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Designing and developing suppository formulations for anti-HIV drug delivery

    Anthony S Ham

    ImQuest BioSciences, Inc., 7340 Executive Way, Suite R, Frederick, MD 21704, USA

    &
    Robert W Buckheit

    *Author for correspondence:

    E-mail Address: rbuckheit@imquestbio.com

    ImQuest BioSciences, Inc., 7340 Executive Way, Suite R, Frederick, MD 21704, USA

    Published Online:https://doi.org/10.4155/tde-2017-0056

    Despite a long history of use for rectal and vaginal drug delivery, the current worldwide market for suppositories is limited primarily due to a lack of user acceptability. Therefore, virtually no rational pharmaceutical development of antiviral suppositories has been performed. However, suppositories offer several advantages over other antiviral dosage forms. Current suppository designs have integrated active pharmaceutical ingredients into existing formulation designs without optimization. As such, emerging suppository development has been focused on improving upon the existing classical design to enhance drug delivery and is poised to open suppository drug delivery to a broader range of drugs, including antiretroviral products. Thus, with continuing research into rational suppository design and development, there is significant potential for antiretroviral suppository drug delivery.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 History of the Suppository Form. Aiache JM, Renoux R, Fistre D (Eds). J.R. Prous Publishers, Barcelona, Spain (1984).
    • 2 Shah SM, Sultan AH, Thakar R. The history and evolution of pessaries for pelvic organ prolapse. Int. Urogynecol. J. Pelvic Floor Dysfunct. 17(2), 170–175 (2006).
    • 3 FDA. U.S. Food and Drug Administration: Rectal Drugs. 2017(03–01). www.fda.gov.
    • 4 FDA. U.S. Food and Drug Administration: Vaginal Drugs. 2017(4/20). www.fda.gov.
    • 5 Jannin V, Lemagnen G, Gueroult P, Larrouture D, Tuleu C. Rectal route in the 21st Century to treat children. Adv. Drug. Deliv. Re.v 73, 34–49 (2014). •• A comprehensive review of suppositories for pediatric administration and the role of suppositories in the world market.
    • 6 Pharmacopoeia E. European Directorate for the Quality of Medicines and Healthcare. Rectal Preparations EP 01/2008:1145 (2011).
    • 7 Pharmacopoeia US. The U.S. Pharmacopoeia. Nomenclature Guidlines <1121> 36 (2016).
    • 8 Pharmacopoeia J. The Japanese Pharmacopoeia: 17th Edition. Monogrpahs for Preparations 18–19 (2016).
    • 9 Ham AS, Ugaonkar SR, Shi L et al. Development of a combination microbicide gel formulation containing IQP-0528 and tenofovir for the prevention of HIV infection. J. Pharm. Sci. 101(4), 1423–1435 (2012).
    • 10 Dezzutti CS, Rohan LC, Wang L et al. Reformulated tenofovir gel for use as a dual compartment microbicide. J. Antimicrob. Chemother. 67(9), 2139–2142 (2012).
    • 11 Rohan LC, Moncla BJ, Kunjara Na Ayudhya RP et al. In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. PLoS ONE 5(2), e9310 (2010).
    • 12 Akil A, Parniak M, Dezzutti C 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. 1(3), 209–222 (2011).
    • 13 Gupta KM, Pearce SM, Poursaid AE et al. Polyurethane intravaginal ring for controlled delivery of dapivirine, a nonnucleoside reverse transcriptase inhibitor of HIV-1. J. Pharm. Sci. 97(10), 4228–4239 (2008).
    • 14 Ham AS, Rohan LC, Boczar A, Yang L, Buckheit K, Buckheit RW Jr. Vaginal film drug delivery of the pyrimidinedione IQP-0528 for the prevention of HIV infection. Pharm. Res. (2012).
    • 15 Ham AS, Nugent ST, Peters JJ et al. The rational design and development of a dual chamber vaginal/rectal microbicide gel formulation for HIV prevention. Antiviral. Res. 120, 153–164 (2015).
    • 16 Dezzutti CS, Yandura S, Wang L et al. Pharmacodynamic activity of dapivirine and maraviroc single entity and combination topical gels for HIV-1 prevention. Pharm. Res. 32(11), 3768–3781 (2015).
