96孔板，设有未加PDRN的水溶液作为空白对照组，每种处理3个复孔。继续培养24h后，加入202g/mL MTT溶液，培养箱培养3～4h，吸走孔内液体，加入100μL DMSO完全溶解结晶，摇床轻晃5min，490nm测定吸光值。
上述实验结果参见图1，结果显示，PDRN在Vero细胞上对HSV-1的IC50值为226.2μg/mL，对HSV-2的IC50值为241.5μg/mL，对HCMV的IC50值为176.5μg/mL，在100-1000μg/mL浓度范围内能明显抑制HSV感染抑制病毒复制，且具有剂量依赖性。
实时荧光定量PCR：Vero细胞接种于6孔板中，待单层细胞长满，用HSV-1F株、HSV-2E和HCMVTowne病毒株感染细胞2h，然后将含有不同浓度(250μg/mL和500μg/mL)的PDRN(以脂质体体积ul：PDRN质量ug的比例为1:2将lipo2000与PDRN混匀静置5min，以便让PDRN顺利进入细胞)加入相应孔中，同时设有病毒对照组(病毒感染但未进行PDRN或者阳性药利巴韦林处理)和空白对照组(未进行病毒感染且未PDRN或者阳性药利巴韦林处理)。16h后用RNA提取试剂盒提取总RNA，根据罗氏逆转录试剂盒进行反转录，取1μg总RNA进行反应。所用PCR引物如下：
HSV-1(gD)正向：5'-AGCAGGGGTTAGGGAGTTG-3'；
HSV-1(gD)反向：5'-CCATCTTGAGAGAGGCATC-3'；
HSV-2(gD)正向：5'-AGCATCCCGATCACTGTGTACTA-3'；
HSV-2(gD)反向：5'-GCGATGGTCAGGTTGTACGT-3'；
GAPDH正向5’-ATGCCTGCTTCACCACCTTCT-3’；
GAPDH反向5’-CATGGCCTTCCGTGTTCCTA-3’；
HCMV UL123正向：5′-TCTGCCAGGACATCTTTCTC-3′；
HCMV UL123反向：5′-GTGACCAAGGCCACGACGTT-3′。
所有引物使用58℃作为退火温度，延伸15s。
通过实时荧光定量RT-PCR法检测了PDRN对病毒gD蛋白mRNA的表达的影响。结果参见图2，200μg/mL以上的PDRN对HSV-1、HSV-2以及HCMV的，gD蛋白的mRNA表达具有明显的抑制作用。
二、对上述提取方法制得的PDRN对HSV-1病毒感染的小鼠体内抑制活性
挑选4周龄体重在15g左右的BALB/c雌鼠，腹腔内注射戊巴比妥钠(40mg/kg体重)麻醉，用无菌1号针头呈“#”形划伤每只小鼠的左眼角膜，空白对照组滴5μL生理盐水于角膜表面，设为空白对照组，其余小鼠点滴5μLHSV-1F株于角膜表面，同时轻轻按摩眼睑约30s，随机分为病毒对照组，阳性药阿昔洛韦(10mg/kg/d)组，PDRN(10mg/kg/d)组，每组10只，接毒后4h给药，连续给药5d。接毒后72h解剖，取小鼠脊髓组织，并通过实时荧光定量RT-PCR验证药物在体内抗HSV-1的作用效果。连续10d每天记录小鼠体重变化及生存情况。
利用实时荧光定量RT-PCR方法检测小鼠脊髓组织中的病毒载量(附图3)，与病毒对照组相比，阳性药阿昔洛韦(10mg/kg)降低了小鼠脊髓组织中约80％的病毒载量，PDRN(10mg/kg)组降低了小鼠脊髓组织中约60％的病毒载量，上述结果表明，PDRN作用效果随不如阳性药作用明显，但相比于病毒对照组，PDRN在体内水平上能够明显降低小鼠组织中的病毒载量。
小鼠体重结果表明(附图4)，与空白组相比，病毒对照组小鼠体重在接毒后持续下降，并始终轻于原始体重。阳性药阿昔洛韦组(10mg/kg)体重从d1时缓慢下降，d3后开始持续回升；PDRN组(10mg/kg)从d1一直缓慢下降，d7后开始缓慢回升，阳性药组和PDRN组的小鼠体重都高于病毒对照组但低于空白组。
小鼠生存率结果表明(附图5)，病毒对照组小鼠在接毒后d2开始出现死亡，在d5时生存率降至20％；而阳性药阿昔洛韦组(10mg/kg)在接毒后d2开始出现死亡，d9时生存率降至70％；PDRN组(10mg/kg)在接毒后未出现死亡现象，说明PDRN能够明显改善小鼠感染HSV-1后的生存状况，显著的提高了小鼠生存率。
本实施例利用HSV-1F株、HSV-2E以及HCMV Towne病毒株感染非洲绿猴肾细胞(Vero)模型，通过细胞毒性实验、实时荧光定量PCR等方法探究PDRN对病毒感染的体外抑制活性，并以HSV-1感染BALB/c小鼠模型评价PDRN的体内抗HSV-1活性。
