Composite Microparticles Based on Natural Mucoadhesive Polymers with Promising Structural Properties to Protect and Improve the Antifungal Activity of Miconazole Nitrate


Oropharyngeal candidiasis is a recurrent oral infection caused by Candida species. Gel formulation containing miconazole nitrate is the most common approach for treating oral candidiasis. However, traditional oral topical antifungal therapies have many limitations, including short contact time with the oral mucosa and the necessity to administrate various doses per day. Thus, the aim of this work was to formulate composited microparticulated systems based on combinations of mucoadhesive cationic, anionic, and nonionic polymers that could protect and modify the drug release rate and therefore avoid a fast dilution of the drug by saliva. Microparticulated systems were prepared by the spray drying method employing chitosan, gelatin, and hydroxypropyl methylcellulose. The morphology of the systems was investigated by scanning electron microscopy; drug crystallinity was studied by X-ray, while interactions between polymers were analyzed by infrared spectroscopy. Drug release and halo zone test were employed to analyze the release and activity of the systems loaded with miconazole against Candida albicans cultures. The most appropriate microparticulated system was the one based on chitosan and gelatin which showed homogeneous morphology (mean size of 1.7 ± 0.5 μm), a protective effect of the drug, and better antifungal effect against Candida culture than miconazole nitrate and the other assayed systems. Taking into account these results, this approach should be seriously considered for further evaluation of its safety and in vivo efficacy to be considered as an alternative therapeutic system for the treatment of oral candidiasis.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. 1.

    Spampinato C, Leonardi D. Candida infections, causes, targets, and resistance mechanisms: traditional and alternative antifungal agents. Biomed Res Int. 2013:1–13.

    Google Scholar 

  2. 2.

    Dongari-Bagtzoglou A, Dwivedi P, Ioannidou E, Shaqman M, Hull D, Burleson J. Oral Candida infection and colonization in solid organ transplant recipients. Mol Oral Microbiol. 2009;24(3):249–54.

    CAS  Google Scholar 

  3. 3.

    Andrés F, Klein T, Amanda L, Amanda M, Farago PV, Campanha NH. Development and validation of an RP-HPLC/UV method for determination of miconazole nitrate in spray-dried polymeric microparticles. Lat Am J Pharm. 2016;35(6):1354–60.

    Google Scholar 

  4. 4.

    Abruzzo A, Cerchiara T, Bigucci F, Gallucci MC, Luppi B. Mucoadhesive buccal tablets based on chitosan/gelatin microparticles for delivery of propranolol hydrochloride. J Pharm Sci. 2015;104(12):4365–72.

    CAS  PubMed  Google Scholar 

  5. 5.

    Tejada G, Barrera MG, Piccirilli GN, Sortino M, Frattini A, Salomón CJ, et al. Development and evaluation of buccal films based on chitosan for the potential treatment of oral candidiasis. AAPS PharmSciTech. 2017;18(4):936–46.

    CAS  PubMed  Google Scholar 

  6. 6.

    Tejada G, Piccirilli GN, Sortino M, Salomón CJ, Lamas MC, Leonardi D. Formulation and in-vitro efficacy of antifungal mucoadhesive polymeric matrices for the delivery of miconazole nitrate. Mater Sci Eng C. 2017;79(Supplement C):140–50.

    CAS  Google Scholar 

  7. 7.

    Mura P, Cirri M, Mennini N, Casella G, Maestrelli F. Polymeric mucoadhesive tablets for topical or systemic buccal delivery of clonazepam: effect of cyclodextrin complexation. Carbohydrate Polymers. 2016;152(Supplement C):755–63.

    CAS  PubMed  Google Scholar 

  8. 8.

    Alqurshi A, Kumar Z, McDonald R, Strang J, Buanz A, Ahmed S, et al. Amorphous formulation and in vitro performance testing of instantly disintegrating buccal tablets for the emergency delivery of naloxone. Mol Pharm. 2016;13(5):1688–98.

    CAS  PubMed  Google Scholar 

  9. 9.

    Sander C, Madsen KD, Hyrup B, Nielsen HM, Rantanen J, Jacobsen J. Characterization of spray dried bioadhesive metformin microparticles for oromucosal administration. Eur J Pharm Biopharm. 2013;85(3, Part A):682–8.

    CAS  PubMed  Google Scholar 

  10. 10.

