CN115089732A - 用于增强角膜生物力学的光敏剂光黄素-环糊精包合物 - Google Patents

用于增强角膜生物力学的光敏剂光黄素-环糊精包合物 Download PDF

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CN115089732A
CN115089732A CN202210870130.5A CN202210870130A CN115089732A CN 115089732 A CN115089732 A CN 115089732A CN 202210870130 A CN202210870130 A CN 202210870130A CN 115089732 A CN115089732 A CN 115089732A
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cyclodextrin
corneal
riboflavin
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叶琳
吉顺梅
戴锦晖
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Zhongshan Hospital Fudan University
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Abstract

本发明公开了一种用于增强角膜生物力学的光敏剂光黄素‑环糊精包合物。本发明的光敏剂是采用包合技术将光黄素用磺丁基‑β‑环糊精包合后制备而成。所述的光黄素和磺丁基‑β‑环糊精的质量比≥1.08：1000；其可以为液体制剂或固体制剂。相比于现有角膜胶原交联术中使用的光敏剂‑核黄素盐而言，本发明的光敏剂光黄素‑环糊精包合物渗透性更强，稳定性更高，具有良好的上皮细胞渗透性能，且能够提高角膜生物力学性能，可以很好的克服核黄素盐在角膜胶原交联术中的应用缺陷，在治疗圆锥角膜等疾病的CXL(角膜胶原交联)手术中具有较好的应用前景。

