布洛芬缓释微球的释放性能及体内外相关性研究

目的以壳聚糖及海藻酸钠为载体制备布洛芬缓释微球。方法对微球的体外释放特性、体内药物动力学及体内外相关性进行研究。结果布洛芬缓释微球体外药物释放行为符合Higuchi方程；与普通片剂相比，体内药代动力学中布洛芬缓释微球的达峰时间及半衰期延长，达峰浓度降低，生物利用度提高。结论所制布洛芬缓释微球达到了缓慢释放药物的目的，并且布洛芬缓释微球的体内外参数间有明显的相关性。     

布洛芬缓释制剂的研究概况

综述了布洛芬缓释制剂的近年来的研究概况。目前上市的布洛芬缓释制剂主要包括不溶性骨架片剂、溶蚀性骨架片剂、多单元缓释丸装硬胶囊剂、缓释微丸、缓释微球等剂型．以国内外发表的文献为依据．对布洛芬的各种缓释制剂制备原理、处方设计、辅料选择和制备工艺进行了介绍。最后简要归纳出难溶性药物（如布洛芬）缓释制剂的处方设计思路和辅料的选择原则。     

两种布洛芬剂型对儿童发热的疗效及安全性比较

目的通过对布洛芬缓释混悬液和布洛芬混悬液对儿童发热的退热效果及安全性比较,为临床合理选用药物提供依据。方法将体温≥38.5℃的患者分为观察组(布洛芬缓释混悬液组)和对照组(布洛芬混悬液组),分别于用药后0.5 h、1 h、2 h、4 h观察体温下降情况。结果两组降温的总有效率、降温速度、不良反应的发生率均无显著性差异(P>0.05),观察组作用维持时间较长。结论布洛芬缓释混悬液和布洛芬混悬液对儿童发热均具良好的效果和可告的安全性,但布洛芬缓释混悬液费用少,值得临床推荐。     

温敏壳聚糖凝胶共混环糊精对布洛芬的体外缓释性能

目的研究壳聚糖/甘油磷酸钠（CS/GPS）温敏性水凝胶共混β-CD包合物对药物的缓释性能。方法试管倒置法研究不同配比的CS/GPS温敏凝胶化性能;饱和水溶液法制备布洛芬/β-CD包合物,红外光谱表征包合物;紫外分光光度法测定包合物载药量和药物的累积释放度。结果体积配比5/1的2%CS/56%GPS体系（pH6.9）在37℃下可实现快速凝胶化。分别以布洛芬和布洛芬/β-CD包合物为模型药物,考察在温敏凝胶中的缓释行为,载有布洛芬凝胶24h药物累积释放度为81.5%,载有布洛芬/β-CD包合物凝胶累积释放度为69.1%。而24h布洛芬原药累积释放度为98.1%,布洛芬/β-CD包合物的累积释放度为82.2%。结论温敏性凝胶共混β-CD包合物,比单纯使用凝胶包埋药物或β-环糊精包合对药物具有更加明显缓释效果。CS/GPS凝胶体系有望作为温度敏感性给药系统的理想载体。     

Box-Behnken效应面法优化布洛芬缓释滴丸的处方

摘 要 目的：制备布洛芬缓释滴丸,考察其体外累积释放度,并验证药物在基质中存在的状态。方法: 以含药量、水溶性与难溶性基质比、硬脂酸与单硬脂酸甘油脂用量比为考察因素,以2 h和10 h累积溶出率的综合评分为评价指标,应用Box Behnken 效应面法筛选布洛芬缓释滴丸的最优处方。采用差示扫描量热法（DSC）考察药物在基质中存在的状态。结果: 布洛芬缓释滴丸的最优处方为：含药量10%,水溶性与难溶性基质比为4∶1,硬脂酸与单硬脂酸甘油酯用量比为3∶1。制得的布洛芬缓释滴丸10 h的最大累积溶出率可达78.85%。DSC分析表明,在缓释滴丸中药物结晶峰消失,形成了固体分散体。结论:所制得的布洛芬缓释滴丸具有良好的缓释效果,且制备工艺简单。     

