CN112156065A - 一种含地夸磷索钠的隐形眼镜及其制备方法 - Google Patents
一种含地夸磷索钠的隐形眼镜及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种含地夸磷索钠的隐形眼镜及其制备方法，属于药物制剂技术领域。本发明通过将药物溶液与聚合物单体溶液混合后进行自由基聚合反应，再通过紫外照射使聚合物凝胶固化，从而制备的含有地夸磷索钠的隐形眼镜。与市售地夸磷索钠滴眼剂相比，本发明所得制剂可延长药物的释放时间，提高药物的生物利用度，减少给药次数，提高患者的依从性。
Description
技术领域
本发明属于药物制剂技术领域，具体涉及一种含地夸磷索钠的隐形眼镜及其制备方法。
背景技术
干眼综合症是指结膜和角膜没有被健康量或质量的泪液包裹的情况，仅在美国，就有超过五千万人患有干眼症。干眼症包括眼睛瘙痒和灼热、沙粒感、光敏性、视力模糊和炎症，所有这些都会严重影响患者的生活质量。眼睛干涩的患者通过滴眼液、润滑剂、舒适剂或人工泪液，以增加眼泪的黏度，减慢泪液引流并增加眼表水分。
地夸磷索钠滴眼剂是由参天制药获得Inspire制药公司授权后开发，最早于2010年10月在日本获批用于干眼症的治疗，商品名为
规格为3％(5mL)。国内在2017年10月获批进口，商品名为丽爱思。地夸磷索钠是一种P2Y2受体激动剂，其作用于结膜上皮及杯状细胞膜上的P2Y2受体，通过上调细胞内的钙离子浓度，促进水分及黏蛋白的分泌，进而改善干眼病症状。目前，上市的地夸磷索钠制剂仅有滴眼剂，需一天给药六次。
传统滴眼液有许多缺点，如生物利用度低、眼部停留时间短，为了弥补这些问题，就需要增加药物的剂量或者需要频繁局部用药，这导致患者依从性较差。
目前，已经出现了一些新颖的药物递送系统来改善眼用药物的停留时间和角膜渗透性，例如软膏剂、眼用凝胶等，但是它们有其自身的局限性。因此，需要一种新型的药物递送系统，可以增加药物的生物利用度，最小化药物的全身暴露并改善患者依从性以取得更好的临床效果。通过隐形眼镜进行药物递送就是其中一种，与滴眼剂疗法相比，它们具有独特的优势，是用于眼部药物输送的理想载体，这是因为：1)软性隐形眼镜可长时间安全舒适地佩戴；2)与滴眼剂相比，药物在角膜停留时间大大增加，可提高生物利用度(＞50％)；3)易于终止治疗(通过移除隐形眼镜)；4)对于需要屈光校正的患者依从性也较好。
现有的制备载药隐形眼镜的方法有：1)药物浸泡法，此方法最简便易操作，但是存在药物突释和缓释效果差的问题，并且载药量受到比较大的限制，例如药物的分子量、药物在水凝胶中的溶解性等，难以达到长期释放有效药物浓度的效果；2)官能团引入法，具有与水凝胶结合位点的药物可通过此法进行载药，在泪液中，离子通过与药物竞争水凝胶上的结合位点，从而释放药物，但此类方法研究较少；3)载药胶体颗粒引入法，可先将药物负载与纳米粒、脂质体等胶体颗粒中，再将胶体颗粒分散在凝胶聚合液中，形成负载胶体颗粒的水凝胶，但是该方法的缺陷在于胶体颗粒的结构可能影响隐形眼镜的透氧性；4)分子印迹法，该方法是在药物存在的情况下聚合官能团，然后去除药物使得产生空腔，再通过空腔内的官能团与药物发生共价作用，使得药物装载于空腔内，从而改变药物的装载和释放，但是分子印迹中的高度交联会改变隐形眼镜的光学和物理特性。
目前地夸磷酸钠仅有滴眼液产品上市，开发给药次数少或给药剂量小，使用方便的产品，更好的提高地夸磷索钠的疗效具有非常好的市场前景。
发明内容
本发明的目的在于提供一种含地夸磷索钠的隐形眼镜及其制备方法，该制剂与传统的滴眼剂相比，能够增加药物在眼表的停留时间，达到缓释给药，提高生物利用度，解决了传统滴眼剂存在的给药频繁的问题。
为了实现上述发明目的，本发明采用以下技术方案：
一种含地夸磷索钠的隐形眼镜，所述隐形眼镜为固化的聚合物凝胶；
所述聚合物凝胶由聚合物混合液经自由基聚合反应得到，所述聚合物混合液的原料包括：聚合物单体、交联剂、光引发剂和地夸磷索钠。
