Development of levofloxacin-loaded PLGA microspheres of suitable properties for sustained pulmonary release

Marisa C Gaspar,Alberto A.C.C Pais,João J.S Sousa,Julien Brillaut,Jean-Christophe Olivier

doi:10.1016/j.ijpharm.2018.12.005

Marisa C Gaspar, Alberto A.C.C Pais + Show 3 more

Open Access

https://doi.org/10.1016/j.ijpharm.2018.12.005

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Abstract

Aerosol antibiotics are an interesting alternative to oral or intravenous therapy in Cystic Fibrosis lung infections. Levofloxacin (LVX) inhaled solution is already an effective option. In this study, the aim was the development of LVX-loaded PLGA microspheres (MS) for pulmonary administration as a dry powder. MS were prepared, for the first time, by a modified double emulsion solvent evaporation method with premix membrane homogenization. Aqueous phases were saturated with LVX and a fatty acid (lauric acid) was added to avoid the drug escaping from the organic phase. MS were characterized in terms of size, drug content, morphology and in vitro release properties. X-ray diffraction, Fourier-transform infrared spectroscopy, differential and gravimetric thermal analysis, and cytotoxicity analyses were performed. Results showed this new method increased the drug loading while maintaining an adequate (∼5 µm) particle size and controlled release. Compared to a solution for inhalation, these properties combined with the dry-powder nature of these MS will improve patient compliance. The incorporation of lauric acid was not advantageous because the particle size was higher and no improvements concerning the sustained release occurred. LVX was molecularly dispersed in the matrix, or it was in amorphous state, as confirmed by the physico-chemical analyses. Calu-3 cell viability assays demonstrated no cytotoxicity for these MS, making them a promising system for LVX pulmonary delivery.

Highlights

The delivery of antibiotics at the site of infection has been demonstrated to be efficient in the treatment of lung infections (Giron Moreno et al, 2011)
In the Cystic Fibrosis (CF) lung disease, the development of chronic infection by Pseudomonas aeruginosa is the predominant cause of the morbidity and mortality and its control is the main objective of long term antibiotherapy (Geller, 2009; Giron Moreno et al, 2011; Bjarnsholt et al, 2009)
The resulting W1/O/W2 emulsion was subjected to three homogenization cycles through a Shirasu porous glass (SPG) membrane (19.9 μm porosity) under 25 kPa transmembrane pressure using an external pressure-type micro kit emulsification device (SPG Technology, Sadowara, Japan)

Summary

Introduction

The delivery of antibiotics at the site of infection has been demonstrated to be efficient in the treatment of lung infections (Giron Moreno et al, 2011). The nebulized solution of levofloxacin (LVX, Fig. 1) (Quinsair® in Europe or AeroquinTM in EUA) was demonstrated to be effective in improving the lung function of CF patients (EMA, 2015; Foundation, 2015). The formulation of LVX as readily administrable dry powder for inhalation is an interesting option to improve drug product stability, CF patients’ comfort and treatment efficiency. The use of sustained-release biodegradable and biocompatible polymerbased microspheres (MS), administered in a dry powder inhaler, may further improve patients’ comfort by reducing the frequency of administration. The hydrophobic copolymer poly (DL-lactide-co-glycolide) (PLGA) is of particular relevance for the preparation of sustained release drug delivery systems, since it is biodegradable and biocompatible.

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