Microsphere-based once-daily modified release matrix tablets for oral administration in angina pectoris

The objective of this research was to develop microsphere-based once-daily modified release tablet formulations of diltiazem hydrochloride (DH), a potent calcium channel blocker used in angina pectoris. For this purpose, DH-loaded microspheres were prepared by the solvent evaporation technique using Eudragit®RS 100. The effect of variation in the drug/polymer ratio on the physical and release characteristics of the microspheres was investigated. After the selection of the suitable microspheres, tablets were compressed using Compritol®888 ATO, Ludipress® and Cellactose®80 as different direct tableting agents and excipients. As a result, modified release tablet formulations of DH-loaded microspheres were designed successfully for oral administration once rather than two or three times a day in angina pectoris.     

Microsphere-based once-daily modified release matrix tablets for oral administration in angina pectoris

The objective of this research was to develop microsphere-based once-daily modified release tablet formulations of diltiazem hydrochloride (DH), a potent calcium channel blocker used in angina pectoris. For this purpose, DH-loaded microspheres were prepared by the solvent evaporation technique using Eudragit RS 100. The effect of variation in the drug/polymer ratio on the physical and release characteristics of the microspheres was investigated. After the selection of the suitable microspheres, tablets were compressed using Compritol 888 ATO, Ludipress and Cellactose 80 as different direct tableting agents and excipients. As a result, modified release tablet formulations of DH-loaded microspheres were designed successfully for oral administration once rather than two or three times a day in angina pectoris.     

Development and release mechanism of diltiazem HCl prolonged release matrix tablets

A coated matrix tablet formulation has been used to develop controlled release diltiazem HCl (DIL) tablets. The developed drug delivery system provided prolonged drug release rates over a defined period of time. DIL tablets prepared using dry mixing and direct compression and the core consisted of hydrophilic and hydrophobic polymers such as hydroxypropylmethylcellulose (HPMC), Eudragits RLPO/RSPO, microcrystalline cellulose, and lactose. Tablets were coated with Eudragit NE 30D, and the influence of varying the inert hydrophobic polymers and the amount of the coating polymer were investigated. The release profile of the developed formulation was described by the Higuchi model. Stability trials up to 6 months displayed excellent reproducibility.     

Controlled release of saccharides from matrix tablets.

The aim of this study was to design site specific, controlled release tablets of N-acetyl-d-glucosamine (NAG), maltose monohydrate and maltopentaose by using hydrophobic matrix formers starch acetate (SA) and ethyl cellulose (EC). The optimized matrices, which had either low porosity and high drug load or high porosity and low drug load, released the saccharides within the desired 2-4 h. In general, it was possible to control the release rate of saccharides by altering the relative amount of hydrophobic matrix former in the tablet and tablet porosity. The release type of saccharides from these formulations varied from immediate release to sustained release. In the case of sustained release formulations, it was found that the release of maltose monohydrate and maltopentaose was biphasic and slower than the release rate of NAG from similar tablets. NAG release kinetics followed square root of time kinetics, while in the case of maltose monohydrate and maltopentaose, the release kinetics were zero order in both phases. The biphasic dissolution profile was proposed to be caused by water mediated recrystallisation of the disordered material formed during the dissolution. Both SA and EC matrices were found to represent suitable controlled oral delivery vehicles for saccharides.     

Development and optimization of the drug release determination of iron from iron prolonged release tablets

The aim of this research was to develop and optimize the drug release determination of iron from iron prolonged release tablets. First, solubility characteristics of ferrous sulfate in different aqueous media with a pH in the range of 1 to 8 were studied. According to the results obtained different physicochemical conditions that influence drug release of iron from iron prolonged release tablets were checked. Various aqueous media with a pH in the range of 1 to 7.4, different volumes of dissolution media, various rotation speeds of stirring elements, different dissolution apparatus (apparatus 1/basket apparatus and apparatus 2/paddle apparatus according to USP/Ph. Eur.) were verified. For evaluation of dissolved iron two different methods were checked: atomic absorption spectrometry and redox titration. Redox titration was proved to be a reproducible, discriminatory, selective and cost effective method for evaluation of dissolved iron from iron prolonged release tablets and can be applied in the quality control of solid dosage forms containing iron compounds.     