芬必得

芬必得系将布洛芬制成缓释剂型(布洛芬缓释胶囊),它能使药物在体内逐渐释放,2～3小时血药浓度达到高峰,血浆半衰期为4～5小时。因而该药血药浓度波动较小,其血清浓度说     

多剂量口服布洛芬缓释胶囊在健康人体的相对生物利用度

本文通过ＨＰＬＣ法对布洛芬和芬必得两种缓释胶囊达稳态后，血浆中布洛芬的药物动力学与相对生物利用度研究，观察缓释效果和波动系数，为临床提供合理的用药依据。     

不同取样位置对溶出度测定结果的影响

以非崩解型溶出度校正片水杨酸片和布洛芬缓释胶囊为模型药物,考察中外药典不同取样位置对药物溶出度测定的影响.两种方法所得溶出曲线经威布尔(Weibull)分布模型拟合,水杨酸片、布洛芬缓释胶囊的AUC、Td和T50等均无显著性差异(P＞0.05).     

扎托布洛芬缓释微丸的制备及释放特性

目的 以不同处方制备扎托布洛芬缓释微丸,考察包衣层处方对药物释放的影响及其释药特性.方法 采用空白丸芯流化床混悬液上药法制备扎托布洛芬载药微丸,以HPMC为隔离材料包隔离衣、以乙基纤维素水分散体为缓释材料,考察不同种类、用量的致孔剂以及包衣增重对药物释放行为的影响.结果 以10％ HPMC为致孔剂、缓释衣层包衣增重为4.5％时,制得的微丸具明显的缓释效果,其释放曲线符合一级动力学,且批内及批间重复性良好.结论 制得的扎托布洛芬缓释微丸具有较理想的体外缓释效果.     

布洛芬缓释滴丸的处方工艺优化及体外释药行为评价

目的:优化布洛芬缓释滴丸的处方工艺并评价其体外释药特征。方法:以硬脂酸为缓释基质、聚乙二醇6000为速释基质,采用熔融法制备布洛芬缓释滴丸。以圆整度、丸重差异、载药率、体外释药时间的综合评分为指标,以药物与基质质量比、药液温度、冷凝温度、滴距为因素,通过正交试验优化处方工艺并验证。在去离子水、盐酸溶液(pH 1.2)、磷酸盐缓冲液(pH 4.5、6.8)4种介质中,比较自制缓释滴丸与市售布洛芬缓释胶囊的体外释药行为,并对前者的释药行为进行拟合。结果:最优处方工艺为布洛芬-聚乙二醇6000-硬脂酸的质量比为4.0∶15.3∶0.7,药液温度为83℃,冷凝温度为8℃,滴距为11 cm;所制3批布洛芬缓释滴丸的丸重差异为2.067%、圆整度为96.73%、载药率为96.31%、12 h的累积释放度为93.05%,RSD分别为1.19%、0.28%、0.19%、0.81%。自制缓释滴丸与市售布洛芬缓释胶囊体外释药行为的相似因子f2均大于50,前者释药更符合Higuchi方程(r为0.988 1~0.997 2)。结论:成功优化布洛芬缓释滴丸的处方工艺,所制缓释滴丸的体外释药行为与市售布洛芬缓释胶囊相似。     

The effect of the amount of binder liquid on the granulation mechanisms and structure of microcrystalline cellulose granules prepared by high shear granulation

