Preparation, characterization, and in vivo evaluation of intranasally administered liposomal formulation of donepezil

Abstract

The adequate amount of drug delivery to the brain in neurological patients is a major problem faced by the physicians. Recent studies suggested that intranasal administration of liposomal formulation may improve the drug delivery to the brain. In the present study, an attempt was made to study the brain bioavailability of commonly used anti-Alzheimer drug donepezil (DNP) liposomal formulation by intranasal route in rats. We adopted the thin layer hydration technique for the preparation of liposomes by using cholesterol, polyethylene glycol, and 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC). The prepared liposomes were characterized by determining particle size, shape, surface morphology, zeta potential, encapsulation efficiency, and in vitro release of DNP. The pharmacokinetic parameters of liposomal DNP in plasma and brain of rats were determined following oral and nasal administration. The results of this study showed that the DNP liposomal formulation was stable with a consistent size (102 ± 3.3 nm) and shape. The prepared liposomes showed high encapsulation efficiency (84.91% ±3 .31%) and sustained-release behavior. The bioavailability of DNP in plasma and brain increased significantly (P<0.05) after administration of liposomal formulation by the intranasal route. Histopathological examination showed that the formulation was safe and free from toxicity. It can be concluded that the nasal administration of liposomal preparation may provide an efficient and reliable mode of drug delivery to the central nervous system.

Keywords: bioavailability; blood–brain barrier; donepezil; intranasal; liposomes.

Figure 1

Chemical structure of donepezil (CAS: 120014-06-4).

Figure 2

SEM micrographs of the prepared liposomes of DNP. Note: Micrographs at a scale of 200 nm (A) and 100 nm (B). Abbreviations: SEM, scanning electron microscopy; DNP, donepezil.

Figure 3

In vitro release of DNP from liposomes (mean ± standard deviation, n=3). Abbreviation: DNP, donepezil.

Figure 4

Mean plasma concentration and time profile of donepezil with various routes of administration (mean ± standard deviation, n=6).

Figure 5

Mean brain concentrations and time profile of donepezil with various routes of administration (mean ± standard deviation, n=6).

Figure 6

Histopathological examinations of heart, lung, kidney, spleen, and liver. Notes: Sections were processed with hematoxylin and eosin stain for the analysis of level of inflammation and morphology of the tissues. (A) Free donepezil intranasal. (B) Liposomal donepezil intranasal. The scale bars represent 200 µm.

Figure 7

Histopathological examinations of brain and olfactory bulb. Notes: Sections were processed with hematoxylin and eosin stain for the analysis of level of inflammation and morphology of the tissues. (A) Free donepezil intranasal. (B) Liposomal donepezil intranasal. The scale bars represent 200 µm.