Effect of formulation and processing factors on the characteristics of biodegradable microcapsules of zidovudine

Abstract

Biodegradable microcapsules of zidovudine (AZT) were prepared using poly-(lactide/glycolide) by the solvent evaporation technique. The objective of this project was to focus on the effect of several formulation and processing factors on the efficiency of encapsulation, surface morphology, and drug release profiles. When the drug was incorporated as powder or as aqueous suspension containing a high amount of insoluble particles, to the organic phase the surface of the microcapsules was appeared to be wrinkled. The efficiency of encapsulation decreased when AZT powder was dispersed directly into the organic solvent instead of adding as an aqueous solution. When the relative volume of the aqueous phase containing 1% PVA was changed from 25 up to 125% of the volume of the organic phase, the efficiency of encapsulation, surface morphology, and release profiles did not change significantly. The efficiency of encapsulation decreased from 9 to 3·8% when the drug loading was increased from 10 to 50% of the weight of the polymer.     

Effect of pH on the release characteristics of pentaestergum microcapsules and a study of dissolution kinetics

Rosin and rosin esters have excellent film-forming properties. Pentaerythritol-rosin ester (penta-ester gum) is found to be useful as moisture-protecting material with delayed release of drug. This communication relates the effect of pH on the release characteristics of a drug from penta-ester gum coated microcapsules. Salicylic acid granules were encapsulated using a 10 per cent solution of penta-ester gum in acetone. The microcapsules were evaluated for their drug release characteristics. Various pH media (pH 1.2, 3.0, 5.0, 7.2 and 8.0) were used. The results showed that penta-ester gum exhibits excellent resistance to higher pH levels and can be used for the sustained release of the drug. Dissolution rate constants were calculated and they agree with the assumption of Hixson and Crowell's cube-root equation.     

33 factorial design-based optimization of the formulation of nitrofurantoin microcapsules

A microcapsule form of nitrofurantoin was prepared by a simple coacervation method with carboxymethylcellulose and aluminium sulfate. 3³ factorial design was performed for three independent variables, namely, the particle size of the drug, the size of the microcapsules and the pH of the dissolution medium. The dissolution tests with the formulated microcapsules were carried out according to the United States Pharmacopeia XXII rotating basket method at pH 1.2, 5 and 7.5, which represent the pH of gastrointestinal fluids. Release data were examined kinetically and the ideal kinetic models were estimated and t _63.2 values obtained from RRSBW distribution were used in the factorial design experiment. The influence of the independent variables on the dissolution of nitrofurantoin microcapsules could be expressed as the pH of the dissolution medium > particle size of the microcapsule > particle size of nitrofurantoin. The other aim of this study was to evaluate microcapsule formulation in terms of the United States Pharmacopeia criteria with a minimum of experiments. Our findings suggest that dosage forms which comply with the pharmacopoeia criteria for dissolution can be prepared and selected by factorial design.     

盐酸二甲双胍缓释片释药因素考察及处方筛选

目的制备盐酸二甲双胍缓释片并对释药因素进行考察。方法采用HPMC为基本骨架材料制备了盐酸二甲双胍骨架片 ,对影响释药的因素 ,如HPMC规格、粘合剂的种类、润滑剂的用量、制片工艺、制片压力及释放介质 pH等进行了考察 ,并在此基础上进行处方的筛选。结果盐酸二甲双胍缓释骨架片的体外释药行为符合Higuchi方程 ,HPMC规格和制片压力对盐酸二甲双胍骨架片的释药几乎无影响 ,而粘合剂的种类 ,润滑剂的用量 ,制片工艺对药物的释放产生一定的影响 ,介质的pH对药物释放的影响较大。结论采用HPMC作为基本骨架材料 ,结合其他辅料 ,制备了日服 1次的盐酸二甲双胍缓释片     

Evaluation of different formulation studies on air-filled polymeric microcapsules by multivariate analysis

