Mucoadhesive, Fluconazole-Loaded Nanogels Complexed with Sulfhydryl-β-cyclodextrin for Oral Thrush Treatment
Tóm tắt
The objective of this study was to generate fluconazole-loaded mucoadhesive nanogels to address the problem of hydrophobicity of fluconazole (FL). An inclusion complex was formulated with sulfhydryl-β-CD (SH-β-CD) followed by nanogels formation by a Schiff base reaction of carbopol 940 (CA-940) and gelatin (GE). For characterization, PXRD, FT-IR analysis, drug content, and phase solubility studies were performed. Similarly, nanogels were assessed for particle size, zeta potential, organoleptic, and spreadability studies. Moreover, drug contents, rheological, in vitro drug permeation, release kinetics, toxicity, and stability studies of nanogels were performed. Furthermore, mucoadhesive characteristics over the buccal mucosal membrane of the goat were evaluated. The nanogels formulated with a higher amount of CA-940 and subsequently loaded with the inclusion complexes of FL showed promising results. PXRD and FT-IR analysis confirmed the physical complexes by displaying a reduction in the intensity of peaks of FL. The average particle size of nanogels was in the range of 257 to 361 nm. The highest drug content of 88% was encapsulated within the FL-SH-β-CD complex. All formulations at 0.5–1% concentration displayed no toxicity to the Caco-2 cell lines. Nanogels loaded with FL-SH-β-CD complexes showed 18-fold improved mucoadhesion on the buccal mucous membrane of the goat when compared to simple nanogels. The in vitro permeation study exhibited significantly enhanced permeation and first-order concentration-dependent drug release was observed. On the bases of these findings, we can conclude that a mucoadhesive nanogel-based drug delivery system can be an ideal therapy for candidiasis.
Tài liệu tham khảo
Semnani D, et al. Investigating the performance of drug delivery system of fluconazole made of nano–micro fibers coated on cotton/polyester fabric. J Mater Sci. 2017;28(11):1–8.
Quindós G, et al. Therapeutic tools for oral candidiasis: current and new antifungal drugs. Medi Oral Patol Oral Cir Bucal. 2019;24(2): e172.
Kraisit P, et al. Fluconazole-loaded solid lipid nanoparticles (SLNs) as a potential carrier for buccal drug delivery of oral candidiasis treatment using the Box-Behnken design. J Drug Deliv Sci Technol. 2021;63: 102437.
Shahzadi I, et al. Less reactive thiol ligands: key towards highly mucoadhesive drug delivery systems. Polymers. 2020;12(6):1259.
Ijaz M, et al. Synthesis and characterization of thiolated β-cyclodextrin as a novel mucoadhesive excipient for intra-oral drug delivery. Carbohydr Polym. 2015;132:187–95.
Di Pietro ME, Ferro M, Mele A. Drug encapsulation and chiral recognition in deep eutectic solvents/β-cyclodextrin mixtures. J Mol Liq. 2020;311: 113279.
Bidkar S, et al. Formulation development and evaluation of fluconazole gel in various polymer bases. Asian J Pharm. 2007;1(1):63–8.
Alekha K, William F. Fluconazole In: Florey K., editor.(ed.) Analytical profiles of drug substances and excipients. 2006, London, UK: Academic Press.
More PP, et al. Formulation development and evaluation of fluconazole gel in various polymer bases. Asian J Pharm. 2007;1(1):63–8.
Jiang Y, et al. Click hydrogels, microgels and nanogels: emerging platforms for drug delivery and tissue engineering. Biomaterials. 2014;35(18):4969–85.
Sahiner N, et al. Microgel, nanogel and hydrogel–hydrogel semi-IPN composites for biomedical applications: synthesis and characterization. Colloid Polym Sci. 2006;284:1121–9.
Richtering W, Pich A. The special behaviours of responsive core–shell nanogels. Soft Matter. 2012;8(45):11423–30.