The structure of granules changes during the high shear granulation process. The purpose of this research was to investigate the effect of the amount of binder liquid on the structure of the granules and the structural changes which occur during the granulation process, using microcrystalline cellulose (MCC) and water as the model system. The structure is the result of the granulation mechanism; therefore, conclusions can be drawn about the latter by studying the former. X-ray microtomography and scanning electron microscopy (SEM) were applied in order to visualise the densification process of granules, which were first freeze dried in order to preserve their structure. Variations in their porosity were quantified by applying image analysis to the tomography results. In order to link the granule mechanical properties to their structural differences, a micromanipulation technique was used to measure granule resistance to deformation. MCC granules granulated with 100% (w/w) water showed increased densification with time, as expected; detailed examination showed that densification is more pronounced in the core of the granule; whereas the outer part remained more porous. Increased densification reduces deformability, so that granules become more resistant to breakage. The lower deformability of the densified granules in the final stages of granulation might result in establishment of equilibrium between attrition and growth, without substantial gross breakage. On the other hand, when more water was used (125%, w/w), densification was hardly observed; the porosity of the granule core was still high even after prolonged granulation times. This may be explained by the fact that higher water content increases the ease of deformation of granules. This increased deformability led to significant granule breakage even during the final phases of the granulation process. Therefore, for these granules a final equilibrium between breakage and coalescence might be established. This also explains why more granules produced with 125% granulation liquid were composed of fragments of irregular shape.

Our results establish the link between the granulation behaviour of MCC in the latter stages and the material structure of these granules, which is determined by their liquid content. The process conditions (amount of liquid) to be chosen depend largely on the final purpose for which the granular material is produced.     

Microcrystalline cellulose and its microstructure in pharmaceutical processing.

Mercury porosimetry and nitrogen adsorption methods were used in pore structure and pore surface area characterisation of microcrystalline cellulose powder, granules and tablets. The effect of compression on pore structure and surface area of tablets compressed with three different compression pressures of powder and granules was determined. Densification of MCC in wet granulation led to decreased compactibility in tableting. Effects of granulation on the microstructure of microcrystalline cellulose and plastic deformation of powder during compression were detected with nitrogen adsorption, at the diameter range 3-200 nm. Structure of granules was destroyed during tableting when compression pressures of 196 MPa were used. Fragmentation and deformation of granules were observed from the results determined using both methods. Due to different measurement ranges, different theoretical basis of the methods and behaviour of the samples during analysis, results obtained with mercury porosimetry and nitrogen adsorption methods are not strictly comparable. Results obtained with mercury porosimetry give information on the behaviour of powder and granule particles in granulation or compression, whereas nitrogen adsorption brings out the changes in intraparticular structure of particles. The results obtained using these methods together can be used in the characterisation of behaviour of materials in granulation and tableting.     

Change in porosity parameters of lactose, glucose and mannitol granules caused by low compression force

The change in porosity parameters, i.e., total pore volume, porosity percentage and pore volume size distribution of lactose, glucose and mannitol granules caused by compression with a low force was investigated. In compression, fragmentation of lactose and glucose granules increased total pore volume and porosity percentage, whereas the total pore volume and porosity percentage of mannitol granules was clearly decreased. This was due to the highly porous structure of mannitol granules, which densified easily in compression. Lactose and glucose granules were shown to resist deformation more. The pore volume size distributions of lactose and glucose tablets showed that large pores ( > 14 μm) decreased in size. For mannitol tablets, the large pores vanished and simultaneously the small granule pores ( < 14 μm) reduced in size. The features of the pore structure of granules were detected in the pore volume size distributions of compressed tablets. Mercury porosimetry, assisted by scanning electron microscopy, was shown to be an adequate method to evaluate the deformation of granules in compression.     

