注射载药微球表面修饰研究进展

注射用微球载药系统可使药物在数周或数月内以一定速率释放,可以维持有效血药浓度,减少给药次数,提高疗效。但是,微球易被网状内皮系统摄取、体内循环时间短等因素也制约其应用。控制微球的粒径、表面亲水性修饰等可以有效减少网状内皮系统对微球的摄取,延长载药微球在体内的循环时间及其在吸收部位的滞留时间。该文就此问题进行了综述。     

PLGA微球控释系统的突释及其控制

针对目前限制PLGA微球控释系统临床应用的突释问题，重点介绍了近年来国内外有关的研究进展，包括突释现象、突释原因、影响因素和控制突释的方法和技术。     

多孔利福平 PLGA 微球的制备工艺研究

目的：以利福平为模型药物,研究多孔聚乳酸—羟基乙酸共聚物（poly（lactic-co-glycolic acid）,PLGA）微球的最佳制备工艺。方法乳化溶剂扩散法制备多孔微球,采用扫描电镜观察微球形态,HPLC 法测定微球包封率。通过单因素考察实验,筛选影响微球形态和包封率的主要因素并优选条件。结果制备过程中 PLGA 种类、PLGA 浓度、致孔剂浓度、均质速度、外水相 PVA 浓度等影响微球的粒径、多孔结构和包封率。按优化工艺制备的微球平均粒径为8．6μm,密度为0．1 g·cm －3,易于吸入并提高肺部的沉积率。结论低密度多孔微球具有适宜的吸入特性和肺部沉积率,或可成为递送抗结核药物的新载体。     

白藜芦醇PLGA长效注射微球的制备及工艺考察

目的采用乳化溶剂挥发法制备白藜芦醇聚乳酸羟基乙酸[poly(lactic-co-glycolic acid),PL-GA]长效微球,评价各因素对微球性质的影响。方法以微球的包封率、载药量、突释和粒径作为微球的质量评价指标,研究分散相与连续相的体积比、PLGA浓度、聚乙烯醇(polyvinyl alcohol,PVA)浓度、搅拌速度对微球性质的影响,并优化白藜芦醇PLGA微球的制备工艺。结果分散相与连续相的体积比为1∶50时,包封率高,但4 h突释量达到76%,当分散相与连续相体积比由1∶50提升到1∶150时,突释降低了22%;随着聚合物浓度的增加粒径明显增大,突释显著降低;理论载药量对粒径影响不大,在高载药量时突释显著减少;搅拌速度的增加使粒径减小,突释增加;PVA浓度的增加对粒径没有明显的影响,但当PVA的质量浓度从1 g.L-1增加到5 g.L-1时,包封率从93.57%降低到80.31%。结论分散相与连续相的体积比、PLGA浓度、PVA浓度、搅拌速度对微球性质有很大的影响。优化条件下制备的微球形态完整,载药量为(27.86±1.00)%,包封率为(93.57±2.87)%,平均粒径约为21.12μm。白藜芦醇PLGA微球体外释放25 d的累积释药率达(94.04±4.94)%,有望研制成1个月给药1次的给药系统。     

紫杉醇PLGA微球制备及体外性质评估

目的：以乳酸-羟基乙酸共聚物（PLGA）为材料,制备用于肿瘤内注射的紫杉醇PLGA长效缓释微球.方法：采用改良溶剂蒸发法制备,对微球的体外性质以及不同剂量（10,15,25 kGy）60Coγ射线对微球性质的影响进行考察.结果：制得的微球形态圆整,载药量、包封率、平均粒径和跨距分别为1.53%,97.29%,42.72μm和0.95.药物体外释放30 d累计释放达到56.19%,体外降解30 d后微球失去完整结构,表面粗糙.3个剂量60Coγ射线的灭菌效果均良好,且对微球的体外性质均无明显影响.微球中二氯甲烷的残留量低于药典规定的限度.结论：紫舷杉醇PLGA微球满足缓释长效的要求,对恶性肿瘤的间质化疗具有一定前景.     

