A Rapid, Sensitive, and High-throughput Method for the Simultaneous Determination of Antihypertensive Drug Combinations in Dog Plasma by UHPLC-MS/MS: The Assessment of Predicable Bioequivalence of In-vitro Dissolution Condition
  • * (Excluding Mailing and Handling)

Abstract

Background: Essential hypertension is a common clinical disease and a risk factor for cardiovascular and cerebrovascular diseases. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide are commonly used antihypertensive drugs. The aim of this study was to establish a robust UPLC-MS/MS method for the simultaneous determination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in dog plasma. At the same time, the release in vivo and in vitro studies were conducted, and a preliminary in vitro-in vivo correlation (IVIVC) evaluation was performed.

Methods: The bioequivalence experiment was conducted with a double-crossed design. Three major components were extracted and analyzed by UHPLC-MS/MS. With the MRM scan, olmesartan and amlodipine were quantified by fragment conversion (m/z 447.10→190.10) and (m/z 408.95→294.00) under positive ESI mode, while hydrochlorothiazide was quantified with fragment conversion (m/z 295.90→268.90) under negative ESI mode. The in vitro release studies were performed using a USP paddle, and the dissolution medium was chosen from pH 6.0 to pH 6.8 according to the BCS classification of compounds. The IVIVC was calculated using the Wagner-Nelson equation.

Results: The linear ranges of olmesartan, amlodipine, and hydrochlorothiazide in the plasma were 5.0-2500, 0.1-50, and 3.0-1500 ng/mL, respectively. All accuracies were within 3.8% of the target values, and the findings revealed that intra-day and inter-day accuracy was less than 12.1%. Moreover, the recoveries exceeded 88.3%, the matrix effect tests were positive, and the stability tests were positive. With the establishment of correlation, the distinguishable dissolution condition (pH 6.8) was selected as the predictable condition.

Conclusion: The established method was suitable for the preclinical pharmacokinetic study of tripartite drugs with strong specificity and high sensitivity. Through the evaluation of IVIVC, the connection between in vivo and in vitro drug testing was initially established.

[1]
Heidari B, Avenatti E, Nasir K. Pharmacotherapy for essential hypertension: A brief review. Methodist DeBakey Cardiovasc J 2022; 18(5): 5-16.
[http://dx.doi.org/10.14797/mdcvj.1175] [PMID: 36561082]
[2]
Unger T, Borghi C, Charchar F, et al. 2020 international society of hypertension global hypertension practice guidelines. Hypertension 2020; 75(6): 1334-57.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15026] [PMID: 32370572]
[3]
Huang M, Long L, Deng M, et al. Effectiveness and safety of Yufeng Ningxin for the treatment of essential hypertension. Medicine 2021; 100(9): e24858.
[http://dx.doi.org/10.1097/MD.0000000000024858] [PMID: 33655947]
[4]
Vallée A, Safar ME, Blacher J. Permanent essential hypertension: Definitions and hemodynamic, clinical and therapeutic review. Presse Med 2019; 48(1): 19-28.
[http://dx.doi.org/10.1016/j.lpm.2018.11.017] [PMID: 30665781]
[5]
Guarner-Lans V, Ramírez-Higuera A, Rubio-Ruiz ME, Castrejón-Téllez V, Soto ME, Pérez-Torres I. Early programming of adult systemic essential hypertension. Int J Mol Sci 2020; 21(4): 1203.
[http://dx.doi.org/10.3390/ijms21041203]
[6]
Abo El-Nasr NME, Saleh DO, Hashad IM. Role of olmesartan in ameliorating diabetic nephropathy in rats by targeting the AGE/PKC, TLR4/P38-MAPK and SIRT-1 autophagic signaling pathways. Eur J Pharmacol 2022; 928: 175117.
[http://dx.doi.org/10.1016/j.ejphar.2022.175117] [PMID: 35752350]
[7]
Brousil JA, Burke JM. Olmesartan medoxomil: An angiotensin II-receptor blocker. Clin Ther 2003; 25(4): 1041-55.
[http://dx.doi.org/10.1016/S0149-2918(03)80066-8] [PMID: 12809956]
[8]
Salim H, Jones AM. Angiotensin II receptor blockers (ARBs) and manufacturing contamination: A retrospective national register study into suspected associated adverse drug reactions. Br J Clin Pharmacol 2022; 88(11): 4812-27.
