Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: A comparison with conventional tablets

The pharmacokinetic and pharmacodynamic properties of a new multiple-unit, controlled-release (CR) formulation of metoprolol¹ (metoprolol succinate, 95 mg once daily), which has almost constant (zero-order) release properties over most of a 24-h dose interval, have been compared with those of conventional metoprolol tablets (metoprolol tartrate, 100 mg once daily and 50 mg twice daily), in 12 healthy male volunteers.The steady-state plasma concentrations of metoprolol after five days of treatment varied less throughout the day with the CR than with the conventional formulation. This was associated with a considerably lower peak plasma concentration and the achievement of a significantly higher plasma concentration at the end of the dose interval.     

24-hour antiarrhythmic effect of conventional and slow-release verapamil in chronic atrial fibrillation

Summary Twenty-four-hour heart rate control by verapamil given as conventional tablets t.d.s., or as a new slow release formulation once daily, has been compared in an open cross-over trial. Eight patients with chronic atrial fibrillation and one with chronic atrial flutter were studied outside hospital.Trough serum concentration of verapamil did not differ during the two dosage regimens (59 ng/ml — conventional formulation and 49.3 ng/ml — slow release tablet). The average serum concentration of digoxin in the patients was not changed. Compared to the control phase, both dosage regimens significantly and equally reduced individual and average heart rates throughout the entire 24-h period. A positive correlation between the serum concentration of verapamil and the relative increase in average R-R interval was demonstrated.It is concluded that dosage t.d.s. with conventional tablets of verapamil or once daily with the slow release formulation gave the same antiarrhythmic efficacy over 24 h, and was associated with equal trough serum concentrations of verapamil.     

Efficacy and safety of the 200–300 mg sustained release formulation of diltiazem administered once daily in patients with stable angina

The aim of this multicentre randomised double blind study was to compare the efficacy and safety of the 200–300 mg sustained release diltiazem formulation administered once daily (200–300 SR) with standard diltiazem (D) given three or four times daily to patients with stable angina. Patients aged 59 years, with a reproducible exercise test on placebo, were randomised to 4 weeks of treatment with 200–300 SR (n=70) or D (n=74). The initial dosage was 200 mg in the 200–300 SR group and 60 mg t.i.d. in the D group, increased to 300 mg once daily or 60 mg q.i.d., respectively, if ergometric parameters, which were always measured at the end of the dosing period, had not improved after two weeks. After 4 weeks of treatment, the antianginal efficacy at rest was comparable in the 200–300 SR and the D group; there was a prolongation of the total duration of exertion of 14% and 18% respectively (P<0.01 vs placebo for both groups with no intergroup difference). A dose-effect relation was found with both formulations.The 200–300 SR formulation gave full 24 hour anti-ischaemic protection when administered once daily. Its efficacy and safety were comparable to those of standard diltiazem t.i.d. or q.i.d. in patients with stable angina. The once daily administration should improve treatment compliance.     

Controlled release metoprolol formulations. A review of their pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and ischaemic heart disease.

