香草醛交联壳聚糖载药微球的性能及其成球机理分析

以壳聚糖溶液为水相、液体石蜡为油相形成油包水型乳液, 以香草醛为交联剂, 采用乳化交联法制得壳聚糖微球. 结合IR光谱和XRD测试, 分析了壳聚糖交联固化成球的机理: 壳聚糖和香草醛之间所发生的Schiff碱反应和氢键的形成以及缩醛化反应, 以此为基础共同形成交联结构从而使壳聚糖交联固化成球. 探讨了交联后壳聚糖微球结晶度降低的原因: 壳聚糖固化时分子链未充分进行有序的结晶排列, 交联后的壳聚糖结构较复杂, 从而破坏了原壳聚糖分子的规整性. 选用盐酸小檗碱为模型药物, 制备了香草醛交联的壳聚糖载药微球, SEM结果显示, 载药微球表面致密且球形度好, 微球粒径在5-15 μm之间. 此外, 采用分光光度计对载药微球的载药率、药物包封率和药物体外释放性质进行了测试和分析, 结果表明载药微球缓释效果明显.     

基于壳聚糖衍生物的蛋白质药物载体材料的制备及性能

在离子液体均相体系中合成了一种新型两亲性窄分子量分布的低聚壳聚糖衍生物月桂基-琥珀酰化壳聚糖(LSCOS). 以LSCOS为载体材料, 以牛血清蛋白(BSA)为模板蛋白, 以戊二醛为交联剂, 用油包水(W/O)乳化交联法制备了包载BSA的BSA/LSCOS缓释载药微球. 通过扫描电子显微镜(SEM)、 透射电子显微镜(TEM)及紫外-可见光谱(UV-Vis)研究了BSA/LSCOS比率和戊二醛/LSCOS比率对微球的形貌结构、 包埋率、 载药率和体外药物释放特性的影响. 结果表明, 在离子液体中合成的LSCOS包覆了BSA, 形成的微球粒径约为1 μm, 微球表面随BSA用量的增加变得光滑, 随戊二醛用量的增加变得粗糙. BSA的累积释放率与BSA包载量成正比, 与交联剂添加量成反比, 因此, 可通过控制蛋白质药物的添加比率和交联剂用量来控制蛋白质药物体外释放率.     

左旋多巴-壳聚糖微球的制备及其释药性能

采用乳化分散-离子交联法,以三聚磷酸钠为离子交联剂,制备了左旋多巴-壳聚糖微球,并考察其理化性质和药物释放性能。偏光显微镜观察表明,得到的微粒基本成球;经激光粒度仪测定,其平均粒径约为3.5μm。红外光谱分析表明,壳聚糖中的氨基质子化后与三聚磷酸钠以静电结合,而左旋多巴则被包裹在壳聚糖微球内。DSC及XRD分析结果表明,微球内部存在左旋多巴结晶,而壳聚糖则以无定形聚集态存在。TG分析结果表明,壳聚糖与三聚磷酸钠结合后分解温度降低。微球的药物释放性能显pH依赖性,在酸性环境下,微球的释药速率随壳聚糖浓度的增加而降低,随载药比例的增大而降低;而在碱性介质中总体的释药速率要比酸性介质中的大。     

阿司匹林-蒙脱土-壳聚糖缓释微球的制备及其体外释放性能

利用溶液法预先制备壳聚糖(Cs)-蒙脱土(MMT)复合材料(Cs-MMT),以Cs-MMT、Cs为原料,采用反相悬浮聚合法制得一种新型药物缓释体系阿司匹林-蒙脱土-壳聚糖载药微球(Asp-MMT-Cs)。采用FT-IR、SEM表征了Cs-MMT和Asp-MMT-Cs载药微球的结构及形态;设计正交实验优化了Asp-MMT-Cs载药微球的制备工艺;通过体外释放实验探讨了载药微球在不同模拟释放液中的释药规律。结果表明:所得微球球形度好,粒径分布较均匀;最优工艺制得的载药微球平均粒径为81.20μm,载药量为9.61%,包封率为76.78%。该缓释体系具有pH敏感性,更倾向于在pH较高的磷酸盐缓冲溶液中释放。     