[http://dx.doi.org/10.1111/bcp.15411] [PMID: 35585835]
[9]
Kreutz R. Olmesartan/amlodipine: A review of its use in the management of hypertension. Vasc Health Risk Manag 2011; 7: 183-92.
[http://dx.doi.org/10.2147/VHRM.S16852] [PMID: 21490944]
[10]
Chen B, Chen Z, Lv D, Sun Y, Chen H. Pharmacokinetics, bioequivalence, and safety studies of amlodipine besylate in healthy subjects. Clin Pharmacol Drug Dev 2022; 11(6): 717-23.
[http://dx.doi.org/10.1002/cpdd.1064] [PMID: 34981666]
[11]
Wang JG, Palmer BF, Vogel Anderson K, Sever P. Amlodipine in the current management of hypertension. J Clin Hypertens 2023; 25(9): 801-7.
[http://dx.doi.org/10.1111/jch.14709] [PMID: 37551050]
[12]
Syed YY. Perindopril/indapamide/amlodipine in hypertension: A profile of its use. Am J Cardiovasc Drugs 2022; 22(2): 219-30.
[http://dx.doi.org/10.1007/s40256-022-00521-0] [PMID: 35257306]
[13]
Li X, Mo E, Chen L. Pharmacokinetics and bioequivalence evaluation of 2 olmesartan medoxomil and amlodipine besylate fixed- dose combination tablets in healthy Chinese volunteers under fasting and fed conditions. Clin Pharmacol Drug Dev 2022; 11(6): 761-9.
[http://dx.doi.org/10.1002/cpdd.1086] [PMID: 35289500]
[14]
Carey RM, Moran AE, Whelton PK. Treatment of hypertension. JAMA 2022; 328(18): 1849-61.
[http://dx.doi.org/10.1001/jama.2022.19590] [PMID: 36346411]
[15]
Ishani A, Cushman WC, Leatherman SM, et al. Chlorthalidone vs. Hydrochlorothiazide for hypertension-cardiovascular events. N Engl J Med 2022; 387(26): 2401-10.
[http://dx.doi.org/10.1056/NEJMoa2212270] [PMID: 36516076]
[16]
Cho M, Oh E, Ahn B, Yoon M. Response surface analyses of antihypertensive effects of angiotensin receptor blockers and amlodipine or hydrochlorothiazide combination therapy in patients with essential hypertension. Transl Clin Pharmacol 2023; 31(3): 154-66.
[http://dx.doi.org/10.12793/tcp.2023.31.e15] [PMID: 37810629]
[17]
Duprez D, Ferdinand K, Wright , Samuel R, Wright R. Ambulatory blood pressure response to triple therapy with an angiotensin-receptor blocker (ARB), calcium-channel blocker (CCB), and HCTZ versus dual therapy with an ARB and HCTZ. Vasc Health Risk Manag 2011; 7: 701-8.
[http://dx.doi.org/10.2147/VHRM.S25743] [PMID: 22174580]
[18]
Chakraborty DS, Lahiry S, Choudhury S. Hypertension clinical practice guidelines (ISH, 2020): What is new? Med Princ Pract 2021; 30(6): 579-84.
[http://dx.doi.org/10.1159/000518812] [PMID: 34348319]
[19]
González R, Torrado G, Arribas JM, Peña MA. Development of an analytical method for the determination and quantification of n-nitrosodimethylamine in olmesartan by HPLC-MS/MS. Microchem J 2022; 179(179): 107402.
[http://dx.doi.org/10.1016/j.microc.2022.107402]
[20]
Elkady EF, Mandour AA, Algethami FK, Aboelwafa AA, Farouk F. Sequential liquid-liquid extraction coupled to LC-MS/MS for simultaneous determination of amlodipine, olmesartan and hydrochlorothiazide in plasma samples: Application to pharmacokinetic studies. Microchem J 2020; 155(155): 104757.
[http://dx.doi.org/10.1016/j.microc.2020.104757]
[21]
Kurbanoğlu S, Yarman A. Simultaneous determination of hydrochlorothiazide and irbesartan from pharmaceutical dosage forms with RP-HPLC. Turk J Pharm Sci 2020; 17(5): 523-7.