Conventional formulations of metoprolol have become well established in cardiovascular medicine and are particularly useful in the management of hypertension and ischaemic heart disease. Recently developed controlled release metoprolol delivery systems (metoprolol CR/ZOK and metoprolol OROS) were designed to overcome the drug delivery problems of matrix-based sustained release forms by releasing the drug at a relatively constant rate over a 24-hour period, and thus producing sustained and consistent metoprolol plasma concentrations and beta 1-blockade while retaining the convenience of once daily administration. Clinically and statistically significant reductions in blood pressure have been observed with metoprolol CR/ZOK and metoprolol OROS 24 hours after administration in mildly or moderately hypertensive patients. Studies in patients with mild to moderate hypertension have demonstrated that a similar or higher percentage of patients achieved a goal response with metoprolol CR/ZOK compared with matrix-based sustained release formulations of metoprolol, or conventional atenolol or bisoprolol, while metoprolol OROS achieved an equal or greater response rate compared with conventional or matrix-based sustained release metoprolol preparations. In patients with stable effort angina pectoris, once daily administration of metoprolol CR/ZOK provided at least equal antianginal efficacy as conventional metoprolol in divided doses, while metoprolol OROS reduced the mean number of anginal attacks by the same margin as atenolol. Controlled release metoprolol formulations have been well tolerated in clinical trials. Metoprolol CR/ZOK was associated with a similar or lesser degree of adverse effects related to the central nervous system compared with atenolol or long acting propranolol. Metoprolol CR/ZOK also demonstrated less pronounced beta 2-mediated bronchoconstrictor effects than atenolol in asthmatics, and less general fatigue and leg fatigue in healthy subjects. Metoprolol OROS produced less pronounced bronchoconstrictor effects than atenolol, matrix-based sustained release metoprolol or long acting propranolol in patients with asthma or obstructive airways disease, and healthy volunteers. These results are presumably due to the beta 1-selectivity of metoprolol in addition to the relatively low plasma concentrations maintained by metoprolol CR/ZOK and metoprolol OROS, and the avoidance of high peak plasma concentrations with these agents. Despite the relative safety of the controlled release forms of metoprolol, the use of all beta-adrenoceptor antagonists should be avoided in patients with a history of bronchospasm. Thus, controlled release metoprolol formulations offer the potential to maximise the confirmed benefits of this agent in the management of hypertension and angina, by maintaining clinically effective plasma concentrations within a narrow therapeutic range over a 24-hour dose interval.     

Twenty-four hour efficacy of two dose levels of a once daily sustained-release diltiazem formulation in stable angina: a placebo-controlled trial. The Dildurang Study Group.

1. This placebo-controlled study assessed once daily sustained-release (SR) diltiazem, 200 and 300 mg, in 182 stable angina patients with positive exercise test. 2. Exercise testing was performed at baseline after a 7 day placebo run-in period, and repeated after 7 days of treatment, 25.0 +/- 0.1 h postdose. 3. Diltiazem (200 and 300 mg) produced respectively a 68% and a 64% decrease in weekly angina episodes, and placebo a 15% decrease (P < 0.05). Similarly, both dose levels produced a 70% decrease in nitroglycerin consumption, whereas no difference was obtained with placebo (P < 0.01). The increase in time to ischaemic threshold was significantly superior for 200 mg and 300 mg diltiazem when compared with placebo (75.2 and 91.5 s respectively vs 47.0 s) (P < 0.05); increase in time to anginal threshold was also significantly greater for diltiazem when compared with placebo (84.6 and 85.9 s respectively vs 43.9 s) (P < 0.05). 4. Only one patient experienced worsening of angina and had to be withdrawn from the study. 5. This study demonstrates 200 and 300 mg SR diltiazem is effective when given once-a-day in the prophylaxis of stable exertional angina. This once daily formulation should improve patients' compliance and comfort.     

Drug delivery systems for treatment of systemic hypertension

Novel drug delivery systems are available in many areas of medicine. Their application in the treatment of hypertension continues to widen. Oral drug delivery systems permit antihypertensive agents that were previously administered two to four times daily to be administered once daily. Biotechnical use of chemical-dispensing systems has been applied to propranolol (polymer coated beads), clonidine (transdermal therapeutic system), nifedipine (osmotic pump and coat-core), isradipine (osmotic pump), verapamil (sodium alginate and spheroidal oral delivery absorption system), felodipine (coat-core), nisoldipine (coat-core) and diltiazem (polymer coated beads and Geomatrix. The initial goal was to lower blood pressure by a uniform amount throughout the entire day. Now, new drug delivery systems are being developed to target blood pressure in the early morning hours when most cardiovascular events occur. Two chronotherapeutic drug delivery systems are now available for verapamil (chronotherapeutic oral delivery absorption system and delayed coat osmotic pump). Disadvantages of sustained-release products include delayed achievement of pharmacodynamic effect, unpredictable bioavailability, enhanced first-pass hepatic metabolism, dose dumping, sustained toxicity, dosage inflexibility and increased cost. Potential advantages include reduced administration frequency, enhanced adherence and convenience, reduced toxicity, stable drug concentrations, uniform drug effect, decreased cost (occasionally) and decreased daily dosage.     

