CN114224821A - 包含基于渗透压机制增加药物眼后部递送系统的覆膜接触镜及其制备方法 - Google Patents
包含基于渗透压机制增加药物眼后部递送系统的覆膜接触镜及其制备方法 Download PDFInfo
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Abstract
本发明涉及包含基于渗透压机制增加药物眼后部递送系统的覆膜接触镜及其制备方法和用途。所述覆膜接触镜通过载药的圆环外覆膜和接触镜基底层组成的多层接触镜实现。其中，载药圆环外覆膜包含药学活性物质，渗透压调节剂，pH触发释放调节剂，基质材料，引发剂，交联剂。本发明包含递药系统的覆膜接触镜有如下优势，促进药物从接触镜中释放，提高角膜透过率，增加药物眼后段组织的分布，从而增加了药物的眼后部递送能力，达到采用无创方式治疗眼后部疾病的目的，并通过维持接触镜的透光性透氧性提高患者佩戴舒适度。
Description
技术领域
本发明属于医药技术领域，具体地涉及一种包含基于渗透压机制增加药物眼后部递送系统的覆膜接触镜及其制备方法和用途。本发明通过渗透压机制以多层接触镜给药促进药物从接触镜中释放，提高角膜渗透能力，增加局部给药后药物向眼后段组织的分布，以达到采用无创方式治疗眼后部疾病的治疗目的。
背景技术
由于人口老龄化、电子产品广泛使用、用眼不当等生活习惯转变，各类眼部疾病发病率呈不断上升趋势。目前国内眼部疾病致盲的原因中，除常见的白内障，角膜疾病外，眼后段疾病老年性黄斑变性和糖尿病引起的视网膜病变也居高位。以老年性黄斑变性为例，它是全球50岁以上成年人首要致盲疾病之一，而在我国患病人数超过3000万，并且每年以30万人次的速度增加。在临床上，以老年性黄斑变性，糖尿病视网膜病变为代表的眼后段疾病通常是以眼后部新生血管异常和/或炎症反应为特征的视网膜退行性疾病，发病机制复杂，病程长且难以治愈。目前针对这类疾病临床上主要采用激光治疗和药物治疗。激光治疗是利用高能激光破坏视网膜中的异常血管。但激光稍一过量，本身可以使脉络膜新生血管增生，且对附近的正常组织也产生损坏。这种治疗方法有复发的风险，复发时还伴随着患者严重的视力丧失。而药物治疗主要是采用抑制新生血管药物，如单抗类，目前上市的产品有雷珠单抗
贝伐单抗
阿柏西普
但这类药物需要通过玻璃体注射给药以达到在眼后段较高治疗浓度。并且单抗类药物半衰期短需要频繁给药。早期于2004年被FDA批准的雷珠单抗需要每个月注射一次。之后于2011年批准上市的阿柏西普
在第一个月注射一次，之后每两个月注射一次。虽然后期注射频次由每月一次降为每两月一次，但对于眼后段疾病这种慢性疾病，玻璃体注射带来的患者不适和注射后不良反应严重，同时因治疗时间长花费高。因此寻求非损伤性的眼后部药物递送策略是针对眼后部疾病治疗的最终目标。
局部给药是眼部给药策略中理想的非损伤性给药手段，可以实现患者独立给药。但传统局部给药方式药物很快被清除，生物利用度较低。针对这一问题研究了多种增加眼前部药物滞留的策略，如原位凝胶，生物粘附性材料。其中载药接触镜通过长时间佩戴可以显著延长药物在眼前滞留，提高眼内生物利用度(参见，例如，CN109985025A)。但是接触镜简单附着在眼前部使释放的药物经被动扩散后集中分布在泪液和角膜中，主要用于治疗眼表疾病，例如，青光眼以及眼表细菌和真菌感染等(参见，例如，CN111840222A)，想要进一步跨过诸多生理屏障如角膜上皮层，房水循环和血液循环，向眼后段病变组织视网膜分布难度较大，这也是目前接触镜递药到达眼后部的主要难点。
