Comparative in vitro dissolution and in vivo bioequivalence of two diclofenac enteric coated formulations

Abstract

The aim of this study was the comparison of in vitro dissolution and in vivo bioavailability of two different brands of diclofenac sodium (CAS 15307-86-5) enteric coated tablets in healthy male Iranian volunteers in a single-dose, randomized, open-label, single blind study, which was conducted according to a crossover design in healthy volunteers. A washout interval of two weeks was selected between administrations to each subject in this study. Serial venous blood samples over 10 h after each administration to measure diclofenac sodium concentration in serum were obtained, and placed into tubes containing sodium heparin. Then the plasma was separated and kept frozen at −20 °C for subsequent analysis with a modified HPLC method with UV detection. In addition, the in vitro dissolution study was performed on the brands. For the test and reference formulation, mean C_max values were 2257.3 (ng/ml) and 2156 (ng/ml), respectively. The mean AUC^t ₀ and AUC₀ ^∞ were 5726.1 (ng. h/ml) and 5917.8 (ng · h/ml) for the test and 5689.9 (ng · h/ml) and (ng · h/ml) for the reference formulation, respectively. Results show that the 90% confidence intervals for the ratio of test and reference products in C_max (101.4–114.9%), AUC ^t ₀ (96.3–109.1%) and AUC ^∞ ₀ (94.7–107.3%) were all within the 80–125% interval proposed by the FDA and EMA. Both formulations released > 80% of drug within 30 min in buffer pH = 6.8 medium. Therefore the diclofenac sodium enteric coated tablets of the test and reference formulations are bioequivalent in terms of rate and extent of absorption.

