Characterization and pharmacokinetic analysis of crystalline versus amorphous rapamycin dry powder via pulmonary administration in rats

• We prepared amorphous and crystalline dry powder formulations of rapamycin.
• Pharmacokinetics of inhaled amorphous and crystalline powder of rapamycin is compared.
• Amorphous powder presented higher systemic bioavailability than crystalline powder.
• Amorphous powder stays in the lung for the same period of time as crystalline powder.

The pharmacokinetics of inhaled rapamycin (RAPA) is compared for amorphous versus crystalline dry powder formulations. The amorphous formulation of RAPA and lactose (RapaLac) was prepared by thin film freezing (TFF) using lactose as the stabilizing agent in the weight ratio 1:1. The crystalline formulation was prepared by wet ball milling RAPA and lactose and posteriorly blending the mixture with coarse lactose (micronized RAPA/micronized lactose/coarse lactose = 0.5:0.5:19). While both powders presented good aerosolization performance for lung delivery, TFF formulation exhibited better in vitro aerodynamic properties than the crystalline physical mixture. Single-dose 24 h pharmacokinetic studies were conducted in Sprague–Dawley rats following inhalation of the aerosol mist in a nose-only inhalation exposure system. Lung deposition was higher for the crystalline group than for the TFF group. Despite higher pulmonary levels of drug that were found for the crystalline group, the systemic circulation (AUC0–24) was higher for the amorphous group (8.6 ng h/mL) than for crystalline group (2.4 ng h/mL) based on a five-compartmental analysis. Lung level profiles suggest that TTF powder stays in the lung for the same period of time as the crystalline powder but it presented higher in vivo systemic bioavailability due to its enhanced solubility, faster dissolution rate and increased FPF at a more distal part of the lungs.

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