基于现有技术中使用载药接触镜进行眼内药物递送存在的缺陷，为了增加药物向眼后部递送的能力，本发明人首次设计借助渗透压机制，加入可以产生高渗透压的物质，加快药物从接触镜中释放。为释放药物提供额外推动力，提高角膜透过率，使药物释放后不只是聚集在角膜，进一步促进药物向眼后段组织转运并在眼后段组织如脉络膜，视网膜等有更多分布。
考虑到接触镜基质材料中混入过多其它材料和药物会影响最终接触镜的含水量透氧性。因此，本发明设计采用多层接触镜的方法，在接触镜基底层外覆一层载药膜，在不影响柔韧性的前提下增加载药膜中可添加材料的选择。同时，因为接触镜厚度增加，会对瞳孔处的透光性和角膜处的透氧性产生影响，因此采用了中空的圆环状外覆膜的设计，根据人体工学瞳孔大小设计圆环内径，使关键部位角膜前接触镜的厚度仅为接触镜基底层的厚度。基于以上设想，保证了多层接触镜的柔韧性和透光透氧性。
综上所述，本发明基于渗透压机制眼后部递送系统实现了通过在眼局部使用覆膜接触镜体系，增加药物在眼部的滞留和眼后部药物递送。同时，还解决了临床上注射给药带来的患者顺应性差及副作用明显的缺点，达到了无创治疗眼后段疾病的目的，极大提高了患者治疗的顺应性。最后，圆环状载药膜外覆的多层接触镜结构不影响瞳孔角膜处的透光性和透氧性。
发明内容
为了解决上述技术问题，本发明提供了一种包含基于渗透压机制增加眼后部递送系统的覆膜接触镜。本发明的眼后部递药系统及其覆膜接触镜是通过以载药圆环膜外覆在接触镜基底层组成的多层接触镜实现的。通过在载药膜中加入渗透压调节剂促进药物从接触镜中释放，不仅提高了角膜透过率，增加药物在眼后段组织的分布，增加了药物的眼后部递送能力。最后，圆环状载药膜外覆的多层接触镜保证了瞳孔角膜处的透光性和透氧性，不影响患者佩戴的舒适度。
具体地，通过以下几个方面的技术方案实现了本发明：
在第一个方面中，本发明提供了一种包含基于渗透压机制增加眼后部递送系统的覆膜接触镜，所述覆膜接触镜包含载药圆环外覆膜和接触镜基底层，所述载药圆环外覆膜层通过界面聚合反应附着在所述接触镜基底层上组成多层接触镜，
其中，所述载药圆环外覆膜包含药学活性物质，渗透压调节剂，pH触发释放调节剂，基质材料，交联剂，引发剂，上述各组分所占的质量百分比范围为：药学活性物质0.01-70.0％，渗透压调节剂0.01-12.0％，pH触发释放调节剂0.01-10.0％，交联剂0.1-2.0％，引发剂0.1-2.0％，其余为基质材料；
所述接触镜基底层包含基质材料，交联剂和引发剂，上述各组分所占的质量百分比范围为：交联剂0.1-2.0％，引发剂0.1-2.0％，其余为基质材料。
作为可选的方式，在上述覆膜接触镜中，所述载药圆环外覆膜是所述覆膜接触镜的主要功能层，所述膜中含有药学活性物质和调控药物释放行为的材料，所述载药圆环外覆膜呈圆环状，厚度为25-200μm；内径为3-7μm，外径为9-13μm；
所述接触镜基底层是所述覆膜接触镜的基础层，起支撑所述载药圆环外覆膜的作用，厚度为10-200μm。
作为可选的方式，在上述覆膜接触镜中，所述载药圆环外覆膜中含有渗透压调节剂，基于渗透压机制增加眼后部递送，具体地是在所述载药圆环外覆膜中加入可产生高渗透压的物质，所述渗透压调节剂包括但不限于丙三醇，氯化钠，甘露醇，葡萄糖。
作为可选的方式，在上述覆膜接触镜中，所述载药圆环外覆膜中含有pH触发释放调节剂，其选自具有pH依赖溶解行为的任一聚合物，所述pH触发释放调节剂包括但不限于邻苯二甲酸醋酸纤维素，邻苯二甲酸羟丙甲纤维素，羧甲基乙基纤维素，尤特奇L100，尤特奇S100。