Air-filled polymeric microcapsules have been prepared by freeze-drying of emulsions containing the wall-forming polymer in the organic phase of oil in water emulsions. Echogenic air-filled microcapsules were prepared from emulsions containing either (-)-camphene, cyclohexane or cyclooctane as the solvent in the organic phase. Formulation studies have been performed to improve the yield and acoustic quality of the microcapsule suspensions. The yield was measured as particle concentration or efficacy, i.e. normalised attenuation at 3.5 MHz, related to the amount of polymer used.No overall conclusion could be made for all the variables when visually comparing the results from the different investigations. Multivariate analyses (PCA and PLS) were therefore necessary to be able to reveal any relevant systematic information from all the investigations. Different parameters describing the formulation, the production process and parameters describing the characterisation of the intermediates and the final product were set as independent X-variables.Three to four percent (w/v) of polymer was found to be the appropriate concentration of wall forming polymer. Including PEG 3000 resulted in improved freeze-dried product and suspension. Quenching of the emulsions by freezing in dry ice/methanol prior to freeze-drying was not necessary.Process parameters for homogenising and freeze-drying should be optimised with regard to the single systems, due to the different physico-chemical properties of the different solvents, especially melting point and vapour pressure.     

Effect of formulation variables on drug and polymer release from HPMC-based matrix tablets

The objective of this work was to assess the effect of two formulation variables, hydroxypropylmethylcellulose (HPMC)/lactose ratio and HPMC viscosity grade, on the release of a model drug and HPMC, as well as the mechanism of drug release from HPMC-based matrix tablets. A water-soluble compound, adinazolam mesylate, was used as the model drug. Both drug and HPMC release were found to be a function of the formulation variables, with higher drug and HPMC release rates for formulations with lower HPMC/lactose ratios and lower HPMC viscosity grades. However, the K15M and K100M formulations had identical drug release profiles. All the drug release data fit well to the Higuchi expression. By comparing the drug and HPMC release data, it was concluded that diffusion of drug through the hydrated gel layer was the predominant drug release mechanism for most of the formulations studied.     

Effect of dosage form and formulation factors on the adherence of drugs to the esophagus

In recent years, many case reports concerning esophageal injuries caused by drugs have been published. The primary cause has apparently been the adherence of the drug product to the esophagus. In the present study, the adherent tendency of a number of types of tablets and capsules were tested in vitro using a recently developed isolated porcine esophagus preparation. The results showed that the tendency of products to adhere to the esophageal mucosa can be modified to a great extent by shape and formulation. Products with low adherence can be obtained by film coating with aqueous dispersions or by sugarcoating. In contrast, gelatin capsules and some cellulose films appear to have a high tendency to adhere to the esophagus.     

大黄紫草巴布剂基质处方研究

目的筛选大黄紫草巴布剂的基质处方。方法采用均匀设计方法,以初黏力、持黏力为评价指标,各基质及其用量为因素和水平进行均匀设计实验,采用SPSS16．0进行方程拟合,分析各因素对基质性能的影响并得出最优配比组成。结果巴布剂最佳配比为NP-700-氢氧化铝-甘油0．2％酒石酸溶液-4．0：0．2：20：10。结论该基质具有良好的外观和黏附性能,与大黄紫草提取物有良好的相容性。     

Box-Behnken设计-响应面法优化维生素D_3微囊的处方工艺

目的优选维生素D_3微囊的制备工艺,对维生素D_3微囊的质量进行初步评价。方法以辛烯基琥珀酸淀粉钠为主要壁材,β-环糊精为辅助壁材,采用喷雾干燥法制备维生素D_3微囊,通过Box-Behnken设计-响应面法优化维生素D_3微囊的制备工艺。结果维生素D_3微囊的最佳工艺处方为均质温度70℃、固形物含量26%、壁材质量比为1∶1、芯壁质量比为1∶4。外观呈球形、表面较为光滑、未出现黏连现象,粒径分布比较集中,平均粒径为19.90μm。结论以最佳工艺处方制备的维生素D_3微囊工艺合理、稳定,综合质量评价结果表明该微囊质量较好。同时对维生素D_3微囊进行稳定性测定,结果表明维生素D_3微囊可有效提高维生素D_3的稳定性。     

正交实验法优选巴布剂基质配方的研究

目的研究巴布剂基质的最佳配方。方法采用正交设计法,以黏着力为指标,对巴布剂基质配比进行实验研究。结果优化的基质配方为胶液∶甘油∶聚乙烯醇=5∶4∶0.2。结论优化处方具有良好的涂展性、保湿性,且黏着力适中。     

