Formulation Of Propranolol Research Articles

Pediatric Orally Disintegrating Tablets (ODTs) with Enhanced Palatability Based on Propranolol HCl Coground with Hydroxypropyl-β-Cyclodextrin.

Propranolol, largely prescribed as an antihypertensive and antiarrhythmic drug in pediatrics, is characterized by a bitter taste and an astringent aftertaste. Currently, the therapy requires crushing of tablets for adults and their dispersion in water many times a day, leading to loss of dosing accuracy, low palatability, and poor compliance for both patients and caregivers. This work aimed to exploit cyclodextrin complexation by cogrinding to develop orally disintegrating tablets (ODTs) endowed with reliable dosing accuracy, good palatability and safety, ease of swallowability, and ultimately better compliance for both pediatric patients and caregivers. Different formulation variables and process parameters were evaluated in preparing ODTs. The technological and morphological characterization and disintegration tests were performed according to official and alternative tests to select the ODT formulation based on the drug Hydroxypropyl-β-cyclodextrin (HPβCD) coground complex form containing Pearlitol® Flash as the diluent and 8% Explotab® as the superdisintegrant, which demonstrated the highest % drug dissolution in simulated saliva and acceptable in vitro palatability assessed by the electronic tongue, confirming the good taste-masking power of HPβCD towards propranolol. Such a new dosage form of propranolol could represent a valid alternative to the common extemporaneous preparations, overcoming the lack of solid formulations of propranolol intended for pediatric use.

CLINICAL ASPECTS OF DIFFERENT PHARMACEUTICAL FORMULATIONS OF PROPRANOLOL IN THE TREATMENT OF INFANTILE HEMANGIOMA

Infantile hemangiomas are one of the most common benign vascular tumors in infants and children.Because hemangiomas can resolve spontaneously, they usually do not require specific treatment unless theproliferation interferes with normal function or causes interference with the function of essential vital organs. Thereare several types of therapy, but in recent decades the use of propranolol has become more common due to itsexcellent effectiveness.The purpose of this paper is to analyze different pharmaceutical formulations of propranolol in the treatment ofinfantile hemangioma, including technological differences of the oral and topical pharmaceutical dosage forms ofpropranolol. The European Medicines Agency (EMA) has approved the commercially available oral propranololtherapy in the countries of the European Union, but this is not yet happened in our country. Recommendations tofollow and use the protocols for the oral application of propranolol in the treatment of this disease are difficult dueto the fact that this drug formulation is not registered in our country and patients are forced to obtain it fromcountries where it is registered.The use of syrup as an oral form of therapy has been clinically proven and has a high percentage of efficiency ininfantile hemangioma, but side effects such as sleep disturbance, bronchospasm, hypoglycemia, hypotension.The goal of this publication is to propose the most appropriate topical formulation of propranolol for external use ininfantile hemangioma through a review of relevant published data on the use of various pharmaceutical formulationsof propranolol in clinical studies and documents from the European Medicines Agency,In this paper, we used compilation and comparison methods, as most useful for a high-quality critical evaluation ofthe literature regarding problematic topics, in our case the pharmaceutical formulation of propranolol, the effect ofclinical treatment and the required legislation, and which have the potential to promote clearer, sharedunderstandings and accelerate advances in the research.Our results were focused on obtained and published data related to pharmaceutical-technological aspects ofproduction of topical formulations and the effect of clinical application, especially when it is necessary to defineexactly the amount of the released active compound from the topical form (cream, ointment or gel) and itsabsorption through the skin.Topical form of propranolol avoids the side effects of oral administrated propranolol, can help maintain a high levelof active ingredient in a local or focal region, and has an easy way of administration.The obtained research data showed that the topical application and penetration of propranolol through the skin isgood and has a lower and controlled systemic absorption. To achieve this, the choice of the formulation and theexcipients used are particularly important. Lipophilic formulations have limited release and penetration ofpropranolol. The best results are achieved by using a hydrophilic cream.After the research done, we can conclude that the production of topical formulations containing specific activecomponents with a strong systemic effect, such as propranolol, can be carried out in galenic laboratories or hospitalpharmacies. For this, already existing validated equipment and excipients that are readily available can be used.We believe that the use of topical pharmaceutical forms for local application, even in children such as the case ofpropranolol in infantile hemangioma, is justified, especially to the fact that so far no side effects have beenregistered even after long-term therapy.

