Abstract
Purpose
This study aimed to elucidate the compatibility between levocetirizine dihydrochloride (LCZ) and montelukast sodium (MTL) and to improve their stability through the complexation of LCZ with ion-exchange resins (IERs).
Methods
Compatibility studies between LCZ and MTL were conducted under stress conditions. LCZ-IER complexes (LICs) were prepared via a batch method to prevent interactions with MTL and reduce the acidity and bitterness of LCZ. The physicochemical properties, pH, in vitro taste, and release profiles of the resultant LICs were investigated. The effect of LICs on the stability of the LCZ and MTL was evaluated based on the content of related substances.
Results
Discoloration was observed in the physical mixture of LCZ and MTL, and the contents of LCZ- and MTL-related substances increased. The increase in the content of MTL-related substances was particularly noticeable. LICs with different LCZ-to-IER ratios were prepared, and regardless of the ratio, LCZ was loaded into the IER via intermolecular interactions. Due to the change from LCZ to LICs, the unpleasant taste and acidity of LCZ was effectively reduced without retarding the release of LCZ. In addition, the content of LCZ- and MTL-related substances was significantly reduced, which attributed to the change in the salt form of the LCZ and the absence of LCZ to the surface of LICs.
Conclusion
The incompatibility between LCZ and MTL was elucidated quantitatively and resolved by the complexation of LCZ and IER. This finding may provide a promising approach for formulation design composed of incompatible drugs such as LCZ and MTL.
Similar content being viewed by others
References
Abdul S, Chandewar AV, Jaiswal SB (2010) A flexible technology for modified-release drugs: multiple-unit pellet system (MUPS). J Control Release 147(1):2–16. https://doi.org/10.1016/j.jconrel.2010.05.014
Agha DS, El-Zien H (2018) Solid state compatibility studies between montelukast sodium and levocetirizine. Asian J Pharm Clin Res 11(3):368–374. doi:https://doi.org/10.22159/ajpcr.2018.v11i3.22990
Al Omari MM, Zoubi RM, Hasan EI, Khader TZ, Badwan AA (2007) Effect of light and heat on the stability of montelukast in solution and in its solid state. J Pharm Biomed Anal 45(3):465–471. doi:https://doi.org/10.1016/j.jpba.2007.07.014
Brożek JL, Bousquet J, Agache I, Agarwal A, Bachert C et al (2017) Allergic Rhinitis and its impact on Asthma (ARIA) guidelines—2016 revision. J Allergy Clin Immunol 140(4):950–958. doi:https://doi.org/10.1016/j.jaci.2017.03.050
Chen T, Li J, Chen T, Sun CC, Zheng Y (2017) Tablets of multi-unit pellet system for controlled drug delivery. J Control Release 262:222–231. doi:https://doi.org/10.1016/j.jconrel.2017.07.043
Chong SN, Chew FT (2018) Epidemiology of allergic rhinitis and associated risk factors in Asia. World Allergy Organ J 11(1):17. doi:https://doi.org/10.1186/s40413-018-0198-z
Ciebiada M, Gorska-Ciebiada M, Barylski M, Kmiecik Tomasz, Gorski P (2011) Use of montelukast alone or in combination with desloratadine or levocetirizine in patients with persistent allergic rhinitis. Am J Rhinol Allergy 25(1):e1–6. doi:https://doi.org/10.2500/ajra.2011.25.3540
Ciebiada M, Górska-Ciebiada M, DuBuske LM, Górski P (2006) Montelukast with desloratadine or levocetirizine for the treatment of persistent allergic rhinitis. Ann Allergy Asthma Immunol 97(5):664–671. doi:https://doi.org/10.1016/S1081-1206(10)61098-8
Corren J (1997) Allergic rhinitis and asthma: how important is the link? J Allergy Clin Immunol 99(2):S781–S786. doi:https://doi.org/10.1016/s0091-6749(97)70127-1
Crystal-Peters J, Neslusan C, Crown WH, Torres A (2002) Treating allergic rhinitis in patients with comorbid asthma: the risk of asthma-related hospitalizations and emergency department visits. J Allergy Clin Immunol 109(1):57–62. doi:https://doi.org/10.1067/mai.2002.120554
