Preparation of propranolol hydrochloride cubosomes by pH gradient method / 药学实践杂志

Objective To prepare propranolol hydrochloride loaded cubosomes (PPL-Cubs) with high entrapment efficiency. Methods PPL-Cubs was prepared by pH gradient method. Pressure and cycles of high pressure homogenization, dosage of glyceryl monooleate and poloxamer 407 were optimized to prepare blank cubosomes with particle size and polydispersity index as the indexes. The influences of various factors, including exterior pH values, internal pH values, the ratio of carrier to drug, particle size and polydispersity index of blank cubosomes, incubation temperature and time, and drug concentration on the entrapment efficiency were investigated. Results The blank cubosomes with small particle size and polydispersity index was prepared under homogenization conditions of 900 bar for 7 cycles, glyceryl monooleate dosage of 25%, and poloxamer 407 dosage of 5%. PPL-Cubs showed high entrapment efficiency with exterior pH value of 8.5, internal pH value of 3.0, ratio of carrier to drug of 6∶1, incubation temperature of 20 ℃, and incubation time of 15 min, and drug concentration of 1%. The particle size and polydispersity index of blank cubosomes showed no influence on entrapment efficiency. Conclusion PPL-Cubs with high entrapment efficiency could be prepared under the pH gradient method.

Effects of experimental conditions on solubility measurements for BCS classification in order to improve the biowaiver guidelines

Among the methods described for determining the solubility, shake-flask is suitable to evaluate the equilibrium solubility according to the BCS. Nevertheless, experimental conditions related to the shake-flask method are not well described. Evaluating the effects of experimental conditions on solubility measurements by shake-flask method is important and contributes in biowaiver decision. For this work, propranolol hydrochloride and nimesulide were used as model compound of high and low solubility, respectively. Equilibrium solubility was evaluated at 37 ºC, 100 rpm during 48 hours in buffer media. Effects of the rotation speed, temperature, substance in excess and aliquot withdrawn were evaluated. Small variations of temperature caused significant differences in the solubility and then this parameter must be controlled. Excess of raw material influenced the results of the nimesulide, then, little excess is recommended. Rotation speed did not cause differences in the equilibrium solubilities, but at 150 rpm the equilibrium was reached faster. Aliquot did not present significant differences, but excessive withdrawn should be avoided. Therefore, the evaluation of equilibrium solubility using shake-flask method must be performed in physiological pH conditions, 37 ± 1 ºC, substance in excess 10% above saturation, 50, 100 or 150 rpm and aliquot withdrawn not more than 10% of the media volume.

Preparation and Preliminary Stability Tests of Extemporaneously Prepared Oral Suspending Vehicle for Children / 中国药学杂志

OBJECTIVEP: To prepare the extemporaneously prepared oral suspending vehicle that can be used in divided doses for children, and preliminary stability experiments are performed. METHODS: Preparation of blank suspending vehicle by prescription screening and optimization. The preparation of suspending vehicle is based on the comprehensive scale of viscosity, redispersibility and appearance traits as the evaluation index, and signal factor study is used. The preliminary stability investigation was carried out.Using propranolole hydrochloride and spironolactone as model drugs, the drug concentration in suspension determined by ultraviolet spectrophotometry and high performance liquid chromatography(HPLC) respectively,which are methods prescribed in Chinese Pharmacopoeia. RESULTS: The dosages of CMC-Na, HPMC, xanthan gum and xylitol in the final formulation of suspension medium were 3.33% (g•mL-1), 1.67% (g•mL-1), 1% (g•mL-1) and 0.1% (g•mL-1),respectively. The extemporaneously prepared oral suspension is uniform, stable and dispersed, and the inspection conforms to the relevant regulations. Average recovery rates of propranolole hydrochloride and spironolactone are meet the relevant regulations. No stratification in the appearance of samples in centrifugal tests. Three batches of test samples remained stable at 4 and 25℃ for 10 d. CONCLUSION: The oral suspending vehicle has a simple and convenient preparation process, the drug dispersion is simple and fast, the content determination method is accurate and reliable, and the stability is good,and can be used as a drug-loading vehicle.

Formulation and Evaluation of Tablet using Latex Powder of Jatropha curcas as a Natural Binder.

