Development of Gastro-Retentive Combination Formulation of Montelukast Sodium and Bepotastine Besilate for Allergic Rhinitis and Asthma
Abstract
Aim: The study aimed to develop a once-daily sustained-release gastroretentive combination formulation of bepotastine besilate and montelukast sodium using multilayer tablet technology and gastro-retentive systems for the treatment of allergic rhinitis and asthma.
Background:
Bepotastine besilate and montelukast sodium are commonly used to manage allergic rhinitis and asthma. However, their conventional formulations often require multiple doses per day, leading to poor patient compliance. A gastro retentive system allowing once-daily dosing could improve adherence and therapeutic outcomes.
Materials and Methods: A multilayer tablet was formulated with montelukast sodium in the immediate-release layer and bepotastine besilate in both the immediate- and sustained-release layers, using calcium silicate as a floating agent
for gastric retention. Hydroxypropyl Methylcellulose (HPMC) controlled the sustained release of bepotastine, while the addition of super-disintegrants and a surfactant improved the release of poorly soluble montelukast. The lactose-microcrystalline cellulose ratio was adjusted to meet the target dissolution profile and comparative dissolution tests were conducted to assess similarity to the desired release profile.
Results: Comparative dissolution tests demonstrated high similarity between the combination formulation and the target release profile, with similarity factor (f2) values of 58.5 and 65.9. The formulation successfully allowed for different release rates of the two active ingredients, improving drug absorption and extending the duration of action.
Conclusion: The developed gastro-retentive formulation enabled a transition from twice-daily to once-daily dosing, enhancing patient compliance. The multilayer tablet design efficiently controlled the release profiles of both active ingredients, addressing limitations associated with the absorption sites of each drug.
Introduction
Allegic rhinitis is a significant and independent risk factor for the onset of asthma.1 Allergic responses are characterized by early and late-phase reactions. The early-phase reaction typically occurs within min to an hour and results from the degranulation of mast cells on the mucosal surface, releasing histamine, tryptase, Prostaglandin D2 and leukotrienes, with histamine being primarily involved. The late-phase reaction generally arises 2 to 4 hr post exposure, involving T-cell activation, adhesion molecule production and eosinophil infiltration, leading to chronic inflammation. Leukotrienes, metabolites of arachidonic acid, are known to be among the mediators that induce this late-phase response.2
Allergic rhinitis and asthma are chronic inflammatory diseases of the upper and lower respiratory tracts, respectively, often coexisting and sharing a similar pathophysiology, including inflammation and hyper-responsiveness driven by mast cells, eosinophils and T-helper cells. Antihistamines, which primarily block H1 histamine receptors, are effective in reducing immediate allergic symptoms such as itching, sneezing and nasal discharge. Montelukast, a leukotriene receptor antagonist, acts by inhibiting leukotriene D4, a mediator associated with late-phase allergic responses, thus providing prolonged anti-inflammatory effects.3 While the prevalence of asthma is approximately 5% in the general population, asthma is present in 10-40% of rhinitis patients and rhinitis coexists in 70-80% of asthma patients.4,5 Rhinitis exacerbates asthma and leads to increased respiratory symptoms and exacerbations in patients with concomitant asthma and rhinitis.6 These findings underscore the importance of treating rhinitis in the management of asthma.7 When rhinitis and asthma coexist, treatment should be based on guidelines for each condition, addressing both disorders concurrently.1,8
Bepotastine besilate is a second-generation antihistamine with selective histamine H1 receptor antagonist activity. It is used to treat allergic reactions such as allergic rhinitis, urticaria, erythema and pruritus (Figure 1-a).9,10 Bepotastine besilate, formulated in a dosage form requiring twice-daily administration due to its short half-life in the body, is currently available on the market. However, its rapid elimination kinetics pose challenges in achieving effective plasma concentrations between doses, potentially leading to suboptimal therapeutic outcomes. Moreover, the high systemic exposure of the drug carries the risk of eliciting systemic side effects.11 In the case of bepotastine besilate, the absorption site of the drug is limited to the upper part of the small intestine, making it impossible to achieve adequate bioavailability with conventional sustained-release formulations.12
