PELA疫苗微球载体的正交优化工艺研究

目的：利用正交设计的数学方法进行实验设计，以牛白蛋白为包裹模型，寻求制备不同疫苗微球载体的最佳条件。方法，采用W／O／W法制备PELA微球，考察不同因素对疫苗微球平均粒径，成球率与蛋白包裹率（三指标）的影响。结果：五因素对疫苗微球成球性影响的主次顺序为PVA浓度＞搅拌速度＞PELA浓度＞油外／外水相体积比＞内水相体积；而对粒径与蛋白包裹率的顺序则为PELA浓度＞PVA浓度＞搅拌速度＞油相／外水相体积比＞内水相体积和PELA浓度＞PVA浓度＞搅拌速度＞内水相体积＞油相／外水相体积比。结论：控制工艺条件，可制备适于不同需求的疫苗微球载体。     

重组降血压肽缓释微球的制备与体外释放

目的采用复乳溶剂蒸发法制备重组降血压肽(rAHP)缓释微球。方法以聚乳酸(PLA)为缓释材料,利用正交设计优化微球制备的最佳工艺条件,并考察了微球的体外释药特性。结果微球制备的最优工艺为:油相中PLA的浓度为7.5%、初乳搅拌速度为900 r/min、内水相与油相体积比为1∶10,外水相聚乙烯醇124浓度为5%;按此工艺制备的微球粒径跨度小、分布均匀,包封率为81.35%,载药量在10.92%,微球得率在80.26%,微球的平均粒径分布范围在75～80μm之间;载药微球在磷酸盐缓冲液中0.5 h内的累积释药量为17.5%,第15天累积释药率达到98.6%。结论该微球制备工艺成熟,包封率高,符合我国药典对缓释制剂的指导原则要求。     

γ—干扰素聚乳酸缓释微球处方初步筛选

目的 选择γ-IFN作为蛋白质模型药物，以聚乳酸为栽药聚合物，采用溶剂挥发法，对蛋白质的微球处方及制备条件进行优化。方法 以微球的成球情况、粒径、产率、生物活性为指标，应用正交设计分析筛选PVA浓度、初乳搅拌速度、油水比例、甘油浓度优化空白微球制备工艺；根据空白微球的筛选结果，优选生物活性较高的微球。结果 空白微球筛选结果表明，PVA浓度、水油相比例、初乳搅拌速度是决定产率的主要因素；载药微球筛选结果表明，甘油浓度、水油相比例、初乳搅拌速度对药物活性有较大影响，用甘油作为γ-IFN活性的保护剂取得了较为满意的效果。结论 采用一系列优选方法所得优化处方及制备条件具有可重复性，且与预测值基本吻合，优化方法正确可行。     

乳化溶剂挥发法制备重组人血管内皮抑制素缓释微球

目的:制备重组人血管内皮抑制素(恩度)缓释微球,并对微球理化性质及体外释放行为进行初步考察。方法:采用乳化溶剂挥发法(W/O/O)制备恩度载药微球;对微球载药量、粒径、突释、体外释放速率及降解行为进行考察,同时利用凝胶电泳初步评价体外释放过程中恩度的完整性。结果:增加聚乳酸-羟基乙酸嵌段共聚物(PLGA)中羟基乙酸的比例、提高PLGA浓度、降低内水相体积、提高理论载药量均增加微球载药能力;降低内水相体积、提高分散速度均减小突释。增加PLGA中羟基乙酸的比例,30 d时累积释放可增加到65%。降解实验说明释放初期微球主要以扩散方式释放恩度,释放后期主要表现为微球的降解。凝胶电泳结果表明微球制备过程对蛋白质聚集性的影响不大。结论:用PLGA作为载体材料制备微球,可以延缓恩度的释放。     