正交实验法优选巴布剂基质配方的研究

目的研究巴布剂基质的最佳配方。方法采用正交设计法,以黏着力为指标,对巴布剂基质配比进行实验研究。结果优化的基质配方为胶液∶甘油∶聚乙烯醇=5∶4∶0.2。结论优化处方具有良好的涂展性、保湿性,且黏着力适中。     

Reservoir-type microcapsules prepared by the solvent exchange method: effect of formulation parameters on microencapsulation of lysozyme

A new microencapsulation technique based on the solvent exchange method was implemented using an ultrasonic atomizer system to encapsulate a protein drug in mild conditions. The reservoir-type microcapsules encapsulating lysozyme as a model protein were prepared by inducing collisions between the aqueous droplets containing lysozyme and the droplets of organic solvent with dissolved poly(lactic acid-co-glycolic acid) (PLGA). The main focus of the study was to examine formulation variables on the size and the encapsulation efficiency of the formed microcapsules. The formulation variables examined were concentrations of mannose in the aqueous cores, NaCl in the aqueous collection medium, and PLGA in organic solvent. The mean diameter of the microcapsules ranged from 40 microm to 100 microm. Smaller microcapsules showed lower encapsulation efficiencies. The resulting microcapsules released native lysozyme in a sustained manner, and the release rate was dependent on the formulation conditions, such as the concentration and molecular weight of the polymer used. The solvent exchange method does not induce lysozyme aggregation and loss of its biological activity. The solvent exchange method, implemented by the ultrasonic atomizer system, provides an effective tool to prepare reservoir-type microcapsules for delivering proteins.     

Effect of formulation factors on electroosmotic glucose transport through human skin in vivo

Glucose transport through human skin can be facilitated by electroosmotic flow that results from the application of an electric current across the skin (iontophoresis). A series of studies on human volunteers examined how formulation factors (buffer type, pH, ionic strength, and buffer concentration) affect the amount of glucose extracted from interstitial fluid through the skin. Sampling cells were placed on subjects' forearms and a current of 0.25 mA/cm(2) was passed across the skin for 5 h. Samples were collected every 20 min and analyzed for glucose concentration. Two methods were used. In one method, subjects ingested glucose and one formulation was tested in each pair of sampling cells for the study duration. The ratio of transdermal glucose flux to blood glucose was determined and compared across formulations. In another method, subjects fasted through the study, and different formulations were sequentially tested in each sampling cell. Citrate was found to give higher flux than bicarbonate or phosphate buffers. Transport increased with increasing pH from 4.5 to 6.5 for citrate buffer and 6.5 to 7.5 for bicarbonate buffer. Increased salt concentration in the formulation decreased transport. Increased phosphate concentration increased transport. These results can be used to optimize electroosmotic transport through the skin.     

33 factorial design-based optimization of the formulation of nitrofurantoin microcapsules

A microcapsule form of nitrofurantoin was prepared by a simple coacervation method with carboxymethylcellulose and aluminium sulfate. 3³ factorial design was performed for three independent variables, namely, the particle size of the drug, the size of the microcapsules and the pH of the dissolution medium. The dissolution tests with the formulated microcapsules were carried out according to the United States Pharmacopeia XXII rotating basket method at pH 1.2, 5 and 7.5, which represent the pH of gastrointestinal fluids. Release data were examined kinetically and the ideal kinetic models were estimated and t _63.2 values obtained from RRSBW distribution were used in the factorial design experiment. The influence of the independent variables on the dissolution of nitrofurantoin microcapsules could be expressed as the pH of the dissolution medium > particle size of the microcapsule > particle size of nitrofurantoin. The other aim of this study was to evaluate microcapsule formulation in terms of the United States Pharmacopeia criteria with a minimum of experiments. Our findings suggest that dosage forms which comply with the pharmacopoeia criteria for dissolution can be prepared and selected by factorial design.     

