Purpose: Zolmitriptan (ZT) is a selective serotonin agonist that is used for the treatment of migraine. It belongs to BCS class III with high solubility and low permeability. Besides, the drug is subjected to pre-systemic metabolism. Accordingly, new Zolmitriptan/chitosan nanostructured lipid carriers (ZT/CT NLCs) coated with Tween 80 (stealthy layer) have been developed to overcome such demerits.
Methods: The NLCs were developed by combining ultrasonication and double emulsion (w/o/w) techniques. The lipids were Gelucire and Labrasol. Herein, the quality by design (2³ full factorial design) was scrupulously followed, where critical process parameters and critical quality attributes were predefined. The optimized formulation (F8) was fully characterized with respect to entrapment efficiency (%EE), percentage yield (% yield), particle size, size distribution (PDI), zeta potential (ZP), morphological appearance (TEM). In vitro release, stability study and pharmacodynamic evaluations were also assessed. The optimized freeze dried formula was dispensed in in situ gelling hard gelatin capsule encompassing pectin and guar gum for further in vitro and pharmacodynamic evaluations.
Results: The optimized spherical nanoparticles experienced high percentage EE and yield (78.14% and 60.19%, respectively), low particle size and PDI (343.87 nm and 0.209, respectively), as well as high negative ZP (− 25.5 mV). It showed good physical stability at refrigerated conditions. The NLCs dispensed in in situ gelling hard gelatin capsule comprising pectin and guar gum experienced sustained release for 30 h and significantly maintained the pharmacological effect in mice up to 8 h (p < 0.001).
Conclusion: ZT, a BCS class III drug that suffers from poor permeability and pre-systemic metabolism, was successfully maneuvered as nanostructured lipid carrier particles (NLCs). The incorporation of the NLCs in in situ gelling hard gelatin capsules fulfilled a dual function in increasing permeability, as well as sustaining the pharmacodynamic effect. This result would open new vistas in improving the efficacy of other class III drugs.

Keywords: zolmitriptan, factorial design, nanostructured lipid carrier, in situ gelling, pharmacodynamics


中文翻译：

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佐米曲坦/壳聚糖纳米结构脂质载体颗粒制备的质量设计方法——制剂和药效学评估

目的：佐米曲坦（ZT）是一种选择性5-羟色胺激动剂，用于治疗偏头痛。属于BCS III类，溶解度高，渗透性低。此外，该药物经受系统前代谢。因此，已开发出涂有 Tween 80（隐蔽层）的新型佐米曲坦/壳聚糖纳米结构脂质载体 (ZT/CT NLC) 以克服这些缺点。
方法：通过结合超声处理和双乳液（w/o/w）技术开发 NLC。脂质是Gelucire和Labrasol。在此，质量源于设计（2 ³严格遵循全因子设计），其中预先定义了关键工艺参数和关键质量属性。优化的配方 (F8) 在包封率 (%EE)、产率百分比 (%产率)、粒径、粒径分布 (PDI)、zeta 电位 (ZP)、形态外观 (TEM) 方面进行了充分表征。还评估了体外释放、稳定性研究和药效学评价。将优化的冻干配方分配在包含果胶和瓜尔胶的原位凝胶硬明胶胶囊中，用于进一步的体外和药效学评估。
结果：优化后的球形纳米粒子具有高百分比 EE 和产率（分别为 78.14% 和 60.19%）、低粒径和 PDI（分别为 343.87 nm 和 0.209）以及高负 ZP（- 25.5 mV）。它在冷藏条件下表现出良好的物理稳定性。含有果胶和瓜尔胶的原位凝胶硬明胶胶囊中分配的 NLC 经历了 30 小时的持续释放，并在小鼠中显着维持了长达 8 小时的药理作用（p < 0.001）。
结论：ZT 是一种 BCS III 类药物，具有较差的渗透性和系统前代谢，已成功用作纳米结构脂质载体颗粒 (NLC)。将 NLC 掺入原位凝胶硬明胶胶囊中实现了增加渗透性和维持药效学作用的双重功能。这一结果将为提高其他 III 类药物的疗效开辟新的前景。

关键词：佐米曲坦，析因设计，纳米脂质载体，原位胶凝，药效学