AAPS PharmSciTech

, Volume 13, Issue 4, pp 1045–1053 | Cite as

Development and Evaluation of an In Vitro Vaginal Model for Assessment of Drug’s Biopharmaceutical Properties: Curcumin

  • Katja Berginc
  • Nataša Škalko-Basnet
  • Purusotam Basnet
  • Albin Kristl
Research Article


Vaginal administration is a promising alternative to the per-oral route in achieving systemic or local therapeutic effects, when intestinal drug absorption is hindered by problematic biopharmaceutical drug properties. The aim of this study was to establish an in vitro vaginal model and use it to characterize biopharmaceutical properties of liposomally associated curcumin destined for vaginal delivery. The in vitro permeability, metabolism, and tissue retention of high/low permeable compounds were assessed on cow vaginal mucosa and compared to the permeabilities determined through Caco-2 cells and rat jejunum in vitro. The results showed that the intestinal mucosa was superior to the vaginal one in categorizing drugs based on their permeabilities in high/low permeable classes. Passive diffusion was found to be the main mechanism of drug penetration through vaginal mucosa and it was not affected by transporter–enzyme alliance, as their expression/activity was significantly reduced compared to the intestinal tract. Curcumin permeability from the solution form was the lowest of all tested substances due to its significant tissue retention and curcumin–mucus interactions. The permeability of liposomally associated curcumin was even lower but the binding of liposomally associated curcumin to the vaginal tissue was significantly higher. The permeability and tissue retention of liposomal curcumin were vesicle size dependent. Vaginal application of liposomally associated curcumin provides relatively high levels of curcumin in vaginal tissue, with limited systemic absorption.


