Infectious stomatitis represents the most common oral cavity ailments. Current therapy is insufficiently effective because of the short residence time of topical liquid or semisolid medical formulations. An innovative application form based on bioadhesive polymers featuring prolonged residence time on the oral mucosa may be a solution to this challenge. This formulation consists of a mucoadhesive oral film with incorporated nanocomposite biomaterial that is able to release the drug directly at the target area. This study describes the unique approach of preparing mucoadhesive oral films from carmellose with incorporating a nanotechnologically modified clay mineral intercalated with chlorhexidine. The multivariate data analysis was employed to evaluate the influence of the formulation and process variables on the properties of the medical preparation. This evaluation was complemented by testing the antimicrobial and antimycotic activity of prepared films with the aim of finding the most suitable composition for clinical application. Generally, the best results were obtained with sample containing 20 mg of chlorhexidine diacetate carried by vermiculite, with carmellose in the form of nonwoven textile in its structure. In addition to its promising physicomechanical, chemical, and mucoadhesive properties, the formulation inhibited the growth of Staphylococcus and Candida; the effect was prolonged for tens of hours.

Department of Maxillofacial Surgery University Hospital Ostrava 17 Listopadu 1790 5 Poruba 708 00 Ostrava Czech Republic

Department of Pharmaceutics University of Veterinary and Pharmaceutical Sciences Palackého Třída 1 3 612 42 Brno Czech Republic

Institute of Public Health Ostrava Centre of Clinical Laboratories Partyzánské Náměstí 7 702 00 Ostrava Czech Republic

Nanotechnology Centre VŠB Technical University of Ostrava 17 Listopadu 15 2172 Poruba 708 33 Ostrava Czech Republic ; T4Innovations Centre of Excellence VŠB Technical University of Ostrava 17 Listopadu 15 2172 Poruba 708 00 Ostrava Czech Republic

See more in PubMed

Bertesteanu S., Triaridis S., Stankovic M., et al. Polymicrobial wound infections: pathophysiology and current therapeutic approaches. International Journal of Pharmaceutics. 2014;463(2):119–126. doi: 10.1016/j.ijpharm.2013.12.012. PubMed DOI

Young H., Hirsh J., Hammerberg E. M., Price C. S. Dental disease and periprosthetic joint infection. The Journal of Bone and Joint Surgery—American Volume. 2014;96(2):162–168. doi: 10.2106/jbjs.l.01379. PubMed DOI

Pasich E., Bialecka A., Marcinkiewicz J. Efficacy of taurine haloamines and chlorhexidine against selected oral microbiome species. Medycyna Doświadczalna i Mikrobiologia. 2013;65(3):187–196. PubMed

Pinto A., Hong C. H. Orofacial manifestations of bacterial and viral infections in children. Journal of the California Dental Association. 2013;41:271–279. PubMed

Cawson R. A., Binnie W. H., Barrett A. W., Wright J. M. Oral Disease: Clinical and Pathological Correlations. Edinburgh, UK: Mosby; 2001.

Eisen D., Lynch D. P. The Mouth. Diagnosis and Treatment. St. Louis, Mo, USA: Mosby; 1998.

Rivera-Hidalgo F., Stanford T. W. Oral mucosal lesions caused by infective microorganisms I. Viruses and bacteria. Periodontology 2000. 1999;21(1):106–124. doi: 10.1111/j.1600-0757.1999.tb00171.x. PubMed DOI

Lalla R. V., Patton L. L., Dongari-Bagtzoglou A. Oral candidiasis: pathogenesis, clinical presentation, diagnosis and treatment strategies. Journal of the California Dental Association. 2013;41(4):263–268. PubMed

Coronado-Castellote L., Jimenez-Soriano Y. Clinical and microbiological diagnosis of oral candidiasis. Journal of Clinical and Experimental Dentistry. 2013;5(5):e279–e286. doi: 10.4317/jced.51242. PubMed DOI PMC

Dorko E., Jenča A., Pilipčinec E., Danko J., Švický E., Tkáčiková L. Candida-associated denture stomatitis. Folia Microbiologica (Praha) 2001;46(5):443–446. doi: 10.1007/bf02814436. PubMed DOI

