Formulation of benznidazole-lipid nanocapsules: Drug release, permeability, biocompatibility, and stability studies

Benznidazole, a poorly soluble in water drug, is the first-line medication for the treatment of Chagas disease, but long treatment periods at high dosages cause several adverse effects with insufficient activity in the chronic phase. According to these facts, there is a serious need for novel benznidazole formulations for improving the chemotherapy of Chagas disease. Thus, this work aimed to incorporate benznidazole into lipid nanocapsules for improving its solubility, dissolution rate in different media, and permeability. Lipid nanocapsules were prepared by the phase inversion technique and were fully characterized. Three formulations were obtained with a diameter of 30, 50, and 100 nm and monomodal size distribution with a low polydispersity index and almost neutral zeta potential. Drug encapsulation efficiency was between 83 and 92% and the drug loading was between 0.66 and 1.04%.

Loaded formulations were stable under storage for one year at 4 °C. Lipid nanocapsules were found to protect benznidazole in simulated gastric fluid and provide a sustained release platform for the drug in a simulated intestinal fluid containing pancreatic enzymes. The small size and the almost neutral surface charge of these lipid nanocarriers improved their penetration through mucus and such formulations showed a reduced chemical interaction with gastric mucin glycoproteins. LNCs. The incorporation of benznidazole in lipid nanocapsules improved the drug permeability across intestinal epithelium by 10-fold compared with the non-encapsulated drug while the exposure of the cell monolayers to these nanoformulations did not affect the integrity of the epithelium.

Materials

Benznidazole (BNZ; N-benzyl-2-(2-nitroimidazol-1-yl)acetamide; Abarax, lot 9978 A; Laboratorios Elea, Buenos Aires, Argentina) was provided by Instituto Nacional de Parasitología, ANLIS Malbrán, Ministerio de Salud de la Nación, (Buenos Aires, Argentina). Kolliphor® HS 15 (mixture of free PEG 660 and PEG 660 hydroxy stearate) and Lipoid S100 were obtained from BASF SE and Lipoid GmbH (Ludwigshafen, Germany), respectively. Labrafac® WL 1349 from Gattefossé.

Eva C. Arrua, Olga Hartwig, Brigitta Loretz, Xabier Murgia, Duy-Khiet Ho, Guillaume Bastiat, Claus-Michael Lehr, Claudio J. Salomón, Formulation of benznidazole-lipid nanocapsules: Drug release, permeability, biocompatibility, and stability studies, International Journal of Pharmaceutics, 2023, 123120, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2023.123120.