Influence of pH adjustment on microcapsules obtained from complex coacervation of gelatin and acacia

Abstract

The coacervation behaviour of commercial grade gelatin and acacia mixtures was studied with five different acids to adjust the coacervation pH, i.e. HCI, HNO₃, H₂SO₄, acetic acid, and citric acid. The electrical equivalence pH value (EEP) of the polymer mixture was determined by means of a streaming current detector (SCD). With all acids-except H₂SO₄-maximum coacervate yield was observed at the EEP. Using H₂SO₄ the EEP was found at a lower pH value than compared with the point of maximum coacervate yield. The quantity of coacervate at the EEP was significantly reduced in the presence of H₂SO₄ whereas with all other acids, almost no differences were found. The dependence of the coacervate volume on the added amount of acid did not change in parallel to the dry coacervate yield and there was no coincidence of the maximum coacervate volume and the EEP. The barrier properties of the capsule shells of corresponding microcapsules using indomethacin as a model drug were examined by dissolution studies. Indomethacin microcapsules showed the slowest release rate when the coacervation pH was adjusted to the EEP and not to the pH of maximum coacervate yield. As expected from the coacervation behaviour, dissolution profiles of the microcapsules were quite similar even when different acids were used for pH adjustment.     

Controlled-release matrix tablets of ibuprofen using cellulose ethers and carrageenans: effect of formulation factors on dissolution rates.

The study was conducted to investigate the effects of carrageenans, and cellulose ethers on the drug release rates of ibuprofen controlled-release tablet matrices prepared by direct compression. Polymer blends containing carrageenans or cellulose ethers were used for the formulation and the effect of varying the polymer concentration on the release of the drug was studied. Other factors such as changes in surface topography of the matrices due to hydration were observed using a cryogenic scanning electron microscopy technique. Multiple regression analysis was used to predict the time for 50% release (t50) as a function of the concentration of the polymers used. Most of the formulations showed linear release profiles (r(2)>or=0.96-0.99) and sustained the release of ibuprofen over 12-16 h. The highest t50 (9.3 h) was for the formulation that contained a blend of 1:2 ratio of Viscarin and HPMC, while the lowest (3 h) was for the matrices that contained a 2:1 ratio of methylcellulose and Gelcarin. The majority of the matrix tablets that contained 10% polymer disintegrated prematurely. Of all the polymer blends that were investigated, the combination of Viscarin and HPMC gave almost linear release profiles over the entire range of concentration that was studied. The least effective combination was methylcellulose in combination with HPMC. Most of the formulations released ibuprofen by an anomalous (non-Fickian) transport mechanism, except those matrices that contained methylcellulose and Gelcarin (in a 1:1 and 1:2 ratio), which showed zero-order release.     

Effect of ethylene-vinyl acetate concentration on ethylcellulose-walled microcapsules: preparation and release kinetics of theophylline microcapsules

The effect of concentration of ethylene-vinyl acetate (EVA) copolymer, used as a coacervation-inducing agent, on the preparation of ethylcellulose microcapsules was studied with theophylline as the core material. The influence of EVA concentration on the micromeritic properties of the microcapsules and their drug release behaviour were investigated. Particle size distribution of the microcapsules obtained was dependent on the amount of EVA copolymer. As the EVA concentration increased the quantity of larger particles was reduced and that of the smaller particles was increased. Thus EVA might be used as a protective colloid to prevent aggregation of the microcapsules. The porosity of the microcapsules decreased with respect to EVA concentration, but the wall thickness of the microcapsules showed a corresponding increase. Zero-order release kinetics, from the resulting microcapsules in the initial dissolution phase was obtained. The apparent zero-order release rate in the initial steady-state decreased with the increase of EVA concentration, but T50 increased. The higher concentration of EVA causing a thick, compact wall lead to an effective prolongation of drug release.     

处方和工艺因素对氨茶碱魔芋胶骨架片体外释放度的影响

目的：考察处方和工艺因素对魔芋胶骨架片体外释放度的影响，评价魔芋胶作为新型载体材料用于缓释骨架片制备的可行性。方法：以氨茶碱为模型药物，采用粉末直接压片法和湿法制粒压片法制备魔芋胶骨架片，考察魔芋胶粒度、黏度和用量，填充剂种类，主药粒度，压片工艺，压片压力等对其体外药物释放的影响。结果：氨茶碱魔芋胶骨架片可缓慢释放药物；随魔芋胶粒度降低，骨架材料用量或主药粒度增加，药物释放减慢；与淀粉、微晶纤维素和乳糖相比，Eudragit L100作为填充剂，可明显延缓药物释放；压片工艺，压片压力和魔芋胶黏度对药物释放影响不大。结论：魔芋胶可作为一种新型载体材料用于缓释骨架片的制备，魔芋胶粒度、用量，主药粒度和填充剂种类是影响骨架片体外药物释放的主要因素。