Generic placeholder image

Current Drug Therapy


ISSN (Print): 1574-8855
ISSN (Online): 2212-3903

Research Article

Drug in Adhesive Transdermal Formulation of Valsartan and Nifedipine: Pharmacokinetics and Pharmacodynamics in Rats

Author(s): Jatin Sood, Bharti Sapra and Ashok K. Tiwary*

Volume 14, Issue 2, 2019

Page: [153 - 167] Pages: 15

DOI: 10.2174/1574885514666181120114635

Price: $65


Background: The increasing complications associated with hypertension often require a combination of two or more drugs acting through different routes to counter the elevated blood pressure.

Objective: The present investigation envisaged at preparing and evaluating a transdermal formulation containing gelled microemulsion drug in adhesive (DIA) patch for simultaneous systemic delivery of valsartan and nifedipine aimed at effective management of hypertension.

Methods: An optimized microemulsion was prepared by using Captex® 500 (7.34% w/w), Capmul® MCM (4.24% w/w), Acrysol EL 135 (24.43% w/w), Transcutol P® (5% w/w) and water (58.9% w/w). Gelling was contributed by polyvinylpyrrolidone K 90F and polyethyleneimine where the latter also conferred skin adhesion properties to the patch. DIA patches were evaluated for in vitro drug release as well as in vivo pharmacokinetics and pharmacodynamics in rats.

Results: In vitro permeation of nifedipine or valsartan from the selected DIA patch was 10.67-fold and 1.25-fold higher as compared to their aqueous dispersions. The relative bioavailability of nifedipine was 1.34 and that of valsartan was 2.18 from this DIA patch with respect to the oral administration of their aqueous suspension.

Conclusion: Transdermal delivery of either drug alone was not effective in reducing methyl prednisolone acetate-induced hypertension, whereas, simultaneous transdermal delivery of both drugs from DIA patch effectively maintained systolic blood pressure at a normal level in these rats for 20 h.

Keywords: Pharmacokinetics, pharmacodynamics, valsartan, nifedipine, transdermal patch, microemulsion.