Description

用于增强角膜生物力学的光敏剂光黄素-环糊精包合物
技术领域
本发明涉及一种用于增强角膜生物力学的光敏剂光黄素-环糊精包合物，属于角膜光敏剂技术领域。
背景技术
去上皮角膜胶原交联技术是治疗圆锥角膜和术后角膜扩张等疾病中最有希望的治疗方法。标准去上皮角膜交联治疗方法为：去掉角膜上皮，使用0.1％核黄素-5-磷酸钠(核黄素盐)浸润角膜30分钟后，370nm紫外光下照射触发角膜胶原交联。交联的作用机制主要是：暴露于紫外光下时，核黄素盐作为光敏剂，通过激发到三重态并产生单线态氧为主的活性氧来诱导交联。交联可增加角膜硬度，抑制角膜的软化及进行性扩张，延缓圆锥角膜等角膜扩张症的疾病进展。尽管该核黄素光敏剂已经在临床上使用了多年，但仍然存在以下缺点：
首先，由于核黄素盐的渗透性低，无法穿透角膜上皮层进入胶原基质层产生作用。因此，去除上皮细胞才能保证足够浓度的核黄素盐输送到角膜的深层。然而，去上皮术会增加术后疼痛、角膜感染、混浊和疤痕的发生率。若保留上皮细胞层，通过采用其他方法来增加核黄素盐的渗透性，如添加促渗剂，效果均不理想。迄今为止，研究尚未确定一种合适的促渗方法来提供足量浓度的核黄素盐。
其次，核黄素盐在紫外光下极易被降解。研究表明，在接近环境照明条件下(0.5mW/cm2的紫外光)，有26％的核黄素盐在9分钟内被降解。而在角膜交联期间(3mW/cm2紫外光)30分钟后，有60％的核黄素盐被光降解。角膜交联治疗期间的光紫外光照射诱发的核黄素盐降解将显着降低基质中核黄素盐的浓度，从而降低最终角膜交联效果。
发明内容
本发明的目的是：提供一种具有渗透性较高、光稳定性强的角膜交联光敏剂光黄素-环糊精包合物，可以弥补现有光敏剂配方的缺点，在治疗圆锥角膜等疾病的CXL(角膜胶原交联)手术中具有较好的应用前景。
为了实现上述目的，本发明提供了一种用于增强角膜生物力学的光敏剂光黄素-环糊精包合物，所述的光敏剂是采用包合技术将光黄素用磺丁基-β-环糊精包合后制备而成。
优选地，所述的光黄素和磺丁基-β-环糊精的质量比≥1.08：1000。
所述的光敏剂可以为液体制剂或固体制剂；所述的液体制剂可以是由光黄素和磺丁基-β-环糊精直接在水相体系(生理盐水)体系中复合而成，所述的液体制剂可进一步经过冻干制备成固体制剂。
本发明还提供了上述用于增强角膜生物力学的光敏剂光黄素-环糊精包合物在制备用于诱导角膜胶原交联的试剂和/或试剂盒中的应用。
与现有技术相比，本发明的有益效果在于：
本发明利用磺丁基-β-环糊精与光黄素形成包合物，磺丁基-β-环糊精进行包合后可以增加光黄素的水溶性和渗透性，相比于现有角膜胶原交联术中使用的光敏剂-核黄素盐而言，本发明的光敏剂光黄素-环糊精包合物渗透性更强，稳定性更高，具有良好的上皮细胞渗透性能，能够提高角膜生物力学性能，可以很好的克服核黄素盐在角膜胶原交联术中的应用缺陷，在治疗圆锥角膜等疾病的CXL(角膜胶原交联)手术中具有较好的应用前景。
具体实施方式
为使本发明更明显易懂，兹以优选实施例，作详细说明如下。
实施例
光黄素-环糊精包合物的制备：
以生理盐水作为溶剂，完全溶解0.50g/mL的磺丁基-β-环糊精
Figure BDA0003760734940000021
后，加入2.09mmol/L(0.54mg/mL)光黄素。通过搅拌器在25℃下搅拌24h，得到澄清的橘黄色液体，即得光黄素浓度为2.09mM的光黄素-环糊精液体制剂(2.09mM光黄素-环糊精制剂)。
测试试验：
(1)光黄素-环糊精包合物渗透性更强
用相同摩尔量的2.09mM光黄素-环糊精制剂与核黄素盐对兔角膜进行30分钟的孵育，刮掉角膜上皮和内皮层，取下角膜基质行HPLC含量检测，可发现光黄素-环糊精制剂组的光敏剂-光黄素在兔角膜基质中浓度更高，如表1所示：
表1核黄素盐与光黄素-环糊精制剂的渗透性对比
核黄素盐(μmol/mg) 光黄素-环糊精制剂(μmol/mg) P值
药物浓度 0.18±0.028 0.56±0.058 <0.05
(2)光黄素-环糊精包合物的稳定性更强
用紫外光(5.4J/cm2)对相同摩尔量的1mM光黄素-环糊精包合物(2.09mM光黄素-环糊精制剂稀释1倍左右所得)与核黄素盐溶液进行照射，在不同时间点取溶液进行HPLC测定，发现光黄素-环糊精制剂的稳定性更强，如表2所示：
表2核黄素盐与光黄素-环糊精制剂中光黄素的稳定性对比
照射时间(分钟) 核黄素盐(mM) 光黄素-环糊精制剂(mM) P值
0 1.00±0.027 1.00±0.008 >0.05
9 0.80±0.046 0.98±0.039 <0.05
30 0.76±0.043 0.93±0.032 <0.05
60 0.60±0.072 0.92±0.008 <0.05
(3)光黄素-环糊精制剂在跨上皮与去上皮交联手术中均展示出良好的角膜胶原交联效果
将该光黄素-环糊精制剂用作跨上皮与去上皮CXL交联，并与核黄素盐进行对比(核黄素盐的跨上皮配方参考现跨上皮交联术，为0.01％核黄素盐与0.01％苯扎氯氨混合物)。交联后第二天取角膜条带行单轴拉伸实验，角膜条带的杨氏模量与角膜生物力学强度成正相关。由表3可知，在跨上皮条件中，光黄素-环糊精包合物(无需使用促渗剂)与核黄素盐+苯扎氯氨(BAC)促渗的交联效果相似，本发明的光黄素-环糊精包合物具有良好的上皮渗透性能；由表4可知，在去上皮条件下，光黄素-环糊精包合物在应变为4％和6％时能提高角膜生物力学作用更强。
表3跨上皮交联中角膜生物力学强度对比
Figure BDA0003760734940000031
Figure BDA0003760734940000041
注：上标*表示对照组与处理组之间有统计学差异(p<0.05)。
表4去上皮交联中角膜生物力学强度对比
Figure BDA0003760734940000042
注：上标*表示对照组与处理组之间有统计学差异(p<0.05)；上标#表示核黄素盐组与光黄素-环糊精组有统计学差异(p<0.05)。
本发明的光黄素-环糊精包合物的使用方法：
跨上皮交联术使用方法：将该光黄素-环糊精包合物用在角膜中央孵育30分钟，用10mW/cm2紫外光照射9min。
去上皮交联术使用方法：用25％酒精浸润角膜上皮1分钟后，用角膜上皮刮刀刮去上皮，将该光黄素-环糊精包合物用角膜环罩在角膜中央孵育30分钟，用10mW/cm2紫外光照射9min。
上述实施例仅为本发明的优选实施例，并非对本发明任何形式上和实质上的限制，应当指出，对于本技术领域的普通技术人员，在不脱离本发明的前提下，还将可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。

Claims (3)

1.一种用于增强角膜生物力学的光敏剂光黄素-环糊精包合物，其特征在于，所述的光敏剂是采用包合技术将光黄素用磺丁基-β-环糊精包合后制备而成。
2.如权利要求1所述的用于增强角膜生物力学的光黄素-环糊精包合物光敏剂，其特征在于，所述的光黄素和磺丁基-β-环糊精的质量比≥1.08：1000。
3.权利要求1或2所述的用于增强角膜生物力学的光敏剂光黄素-环糊精包合物在制备用于诱导角膜胶原交联的试剂和/或试剂盒中的应用。
CN202210870130.5A 2022-07-22 2022-07-22 用于增强角膜生物力学的光敏剂光黄素-环糊精包合物 Pending CN115089732A (zh)

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