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Influence of long-term stability conditions on microbicidal nucleoside prodrug (WHI-07)-loaded gel-microemulsion

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Abstract

The objective of this study was to evaluate the long-term stability of the antiretroviral spermicide WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl)-methoxyalaninyl phosphate) in a polymer-based microemulsion. The recovery and stability of WHI-07 in gelmicroemulsion was examined by a validated high-performance liquid chromatography (HPLC) method. The stability was examined over a period of 24 weeks at 3 controlled temperatures (4°C, 25°C, and 40°C). The recovery of the prodrug from 0.5% to 2.0% WHI-07-loaded gel-microemulsion was 99.8%. HPLC analysis revealed that a 2% WHI-07-loaded gel-microemulsion stored at room temperature and cold temperatures for 24 weeks retained >90% of the prodrug, whereas those stored at 40°C maintained 90% of initial WHI-07 for at least 10 weeks. The observed stability of WHI-07 in gel-microemulsion is of great importance for its widespread utility in various climatological conditions.

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References

  1. Centers for Disease Control and Prevention (CDC). Diagnoses of HIV/AIDS—32 states, 2000–2003.MMWR Morb Mortal Wkly Rep. 2004;53:1106–1110.

    Google Scholar 

  2. Mujeeb SA, Altaf A. The AIDS pandemic.N Engl J Med. 2003;349:814–815.

    Article  Google Scholar 

  3. Joint United Nations Programme on HIV/AIDS (UNAIDS). 2006 Report on the global AIDS epidemic. Available at: http://www.unaids. org/en/HIV%5Fdata/2006GlobalReport. Accessed: May 13, 2006.

  4. HIV Infection in Women. National Institute of Allergy and Infectious Diseases Web page. May 2006. Available at: http://www.niaid.nih.gov/ factsheets/womenhiv.htm. Accessed: May 13, 2006.

  5. Quayle AJ, Xu C, Mayer KH, Anderson DJ. T lymphocytes and macrophages, but not motile spermatozoa, are a significant source of human immunodeficiency virus in semen.J Infect Dis. 1997;176: 960–968.

    Article  CAS  Google Scholar 

  6. Zhang H, Dornadula G, Beumont M, et al. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy.N Engl J Med. 1998;339:1803–1809.

    Article  CAS  Google Scholar 

  7. Uckun FM, D’Cruz OJ. Prophylactic contraceptives for HIV/AIDS.Hum Reprod Update. 1999;5:506–514.

    Article  CAS  Google Scholar 

  8. D’Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection.Curr Pharm Des. 2004;10: 315–336.

    Article  Google Scholar 

  9. D’Cruz OJ, Uckun FM. Dawn of non-nucleoside inhibitor-based anti-HIV microbicides.J Antimicrob Chemother. 2006;57:411–423.

    Article  Google Scholar 

  10. D’Cruz OJ, Venkatachalam T, Zhu Z, Shih M, Uckun FM. Aryl phosphate derivatives of bromo-methoxy-azidothymidine are dual-function spermicides with potent anti-HIV activity.Biol Reprod. 1998;59:503–515.

    Article  Google Scholar 

  11. D’Cruz OJ, Shih M-J, Yiv SH, Chen CL, Uckun FM. Synthesis, characterization and preclinical formulation of a dual-action phenyl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07) with potent anti-HIV and spermicidal activities.Mol Hum Reprod. 1999;5:421–432.

    Article  Google Scholar 

  12. D’Cruz OJ, Venkatachalam TK, Uckun FM. Structural requirements for potent human spermicidal activity of dual-function aryl phosphate derivative of bromo-methoxy zidovudine (WHI-07).Biol Reprod. 2000;62:37–44.

    Article  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. D’Cruz OJ, Waurzyniak W, Uckun FM. Antiretroviral spermicide WHI-07 prevents vaginal and rectal transmission of feline immunodeficiency virus in domestic cats.Antimicrob Agents Chemother. 2004;48: 1082–1088.

    Article  Google Scholar 

  15. D’Cruz OJ, Venkatachalam TK, Uckun FM. Thymidine kinase-independent intracellular delivery of bioactive nucleotides by aryl phosphate derivatives of bromo-methoxy zidovudine (WHI-05 and WHI-07) in normal human female genital tract epithelial cells and sperm.Biol Reprod. 2001;64:51–59.

    Article  Google Scholar 

  16. 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.

