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 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.
Gibaud
Stéphane
S
Laboratoire de Pharmacie Clinique, EA 3452, Faculté de Pharmacie, 5 Rue Albert Lebrun, 54000 Nancy, France. stephane.gibaud@pharma.uhp-nancy.fr
Zirar
Siham Ben
SB
Mutzenhardt
Pierre
P
Fries
Isabelle
I
Astier
Alain
A
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003505:Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology; D004339:Drug Compounding; D004355:Drug Stability; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008549:Melarsoprol / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D012995:Solubility
D000970:Antineoplastic Agents; D003505:Cyclodextrins; D008549:Melarsoprol