Melarsoprol-cyclodextrins inclusion complexes

Melarsoprol, a water-insoluble drug, is mainly used in the treatment of trypanosomiasis and has demonstrated an in vitro activity on myeloid and lymphoid leukemia derived cell lines. It is marketed as a very poorly tolerated non-aqueous solution (Arsobal®). The aim of our work was to develop melarsoprol-cyclodextrin complexes in order to improve the tolerability and the bioavailability of melarsoprol. Phase-solubility analysis showed AL-type diagrams with β-cyclodextrin (βCD), randomly methylated β-cyclodextrin (RAMEβCD) and hydroxypropyl-β-cyclodextrin (HPβCD), which suggested the formation of 1:1 inclusion complexes. The solubility enhancement factor of melarsoprol (solubility in 250 mM of cyclodextrin/solubility in water) was about 7.2 × 103 with both β-cyclodextrin derivatives. The 1:1 stoichiometry was confirmed in the aqueous solutions by the UV spectrophotometer using Job's plot method. The apparent stability constants K1:1, calculated from mole-ratio titration plots, were 57 143 ± 4 425 M−1 for RAMEβCD and 50 761 ± 5 070 M−1 for HPβCD. Data from 1H-NMR and ROESY experiments provided a clear evidence of inclusion complexation of melarsoprol with its dithiaarsane extremity inserted into the wide rim of the cyclodextrin torus. Moreover, RAMEβCD had a pronounced effect on the drug hydrolysis and the dissolution rate of melarsoprol. However, the cytotoxic properties of melarsoprol on K562 and U937 human leukemia cell lines was not modified by complexation.