Sustained-release Propranolol Research Articles

Liqui-Mass Technology as a Novel Tool to Produce Sustained Release Liqui-Tablet Made from Liqui-Pellets.

The Liqui-Mass technology (also known as Liqui-Pellet technology) has shown promising results in terms of enhancing the drug release rate of water insoluble drugs in a simplistic approach. However, there is no current study on sustained-release formulation using the Liqui-Mass technology. In this study, an attempt was made to produce a sustained-release Liqui-Tablet for the first time using a matrix-based approach. The non-volatile co-solvent used in the investigation included Tween 80, Tween 20 and Kolliphor EL. The production of sustained-release propranolol hydrochloride Liqui-Tablet was successful, and data from the saturation solubility test and dissolution test did not show much difference among the mentioned non-volatile co-solvent. The best Liqui-Tablet formulation took 24 h for drug release to reach at around 100%. There seemed to be a synergistic retarding drug release effect when a non-volatile co-solvent and Eudragit RS PO were used together. The increase of Eudragit RS PO concentration increased the retardant effect. Kinetic drug release analysis suggests that the best formulation followed the Higuchi model. The flowability of pre-compressed Liqui-Tablet pellets had no issues and its size distribution was narrow. Liqui-Tablet was generally robust and most formulations passed the friability test. The study revealed that Liqui-Mass technology can be employed to sustain drug release.

In vitro and In vivo Evaluation of Propranolol Microspheres Loaded Buccal Gel

The selected propranolol microsphere formulation, S6 was employed for gel formulation with a variety of polymers like Carbopol 934, HPMC and Sodium CMC by mechanical stirring method in order to develop a sustained release propranolol microspheres containing bioadhesive gel. The prepared bioadhesive gels were evaluated for pH, viscosity, %drug content, in vitro drug release studies, bioadhesion, ex vivo permeation studies, accelerated stability and in vivo bioavailability studies. From all the above studies FG3 was found to be optimized formulation. In vitro experiments indicated a sustained release of 98.92% over 12 h and an acceptable bioadhesion quality for formulation FG3. Optimized formulation was characterized for FTIR, SEM and stability studies and found to be stable. Propranolol Optimized formulation exhibited significant increased bioavailability in vivo when compared with marketed tablet. The drug release from the optimized formulation follows zero order kinetics with anomalous Non-fickian diffusion. In vivo studies revealed that Propranolol Optimized formulation FG3 exhibited significant increased bioavailability when compared with marketed product, due to reduced first pass metabolism, when it is administered by the buccal route. Hence, it can be concluded that the formulation FG3 has potential to deliver Propranolol in a controlled and constant manner for prolong period over other formulations and can be adopted for a successful delivery of propranolol for buccal use.

Management of ventricular arrhythmias in suspected channelopathies.

Although structural heart disease remains the predominant substrate for ventricular arrhythmia, channelopathies including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndrome (ERS) are less common but important contributing entities. These etiologies require specific therapies potentially contrary to empirical management of arrhythmias associated with structural heart disease. Conventional therapy including antiarrhythmic drug therapy may not only fail to resolve unstable arrhythmias but worsen them. Additionally, channelopathy patients with implantable cardioverter defibrillators (ICD) and arrhythmic storms represent a major challenge, and the acute care team needs to be cognizant of unique circumstances that require specific acute therapies beyond empirical advanced life support algorithm recommendations.1 Successful and considered acute management of ventricular arrhythmias is contingent on a number of variables, including knowledge of the cardiac substrate or potential substrate; form, mechanism, and precipitants of ventricular arrhythmias; and acute effect of potential therapies. In the longer term, an understanding of the natural history of the channelopathy along with the efficacy of long-term therapy will lead to superior outcomes. This review will present the risk of ventricular arrhythmias associated with these uncommon entities, the evolving understanding of the mechanism of arrhythmia, and the mechanistic basis of therapies along with a clinical approach to summarize the evidence pertaining to acute and long-term management. Patients with a prolonged QT interval are at risk of sudden cardiac death (SCD) due to Torsade de Pointes (TdP; Figure 1). Most patients with congenital LQTS are asymptomatic and diagnosed incidentally on electrocardiogram screening or following family screening. However, syncope, aborted SCD, or SCD may be the first presentation. Most arrhythmic events in congenital LQT1 occur during physical or emotional stress, at rest or in association with sudden auditory stimulation in LQT2, and during sleep or rest in LQT3 …

Optimization of sustained-release propranolol dosage form using factorial design and response surface methodology.

