AAPS PharmSciTech

, Volume 9, Issue 3, pp 953–965 | Cite as

Effect of Thiolated Polymers to Textural and Mucoadhesive Properties of Vaginal Gel Formulations Prepared with Polycarbophil and Chitosan

  • Erdal Cevher
  • Demet Sensoy
  • Mohamed A. M. Taha
  • Ahmet Araman
Research Article


The aim of this study was to design and evaluate of mucoadhesive gel formulations for the vaginal application of clomiphene citrate (CLM) for local treatment of human papilloma virus (HPV) infections. Chitosan (CHI) and polycarbophil (PC) were covalently modified using the thioglycolic acid and L-cysteine, respectively. The formation of thiol conjugates of chitosan (CHI-TG) and polycarbophil (PC-CYS) were confirmed by FT-IR analysis and PC-CYS and CHI-TG were found to have 148.42 ± 4.16 and 41.17 ± 2.34 μmol of thiol groups per gram of polymer, respectively. One percent CLM gels were prepared by combination of various concentrations of PC and CHI with thiolated conjugates of these polymers. Hardness, compressibility, elasticity, adhesiveness and cohesiveness of the gels were measured by Texture profile analysis and the vaginal mucoadhesion was investigated by mucoadhesion test. The increasing in the amount of the thiol conjugates was found to enhance the elasticity, cohesiveness, adhesiveness and mucoadhesion of the gel formulations but not their hardness and compressibility when compared to gels prepared using their respective parent formulations. Slower release rate of CLM from gels was achieved when the polymer concentrations were increased in the gel formulations. PC and its thiol conjugate were found to prolong the release of CLM longer than 70 h unlike gel formulations prepared using CHI and its thiol conjugate which were able to release CLM up to 12 h. Stability of CLM was preserved during the 3 month stability analysis under controlled room temperature and accelerated conditions.


chitosan–thioglycolic acid clomiphene citrate gel human papilloma virus polycarbophil–cysteine texture profile analysis vaginal mucoadhesion 



This work was supported by the Istanbul University. Project number: T-138/11112002.


