Development and in-vitro evaluation of controlled release drug-loaded polymeric nanoparticles from dry powder inhaler formulation

We investigated the development of ciprofloxacin (CIP) loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) for potential pulmonary delivery from dry powder inhaler (DPI) formulations against LRTIs. NPs were prepared using a straightforward co-assembly reaction carried out by the intermolecular hydrogen bonding among PEtOx, tannic acid (TA), and CIP. The prepared NPs were characterised by scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction analysis (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The CIP was determined by validated HPLC and UV spectrophotometry methods.

The CIP loading into the PEtOx was between 21–67% and increased loading was observed with the increasing concentration of CIP. The NP sizes of PEtOx with or without drug loading were between 196–350 nm and increased with increasing drug loading. The in vitro CIP release showed the maximum cumulative release of about 78% in 168 h with a burst release of 50% in the first 12 h. The kinetics of CIP release from NPs followed non-Fickian or anomalous transport thus suggesting the drug release was regulated by both diffusion and polymer degradation. The in vitro aerosolisation study carried out using a Twin Stage Impinger (TSI) at 60 L/min air flow showed the fine particle fraction (FPF) between 34.4% and 40.8%. The FPF was increased with increased drug loading. The outcome of this study revealed the potential of the polymer PEtOx as a carrier for developing CIP-loaded PEtOx NPs as DPI formulation for pulmonary delivery against LRTIs.

本研究探究了负载环丙沙星（ciprofloxacin, CIP）的聚(2-乙基-2-恶唑啉)（poly(2-ethyl-2-oxazoline), PEtOx）纳米颗粒（nanoparticles, NPs）的开发，该制剂可用于干粉吸入器（dry powder inhaler, DPI）的肺部递送，以对抗下呼吸道感染（lower respiratory tract infections, LRTIs）。纳米颗粒通过简便的共组装反应制备，该反应依托PEtOx、单宁酸（tannic acid, TA）与CIP之间的分子间氢键作用完成。所制备的纳米颗粒采用扫描电子显微镜（scanning electron microscopy, SEM）、动态光散射（dynamic light scattering, DLS）、傅里叶变换红外光谱（Fourier transform infrared spectroscopy, FTIR）、粉末X射线衍射分析（powder X-ray diffraction analysis, PXRD）、差示扫描量热法（differential scanning calorimetry, DSC）以及热重分析（thermogravimetric analysis, TGA）进行表征。环丙沙星的含量通过经过验证的高效液相色谱（high performance liquid chromatography, HPLC）与紫外分光光度法进行测定。

PEtOx纳米颗粒的CIP载药量介于21%~67%之间，且载药量随CIP浓度升高而提升。载药与未载药的PEtOx纳米颗粒粒径介于196~350 nm之间，且粒径随药物载药量增加而增大。体外CIP释放实验结果显示，168 h内的最大累积释放量约为78%，且前12 h存在突释效应，释放量达50%。纳米颗粒的CIP释放动力学符合非菲克（non-Fickian）或异常转运模型，表明药物释放同时受扩散作用与聚合物降解调控。采用双级撞击器（Twin Stage Impinger, TSI）在60 L/min气流下开展的体外气溶胶化研究显示，细粒子分数（fine particle fraction, FPF）介于34.4%~40.8%之间，且FPF随药物载药量升高而提升。本研究结果表明，聚合物PEtOx可作为载体，用于开发负载CIP的PEtOx纳米颗粒干粉吸入剂，以实现肺部递送对抗下呼吸道感染。