两种前处理方法对LC - MS/MS测定家兔血清中淫羊藿黄酮类化合物基质效应的影响

考察了两种前处理方法对采用液相色谱-串联质谱联用法( LC - MS/MS)测定家兔血清中淫羊藿黄酮类化合物时基质效应的影响.家兔空白血清分别以乙酸乙酯液-液萃取和C18小柱固相萃取,提取前、后各自加入一定浓度的4种淫羊藿黄酮类化合物的混合对照品溶液(淫羊藿苷、淫羊藿次苷I、淫羊藿次苷Ⅱ、淫羊藿素),评价家兔血清中淫羊...     

生物降解聚酯包埋利福平缓释微球的制备及释放行为

以生物可降解乙交酯和丙交酯的无规共聚物(PLGA)为载体,将抗结核病药利福平溶解于PLGA的有机溶液中,采用通常乳化-溶剂挥发方法制备了药物缓释微球.研究了影响微球制备的工艺条件.用电子显微镜观察了微球及降解后的表面形态,测定了微球粒径及载药量,评价了载药微球的体外释放行为.结果表明,以质量分数为1%的明胶为稳定剂,制备的微球形态完整,粒径范围为10～30μm,微球中利福平的平均质量分数为24.3%.体外释药时间可以通过高分子的降解速率来调控,本实验的释药时间可以在42～84d之间调控,药物缓释达到了理想的零级动力学释放.因此,利福平PLGA微球具有显著的长效、恒量药物缓释作用.     

壳交联pH响应型PLGA载药微球的制备与研究

首先采用一次乳化法制备出PLGA[聚(乳酸-羟基乙酸)]纳米微球,并通过静电吸附将阳离子聚合物壳聚糖修饰到PLGA微球表面,然后以香草醛为交联剂对壳聚糖进行化学交联,得到一种壳交联的p H响应型纳米微球(PCV),微球粒径为(277.60±38.01)nm,表面电位为(21.60±4.51)m V.微球稳定性评价结果显示微球在24 h内粒径变化较小;流式细胞仪检测显示细胞对PCV微球的摄取量比未经修饰的PLGA微球的摄取量高;空白微球细胞毒性实验表明在空白微球浓度小于80μg/m L时细胞的存活率达93.24%.以多西他赛(DTX)为模型药物进行包载,该纳米微球DTX的载药率为7.48%,包封率为34.98%;体外药物释放实验显示,该微球在p H=5.0环境下孵育90 h的药物积累释放率达58.66%,而在p H=7.4的环境下的药物积累释放率为50.63%;此外,载DTX微球毒性试验结果表明该载药微球对A549肺癌细胞有较强的杀伤作用,其IC50值可达0.0009μg/m L.     

双重载药多层海藻酸盐-壳聚糖缓释微球的制备及体外释放

采用滴注法将海藻酸钠与钙离子交联,制成负载血管内皮生长因子(VEGF)的藻酸钙核心球,利用层层自组装技术在核心球的表面依次包覆壳聚糖、海藻酸和壳聚糖,壳聚糖中负载万古霉素(VAN),形成多药载药缓控体系.采用正交实验考察海藻酸钠浓度、钙离子浓度及壳聚糖浓度对VEGF和VAN的药物包封率和载药量的影响,优化了制备工艺.采用扫描电子显微镜观察多层微球的表面、截面形貌及粒径,采用傅里叶变换红外光谱检测海藻酸盐与壳聚糖的自组装情况,分别采用酶联免疫吸附(ELISA)双抗体夹心法和紫外分光光度法检测VEGF和VAN的包封率、载药量及体外释放情况.结果表明,海藻酸钠最优浓度为0.04g/mL,氯化钙最优浓度为0.15g/mL,壳聚糖最优浓度为0.01g/mL.微球光滑圆整,均质实心,直径900~1100μm,VEGF的包封率达61.31%,VAN的包封率为3.48%.体外释放实验结果表明,VEGF缓释时间为15.5d,并出现2个释放高峰;VAN缓释时间为4.5d,释药情况平稳持续,无明显突释.双重载药多层包覆微球兼具控制感染和促进血管生成两种潜能,有望应用于组织工程骨的基础研究和临床实践.     