[http://dx.doi.org/10.4274/tjps.galenos.2019.76094] [PMID: 33177933]
[22]
Kamal AH, Hammad SF, Marie AA. Validated spectrophotometric methods for simultaneous determination of atorvastatin calcium and olmesartan medoxomil in their pharmaceutical formulation. J AOAC Int 2022; 105(2): 387-95.
[http://dx.doi.org/10.1093/jaoacint/qsab151] [PMID: 34850012]
[23]
Palabıyık İM, Dogan A, Süslü İ. Simultaneous determination of amlodipine and irbesartan in their pharmaceutical formulations by square-wave voltammetry. Comb Chem High Throughput Screen 2022; 25(2): 241-51.
[http://dx.doi.org/10.2174/1386207324666210121110819] [PMID: 33475067]
[24]
Tiris G, Mehmandoust M, Lotfy HM, et al. Simultaneous determination of hydrochlorothiazide, amlodipine, and telmisartan with spectrophotometric and HPLC green chemistry applications. Chemosphere 2022; 303(Pt 3): 135074.
[http://dx.doi.org/10.1016/j.chemosphere.2022.135074] [PMID: 35667505]
[25]
Jeong HC, Seo YH, Gu N, Rhee MY, Shin KH. Determination of candesartan or olmesartan in hypertensive patient plasma using UPLC-MS/MS. Transl Clin Pharmacol 2021; 29(4): 226-38.
[http://dx.doi.org/10.12793/tcp.2021.29.e21] [PMID: 35024363]
[26]
Amira H. Four chemometric spectrophotometric methods for simultaneous estimation of amlodipine besylate and olmesartan medoxomil in their combined dosage form. Spectrochim Acta A Mol Biomol Spectrosc 2022; 266: 120455.
[http://dx.doi.org/10.1016/j.saa.2021.120455]
[27]
Johannsen JO, Reuter H, Hoffmann F, et al. Reliable and easy-to-use LC-MS/MS-method for simultaneous determination of the antihypertensives metoprolol, amlodipine, canrenone and hydrochlorothiazide in patients with therapy-refractory arterial hypertension. J Pharm Biomed Anal 2019; 164: 373-81.
[http://dx.doi.org/10.1016/j.jpba.2018.11.002] [PMID: 30439665]
[28]
Guidance for industry. Extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. Available from: https:// www.fda.gov/media/70939/ Accessed January 25, 2023.
[29]
Kim TH, Bulitta JB, Kim DH, Shin S, Shin BS. Novel extended in vitro-in vivo correlation model for the development of extended-release formulations for baclofen: From formulation composition to in vivo pharmacokinetics. Int J Pharm 2019; 556: 276-86.
[http://dx.doi.org/10.1016/j.ijpharm.2018.12.007] [PMID: 30543888]
[30]
Lim JY, Kim TH, Song CH, Kim DH, Shin BS, Shin S. Novel extended IVIVC combined with DoE to predict pharmacokinetics from formulation compositions. J Control Release 2022; 343: 443-56.
[http://dx.doi.org/10.1016/j.jconrel.2022.01.048] [PMID: 35124130]
[31]
[32]
Gao YY, Sang KN, Li PP, et al. Bioequivalence of two tablet formulations of cefpodoxime proxetil in beagle dogs. Front Vet Sci 2022; 9: 1048823.
[http://dx.doi.org/10.3389/fvets.2022.1048823] [PMID: 36311679]
[33]
Dai T, Jiang W, Wang M, Guo Z, Dai R. Influence of two-period cross-over design on the bioequivalence study of gefitinib tablets in beagle dogs. Eur J Pharm Sci 2021; 165: 105933.
[http://dx.doi.org/10.1016/j.ejps.2021.105933] [PMID: 34260895]
[34]
Cui Y, Li Y, Li X, 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; 27(4): 1291.
[http://dx.doi.org/10.3390/molecules27041291] [PMID: 35209080]
[35]
Jeon SY, Jeon JH, Park JH, et al. Simultaneous analysis of a combination of anti-hypertensive drugs, fimasartan, amlodipine, and hydrochlorothiazide, in rats using LC-MS/MS and subsequent application to pharmacokinetic drug interaction with red ginseng extract. Toxics 2022; 10(10): 576.
