CN115919759A - 一种低聚集体眼用纳米制剂及其制备方法和用途 - Google Patents
一种低聚集体眼用纳米制剂及其制备方法和用途 Download PDFInfo
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- CN115919759A CN115919759A CN202211687184.4A CN202211687184A CN115919759A CN 115919759 A CN115919759 A CN 115919759A CN 202211687184 A CN202211687184 A CN 202211687184A CN 115919759 A CN115919759 A CN 115919759A
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Abstract
本发明属于药物制剂技术领域，具体涉及一种用于高效递送药物的低聚集体眼用纳米制剂及其制备方法和用途，其用途主要涉及眼部疾病的治疗。本发明的所述低聚集体眼用纳米制剂由药物分子、磷脂或其衍生物以及两亲性表面活性剂制成，按照重量百分比计，磷脂或其衍生物的浓度为0.05％‑60％，两亲性表面活性剂的浓度为0.05％‑25％。本发明制备的低聚集体纳米制剂眼部递送系统，具有粒径小于10nm、组织渗透性好、稳定性好、刺激性小的优势，极大提高了药物眼部给药的生物利用度。
Description
技术领域
本发明属于药物制剂技术领域，具体涉及一种用于高效递送药物的低聚集体眼用纳米制剂及其制备方法和用途，其用途主要涉及眼部疾病的治疗。
背景技术
近年来，随着生活习惯的改变、工作压力和用眼频率的增加，眼部疾病发病率逐年升高。眼表局部给药是治疗眼部疾病最常用的给药方式，具有使用简便、患者接受度高等优势。由于眼睛具有独特的生理学特点，以滴眼液形式给药的眼用制剂极易从眼部流失。眼表局部给药的生物利用度普遍低于5％，极大地阻碍了眼用制剂的治疗效果。眼前段疾病的主要屏障包括：角膜屏障、结膜屏障等，眼后段疾病的主要屏障还包括：玻璃体屏障、巩膜屏障、脉络膜屏障等。其中，角膜位于眼球前部，由上皮细胞层、前弹力层、基质层、后弹力层和内皮细胞层组成，是眼部药物递送最主要的屏障之一。角膜上皮细胞层由亲脂性的上皮细胞构成，是亲水性药物分子渗透的屏障，基质层由水、胶原、蛋白聚糖和角膜基质细胞组成，占角膜厚度的90％，是亲脂性药物渗透的屏障。因此，滴眼剂对角膜的穿透力是十分有限的，角膜的渗透性从药物治疗的角度具有及其重要的意义。
随着纳米制剂技术的发展，以纳米乳、脂质体、胶束等为代表的新型眼局部给药系统为提高药物的眼部递送效率提供了技术手段。纳米乳剂和脂质体有助于提高药物在角膜的渗透性及眼部药物的生物利用度，例如，Allergan公司研制的O/W型环孢素A纳米乳剂
尽管纳米乳和脂质体提高了药物眼局部眼给药的生物利用度，但仍然面临一些难以解决的技术问题，比如：纳米乳剂和脂质体颗粒尺寸通常介于100-200nm左右，其在眼部组织中的渗透性有待进一步提升。与脂质体和脂肪乳相比，胶束的粒径更小，一般介于20-50nm，在眼部组织中的渗透性更好。例如，Sun Pharma公司研制的一款环孢素A纳米胶束
是FDA批准上市的首个眼用胶束制剂。然而，普通的胶束粒子要维持稳定性，载体分子和药物分子的聚集数目较高，形成的胶束粒径普遍大于20nm，其在眼部组织的渗透性仍然需要提高。
