CN116172885A - 一种抗后发性白内障药物制剂及其制备方法 - Google Patents
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Abstract
本发明属于生物医用材料与医学交叉领域，公开一种抗后发性白内障药物制剂及其制备方法。制备步骤如下：（1）、称取聚乙二醇15‑羟基硬脂酸酯、雷公藤红素，共同溶解于乙醇中；其中，聚乙二醇15‑羟基硬脂酸酯、雷公藤红素、乙醇的用量配比为10 g∶（0.1‑1.5）g∶（2‑20）mL；（2）、在超声搅拌下将步骤（1）所得混合液滴加到注射用水中，旋蒸除去乙醇，得载药聚合物胶束；该步骤中的注射用水的用量为步骤（1）中乙醇用量的5‑15体积倍；（3）、将载药聚合物胶束0.05~5 g和温敏性聚合物水凝胶1~50 g混合均匀后，补加注射用水定容至1000 mL，即得抗后发性白内障药物制剂。本发明所得药物制剂能够有效抑制白内障术后PCO的发展。
Description
技术领域
本发明属于生物医用材料与医学交叉领域，具体涉及一种抗后发性白内障药物制剂及其制备方法。
背景技术
白内障为全球首位致盲性眼病，占所有致盲眼病的50％以上。据世界卫生组织估计，目前全世界因白内障致盲的人数大约有2000万，且随着社会老龄化的进程呈继续上升趋势，至2050年可能达到5000万。手术是治疗白内障唯一有效手段。后发性白内障(posterior capsular opacification，PCO)，是白内障术后最常见并发症，术后发生率在成人为12% ~ 67%，在婴幼儿中高达100%。PCO显著降低患者视力和对比敏感度，造成生活不便，同时影响婴幼儿患者视力发育，造成弱视。PCO可以通过YAG激光治疗，但激光治疗有引起青光眼、黄斑囊样水肿、视网膜脱离、人工晶状体移位的风险，同时增加患者经济负担。对于不能配合YAG激光治疗的婴幼儿患者，需要再次手术切除。人们还通过多种其他方法，包括：人工晶体表面改性、术中术后局部药物应用等方法试图降低甚至消除PCO的发生，但由于房水循环的存在，约2小时前房药物将被稀释并从小梁网排出；眼局部生物屏障的存在，使得术后药物局部点眼的生物利用度仅5%，以上这些方法均不能有效阻止PCO的发生、发展。如何有效抑制PCO的形成，探寻新的治疗靶点及特效药物，从而研发副作用低、特异性强的抗PCO新型药物，具有重要的临床意义。
雷公藤红素（Celastrol，CEL）是从中药雷公藤中提取的生物活性单体，其分子式为C29H38O4，分子量为450.61。Celastrol 具有抗炎、抗肿瘤、抑制新生血管和肥胖等多种生物学活性，对自身免疫性疾病、肿瘤、肥胖及神经退行性疾病显示了强大的治疗效果。最新的研究提示，Celastrol可抑制肺等多种组织纤维化。尽管Celastrol有强大的生物活性，但极差的水溶性限制了其进一步应用。如何增强其水溶性，提高眼部靶组织的药物浓度及其生物利用度是亟待解决的关键难题。目前尚未发现将其药物制剂应用到术中以治疗PCO的报道。
发明内容
针对上述现有技术的缺陷与不足，本发明的目的在于提供一种抗后发性白内障药物制剂及其制备方法。
为实现上述目的，本发明采取的技术方案如下：
一种抗后发性白内障药物制剂的制备方法，制备步骤如下：
（1）、称取聚乙二醇15-羟基硬脂酸酯、雷公藤红素，共同溶解于乙醇中；其中，聚乙二醇15-羟基硬脂酸酯、雷公藤红素、乙醇的用量配比为10 g∶（0.1-1.5）g∶（2-20）mL；
（2）、在超声搅拌下将步骤（1）所得混合液滴加到注射用水中，旋蒸除去乙醇，得载药聚合物胶束；该步骤中的注射用水的用量为步骤（1）中乙醇用量的5-15体积倍；
