Formulations Of Nifedipine Research Articles

The efficacy and safety of once-daily nifedipine: the coat-core formulation compared with the gastrointestinal therapeutic system formulation in patients with mild-to-moderate diastolic hypertension

The efficacy and safety of two sustained-release formulations of nifedipine, the coat-core system (NIF CC) and the gastrointestinal therapeutic system (NIF GITS), were examined in 228 patients with mild-to-moderate essential hypertension in this 16-week, multicenter, randomized, double-blind study. The coadministration of food affects the nifedipine pharmacokinetics with differing magnitudes for the two formulations. To evaluate drug safety under the most rigorous circumstances, all medication was given with food. After a 4-week placebo lead-in period, eligible patients were randomized to a parallel-group treatment period of either NIF CC or NIF GITS, 30 mg daily with food for 4 weeks, followed by forced titration to nifedipine 60 mg daily for an additional 4 weeks. For the final 4-week period, half of the patients receiving each formulation were switched to the alternate formulation at a dose of 60 mg daily. Within treatment groups, all four blood pressure variables (systolic and diastolic measurements for both trough and 24-hour periods) demonstrated significant reductions ( P < 0.05) from baseline (established after the placebo lead-in period) for both formulations at every subsequent visit and end point. When comparing the two formulations, the mean change from baseline in 24-hour systolic and diastolic blood pressure measurements, determined by using ambulatory monitoring, was not statistically different for both doses ( P > 0.05). The mean change in trough blood pressure from baseline during the parallel-group treatment period was statistically significant in favor of NIF GITS for both the 30-mg and 60-mg doses ( P < 0.05). The treatment-emergent adverse-event rates for both formulations were similar during the parallel-group period, with the exception of dizziness, which was higher for patients receiving NIF CC. Both formulations were well tolerated and reduced blood pressure over the 24-hour dosing interval even when coadministered with food. When half of the patients receiving NIF GITS 60 mg daily were randomly crossed over to NIF CC 60 mg daily, there were no significant changes in either the trough or 24-hour mean blood pressure measurements ( P > 0.05), adverse events, or dropout rates. When patients receiving NIF CC 60 mg were crossed over to NIF GITS 60 mg daily, they exhibited no significant change in diastolic blood pressure ( P > 0.05). This study demonstrated that when given with food, both NIF CC and NIF GITS reduce 24-hour mean blood pressure measurements similarly. Although NIF GITS exhibited a greater reduction in the trough blood pressure, patients could be crossed over from NIF GITS 60 mg daily to NIF CC 60 mg daily without any change in dose, blood pressure response, or adverse reactions.

Determination of nifedipine in human plasma by high performance liquid chromatography using column-switching technique

A highly sensitive reversed-phase HPLC method has been developed for the determination of nifedipine in human plasma with electrochemical detection. A liquid-liquid extraction procedure is used in sample preparation with an average extraction recovery of 75%. Removing the highly lipophilic plasma components using a special column switching technique reduced the duration of the HPLC measurement from 30 to 9 min. The method is applicable for the pharmacokinetic characterization and bioavailability study of a sustained-release (retard) formulation of nifedipine and for human drug monitoring as it is indicated by the validation of the analysis method. The assay gave a linear response over the concentration range 2.5–50 ng/ml. All the validation parameters are within the internationally required limits.

Effects of nifedipine coat-core compared with nifedipine retard at trough. A clinical study with exercise tests in patients with stable angina pectoris