从眼部组织的生理特点考虑，给药后的纳米粒主要通过扩散的方式在眼部组织中渗透，其扩散行为与纳米粒的粒径显著相关，纳米粒的粒径越小越有利于其扩散，在眼部组织的渗透性越好。纳米粒的分子聚集数可以显著影响其粒径，分子聚集数越小，粒径越小，越有利于其在眼部组织的扩散、渗透和药物分子的释放。对于药物递送技术领域，制备粒径小于10nm的纳米粒存在巨大的技术挑战，这是由于10nm仅约相当于30个水分子聚集的大小。通常对于分子量介于300-1000Da的有机分子来讲，其单个分子的尺寸约为1-1.5nm，10nm以下的纳米粒子意味着相当低的分子聚集数，如果能设计粒径小于10nm的纳米粒将具有接近药物分子的扩散能力，可以显著提高眼部给药的渗透性和生物利用度。
然而，目前尚没有粒径小于10nm的低聚集体眼用纳米制剂的报道。
发明内容
为了克服现有技术中存在的缺陷，本发明人意外发现，磷脂及其衍生物在某些两亲性表面活性剂分子的诱导下，可以改变其分子的自组装行为，形成粒径小于10nm的低聚集体纳米粒。
在此基础上，本发明的目的在于提供一种低聚集体眼用纳米制剂及其制备方法和用途。本发明的所述低聚集体眼用纳米制剂由药物分子、磷脂或其衍生物以及两亲性表面活性剂制成。本发明制备的低聚集体纳米制剂眼部递送系统，具有粒径小于10nm、组织渗透性好、稳定性好、刺激性小的优势，极大提高了药物眼部给药的生物利用度。
为了实现上述目的，本发明采用以下技术方案：
在第一个方面中，本发明提供了一种用于药物眼部高效递送的低聚集体眼用纳米制剂，所述眼用纳米制剂包含药物分子、磷脂或其衍生物以及两亲性表面活性剂。
作为可选的方式，在上述眼用纳米制剂中，所述药物分子参与载体分子的自组装过程，形成稳定的载药低聚集体纳米制剂。
优选地，所述药物分子为疏水性药物分子。
更优选地，所述药物分子选自以下一种或多种：免疫抑制药物(例如，环孢素A、他克莫司等)、类固醇药物(例如，氯替泼诺、地塞米松、氟米龙、醋酸泼尼松等)、前列腺素类药物(例如，拉坦前列素、曲伏前列素、贝美前列素、他氟前列素等)、非甾体抗炎药物(例如，双氯芬酸、普拉洛芬和、溴芬酸等)、抗生素类药物(例如，左氧氟沙星、莫西沙星、加替沙星、阿奇霉素等)、抗病毒药物(例如，阿昔洛韦、更昔洛韦、利巴韦林等)、抗真菌类药物(例如，那他霉素、两性霉素B等)、抗组胺类药物(例如，奥洛他定、氮卓斯汀、左卡巴斯汀等)，或者阿托品或瑞巴派特。
作为可选的方式，在上述眼用纳米制剂中，所述磷脂或其药学可接受的衍生物包括一类生物体内广泛存在的磷脂类分子或其衍生物，是具有两亲性化学结构的分子。
进一步的，磷脂或其药学可接受的衍生物选自天然磷脂、半合成磷脂、合成磷脂中的一种或几种。所述天然磷脂选自天然甘油磷脂或天然鞘磷脂，天然甘油磷脂包括大豆卵磷脂、蛋黄卵磷脂、心磷脂、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰肌醇中的一种或几种。所述半合成磷脂选自氢化大豆卵磷脂、氢化蛋黄卵磷脂、氢化向日葵磷脂中的一种或几种。所述合成磷脂选自合成甘油磷脂、合成鞘磷脂、聚乙二醇磷脂衍生物的一种或几种，合成甘油磷脂选自极性基团为胆碱、乙醇胺、丝氨酸、甘油、肌醇的至少一种甘油磷脂，其中sn-1和sn-2位酯化的脂肪酸为直链或支链、饱和或不饱和C4-C24脂肪酸。