层层自组装芸香叶苷海藻酸钠/壳聚糖盐酸盐微球的制备及释药性研究

为了提高载药微球的成球性和机械性能,以搅拌共沉淀法制得的CaCO_3微球为吸附剂,采用离子交联法制备载芸香叶苷的海藻酸钙(ALG-Ca)模板凝胶,利用层层自组装技术(LBL)将带有相反电荷的海藻酸钠(ALG)和壳聚糖盐酸盐(CHI)逐层络合得到不同膜层的载芸香叶苷微球。通过FT-IR、SEM、溶胀实验和体外释药实验对载药微球的性能进行研究,结果表明,以CaCO_3微球为吸附剂可提高载药ALG-Ca/(CHI/ALG)3微球的机械性能和成球性,微球剖面边缘出现层层膜结构且膜层总厚度约为20.22μm,载芸香叶苷ALG-Ca/(CHI/ALG)n微球释药实验发现,在37℃、pH=1.2生理盐水和pH=6.8 PBS溶液的环境下,聚合物膜层数越多对芸香叶苷缓释能力越强。     

肾上腺髓质素微球复合PLGA/纳米轻基磷灰石支架材料的制备及生物活性评价

利用离子乳化交联法制备了负载肾上腺髓质素的壳聚糖微球,应用热致相分离法制备了乳酸和乙醇酸共聚物/纳米羟基磷灰石(PLGA/nHA)支架材料并在其中包覆载药微球.通过扫描电子显微镜、体外释放行为、材料溶血行为、碱性磷酸酶(ALP)活性的测定、支架材料表面细胞荧光染色和MTT[3-(4,5-二甲基噻唑-2)-2,5-二苯基...     

Study on colon-specific 5-Fu pH-enzyme Di-dependent chitosan microspheres

Colon-specific drug delivery systems (CDDS) can improve the bioavailability of drug through the oral route. A novel formulation for oral administration using pH-enzyme Di-dependent chitosan mcirospheres (MS) and 5-Fu as a model drug has been investigated for colon-specific drug delivery by the emulsification/chemical cross-linking and coating technique, respectively. The influence of polymer concentration, ratio of drug to polymer, the amount of crosslinking agent and the stirring speed on the encapsulation efficiency, particle size in microspheres were evaluated. The best formulation was optimized by an orthogonal design. Drug release studies under conditions mimicking stomach to colon transit have shown that the drug was protected from being released in the physiological environment of the stomach and small intestine. The plasma concentrations of 5-Fu after oral administration of coated chitosan MS to rats were determined and compared with that of 5-Fu solution. The in vivo pharmacokinetics study of 5-Fu loaded pH-enzyme Di-dependent chitosan MS showed sustained plasma 5-Fu concentration-time profile. The in vitro release correlated well with the pharmacokinetics profile. The results clearly demonstrated that the pH-enzyme Di-dependent chitosan MS is potential system for colon-specific drug delivery of 5-Fu.     