    Nerkar P, Gattani S. Spray-dried buccal mucoadhesive microparticles of venlafaxine based on cress seed mucilage: in vitro, in vivo evaluation in rabbits. Dry Technol. 2012;30(9):968–78.

    Google Scholar 

  11. 11.

    Keegan GM, Smart JD, Ingram MJ, Barnes L-M, Burnett GR, Rees GD. Chitosan microparticles for the controlled delivery of fluoride. J Dent. 2012;40(3):229–40.

    CAS  PubMed  Google Scholar 

  12. 12.

    Gad HA, Kamel AO, Ezzat OM, El Dessouky HF, Sammour OA. Doxycycline hydrochloride-metronidazole solid lipid microparticles gels for treatment of periodontitis: development, in-vitro and in-vivo clinical evaluation. Expert Opinion on Drug Delivery. 2017;14(11):1241–51.

    CAS  PubMed  Google Scholar 

  13. 13.

    Monajjemzadeh F, Gholizadeh N, Yousefzadeh Mobaraki N, Jelvehgari M. Physicochemical and in vitro mucoadhesive properties of microparticles/discs of betamethasone for the management of oral lichen planus. Pharm Dev Technol. 2016;21(8):996–1005.

    CAS  PubMed  Google Scholar 

  14. 14.

    Cartagena AF, Lyra A, Kapuchczinski AC, Urban AM, Esmerino LA, Klein T, et al. Miconazole nitrate-loaded microparticles for buccal use: immediate drug release and antifungal effect. Current Drug Delivery. 2016;14(8):1144–53.

    Google Scholar 

  15. 15.

    Cartagena AF, Esmerino LA, Polak-Junior R, Olivieri Parreiras S, Domingos Michél M, Farago PV, et al. New denture adhesive containing miconazole nitrate polymeric microparticles: antifungal, adhesive force and toxicity properties. Dent Mater. 2017;33(2):e53–61.

    CAS  PubMed  Google Scholar 

  16. 16.

    Gierszewska M, Ostrowska-Czubenko J, Chrzanowska E. pH-responsive chitosan/alginate polyelectrolyte complex membranes reinforced by tripolyphosphate. Eur Polym J. 2018;101:282–90.

    CAS  Google Scholar 

  17. 17.

    Tayel AA, Moussa S, El-Tras WF, Knittel D, Opwis K, Schollmeyer E. Anticandidal action of fungal chitosan against Candida albicans. Int J Biol Macromol. 2010;47(4):454–7.

    CAS  PubMed  Google Scholar 

  18. 18.

    Mati-Baouche N, Elchinger P-H, de Baynast H, Pierre G, Delattre C, Michaud P. Chitosan as an adhesive. Eur Polym J. 2014;60:198–212.

    CAS  Google Scholar 

  19. 19.

    Garcia A, Leonardi D, Piccirilli GN, Mamprin ME, Olivieri AC, Lamas MC. Spray drying formulation of albendazole microspheres by experimental design. In vitro-in vivo studies. Drug Dev Ind Pharm. 2015;41(2):244–52.

    CAS  PubMed  Google Scholar 

  20. 20.

    García A, Barrera MG, Piccirilli G, Vasconi MD, Di Masso RJ, Leonardi D, et al. Novel albendazole formulations given during the intestinal phase of Trichinella spiralis infection reduce effectively parasitic muscle burden in mice. Parasitol Int. 2013;62(6):568–70.

    PubMed  Google Scholar 

  21. 21.

    Cigu TA, Vasiliu S, Racovita S, Lionte C, Sunel V, Popa M, et al. Adsorption and release studies of new cephalosporin from chitosan-g-poly(glycidyl methacrylate) microparticles. Eur Polym J. 2016;82:132–52.

    CAS  Google Scholar 

  22. 22.

    Vasiliu S, Popa M, Luca C. Evaluation of retention and release processes of two antibiotics from the biocompatible core-shell microparticles. Eur Polym J. 2008;44(11):3894–8.

    CAS  Google Scholar 

  23. 23.

    Khlibsuwan R, Siepmann F, Siepmann J, Pongjanyakul T. Chitosan-clay nanocomposite microparticles for controlled drug delivery: effects of the MAS content and TPP crosslinking. Journal of Drug Delivery Science and Technology. 2017;40(Supplement C):1–10.

    CAS  Google Scholar 

  24. 24.

