Significant improvement of solubility and dissolution rate of Triclabendazole by complexation with cyclodextrins

SALOMON C.; LEONARDI D.; REAL D.

Santiago de Chile

Congreso; XXIV Congreso Latinoamericano de Parasitología; 2017

Facultad de Medicina de la Universidad de Chile

Objetives: Human fasciolasis, is a neglected tropical disease caused by the parasite Fasciola spp. Triclabendazole (TCBZ), a benzimidazole derivative, is one of the chosen drugs to treat and control fasciolasis. It is a poorly water-soluble (0.24 g/mL) and highly lipophilic (log p of 5.44) being included into the classes II and IV of the Biopharmaceutics Classification System. The aim of this work was to improve its water solubility and dissolution rate, by complexation with HP-β-Cyclodextrin (HP) and M-β-Cyclodextrin (ME). Methods: Physical mixtures (PMs) of TCBZ:HP and TCBZ:ME were prepared at 1:1 and 1:2 molar ratio by homogeneous blending in a mortar. Inclusion Complexes (IC) of TCBZ with HP and ME (1:1 and 1:2 molar ratio) were prepared by the solvent coevaporation procedure. Drug-cyclodextrin interactions in solution were investigated by phase solubility analysis and dissolution studies. Scanning electron microscopy (SEM), infrared spectroscopy (IR) and powder X-ray diffractometry (XRD) were used to characterize the solid state of the systems. The influence of storage conditions was evaluated after 24 months. Results: A significant improvement in the aqueous solubility of TCBZ IC was observed. In particular, drug solubility from TCBZ:ME 1:2 was found to be almost 500 times higher than the raw drug. TCBZ showed poor dissolution (2%) after six hours of the running assay. In contrast, all the systems exhibited better dissolution parameters than the drug alone. At 1:1 ratio TCBZ:ME and TCBZ:HP IC exhibited nearly 37% and 17% drug dissolution at 10 min, while 90% and 45% was found at 180 min, respectively. At 1:2 TCBZ:ME and TCBZ:HP IC showed 37% and 37% drug dissolution at 10 min, while 89% and 63% was observed at 180 min, respectively. Drug dissolution from TCBZ:ME IC, after storage, was almost similar compared to the fresh sample. By SEM, notorious changes in the morphology and shape of particles were seen in the IC, which appeared as pieces of irregular size. The infrared spectra of IC and PMs showed shifting and reduction of the mayor peaks of TCBZ. The XRD spectra of 1:1 IC showed an almost amorphous diffraction pattern which became slightly more crystalline after storage, in contrast, 1:2 IC exhibited an amorphous pattern which was not modified under storage. Conclusion: The interaction between TCBZ and CDs derivatives through the formation of IC lead to significant modifications in the solubility, dissolution rate and crystalline patterns of TCBZ. TCBZ:ME IC exhibited an almost equal solubility and dissolution rate after 2 years of storage, demonstrating that the ME could be considered for developing fast dissolving formulations of TCBZ.