  1. 1.
    A. Ferrera, J. P. Velema, M. Figueroa, R. Bulnes, L. A. Toro, J. M. Claros, O. De Barahona, and W. J. G. Melchers. Human papillomavirus infection, cervical dysplasia and invasive cervical cancer in Honduras: A case-control study. Int. J. Cancer. 82:799–803 (1999).PubMedCrossRefGoogle Scholar
  2. 2.
    D. C. Newton, and M. P. McCabe. The impact of stigma on couples managing a sexually transmitted infection. Sex Relat. Ther. 20:51–63 (2005).CrossRefGoogle Scholar
  3. 3.
    K. F. Czerwenka, H. J. Schön, M. Manavi, R. Zeillinger, E. Kubista, and E. Gitsch. Reliability of in-situ hybridization of smears and biopsies for papilloma virus genotyping of the uterina cervix. Eur. J. Clin. Chem. Clin. Biochem. 29:139–145 (1991).PubMedGoogle Scholar
  4. 4.
    H. J. Schön, K. F. Czerwenka, B. Schurz, R. Kramar, and E. Kubista. Papanicolaou test and enzyme-linked in-situ hybridization a combined diagnostic system for papilloma virus infections with high prognostic value. Eur. J. Clin. Chem. Clin. Biochem. 29:131–138 (1991).PubMedGoogle Scholar
  5. 5.
    J. S. Park, Y. K. Oh, M. J. Kang, and C. K. Kim. Enhanced mucosal and systemic immune responses following intravaginal immunization with human papilloma virus 16L1 virus-like particle vaccine in thermosensitive mucoadhesive delivery systems. J. Medical Virology. 70:633–641 (2003).CrossRefGoogle Scholar
  6. 6.
    M. J. McLeish. Clomiphene citrate. In K. Florey (ed.), Analytical Profiles of Drug Substances and Excipients, Academic, New York, 1998, pp. 85–120.Google Scholar
  7. 7.
    R. Jimenez-Castellanos, H. Zia, and C. T. Rhodes. Mucoadhesive drug delivery systems. Drug Dev. Ind. Pharm. 19:143–194 (1993).CrossRefGoogle Scholar
  8. 8.
    H. G. Choi, Y. K. Oh, and C. K. Kim. In situ gelling and mucoadhesive liquid suppository containing acetaminophen: enhanced bioavailability. Int. J. Pharm. 165:23–32 (1998).CrossRefGoogle Scholar
  9. 9.
    J. M. Ryu, S. J. Chung, M. H. Lee, C. K. Kim, and C. K. Shim. Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum. J. Control Release. 59:163–172 (1999).PubMedCrossRefGoogle Scholar
  10. 10.
    C. Valenta, C. E. Kast, I. Harich, and A. Bernkop-Schnürch. Development and in vitro evaluation of mucoadhesive vaginal delivery system for progesterone. J. Control. Release. 77:323–332 (2001).PubMedCrossRefGoogle Scholar
  11. 11.
    E. Cevher, O. Sahin, and A. Araman. Investigations on topical formulations of clomiphene citrate for treatment of HPV lesion. Pharmazie. 57:72–73 (2002).PubMedGoogle Scholar
  12. 12.
    Y. W. Chien, C. H. Lee. Drug Delivery-Vaginal Route. In J. Swarbrick, J. C. Boylan (eds.), Encyclopedia of Pharmaceutical Technology, second edition, PharmaceuTech, Pinehurst, North Carolina, 2002, pp. 961–985.Google Scholar
  13. 13.
    H. Takeuchi, Y. Matsui, H. Yamamoto, and Y. Kawashima. Mucoadhesive properties of carbopol or chitosan-coated liposomes and their effectiveness in the oral administration of calcitonin to rats. J. Control. Release. 86:235–242 (2003).PubMedCrossRefGoogle Scholar
  14. 14.
    R. Y. Han, J. Y. Fang, K. C. Sung, and O. Y. P. Hu. Mucoadhesive buccal disks for novel nalbuphine prodrug controlled delivery: Effect of formulation variables on drug release and mucoadhesive performance. Int. J. Pharm. 177:201–209 (1999).PubMedCrossRefGoogle Scholar
  15. 15.
    G. C. Ceschel, P. Maffei, and B. S. Lombardi. Design and evaluation of a new mucoadhesive bi-layered tablet containing nimesulide for buccal administration. STP Pharm. Sci. 11:151–156 (2001).Google Scholar
  16. 16.
    L. Perioli, V. Ambrogi, D. Rubini, S. Giovagnoli, M. Ricci, P. Blasi, and C. Rossi. Novel mucoadhesive buccal formulation containing metronidazole for the treatment of periodontal disease. J. Control. Release. 95:521–533 (2004).PubMedCrossRefGoogle Scholar
  17. 17.