Optimization of pH-independent release of nicardipine hydrochloride extended-release matrix tablets using response surface methodology

The purpose of this study was to optimize the pH-dependent release of nicardipine hydrochloride extended release formulations by using simultaneously combination two hydrophilic polymers: hydroxypropylmethylcellulose (HPMC) and sodium alginate as retardant and avicel as additive. The constrained mixture experimental design was used to prepare systematic model formulations which were composed of three formulation variables: the content of HPMC (X1), avicel (X2), and sodium alginate (X3). The response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to search for the optimal formulation with specific release rate at different time intervals and to quantify the effect of each formulation variables. The drug release percent at 3, 6 and 12 h were the target responses and were restricted to 10-30% (Y3h), 40-65% (Y6h) and not less than 80% (Y12h), respectively. The results showed that the effect of combination of HPMC and sodium alginate was the most influence factor on the drug release from extended-release matrix tablets. The observed results of Y3h, Y6h and Y12h coincided well with the predictions in the RSM optimization technique, indicating it was quite useful for optimizing pharmaceutical formulation. The mechanism of drug release from extended-release matrix tablets was dependent on the added amount of alginate. The release kinetic of drug from HPMC matrix tablets with alginate was followed the zero-order release pattern.     

Development and validation of a new HPLC analytical method for the determination of alprazolam in tablets

A new analytical method is developed together with its latter validation study, by means of a high resolution liquid chromatography (HPLC) of reverse phase to quantify alprazolam (8-chloro-1-methyl-6-phenyl-4H-[1,2,4] triazole [4,3,-]-[1,4] benzodiazepine) in tablets. Determination is carried out by means of an ODS C18 column (200 mm×4.6 mm i.d., 5 μm particle size); the mobile phase consisted of a mixture of 0.02 M buffer solution of phosphates (pH 6.0) and acetonitrile (45:55, v/v). It is pumped through the chromatographic system at a flow rate of 0.50 ml min⁻¹. The UV detector is operated at 254 nm. The validation study is carried out fulfilling the ICH guidelines in order to prove that the new analytical method, meets the reliability characteristics, and these characteristics show the capacity of an analytical method to keep, throughout the time, the fundamental criteria for validation: selectivity, linearity, precision, accuracy and sensitivity. The method is applied during the working day for the quality control of commercial alprazolam tablets in order to quantify the drug and its degradation products and to check the content uniformity test.     

Development and validation of a new HPLC analytical method for the determination of diclofenac in tablets

A new selective and sensitive high-performance liquid chromatography (HPLC) method was developed for the quantification of diclofenac sodium (DS) in pharmaceutical dosage form using lidocaine as internal standard (IS). Chromatographic separation was achieved on a symmetry C18 column (4.6?mm?×?150?mm, 3?μm spherical particles) using 0.05?M orthophosporic (pH 2.0) 35% and acetonitrile as 65%, as the mobile phase at a flow rate of 2.0?mL/min and monitored at 210?nm. The run time was 2?min.The method was validated to fulfill International Conference on Harmonisation (ICH) requirements and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The calibration curve was linear over the concentration range from 10 to 200?µg/ml, and lower limit of detection of 12.5?ng/ml. The accuracy and precision of the method were within the acceptable limit of ±20% at the lower limit of quantitation and ±15% at other concentrations. Diclofenac was unstable at room temperature it showed more than 25% loss after 24?h. While, DS is very stable at refrigerator 4?°C auto-sampler, freeze/thaw cycles and 30?days storage in a freezer at ?35?±?2?°C.All results were acceptable and this confirmed that the method is suitable for its intended use in routine quality control and assay of drugs.     