胆碱为极性基团的甘油磷脂可选自二硬脂酰磷脂酰胆碱，二棕榈酰磷脂酰胆碱、二油酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二辛酰磷脂酰胆碱；甘油为极性基团的甘油磷脂可选自二硬脂酰磷脂酰甘油，二棕榈酰磷脂酰甘油，二肉豆蔻酰磷脂酰甘油，二月桂酰磷脂酰甘油、二辛酰磷脂酰甘油及其上述磷脂的盐；乙醇胺为极性基团的甘油磷脂可选自二硬脂酰磷脂酰乙醇胺，二棕榈酰磷脂酰乙醇胺、二油酰磷脂酰乙醇胺，二肉豆蔻酰磷脂酰乙醇胺、二月桂酰磷脂酰乙醇胺；肌醇为极性基团的甘油磷脂可选自二硬脂酰磷脂酰肌醇、二棕榈酰磷脂酰肌醇、二油酰磷脂酰肌醇、二肉豆蔻酰磷脂酰肌醇、二月桂酰磷脂酰肌醇中的一种或几种。聚乙二醇磷脂衍生物可选自二肉豆蔻酰甘油聚乙二醇、二硬脂酰酰甘油聚乙二醇、二硬脂酰磷脂酰乙醇胺聚乙二醇、二肉豆蔻酰磷脂酰乙醇胺聚乙二醇、二棕榈酰磷脂酰乙醇胺聚乙二醇、磷脂酰乙醇胺聚乙二醇。
优选地，所述磷脂或其药学可接受的衍生物选自大豆卵磷脂、蛋黄卵磷脂、氢化大豆卵磷脂、氢化蛋黄卵磷脂、sn-1和sn-2位硬脂酰化、榈酰化、油酰化胆碱、sn-1和sn-2位硬脂酰化、榈酰化、油酰化甘油、sn-1和sn-2位硬脂酰化、榈酰化、油酰化乙醇胺、sn-1和sn-2位硬脂酰化、榈酰化、油酰化肌醇、二肉豆蔻酰甘油聚乙二醇、二硬脂酰酰甘油聚乙二醇、二棕榈酰磷脂酰乙酰胺聚乙二醇、二硬脂酰磷脂酰乙酰胺聚乙二醇、磷脂酰乙醇胺聚乙二醇的一种或几种。
磷脂是构成生物膜的主要成分之一，具有两亲性。众所周知，磷脂及其衍生物分子在水性介质中可优先形成脂质体。本发明中意外发现，某些两亲性表面活性剂可以诱导磷脂分子的自组装行为，形成非脂质体结构的低聚集体纳米粒，其最显著的理化特征是粒径小于10nm。此外，表面活性剂分子还可与生物膜产生相互作用或亦可减少P-糖蛋白引起的药物分子外排，有效促进药物分子在眼部组织中的渗透，增加药物的生物利用度。
作为可选的方式，在上述眼用纳米制剂中，本发明中两亲性表面活性剂聚氧乙烯类表面活性剂、甾族类表面活性剂的一种或几种。聚氧乙烯类表面活性剂优选为聚氧乙烯蓖麻油类表面活性剂、聚氧乙烯15羟基硬脂酸酯(
HS 15)更优选为聚氧乙烯15羟基硬脂酸酯(
HS 15)。甾族类表面活性剂优选为自胆甾酸及其盐、胆甾酸-氨基酸缀合物及其盐，更优选为去氧胆酸、鹅去氧胆酸盐、胆甾酸-甘氨酸缀合物及其盐、胆甾酸-牛磺酸缀合物及其盐。另外更优选为甘氨胆酸及其盐、去氧胆酸及其盐、甘氨去氧胆酸及其盐、牛磺胆酸及其盐、牛磺去氧胆酸及其盐。
作为可选的方式，在上述眼用纳米制剂中，还包含眼用制剂的其他常用辅料。
所述眼用制剂的其他常用辅料，例如但不限于缓冲剂、润滑剂、渗透压调节剂、抗菌剂、抗氧化剂、生物黏附剂、增稠剂、润湿剂、防腐剂。
所述眼用纳米制剂优选在pH 4-8的条件下配制，可以通过加入缓冲盐调节制剂的pH。所述缓冲剂包括但不限于磷酸盐、硼酸盐、醋酸盐、柠檬酸盐、碳酸盐及其上述混合物。
所述渗透压调节剂包括但不限于甘露醇、葡萄糖、氯化钠、甘油、丙二醇、木糖醇及其混合物。这些渗透压调节剂可以用于调节本发明眼用纳米制剂的摩尔渗透压。
所述防腐剂包括但不限于苯甲醇、苯扎溴铵、苯扎氯胺、氯己定、尼泊金类如尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、苯甲酸及其上述混合物。需要说明的是，防腐剂不是一定需要加入的，如果本发明眼用纳米制剂采用单剂量的包装形式，制剂中可不含有防腐剂。