Rauh A, Honold T, Karg M. Seeded precipitation polymerization for the synthesis of gold-hydrogel core-shell particles: the role of surface functionalization and seed concentration. Colloid Polym Sci. 2016;294:37–47.
Topuz F, Uyar T. Advances in the development of cyclodextrin-based nanogels/microgels for biomedical applications: drug delivery and beyond. Carbohydr Polym. 2022;297:120033.
Asim MH, et al. Tetradeca-thiolated cyclodextrins: highly mucoadhesive and in-situ gelling oligomers with prolonged mucosal adhesion. Int J Pharm. 2020;577: 119040.
Ijaz M, et al. Thiolated α-cyclodextrin: the invisible choice to prolong ocular drug residence time. J Pharm Sci. 2016;105(9):2848–54.
Yurtdaş G, Demirel M, Genç L. Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation. J Incl Phenom Macrocycl Chem. 2010;70(3–4):429–35.
Li J, et al. Inclusion complexes of fluconazole with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin in aqueous solution: preparation, characterization and a structural insight. J Incl Phenom Macrocycl Chem. 2016;84(3–4):209–17.
Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007;59(7):645–66.
Siva S, et al. Encompassment of isoeugenol in 2-hydroxypropyl-β-cyclodextrin using ultrasonication: characterization, antioxidant and antibacterial activities. J Mol Liq. 2019;296: 111777.
Malkoch M, et al. Synthesis of well-defined hydrogel networks using click chemistry. Chem Commun. 2006;26:2774–6.
Asim MH, et al. Per-6-thiolated cyclodextrins: a novel type of permeation enhancing excipients for BCS class IV drugs. ACS Appl Mater Interfaces. 2020;12(7):7942–50.
Yurtdaş G, Demirel M, Genç L. Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation. J Incl Phenom Macrocycl Chem. 2011;70(3–4):429–35.
Göğer NG, Aboul-Enein HY. Quantitative determination of fluconazole in capsules and IV solutions by UV spectrophotometric methods. Anal Lett. 2001;34(12):2089–98.
Tejada G, et al. Formulation and in-vitro efficacy of antifungal mucoadhesive polymeric matrices for the delivery of miconazole nitrate. Mater Sci Eng: C. 2017;79:140–50.
Aslani A, Zolfaghari B, Davoodvandi F. Design, formulation and evaluation of an oral gel from Punica granatum flower extract for the treatment of recurrent aphthous stomatitis. Adv Pharm Bull. 2016;6(3):391.
Rompicherla NC, et al. Formulation and evaluation of mucoadhesive oral gel containing miconazole nitrate for oral candidiasis. Res J Pharm Technol. 2013;6(11):1251–7.
Rathna G, Mohan Rao D, Chatterji P. Hydrogels of gelatin-sodium carboxymethyl cellulose: synthesis and swelling kinetics. J Macromol Sci, Part A: Pure Appl Chem. 1996;33(9):1199–207.
Kardos A, Gilányi T, Varga I. How small can poly (N-isopropylacrylamide) nanogels be prepared by controlling the size with surfactant? J Colloid Interf Sci. 2019;557:793–806.
Elnaggar YS, et al. Novel lecithin-integrated liquid crystalline nanogels for enhanced cutaneous targeting of terconazole: development, in vitro and in vivo studies. Int J Nanomedicine. 2016;11:5531.
Chaudhary H, et al. Optimization and formulation design of carbopol loaded Piroxicam gel using novel penetration enhancers. Int J Biol Macromol. 2013;55:246–53.
Shah PP, et al. Skin permeating nanogel for the cutaneous co-delivery of two anti-inflammatory drugs. Biomaterials. 2012;33(5):1607–17.
Kang W, et al. Study on the enhanced viscosity mechanism of the cyclodextrin polymer and betaine-type amphiphilic polymer inclusion complex. J Mol Liq. 2019;296: 111792.
Asim, et al. Tetradeca-thiolated cyclodextrins: highly mucoadhesive and in-situ gelling oligomers with prolonged mucosal adhesion. Int J Pharm. 2020;577:119040.