[http://dx.doi.org/10.3390/toxics10100576] [PMID: 36287856]
[36]
Shah JV, Shah PA, Shah PV, Sanyal M, Shrivastav PS. Fast and sensitive LC-MS/MS method for the simultaneous determination of lisinopril and hydrochlorothiazide in human plasma. J Pharm Anal 2017; 7(3): 163-9.
[http://dx.doi.org/10.1016/j.jpha.2016.11.004] [PMID: 29404033]
[37]
Sengupta P, Sarkar AK, Bhaumik U, et al. Development and validation of an LC-ESI-MS/MS method for simultaneous quantitation of olmesartan and pioglitazone in rat plasma and its pharmacokinetic application. Biomed Chromatogr 2010; 24(12): 1342-9.
[http://dx.doi.org/10.1002/bmc.1447] [PMID: 21077253]
[38]
Patel JR, Pethani TM, Vachhani AN, Sheth NR, Dudhrejiya AV. Development and validation of bioanalytical method for simultaneous estimation of ramipril and hydrochlorothiazide in human plasma using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 970: 53-9.
[http://dx.doi.org/10.1016/j.jchromb.2014.08.023] [PMID: 25240204]
[39]
Dubey R, Ghosh M. Simultaneous determination and pharmacokinetic study of losartan, losartan carboxylic acid, ramipril, ramiprilat, and hydrochlorothiazide in rat plasma by a liquid chromatography/tandem mass spectrometry method. Sci Pharm 2015; 83(1): 107-24.
[http://dx.doi.org/10.3797/scipharm.1410-15] [PMID: 26839805]
[40]
Sun Y, Xue J, Li B, et al. Simultaneous quantification of triterpenoid saponins in rat plasma by UHPLC-MS/MS and its application to a pharmacokinetic study after oral total saponin of Aralia elata leaves. J Sep Sci 2016; 39(22): 4360-8.
[http://dx.doi.org/10.1002/jssc.201600801] [PMID: 27670645]
[41]
Wang G, Wang H, Lin Z, Hou L, Wang JY, Sun L. Simultaneous determination of 11 alkaloids in rat plasma by LC-ESI-MS/MS and a pharmacokinetic study after oral administration of total alkaloids extracted from Nauclea officinalis. J Ethnopharmacol 2022; 282: 114560.
[http://dx.doi.org/10.1016/j.jep.2021.114560] [PMID: 34454053]
[42]
Rezk MR, Badr KA. Determination of amlodipine, indapamide and perindopril in human plasma by a novel LC-MS/MS method: Application to a bioequivalence study. Biomed Chromatogr 2021; 35(5): e5048.
[http://dx.doi.org/10.1002/bmc.5048] [PMID: 33314205]
[43]
Rezk MR, Badr KA. Quantification of amlodipine and atorvastatin in human plasma by UPLC-MS/MS method and its application to a bioequivalence study. Biomed Chromatogr 2018; 32(7): e4224.
[http://dx.doi.org/10.1002/bmc.4224] [PMID: 29498757]
[44]
Li H, Wang Y, Jiang Y, et al. A liquid chromatography/tandem mass spectrometry method for the simultaneous quantification of valsartan and hydrochlorothiazide in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 852(1-2): 436-42.
[http://dx.doi.org/10.1016/j.jchromb.2007.02.014] [PMID: 17331816]
[45]
Jin C, Wang T, Zhao T, Jiang W, Zhen X, Li H. Determination of nine cardiovascular drugs in human plasma by QuEChERS-UPLC-MS/MS. Heliyon 2023; 9(12): e22543.
[http://dx.doi.org/10.1016/j.heliyon.2023.e22543] [PMID: 38094060]
[46]
Zhou L, Wang S, Chen M, et al. Simultaneous and rapid determination of 12 tyrosine kinase inhibitors by LC-MS/MS in human plasma: Application to therapeutic drug monitoring in patients with non-small cell lung cancer. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1175: 122752.
[http://dx.doi.org/10.1016/j.jchromb.2021.122752] [PMID: 33991955]
[47]
Sun W, Jiang Z, Zhou L, et al. Determination and pharmacokinetic study of pirfenidone in rat plasma by UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2015; 981-982: 14-8.
