AAPS PharmSciTech

, 20:239 | Cite as

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

  • Galit Regev
  • Sravan Kumar Patel
  • Bernard J. Moncla
  • John Twist
  • Brid Devlin
  • Lisa C. RohanEmail author
Research Article


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.


hot melt extrusion (HME) vaginal film microbicide quality by design (QbD) HIV prevention 



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.

Supplementary material

12249_2019_1442_MOESM1_ESM.docx (815 kb)
ESM 1 (DOCX 815 kb)


  1. 1.
    Garg S, Vermani K, Garg A, Anderson RA, Rencher WB, Zaneveld LJ. Development and characterization of bioadhesive vaginal films of sodium polystyrene sulfonate (PSS), a novel contraceptive antimicrobial agent. Pharm Res. 2005;22(4):584–95.CrossRefGoogle Scholar
  2. 2.
    Akil A, Parniak MA, Dezzuitti CS, Moncla BJ, Cost MR, Li M, et al. Development and characterization of a vaginal film containing dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), for prevention of HIV-1 sexual transmission. Drug Deliv Transl Res. 2011;1(3):209–22.CrossRefGoogle Scholar
  3. 3.
    Mishra R, Joshi P, Mehta T. Formulation, development and characterization of mucoadhesive film for treatment of vaginal candidiasis. Int J Pharm Investig. 2016;6(1):47–55.CrossRefGoogle Scholar
  4. 4.
    Dunkle KL, Jewkes RK, Brown HC, Gray GE, McIntryre JA, Harlow SD. Gender-based violence, relationship power, and risk of HIV infection in women attending antenatal clinics in South Africa. Lancet. 2004;363(9419):1415–21.CrossRefGoogle Scholar
  5. 5.
    Quinn TC, Overbaugh J. HIV/AIDS in women: an expanding epidemic. Science (New York, NY). 2005;308(5728):1582–3.CrossRefGoogle Scholar
  6. 6.
    Romano J, Malcolm RK, Garg S, Rohan LC, Kaptur PE. Microbicide delivery: formulation technologies and strategies. Curr Opin HIV AIDS. 2008;3(5):558–66.CrossRefGoogle Scholar
  7. 7.
    Raymond EG, Chen PL, Condon S, Luoto J, Barnhart KT, Creinin MD, et al. Acceptability of five nonoxynol-9 spermicides. Contraception. 2005;71(6):438–42.CrossRefGoogle Scholar
  8. 8.
    Nel AM, Mitchnick LB, Risha P, Muungo LT, Norick PM. Acceptability of vaginal film, soft-gel capsule, and tablet as potential microbicide delivery methods among African women. J Women's Health (Larchmt). 2011;20(8):1207–14.CrossRefGoogle Scholar
  9. 9.
    Elias C, Coggins C. Acceptability research on female-controlled barrier methods to prevent heterosexual transmission of HIV: where have we been? Where are we going? J Womens Health Gend Based Med. 2001;10(2):163–73.CrossRefGoogle Scholar
  10. 10.
    Koppolu S, Wang L, Mathur A, Nigam JA, Dezzutti CS, Isaacs C, et al. Vaginal product formulation alters the innate antiviral activity and glycome of cervicovaginal fluids with implications for viral susceptibility. ACS Infect Dis. 2018;4(11):1613–22.CrossRefGoogle Scholar
  11. 11.
    Bunge KE, Dezzutti CS, Rohan LC, Hendrix CW, Marzinke MA, Richardson-Harman N, et al. A phase 1 trial to assess the safety, acceptability, pharmacokinetics, and pharmacodynamics of a novel dapivirine vaginal film. J Acquir Immune Defic Syndr. 2016;71(5):498–505.CrossRefGoogle Scholar
  12. 12.
    Robinson JA, Marzinke MA, Bakshi RP, Fuchs EJ, Radebaugh CL, Aung W, et al. Comparison of dapivirine vaginal gel and film formulation pharmacokinetics and pharmacodynamics (FAME 02B). AIDS Res Hum Retrovir 2016;33(4):339–46.CrossRefGoogle Scholar
  13. 13.
    Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, et al. Pharmaceutical applications of hot-melt extrusion: part II. Drug Dev Ind Pharm. 2007;33(10):1043–57.CrossRefGoogle Scholar
