Matryoshka-type enteric microparticles for the treatment of tuberculosis

Introduction The World Health Organization reported in 2015 that the tuberculosis still constitutes a major cause of morbidity and mortality worldwide. The treatment used nowadays presents different limitations such as... [ view full abstract ]

Introduction
The World Health Organization reported in 2015 that the tuberculosis still constitutes a major cause of morbidity and mortality worldwide. The treatment used nowadays presents different limitations such as non-localised delivery of drugs, high dose and large treatment duration as well as the side effects that it produces.
The aim of this work was to investigate a new polymeric drug-delivery system that may provide enhanced drug delivery at the site of infection, hence reducing drug associated side-effects and the probability of developing drug resistance. In that sense, matryoshka-type enteric microparticles containing rifampicin-loaded PLGA nanoparticles were developed as a potential effective oral therapeutic alternative to achieve appropriate intracellular concentrations in tuberculosis-infected alveolar macrophages.

Methods
Rifampicin-loaded PLGA nanoparticles (NPs) were prepared by the oil-in-water single-emulsion solvent-evaporation method and those NPs were encapsulated in turn within enteric monodisperse Eudragit-based-microcapsules using the double emulsification and evaporation method. The morphological characterization of micro- and nanoparticles has been carried out by several techniques (SEM, TEM, DLS, FT-IR).
In vitro antimycobacterial activity of rifampicin, unloaded-PLGA nanoparticles and rifampicin-loaded PLGA nanoparticles were determined on M. tuberculosis H37Rv at intracellular and extracellular pH. Also, in vitro permeability of these NPs through the intestinal epithelium was evaluated using an artificial monolayer of gastroinstestinal epithelial cells.

Results
The colloidal hydrodynamic sizes of rifampicin-PLGA NPs were 145.2 ± 31.2 nm. HPLC analysis indicated that the EE and DL achieved for these NPs were 5.4 ± 0.55 and 1.08 ± 0.11 w/w %, respectively. SEM morphological analysis of enteric Eudragit-microcapsules revealed a bipyramidal structure of micrometric size (6.1 ± 1.9 µm). The enteric coating remains unaltered under simulated gastric conditions and the inner antibiotic-loaded NPs were rapidly released under simulated intestinal conditions.
Antimicrobial activity of the free and the encapsulated rifampicin showed similar levels of bacterial eradication.

Discussion
An intracellular accumulation and slow antibiotic release can be achieved using orally administered enteric microparticles containing rifampicin-loaded PLGA NPs if they were able to extravasate through the intestinal epithelium into the blood stream with the sufficient blood circulation half-life to reach tuberculosis-infected alveolar macrophages.