Pharmacokinetics of isosorbide-5-mononitrate after oral administration of an extended-release mononitrate formulation versus a standard dinitrate formulation (original) (raw)
Related papers
European Journal of Pharmaceutics and Biopharmaceutics, 2002
The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab w ) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration (C max ) for the latter, while the time to peak (T max ) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C max by 18% and AUC by 21%, and slightly delayed T max from 5 to 6 h. During fractional dosing, morning and evening C max reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC 0-24 h on the last day to AUC1 on the first day, was 82.1% (confidence limits 71.7-94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab w are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC 0-24 h, s.s. of 5.55^1.78 and 5.71^1.08 mg h/ml). q
Clinical chronopharmacology of oral sustained-release isosorbide-5-mononitrate in healthy subjects
European Journal of Clinical Pharmacology, 1991
In 10 healthy male subjects the pharmacokinetics and haemodynamic effects of sustained-release isosorbide-5-mononitrate 60 mg (IS-5-MN) were studied after oral administration at two different times in the day (08.00 h and 20.00 h). Effects on blood pressure and heart rate after 3 min standing upright were measured in relation to the individual circadian control values. The pharmacokinetic parameters (C .... t .... AUC, tin) did not differ after morning and after evening dosing, tmax being 5.2 h and 4.9 h, respectively. In contrast, the cardiovascular effects of 1S-5-MN were clearly circadian phase-dependent. The maximum decrease in blood pressure decrease and increase in heart rate occurred significantly earlier after the evening (BPsys 2.8 h; BPdia 2.9 h; HR 3.8 h) than after the morning dose (BPsys 5.0 h; BPdia 6.0 h; HR 5.2 h). Thus, the peak haemodynamic effects coincided with the peak drug concentration after the morning dose, whereas the peak effect was in advance of the peak drug concentration after the evening dose of IS-5-MN. The data provide evidence of circadian phase-dependency in the dose-response relationship of oral IS-5-MN.
LC Determination of Isosorbide5-Mononitrate in Human Plasma
Chromatographia, 2009
A simple, sensitive, selective and cost effective LC–UV method was developed for determination of isosorbide mononitrate in human plasma using guaifenesin as an internal standard. Isosorbide mononitrate in plasma was extracted by a single step liquid extraction using tert-butyl methyl ether and chromatographed on a C18 column using water and acetonitrile (80:20 v/v) as mobile phase. The method was validated and exhibited a linear range from 51.6 to 2064.4 ng mL−1. The inter- and intra-assay accuracy ranged from 97.2–102.7 to 94.2–105.5%, respectively, with precision less than 10% in both the cases. The LLQ was 51.6 ng mL−1. The validated method was applied to the quantitation of isosorbide mononitrate from plasma samples in a pharmacokinetic study.
Duration of effects and tolerance of slow-release isosorbide-5-mononitrate for angina pectoris
The American Journal of Cardiology, 1987
(IS-SMN) is an active metabolite of isosorbkfe dinitrate, but unlike its parent compound, is nearly 100% bioavailable after oral administration. Once-a-day therapy with a slow-release formulation of IS-SMN is used widely in Europe for 24-hour prophylaxis of angina pectoris. In a randomized, crossover, double-blind, placebo-controlled study, the duration of effects of 50 and 100 mg of slow-release IS-5MN were evaluated after the first dose and after once-a-day therapy for 1 week in 9 patients with stable anglna pectoris. Compared with placebo values, standing blood pressure decreased (p <O.OOl) and exercise time to the onset of angina and total exercise duration in-creased (p <0.008 and p <0.003) at 4 hours, but not at 20 or 24 hours after first dose of 50 and 100 nq of slow-release IS-5MN. After once-a-day therapy for 1 week, no improvement in exercise duration or reductlon In ST-segment depression was seen after 50 or 100 mg of slow-release IS-5MN at 4, 20 or 24 hours despite high plasma IS-5MN concentrations. Thus, despite therapeutic plasma concentrations, 50 and 100 nq of slow-release IS-5MN dM not exert antianginal or anti-kchemk effects at 20 and 24 hours after the first dose and at 4, 20 and 24 hours after sustained once-a-day therapy for 1
FORMULATIONS OF ISOSORBIDE MONONITRATE (ISMN) TABLET AND COMPARATIVE STUDY WITH AVAILABLE BRANDS
In the present study new formulations of Isosorbide mononitrate were manufactured by dry granulation method using Talc instead of magnesium stearate and compared with different brands of isosorbide mononitrate tablets available in the market. The present study is divided into two phases. For the first phase new formulation of Isosorbide mononitrate was prepared by dry granulation method and during manufacturing magnesium stearate was replaced by Talc as it is cheaper, less process dependant and requires less blending time as compared to magnesium stearate. Mixing time differences of as little as two minutes can significantly alter the dissolution pattern of finished tablets. In the 2 nd phase of present study three different brands of isosorbide dinitrate tablets were randomly selected from the local market using probability sampling tools and evaluated for weight variation test, friability test and hardness test. Disintegration was also conducted according to the methods and guidelines given in BP/USP. The results showed that all parameters like weight-variation, disintegration, hardness, thickness and friability of new formulations are in accordance with the BP/USP limits and the new formulation containing talc showed better potency as compared to other market brands. The most obvious advantage of replacement of magnesium stearate by talc is its better economy, resulting to reduce processing time, less equipment and space required less process validation and lower energy utilization with equal potency and safety.