作为可选的方式，在上述覆膜接触镜中，所述载药圆环外覆膜和所述接触镜基底层中的基质材料选自醋酸丁酸纤维素，聚甲基丙烯酸甲酯，甲基丙烯酸羟乙酯，硅氧烷/甲基丙烯酸酯共聚物，氟硅丙烯酸酯，聚氨基甲酸酯水凝胶，丙烯酰-倍半硅氧烷共聚物，甲基丙烯酸甲酯-硅氧烷共聚物，甲基丙烯酸羟乙酯-丙烯酸共聚物中的一种或几种，所述基质材料占所述覆膜接触镜的质量百分比范围为0.5-95.0％。
所述载药圆环外覆膜和所述接触镜基底层中的交联剂选自二甲基丙烯酸乙二醇酯(EGDMA)，四甘醇二甲基丙烯酸酯(TEGDMA)中的一种或两种，所述交联剂占所述覆膜接触镜的质量百分比范围为0.1-2.0％。
所述载药圆环外覆膜和所述接触镜基底层中的引发剂选自Darocur，2-羟基-2-甲基-1-苯基-1-丙酮中的一种或两种，所述引发剂占所述覆膜接触镜的质量百分比范围为0.1-2.0％。
作为可选的方式，在上述覆膜接触镜中，由所述载药圆环外覆膜和所述接触镜基底层组成的多层接触镜的透光率>90％，氧传导性/传导速率>24barrer。
作为可选的方式，在上述覆膜接触镜中，所述药学活性物质以游离药物形式或是以包载在不同载体中的形式添加在圆环外覆膜中，其中所述不同载体形式包括但不限于纳米胶束，脂质体，脂质纳米粒，微球。
作为可选的方式，在上述覆膜接触镜中，所述药学活性物质是治疗眼局部疾病的任何药物，尤其是治疗眼后段疾病的药物。
所述药学活性物质包括但不限于皮质激素类(如曲安奈德，地塞米松，醋酸地塞米松，倍他米松，氟轻松，可的松，磷酸倍他米松，布地奈德，醋酸阿奈可他，醋酸泼尼松，甲泼尼龙琥珀酸钠)，非甾体抗炎药(如水杨酸酯，塞来昔布，吲哚美辛，布洛芬，普拉洛芬，双氯芬酸，氟比洛芬，吡罗昔康，萘丁美酮)，免疫抑制剂(如环孢霉素，硫唑嘌呤，甲氨蝶呤)，酪氨酸激酶抑制剂(如帕唑帕尼)，碳酸酐酶抑制剂(如布林佐胺)，抗生素类(如四环素，金霉素，杆菌肽，新霉素，多粘菌素，短杆菌肽，头孢氨苄，土霉素，氯霉素，利福平，环丙沙星，妥布霉素，庆大霉素，红霉素，青霉素，磺胺嘧啶，磺胺嘧啶，磺胺乙酰胺，磺胺咪唑，丙酸钠)，抗真菌类(如两性霉素B和咪康唑)，抗病毒类(如艾司西定三氟胸苷，阿昔洛韦，甘哌昔洛韦)，其它类(如维替泊芬，卵磷脂络合碘片，醋氮酰胺)
另外，所述药学活性物质还包括但不限于抗胆碱酯酶(如毛果芸香碱，水杨酸酯，卡巴胆碱，乙酰胆碱氯化物，毒扁豆碱，埃赛烯，氟磷酸二异丙酯，磷酸碘，溴化镉)，β受体拮抗剂(如噻吗洛尔，倍他洛尔)，喹诺酮类(如诺氟沙星，左氧氟沙星)，散瞳药(如阿托品，托吡卡胺)，抗过敏原药(如色原酸钠，安曲唑啉，甲吡啶，氯苯那敏，西替利嗪，吡拉明，丙苯胺等)；抗增殖剂(如1,3-顺式视黄酸，5-氟尿嘧啶，紫杉醇，雷帕霉素，丝裂霉素C和顺铂)；减充血剂(如去氧肾上腺素，萘唑啉，四氢吡嗪)。
应当理解的是，药物制剂领域的技术人员可以根据所使用的药学活性物质的不同理化性质，采用适当的溶剂或操作方法对其进行处理，以便于将所述药学活性物质制备成制剂。
在第二方面中，本发明提供了上述第一个方面所述的覆膜接触镜的制备方法，包括以下步骤：
(1)准确称取处方量的药学活性物质，渗透压调节剂，pH触发释放调节剂，交联剂，引发剂和基质材料置于适当容器，混合均匀后倾倒入模具中，在紫外灯下聚合成膜得到载药圆环外覆膜；和
(2)另外称取基质材料，交联剂和引发剂混合均匀并置于接触镜模具中，将步骤(1)得到的所述载药圆环外覆膜放在模具底部，整体置于紫外灯下聚合，制备所述载药圆环膜外覆的所述覆膜接触镜。
