Abstract
The role of mycobacterial efflux pumps in drug-resistant tuberculosis has been widely reported. Recently, a new compound, named SS13, has been synthesized, and its activity as a potential efflux inhibitor has been demonstrated. In this work, the chemical–physical properties of the SS13 were investigated; furthermore, a formulative study aimed to develop a formulation suitable for oral administration was performed. SS13 shows nonintrinsic antitubercular activity, but it increases the antitubercular activity of all the tested drugs on several strains. SS13 is insoluble in different simulated gastrointestinal media; thus, its oral absorption could be limited. Solid lipid nanoparticles (SLNs) were, therefore, developed by using two different lipids, Witepsol and/or Gelucire. Nanoparticles, having a particle size (range of 200–450 nm with regards to the formulation composition) suitable for intestinal absorption, are able to load SS13 and to improve its permeation through the intestinal mucosa compared to the pure compound. The cytotoxicity is influenced by the concentration of nanoparticles administered. These promising results support the potential application of these nanocarriers for increasing the oral permeation of SS13 in multidrug-resistant tuberculosis management.
Highlights
Tuberculosis (TB) is a lung infection caused by Mycobacterium tuberculosis
The negatively stained Solid lipid nanoparticles (SLNs) were observed by TEM, and data and images were analyzed with a Digital Micrograph from Gatan and with TIA software
The SS13 content recovered inside the mucosa and on the intestinal surface was expressed as a percentage with respect to the amount of SS13 in SLNs (n = 3 ± SD) [33]
Summary
Tuberculosis (TB) is a lung infection caused by Mycobacterium tuberculosis. The World Health Organization reported that, after HIV, TB is the second leading cause of death induced by one infectious agent. Treatment outcomes for MDR and XDR-TB are still poor, resulting in high rates of deaths This highlights the urgent need to improve the development of innovative treatment regimens by introducing new drugs that may overcome the growing diffusion of MDR/XDR-TB, such as new compounds that elude the target mutation [8] or efflux-pump inhibitors (EPIs) that revert the drug resistance. On the basis of the results obtained, novel derivatives (EPIs) were designed to be more selective against M. tuberculosis efflux pumps to restore the activity of anti-TB drugs by reducing their cell extrusion. Gelucire is a lipid excipient derived from a mixture of glyceride-based materials and esters of polyethylene glycol widely studied to enhance solubility, stability and dissolution rate after oral administration [25]. The improvement of bioavailability associated with this excipient can be due to its excellent surface-active property that increases drug solubilization, favoring absorption [26]
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