In Process Citation

This double-blind dose-response crossover study was designed to compare the efficacy and tolerability of sustained-release (SR) and conventional diltiazem over 4 weeks in patients with stable angina pectoris. Following a 2-week placebo run-in period, 26 patients were randomised into 3 parallel groups to receive either diltiazem SR (180, 240 or 300mg once daily) or conventional diltiazem 60mg three times daily for 2 weeks. Treatments were then crossed over for a further 2-week study period. Antianginal efficacy was evaluated using submaximal treadmill exercise testing. At baseline, all 3 treatment groups were comparable for all parameters. Treatment with both conventional and SR formulations improved exercise time and reduced intensity of ischaemia, but the difference between groups at the end of each 2-week treatment phase was not statistically significant. The results did not suggest a dose-response relationship. Adverse reactions necessitated treatment discontinuation in two patients being treated with conventional diltiazem and in one patient receiving diltiazem SR 240mg. In conclusion, this study demonstrated that diltiazem SR 180, 240 and 300mg did not differ from the conventional formulation in terms of anti-ischaemic efficacy.     

Pharmacokinetic and pharmacodynamic comparison of a new controlled-release formulation of metoprolol with a traditional slow-release formulation

The plasma concentration-time profile and haemodynamic effects of metoprolol after the administration of metoprolol CR¹ (a new multiple-unit controlled-release formulation) and metoprolol SR² (a traditional slow-release formulation) once daily, were investigated in 12 healthy men. Data were collected over one 24-h dose interval at steady state after five days of treament.The study was a randomized, three-way, crossover comparison of metoprolol CR, 100 mg, metoprolol SR, 100 mg, and placebo. The reduction in exercise heart rate in relation to placebo treatment was used as a measure of ₁-blockade.     

Atenolol: a review of its pharmacological properties and therapeutic efficacy in angina pectoris and hypertension.

Atenolol is a beta-selective (cardioselective) adrenoceptor blocking drug without partial agonist or membrane stabilising activity. Its profile of action most closely resembles that of metoprolol which differs only in that it has some membrane stabilising activity. Atenolol has been well studied and is effective in the treatment of hypertension and in the prophylactic management of angina. Its narrow dose response range obviates the need for highly individualised dose titration. In patients with angina its long duration of beta-blocking activity allows once daily dosage, whereas other beta-blockers, unless in sustained release dosage forms, need to be given in divided doses. Other beta-blockers can be given once daily in hypertension, but at presnt the evidence for effective control with a once daily regimen is more convincing with atenolol. Further studies are need to clarify any important differences in blood pressure control between the various beta-blocking drugs, both in conventional or sustained release dosage forms. As with metoprolol, atenolol is preferable to non-selective beta-blockers in patients with asthma or diabetes mellitus. Atenolol has been well tolerated in most patients, its profile of adverse reactions generally resembling that of other beta-blocking drugs, although its low lipid solubility and limited penetration into the brain results in a lower incidence of central nervous system effects than seen with propranolol. Atenolol is eliminated virtually entirely as unchanged drug in the urine and dosage needs to be reduced in patients with moderate to severely impaired renal function (glomerular filtration rate less than 30 ml/min). There is no need for modification of dosage of atenolol in liver disease.     