    Yu C-Y, Yin B-C, Zhang W, Cheng S-X, Zhang X-Z, Zhuo R-X. Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH-sensitive drug release property. Colloids Surf B: Biointerfaces. 2009;68(2):245–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Chowdary K, Rao YS. Design and in vitro and in vivo evaluation of mucoadhesive microcapsules of glipizide for oral controlled release: a technical note. AAPS PharmSciTech. 2003;4(3):87–92.

    PubMed Central  Google Scholar 

  26. 26.

    Campos E, Branquinho J, Carreira AS, Carvalho A, Coimbra P, Ferreira P, et al. Designing polymeric microparticles for biomedical and industrial applications. Eur Polym J. 2013;49(8):2005–21.

    CAS  Google Scholar 

  27. 27.

    Mahmoudian M, Ganji F. Vancomycin-loaded HPMC microparticles embedded within injectable thermosensitive chitosan hydrogels. Progress in Biomaterials. 2017;6:49–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Kwon K, Kim J-C. Preparation of microparticles composed of cinnamoyl gelatin and cinnamoyl alginate by spray-drying method and effect of UV irradiation and pH value on their release property. J Dispers Sci Technol. 2017;38(2):187–93.

    CAS  Google Scholar 

  29. 29.

    Alburquenque C, Bucarey SA, Neira-Carrillo A, Urzúa B, Hermosilla G, Tapia CV. Antifungal activity of low molecular weight chitosan against clinical isolates of Candida spp. Med Mycol. 2010;48(8):1018–23.

    CAS  PubMed  Google Scholar 

  30. 30.

    Elsabee MZ, Abdou ES. Chitosan based edible films and coatings: a review. Mater Sci Eng C. 2013;33(4):1819–41.

    CAS  Google Scholar 

  31. 31.

    Hausberger AG, DeLuca PP. Characterization of biodegradable poly (D, L-lactide-co-glycolide) polymers and microspheres. J Pharm Biomed Anal. 1995;13(6):747–60.

    CAS  PubMed  Google Scholar 

  32. 32.

    Singh S, Jain S, Muthu M, Tiwari S, Tilak R. Preparation and evaluation of buccal bioadhesive films containing clotrimazole. AAPS PharmSciTech. 2008;9(2):660–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Shidhaye SS, Saindane NS, Sutar S, Kadam V. Mucoadhesive bilayered patches for administration of sumatriptan succinate. AAPS PharmSciTech. 2008;9(3):909–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Patel VF, Liu F, Brown MB. Modeling the oral cavity: in vitro and in vivo evaluations of buccal drug delivery systems. J Control Release. 2012;161(3):746–56.

    CAS  PubMed  Google Scholar 

  35. 35.

    Priotti J, Codina AV, Leonardi D, Vasconi MD, Hinrichsen LI, Lamas MC. Albendazole microcrystal formulations based on chitosan and cellulose derivatives: physicochemical characterization and in vitro parasiticidal activity in Trichinella spiralis adult worms. AAPS PharmSciTech. 2017;18(4):947–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Clinical and Laboratory Standards Institute W, PA. Method for antifungal disk diffusion susceptibility testing of yeasts. Approved guideline. Second edition. Document M44-A2. 2008.

  37. 37.

    Yeo Y, Park K. Control of encapsulation efficiency and initial burst in polymeric microparticle systems. Arch Pharm Res. 2004;27(1):1–12.

    CAS  PubMed  Google Scholar 

  38. 38.

    Craig DQ. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm. 2002;231(2):131–44.

    CAS  PubMed  Google Scholar 

  39. 39.

    Kumar CG, Poornachandra Y. Biodirected synthesis of miconazole-conjugated bacterial silver nanoparticles and their application as antifungal agents and drug delivery vehicles. Colloids Surf B: Biointerfaces. 2015;125(Supplement C):110–9.

    CAS  PubMed  Google Scholar 

  40. 40.

    Ribeiro A, Figueiras A, Santos D, Veiga F. Preparation and solid-state characterization of inclusion complexes formed between miconazole and methyl-β-cyclodextrin. AAPS PharmSciTech. 2008;9(4):1102–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Real DA, Martinez MV, Frattini A, Soazo M, Luque AG, Biasoli MS, et al. Design, characterization, and in vitro evaluation of antifungal polymeric films. AAPS PharmSciTech. 2013;14(1):64–73.