在第三个方面中，本发明提供了上述第一个方面所述的覆膜接触镜在制备治疗眼后部疾病的药物中的用途，通过在眼局部使用所述覆膜接触镜，增加药物在眼部的滞留和眼后部药物递送，无创治疗眼后部疾病。
优选地，所述眼后部疾病包括但不仅限于老年性黄斑变性，眼后部葡萄膜炎，糖尿病黄斑水肿，糖尿病视网膜病变，脉络膜新生血管，色素性视网膜炎，真菌性眼内炎。
本发明相对于现有技术，具有以下有益效果：
本发明设计的包含基于渗透压机制增加眼后部递送系统的覆膜接触镜，显著延长了释放药物在眼部滞留时间，为药物向眼后部组织递送提供了前提保证。在普通单层接触镜的基础上，将载药层单独设计制成多层接触镜可以加入更多调控药物释放的材料而不改变接触镜的柔韧性。因为多层接触镜厚度增加对透光透氧性产生影响，因此将载药层设计成圆环状得到载药圆环外覆膜，没有额外增加瞳孔前接触镜的厚度，维持了瞳孔和角膜的透光性和透氧性。最终透光率>90％，氧气透过率>24barrer，与普通单层接触镜均没有显著性差异。
基于渗透压机制的增加眼后部递送系统及其给药体系中引入可以产生高渗透压力的物质，与普通接触镜比较，使药物除了基于浓度梯度的被动扩散外，还有基于渗透压机制的促进药物扩散，促进了接触镜中药物释放，提高了角膜透过能力，增强了药物在眼后段组织(玻璃体液，结膜-巩膜，脉络膜-视网膜)的分布。
总之，本发明采用基于渗透压机制的眼后部递送策略和体系，促进了药物释放，显著提高了药物的角膜透过能力，增加药物在眼后段组织的分布，增加了药物的眼后部递送能力，达到采用无创方式治疗眼后部疾病的目的，并通过维持接触镜的透光透氧性提高了患者佩戴的舒适度。
附图说明
图1：不同渗透压调节剂浓度对接触镜中曲安奈德释放的影响(n＝3)(对应实施例1)。
图2：不同渗透压调节剂浓度对接触镜中曲安奈德跨角膜转运的影响(n＝3)(对应实施例2)。
图3：应用载药圆环外覆膜多层接触镜后的曲安奈德泪液分泌动力学(n＝4)(对应实施例3)。
图4：应用载药圆环外覆膜多层接触镜后的曲安奈德在眼部的组织分布(n＝4)(对应实施例4)。
图5：不同接触镜(单层接触镜，普通多层接触镜，载药圆环外覆膜多层接触镜)对透光性(图5A)、透氧性(图5B)的影响(n＝3)(对应实施例6)。
图6：多层覆膜接触镜体系结构示意图。
具体实施方式
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
以曲安奈德作为药学活性化合物，丙三醇作为渗透压调节剂的基于渗透压机制眼后部递送系统及其覆膜接触镜的设计。但是需要说明的是，本发明不仅限于上述药学活性成分和渗透压调节剂。
实施例1：不同渗透压调节剂浓度对接触镜中曲安奈德释放的影响，以丙三醇为例进行说明
处方组成与制备：
将曲安奈德2.5mg和壳聚糖-单辛酸甘油酯5.0mg溶于1mL 0.25％的醋酸水溶液中搅拌2h。向上述溶液中加入不同比例丙三醇(1.0％-3.0％)，加入5％尤特奇S100溶液0.1mL，二甲基丙烯酸乙二醇酯20μL，Darocur 20μL，混和均匀后倾倒在圆环模具上，在365nm紫外光下聚合15min，即得载药圆环膜。另取甲基丙烯酸羟乙酯5mL，二甲基丙烯酸乙二醇酯20μL，Darocur20μL，将混合物通氮气15min以除去溶解氧。然后将得到的混合物注入接触镜模具中，将上面得到的载药膜放在模具底部，将模具置于紫外灯下，在365nm下照射15min，即可得到含有丙三醇浓度的载药圆环膜外覆的多层接触镜。
实验操作：