    • 17 Das Neves J, Martins JP, Sarmento B. Will dapivirine redeem the promises of anti-HIV microbicides? Overview of product design and clinical testing. Adv. Drug. Deliv. Rev. 103, 20–32 (2016).
    • 18 Naicker N, Naidoo A, Werner L et al. Efficacy and safety of tenofovir-containing antiretroviral therapy in women who acquired HIV while enrolled in tenofovir gel prophylaxis trials. Antivir. Ther. (2016).
    • 19 Pereira LE, Mesquita PM, Ham A et al. Pharmacokinetic and pharmacodynamic evaluation following vaginal application of IQB3002, a dual-chamber microbicide gel containing the nonnucleoside reverse transcriptase inhibitor IQP-0528 in Rhesus macaques. Antimicrob. Agents. Chemother. 60(3), 1393–1400 (2015).
    • 20 Marrazzo JM, Ramjee G, Richardson BA et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 372(6), 509–518 (2015).
    • 21 Rees H, Delany-Moretlwe S, Baron D et al. FACTS 001 Phase III trial of pericoital tenofovir 1% gel for HIV prevention in women. CROI (2015). • A report on the clinical trial of a vaginally administered microbicide in African women. The results illustrate the need to consider user acceptability in HIV prevention design.
    • 22 Abdool Karim Q, Abdool Karim SS, Frohlich JA et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329(5996), 1168–1174 (2010).
    • 23 Van Der Straten A, Stadler J, Montgomery E et al. Women's experiences with oral and vaginal pre-exposure prophylaxis: the VOICE-C qualitative study in Johannesburg, South Africa. PLoS ONE 9(2), e89118 (2014).
    • 24 Zhang W, Hu M, Shi Y et al. Vaginal microbicide film combinations of two reverse transcriptase inhibitors, EFdA and CSIC, for the prevention of HIV-1 sexual transmission. Pharm. Res. 32(9), 2960–2972 (2015).
    • 25 Grammen C, Van Den Mooter G, Appeltans B et al. Development and characterization of a solid dispersion film for the vaginal application of the anti-HIV microbicide UAMC01398. Int. J. Pharm. 475(1–2), 238–244 (2014).
    • 26 Peitzmeier SM, Tomko C, Wingo E et al. Acceptability of microbicidal vaginal rings and oral pre-exposure prophylaxis for HIV prevention among female sex workers in a high-prevalence US city. AIDS Care 1–5 (2017).
    • 27 Clark JT, Clark MR, Shelke NB et al. Engineering a segmented dual-reservoir polyurethane intravaginal ring for simultaneous prevention of HIV transmission and unwanted pregnancy. PLoS ONE 9(3), e88509 (2014).
    • 28 Baeten JM, Palanee-Phillips T, Brown ER et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N. Engl. J. Med. 375(22), 2121–2132 (2016).
    • 29 Pines HA, Gorbach PM, Weiss RE et al. Acceptability of potential rectal microbicide delivery systems for HIV prevention: a randomized crossover trial. AIDS Behav. 17(3), 1002–1015 (2013).
    • 30 Newman PA, Cameron MP, Roungprakhon S, Tepjan S, Scarpa R. Acceptability and preferences for hypothetical rectal microbicides among a community sample of young men who have sex with men and transgender women in Thailand: a discrete choice experiment. AIDS Behav. 20(11), 2588–2601 (2016).
    • 31 Vargas SE, Fava JL, Severy L et al. Psychometric properties and validity of a multi-dimensional risk perception scale developed in the context of a microbicide acceptability study. Arch. Sex. Behav. 45(2), 415–428 (2016).
    • 32 Weld ED, Hiruy H, Guthrie KM et al. A comparative pre-Phase I study of the impact of gel vehicle volume on distal colon distribution, user experience, and acceptability. AIDS. Res. Hum. Retroviruses (33(5), 440–447 (2016).
    • 33 Morrow KM, Underhill K, Van Den Berg JJ, Vargas S, Rosen RK, Katz DF. User-identified gel characteristics: a qualitative exploration of perceived product efficacy of topical vaginal microbicides. Arch. Sex. Behav. 43(7), 1459–1467 (2014).
