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Novel Application of Hot Melt Extrusion for the Manufacturing of Vaginal Films Containing Microbicide Candidate Dapivirine

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Abstract

Polymeric films are safe and effective and can be used for vaginal administration of microbicide drug candidates. Dapivirine (DPV), an investigational and clinically advanced antiretroviral drug, was selected as a model compound for this study. We have previously developed and clinically tested a quick-dissolving DPV film using solvent cast (SC) manufacturing technique. As an alternative to current pharmaceutical film manufacturing techniques, we investigated hot melt extrusion (HME) process in this study because it has several benefits, including its capacity as a continuous manufacturing process, lack of solvents, smaller footprint, and ease of scalability. The goal of this work was to evaluate the feasibility of using HME for DPV vaginal film manufacturing and to develop a robust manufacturing process using HME by evaluating the effect of process parameters on film quality and performance. DPV was successfully incorporated into a vaginal film using HME and maintained acceptable characteristics. Three process parameters (zone temperature, screw speed, and feed rate) had an impact on film quality and performance. Of these, the zone temperature was found to most significantly affect weight, thickness, puncture strength, and dissolution of films. Additionally, film manufacturing using HME was highly reproducible. Finally, the DPV HME film was comparable to films manufactured using SC in terms of physicochemical, biological, and safety characteristics including in vitro drug release, mechanical strength, tissue permeability, compatibility with commensal vaginal Lactobacilli, and in vitro bioactivity. These results demonstrate that HME is an effective, robust, and viable manufacturing method to produce vaginal films.

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ACKNOWLEGMENTS

The project was supported by the Bill and Melinda Gates foundation (grant no. OPP1110953) and the National Institute of Allergy and Infectious Diseases at the National Institute of Health (grant no. U19 AI082639). We would like to acknowledge the International Partnership for Microbicides for providing the DPV drug for these studies; Ms. Lucia Cencia, Ms. Christina Bagia, Ms. Amanda Micklo, and Ms. Elaine Xu, for assisting with the DPV sample preparation and HPLC runs for the process analysis study; and Ms. Taryn Serman for assisting with tissue processing. We would like to acknowledge the contribution of Dr. Charlene S. Dezzutti (deceased) for her support with bioactivity evaluation.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Galit Regev, Sravan Kumar Patel & Lisa C. Rohan

  2. Magee-Womens Research Institute, Pittsburgh, PA, 15213, USA

    Galit Regev, Sravan Kumar Patel & Lisa C. Rohan

  3. Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Bernard J. Moncla & Lisa C. Rohan

  4. Mylan® Pharmaceuticals Inc., Morgantown, WV, 26505, USA

    John Twist

  5. International Partnership of Microbicides, Silver Spring, MD, 20910, USA

    Brid Devlin

Authors
  1. Galit Regev
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  2. Sravan Kumar Patel
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  3. Bernard J. Moncla
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  4. John Twist
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  5. Brid Devlin
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  6. Lisa C. Rohan
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Correspondence to Lisa C. Rohan.

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Regev, G., Patel, S.K., Moncla, B.J. et al. Novel Application of Hot Melt Extrusion for the Manufacturing of Vaginal Films Containing Microbicide Candidate Dapivirine. AAPS PharmSciTech 20, 239 (2019). https://doi.org/10.1208/s12249-019-1442-8

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