  14. 14.
    Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Battu SK, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm. 2007;33(9):909–26.CrossRefGoogle Scholar
  15. 15.
    Crowley MM, Zhang F, Koleng JJ, McGinity JW. Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion. Biomaterials. 2002;23(21):4241–8.CrossRefGoogle Scholar
  16. 16.
    Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm. 2002;54(2):107–17.CrossRefGoogle Scholar
  17. 17.
    Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, et al. Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2009;53(2):487–95.CrossRefGoogle Scholar
  18. 18.
    Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, Soto-Torres LE, Govender V, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016;375(22):2121–32.CrossRefGoogle Scholar
  19. 19.
    Nel A, van Niekerk N, Kapiga S, Bekker LG, Gama C, Gill K, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016;375(22):2133–43.CrossRefGoogle Scholar
  20. 20.
    Gupta KM, Pearce SM, Poursaid AE, Aliyar HA, Tresco PA, Mitchnik MA, et al. Polyurethane intravaginal ring for controlled delivery of dapivirine, a nonnucleoside reverse transcriptase inhibitor of HIV-1. J Pharm Sci. 2008;97(10):4228–39.CrossRefGoogle Scholar
  21. 21.
    Aaltonen T, Adelman J, Akimoto T, Alvarez Gonzalez B, Amerio S, Amidei D, et al. Search for charged Higgs bosons in decays of top quarks in pp collisions at square root s = 1.96 TeV. Phys Rev Lett. 2009;103(10):101803.CrossRefGoogle Scholar
  22. 22.
    Moncla BJ, Pryke K, Rohan LC, Yang H. Testing of viscous anti-HIV microbicides using Lactobacillus. J Microbiol Methods. 2012;88(2):292–6.CrossRefGoogle Scholar
  23. 23.
    Nixon B, Stefanidou M, Mesquita PM, Fakioglu E, Segarra T, Rohan L, et al. Griffithsin protects mice from genital herpes by preventing cell-to-cell spread. J Virol. 2013;87(11):6257–69.CrossRefGoogle Scholar
  24. 24.
    Meuleman P, Albecka A, Belouzard S, Vercauteren K, Verhoye L, Wychowski C, et al. Griffithsin has antiviral activity against hepatitis C virus. Antimicrob Agents Chemother. 2011;55(11):5159–67.CrossRefGoogle Scholar
  25. 25.
    Maniruzzaman M, Boateng JS, Snowden MJ, Douroumis D. A review of hot-melt extrusion: process technology to pharmaceutical products. ISRN Pharm. 2012;2012:436763.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Vynckier AK, Dierickx L, Voorspoels J, Gonnissen Y, Remon JP, Vervaet C. Hot-melt co-extrusion: requirements, challenges and opportunities for pharmaceutical applications. J Pharm Pharmacol. 2014;66(2):167–79.CrossRefGoogle Scholar
  27. 27.
    Vallor AC, Antonio MAD, Hawes SE, Hillier SL. Factors associated with acquisition of, or persistent colonization by, vaginal lactobacilli: role of hydrogen peroxide production. J Infect Dis. 2001;184(11):1431–6.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Galit Regev
    • 1
    • 2
  • Sravan Kumar Patel
    • 1
    • 2
  • Bernard J. Moncla
    • 3
  • John Twist
    • 4
  • Brid Devlin
    • 5
  • Lisa C. Rohan
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyUniversity of PittsburghPittsburghUSA
  2. 2.Magee-Womens Research InstitutePittsburghUSA
  3. 3.Department of Obstetrics, Gynecology and Reproductive Sciences, School of MedicineUniversity of PittsburghPittsburghUSA
  4. 4.Mylan® Pharmaceuticals Inc.MorgantownUSA
  5. 5.International Partnership of MicrobicidesSilver SpringUSA

Personalised recommendations