A surface modification of clozapine-loaded nanocapsules improves their efficacy: A study of formulation development and biological assessment

• Preparation of clozapine-loaded PCL nanocapsules coated with P80, CS or PEG.
• In vitro release half-life time in pH 7.4: free clozapine < P80-coated < PEG-coated ∼ CS-coated nanocapsules.
• PEG and CS-coated nanocapsules increased antipsicotic effect and duration in relation to P80-coated nanocapsules in animal model.
• In vivo plasma half-life time: free clozapine < P80-coated < PEG-coated ∼CS-coated nanocapsules.
• In vitro release is shown as a useful tool to predict plasma half-life in the case of CZP and its derived formulations.

This work aimed to develop nanocapsules (NC) coated with polysorbate 80 (P80), cationic chitosan (CS) or polyethylene glycol (PEG) using clozapine (CZP) as the drug model. The zeta potential, pH and encapsulation efficiency were directly affected by the CS coating. Using the bag dialysis method, the in vitro CZP release from CS-coated nanocapsules was similar to the PEG-coated at pH 7.4. Nanocapsules coated with PEG and CS exhibited an increased action duration compared to the P80-coated nanocapsules in pseudo-psychosis induced by d,l-amphetamine in rats. When comparing both groups, the group administered CS-coated nanocapsules showed better activity than the PEG-coated nanocapsules at 6, 10 and 12 h after d,l-amphetamine administration. The pharmacokinetic assessment in rats demonstrated that the observed half-lives were free CZP < P80-coated < PEG-coated ̴ CS-coated nanocapsules. Both the P80- and PEG-coated nanocapsules showed a statistically significant increase in their volume of distribution compared to free CZP. On the other hand, the cationic nanocapsules showed a decrease in total clearance. Together, these results indicate that the PEG and CS coatings are a promising delivery system for CZP in the treatment of schizophrenia.

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