Transdermal delivery of beta-blockers

Beta-adrenoceptor blocking drugs (beta-blockers) are one of the most frequently used class of cardiovascular drugs that are mainly used in conventional dosage forms., which have their own limitations including hepatic first-pass metabolism, high incidence of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Essentially, attempts have been made to develop novel drug delivery systems for beta-blockers, including transdermal delivery systems, to circumvent the drawbacks of conventional drug delivery. However, so far none of the beta-blocker drugs have been marketed as transdermal delivery systems. Nevertheless, there have been noteworthy research endeavours worldwide at the laboratory level to investigate the skin permeation and to develop transdermal formulations of beta-blockers including: propranolol, metoprolol, atenolol, timolol, levobunolol, bupranolol, bopindolol, mepindolol, sotalol, labetolol, pindolol, acebutolol and oxprenolol. Innovative research exploiting penetration-enhancing strategies, such as iontophoresis, electroporation, microneedles and sonophoresis, holds promise for the successful use of these drugs as consumer-friendly transdermal dosage forms in clinical practice. This paper presents an overview of the transdermal research on this important class of drugs.     

Transdermal delivery of β-blockers

β-Adrenoceptor blocking drugs (β-blockers) are one of the most frequently used class of cardiovascular drugs that are mainly used in conventional dosage forms., which have their own limitations including hepatic first-pass metabolism, high incidence of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Essentially, attempts have been made to develop novel drug delivery systems for β-blockers, including transdermal delivery systems, to circumvent the drawbacks of conventional drug delivery. However, so far none of the β-blocker drugs have been marketed as transdermal delivery systems. Nevertheless, there have been noteworthy research endeavours worldwide at the laboratory level to investigate the skin permeation and to develop transdermal formulations of β-blockers including: propranolol, metoprolol, atenolol, timolol, levobunolol, bupranolol, bopindolol, mepindolol, sotalol, labetolol, pindolol, acebutolol and oxprenolol. Innovative research exploiting penetration-enhancing strategies, such as iontophoresis, electroporation, microneedles and sonophoresis, holds promise for the successful use of these drugs as consumer-friendly transdermal dosage forms in clinical practice. This paper presents an overview of the transdermal research on this important class of drugs.     

Clinical efficacy of current transdermal drug delivery systems: a retrospective evaluation

In spite of intensive research on transdermal drug delivery systems (TDDSs), only four--nitroglycerin, clonidine, estradiol, and scopolamine--have reached the market, and the clinical effectiveness of these systems has yet to be clearly demonstrated. Ideally, a candidate for transdermal drug delivery should demonstrate clinical significance within a wide therapeutic range for a well-documented indication for use. Continuous administration of a drug should result in better control of the disease with fewer side effects and a marked increase in patient compliance than when traditional dosage forms are used. It appears that nitroglycerin is a poor candidate for transdermal drug delivery by virtue of the ambiguity associated with its clinical pharmacology, substantial interpatient variation in dose-response relationship, and development of tolerance with potential toxicity risks in chronic administration. Clonidine's well-defined indication for use coupled with its high potency and low molecular weight with high lipid solubility is well suited to transdermal therapy. Because estradiol is unsuitable for use in people who smoke and has dermatotoxic potential, it is a marginal candidate for use in TDDSs. Transdermal scopolamine was not reviewed because it is a unique entity (no conventional dosage forms of this product are available) intended for short-term use. Its use is dictated more by the patient's unique circumstances, such as travel requirements, than by physiological condition. Although TDDSs provide a convenient and effective means of administering medications, the aforementioned clinical constraints need to be evaluated in depth before more widespread application of TDDSs can be recommended. In particular; conclusive demonstration of biocompatibility of a TDDS is warranted.     

Pharmacokinetics of verapamil and norverapamil in patients with hypertension: a comparison of oral conventional and sustained release formulations

A double blind, double dummy, randomized cross-over pharmacokinetic study comparing verapamil 120 mg, conventional tablets administered twice daily and verapamil 240 mg sustained release tablets once daily was performed in 12 patients with essential hypertension. After frequent blood sampling, analyses of verapamil and norverapamil were made with high pressure liquid chromatography. The absorption rate of the sustained release formulation was significantly slower than for the conventional formulation. Also the mean residence time was significantly longer for the sustained release tablet. It can be concluded that verapamil sustained release tablets meet with the following requirements for these formulations: (1) a slower absorption with an acceptable bioavailability relative to conventional tablets (89%); (2) no initial high peak concentration; (3) little fluctuation in the plasma concentration compared to the conventional formulation; (4) no differences in the elimination half lives for the two formulations; (5) maintenance of a therapeutic plasma level for a longer period of time than for the conventional formulation; (6) no increase in unwanted side effects.     

