CN114191378A - 一种地夸磷索缓释凝胶及其制备方法与应用 - Google Patents

一种地夸磷索缓释凝胶及其制备方法与应用 Download PDF

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CN114191378A
CN114191378A CN202111390343.XA CN202111390343A CN114191378A CN 114191378 A CN114191378 A CN 114191378A CN 202111390343 A CN202111390343 A CN 202111390343A CN 114191378 A CN114191378 A CN 114191378A
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diquafosol
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南开辉
王静洁
王天佐
管彬
刘欣欣
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Eye Hospital of Wenzhou Medical University
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Abstract

一种地夸磷索缓释凝胶及其制备方法与应用，本发明以含有硼酸的水凝胶作为地夸磷索钠递送载体，通过硼酸与水凝胶网络高分子基质分子链上的顺式二醇结构和地夸磷索钠的顺式二醇结构同时形成动态共价键，使地夸磷索钠与水凝胶网络具有亲和力，进而实现药物缓释。该凝胶具有剪切变稀和自愈合特性，能够延长药物的眼表滞留时间，通过实现地夸磷索钠的缓释提高其干眼治疗效果。

Description

一种地夸磷索缓释凝胶及其制备方法与应用
技术领域
本发明涉及眼科药物制剂技术领域，具体涉及一种地夸磷索缓释凝胶及其制备方法与应用。
背景技术
干眼是眼科门诊最常见的疾病之一，可导致眼睛干涩、疲劳、瘙痒、疼痛、红肿及视力模糊等症状。据统计，世界范围内干眼的发病率在6.5%-52.4%之间，并且老年人患病率高于年轻人，女性患病率高于男性。现代人频繁使用空调、视频终端（电脑、手机等）及佩戴隐形眼镜等日常活动使干眼发病率进一步提高。在发达国家，由干眼造成的直接和间接经济损失达6000-10000美金/人/年。
根据病情不同，干眼治疗可分为人工泪液、泪小点栓塞、抗氧化剂（乙酰半胱氨酸等）、分泌刺激剂（地夸磷索钠、瑞巴派特）、抗炎药物（氟米龙等激素）、免疫抑制药物（他克莫司、环孢霉素、立他司特等）、自体/异体血清等方式。其中地夸磷索钠是一种P2Y2受体激动剂，可刺激结膜上皮细胞及结膜杯状细胞分泌泪液和黏蛋白。大量研究显示3%地夸磷索钠滴眼液（丽爱思，日本参天）能有效改善泪液缺乏型干眼、睑板腺功能障碍、眼科术后干眼等干眼亚型，并且安全性和耐受性良好。
由于眼表静态屏障和动态屏障的存在，滴眼液生物利用度往往极低（绝大多数小于5%），滴到眼表的药物大部分通过泪液引流系统进入鼻腔，导致系统暴露，而泪液中的药物浓度则每隔1-3分钟就下降1倍。对于地夸磷索钠等亲水药物，滴眼液的缺陷则更加明显，因而需要频繁给药（丽爱思需每日给药6次），造成患者依从性差，治疗效果受限。考虑到目前临床仅有滴眼液一种地夸磷索钠制剂，开发新的地夸磷索钠缓释体系对干眼治疗具有重要意义。有报道将隐形眼镜或即用型结冷胶用于地夸磷索钠缓释，但这些载体没有针对地夸磷索钠的化学结构进行针对性设计，缺乏特异性。地夸磷索钠分子具有两个二醇结构，可与硼酸形成动态共价键，为设计具有地夸磷索钠亲和特性的缓释载体提供了理论基础。
发明内容
为了解决现有技术存在的技术缺陷，本发明提供了一种地夸磷索缓释凝胶及其制备方法与应用，通过使地夸磷索钠与凝胶网络产生亲和力实现药物缓释，从而更有效地治疗干眼。
本发明采用的技术解决方案是：一种地夸磷索缓释凝胶，所述的地夸磷索缓释凝胶由地夸磷索盐或保存地夸磷索盐活性和其顺式二醇结构的地夸磷索盐衍生物、高分子基质材料及硼酸组成，所述的硼酸通过动态共价键同时结合高分子基质材料分子链上的顺式二醇结构和地夸磷索盐及其衍生物的顺式二醇结构。
所述的高分子基质材料为含顺式二醇结构的天然或合成高分子及其衍生物的一种或几种。
所述的顺式二醇结构为1, 2二醇或1, 3二醇结构。
所述的高分子基质材料为瓜尔胶或聚乙烯醇及其衍生物的一种或几种。
一种地夸磷索缓释凝胶的制备方法，包括以下步骤：将硼酸、硼砂或两者的混合物溶于水，调整pH；配制地夸磷索钠溶液；配制高分子基质溶液；将上述溶液以一定比例混合，即得所述的地夸磷索缓释凝胶。
所述的地夸磷索缓释凝胶中的高分子基质材料的质量浓度为0.1-20%。
所述的硼酸、硼砂或两者的混合物溶于水共混形成的缓冲液的pH在7.4-8.5之间。
所述的地夸磷索缓释凝胶中的硼酸根浓度为1-1000 mM。
所述的地夸磷索缓释凝胶的地夸磷索钠的质量浓度为0.3-10%。
一种地夸磷索缓释凝胶在制备治疗干眼药物上的应用。
本发明的有益效果是：本发明提供了一种地夸磷索缓释凝胶及其制备方法与应用，本发明以含有硼酸的水凝胶作为药物载体，通过硼酸与水凝胶网络高分子基质分子链上的顺式二醇结构和地夸磷索钠的顺式二醇结构同时形成动态共价键，使地夸磷索钠与水凝胶网络具有亲和力，进而实现药物缓释。该凝胶具有剪切变稀和自愈合特性，能够延长药物的眼表滞留时间，通过实现地夸磷索钠的缓释提高其干眼治疗效果。