进一步地，所述聚合物混合液中地夸磷索钠、聚合物单体、交联剂和光引发剂的浓度分别为：3wt％、0.05wt％～0.5wt％、0.003～0.015wt％、0.1～1wt％。
进一步地，所述聚合物单体选自甲基丙烯酸羟乙酯、N-乙烯基吡咯烷酮、甲基丙烯酸中的一种或多种。
进一步地，所述交联剂选自聚乙二醇二丙烯酸酯、乙二醇二甲基丙烯酸酯或乙二醇二缩水甘油醚中的一种或多种。
进一步地，所述光引发剂选自Irgacure 2959、安息香乙醚、硫酸氨或四甲基乙二胺中的一种或多种。
上述含地夸磷索钠的隐形眼镜的制备方法，包括以下步骤：
步骤1，将地夸磷索钠溶于水中，搅拌使其完全溶解，得到药物溶液；
步骤2，将聚合单体、交联剂加至水中混合，向混合溶液中加入药物溶液，配制成含药物的聚合液；
步骤3，向聚合液中加入光引发剂水溶液，搅拌使其溶解，向混合溶液中通入氮气以除去溶液中的氧气；
步骤4，将聚合物混合液倒入模具中，通过紫外照射使凝胶固化，即可得到隐形眼镜。
有益效果：与市售传统滴眼剂相比，本发明的隐形眼镜采用聚合物水凝胶作为药物载体，地夸磷索钠缓释效果显著，并且不存在明显的突释现象。聚合物凝胶固化后得到的隐形眼镜，镜片的关键特性如溶胀率，透射率等均较好，符合镜片要求。
附图说明
图1为实施例1-5的隐形眼镜的体外释放度曲线。
具体实施方式
以下将通过具体实施例进一步阐述本发明，应当理解，本发明的实施例仅用于理解本发明，而非对本发明的限制。未特别说明，本发明的术语具有本领域的常规含义，所有试剂均为市售购得后直接使用。
实施例1
精密称定甲基丙烯酸羟乙酯10mg、N-乙烯基吡咯烷酮4mg、聚乙二醇二丙烯酸酯0.3mg，加水9mL，反应形成自由基聚合溶液，然后添加300mg/mL地夸磷索钠水溶液1mL，搅拌均匀后，添加12.5mg的Irgacure 2959，搅拌均匀。将反应混合物用氮气脱气15min后，将混合物倒入模具，在325nm处进行紫外照射，照射时间为30min，使凝胶固化，即得。
实施例2
精密称定甲基丙烯酸羟乙酯10mg，N-乙烯基吡咯烷5mg，聚乙二醇二丙烯酸酯0.3mg，加水9mL，反应形成自由基聚合溶液，然后添加300mg/mL地夸磷索钠水溶液1mL，搅拌均匀后，添加12.5mg的Irgacure 2959，搅拌均匀。将反应混合物用氮气脱气15min后，将混合物倒入模具，在325nm处进行紫外照射，照射时间为30min，使凝胶固化，即得。
实施例3
精密称定甲基丙烯酸羟乙酯10mg，N-乙烯基吡咯烷4mg，聚乙二醇二丙烯酸酯0.8mg，加水9mL，反应形成自由基聚合溶液，然后添添加300mg/mL地夸磷索钠水溶液1mL，搅拌均匀后，添加12.5mg的Irgacure 2959，搅拌均匀。将反应混合物用氮气脱气15min后，将混合物倒入模具，在325nm处进行紫外照射，照射时间为30min，使凝胶固化，即得。
实施例4
精密称定甲基丙烯酸羟乙酯10mg，N-乙烯基吡咯烷酮5mg，聚乙二醇二丙烯酸酯0.8mg，加水9mL，反应形成自由基聚合溶液，然后添加300mg/mL地夸磷索钠水溶液1mL，搅拌均匀后，添加12.5mg的Irgacure 2959，搅拌均匀。将反应混合物用氮气脱气15min后，将混合物倒入模具，在325nm处进行紫外照射，照射时间为30min，使凝胶固化，即得。
实施例5
精密称定甲基丙烯酸羟乙酯10mg，N-乙烯基吡咯烷酮6mg，聚乙二醇二丙烯酸酯1.5mg，加水9mL，反应形成自由基聚合溶液，然后添加300mg/mL地夸磷索钠水溶液1mL，搅拌均匀后，添加12.5mg的Irgacure 2959，搅拌均匀。将反应混合物用氮气脱气15min后，将混合物倒入模具，在325nm处进行紫外照射，照射时间为30min，使凝胶固化，即得。
下面对实施例1-5制得的隐形眼镜进行溶胀率、透射率和体外释放度的检测。
1.溶胀率测定