可生物降解的聚乳酸-羟基乙酸共聚微球制备与性能研究进展

生物可降解材料乳酸-羟基乙酸共聚物(PLGA)有良好的生物相容性和安全性,在体内降解为二氧化碳和水.由于PLGA易于合成、质量稳定,具有生物兼容性、生物可降解性、机械强度、降解速度可调节性和良好的可塑性,自2000年后被大量用作微球控释系统的载体材料.     

缓释微球抗肿瘤研究进展

目的介绍聚乳酸-羟基乙酸共聚物缓释微球在抗肿瘤研究方面的进展。方法查阅国内外近年来的期刊。结果国外学者的研究热点是通过在聚乳酸-羟基乙酸共聚物缓释微球外包裹小分子、外加保护剂或黏附壳聚糖达到靶向肿瘤组织的作用,降低抗肿瘤药物对正常组织的毒副作用。国内学者将聚乳酸-羟基乙酸共聚物缓释微球技术应用于一些半衰期短但疗效明显的抗癌药物,通过包裹到微球中延长其抗肿瘤作用。结论以聚乳酸-羟基乙酸共聚物为微球骨架材料,能提高药物疗效,降低抗肿瘤药物对正常组织的毒副作用,在体内达到缓释、长效的目的。     

微球的制备和表征

目的制备葡激酶突变体(K35R，DGR)的聚乳酸-羟基乙酸(PLGA)微球，使其在包封和释放过程中都能保持活性。方法使用复乳溶剂挥发法制备DGR的PLGA微球，研究了搅拌速度、PLGA浓度、内水相和外水相中的添加剂对蛋白包封率以及微球性质的影响，并进行了DGR微球的体外和体内释放试验。结果2%聚乙烯醇可以有效抑制超声乳化时DGR在水/二氯甲烷界面上的变性，将DGR的活性回收率从16%提高到几乎100%。在外水相中加入NaCl可以显著提高蛋白包封率，同时对微球的粒径分布和表面形态也产生了重要影响。DGR微球的体外释放呈现两个时相，15 d释放大约DGR总活性的50%。DGR微球在体内持续释放5 d。结论制备的PLGA微球，DGR包封率高，稳定性较好，是DGR的良好载药系统。     

聚乳酸羟基乙酸载药微球的研究进展

综述聚乳酸羟基乙酸(PLGA)载药微球的制备方法及其微球中药物释放的研究。     

关节腔注射用氟比洛芬PLGA缓释微球的制备及体外释放特性研究

目的制备关节腔注射用氟比洛芬(FP)缓释微球并研究其体外释药特性。方法以聚乳酸-羟基乙酸共聚物(PLGA)为材料,采用乳化-溶剂挥发法制备微球;正交设计法优化微球的制备工艺;采用透析法研究体外释药特性,UV法测定FP的含量。结果正交试验表明,PLGA的浓度是影响微球包封率的非常显著性因素。微球粒径范围为1.5~24.3μm,平均粒径为10.6μm,载药量为7.1%(W/W),包封率为92.7%,体外释药符合Higuchi方程,释放时间显著延长。结论本法制备的FP微球粒径大小适宜,具有明显的缓释作用,符合关节腔注射给药设计要求。     

聚乳酸／乳酸／-乙醇酸共聚物微球制剂研究的新进展

简要介绍了PLA／PLGA及其制剂的原理，并叙述近年来国内PLA／PLGA在新型微球基材、蛋白质和多肽类药物微球、疫苗佐剂类微球和化学合成药物微球的进展情况。     

Respirable PLGA Microspheres Containing Rifampicin for the Treatment of Tuberculosis: Manufacture and Characterization

