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 Cmax, AUC0-t, AUC0-∞, tmax, and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of Cmax, AUC0-t, and AUCt-∞ 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.

Validated HPLC‐UV method for determination of naproxen in human plasma with proven selectivity against ibuprofen and paracetamol

“…Sample pretreatment in the previous studies was based on solid‐phase extraction (Gopinath et al ., ; Patel et al ., ), protein precipitation (Bae et al ., ; Elsinghorst et al ., ; Helmy and El Bedaiwy, ; Martín et al ., ; Palma‐Aguirre et al ., ; Sakaguchi et al ., ; Sultana et al ., ; Xiong et al ., ) and liquid–liquid extraction (Carrasco‐Portugal et al ., ; Marzo et al ., ; Niazi et al ., ; Setiawati et al , ; Shimek et al ., ; Sun et al ., ; Yilmaz et al ., ; Toothaker et al ., ). Solid‐phase extraction methods are very effective and provide a selective cleanup, but they require the use of expensive instruments and cartridges.…”

“…Another limitation of the reported methods is the application of commonly used drugs, such as ibuprofen, as the internal standards (Gopinath et al ., ; Helmy and El Bedaiwy, ; Niazi et al ., ; Yilmaz et al ., ). A concomitant medication may be used in healthy volunteers during a bioequivalence study only in the case of adverse events, for example, headache (European Medicines Agency, ).…”

“…The proposed method is simple and rapid with a 5 s mixing time during extraction and a relatively short (7 min) chromatographic run time. Therefore, contrary to previously reported assays (Helmy and El Bedaiwy, ; Martín et al ., ; Niazi et al ., ; Palma‐Aguirre et al ., ; Sun et al ., ), it is suitable for analyzing a large number of samples in a short time (1000 samples during about 6 days). The method presents a good linearity over the range of 0.50–80.00 µg/mL, which in opposite to results in earlier papers (Bae et al ., ; Martín et al ., ; Marzo et al ., ; Palma‐Aguirre et al ., ; Sultana et al ., ; Yilmaz et al ., ), and is appropriate for pharmacokinetic studies of 220 mg naproxen sodium dose.…”

“…The majority of methods for naproxen quantification in human plasma or serum samples are based on high-performance liquid chromatography technique (HPLC) with various detections, such as chemiluminescent (Xiong et al, 2008), fluorometric (Sakaguchi et al, 2011;Shimek et al, 1982;Toothaker et al, 2000), mass spectrometric (Choi et al, 2015;Elsinghorst et al, 2011;Gopinath et al, 2013;Patel et al, 2012) and the most common ultraviolet (UV) (Bae et al, 2009;Carrasco-Portugal et al, 2006;Helmy and El Bedaiwy, 2013;Martín et al, 1999;Marzo et al, 1997;Niazi et al, 1997;Palma-Aguirre et al, 2009;Setiawati et al, 2009;Sultana et al, 2013;Sun et al, 2003;Yilmaz et al, 2014). For the HPLC-UV assays the lowest reported lower limit of quantitation (LLOQ) value is 100 ng/mL (Sun et al, 2003;Yilmaz et al, 2014).…”

“…For the HPLC-UV assays the lowest reported lower limit of quantitation (LLOQ) value is 100 ng/mL (Sun et al, 2003;Yilmaz et al, 2014). However, based on data (Elsinghorst et al, 2011;Helmy and El Bedaiwy, 2013;Toothaker et al, 2000) the LLOQ of 0.5 μg/mL seems to be appropriate for the determination of naproxen pharmacokinetic profile following the administration of a single 220 mg oral dose of its sodium salt. Therefore, less expensive and more accessible UV detection is preferred in this case.…”