Enhanced Stability and Compatibility of Montelukast and Levocetirizine in a Fixed-Dose Combination Monolayer Tablet
The purpose of this study was to enhance the stability of montelukast and levocetirizine for the development of a fixed-dose combination (FDC) monolayer tablet. To evaluate the compatibility of montelukast and levocetirizine, a mixture of the two drugs was prepared, and changes in the appearance characteristics and impurity content were observed in a dry oven at 60 °C. Excipients that contributed minimally to impurity increases were selected to minimize drug interactions. Mannitol, microcrystalline cellulose, croscarmellose sodium, hypromellose, and sodium citrate were chosen as excipients, and montelukast–levocetirizine FDC monolayer tablets were prepared by wet granulating the two drugs separately. A separate granulation of montelukast and levocetirizine, along with the addition of sodium citrate as a pH stabilizer, minimized the changes in tablet appearance and impurity levels. The prepared tablets demonstrated release profiles equivalent to those of commercial products in comparative dissolution tests. Subsequent stability testing at 40 ± 2 °C and 75 ± 5% RH for 6 months confirmed that the drug content, dissolution rate, and impurity content met the specified acceptance criteria. In conclusion, the montelukast–levocetirizine FDC monolayer tablet developed in this study offers a potential alternative to commercial products.
1. Introduction
In recent decades, the prevalence of respiratory and allergic diseases, such as allergic rhinitis and asthma, has increased [1]. While not directly life-threatening, respiratory allergic diseases significantly deteriorate quality of life [2]. Two prominent types of these allergic diseases are asthma and rhinitis [3]. Asthma, a common chronic condition, induces persistent difficulty in breathing, coughing, and other respiratory symptoms [4]. Allergic rhinitis, which is characterized by inflammation of the nasal mucosa, results in symptoms such as nasal discharge and sneezing [5]. Although asthma and allergic rhinitis can occur independently, up to 40% of rhinitis patients may also have asthma, and as much as 80% of asthma patients may experience rhinitis, which indicates a high co-occurrence within the same patient population [6]. Therefore, integrated treatment of allergic rhinitis and asthma is recommended according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines, which advise combining antihistamines and leukotriene receptor antagonists [7,8]. Levocetirizine, a second-generation antihistamine, is frequently used to treat allergic rhinitis [9], while montelukast, a CysLT1 receptor antagonist, helps improve asthma symptoms by blocking the binding of leukotrienes to a receptor [10]. In patients with persistent allergic rhinitis, combination therapy with montelukast and levocetirizine is more effective than montelukast monotherapy [11]. Additionally, fixed-dose combination (FDC) therapy with montelukast and levocetirizine has proven its superiority through phase III clinical trials for treating allergic rhinitis in asthma patients [12,13]. Furthermore, in terms of safety, there is no difference between short-term administration (1–4 weeks) and long-term administration (3–6 months), thus making it an effective and safe drug for improving the symptoms of perennial allergic rhinitis with asthma, even after long-term use [14].
The purpose of this study was to investigate the compatibility and stability of montelukast and levocetirizine for the development of an FDC monolayer tablet to treat allergic rhinitis and asthma. Previous studies have investigated the FDC bilayer tablets of montelukast and levocetirizine, but research on monolayer tablets has not yet been sufficiently conducted [15,16]. While a combination monolayer tablet offers economic advantages when compared to taking each commercial product separately, challenges such as decreased stability may emerge due to the interactions between the two main drugs [17]. Therefore, in the initial study stage, an impurity test was performed to confirm the compatibility of the two drugs and select excipients to ensure the stability of the combination tablet [18]. Afterward, granules were prepared with selected excipients through wet granulation, which is a common granulation method, and, subsequently, the tablets were compressed [19]. The stability of the prepared tablets was confirmed by evaluating the changes in appearance characteristics and impurity content under stress conditions at 60 °C. Comparative dissolution tests were conducted on the final selected formulation and the commercial product under the pH conditions of the entire gastrointestinal tract to predict the bioequivalence. Subsequently, the tablets were stored at 40 ± 2 °C and 75 ± 5% RH for 6 months to assess any decrease in the drug content, reduction in the dissolution rate, and increase in the impurity content.
2. Materials and Methods
2.1. Materials
Montelukast sodium was purchased from Macleods Pharmaceuticals Ltd. (Mumbai, India), and levocetirizine dihydrochloride was obtained from RA Chem Pharma Ltd. (Polepally, Telangana, India). The impurity standards of montelukast for the HPLC analysis of the impurity were purchased from SynZeal Research Private Ltd. (Ahmedabad, Gujarat, India). The excipients used in the formulation study, including microcrystalline cellulose (abbreviated as Avicel®), lactose, hypromellose (HPMC 2910 P645), povidone, croscarmellose sodium, sodium starch glycolate, crospovidone, and magnesium stearate, were kindly provided by Hanmi Pharmaceutical Co., Ltd. (Hwaseong, Republic of Korea). Mannitol (Mannitol 100SD) and hydroxypropyl cellulose were supplied by Cosmax Pharma Co., Ltd. (Cheongju, Republic of Korea). All pH stabilizers were purchased from Daejung Chemicals & Metals Co., Ltd. (Siheung, Republic of Korea). Acetonitrile and methanol were sourced from Thermo Fisher Scientific (Waltham, MA, USA), and the trifluoroacetic acid was obtained from Daejung Chemicals & Metals Co., Ltd. (Siheung, Republic of Korea). The deionized water used in the laboratory was produced using a distillation device. All other chemicals were of analytical grade.
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Yun, T.H.; Kim, M.J.; Lee, J.G.; Bang, K.H.; Kim, K.S. Enhanced Stability and Compatibility of Montelukast and Levocetirizine in a Fixed-Dose Combination Monolayer Tablet. Pharmaceutics 2024, 16, 963. https://doi.org/10.3390/pharmaceutics16070963