卡铂-乳酸/羟基乙酸共聚物微球的制备和体外性质

目的制备卡铂-乳酸/羟基乙酸共聚物(PLGA)微球,比较不同方法所得微球的形态、载药量和体外释药特点。方法采用相分离法和溶剂挥发法制备卡铂-PLGA微球,显微镜下测定微球的粒径和粒径分布,电子扫描显微镜观察微球表面形态。用电感耦合等离子体发射光谱法(ICP-AES)测定微球含药量,计算包封率,考察微球体外释药行为。结果两种方法所得微球球形较好,相分离法制得的卡铂-PLGA微球,平均粒径为22~31μm,含药量为42~61μg·mg-1、包封率21%~31%;体外释放试验中药物于24h完全溶出。溶剂挥发法所得微球平均粒径为38~54μm,含药量为7.2μg·mg-1、包封率约为20%;体外药物突释率约为39%,缓释期药物释放符合Higuchi模型,PLGA75/25、η=0.19和PLGA50/50、η=0.18的微球药物释放速度常数分别为2.40h-1/2和0.85h-1/2;体外14d累计释药分别达到71%和54%。结论相分离法制备卡铂-PLGA微球含药量高,但体外释药快,没有缓释作用;溶剂挥发法所得微球药物突释率较低,体外能控制药物缓慢释放。     

尼索地平微球体外释药的研究

 目的研究尼索地平缓释微球的体外释药行为.方法建立检测尼索地平微球释药量的高效液相色谱法(HPLC),考察自制微球在3种释放条件下的释药情况.结果动态透析法能较好地反映微球的实际释药行为.微球的体外释药行为的拟合方程为:1-Q=0.7610(1-t/too)3+0.1901(r=0.9983).结论微球释药缓慢而平稳.     

双氯芬酸钠壳聚糖-海藻酸钠微球的制备和性质简

目的制备双氯芬酸钠微球,获得理想的释药行为。方法以微球的载药量、包封率及体外释药行为评价指标,采用单因素考察确立了最佳处方;结果最佳处方为：壳聚糖分子量为150kD,海藻酸钠：壳聚糖=3：1,药物：空白微球=1：4,吸附时间为12h,吸附温度为37℃,得到药物浓度为5．0mg·ml-1结论以该最佳处方制备的微球,具有均匀的粒径和理想的释药行为。     

阿霉素磁性明胶微球的制备及特性检测

目的制备阿霉素磁性明胶微球检测其特性。方法采用乳化-交联法制备阿霉素磁性明胶微球。高倍显微镜观察微球粒径大小及形态,紫外分光光度法检测微球中阿霉素的含量,测定微球磁吸附率,计算求和值S,确定最佳投料比（药物∶载体）,绘制药物微球体外释放曲线。结果制备的阿霉素磁性明胶微球最佳投料比为1∶15,磁吸附率为100%。微球外形圆整,分散性好。阿霉素60min释放70%左右,240min持续释放90%以上。结论制备的阿霉素磁性明胶微球缓释性好,磁响应性强,可作为一种治疗顽固性疼痛的靶向神经损毁剂。     

环胞素A植入微球的体外释放研究

目的:研究长效环胞素A(CyA)/PLA微球的体外释药特性.方法:以聚乳酸(PEA)为基质,采用乳化-挥发法制备CyA/PLA微球,采用HPLC法测定CyA/PLA微球中的含量,考察微球的体外释药性能.结果:CyA在5～80μg·mL<'-1>范围内呈线性,平均回收率为99.6%,RSD=1.12%(n=9).28 d的体外释药百分率为(65.32.4)%.结论:CyA/PLA微球体系具有一定的缓释性能.     

紫杉醇长效缓释微球的制备与评价

目的：制备包含肉豆蔻酸异丙酯(IPM)的紫杉醇长效缓释微球，并对制备工艺及体内外缓释效果进行评价。方法：使用改良的单乳溶剂蒸发法制备紫杉醇长效缓释微球。通过分析粒径分布、突释、体外释放及体内的抑瘤效果等指标，对其进行评价。结果：所得微球平均粒径小于10μm，外观圆整，具有良好的体外释放曲线。含有30％IPM的微球体内抑瘤效果明显。结论：使用改良的单乳溶剂蒸发法制备的微球，可以达到缓释效果，体外释放4周的微球对小鼠体内的固体肿瘤有良好的抑制效果。     