Purpose. Particles with aerodynamic diameters of 1–5m deposit in the periphery of the lungs and are phagocytized by alveolarmacrophages, the primary site of Mycobacterium tuberculosisinfection. Aerosols of biodegradable polymeric microspheres containingantitubercular agents may be delivered to the lungs to improve the treatmentof tuberculosis. Methods. Poly(lactide-co-glycolide) (PLGA) microspherescontaining rifampicin were prepared using solvent evaporation and spraydrying methods. The solvent evaporation process was optimized usingfactorial experimental design and surface response methodology. Themorphology, particle size, drug loading, and dissolution of microspheres wasevaluated. Results. The spray dried rifampicin loaded PLGAmicroparticles were shriveled, unlike the spherical particles produced bysolvent evaporation. Drug loadings of 20;pc and 30;pc were achieved forsolvent evaporation and spray dried products, respectively. The particlesprepared by solvent evaporation and spray drying had 3.45 m and 2.76m median diameters by volume, respectively. Conclusions. Respirable rifampicin loaded PLGAmicrospheres were produced by both solvent evaporation and spray dryingmethods. These particles are being evaluated in an animal model oftuberculosis.     

Immune Augmentation of Single Contact Hepatitis B Vaccine by Using PLGA Microspheres as an Adjuvant

The present study was aimed to replace the alum type adjuvant for hepatitis B vaccine. The hepatitis B vaccine was encapsulated in poly (DL-lactide-co-glycolide) microspheres by solvent evaporation technique. The formulated microspheres were characterized in terms of morphology, particle size analysis, in vitro release study and in vivo immune response in male Wistar rats. The FT IR spectrum illustrates the characteristics bands of poly (DL-lactide-co-glycolide) microspheres and hepatitis B vaccine at 1750 cm^-1 and 1650 cm^-1, respectively. The hepatitis B vaccine loaded poly (DL-lactide-co-glycolide) microspheres were able to release antigens till day 42. Significant enhancement of specific antibodies to HBsAg was produced till day 90 after a single administration of HBsAg encapsulated poly (DL-lactide-co-glycolide) microspheres. However, the conventional alum adsorbed hepatitis B vaccine was not found to produce any significant specific antibody levels till day 90 after a single dose. The results showed that poly (DL-lactide-co-glycolide) microspheres show potential as an adjuvant for hepatitis B vaccine.     

Visual Evidence of Acidic Environment Within Degrading Poly(lactic-co-glycolic acid) (PLGA) Microspheres

Purpose. In the past decade, biodegradable polymers have becomethe materials of choice for a variety of biomaterials applications. Inparticular, poly(lactic-co-glycolic acid) (PLGA) microspheres havebeen extensively studied for controlled-release drug delivery. However,degradation of the polymer generates acidic monomers, andacidification of the inner polymer environment is a central issue in thedevelopment of these devices for drug delivery. Methods. To quantitatively determine the intrapolymer acidity, weentrapped pH-sensitive fluorescent dyes (conjugated to 10,000 Dadextrans) within the microspheres and imaged them with confocalfluorescence microscopy. The technique allows visualization of thespatial and temporal distribution of pH within the degradingmicrospheres (1). Results. Our experiments show the formation of a very acidicenvironment within the particles with the minimum pH as low as 1.5. Conclusions. The images show a pH gradient, with the most acidicenvironment at the center of the spheres and higher pH near the edges,which is characteristic of diffusion-controlled release of the acidicdegradation products.     

乳酸羟乙醇酸共聚物微球中蛋白包封率的测定

目的:寻求一种合适的方法测定蛋白在乳酸羟乙醇酸共聚物(PLGA)微球中的包封率。方法:采用复乳 溶剂挥发法制备 BSA的PLGA微球,应用考马斯亮蓝法测定总蛋白浓度,根据文献报道的7种不同方法进行包封率测定。结果:不同的测定方法对 PLGA微球中真实的药物包封率的反映程度不同,相互间差异很大。结论:以水解法测定BSA在PLGA微球中包封率的方法提取 最完全。水解法中,又以乙腈作溶剂、再用氢氧化钠水解两步提取法最为简便、快速、准确。     

