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 A(L)-type diagrams with
beta-cyclodextrin (betaCD), randomly methylated
beta-cyclodextrin (RAMEbetaCD) and
hydroxypropyl-beta-cyclodextrin (
HPbetaCD), 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 7.2x10(3) with both
beta-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 K(1:1), calculated from mole-ratio titration plots, were 57 143+/-4 425M(-1) for RAMEbetaCD and 50 761+/-5 070 M(-1) for
HPbetaCD. 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, RAMEbetaCD 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.