Gurusamy K. S., Koti R., Toon C. D., Wilson P., Davidson B. R. Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in surgical wounds. The Cochrane Database of Systematic Reviews. 2013;8CD009726 PubMed PMC

ŠLširak M., Zvizdić A., Hukić M. Methicillin-resistant staphylococcus aureus (MRSA) as a cause of nosocomial wound infections. Bosnian Journal of Basic Medical Sciences. 2010;10(1):32–37. PubMed PMC

Bali R., Sharma P., Nagrath S., Gupta P. Microbial isolations from maxillofacial operation theatre and its correlation to fumigation in a teaching hospital in India. Journal of Maxillofacial and Oral Surgery. 2014;13(2):128–132. doi: 10.1007/s12663-012-0458-3. PubMed DOI PMC

Salamat-Miller N., Chittchang M., Johnston T. P. The use of mucoadhesive polymers in buccal drug delivery. Advanced Drug Delivery Reviews. 2005;57(11):1666–1691. doi: 10.1016/j.addr.2005.07.003. PubMed DOI

Dubolazov A. V., Nurkeeva Z. S., Mun G. A., Khutoryanskiy V. V. Design of micoadhesive polymeric films based on blends of poly(acrylic acid) and (hydroxypropyl)cellulose. Biomacromolecules. 2006;7(5):1637–1643. doi: 10.1021/bm060090l. PubMed DOI

Sudhakar Y., Kuotsu K., Bandyopadhyay A. K. Buccal bioadhesive drug delivery—a promising option for orally less efficient drugs. Journal of Controlled Release. 2006;114(1):15–40. doi: 10.1016/j.jconrel.2006.04.012. PubMed DOI

Averineni R. K., Sunderajan S. G., Mutalik S., et al. Development of mucoadhesive buccal films for the treatment of oral sub-mucous fibrosis: a preliminary study. Pharmaceutical Development and Technology. 2009;14(2):199–207. doi: 10.1080/10837450802498928. PubMed DOI

Morales J. O., McConville J. T. Manufacture and characterization of mucoadhesive buccal films. European Journal of Pharmaceutics and Biopharmaceutics. 2011;77(2):187–199. doi: 10.1016/j.ejpb.2010.11.023. PubMed DOI

Prajapati V., Bansal M., Kumar Sharma P. Mucoadhesive buccal patches and use of natural polymer in its preparation—a review. International Journal of PharmTech Research. 2012;4(2):582–589.

Gajdziok J., Vetchý D. Mucoadhesive polymers in medical forms. Chemicke Listy. 2012;106(7):632–638.

Vetchý D., Landová H., Gajdziok J., Doležel P., Daněk Z., Štembírek J. Determination of dependencies among in vitro and in vivo properties of prepared mucoadhesive buccal films using multivariate data analysis. European Journal of Pharmaceutics and Biopharmaceutics. 2014;86(3):498–506. doi: 10.1016/j.ejpb.2013.12.002. PubMed DOI

Carretero M. I., Pozo M. Clay and non-clay minerals in the pharmaceutical industry. Part I. Excipients and medical applications. Applied Clay Science. 2009;46(1):73–80. doi: 10.1016/j.clay.2009.07.017. DOI

Carretero M. I., Pozo M. Clay and non-clay minerals in the pharmaceutical and cosmetic industries. Part II. Active ingredients. Applied Clay Science. 2010;47(3-4):171–181. doi: 10.1016/j.clay.2009.10.016. DOI

Bergaya F., Theng B. K. G., Lagaly G. Handbook of Clay Science. Oxford, UK: Elsevier; 2006.