Purpose of this work was to evaluate binding efficiency of latex powder of Jatropha curcas in tablet dosage form. Tablets of BCS class I and II drugs Propoanolol hydrochloride and Oxcarbazepine respectively were prepared by wet granulation method. Various concentrations of latex powder of Jatropha curcas were tried for optimization of binder concentration. Tablets prepared were evaluated for weight variation, content uniformity, hardness, disintegration time, friability and drug release. Also tablet with standard binder Poly Vinyl Pyrolidone was prepared and compared with optimized formulations of natural binder. Tablets were successfully prepared by wet granulation method with all evaluation parameters well within official limits for all concentrations of binder for both the drugs. It has been observed that as concentration of binder increases hardness and disintegration time increases with decrease in friability and drug release. As compared with tablet prepared by standard binder, Poly Vinyl Pyrolidone, our optimized formulations have shown comparable results. The study revealed that latex powder of Jatropha Curcus can be used as alternative binder than synthetic binders as it is cost effective and easily available.

Effect of novel terpenes penetration enhancer on in-vitro percutaneous penetration of propranolol hydrochloride hydrogel / 中国药学杂志

OBJECTIVE: To investigate the effects of different novel terpenes penetration enhancers and their combinations on percutaneous absorption of propranolol hydrochloride hydrogel and screen the best penetration enhancers so as to increase the cumulative permeation quantity in the target site. METHODS: The percutaneous permeation experiment was carried out with modified Franz-type diffusion cell with isolated piglet skin as the barrier. The effects of the types, concentrations, and combinations of penetration enhancers on the transdermal penetration of propranolol hydrochloride hydrogel were compared using cumulative permeation quantity (Q) and enhancing rate (ER) as indexes. RESULTS: The effectiveness of terpenes was found to be the optimal at concentration of 3% in the following order; farnesol > L-menthol > nerolidol > tetrahydrogeraniol > 1, 4-cineole≈geraniol > limonene > anethole > borneol > negative control > dipotassium glycyrrhizic acid. The release profiles from the hydrogel formulations obeyed zero-order kinetics. Farnesol, L-menthol, and nerolidol effectively promoted the percutaneous penetration of propranolol hydrochloride over the concentration range of 1% - 5%. The enhancement ratio was the highest at 3% and decreased if the concentration increased to 5%. Significant synergism was observed when the enhancers were used in combination (P < 0.05), while there was an antagonistic effect when 3% farnesol or 3% L-menthol was combined with propylene glycol (P < 0.05). CONCLUSION: The percutaneous absorption of propranolol hydrochloride is increased by the terpenes enhancers and reached the peak value with 3% farnesol plus 10% isopropanol. These findings provide a basis for the further transdermal delivery studies of propranolol hydrochloride.

Formulation Optimization of Propranolol Hydrochloride Gels by Central Composite Design-Response Surface Methodology / 医药导报

Objective To optimize the matrix formula of propranolol hydrochloride gels. Methods On the basis of single factor experiment, central composite design-response surface method was used to optimize the formula. Addition levels of glycerol (A), PEG-400 (B) and HPMC (C) were evaluated as the independent variables.Eight-hour accumulative penetration amount per unit area measured by HPLC was used as the index. Quadratic polynomial was used to estimate the relationship between the index and the independent variables, and to delineate response surface and overlay contour plots in order to select the optimal formulations.Finally, predicted responses were verified. Results The optimized formula consisted of 18.53% glycerol, 8.54% PEG-400 and 2.35% HPMC.The quadratic polynomial regression model of 8-h accumulative penetration amount per unit area:R1=-7 415. 69+306. 10A+167. 47B+4 820. 59C-8. 26A2-9. 81B2-1 025. 75C2 , and the cumulative transmittance was 49.6%. Conclusion A credible model is established by using central composite design-response surface method and the formula of propranolol hydrochloride gels is optimized and the gel is stable and controllable.

Thermodynamics of mixing of the β-adrenergic blocker propranolol-HCl in ethanol + water mixtures / Estudio termodinámico del proceso de mezcla del bloqueador β-adrenérgico propranolol-HCl en mezclas etanol + agua

Thermodynamic functions Gibbs energy, enthalpy, and entropy of mixing of propranolol hydrochloride in ethanol + water mixtures were evaluated. Mixing quantities were calculated based on fusion calorimetric values obtained from differential scanning calorimetry measurements and equilibrium solubility values reported in the literature for this drug in these cosolvent mixtures. By means of enthalpy-entropy compensation analysis, a non-linear ΔmixHº vs. ΔmixGº plot was obtained indicating different mechanisms involved in the dissolution and mixing of this drug according to mixtures composition. Nevertheless, the molecular and ionic events involved in the dissolution of this drug in this cosolvent system are unclear.

