Multilayer Films Based on Chitosan/Pectin Polyelectrolyte Complexes as Novel Platforms for Buccal Administration of Clotrimazole

Buccal films are recognized as easily applicable, microbiologically stable drug dosage forms with good retentivity at the mucosa intended for the therapy of oromucosal conditions, especially infectious diseases. Multilayer films composed of layers of oppositely charged polymers separated by ionically interacting polymeric chains creating polyelectrolyte complexes represent very interesting and relatively poorly explored area. We aimed to develop the antifungal multilayer systems composed of cationic chitosan and anionic pectin as potential platforms for controlled delivery of clotrimazole. The systems were pharmaceutically characterized with regard to inter alia their release kinetics under different pH conditions, physicomechanical, or mucoadhesion properties with using an animal model of the buccal mucosa.

The antifungal activity against selected Candida sp. and potential cytotoxicity with regard to human gingival fibroblasts were also evaluated. Interactions between polyions were characterized with Fourier transform infrared spectroscopy. Different clotrimazole distribution in the films layers highly affected their in vitro dissolution profile. The designed films were recognized as intelligent pH-responsive systems with strong antifungal effect and satisfactory safety profile. As addition of chitosan resulted in the improved antifungal behavior of the drug, the potential utilization of the films in resistant cases of oral candidiasis might be worth of further exploration.

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Materials

High molecular weight CS derived from snow crabs (degree of deacetylation: 79.1%, viscosity of 1% solution in 1% acetic acid: 756 mPa·s, molecular weight: 200–500 kDa) was provided by Heppe Medical CS GmbH (Haale, Germany). High methoxy amidated PC from citrus peel (GENU® pectin, USP–H type) was kindly obtained from CP Kelco (Atlanta, GA, USA) (degree of esterification: 65–75%, methoxy groups content: 6.7–12.0%, viscosity of 2% solution: 200–450 mPa·s, galacturonic acid content: ≥74%). CLO and glycerol were purchased from Fagron (Kraków, Poland). Disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydroxide, and 85% lactic acid were purchased from Chempur (Piekary Śląskie, Poland). In turn, PEG 400 was obtained from Avantor Performance Materials Poland S. A. (Gliwice, Poland). Tween 80 and dimethyl sulfoxide (DMSO) were provided by Sigma Aldrich (St. Louis, MO, USA). Methanol for HPLC analysis was obtained from J. T. Baker (Phillipsburg, NJ, USA), while water for HPLC was distilled and passed through a reverse osmosis system Milli-Q Reagent Water System (Billerica, MA, USA). Stock cultures of Candida albicans ATCC® 10231, C. krusei ATCC® 6528, and C. Parapsilosis ATCC® 22019 and Sabouraud’s dextrose agar were obtained from Biomaxima (Lublin, Poland). Sodium chloride (0.9%) was from Polpharma S. A. (Starogard Gdański, Poland). Nylon membrane filters (0.45 µm) were provided by Millipore (Billerica, MA, USA). Commercially available product with 10 mg/g CLO (Clotrimazolum GSK, GlaxoSmithKline Pharmaceuticals S. A., Poznań, Poland, series: FW2D, expiry date: 08.2023) was utilized as a reference in the antifungal test. Human gingival fibroblasts (PCS–201–018) were obtained from ATCC (Manassas, VA, USA). Fetal bovine serum (FBS), Dulbecco’s modified Eagle’s medium (DMEM), phosphate-buffered saline (PBS) pH 7.0, and trypsin were purchased from Gibco (Gaithersburg, MD, USA). Penicillin, streptomycin (solution stabilized with 10,000 units penicillin and 10 mg streptomycin per mL, 0.1 μm filtered, BioReagent, suitable for cell culture, cat. no P4333–100 mL), 3–(4,5–dimethylthiazol–2–yl)–2,5–diphenyltetrazolium bromide (MTT), glycine, sodium chloride, scintillation fluid Ultima Gold XR, H2O2, 2′,7′–dichlorofluorescein diacetate (DCFH–DA) and sodium dodecyl sulphate were purchased from Sigma-Aldrich (St. Louis, MO, USA or Steinheim, Germany). RealTime–GloTM Annexin V Apoptosis and Necrosis Assay Kit was obtained from Promega (Madison, WI, USA).

Potaś, J.; Szymańska, E.; Wróblewska, M.; Kurowska, I.; Maciejczyk, M.; Basa, A.; Wolska, E.; Wilczewska, A.Z.; Winnicka, K. Multilayer Films Based on Chitosan/Pectin Polyelectrolyte Complexes as Novel Platforms for Buccal Administration of Clotrimazole. Pharmaceutics 2021, 13, 1588. https://doi.org/10.3390/pharmaceutics13101588

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