将载药圆环外覆膜多层载药接触镜浸入8mL释放介质模拟泪液(STF)中，然后放入气浴震荡箱中(35℃，100rpm)进行体外药物释放。在预定的时间间隔取出1mL的释放介质用于测量，同时补加相同体积的新鲜释放介质。使用Agilent 1100 HPLC系统进行分析。
色谱条件：色谱柱：GP-C18(5μm，4.6×150mm)；流动相：乙腈：水(35:65)；柱温：30℃；流速：1.0mL/min；检测波长：240nm；进样量：20μL。
药物释放曲线如图1所示。从曲线斜率看，丙三醇的加入使曲线斜率逐渐增加。表明丙三醇的加入促进了药物从接触镜中释放。
实施例2：不同渗透压调节剂浓度对接触镜中曲安奈德跨角膜转运的影响，以丙三醇为例具体说明
处方组成与制备：
组成及制备方法与实施例1中的组成与制备一致。
实验操作：
将家兔静脉注射空气处死后，快速摘取眼球，将角膜剥离。将角膜放置在给药池和扩散池中间。给药池中放置的是用模拟泪液润湿的圆环载药膜外覆的多层接触镜，接收池中是STF溶液。在预定的时间点收集1mL接收池中的液体，同时补加入相同体积的STF溶液。使用Agilent 1100 HPLC系统进行分析。色谱条件同实施例1。
药物透过曲线如图2所示。结果显示，与不含丙三醇组相比，加入丙三醇的组(1％，2％和3％)角膜透过效率(Papp)在前60min分别提高了28.8-47.3％，75.2-107.5％和110.1-160.5％。表明丙三醇的加入提高了药物的角膜透过能力。
实施例3：载药圆环外覆膜多层接触镜的动物泪液分泌动力学，以丙三醇为例具体说明
处方组成与制备：
将曲安奈德2.5mg和壳聚糖-单辛酸甘油酯5.0mg溶于1mL 0.25％的醋酸水溶液中搅拌2h。向上述溶液中加入丙三醇27/0μL，加入5％尤特奇S100溶液0.1mL，二甲基丙烯酸乙二醇酯20μL，Darocur 20μL，混和均匀后倾倒在圆环模具上，在365nm紫外光下聚合15min，即得载药圆环膜。另取甲基丙烯酸羟乙酯5mL，二甲基丙烯酸乙二醇酯20μL，Darocur 20μL，将混合物通氮气15min以除去溶解氧。然后将得到的混合物注入接触镜模具中，将上面得到的载药膜放在模具底部，将模具置于紫外灯下，在365nm下照射15min，即可得到含有3.0％/不含丙三醇的载药圆环外覆膜多层接触镜。实验操作：
使用从沈阳药科大学动物中心提供的1.8-2.0kg体重的雄性日本大耳白兔进行体内药代动力学研究。对兔子的右眼进行给药，将含有3％丙三醇和不含丙三醇的接触镜用人工泪液STF洗涤30s后分别给动物佩戴。在一定的时间间隔，使用一次性玻璃毛细管收集泪液10μL，加入20μL泼尼松龙溶液作为内标物质，加入500μL甲醇沉淀蛋白质。将混合物涡旋5min，离心(12,000rpm，10min)，将上清液在氮气下挥干，加入100μL流动相复溶，离心(12,000rpm，10min)，取上清液然后使用Agilent1100 HPLC系统进行分析。
色谱条件：色谱柱：GP-C18((5μm，4.6×150mm)；流动相：乙腈：水(40:60)；柱温：30℃；流速：1.0mL/min；检测波长：240nm；进样量：10μL。
外覆膜多层接触镜的药物泪液浓度-时间曲线如图3所示。结果表明，含有丙三醇与不含丙三醇的给药组因为接触镜延长滞留的原因均可以在泪液中维持较长时间的药物浓度至72h，两条浓度-时间曲线趋势基本一致。在丙三醇的帮助下，曲安奈德在泪液中的Cmax提高了1.3-3μg/mL，在泪液中的生物利用度提高了4.4-36.7％，表明丙三醇促进了药物从接触镜中释放，提高了泪液中药物水平。
实施例4：渗透压调节剂的加入对接触镜中药物体内分布的影响，以丙三醇为例进行具体说明