将称重的干凝胶(Wdry)浸入35℃的磷酸盐缓冲溶液(PBS，pH＝7.4)中，定期从水中移出，表面轻轻干燥，然后称重(Wwet)。吸水能力使用以下公式计算：
结果如下表：
| 处方名称 | 含水量(％) |
| 实施例1 | 51.40 |
| 实施例2 | 52.80 |
| 实施例3 | 59.68 |
| 实施例4 | 60.79 |
| 实施例5 | 67.11 |
由上表可知，随着亲水性共聚单体N-乙烯基吡咯烷酮以及交联剂聚乙二醇二丙烯酸酯含量增加，所制得隐形眼镜的溶胀率增加，因为亲水性单体可增加亲水基团的数量，交联剂增加会导致交联密度增加，水分子在“刚性结构”中的迁移率降低，故所形成的凝胶中的水都以紧密的方式结合在凝胶中。
2.透射率测定
将实施例1-5所得隐形眼镜置于磷酸盐缓冲溶液(PBS，pH＝7.4)中浸泡过夜。使用紫外可见分光光度计在200至900nm的范围内测量了隐形眼镜的光学特性。结果如下表：
| 处方名称 | 透射率(％) |
| 实施例1 | 96.5 |
| 实施例2 | 96.1 |
| 实施例3 | 97.1 |
| 实施例4 | 97.4 |
| 实施例5 | 98.7 |
由上表可知，亲水性共聚单体N-乙烯基吡咯烷酮对透射率无影响，随着交联剂聚乙二醇二丙烯酸酯含量增加，所制得隐形眼镜的透射率增加，说明交联剂增加，隐形眼镜的透明度越好。
3.体外释放度考察
将实施例1-5所得隐形眼镜放入装有100mL人工泪液的烧杯中，置于气浴恒温振荡器中，温度为(37±0.5)℃，转速为100rpm/min，分别于5min、10min、15min、30min、1h、2h、4h、6h、8h及12h取样5mL，过0.45μm水系滤器，取续滤液用人工泪液稀释至合适范围浓度，取市售地夸磷索钠滴眼剂适量，装于透析袋中，也置于同一条件下，操作同上。以人工泪液为空白溶液，参照2020版《中华人民共和国药典》四部中的紫外—可见分光光度法(通则0401)，分别测定吸光度，以外标法计算浓度，并计算累计释放度。
结果如图1所示。由图1可知，市售滴眼剂在不到10h就已经基本释放完毕，实施例1～5的释放均较慢，其中，实施例1～4的释放速率差异不大，均在24h时释放完毕，实施例5缓释效果最佳，24h后仍未完全释放，相较于市售滴眼剂，释药时间大大延长，表明，本发明所制得含地夸磷索钠的隐形眼镜能延长药物的释放时间，较好的解决给药频繁的问题。
Claims (6)
1.一种含地夸磷索钠的隐形眼镜，其特征在于：所述隐形眼镜为固化的聚合物凝胶；
所述聚合物凝胶由聚合物混合液经自由基聚合反应得到，所述聚合物混合液为地夸磷索钠、聚合物单体、交联剂和光引发剂的混合水溶液。
2.根据权利要求1所述的隐形眼镜，其特征在于：所述聚合物混合液中地夸磷索钠、聚合物单体、交联剂和光引发剂的浓度分别为：3wt%、0.05wt%~0.5wt%、0.003~0.015wt%、0.1~1wt%。
3.根据权利要求1或2所述的隐形眼镜，其特征在于：所述聚合物单体选自甲基丙烯酸羟乙酯、N-乙烯基吡咯烷酮、甲基丙烯酸中的一种或多种。
4.根据权利要求1或2所述的隐形眼镜，其特征在于：所述交联剂选自聚乙二醇二丙烯酸酯、乙二醇二甲基丙烯酸酯或乙二醇二缩水甘油醚中的一种或多种。
5.根据权利要求1或2所述的隐形眼镜，其特征在于：所述光引发剂选自Irgacure2959、安息香乙醚、硫酸氨或四甲基乙二胺中的一种或多种。
6.权利要求1所述的含地夸磷索钠的隐形眼镜的制备方法，其特征在于：包括以下步骤：
步骤1，将地夸磷索钠溶于水中，搅拌使其完全溶解，得到药物溶液；
步骤2，将聚合物单体、交联剂加至水中混合，向混合溶液中加入药物溶液，配制成含药物的聚合液；
步骤3，向聚合液中加入光引发剂，搅拌使其溶解，向混合溶液中通入氮气以除去溶液中的氧气；
步骤4，将聚合物混合液倒入模具中，通过紫外照射使凝胶固化，即可得到隐形眼镜。
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