A multilayered nanofibrous mucoadhesive system for chamomile and Lidocaine controlled delivery in aphthous

Document Type : Research Paper

Authors

1 School of Pharmacy, Lorestan University of Medical Sciences, Khorramabad, Iran

2 Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.

10.22038/nmj.2025.78207.1912

Abstract

Objective(s): The mucoadhesive systems are among the preferred dosage forms for oral disorders. They can be designed to concentrate the drug at the site of action, control the drug release, and reduce both the frequency of medication and the systemic side effects. This study aims to design and evaluate a multilayered oro-mucoadhesive film encompassing chamomile hydroalcoholic extract and Lidocaine to manage oral aphthous disorder. 
Materials and Methods: A three-layer film for controlled release of Lidocaine and chamomile extract was prepared stepwise. The solvent casting method was used to prepare the fast-dissolving layer containing Lidocaine and chitosan/eudragit® S100 mucoadhesive layers. The middle layer, i.e. polycaprolactone nanofiber loaded with chamomile hydroalcoholic extract, was prepared by electrospinning. Layers were evaluated for appearance, thickness, pH, mucoadhesion, folding endurance, swellability, film disintegration time, content uniformity, chemical structure, and drug release. By attaching layers, the final system was prepared while DDSolver software was used to assess the release mechanism of Lidocaine and chamomile extract.
Results: The final dosage form had desirable physicochemical features, including mucoadhesive strength. The entire Lidocaine was released by diffusion over the first 4 hours, while the extract reached its maximum cumulative release (%) after about 24 hours under a combined release mechanism of diffusion and polymer relaxation. 
Conclusion: Due to having polymers with different properties in each layer, our multilayered system allowed the controlled release of Lidocaine and chamomile extract, enabling it effectively used in the treatment of oral disorders.

