Anders Sandberg

Gastro-intestinal transit of a multiple-unit formulation (metoprolol CR/ZOK) and a non-disintegrating tablet with the emphasis on colon

Abstract The main aim of the present study was to compare the transit through the entire gastro-intestinal channel of a membrane-coated, multiple-unit system containing metoprolol and a single-unit placebo tablet using gamma-scintigraphy. The two formulations were simultaneously administered, together with a breakfast (2800 kJ), to eight healthy male volunteers. The mean gastric emptying time for the pellets was 3.6 (range 1.5–5.0) h on average and the mean gastric emptying time for the tablet was 9.6 (range 3.3-(14–24)) h. This difference was statistically significant. The mean transit through the small intestine, 3.1 (range 1.5–5.7) h and 2.0 (range 1.0–3.3) h for the pellets and the tablet respectively, did not differ significantly between the formulations. The pellets had a longer residence time in the colon in all subjects compared with the tablet. The mean colon transit time was 28 (range 6.0–48) h on average for the pellets and 15 (range 3.8–26) h for the tablet. The tablet was expelled 26 (range 9.5–42) h after intake on average, whereas the pellets remained for a significantly longer time period (mean 35, range 10–55 h). The desired extended-release properties and metoprolol absorption was obtained throughout the entire gastrointestinal (GI) tract.

The Relationship Between Metoprolol Plasma Concentration and Beta1‐Blockade in Healthy Subjects: A Study on Conventional Metoprolol and Metoprolol CR/ZOK Formulations

Four studies using different daily doses (100 mg, 200 mg, 300 mg and 400 mg) have examined the bioequivalence of the once daily formulation metoprolol CR/ZOK and conventional metoprolol tablets (CT). These studies showed metoprolol CR/ZOK to have a similar beta1‐blocking activity to metoprolol CT but that the bioavailability of the new formulation was lower. This paper presents the analysis of data from all four studies, looking at the relationship between plasma concentrations and beta1‐blockade measured as reduction of exercise induced tachycardia.

Controlled release metoprolol. Clinical pharmacokinetic and therapeutic implications.

SummaryMetoprolol is a relatively β1-selective β-blocker used extensively to treat hypertension and angina and as a prophylaxis after myocardial infarction. Conventional formulations are usually administered twice daily and the drug has a tendency to lose its selectivity of action at higher plasma concentrations. Two controlled release formulations, metoprolol CR and metoprolol ‘Oros’, have made it possible to achieve sustained β1-blockade over an entire 24h period and to minimise the loss of selectivity associated with higher plasma concentrations. The CR formulation has been extensively investigated and is the major subject of this review. The ‘Oros’ formulation is pharmaceutically different from the CR, yet both produce similar plasma concentration profiles and comparable β1-blocking effects. The availability of these preparations occurs at a time when increasingly persuasive data are becoming available on the cardioprotective or coronary preventive action of metoprolol.

Pharmacokinetic and Biopharmaceutic Aspects of Once Daily Treatment with Metoprolol CR/ZOK: A Review Article

In the development of a new controlled release preparation and its subsequent assessment there are a number of factors that need to be considered both related to the drug itself and to the pharmaceutical preparation. This review describes the biopharmaceutical and pharmacokinetic properties of metoprolol CR/ZOK, a recently introduced formulation of a widely used beta1‐selective adrenoceptor antagonist intended for once daily usage.

In vitro release characteristics of a membrane-coated pellet formulation — influence of drug solubility and particle size

Abstract The impact of drug solubility and particle size on the in vitro release characteristics of membrane-coated pellets has been investigated for the metoprolol salts, sorbate, benzoate, succinate and fumarate. Three well-defined size fractions of small spherical pellets were prepared for each salt and coated with a membrane of ethylcellulose and hydroxypropyl methylcellulose (proportion 3:1). The particle diameter, surface area, volume and apparent density were determined for each fraction of coated pellets and their drug release properties were characterized by an initial lag-time, a constant release rate phase and a final declining release rate phase. Both the particle size and drug solubility were shown to be important for the release properties of the pellets. Thus, the constant release rate was approximately proportional to the surface area of the pellets over the entire solubility range (~ 20–500 mg/ml). All three phases of the drug release curve were strongly influenced by the drug solubility. This was explained on the basis of the different concentration gradients over the membrane as well as by osmotic effects. Although the release rate was shown to be markedly affected by the osmotic pressure, evaluation of the release kinetics did not reveal osmotic pumping to be the major mechanism for the release. Also, diffusion appears to be important for the drug release from the investigated formulations.

Steady-state bioavailability and day-to-day variability of a multiple-unit (CR/ZOK) and a single-unit (OROS) delivery system of metoprolol after once-daily dosing.