GM-1 PLGA微球的制备工艺优化研究

目的优化W/O/W型乳化溶剂挥发法制备GM-1PLGA微球的工艺。方法以载药量为检测指标,通过单因素分析和均匀设计法筛选影响微球制备工艺的10种因素,优化GM-1PLGA微球的制备工艺。结果在优化条件下制备的微球形态规则,粒径为(18.9±8.1)μm,载药量为4.91%,微球体外释药规律符合Higuchi方程:Q=0.153t1/2 0.03705,r=0.995。结论该制备工艺合理,为制备GM-1PLGA微球提供了理论依据。     

重组人骨形态发生蛋白-2缓释凝胶微球的研制及其溶胀、降解、载药、释药特征

目的制备载人骨形态发生蛋白-2(rhBMP-2)的甲基丙烯酸缩水甘油酯右旋糖酐(dex-GMA)凝胶微球并初步考察其体外溶胀、降解、载药与释药特征。方法以液体石蜡为油相,Span-80为乳化剂,采用乳化化学交联技术制备载rhBMP-2的凝胶微球(BMP-HMs)并通过正交设计法优化其制备工艺;观察BMP-HMs形态和粒径,测定其包封率与载药量;用微球的吸水能力表示微球的溶胀率(Rs),扫描电镜观察微球的体外降解,动态观察体外释药特征及其与微球溶胀、降解的关系。结果所制备的BMP-HMs形态规整,粒径40～50μm,分布均匀;rhBMP-2载药量(10.6±4.8)%,包封率(88.9±1.0)%,BMP-HMs冻干剂4℃以下存放6个月性能稳定,但在磷酸盐缓冲液(PBS)中20～40d内可以完全降解。微球Rs随反应促进剂四甲基乙二胺(TEMED)用量的增大而减小,0.3mlTEMED制备的BMP-HMs体外释药实验表明80%的rhBMP-2在前20d左右释放。结论BMP-HMs对rhBMP-2具有确定的缓释作用,并可以通过制备工艺的改变控制其释药。     

盐酸多西环素牙周用微球温敏性凝胶的制剂学研究简

目的构建盐酸多西环素牙周用微球温敏性凝胶缓释系统。方法通过乳化一交联固化法制备盐酸多西环素羧甲基壳聚糖微球（DXY-CMCTS-MS）。采用壳聚糖和卢．甘油磷酸钠（β-GP）制备凝胶。用扫描电镜和光学显微镜观察微球表面形态;体外动态透析法测定释药性能。结果制备的DXY—CMCTS—MS形态圆整,粒径分布较为均匀,平均粒径约25μm,载药量18．9％,包封率64．6％。DXY微球凝胶在室温下为自由流动的液体,37℃的平均凝胶时间为（1．1±0．3）min,明显低于凝胶剂的凝胶时间。微球凝胶复合载体的释药速度明显低于微球剂,体外释药曲线符合Higuchi拟合方程。结论盐酸多西环素微球温敏凝胶复合载体的处方和制备工艺可行,作为牙周用缓释制剂值得进一步研究。     

血管内皮生长因子长效缓释微球不同配比对体外释放行为改善的研究

目的用生物可降解聚乳酸羟基乙酸共聚物(PLGA)制备载药微球包埋血管内皮生长因子(VEGF),并探索不同配比对释放行为的影响。方法采用不同分子量的PLGA制备不同粒径的载药微球,并经载药微球的合理配比改善其体外释放行为,达到优化工艺、降低成本的目的。结果载药微球粒径约为20μm、分子量10 kU:24 kU的配比为1:2组,粒径为20μm、分子量为24 kU和分子量为10 kU、粒径为6μm的载药微球配比为2:1组的体外释放突释较低,且在14 d内呈线性的零级释放趋势,体外释放行为得到改善。结论 VEGF长效缓释PLGA微球经优化配比后的持续释放能力较传统VEGF微球明显提高。     

不同制备工艺对胶质细胞源性神经营养因子微球理化性质及生物活性的影响

目的 评价不同制备工艺对胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)缓释微球的影响及微球所包裹的GDNF生物学活性.方法 以聚乳酸-羟基乙酸共聚物(polylactide-co-glycolide,PLGA)为包裹材料,采用复乳法(W1/O/W2)制备GDNF-PLGA微球,通过两因素析因设计方差分析,研究PLGA中乳酸(LA)与羟基乙酸(GA)单体组成比例和复乳搅拌速度对GDNF微球的粒径、包封率、突释率和体外释放行为的影响,并用PC-12细胞检测微球所释放的GDNF生物学活性,确定最佳制备工艺.结果 PLGA的单体组成比例可影响微球的突释率(P＜0.05),对粒径和包封率的影响无统计学意义,随着GA比例的增加,微球中GDNF释放速度加快.复乳搅拌速度由1 000 r/min增加到3 000 r/min后,微球的粒径显著减小(P＜0.01),突释率显著增加(P＜0.01),体外释放更为快速.微球中的GDNF在37℃下活性有效期可达20 d左右,较单独存放的GDNF活性有效期延长10 d以上.结论 复乳法可制备具有较高包封率和适宜体外释放时间的GDNF缓释微球,且活性有效期延长.