Sustained-release and instant-release verapamil in treatment of angina pectoris

Summary The efficacy of a sustained-release preparation of verapamil (verapamil-IR) has been compared with that of a conventional instant-release formulation (verapamil-IR) in 10 patients with stable angina pectoris treated for 3 weeks with both preparations.The diurnal serum concentrations of verapamil and norverapamil did not differ significantly during treatment with verapamil-IR 120 mg t.i.d. and verapamil-SR 360 mg once daily, but verapamil-SR 240 mg produced significantly lower serum concentrations. The differences did not affect the exercise capacity or the occurrence of ST-segment depression during maximal exercise.Verapamil-SR was well tolerated. A multiple instant-release dosage regime can now be replaced by once daily administration of the sustained-release preparation.     

Effect of controlled-release metoprolol on blood pressure and exercise heart rate in hypertension: A comparison with conventional tablets

In a double-blind study with parallel groups a new controlled-release (CR) formulation of metoprolol¹, 100 mg once daily, was compared with conventional metoprolol tablets, 100 mg once daily, in 27 patients with primary hypertension.Exercise tests on a bicycle ergometer were undertaken 24 h after intake of the last dose of the drug following a four-week placebo run-in period and after four weeks of active treatment.     

Transdermal clonidine as an adjunct to enalapril: an evaluation of efficacy and patient compliance.

This four-center, 20-week, open-label study evaluated transdermal clonidine as an adjunct to enalapril 10 mg daily and demonstrated patterns of compliance. Seventy-four mildly to moderately hypertensive patients (mean seated blood pressure, 150/101 mm Hg) received enalapril 10 mg once daily as initial monotherapy. In 66 patients, the seated diastolic blood pressure remained greater than or equal to 90 mm Hg at the trough blood levels of enalapril. Transdermal clonidine (3.5 cm2, 7.0 cm2, or 10.5 cm2, equivalent to 0.1 mg, 0.2 mg, and 0.3 mg clonidine/day, respectively) then was added as needed to achieve blood pressure control. Forty-eight patients achieved diastolic blood pressures less than 90 mm Hg on concomitant therapy; 44 patients completed 8 weeks of maintenance dosing with a mean blood pressure of 134/85 mm Hg. Oral compliance, as measured by an electronic device that was actuated each time the medication vial was opened, varied from 48 to 140%. Compliance with the transdermal clonidine regimen was excellent; the patch was worn as directed during 96% of the patient-weeks of therapy. The authors conclude that blood pressure can be controlled by a combination of transdermal clonidine and enalapril in patients that do not adequately respond to enalapril monotherapy. Patients poorly complying with oral regimens may be candidates for a trial of transdermal clonidine monotherapy.     

Conventional and controlled release diltiazem

Diltiazem CR tablets 120 mg b.i.d. for 1 week were compared with plain tablets 60 mg q.i.d. in 13 healthy male volunteers in a study of pharmcokinetic variables. Their antianginal efficacy was also compared in 23 patients with stable angina pectoris who were already on metoprolol. Both studies were of randomised, cross over design, and the clinical study was double blind.The pharmacokinetic variables of the two formulations were very similar except for the longer t_max of 4.4 h for diltiazem CR in comparison to 2.9 h for the plain tablets. The mean relative bioavailability of diltiazem CR in comparison with plain tablets was 1.14.The clinical study showed that after four weeks on diltiazem CR 120 mg b.i.d. or diltiazem plain tablets 60 mg q.i.d. in addition to metoprolol, there were significant decreases in weekly anginal attacks from 11 to 5 attacks/week, the number of nitroglycerin tablets consumed from 6 to 3 tablets/week, and an increase in the maximum workload from 116 to 126 and 123 W for diltiazem CR and plain diltiazem tablets, respectively, as compared to placebo. Five of the patients were angina free during diltiazem treatment. No difference in antianginal efficacy between the two preparations was seen. It was concluded that CR 120 mg b.i.d. appears bioequivalent to plain diltiazem tablets 60 mg q.i.d.     

