Abstract
Levofloxacin (LEV) is a relatively new-generation fluoroquinolone antibiotic that has good activity against Mycobacterium tuberculosis. The aims of this study were to develop and evaluate LEV-proliposomes in a dry powder aerosol form for pulmonary delivery. LEV-proliposomes containing LEV, soybean phosphatidylcholine, cholesterol and porous mannitol were prepared by a spray drying technique. The physicochemical properties of LEV-proliposomes were determined using a cascade impactor, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The toxicity of proliposomes to respiratory-associated cell lines and its potential to provoke immunological responses from alveolar macrophages (AMs) were evaluated. Antimycobacterial activity using flow cytometry and an in vivo repeated dose toxicity test in rats were carried out. LEV-proliposomes were successfully prepared with mass median aerodynamic diameters of 4.15–4.44 μm and with fine particle fractions (aerosolized particles of less than 4.4 µm) of 13%–38% at 60 L/min. LEV-proliposomes were less toxic to respiratory-associated cells than LEV, and did not activate AMs to produce inflammatory mediators that included interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide. The minimum inhibitory concentration (MIC) against M. bovis of LEV and LEV-proliposomes containing LEV 10% were 1 and 0.5 µg/mL, respectively. The efficacy of LEV-proliposomes against M. bovis was significantly higher than that of free LEV (p < 0.05). The efficacy of the LEV-proliposomes against M. tuberculosis was equal to that of the free LEV (MIC = 0.195 µg/mL). In a repeated dose toxicity study in rats, renal and liver toxicity was not observed. LEV-proliposomes should now be tested as an alternative formulation for delivering LEV to the lower airways.
Highlights
Tuberculosis (TB) is a contagious disease that has caused many problems for developing countries.Poverty, immigration and the rapid spread of acquired immunodeficiency syndrome (AIDS) have significantly reduced the effectiveness of controlling the disease [1]
Porous mannitol had a lower density than the non-porous one because of its porosity, and this should improve the aerodynamic properties of the mannitol particles
Porous mannitol was used as a core carrier for proliposome, so the proliposomes were expected to have improved aerodynamic properties [16,17]
Summary
Tuberculosis (TB) is a contagious disease that has caused many problems for developing countries. Immigration and the rapid spread of acquired immunodeficiency syndrome (AIDS) have significantly reduced the effectiveness of controlling the disease [1]. About 20%–25% of AIDS patients are infected with TB (pulmonary and extra-pulmonary TB infections), so TB is perhaps the most important opportunistic disease associated with AIDS [3]. The first line medication drugs such as isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin have high efficacy. The second line medication drugs are ethionamide, cycloserine, para-amino-salicylic acid (PAS), capreomycin, and fluoroquinolones, generally with a lower efficacy, and some have debilitating side effects and are expensive but can be useful in cases of MDR-TB patients [4]. The first line medication drugs have high efficacy, long-term treatment (at least six months) can result in liver and renal toxicity
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