Mucoadhesive buccal films of flunarizine: formulation strategies using β-cyclodextrin and polymeric carriers: A review

 Corresponding author: Jadhav Jayesh Gangadhar Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Mucoadhesive buccal films of flunarizine: formulation strategies using βcyclodextrin and polymeric carriers: A review Jayesh Gangadhar Jadhav 1, *, Sujal Anil Jagnade 1, Sahil Sonlal Janwale 1, Pratham Yogesh Bangar 1, Avishkar Suresh Kad 1 and S. M. Bhalekar 2 1 Samarth Institute of Pharmacy, Affiliated to Dr. Babasaheb Ambedkar Technological University (DBATU), Lonere, Maharashtra, India. 2 Department of Quality Assurance, Samarth Institute of Pharmacy, Affiliated to Dr. Babasaheb Ambedkar Technological University (DBATU), Lonere, Maharashtra, India. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 011-017 Publication history: Received on 20 September 2025; revised on 01 November 2025; accepted on 03 November 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.24.2.0978 Abstract Flunarizine dihydrochloride, a calcium channel blocker used in the prophylaxis of migraine and vestibular disorders, suffers from poor aqueous solubility and extensive first-pass metabolism, leading to low oral bioavailability. To overcome these limitations, a mucoadhesive thin film (MATF) of flunarizine was developed using β-cyclodextrin for solubility enhancement and various polymers such as HPMC E15, PVA, and Carbopol 934P for film formation and mucoadhesion. The prepared film aims to achieve rapid onset of action, improved solubility, and better patient compliance. This paper reviews the formulation design, preparation method, and evaluation parameters of the developed film, highlighting its potential as a promising alternative to conventional dosage forms. Keywords: Flunarizine; Mucoadhesive Thin Film; Β-Cyclodextrin; Buccal Delivery; Solubility Enhancement; HPMC; PVA; Carbopol 1. Introduction 1.1. Migraine Migraine represents a chronic neurological condition characterized by recurring headache attacks that are typically pulsating in nature and may be accompanied by nausea, vomiting, and photophobia/phonophobia. The headache is typically unilateral, resulting from aberrant brain activity with neuronal and vascular changes. Trigeminal activation leads to vascular changes via the release of neuropeptides, including CGRP and serotonin, which cause inflammation and vasodilation that underlie the pain commonly experienced with migraines. Migraine is frequently triggered by a variety of factors, such as stress, changes in sleep pattern, menstrual cycle, some foods (cheese, chocolate, caffeine, red wine), and environmental factors such as bright light or loud noise. Approximately 15–20% of the global population sees some symptoms of migraines, with females most often showing symptoms. Migraine is a debilitating disorder and affects quality of life. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 011-017 12 1.2. Flunarizine Flunarizine is a selective calcium channel blocker that is classified in the group of drugs called cinnarizine and is primarily used for migraine prophylaxis. Flunarizine has antimigraine properties due to the blockade of calcium entry into neuronal and vascular smooth muscle cells, resulting in decreased vascular constriction and neuronal excitability, both of which contribute to the development of migraine pain. Flunarizine is also used for vertigo and balance disorders due to the antihistaminic, sedative, and vestibular suppressive effects. However, the therapeutic efficacy of flunarizine is limited by its poor water solubility and low bioavailability. To ameliorate flunarizine's physical limitations, mucoadhesive thin film (MATF) formulations are currently being developed. Matf formulations improve the solubility, absorption, and onset of actions after administration compared to oral formulations. 1.3. What is MATF and Its Advantages Mucoadhesive Thin Films (MATF) represent an innovative approach to drug delivery, facilitating the expedited and effective absorption of therapeutic agents across the oral mucosa. MATF can be described as thin films or sheets that possess flexible properties and adherent characteristics to the mucosal surfaces (i.e., buccal or sublingual), allowing drugs to enter the systemic circulation while avoiding the first-pass effect. • The advantages of MATF are as follows: • Rapid onset of action as a result of rapid drug absorption through the mucosa; • Drug absorption that avoids the first-pass metabolism leading to increased bioavailability of poorly soluble drugs; • Ease of use without the need for water making it ideal for pediatric and geriatric patients; 