Rawat Pradeep Singh, Ravi Punna Rao, Khan Mohammed Shareef, Mahajan Radhika Rajiv, Szeleszczuk Łukasz
Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, Hyderabad 500078, Telangana, India.
Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-093 Warsaw, Poland.
Nanomaterials (Basel). 2024 Aug 14;14(16):1347. doi: 10.3390/nano14161347.
Nebivolol hydrochloride (NEB), a 3rd-generation beta-blocker, was recently explored in managing open-angle glaucoma due to its mechanism of action involving nitric oxide release for the vasodilation. To overcome the issue of low ocular bioavailability and the systemic side effects associated with conventional ocular formulation (aqueous suspension), we designed and optimized polycaprolactone polymeric nanoparticles (NEB-PNPs) by applying design of experiments (DoE). The particle size and drug loading of the optimized NEB-PNPs were 270.9 ± 6.3 nm and 28.8 ± 2.4%, respectively. The optimized NEB-PNPs were suspended in a dual-sensitive in situ gel prepared using a mixture of P407 + P188 (as a thermo-sensitive polymer) and κCRG (as an ion-sensitive polymer), reported previously by our group. The NEB-PNPs-loaded in situ gel (NEB-PNPs-ISG) formulation was characterized for its rheological behavior, physical and chemical stability, in vitro drug release, and in vivo efficacy. The NEB-PNPs-loaded in situ gel, in ocular pharmacokinetic studies, achieved higher aqueous humor exposure (AUC = 329.2 ng × h/mL) and for longer duration (mean residence time = 9.7 h) than compared to the aqueous suspension of plain NEB (AUC = 189 ng × h/mL and mean residence time = 6.1 h) reported from our previous work. The pharmacokinetic performance of NEB-PNPs-loaded in situ gel translated into a pharmacodynamic response with 5-fold increase in the overall percent reduction in intraocular pressure by the formulation compared to the aqueous suspension of plain NEB reported from our previous work. Further, the mean response time of NEB-PNPs-loaded in situ gel (12.4 ± 0.6 h) was three times higher than aqueous suspension of plain NEB (4.06 ± 0.3 h).
盐酸奈必洛尔（NEB）是一种第三代β受体阻滞剂，由于其作用机制涉及释放一氧化氮以实现血管舒张，最近被用于治疗开角型青光眼。为了克服传统眼用制剂（水悬浮液）眼部生物利用度低和全身副作用的问题，我们应用实验设计（DoE）设计并优化了聚己内酯聚合物纳米颗粒（NEB-PNPs）。优化后的NEB-PNPs的粒径和载药量分别为270.9±6.3nm和28.8±2.4%。优化后的NEB-PNPs悬浮于一种双敏感原位凝胶中，该凝胶由P407+P188（作为热敏聚合物）和κCRG（作为离子敏感聚合物）的混合物制备而成，这是我们小组之前报道过的。对载有NEB-PNPs的原位凝胶（NEB-PNPs-ISG）制剂的流变行为、物理和化学稳定性、体外药物释放和体内疗效进行了表征。在眼部药代动力学研究中，与我们之前工作报道的普通NEB水悬浮液（AUC = 189 ng×h/mL，平均驻留时间 = 6.1 h）相比，载有NEB-PNPs的原位凝胶实现了更高的房水暴露量（AUC = 329.2 ng×h/mL）和更长的持续时间（平均驻留时间 = 9.7 h）。载有NEB-PNPs的原位凝胶的药代动力学性能转化为药效学反应，与我们之前工作报道的普通NEB水悬浮液相比，该制剂使眼压总体降低百分比提高了5倍。此外，载有NEB-PNPs的原位凝胶的平均反应时间（12.4±0.6 h）是普通NEB水悬浮液（4.06±0.3 h）的三倍。