Key words

Bioavailability - Bioequivalence - Diclofenac - Dissolution

• References

• 1 Escribano E, Calpena AC, Queralt J, Obach R, Doménech J. Assessment of diclofenac permeation with different formulations: anti-inflammatory study of a selected formula. Eur J Pharm Sci. 2003; 19 (4) 203-10
• 2 Gabard B, Ellgehausen P. Comparative clinical trial with immediate-release diclofenac pellets, 50 mg tid, and slow-release diclofenac pellets, 75 mg bid. Curr Ther Res. 1993; 54 (2) 152-60
• 3 Hosny EA, Al-Helw AARM. Effect of coating of aluminum carboxymethylcellulose beads on the release and bioavailability of diclofenac sodium. Pharm Acta Helv. 1998; 72 (5) 255-61
• 4 Ayhan S, Yalcin O, Askin I. Preparation and in vitro evaluation of sustained release tablet formulations of diclofenac sodium. Farmaco. 2005; 60 (2) 171-7
• 5 Biasi G, Canova N, Palazzini E, Marcolongo R. Comparative pharmacokinetic study of a single dose of two prolonged-release formulations of diclofenac in healthy subjects. Curr Ther Res. 1998; 59 (ll) 785-92
• 6 WHO/DMP/RGS. Marketing authorization of pharmaceutical products with special reference to multisource (generic) products: a manual for a drug regulatory authority. Geneva, Switzerland: World Health Organization; 1998.
• 7 Esimone CO, Okoye FB, Onah BU, Nworu CS, Omeje EO. In vitro bioequivalence study of nine brands of artesunate tablets marketed in Nigeria. J Vector Borne Dis. 2008; 45 (1) 60-5
• 8 Note for guidance on the investigation of bioavailability and bioequivalence. The European agency for the evaluation of medicinal products. London: Committee for Proprietary Medicinal Products; 2001.
• 9 El-Samaligy MS, Yahia SA, Basalious EB. Formulation and evaluation of diclofenac sodium buccoadhesive discs. Int J Pharm. 2004; 286 (l–2) 27-39
• 10 Su SF, Chou CH, Kung CF, Huang JD. In vitro and in vivo comparison of two diclofenac sodium sustained release oral formulations. Int J Pharm. 2003; 260 (1) 39-46
• 11 Arcelloni C, Lanzi R, Pedercini S, Molteni G, Fermo I, Pontiroli A et al. High-performance liquid chromatographic determination of diclofenac in human plasma after solid-phase extraction. J Chromatogr B Biomed Sci Appl. 2001; 763 (l–2) 195-200
• 12 Giagoudakis G, Markantonis SL. An alternative high-performance liquid-chromatographic method for the determination of diclofenac and flurbiprofen in plasma. J Pharm Biom Anal. 1998; 17 (4–5) 897-901
• 13 Oberle RL, Das H, Wong SL, Chan KK, Sawchuk RJ. Pharmacokinetics and metabolism of diclofenac sodium in Yucatan miniature pigs. Pharm Res. 1994; 11 (5) 698-703
• 14 Lissy M, Stiff DD, Kowalski MM, Moore KA. Single-dose pharmacokinetic study of rapidly dispersing diclofenac potassium formulations in healthy volunteers. Curr Med Res Opin. 2009; 25 (10) 2423-8
• 15 Leon-Reyes MR, Castaneda-Hernandez G, Ortiz MI. Pharmacokinetic of diclofenac in the presence and absence of glibenclamide in the rat. J Pharm Pharm Sci. 2009; 12 (3) 280-7
• 16 Ahmad M, Iqbal M, Murtaza G. Comparison of bioavailability and pharmacokinetics of diclofenac sodium and diclofenac potassium in normal and dehydrated rabbits. Yao Xue Xue Bao. 2009; 44 (1) 80-4
• 17 Cui Y, Lin X, Guan TT, Zhang Y, Tang X. A new rapid ultra-performance liquid chromatography method for the pharmacokinetic and bioavailability study of diclofenac sodium aqueous injection and lipid microsphere injection in rats. Biomed Chromatogr. 2010; 24 (4) 406-12
• 18 El-Sayed YM, Abdel-Hameed ME, Suleiman MS, Najib NM. A rapid and sensitive high-performance liquid chromatographic method for the determination of diclofenac sodium in serum and its use in pharmacokinetic studies. J Pharm Pharmacol. 1988; 40: 727-9
• 19 Valizadeh H, Zakeri-Milani P, Islambulchilar Z, Tajerzadeh H. A simple and rapid high-performance liquid chromatography method for determining furosemide, hydrochlorothiazide, and phenol red: applicability to intestinal permeability studies. J AOAC Int. 2006; 89 (1) 88-93
• 20 Zakeri-Milani P, Barzegar-Jalali M, Tajerzadeh H, Azarmi Y, Valizadeh H. Simultaneous determination of naproxen, ketoprofen and phenol red in samples from rat intestinal permeability studies: HPLC method development and validation. J Pharm Biomed Anal. 2005; 39 (3–4) 624-30
• 21 Fujii A, Yasui-Furukori N, Nakagami T, Niioka T, Saito M, Sato Y et al. Comparative in vivo bioequivalence and in vitro dissolution of two valproic acid sustained-release formulations. Drug Design Develop Ther. 2008; (2) 139-44
• 22 Dutta S, Reed RC, Cavanaugh JH. Pharmacokinetics and safety of extended-release divalproex sodium tablets: Morning versus evening administration. American Journal of Health-System Pharmacy. 2004; 61 (21) 2280-2283
• 23 Dutta S, Zhang Y, Lee LL, O’Dea R. Comparison of the bioavailability of 250 and 500 mg divalproex sodium extended-release tablets in healthy volunteers. Biopharm Drug Dispos. 2004; 25 (8) 353-7
• 24 Zakeri-Milani P, Valizadeh H, Ghanbarzadeh S, Nemati M. Pharmacokinetics and comparative bioavailability study of two clarithromycin suspensions following administration of a single oral dose to healthy volunteers. Arzneimittelforschung. 2009; 59 (8) 429-32
• 25 Zakeri-Milani P, Valizadeh H, Islambulchilar Z, Nemati M. Pharmacokinetic and bioequivalence study of two brands of valsartan tablets in healthy male volunteers. Arzneimittelforschung. 2010; 60 (2) 76-80
• 26 Valizadeh H, Barghi L, Jalilian H, Islambulchilar Z, Zakeri-Milani P. Bioequivalence of fexofenadine tablet formulations assessed in healthy Iranian volunteers. Arzneimittelforschung. 2009; 59 (7) 345-9
• 27 Valizadeh H, Nemati M, Hallaj-Nezhadi S, Ansarin M, Zakeri-Milani P. Single dose bioequivalence study of alpha-methyldopa tablet formulations using a modified HPLC method. Arzneimittelforschung. 2010; 60 (10) 607-11
• 28 Islambulchilar Z, Valizadeh H, Zakeri-Milani P. Rapid HPLC determination of pioglitazone in human plasma by protein precipitation and its application to pharmacokinetic studies. J AOAC Int. 2010; 93 (3) 876-81
• 29 Marzo A, Reiner V. Open questions on bioequivalence: the case of multiple peak phenomenon. J Pharm Pharmacol. 2004; 56 (2) 281-2
• 30 Shargel L, Wu-Pong S, Yu A. Applied Biopharmaceutics & Pharmacokinetics. New York: McGraw-Hill; 2004
• 31 Krishna R, Yu L editors. Biopharmaceutics Applications in Drug Development. New York: Springer Science + Business Media; 2008
• 32 Zakeri-Milani P, Valizadeh H, Islambulchilar Z. Comparative bioavailability study of two cefixime formulations administered orally in healthy male volunteers. Arzneimittelforschung. 2008; 58 (2) 97-100