Increase of solubility and transmembrane permeability of niclosamide from its mechanochemically synthesized solid dispersions

Abstract

More than 4.5 billion people worldwide are affected by parasitic diseases, with helminth infections accounting for 99% of the total number. Niclosamide (NS) is a weakly acidic active pharmaceutical ingredient (API) used to treat helminth infections. However, the pharmaceutical use of pure niclosamide is limited by its low bioavailability due to its poor aqueous solubility. The aim of this work is a mechanochemical preparation of niclosamide solid dispersions with increased solubility. Due to the pH dependence of NS water solubility and possible complexes formation, NS solid dispersions (SD) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and alkalizing agents, such as calcium carbonate (CaCO3) and N-methyl-D-glucamine (MG) are mechanochemically prepared in this study. The physical properties of NS SD in solid state are characterized by differential scanning calorimetry, X-ray diffraction, FT-IR spectroscopy, and scanning electron microscopy studies. The characteristics of the water solutions formed from the obtained SDs are analyzed by HPLC. It is shown that the solubility increases for all studied compositions. These phenomena are obliged by complexation with HP-β-CD, which was shown by 1H-NMR methods, and enhanced ionization in the cases of using calcium carbonate and MG. Results of the parallel artificial membrane permeability assay (PAMPA) have shown that mechanochemically obtained NS/MG SD (1/1 mass ratio, 8 h milling) significantly enhances permeation of NS across an artificial membrane. Thus, the obtained compositions are a promising basis for the development of NS-based preparations for oral administration, with reduced dose and high pharmacological effect.