Topical Formulations of Propranolol for Infantile Hemangiomas: Characteristics of Formulations and Three Cases of Infants Administered Topical Propranolol Cream.

Propranolol is used as the first-line treatment for infantile hemangiomas (IHs). As oral formulations can cause systemic adverse drug reactions (ADRs), we prepared topical propranolol formulations and evaluated their pharmaceutical profiles. We also present three cases of pediatric patients with IHs who were treated with the propranolol formulations. Propranolol cream (hydrophilic cream, 1, 3, and 5%) and gels (carboxyvinyl polymer, hydroxypropyl methylcellulose, gellan gum, 1%) were prepared. The in vitro skin permeability of these formulations was assessed using Franz-type diffusion cells. The pharmaceutical profiles, including propranolol content, pH, and ductility, of the propranolol creams were evaluated. For the stability test, similar pharmaceutical evaluations were performed after the creams were stored at 25 °C and 56% relative humidity for 3 months. We examined three patients treated with propranolol cream to investigate the clinical course of IH and adverse events after the propranolol cream was applied for 5-12 months. In the in vitro skin permeability assay, topical propranolol formulations made of hydrophilic cream and gellan gum permeated the most. The amount of propranolol that permeated increased with propranolol concentration. After storage for 3 months, no substantial changes were observed in any pharmaceutical profile. The IHs were discolored in all patients. Tumor size also decreased in some patients. Furthermore, no adverse events caused by propranolol cream were observed during application. In conclusion, propranolol cream can be prepared as a hospital formulation with adequate quality. Topical propranolol therapy is effective in reducing the incidence of systemic ADRs.

P51 Evaluating propranolol preparations for use in infantile haemangioma

AimTo evaluate oral liquid formulations of propranolol and to select the optimal preparation for use in Infantile Haemangioma.MethodFour oral liquid preparations of propranolol were considered:A – an alcohol-free suspension prepared as a ‘special’ (the current treatment of choice)B and C – generic solutions available in four different strengthsD – a French solution not marketed in the United Kingdom (UK)Preparations were evaluated against six criteria:Licensing statusEase of purchaseShelf lifeExcipientsEase of dosingCostResultsLicensing status: Preparation A is unlicensed and should not be used if a licensed product is suitable. Preparations B and C are licensed in children but not for Infantile Haemangioma. Preparation D has a European license for Infantile Haemangioma.Ease of purchase: Preparation A is made to order but has a short lead time. Preparations B and C are available from wholesalers. No current importer for Preparation D was found.Shelf life: The licensed preparations have 2–3 years shelf life. Preparation A has a 1 month shelf life.Excipients: All excipients were considered. Aspartame, ethanol, maltitol, methylhydroxybenzoate, propylhydroxybenzoate, propylene glycol, saccharin sodium and Sunset Yellow can all cause adverse effects. The excipient most likely to cause problems was propylene glycol. This is eliminated by both renal excretion and liver metabolism but, in infants, these processes are immature and accumulation occurs with resultant toxicity. Preparation A contains no propylene glycol and can be used in children of all ages. Levels in Preparations B and C are safe for use in children over 1 month.1 The propylene glycol content of Preparation D could not be ascertained. Preparation B contained ethanol. Levels were below safety limits2 but ethanol competes with propylene glycol for metabolism via alcohol dehydrogenase increasing the risk of propylene glycol toxicity.Ease of dosing: Dose volumes were calculated for a neonate (3.5 kg), a 6 month-old (7.6 kg) and a 1 year-old (9 kg). All preparations with strengths between 1 mg/ml and 3.75 mg/ml gave suitable dose volumes. Doses for Preparation D are expressed as propranolol base. In the UK, doses are expressed as propranolol hydrochloride. This could be confusing and lead to prescribing or dispensing errors.Cost: Preparation A was more expensive than B or C. The cost of Preparation D could not be established.ConclusionsAlthough Preparation D is licensed for Infantile Haemangioma, its use would be complicated by difficulties in obtaining supplies, likely cost and the risk of confusion between propranolol base and hydrochloride when prescribing and dispensing. Preparations B and C are suitable for use in children over 1 month of age. Preparation C is recommended because it contains less propylene glycol and no alcohol. Preparation A should only be used in children under 28 days. Using Preparation C instead of Preparation A gives the benefits that a licensed preparation is used, dispensing delays are reduced and costs are reduced.ReferencesEuropean Medicines Agency Committee for Human Medicinal Products (CHMP). Background review for the excipient propylene glycol, EMA/CHMP/334655/2013. [Internet]. 2014 [cited 30.3.19.]. Available from: https://www.ema.europa.eu/en/documents/report/background-review-excipient-propylene-glycol-context-revision-guideline-excipients-label-package_en.pdfEuropean Medicines Agency Committee for Human Medicinal Products (CHMP). Questions and Answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00), EMA/CHMP/507988/2013. [Internet]. 2014 [cited 30.3.19.]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-ethanol-context-revision-guideline-excipients-label-package-leaflet-medicinal_en.pdf

