UC781: BETA-CYCLODEXTRIN COMPLEXATION AND FORMULATION AS AN ANTI-HIV MICROBICIDE

摘要

ABSTRACTBackground: UC781, a tight-binding non-nucleotide reverse transcriptase inhibitor (NNRTI) of HIV-1, is a thiocarboxanilide that has been identified as a potential microbicide agent. UC781 prevents HIV-1 infection by potently inhibiting HIV-1 replication (EC50„l8nM) with a broad therapeutic index (>62,000). However, its extremely poor water solubility leads to a great challenge for its formulation development. A beta-cyclodextrin (beta-CD) based drug delivery system was developed for UC781 to overcome this issue.Method: The complex of UC781: beta-CD was assessed with UV, FTIR, DSC, and NMR. An HPLC method was used to investigate the thermodynamic behavior of the UC781 complex. Complexation of UC781 with either hydroxypropyl -beta-Cyclodextrin (HP-beta-CD) or methyl-beta-cyclodextrin (M-beta-CD) was optimized by evaluation of four processing methods (autoclave, lyophilization, shaking, and kneading), incorporation of four water-soluble polymers (HPMC, HEC, PVA, and PVP K30), and utilization of three buffering systems (pH 7.0, 9.0 and 11.0). Finally, three formulations¡Xmethylcellulose (MC) gel, hydroxyethylcellulose (HEC) gel, and polyvinyl alcohol (PVA) film¡Xwere developed for UC781. The physical properties, toxicity, and anti-HIV activity of UC781 containing formulations were evaluated with in vitro and ex vivo models. Results: Complexation of UC781 with beta-CDs was confirmed and characterized with UV, FTIR, DSC, and NMR. UC781¡¦s complexation was found to be an enthalpy driven process. The solubility of UC781 was increased from almost none to 35 ug/ml in 15% HP-beta- CD and 180 ug/ml in 15% M-beta- CD solutions after optimization.Complexation technique significantly improved the release of UC781 from all three formulations. The complexation of UC781 with HP-beta- CD or M-beta- CD greatly increased the osmolality and decreased the viscosity of MC and HEC gel; shortened the disintegration time of PVA film; and reduced IC50 for UC781 in all three formulations. No observed toxicity was found in all complexed UC781 containing formulations.Conclusion:beta-CD complexation technique provided an effective method to overcome the aqueous solubility challenge for UC781. UC781 complexation can be used as a safe and effective drug delivery system for UC781. Of the formulations tested, PVA film with complexed UC781 provided the most promising option for microbicide product development.