Inhaled dry powder containing lipid-nanoparticles: particle engineering by spray-drying technology.

INTRODUCTION:
Dry powders for inhalation (DPI) are a promising lung delivery system for the treatment of local respiratory diseases such as asthma and chronic obstructive pulmonary diseases (COPD). Beside many advantages including drug stability and the lack of propellant gases, the main interest lies in the faculty to improve dry powders properties using “particle engineering” [1]. Engineered inhaled particles are mostly achieved by spray-drying
method (SD). Variation of liquid composition and drying parameters can lead to DPI development and optimization improving aerodynamic, dispersibility and flowability properties [2]. In addition, the use of liposomal drug DPIs for lung administration offers various advantages like reduced toxicity, decreased APIs' degradation, or increased
drug bioavailability which will consequently improve drug efficiency. The goal of this study is to develop an inhaled powder having appropriate lung deposition profile and encompassing stable lipid-nanoparticle. To do so, preliminary drying tests on liposomal suspension are carried out. The aim is to select excipients and drying parameters ranges allowing the set-up of a design of experiments (DOE). This will ultimately lead to optimized liposomal dry powders for lung administration carrying active pharmaceutical ingredients.
METHODS:
Spray-dried suspension: The suspension consists of a solid content of 5% made of carbohydrates (trehalose, raffinose…) and liposomes. Different ratios between carbohydrates and liposomes are tested (96-4%; 99-1%, respectively). Liposomes composed of soybean phosphatidylcholine, cholesterol, and PEGylated lipid (65/30/5%
(m/m)) are produced using supercritical fluid extraction using CO2.
Spray-drying: Procept 4 M8-Trix Formatrix spray-dryer (Procept, Zelzate, Belgium) with a bi-fluid nozzle (0,4mm) is being used. Multiple parameters are changed as the inlet temperature, the nozzle gas pressure, or the feed rate (pump speed).
Characterization of dried powders: The yield process determination is evaluated as well as the particle size distribution measurement by a laser diffractometer Mastersizer 2000. The moisture content is measured by thermogravimetric analysis (TGA). Liposomal hydrodynamic diameters and polydispersity index along with the zeta potential analysis are performed using the Zetasizer Nano ZS. The detection of liposomal loss is made by
nanoparticle tracking analysis using the NanoSight NS300.
RESULTS AND DISCUSSION:
Results obtained with an inlet temperature of 60°C show that dry powders containing 4% of lipid content at 45mM induce size particles below 5µm, moisture content below 5% leading to procedure yield above 70 %. Liposomes sizes before and after atomization are stable but lipid degradation is observed. Decreasing lipid concentration at 5mM and lipid content at 1% allow liposomes loss to reduce while maintaining dry powdercharacteristics and lipid size.
CONCLUSION:
Preliminary results allowed to define critical parameters leading to future improvement using a DOE. Liposomes integrity and aerosolisation behavior of optimized powders will be evaluated. Incorporation of two drugs (ciclesonide and indacaterol) into the liposomes is one other perspectives of this project.