Application of Carbopol/PVP interpolymer complex to prepare mucoadhesive floating granule

Novel mucoadhesive floating granule was prepared using Carbopol/PVP interpolymer complex to deliver hydrophilic drugs in a controlled manner. Acetaminophen was used as a model drug. Maximum floatability of the granules was obtained at the ratio of 1/1, where 95 % of the granules floated for 12 h. As the concentration of sodium bicarbonate increased, both the floating duration and the release rate of the drug increased. The granules without sodium bicarbonate floated only for 2 h and floating onset time was 15 min. The release rate of drug gradually increased as the drug content in the granule increased. As the drug content in the granules increased, duration of adhesion decreased. However, the decrease in adhesion duration was minimal up to 40 % of drug content. The release rate from the granules prepared by dry granulation method was faster than that by wet granulation. The granules prepared by dry granulation method led to formation of highly porous structure; whereas, that by wet granulation method showed non-porous structure. The optimum size of the granules to retard the release of the model drug was within the range of 3–4 mm. Based on both mucoadhesive and buoyant properties, the floating granules are expected to reside in the upper part of the stomach for sufficient period of time and release the drug in a sustained manner.     

The effect of shape and porosity on the compression behaviour and tablet forming ability of granular materials formed from microcrystalline cellulose.

The compression behaviour of two types of granules prepared from microcrystalline cellulose was evaluated. Three sets (low, intermediate and high intragranular porosity) of irregular granules and three sets of nearly spherical granules (called pellets) were prepared from microcrystalline cellulose by wet agglomeration or wet agglomeration followed by extrusion/spheronisation. The granules and pellets were similar in size. The range of intragranular porosity, although wide, was also similar for both types. The compression behaviour was evaluated in terms of the degree of compression, the appearance of the tablets and the size distribution of retrieved aggregates (after deaggregation). The compactability of the granules and pellets was also studied. Both types of granules kept their integrity during compression. The dominant mechanism during compression appeared to be permanent deformation. However, during compression of high porosity granules, fragmentation or attrition seemed to occur alongside deformation. Tablets formed from granules had a closer pore structure than those formed from pellets of equal intragranular porosity and the granules seemed to deform to a higher degree during compression. The total tablet porosity was almost independent of the intragranular porosity and the shape of the granules before compression. It is suggested that the degree of granule deformation was controlled by the intragranular porosity and voidage of each bed of granules before compression. The tensile strength of the tablets was also dependent on the porosity and the shape of the granules; tablets formed from irregular granules were stronger than those formed from pellets of an equal intragranular porosity.     

Histological observations on intrahepatocytic copper-containing granules in rainbow trout reared on diets containing elevated levels of copper

The histological nature of hepatic copper deposition in the liver of rainbow trout reared on diets containing elevated levels of copper was investigated.

Two growth trials were conducted using practical diets with graded levels of supplemental copper, with determined maximum levels of 3088 mg/kg and 664 mg/kg copper. Histochemical observations using a rhodanine stain with a Harris hematoxylin counterstain revealed the presence of many rhodanine-positive granules in the hepatocytes of trout reared on diets containing the highest levels of copper supplementation. Ultrastructurally, electron-dense granules were visible in the cytoplasm of individual hepatocytes. Electron microprobe analysis confirmed the presence of large amounts of copper in these granules, along with a substantial amount of sulphur. These observations show that rainbow trout have the ability to sequester dietary copper in discrete granules in the cytoplasm of hepatocytes. The pericanalicular arrangement of the granules within the hepatocyte may suggest that these granules function in the excretion of excess copper in the bile.     

羚羊角类药材的宏观与微观鉴别研究

作者对常用中药羚羊(赛加羚羊Saiga tatarica L.)角及其类似品——鹅喉羚羊(Gazella subgutturosa Guldenstaedt)角、黄羊(Procapra gutturosa Pallas)角和藏羚羊(Pantholops hodgsoni Abel)角的形态、显微构造和粉末特征作了详细的研究和比较。从横切面观察,这四种动物角的组织均呈波浪状起伏,可分为波峰与波谷部,束常居波峰部。束呈类三角形、双凸透镜形或类圆形;束的周围同心性皮层细胞比较少(少于10层);束间为宽广的基本角质组织。这四种角从组织构造上很难互相区别,只能根据其细胞所含色素颗粒的不同颜色和颗粒的多少等加以鉴别。文后附有外形检索表与显微检索表。     