所述的用于药物眼部高效递送的低聚集体眼用纳米制剂，还包含一种或多种药学上可接受的生物黏附剂，用于提高制剂的黏度，进一步增加本发明制剂在眼部的滞留时间。本发明的生物黏附剂包括羧基聚合物如卡波姆、聚卡波非等；纤维素衍生物包括烷基和羟烷基纤维素如甲基纤维素、羟丙基纤维素、羟丙甲基纤维素、羧甲基纤维素等；树胶如黄原胶、卡拉胶等；以及其他药学上可接受的聚合物，包括但不限于聚乙烯醇、聚乙烯吡咯烷酮、泊洛沙姆及其衍生物、透明质酸及其盐、海藻酸及其盐等。这类聚合物可以单独或者联合使用。
作为可选的方式，在上述眼用纳米制剂中，所述眼用纳米制剂的粒径尺寸范围为小于10nm。优选地，所述眼用纳米制剂的粒径尺寸范围为1nm-10nm。所述眼用纳米制剂的包封率大于90％。
作为可选的方式，在上述眼用纳米制剂中，按照重量百分比计，磷脂或其衍生物的浓度为0.05％-60％，优选为1％-50％，更优选为2％-40％；两亲性表面活性剂的浓度为0.05％-25％，优选为0.1％-20％，更优选为0.5％-15％。
在第二个方面中，本发明提供了上述第一个方面所述的眼用纳米制剂的制备方法，包括以下步骤：将所述的药物成分与两亲性载体溶解或分散于适量的有机溶剂或有机溶剂的混合溶液中，减压蒸发除去溶剂后，与含有水溶性辅料成分的溶液混合均匀，溶液经微孔滤膜过滤，灭菌，即得含药眼用纳米制剂溶液。将制备好的含药眼用纳米制剂溶液经无菌分装，灌装至多剂量或单剂量包装容器中。
优选地，有机溶剂可以选自以下一种或多种：甲醇、乙醇、异丙醇、二氯甲烷或三氯甲烷。
此外，本领域技术人员知晓，还可以采用药物制剂领域公知的其他方法制备上述第一个方面所述的眼用纳米制剂。
在第三个方面中，本发明提供了上述第一个方面所述的眼用纳米制剂在制备眼用药物中的用途。
作为可选的方式，在上述用途中，所述眼用药物用于眼部疾病预防、治疗或辅助治疗。
优选地，所述眼用药物具有更高的药物渗透性和生物利用度。
本发明相对于现有技术，具有以下有益效果：
本发明的用于药物眼部高效递送的低聚集体眼用纳米制剂，其作用原理是：药物成分、磷脂及其衍生物及两亲性表面活性剂自组装形成低聚集体纳米粒子，用于活性药物分子的递送。令人吃惊发现的是，药物活性成分与磷脂及其衍生物和两亲性表面活性剂可形成粒径为1nm-10nm的粒子，粒径远远小于普通的两亲性聚合物胶束和市售的
产品。本发明的用于药物眼部高效递送的低聚集体眼用纳米制剂的最显著优势是眼部组织的渗透性好，由于低聚集体纳米粒子尺寸已经接近普通药物分子的大小，磷脂及其衍生物与细胞膜的组成成分具有良好的细胞亲和性，并且两亲性表面活性剂可以促进药物成分在眼部组织中的渗透行为，其在眼部组织的渗透性远强于其他普通纳米给药系统。
附图说明
图1为本发明所述实施例1样品3的代表性粒径测定结果。
图2为本发明所述实施例3低聚集体纳米粒的体外释放曲线。
图3为本发明所述实施例4的角膜荧光素钠染色结果。
图4为本发明所述实施例4的泪膜破裂时间。
图5为本发明所述实施例4的炎症因子浓度变化水平。
图6为本发明所述实施例5的眼部组织和血浆中分布曲线。
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。
实施例1：载药低聚集体纳米粒的制备与制剂学性质测定