    CAS  PubMed  Google Scholar 

  42. 42.

    Park S-H, Chun M-K, Choi H-K. Preparation of an extended-release matrix tablet using chitosan/carbopol interpolymer complex. Int J Pharm. 2008;347(1):39–44.

    CAS  PubMed  Google Scholar 

  43. 43.

    de Britto D, Campana-Filho SP. A kinetic study on the thermal degradation of N,N,N-trimethylchitosan. Polymer Degradation and Stability. 2004;84(2):353–61.

    Google Scholar 

  44. 44.

    Mainardes RM, Gremião MPD, Evangelista RC. Thermoanalytical study of praziquantel-loaded PLGA nanoparticles. Revista Brasileira de Ciências Farmacêuticas. 2006;42(4):523–30.

    CAS  Google Scholar 

  45. 45.

    Li XG, Huang MR, Bai H. Thermal decomposition of cellulose ethers. J Appl Polym Sci. 1999;73(14):2927–36.

    CAS  Google Scholar 

  46. 46.

    Ling WC. Thermal degradation of gelatin as applied to processing of gel mass. J Pharm Sci. 1978;67(2):218–23.

    CAS  PubMed  Google Scholar 

  47. 47.

    Dranca I, Vyazovkin S. Thermal stability of gelatin gels: effect of preparation conditions on the activation energy barrier to melting. Polymer. 2009;50(20):4859–67.

    CAS  Google Scholar 

  48. 48.

    Chen CH, Wang FY, Mao CF, Yang CH. Studies of chitosan. I. Preparation and characterization of chitosan/poly (vinyl alcohol) blend films. J Appl Polym Sci. 2007;105(3):1086–92.

    CAS  Google Scholar 

  49. 49.

    Chavan RB, Thipparaboina R, Kumar D, Shastri NR. Evaluation of the inhibitory potential of HPMC, PVP and HPC polymers on nucleation and crystal growth. RSC Adv. 2016;6(81):77569–76.

    CAS  Google Scholar 

  50. 50.

    Eldridge JE, Ferry JD. Studies of the cross-linking process in gelatin gels. III. Dependence of melting point on concentration and molecular weight. J Phys Chem. 1954;58(11):992–5.

    CAS  Google Scholar 

  51. 51.

    Blasi P, Schoubben A, Giovagnoli S, Perioli L, Ricci M, Rossi C. Ketoprofen poly (lactide-co-glycolide) physical interaction. AAPS PharmSciTech. 2007;8(2):E78–85.

    PubMed Central  Google Scholar 

  52. 52.

    Li X, Xie H, Lin J, Xie W, Ma X. Characterization and biodegradation of chitosan–alginate polyelectrolyte complexes. Polym Degrad Stab. 2009;94(1):1–6.

    CAS  Google Scholar 

  53. 53.

    Dong Z, Wang Q, Du Y. Alginate/gelatin blend films and their properties for drug controlled release. J Membr Sci. 2006;280(1–2):37–44.

    CAS  Google Scholar 

  54. 54.

    Wang L, Dong W, Xu Y. Synthesis and characterization of hydroxypropyl methylcellulose and ethyl acrylate graft copolymers. Carbohydr Polym. 2007;68(4):626–36.

    CAS  Google Scholar 

  55. 55.

    Nart V, Franca MT, Anzilaggo D, Riekes MK, Kratz JM, de Campos CEM, et al. Ball-milled solid dispersions of BCS class IV drugs: impact on the dissolution rate and intestinal permeability of acyclovir. Mater Sci Eng C. 2015;53:229–38.

    CAS  Google Scholar 

  56. 56.

    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47–60.

    CAS  PubMed  Google Scholar 

Download references


G.T. is grateful to CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) for a doctoral fellowship. The authors acknowledge ANPCyT, UNMdP, UNR, and CONICET for the financial support.

Author information



Corresponding authors

Correspondence to V. A. Alvarez or D. Leonardi.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tejada, G., Lamas, M.C., Sortino, M. et al. Composite Microparticles Based on Natural Mucoadhesive Polymers with Promising Structural Properties to Protect and Improve the Antifungal Activity of Miconazole Nitrate. AAPS PharmSciTech 19, 3712–3722 (2018).

Download citation


  • antifungal
  • composite microparticles
  • chitosan
  • gelatin
  • hydroxypropyl methylcellulose
  • thermal protective effect