Natamycin solid lipid nanoparticles - sustained ocular delivery system of higher corneal penetration against deep fungal keratitis: preparation and optimization
Natamycin solid lipid nanoparticles - sustained ocular delivery system of higher corneal penetration against deep fungal keratitis: preparation and optimization
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DOI：
10.2147/ijn.s190502
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发表时间：
2019-01-01
影响因子：
8
通讯作者：
El-Nezhawy, Ahmed Oh
中科院分区：
文献类型：
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作者：
Khames, Ahmed;Khaleel, Mohammad A.;El-Nezhawy, Ahmed Oh
背景：真菌性角膜炎(FK)是一种严重的病原性疾病，常伴有严重的眼部并发症。那他霉素(NAT)是美国食品和药物管理局批准的治疗FK的一线药物，也是唯一的药物。目的：制备NAT固体脂质纳米粒(NAT-SLNS)，以实现药物的缓释，增加角膜穿透性。采用Box-Behnken实验设计，优化独立工艺变量(脂类浓度[X-1]、表面活性剂浓度[X-2]和超声频率[X-3])对微球粒径(R-1)、Zeta电位(ZP；R-2)和药物包封率(EE%)(R-3)的影响。结果：优化处方的平均粒径为42 r.nm(半径为纳米)，ZP为26 mV，EE%接近85%。NAT-SLNS的药物释放曲线延长了10小时，角膜渗透增强，表观渗透系数(P-APP)和稳态通量(J(Ss))分别达到11.59×10(-2)cm h(-1)和3.94molh(-1)，而未处方药物分别为7.28×10(-2)cm h(-1)和2.48molh(-1)。对烟曲霉ATCC 1022和白色念珠菌临床分离株的抑菌圈分别为8 mm和6 mm，对这两种致病菌的最低抑菌浓度均降低了2.5倍。NAT-SLN对角膜组织无刺激性。结论：NAT-SLNS具有较长的药物释放速率，提高了角膜穿透性，增强了抗真菌活性，且对角膜组织无细胞毒性作用。结论：NAT-SLNS是一种具有良好应用前景的角膜深部角膜炎的眼部给药系统。
Background: Fungal keratitis (FK) is a serious pathogenic condition usually associated with significant ocular morbidity. Natamycin (NAT) is the first-line and only medication approved by the Food and Drug Administration for the treatment of FK. However, NAT suffers from poor corneal penetration, which limits its efficacy for treating deep keratitis.Purpose: The objective of this work was to prepare NAT solid lipid nanoparticles (NAT-SLNs) to achieve sustained drug release and increased corneal penetration.Methods: NAT-SLNs were prepared using the emulsification-ultrasonication technique. Box-Behnken experimental design was applied to optimize the effects of independent processing variables (lipid concentration [X-1], surfactant concentration [X-2], and sonication frequency [X-3]) on particle size (R-1), zeta potential (ZP; R-2), and drug entrapment efficiency (EE%) (R-3) as responses. Drug release profile, ex vivo corneal permeation, antifungal susceptibility, and cytotoxicity of the optimized formula were evaluated.Results: The optimized formula had a mean particle size of 42 r.nm (radius in nanometers), ZP of 26 mV, and EE% reached similar to 85%. NAT-SLNs showed an extended drug release profile of 10 hours, with enhanced corneal permeation in which the apparent permeability coefficient (P-app) and steady-state flux (J(ss)) reached 11.59x10(-2) cm h(-1) and 3.94 mol h(-1), respectively, in comparison with 7.28x10(-2) cm h(-1) and 2.48 mol h(-1) for the unformulated drug, respectively. Antifungal activity was significantly improved, as indicated by increases in the inhibition zone of 8 and 6 mm against Aspergillus fumigatus ATCC 1022 and a Candida albicans clinical isolate, respectively, and minimum inhibitory concentration values that were decreased 2.5-times against both of these pathogenic strains. NAT-SLNs were found to be non-irritating to corneal tissue. NAT-SLNs had a prolonged drug release rate, that improved corneal penetration, and increased antifungal activity without cytotoxic effects on corneal tissues.Conclusion: Thus, NAT-SLNs represent a promising ocular delivery system for treatment of deep corneal keratitis.