Long Acting Ionically Paired Embonate Based Nanocrystals of Donepezil for the Treatment of Alzheimer’s Disease: a Proof of Concept Study

ABSTRACT

Purpose

The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation.

Methods

D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc. Later, we converted the bulk ion pair into NCs using high pressure homogenization technique to study further in-vitro and in-vivo.

Results

The bulk ion pair has a drug content of 66% w/w and an 11,000 reduced solubility in comparison to native D hydrochloride. Also, its crystalline nature was confirmed by DSC and PXRD. The possible interaction sites responsible for the ion pair formation were identified though NMR. The prepared NCs has mean particle size 677.5 ± 72.5 nm and PDI 0.152 ± 0.061. In-vitro release showed a slow dissolution of NCs. Further, excellent bio compatibility of NCs were demonstrated in 3T3 cells. Following i.m administration of single dose of NCs, the D plasma level was found to be detectable up to 18 days. In vivo pharmacodynamic studies revealed that the single dose NCs i.m injection improved spatial memory learning and retention in ICV STZ model.

Conclusion

Our results suggest that the developed formulation has a potential to replace the current daily dosing regimen to a less frequent dosing schedule.

Graphical Abstract

Improved pharmacokinetic and pharmacodynamic profile after administration of single dose donpezil embonate nanocrystals in Rats

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