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

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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 1H 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.

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Acknowledgements

We gratefully acknowledge Drs. Billy Day, Stephen Weber, and Bernard Moncla for providing access to critical instrumentation for use in these studies. We also acknowledge CONRAD for providing UC781 for these studies. This work was supported in part by NIH grant AI051661.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Haitao Yang & Lisa C. Rohan

  2. Magee-Womens Research Institute, 204 Craft Avenue, B509, Pittsburgh, Pennsylvania, 15213, USA

    Haitao Yang, Sharon L. Hillier & Lisa C. Rohan

  3. Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Michael A. Parniak

  4. Department of Developmental Biochemistry, New York State Institute for Basic Research, Staten Island, New York, USA

    Charles E. Isaacs

  5. Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Sharon L. Hillier & Lisa C. Rohan

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  1. Haitao Yang
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  2. Michael A. Parniak
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Correspondence to Lisa C. Rohan.

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Yang, H., Parniak, M.A., Isaacs, C.E. et al. Characterization of Cyclodextrin Inclusion Complexes of the Anti-HIV Non-Nucleoside Reverse Transcriptase Inhibitor UC781. AAPS J 10, 606–613 (2008). https://doi.org/10.1208/s12248-008-9070-3

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  • DOI: https://doi.org/10.1208/s12248-008-9070-3

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