    • 34 Morrow K, Ruiz M. Assessing microbicide acceptability: a comprehensive and integrated approach. AIDS Behav. 12(2), 272–283 (2008).
    • 35 Exner TM, Correale J, Carballo–Diéguez A et al. Women's anal sex practices: implications for formulation and promotion of a rectal microbicide. AIDS Education and Prevention 20(2), 148–159 (2008).
    • 36 Mcgowan I, Dezzutti C. Rectal microbicide development. Curr. Top. Microbiol. Immunol. 383, 117–136 (2014). •• A discussion on the need and current development of rectal microbicides to prevent HIV infection in the growing ‘men who have sex with men’ community.
    • 37 Gorbach PM, Weiss RE, Fuchs E et al. The slippery slope: lubricant use and rectal sexually transmitted infections: a newly identified risk. Sex. Transm. Dis. 39(1), 59–64 (2012).
    • 38 Mcgowan I. Rectal microbicides: can we make them and will people use them? AIDS Behav. 15(0), 66–71 (2011).
    • 39 Abd-El-Maeboud KH, El-Naggar T, El-Hawi EMM, Mahmoud SaR, Abd-El-Hay S. Rectal suppository: commonsense and mode of insertion. Lancet 338(8770), 798–800 (1999).
    • 40 Bradshaw A, Price L. Rectal suppository insertion: the reliability of the evidence as a basis for nursing practice. J. Clin. Nurs. 16(1), 98–103 (2007).
    • 41 Saleem MA, Taher M, Sanaullah S et al. Formulation and evaluation of tramadol hydrochloride rectal suppositories. Indian. J. Pharm. Sci. 70(5), 640–644 (2008).
    • 42 Wada K, Uehara S, Ishii A et al. A Phase II clinical trial evaluating the preventive effectiveness of lactobacillus vaginal suppositories in patients with recurrent cystitis. Acta. Med. Okayama 70(4), 299–302 (2016).
    • 43 Naz S, Memon NY, Sattar A, Baloch R. Diclofenac rectal suppository: an effective modality for perineal pain. J. Pak. Med. Assoc. 66(8), 1005–1008 (2016).
    • 44 Ye X, Yin H, Lu Y, Zhang H, Wang H. Evaluation of hydrogel suppositories for delivery of 5-aminolevulinic acid and hematoporphyrin monomethyl ether to rectal tumors. Molecules 21(10), (2016).
    • 45 Verdenelli MC, Cecchini C, Coman MM et al. Impact of probiotic SYNBIO® administered by vaginal suppositories in promoting vaginal health of apparently healthy women. Curr. Microbiol. 73(4), 483–490 (2016).
    • 46 Lowry M. Rectal drug administration in adults: how, when, why. Nurs. Times. 112(8), 12–14 (2016).
    • 47 Li B, Zaveri T, Ziegler GR, Hayes JE. Shape of vaginal suppositories affects willingness-to-try and preference. Antiviral. Res. 97(3), 280–284 (2013). •• A study into determining the willingness to try a vaginal suppository in relation to the shape and size of the suppository.
    • 48 Morrow KM, Hendrix C. Clinical evaluation of microbicide formulations. Antiviral Res. 88, Supplement(0), S40–S46 (2010).
    • 49 Morrow K, Rosen R, Richter L et al. The acceptability of an investigational vaginal microbicide, PRO 2000 gel, among women in a Phase I clinical trial. J. Women's Health 12(7), 655–666 (2003).
    • 50 Whitehead SJ, Kilmarx PH, Blanchard K et al. Acceptability of Carraguard vaginal gel use among Thai couples. AIDS 20(17), 2141–2148 (2006).
    • 51 Mahan ED, Morrow KM, Hayes JE. Quantitative perceptual differences among over-the-counter vaginal products using a standardized methodology: implications for microbicide development. Contraception 84(2), 184–193 (2011).
    • 52 Moreton RC. Suppository Bases, Hard Fat. Pharmaceutical Press, PA, USA, 945–950 (2012).
    • 53 Brown JM, Hess KL, Brown S, Murphy C, Waldman AL, Hezareh M. Intravaginal practices and risk of bacterial vaginosis and candidiasis infection among a cohort of women in the United States. Obstet. Gynecol. 121(4), 773–780 (2013).
    • 54 Porter TL, Stewart R, Reed J, Morton K. Models of hydrogel swelling with applications to hydration sensing. Sensors (Basel, Switzerland) 7(9), 1980–1991 (2007).
    • 55 Wu CY, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm. Res. 22(1), 11–23 (2005).