Tissue distribution and subcellular localization of trace metals in the pond snail Lymnaea stagnalis with special reference to the role of lysosomal granules in metal sequestration

The present study was undertaken to elucidate the cellular mechanisms, which govern metal sequestration and detoxification in gastropods. For this purpose the pond snail, Lymnaea stagnalis was exposed to environmentally relevant concentrations of three species of metals (Al, Zn and Cd) for 30 days and the localization and fate of these metals were followed in different tissues of the snails. The measurement of relative distribution of metals between tissues revealed that the digestive gland and kidney account for most of the accumulated metals. Al and Cd (non-essential metals) were redistributed to the digestive gland, possibly because of the presence of specific binding entities in the digestive glands of the herein species. This study focuses on the role of intracellular metal-containing granules on metal sequestration. Three main types of granules were identified in the digestive gland cells namely small, green and yellow granules. The morphological examination and the progressive accumulation of elements within these granules revealed that they are developmental stages with the yellow granule being the mature one. The total number of these granules was found to be significantly increased upon exposure of the snails to Al only. This increase may be a response to the large amount of Al that is accumulated through feeding route of this grazing snail. X-ray microanalysis (XRMA) revealed that metals were localized in all three types of digestive gland granules. The increased amount of ligands (P and S) in the granules may give evidence for their role in metal sequestration. Levels of Al and P were positively correlated in the digestive gland granules. It is possible that aluminium is bound to phosphorus to render it insoluble and so to both immobilize it within the lysosome and to be excreted in a highly insoluble form. On the other hand, both Zn and Cd induced marked upregulation of S in mature (yellow) granules by 26- and 11-folds, respectively. The lysosomal codeposition of S and either Cd or Zn in the lysosomal granules in addition to the increase in RER cisternae may indicate that the exposure to these metals could induce metallothionein synthesis in the cells. The microscopical examinations in the present study revealed that metal detoxification from the digestive gland cells may occur via faeces or via basal exocytosis towards hemocytes dispersed by the connective tissue in the visceral mass. In the kidney, one type of granules, the excretory concretions, was identified in the nephrocytes. The significant increase in the number of these concretions in the snail L. stagnalis upon exposure to metals may give further evidence for their role in metal excretion.     

Characterization of microcrystalline cellulose and silicified microcrystalline cellulose wet masses using a powder rheometer.

A powder rheometer has been used to study the properties of wet powder masses and the results have been compared to the mixer torque rheometer (MTR). Two different microcrystalline cellulose (MCC) grades (Avicel and Emcocel) and silicified microcrystalline cellulose (SMCC, Prosolv) were used as model powders. The wet massing behaviour of one material (Prosolv) was studied by the powder rheometer using liquid addition experiments, while the rheological properties of wet granules were studied using both the powder rheometer and the MTR. In water addition measurements the torque behaved in a similar way to MTR measurements and the maximum value of ZTL (zero torque limit) was achieved at the capillary state of wet mass. The wet granules exhibited different behaviour in the powder rheometer and the MTR experiments, which indicates that these rheometers involve different shear forces or they measure different properties of the wet granules. Emcocel wet masses achieved the capillary state at lower liquid amount than Avicel and Prosolv masses, which indicates that Emcocel is not able to hold as much water in the internal structure as Avicel and Prosolv. The powder rheometer proved to be a sensitive piece of equipment, which can be used to study both dry and wet powder masses. It was able to distinguish wet granules from wet powder masses after liquid addition, whereas the MTR could not. However, before the powder rheometer can be properly utilised in wet powder mass studies, the problem of torque overload requires resolution.     

藿香正气全浸膏剂薄层色谱分析法研究

藿香正气全浸膏剂是由１３味中药组成的新剂型。用薄层色谱法对该全浸膏剂中的甘草与陈皮，厚朴与生姜的同时定性鉴别方法，并用该法对不同批号和加速试验样品进行了鉴别，结果表明本法简便、可靠，可作为本品上述药材的良好鉴别方法。