（3）、将载药聚合物胶束0.05~5 g和温敏性聚合物水凝胶1~50 g混合均匀后，补加注射用水定容至1000 mL，即得抗后发性白内障药物制剂。
较好地，所述温敏性聚合物水凝胶为泊洛沙姆水凝胶、聚异丙基丙烯酰胺水凝胶、聚[甲基丙烯酸-2-（N，N-二甲氨基）乙酯水凝胶、聚乙二醇水凝胶、壳聚糖基聚合物水凝胶中的一种或几种的组合物。本发明中，壳聚糖基聚合物水凝胶可按现有技术制备。
较好地，所述乙醇为95 v%乙醇或无水乙醇。
一种如上述述制备方法制备的抗后发性白内障药物制剂。
有益效果：雷公藤红素水溶性极差，37℃在水中的溶解度仅为3.8微克每毫升，现有技术中尚无将其制成可注射制剂用于术中以治疗后发性白内障；本发明采用纳米技术，首先制备负载雷公藤红素的载药聚合物胶束，以增强其表观溶解度，再将载药聚合物胶束与温敏性聚合物水凝胶自组装，形成载药、可注射的负载雷公藤红素的抗后发性白内障药物制剂，在白内障摘除术中将其注射于囊袋内，实现药物雷公藤红素在靶组织的缓慢释放，有效抑制白内障术后PCO的发展。
附图说明
图1：术后第7天（第一行）、28天（第一行），Control组、TSG组及TSG/CEL组眼前节照片。
图2：术后第28天，Control组、TSG组及TSG/CEL组角膜、视网膜HE染色结果。
具体实施方式
为使本发明更加清楚、明确，以下对本发明进一步详细说明。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。
下面实施例中的壳聚糖基聚合物水凝胶参考文献ACS Applied Materials &Interfaces 2021, 13, 49369-49379制备。
实施例1
称取聚乙二醇15-羟基硬脂酸酯(Kolliphor HS 15) 10 g、雷公藤红素0.75 g，共同溶解于10 mL无水乙醇中；然后，在超声搅拌下将混合液滴加到100 mL的注射用水中，旋蒸除去乙醇，得载药聚合物胶束；将载药聚合物胶束1 g和15 g壳聚糖基聚合物水凝胶混合均匀后，补加注射用水至100 mL，即得抗后发性白内障药物制剂。
实施例2
与实施例1的不同之处在于：雷公藤红素的用量改为1.5 g，其它同实施例1。
实施例3
与实施例1的不同之处在于：雷公藤红素的用量改为素0.3 g，其它同实施例1。
实施例4
与实施例1的不同之处在于：雷公藤红素的用量改为0.1 g，其它同实施例1。
动物试验
以新西兰白兔后发性白内障模型为动物模型，评估药物制剂的抗后发性白内障效果。具体方法参照已发表文章（ACS Applied Bio Materials 2021 4 (4), 3579-3586），详细步骤如下：
3%（g/mL）戊巴比妥钠盐溶液耳缘静脉注射诱导新西兰白兔全身麻醉，剂量按3ml/kg计算，以钳夹嘴唇无明显反射为麻醉起效；0.5%（g/mL）复方托吡卡胺滴眼液散瞳，无菌生理盐水5 mL冲洗术眼结膜囊，碘伏消毒眼周，0.5%（g/mL）盐酸丙美卡因滴眼液进行眼表局部麻醉；显微镜下制作3 mm透明角膜切口，前房注入100μL粘弹剂医用透明质酸钠凝胶，连续环形撕囊，撕囊口直径5 mm，注吸针头抽吸干净晶体核及皮质，晶体囊袋内注射药物，形成前房，透明角膜切口10-0线缝合1针关闭切口；术毕加替沙星眼用凝胶涂于结膜囊内，预防感染；手术均在动物右眼进行；术后实验动物每天结膜囊局部点眼妥布霉素地塞米松滴眼液，一天三次，一次一滴，共七天。