按表1的比例称取所需的磷脂或其衍生物，两亲性表面活性剂、活性药物，加入约10mL乙醇溶液或其他有机溶液，搅拌直至获得澄清溶液，在真空条件下加热蒸发溶剂，加入水或缓冲盐溶液，混合，搅拌均匀，即得载药低聚集体纳米粒溶液。
表1包载活性药物的低聚集体纳米粒处方组成
对比例1制备方法同实施例1。
表2对比例1的纳米粒处方组成
表3样品1-9的主要制剂学性质
图1为实施例1样品3的代表性粒径测定结果。表3中的结果表明，本品发明制备的低聚集体纳米粒的平均光强度粒径均小于10nm，远远小于市售
产品(20.32nm)。
实施例2：含有水溶性辅料的低聚集体纳米粒制剂
按表4的比例称取所需的磷脂或其衍生物，两亲性表面活性剂、活性药物，加入约10mL乙醇溶液或其他有机溶液，搅拌直至获得澄清溶液，在真空条件下加热蒸发溶剂，加入水溶性辅料的溶液，混合，搅拌均匀。用NaOH或HCl调节pH约6.8，加入NaCl调节渗透压至280-300mOSmol/kg的范围内，加去离子水定容至100mL，过滤除菌或热压灭菌后，灌装，即得。
表4低聚集体纳米粒制剂组成
| 成分 | 1 | 2 | 3 |
| 环孢素A | 0.09g | ||
| 甘氨胆甾酸钠 | 5g | ||
| 豆磷脂 | 15g | ||
| 他氟前列素 | 0.0015g | ||
| 豆磷脂 | 5g | ||
| 聚氧乙烯40氢化蓖麻油 | 2g | ||
| 氯替泼诺 | 0.5g | ||
| 磷脂酰甘油 | 35g | ||
| 牛磺去氧胆甾酸钠 | 15g |
表5水溶性辅料溶液组成
实施例3：环孢素A低聚集体纳米粒的体外释放
取2mL实施例1中样品3溶液，置于透析袋(MW＝3500)内，两端扎紧后置于10mL含1％SDS(w/w)的PBS缓冲液(pH＝7.4)中，置于恒温震荡器中，37度恒温震荡，转速为100rpm，分别于1、2、4、6、8、10、24、48h后取出1mL释放介质，并补充1mL释放介质，样品过0.22微米滤膜后，用甲醇适当稀释，用HPLC测定介质中药物含量并计算其累计释放率。
图2中的结果表明，低聚集体纳米粒的体外释放速率略低于药物溶液，呈现一定的缓释特征。
实施例4：环孢素A低聚集体纳米粒的药效学研究
取健康日本大耳白兔，每日向双眼滴加0.2％苯扎氯铵溶液，早、中、晚各1次，连续给药7天。使用泪膜破裂时间(TBUT)和泪液分泌量监测整个造模和治疗过程，TBUT小于10s，泪液分泌量小于5mm，证明干眼症造模成功。对各组干眼症模型兔分用生理盐水、对比例1溶液(Cequa)和实施例1样品3溶液进行治疗，治疗周期为2周。
(1)角膜荧光素钠染色
如图3所示，角膜荧光素钠染色结果显示，在经历14天的治疗后，生理盐水组荧光染色情况并没有得到改善，染色情况更加严重。与生理盐水组相比，制剂组的荧光素钠染色都有明显的改善。样品3制剂治疗组的染色改善程度明显好于对比例1制剂治疗组。
(2)泪膜破裂时间
如图4所示，生理盐水组的TBUT基本没有变化，制剂组均有明显改善。样品3和的泪膜破裂时间与对比例1溶液的TBUT值均大于10s。样品3制剂治疗组的泪膜破裂时间明显大于对比例1制剂治疗组。
(3)泪液炎症因子
应用不同滴眼剂治疗后，测定泪液中炎症因子浓度的变化趋势。在指定的时间点，使用毛细管收集泪液，测量泪液中IL-1，IL-2，IL-6和TNF-α的浓度。
