Purpose: Development of new strategies for oral delivery of existing antibiotics administered exclusively through intravenous route is one of the global priorities of pharmaceutical research. The encapsulation of these active pharmaceutical agents within nanosized natural products offers several traits due to their tunable surface properties. Ceftriaxone (CTX) is an injectable, third-generation cephalosporin that suffers poor oral bioavailability.
Methods: In the present study, ionic gelation of two biopolymers, namely chitosan (CH) and shellac (SH), was implemented to consolidate CTX, within elegant nanoparticles (NPs) for oral administration that would increase its bioavailability and sustainability. Quality by design approach (2³ full factorial design) was adopted to optimize CTX-loaded nanoparticles. The optimized formula (F2) was characterized through transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC). In vitro release behavior and stability study were also evaluated. Pharmacokinetic studies of enteric-coated hard gelatin capsules (HGCs) loaded with F2-NPs were finally assessed.
Results: The optimized spherical F2-NPs had a mean particle size of 258 nm, zeta potential of about +30.1 and appreciable drug entrapment efficiency of 83%. The in vitro drug release profile of F2-NPs in pH 7.4 experienced biphasic configuration with an initial burst release for an hour, followed by a sustained release over 15 h with Higuchi model and non-Fickian diffusion mechanism (R²=0.9852). High stability upon storage at refrigerated and room temperature for 3 months and good flow properties (θ= 32.2 and HR= 1.13) of the optimized formula were also conferred. In vivo pharmacokinetic assessment in rabbits fruitfully displayed 92% absolute bioavailability of CTX.
Conclusion: The obtained results provide evidence for the potential combination of CH and SH in NPs preparation to enhance the oral bioavailability of CTX.

Keywords: ceftriaxone, chitosan, shellac, nanoparticles, oral, factorial design


中文翻译：

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用于口服给药的新型头孢曲松肠溶纳米颗粒的设计和优化：体外和体内评估


目的：开发仅通过静脉途径口服现有抗生素的新策略是全球药物研究的优先事项之一。将这些活性药剂封装在纳米级天然产物中，由于其可调节的表面特性而具有多种特性。头孢曲松 (CTX) 是一种可注射的第三代头孢菌素，口服生物利用度较差。

方法：在本研究中，对两种生物聚合物（即壳聚糖（CH）和虫胶（SH））进行离子凝胶化，以将 CTX 固结在口服给药的精美纳米颗粒（NP）中，从而提高其生物利用度和可持续性。采用质量源于设计方法（2 ³全因子设计）来优化 CTX 负载的纳米颗粒。通过透射电子显微镜（TEM）、傅里叶变换红外（FT-IR）光谱和差示扫描量热法（DSC）对优化后的配方（F2）进行了表征。还评估了体外释放行为和稳定性研究。最后评估了装载 F2-NP 的肠溶硬明胶胶囊 (HGC) 的药代动力学研究。

结果：优化后的球形F2-NPs平均粒径为258 nm，zeta电位约为+30.1，药物包封率为83%。 F2-NPs 在 pH 7.4 下的体外药物释放曲线经历了双相构型，初始突发释放 1 小时，随后采用 Higuchi 模型和非 Fickian 扩散机制持续释放 15 小时以上（R ² =0.9852）。优化配方在冷藏和室温下储存3个月后也具有高稳定性和良好的流动性能（θ= 32.2和HR= 1.13）。兔子体内药代动力学评估结果显示，CTX 的绝对生物利用度为 92%。

结论：所获得的结果为纳米颗粒制剂中 CH 和 SH 的潜在组合提供了证据，以提高 CTX 的口服生物利用度。


关键词：头孢曲松、壳聚糖、虫胶、纳米颗粒、口服、因子设计