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Preformulation and Vaginal Film Formulation Development of Microbicide Drug Candidate CSIC for HIV Prevention

Journal of Pharmaceutical Innovation volume 12, pages 142–154 (2017)Cite this article

Abstract

Purpose

5-Chloro-3-[phenylsulfonyl] indole-2-carboxamide (CSIC) is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 which has been shown to have a more desirable resistance profile than other NNRTIs in the development as HIV prevention strategies. This work involves generation of preformulation data for CSIC and systematic development of a cosolvent system to effectively solubilize this hydrophobic drug candidate. This system was then applied to produce a polymeric thin film solid dosage form for vaginal administration of CSIC for use in prevention of sexual acquisition of HIV.

Methods

Extensive preformulation, formulation development, and film characterization studies were conducted. An HPLC method was developed for CSIC quantification. Preformulation tests included solubility, crystal properties, stability, and drug-excipient compatibility. Cytotoxicity was evaluated using both human epithelial and mouse macrophage cell lines. Ternary phase diagram methodology was used to identify a cosolvent system for CSIC solubility enhancement. Following preformulation evaluation, a CSIC film formulation was developed and manufactured using solvent casting technique. The developed film product was assessed for physicochemical properties, anti-HIV bioactivity, and Lactobacillus biocompatibility during 12-month stability testing period.

Results

Preformulation studies showed CSIC to be very stable. Due to its hydrophobicity, a cosolvent system consisting of polyethylene glycol 400, propylene glycol, and glycerin (5:2:1, w/w/w) was developed, which provided a uniform dispersion of CSIC in the film formulation. The final film product met target specifications established for vaginal microbicide application.

Conclusions

The hydrophobic drug candidate CSIC was successfully formulated with high loading capacity in a vaginal film by means of a cosolvent system. The developed cosolvent strategy is applicable for incorporation of other hydrophobic drug candidates in the film platform.

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Acknowledgements

The current work was funded through the Integrated Preclinical/Clinical Program for Microbicide Development (grant number U19 AI082623) and the Microbicide Innovation Program (grant number AI079801) of the National Institute of Allergy and Infectious Diseases, Division of AIDS. We would like to acknowledge Eva Nagy (University of Pittsburgh, School of Medicine) for her assistance with the bioactivity study. We also would like to thank Albert Stewart for his kind help with the SEM imaging conducted in this study. We would like to acknowledge Sravan Kumar Patel for his help with the editing/proofreading of this manuscript.

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Affiliations

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

    Tiantian Gong, Wei Zhang & Lisa C. Rohan

  2. Magee-Womens Research Institute, Pittsburgh, PA, USA

    Tiantian Gong, Wei Zhang, Phillip W. Graebing, Bernard Moncla & Lisa C. Rohan

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

    Michael A. Parniak

  4. Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Bernard Moncla & Lisa C. Rohan

  5. Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Phalguni Gupta

  6. Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Kerry M. Empey

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  1. Tiantian Gong
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  2. Wei Zhang
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Correspondence to Lisa C. Rohan.

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Gong, T., Zhang, W., Parniak, M.A. et al. Preformulation and Vaginal Film Formulation Development of Microbicide Drug Candidate CSIC for HIV Prevention. J Pharm Innov 12, 142–154 (2017). https://doi.org/10.1007/s12247-017-9274-0

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  • DOI: https://doi.org/10.1007/s12247-017-9274-0

Keywords

  • Microbicide
  • Ternary phase diagram
  • Drug-excipient compatibility
  • Solvent cast
  • Vaginal drug delivery