附图说明
图1地夸磷索钠缓释凝胶的形貌。a) 地夸磷索钠缓释凝胶的外观；b) 空白凝胶的SEM图片；c) 地夸磷索钠缓释凝胶的SEM图片。
图2地夸磷索钠缓释凝胶的流变学特性。a) 剪切变稀；b) 自愈合（黑线：空白凝胶；红线：地夸磷索钠缓释凝胶）。
图3 地夸磷索钠缓释凝胶延长模型药物（荧光素钠）的眼表滞留时间。
图4 地夸磷索钠缓释凝胶实现地夸磷索钠缓释。
图5小鼠干眼模型用不同制剂治疗后的泪液分泌情况。PBS：PBS治疗组；Gel：空白凝胶治疗组；Diquafosol：地夸磷索钠裸药治疗组；Diquafosol Gel：地夸磷索钠缓释凝胶治疗组。单因素方差分析，*P＜0.05，**P＜0.01， ***P＜0.001。
图6 小鼠干眼模型用不同制剂治疗后的荧光素钠染色图片及定量分析。PBS：PBS治疗组；Gel：空白凝胶治疗组；Diquafosol：地夸磷索钠裸药治疗组；Diquafosol Gel：地夸磷索钠缓释凝胶治疗组。Kruskal-Wallis检验，*P＜0.05。
图7 小鼠干眼模型用不同制剂治疗后的杯状细胞密度。PBS：PBS治疗组；Gel：空白凝胶治疗组；Diquafosol：地夸磷索钠裸药治疗组；Diquafosol Gel：地夸磷索钠缓释凝胶治疗组。单因素方差分析，*P＜0.05，**P＜0.01。
图8本发明地夸磷索钠缓释凝胶机理示意图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整的描述，显然，所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获的所有其他实施例，都属于本发明保护的范围。
实施例1 地夸磷索钠缓释凝胶的制备
去离子水配制1%羟丙基瓜尔胶溶液，记为A；去离子水配制硼酸根浓度为200 mM的硼酸溶液，调整pH为7.6，记为B；去离子水配制30%的地夸磷索钠溶液，记为C；溶液A、B、C以8:1:1的体积比混合，即得地夸磷索钠缓释凝胶（图1a）。
实施例2 地夸磷索钠缓释凝胶的SEM观察
实施例1的产物通过冷冻干燥机干燥，随后置于液氮环境孵育20 min，将产物取出淬断，固定在导电胶上喷金，最后进行扫描电子显微镜观察。结果显示凝胶产物具有多孔网络结构（图1b、c）。
实施例3 地夸磷索钠缓释凝胶的流变学表征
利用流变仪测定实施例1产物的粘度随剪切速率（0.1-50 1/s）的变化，如图2a所示，凝胶粘度随剪切速率增大而变小，说明其具有剪切变稀特性；利用流变仪对实施例1产物进行阶梯应变扫描，结果显示高应变区间（1000%应变）凝胶强度变低，低应变区间（0.1%应变）凝胶强度恢复，说明凝胶具有自愈合特性（图2b）。
实施例4 眼表滞留时间的评价
以荧光素钠作为模型药物替换地夸磷索钠，参照实施例1制备凝胶，并以荧光素钠溶液作为对照；小鼠用戊巴比妥钠麻醉，将凝胶或荧光素钠溶液滴于眼球表面（每组3只），每隔30s手动眨眼，并于0 min、5 min、10 min使用裂隙灯观察眼球表面的荧光强度，由图3可知凝胶可以明显延长药物的眼表滞留时间，因而有可能提高药物生物利用度，降低给药频率。
实施例5 地夸磷索钠缓释凝胶的体外释放性能
1 mL 3%地夸磷索钠溶液或含等量地夸磷索钠的凝胶（实施例1产物）置于截留分子量14000Da的透析袋，然后转移至5mL PBS，37℃ 100rpm孵育，并于特定时间置换1 mLPBS，高效液相色谱测定置换液的地夸磷索钠浓度。如图4所示，地夸磷索钠缓释凝胶的体外释放速率明显慢于地夸磷索钠溶液，因而有望降低其给药频率，改善疗效。
实施例6 地夸磷索钠缓释凝胶促进小鼠干眼模型的泪液分泌
C57BL/6小鼠皮下注射东莨菪碱（每日3次，每次0.5mg）制作干眼模型，并于造模第10天开始给予PBS、空白凝胶、地夸磷索钠裸药溶液或实施例1制备的地夸磷索钠缓释凝胶（每组9只小鼠，每日给药2次）；治疗第7天用酚红棉线测定小鼠泪液分泌量，由图5可知地夸磷索钠缓释凝胶促进泪液分泌效果最好，有利于干眼治疗。
实施例7 地夸磷索钠缓释凝胶促进小鼠干眼模型的角膜修复
C57BL/6小鼠皮下注射东莨菪碱（每日3次，每次0.5mg）制作小鼠干眼模型，并于造模第10天开始给予PBS、空白凝胶、地夸磷索钠裸药溶液或实施例1制备的地夸磷索钠缓释凝胶（每组9只小鼠，每日给药2次）；治疗第3天用荧光素钠染色，并通过NEI/IndustryGrading System法评分，量化角膜损伤情况。由图6可知，地夸磷索钠缓释凝胶治疗组治疗效果最佳。
实施例8 地夸磷索钠缓释凝胶促进小鼠干眼模型的结膜杯状细胞密度增加
C57BL/6小鼠皮下注射东莨菪碱（每日3次，每次0.5mg）制作小鼠干眼模型，并于造模第10天开始给予PBS、空白凝胶、地夸磷索钠裸药溶液或实施例1制备的地夸磷索钠缓释凝胶（每组9只小鼠，每日给药2次）；治疗第7天分离眼球，固定后行PAS染色计算结膜杯状细胞密度，评价治疗效果。由图7可知，地夸磷索钠缓释凝胶治疗组的结膜杯状细胞密度最高，因而治疗效果最佳。
各位技术人员须知：虽然本发明已按照上述具体实施方式做了描述，但是本发明的发明思想并不仅限于此发明，任何运用本发明思想的改装，都将纳入本专利专利权保护范围内。
以上所述仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