Development of sustained release gastroretentive drug delivery system for ofloxacin: in vitro and in vivo evaluation

Sustained release (SR)-gastroretentive dosage forms (GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new strategy is proposed for the development of gastroretentive dosage forms for ofloxacin preferably once daily. The design of the delivery system was based on the sustained release formulation, with floating and swelling features in order to prolong the gastric retention time of the drug delivery systems. Different polymers, such as psyllium husk, HPMC K100M, crospovidone and its combinations were tried in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and in vitro drug release profile. It was found that dimensional stability of the formulation increases with the increasing psyllium husk concentration. It was also found that in vitro drug release rate increased with increasing amount of crospovidone due to the increased water uptake, and hence increased driving force for drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. In vivo studies were carried out for the optimized formulation in 24 healthy human volunteers and the pharmacokinetic parameters of developed formulations were compared with the marketed once daily (Zanocin) formulation. Based on the in vivo performance in a parallel study design in healthy subjects, the developed formulation shows promise to be bioequivalent to the marketed product (Zanocin). The percent relative bioavailability of developed formulation was found to be 97.55%.     

High sensitivity of chicken's skeletal muscle sarcoplasmatic reticulum to effects of diltiazem or verapamil on calcium uptake and release

In this study, the effects of two different calcium channel blockers, diltiazem and verapamil on calcium uptake and release from the membrane of heavy sarcoplasmic reticulum (SR) of chicken skeletal muscle were investigated. A fluorescent chelate probe technique was employed to determine calcium movement through the SR. Chlortetracycline was used as a fluorescent indicator which is able to penetrate the membrane, bind to the calcium on the inner face of the membrane and show an increase in fluorescence intensity when calcium uptake occurs. Addition of tris-ATP to the microsomes caused ATP-induced calcium uptake in a concentration dependent manner with half-maximal calcium uptake around 0.126 mM. Pretreatment of the medium containing sarcoplasmic reticulum with different concentrations of diltiazem or verapamil followed by added tris-ATP resulted a significant decrease in the fluorescence intensity of chlortetracycline, showing that these calcium channel blockers can diminish ATP-induced calcium uptake in a concentration-dependent manner. The maximum fluorescence intensity of tris-ATP falls to 50% in the presence of 1.75 microM diltiazem and 25 nM verapamil. In addition, diltiazem and verapamil can significantly induce rapid calcium release from the membrane of sarcoplasmic reticulum in a concentration-dependent manner. Therefore, membrane-bound or sequestered calcium in the sarcoplasmic reticulum may be targeted by these two calcium channel blockers in chicken skeletal muscle. Chicken SR is about 1000 times more sensitive to the effects of diltiazem on Ca2+ uptake and release than rabbit SR as shown previously.     

Once daily administration of a beta-blocker in hypertension.

In 156 patients in general practice, a slow release formulation of oxprenolol given once daily was substituted for conventional beta-receptor-blockers given two or three times daily. At the end of eight weeks there was a significant improvement in blood pressure control which was thought to be due to improved patient compliance. There was also a reduction in the frequency and severity of side-effects which was not drug specific but could be partly explained by the reduction in blood pressure. As 77 percent of the patients considered the once daily dose in a calendar pack to be helpful, simplification of dosage was thought to be an important factor in improving patient compliance, which resulted in better blood pressure control without an increase in unwanted effects.