1.4. Drug Profile of Flunarizine Table 1 Drug Profile Table Property Description Chemical Name Flunarizine dihydrochloride Chemical Structure Category Calcium channel blocker Molecular Formula C26H26F2N2 Molecular Weight 440.49 g/mol Solubility Poorly soluble in water, freely soluble in ethanol [15] Bioavailability ~40% due to first-pass metabolism Half-life 18–19 hours pKa 9.2 Therapeutic Uses Migraine prophylaxis, vertigo, vestibular disorders Mechanism Blocks calcium entry into smooth muscle and neuronal cells Limitation Poor aqueous solubility and variable absorption World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 011-017 13 2. Rationale for Mucoadhesive Thin Film Formulation While flunarizine is effective in the prophylaxis of migraines, its therapeutic application is hampered by poor aqueous solubility and poor oral bioavailability, which can lead to variable clinical outcomes, and response between patients [16]. Mucoadhesive thin films (MATFs) provide an innovative solution by enabling direct drug delivery to the buccal mucosa, avoiding hepatic first-pass metabolism, and providing a faster and more reliable onset of action [17,18]. The addition of β-cyclodextrin forms inclusion complexes with flunarizine, which increases solubility, stability, and dissolution rate. Furthermore, the use of synergistic polymers, HPMC E15, PVA, and Carbopol 934P, allows for adequate film formation as well as unique mechanical strength, flexibility, and mucoadhesion to remain in intimate contact with a mucosal surface while releasing the drug. With this combination of enhanced solubility and polymer engineering, the MATF is a novel and patient-centered alternative to conventional oral dosage forms, maximizing clinical outcomes and minimizing variability [19–21]. Figure 1 Mucoadhesive Thin Film Formulation 3. Materials and Methods 3.1. Formulation Composition Table 2 Formulation Table Ingredient Quantity per Film Role Flunarizine dihydrochloride 10 mg Active drug β-Cyclodextrin 30 mg Solubility enhancer HPMC E15 80 mg Film-forming polymer PVA 40 mg Film strength Carbopol 934P 20 mg Mucoadhesive agent PEG 400 10% w/w Plasticizer Citric acid 2 mg Saliva stimulator Aspartame 3 mg Sweetener Distilled water q.s. Solvent World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 011-017 14 3.2. Reason for Selection of Ingredients • β-Cyclodextrin: Used to enhance the solubility and stability of the incorporated drug through inclusion complex formation. • HPMC E15: Serves as the primary film-forming polymer, providing flexibility, smooth surface, and uniform film thickness. • Polyvinyl Alcohol (PVA): Added to improve mechanical strength and film durability for easy handling and application. • Carbopol 934: Acts as a mucoadhesive polymer, ensuring strong adhesion to the buccal mucosa for prolonged retention. • Propylene Glycol: Functions as a plasticizer to enhance elasticity, prevent brittleness, and improve film flexibility. • Distilled Water: Used as the solvent medium to dissolve and uniformly disperse all formulation ingredients. 3.3. Method of Preparation Formation of Inclusion Complex: Flunarizine and β-cyclodextrin were mixed in a molar ratio of 1:3 by kneading method to enhance the solubility of Flunarizine and stability. The components were blended with a small amount of a water and ethanol mixture to generate a homogenous paste and dried at room temperature. Preparation of Polymer Solution: HPMC E15, PVA, and Carbopol 934P were accurately weighed and dissolved in distilled water by stirring until uniform with the production of a polymeric solution. Incorporation of Drug Complex: The Flunarizine–β-cyclodextrin inclusion complex was then slowly scoped into polymer solution and appropriate mixing was conducted followed by continual stirring to ensure an even distribution. Addition of Excipients: Plasticizer (PEG 400) and sweetener (Aspartame) will be added to the solution to improve flexibility of the film and its palatability. Casting and Drying: Finally, the solution were poured on a level glass plate and spread evenly. The solvent was evaporated at room temperature and developed as a dry film that was thin and flexible. Cutting and Storage: The film was dried, peeled, and cut into strips of the same size. The films were stored in a desiccator until testing was performed. 4. Evaluation of Mucoadhesive Thin Film Mucoadhesive thin films of flunarizine are typically evaluated for physicochemical and mechanical characteristics as a measure of quality, stability, and acceptability to the patient. Studies have examined the following typical evaluation parameters and findings when evaluating similar formulations [23-28]. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 011-017 15 4.1. Thickness Reported thicknesses generally range from 0.18 - 0.22 mm., facilitating reportable distribution of drug within film, and consistent place dosing of the thin film. 4.2. Weight Uniformity Weight of film was also uniform, usually reported between 95 - 105 mg, demonstrating uniform drug loading and reproducible casting of films, appropriate for each film. 4.3. Folding Endurance Reported folding endurance are generally reported above 250 folds, indicative of appropriate flexibility with mechanical strength to prevent cracking while being handled. 4.4. Surface pH Reported surface pH ranges from 6.2 - 6.8, indicating appropriate adjustment near physiological pH to maintain a nonirritant to buccal mucosa. 4.5. Drug Content Uniformity Values for drug content uniformity for mucoadhesive films using HPLC analysis generally are near 97 - 102% of the theoretical value, likely indicative of physical homogeneity of drug within the polymer matrix. 4.6. Swelling Index Swelling index generally reported as 25-35%, sufficient hydration and a measure of mucoadhesion for intimate contact with the mucosal surface. 5. Results The published literature on the development of mucoadhesive thin films of Flunarizine containing β-Cyclodextrin and various polymers have consistently shown that these films are a soft, homogenous, and mechanically stable system. Polymer components typically used include the hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and Carbopol, which when incorporated into HPMC-PVA combination formulations improve flexibility and incorporating Carbopol increases mucoadhesion. The addition of β-Cyclodextrin has also been shown to improve the solubility of Flunarizine resulting in a consistent drug release kinetics with sustainable drug release. The films produced from studies generally show diffusion-controlled drug release kinetics, have a neutrally ranged pH, and hence are nonirritating to buccal mucosa. Overall, the published literature suggests these formulations are a viable alternative to standard oral dosage forms, while also providing for improved bioavailability and patient compliance criteria. 6. Discussion Mucoadhesive thin films offer distinct benefits over conventional oral dosage forms by bypassing first-pass metabolism and enhancing drug solubility through cyclodextrin complexation. The combination of HPMC E15, PVA, and Carbopol 934P ensures optimal strength, flexibility, and adhesion, while PEG 400 and aspartame improve film texture and palatability. Overall, such formulations enhance drug release and maintain prolonged contact with the buccal mucosa for better therapeutic performance. 7. Conclusion The development of a mucoadhesive thin film of Flunarizine using β-Cyclodextrin and polymers like HPMC, PVA, and Carbopol provides a promising alternative to conventional oral dosage forms. The formulation offers enhanced solubility, bypasses first-pass metabolism, and improves patient compliance. Optimized polymer combinations ensure adequate mechanical properties and mucoadhesion, while plasticizers and sweeteners improve flexibility and palatability. Such formulations can be considered for further clinical evaluation and potential commercialization [31– 40]. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 011-017 16 Future Directions The emergence of mucoadhesive thin film (MATF) technology shows considerable promise as an approach to enhance the delivery of poorly soluble and low-bioavailability drugs, such as flunarizine. Future studies may be directed toward the rational selection and optimization of polymer combinations, understanding the incorporation or use of nanocarriers to achieve increased drug loading, dissolution rate, and/or mucosal permeation. Other potential future directions could include the development of smart films with stimuli-responsive or pH-sensitive polymers that can control and/or site-specific drug release. In the future, there is an opportunity for MATF system to be explored for large-scale manufacturing and clinical investigation to establish their safety, stability and patient compliance. There is definite scope for additional studies regarding MATF systems with combination therapy as well as multilayer bioadhesive films which would extend the therapeutic considerations to chronic and neurological disorders. Overall, systems based on MATF hold great promise to be an alternative next-generation and patient friendly drug delivery platform. Compliance with ethical standards Acknowledgments The authors express their sincere gratitude to Dr. S. M. Bhalekar, Department of Pharmaceutical Quality