    R. Yahagi, Y. Machida, H. Onishi, and Y. Machida. Mucoadhesive suppositories of ramosetron hydrochloride utilizing Carbopol®. Int. J. Pharm. 193:205–212 (2000).PubMedCrossRefGoogle Scholar
  18. 18.
    D. Sales, D. Sae-Lee, S. Matsuya, and I. D. Ana. Short-term fluoride and cations release from polyacid-modified composites in a distilled water, and an acidic lactate buffer. Biomaterials. 24:1687–1696 (2003).PubMedCrossRefGoogle Scholar
  19. 19.
    M. Yun, H. Choi, J. Jung, and C. Kim. Development of a thermo-reversible insulin liquid suppository with bioavailability enhancement. Int. J. Pharm. 189:137–145 (1999).PubMedCrossRefGoogle Scholar
  20. 20.
    J. Ceulemans, A. Vermeire, E. Adriaens, J. P. Remon, and A. Ludwig. Evaluation of a mucoadhesive tablet for ocular use. J. Control. Release. 77:333–344 (2001).PubMedCrossRefGoogle Scholar
  21. 21.
    J. D. Smart, I. W. Kellaway, and H. E. C. Worthington. An in vitro investigation of mucosa adhesive materials for use in controlled drug delivery. J. Pharm. Pharmacol. 36:295–299 (1984).PubMedGoogle Scholar
  22. 22.
    C. H. Lee, and Y. W. Chien. Development and evaluation of a mucoadhesive drug delivery system for dual-controlled delivery Nonoxynol-9. J. Control. Release. 39:93–103 (1996).CrossRefGoogle Scholar
  23. 23.
    H. Park, and J. R. Robinson. Physico-chemical properties of water insoluble polymers important to mucin/epithelial adhesion. J. Control. Release. 2:47–57 (1985).CrossRefGoogle Scholar
  24. 24.
    A. H. Shojaei, S. L. Zhou, and X. Li. Transbuccal delivery of acyclovir (II): feasibility, system design, and in vitro permeation studies. J. Pharm. Pharmaceut. Sci. 1:66–73 (1998).Google Scholar
  25. 25.
    A. Bernkop-Schnürch, H. Zarti, and G. F. Walker. Thiolation of polycarbophil enhances its inhibition of intestinal brush border membrane bound aminopeptidase. J. Pharm. Sci. 90:1907–1914 (2001).PubMedCrossRefGoogle Scholar
  26. 26.
    C. E. Kast, C. Valenta, M. Leopold, and A. Bernkop-Schnürch. Design and in vitro evaluation of a novel bioadhesive vaginal drug delivery system for clotrimazole. J. Control. Release. 81:347–354 (2002).PubMedCrossRefGoogle Scholar
  27. 27.
    N. Langoth, J. Kalbe, and A. Bernkop-Schnürch. Development of buccal drug delivery systems based on a thiolated polymer. Int. J. Pharm. 252:141–148 (2003).PubMedCrossRefGoogle Scholar
  28. 28.
    C. E. Kast, and A. Bernkop-Schnürch. Thiolated polymers-thiomers: development and in vitro evaluation of chitosan–thioglycolic acid conjugates. Biomaterials. 22:2345–2352 (2001).PubMedCrossRefGoogle Scholar
  29. 29.
    D. S. Jones, A. D. Woolfson, and A. F. Brown. Textural, viscoelastic and mucoadhesive properties of pharmaceutical gels composed of cellulose polymers. Int. J. Pharm. 151:223–233 (1997).CrossRefGoogle Scholar
  30. 30.
    S. Tamburic, and D. Q. M. Craig. An investigation into the rheological, dielectric and mucoadhesive properties of poly(acrylic acid) gel systems. J. Control. Release. 37:59–68 (1995).CrossRefGoogle Scholar
  31. 31.
    M. J. Tobyn, J. R. Johnson, and P. W. Dettmar. Factors affecting in vitro gastric mucoadhesion I. Test Conditions and instrumental parameters. Eur. J. Pharm. Biopharm. 41:235–241 (1995).Google Scholar
  32. 32.
    E. Cevher, M. A. M. Taha, M. Orlu, and A. Araman. Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gel formulations containing carbomers and their thiolated derivatives. Drug Deliv. 15:57–67 (2007).CrossRefGoogle Scholar
  33. 33.
    A. A. Deshpande, C. T. Rhodes, and M. Danish. Intravaginal drug delivery. Drug Dev. Ind. Pharm. 18:1225–1279 (1992).CrossRefGoogle Scholar
  34. 34.
    N. O. Schwartz. Adaptation of sensory textile profile method to skin care products. J. Text. Studies. 42:33–42 (1975).CrossRefGoogle Scholar
  35. 35.