结果显示，PDRN在Vero细胞上对HSV-1的IC50值为226.2μg/mL，对HSV-2的IC50值为241.5μg/mL，对HCMV的IC50值为176.5μg/mL，在100-1000μg/mL浓度范围内能明显抑制HSV感染抑制病毒复制，且具有剂量依赖性。在RNA水平上，通过实时荧光定量RT-PCR法检测了PDRN对病毒gD蛋白mRNA的表达的影响。结果显示，200μg/mL以上的PDRN对HSV-1、HSV-2以及HCMV的gD蛋白的mRNA表达具有明显的抑制作用。进一步的，PDRN可提高HSV-1感染小鼠的存活率，明显降低小鼠组织中的病毒载量，总体治疗效果优于阿昔洛韦。
本实施例采用上述PDRN抗炎抗病毒的配方以质量份计，包括以下组分：
采用上述配方制备含PDRN的抗炎抗病毒的滴眼液，采用如下原料步骤制备：
以100mL滴眼液计：PDRN 0.10g；氯霉素0.20g；透明质酸钠0.10g；硼砂0.03g；琼脂0.01g；防腐剂0.05g；生理盐水0.50g，其余是蒸馏水，其中防腐剂采用苯扎溴铵。
制取100mI滴眼液，将0.10g透明质酸钠和0.10gPDRN分别浸入10mL水中；使其溶解备用，将0.01g琼脂溶于10mL水中，加热至沸腾使其溶解冷却备用；取0.03g硼砂至50mL水中，80℃加热溶解后，再加入0.20g氯霉素、0.05g苯扎溴铵和0.50g生理盐水，55℃加热溶解后冷至30℃时，将透明质酸钠、PDRN和琼脂混合均匀后加入蒸馏水至100mL，用0.2μm的微孔滤膜除菌过滤，分装封口。
以上所述仅为本发明的较佳实施例，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、改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.一种抗炎抗病毒的组合物的应用，其特征在于，应用于制备治疗单纯疱疹病毒引起的基质型角膜炎的滴眼液；
所述抗炎抗病毒的组合物以100mL计，由以下组分组成：
PDRN0.1g；
氯霉素0.2g；
透明质酸0.1g；
硼砂0.03g；
琼脂0.01g；
防腐剂0.05g；
生理盐水0.5g；
蒸馏水余量；
所述PDRN的纯化方法包括如下步骤：①鱼精巢预处理：取出在-20℃下冷冻的三文鱼鱼白，在冰上解冻，然后在生理盐水中挑出杂质，蒸馏水洗涤两次，称取精巢20g，溶于120mL生理盐水中，将鱼精巢彻底粉碎，得到混合物；
②鱼精细胞收集：将步骤①中得到的混合物在4℃，3500rpm条件下离心30min，弃掉上清，收集沉淀物；
③酶解鱼精细胞中的鱼精蛋白：在37℃下，将步骤②得到的含鱼精细胞的沉淀物加入0.15M NaCl/0.5mM EDTA的混合盐溶液中搅拌均匀，其中，沉淀物与混合盐的比例为1:5，即沉淀物20g，混合盐溶液100mL；再按照鱼精巢原料质量20g与胰蛋白酶质量比为250:1的比例，即胰蛋白酶80 mg，加入至沉淀物与混合盐的反应体系中，并在37℃下搅拌酶解20h；
④SDS除鱼精蛋白，离心获得含PDRN上清液：继续在上述步骤③的反应体系中加入鱼精巢原料重量8%的SDS、终浓度为1.8M的NaCl溶液，持续搅拌4h后，在6000rpm、室温条件下，离心1h，收集上清液；
⑤无水乙醇沉淀获得PDRN：将上述步骤④得到的上清液加入预先冷却的无水乙醇中搅拌，其中，按照上清液与无水乙醇的体积比为1:2的比例加入，低温下使絮状的DNA析出，将上述DNA取出，采用75％乙醇水溶液洗涤2次，使沉淀泛起，轻缓颠倒数次，4000rpm离心5min，倾去上部液体，残留乙醇用枪头吸除，粉碎沉淀，冷冻干燥机进行干燥；
⑥PDRN溶解：将上述步骤⑤获得的DNA溶解于生理盐水中，溶解度为10mg/mL，4℃下，每隔5min混匀，持续3h，测定DNA纯度；
⑦PDRN破碎：将上述步骤⑥得到的DNA溶液，利用超声波分解仪进行DNA分解，冰浴下，300w分解30min，期间，超声10s停5s，降低DNA分子量，利用凝胶电泳观察DNA分子量大小；
⑧PDRN干燥：将上述步骤⑦分解后的DNA经过0.2μm的精密滤膜进行过滤，-20℃预冻1h，-80℃预冻至少3h，冷冻干燥机进行干燥以获得最终成品。
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