Abstract

The aim of the study was the production of solid lipid nanoparticles (SLN) loaded with ciprofloxacin (CIP) through two different production techniques, quasi-emulsion solvent diffusion (QESD) and solvent injection (SI). In order to efficaciously entrap the commercial salt form (hydrochloride) of the antibiotic in these lipid systems, a conversion of CIP hydrochloride to the free base was realized in situ, through the addition of triethylamine. To ensure physical stability to the carriers over time and ameliorate the interaction with bacterial cell membranes, positively charged SLN were produced by addition of the cationic lipid didecyldimethylammonium bromide (DDAB). Homogeneous SLN populations with a mean particle sizes of 250–350 nm were produced by both methods; drug encapsulation was over 85% for most samples. The SLN were physically stable for up to nine months both at 4 °C and 25 °C, although the former condition appears more suitable to guarantee the maintenance of the initial particle size distribution. As expected, CIP encapsulation efficiency underwent a slight reduction after nine months of storage, although the initial high drug content values would ensure a residual concentration of the antibiotic in the SLN still appropriate to exert an acceptable antibacterial activity. Selected SLN formulations were subjected to an in vitro microbiological assay against different bacterial strains, to verify the effect of nanoencapsulation on the cell growth inhibitory activity of CIP. In general, CIP-SLN produced without DDAB showed MIC values for CIP comparable to those of the free drug. Conversely, addition of increasing percentages of the cationic lipid, reflected by a progressive increase of the positive value of the Zeta potential, showed a variety of MIC values against the various bacterial strains, but with values 2–4 order of dilution lower than free CIP. An hypothesis of the effect of the cationic lipid upon the increased antibacterial activity of CIP in the nanocarriers is also formulated.

Highlights

  • Ciprofloxacin (CIP) is a broad spectrum bactericidal antibiotic highly effective against Gram-positive and Gram-negative bacteria, frequently used in urinary tract infections [1], respiratory infections [2], otitis media treatment [3], and in external ocular infections [4,5]

  • This action very selective on these two types of enzymes is due to the remarkable conservation of protein sequences between the DNA gyrase subunit A and topoisomerase IV subunit C in the quinolone resistance determining region (QRDR), present in bacteria

  • The solubility of the drug is a key factor, because the methodology used for the preparation of nanoparticles requires that the drug is dissolved in an organic solvent, which in turn must be miscible with the aqueous phase

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Summary

Introduction

Ciprofloxacin (CIP) is a broad spectrum bactericidal antibiotic highly effective against Gram-positive and Gram-negative bacteria, frequently used in urinary tract infections [1], respiratory infections [2], otitis media treatment [3], and in external ocular infections [4,5]. CIP is used in cases of sexually transmitted bacteria, sepsis, and legionella. As other molecules of quinolones class, CIP acts by inhibiting DNA gyrase and topoisomerase IV. This action very selective on these two types of enzymes is due to the remarkable conservation of protein sequences between the DNA gyrase subunit A (gyrA) and topoisomerase IV subunit C (parC) in the quinolone resistance determining region (QRDR), present in bacteria. Progressively more cases of resistance to fluoroquinolones have been registered [6,7]. Resistance is mediated mainly by spontaneous mutations in the QRDR of gyrA and parC genes, causing reduced drug accumulation [8]

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