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Salmon calcitonin, for the treatment of calcium homeostasis and bone remodeling, was used as a model peptide drug and adsorbed on the surface of biodegradable polymeric poly(dl-lactic-co-glycolic acid) (PLGA) nanospheres. Subsequently, the nanospheres were treated using lyophilizer and loaded onto inhalable carrier using Mechanofusion to obtain nanocomposite particles suitable for inhalation. The physicochemical properties and in vitro inhalation properties of the nanocomposite particles were investigated. The pulmonary distribution and pharmacological effect were also evaluated in male Wistar rats. The results showed that the drug loading efficiency of salmon calcitonin on PLGA nanospheres were exceeding 96% (w/w). Inhalation efficiency of the lyophilized PLGA nanospheres was largely improved after they were loaded on the surface of inhalable carrier. Over 50% (w/w) of the lyophilized PLGA nanospheres could be deposited in the alveoli section after intratracheal administration to male Wistar rats, while a rapid elimination rate of the lyophilized nanospheres from the lung was found in pulmonary distribution study. The in vivo pharmacological study showed that the nanocomposite particles exhibited superior hypocalcemic action over salmon calcitonion solution and the lyophilized nanospheres. It suggested that the Mechanofusion(TM) technique can impart improved inhalation properties to the lyophilized nanospheres for pulmonary delivery of therapeutic peptide drugs., (Copyright © 2012. Published by Elsevier B.V.)

Abstract: The aim of this study was to investigate two types of chitosan-modified poly (dl-lactic-co-glycolic acid) (PLGA) nanocomposite particles containing salmon calcitonin for pulmonary delivery, which were obtained using spray drying fluidized bed granulation (Agglomaster™) and dry powder coating techniques (Mechanofusion™), respectively. The physicochemical properties, pulmonary distribution, pulmonary clearance rate as well as in vivo hypocalcemia actions of the two types of nanocomposite particles were investigated. As indicated by scanning electron micrographs, soft matrix nanocomposite particles and soft ordered nanocomposite particles were produced by Agglomaster™ and Mechanofusion™, respectively. Both forms of chitosan-modified PLGA nanocomposite particles exhibited a high inhalation efficiency, i.e. more than 50% of the two types of nanocomposite particles could be deposited in the deep lung of male Wistar rats. However, the chitosan-modified PLGA nanocomposite particles designed by Agglomaster™ exhibited superior properties to those obtained by Mechanofusion™ with respect to the redispersibility of fine particles in aqueous liquid, the pulmonary retention time and pharmacological effects. In addition, compared with non-modified PLGA nanocomposite particles, the chitosan-modified PLGA nanocomposite particles obtained by Agglomaster™ exhibited enhanced pulmonary absorption of salmon calcitonin via the lung. The findings in this study suggest that the spray drying fluidized bed granulation technique is superior to the dry powder coating technique for producing chitosan-modified dry powder formulations containing salmon calcitonin for inhalation. This can be attributed to the avoidance of aggregation of chitosan-modified PLGA nanocomposite particles when using Agglomaster™ rather than Mechanofusion™. [Copyright &y& Elsevier]