Graphical Abstract
Danaei G, Finucane MM, Lin JK, et al. Global burden of metabolic risk factors of chronic diseases collaborating group blood pressure. National, regional, and global trends in systolic blood pressure since 1980: systemic analysis of health examination surveys and epidemiologyical studies with 786 county-years and 5.4 million participants. Lancet 2011; 377: 568-77.
Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-32.
Zanchetti A. Intermediate endpoints for atherosclerosis in hypertension. Blood Press Suppl 1997; 2: 97-102.
Iwashima Y, Kokubo Y, Ono T, et al. Additive interaction of oral health disorders on risk of hypertension in a Japanese urban population: the Suita study. Am J Hypertens 2014; 27: 710-9.
Zelkha SA, Freilich RW, Amar S. Periodontal innate immune mechanisms relevant to atherosclerosis and obesity. Periodontol 2000 2010; 54: 207-21.
Bussemaker E, Hillebrand U, Hausberg M, Pavenstadt H, Oberleithner H. Pathogenesis of hypertension: interactions among sodium, potassium, and aldosterone. Am J Kidney Dis 2010; 55: 1111-20.
Kokubo Y, Nakamura S, Okamura T, et al. Relationship between blood pressure category and incidence of stroke and myocardial infarction in an urban Japanese population with and without chronic kidney disease: the Suita study. Stroke 2009; 40: 2674-9.
Kokubo Y. The mutual exacerbation of decreased kidney function and hypertension. J Hypertens 2012; 30: 468-9.
Kokubo Y, Okamura T, Watanabe M, et al. The combined impact of blood pressure category and glucose abnormality on the incidence of cardiovascular diseases in a Japanese urban cohort: the Suita study. Hypertens Res 2010; 33: 1238-43.
James PA, Oparil S, Carter BL, et al. Evidence-based guideline for the management of high blood pressure in adults. JAMA 2014; 311: 507-20.
Herbert JM, Delisée C, Dol F, et al. Effect of SR 47436, a novel angiotensin II AT1 receptor antagonist, on human vascular smooth muscle cells in vitro. Eur J Pharmacol 1994; 251: 143-50.
deGasparo M, Whitebread S. Binding of valsartan to mammalian angiotensin AT1 receptors. Regul Pept 1995; 59: 303-11.
McConnaughey MM, McConnaughey JS, Ingenito AJ. Practical considerations of pharmacology of angiotensin receptor blockers. J Clin Pharmacol 1999; 39: 547-59.
Muller JE, Gunther SJ. Nifedipine therapy for prinzmetal’s angina. Circulation 1978; 57: 137-40.
Hugenholtz PG, Michels FHR, Serruys PW, Brower RW. Nifedipine in the treatment of unstable angina, coronary spasm and myocardial ischemia. Am J Cardiol 1981; 47: 163-73.
Stason WB, Schmid CH, Niedzwiecki B, et al. Safety of nifedipine in angina pectoris - A Meta Analysis. Hypertension 1999; 33: 24-31.
Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366-72.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker versus diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981-97.
Saito I, Fujikawa K, Saruta T. ADVANCE-Combi Study Group. Cost effectiveness analysis: controlled release nifedipine and valsartan combination therapy in patients with essential hypertension: the adalat CR and valsartan cost effectiveness combination (ADVANCE-Combi) study. Hypertens Res 2008; 31: 1399-405.
Horster FA, Duhm B, Maul W, Medenwald H, Patzschke K, Wegner LA. Clinical investigations on the pharmacokinetics of radioactively marke 4-(2'nitrophenyl)-2,6-dimethyl-1,-4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester. Arzneimittel-Forsch 1972; 22: 330-4.
Nathan HJ, Laganiere S, Dube L. Intravenous nifedipine to treat hypertension after coronary artery revascularization surgery, A comparison with sodium. Anesth Analg 1992; 74: 809-17.
Israili ZH. Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. J Hum Hypertens 2000; 14: 73-86.
European Parliament, Council of the European Union, Directive 2010/63/EU of the European parliament and of the council on the protection of animals used for scientific purpose, O.J.E.U.. 2010; 276: 33-79.
Sood J, Sapra B, Tiwary AK. Microemulsion transdermal formulation for simultaneous delivery of valsartan and nifedipine: formulation by design. AAPS PharmSciTech 2016; 18: 1901-16.
Lorenz DH. Skin adhesive hydrogel, its preparation and uses US Patent 5,306,504A 1994.
Kligman AM, Christophers E. Preparation of isolated sheets of human stratum corneum. Arch Dermatol 1963; 88: 702-5.
Thirawong N, Nunthanid J, Puttipipatkhachorn S, Sriamornsak P. Mucoadhesive properties of various pectins on gastrointestinal mucosa: An in vitro evaluation using texture analyser. Eur J Pharm Biopharm 2007; 67: 132-40.
ASTM D903-98. Standard test method for peel or stripping strength of adhesive bonds. ASTM Standard 2004; 15: 6-9.
Che J, Wu Z, Shao W, et al. Synergetic skin targeting effect of hydroxyproply-β-cyclodextrin combined with microemulsion for ketoconazole. Eur J Pharm Biopharm 2015; 93: 136-48.
Xie WJ, Zhang YP, Xu J, Sun XB, Yang FF. The effect and mechanism of transdermal penetration enhancement of Fu’s cupping the new physical penetration technology for transdermal administration with traditional Chinese medicine characteristics. Molecules 2016; 22: 525-40.
ICH. Q1A (R2), FDA. Stability testing of new drug substances and products. Fed Regist 2003; 68: 65717-8.
Ahad A, Aqil M, Kohli K, Sultana Y, Mujeeb M, Ali A. Formulation and optimization of nanotransfersomes using experimental design technique for accentuated transdermal delivery of valsartan. Nanomedicine 2012; 8: 237-49.
Feldstein MM, Plate NA, Gleary GW. Molecular design of hydrophilic pressure sensitive adhesives for medical applications.In: Developments in Pressure-Sensitive Products. 2nd Edition;. Benedek I, Ed.. CRC Press, Boca Raton 2005; pp. 473-503.
EMEA Guideline on Bioanalytical Method Validation,. EMEA/CHMP/EWP/192217/2009 Rev 1 2011.
Saydam M, Takka S. Bioavaiability file: valsartan. FABAD J Pharm Sci 2007; 32: 185-96.
Wood JM, Schnell CR, Cumin F, Menard J, Webb RL. Aliskiren, a novel orally effective renin inhibitor, lower blood pressure in marmosets and spontaneously hypertensive rats. J Hypertens 2005; 23: 417-26.
Smith TR, Philipp T, Baisse B, et al. Amlodipine and valsartan combined and as mono therapy in stage 2 elderly, and black hypertensive patients: subgroup analyses of 2 randomized, placebo-controlled studies. J Clin Hypertens 2007; 9: 355-64.
Goldberg S, Reichek N, Wilson J, Hirshfeld JW, Muller J, Kastor JA. Nifedipine in treatment of prinzmetal’s (variant) angina. Am J Cardiol 1979; 44: 804-10.

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy