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Thermosensitive mucoadhesive gel formulation loaded with 5-Fu: cyclodextrin complex for HPV-induced cervical cancer

  • Erem Bilensoy
  • Yasemin Çırpanlı
  • Murat Şen
  • A. Lale Doğan
  • Sema Çalış
Original Article

Abstract

Human Papilloma Virus (HPV) infections are the major cause of cervical cancers. To achieve a better therapeutic efficacy and patient compliance in the treatment for HPV-induced cervical cancers, anticancer agent 5-fluorouracil has been formulated in a vaginal gel using the thermosensitive polymer Pluronic® F127 together with alternative mucoadhesive polymers e.g., hyaluronic acid, Carbopol 934 and hydroxypropylmethylcellulose. To increase its aqueous solubility and to achieve the complete release of 5-FU from the gel, the drug was incorporated as its inclusion complex with 1:1 molar ratio with either β-cyclodextrin or hydroxypropyl-β-cyclodextrin. Following the characterization of drug:CD complexes, thermosensitive gel formulations containing different mucoadhesive polymers and the drug in free or complexed form were characterized in vitro by determining the gelation temperature and the rheological behavior of different formulations along with the in vitro release profiles of these formulations in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin accelerated the release of 5-FU with the exception of formulation containing Carbopol 934 as mucoadhesive polymer. As far as rheological properties are concerned, favorable thermosensitive in situ gelling properties were obtained with formulations containing HPMC as mucoadhesive polymer. Complete release of 5-FU from gels were obtained with both complexes of β-CD and HP-β-CD and cytotoxicity studies against HeLa human cervical carcinoma cells demonstrated that 1% 5-FU:CD complexes were equally effective as 1% free 5-FU indicating better therapeutic efficacy with lower dose.

Keywords

5-Fluorouracil β-Cyclodextrin Hydroxypropyl-β-cyclodextrin Thermosensitive Mucoadhesive Cyclodextrin Vaginal gel Cervical cancer HPV 

References

  1. 1.
    Bosch, F.X., Manos, M.M., Manoz, N.: Relevance of human papilloma virus in cervical cancer: a worldwide perspective. J. Natl. Cancer Invest. 87, 796–799 (1995).CrossRefGoogle Scholar
  2. 2.
    Koutsky, L.: Epidemiology of human papilloma virus infection. Am. J. Med. 102(5A), 3–8 (1997).CrossRefGoogle Scholar
  3. 3.
    Lacey, C.J.N.: Therapy for genital human papilloma virus-related disease. J. Clin. Virol. 32S, S82–S90 (2005).CrossRefGoogle Scholar
  4. 4.
    Rose, P.G.: Chemoradiotherapy, the new standard care for invasive cervical cancer. Drugs 50(6), 1239–1244 (2000).CrossRefGoogle Scholar
  5. 5.
    Parkin, D.M.: Cancer in developing countries. Cancer Surv. 19(20), 519–561 (1994).Google Scholar
  6. 6.
    Gross, G.: Therapy of human papillomavirus infection and associated epithelial tumors. Intervirology 40, 368–377 (1997).CrossRefGoogle Scholar
  7. 7.
    Brown, D.R., Schroeder, J.M., Bryan, J.M., Stoler, M.H., Fife, K.H.: detection of multiple human papillomavirus types in condyloma acuminate lesions from otherwise healthy and immunosuppressed patients. J. Clin. Microbiol. 37, 3316–3322 (1999).Google Scholar
  8. 8.
    Walboomers, J.M., Jacobs, M.V., Manos, M.M., Bosch, F.X., Kummer, J.A., Shah, K.V.: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol. 189, 12–18 (1999).CrossRefGoogle Scholar
  9. 9.
    Lacey, C.J.N., Goodall, R., Tennvall, G.T., Maw, R., Kinghorn, G.R., Fisk, P.G.: Randomized controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream and podophyllin in the treatment of genital warts. Sex. Transm. Infect. 79, 270–275 (2003).CrossRefGoogle Scholar
  10. 10.
    Snoeck, R., Bossens, M., Parent, D.: Phase II double-blind placebo controlled study of the safety and efficacy of cidofovir topical gel for the treatment of patients with human papilloma virus infection. Clin. Infect. Dis. 33, 597–602 (2001).CrossRefGoogle Scholar
  11. 11.
    Mansell, P.W.A., Litwin, M.S., Ichinose, H., Krementz, E.T.: Delayed hypersensitivity to 5-fluorouracil following topical chemotherapy of cutaneous cancers. Cancer Res. 35, 1288–1294 (1975).Google Scholar
  12. 12.
    Pall, A., Mahajan, B.B., Puri, K.P.S., Gupta, R.R.: Therapeutic evalulation of intralesional 5% 5-fluorouracil in condyloma acuminata. J. Dermatol. 31, 314–325 (2004).Google Scholar
  13. 13.
    Beutner, K.R., Ferenczy, A.: Therapeutic approaches to genital warts. Am. J. Med. 102(5A), 28–37 (1997).CrossRefGoogle Scholar
  14. 14.
    Bonnez, W., Oakes, D., Bailey-Farchione, A.: A randomized double blind placebo controlled trial of systemically administered interferon-α, -β or -γ in combination with cryotherapy for treatment of condyloma acuminate. J. Infect. Dis. 171, 1081–1089 (1995).Google Scholar
  15. 15.
    Garland, S.M., Sellors, J.W., Wikstrom, A.: Imiquimod 5% cream is a safe and effective self-applied treatment for anogential warts-results of an open-label multicentre phase IIIB trial. Int. J. STD AIDS 12, 22–28 (2001).CrossRefGoogle Scholar
  16. 16.
    Gollnick, H., Barasso, R., Jappe, U., Ward, K., Eul, A., Carey-Yard, M.: Safety and efficacy of imiquimod 5% cream in the treatment penile warts in uncircumcised men when applied three times (2001).Google Scholar
  17. 17.
    Deshpande, A.A., Rhodes, C.T., Danish, M.: Intravaginal drug delivery. Drug Dev. Ind. Pharm. 18, 1225–1279 (1992).Google Scholar
  18. 18.
    Wolfsson, A.D.: Intravaginal drug delivery technologies. In: Rathbone M, (ed.). Modified-Release Drug Delivery Technology, pp. 759–774. Marcel Dekker, New York (2002).Google Scholar
  19. 19.
    Hardy, E., Jimenes, A.L., de Padua, K.S., Zanewald, L.J.D.: Women’s preferences for vaginal antimicrobial contraceptives III. Choice of a formulation, applicator and packaging. Contraception 58, 245–249 (1998).CrossRefGoogle Scholar
  20. 20.
    Ceschel, G.C., Maffei, P., Lombardi Borgia S., Ronchi, C., Rossi, S.: (2001) Development of a mucoadhesive dosage form for vaginal administration, Drug Dev. Ind. Pharm. 27(6), 541–547.CrossRefGoogle Scholar
  21. 21.