1.一种地夸磷索缓释凝胶，其特征在于，所述的地夸磷索缓释凝胶包括有地夸磷索盐或保存地夸磷索盐活性和其顺式二醇结构的地夸磷索盐衍生物、高分子基质材料及硼酸，所述的硼酸通过动态共价键同时结合高分子基质材料分子链上的顺式二醇结构和地夸磷索盐及其衍生物的顺式二醇结构。
2.根据权利要求1所述的地夸磷索缓释凝胶，其特征在于，所述的高分子基质材料为含顺式二醇结构的天然或合成高分子及其衍生物的一种或几种。
3.根据权利要求2所述的地夸磷索缓释凝胶，其特征在于，所述的顺式二醇结构为1, 2二醇或1, 3二醇结构。
4.根据权利要求2所述的地夸磷索缓释凝胶，其特征在于，所述的高分子基质材料为瓜尔胶或聚乙烯醇及其衍生物的一种或几种。
5.一种权利要求1所述的地夸磷索缓释凝胶的制备方法，其特征在于，包括以下步骤：将硼酸、硼砂或两者的混合物溶于水，调整pH；配制地夸磷索钠溶液；配制高分子基质溶液；将上述溶液以一定比例混合，即得所述的地夸磷索缓释凝胶。
6.根据权利要求5所述的制备方法，其特征在于，所述的地夸磷索缓释凝胶中的高分子基质材料的质量浓度为0.1-20%。
7.根据权利要求5所述的制备方法，其特征在于，所述的硼酸、硼砂或两者的混合物溶于水共混形成的缓冲液的pH在7.4-8.5之间。
8.根据权利要求5所述的制备方法，其特征在于，所述的地夸磷索缓释凝胶中的硼酸根浓度为1-1000 mM。
9.根据权利要求5所述的制备方法，其特征在于，所述的地夸磷索缓释凝胶的地夸磷索钠的质量浓度为0.3-10%。
10.一种权利要求1所述的地夸磷索缓释凝胶在制备治疗干眼药物上的应用。
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