罗哌卡因-醋酸地塞米松PLGA微球的制备及体外释药特性研究

目的 制备罗哌卡因 醋酸地塞米松聚乳酸羟基乙酸共聚物（PLGA）微球（简称微球）并研究其体外释药特性。方法以PLGA为载体,采用W1/O/W2双重乳化 溶剂挥发法制备微球,研究实验过程中有机相PLGA浓度、外水相/有机相体积比、内水相体积、外水相聚乙烯醇（PVA）浓度几项因素变化对罗哌卡因 醋酸地塞米松PLGA微球粒径、表面形态﹑载药量﹑包封率和突释行为的影响。结果有机相PLGA浓度在制备微球的过程中是一个关键性因素。随着PLGA浓度增加,微球粒径增大,载药量﹑包封率明显提高,突释降低;外水相/有机相体积比增大,微球粒径增大, 载药量﹑包封率明显提高,微球表面更加光滑﹑微孔减少,突释降低;随着内水相体积增加使得微球表面的微孔明显增多,突释增加,载药量﹑包封率降低;当外水相PVA浓度由0.5%增加到2%,微球粒径变小,突释效应增加。通过优化条件制备的微球形状为球形,外观光滑圆整,粒径分布均匀,其中＞90%分布在20～70 μm。罗哌卡因载药量（7.48±0.33）%,包封率（70.97±2.36）%;醋酸地塞米松载药量（1.52±0.16）%,包封率（57.30±1.17）%。结论采用W1/O/W2双重乳化 溶剂挥发法成功制备罗哌卡因加醋酸地塞米松PLGA微球;以优化工艺制备的微球,在体外具有明显的缓释行为,释药曲线呈典型S形三阶段模式。     

艾塞那肽W/O/W复乳稳定性优化及评价

摘 要 目的：增加艾塞那肽W/O/W复乳的稳定性。方法: 通过对内水相中电解质氯化钠及外水相中增稠剂聚乙烯吡咯烷酮（PVP）用量的筛选,同时结合冻干保护剂的品种及用量优化,进一步完善艾塞那肽W/O/W复乳的处方及工艺。通过验证试验对优化后的艾塞那肽复乳的主要体外性质进行了考察。结果:内水相中氯化钠的最佳质量体积百分浓度为0.10%,内水相中PVP的最佳质量体积百分浓度为0.15%,冻干保护剂为10%的海藻糖。由最佳处方及工艺制备的艾塞那肽复乳在冻干前及冻干复水化后的主要性质无明显变化。结论:通过内外水相的优化及冻干技术的采用,艾塞那肽复乳具有较好的稳定性,为进一步体内实验奠定了基础。     

Box-Behnken效应面法优化塞来昔布微球制备工艺

目的：制备塞来昔布聚乳酸-羟基乙酸共聚物（PLGA）载药微球,优化其处方和制备工艺,考察其体外释药行为。方法：分别以油相中PLGA浓度、水相PVA浓度和油/水相体积比为考察因素,以包封率为考察指标,采用Box-Behnken效应面法优化塞来昔布微球的处方和工艺;透析袋法评估其体外释放能力。结果：塞来昔布PLGA微球的最佳处方工艺条件为：PLGA浓度75 g·L^-1,水相PVA体积分数1.5%,油/水相体积比1∶30。所制备的微球形态圆整,大小均一,实测包封率为66.1%,与预测值67.3%相比,偏差为1.8%。最优处方体外14 d累积释药56%,体外释放曲线符合Higuchi方程。结论：Box-Behnken效应面法简便可行,可用于优化塞来昔布PLGA微球的制备,微球体外释放具有缓释效果。     

白益母草总生物碱聚乳酸-羟基乙酸共聚物微球的制备

目的:优化蒙药白益母草总生物碱的聚乳酸-羟基乙酸共聚物(PLGA)微球的处方工艺,制备微球并对其进行质量考察。方法:采用复乳-液中干燥法制备白益母草总生物碱PLGA微球,以处方中PLGA质量浓度、聚乙烯醇(PVA)浓度及内水相/油相体积比为因素,以微球的载药量、包封率、收率的综合评分为指标,采用L9(34)正交试验优化制备微球的处方工艺,并考察微球形态、粒径及体外释药情况。结果:最优工艺为PLGA 200 mg/ml、PVA 2%、内水相/油相的体积比为1∶5;验证试验中平均包封率为(83.2±2.4)%,平均载药量为(4.16±0.17)%,平均收率为(86.7±3.6)%,综合评分结果为(95.7±4.4)%,RSD均小于5.0%(n=3);制备的微球形态圆整,表面光滑,粒径分布均匀,平均粒径为(22.3±2.4)μm;微球24 h体外累积释放度为(82.3±3.5)%,符合一级释放模型(r=0.972 4)。结论:优选工艺稳定;制备的微球具有良好的缓释性能,质量符合要求。     