Elder DP (2005) Pharmaceutical applications of ion-exchange resins. J Chem Educ 82(4):575–587. doi:https://doi.org/10.1021/ed082p575
Hammad H, Lambrecht BN (2021) The basic immunology of asthma. Cell 184(6):1469–1485. doi:https://doi.org/10.1016/j.cell.2021.02.016
Han X, Zhang S, Chai Z, Dong Y, He W et al (2019) In vitro and in vivo evaluation of the taste-masking efficiency of Amberlite IRP88 as drug carries in chewable tablets. J Drug Deliv Sci Technol 49:547–555. doi:https://doi.org/10.1016/j.jddst.2018.12.002
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (2006a) Impurities in new drug products Q3B (R2)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (2006b) Impurities in new drug substances Q3A (R2)
Jeong SH, Park K (2008a) Development of sustained release fast-disintegrating tablets using various polymer-coated ion-exchange resin complexes. Int J Pharm 353(1–2):195–204. doi:https://doi.org/10.1016/j.ijpharm.2007.11.033
Jeong SH, Park K (2008b) Drug loading and release properties of ion-exchange resin complexes as a drug delivery matrix. Int J Pharm 361(1–2):26–32. doi:https://doi.org/10.1016/j.ijpharm.2008.05.006
Ki M-H, Choi M-H, Ahn K-B, Kim B-S, Im DS et al (2008) The efficacy and safety of clopidogrel resinate as a novel polymeric salt form of clopidogrel. Arch Pharm Res 31(2):250–258. https://doi.org/10.1007/s12272-001-1149-7
Kim B-H(2022) A study on the development of fixed dose combination chewable tablets containing montelukast and levocetirizine. Dissertation, Sungkyunkwan University
Kim J-I, Cho S-M, Cui J-H, Cao Q-R, Oh E et al (2013a) In vitro and in vivo correlation of disintegration and bitter taste masking using orally disintegrating tablet containing ion exchange resin-drug complex. Int J Pharm 455(1–2):31–39. doi:https://doi.org/10.1016/j.ijpharm.2013.07.072
Kim YI, Kim DH, Kwon TK, Kim KS, Park JH et al(2013b) Capsule formulation comprising montelukast and levocetirizine.WO PatentWO2013012199A1
Kim M-K, Lee SY, Park H-S, Yoon HJ, Kim S-H et al (2018) A randomized, multicenter, double-blind, phase III study to evaluate the efficacy on allergic rhinitis and safety of a combination therapy of montelukast and levocetirizine in patients with asthma and allergic rhinitis. Clin Ther 40(7):1096–1107. https://doi.org/10.1016/j.clinthera.2018.04.021
Kumar N, Sangeetha D, Sunil Reddy P (2013) Development and validation of a stability indicating RP-UPLC method for simultaneous determination of rupatadine and montelukast in pharmaceutical formulation. Curr Pharm Anal 9:61–68. doi:https://doi.org/10.2174/157341213804806133
Kwon TK, Lee KY, Im HT, Kim YI(2019) Composite chewable tablet including levocetirizine and montelukast with improved stability and drug compliance, and method of preparing the same.WO PatentWO2019004776A2
Labib GS (2015) Novel levocetirizine HCl tablets with enhanced palatability: synergistic effect of combining taste modifiers and effervescence technique. Drug Des Devel Ther 9:5135–5146. doi:https://doi.org/10.2147/DDDT.S92245
Marzouk MA, Darwish MK, Abd El-Fattah MA (2020) Development of medicated chewing gum of taste masked levocetirizine dihydrochloride using different gum bases: in vitro and in vivo evaluation. Drug Dev Ind Pharm 46(3):395–402. doi:https://doi.org/10.1080/03639045.2020.1724130
McLeod RL, Mingo GG, Xu X, Palamanda J, Hunter JC et al (2009) Loratadine and montelukast administered in combination produce decongestion in an experimental feline model of nasal congestion. Am J Rhinol Allergy 23(6):e17–22. doi:https://doi.org/10.2500/ajra.2009.23.3365
Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX et al (2000) Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol 105(5):917–922. doi:https://doi.org/10.1067/mai.2000.106040
Moon C, Oh E (2016) Rationale and strategies for formulation development of oral fixed dose combination drug products. J Pharm Investig 46:615–631. doi:https://doi.org/10.1007/s40005-016-0286-4