Madejová J. FTIR techniques in clay mineral studies. Vibrational Spectroscopy. 2003;31(1):1–10. doi: 10.1016/S0924-2031(02)00065-6. DOI

Magaña S. M., Quintana P., Aguilar D. H., et al. Antibacterial activity of montmorillonites modified with silver. Journal of Molecular Catalysis A: Chemical. 2008;281(1-2):192–199. doi: 10.1016/j.molcata.2007.10.024. DOI

Malachová K., Praus P., Rybková Z., Kozák O. Antibacterial and antifungal activities of silver, copper and zinc montmorillonites. Applied Clay Science. 2011;53(4):642–645. doi: 10.1016/j.clay.2011.05.016. DOI

Valášková M., Hundáková M., Kutláková K. M., et al. Preparation and characterization of antibacterial silver/vermiculites and silver/montmorillonites. Geochimica et Cosmochimica Acta. 2010;74(22):6287–6300. doi: 10.1016/j.gca.2010.08.025. DOI

Hu C.-H., Xia M.-S. Adsorption and antibacterial effect of copper-exchanged montmorillonite on Escherichia coli K88 . Applied Clay Science. 2006;31(3-4):180–184. doi: 10.1016/j.clay.2005.10.010. DOI

Hu C. H., Xu Y., Xia M. S., Xiong L., Xu Z. R. Effects of Cu2+-exchanged montmorillonite on growth performance, microbial ecology and intestinal morphology of Nile tilapia (Oreochromis niloticus) Aquaculture. 2007;270(1–4):200–206. doi: 10.1016/j.aquaculture.2007.01.027. DOI

Tan S.-Z., Zhang K.-H., Zhang L.-L., Xie Y.-S., Liu Y.-L. Preparation and characterization of the antibacterial Zn2+ or/and Ce3+ loaded montmorillonites. Chinese Journal of Chemistry. 2008;26(5):865–869. doi: 10.1002/cjoc.200890160. DOI

Herrera P., Burghardt R. C., Phillips T. D. Adsorption of Salmonella enteritidis by cetylpyridinium-exchanged montmorillonite clays. Veterinary Microbiology. 2000;74(3):259–272. doi: 10.1016/s0378-1135(00)00157-7. PubMed DOI

Ma Y.-L., Yang B., Guo T., Xie L. Antibacterial mechanism of Cu2+-ZnO/cetylpyridinium-montmorillonite in vitro . Applied Clay Science. 2010;50(3):348–353. doi: 10.1016/j.clay.2010.08.025. DOI

Malachová K., Praus P., Pavlíčková Z., Turicová M. Activity of antibacterial compounds immobilised on montmorillonite. Applied Clay Science. 2009;43(3-4):364–368. doi: 10.1016/j.clay.2008.11.003. DOI

Özdemir G., Limoncu M. H., Yapar S. The antibacterial effect of heavy metal and cetylpridinium-exchanged montmorillonites. Applied Clay Science. 2010;48(3):319–323. doi: 10.1016/j.clay.2010.01.001. DOI

Holešová S., Valášková M., Plevová E., Pazdziora E., Matějová K. Preparation of novel organovermiculites with antibacterial activity using chlorhexidine diacetate. Journal of Colloid and Interface Science. 2010;342(2):593–597. doi: 10.1016/j.jcis.2009.10.051. PubMed DOI

Holešová S., Samlíková M., Pazdziora E., Valášková M. Antibacterial activity of organomontmorillonites and organovermiculites prepared using chlorhexidine diacetate. Applied Clay Science. 2013;83-84:17–23. doi: 10.1016/j.clay.2013.07.013. DOI

Perumal V. A., Lutchman D., Mackraj I., Govender T. Formulation of monolayered films with drug and polymers of opposing solubilities. International Journal of Pharmaceutics. 2008;358(1-2):184–191. doi: 10.1016/j.ijpharm.2008.03.005. PubMed DOI

Repka M. A., Repka S. L., McGinity J. W. Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof. U.S. Patent; US6375963 B1, 2002.

Lee J. W., Park J. H., Robinson J. R. Bioadhesive-based dosage forms: the next generation. Journal of Pharmaceutical Sciences. 2000;89(7):850–866. PubMed

Andrews G. P., Laverty T. P., Jones D. S. Mucoadhesive polymeric platforms for controlled drug delivery. European Journal of Pharmaceutics and Biopharmaceutics. 2009;71(3):505–518. doi: 10.1016/j.ejpb.2008.09.028. PubMed DOI

Roy S. K., Prabhakar B. Bioadhesive polymeric platforms for transmucosal drug delivery systems—a review. Tropical Journal of Pharmaceutical Research. 2010;9(1):91–104.

