Design and optimization of a chitosan coated nanostructured lipid carriers of paliperidone

Abstract

Schizophrenia is a chronic, severe psychiatric disease characterized by delusions and hallucinations, disorganized speech and behavior, social withdrawal, affective flattening and amotivation, and cognitive dysfunction (Lewis and Lieberman, 2000). Paliperidone (9-hydroxyrisperidone) (PAL), which is the main active metabolite of risperidone, belongs to the class of secondgeneration antipsychotics as a benzisoxazole derivative. In 2006, it was approved by the U.S. Food and Drug Administration for the acute and maintenance treatment of schizophrenia. Like other atypical antipsychotics, paliperidone acts by inhibiting serotonergic type 2 receptors (5-HT2A) and dopamine type 2 (D2) receptors in the brain (Chue and Chue, 2012). The brain, which is the most vital organ in our body, is protected by the Blood-Brain Barrier (BBB), a highly sophisticated brain support system. The BBB acts as a barrier that prevents the entry of unwanted substances from the bloodstream into the brain (Dong, 2018). As the BBB is also the primary obstacle to drug delivery to the brain, various approaches have been attempted to overcome this barrier (Bourganis et al., 2018). Intranasal administration, which is among the non-invasive strategies, offers a safe means of drug targeting to the brain, allowing direct passage to the central nervous system (CNS) without encountering the BBB and hepatic first-pass effect associated with oral administration (Keller et al., 2022). Numerous approaches have been investigated for nose-to-brain delivery of nanostructured lipid carriers (NLCs) which are composed of a mixture of solid and liquid lipids to form a matrix and stabilized with surfactants. The major disadvantage of intranasal administration is the mucociliary clearance, which reduces the residence time and consequently the drug absorption in the nasal cavity. This condition can be resolved through the surface modification of lipid nanoparticles using a cationic polymer such as chitosan (CH). Recent studies have reported that CH has mucoadhesive, penetrationenhancing properties across epithelial mucus and increases the duration of nasal retention (Bruinsmann et al., 2019). In light of above discussion, it was proposed to develop and evaluate CH-coated PAL loaded NLCs for brain delivery after intranasal administration to overcome the limitations. In this context, in vitro characterization studies were carried out by coating PAL-loaded NLC formulations with low molecular weight CH. The effect of different surfactants on CH coating was investigated.