Overeem A, van den Heuvel DJM(2009) Solid state montelukast. US Patent 7553853B2
Park H-R, Seok SH, Hwang K-M, Kim J-Y, Park C-W et al (2022) Formulation of sustained-release orodispersible film containing drug-resin complexes of donepezil hydrochloride. J Pharm Investig 52:259–272. doi:https://doi.org/10.1007/s40005-022-00560-4
Patel P, Philip G, Yang W, Call R, Horak F et al (2005) Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis. Ann Allergy Asthma Immunol 95(6):551–557. doi:https://doi.org/10.1016/S1081-1206(10)61018-6
Pawankar R (2004) Allergic rhinitis and asthma: the link, the new ARIA classification and global approaches to treatment. Curr Opin Allergy Clin Immunol 4(1):1–4. doi:https://doi.org/10.1097/00130832-200402000-00002
Peterka TR, Grahek R, Hren J, Bastarda A, Bergles J et al (2015) Solid state compatibility study and characterization of a novel degradation product of tacrolimus in formulation. J Pharm Biomed Anal 110:67–75. doi:https://doi.org/10.1016/j.jpba.2015.02.047
Qu Y, Lai W-L, Xin Y-R, Zhu F-Q, Zhu Y et al (2019) Development, optimization, and evaluation in Vitro/In vivo of oral liquid system for synchronized sustained release of levodopa/benserazide. AAPS Pharm Sci Tech 20(8):312. https://doi.org/10.1208/s12249-019-1511-z
Redasani VK, Kothawade AR, Surana SJ (2014) Stability indicating RP-HPLC method for simultaneous estimation of rupatadine fumarate and montelukast sodium in bulk and tablet dosage form. J Anal Chem 69(4):384–389. doi:https://doi.org/10.1134/S1061934814040121
Shang R, Liu C, Quan P, Zhao H, Fang L (2018) Effect of drug-ion exchange resin complex in betahistine hydrochloride orodispersible film on sustained release, taste masking and hygroscopicity reduction. Int J Pharm 545(1–2):163–169. doi:https://doi.org/10.1016/j.ijpharm.2018.05.004
Tan DCT, Ong JJ, Gokhale R, Heng PWS (2018) Hot melt extrusion of ion-exchange resin for taste masking. Int J Pharm 547(1–2):385–394. doi:https://doi.org/10.1016/j.ijpharm.2018.05.068
Testa B, Pagliara A, Carrupt PA (1997) The molecular behavior of cetirizine. Clin Exp Allergy 27:13–18. doi:https://doi.org/10.1111/j.1365-2222.1997.tb02578.x
Testa D, Bari MDI, Nunziata M, Cristofaro GDE, Massaro G et al (2020) Allergic rhinitis and asthma assessment of risk factors in pediatric patients: a systematic review. Int J Pediatr Otorhinolaryngol 129:109759. doi:https://doi.org/10.1016/j.ijporl.2019.109759
Won DH, Park H, Seo J-W, Jang SW, Ha E-S et al (2022) Active coating of immediate-release evogliptin tartrate to prepare fixed dose combination tablet with sustained-release metformin HCl. Int J Pharm 623:121927. doi:https://doi.org/10.1016/j.ijpharm.2022.121927
Yewale CP, Rathi MN, Kore GG, Jadhav GV, Wagh MP (2013) Formulation and development of taste masked fast-disintegrating tablets (FDTs) of chlorpheniramine maleate using ion-exchange resins. Pharm Dev Technol 18(2):367–376. doi:https://doi.org/10.3109/10837450.2011.627870
Yi E-J, Kim J-Y, Rhee Y-S, Kim S-H, Lee H-J et al (2014) Preparation of sildenafil citrate microcapsules and in vitro in vivo evaluation of taste masking efficiency. Int J Pharm 466(1–2):286–295. doi:https://doi.org/10.1016/j.ijpharm.2014.03.001
Acknowledgements
This work was supported by Korea Initiative for fostering University of Research and Innovation Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. 2020M3H1A1077095).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Reasearch involving human and animal rights
This article does not contain any studies with human and animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Park, HR., Seok, S.H. & Park, ES. Complexation of levocetirizine with ion-exchange resins and its effect on the stability of powder mixtures containing levocetirizine and montelukast. J. Pharm. Investig. 53, 377–388 (2023). https://doi.org/10.1007/s40005-022-00604-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40005-022-00604-9