Madhav N. V. S., Semwal R., Semwal D. K., Semwal R. B. Recent trends in oral transmucosal drug delivery systems: an emphasis on the soft palatal route. Expert Opinion on Drug Delivery. 2012;9(6):629–647. doi: 10.1517/17425247.2012.679260. PubMed DOI

Ding J., He R., Zhou G., Tang C., Yin C. Multilayered mucoadhesive hydrogel films based on thiolated hyaluronic acid and polyvinylalcohol for insulin delivery. Acta Biomaterialia. 2012;8(10):3643–3651. doi: 10.1016/j.actbio.2012.06.027. PubMed DOI

Bernkop-Schnürch A. Thiomers: a new generation of mucoadhesive polymers. Advanced Drug Delivery Reviews. 2005;57(11):1569–1582. doi: 10.1016/j.addr.2005.07.002. PubMed DOI

Rácz I., Borsa J. Swelling of carboxymethylated cellulose fibres. Cellulose. 1997;4(4):293–303. doi: 10.1023/A:1018400226052. DOI

Barba C., Montané D., Rinaudo M., Farriol X. Synthesis and characterization of carboxymethylcelluloses (CMC) from non-wood fibers I. Accessibility of cellulose fibers and CMC synthesis. Cellulose. 2002;9(3-4):319–326. doi: 10.1023/a:1021184509189. DOI

Aqualon: Sodium Carboxymethylcellulose, Physical and Chemical Properties, 2000, http://www.ashland.com.

Kulicke W.-M., Kull A. H., Kull W., Thielking H., Engelhardt J., Pannek J.-B. Characterization of aqueous carboxymethylcellulose solutions in terms of their molecular structure and its influence on rheological behaviour. Polymer. 1996;37(13):2723–2731. doi: 10.1016/0032-3861(96)87634-8. DOI

Jain D., Carvalho E., Banerjee R. Biodegradable hybrid polymeric membranes for ocular drug delivery. Acta Biomaterialia. 2010;6(4):1370–1379. doi: 10.1016/j.actbio.2009.11.001. PubMed DOI

Prusov A. N., Prusova S. M. Viscosity properties of aqueous solutions of carboxymethylcellulose and hydroxyethylcellulose blends. Fibre Chemistry. 2007;39(1):12–15. doi: 10.1007/s10692-007-0003-1. DOI

Kube T., Sutter M., Trittler R., Feltgen N., Hansen L. L., Agostini H. T. Carboxymethylcellulose as a new carrier substance for intravitreal injection of reproducible amounts of triamcinolone. Graefe's Archive for Clinical and Experimental Ophthalmology. 2006;244(11):1385–1390. doi: 10.1007/s00417-006-0326-2. PubMed DOI

Cho H.-J., Balakrishnan P., Shim W.-S., Chung S.-J., Shim C.-K., Kim D.-D. Characterization and in vitro evaluation of freeze-dried microparticles composed of granisetron-cyclodextrin complex and carboxymethylcellulose for intranasal delivery. International Journal of Pharmaceutics. 2010;400(1-2):59–65. doi: 10.1016/j.ijpharm.2010.08.030. PubMed DOI

Li H.-Y., Song X., Seville P. C. The use of sodium carboxymethylcellulose in the preparation of spray-dried proteins for pulmonary drug delivery. European Journal of Pharmaceutical Sciences. 2010;40(1):56–61. doi: 10.1016/j.ejps.2010.02.007. PubMed DOI

Esbensen K. H., Guyot D., Westad F., Houmøller L. P. Multivariate Data Analysis—In Practice: An Introduction to Multivare Data Analysis and Experimental Design. Oslo, Norway: CAMO Process AS; 2004.