Optimization and prediction of drug release from matrix tablets using response surface methodology and near infrared chemical imaging

The purpose of this work was to understand the formulation effect on the drug release from a hydrophilic matrix tablet of niacin using a multivariate statistical technique and Near Infrared Chemical Imaging (NIR-CI). Tablets were composed of ethyl cellulose (EC) and polyethylene oxide (PEO) as release retarding polymers and lactose as the release modulator. D-optimal experimental design was composed of three formulation variables: the content of EC(X(1)), PEO (X(2)), and lactose (X(3)). Response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to predict the optimal formulation. Results showed that the interaction effect of lactose with the polymers PEO and EC and lactose by itself were the most influential factors on the drug release rate. While lactose enhances the drug release rate by forming pores it also promotes water penetration into the tablet core. This in turn helps the formation of the gel layer which acts as barrier to drug diffusion. NIR-CI showed that tablets with higher level of PEO swells at a faster rate and greater extent than formulations with higher level of EC. NIR-CI was thus found to be a very useful technique to predict the drug release rate from hydrophilic matrix systems.     

Optimization and prediction of drug release from matrix tablets using response surface methodology and near infrared chemical imaging

The purpose of this work was to understand the formulation effect on the drug release from a hydrophilic matrix tablet of niacin using a multivariate statistical technique and Near Infrared Chemical Imaging (NIR-CI). Tablets were composed of ethyl cellulose (EC) and polyethylene oxide (PEO) as release retarding polymers and lactose as the release modulator. D-optimal experimental design was composed of three formulation variables: the content of EC(X₁), PEO (X₂), and lactose (X₃). Response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to predict the optimal formulation. Results showed that the interaction effect of lactose with the polymers PEO and EC and lactose by itself were the most influential factors on the drug release rate. While lactose enhances the drug release rate by forming pores it also promotes water penetration into the tablet core. This in turn helps the formation of the gel layer which acts as barrier to drug diffusion. NIR-CI showed that tablets with higher level of PEO swells at a faster rate and greater extent than formulations with higher level of EC. NIR-CI was thus found to be a very useful technique to predict the drug release rate from hydrophilic matrix systems.     

酒石酸美托洛尔骨架缓释片的制备及释放度测定

目的：制备酒石酸美托洛尔缓释骨架片。方法：采用亲水性高分子材料HPMC为骨架，制备酒石酸美托洛尔缓释片，采用正交试验法以药物体外释药百分率为指标优选制剂处方。结果：最佳处方为30％HPMC K4M作阻滞剂、淀粉和乳糖（1：1）为填充剂，10％PVP乙醇液为黏合剂，1％硬脂酸镁为润滑剂，采用湿法制粒，压片。结论：本品制备工艺简便，药物体外释放符合Higuchi模型，自制缓释骨架片较市售缓释片具有更好的缓释效果，能维持药物12h内缓慢释放。     

使用亲水性聚合物调节硝苯地平从缓释骨架片中的释放(英文)

目的根据体外释放曲线调节硝苯地平缓释片(20 mg)的药物释放特性同时评价不同羟丙甲纤维素(HPMC)作为骨架材料的作用。方法硝苯地平HPMC骨架片使用不同粘度的HPMC和其他辅料由湿法制粒后压片制得。自制制剂和参比制剂的释放曲线采用美国药典中桨法进行评价,硝苯地平药物含量采用高效液相色谱法进行测定。结果使用不同的骨架材料药物的释放具有显著性差异,通过改变HPMC的种类调节和控制硝苯地平的释放。聚合度相同,与低粘度的HPMC(K4M,K100LV,E5)相比高粘度的HPMC(K15M)会使硝苯地平释放变慢。最终的处方用10 mg K4M作为主要的骨架材料,10 mg PVP K30作为释药调节剂。结论制备硝苯地平缓释片使用骨架材料HPMC K4M和释药调节剂PVP K30;口服缓释剂型可以改善慢性治疗顺应性并且可维持有效血药浓度。     

Sustained release of isomazole from matrix tablets administered to dogs

Isomazole matrix tablet formulations, with various concentrations of hydroxypropyl methylcellulose (HPMC) hydrogel, were prepared and tested for sustained-release activity. Sustained-release activity was determined by administering isomazole test formulations orally to conscious dogs, instrumented with an indwelling left ventricular pressure transducer, and monitoring cardiac inotropic changes for 12 h thereafter. The HPMC hydrogel incorporated into the tablets at a concentration of 20-30% did not significantly change the magnitude of inotropic response or duration of action. Increasing the HPMC concentration to 40 and 42.5% in the formulations decreased the peak LVdP/dt60 response (cardiac inotropic activity) to isomazole, increased the response duration, and maintained the area under the curve (AUC) of LVdP/dt60 versus time. Higher concentrations of HPMC decreased both LVdP/dt60 peak activity and AUC without producing a sustained response. A very narrow range of HPMC concentration in the matrix tablet is thus required to achieve isomazole sustained-release activity.     