curcumin intestinal models liposomes permeability vaginal mucosa 


  1. 1.
    Alexander NJ, Baker E, Kaptein M, Karck U, Miller L, Zampaglione E. Why consider vaginal drug administration? Fertil Steril. 2004;82:1–12. doi: 10.1016/j.fertnstert.2004.01.025.PubMedCrossRefGoogle Scholar
  2. 2.
    Hani U, Bhat RS, Sisodiya R, Hosakote SG. Novel vaginal drug delivery systems: a review. Curr Drug Ther. 2010;5:95–104.CrossRefGoogle Scholar
  3. 3.
    Valenta C. The use of mucoadhesive polymers for vaginal delivery. Adv Drug Deliv Rev. 2005;57:1692–712. doi: 10.1016/j.addr.2005.07.004.PubMedCrossRefGoogle Scholar
  4. 4.
    van der Bijl P, Thompson IOC, Squier CA. Comparative permeability of human vaginal and bucal mucosa to water. Eur J Oral Sci. 1997;105:571–5. doi: 10.1111/j.1600-0722.1997.tb00219.x.PubMedCrossRefGoogle Scholar
  5. 5.
    van der Bijl P, van Eyk AD, Thompson IOC. Permeation of 17β-estradiol through human vaginal and bucal mucosa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85:393–8. doi: 10.1016/S1079-2104(98)90063-4.PubMedCrossRefGoogle Scholar
  6. 6.
    van der Bijl P, van Eyk AD, Thompson IOC, Stander IA. Diffusion rates of vasopressin through human vaginal and buccal mucosa. Eur J Oral Sci. 1998;106:958–62. doi: 10.1046/j.0909-8836.1998.eos106509.x.PubMedCrossRefGoogle Scholar
  7. 7.
    van der Bijl P, Penkler L, van Eyk AD. Permeation of sumatriptan through human vaginal and buccal mucosa. Headache. 2000;40:137–41. doi: 10.1046/j.1526-4610.2000.00019.x.PubMedCrossRefGoogle Scholar
  8. 8.
    Değim IT, Tuğcu-Demiröz F, Tamer-İlbasmış S, Acartürk F. Development of controlled release sildenafil formulations for vaginal administration. Drug Deliv. 2008;15:259–65. doi: 10.1080/10717540802006781.PubMedCrossRefGoogle Scholar
  9. 9.
    Pauletti GM, Liu JH, Benet LZ, Ritschel WA, inventors; UMD Inc., assignee. Vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy. United States Patent US 6982091 B1, 2006 Jan 3.Google Scholar
  10. 10.
    Pauletti GM, Harrison DC, Desai KJ, inventors. Method for augmentation of intraepithelial and systemic exposure of therapeutic agents having substrate activity for cytochrome P450 enzymes and membrane efflux systems following vaginal or oral cavity administration. United States Patent US 2007/0036834 A1, 2007 Feb 15.Google Scholar
  11. 11.
    Wu SJ, Robinson JR. Vaginal epithelial models. In: Borchardt RT, Smith PL, Wilson G, editors. Models for assessing drug absorption and metabolism, Pharmaceutical biotechnology. New York: Plenum Press; 1996. p. 409–24.Google Scholar
  12. 12.
    das Neves J, Amaral MH, Bahia MF. Performance of an in vitro mucoadhesion testing method for vaginal semisolids: influence of different testing conditions and instrumental parameters. Eur J Pharm Biopharm. 2008;69:622–32. doi: 10.1016/j.ejpb.2007.12.007.PubMedCrossRefGoogle Scholar
  13. 13.
    Deutscher GH. G80-537 Reproductive trace anatomy and physiology of the cow. In: Historical materials from the University of Nebrasca-Lincoln extension, University of Nebrasca. 1980. Accessed 17 May 2012.
  14. 14.
    Bondurant RH. Inflammation in the bovine female reproductive tract. J Anim Sci. 1999;77:101–10.PubMedGoogle Scholar
  15. 15.
    Lamond DR, Shanahan AG. Chemical changes in cervical mucus from normal and ovariectomized cows treated with hormones. Biol Reprod. 1969;1:335–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Roberts GP. Structural studies on the glycoproteins from bovine cervical mucus. Biochem J. 1978;173:941–7.PubMedGoogle Scholar
  17. 17.
    Wrobel KH, Laun G, Hees H, Zwack M. Histologische und ultrastrukturelle Untersuchungen am Vaginalepithel des Rindes. Anat Histol Embryol. 1986;15:303–28. German.PubMedCrossRefGoogle Scholar
  18. 18.
    Sergin NP, Kuznecov MP, Kozlova VM, Nesmejanova TN. Physico-chemical conditions in the genital tract of the cow and survival of spermatozoa. 1940;15:24–8. Accessed 17 May 2012.
  19. 19.
    Heydon RA, Adams NR. Comparative morphology and mucus histochemistry of the ruminant cervix: differences between crypt and surface epithelium. Biol Reprod. 1979;21:557–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Baloğlu E, Özyazıcı M, Hızarcıoğlu SY, Karavana HA. An in vitro investigation for vaginal bioadhesive formulations: bioadhesive properties and swelling states of polymer mixtures. Farmacol. 2003;58:391–6.CrossRefGoogle Scholar
  21. 21.
    Baloğlu E, Ozyazici M, Yaprak Hizarcioğlu S, Senyiğit T, Ozyurt D, Pekçetin C. Bioadhesive controlled release systems of ornidazole for vaginal delivery. Pharm Dev Technol. 2006;11:477–84.PubMedCrossRefGoogle Scholar
  22. 22.
    Hombach J, Palmberger TF, Bernkop-Schnürch A. Development and in vitro evaluation of a mucoadhesive vaginal delivery system for nystatin. J Pharm Sci. 2009;98:555–64.PubMedCrossRefGoogle Scholar
  23. 23.
    Otero CM, Nader-Macias ME. Lactobacillus adhesion to epithelial cells from bovine vagina. In: Mendez-Vilas A, editors. Communicating current research and education topics and trends applied microbiology. Accessed 17 May 2012.
  24. 24.
    Rutllant J, López-Béjar M, López-Gatius F. Ultrastructural and rheological properties of bovine vaginal fluid and its relation to sperm motility and fertilization: a review. Reprod Domest Anim. 2005;40:79–86.PubMedCrossRefGoogle Scholar
  25. 25.