The influence of chitosan on in vitro properties of Eudragit RS microspheres

Eudragit RS microspheres containing chitosan hydrochloride were prepared by the solvent evaporation method using acetone/liquid paraffin solvent system and their properties were compared with Eudragit RS microspheres without chitosan, prepared in our previous study. Different stirring rates were applied (400-1200 rpm) and drug content, Higuchi dissolution rate constant, surface and structure characteristics of the microspheres were determined for each size fraction. An increase in average particle size with a reduction of stirring rate appeared in limited interval in both series. The average particle size of microspheres without chitosan, prepared at the same stirring rate, was smaller. Pipemidic acid content increased with increasing fraction particle size, but not with increasing stirring rate as it was observed for microspheres without chitosan. We presume that high pipemidic acid content in larger microspheres is a consequence of cumulation of undissolved pipemidic acid particles in larger droplets during microspheres preparation procedure. Pipemidic acid release was faster from microspheres with chitosan and no correlation between Higuchi dissolution rate constant and stirring rate or fraction particle size was found, though it existed in the system without chitosan. Structure and surface characteristics of microspheres observed by scanning electron microscope (SEM) were not changed significantly by incorporation of chitosan. But in contrast with microspheres without chitosan, the surface of chitosan microspheres was more porous after three hours of dissolution. It is supposed that the influence of particle size fraction and stirring rate on release characteristics is expressed to a great extent through porosity and indirectly through total effective surface area, but the incorporation of highly soluble component i.e. chitosan salt hides these effects on drug release. In conclusion, changes in biopharmaceutical properties due to varying stirring rate and fraction particle size exhibited the same direction as those reported for the microspheres without chitosan, although they are less expressed because of increased experimental variability, likely caused by chitosan.     

Preparation of uniform-sized pH-sensitive quaternized chitosan microsphere by combining membrane emulsification technique and thermal-gelation method

In this study, uniform-sized pH-sensitive quaternized chitosan microsphere was prepared by combining Shirasu porous glass (SPG) membrane emulsification technique and a novel thermal-gelation method. In this preparation process, the mixture of quaternized chitosan solution and alpha-beta-glycerophosphate (alpha-beta-GP) was used as water phase and dispersed in oil phase to form uniform W/O emulsion by SPG membrane emulsification technique. The droplets solidified into microspheres at 37 degrees C by thermal-gelation method. The whole process was simple and mild. The influence of process conditions on the property of prepared microspheres was investigated and the optimized preparation condition was obtained. As a result, the coefficient of variation (C.V.) of obtained microspheres diameters was below 15%. The obtained microsphere had porous structure and showed apparent pH-sensitivity. It dissolved rapidly in acid solution (pH 5) and kept stable in neutral solution (pH 7.4). The pH-sensitivity of microspheres also affected its drug release behavior. Bovine serum albumin (BSA) as a model drug was encapsulated in microspheres, and it was released rapidly in acid solution and slowly in neutral medium. The novel quaternized chitosan microspheres with pH-sensitivity can be used as drug delivery system in the biomedical field, such as tumor-targeted drug carrier.     

Colon specific chitosan microspheres for chronotherapy of chronic stable angina

In the present work, chitosan microspheres with a mean diameter between 6.32 μm and 9.44 μm, were produced by emulsion cross-linking of chitosan, and tested for chronotherapy of chronic stable angina. Aiming at developing a suitable colon specific strategy, diltiazem hydrochloride (DTZ) was encapsulated in the microspheres, following Eudragit S-100 coating by solvent evaporation technique, exploiting the advantages of microbiological properties of chitosan and pH dependent solubility of Eudragit S-100. Different microsphere formulations were prepared varying the ratio DTZ:chitosan (1:2 to 1:10), stirring speed (1000-2000 rpm), and the concentration of emulsifier Span 80 (0.5-1.5% (w/v)). The effect of these variables on the particle size and encapsulation parameters (production yield (PY), loading capacity (LC), encapsulation efficiency (EE)) was evaluated to develop an optimized formulation. In vitro release study of non-coated chitosan microspheres in simulated gastrointestinal (GI) fluid exhibited a burst release pattern in the first hour, whereas Eudragit S-100 coating allowed producing systems of controlled release diffusion fitting to the Higuchi model, and thus suitable for colon-specific drug delivery. DSC analysis indicated that DTZ was dispersed within the microspheres matrix. Scanning electron microscopy revealed that the microspheres were spherical and had a smooth surface. Chitosan biodegradability was proven by the enhanced release rate of DTZ in presence of rat caecal contents.     