The effect of two formulations of nifedipine in patients with angina pectoris was compared in a placebo run-in, randomized, crossover trial. After 2 weeks of placebo twice daily, 36 patients were randomized to receive either nifedipine retard 20 mg twice daily (R40) or nifedipine coat-core 60 mg once daily (CC60), double-dummy for 2 weeks. Six patients withdrew, 3 because of adverse events and 3 because of technical reasons. Time to 0.1 mV ST-depression and exercise tolerance time were assessed at baseline and at weeks 2, 3, and 4 in the double-blind phase. Frequency of angina attacks and nitroglycerine (NTG) consumption were recorded in weekly patient diaries. Trough (12 and 24 hours after drug intake) effects after 2 weeks of double-blind treatment showed equivalency between the two formulations in time to onset of 1 mm ST-segment depression and in duration of exercise. The number of anginal attacks and amount of NTG consumption was lower in the CC60 group. Analysis of long-term electrocardiogram monitoring showed no effect on ischemic events by either formulation, nor was there a difference between the two formulations. Patient compliance was high throughout the study. Although more adverse effects were observed with the CC60 formulation, CC60 appears to be equally effective as the R40 formulation. The higher occurrence of adverse effects in patients using CC60 tablets indicates that treatment should preferably start with a lower dosage to diminish the initial vasoreactions to the drug.

The 24-Hour Efficacy of a New Once-Daily Formulation of Nifedipine

Nifedipine GITS (Gastro-Intestinal Therapeutic System) is a recently launched long-acting formulation of nifedipine. The aim of the Italian Nifedipine GITS Study was to determine the duration of the antihypertensive effect of once-daily nifedipine GITS in outpatients with essential hypertension. After a 2-week placebo run-in period, 126 patients with mild to moderate essential hypertension (diastolic BP95 to 114mm Hg) were randomised to receive nifedipine GITS 30mg (n = 42), nifedipine GITS 60mg (n = 42) or placebo (n = 42), once daily in a double-blind fashion for 4 weeks. At the end of the run-in and treatment periods, ambulatory BP monitoring was performed (Spacelabs 90202 or 90207 device) to provide regular 15-minute BP readings for 24 to 36 hours. In the 81 patients with at least 24 hours of valid ambulatory BP data, the average systolic and diastolic BP changes after treatment with nifedipine GITS 30mg (n = 25), nifedipine GITS 60mg (n = 28) and placebo (n = 28) were -16.5/-10.8, -16.3/-10.0 and +0.4/+0.9mm Hg, respectively. BP changes with nifedipine GITS differed significantly (p < 0.01) from those with placebo. Heart rate was not significantly altered by nifedipine GITS. The effects of nifedipine GITS and placebo on ambulatory BP 24 hours and 36 hours after the last dose were evaluated in 56 patients with complete 36-hour ambulatory BP profiles. After 24 hours, both doses of nifedipine GITS caused significant (p < 0.01) reductions in systolic and diastolic BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Application of Flow-Through Dissolution Method for the Evaluation of Oral Formulations of Nifedipine

AbstractThe drug release characteristics of three oral formulations (one conventional and 2 extended-release) of nifedipine were evaluated using a flow-through apparatus. The experiments were conducted for 4 to 24 hours using water or phosphate buffer (0.05 or 0.1 M; pH 7.4) with or without solubilizing agent, Tween, as a dissolution medium at a flow rate of 12.5 mL/min. The drug concentrations were determined using an HPLC method based on ratios of peak heights corresponding to UV absorbances at 254 nm for nifedipine and nitrendipine (internal standard). Dissolution characteristics in various media correspond to the nifedipine solubility in the medium. Peak nifedipine concentrations with 0.05 M phosphate buffer containing 0.5% Tween were significantly higher than those in the medium without Tween (21.5±1.0 vs 8.3±0.2 μg/mL, p c 0.001). Using a 0.05 M phosphate buffer with no Tween, the products tested showed distinct dissolution profiles representative of the respective formulation type. The conventional...

Effect of 2-hydroxypropyl-beta-cyclodextrin on crystallization and polymorphic transition of nifedipine in solid state.

