Evaluation of chitosan based vaginal bioadhesive gel formulations for antifungal drugs

Open access


The aim of the present study was to evaluate chitosan as a vaginal mucoadhesive gel base for econazole nitrate and miconazole nitrate. To this aim, different types of chitosan with different molecular masses and viscosity properties [low molecular mass chitosan (viscosity: 20,000 mPa s), medium molecular mass chitosan (viscosity: 200,000 mPa s), high molecular mass chitosan (viscosity: 800,000 mPa s)] have been used. First, rheological studies were conducted on chitosan gels. Mechanical, syringeability and mucoadhesive properties of chitosan gels were determined. Release profiles of econazole nitrate and miconazole nitrate from chitosan gels were obtained and evaluated kinetically. In addition, anticandidal activities of formulations were determined. Finally, vaginal retention of chitosan gels in rats was evaluated by in vivo distribution studies. Based on the results, it can be concluded that gels prepared with medium molecular mass chitosan might be effectively used for different antifungal agents in the treatment of vaginal candidiosis, since it has high mucoadhesiveness, suitable mechanical and release properties with good vaginal retention

1. B. Albertini, N. Passerini, M. Di Sabatino, B. Vitali, P. Brigidi and L. Rodriguez, Polymer-lipid based mucoadhesive microspheres prepared by spray-congealing for the vaginal delivery of econazole nitrate, Eur. J. Pharm. Sci. 36 (2009) 591-601; DOI: 10.1016/j.ejps.2008.12.009.

2. J. A. Kamarashev and S. G. Vassileva, Dermatologic diseases of the vulva, Clin. Dermatol. 15 (1997) 53-65; DOI: 10.1016/j.bbr.2011.03.031.

3. R. Gurny, J. M. Meyer and N. A. Peppas, Bioadhesive intraoral release systems: design, testing and analysis, Biomaterials 5 (1984) 336-340; DOI: 10.1016/0142-9612(84)90031-0.

4. A. Bernkop-Schnürch and S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. 81 (2012) 463-469; DOI: 10.1016/j.ejpb.2012.04.007.

5. C. Valenta, The use of mucoadhesive polymers in vaginal delivery, Adv. Drug Deliv. Rev. 57 (2005) 1692-1712; DOI: 10.1016/j.addr.2005.07.004.

6. J. E. Codd and P. B. Deasy, Formulation development and in vivo evaluation of a novel bioadhesive lozenge containing a synergistic combination of antifungal agents, Int. J. Pharm. 173 (1998) 13-24; DOI: 10.1016/S0378-5173(98)00228-2.

7. 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 (1997) 223-233; DOI: 10.1016/S0378-5173(97)04904-1.

8. S. K. Yellanki, N. K. Nerella, S. Goranti and S. K. Deb, Development of metronidazole intravaginal gel for the treatment of bacterial vaginosis: Effect of mucoadhesive natural polymers on the release of metronidazole, Int. J. Pharm. Tech. Res. 2 (2010) 1746-1750.

9. D. S. Jones, A. D. Woolfson and A. F. Brown, Textural analysis and flow rheometry of novel, bioadhesive antimicrobial oral gels, Pharm. Res. 14 (1997) 450-457; DOI: 10.1023/A: 1012091231023.

10. G. P. Andrews, S. P. Gorman and D. S. Jones, Rheological characterisation of primary and binary interactive bioadhesive gels composed of cellulose derivatives designed as ophthalmic viscosurgical devices, Biomaterials 26 (2005) 571-580; DOI: 10.1016/j.biomaterials.2004.02.062.

11. D. S. Jones, A. D. Woolfson and J. Djokic, Texture profile analysis of bioadhesive polymeric semisolids: mechanical characterization and investigation of interactions between formulation components, J. Appl. Polym. Sci. 61 (1996) 2229-2234; DOI: 10.1002/(SICI)1097-4628(19960919)61.

12. D. S. Jones, A. D. Woolfson, A. F. Brown, W. A. Coulter, C. McClelland and 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 (2000) 357-368; DOI: 10.1016/S0168-3659(00)00231-5.

13. G. Sandri, M. C. Bonferoni, S. Rossi, F. Ferrari, M. Mori, C. Del Fante, C. Perotti, L. Scudeller and C. Caramella, Platelet lysate formulations based on mucoadhesive polymers for the treatment of corneal lesions, J. Pharm. Pharmacol. 63 (2011) 189-198; DOI: 10.1111/j.2042-7158.2010. 01208.x.

14. 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 (2002) 347-354; DOI: 10.1016/S0168-3659(02)00077-9.

15. N. A. Peppas, Analysis of fickian and non-fickian drug release polymers, Pharm. Acta Helv. 60 (1985) 110-111.

16. P. L. Ritger and N. A. Peppas, A simple equation for description of solute release II. Fickian and anomalous release from swellable devices, J. Control. Release 5 (1987) 37-42; DOI: 10.1016/ 0168-3659(87)90035-6.

17. J. Parekh and S. Chanda, In vitro antimicrobial activity and phytochemical analysis of some Indian medicinal plants, Turk. J. Biol. 31 (2007) 53-58.

18. X. He, J. Ma, A. E. Mercado, W. Xu and E. Jabbari, Cytotoxicity of paclitaxel in biodegradable self-assembled core-shell poly (lactide-co-glycolide ethylene oxide fumarate) nanoparticles, Pharm. Res. 25 (2008) 1552-1562; DOI: 10.1007/s11095-007-9513-z.