    Chang, J.Y., Oh, Y.K., Choi, H., Kim, Y.B., Kim, C.K.: Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions. Int. J. Pharm. 241, 155–163 (2002).CrossRefGoogle Scholar
  22. 22.
    Chang, J.Y., Oh, Y.K., Kong, H.S., Kim, E.J., Jang, D.D., Nam, K.T., Kim, C.K. Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels in vaginitis. J. Controlled Rel. 82, 39–50 (2002).CrossRefGoogle Scholar
  23. 23.
    Chu, J.S., Amidon, G.L., Weiner, N.D., Goldberg, A.H.: Mixture experimental design in the development of a mucoadhesive gel formulation. Pharm. Res. 8, 1401–1407 (1991).CrossRefGoogle Scholar
  24. 24.
    Park, H., Robinson, J.R.: Physicochemical properties of water insoluble polymers important to mucin/epithelial adhesion. J. Controlled Rel. 2, 42–57 (1985).CrossRefGoogle Scholar
  25. 25.
    Veyries, M.L., Couarrazze, G., Geiger, S., Agnely, F., Massias, L., Kunzli, B., Faurisson, R., Rouveix, B.: Controlled release of vancomycin from poloxamer 407 gels. Int. J. Pharm. 192, 183–193 (1999).CrossRefGoogle Scholar
  26. 26.
    Desai, S.D., Blanchard, J.: Pluronic F127 based ocular delivery system containing biodegradable polyisobutylcyanoacrylate nanocapsules of pilocarpine. Drug Deliv. 7, 201–207 (2000).CrossRefGoogle Scholar
  27. 27.
    Bochot, A., Fattal, E., Grossiord, J.L., Puisieux, F., Couvreur, P.: Characterization of a new ocular delivery system based on a dispersion of liposomes in a thermosensitive gel. Int. J. Pharm. 162, 119–127 (1998).CrossRefGoogle Scholar
  28. 28.
    Kim, E.Y., Gao, Z.G., Park, J.S., Li, H., Han, K.: rhEGF/HP-β-CD complex in poloxamer gel for ophthalmic delivery. Int. J. Pharm. 233, 159–167 (2002).CrossRefGoogle Scholar
  29. 29.
    Thompson, D.O.: Cyclodextrins as enabling excipients: their present and future use in pharmaceuticals. CRC Crit. Rev. Ther. Drug Carrier Syst. 14(1), 1–104 (1997).Google Scholar
  30. 30.
    Loftsson, T., Brewster, M.E.: Pharmaceutical applications of cyclodextrins I Drug solubilization and stabilization. J. Pharm. Sci. 85(10), 1017–1025 (1996).CrossRefGoogle Scholar
  31. 31.
    Yashida, A., Yamamoto, M., Irie, T., Hirayama, F., Uekama, K.: Some pharmaceutical properties of 3-hydroxypropyl and 2,3-dihydroxypropyl β-cyclodextrins and their solubilizing and stabilizing ability. Chem. Pharm. Bull. 37, 1059–1063 (1989).Google Scholar
  32. 32.
    Hedges, A.R.: Industrial applications of cyclodextrins. Chem. Rev. 98, 2035–2044 (1998).CrossRefGoogle Scholar
  33. 33.
    Choi, H.G., Jung, J.H., Ryu, J.M., Yoon, S.J., Oh, Y.K., Kim, C.K.: Development of in situ gelling and mucoadhesive acetaminophen liquid suppository. Int. J. Pharm. 165, 33–44 (1998).CrossRefGoogle Scholar
  34. 34.
    Miyazaki, S., Nakamura, T., Takada, M.: Thermo-sensitive sol–gel transition of Pluronic F-127. Yakuzaigaku 51, 36–43 (1991).Google Scholar
  35. 35.
    Blanco-Fuente, H., Esteban-Fernandez, B., Blanco-Mendez, J., Otero-Espinar, F.J.: Use of β-cyclodextrins to prevent modifications of the properties of carbopol hydrogels due to carbopol-drug interactions, Chem. Pharm. Bull. 50(1), 40–46 (2002).CrossRefGoogle Scholar
  36. 36.
    Boulmedarat, L., Grossiord, J.L., Fattal, E., Bochot, A.: Influence of methyl β-cyclodextrin and liposomes on rheological properties of Carbopol®974 NF gels. Int. J. Pharm. 254, 59–64 (2003).CrossRefGoogle Scholar
  37. 37.
    Anderson, B.C., Pandit, N.K., Mallapragada, S.: Understanding drug release from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) gels. J. Controlled Rel. 70, 157–167 (2001).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2007

Authors and Affiliations

  • Erem Bilensoy
    • 1
  • Yasemin Çırpanlı
    • 1
  • Murat Şen
    • 2
  • A. Lale Doğan
    • 3
  • Sema Çalış
    • 1
  1. 1.Faculty of Pharmacy, Department of Pharmaceutical TechnologyHacettepe UniversityAnkaraTurkey
  2. 2.Department of Chemistry Polymer Chemistry DivisionHacettepe UniversityBeytepe, AnkaraTurkey
  3. 3.Department of Basic OncologyHacettepe University Oncology InstituteAnkaraTurkey

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