兔眼局部应用两性霉素B缓释制剂的研究

Study on tropical amphotericin B sustained releasing agents in rabbit eyes

目的探索兔眼局部应用两性霉素B脂质体(AmBL)和两性霉素B卡波姆(AmBC)滴眼液后,房水中的药代动力学状况。方法用32只新西兰白兔,在角膜上皮完整和刮除时,分别应用0·5%AmBL或0·5%AmBC滴一眼,并用0·5%两性霉素B滴眼液(AmBS)滴对侧眼作对照,分别在用药后0·25、0·5、1、2、3、4h6个时点,抽取兔眼房水,用HPLC方法测定房水中两性霉素B的质量浓度。结果AmBL滴眼后,房水中AmB的有效抑菌浓度可维持2h,AmBC和AmBS滴眼1h后即近全部消除。角膜上皮完整时,AmBL的药效曲线下面积(AUC)和药物半衰期(T1/2)是AmBS的3·6倍和5倍;角膜上皮刮除后,AmBL的AUC和T1/2是AmBS的3·9倍和3·2倍。AmBC的AUC和T1/2与AmBS相似。结论AmBL具有较好的缓释作用和生物利用度,是较有前途的局部治疗真菌性角膜炎的新型缓释制剂。

Objective Fungal keratitis is an infectious keratopathy that seriously damages the visual functions with high prevalence in some areas of China in recent years. Drug therapy is the basic treatment of fungal keratitis and amphotericin B is one of the most potent anti-fungal agents,but it is poorly absorbed when applied tropically,with low bioavailability,strong irritation and low patient compliance. The purpose of this study was to investigate the pharmacokinetics of new sustained releasing preparations of bioadhesive amphotericin B liposome （AmBL） and amphotericin B carbomer （AmBC） in rabbit eyes to see if it could increase the local absorption and bioavailability and improve the effectiveness of fungal keratitis treatment. Methods In 32 rabbits with or without corneal epithelia,either 0. 5% AmBL or 0. 5% AmBC was applied tropically in one lateral eye of each rabbit,and 0. 5% AmBS was used at the same way in the fellow eye as control. Aqueous humor was aspirated from each eye after 0. 25,0. 5,1,2,3 and 4 hours and amphotericin B （AmB） concentration was determined by high performance liquid chromatography（HPLC）. Results After tropical administration of AmBL,aqueous AmB concentration could maintain over and near MIC for about 2 hours,while that after use of AmBC and AmBS was below the MIC at 1 hour and afterwards. The area under curve （AUC） and drug elimination half-time （T1/2 ） of AmBL were 3.6 and 5 times higher than those of AmBS respectively in the rabbits with corneal epithelium and were 3.9 and 3.2 times respectively in the rabbit without corneal epithelium. The AUC and T1/2 of AmBC were similar to those of AmBS in the rabbits with and without corneal epithelia. Conclusion AmBL is a promising sustained releasing agent with relatively stable drug concentration,high bioavailability and long effective time after tropical administration for fungal keratitis.