Local and systemic pharmacokinetic evaluation of immediate-release and controlled-release cisplatin dry powders for inhalation against lung cancer

Vincent Levet, Rémi Rosière, Karim Amighi & Nathalie Wauthoz

Immediate-release and controlled-release cisplatin dry powder formulations based on solid-lipid microparticles (SLMs) with high drug-content (≥ 50%) and exhibiting high deposition abilities in vitro (fine particle fractions (FPF) between 37% and 52%), were produced by high-pressure homogenization and spray-drying using tristearin and polyethylene glycol (1000) tocopheryl-vitamin E succinate[1]. Dry powder blends (DPB) were realized using a spray-dried Mannitol:L-Leucine (9:1) diluent and mixed with the formulations for accurate and reliable administration to mice. DPB were characterized by their drug-content, uniformity of content, recovered mass, recovered cisplatin and particle size distribution by laser diffraction with a Malvern Spraytec® through the actuation of a Penn-Century Dry Powder Insufflator™ model DP-4M for mouse. All but one of the DPB were able to be reliably delivered in vitro. The local and systemic pharmacokinetic distributions of cisplatin from formulations were then evaluated in vivo in CD-1 mice vs. IV and vs. a nebulized cisplatin aqueous solution. Quantification of platinum (Pt) content in organs was realized using validated methods by electrothermal atomic absorption spectrometry (ETAAS) in lungs, kidneys, liver, spleen, mediastinum and total blood of mice after a single 1.25 mg/kg administration and dosed over 48 hours. It showed (1) that the inhaled route could effectively lower systemic exposure while increasing lung exposure when compared to IV, (2) that immediate-release formulations were very quickly absorbed in the lungs and (3) that controlled-release formulations promoted higher total exposure in the lungs, but that the presence of PEGylated excipient was needed to avoid active and fast elimination of particles from the lungs.

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