Nanostructured lipid carriers for enhanced brain delivery of paliperidone

Abstract

Schizophrenia is ranked by WHO as one of the topmost ten diseases impacting the global burden of disease. It is a chronic psychiatric illness affecting around 2.7% of the population worldwide. The management of such neurodegenerative diseases is the most challenging task as the availability of antipsychotics in the brain is very low, leading to their sub-therapeutic effect in the patients. Moreover, increasing the dose to achieve the desired therapeutic effect leads to dose-related extrapyramidal side-effects. Patient non-compliance also serves as a major issue due to frequent dose administration, resistance to swallow tablets, and chronic lifelong-treatment involving high doses eventually leading to debilitating side-effects. This leads to failures in the posological scheme and ultimately relapses. Most of the antipsychotics are BCS class II compounds, presenting poor aqueous solubility leading to dissolution rate-limited absorption hence consequently resulting in poor oral bioavailability. Additionally, these agents suffer from extensive presystemic metabolism, Cytochrome P450 metabolism, and efflux by P-glycoprotein transporters. Furthermore, the conventional formulations are unable to deliver the antipsychotics directly to the brain owing to the presence of various protective mechanisms present in the brain such as BBB and blood-CSF barrier. Such barriers lead to less availability of the drug at the target site contributing to low bioavailability and thus eliciting a subtherapeutic effect. Paliperidone is a new generation atypical antipsychotic prescribed for schizophrenia and stressinduced short term psychotic disorders acting by antagonizing D2 and 5HT2A receptors. It forms one-third (31.5%) of total antipsychotic prescription and is the second most frequently prescribed drug in schizophrenia. It is a BCS Class II drug, practically insoluble in water, and has a high molecular weight, consequently leading to low oral bioavailability (28%). Further, for attaining a desired therapeutic effect, higher.....