处方组成与制备：
组成及制备方法与实施例3中的组成与制备一致。
实验操作：
使用从沈阳药科大学动物中心提供的1.8-2.0kg体重的雄性日本大耳白兔进行体内药代动力学研究。对兔子的右眼进行给药，将含有3％丙三醇和不含丙三醇的接触镜用人工泪液STF洗涤30s后分别给动物佩戴。在特定的时间间隔通过耳缘静脉注射空气处死兔子，摘取眼球，吸取房水，玻璃体液，并剥离角膜，结膜-巩膜，虹膜-睫状体和脉络膜-视网膜。精密称重，加入缓冲盐溶液匀浆。吸取房水(玻璃体液)100(200)μL，加入内标溶液200(300)μL，蛋白沉淀剂100(200)μL。其余组织加入700μL缓冲盐匀浆。吸取匀浆液200μL，加入内标溶液200μL，蛋白沉淀剂1mL。以上混合物涡旋5min，离心(12,000rpm，10min)。在氮气下挥干。加入100μL流动相复溶，离心(12,000rpm，10min)，取上清液然后使用Agilent1100HPLC系统进行分析。
色谱条件同实施例3。
有无丙三醇对接触镜中药物在体内分布的影响如图4所示。结果表明加入丙三醇的接触镜组与未加入丙三醇的组在眼前部组织如角膜，房水，虹膜-睫状体这些组织的Cmax与生物利用度均没有显著差异(*p>0.05，组别数据采用t-检验进行统计学分析，p<0.05认为有显著性差异)，而在眼后部的组织玻璃体液，结膜-巩膜和脉络膜-视网膜，丙三醇的加入，使玻璃体液中的Cmax提高了42.9-77.8％，生物利用度提高了37.0-95.6％，结膜-巩膜处的Cmax提高了33.7-157.0％，生物利用度提高了14.3-115.2％，脉络膜-视网膜处的Cmax提高了70.4-174.5％，生物利用度提高了39.4-161.4％。因为丙三醇的加入使接触镜中渗透压力增加，促进了药物的释放以及向后递送的能力。而没有丙三醇的组，在单一浓度梯度的作用下，药物从接触镜中平稳释放，更多的聚集在眼前段组织。说明丙三醇的加入增加了药物向眼后部组织递送的能力。
实施例5：圆环载药膜外覆的多层接触镜的眼刺激性研究
处方组成与制备：
组成及制备方法与实施例3中的组成与制备一致。
实验操作：
根据Draize试验，使用从沈阳药科大学动物中心提供的1.8-2.0kg体重的雄性日本大耳白兔进行眼刺激性评价。将接触镜佩戴在兔子右眼，同时以对侧眼(即左眼)为对照。接触镜佩戴24h后取走。根据Draize测试，进行眼部(角膜，虹膜和结膜)刺激性打分：无刺激(评分0-3分)；轻微刺激(评分4-8分)；适度刺激(评分9-12分)；严重刺激(得分13-16分)。
处方中的接触镜在佩戴24h后每24h至5天检查动物眼部反应，经过眼刺激性的Draize试验得到评分，每天评分均<4，证明其使用安全性。
实施例6：多层接触镜对透光性、透氧性的影响
处方组成与制备：
单层接触镜：取甲基丙烯酸羟乙酯5mL，二甲基丙烯酸乙二醇酯20μL，Darocur 20μL，将混合物通氮气15min以除去溶解氧。然后将得到的混合物注入接触镜模具中，置于紫外灯下，在365nm下照射15min，即可得到普通单层接触镜。
普通多层接触镜：组成及制备方法与实施例3中的组成与制备一致，只是制备载药膜时所用模具为圆柱形凹槽的模具。
圆环外覆膜接触镜：组成及制备方法与实施例3中的组成与制备一致。
实验操作：
透光性：将接触镜切成小片放入96孔板中放入酶标仪中，在波长400-900nm范围内，步长为20nm，记录透光率。