Asim MH, et al. Thiolated cyclodextrins: mucoadhesive and permeation enhancing excipients for ocular drug delivery. Int J Pharm. 2021;599: 120451.
Asim, et al. Per-6-thiolated cyclodextrins: a novel type of permeation enhancing excipients for BCS class IV drugs. ACS Appl Mater Interfaces. 2020;12(7):7942–50.
Asim, et al. S-protected thiolated cyclodextrins as mucoadhesive oligomers for drug delivery. J Colloid Interface Sci. 2018;531:261–8.
Basha BN, Prakasam K, Goli D. Formulation and evaluation of gel containing fluconazole-antifungal agent. Int J Drug Dev Res. 2011;3(4):109–28.
Ribeiro AM, et al. Combining strategies to optimize a gel formulation containing miconazole: the influence of modified cyclodextrin on textural properties and drug release. Drug Dev Ind Pharm. 2010;36(6):705–14.
Gafitanu CA, et al. Design, preparation and evaluation of HPMC-Based PAA or SA freeze-dried scaffolds for vaginal delivery of fluconazole. Pharm Res. 2017;34(10):2185–96.
Panonnummal R, Jayakumar R, Sabitha M. Comparative anti-psoriatic efficacy studies of clobetasol loaded chitin nanogel and marketed cream. Eur J Pharm Sci. 2017;96:193–206.
Asim MH, et al. Mucoadhesive S-protected thiolated cyclodextrin-iodine complexes: a promising strategy to prolong mucosal residence time of iodine. Futur Microbiol. 2019;14(5):411–24.
Yurtdaş Kırımlıoğlu G, Demirel M, Genç L. Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation. J Incl Phenom Macrocycl Chem. 2011;70:429–35.
Zhang X, et al. Investigation and physicochemical characterization of clarithromycin–citric acid–cyclodextrins ternary complexes. Drug Dev Ind Pharm. 2007;33(2):163–71.
Gursalkar T, Bajaj A, Jain D. Cyclodextrin based nanosponges for pharmaceutical use. Acta Pharma. 2013;63:335–58.
Stephenson GA. Applications of X-ray powder diffraction in the pharmaceutical industry. Rigaku J. 2005;22(1):2–15.
Brittain HG, et al. Physical characterization of pharmaceutical solids. Pharm Res. 1991;8(8):963–73.
Yurtdaş G, Demirel M, Genç L. Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation. J Incl Phenom Macrocycl Chem. 2011;70:429–35.
Li Z, Huang J, Wu J. pH-sensitive nanogels for drug delivery in cancer therapy. Biomater Sci. 2021;9(3):574–89.
Dantas MGB, et al. Development and evaluation of stability of a gel formulation containing the monoterpene borneol. Sci World J. 2016;2016:7394685.
Elsayed MM, et al. PG-liposomes: novel lipid vesicles for skin delivery of drugs. J Pharm Pharmacol. 2007;59(10):1447–50.
Tang S, et al. Facile aqueous-phase synthesis of multi-responsive nanogels based on polyetheramines and bisepoxide. J Mater Chem B. 2013;1(11):1628–34.
Islam P, et al. Chitosan-based nano-embedded microparticles: impact of nanogel composition on physicochemical properties. Pharmaceutics. 2016;9(1):1.
Harish NM, et al. Formulation and evaluation of in situ gels containing clotrimazole for oral Candidiasis. Indian J Pharm Sci. 2009;71(4):421–7.
Deshkar SS, Palve VK. Formulation and development of thermosensitive cyclodextrin-based in situ gel of voriconazole for vaginal delivery. J Drug Deliv Sci Technol. 2019;49:277–85.
Moya-Ortega MD, et al. Cross-linked hydroxypropyl-β-cyclodextrin and γ-cyclodextrin nanogels for drug delivery: physicochemical and loading/release properties. Carbohydr Polym. 2012;87(3):2344–51.