Solid microparticles based on chitosan or methyl-β-cyclodextrin: a first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate

Abstract

We propose the formulation and characterization of solid microparticles as nasal drug delivery systems able to increase the nose-to-brain transport of deferoxamine mesylate (DFO), a neuroprotector unable to cross the blood brain barrier and inducing negative peripheral impacts. Spherical chitosan chloride and methyl-β-cyclodextrin microparticles loaded with DFO (DCH and MCD, respectively) were obtained by spray drying. Their volume-surface diameters ranged from 1.77 ± 0.06 μm (DCH) to 3.47 ± 0.05 μm (MCD); the aerodynamic diameters were about 1.1 μm and their drug content was about 30%. In comparison with DCH, MCD enhanced the in vitro DFO permeation across lipophilic membranes, similarly as shown by ex vivo permeation studies across porcine nasal mucosa. Moreover, MCD were able to promote the DFO permeation across monolayers of PC 12 cells (neuron-like), but like DCH, it did not modify the DFO permeation pattern across Caco-2 monolayers (epithelial-like). Nasal administration to rats of 200 μg DFO encapsulated in the microparticles resulted in its uptake into the cerebrospinal fluid (CSF) with peak values ranging from 3.83 ± 0.68 μg/mL (DCH) to 14.37 ± 1.69 μg/mL (MCD) 30 min after insufflation of microparticles. No drug CSF uptake was detected after nasal administration of a DFO water solution. The DFO systemic absolute bioavailabilities obtained by DCH and MCD nasal administration were 6% and 15%, respectively. Chitosan chloride and methyl-β-cyclodextrins appear therefore suitable to formulate solid microparticles able to promote the nose to brain uptake of DFO and to limit its systemic exposure.

Keywords: Chitosan chloride; Deferoxamine mesylate; Methyl-β-cyclodextrin; Nasal formulations; Nose-to-brain transport; Pharmacokinetic studies.