The purpose of this study was to develop propranolol extended release formulations containing hydroxypropylmethylcellulose (HPMC). The results indicate that the drug release from the tablet form containing a high amount of HPMC was incomplete, and avicel addition could increase the release percent at a later stage. In order to readily obtain an optimal formulation, response surface methodology and multiple response optimization utilizing a quadratic polynomial equation was used. The model formulations were prepared according to a factorial design. The effects of causal factors including the HPMC/drug ratio (X1) and avicel level (X2), on drug release were also measured. The drug release percentage at 1.5, 4, 8, 14 and 24 h were the target response and were restricted to not more than 25%, 35-50%, 55-70%, 75-90%, and 95-110%, respectively. The results showed that the optimized formulation provided a dissolution pattern equivalent to the predicted curve, which indicated that the optimal formulation could be obtained using response surface methodology. The mechanism of drug release from HMPC matrices tablets followed quasi-Fickian diffusion.

Development and evaluation of sustained-release propranolol wax microspheres

To obtain a sustained-release dosage form with a lack of gastric unwanted effects, wax microspheres containing propranolol (I) were prepared by a congealable dispersion microencapsulation technique. The effects of the process variables; type of wax, speed of emulsification, amount of drug loaded, type and amount of emulsifier, were studied on the entrapment efficiency, angle of repose, dissolution efficiency (DE), in-vitro drug release and mean particle size of (I) microspheres, by a factorial design. The results showed that changes in the amount of emulsifier (Tween), 0.04% and 0.08%, the type of Tween (80 and 20) and the wax type; beeswax or ceresine, caused a significant decrease in the entrapment efficiency. All the variables had an effect on the angle of repose and particle size of the (I) microspheres. The only significant parameter affecting the DE was the nature of the wax. The drug release in pH 6.8 was affected by all the variables except the amount of emulsifier. The formulation with a 0.25:4 ratio of drug:ceresine wax and 0.04% of Tween 80 in 600 rpm emulsification speed showed a suitable multiparticulate delivery system for the retarded dissolution of entrapped active ingredients, allowing absorption only in the intestinal tract.

Discordance between effects of anti-ischemic therapy on ambulatory ischemia, exercise performance and anginal symptoms in patients with stable angina pectoris

Objectives. We sought to define the extent to which the therapeutic efficacy of three single-drug regimens on ambulatory ischemia paralleled efficacy on other clinical manifestations of ischemia, specifically exercise test performance and anginal symptoms.Background. Some studies have shown that the presence and severity of ambulatory ischemia are predictive of anginal symptoms and exercise test performance, whereas other studies have not. Less is known about effects of antianginal treatment and whether response to therapy for one clinical manifestation reflects therapeutic responses for other clinical manifestations.Methods. We studied 50 patients in the Angina and Silent Ischemia Study who had documented coronary disease, an exercise test positive for ischemia, the presence of ambulatory and asymptomatic ischemia on ambulatory electrocardiographic (ECG) Holter monitoring and stable anginal symptoms. Patients received maximally tolerated dose of sustained release propranolol (mean 293 mg/day), sustained release diltiazem (mean 350 mg/day), nifedipine (mean 79 mg/day) and placebo, each for 2-week periods in a double-blind, crossover fashion. Patients' responses to treatment were assessed by 48-h ambulatory ECG monitoring, exercise test (standard Bruce protocol) and diaries of angina. Levels of efficacy for each agent and for each clinical measure were compared using Spearman correlation analysis.Results. With placebo there was no correlation among the frequency of ischemic episodes by ambulatory ECG monitoring, exercise time to 1.0-mm ST segment depression or frequency of anginal episodes. Furthermore, for a given patient the efficacy of each active medication in reducing ambulatory ischemia was not correlated with response in anginal symptoms or exercise test performance (r = -0.21 to 0.24, p = NS). Within each of these clinical measures, efficacy of one drug was more strongly correlated with efficacy of another drug (r = 0.64 to 0.81 for ambulatory ischemia, 0.48 to 0.56 for exercise test performance and 0.16 to 0.54 for anginal symptoms).Conclusions. Different measures of ischemia, specifically ambulatory ischemia assessed by ambulatory ECG monitoring, exercise performance on exercise test and anginal symptoms, are independent. Efficacy for each clinical end point must be assessed separately when considering response to drug treatment.

The influence of antihypertensive agents on circadian rhythms of blood pressure and heart rate in patients with essential hypertension.