Keywords

References

Wei L, Wu S, Shi W, Aldrich AL, Kielian T, Carlson MA, et al. Large-scale and rapid preparation of nanofibrous meshes and their application for drug-loaded multilayer mucoadhesive patch fabrication for mouth ulcer treatment. ACS Appl Mater Interfaces. 2019;11(32):28740-28751.
2.    Suter VGA, Sjolund S, Bornstein MM. Effect of laser on pain relief and wound healing of recurrent aphthous stomatitis: a systematic review. Lasers Med Sci. 2017;32(4):953-963.
3.    Sharma D, Garg R. A comprehensive review on aphthous stomatitis, its types, management and treatment available. J Dev Drugs. 2018;7(2):1-8.
4.    Halboub E, Al-Maweri SA, Parveen S, Al-Wesabi M, Al-Sharani HM, Al-Sharani A, et al. Zinc supplementation for prevention and management of recurrent aphthous stomatitis: a systematic review. J Trace Elem Med Biol. 2021;68:126811.
5.    Al-Maweri SA, Halboub E, Ashraf S, Alqutaibi AY, Qaid NM, Yahya K, et al. Single application of topical doxycycline in management of recurrent aphthous stomatitis: a systematic review and meta-analysis of the available evidence. BMC Oral Health. 2020;20:1-8.
6.    Arany P. Craniofacial wound healing with photobiomodulation therapy: new insights and current challenges. J Dent Res. 2016;95(9):977-984.
7.    Zhang C, Liu Y, Li W, Gao P, Xiang D, Ren X, et al. Mucoadhesive buccal film containing ornidazole and dexamethasone for oral ulcers: in vitro and in vivo studies. Pharm Dev Technol. 2019;24(1):118-126.
8.    Li CL, Huang HL, Wang WC, Hua H. Efficacy and safety of topical herbal medicine treatment on recurrent aphthous stomatitis: a systemic review. Drug Des Devel Ther. 2016;10:107-115.
9.    Rezvaninejad R, Nabavi N, Khoshroo SM, Torabi N, Atai Z. Herbal Medicine in Treatment of Recurrent Aphthous Stomatitis: A Literature Review. J Iran Dent Assoc. 2017;29(3):127-134.
10.    Sah A, Naseef PP, Kuruniyan MS, Jain GK, Zakir F, Aggarwal G. A comprehensive study of therapeutic applications of chamomile. Pharmaceuticals. 2022;15(10):1284.
11.    Kani VT, Bharathwaj V, Nimmy P, Sindhu R, Dhamodhar D, Sathiapriya S, et al. Therapeutic effects of Chamomilla extract in oral diseases-A Systematic Review.  J Adv Med Dent Scie Res. 2023;11(4):50-55.
12.    Mamatha K, Venkatesh P. A review on: mucoadhesive drug delivery systems. J Innov Appl Pharm Sci. 2022:32-36.
13.    Wang T, Fleming E, Luo Y. An overview of the biochemistry, synthesis, modification, and evaluation of mucoadhesive polymeric nanoparticles for oral delivery of bioactive compounds.  Adv Compos Hybrid Mater. 2023;6(1):6.
14.    Joshi R, Akram W, Chauhan R, Garud N. Thin Films: A Promising Approach for Drug Delivery System.  Drug Carriers: IntechOpen. 2022.
15.    TM MW, Lau WM, Khutoryanskiy VV. Chitosan and Its Derivatives for Application in Mucoadhesive Drug Delivery Systems. Polymers (Basel). 2018;10(3):267.
16.    Yermak IM, Davydova VN, Volod’ko AV. Mucoadhesive marine polysaccharides. Mar Drugs. 2022;20(8):522.
17.    Nikam A, Sahoo PR, Musale S, Pagar RR, Paiva-Santos AC, Giram PS. A systematic overview of Eudragit® based copolymer for smart healthcare. Pharmaceutics. 2023;15(2):587.
18.    Szekalska M, Czajkowska-Kośnik A, Maciejewski B, Misztalewska-Turkowicz I, Wilczewska AZ, Bernatoniene J, et al. Mucoadhesive alginate/pectin films crosslinked by calcium carbonate as carriers of a model antifungal drug—Posaconazole. Pharmaceutics. 2023;15(10):2415.
19.    Villanova J, Ayres E, Oréfice R. Design, characterization and preliminary in vitro evaluation of a mucoadhesive polymer based on modified pectin and acrylic monomers with potential use as a pharmaceutical excipient. Carbohydr Polym. 2015;121:372-81.
20.    Jantrawut P, Chaiwarit T, Jantanasakulwong K, Brachais CH, Chambin O. Effect of Plasticizer Type on Tensile Property and In Vitro Indomethacin Release of Thin Films Based on Low-Methoxyl Pectin. Polymers (Basel). 2017;9(7):289.
21.    Fernandes FP, Fortes AC, da Cruz Fonseca SG, Breitkreutz J, Ferraz HG. Manufacture and characterization of mucoadhesive buccal films based on pectin and gellan gum containing triamcinolone acetonide. Int J Polym Sci. 2018;2018.
22.    Jacob S, Nair AB, Boddu SH, Gorain B, Sreeharsha N, Shah J. An updated overview of the emerging role of patch and film-based buccal delivery systems. Pharmaceutics. 2021;13(8):1206.
23.    Sung YK, Kim SW. Recent advances in polymeric drug delivery systems. Biomater Res. 2020;24(1):12.
24.    Mohamed RM, Yusoh K. A review on the recent research of polycaprolactone (PCL). Adv Mat Res. 2016;1134:249-255.
25.    Potrč T, Baumgartner S, Roškar R, Planinšek O, Lavrič Z, Kristl J, et al. Electrospun polycaprolactone nanofibers as a potential oromucosal delivery system for poorly water-soluble drugs. Eur J Pharm Sci. 2015;75:101-113.
26.    Adhikari U, An X, Rijal N, Hopkins T, Khanal S, Chavez T, et al. Embedding magnesium metallic particles in polycaprolactone nanofiber mesh improves applicability for biomedical applications. Acta Biomater. 2019;98:215-234.
27.    Shan W, Zhu X, Liu M, Li L, Zhong J, Sun W, et al. Overcoming the diffusion barrier of mucus and absorption barrier of epithelium by self-assembled nanoparticles for oral delivery of insulin. ACS Nano. 2015;9(3):2345-2356.
28.    Kouchak M, Handali S, Naseri Boroujeni B. Evaluation of the Mechanical Properties and Drug Permeability of Chitosan/Eudragit RL Composite Film. Osong Public Health Res Perspect. 2015;6(1):14-19.