    Article  Google Scholar 

  17. D’Cruz OJ, Uckun FM. Preclinical Overview of WHI-07, a Novel Nucleoside Analog-based Dual-function Microbicide.Curr Med Chem—Anticancer Agents. 2004;3:15–29.

    Article  Google Scholar 

  18. Uckun FM, Tai D’Cruz OJ. Antileukemic activity and cellular metabolism of the aryl phosphate derivative of bromo-methoxy zidovudine (WHI-07).Arzneimittelforschung. 2005;55:50–65.

    CAS  PubMed  Google Scholar 

  19. Gasco MR, Gallarate M, Trotta M, Bauchiero L, Gremmo E, Chiappero O. Microemulsions as topical delivery vehicles: ocular administration of timolol.J Pharm Biomed Anal. 1989;7:433–439.

    Article  CAS  Google Scholar 

  20. Osborne DW, Ward AJ, O’Neill KJ. Microemulsions as topical drug delivery vehicles: in-vitro transdermal studies of a model hydrophilic drug.J Pharm Pharmacol. 1991;43:450–454.

    CAS  PubMed  Google Scholar 

  21. Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems.Adv Drug Deliv Rev. 2000;45:89–121.

    Article  CAS  Google Scholar 

  22. D’Cruz OJ, Waurzyniak B, Yiv SH, Uckun FM. Evaluation of subchronic (13-week) and reproductive toxicity potential of intravaginal gel-microemulsion formulation of a dual-function phenyl phosphate derivative of bromo-methoxy zidovudine (WHI-07) in B6C3F1 mice.J Appl Toxicol. 2000;20:319–325.

    Article  Google Scholar 

  23. D’Cruz OJ, Uckun FM. Lack of adverse effects on fertility of female CD-1 mice exposed to repetitive intravaginal gel-microemulsion formulation of a dual-function anti-HIV agent: aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07).J Appl Toxicol. 2001;21:317–322.

    Article  Google Scholar 

  24. D’Cruz OJ, Uckun FM. Short-term (13-week) toxicity study of 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), a novel anti-HIV and contraceptive agent, in B6C3F1 mice.Toxicol Sci. 2001;60:373–378.

    Article  Google Scholar 

  25. D’Cruz OJ, Uckun FM. Gel-microemulsions as vaginal spermicides and intravaginal drug delivery vehicles.Contraception. 2001;64: 113–123.

    Article  Google Scholar 

  26. D’Cruz OJ, Erbeck D, Waurzyniak W, Uckun FM. Two-year toxicity and carcinogenicity studies in B6C3F1 mice with 5-bromo-6-methoxy-5, 6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxy alaninyl phosphate (WHI-07), a novel anti-HIV and contraceptive agent.Toxicology. 2002;179:61–67.

    Article  Google Scholar 

  27. D’Cruz OJ, Erbeck D, Uckun FM. Developmental toxicology studies of WHI-07, a novel nucleoside analogue-based dual-function microbicide, administered intravaginally to rabbits.Toxicol Pathol. 2003;31:698–708.

    Article  Google Scholar 

  28. D’Cruz OJ, Erbeck D, Uckun FM. A study of the potential of the pig as a model for the vaginal irritancy of benzalkonium chloride in comparison to the nonirritant microbicide PHI-443 and the spermicide vanadocene dithiocarbamate.Toxicol Pathol. 2005;33:465–476.

    Article  Google Scholar 

  29. Eccleston GM. Microemulsion. In: Swarbrick J, Boylan JC, eds.Encyclopedia of Pharmaceutical Technology. New York, NY: Marcel Dekker; 1992:375–421.

    Google Scholar 

  30. Tenjarla S. Microemulsions: an overview and pharmaceutical applications.Crit Rev Ther Drug Carrier Syst. 1999;16:461–521.

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Drug Discovery Program, Parker Hughes Institute, 55113, St Paul, MN, USA

    Osmond J. D’Cruz

  2. Paradigm Pharmaceuticals, LLC, 2685 Patton Road, 55113, St. Paul, MN, USA

    Osmond J. D’Cruz & Fatih M. Uckun

Authors
  1. Osmond J. D’Cruz
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  2. Fatih M. Uckun
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Correspondence to Osmond J. D’Cruz.

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Published: September 1, 2006

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D’Cruz, O.J., Uckun, F.M. Influence of long-term stability conditions on microbicidal nucleoside prodrug (WHI-07)-loaded gel-microemulsion. AAPS PharmSciTech 7, 73 (2006). https://doi.org/10.1208/pt070373

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