FORMULATION AND EVALUATION OF ORODISPERSIBLE TABLETS OF A MODEL ANTI-HYPERTENSIVE DRUG

Objective: The rationale of the current work was to formulate and evaluate orodispersible tablets by direct compression technique with a vision to augment patient compliance and rapid onset of action.Methods: Nine orodispersible formulations of propranolol were formulated by direct compression method using sodium starch glycolate, crospovidone and croscarmellose sodium as the super disintegrants. The prepared formulations were evaluated for wetting time, drug content, in vitro disintegration time, dispersion time, dissolution time and also projected to kinetic treatment to know the pattern of drug release. Further, the discovered promising formulation was subjected to stability studies.Results: Based on the results obtained, formulation F9 containing6 mg of croscarmellose sodium exhibited good wetting time, dispersion time, and disintegration time and drug release compared to orodispersible tablets prepared with other super disintegrants. The stability studies piloted as per International Conference on Harmonisation guidelines on the promising formulationF9disclosedno significant changes in the colour (white), drug content (94.87±0.141 mg), hardness (2.93±0.18 kg/cm2), disintegration time (17.11±0.089 s), and drug release after 4 w. After 60 s, the percentage drug release of F9 was found to be 98.52 % and 96.30 % after 1 and 4 w, respectively.Conclusion: Orodispersible tablets of propranolol hydrochloride were formulated successfully by employing direct compression technique. From the investigation, it can be reasonably concluded that F9 batch orodispersible tablets of propranolol with 6 mg of crospovidone exhibited maximum cumulative drug release in 60 s.

The Role of the Pharmacist in the Treatment of Patients with Infantile Hemangioma Using Propranolol.

IntroductionInfantile hemangiomas (IH) are the most common benign vascular tumors of childhood, with an incidence of 5–10% during the first year of age. Propranolol is considered the first-line treatment for this condition. Potentially there is a high probability of negative results to therapy, because in many countries there are no treatment protocols or propranolol formulations appropriate for the pediatric population. The objective of the present study was to evaluate the impact of pharmacist interventions such as detecting, analyzing, and solving problems presented during treatment with propranolol in patients with IH.MethodsAn open observational prospective study was performed over 25 months in a group of pediatric patients diagnosed with infantile hemangioma treated with propranolol. Pharmacist participation consisted of development of an extemporaneous formulation and counseling the child’s parents. At each visit to the pharmacy service, family members were interviewed, detecting and classifying problems related to treatment.ResultsSixty-three children with IH were treated during the period under review. Patient ages ranged from 3 to 11 months old; 64% were female and 36% were male. Forty-nine problems in 30 patients were detected, principally inadequate dose (18.4%), non-adherence to treatment (16.3%), side effects (14.3%), and wrong administration (14.3%). Of the problems detected, 81.6% were resolved. Interventions by the pharmacist in 27 patients were intensive counseling on adherence to therapy (20%), detection of adverse effects (11.4%), and adjustment of the dose (22.9%). In 95.2% of patients a good response to treatment was obtained compared with 77.2% reported in European studies without pharmacist intervention.ConclusionIt seems that pharmacist participation increases adherence to treatment and reduces the likelihood of adverse effects, allowing for safe and effective therapy in patients with IH.

