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. 2005 Sep 20;6(1):E56–E64. doi: 10.1208/pt060111

Conceival, a novel noncontraceptive vaginal vehicle for lipophilic microbicides

Osmond J D'Cruz 1,2,3,✉, Peter Samuel 1,4, Fatih M Uckun 1,5
PMCID: PMC2750412  PMID: 16353964

Abstract

The objective of this study was to develop a nontoxic and noncontraceptive vaginal drug delivery vehicle for lipophilic anti-human immunodeficiency virus (HIV) microbicides. Three representative poorly water-soluble novel broad-spectrum anti-HIV microbicides, PHI-113, PHI-346, and PHI-443, were evaluated in 11 different solvent systems. Based on their solubility profiles, a novel non-spermicidal self-emulsifying gel (viz Conceival) composed of pharmaceutical excipients, sorbitol, polyethylene glycol 400, polysorbate 80, microcrystalline cellulose, xanthan gum, and water was optimized. Conceival enhanced the solubility of these poorly water-soluble (<0.001 mg/mL) anti-HIV drugs by at least 150- to 270-fold. Conceival was evaluated in vivo in the New Zealand white rabbit model for the preservation of sperm function based on pregnancy outcome and the potential for vaginal irritation following single and multiple intravaginal applications, respectively. Conceival administered intravaginally immediately prior to artificial insemination with semen had no adverse effects on subsequent reproductive performance, neonatal survival, or pup development when compared with untreated control group. Histologic evaluation of vaginal tissues of rabbits exposed intravaginally to Conceival for 14 consecutive days revealed lack of epithelial, submucosal, and vascular changes at the gel application site (total irritation score <3 out of a possible 16). These findings indicate that Conceival has potential to become a clinically useful, safe noncontraceptive vaginal vehicle for lipophilic microbicides.