[http://dx.doi.org/10.1016/j.jchromb.2014.12.027] [PMID: 25596380]
[48]
Shah JV, Parekh JM, Shah PA, Shah PV, Sanyal M, Shrivastav PS. Application of an LC-MS/MS method for the analysis of amlodipine, valsartan and hydrochlorothiazide in polypill for a bioequivalence study. J Pharm Anal 2017; 7(5): 309-16.
[http://dx.doi.org/10.1016/j.jpha.2017.06.001] [PMID: 29404054]
[49]
Eser B, Özkan Y, Sepici Dinçel A. Determination of tryptophan and kynurenine by LC-MS/MS by using amlodipine as an internal standard. J Am Soc Mass Spectrom 2020; 31(2): 379-85.
[http://dx.doi.org/10.1021/jasms.9b00007] [PMID: 32031396]
[50]
Giri P, Joshi V, Giri S, Delvadia P, Jain MR. Simultaneous determination of sacubitrilat and fimasartan in rat plasma by a triple quad liquid chromatography-tandem mass spectrometry method utilizing electrospray ionization in positive mode. Biomed Chromatogr 2021; 35(2): e4981.
[http://dx.doi.org/10.1002/bmc.4981] [PMID: 32895916]
[51]
Sultan MA, El-Eryan RT, Attia AK, Eissa MJ. Development and validation of liquid chromatography-electrospray-tandem mass spectrometry method for determination of flibanserin in human plasma: Application to pharmacokinetic study on healthy female volunteers. Biomed Chromatogr 2019; 33(8): e4545.
[http://dx.doi.org/10.1002/bmc.4545] [PMID: 30937940]
[52]
Abdel-Megied AM, Eldehna WM, Abdelrahman MA, Elbarbry FA. Development and validation of high-throughput bioanalytical liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of newly synthesized antitumor carbonic anhydrase inhibitors in human plasma. Molecules 2020; 25(23): 5753.
[http://dx.doi.org/10.3390/molecules25235753] [PMID: 33291270]
[53]
Wang B, Sheng L, Li Y. Simultaneous determination of telmisartan and amlodipine in dog plasma by LC-MS-MS. J Chromatogr Sci 2015; 53(10): bmv078.
[http://dx.doi.org/10.1093/chromsci/bmv078] [PMID: 26142429]
[54]
Kumar A, Dwivedi SP, Prasad T. Method validation for simultaneous quantification of olmesartan and hydrochlorothiazide in human plasma using LC-MS/MS and its application through bioequivalence study in healthy volunteers. Front Pharmacol 2019; 10: 810.
[http://dx.doi.org/10.3389/fphar.2019.00810] [PMID: 31396085]
[55]
Abdallah OM, Abdel-Megied AM, Gouda AS. Development and validation of LC-MS/MS method for simultaneous determination of sofosbuvir and daclatasvir in human plasma: Application to pharmacokinetic study. Biomed Chromatogr 2018; 32(6): e4186.
[http://dx.doi.org/10.1002/bmc.4186] [PMID: 29314090]
[56]
da Silva CP, Dalpiaz LPP, Gerbase FE, et al. Determination of cannabinoids in plasma using salting-out-assisted liquid-liquid extraction followed by LC-MS/MS analysis. Biomed Chromatogr 2020; 34(12): e4952.
[http://dx.doi.org/10.1002/bmc.4952] [PMID: 32706449]
[57]
Desai R, Roadcap B, Goykhman D, Woolf E. Determination of doravirine in human plasma using liquid-liquid extraction and HPLC-MS/MS. Bioanalysis 2019; 11(16): 1495-508.
[http://dx.doi.org/10.4155/bio-2019-0116] [PMID: 31502859]
[58]
Breidinger SA, Simpson RC, Mangin E, Woolf EJ. Determination of suvorexant in human plasma using 96-well liquid-liquid extraction and HPLC with tandem mass spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci 2015; 1002: 254-9.
[http://dx.doi.org/10.1016/j.jchromb.2015.07.056] [PMID: 26343269]
[59]
Furugen A, Nishimura A, Kobayashi M, Umazume T, Narumi K, Iseki K. Quantification of eight benzodiazepines in human breastmilk and plasma by liquid-liquid extraction and liquid-chromatography tandem mass spectrometry: Application to evaluation of alprazolam transfer into breastmilk. J Pharm Biomed Anal 2019; 168: 83-93.
