Novel Phenobarbital-Loaded Nanostructured Lipid Carriers for Epilepsy Treatment: From QbD to In Vivo Evaluation

SCIOLI-MONTOTO, SEBASTIAN; SBARAGLINI, MARIA LAURA; CISNEROS, JOSE SEBASTIAN; CHAIN, CECILIA YAMIL; FERRETTI, VALERIA; LEÓN, IGNACIO ESTEBAN; ALVAREZ, VERA ALEJANDRA; CASTRO, GUILLERMO RAUL; ISLAN, GERMAN ABEL; TALEVI, ALAN; RUIZ, MARIA ESPERANZA

Frontiers in Chemistry

mdpi

Año: 2022 vol. 10

Pharmacological treatments of central nervous system diseases are always challengingdue to the restrictions imposed by the blood–brain barrier: while some drugs can effectivelycross it, many others, some antiepileptic drugs among them, display permeability issues toreach the site of action and exert their pharmacological effects. The development of lastgenerationtherapeutic nanosystems capable of enhancing drug biodistribution has gainedground in the past few years. Lipid-based nanoparticles are promising systems aimed toimprove or facilitate the passage of drugs through biological barriers, which havedemonstrated their effectiveness in various therapeutic fields, without signs ofassociated toxicity. In the present work, nanostructured lipid carriers (NLCs) containingthe antiepileptic drug phenobarbital were designed and optimized by a quality by designapproach (QbD). The optimized formulation was characterized by its entrapmentefficiency, particle size, polydispersity index, and Z potential. Thermal properties wereanalyzed by DSC and TGA, and morphology and crystal properties were analyzed by AFM,TEM, and XRD. Drug localization and possible interactions between the drug and theformulation components were evaluated using FTIR. In vitro release kinetic, cytotoxicity onnon-tumoral mouse fibroblasts L929, and in vivo anticonvulsant activity in an animal modelof acute seizures were studied as well. The optimized formulation resulted in sphericalparticles with a mean size of ca. 178 nm and 98.2% of entrapment efficiency, physicallystable for more than a month. Results obtained from the physicochemical and in vitrorelease characterization suggested that the drug was incorporated into the lipid matrixlosing its crystalline structure after the synthesis process and was then released following a slower kinetic in comparison with the conventional immediate-release formulation. TheNLC was non-toxic against the selected cell line and capable of delivering the drug to thesite of action in an adequate amount and time for therapeutic effects, with no appreciableneurotoxicity. Therefore, the developed system represents a promising alternative for thetreatment of one of the most prevalent neurological diseases, epilepsy.