如图5所示，治疗前各炎症因子的浓度均上升到一个很高的水平，经过14天的治疗，各炎症因子均有比较明显的下降趋势。采用独立样本T检验分别对样品3制剂组与对比例1组、样品3制剂组与空白对照组的炎性因子水平进行统计分析，结果表明，样品3制剂组治疗组的炎性因子水平显著低于对比例1制剂(Cequa)组(p<0.05)和空白对照组(p<0.001)。
实施例5：环孢素A低聚集体纳米粒的眼组织分布与动力学研究
将日本大耳白兔随机分为2组，分别给予实施例1样品3溶液(0.09％)和对比例1(Cequa)溶液(0.09％)，给药剂量为50μL/眼，单侧、单剂量给药。给药后分别于0.25h，1h和6h取血，并将动物麻醉处死，解剖收集球结膜、睑结膜、角膜、巩膜、虹膜组织。取组织样品约0.1g，精密称重，加50％甲醇适量，用组织匀浆机匀浆(8000rpm/次，3次)，制成5％的组织匀浆液，取匀浆液置于2mL塑料聚丙烯管中，-60℃--90℃保存。将上述处理后的样品用LC/MS/MS测定药物的浓度。自制制剂(实施例1样品3)和对照制剂(对比例1)的眼组织分布和药动学曲线如图5所示。由结果可知，本发明的环孢素A低聚集体纳米粒在眼部各主要组织中的分布浓度和血浆中的浓度均显著高于市售对照制剂。上述结果证明，与市售对比例1制剂相比，本发明的低聚集体纳米粒制剂具有更好的眼部组织渗透性和吸收行为，眼部给药的生物利用度更高。
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)
1.一种低聚集体眼用纳米制剂，其特征在于：所述眼用纳米制剂包含药物分子、磷脂或其衍生物以及两亲性表面活性剂，所述眼用纳米制剂的粒径尺寸范围小于10nm，所述眼用纳米制剂的包封率大于90％。
2.根据权利要求1所述的眼用纳米制剂，其特征在于：所述药物分子为疏水性药物分子，所述药物分子选自以下一种或多种：免疫抑制药物、类固醇药物、前列腺素类药物、非甾体抗炎药物、抗生素类药物、抗病毒药物、抗真菌类药物、抗组胺类药物，或者阿托品或瑞巴派特，所述眼用纳米制剂的粒径尺寸范围为1nm-10nm。
3.根据权利要求1或权利要求2所述的眼用纳米制剂，其特征在于：所述磷脂或其衍生物选自以下一种或多种：天然磷脂、半合成磷脂或合成磷脂；所述两亲性表面活性剂选自以下一种或多种：甾族类表面活性剂或聚氧乙烯类表面活性剂。
4.根据权利要求3所述的眼用纳米制剂，其特征在于：所述天然磷脂选自以下一种或多种：大豆卵磷脂、蛋黄卵磷脂、心磷脂、磷脂酰乙醇胺、磷脂酰甘油、鞘磷脂、磷脂酰肌醇；所述半合成磷脂选自以下一种或多种：氢化大豆卵磷脂、氢化蛋黄卵磷脂；所述合成磷脂选自以下一种或多种：极性基团为胆碱、乙醇胺、丝氨酸、甘油、肌醇且sn-1和sn-2位为直链或支链、饱和或不饱和C4-C24脂肪酸的甘油磷脂、合成鞘磷脂、聚乙二醇磷脂衍生物；所述甾族类表面活性剂选自以下一种或多种：胆甾酸及其盐、胆甾酸-氨基酸缀合物及其盐；所述聚氧乙烯类表面活性剂选自以下一种或多种：聚氧乙烯蓖麻油类表面活性剂、聚氧乙烯15羟基硬脂酸酯(
HS 15)。
5.根据权利要求1至4中任一项所述的眼用纳米制剂，其特征在于：按照重量百分比计，磷脂或其衍生物的浓度为0.05％-60％，优选为1％-50％；两亲性表面活性剂的浓度为0.05％-25％，优选为0.1％-20％。
6.根据权利要求1至5中任一项所述的眼用纳米制剂，其特征在于：所述眼用纳米制剂中还包含眼用制剂的其他常用辅料，所述眼用制剂的其他常用辅料选自以下一种或多种：缓冲剂、润滑剂、渗透压调节剂、抗菌剂、抗氧化剂、生物黏附剂、增稠剂、润湿剂或防腐剂，所述眼用纳米制剂的pH为4-8，优选地，所述眼用纳米制剂的pH为6-7.5。