    • 56 Lane T, Pettifor A, Pascoe S, Fiamma A, Rees H. Heterosexual anal intercourse increases risk of HIV infection amoung young South African men. AIDS 20(1), 123–125 (2006).
    • 57 Buckheit RW Jr, Roberson JL, Lackman-Smith C, Wyatt JR, Vickers TA, Ecker DJ. Potent and specific inhibition of HIV envelope-mediated cell fusion and virus binding by G quartet-forming oligonucleotide (ISIS 5320). AIDS Res. Hum. Retroviruses 10(11), 1497–1506 (1994).
    • 58 Buckheit R Jr, Watson K, Morrow K, Ham A. Development of topical microbicides to prevent the sexual transmission of HIV. Antiviral Res. 85, 142–158 (2010).
    • 59 Zaveri T, Hayes JE, Ziegler GR. Release of tenofovir from carrageenan-based vaginal suppositories. Pharmaceutics 6(3), 366–377 (2014).
    • 60 Zhang G, Zhang H, Yu H, Zhao Z, Yang J, Zhang M. Hypothetical rectal microbicide acceptability and factors influencing it among men who have sex with men in Tianjin, China. PLoS ONE 11(5), e0156561 (2016).
    • 61 Jones DL, Weiss SM, Chitalu N, Bwalya V, Villar O. Acceptability of microbicidal surrogates among Zambian women. J. Sex. Transm. Dis. 35(2), 147–153 (2008).
    • 62 Cranston RD, Lama JR, Richardson BA et al. MTN-017: a rectal Phase 2 extended safety and acceptability study of tenofovir reduced-glycerin 1% gel. Clin. Infect. Dis. 64(5), 614–620 (2017).
    • 63 Zaveri T, Primrose RJ, Surapaneni L, Ziegler GR, Hayes JE. Firmness perception influences women's preferences for vaginal suppositories. Pharmaceutics 6(3), 512–529 (2014).
    • 64 Ham AS, Nugent ST, Beveridge E et al. Designing the suppository: a rational formulation design for rectal and vaginal administration. Presented at: HIV R4P. Chicago, IL, USA, October 17–21, 2016.
    • 65 Holt BY, Morwitz VG, Ngo L et al. Microbicide preference among young women in California. J. Women's Health 15(3), 281–294 (2006).
    • 66 Malonza IM, Mirembe F, Nakabiito C et al. Expanded Phase I safety and acceptability study of 6% cellulose sulfate vaginal gel. AIDS (London, England) 19(18), 2157–2163 (2005).
    • 67 Schwartz JL, Mauck C, Lai JJ et al. Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study. Contraception 74(2), 133–140 (2006).
    • 68 Cao YJ, Caffo BS, Fuchs EJ et al. Quantification of the spatial distribution of rectally applied surrogates for microbicide and semen in colon with SPECT and magnetic resonance imaging. Br. J. Clin. Pharmacol. 74(6), 1013–1022 (2012).
    • 69 Hendrix CW, Fuchs EJ, Macura KJ et al. Quantitative imaging and sigmoidoscopy to assess distribution of rectal microbicide surrogates. Clin. Pharmacol. Ther. 83(1), 97–105 (2008).
    • 70 Yahagi R, Machida Y, Onishi H. Mucoadhesive suppositories of ramosetron hydrochloride utilizing Carbopol. Int. J. Pharm. 193(2), 205–212 (2000).
    • 71 Yahagi R, Onishi H, Machida Y. Preparation and evaluation of double-phased mucoadhesive suppositories of lidocaine utilizing Carbopol and white beeswax. J. Control. Rel. 61(1–2), 1–8 (1999).
    • 72 Kawashima S, Inoue Y, Shimeno T, Fujiwara H. Studies on sustained-release suppositories. III. Rectal absorption of morphine in rabbits and prolongation of its absorption by alginic acid addition. Chem. Pharm. Bull. (Tokyo) 38(2), 498–505 (1990).
    • 73 Takatori T, Shimono N, Higaki K, Kimura T. Evaluation of sustained release suppositories prepared with fatty base including solid fats with high melting points. Int. J. Pharm. 278(2), 275–282 (2004).
    • 74 Carpenter CC, Cooper DA, Fischl MA et al. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel. JAMA 283(3), 381–390 (2000).
    • 75 Richman DD. HIV therapeutics. Science 272(5270), 1886–1888 (1996).
    • 76 Trabattoni D, Lo Caputo S, Biasin M et al. Modulation of human immunodeficiency virus (HIV)-specific immune response by using efavirenz, nelfinavir, and stavudine in a rescue therapy regimen for HIV-infected, drug-experienced patients. Clin. Diagn. Lab. Immunol. 9(5), 1114–1118 (2002).