PhD defense – Barbara Lamy – 6th July 2018

The dissertation entitled

Development and biopharmaceutical evaluation of fluoroquinolone-loaded microparticles for inhalation

By

Barbara LAMY

Will be presented on July 6, 2018 in partial fulfillment

of the requirements for the Degree of Doctor of Philosophy of the University of Poitiers

Committee : Pr. Sandrine MARCHAND (Thesis Supervisor), Pr. Franck BOURY, Pr. Rita VANBEVER,

Pr. Elias FATTAL, Dr. Malika SKIBA, Dr. Frédéric TEWES

Ciprofloxacin (CIP) is an antibiotic that has been clinically trialed for the treatment of P. aeruginosa (PA) lung infections by aerosolization. However, CIP is rapidly systemically absorbed after lung delivery, increasing the risk for subtherapeutic concentrations and resistant bacteria selection. The aim of this study was to develop an inhalable dry powder (DP) of CIP which would allow the concentration of CIP in the lung epithelial lining fluid (ELF) to be controlled to provide a more efficient effect against extracellular PA. CIP can form complexes with cations (Ca2+,…) reducing its intestinal permeability. While these interactions prove a limitation in terms of oral delivery, it was envisaged as beneficial to slowdown CIP absorption through the lung. This work includes two main parts. First, a proof of concept study that has shown the ability to precisely control the CIP apparent permeability across a pulmonary epithelium model thanks to a Ca−CIP interaction, while keeping antibacterial activity. In this study, CaCO3-based particles were developed to deliver CIP as (CIP-Ca)2+ complex to the lung by a DP inhaler. A second study allowed validating the concept in vivo in healthy rats. In this study, two types of inhalable microparticles loaded with the low-affinity CIP-calcium complex (CIP-Ca)2+ or with the high-affinity CIP-copper complex(CIP-Cu)2+ were developed. Then, ELF and plasma pharmacokinetics of CIP were studied after intratracheal delivery of these particles and of a CIP solution. The dry powder loaded with (CIP-Cu)2+ allowed a 100-times higher pulmonary ELF CIP exposure to be obtained compared to the intratracheal administration of a CIP solution.

Recherche

Menu principal

Haut de page