7.根据权利要求6所述的眼用纳米制剂，其特征在于：所述缓冲剂选自以下一种或多种：磷酸盐、硼酸盐、醋酸盐、柠檬酸盐或碳酸盐；所述渗透压调节剂选自以下一种或多种：甘露醇、葡萄糖、氯化钠、甘油、丙二醇或木糖醇；所述防腐剂选自以下一种或多种：苯甲醇、苯扎溴铵、苯扎氯胺、氯己定、尼泊金类如尼泊金甲酯、尼泊金乙酯、尼泊金丙酯或苯甲酸；所述生物黏附剂选自以下一种或多种：羧基聚合物、纤维素衍生物、树胶、聚乙烯醇、聚乙烯吡咯烷酮、泊洛沙姆或其衍生物、透明质酸或其盐或者海藻酸或其盐。
8.权利要求1至7中任一项所述的眼用纳米制剂的制备方法，其特征在于：所述制备方法包括以下步骤：
S1：将所述药物分子与两亲性载体溶解或分散于适量的有机溶剂或有机溶剂的混合溶液中，减压蒸发除去溶剂后，与含有水溶性辅料成分的溶液混合均匀，溶液经微孔滤膜过滤，灭菌，即得含药眼用纳米制剂溶液；
S2：将制备好的含药眼用纳米制剂溶液经无菌分装，灌装至多剂量或单剂量包装容器中。
9.权利要求1至7中任一项所述的眼用纳米制剂或者采用权利要求8所述的制备方法制备得到的眼用纳米制剂在制备眼用药物中的用途。
10.根据权利要求9所述的用途，其特征在于：所述眼用药物用于眼部疾病预防、治疗或辅助治疗，所述眼用药物具有更高的药物渗透性和生物利用度。
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| US20120064123A1 (en) * | 2010-09-09 | 2012-03-15 | Sawaya Assad S | Composition for a topical ophthalmic clear colloidal liquid which undergoes a liquid-gel phase transition in the eye |
| CN103860467A (zh) * | 2012-11-22 | 2014-06-18 | 苏州太湖美药业有限公司 | 溴芬酸钠脂质体滴眼液 |
| CN109820825A (zh) * | 2017-11-23 | 2019-05-31 | 河北嘉硕生物科技有限公司 | 一种用于治疗眼部疾病的药物组合物 |
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| US20120064123A1 (en) * | 2010-09-09 | 2012-03-15 | Sawaya Assad S | Composition for a topical ophthalmic clear colloidal liquid which undergoes a liquid-gel phase transition in the eye |
| CN103860467A (zh) * | 2012-11-22 | 2014-06-18 | 苏州太湖美药业有限公司 | 溴芬酸钠脂质体滴眼液 |
| CN109820825A (zh) * | 2017-11-23 | 2019-05-31 | 河北嘉硕生物科技有限公司 | 一种用于治疗眼部疾病的药物组合物 |
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