In vitro Dissolution and in vivo Bioequivalence Evaluation of Two Brands of Isosorbide 5-mononitrate Sustained Release Tablets

Abstract

The purpose of the present study was to test a sustained release-tablet newly formulated with synthetic paraffin and compare its bioequivalence to that of the Imdur® Long-Acting tablet, based on the guidelines of the Korean Food and Drug Administration.Dissolution test was performed in 4 different dissolution media. A LC/MS/MS method of isosorbide 5-mononitrate in human plasma was validated. In vivo bioequivalence tests of the 2 isosorbide 5-mononitrate tablets were performed in both preprandial and postprandial states.A comparative dissolution test gave similar results for both tablets in all dissolution media tested: 40% dissolution in pH 1.2 at 2 h and 80% dissolution in pH 4.0, pH 6.8, or water at 10 h. In a bioequivalence study to compare 2 tablets, the mean total area under the curve (AUCt) and peak concentration (Cmax) in the fasted state were 8 476.0 ng · h/mL and 540.4 ng/mL, respectively, for the Imdur® Long Acting Tablet 60 mg, and 8 701.4 ng · h/mL and 564.2 ng/mL, respectively, for the test tablet. The mean AUCt and Cmax in the fed state were 8 793.5 ng · h/mL and 559.9 ng/mL, respectively, for the Imdur® Long-Acting tablet 60 mg, and 8 639.8 ng · h/mL and 617.9 ng/mL, respectively, for the test tablet. The 90% confidence intervals using log transformed data were within the acceptable range of 0.8 - 1.25.Based on these statistical analyses, we conclude that the test tablet is bioequivalent to the Imdur® Long-Acting tablet 60 mg in both the preprandial and postprandial states.

Determination of Isosorbide-5-Mononitrate in Human Plasma by High-Performance Liquid Chromatography-Tandem Mass Spectrometry and Its Application to a Bioequivalence Study

“…5-ISMN has been extensively used for cardiovascular diseases such as coronary heart disease and angina pectoris to prevent or at least reduce the occurrence of angina for many years [3], and it has been developed into various formulations such as tablets, immediate-release formulations, and sustained-release formulations [4]. Published analytical methods such as gas chromatography-mass spectrometry (GC-MS) [5][6][7][8] and liquid chromatographytandem mass spectrometry (LC-MS/MS) [9][10][11][12][13] have been established for the identification or quantification of parent isosorbide dinitrate (ISDN) and its two active metabolites isosorbide-2-dinitrate (2-ISMN) or isosorbide-5-monoitrate (5-ISMN) in previous years. However, these assay methods presented some disadvantages such as time-consuming (long-term operation of more than 20 minutes [6] or tedious derivatization [7,8]), low sensitivity (20 ng/mL [11] or 10 ng/ mL [12]), requiring a large amount of plasma samples (0.2-0.5 mL) [11,12] or reagents for sample preparation (3-4 mL) [9,11], or requiring relatively expensive solid-phase extraction (SPE) accompanied with an LLOQ of 9.02 ng/mL [10], which may result in limited application to clinical studies.…”

“…Published analytical methods such as gas chromatography-mass spectrometry (GC-MS) [5][6][7][8] and liquid chromatographytandem mass spectrometry (LC-MS/MS) [9][10][11][12][13] have been established for the identification or quantification of parent isosorbide dinitrate (ISDN) and its two active metabolites isosorbide-2-dinitrate (2-ISMN) or isosorbide-5-monoitrate (5-ISMN) in previous years. However, these assay methods presented some disadvantages such as time-consuming (long-term operation of more than 20 minutes [6] or tedious derivatization [7,8]), low sensitivity (20 ng/mL [11] or 10 ng/ mL [12]), requiring a large amount of plasma samples (0.2-0.5 mL) [11,12] or reagents for sample preparation (3-4 mL) [9,11], or requiring relatively expensive solid-phase extraction (SPE) accompanied with an LLOQ of 9.02 ng/mL [10], which may result in limited application to clinical studies. e mostly reported LC-MS methods to determine 5-ISMN showed relatively low sensitivity (the LLOQ of 10-20 ng/mL) [9][10][11][12][13] except for the report by Sun et al [9].…”

“…However, these assay methods presented some disadvantages such as time-consuming (long-term operation of more than 20 minutes [6] or tedious derivatization [7,8]), low sensitivity (20 ng/mL [11] or 10 ng/ mL [12]), requiring a large amount of plasma samples (0.2-0.5 mL) [11,12] or reagents for sample preparation (3-4 mL) [9,11], or requiring relatively expensive solid-phase extraction (SPE) accompanied with an LLOQ of 9.02 ng/mL [10], which may result in limited application to clinical studies. e mostly reported LC-MS methods to determine 5-ISMN showed relatively low sensitivity (the LLOQ of 10-20 ng/mL) [9][10][11][12][13] except for the report by Sun et al [9]. Sun et al [9] reported the LC-MS method with an LLOQ of 1.04 ng/mL, but it required a large amount of plasma (0.5 mL) and reagents (3 mL) for the sample preparation [9].…”