    Corbeil LB, Munson L, Campero C, BonDurant RH. Bovine Trichomoniasis as a model for development of vaccines against sexually-transmitted disease. Am J Reprod Immunol. 2001;45:310–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Mariano RN, Turino LN, Cabrera MI, Scándolo DE, Maciel MG, Grau RJ. A simple pharmacokinetic model linking plasma progesterone concentrations with the hormone release from bovine intravaginal inserts. Res Vet Sci. 2010;89:250–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Garcea G, Berry DP, Jones DJL, Singh R, Dennison AR, Farmer PB, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev. 2005;14:120–5.PubMedGoogle Scholar
  28. 28.
    Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4:817–8. doi: 10.1021/mp700113r.CrossRefGoogle Scholar
  29. 29.
    Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14:4491–9. doi: 10.1158/1078-0432.CCR-08-0024.PubMedCrossRefGoogle Scholar
  30. 30.
    Basnet P, Hussain H, Tho I, Skalko-Basnet N. Liposomal delivery system enhances anti-inflammatory properties of curcumin. J Pharm Sci. 2012. doi: 101:598–609.doi.10.1002/jps.22785.
  31. 31.
    Berginc K, Trontelj J, Skalko-Basnet N, Kristl B. The physiological barriers to oral delivery of curcumin. Die Pharm. 2012;67:1–7.Google Scholar
  32. 32.
    Yu LX, Amidon GL, Polli JE, Zhao H, Mehta MV, Conner DP, et al. Biopharmaceutical classification system: the scientific basis for biowaiver extensions. Pharm Res. 2002;19:921–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Chungi VS, Dittert LW, Smith RB. Gastrointestinal sites of furosemide absorption in rats. Int J Pharm. 1979;4:27–38.CrossRefGoogle Scholar
  34. 34.
    Taylor DC, Rownall R, Burke W. The absorption of β-adrenoreceptor antagonists in rat in-situ small intestine: the effect of lipophilicity. J Pharm Pharmacol. 1985;37:280–3.PubMedCrossRefGoogle Scholar
  35. 35.
    Zvonar A, Berginc K, Kristl A, Gašperlin M. Microencapsulation of self-microemulsifying system: improving solubility and permeability of furosemide. Int J Pharm. 2010;388:151–8. doi: 10.1016/j.ijpharm.2009.12.055.PubMedCrossRefGoogle Scholar
  36. 36.
    van der Bijl P, van Eyk AD. Comparative in vitro permeability of human vaginal, small intestinal and colonic mucosa. Int J Pharm. 2003;261:147–52. doi: 10.1016/S0378-5173(03)00298-9.PubMedCrossRefGoogle Scholar
  37. 37.
    Takano R, Furumoto K, Shiraki K, Takana N, Hayashi Y, Y A, et al. Rate-limiting steps of oral absorption for poorly-water soluble drugs in dogs; prediction from a miniscale dissolution test and physiologically-based computer simulation. Pharm Res. 2008;25:2334–44. doi: 10.1007/s11095-008-9637-9.PubMedCrossRefGoogle Scholar
  38. 38.
    Bourdet DL, Pollack GM, Thakker DR. Intestinal absorptive transport of the hydrophilic cation ranitidine: a kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs. transcellular transport in Caco-2 cells. Pharm Res. 2006;23:1178–87. doi: 10.1007/s11095-006-0204-y.PubMedCrossRefGoogle Scholar
  39. 39.
    Takano M, Hasegawa R, Fukuda T, Yumoto R, Nagai J, Murakami T. Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur J Pharmacol. 1998;358:289–94. doi: 10.1016/S0014-2999(98)00607-4.PubMedCrossRefGoogle Scholar
  40. 40.
    Kuchiiwa T, Nio-Kobayashi J, Takahashi-Iwanaga H, Yajima T, Iwanaga T. Cellular expression of monocarboxylate transporters in the female reproductive organ of mice: implications for the genital lactate shuttle. Histochem Cell Biol. 2011;135:351–60. doi: 10.1007/s00418-011-0794-2.PubMedCrossRefGoogle Scholar
  41. 41.
    Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci. 2008;65:1631–52. doi: 10.1007/s00018-008-7452-4.PubMedCrossRefGoogle Scholar
  42. 42.
    Gupta SC, Prasad S, Kim JH, Patchva S, Webb LJ, Priyadarsini IK, et al. Multitargeting by curcumin as revealed by moledular interaction studies. Nat Prod Rep. 2011;28:1937–55. doi: 10.1039/c1np00051a.PubMedCrossRefGoogle Scholar
  43. 43.
    Pavelić Ž, Škalko-Basnet N, Jalšenjak I. Characterization and in vitro evaluation of bioadhesive liposome gels for local therapy of vaginitis. Int J Pharm. 2005;301:140–8. doi: 10.1016/j.ijpharm.2005.05.022.PubMedCrossRefGoogle Scholar
  44. 44.
    Berg OA, Hurler J, Skalko-Basnet N. Advanced delivery system for skin and burns therapy: mupirocin as an antibacterial model drug. Eur J Pharm Sci. 2011;44:46–7.Google Scholar
  45. 45.
    Brittain HG. Profiles of drug substances, excipients and related methodology. 1st ed. Oxford: Elsevier; 2007.Google Scholar
  46. 46.
    PhysProp database. Accessed at 22 March 2012.
  47. 47.
    Zaki NM, Artursson P, Bergström CA. A modified physiological BCS for prediction of intestinal absorption in drug discovery. Mol Pharm. 2010;7:1478–87. doi: 10.1021/mp100124f.CrossRefGoogle Scholar
  48. 48.
    Kim JS, Mirchell S, Kijek P, Tsume Y, Hilfinger J, Amidon GL. The suitability of an in situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests. Mol Pharm. 2006;65:681–94. doi: 10.1021/mp060042f.Google Scholar
  49. 49.
    Avdeef A. Absorption and drug development—solubility, permeability, and charge state. New Jersey: Wiley; 2003.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Katja Berginc
    • 1
  • Nataša Škalko-Basnet
    • 2
  • Purusotam Basnet
    • 2
  • Albin Kristl
    • 1
  1. 1.Faculty of PharmacyUniversity of LjubljanaLjubljanaSlovenia
  2. 2.Drug Transport and Delivery Research Group, Department of Pharmacy, Faculty of Health SciencesUniversity of TromsøTromsøNorway

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