实验动物分三组：第一组（标记为TSG/CEL组），术中抽吸皮质后在晶体囊袋内注射5μL微升实施例1所得抗后发性白内障药物制剂；第二组（标记为TSG组），术中抽吸皮质后在晶体囊袋内注射5μL不负载任何药物的壳聚糖基聚合物水凝胶；第三组（标记为Control组），术中抽吸皮质后在晶体囊袋内注射5μL生理盐水；术后每天裂隙灯下观察动物手术眼，记录角膜、前房及后发障情况。观察期为28天；实验动物每组三只，统计PCO评分，PCO评分采用EPCO标准，见表1。通过面积、类型和密度分析，分别在第7、28天进行临床评估和PCO评分计算。实验结束后使用空气栓塞法处死白兔，方法为耳缘静脉注射20-40 mL空气。留取动物眼球标本固定，进行HE染色。
图1为术后第7天（第一行）、28天（第二行），Control组、TSG组及TSG/CEL组眼前节照片。由图1可以看出；眼前节照片显示第7天三组后囊混浊无显著差异；第28天时，Control组和TSG组后囊周围出现白色混浊，提示晶状体上皮细胞纤维化，囊皱，在此二组发生了后发性白内障，TSG/CEL组的后囊几乎保持透明和光滑；根据后囊浑浊图像分析评价，浑浊密度从0到4分，分别为无(0)、极(1)、轻度(2)、中度(3)和严重(4)，术后28天，Control组和TSG组部分区域浊度达4级或严重(暗灰色区)，PCO评分分别为1.5、1.7，两组间差异无统计学意义；TSG/CEL组后囊只有几个浅灰色区域的边缘后囊混浊(1级)，PCO评分为0.07。TSG/CEL组较生理盐水的Control组和不负载药物的TSG组的PCO评分差异均有统计学意义。以上表明：TSG/CEL组PCO的发展明显低于Control组和TSG组，即本发明所得药物制剂能有效抑制白内障术后PCO的发展。
此外，我们进一步评估了TSG/CEL和TSG的药物安全性，结果显示，在术后观察期28天内，无论是TSG/CEL组还是TSG组，均未出现明显的异常眼部炎症反应(如角膜增厚、角膜基质纤维化、出血或水肿等)。透明晶体摘除术后28天，分离角膜和视网膜组织进行观察，Control组、TSG组及TSG/CEL组的角膜、视网膜HE染色结果如图2所示，各组间细胞形态无明显差异，角膜内皮层完整，表明本发明所得药物制剂具有良好的药物安全性。
综上，动物实验表明，注射本发明药物制剂可明显减轻白内障术后后囊浑浊程度，并且对眼角膜、视网膜等组织无毒性，其具有安全的抗后发性白内障效果。
Claims (4)
1.一种抗后发性白内障药物制剂的制备方法，其特征在于，制备步骤如下：
（1）、称取聚乙二醇15-羟基硬脂酸酯、雷公藤红素，共同溶解于乙醇中；其中，聚乙二醇15-羟基硬脂酸酯、雷公藤红素、乙醇的用量配比为10 g∶（0.1-1.5）g∶（2-20）mL；
（2）、在超声搅拌下将步骤（1）所得混合液滴加到注射用水中，旋蒸除去乙醇，得载药聚合物胶束；该步骤中的注射用水的用量为步骤（1）中乙醇用量的5-15体积倍；
（3）、将载药聚合物胶束0.05~5 g和温敏性聚合物水凝胶1~50 g混合均匀后，补加注射用水定容至1000 mL，即得抗后发性白内障药物制剂。
2.如权利要求1所述的抗后发性白内障药物制剂的制备方法，其特征在于：所述温敏性聚合物水凝胶为泊洛沙姆水凝胶、聚异丙基丙烯酰胺水凝胶、聚[甲基丙烯酸-2-（N，N-二甲氨基）乙酯水凝胶、聚乙二醇水凝胶、壳聚糖基聚合物水凝胶中的一种或几种的组合物。
3.如权利要求1所述的抗后发性白内障药物制剂的制备方法，其特征在于：所述乙醇为95 v%乙醇或无水乙醇。
4.一种如权利要求1-3任一项所述制备方法制备的抗后发性白内障药物制剂。
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