Pharmacokinetic Evaluation of Telmisartan and Cilnidipine Bilayer Tablet in A Rabbit Model
Pharmaceutical Science-Pharmacy
DOI:
https://doi.org/10.22376/ijlpr.2023.13.4.P87-P94Keywords:
Pharmacokinetics, HPLC-UV, Telmisartan, Cilnidipine, Rabbit plasma.Abstract
Hypertension is a chronic medical condition affecting a significant proportion of the global population. It is a major risk factor for cardiovascular diseases, stroke, and kidney failure. Telmisartan and cilnidipine combination are commonly used in managing hypertension due to their complementary mechanism of action. Therefore, a bilayer tablet design that enhances the pharmacokinetic profile of cilnidipine as a sustained-release drug while telmisartan act as an immediate-release drug may provide a better therapeutic option for hypertension management. We aim to evaluate the pharmacokinetic parameters of the bilayer tablet of Telmisartan and Cilnidipine. Our objective is to observe the bioavailability of the bilayer tablet in rabbit plasma. The formulation aims to achieve an immediate release effect for Telmisartan and a sustained release effect for Cilnidipine. The solubility and bioavailability of Telmisartan were enhanced by complexation with beta-cyclodextrin. To achieve our aim, we observe the drug concentration in rabbit plasma. Telmisartan is an angiotensin receptor blocker, while Cilnidipine is a calcium channel blocker. The pharmacokinetics of the drugs were evaluated in New Zealand rabbits following oral administration. Systemic drug bioavailability was assessed, and an HPLC method was developed to estimate Telmisartan and Cilnidipine's plasma concentration simultaneously. A Gemini C-18 column (250 mm X 4.6 mm X 5 microns) Phenomenex was used for peak separation. The mobile phase consisted of acetonitrile with phosphate buffer pH 3.5 v/v, with a flow rate of 1.5 ml per minute. The calibration curve analysis indicated a correlation coefficient of 0.9996 and 0.9997 for Telmisartan and Cilnidipine, respectively. The pharmacokinetics of the optimized batch, including Cmax, Tmax, and AUC values, were compared to those of the pure drug. Drug concentration was detected using a DAD detector with an excitation wavelength of 241nm. No interaction was observed between the drugs and excipients. The in-vivo study of the formulation showed higher bioavailability, indicating that the developed bilayer tablet formulation could be an effective means of delivering Telmisartan and Cilnidipine.
References
Nandi U, Karmakar S, Das AK, Ghosh B, Padman A, Chatterjee N, et al. Pharmacokinetics, pharmacodynamics, and toxicity of a combination of metoprolol succinate and Telmisartan in Wistar albino rats: safety profiling. Regul Toxicol Pharmacol. 2013 Feb;65(1):68-78. doi: 10.1016/j.yrtph.2012.11.001, PMID 23201407.
Hypertension [Internet] [cited Aug 11, 2022]. Available from: https://www.who.int/news-room/fact-sheets/detail/hypertension.
Rao RN, Guru Prasad K, Gangu Naidu Ch, Maurya PK. Development of a validated liquid chromatographic method for the determination of related substances of Telmisartan in bulk drugs and formulations. J Pharm Biomed Anal. 2011 Nov 1;56(3):471-8. doi 10.1016/j.jpba.2011.05.043, PMID 21719227.
Yang L, Shao Y, Han HK. Improved pH-dependent drug release and oral exposure of Telmisartan, a poorly soluble drug, through forming the drug-aminoclay complex. Int J Pharm. 2014 Aug 25;471(1-2):258-63. doi: 10.1016/j.ijpharm.2014.05.009, PMID 24834880.
Patel K, Dhudasia K, Patel A, Dave J, Patel C. Stress degradation studies on Telmisartan and development of a validated method by UV spectrophotometry in bulk and pharmaceutical dosage forms. Pharm Methods. 2011;2(4):253-9. doi: 10.4103/2229-4708.93396, PMID 23781466.
Lacourcière null, Lenis null, Orchard null, Lewanczuk null, Houde null, Pesant null, et al. A comparison of the efficacies and duration of action of the angiotensin II receptor blockers telmisartan and amlodipine. Blood Press Monit. 1998 Oct;3(5):295–302.
Neutel JM, Frishman WH, Oparil S, Papademitriou V, Guthrie G. Comparison of telmisartan with lisinopril in patients with mild-to-moderate hypertension. Am J Ther. 1999 May;6(3):161-6. doi: 10.1097/00045391-199905000-00007, PMID 10423659.
Stangier J, Su CA, Roth W. Pharmacokinetics of orally and intravenously administered Telmisartan in healthy young and elderly volunteers and hypertensive patients. J Int Med Res. 2000 Aug;28(4):149-67. doi: 10.1177/147323000002800401, PMID 11014323.