    D. S. Jones, C. R. Irwin, A. D. Woolfson, J. Djokic, and V. Adams. Physochemical characterization and preliminary in vivo efficiacy of bioadhesive, semisolid formulations containing flurbiprofen for the treatment of gingivitis. J. Pharm. Sci. 88:592–598 (1999).PubMedCrossRefGoogle Scholar
  36. 36.
    Y. T. F. Tan, K. K. Peh, and O. Al-Hanbali. Effect of carpobol and polyvinylpyrrolidone on the mechanical, rheological and release properties of bioadhesive polyethylene glycol gels. AAPS PharmSciTech. 1:E24 (2000).PubMedCrossRefGoogle Scholar
  37. 37.
    F. Ferrari, M. Bertoni, C. Caramella, and A. La Manna. Description and validation of an apparatus for gel strength measurements. Int. J. Pharm. 109:115–124 (1994).CrossRefGoogle Scholar
  38. 38.
    D. S. Jones, A. D. Woolfson, and A. F. Brown. Textural analysis and flow rheometry of novel, bioadhesive antimicrobial oral gels. Pharm. Res. 114:450–457 (1997).CrossRefGoogle Scholar
  39. 39.
    T. Kachanechaia, P. Jantawata, and R. Pichyangkurab. The influence of chitosan on physico-chemical properties of chicken salt-soluble protein gel. Food Hydrocoll. 22:74–83 (2008).CrossRefGoogle Scholar
  40. 40.
    D. S. Jones, D. A. Woolfson, A. F. Brown, and M. J. O’Neill. Mucoadhesive, syringeable drug delivery systems for controlled application of metronidazole to the periodontal pocket: In vitro release kinetics, syringeability, mechanical and mucoadhesive properties. J. Control. Release. 49:71–79 (1997).CrossRefGoogle Scholar
  41. 41.
    S. Tamburic, and D. Q. M. Craig. A comparison of different in vitro methods for measuring mucoadhesive performance. Eur. J. Pharm. Biopharm. 44:159–167 (1997).CrossRefGoogle Scholar
  42. 42.
    D. S. Jones, A. D. Woolfson, J. Djokic, and W. A. Coulter. Development and mechanical characterization of bioadhesive semi-solid, polymeric systems containing tetracycline for the treatment of periodontal diseases. Pharm. Res. 13:1734–1738 (1996).PubMedCrossRefGoogle Scholar
  43. 43.
    D. S. Jones, A. D. Woolfson, A. F. Brown, W. A. Coulter, C. McClelland, C. R. Irwin. Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease. J. Control. Release. 67:357–368 (2000).Google Scholar
  44. 44.
    D. S. Jones, A. D. Woolfson, and J. Djokic. Texture profiles analysis of bioadhesive polymeric semisolids: mechanical characterisation and investigation of interactions between formulation components. J. App. Polymer Sci. 16:2229–2234 (1996).CrossRefGoogle Scholar
  45. 45.
    N. A. Peppas, and P. A. Buri. Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues. J. Control Release. 2:257–275 (1985).CrossRefGoogle Scholar
  46. 46.
    J. Richardson, and L. Illum. Routes of delivery: Case studies, the vaginal route of peptide and protein drug delivery. Adv. Drug Del. Rev. 8:341–366 (1992).CrossRefGoogle Scholar
  47. 47.
    J. Y. Chang, Y. K. Oh, H. S. Kong, E. J. Kim, D. D. Jang, K. T. Nam, and C. K. Kim. Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis. J. Control. Release. 82:39–50 (2002).PubMedCrossRefGoogle Scholar
  48. 48.
    A. El-Kamel, M. Sokar, V. Naggar, and S. A. Gamal. Chitosan and sodium alginate-based bioadhesive vaginal tablets. AAPS PharmSci. 4:article 44 (2002).Google Scholar
  49. 49.
    M. C. Bonferoni, P. Giunchedi, S. Rossi, G. Sandri, and C. Caramella. Chitosan gels for the vaginal delivery of lactic acid: Relevance of formulation parameters to mucoadhesion and release mechanisms. AAPS PharmSciTech. 7:article 104 (2006).Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2008

Authors and Affiliations

  • Erdal Cevher
    • 1
  • Demet Sensoy
    • 1
  • Mohamed A. M. Taha
    • 2
  • Ahmet Araman
    • 1
  1. 1.Faculty of Pharmacy, Department of Pharmaceutical TechnologyIstanbul UniversityIstanbulTurkey
  2. 2.D.G. PharmacyKhartoumSudan

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