透氧性：使用扩散池进行透氧性的测量。接触镜放置在给药池和接收池中间，给药池中放入普通蒸馏水，接收池中放入用氮气除过水中气体的蒸馏水。每60s用极谱溶解氧传感器测定一次接收池中的溶解氧浓度，记录电流大小，计算氧气透过接触镜的透过速率。
多层接触镜对透光性的影响结果如图5A所示。与单层接触镜透光性(100.0±0.0％)相比，普通多层接触镜的透光性显著降低，仅为80.5±0.9％，而本申请中的圆环状外覆膜的多层接触镜可以改善普通多层接触镜透光性差的问题，最终与单层接触镜在透光率上没有显著性差异，达到97.4±0.7％(*p>0.05，组别数据采用t-检验进行统计学分析，p<0.05认为有显著性差异)。
多层接触镜对透氧性的影响结果如图5B所示。与单层接触镜透氧性(39.3±3.0barrer)相比，普通多层接触镜透氧性显著下降，仅为21.8±3.5barrer，而将外覆层改为圆环状后解决了透氧性差的问题，显著提高了多层接触镜的透氧性，达到32.4±1.2barrer，与单层接触镜没有显著性差异(*p>0.05，组别数据采用t-检验进行统计学分析，p<0.05认为有显著性差异)。
综上所述，本发明包含递药系统的覆膜接触镜能够促进药物从接触镜中释放，提高角膜透过率，增加药物眼后段组织的分布，从而增加了药物的眼后部递送能力，达到采用无创方式治疗眼后部疾病的目的，并通过维持接触镜的透光性透氧性提高患者佩戴舒适度。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (10)
1.一种包含基于渗透压机制增加眼后部递送系统的覆膜接触镜，其特征在于：所述覆膜接触镜包含载药圆环外覆膜和接触镜基底层，所述载药圆环外覆膜层通过界面聚合反应附着在所述接触镜基底层上组成多层接触镜，
其中，所述载药圆环外覆膜包含药学活性物质，渗透压调节剂，pH触发释放调节剂，基质材料，交联剂，引发剂，上述各组分所占的质量百分比范围为：药学活性物质0.01-70.0％，渗透压调节剂0.01-12.0％，pH触发释放调节剂0.01-10.0％，交联剂0.1-2.0％，引发剂0.1-2.0％，其余为基质材料；
所述接触镜基底层包含基质材料，交联剂和引发剂，上述各组分所占的质量百分比范围为：交联剂0.1-2.0％，引发剂0.1-2.0％，其余为基质材料。
2.根据权利要求1所述的覆膜接触镜，其特征在于：所述载药圆环外覆膜是所述覆膜接触镜的主要功能层，所述膜中含有药学活性物质和调控药物释放行为的材料，所述载药圆环外覆膜呈圆环状，厚度为25-200μm；内径为3-7μm，外径为9-13μm；
所述接触镜基底层是所述覆膜接触镜的基础层，起支撑所述载药圆环外覆膜的作用，厚度为10-200μm。
3.根据权利要求1或权利要求2所述的覆膜接触镜，其特征在于：所述载药圆环外覆膜中含有渗透压调节剂，基于渗透压机制增加眼后部递送，具体地是在所述载药圆环外覆膜中加入可产生高渗透压的物质，所述渗透压调节剂包括但不限于丙三醇，氯化钠，甘露醇，葡萄糖。
4.根据权利要求1至3中任一项所述的覆膜接触镜，其特征在于：所述载药圆环外覆膜中含有pH触发释放调节剂，其选自具有pH依赖溶解行为的任一聚合物，所述pH触发释放调节剂包括但不限于邻苯二甲酸醋酸纤维素，邻苯二甲酸羟丙甲纤维素，羧甲基乙基纤维素，尤特奇L100，尤特奇S100。