Kaur M, Bhatia RK, Pissurlenkar RRS, Coutinho EC, Jain UK, Katare OP, et al. Telmisartan complex augments solubility, dissolution, and drug delivery in prostate cancer cells. Carbohydr Polym. 2014 Jan 30;101:614-22. doi: 10.1016/j.carbpol.2013.09.077, PMID 24299818.
Patel M, Kothari C. Quantitative bio-analysis of pitavastatin and candesartan in rat plasma by HPLC-UV: assessment of pharmacokinetic drug-drug interaction. J Chromatogr B Analyt Technol Biomed Life Sci. 2020 Feb 1;1138:121962. doi: 10.1016/j.jchromb.2019.121962, PMID 31915110.
Zhang H, Jiang Y, Wen J, Zhou T, Fan G, Wu Y. Rapid determination of Telmisartan in human plasma by HPLC using a monolithic column with fluorescence detection and its application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Nov 1;877(29):3729-33. doi: 10.1016/j.jchromb.2009.08.028, PMID 19744898.
Shen J, Jiao Z, Li ZD, Shi XJ, Zhong MK. HPLC determination of Telmisartan in human plasma and its application to a pharmacokinetic study. Pharmazie. 2005 Jun;60(6):418-20. PMID 15997829.
Kai T, Kuzumoto Y. Effects of a dual L/N-type calcium channel blocker cilnidipine on blood pressure, pulse rate, and autonomic functions in patients with mild to moderate hypertension. Clin exp hypertension NYN 1993. 2009 Oct;31(7):595-604.
Hu L, Zhang H, Song W, Gu D, Hu Q. Investigation of inclusion complex of cilnidipine with hydroxypropyl-β-cyclodextrin. Carbohydr Polym. 2012 Nov 6;90(4):1719-24. doi: 10.1016/j.carbpol.2012.07.057, PMID 22944438.
Ueno D, Masaki T, Gotoh K, Chiba S, Kakuma T, Yoshimatsu H. Cilnidipine regulates glucose metabolism and levels of high-molecular adiponectin in diet-induced obese mice. Hypertens Res. 2013 Mar;36(3):196-201. doi 10.1038/hr.2012.141, PMID 23051658.
Araki K, Masaki T, Katsuragi I, Tanaka K, Kakuma T, Yoshimatsu H. Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice. Hypertens Dallas Tex 1979. 2006 Jul;48(1):51-7.
Yagi S, Goto S, Yamamoto T, Kurihara S, Katayama S. Effect of cilnidipine on insulin sensitivity in patients with essential hypertension. Hypertens Res. 2003 May;26(5):383-7. doi 10.1291/hypes.26.383, PMID 12887129.
Main Applications of Cyclodextrins in the Food Industry as the Compounds of Choice to Form Host–Guest Complexes.
Teaima MH, Yasser M, El-Nabarawi MA, Helal DA. Proniosomal telmisartan tablets: formulation, in vitro evaluation and in vivo comparative pharmacokinetic study in rabbits. Drug Des Devel Ther. 2020;14:1319-31. doi: 10.2147/DDDT.S245013, PMID 32280201.
Gaikwad SS, Avari JG. Improved bioavailability of azelnidipine gastro retentive tablets-optimization and in-vivo assessment. Mater Sci Eng C Mater Biol Appl. 2019 Oct 1;103:109800. doi: 10.1016/j.msec.2019.109800, PMID 31349458.
Srinivas M. Simultaneous estimation of Telmisartan and cilnidipine in bulk and tablet formulation using Rp-HPLC. Volume. Jun 2014;5.
Momin MM, Kane S, Abhang P. Formulation and evaluation of bilayer tablet for bimodal release of venlafaxine hydrochloride. Front Pharmacol. 2015 Jul 9;6:144. doi: 10.3389/par.2015.00144, PMID 26217229.
Validated RP-HPLC method for quantification of felodipine in rabbit plasma: application in a bioequivalence study; Jan 2019.
Kaur M, Bhatia RK, Pissurlenkar RRS, Coutinho EC, Jain UK, Katare OP, et al. Telmisartan complex augments solubility, dissolution, and drug delivery in prostate cancer cells. Carbohydr Polym. 2014 Jan 30;101:614-22. doi: 10.1016/j.carbpol.2013.09.077, PMID 24299818.
GA, KB, Prasad K. Development and validation of bioanalytical HPLC method for simultaneous estimation of cilnidipine and nebivolol in human plasma. Int J Pharm Pharm Sci. 2017 Oct 2:253-9.
Cui Y, Li Y, Li X, Fan L, He X, Fu Y, et al. A Simple UPLC/MS-MS Method for Simultaneous Determination of lenvatinib and Telmisartan in Rat plasma, and Its Application to pharmacokinetic drug-drug Interaction Study. Molecules. 2022 Feb 15;27(4):1291. doi: 10.3390/molecules27041291, PMID 35209080.
Published
How to Cite
Issue
Section
Copyright (c) 2023 Pooja Kadu, Amar Zalte, Vishal Gulecha
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
