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

JOURNAL OF CONTROLLED RELEASE

卷:201

Article

Rassu, Giovanna¹  Soddu, Elena¹  Cossu, Massimo¹  Brundu, Antonio²  Cerri, Guido²  Marchetti, Nicola³  Ferraro, Luca⁴  Regan, Raymond F.⁵  Giunchedi, Paolo¹  Gavini, Elisabetta¹  Dalpiaz, Alessandro³ 

[1] Univ Sassari, Dept Chem & Pharm, I-07100 Sassari, Italy

[2] Univ Sassari, Dept Nat & Terr Sci, I-07100 Sassari, Italy

[3] Univ Ferrara, Dept Chem & Pharmaceut Sci, I-44121 Ferrara, Italy

[4] Univ Ferrara, Dept Life Sci & Biotechnol, I-44121 Ferrara, Italy

[5] Thomas Jefferson Univ, Dept Emergency Med, Philadelphia, PA 19107 USA

关键词: Deferoxamine mesylate;    Chitosan chloride;    Methyl-beta-cyclodextrin;    Nasal formulations;    Nose-to-brain transport;    Pharmacokinetic studies;   

DOI  :  10.1016/j.jconrel.2015.01.025

来源: Elsevier

【 摘 要 】

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-beta-cyclodextrin microparticles loaded with DFO (DCH and MCD, respectively) were obtained by spray drying. Their volume-surface diameters ranged from 1.77 +/- 0.06 mu m(DCH) to 3.47 +/- 0.05 mu m(MCD); the aerodynamic diameters were about 1.1 mu m 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 mu g DFO encapsulated in the microparticles resulted in its uptake into the cerebrospinal fluid (CSF) with peak values ranging from 3.83 +/- 0.68 mu g/mL (DCH) to 14.37 +/- 1.69 mu g/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-beta-cyclodextrins appear therefore suitable to formulate solid microparticles able to promote the nose to brain uptake of DFO and to limit its systemic exposure. (C) 2015 Elsevier B.V. All rights reserved.

【 授权许可】

Free