Formulating propranolol as an amorphous melt affords reduced skin irritation potential for transdermal drug delivery

Oral propranolol is commonly the first-line treatment of infantile hemangioma. However, oral delivery of propranolol is limited by systemic side effects, particularly in infants. Topical application may be a more patient friendly alternative while concurrently affording targeted delivery to the site of the skin lesion. Unfortunately, dose-dependent skin irritation is typically observed when propranolol is applied topically. Of additional concern, irritation is often exacerbated by organic solvents required to formulate propranolol. To address these concerns, we present novel formulations of propranolol as amorphous melts. Propranolol melts were successfully synthesized, and their physicochemical properties were tuned suitably for transdermal delivery using dialkyl sulfosuccinates as the counter species. Melts used in this study possessed the ability to penetrate skin when applied neat, without the need of any addition of solvent. Moreover, skin irritation potential of the lead melt was reduced compared to that of the propranolol free base (PFB). This reduction may be due to association of propranolol with the counter species in amorphous melts. The results presented here suggest amorphous melt formulations may open up the possibility to topically deliver drugs that traditionally elicit skin irritation.

Sustained delivery of propranolol by using multiparticulate gastroretentive drug delivery system

PURPOSE: Gastroretentive systems can significantly prolong the gastric residence time of drugs. If a drug is stable in gastric acid, prolonged gastric retention improves bioavailability. The objective of the present investigation was to develop an extended and controlled release composition and formulation of propranolol using expandable, gelling, swellable hydrocolloid polymer along with mineral oil. METHODS: A formulation was prepared without using mineral oil by conventional ionotropic gelation method. All other formulations of oil entrapped floating gel beads of propranolol hydrochloride were prepared by using emulsion gelation method in which sodium alginate was used as a gelling agent and mineral oil was used to impart buoyancy to the formulation Spherical gel beads were formed instantaneously. The prepared beads were evaluated for diameter, surface morphology, encapsulation efficiency and drug release. RESULTS: Low concentration of oil containing formulation exhibited greater release of drug. As the concentration of oil increases, drug release decreases to certain extent. Percentage buoyancy of floating propranolol hydrochloride gel beads was found satisfactory. The highest mean diameter was observed in the formulation with 30% of mineral oil. The formulation with 35% of mineral oil had the highest drug loading and scanning electron microscopy revealed that the beads were spherical in shape with rough surfaces. CONCLUSION: Oil entrapped gel beads can be used as floating drug delivery system for extended drug release for both local and systemic drug delivery. Keywords: Floating drug delivery system; Emulsion gelation; Sodium alginate; Mineral oil; Propranolol hydrochloride.