The effects of once-daily administration of calcium (Ca) channel blockers, beta-blockers and and angiotensin-converting enzyme (ACE) inhibitors on circadian rhythms of blood pressure (BP) and heart rate (HR) were studied using the cosinor method. Sixty-two recruited patients with essential hypertension (WHO stage I or II) were divided into three groups based on the class of administered drugs. In the Ca channel blocker group (n = 37, age 54 +/- 9.0 years), 18 patients were given YM 730 at a mean dose of 11 +/- 4.0 mg/day (mean +/- S.D.), 8 were given nitrendipine (11 +/- 6.7 mg/day), and 11 were given nisoldipine (8 +/- 6.4 mg/day). In the beta-blocker group (n = 15, age 42 +/- 13.5 years), 13 patients were given atenolol (44 +/- 11.0 mg/day), 1 was given nadolol (30 mg/day), and 1 was given sustained-release propranolol (60 mg/day). In the ACE inhibitor group (n = 10, age 56 +/- 8.7 years), 7 patients were given enalapril (6 +/- 2.8 mg/day), and 3 were given lisinopril (20 mg/day). Ambulatory BP monitoring (ABPM) was performed before and during treatment. Mean arterial pressure (MAP) and HR were monitored under ambulatory conditions every five minutes for 24 hr with a finger volume oscillometric device. In all three groups, the mesor of MAP decreased significantly, while the amplitude and acrophase did not change during treatment. beta-Blockers reduced the amplitude as well as the mesor of HR. Ca channel blockers increased the amplitude of HR without influencing the mesor. ACE inhibitors had no effect on the circadian rhythm parameters of HR. These results suggest that Ca channel blockers, beta-blockers and ACE inhibitors lowered BP throughout the day without changing the circadian BP rhythm. However, the three drug classes may have different influences on the autonomic nervous system that regulates circadian cardiac rhythm.

Cilazapril

Cilazapril is a new nonthiol group containing angiotensin converting enzyme (ACE) inhibitor, which was designed by a computer-modelling technique in order to obtain a compound with high specificity and selectivity for the target enzyme. Cilazapril has been investigated in more than 4000 patients with all degrees of hypertension, as well as in the special patient groups such as the elderly, renally impaired, and patients with concomitant diseases, such as congestive cardiac failure or chronic obstructive pulmonary disease. In these studies, the blood pressure-lowering effect of a single daily dose has been clearly established. The tolerability profile is similar to other frequently prescribed antihypertensive drugs, such as sustained-release propranolol, enalapril, captopril, atenolol and hydrochlorothiazide. Recently, investigations have revealed that cilazapril, in addition to its blood pressure-lowering abilities, can moderate the proliferative response seen in vessels after vascular injury caused by techniques such as ballooning. Clinical studies to verify these findings are currently ongoing.

Decreased Absorption as a Possible Cause for the Lower Bioavailability of a Sustained-Release Propranolol

The influence of sustained absorption on the oral availability of propranolol (P) and the metabolic disposition of P were investigated by obtaining the partial metabolic clearances (CLm) following long-acting P (LA) dosing in comparison with the conventional propranolol tablet (CP). Ten healthy volunteers were given a single oral dose of an LA capsule (60 mg) and CP (20 mg × 3) using a crossover design. Blood and urine samples were collected over 24- and 48-h postdose periods, respectively. Concentrations of P, propranolol glucuronide (PG), 4-hydroxypropranolol (4P), 4-hydroxypropranolol glucuronide (4PG), 4-hydroxypropranolol sulfate (4PS), and naphthoxylactic acid (NLA) were determined by HPLC with fluorescence and UV detection. Significant differences were observed between LA and CP in the area under the plasma concentration–time curves (AUCs) for P, PG, and NLA and in the amounts excreted into urine (Ae) for all measured metabolites (i.e., PG, 4P, 4PG, 4PS, and NLA). The parallel decrease of the AUC for P and the excreted amounts of all measured metabolites following LA dosing resulted in partial metabolic clearances (CLm) and renal clearances (CLr) for P and its metabolic that were similar to those observed for CP. Therefore, the hepatic metabolism of P would not be affected by the slower absorption at a single oral dose of 60 mg. These results indicate that the poor absorption of P from the gastrointestinal tract might be one of the factors causing the low bioavailability of P observed after administration of the sustained-release formulation.