Holešová S., Štembírek J., Bartošová L., et al. Antibacterial efficiency of vermiculite/chlorhexidine nanocomposites and results of the in vivo test of harmlessness of vermiculite. Materials Science and Engineering C. 2014;42:466–473. doi: 10.1016/j.msec.2014.05.054. PubMed DOI

European Directorate for the Quality of Medicines & Health Care. The European Pharmacopoeia 8.0. 8th. Strasbourg, France: European Directorate for the Quality of Medicines & Health Care; 2013. http://online6.edqm.eu/ep800/

Nafee N. A., Ismail F. A., Boraie N. A., Mortada L. M. Mucoadhesive delivery systems. I. Evaluation of mucoadhesive polymers for buccal tablet formulation. Drug Development and Industrial Pharmacy. 2004;30(9):985–993. doi: 10.1081/ddc-200037245. PubMed DOI

Shidhaye S. S., Saindane N. S., Sutar S., Kadam V. Mucoadhesive bilayered patches for administration of sumatriptan succinate. AAPS PharmSciTech. 2008;9(3):909–916. doi: 10.1208/s12249-008-9125-x. PubMed DOI PMC

Kneiflová J. Hodnocení baktericidní účinnosti dezinfekčních prostředků suspenzní mikrometodou. Československá Epidemiologie, Mikrobiologie, Imunologie. 1988;37:97–103. PubMed

Walker G. F. Vermiculite minerals. In: Brown G., editor. The X-Ray Identification and Crystal Structures of Clay Minerals. London, UK: The Mineralogical Society; 1961. pp. 297–324.

Shizoru H., Bailey S. W. Crystal structure of a two-layer Mg-vermiculite. American Mineralogist. 1966;51:1124–1143.

de la Calle C., Suquet H. Vermiculite. Reviews in Mineralogy and Geochemistry. 1988;19:455–496.

Farmer V. C. The Infrared Spectra of Minerals. London, UK: The Mineralogical Society; 1974.

Russel J. D., Fraser A. R. Infrared methods. In: Wilson M. J., editor. Clay Mineralogy: Spectroscopic and Chemical Determinative Methods. London, UK: Chapman & Hall, CRC Press; 1994. pp. 11–67.

Silverstein R. M., Basser G. C., Morrill T. C. Spectrometric Identification of Organic Compounds. New York, NY, USA: John Wiley & Sons; 1991.

Socrates G. Infrared and Raman Characteristic Group Frequencies, Tables and Charts. Chichester, UK: John Wiley & Sons; 2001.

Dixit R. P., Puthli S. P. Oral strip technology: overview and future potential. Journal of Controlled Release. 2009;139(2):94–107. doi: 10.1016/j.jconrel.2009.06.014. PubMed DOI

Nair A. B., Kumria R., Harsha S., Attimarad M., Al-Dhubiab B. E., Alhaider I. A. In vitro techniques to evaluate buccal films. Journal of Controlled Release. 2013;166(1):10–21. doi: 10.1016/j.jconrel.2012.11.019. PubMed DOI

Kumar V., Aggarwal G., Zakir F., Choudhary A. Buccal bioadhesive drug delivery—a novel technique. International Journal of Pharmacy and Biological Sciences. 2011;1:89–102.

Holzbecher. 2013, http://www.holzbecher.net.

Tu Y. Y., Yuang C. Y., Chen R. S., Chen M. H. Effects of chlorhexidine on stem cells from exfoliated deciduous teeth. Journal of the Formosan Medical Association. 2015;114(1):17–22. doi: 10.1016/j.jfma.2012.12.008. PubMed DOI

Puratchikody A., Prasanth V. V., Mathew S. T., Kumar B. A. Development and characterization of mucoadhesive patches of salbutamol sulfate for unidirectional buccal drug delivery. Acta Pharmaceutica. 2011;61(2):157–170. doi: 10.2478/v10007-011-0011-9. PubMed DOI

Slezák R. Preklinická parodontologie. Hradec Králové, Czech Republic: NUCLEUS HK; 2007.

Macias J. H., Arreguin V., Munoz J. M., Alvarez J. A., Mosqueda J. L., Macias A. E. Chlorhexidine is a better antiseptic than povidone iodine and sodium hypochlorite because of its substantive effect. American Journal of Infection Control. 2013;41(7):634–637. doi: 10.1016/j.ajic.2012.10.002. PubMed DOI