par Levet, Vincent 
;Amighi, Karim ;Wauthoz, Nathalie
Référence Forum of Pharmaceutical Sciences of the Belgian Society of Pharmaceutical Sciences (18th: May 28-29th, 2015: Blankenberge, Belgique)
Publication Non publié, 2015-05-28
;Amighi, Karim ;Wauthoz, Nathalie Référence Forum of Pharmaceutical Sciences of the Belgian Society of Pharmaceutical Sciences (18th: May 28-29th, 2015: Blankenberge, Belgique)
Publication Non publié, 2015-05-28
Communication à un colloque
| Résumé : | Background: Lung cancers present a very high prevalence worldwide (involved in 1 in 7 cancer, 1.8M new cases per year) and a very poor prognosis (overall ratio of mortality to incidence of 0.87, 1.6M death per year) [1]. Current treatment modalities include a combination of surgery, radiotherapy and/or chemotherapy depending on the disease stage. Because of its therapeutic potency and despite its severe side effects, cisplatin has remained the backbone of lung cancer chemotherapy. Cisplatin is currently administered by slow I.V. infusion with a concomitant forced diuresis as nephroprotection [2]. Local delivery of cisplatin to the lungs seems a very promising approach for a lower systemic exposure and a higher drug concentration at the tumor site [3]. Moreover, Dry Powders for Inhalation (DPI) are a highly efficient, quick, reproducible and low-cost patient-driven approach for the delivery of large amounts of medication for pulmonary diseases [4].Objectives: 1. The first aim of the study was to compare the local and systemic pharmacokinetics (PK) of cisplatin solution administered by the pulmonary route or by the conventional I.V. route. 2. A DPI was then developed for human use.Methods: 1. Cisplatin solution was administered to mice in I.V. bolus or by endotracheal instillation with a Penn-Century Microsprayer® IA-1C. Blood and organs were removed at different times, digested in nitric acid and analyzed for platinum concentration using a Varian SpectrAA® 300 Zeeman Graphite Furnace Atomic Absorption Spectrometer (Z-GFAAS).2. Cisplatin microcrystals were produced by reduction of a cisplatin suspension with an Avestin Emulsiflex® C5 High-Pressure Homogenizer. The solvent was then evaporated with a Büchi Mini Spray-dryer B290 to produce the DPI. Particle size distribution (PSD) of individualized particle and during aerosolization through a dry powder inhaler was assessed by laser diffraction with a Malvern Mastersizer® 3000 Hydro and a Malvern Spraytec®, respectively. Aerosol performance was then assessed using a Copley Multistage Liquid Impinger and dissolution profile was established in simulated lung fluid on the respirable fraction deposited on a Copley Fast Screening Impactor.Results: 1. Cisplatin PK after local vs. systemic delivery unveiled a 3-fold increase in AUC in the lungs and a 7-, 3- and 5-fold decrease in blood, kidneys and liver exposure, respectively. It also exhibited a 9-, 4- and 5-fold decrease of Cmax in blood, kidneys and liver respectively.2. PSD of the generated DPI was small, narrow and showed low aggregation with 91% and 80% of particles below 5 μm, individualized and in the aerosol plume, respectively. The emitted DPI showed a high Fine Particle Fraction of 52 ± 3%, a median mass aerodynamic diameter of 2.5 ± 0.3 μm and a fast dissolution with 98.3 ± 3.9% dissolved within 15 min.Discussion: The pulmonary route increases cisplatin concentration in the lungs and decreases both systemic and acute exposure in sensitive organs compared to I.V. Therefore, a DPI was produced by efficient and up-scalable size-reduction and spray-drying techniques and exhibited good aerodynamic and dissolution properties for human use. The local and systemic PK evaluation is underway. |
