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

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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References

  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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    Article  Google Scholar 

  5. 5.

    Quinn TC, Overbaugh J. HIV/AIDS in women: an expanding epidemic. Science (New York, NY). 2005;308(5728):1582–3.

    CAS  Article  Google 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.

    Article  Google 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.

    CAS  Article  Google 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.

    Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

  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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google Scholar 

  16. 16.

    Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm. 2002;54(2):107–17.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    PubMed  PubMed Central  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google Scholar 

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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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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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KEY WORDS

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