Acyclovir-Loaded Chitosan Microspheres for Gastroretention: Development and Evaluation

Mucoadhesive chitosan microspheres of acyclovir were prepared to prolong the gastric residence time using simple emulsification phase separation technique. The particle morphology of drug-loaded formulations was measured by SEM and the particle size distribution was determined using an optical microscope. The release profile of acyclovir from microspheres was examined in simulated gastric fluid (SGF pH 1.2). The particles were found to be discreet and spherical with the maximum particles of an average size (31.62 ± 4.64). The entrapment efficiency was found to be in the range of 40.24 to 67.29%. The concentration of the glutaraldehyde (25%v/v) as a cross-linker 2 ml and drug polymer ratio of 1:2 caused an increase in the entrapment efficiency and the extent of drug release. The optimized chitosan microspheres were found to possess good bioadhesion (79.89 ± 1.01%). The gamma-scintigraphy study showed the gastric residence time of more than 6 hours which revealed that optimized formulation could be a good choice for gastroretentive systems.     

Effect of method of preparation and process variables on controlled release of insoluble drug from chitosan microspheres

An inexpensive and simple method was adopted for the preparation of chitosan microspheres, crosslinked with glutaraldehyde (GA), for the controlled release of an insoluble drug‐ibuprofen, which is a commonly used NSAID (non‐steroidal anti‐inflammatory drug). The chitosan microspheres were prepared by different methods and varying the process conditions such as rate of stirring, concentration of crosslinking agent, and drug:polymer ratio in order to optimize these process variables on microsphere size, size distribution, degree of swelling, drug entrapment efficiency, and release rates. The absence of any chemical interaction between drug, polymer, and the crosslinking agent was confirmed by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analyses (TGA) techniques. The microspheres were characterized by optical microscopy, which indicated that the particles were in the size range of 30–200 µm and scanning electron microscopy (SEM) studies revealed a smooth surface and spherical shape of microspheres. The microsphere size/size distributions were increased with the decreased stirring rates as well as GA concentration in the suspension medium. Decreasing the concentration of crosslinker increased the swelling ratio whereas extended crosslinking exhibited lowered entrapment efficiency. The in vitro drug release was controlled and extended up to 10 hr. Copyright © 2007 John Wiley & Sons, Ltd.     

Alginate/gelatin blend films and their properties for drug controlled release

Films of alginate and gelatin, cross-linked with Ca²⁺, with ciprofloxacin hydrochloride as model drug incorporated in different concentrations, were obtained by a casting/solvent evaporation method. Chemical, morphological and mechanical properties characterization was carried out, as well as the studies of the factors that influence the drug releasing from alginate and gelatin films. These factors included the component ratio of alginate and gelatin, the loaded amount of ciprofloxacin hydrochloride, the pH and ionic strength of the release solution, the thickness of the drug loaded films and the cross-linking time with Ca²⁺ and others. The best values of the tensile strength at 101.5 MPa and breaking elongation at 19.4% of blend films were obtained when the gelatin content was 50 wt.%. The results of controlled release tests showed that the amount of ciprofloxacin hydrochloride released decreased with an increase in the proportion of gelatin present in the film. Moreover, the release rate of drug decreased as the amount of drug loaded in the film increased. The alginate/gelatin films were also sensitive to pH and ionic strength. For pH 7.4 the drug release was faster compared to pH 3.6, being simultaneously accelerated by a higher ionic strength. It was observed that in simulated intestinal fluid, the thickness of the film increased from 30 μm to 55 μm with a concomitant reduction of the ciprofloxacin hydrochloride concentration from 100% to 83.5%. When the cross-linking time of these films in the Ca²⁺ solution were 0 min, 5 min, 15 min and 30 min, the drug release rate attained 100%, 100%, 77.6% and 52.4%, respectively, within 24 h. All the results indicated that the alginate/gelatin film was potentially useful in drug delivery systems.