The nifedipine gastrointestinal therapeutic system in the treatment of hypertension

As the number of antihypertensive agents increases, the choice of optimal therapy becomes more difficult. Certainly, hemodynamic derangements caused by the disease state as well as therapy must be considered. Patient convenience and quality of life are also issues that must be addressed. Preliminary experience suggests that the gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation of nifedipine is safe and efficacious in the treatment of hypertension. In 1 study, nifedipine GITS was compared with sustained-release propranolol in patients with mild to moderate hypertension already receiving diuretics. Using a 2-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 31) in doses of 30, 60 or 90 mg once daily, or sustained-release propranolol (n = 32) in doses of 80, 160 or 240 mg once daily. Previous diuretic therapy was continued. Sitting and 5-minute standing blood pressure and heart rate measurements were obtained 24 hours after dosing. At the end point of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p < 0.001) in the sitting and standing positions. Nifedipine GITS was more effective than sustained-release propranolol in reducing standing (p < 0.005) and sitting (p < 0.001) systolic blood pressure and sitting diastolic blood pressure (p < 0.02). Sustained-release propranolol caused a greater reduction in standing (p < 0.001) and sitting (p < 0.0006) resting heart rate than nifedipine GITS. Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension already receiving diuretics, and may be more effective than sustained-release propranolol and better tolerated than conventional nifedipine capsule treatment.

Hollow fibers as an oral sustained-release delivery system using propranolol hydrochloride.

Fibers were spun by the downward configuration of the wet spinning technique. This configuration is capable of encapsulating nonspherical and/or coarse particles. We examined encapsulation of propranolol hydrochloride and the ability of the fibers to act as a sustained-release delivery system for propranolol hydrochloride as a model drug. The U.S.P. basket dissolution method was used to evaluate the in vitro drug release kinetics and the effect of the aspect ratio (length/diameter) on drug release. For in vivo evaluation, selected fibers were administered to dogs in gelatin capsules. The results of these in vitro and in vivo studies were compared to those obtained with a marketed sustained-release propranolol product (Inderal LA). The fiber delivery system provided a sustained-release profile of plasma propranolol concentrations similar to that observed with Inderal LA.

Multicenter comparison of the nifedipine gastrointestinal therapeutic system and long-acting propranolol in patients with mild to moderate systemic hypertension receiving diuretics: A preliminary experience

The efficacy and safety of nifedipine in a gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation was compared with long-acting propranolol in 49 patients with mild to moderate hypertension already receiving diuretics. Using a two-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 24) in doses of 30 mg, 60 mg, or 90 mg once daily; or long-acting propranolol (n = 25) in doses of 80, 160, or 240 mg once daily. Previous diuretic therapy was continued. Sitting and five-minute standing blood pressure and heart rate measurements were made 24 hours after dosing. At the endpoint of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p <0.001) in the sitting and standing positions. Nifedipine GITS was more effective in lowering standing systolic blood pressure than was propranolol (p <0.02). Propranolol caused a greater reduction in resting heart rate than did nifedipine GITS (p <0.003). Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension who are already receiving diuretics, may be more effective than sustained-release propranolol, and may be better tolerated than conventional nifedipine capsules.

Nonlinear Pharmacokinetics of Unbound Propranolol after Oral Administration

After multiple oral doses, propranolol has been reported to accumulate to a greater degree than expected based on its terminal elimination rate constant and dosage interval. To determine whether the decrease in presystemic elimination can be attributed solely to a decrease in unbound intrinsic clearance or possibly a decrease in unbound fraction, we studied the pharmacokinetics of unbound propranolol in nine healthy subjects who were given 160mg of regular or sustained-release propranolol orally as single doses, and once daily for 7 d. Unbound propranolol concentrations were calculated by HPLC and equilibrium dialysis on each serum sample. With regular propranolol, the mean unbound oral clearance (CLorat) decreased 29%, from 503 ± 281 after a single dose to 359 ± 143mL/min/kg at steady state (p<0.05). Similarly, CLoral decreased 33% with sustained-release propranolol from 1077 ± 514 to 721 ± 385mL/min/kg (NS). The corresponding accumulation ratios for regular and sustained-release propranolol were 1.39 ± 0.49 and 1.61 ± 0.81, respectively (NS). Therefore, the mean bioavailability of sustained-release relative to that of regular propranolol was 0.52 ± 0.23 and 0.54 ± 0.17 for single doses and at steady-state, respectively. The percent unbound of propranolol ranged from 6.8 to 14.0 with an average of 10.1. Neither the percent unbound nor α1-acid glycoprotein (AAG) serum concentrations were statistically different between single and multiple doses. The binding ratio was significantly correlated to AAG concentration (r=0.776, p<0.05). The data support a decrease in unbound intrinsic clearance of propranolol with no change in unbound fraction, leading to an increase in bioavailability at steady state.

Propranolol pharmacokinetics and pharmacodynamics after single doses and at steady-state.

The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.

