(T0930-03-15) Optimization of Donepozil Loaded Liposome for Nose-to-Brain Delivery – An In Vitro Mucoadhesion, and Ex Vivo Permeability Study

Purpose: Drug delivery to the brain has been a major problem due to very limited permeability of the blood brain barrier (BBB). A number of different strategies for delivering drug molecules into the brain have been developed in order to treat neurological diseases. One such strategy involves bypassing the BBB by nose-to-brain administration via the intranasal route [1-2]. Therefore, the aim of this study was to develop an optimized liposomal nano-drug delivery system of donepezil for targeting the brain via the intranasal route and evaluate its nasal residence percentage and permeability through the nasal tissue.

Methods: A full-factorial design of experiment (DoE) was used to prepare liposomal drug delivery system of donepezil using 4 factors (Stirring speed, Injection speed, Phospholipid: Drug ratio and Type of Stabilizer) at 2 levels (High & Low) by the ethanol injection method. The prepared liposomal batches were characterized in terms of average particle size, zeta potential, polydispersity index and entrapment efficiency. In-vitro mucoadhesion study was performed using the optimized liposomal batches to evaluate the percentage amount of donepezil retained in simulated nasal environment. The permeability of the optimized liposomal batches of donepezil was also studied in a vertical Franz Diffusion cell using excised goat olfactory mucosa.

Results: Liposomal drug delivery system developed using poloxamer 407 showed low average particle size (184.1 ± 2.95 nm) and PDI (0.173 ± 0.02) with high entrapment efficiency (70 ± 0.13 %) compared to that prepared using Chitosan (Table 1). In-vitro mucoadhesion study data indicated that donepezil delivered using liposomes showed higher retention (75 ± 1.15 %) compared to donepezil delivered as solution (57 ± 0.51 %) (Fig 1). Ex-vivo permeability data for donepezil loaded liposomes showed 2.5-fold greater permeation after 180 minutes compared to donepezil solution (Fig 2).

Conclusion: Optimized liposomal batches of donepezil were developed using DoE. Liposomal donepezil formulation prepared using poloxamer might be a promising platform for targeting the brain through the intranasal route to treat neurodegenerative diseases. Future in-vivo study will be conducted to evaluate the bioavailability of donepezil in the brain when administered through the intranasal route.

References: [1] E. Gavini, G. Rassu, V. Sanna, M. Cossu, and P. Giunchedi, “Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide: in-vitro/ex-vivo studies,” J. Pharm. Pharmacol., vol. 57, no. 3, pp. 287–294, 2005.
[2] L. Salade, N. Wauthoz, J. Goole, and K. Amighi, “How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods,” Int. J. Pharm., vol. 561, pp. 47–65, 2019.

Acknowledgements: The authors would like to thank North South University, Bangladesh and all other collaborative universities and institutions for supporting this project work.


Table 1. Average particle size, PDI, zeta potential, and encapsulation efficiency (EE) of liposomal batches prepared using DoE


Fig 1. Liposomal preparation showed higher residence percentage than Donepezil solution (p < 0.01).


Fig 2. Liposomal preparation showed 2.5 fold higher ex-vivo permeability than Donepezil solution (p < 0.01) across the goat olfactory mucosa.