The glassy state of nifedipine (NP) was prepared in the absence and presence of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and its crystallization and polymorphic transition behavior was investigated by differential scanning calorimetry (DSC) and powder X-ray diffractometry. In DSC thermograms, the glassy NP exhibited an endothermic peak at 48 degrees C representing the glass transition of NP, an exothermic peak at 105 degrees C for the crystallization to a metastable form of NP (Form B), an exothermic peak at 125 degrees C for the polymorphic transition of Form B to a stable form of NP (Form A), and an endothermic peak at 171 degrees C for the melting of Form A. The powder X-ray diffractogram of Form B was apparently different from that of Form A. In the presence of HP-beta-CyD, the exothermic peak at 125 degrees C for the Form B to A transition disappeared and a new endothermic peak appeared at 163 degrees C. This new peak was ascribed to the melting of Form B, and the conversion of Form B to Form A was significantly suppressed in HP-beta-CyD matrix. Upon storage at 60 degrees C, the glassy NP was converted to Form A with an activation energy of 18 kcal/mol. The apparent dissolution rate of the NP/HP-beta-CyD (molar ratio 1:1) increased in the order of glassy NP < Form A < Form B, because the glassy NP was readily converted to Form A upon contact with water, resulting in a lower dissolution rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of antihypertensive drugs given once a day

A large number of antihypertensive drugs have been approved for administration once or twice a day, but no standardized evidence is required to demonstrate that the reduction in blood pressure is sustained over 24 h. To test the validity of claims of a long duration of action for second-generation calcium antagonists. Literature search. FLAWS IN REPORTED STUDIES: Most studies relied on ambulatory blood pressure monitoring. However, several reports were difficult to interpret because (1) the study was not blinded or random; (2) the statistical analysis was inappropriate for the study design; (3) analyses were confined to the means of 24-h, daytime and night-time blood pressure; (4) there was no baseline adjustment or formal statistical testing; (5) patients were subdivided into responders and non-responders after treatment; (6) there was no specified time frame linking drug intake to the observed antihypertensive effects. CLAIMS NOT SUBSTANTIATED: The authors of the articles reviewed concluded that amlodipine, nitrendipine and modified (slow-release) formulations of diltiazem, isradipine, nifedipine and verapamil reduced both conventional (clinic) and the 24-h blood pressure levels. In some studies separate results were presented for the daytime (awake) and night-time (sleeping) periods; some investigated the reduction in blood pressure at the end of the dose interval; and some compared the diurnal blood pressure profiles with different drug treatments. However, these reports gave discrepant results, suggesting that at least under certain study conditions the effect of nitrendipine and of slow-release diltiazem, isradipine and nifedipine did not give full 24-h cover with a single daily dose. We conclude that the interpretation of studies on long-acting antihypertensive agents using ambulatory blood pressure monitoring would be easier if the same standards were applied as required in clinical studies using conventional blood pressure measurements.

Use of Calcium Channel Antagonists for cardiovascular disease: This CE program reviews the role of calcium channel antagonists in managing certain diseases and compares agents

Until recently, only three calcium channel antagonists--verapamil, diltiazem and nifedipine--were available for managing cardiovascular disorders such as hypertension and ischemic heart disease. In the past few years, however, several dihydropyridine calcium channel antagonists, including nicardipine, isradipine, felodipine, nimodipine, and amlodipine, have been marketed. Others are currently awaiting FDA approval. In addition, bepridil, which belongs to a new class of calcium channel antagonists, has recently been marketed for refractory angina pectoris. Clinical uses of calcium channel antagonists have been expanded since the 1970s to include management of cardiovascular disorders such as supraventricular arrhythmias, CHF secondary to diastolic dysfunction, and myocardial reinfarction in selected patients. Calcium channel antagonists are also being investigated for prevention of atherosclerosis. Calcium channel antagonists are a heterogeneous group of pharmacologic agents. Differences in tissue selectivity are largely responsible for the variations in hemodynamic and electrophysiologic properties of these agents. Thus, their clinical uses and side effect profiles differ. These differences must be taken into consideration in the selection of the most appropriate agent for a specific indication. Potential advantages of some of the newer dihydropyridine calcium channel antagonists include less frequent dosing (amlodipine and isradipine) and little or no negative inotropic effect (nicardipine, felodipine, amlodipine, isradipine) compared with the prototype calcium channel antagonists. Additional clinical experience with these newer agents is required, however, before their role in the management of cardiovascular disorders can be fully delineated. The availability of sustained-release formulations of verapamil, diltiazem, nifedipine, felodipine, and nicardipine, as well as the recent marketing of calcium channel antagonists with relatively long half-lives (amlodipine and isradipine), makes once- or twice-daily dosing possible with most calcium channel blockers. However, selection of a particular agent will depend on several factors, including clinical efficacy, side effect profile, cost, and patient characteristics such as concomitant disease states and baseline hemodynamic status.