牛血清白蛋白阳离子微球的制备及体外评价

目的 制备牛血清白蛋白(BSA)口服阳离子微球,考察天然阳离子物质壳聚糖(CHS)的加入对蛋白微球的粒径、电动电势、包封率、载药量及体外释放情况的影响。方法 以乳酸/羟基乙酸共聚物(PLGA)和壳聚糖(CHS)为载体材料,采用W/O/W复乳-溶剂挥发法制备牛血清白蛋白乳酸/羟基乙酸共聚物-壳聚糖(PLGA/CHS)阳离子微球。通过正交设计优化制备工艺,确定最佳处方。建立准确而简便的蛋白含量测定方法,并对微球进行体外评价。结果 最佳处方为：BSA浓度为150 g·L^-1、PLGA浓度为8%、外水相体积为80 mL、壳聚糖浓度为0.2%。制得的微球形态圆整,平均粒径为(6.9±5.5)μm,为表面荷正电的阳离子微球[ζ电势=(10.0±0.6)mV],包封率为(75.4±4.6)%,载药量为(9.3±0.2)%。体外释放结果表明,在模拟胃液和模拟肠液中,壳聚糖的加入均能减少突释,延缓药物的释放。结论 与PLGA微球相比,制得的PLGA/CHS阳离子微球表面带正电,具有较高的包封率和载药量,可以延缓药物释放,同时减少突释现象。     

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。     

Lappaconitine-loaded microspheres for parenteral sustained release: effects of formulation variables and in vitro characterization

Lappaconitine instead of its hydrobromide salts has been encapsulated in poly (lactide-co-glycolide) acid (PLGA) microspheres by the simple o/w emulsion solvent evaporation technique. The effects of several variables including emulsifier (polyvinyl alcohol, PVA) concentration, stirring speed, PLGA concentration and drug/polymer mass ratios on quality of microspheres have been investigated. The particle size and size distribution can be controlled by PVA concentration, stirring speed and PLGA concentration. The entrapment efficiency and the burst release of lappaconitine from drug-loaded microspheres were dominantly affected by the drug/polymer mass ratio and PVA concentration. The best parameters of formulation were 1.5% PVA, the PLGA concentration of 50 g/L, and the stirring speed of 800 rpm and drug/polymer of 1:5. The optimized formulation has a mean particle size of 19.3 +/- 0.93 microm, mean entrapment efficiency of 70.77 +/- 3.23% and mean drug loading of 11.45 +/- 0.47%. Based on the optimized parameters of formulation, the effects of oil/aqueous solubility partition ratio of drug on entrapment efficiency of drug-loaded microspheres prepared by o/w emulsion solvent evaporation were further studied. A good linear relation existed between the partition ratio and entrapment efficiency. The optimized microspheres were characterized by SEM, FT-IR, DSC and XRD. SEM shows spherical and smooth surface and uniform size distribution. The results of DSC, FT-IR study reveal no interaction between drug and polymer. The results of the XRD study indicate lappaconitine trapped in microsphere exists in form of an amorphous or disordered crystalline status in polymer matrix. The in vitro release models were evaluated with two different groups of drug-loaded microspheres including microspheres washed with distilled water and 0.01N HCL, respectively. The drug release profile of lappaconitine-loaded microspheres washed with distilled water agreed with zero order equation and that of the latter better agreed with first order equation.     

In vitro characterization of methotrexate loaded poly(lactic-co-glycolic) acid microspheres and antitumor efficacy in Sarcoma-180 mice bearing tumor

Methotrexate (MTX) loaded poly (lactic-co-glycolic) acid (PLGA) microspheres were prepared by emulsion solvent evaporation technique. The mean diameter of the microspheres was affected by the type of emulsion stabilizer, polymer concentration, aqueous and organic phase volume and stirring speed. The in vitro release was triphasic and was dependent on copolymer composition and molecular weight of the polymer. Antitumor efficacy in Sarcoma-180 tumor bearing mice exhibited increased volume doubling time (18 ± 2.7 days) compared to plain subcutaneous injection of methotrexate (8 ± 0.7 days). Preliminary pharmacokinetic studies following subcutaneous administration of MTX loaded PLGA microspheres illustrated the controlled release of the drug. The studies demonstrated the feasibility of employing PLGA as an effective carrier for antineoplastic drug like methotrexate.     