Abstract：

Objective To evaluate the effect of different preparation processes on preparation of the glial cell line-derived neurotrophic factor(GDNF)loaded microspheres and observe the biological activity of GDNF.Methods With polylactide-co-glycolide(PLGA)as the coating material,the GDNF-loaded microspheres were prepared by using double emulsion(W1/O/W2).Two-factor factorial design variance analysis was done to analyze the effects of the composition proportion of lactic acid(LA)and glycolic acid(GA)in PLGA and the stirring speed of multiple emulsion on particle size,entrapment efficiency,burst release and in vitro release characteristics of the GDNF-loaded microspheres.PC-12 bioassay was employed to detect the biological activity of the released GDNF so as to determine the optimal preparation process.Results The composition proportion of PLGA could affect the microspheres'burst release(P ＜ 0.05),with no effect on particle size and entrapment efficiency.with the higher.With higher proportion of GA,the release speed of GDNF in the microspheres was increased.When the stirring speed of multiple emulsion was increased from 1 000 r/min to 3 000 r/min,the particle size of the microspheres was decrease significantly(P ＜ 0.01),the burst release was increased markedly(P ＜ 0.01)and the in vitro release rate was accelerated.The activity of GDNF in the microspheres could last for about 20 days at 37℃,which was 10 days longer than that of single GDNF.Conclusions Double emulsioncan prepare the GDNF-loaded microspheres with high entrapment efficiency and suitable in vitro release time.In the meantime,the microspheres can extend the validity of GDNF.     

常用的蛋白质保护剂对NGF-PLGA微球性质的影响

目的研究常用的蛋白质保护剂对微球性质的影响特点。方法复乳化溶剂挥发法制备NGF-PLGA微球，分别添加葡萄糖，聚乙二醇，卵清蛋白作保护剂，观察微球的形态，载药量、包封率及体外释放特点，研究保护剂的作用特点。结果保护剂对微球的粒径、包封率和载药量影响不明显，粒径集中分布在10-40μm，载药量0．0007％-0．0011％，包封率7％～11％。保护剂主要影响微球的形态和体外释放。添加不同的保护剂，微球表面的光滑度和孔隙差别较大；体外释放的突释较小，存在明显的缓慢释放期，进入快速释放期的起始时间和释药速度受保护剂影响显著，一个月内的累积释放药量达到80％以上。结论保护剂的分子量可能是微球形态和释放不同的原因，添加分子量大的保护剂形成的微球的表面比添加分子量小的保护剂时致密光滑，体外的缓慢释放期长。     

重组人表皮细胞生长因子缓释微球治疗糖尿病大鼠溃疡

目的 制备重组人表皮细胞生长因子(rhEGF)缓释微球,并对其形貌、释药行为和在体外促进细胞增殖的能力进行评价;同时比较rhEGF缓释微球与rhEGF原液对糖尿病大鼠溃疡促愈作用的差异. 方法 (1)用改进的复乳法制备rhEGF缓释微球.透射电镜检测rhEGF微粒形貌表征,激光粒度仪/Zeta电位仪分析微球粒径分布,ELISA法测定rhEGF微球释药行为.(2)以小鼠成纤维细胞L929细胞系为对象,采用MTT法鉴定rhEGF缓释微球的生物学活性.(3)制备糖尿病大鼠溃疡模型,成模后采用随机数字表法将大鼠分为4组:rhEGF缓释微球组(A组)、rhEGF原液组(B组)、空白微球组(C组)、PBS溶媒对照组(D组),每天给药1次.分别于给药后3,7,14,21 d对溃疡创面照相计算创面愈合率.创缘皮肤取材,测定羟脯氨酸含量,免疫组化检测β1整合素和角蛋白-19并测量其阳性染色面积比. 结果 (1)rhEGF缓释微球平均粒径为193.5nm,粒径分布均匀,微球之间元粘连,分散性好.释药过程符合Higuchi释放动力学模型,释放时间长达24 h.(2)不同浓度rhEGF缓释微球均有促进小鼠成纤维细胞增殖的作用,其中以10μg/L浓度促小鼠成纤维细胞增殖的作用最强.(3)从治疗第7天开始,愈合率以A组最快,A组与其他三组比较,差异均有统计学意义(P<0.05).羟脯氨酸含量、β1整合素和角蛋白-19阳性染色面积比A组均高于B组. 结论 用改进的复乳法制备的rhEGF缓释微球,粒径大小分布均一,释放时间长达24 h.rhEGF缓释微球促进糖尿病大鼠溃疡创面愈合速度较rhEGF原液更快,溃疡创面愈合质量更高.     