Steady-state bioavailability and day-to-day variability of plasma levels were evaluated in 18 healthy male subjects in a crossover study of multiple once-daily administration of two novel oral drug delivery systems of metoprolol and an immediate-release tablet (100 mg metoprolol tartrate). Data were collected over two consecutive 24-hr dosing intervals on treatment days 6 and 7. The two extended-release formulations investigated were metoprolol CR/ZOK (95 mg metoprolol succinate), a multiple-unit system consisting of several hundred membrane-coated delivery units, and metoprolol OROS (95 mg metoprolol fumarate), a single-unit osmotic delivery system. The extended drug release and absorption observed after administration of metoprolol CR/ZOK and metoprolol OROS resulted in similar steady-state plasma concentrations after once-daily dosing. Compared to the immediate-release tablet, they produced considerably lower plasma peaks, three- to fourfold higher trough concentrations, 8–9 hr longer mean residence times, and 20% lower relative bioavailability. Moreover, the two once-daily metoprolol products were found bioequivalent in Cmax and AUC based on 90% confidence intervals for the mean ratio CR/OROS. Repeated plasma concentration measurements on two consecutive 24-hr periods suggested that all three metoprolol treatments produced reproducible and consistent plasma concentrations from day to day at steady state. Assessment of day-to-day variability, however, resulted in significantly lower variation in AUC for the multiple-unit CR/ZOK formulation compared to the single-unit OROS tablet. These results imply that there may be formulation-related differences in the in vivo behavior of the two products despite their being bioequivalent in extent and rate of absorption.

Influence of dissolution rate on the extent and rate of bioavailability of metoprolol

Abstract Three extended release formulations of metoprolol (95 mg metoprolol succinate) with different in vitro release rates were administered to ten healthy males (20–29 years) as single oral doses. The bioavailability properties of the three formulations were evaluated in relation to an intravenous dose (10 mg metoprolol tartrate) and an oral solution (95 mg metoprolol succinate). Both the rate and extent of metoprolol absorption were related to the drug release rate as shown by the plasma concentration-time profiles and resultant pharmacokinetic variables. Individual absorption-time profiles reflected well the corresponding in vitro release curves, showing a good correlation over the entire time interval for all three formulations. For the slowest formulations, drug absorption continued at very delayed times (24–30 h) in most individuals, confirming the good distal gastrointestinal absorption of metoprolol. A reduced bioavailability was seen with all extended release formulations compared with the solution and was probably caused by increased hepatic first-pass metabolism. Incomplete absorption may also contribute to the more markedly reduced bioavailability of the slowest formulation. Evaluation of compartmental (Wagner-Nelson, Loo-Riegelman) and noncompartmental (numerical deconvolution) methods for assessing drug absorption suggests that all three methodologies are appropriate when applied to extended release formulations of metoprolol.

Pharmacokinetic and Pharmacodynamic Evaluation of Metoprolol Controlled Release (CR/ZOK) 50 mg in Young Subjects

In this steady state, cross‐over study, the bioavailability and beta1‐blocking effects of metoprolol CR/ZOK 50 mg, conventional metoprolol 50 mg tablets and placebo were evaluated in 12 healthy male subjects (mean age 25 years) after once daily treatment in 5 days. The drugs were administered in a randomized order. The beta1‐blocking effect was defined as percent reduction from baseline in exercise heart rate.

Pharmacokinetics of Metoprolol Enantiomers after Administration of the Racemate and the S-Enantiomer as Oral Solutions and Extended Release Tablets

SummaryPlasma concentrations of S- and R-metoprolol were measured by an enantioselective assay method after single dosing of racemic metoprolol (metoprolol succinate 190mg) given as an oral solution and an extended release formulation in 12 healthy male subjects. Nine subjects were phenotyped as extensive metabolisers (EM) and 3 as poor metabolisers (PM) of metoprolol. The same subjects also received a single dose of enantiomerically pure S-metoprolol (S-metoprolol sorbate 110mg) in corresponding administration forms, providing fast and slow drug input.The results confirmed stereoselective kinetics of metoprolol enantiomers in the EM subgroup, although there was no sign of such an effect in the 3 PMs. Stereoselectivity also appeared to be dependent on the drug input rate since the area under the concentration-time curve (AUC) ratio of S-metoprolol to R-metoprolol was higher in all 9 EM subjects after extended release administration compared with the oral solution of the racemate. There was no apparent difference in systemic clearance between the enantiomers as indicated by their similar elimination half-lives (2.8 hours for S- versus 2.6 hours for R-metoprolol).In addition, the oral bioavailability of S-metoprolol was significantly lower after administration of the pure S-enantiomer solution than when the same dose of the S-form was given as the racemic solution [95% confidence interval (CI) for the AUC ratio was 61 to 81%]. Dose-dependent first-pass extraction and/or inhibition of the S-metoprolol metabolism by the R-form are suggested as possible causes of this difference. The reverse situation was seen when comparing the 2 extended release forms, although the difference in their AUCs was smaller (95% CI was 104 to 137%).A possible therapeutic implication of the stereoselective properties of metoprolol is a somewhat greater pharmacological response in EMs following treatment with an extended release than following treatment with an immediate release preparation at the same total drug concentration. Furthermore, the differences in bioavailability of S-metoprolol imply that definition of therapeutically equivalent doses of racemic metoprolol and an enantiomerically pure formulation must be made on a formulation-by-formulation basis considering dissolution (input rate) characteristics and using enantioselective analysis in the pharmacokinetic evaluation.