口腔用奥硝唑微球的制备研究

目的:以奥硝唑为主药,以乳酸-羟基乙酸共聚物(PLGA)为包裹材料,探索释药时间为7 d的微球的制备方法并优化工艺.方法:采用液中干燥法制备奥硝唑微球,考查搅拌速度、PVA浓度和PLGA浓度对微球粒径的影响,以紫外分光光度法测定微球中奥硝唑的含量及奥硝唑从微球的释放.结果:通过控制不同的因素可以得到释药时间为7 d的微球,测得的载药量及包封率符合药典规定.结论:采用液中干燥法通过控制不同的因素可以得到释药周期为7 d的奥硝唑缓释微球.     

Compressed biodegradable matrices of spray-dried PLGA microspheres for the modified release of ketoprofen

A spray-drying technique was used to prepare poly(lactide-co-glycolide) (PLGA) drug loaded microspheres. Ketoprofen was chosen as a model NSAID drug. The microspheres were characterized in terms of morphology, drug content and release behaviour. The spray-dried particles were subject to a direct compression process for the preparation of biodegradable matrix tablets. The spray-dried powders were found to have good compaction properties. Tablets were also prepared from a mixture of microspheres and microcrystalline cellulose, mannitol and hydroxypropylmethylcellulose or sodium alginate. The release of ketoprofen in phosphate buffer (pH 7.4) was significantly sustained, indicating the suitability of using tabletted spray-dried PLGA microspheres for controlled drug delivery. The results show that spray-dried PLGA particles have promising properties as direct compression and release controlling excipients in matrix tablets for oral administration.     

Alendronate PLGA microspheres with high loading efficiency for dental applications

PURPOSE: Alendronate sodium, used systemically as a bone protective agent, proved to also be effective locally in various dental bone applications. Development of alendronate-loaded microspheres with high loading efficiency for such applications would be greatly challenged by the hydrophilicity and low MW of the drug. The aim of this study was to incorporate alendronate sodium, into poly (lactide-co-glycolide) (PLGA) microspheres (MS) with high loading efficiency. METHODS: Three multiple emulsion methods: water-in-oil-in-water (W/O/W), water-in-oil-in-oil (W/O(1)/O(2)) and solid-in-oil-in-oil (S/O(1)/O(2)) were tested. In addition to entrapment efficiency, MS were characterized for surface morphology, particle size, in vitro drug release and in vitro degradation of the polymer matrix. Alendronate microspheres with maximum drug loading and good overall in vitro performance were obtained using the W/O(1)/O(2) emulsion technique. RESULTS: Drug release from the microspheres exhibited a triphasic release pattern over a period of 13 days, the last fast release phase being associated with more rapid degradation of the PLGA matrix. CONCLUSIONS: Biocompatible, biodegradable PLGA microspheres incorporating alendronate sodium with high loading efficiency obtained in this study may offer promise as a delivery system for bisphosphonates in dental and probably other clinical applications.     

Carboplatin-loaded PLGA microspheres for intracerebral injection: formulation and characterization.

The purpose of this study is to prepare and characterize injectable carboplatin-loaded poly(D,L,-lactic-co-glycolic) acid copolymer (PLGA) microspheres for the intracerebral treatment of malignant glioma. The microspheres were prepared by an acetone/mineral oil emulsion and solvent evaporation method. Preparation variables were optimized and the following processing conditions resulted in the highest drug loading and best yields of the microspheres compared with those prepared with the other variables: the PLGA concentration was 8% (w/w) in the internal phase; the emulsifier (Span 80) concentration was 8% (w/w) in the external phase; the ratio of the internal phase: the external phase was 1:8; the stirring speed was 1500 rpm; the emulsion time was 15 min; the solvent evaporation time was 3.75 hr. Microspheres so prepared were analysed for size distribution, drug loading, in vitro release and morphological characteristics. The drug release in phosphate buffer solution started with a 10-day slow release period, followed by a fast near zero order release period from 12 to 22 days. The carboplatin release in brain homogenate was slower than in phosphate buffer solution. The morphological changes of the microspheres during the in vitro degradation correlated with the drug relase profile. In conclusion, the carboplatin-loaded PLGA microspheres were specifically prepared to meet the specification as an injectable and biodegradable brain implant.     