En este trabajo se estudiaron las funciones termodinámicas de mezcla de propranolol clorhidrato en mezclas etanol + agua, las cuales fueron calculadas a partir de las propiedades calorimétricas de fusión y de los valores de solubilidad en equilibrio en estas mezclas cosolventes que fueron publicados en la literatura. Mediante análisis de compensación entálpica-entrópica ΔmixHº vs. ΔmixGº se obtuvo un gráfico no lineal lo que indica la presencia de diferentes mecanismos implicados en el proceso de disolución según la composición cosolvente. Sin embargo, los eventos moleculares e iónicos involucrados en el proceso de disolución de este fármaco en este sistema cosolvente no son claros.

Formulation and evaluation of transdermal patches and to study permeation enhancement effect of eugenol.

Since oral bioavailability of Propranolol Hydrochloride is poor due to high first pass metabolism different matrix- type transdermal patches incorporating Propranolol Hydrochloride were formulated with an objective to study the effect of polymers on transdermal release of the drugs. The polymers selected for sustaining the release of drug were polyvinylpyrrolidone, Hydroxypropylmethycellulose (HPMC) and Ethyl cellulose (EC). The patches were formulated using combination of polymers and propylene glycol as plasticizer. The physicochemical evaluation of the polymer matrices was performed for suitability. In vitro permeation studies were performed using rat abdominal skin as the permeating membrane in Franz diffusion cell. The result indicated that maximum release was obtained at 2% solution of EC. Optimized batch was evaluated for permeation enhancement through rat skin using natural permeation enhancer Eugenol and it was concluded that permeation enhancement through Eugenol was comparable to the commercially available permeation enhancer Dimethyl sulfoxide 1% (DMSO). All the films were found to be stable at 37ºC and 45ºC with respect to their physical parameters and drug content.

Determination of Terbutaline Sulfate and Its Combination with β_2 Adrenergic Receptor in Erythrocyte Membrane by High Performance Liquid Chromatography / 分析化学

A high performance liquid chromatographic method with hypersil C_(18) column, 0.020 mol/L potassium dihydrogen phosphate solution(which contains 0.25% triethylamine, pH 5.1)-methanol(20∶ 80, V/V) as mobile phase and fluorescence detection with 280 nm as excitation wavelength and 320 nm as emission wavelength has been developed for the determination of terbutaline sulfate and propranolol hydrochloride in Erythrocyte suspensions. Erythrocyte surface receptor oscillating reacted 1 h with terbutaline in 37 ℃ water bath. Free terbutaline and propranolol were separated from the membrane receptor-binding complex through 1500 r/min centrifugal in 5 min. The linear range was 0.010-3.000 mg/L in Alsever's solutions and the correlation coefficients were 0.9999 and 0.9998. The relative standard deviations(RSDs) of terbutaline and propranolol were 0.8% and 1.2%, respectively. The limits of detection(LODs) of both were 1.00 and 3.00 mg/L. This simple, safety and sensitive method was suitable for the determination of terbutaline and propranolol in erythrocyte suspensions and for the study of receptor-ligand binding.

Enantioselective transport of R/S-propranolol in Caco-2 cell monolaysers / 重庆医科大学学报

Objective:to study the absorption and absorption characteristics of isomer of propranolol hydrochloride in Caco-2cell monolayers model,which have taken as the most representative model to investigate the absorption mechanism of oral drug in recent years. Methods:Caco-2 cell monolayers model was set up to study transport of isomer of propranolol hydrochloride. RP-HPLC method was applied to analyze isomer of propranolol hydrochloride through precolumn derivatization. Results: Propranolol hydrochloride was absorbed completely,and was a passive diffusion mechanism. There was no chiral selectivity of transport and absorption of them across Caco-2 cell monolayers. Conclusion: Caco-2 cell model was established and the cell integrity was evaluated. The integrity of Caco-2 cell was in good condition,which could be used to study the absorption and transport. RP-HPLC method was established to separated isomer of propranolol hydrochloride within 20 min by precolumn derivatization. The method is convenient, sensitive,accurate and suitable for the analysis of telbivudine.