Single Dose and Steady-State Pharmacokinetic Profiles of Nifedipine GITS Tablets in Healthy Elderly and Young Volunteers

The pharmacokinetics of a once-daily extended-release nifedipine formulation [Gastro-Intestinal Therapeutic System (GITS)] was studied in 23 young males and 24 elderly male and female volunteers, after single and multiple dosing of 60mg nifedipine GITS tablets once daily for 7 days, in an open nonrandomised study. Serial blood samples for plasma nifedipine levels were drawn on days 1 and 7, and the pharmacokinetic profiles of the elderly and young volunteers were compared after both single and multiple dosing.

Preparation and evaluation of a controlled-release formulation of nifedipine using alginate gel beads.

Alginate gel beads containing nifedipine (NP) were prepared using a gelation of alginate with calcium cations. The dissolution and absorption of NP from alginate gel beads were evaluated as a controlled-release formulation of NP. The release of NP from alginate gel beads was affected by the composition of uronic acid in alginate, and by the NP content in alginate gel beads. NP absorption after oral administration to beagle dogs of alginate gel beads prepared by air-drying was significantly lower than that after the administration of NP powder alone, due to the limited release of NP from the alginate gel beads in the gastrointestinal tract. On the other hand, the alginate gel beads prepared by freeze-drying improved the absorption of NP because of the increasing disintegration of alginate gel beads with decreasing structural strength. However, this method had poor reproducibility, compared with air-dried alginate gel beads. The gel beads with added alginate propylene glycol ester (PGA) swelled and released calcium ions rapidly, even in water. This is because PGA gels weakly to the calcium cation. Consequently, it was observed that NP release from the PGA gel beads was highly accelerated compared to the release from alginate gel beads. The higher serum level of NP with large variance was obtained after the oral administration of the PGA gel beads. Gel beads consisting of a 1:1 ratio of PGA to alginate had intermediate characteristics between the alginate and PGA gel beads in respect to NP release and absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of gastric emptying in the absorption and metabolism of nifedipine given in a modified release pellet formulation

Abstract Plasma drug concentrations after a single oral administration of a modified release pellet formulation of nifedipine (20 mg) were measured in 18 healthy male volunteers after a light breakfast. The distribution of the radiolabelled pellets in the gastrointestinal tract was followed by gamma scintigraphy. The time for 50% gastric emptying ranged from 74 to 254 min (median 127 min), which is in good agreement with values reported for other multiparticulate formulations. In some subjects, periods of gastric stasis were observed, which may have been due to the inhibitory effect of nifedipine on gastric muscle contraction. Substantial spreading of the pellets occurred in both the small intestine and the colon, although in the majority of cases there was re-grouping at the ileo-caecal junction, prior to entry into the large bowel. The mean (±SD) C max was 36 ± 16 ng/ml (range 8.4–70.0 ng/ml), achieved 2–12 h post-dose (median t max 3 h). The pharmacokinetic data were consistent with twice daily dosage. Extended gastric residence may be an advantage for a modified release formulation. However, for nifedipine, a drug which undergoes a significant first-pass metabolism, slow gastric emptying may lead to a reduced systemic bioavailability as a result of the gradual presentation of the drug to enzymes on first pass through the intestine and liver.

