title: 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.
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Rassu
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Soddu
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cossu
authors.affiliation: Department of Natural and Territorial Sciences, University of Sassari, via Piandanna 4, 07100 Sassari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Brundu
authors.affiliation: Department of Natural and Territorial Sciences, University of Sassari, via Piandanna 4, 07100 Sassari, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Cerri
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44121 Ferrara, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchetti
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, via Borsari 46, 44121 Ferrara, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ferraro
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Regan
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giunchedi
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy. Electronic address: eligav@uniss.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gavini
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44121 Ferrara, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dalpiaz
mesh_terms: D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry*; D003676:Deferoxamine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008567:Membranes, Artificial; D008863:Microspheres; D009297:Nasal Mucosa / Q000378:metabolism; D010539:Permeability; D017208:Rats, Wistar; D017262:Siderophores / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D013552:Swine; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D008567:Membranes, Artificial; D017262:Siderophores; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D048271:Chitosan; D003676:Deferoxamine
keywords: Chitosan chloride; Deferoxamine mesylate; Methyl-β-cyclodextrin; Nasal formulations; Nose-to-brain transport; Pharmacokinetic studies