氨茶碱魔芋胶骨架片的释药机制研究

目的研究氨茶碱魔芋胶骨架片的体外释药机制。方法以氨茶碱为模型药物,采用粉末直接压片法制备氨茶碱魔芋胶骨架片,测定不同搅拌转速条件下骨架片的体外溶蚀度与释放度,分别采用零级方程和Peppas方程对释药过程中骨架片的溶蚀度和释放度数据进行处理。结果骨架片的溶蚀符合零级方程,溶蚀量随搅拌转速增加而增加;骨架片的药物释放为扩散和溶蚀协同作用,随搅拌转速增加或释药时间延长,骨架片释药过程中扩散释放所占比例下降,溶蚀释放所占比例增加。结论氨茶碱魔芋胶骨架片的释药机制为非Fick扩散,即药物扩散和骨架溶蚀协同作用。     

Extended release of flurbiprofen from tromethamine-buffered HPMC hydrophilic matrix tablets

Abstract

The pH-dependent solubility of a drug can lead to pH-dependent drug release from hydrophilic matrix tablets. Adding buffer salts to the formulation to attempt to mitigate this can impair matrix hydration and negatively impact drug release. An evaluation of the buffering of hydrophilic matrix tablets containing a pH-dependent solubility weak acid drug (flurbiprofen), identified as possessing a deleterious effect on hydroxypropyl methylcellulose (HPMC) solubility, swelling and gelation, with respect to drug dissolution and the characteristics of the hydrophilic matrix gel layer in the presence of tromethamine as a buffer was undertaken. The inclusion of tromethamine as an alkalizing agent afforded pH-independent flurbiprofen release from matrices based on both HPMC 2910 (E series) and 2208 (K series), while concomitantly decreasing the apparent critical effect on dissolution mediated by this drug with respect to the early pseudo-gel layer formation and functionality. Drug release profiles were unaffected by matrix pH-changes resulting from loss of tromethamine over time, suggesting that HPMC inhibited precipitation of drug from supersaturated solution in the hydrated matrix. We propose that facilitation of diffusion-based release of potentially deleterious drugs in hydrophilic matrices may be achieved through judicious selection of a buffering species.     

Voltammetric methods for analytical determination of fleroxacin in quinodis tablets

The direct current (dc) and differential pulse (dp) polarographic reduction of fleroxacin was done in a wide pH range from 2.48 to 13.00. The appropriate buffer choice was made for its dp polarographic determination in a range from 1.845 to 16.926 μg/ml, at pH 8.50. The adsorptive properties of fleroxacin were investigated in order to achieve an increase in sensitivity and a possibility of fleroxacin determination by applying the adsorptive stripping voltammetric method. The adsorptive processes at the hanging mercury drop electrode were investigated in Britton–Robinson and borate buffers. Adsorptive preconcentration followed by differential-pulse cathodic stripping showed one wave at −1.1 V being the most sensitive for analytical determination of fleroxacin. Two linear ranges were obtained, the first one from 18.465 to 258.51 ng/ml, and the second one from 3.693 to 18.465 ng/ml.     

Verapamil hydrochloride release characteristics from new copolymer zwitterionic matrix tablets

The aim of this study was to synthesize stable copolymer (vinyl acetate-co-3-dimethyl[methacryloyloxyethyl] ammonium propane sulfinate) zwitterionic latex with different compositions for the first time by emulsifier-free emulsion copolymerization. Throughout the course of the study, a proposal was made for the explanation of the relationship between the "overshooting" phenomenon (a swelling kinetics with a maximum) and the specific self-association of the zwitterionic copolymers. The zwitterionic monomer unit mole fraction, pH, and ionic strength effects on this relationship, on the swelling kinetics of the zwitterionic copolymers, and on the sustained verapamil hydrochloride release from the model tablets were established by the study's authors.