Preparation of PLA or PLGA Microspheres with Estradiol the Effects of THF—adding on the Properties of MS

Aim: polylactic acid(PLA) or polylactide-co-glycolide(PLGA) was used as biodegradable and biocompatible carriers to achieve sustained release of estradial-PLGA/PLA-Microspheres(E2-PLGA/PLA-MS).THF was added in the organic phase to study its effects on the properties of MS.Methods:MS were formed by an emulsification-solvent extraction method with mixture of ethyl acetate(EtoAc) and tetraphydrofuran(THF) as the organic solvents,and then the properties and in vitro drug release behavior were examined.Results:The results indicated that the drug loading efficiency decreased when THF added.but when the ratio of EtoAc was more than 50%,there was no obvious effcet of THF ration,but the particle size increased accordingly.The carriers‘ properties and the drug contents were the main factors influencing the in vitro drug release.Conclusions:By controlling the technology and formulation,we can get sustained-release E2 biodegradable microsperes with proper particle size,drug content and low burst-release,although THF with readily solubility in water was used in the organic phase.     

雌二醇生物可降解缓释微球的制备四氢呋喃的加入对微球性质的影响

目的　在本实验中 ,以生物可降解和生物相容性良好的聚乳酸 (PLA)或乳酸 -乙醇酸共聚物 (PLGA)为载体材料制备含有雌二醇药物的缓释微球 ,考察在制备过程中水溶性更强的四氢呋喃的加入对微球性质的影响。方法　以乙酸乙酯和四氢呋喃为有机溶剂、采用乳化 -溶剂萃取法制备含药微球 ,分别从成球性、粒径、包封率和体外释药等方面 ,进行制备工艺研究以及微球相关性质的研究。结果　在乙酸乙酯中加入四氢呋喃 ,使包封率降低 ,但在乙酸乙酯体积比大于 5 0 %时 ,增加四氢呋喃的用量对包封率无明显影响。相同条件下 ,在考察范围内 ,粒径随四氢呋喃用量比例的增大而增大 ,而载体的性质和微球含药量是影响微球释药的主要因素。结论　尽管在制备过程中的油相中加入了水溶性更强的四氢呋喃 ,但是通过控制制备工艺和条件 ,仍然可以得到球形态好、有适当粒径分布范围、载药量高并且突释程度小的雌二醇生物可降解缓释微球     

聚乳酸聚乙醇酸微球体外突释的影响因素的研究

目的 考察几种影响干扰素α-2b聚乳酸聚乙醇酸(PLGA)微球体外释放突释的主要因素.方法 在复乳法的基础上结合海藻酸钠与钙离子螯合形成缓释凝胶的原理制备微球,研究海藻酸钠种类和浓度、PLGA黏度和浓度对微球突释的影响.结果 制备的微球形态圆整,结构致密,平均粒径范围为25～55 μm.微球的突释随着PLGA黏度或浓度...     

GM-1PLGA肌注微球的制备及其体外释药评价

目的 研究以聚乳酸羟基乙酸共聚物为囊材,制备长效缓释的单唾液酸四己糖神经节苷脂微球制剂.方法运用复乳溶剂挥发法,考虑多个条件对制备工艺的影响,并采用正交设计对处方进行优化.测定微球的载药量、包封率和释放曲线.结果制备得到的GM-1微球粒径大小均匀,球形致密圆整,微球粒径为(8.2±6.0)μm,载药量和包封率分别为18...     

阿霉素微球的制备工艺的优选

目的:研究阿霉素PLGA(乳酸-羟基醋酸共聚物)微球制备的最佳工艺。方法:采用“复乳-液中干燥”法制备阿霉素PLGA微球。通过正交试验结合多指标综合评价法优选最佳制备工艺。结果:通过对正交实验Z值结果进行分析,最佳制备工艺为:A3B1C1。结论:正交试验结合多指标综合评价法用于载药微球的制备工艺优化实用有效。