单剂HBsAg-PLGA控释疫苗微球小鼠体内免疫学研究

目的研究小鼠皮下注射重组乙型肝炎病毒表面抗原(HBsAg)-乳酸/乙醇酸共聚物(PLGA)微球后的体内抗体应答水平和免疫学机制。方法采用复乳法制备疫苗微球后，单剂注射到BALB/c小鼠皮下，在一定时间内检测全抗体、IgG抗体亚型及细胞因子的应答水平。结果HBsAg-PLGA微球在小鼠体内主要引发体液免疫应答；其中单剂注射HBsAg-PLGA50/50-COOH微球在免疫早期产生较高免疫表达，6周后降低，全抗体水平显著低于常规铝佐剂疫苗(P<0.01)；分别单剂注射HBsAg-PLGA50/50微球及HBsAg-PLGA75/25微球后产生的免疫应答在18周内与铝佐剂疫苗相当(P>0.05)。结论PLGA微球作为乙肝疫苗的长效缓释可生物降解载体，具有一定潜在优势。     

蛋白质/多肽药物聚乳酸/乳酸-羟基乙酸共聚物微球研究进展

缓释微粒给药系统是蛋白质/多肽药物传输系统的一个重要研究方向，聚乳酸和乳酸-羟基乙酸共聚物是制备缓释微球最常用的载体材料。蛋白质/多肽药物聚乳酸/乳酸-羟基乙酸共聚物微球常用的制备方法包括溶剂萃取/挥发法(复乳法)、相分离法和喷雾干燥法。本文总结了微球制备中面临的难点如蛋白质/多肽药物稳定性、包封率、药物突释和药物吸附等问题，并综述了保持药物结构稳定性和生物活性、提高包封率、改善药物释放曲线等微球制备方法和进展。     

PLGA微球的制备及其用于脉冲给药的初步研究

目的：制备聚乳酸-羟基乙酸共聚物（PLGA）微球,并考察其用于脉冲式释药系统的可行性。方法：以牛血清白蛋白（BSA）为模型药物,用S/O/W（Solid-in-oil-in-water）法和S/O/O（Solid-in-oil-in-oil）法制备PLGA（75：25）和PLGA（50：50）微球,比较2种方法制备的微球的表面形态、包封率及载药量等,并考察2种微球的体外释放行为。结果：S/O/W法和S/O/O法制备的微球均圆整、无粘连、形态良好,但S/O/W法制备的微球表面较为平整,而S/O/O法表面均匀分布有较大的凹陷。S/O/W法制备的PLGA（75：25）和PLGA（50：50）微球包封率分别为（60.15±5.95）%、（49.50±3.69）%,载药量分别为（2.56±0.25）%、（2.10±0.16）%,10h内药物释放均为10%左右,而后随着聚合物的降解药物的释放量突然增加;S/O/O法所制微球包封率分别为（84.36±1.11）%、（77.94±1.42）%,载药量分别为（3.58±0.05）%、（3.31±0.06）%,24h内药物释放均可达50%左右,而后呈现较为平稳的释放行为。S/O/O法制备的微球包封率及载药量均较S/O/W法高;S/O/W法制备的PLGA微球药物释放呈现一定的脉冲行为,其中PLGA（75：25）微球体外释放行为受微球粒径的影响较大。结论：S/O/W法制备的PLGA微球具有一定的脉冲式释药效果,微球的粒径最好控制在120μm以下。     

聚乳酸、聚乳酸乙醇酸共聚物微球的制备及体外释放影响因素研究进展

目的：对近年来以PLA，PLGA为载体的微球剂的研究进展进行综述。方法：查阅近10年来有关PLA，PLGA微球研究的国内外文献，介绍此类微球的制备方法和影响其体外释放等性质的主要因素。结果：PLA，PLGA的性质，药和折性质及微球的制备工艺等对微球的体外释放等性质均有重要的影响。结论：对以PLA，PLGA为载体制备的药物微球，有待于更进一步的研究和开发。