Journal of Chromatography B-analytical Technologies in The Biomedical and Life Sciences, 2006
Isosorbide 5-mononitrate (5-ISMN) is an organic nitrate widely used for its vasodilating properties in the treatment of angina pectoris. In the present study, an efficient, sensitive, robust method was developed for the determination and quantification of isosorbide 5-mononitrate, in human plasma, by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), using photospray ionization. Isosorbide 5mononitrate was extracted from 0.5 mL human plasma by liquid-liquid extraction (LLE). The method had a chromatographic run of 2.0 min using a C 8 analytical column (100 mm × 2.1 mm i.d.) and the linear calibration curve over the range was linear from 20 to 2000 ng mL −1 (r 2 > 0.995). The between-run precision, based on the relative standard deviation replicate quality controls, was 7.9% (60 ng mL −1 ), 5.2% (300 ng mL −1 ) and 7.0% (1800 ng mL −1 ). The between-run accuracy was 94.9%, 94.1% and 88.8% for the above-mentioned concentrations, respectively. The method herein described was employed in a bioequivalence study of two tablet formulations of isosorbide 5-mononitrate 40 mg.
Fresenius' Zeitschrift f�r Analytische Chemie, 1985
Bestimmung von Isosorbiddinitrat und seinen beiden Mononitrat-Metaboliten in menschlichem Plasma und Speichel durch Gas-Fliissig-Chromatographie mit Electron-Capture Detektor Zusammenfassnng. Zwei Retard-Pr/iparate von Isosorbiddinitrat (ISDN) wurden acht gesunden m/innlichen Probanden verabreicht. Die Bestimmung von ISDN und den beiden Metaboliten 2-Isosorbidmononitrat (2ISMN) und 5-Isosorbidmononitrat (5 ISMN) in Plasma-und Speichelproben erfolgte nach Extraktion durch Gas-Chromatographie mit einem Electron-Capture Detektor. Verschiedene gepaekte S/iulen und Capillars/iulen wurden getestet und optimale chromatographische Bedingungen sowie gfinstige Extraktionsparameter ausgearbeitet. Nach Verabreichung einer Dosis yon 120 mg in Form der ISDN Retard-Pr/iparate betrugen die Plasmakonzentrationen w/ihrend 48 h fiir ISDN zwischen Iund 42 ng/ml, fiir 2ISMN zwischen Iund 76 ng/ml sowie ffir 5ISMN zwischen 12 und 475 ng/ml. Bei den Speichelproben konnte nur ffir das 5ISMN gute Korrelation mit den Plasmaproben erreicht werden. Kontakte yon Plasmaproben mit Plastikgef/iBen sollten vermieden werden, da evtl. niedrigere Ergebnisse fiir ISDN und die Mononitrate durch Adsorption erhalten werden. Die relative Standardabweichung betrfigt ffir ISDN und 2ISMN _+ 3-7% und ffir 5ISMN _ 2-5%. Summary. Two sustained-release formulations of isosorbide dinitrate (ISDN) were administered to eight healthy male subjects and plasma and saliva samples were analysed. The determination of ISDN and its two metabolites 2-isosorbide mononitrate (2ISMN) and 5-isosorbide mononitrate (5ISMN) was carried out after extraction through gas chromatography with an electron-capture detector. Different packed and capillary columns were tested and optimal chromatographic and extraction parameters for the measurement were worked out. A dose of 120mg ISDN sustained-release preparation results in a plasma concentration of 1-42 ng/ml ISDN, 1-76 ng/ml 2ISMN and 12-475 ng/ml 5ISMN, respectively, during 48 h after drug administration. Good saliva-plasma correlation was obtained only for 5ISMN. Plasma samples should not come into contact with plastic materials in order to avoid losses of ISDN and mononitrates due to adsorption. The relative