Once-Daily Monotherapy of Hypertension with Nifedipine Sustained Release (20mg to 100mg)

A 2-centre double-blind randomised clinical study was conducted to evaluate the efficacy and tolerability of fixed doses of a new sustained release (SR) formulation of nifedipine compared with placebo in 207 patients with mild to moderate uncomplicated essential hypertension. After a 3- to 6-week placebo washout period, patients were randomised to receive either placebo, nifedipine SR 20mg, nifedipine SR 50mg or nifedipine SR 100mg. All doses were taken once daily in the morning without food. Among the 157 patients who completed 6 weeks of active therapy, the mean diastolic blood pressure reductions from baseline at 24 hours postdose were 5.3mm Hg, 9.3mm Hg, 9.7mm Hg and 11.1mm Hg in the placebo and nifedipine SR 20mg, 50mg and 100mg groups, respectively (p < 0.01). Nifedipine SR given in fixed doses once daily produced a relatively uniform antihypertensive effect throughout the 24-hour dosing interval, as determined by ambulatory blood pressure monitoring. All 3 dosages of nifedipine SR were generally well tolerated. A major finding of this study was the efficacy and safety of the once-daily 20mg dose.

Effectiveness of once-daily monotherapy with a new nifedipine sustained release calcium antagonist

Data from 2 separate multicenter, double-blind clinical studies following the same protocol, except for the selection of doses, were pooled to evaluate the efficacy and tolerability of fixed doses of a new sustained-release (SR) formulation of nifedipine compared with placebo in 388 patients wtth mild to moderate uncomplicated essential hypertension. After a 3–6 week placebo washout period, the patients were randomized to receive either placebo or nifedipine SR-20 mg (study I only), 50 mg, 100 mg, or 150 mg (study II only). Among the 278 patients who completed 6 weeks of active therapy, mean supine diastolic blood pressure reductions from pretreatment baseline were 5.9,9.3,9.2,111, and 13.2 mm Hg hi the placebo, 20-, 50-, 100-, and 150-mg groups, respectively. The reductions achieved in each of the nifedipine SR groups were statistically significant versus baseline values (p <0.001). All nifedipine-SR doses reduced supine systolic blood pressure significantly more than placebo (p <0.001). In addition, there was a significant linear relationship between the log of the dose and the blood pressure reduction (p <0.05). Automated ambulatory blood pressure recordings performed in 221 of the patients showed that the blood pressure was lowered evenly through the entire 24-hour dosing period. The doses that were effective and associated with the fewest adverse reactions were 20 mg and 50 mg once daily.

Hypertension in the elderly with a special focus on treatment with angiotensin-converting enzyme inhibitors and calcium antagonists

Age-related changes (e.g., decrease in plasma rental activity and total body potassium, increase in plasma catecholamines, volume depletion) need to be taken into account when selecting an airtihypertensive agent for the elderly patient. A number of large scale clinical trials (e.g., Systolic Hypertension in the Elderly Program, Veterans Administration Cooperative Study, European Working Party on High Blood Pressure in the Elderly) have demonstrated that antihypertensive therapy with diuretics substantially reduces cardiovascular mortality and stroke incidence. However, since diuretics, even potassium-sparing agents, may induce hypokalemia, newer antihypertensive agents (angliotensin-converting enzyme [ACE]inhibitors and calcium antagonists) may also be appropriate as first-line monotherapy for this patient population. ACE inhibitors are effective antihypertensive agents and are associated 3 with a lower rate of adverse effects than diuretics, β blockers, and centrally acting agents. Nevertheless, periodic monitoring of serum potassium, creatinine levels, and renal function is advisable. An important feature of calcium antagonists is that they lower blood pressure with no negative effect on serum lipids or glucose metabolism. Typically, they have few side effects, peripheral edema being the most commonly reported. A recent double-bind randomized study comparing a new sustained release nifedipine formulation and the ACE inhibitor lisinopril found the 2 drugs equivalent in efficacy with no differences in the rate of adverse events.

