Macrophage targeting of nitazoxanide-loaded transethosomal gel in cutaneous leishmaniasis

Topical delivery is preferable over systemic delivery for cutaneous
leishmaniasis (CL), because of its easy administration, reduced systemic
adverse effects, and low cost. Nitazoxanide (NTZ) has broad-spectrum
activity against various parasites and has the potential to avoid drug
resistance developed by enzymatic mutations. NTZ oral formulation is being
associated with severe dyspepsia and stomach pain. Herein,
NTZ-transethosomes (NTZ-TES) were prepared and loaded into chitosan gel
(NTZ-TEG) for topical delivery. NTZ-TES were prepared by
thin-film-hydration method and optimized statistically via Box-Behnken
method. The optimized formulation indicated excellent particle size (176
nm), PDI (0.093), zeta potential (-26.4 mV) and entrapment efficiency (EE,
86%). The TEM analysis showed spherical sized particles and FTIR analysis
indicated no interaction among the excipients. Similarly, NTZ-TEG showed
optimal pH, desirable viscosity and good spreadability. NTZ-TES and
NTZ-TEG showed prolonged release behavior and higher skin penetration and
deposition in epidermal/dermal layer of skin in comparison with the
NTZ-dispersion. Moreover, NTZ-TES showed higher percentage inhibition,
lower IC50 against promastigotes and higher macrophage uptake.
Additionally, skin irritation and histopathology studies indicated the
safe and non-irritant behavior of the NTZ-TEG. The obtained findings
suggested the enhanced skin permeation and improved anti-leishmanial
effect of NTZ when administered as NTZ-TEG.