Nasal delivery of donepezil HCl-loaded hydrogels for the treatment of Alzheimer's disease

Abstract

This study aims to prepare, characterize and evaluate the pharmacokinetics of liposomal donepezil HCl (LDH) dispersed into thiolated chitosan hydrogel (TCH) in rabbits. Various hydrogels including TCH were prepared, and after characterization, TCH was selected for subsequent evaluations, due to the promising results. TCH was then incorporated with LDH prepared by reverse phase evaporation method. The hydrogel was characterized using scanning electron microscope, dialysis membrane technique, and ultra-performance liquid chromatography methods. The optimized resultant was then evaluated in terms of pharmacokinetics in an in vivo environment. The mean size of LDH and drug entrapment efficiency were 438.7 ± 28.3 nm and 62.5% ± 0.6, respectively. The controlled drug release pattern results showed that the half-life of the loaded drug was approximately 3.5 h. Liposomal hydrogel and free liposomes were more stable at 4 °C compared to those in 20 °C. The pharmacokinetics study in the rabbit showed that the optimized hydrogel increased the mean peak drug concentration and area under the curve by 46% and 39%, respectively, through nasal route compared to the oral tablets of DH. Moreover, intranasal delivery of DH through liposomal hydrogel increased the mean brain content of the drug by 107% compared to the oral DH tablets. The results suggested that liposomes dispersed into TCH is a promising device for the nasal delivery of DH and can be considered for the treatment of Alzheimer's disease.

Figure 1

Effect of radiation dose on the hydrogel fraction in different formulations: (A) PVP 3% gels, (B) PVP 4% gels and (C) PVP 6% gels.

Figure 2

Effect of different radiation dose on the swelling degree in different formulations: (A) PVP 3% gels, (B) PVP 4% gels and (C) PVP 6% gels.

Figure 3

Flow properties of the various hydrogels.

Figure 4

Flow curves of the various hydrogels.

Figure 5

Effects of contact time on the adhesion force of different formulations: (A) PVP 3% gels; (B) PVP 4% gels; (C) PVP 6% gels; and (D) chitosan and thiolated chitosan gels.

Figure 6

DH release profile from different formulations: (A) PVP 3% gels; (B) PVP 4% gels; (C) PVP 6% gels; and (D) chitosan, thiolated chitosan, thiolated chitosan ex vivo, PVP 4% + PEG 3%, and PVP 4% + PEG 3% ex vivo.

Figure 7

Histopathological photomicrograph of (A) the normal sheep nasal mucosa (control) (magnification size × 20); (B) nasal mucosa after treatment with hydrogels without additives. Hypotrophy in the Bowman’s gland and cellular infiltration in the connective tissue lamina propria surrounding the gland are perceivable; (C) nasal mucosa after treatment with the PVP + PEG hydrogels; (D) histological characterization of nasal mucosa after using chitosan hydrogel; and (E) nasal mucosa after treatment with thiolated chitosan hydrogel (magnification size × 10).

Figure 8

(A) SEM image of liposomes prepared by first reversible evaporator phase method; (B) SEM image of liposomes prepared by second reversible phase method.

Figure 9

The profile of DH release from various liposomal hydrogels.

Figure 10

SEM images of LDH incorporated into TCH during stability study, (A1) liposomes stored at 4 °C for one week; (A2) liposomes stored at 4 °C for 2 weeks; (A3) liposomes stored at 4 °C for 3 weeks; and (A4) liposomes stored at 4 °C for 4 weeks.

Figure 11

SEM images of LDH incorporated into TCH during stability study, (A1) liposomes stored at 20 °C for one week; (A2) liposomes stored at 20 °C for 2 weeks; (A3) liposomes stored at 20 °C for 3 weeks; and (A4) liposomes stored at 20 °C for 4 weeks.

Figure 12

SEM images of LDH during stability study, (B1) liposomes stored at 4 °C for one week; (B2) liposomes stored at 4 °C for 2 weeks; (B3) liposomes stored at 4 °C for 3 weeks; and (B4) liposomes stored at 4 °C for 4 weeks.

Figure 13

SEM images of LDH during stability study, (B1) liposomes stored at 20 °C for one week; (B2) liposomes stored at 4 °C for 2 weeks; (B3) liposomes stored at 20 °C for 3 weeks; and (B4) liposomes stored at 20 °C for 4 weeks.

Figure 14

(A) Chromatogram of blank plasma; (B) UPLC MS/MS chromatogram of extracted of spiked plasma with 1 ng DH and 40 ng IS; (C) UPLC MS/MS chromatogram of the extracted of DH 12 h after intranasal administration to rabbits and multiple reaction-monitoring (MRM) transitions of IS.

Figure 15

DH plasma concentration time profiles in rabbits after intranasal administration of LDH incorporated into TCH (n = 6) and oral administration of oral DH tablet (n = 6).