5.根据权利要求1至4中任一项所述的覆膜接触镜，其特征在于：所述载药圆环外覆膜和所述接触镜基底层中的基质材料选自醋酸丁酸纤维素，聚甲基丙烯酸甲酯，甲基丙烯酸羟乙酯，硅氧烷/甲基丙烯酸酯共聚物，氟硅丙烯酸酯，聚氨基甲酸酯水凝胶，丙烯酰-倍半硅氧烷共聚物，甲基丙烯酸甲酯-硅氧烷共聚物，甲基丙烯酸羟乙酯-丙烯酸共聚物中的一种或几种，所述基质材料占所述覆膜接触镜的质量百分比范围为0.5-95.0％；和/或所述载药圆环外覆膜和所述接触镜基底层中的交联剂选自二甲基丙烯酸乙二醇酯，四甘醇二甲基丙烯酸酯中的一种或两种，所述交联剂占所述覆膜接触镜的质量百分比范围为0.1-2.0％；和/或所述载药圆环外覆膜和所述接触镜基底层中的引发剂选自Darocur，2-羟基-2-甲基-1-苯基-1-丙酮中的一种或两种，所述引发剂占所述覆膜接触镜的质量百分比范围为0.1-2.0％。
6.根据权利要求1至5中任一项所述的覆膜接触镜，其特征在于：由所述载药圆环外覆膜和所述接触镜基底层组成的多层接触镜的透光率>90％，氧传导性/传导速率>24barrer。
7.根据权利要求1至6中任一项所述的覆膜接触镜，其特征在于：所述药学活性物质以游离药物形式或是以包载在不同载体中的形式添加在圆环外覆膜中，其中所述不同载体形式包括但不限于纳米胶束，脂质体，脂质纳米粒，微球。
8.根据权利要求1至7中任一项所述的覆膜接触镜，其特征在于：所述药学活性物质是治疗眼局部疾病的任何药物，尤其是治疗眼后段疾病的药物，所述药学活性物质包括但不限于皮质激素类(如曲安奈德，地塞米松，醋酸地塞米松，倍他米松，氟轻松，可的松，磷酸倍他米松，布地奈德，醋酸阿奈可他，醋酸泼尼松，甲泼尼龙琥珀酸钠)，非甾体抗炎药(如水杨酸酯，塞来昔布，吲哚美辛，布洛芬，普拉洛芬，双氯芬酸，氟比洛芬，吡罗昔康，萘丁美酮)，免疫抑制剂(如环孢霉素，硫唑嘌呤，甲氨蝶呤)，酪氨酸激酶抑制剂(如帕唑帕尼)，碳酸酐酶抑制剂(如布林佐胺)，抗生素类(如四环素，金霉素，杆菌肽，新霉素，多粘菌素，短杆菌肽，头孢氨苄，土霉素，氯霉素，利福平，环丙沙星，妥布霉素，庆大霉素，红霉素，青霉素，磺胺嘧啶，磺胺嘧啶，磺胺乙酰胺，磺胺咪唑，丙酸钠)，抗真菌类(如两性霉素B和咪康唑)，抗病毒类(如艾司西定三氟胸苷，阿昔洛韦，甘哌昔洛韦)，其它类(如维替泊芬，卵磷脂络合碘片，醋氮酰胺)；所述药学活性物质还包括但不限于抗胆碱酯酶(如毛果芸香碱，水杨酸酯，卡巴胆碱，乙酰胆碱氯化物，毒扁豆碱，埃赛烯，氟磷酸二异丙酯，磷酸碘，溴化镉)，β受体拮抗剂(如噻吗洛尔，倍他洛尔)，喹诺酮类(如诺氟沙星，左氧氟沙星)，散瞳药(如阿托品，托吡卡胺)，抗过敏原药(如色原酸钠，安曲唑啉，甲吡啶，氯苯那敏，西替利嗪，吡拉明，丙苯胺等)；抗增殖剂(如1,3-顺式视黄酸，5-氟尿嘧啶，紫杉醇，雷帕霉素，丝裂霉素C和顺铂)；减充血剂(如去氧肾上腺素，萘唑啉，四氢吡嗪)。
9.权利要求1-8中任一项所述的覆膜接触镜的制备方法，其特征在于：包括以下步骤：
(1)准确称取处方量的药学活性物质，渗透压调节剂，pH触发释放调节剂，交联剂，引发剂和基质材料置于适当容器，混合均匀后倾倒入模具中，在紫外灯下聚合成膜得到载药圆环外覆膜；和
(2)另外称取基质材料，交联剂和引发剂混合均匀并置于接触镜模具中，将步骤(1)得到的所述载药圆环外覆膜放在模具底部，整体置于紫外灯下聚合，制备所述载药圆环膜外覆的所述覆膜接触镜。
10.权利要求1-8中任一项所述的覆膜接触镜在制备治疗眼后部疾病的药物中的用途，其特征在于：通过在眼局部使用所述覆膜接触镜，增加药物在眼部的滞留和眼后部药物递送，无创治疗眼后部疾病，优选地，所述眼后部疾病包括但不仅限于老年性黄斑变性，眼后部葡萄膜炎，糖尿病黄斑水肿，糖尿病视网膜病变，脉络膜新生血管，色素性视网膜炎，真菌性眼内炎。
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