19. K. Vermani and S. Garg, The scope and potential of vaginal drug delivery, PSTT 3 (2000) 359-364; DOI: 10.1016/S1461-5347(00)00296-0.

20. S. Uppuluri, S. E. Keinath, D. A. Tomalia and P. R. Dvornic, Rheology of dendrimers. I. Newtonian flow behavior of medium and highly concentrated solutions of polyamidoamine (PAMAM) dendrimers in ethylenediamine (EDA) solvent, Macromolecules 31 (1998) 4498-4510; DOI: 10.1021/ ma971199b.

21. H. Qi, W. Chen, C. Huang, I. Li, C. Chen, W. Li and C. Wu, Development of a poloxamer analogs/ carbopol-based in situ gelling and mucoadhesive ophthalmic delivery system for puerarin, Int. J. Pharm. 337 (2007) 178-187; DOI: 10.1016/j.ijpharm.2006.12.038.

22. G. Dumortier, J. L. Grossiord, M. Zuber, G. Couarraze and J. C. Chaumeil, Rheological study of a thermoreversible morphine gel, Drug Dev. Ind. Pharm. 17 (1991) 1255-1265; DOI: 10.3109/ 03639049109043858.

23. K. Dillen, W. Weyenberg, J. Vandervoort and A. Ludwig, The influence of the use of viscosifiying agents as dispersion media on the drug release properties from PLGA nanoparticles, Eur. J. Pharm. Biopharm. 58 (2004) 539-549; DOI: 10.1016/j.ejpb.2004.03.035.

24. W. Argüelles-Monal, F. M. Goycoolea, C. Peniche and I. Higuera-Ciapara, Rheological study of the chitosan/glutaraldehyde chemical gel system, Polym. Gels Netw. 6 (1998) 429-440; DOI: 10.1016/S0966-7822(98)00032-X.

25. D. S. Jones, A. D. Woolfson and A. F. Brown, Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease, J. Control. Release 67 (2000) 357-368; DOI: 10.1016/S0168-3659(00) 00231-5.

26. E. Baloglu, Z. Ay Senyigit, S. Y. Karavana and A. Bernkop-Schnürch, Strategies to prolong the intravaginal residence time of drug delivery systems, Pharm. Pharmac. Sci. 12 (2009) 312-336.

27. S. Y. Karavana, Z. Ay Senyigit, S. Hilmioðlu-Polat, D. Y. Metin, O. Zekioðlu and E. Baloðlu, Mucoadhesive In situ gel formulations of miconazole nitrate for the treatment of mucosal candidiasis, Lat. Am. J. Pharm. 31 (2012) 821-829.

28. J. Siepmann and N. A. Peppas, Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC), Adv. Drug Deliv. Rev. 48 (2001) 139-157; DOI: 10.1016/ S0169-409X(01)00112-0.

29. A. A. Tayela, S. Moussa, W. F. El-Tras, D. Knittel, K. Opwis and E. Schollmeyer, Anticandidal action of fungal chitosan against Candida albicans, Int. J. Biol. Macromol. 47 (2010) 454-457; DOI: 10.1016/j.ijbiomac.2010.06.011.

30. R. Muzzarelli, R. Tarsi, O. Filippini, E. Giovanetti, G. Biagini and P. E. Varaldo, Antimicrobial properties of N-carboxybutyl chitosan, Antimicrob. Agents Chemother. 34 (1990) 2019-2023; DOI: 10.1128/AAC.34.10.2019.

31. A. R. Geonnotti, J. J. Peters and D. F. Katz, Erosion of microbicide formulation coating layers: effects of contact and shearing with vaginal fluid or semen, J. Pharm. Sci. 94 (2005) 1705-1712; DOI: 10.1002/jps.20386.

32. K. Vermani, S. Garg and L. J. Zaneveld, Assemblies for in vitro measurement of bioadhesive strength and retention characteristics in simulated vaginal environment, Drug Dev. Ind. Pharm. 28 (2002) 1133-1146; DOI: 10.1081/DDC-120014580.

33. B. E. Chatterton, S. Penglis, J. C. Kovacs, B. Presnell and B. Hunt, Retention and distribution of two 99mTc-DTPA labelled vaginal dosage forms, Int. J. Pharm. 271 (2004) 137-143; DOI: 10.1016/ j.ijpharm.2003.11.006.

34. S. Y. Karavana, E. H. Gökçe, S. Rençber, S. Özbal, Ç. Pekçetin, P. Güneri and G. Ertan, A new approach to the treatment of recurrent aphthous stomatitis with bioadhesive gels containing cyclosporine A solid lipid nanoparticles: in vivo/in vitro examinations, Int. J. Nanomed. 7 (2012) 5693-5704; DOI: 10.2147/IJN.S36883.

35. D. H. Owen, J. J. Peters and D. F. Katz, Rheological properties of contraceptive gels, Contraception 62 (2000) 321-326; DOI: 10.1016/S0010-7824(00)00184-0.

36. S. Di Fabio, J. Van Roey, G. Giannini, G. van den Mooter, M. Spada, A. Binelli, M. F. Pirillo, E. Germinario, F. Belardelli, M. P. de Bethune and S. Vella, Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation, AIDS 17 (2003) 1597-1604; DOI: 10.1097/00002030-200307250-00003.

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

Journal Information

IMPACT FACTOR 2017: 1.071
5-year IMPACT FACTOR: 1.623

CiteScore 2017: 1.46

SCImago Journal Rank (SJR) 2017: 0.362
Source Normalized Impact per Paper (SNIP) 2017: 0.642

Cited By


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 225 225 18
PDF Downloads 116 116 10