Comparative in vitro Dissolution and in vivo Bioavailability of Diflunisal/Naproxen Fixed-Dose Combination Tablets and Concomitant Administration of Diflunisal and Naproxen in Healthy Adult Subjects

Abstract

A simple validated high-performance liquid chromatography (HPLC) assay was developed for determination of diflunisal and naproxen in human plasma samples. This is to compare the bioavailability of diflunisal-naproxen fixed-dose combination (FDC) with their separate dosage forms. The in vitro dissolution study was adopted to compare the dissolution behavior of FDC with respect to separate marketed tablets. In vivo study was conducted according to a single-center, randomized, single-dose, laboratory-blinded, 2 Way, Cross-Over Study with a washout period of 10 days. Under fasting conditions, 24 healthy Egyptian male volunteers were randomly allocated to receive a single oral dose of either one FDC tablet or co-administration of two separate diflunisal and naproxen marketed tablets. Plasma samples were obtained over a 72-h interval and analyzed for diflunisal and naproxen by reversed phase liquid chromatography with UV detection. The pharmacokinetic parameters C_max, AUC_0-t, AUC_0-∞, t_max, and t_1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of C_max, AUC_0-t, and AUC_t-∞ of the 2 treatments were within the acceptable range (0.8–1.25) for bioequivalence. From pharmacokinetic and in vitro studies perspectives, 1 FDC tablet demonstrated similar relative bioavailability with the 2 individual ­reference tablets.