Nicardipine vs propranolol in the treatment of essential hypertension: effect on total body elemental composition

1 Nicardipine 30 mg three times daily was compared with sustained-release propranolol 160 mg once daily in a double-blind parallel trial of essential hypertension in general practice. 2 Both drugs caused similar sustained reduction of lying and standing systolic and diastolic pressures. 3 While propranolol significantly lowered heart rate, no changes were seen with nicardipine; nicardipine slightly but significantly increased QTc interval. 4 The overall side-effect burden was similar with the two drugs, although the pattern of events differed. 5 With neither agent were there significant changes, at the twelfth week of treatment, in the total body composition of sodium, potassium, chlorine, calcium, phosphorus or nitrogen.

Stable oral availability of sustained release propranolol when co‐ administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions.

A study was made of the influence of hydralazine on the oral availability of a sustained release formulation of propranolol (Inderal LA). Sustained release propranolol 160 mg was given orally either alone or in combination with oral hydralazine 25 mg on separate occasions to six healthy volunteers. Blood and urine samples were collected post-dosing over 34 h. Peak concentrations of propranolol, time to peak and area under the plasma concentration-time curve (AUC) were not altered by co-administration of hydralazine with sustained release propranolol. Similarly, there was no change in recovery of 11C-labelled propranolol and metabolites in those individuals to whom tracer label was given. These results contrast with previous reports of marked interaction between the conventional formulation of propranolol and hydralazine or food. Interactions were confirmed between hydralazine and conventional propranolol in three subjects who had been studied previously with sustained release propranolol. Analysis of metabolite profiles in one of these subjects established that the major metabolites do change under hydralazine stimulus. These results indicate that substrate delivery rates may determine presystemic drug interactions, suggesting capacity limitations of hydroxylation processes or short-term flow redistribution following hydralazine, resulting in functional shunting past the hydroxylation enzymes. These results exclude global or lasting enzyme inhibition by hydralazine or simple flow-sensitivity of presystemic clearance.

Pathophysiological mechanisms in essential hypertension

As the number of antihypertensive agents increases, the choice of optimal therapy becomes more difficult. Certainly, hemodynamic derangements caused by the disease state as well as therapy must be considered. Patient convenience and quality of life are also issues that must be addressed. Preliminary experience suggests that the gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation of nifedipine is safe and efficacious in the treatment of hypertension. In 1 study, nifedipine GITS was compared with sustained-release propranolol in patients with mild to moderate hypertension already receiving diuretics. Using a 2-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 31) in doses of 30, 60 or 90 mg once daily, or sustained-release propranolol (n = 32) in doses of 80, 160 or 240 mg once daily. Previous diuretic therapy was continued. Sitting and 5-minute standing blood pressure and heart rate measurements were obtained 24 hours after dosing. At the end point of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p < 0.001) in the sitting and standing positions. Nifedipine GITS was more effective than sustained-release propranolol in reducing standing (p < 0.005) and sitting (p < 0.001) systolic blood pressure and sitting diastolic blood pressure (p < 0.02). Sustained-release propranolol caused a greater reduction in standing (p < 0.001) and sitting (p < 0.0006) resting heart rate than nifedipine GITS. Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension already receiving diuretics, and may be more effective than sustained-release propranolol and better tolerated than conventional nifedipine capsule treatment.

Once daily administration of sustained release propranolol capsules in the treatment of angina pectoris

The effect of once daily administration of sustained release capsules of propranolol 160 mg was compared with treatment with standard 40 mg tablets four times daily, in eight patients with stable angina pectoris, in a four week, double blind crossover, random treatment-order trial. Clinical evaluation and submaximal bicycle ergometry were performed before propranolol therapy and on the last day of each treatment period. Serum propranolol concentration over a 24 hour period on those two days ranged from 34.4 to 65.5 ng/ml for the tablets, and 27.7–76.0 ng/ml for the capsules. The peak increase in heart rate on exercise fell from 59 beats per minute to 43 and 41 bpm following the tablets and capsules, respectively (p<0.05). The degree of ST segment depression decreased from 1.94 mm to 0.94 mm and 0.63 mm, respectively (p<0.05). Serum propranolol concentrations were significantly correlated with the reduction in peak heart rate (r=0.58, p<0.05), and in heart rate-pressure product (r=0.83, p<0.01). Clinical attacks and nitroglycerin requirements were equally reduced by both formulations. Sustained release capsules of propranolol 160 mg given once daily were as effective as standard 40 mg tablets given four times daily in the treatment of stable angina pectoris in patients requiring this dose range.

Raynaud's phenomenon in hypertensive dialysis patients taking a sustained-release propranolol formulation.

Five dialysis patients with residual hypertension were treated with a new sustained-release formulation of propranolol (160 mg per capsule) in a dosage of 1 to 2 capsules per day. Four of these patients developed persistent cold, numb, blue and clumsy fingers. The symptoms resolved when the drug was withdrawn.