29.    Sardou HS, Akhgari A, Garekani HA, Sadeghi F. Screening of different polysaccharides in a composite film based on Eudragit RS for subsequent use as a coating for delivery of 5-ASA to colon. Int J Pharm. 2019;568:118527.
30.    Mašek J, Lubasova D, Lukáč R, Turanek-Knotigova P, Kulich P, Plockova J, et al. Multi-layered nanofibrous mucoadhesive films for buccal and sublingual administration of drug-delivery and vaccination nanoparticles-important step towards effective mucosal vaccines. J Control Release. 2017;249:183-195.
31.    Jelvehgari M, Montazam SH, Soltani S, Azar K, Montazam SA. Fast dissolving oral thin film drug delivery systems consist of ergotamine tartrate and caffeine anhydrous. Pharm Sci. 2015;21(2):102-10.
32.    Begum MY, Alqahtani A, Ghazwani M, Ramakrishna M, Hani U, Atiya A, et al. Preparation of Carbopol 934 based ketorolac tromethamine buccal mucoadhesive film: in vitro, ex vivo, and in vivo assessments. Int J Polym Sci. 2021;2021(1):4786488.
33.    Paczkowska-Walendowska M, Szymanowska D, Cielecka-Piontek J. Mechanochemical Properties of Mucoadhesive Tablets Based on PVP/HPβCD Electrospun Nanofibers as Local Delivery of Polygoni Cuspidati Extract for Treating Oral Infections. Pharmaceuticals. 2023;16(4):579.
34.    Nowakowska-Toporowska A, Malecka K, Raszewski Z, Wieckiewicz W. Changes in hardness of addition-polymerizing silicone-resilient denture liners after storage in artificial saliva.  J Prosthet Dent. 2019;121(2):317-321.
35.    Akbari J, Saeedi M, MortezaSemnani K, Ameri M. The effect of type and amount of polymer on the bioadhesive properties and drug release of diclofenac sodium buccoadhesive films. J Mazandaran Univ Med Sci. 2014;24(113):92-103.
36.    Bruschi ML, de Souza Ferreira SB, da Silva JB. Mucoadhesive and mucus-penetrating polymers for drug delivery.  Nanotech Oral Drug Deliv: Elsevier. 2020;77-141.
37.    Kumar A, Naik PK, Pradhan D, Ghosh G, Rath G. Mucoadhesive formulations: Innovations, merits, drawbacks, and future outlook. Pharm Dev Technol. 2020;25(7):797-814.
38.    Parlinska-Wojtan M, Kus-Liskiewicz M, Depciuch J, Sadik O. Green synthesis and antibacterial effects of aqueous colloidal solutions of silver nanoparticles using camomile terpenoids as a combined reducing and capping agent. Bioprocess Biosyst Eng. 2016;39:1213-1223.
39.    Bruschi ML. Strategies to modify the drug release from pharmaceutical systems: Woodhead Publishing; 2015.
40.    Alawdi S, Solanki AB. Mucoadhesive drug delivery systems: A review of recent developments. J Sci Res Med Biol Sci. 2021;2(1):50-64.
41.    Li A, Khan IN, Khan IU, Yousaf AM, Shahzad Y. Gellan Gum-Based Bilayer Mucoadhesive Films Loaded with Moxifloxacin Hydrochloride and Clove Oil for Possible Treatment of Periodontitis. Drug Des Devel Ther. 2021;15:3937-3952.
42.    Gilhotra RM, Mishra DN. Alginate-chitosan film for ocular drug delivery: effect of surface cross-linking on film properties and characterization. Pharmazie. 2008;63(8):576-579.
43.    Lefnaoui S, Moulai-Mostefa N, Yahoum MM, Gasmi SN. Design of antihistaminic transdermal films based on alginate–chitosan polyelectrolyte complexes: characterization and permeation studies. Drug Dev Ind Pharm. 2018;44(3):432-443.
44.    Vasantha PV, Puratchikody A, Mathew ST, Balaraman AK. Development and characterization of Eudragit based mucoadhesive buccal patches of salbutamol sulfate. Saudi Pharm J. 2011;19(4):207-214.
45.    Cazorla-Luna R, Martín-Illana A, Notario-Pérez F, Bedoya LM, Tamayo A, Ruiz-Caro R, et al. Vaginal polyelectrolyte layer-by-layer films based on chitosan derivatives and Eudragit® S100 for pH responsive release of tenofovir. Mar drugs. 2020;18(1):44.
46.    Koland M, Charyulu RN, Vijayanarayana K, Prabhu P. In vitro and in vivo evaluation of chitosan buccal films of ondansetron hydrochloride. Int J Pharm Investig. 2011;1(3):164-171.
47.    Kolbuk D, Guimond-Lischer S, Sajkiewicz P, Maniura-Weber K, Fortunato G. The effect of selected electrospinning parameters on molecular structure of polycaprolactone nanofibers. Int J Polym Mater Polym Biomater. 2015;64(7):365-377.
48.    Chinnappan BA, Krishnaswamy M, Xu H, Hoque ME. Electrospinning of biomedical nanofibers/nanomembranes: effects of process parameters. Polymers. 2022;14(18):3719.
49.    Cavallari C, Fini A, Ospitali F. Mucoadhesive multiparticulate patch for the intrabuccal controlled delivery of lidocaine. Eur J Pharm Biopharm. 2013;83(3):405-414.
50.    Pleguezuelos-Villa M, Nacher A, Hernandez MJ, Buso M, Barrachina M, Penalver N, et al. A novel lidocaine hydrochloride mucoadhesive films for periodontal diseases. J Mater Sci Mater Med. 2019;30(1):14.
51.    Talevi A, Ruiz ME. Korsmeyer-Peppas, Peppas-Sahlin, and Brazel-Peppas: Models of Drug Release.  The ADME Encyclopedia: A Comprehensive Guide on Biopharmacy and Pharmacokinetic. Cham: Springer International Publishing. 2022; 613-621.
52.    Shokrollahi M, Bahrami SH, Nazarpak MH, Solouk A. Multilayer nanofibrous patch comprising chamomile loaded carboxyethyl chitosan/poly (vinyl alcohol) and polycaprolactone as a potential wound dressing. Int J Biol Macromol. 2020;147:547-559.
53.    Motealleh B, Zahedi P, Rezaeian I, Moghimi M, Abdolghaffari AH, Zarandi MA. Morphology, drug release, antibacterial, cell proliferation, and histology studies of chamomile-loaded wound dressing mats based on electrospun nanofibrous poly(varepsilon-caprolactone)/polystyrene blends. J Biomed Mater Res B Appl Biomater. 2014;102(5):977-987.
Nanomedicine Journal
Volume 12, Issue 2
April 2025
Pages 262-278

Files

Share

How to cite

Statistics