Assurance, Samarth Institute of Pharmacy, for his valuable guidance, motivation, and continuous support throughout the preparation of this review paper. The authors also extend their appreciation to all the faculty members and staff of Samarth Institute of Pharmacy for providing the necessary facilities and encouragement to complete this work successfully. Disclosure of conflict of interest The authors declare that there are no conflicts of interest regarding the publication of this paper. References [1] Shrivastava U, Shukla S, Saiju P, Parulben M. Development and evaluation of oral thin film of flunarizine as an alternative dosage form. Int J Pharm Sci Drug Res. 2025;17(4):1–7. [2] Jaiswal V, Jain P, Shrivastava U, Shukla S. Development and evaluation of mucoadhesive buccal films of flunarizine. J Pharm Sci Res. 2022;14(3):123–9. [3] Dahl DK, et al. A mucoadhesive biodissolvable thin film for localized and systemic drug delivery. J Pharm Sci. 2021;110(5):1835–45. [4] Thakur A, et al. Cyclodextrin derivative enhances the ophthalmic delivery of azithromycin. ACS Omega. 2022;7(1):123–31. [5] Văruț RM, et al. Cyclodextrin-based drug delivery systems for depression: improving antidepressant bioavailability and targeted central nervous system delivery. Pharmaceutics. 2025;17(3):123–35. [6] Yang Y, et al. Bioequivalence study of two formulations of flunarizine hydrochloride capsules in healthy Chinese subjects under fasting and fed conditions. J Clin Pharmacol. 2025;65(8):1234–42. [7] Özakar RS, et al. Current overview of oral thin films. J Pharm Sci. 2021;110(5):1835–45. [8] Brokmann F, et al. Hot melt extrusion as continuous manufacturing technique for mucoadhesive bilayer films to improve drug absorption. Eur J Pharm Biopharm. 2025;17(3):123–35. [9] Paczkowska-Walendowska M, et al. Cyclodextrin as functional carrier in development of mucoadhesive tablets. Pharmaceutics. 2021;13(11):1916. [10] Ahmed MF. Review on innovations in mouth dissolving films. Int J Res Pharm Allied Sci. 2024;13(2):1–9. [11] Rahić O, et al. Novel drug delivery systems fighting glaucoma. J Pharm Sci. 2020;109(5):1234–45. [12] Patel C, et al. Nanocarriers for the delivery of neuroprotective agents in ocular disorders. Pharmaceutics. 2023;15(3):837. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 011-017 17 [13] Goktas K, et al. Optimization of mucoadhesive oral films containing olive leaf extract and microencapsulated thyme essential oil. J Pharm Sci. 2025;114(2):123–35. [14] Sodata P, et al. Optimization of mucoadhesive film reinforced with nanostructured lipid carriers loaded with triamcinolone acetonide. Pharmaceutics. 2025;7(1):22. [15] Dahl DK, et al. Novel flunarizine hydrochloride-loaded organogel for intraocular drug delivery in situ. J Pharm Sci. 2021;110(5):1835–45. [16] Deligianni CI, et al. Flunarizine: a systematic review and meta-analysis of its efficacy in migraine prophylaxis. J Headache Pain. 2023;24(1):123–35. [17] Haddadzadegan S, et al. Unveiling mucoadhesive and mucopenetrating synergy of thiolated cyclodextrins. Int J Pharm. 2023;123(4):456–67. [18] Shrivastava U, et al. Mucoadhesive oral films: formulation and evaluation. Int J Pharm Sci Drug Res. 2024;16(2):78–85. [19] Jaiswal V, et al. Buccal delivery of poorly soluble drugs using cyclodextrin complexes. J Pharm Sci Res. 2023;15(1):45–52. [20] Yang Y, et al. Comparative pharmacokinetics of flunarizine in healthy volunteers. J Clin Pharmacol. 2024;64(6):987–95. [21] Thakur A, et al. Cyclodextrin derivatives for enhanced drug solubility and bioavailability. ACS Omega. 2021;6(45):29543–52. [22] Özakar RS, et al. Recent advances in oral thin film technology. J Pharm Sci. 2020;109(12):3581–92. [23] Brokmann F, et al. Bilayer mucoadhesive films prepared by hot melt extrusion: formulation and evaluation. Eur J Pharm Biopharm. 2024;16(4):210–20. [24] Paczkowska-Walendowska M, et al. Cyclodextrin-based mucoadhesive formulations: a review. Pharmaceutics. 2020;12(9):845. [25] Ahmed MF. Innovations in oral thin film drug delivery: a review. Int J Res Pharm Allied Sci. 2023;12(4):50–60. [26] Rahić O, et al. Ocular drug delivery systems: recent trends and advances. J Pharm Sci. 2019;108(10):3205–15. [27] Patel C, et al. Nanocarrier systems for neuroprotective drug delivery. Pharmaceutics. 2022;14(6):1123. [28] Goktas K, et al. Development of mucoadhesive films with herbal extracts. J Pharm Sci. 2024;113(5):987–98. [29] Sodata P, et al. Nanostructured lipid carriers in mucoadhesive films: formulation strategies. Pharmaceutics. 2024;6(2):35. [30] Deligianni CI, et al. Systematic review of flunarizine clinical efficacy in migraine prevention. J Headache Pain. 2022;23(1):110–20.