Pharmacokinetics of propranolol following single and multiple-dosing with Inderal-LA or a chrontherapeutic form of propranolol

Blood pressure rises rapidly upon waking and may be responsible in part for the increased incidence of myocardial infarction and stroke during the morning hours. Current formulations and dosing of antihypertensive drugs do not provide maximum coverage during this vulnerable period. This study was performed to demonstrate that propranolol CR, a novel chronotherapeutic formulation of propranolol designed for nighttime dosing, had appropriate pharmacokinetics to provide maximum effect in the morning. Beta-blockers may be well-suited for the purpose of chronotherapy since they attenuate sympathetic activity and thereby decrease the increase in heart rate and contractility that are seen upon waking. Pharmacokinetics of propranolol CR and Inderal LA following single and multiple doses were determined in normal male volunteers in this open-label, two-period, crossover study. The drugs were dosed in the evening and serial blood samples were taken for determination of propranolol concentration the next 24 to 72 hours. Following a single 160 mg dose of propranolol CR administered at 10 PM, absorption was delayed by about 4 hrs, after which plasma concentration rose steadily, reaching a peak at about 10 AM. In contrast, after dosing with Inderal LA, plasma levels of propranolol began to rise almost immediately, reaching a plateau between 4 AM and 10 AM. During multiple dosing, steady-state trough plasma concentrations were achieved after 2 days with either drug. Following the final dose, the changes in plasma concentration were similar to those observed in the single dose study. Bioavailability was similar for both formulations of propranolol. In conclusion, Propranolol CR exhibited appropriate pharmacokinetics for the chronotherapeutic treatment of hypertension; moreover, the higher peak plasma levels and the slightly greater bioavailability observed after dosing with propranolol CR offer potential advantages over Inderal LA. See Figure 1.

Improvement in exercise tolerance and immediate beta-adrenergic blockade with intranasal propranolol in patients with angina pectoris

A new intranasal spray formulation of propranolol was developed to provide β-adrenergic blocking medication on an immediate basis to patients with angina pectoris. The effects of this spray or placebo were assessed in 16 patients with effort-induced angina in a blinded, randomized, crossover design study that compared placebo with intranasal propranolol spray (5 mg/puff) 15 minutes before exercise on a treadmill (Bruce protocol). One week later, each patient, acting as his/ her own control, received the alternative treatment and repeated exercise. Mean plasma propranolol level with active therapy was 20 ng/ml. Patients with active spray demonstrated a significant increase in total exercise time than patients taking placebo (530 ± 197 vs 460 ± 177 seconds, p = 0.05), an increase in the time to 1 mm ST-segment depression on the electrocardiogram (384 ± 202 vs 327 ± 144 seconds, p <0.05), and an increase in time to onset of angina (452 ± 149 vs 363 ± 175 seconds, p = 0.0005). There was a blunting of maximal exercise heart rate with active therapy compared with placebo (120 ± 13 vs 133 ± 17 beats/min, p <0.01), blunting of maximal exercise systolic blood pressure (185 ± 22 vs 194 ± 21 mm Hg, p < 0.05), and blunting of peak double product (p < 0.0005), with more modest effects on resting heart rate. Propranolol spray is an effective approach for providing immediate β blockade and improving exercise tolerance in patients with angina pectoris.

Improved oral bioavailability of propranolol in healthy human volunteers using a liver bypass drug delivery system containing oleic acid

Propranolol, a clinically proven lipophilic β-adrenergic blocking agent, undergoes extensive and unpredictable first-pass hepatic metabolism when administered as a conventional oral formulation. A nine-subject three-way cross-over study was performed in healthy human volunteers to assess the relative bioavailability of two novel oral formulations of propranolol, designed to bypass hepatic first-pass metabolism. These formulations contained a mixture of unsaturated fatty acids, mainly oleic acid, and surfactants in enteric-coated liquid-filled hard gelatin capsules. Using these formulations selective increases of up to more than 6-fold in AUC and 4-fold in C max were achieved in subjects who responded poorly to Inderal ®. The increased propranolol bioavailability achieved using the liver by pass formulations was associated with a reduction in the coefficient of variance for both C max and AUC of up to 44%, when compared to Inderal ®. The results of the present study suggest the possibility of developing a predictable reduced dose delivery system for basic lipophilic drugs which undergo extensive hepatic first-pass metabolism.