New Sustained-Release Nifedipine Formulation in Treatment of Essential Hypertension

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Sustained release nifedipine formulations: Moment, Modelling and Simulation as pharmacokinetic analysis approach

AbstractThe bioequivalence of three sustained release nifedipine formulations designed in this laboratory, was assayed in rabbits by comparing their plasma time profiles to a reference (AdalatR retard).The analysis of data was performed by using the statistical moments as a measure of drug release. Results show a slowler absorption rate in the experimental formulations than in AdalatR retard, and not differences in the absorption extent.The composed one-compartment model, described for humans, showed to be also succesfull for rabbits.

Hemodynamic comparison of two nifedipine formulations in patients with essential hypertension

The hemodynamic and humoral effects and trough-to-peak 24-hour blood pressure responses of 2 nifedipine formulations, capsules and continuous-release once-daily formulation tablets, were evaluated in 10 patients with mild to moderate essential hypertension. Both formulations reduced mean arterial pressure similarly from 120 ± 3 (baseline) to 107 ± 2 (p < 0.005) and 105 ± 2 mm Hg (p < 0.005) and total peripheral resistance index from 65 ± 9 (baseline) to 47 ± 4 (p < 0.05) and 45 ± 3 U/m 2 (p < 0.05), respectively. Renal, splanchnic and total forearm (including skin and skeletal muscle) blood flows were maintained or even increased slightly associated with reductions in regional vascular resistances. Decreases in renal, total forearm and skeletal muscle resistances were significant (p < 0.05) with the capsules, but the decrease was only significant in renal resistance with the long-acting tablets. Intravascular volume did not expand with reduction in arterial pressure. This antihypertensive effect was not related to baseline plasma renin activity levels or age. Nifedipine tablets provided a better control of mean arterial pressure (66%) than did capsules (44%).

Control angina with a new formulation of nifedipine

Control angina with a new formulation of nifedipine

Erratum to: Sustained Released Nifedipine Formulations

Erratum to: Sustained Released Nifedipine Formulations

Sustained Release Nifedipine Formulations

Nifedipine antagonises influx of calcium through cell membrane slow channels, and sustained release formulations of the calcium channel blocker have been shown to be effective in the treatment of mild to moderate hypertension and both stable and variant angina pectoris. Preliminary findings also indicate that these formulations are effective in the treatment of Raynaud's phenomenon and hypertension in pregnancy, and that they reduce the frequency of ischaemic episodes in some patients with silent myocardial ischaemia. The exact mechanism of action of nifedipine in all of these disorders has not been defined. However, its potent peripheral and coronary arterial dilator properties, together with improvements in oxygen supply/demand, are of particular importance. A major goal of sustained release therapy is to permit reductions in the frequency of nifedipine administration, preferably to once daily, and thus improve patient compliance. Two new once-daily formulations--the nifedipine gastrointestinal therapeutic system (GITS) and a fixed combination capsule comprising sustained release nifedipine 20 mg and atenolol 50 mg--have exhibited marked antihypertensive efficacy. The GITS preparation has also been used effectively in the treatment of stable angina pectoris, and both formulations appear to be well tolerated. Sustained release nifedipine formulations are generally better tolerated than their conventionally formulated counterparts, particularly with regard to reflex tachycardia. Adverse effects seem to be dose related, are mainly associated with the drug's potent vasodilatory action, and include headache, flushing and dizziness. Generally, these effects are mild to moderate in severity and transient, usually diminishing with continued treatment. Thus, sustained release nifedipine formulations are useful and established cardiovascular therapeutic agents which have demonstrable efficacy in various forms of angina, mild to moderate hypertension and Raynaud's phenomenon. Further, promising results shown by the nifedipine GITS formulation, with its advantage of once daily administration suggest that it is likely to become one of the preferred nifedipine formulations for the treatment of hypertension and the various forms of angina.