Drug-Eluting Beads Loaded with Antiangiogenic Agents for Chemoembolization: In Vitro Sunitinib Loading and Release and In Vivo Pharmacokinetics in an Animal Model

PurposeThe combination of embolic beads with a multitargeted tyrosine kinase inhibitor that inhibits tumor vessel growth is suggested as an alternative and improvement to the current standard doxorubicin-eluting beads for use in transarterial chemoembolization. This study demonstrates the in vitro loading and release kinetics of sunitinib using commercially available embolization microspheres and evaluates the in vitro biologic efficacy on cell cultures and the resulting in vivo pharmacokinetics profiles in an animal model.Materials and MethodsDC Bead microspheres, 70–150 µm and 100–300 µm (Biocompatibles Ltd., Farnham, United Kingdom), were loaded by immersion in sunitinib solution. Drug release was measured in saline in a USP-approved flow-through apparatus and quantified by spectrophotometry. Activity after release was confirmed in cell culture. For pharmacokinetics and in vivo toxicity evaluation, New Zealand white rabbits received sunitinib either by intraarterial injection of 100–300 µm sized beads or per os. Plasma and liver tissue drug concentrations were assessed by liquid chromatography–tandem mass spectroscopy.ResultsSunitinib loading on beads was close to complete and homogeneous. A total release of 80% in saline was measured, with similar fast-release profiles for both sphere sizes. After embolization, drug plasma levels remained below the therapeutic threshold (< 50 ng/mL), but high concentrations at 6 hours (14.9 µg/g) and 24 hours (3.4 µg/g) were found in the liver tissue.ConclusionsDC Bead microspheres of two sizes were efficiently loaded with sunitinib and displayed a fast and almost complete release in saline. High liver drug concentrations and low systemic levels indicated the potential of sunitinib-eluting beads for use in embolization.     

尼美舒利双层缓释片体外释放和体内外相关性研究

目的建立尼美舒利体外释放评价方法,并考察体内外相关性。方法采用转篮法,以pH 9.0的三羟甲基氨基甲烷缓冲液为释放介质,测定尼美舒利体外释放度;LC-MS/MS法测定犬体内血药浓度,应用Wagner-Nelson法评价尼美舒利双层缓释片体内外相关性。结果与结论测得的体外累计释放度（Y）与吸收分数（X）回归方程为：Y=2.683X-40.21（r=0.9618）,表明尼美舒利双层缓释片体内外相关性良好。     

载荷双氯芬酸钠海藻酸钠-壳聚糖微球的制备及其药效学性质研究

目的考察双氯芬酸钠（DS）海藻酸钠-壳聚糖微球的性质。方法通过对微球进行电镜扫描、差示扫描、红外光谱分析、体外释药行为及镇痛作用研究,考察其性质。结果差热分析与红外光谱分析结果表明DS原料药和海藻酸钠-壳聚糖空白微球之间不是化学结合而是物理吸附。Ds微球在不同溶出介质里释药行为随溶媒的pH及离子强度的不同而不同。DS海藻酸钠-壳聚糖微球高、中剂量在醋酸扭体实验中镇痛作用较强,与空白对照组相比具有显著性差异。镇痛作用随给药剂量的增大而增强。DS海藻酸钠-壳聚糖微球高、中、低剂量均能提高热板法小鼠痛阈（P〈0．05）。结论DS海藻酸钠-壳聚糖微球镇痛作用起效快,效果好。     

Positron-emitting resin microspheres as surrogates of 90Y SIR-Spheres: a radiolabeling and stability study

Commercially available resin microspheres and SIR-Spheres were labeled with metallic positron emitters and evaluated as positron emission tomography (PET) imaging surrogates of (90)Y SIR-Spheres. Radiolabeling was performed using a batch method, and in vitro stability over 24 h was evaluated in saline at physiological pH at 37 degrees C. The activity per microsphere distribution, as evaluated by autoradiography, showed the activity per microsphere to be proportional to the square radius of the spheres, suggesting surface binding. The in vivo stability of radiolabeling was evaluated in rats by micro-PET imaging after the intravenous injection of labeled microspheres. The different resin microspheres and radionuclides evaluated in this study all showed good radiolabeling efficiency and in vitro stability. However, only resins labeled with (86)Y and (89)Zr proved to have the in vivo stability required for clinical applications.