Long-Acting Propranolol in the Prophylaxis of Migraine: A Comparative Study of Two Doses

A randomized double-blind, cross-over study using treatment periods of 12 weeks with a 2-week washout, comparing two long-acting formulations of propranolol ('Inderal' LA 160 mg daily and Half-'Inderal' LA 80 mg daily) was performed after a placebo run-in of 4 weeks on 51 patients. The study indicated that both long-acting formulations were significantly better than placebo in reducing the frequency of migraine attacks (p less than 0.01). After 12 weeks there was a significantly lower (p = 0.03) frequency of migraine attacks in patients on the higher dose formulation than in those on the lower dose formulation. There was no significant difference in the frequency of side effects produced by the two formulations.

Pharmacodynamic and pharmacokinetic study of propranolol in patients with cirrhosis and portal hypertension.

1. The aim of this study was to investigate the pharmacokinetics and the beta-adrenoceptor blocking activity according to time of conventional (C) and long acting (LA) propranolol in cirrhotic patients. Twenty-four patients with alcoholic cirrhosis and oesophageal varices were randomly assigned to receive either 160 mg C propranolol, 160 mg LA propranolol or placebo acutely and then following repeated administration (acute and chronic phases). Thereafter propranolol concentrations and beta-adrenoceptor blockade (resting and exercise heart rates) were measured at different intervals. 2. The Cmax was significantly higher with C propranolol in both phases. The time of Cmax was significantly later with LA propranolol in both phases. The AUCs were significantly higher after chronic administration with both formulations of propranolol. 3. The exercise peaks of beta-adrenoceptor blockade were similar between the two formulations and between the two phases of administration of propranolol. The duration of effective beta-adrenoceptor blockade was significantly longer in the chronic phase and seemed to be longer with LA than with C propranolol although this was not significant (72 +/- 31 vs 48 +/- 18 h, respectively). 4. There was a significant correlation between the log propranolol concentration and exercise heart rate but not with resting heart rate. No correlation could be demonstrated between pharmacological data and the Child Pugh score. 5. We conclude that in cirrhotic patients exercise testing was a reliable method in the assessment of beta-adrenoceptor blockade. Pharmacology of propranolol was found to be different according to the formulation or to the phase of administration.

Once‐Daily Propranolol for Hypertension: A Comparison of Regular‐Release, Long‐Acting, and Generic Formulations

This randomized, single-blind, crossover study compared three formulations of propranolol, each given once daily for hypertension. After an initial titration phase, subjects randomly received regular-release, long-acting, or a generic propranolol formulation. Each drug was given for 4 weeks and each active treatment was separated by a washout phase to allow blood pressure to return to baseline. Twelve subjects received all three active treatments. Systolic and diastolic blood pressures and pulses were significantly reduced from baseline by all formulations. There was no significant difference among drugs. Examination of diastolic blood pressures suggested some loss of antihypertensive control at the end of the dosing interval. These results indicate that it may be possible to administer propranolol once daily for hypertension and that there is no advantage for using the long-acting form.

Antihypertensive treatment with a long-acting formulation of propranolol in the aged

高齢者本態性高血圧症入院患者30名 (年齢77.6±6.1歳, 男9, 女21) を対象とし, 4週間の観察期に続いてプロプラノロール徐放剤 (インデラルLA(R)) 60mgを1日1回朝食後に12週間連続経口投与し, 投与前後における血圧変化, 血漿プロプラノロール濃度, 24時間連続記録心電図から平均分時心拍数, 最低分時心拍数, さらに血漿レニン活性について検討した. 1) 血圧は収縮期, 拡張期共に有意に低下した. 2) プロプラノロール徐放剤初回投与時に血漿プロプラノロール濃度を経時的に測定したところ, 投与5時間後に41.5±37.7ng/mlとピークとなり, 24時間後も28.6±30.5ng/mlであった. また投与12週目の血漿プロプラノロール濃度は投与前値61.8±50.5ng/ml, 5時間値99.8±66.7ng/mlとなり高値で個人差も大であった. 3) 平均及び最低分時心拍数は共に有意に減少したが, 最低分時心拍数の減少は平均分時心拍数に比して軽度であった. 4) 収縮期血圧変化と12週目5時間後血漿プロプラノロール濃度とはr=0.645の粗な相関を認めたが, 血漿レニン活性前値並びに変化と降圧との間には有意な相関を認めなかった. 5) 副作用は6例に認められ, 5例は気管支肺炎併発, 1例は徐脈性不整脈のため投薬中止とした. 高齢者高血圧に対するプロプラノロール徐放剤投与に際しては血漿プロプラノロール濃度の高値, 個人差を考慮し注意深い観察が必要で, 慎重に投薬されるべきと考えられた.