To address these issues, applying a gastro-retentive system capable of delaying passage through the upper part of the small intestine can improve bioavailability by ensuring sustained drug release and demonstrating biological equivalence with the twice-daily dosing regimen.13
Montelukast, a leukotriene receptor antagonist, is effective as a first-line treatment for asthma and mild persistent allergic rhinitis. It can be used either as monotherapy or in combination with antihistamines (Figure 1-b). Leukotrienes do not stimulate the sensory nerves in the nasal mucosa; therefore, they do not affect nasal itching or sneezing. In numerous studies, leukotriene receptor antagonists have significantly improved symptoms in patients with both seasonal and perennial allergic rhinitis.14
When compared to antihistamines, there was no significant difference in efficacy15-17 and they were found to be less effective than intranasal corticosteroids.18,19 Patients with allergic rhinitis who require corticosteroid treatment due to comorbid allergic conditions such as asthma or urticaria may experience adverse effects if the dosage is excessive. These effects can include psychiatric disturbances, growth suppression in children and skin abnormalities.20 When antihistamines and leukotriene receptor antagonists are used in combination, their efficacy is superior to when each drug is used alone and they demonstrate comparable efficacy to intranasal corticosteroids.18,21 Considering that approximately 40% of allergic rhinitis patients also have concurrent asthma, leukotriene receptor antagonists, either alone or in combination therapy, can be clinically useful in both upper and lower airway allergic diseases, particularly in patients with allergic rhinitis accompanied by asthma.22
In the design of combination formulations, such as those containing montelukast and bepotastine, where different drug release rates are required, the most commonly employed technique is the use of multilayer tablet formulations to achieve distinct release profiles for each drug.13 However, due to the limited absorption sites of the drugs in the combination formulation, achieving the target release profile solely through conventional multilayer tablet technology poses challenges. Therefore, in this study, we aimed to address this issue by incorporating floating technology into the multilayer tablet formulation (Figure 2).
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Materials
The Active Pharmaceutical Ingredients (API), montelukast sodium and bepotastine besilate (Figure 1), were provided by Kukjeon Pharm (Korea) and HL Genomix (Korea), respectively. For comparison, Talion® tablets from Dong-A Pharmaceutical Co.Ltd. and Singulair® tablets from Organon Korea Pharmaceutical Co.Ltd. were used as reference drugs.
For the dissolution testing and analysis, Sodium chloride and Potassium phosphate monobasic were sourced from Daejung (Korea) and Hydrochloric acid was obtained from DukSan Pharm. Co., Ltd. (Korea). Sodium acetate trihydrate, Acetic acid, Sodium hydroxide and Trifluoroacetic acid were provided by SamJeonSoon Pharm. Co., Ltd. (Korea). Sodium 1-pentanesulfonate was acquired from Avantor Inc. (USA) and Acetonitrile was purchased from Honeywell (USA).
The excipient lactose 75%+microcrystalline cellulose 25% mixture (spray-drying co-processed) were purchased as cellactose 80 from Meggle (Germany). The sustaining agent, hydroxypropyl methylcellulose (2208/15,000cps), was obtained from Shin-Etsu (Japan). The floating agent, calcium silicate, was procured as Florite R from Tomita (Japan). The disintegrant sodium starch glycolate was sourced from DMV (Netherlands), cross-linked carboxymethyl cellulose sodium from JRS Pharma (China) and cross-linked polyvinylpyrrolidone from BASF (USA). The binder, hydroxypropyl cellulose (HPC-LF), was acquired from Ashland (USA) and the lubricant, magnesium stearate, was obtained from Faci Asia Pacific Pte Ltd (Singapore).
Development of Gastro-Retentive Combination Formulation of Montelukast Sodium and Bepotastine Besilate for Allergic Rhinitis and Asthma, Prof. Sung-Hoon Lee, Ind. J. Pharm. Edu. Res., 2025; 59(3):960-969., https://www.ijper.org Original Article, 960 Indian Journal of Pharmaceutical Education and Research, Vol 59, Issue 3, Jul-Sep, 2025, DOI: 10.5530/ijper.20250933
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