Characterization of Cyclodextrin Inclusion Complexes of the Anti-HIV Non-Nucleoside Reverse Transcriptase Inhibitor UC781

Abstract

Abstract. The highly potent anti-HIV agent UC781 is being evaluated for use in topical microbicides to prevent HIV transmission. However, UC781 is extremely hydrophobic with poor water solubility, a property that may complicate appropriate formulation of the drug. In this study, we examined the ability of several cyclodextrins, beta-cyclodextrin (βCD), methyl-beta-cyclodextrin (MβCD), and 2-hydroxylpropyl-beta-cyclodextrin (HPβCD), to enhance the aqueous solubility of UC781. Each of the cyclodextrins provided dramatic increases in UC781 aqueous solubility, the order being MβCD>HPβCD>βCD. The complexation constants (K 1:1 ) of the inclusion complexes were determined via a phase solubility technique using high-performance liquid chromatography and showed that UC781 solubility increased linearly as a function of cyclodextrin concentration. Ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and 2D 1 H ROESY NMR spectroscopy were used to further characterize these UC781/cyclodextrin complexes. The inhibitory potency of UC781 and its HPβCD inclusion complex were evaluated using an in vitro HIV-1 reverse transcriptase inhibition assay The inhibitory potency of the UC781/HPβCD complex was 30-fold greater than that of UC781 alone, showing that the complexed drug is able to provide substantial inhibition of its target. The enhancement of UC781 aqueous solubility is essential for the development of a useful vaginal microbicide dosage form, and our data suggest that UC781/cyclodextrin inclusion complexes may be useful in this context.

Characterization of UC781-Tenofovir Combination Gel Products for HIV-1 Infection Prevention in an Ex Vivo Ectocervical Model

“…Clinically, as mentioned earlier, TFV proved a reduction of HIV-1 infection incidence (1). On the other hand, UC781 is the first NNRTI proven to be potent against HIV-1 in in vitro and ex vivo studies (3,9,12,14,17,21,28,36,37). In a pig-tailed macaque model, UC781 gel was found to be safe when applied vaginally (31).…”

Advanced topical drug delivery system for the management of vaginal candidiasis

“…Hydroxypropyl-b-cyclodextrin complex was reported to increase solubility of Amphotericin B; when both were formulated as thermo-sensitive, pH-sensitive gel, controlled release was successfully achieved. Cyclodextrin complexes were also successfully employed in anti-viral therapy to deliver anti-HIV agents (Yang et al, 2008). Chang Yun et al (2002 fabricated Clotrimazole-loaded cyclodextrin complex by using combination of poloxamers (P) 407, 188, and polycarbophil (PC).…”

Microbicide Dosage Forms

“…A number of drug candidates being evaluated for their use in HIV prevention have also been formulated as film dosage forms, including several with nonspecific action against HIV such as sodium dodecyl sulfate (SDS) (Yoo et al 2006) and cellulose acetate phthalate (Neurath et al 2001(Neurath et al , 2003 cellulose acetate 1,2 benzenedicarboxylate (Trifonova et al 2006) and the nucleoside reverse transcriptase inhibitor zidovudine (AZT) (Chatterjee et al 2010), the non-nucleoside reverse transcriptase inhibitors UC781 (Yang et al 2008), dapivirine (Akil et al 2011), and the pyrimidinedione IQP-0528 (Ham et al 2012) and the gp120 inhibitor RC-101 (Cole et al 2010;Sassi et al 2011). A number of other anti-HIV agents are being formulated as vaginal films including small molecule drugs, proteins, peptides, monoclonal antibodies, and probiotics.…”