Plasma Propranolol Levels and Their Effect on Plasma Thioridazine and Haloperidol Concentrations

The relationship between chronic oral dosage with a long-acting formulation of propranolol and plasma propranolol levels 22 to 23 hours later is described in 12 adult male patients with organic brain disease. Separately, the effects on plasma levels of thioridazine plus metabolites with concomitant rising dose long-acting propranolol administration were studied in five patients. Significant dose-related increases in levels of thioridazine and metabolites were found when long-acting propranolol was given. No changes in haloperidol levels were found in three patients studied in a similar protocol.

Comparison of a Long-Acting Form of Propranolol and Conventional Propranolol in the Treatment of Hypertension in Elderly Patients

Nineteen elderly hypertensive patients already being treated with a diuretic and, where necessary, another anti-hypertensive agent, were studied in a double-blind, randomized, crossover comparison of conventional propranolol, 40 mg three times daily, with a long-acting propranolol formulation, 160 mg once daily, as a second line agent. Patients were assessed before taking the morning's allocated medication. This was done as near as possible to 24 h after the last dose of once daily propranolol and as near as possible to 15 h after the last dose of three times daily conventional propranolol. Assessment was carried out at the time of randomization and after 4 weeks' treatment with both propranolol formulations. Heart rate and blood pressures were measured in the supine and standing positions and after exercise. Both propranolol formulations were effective as second line agents in these elderly patients and both were well tolerated. Patient compliance on both propranolol formulations was very good although the long-acting formulation may be of value in improving this still further.

Controlled-release formulations of propranolol and verapamil.

The in vitro and clinical behavior of new controlled-release formulations of propranolol and verapamil are reviewed. In vitro dissolution studies have proved to be of little value in determining the clinical activity of these new dosage forms. There is a difference between the blood levels found with the new formulations and those of the reference products. The once-daily verapamil product was evaluated in black hypertensive patients with promising results and suggests that this dosage form of verapamil may be successful as monotherapy for treating this patient population.

A comparative study of conventional and long‐acting formulations of propranolol in essential hypertension

A comparative study of conventional and long‐acting formulations of propranolol in essential hypertension

Plasma concentration-response relationships of two formulations of propranolol.

The time-course of beta blockade induced by two formulations of propranolol was compared to their plasma concentration-time curves. Graded infusions of isoproterenol were used to assess the degree of beta blockade at different times after oral administration of 80 mg of propranolol to 11 healthy volunteers. The time-course of drug effect was measured as the decline of the systolic pressor dose 20 (SPD 20) and the chronotropic dose 20 (CD 20). Variability of plasma propranolol concentration was small, varying within subjects from 27% to 36% and between subjects from 19% to 28% at the various sampling times. Pharmacodynamic effects showed a similar reproducibility: intra-individual variation was 15% to 28% for CD 20 and 17% to 32% for SPD 20; interindividual variation was 10% to 24% for CD 20 and 13% to 23% for SPD 20. Pooling of the data of all subjects indicated a parallel decline of drug concentration and effect. However, three of the 11 subjects showed drug effects declining at a faster rate than drug levels. This dissociation between serum concentrations and effects points out the clinical relevance of complementing kinetic studies of propranolol with pharmacodynamic studies. The good reproducibility within subjects and the small interindividual variation suggests that isoproterenol dose-response curves may be a useful tool for such studies.