Keywords: HIV/AIDS, intravaginal, lipophilic gel, non-contraceptive, microbicide

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References

  • 1.Piot P, Bartos M, Ghys PD, Walker N, Schwartlander B. The global impact of HIV/AIDS. Nature. 2001;410:968–973. doi: 10.1038/35073639. [DOI] [PubMed] [Google Scholar]
  • 2.National Institute of Allergy and Infectious Diseases. HIV infection in women. Fact sheet. NIAID Web site. Available at: www.niaid.nih.gov/factsheets/womenhiv.htm. Accessed December, 2003.
  • 3.United Nations Program on HIV/AIDS. AIDS epidemic update. Available at: www.unaids.org. Accessed December, 2003.
  • 4.Centers for Disease Control and Prevention.HIV AIDS Surveill Rep. 2002;14:1–48. Available at: http://www.cdc.gov/hiv/stats/hasrl1402.htm. Accessed January 10, 2005.
  • 5.Samuel MC, Hessol N, Shiboski S, Engel RR, Speed TP, Winkelstein W. Factors associated with human immunodeficiency virus seroconversion in homosexual men in three San Francisco cohort studies 1984–1989. J Acquir Immune Defic Syndr. 1993;6:303–312. [PubMed] [Google Scholar]
  • 6.Rivers K, Aggleton P, Women & HIV Adolescent sexuality, gender, and the HIV epidemic. BETA. 2001;14:35–40. [PubMed] [Google Scholar]
  • 7.Sexually Transmitted Diseases in America: How Many Cases, and at What Cost? Research Triangle Park, NC: ASHA; 1998. [Google Scholar]
  • 8.Uckun FM, D'Cruz OJ. Prophylactic contraceptives for HIV/AIDS. Hum Reprod Update. 1999;5:506–514. doi: 10.1093/humupd/5.5.506. [DOI] [PubMed] [Google Scholar]
  • 9.D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10:315–336. doi: 10.2174/1381612043386374. [DOI] [PubMed] [Google Scholar]
  • 10.Turpin JA. Considerations and development of topical microbicides to inhibit the sexual transmission of HIV. Expert Opin Investig Drugs. 2002;11:1077–1097. doi: 10.1517/13543784.11.8.1077. [DOI] [PubMed] [Google Scholar]
  • 11.D'Cruz OJ, Venkatachalam TK, Uckun FM. Novel thiourea compounds as dual-function microbicides. Biol Reprod. 2000;63:196–205. doi: 10.1095/biolreprod63.1.196. [DOI] [PubMed] [Google Scholar]
  • 12.D'Cruz OJ, Uckun FM. Pre-clinical safety evaluation of novel nucleoside analogue-based dual-function microbicides (WHI-05 and WHI-07) J Antimicrob Chemother. 2002;50:793–803. doi: 10.1093/jac/dkg001. [DOI] [PubMed] [Google Scholar]
  • 13.D'Cruz OJ, Yiv SH, Waurzyniak B, Uckun FM. Contraceptive efficacy and safety studies of a novel microemulsion-based lipophilic vaginal spermicide. Fertil Steril. 2001;75:115–124. doi: 10.1016/S0015-0282(00)01636-8. [DOI] [PubMed] [Google Scholar]
  • 14.Uckun FM, Pendergrass S, Venkatachalam TK, Qazi S, Richman D. Stampidine is a potent inhibitor of zidovudine- and nucleoside analog reverse transcriptase inhibitor-resistant primary clinical human immunodeficiency virus type 1 isolates with thymidine analog mutations. Antimicrob Agents Chemother. 2002;46:3613–3616. doi: 10.1128/AAC.46.11.3613-3616.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Uckun FM, Pendergrass S, Qazi S, Venkatachalam TK. In vitro activity of stampidine against primary clinical human immunodeficiency virus isolates. Arzneimittleforschung. 2004;54:69–77. doi: 10.1055/s-0031-1296939. [DOI] [PubMed] [Google Scholar]
  • 16.D'Cruz OJ, Uckun FM. Stampidine is a potential nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide. Fertil Steril. 2004;81(suppl 1):831–841. doi: 10.1016/j.fertnstert.2003.08.037. [DOI] [PubMed] [Google Scholar]
  • 17.Uckun FM, Mao C, Pendergrass S, et al. N-[2-(1-cyclohexenyl)-ethyl]-N'-[2-(5-bromopyridyl)]-thiourea and N'-[2-(1-cyclohexenyl)-ethyl]-N'-[2-(5-chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett. 1999;9:2721–2726. doi: 10.1016/S0960-894X(99)00460-6. [DOI] [PubMed] [Google Scholar]
  • 18.D'Cruz OJ, Venkatachalam TK, Mao C, Qazi S, Uckun FM. Structural requirements for potent anti-human immunodeficiency virus (HIV) and sperm-immobilizing activities of cyclohexenyl thiourea and urea non-nucleoside inhibitors of HIV-1 reverse transcriptase. Biol Reprod. 2002;67:1959–1974. doi: 10.1095/biolreprod.102.006478. [DOI] [PubMed] [Google Scholar]
  • 19.Uckun FM, Pendergrass S, Maher D, et al. N'-[2-(2-thiophene)-ethyl[-N'-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett. 1999;9:3411–3416. doi: 10.1016/S0960-894X(99)00624-1. [DOI] [PubMed] [Google Scholar]
  • 20.D'Cruz OJ, Samuel P, Uckun FM. PHI-443: a novel noncontraceptive broad-spectrum anti-human immunodeficiency virus microbicide. Biol Reprod. 2004;71:2037–2047. doi: 10.1095/biolreprod.104.032870. [DOI] [PubMed] [Google Scholar]
  • 21.Kibbe AH, editor. Pharmaceutical Excipients. Washington, DC: American Pharmaceutical Association, the Pharmaceutical Press; 2000. [Google Scholar]
  • 22.Tsujino I, Yamazaki T, Masutani M, Sawada U, Horie T. Effect of Tween-80 on cell killing by etoposide in human lung adenocarcinoma cells. Cancer Chemother Pharmacol. 1999;43:29–34. doi: 10.1007/s002800050859. [DOI] [PubMed] [Google Scholar]
  • 23.Brosin A, Wolf V, Mattheus A, Heise H. Use of XTT-assay to assess the cytotoxicity of different surfactants and metal salts in human keratinocytes (HaCaT). A feasible method for in vitro testing of skin irritants. Acta Derm Venereol. 1997;77:26–28. doi: 10.2340/0001555577026028. [DOI] [PubMed] [Google Scholar]
  • 24.Jansson PE, Kenne L, Linderberg B. Structure of extracellular polysaccharide fromXanthamonas comopestris. Carbohydr Res. 1975;45:275–282. doi: 10.1016/S0008-6215(00)85885-1. [DOI] [PubMed] [Google Scholar]
  • 25.Vig R, Venkatachalam T, Uckun FM. D4T-5′-[p-bromophenyl methoxyalaninyl phosphate] as a potent and non-toxic anti-human immunodeficiency virus agent. Antivir Chem Chemother. 1998;9:445–448. [PubMed] [Google Scholar]
  • 26.D'Cruz OJ, Uckun FM. Gel-microemulsions as vaginal spermicides and intravaginal drug delivery vehicles. Contraception. 2001;64:113–123. doi: 10.1016/S0010-7824(01)00233-5. [DOI] [PubMed] [Google Scholar]
  • 27.Owen DH, Katz DF. A vaginal fluid simutant. Contraception. 1999;59:91–95. doi: 10.1016/S0010-7824(99)00010-4. [DOI] [PubMed] [Google Scholar]
  • 28.D'Cruz OJ, Samuel P, Waurzyniak B, Uckun FM. In vivo evaluation of a gel formulation of stampidine, a novel nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide. Am J Drug Deliv. 2003;1:275–285. doi: 10.2165/00137696-200301040-00006. [DOI] [PubMed] [Google Scholar]
  • 29.Chen CL, Yu G, Venkatachalam TK, Uckun FM. Metabolism of stavudine-5′-[p-bromophenyl methoxyalaninyl phosphate], stampidine, in mice, dogs, and cats. Drug Metab Dispos. 2002;30:1523–1531. doi: 10.1124/dmd.30.12.1523. [DOI] [PubMed] [Google Scholar]
  • 30.D'Cruz OJ, Zhu Z, Yiv SH, Chen CL, Waurzyniak B, Uckun FM. WHI-05, a novel bromo-methoxy substituted phenyl phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity. Contraception. 1999;59:319–331. doi: 10.1016/S0010-7824(99)00041-4. [DOI] [PubMed] [Google Scholar]
  • 31.D'Cruz OJ, Uckun FM. Contraceptive activity of a spermicidal aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07) in rabbits. Fertil Steril. 2003;79:864–872. doi: 10.1016/S0015-0282(02)04845-8. [DOI] [PubMed] [Google Scholar]
  • 32.Eckstein P, Jackson MC, Millman N, Sobrero AJ. Comparison of vaginal tolerance tests of spermicidal preparations in rabbits and monkeys. J Reprod Fertil. 1969;20:85–93. doi: 10.1530/jrf.0.0200085. [DOI] [PubMed] [Google Scholar]

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