[http://dx.doi.org/10.1016/j.jpba.2019.02.011] [PMID: 30798209]
[60]
Al-Shdefat R. Solubility determination and solution thermodynamics of olmesartan medoxomil in (PEG-400 + water) cosolvent mixtures. Drug Dev Ind Pharm 2020; 46(12): 2098-104.
[http://dx.doi.org/10.1080/03639045.2020.1847136] [PMID: 33151111]
[61]
Ghobashy MM, Alshangiti DM, Alkhursani SA, Al-Gahtany SA, Shokr FS, Madani M. Improvement of in vitro dissolution of the poor water-soluble amlodipine drug by solid dispersion with irradiated polyvinylpyrrolidone. ACS Omega 2020; 5(34): 21476-87.
[http://dx.doi.org/10.1021/acsomega.0c01910] [PMID: 32905418]
[62]
Ruponen M, Rusanen H, Laitinen R. Dissolution and permeability properties of co-amorphous formulations of hydrochlorothiazide. J Pharm Sci 2020; 109(7): 2252-61.
[http://dx.doi.org/10.1016/j.xphs.2020.04.008] [PMID: 32315662]
[63]
Jacob S, Nair AB. An updated overview with simple and practical approach for developing in vitro-in vivo correlation. Drug Dev Res 2018; 79(3): 97-110.
[http://dx.doi.org/10.1002/ddr.21427] [PMID: 29697151]
[64]
Andhariya JV, Shen J, Choi S, Wang Y, Zou Y, Burgess DJ. Development of in vitro-in vivo correlation of parenteral naltrexone loaded polymeric microspheres. J Control Release 2017; 255: 27-35.
[http://dx.doi.org/10.1016/j.jconrel.2017.03.396] [PMID: 28385676]
[65]
Mendes TC, Simon A, Menezes JCV, Pinto EC, Cabral LM, de Sousa VP. Development of USP apparatus 3 dissolution method with IVIVC for extended release tablets of metformin hydrochloride and development of a generic formulation. Chem Pharm Bull 2019; 67(1): 23-31.
[http://dx.doi.org/10.1248/cpb.c18-00579] [PMID: 30606948]
[66]
Davanço MG, Campos DR, Carvalho PO. In vitro-in vivo correlation in the development of oral drug formulation: A screenshot of the last two decades. Int J Pharm 2020; 580: 119210.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119210] [PMID: 32173499]
[67]
Cardot JM, Davit BM. In vitro-in vivo correlations: Tricks and traps. AAPS J 2012; 14(3): 491-9.
[http://dx.doi.org/10.1208/s12248-012-9359-0] [PMID: 22547350]
[68]
Jain S, Patel K, Arora S, Reddy VA, Dora CP. Formulation, optimization, and in vitro-in vivo evaluation of olmesartan medoxomil nanocrystals. Drug Deliv Transl Res 2017; 7(2): 292-303.
[http://dx.doi.org/10.1007/s13346-016-0355-2] [PMID: 28116656]
[69]
Chai R, Gao H, Ma Z, et al. In vitro and in vivo evaluation of olmesartan medoxomil microcrystals and nanocrystals: Preparation, characterization, and pharmacokinetic comparison in beagle dogs. Curr Drug Deliv 2019; 16(6): 500-10.
[http://dx.doi.org/10.2174/1567201816666190627143214] [PMID: 31244438]
[70]
Wang T, Wang Y, Lin S, et al. Evaluation of pharmacokinetics and safety with bioequivalence of Amlodipine in healthy Chinese volunteers: Bioequivalence study findings. J Clin Lab Anal 2020; 34(6): e23228.
[http://dx.doi.org/10.1002/jcla.23228] [PMID: 32034814]
[71]
Liu D, Jiang J, Wang C, Zhang J, Hu P. Pharmacokinetics and tolerability of olmesartan medoxomil plus hydrochlorothiazide combination in healthy Chinese subjects: Drug-drug interaction, bioequivalence, and accumulation. Int J Clin Pharmacol Ther 2014; 52(4): 321-7.
[http://dx.doi.org/10.5414/CP202007] [PMID: 24472401]
[72]
Blatnik SU, Dreu R, Srčič S. Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi- and three-layer tablets. Acta Pharm 2015; 65(4): 383-97.
[http://dx.doi.org/10.1515/acph-2015-0031] [PMID: 26677896]