Key words

diflunisal - naproxen - dissolution - pharmacokinetics - bioavailability - HPLC

• References

• 1 Martindale: The Complete Drug Reference. 2005. 34^th ed. Sweetman SC. editor published by the Pharmaceutical Press; London: 34 65
• 2 Takagi T, Ramachandran C, Bermejo M et al. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Mol Pharm 2006; 3: 631-643
• 3 Wu CY, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 2005; 22: 11-23
• 4 Nuernberg B, Koehler G, Brune k. Pharmacokinetics of diflunisal in patients. Clin Pharmacokinet 1991; 20: 81-89
• 5 Verbeeck R, Tjandramaga TB, Mullie A et al. Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency. Br J Clin Pharmacol 1979; 7: 273-282
• 6 Davies NM, Anderson KE. Clinical pharmacokinetics of naproxen. Clin Pharmacokinet 1997; 32: 268-293
• 7 Niazi S, Alam M, Ahmad S. Dose dependent pharmacokinetics of naproxen in man. Biopharm Drug Dispos 1997; 17: 355
• 8 Schulz HU, Steinijans VW. Striving for standards in bioequivalence assessment: a review. Int J Clin Pharmacol Ther Toxicol 1992; 30: S1-S6
• 9 Hauschke D, Steinijans VW. A distribution-free procedure for the statistical analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol 1990; 28: 72-78
• 10 Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987; 15: 657-680
• 11 Barrett JS, Batra V, Chow A et al. PhRMA perspective on population and individual bioequivalence. J Clin Pharmacol 2000; 40: 561-571
• 12 U.S. Food and Drug Administration Centre for Drug Evaluation and Research (FDA) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products–General Considerations, Office of Training and Communications, Division of Communications Management, Drug Information Branch, HFD-210, Rockville MD 20857, March 2003 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070124.pdf [Last accessed January 3^rd, 2013]
• 13 EMEA/CPMP/EWP/1401/98. Note for guidance on the investigation of bioavailability and bioequivalence. EMEA, London, 26 July 2001. EMEA/CPMP/EWP/QWP/1401/98 Rev.1/Corr. Guideline on the investigation of bioequivalence. London, 20 January 2010. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC50007003 pdf [Last accessed January 3^rd, 2013]
• 14 Executive Board of Health Ministries for Gulf States, Approved Guidelines on Drug Bioavailability and Bioequivalence Requirements in the Executive Board of Health Ministries for Gulf States, May 2005.P.O. Box 84983 Riyadh 11681, Kingdom of Saudi Arabia
• 15 Wahbi AA, Mabrouk MM, Moneeb MS et al. Simultaneous determination of the two non-steroidal anti-inflammatory drugs; diflunisal and naproxen in their tablets by chemometric spectrophotometry and HPLC. Pak J Pharm Sci 2009; 22: 8-17
• 16 Bebawy LI, El-Kousy NM. Simultaneous determination of some multicomponent dosage forms by quantitative thin layer chromatography densitometric method. J Pharm Biomed Anal 1999; 20: 663-670
• 17 Maher HM. Simultaneous determination of naproxen and diflunisal using synchronous luminescence spectrometry. J Fluoresc 2008; 18: 909-917
• 18 Wahlin-Boll E, Brantmark B, Hanson A et al. High-pressure liquid chromatographic determination of acetylsalicylic acid, salicylic acid, diflunisal, indomethacin, indoprofen and indobufen. Eur J Clin Pharmacol 1981; 20: 375-378
• 19 Gao L, Xing J, Liu W. Determination of diflunisal in plasma by RP-HPLC after solid-liquid extraction. Yao Xue Xue Bao 1998; 33: 286-289
• 20 Karidas Th, Avgerinos A, Malamataris S. Extractionless HPLC Method for the Determination of Naproxen in Human. Plasma and Urine 1993; 26: 2341-2348
• 21 Wanwimolruk SA. Simple Isocratic High-Performance Liquid Chromatographic (HPLC) Determination of Naproxen in Human Plasma using a Microbore Column Technique. J Liq Chromatogr 1990; 13: 1611-1625
• 22 Slattery JT, Levy G. Determination of naproxen and its desmethyl metabolite in human plasma or serum by high performance liquid chromatography. Clin Biochem 1979; 12: 100-103
• 23 Sultana N, Arayneb M, Iftikhar B. Simultaneous Determination of Atenolol, Rosuvastatin, Spironolactone, Glibenclamide and Naproxen Sodium in Pharmaceutical Formulations and Human Plasma by RP-HPLC. J Chin Chem Soc 2008; 55: 1022-1029
• 24 Ray JE, Day RO. High-performance liquid chromatographic analysis of diflunisal in plasma and urine: application to pharmacokinetic studies in two normal volunteers. J Pharm Sci 1983; 72: 1403-1405
• 25 Davies NM, Anderson KE. Clinical pharmacokinetics of naproxen. Clin Pharmacokinet 1997; 32: 268-293
• 26 Carrasco-Portugal Mdel C, Herrera JE, Reyes-Garcia G et al. Comparative bioavailability of two oral suspensions of naproxen sodium. Arzneimittelforschung 2006; 56: 589-592
• 27 van Loenhout JWA, van Ginneken CAM, Ketelaars HCJ et al. High-Performance Liquid Chromatographic Method for the Quantitative Determination of Naproxen and Des-Methyl-Naproxen in Biological Samples. J Liq Chromatogr 1982; 5: 549-561
• 28 U.S. Food and Drug Administration Centre for Drug Evaluation and Research (FDA) . Guidance for Industry-Bioanalytical Method Validation. Silver Spring, MD: Center for Drug Evaluation and Research, US Department for Health and Human Services; May 2001. Available at: http://www.fda.gov/downloads/Drugs/…/Guidances/ucm070107.pdf [Last accessed January 3^rd, 2013]
• 29 United States Pharmacopeia 28 (2005), Asian edition, United States Pharmacopeial Convention, Inc., The Board of Trustess, pp. 639, 1335
• 30 British Pharmacopoeia . (2005). The Stationary Office; London: pp. 644 1386
• 31 Gibaldi M, Perrier D In: Pharmacokinetics. Swarbrick J. (ed.). Informa Healthcare USA, Inc; New York, USA: 1982
• 32 Hedaya MA In: Basic pharmacokinetics, Taylor and Francis. (eds.) ­Taylor and Francis group, 6000 Broken Sound Parkway NW, Suit 300. Boca Raton, FL: 33487-2742, England 2007
• 33 SAS Institute Inc, SAS/STAT User’s guide, Version 6 4th Edition Vol. 2, SAS Institute; Cary, NC: 1990
• 34 Westlake WF. Use of confidence interval in analysis of comparative bioavailability trials. J Pharm Sci 1972; 61: 1340-1341
• 35 Mandallaz D, Mau J. Comparison of different methods of decision making in bioequivalence assessments. Biometrics 1981; 37: 213-222
• 36 Locke S. An exact confidence interval from untransformed data for the ratio of two formulations means. J Pharmacokinet Biopharm 1984; 12: 649-655
• 37 WHO Expert Committee, Guidelines for good clinical practice (GCP) for trials on pharmaceutical products, The Use of Essential Drugs Sixth report of the WHO Expert Committee, WHO Technical Report Series, No. 850, 1995. [Last accessed December 21, 2010]
• 38 European Community, Investigation of Bioavailability and Bioequivalence, The Rules Governing Medicinal Products in European Community, Vol. III, 1991; 149±169 addendum 2
• 39 Setiawati E, Deniati SH, Yunaidi DA et al. Bioequivalence Study with Two Naproxen Sodium Tablet Formulations in Healthy Subjects. J Bioequiv Availab 2009; 1: 028-033
• 40 Wang Y, Liu X, Sun W. The pharmacokinetics and bioequivalence of diflunisal dispersible tablets in healthy volunteers. Chiosp Pharm 2007; 27: 196-198
• 41 Dolobid (Diflunisal) Drug Information http://www.rxlist.com/­dolobid-drug/clinical-pharmacology.htm Accessed December 21, 2010
• 42 Diflunisal tablet, film coated [Teva Pharmaceuticals USA Inc] http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7a78bb38-14d8-4a90-b883-482d4cebf716)