UCIBIO, MEDTECH, Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; Associate Laboratory i4HB Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal.
Associate Laboratory i4HB Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal; UCIBIO, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, Porto University, Porto, Portugal.
Int J Pharm. 2024 Oct 25;664:124631. doi: 10.1016/j.ijpharm.2024.124631. Epub 2024 Aug 29.
Epilepsy is a highly prevalent neurological disease and valproic acid (VPA) is used as a first-line chronic treatment. However, this drug has poor oral bioavailability, which requires the administration of high doses, resulting in adverse effects. Alternative routes of VPA administration have therefore been investigated, such as the nose-to-brain route, which allows the drug to be transported directly from the nasal cavity to the brain. Here, the use of nanostructured lipid carriers (NLC) to encapsulate drugs administered in the nasal cavity has proved advantageous. The aim of this work was to optimise a mucoadhesive formulation of VPA-loaded NLC for intranasal administration to improve the treatment of epilepsy. The Design of Experiment (DoE) was used to optimise the formulation, starting with component optimisation using Mixture Design (MD), followed by optimisation of the manufacturing process parameters using Central Composite Design (CCD). The optimised VPA-loaded NLC had a particle size of 76.1 ± 2.8 nm, a polydispersity index of 0.190 ± 0.027, a zeta potential of 28.1 ± 2.0 mV and an encapsulation efficiency of 85.4 ± 0.8%. The in vitro release study showed VPA release from the NLC of 50 % after 6 h and 100 % after 24 h. The in vitro biocompatibility experiments in various cell lines have shown that the optimised VPA-loaded NLC formulation is safe up to 75 µg/mL, in neuronal (SH-SY5Y), nasal (RPMI 2650) and hepatic (HepG2) cells. Finally, the interaction of the optimised VPA-loaded NLC formulation with nasal mucus was investigated and mucoadhesive properties were observed. The results of this study suggest that the use of intranasal VPA-loaded NLC may be a promising alternative to promote VPA targeting to the brain, thereby improving bioavailability and minimising adverse effects.
癫痫是一种高发的神经疾病，丙戊酸（VPA）被用作一线慢性治疗药物。然而，这种药物的口服生物利用度较差，需要使用高剂量，从而导致不良反应。因此，已经研究了 VPA 的其他给药途径，例如鼻腔给药途径，该途径可使药物直接从鼻腔输送到大脑。在这里，使用纳米结构脂质载体（NLC）来封装鼻腔内给予的药物已被证明是有利的。本工作旨在优化载 VPA 的 NLC 的鼻用黏附制剂，以改善癫痫的治疗。设计实验（DoE）用于优化制剂，从使用混合设计（MD）进行成分优化开始，然后使用中心复合设计（CCD）优化制造工艺参数。优化后的载 VPA 的 NLC 的粒径为 76.1±2.8nm，多分散指数为 0.190±0.027，Zeta 电位为 28.1±2.0 mV，包封效率为 85.4±0.8%。体外释放研究表明，NLC 中 VPA 在 6 小时后释放 50%，24 小时后释放 100%。在各种细胞系中的体外细胞相容性实验表明，优化的载 VPA 的 NLC 制剂在高达 75µg/mL 的浓度下是安全的，在神经元（SH-SY5Y）、鼻（RPMI 2650）和肝（HepG2）细胞中都是安全的。最后，研究了优化的载 VPA 的 NLC 制剂与鼻黏液的相互作用，并观察到了黏附特性。本研究结果表明，鼻内给予载 VPA 的 NLC 可能是一种有前途的替代方法，可促进 VPA 靶向大脑，从而提高生物利用度并减少不良反应。
