聚羟基烷酸酯缓释微球制备技术研究进展

简要介绍了聚羟基烷酸酯(PHAs)的结构、理化性质及其作为载体进行载药微球制备的主要技术(溶剂挥发法、喷雾干燥法、超临界流体法、纳米沉淀法、冷压法),并探讨了聚羟基烷酸酯缓释微球的体外释药机理,展望了今后的研究方向.     

基于白及多糖多孔载药微球的制备与质量评价

目的 以白及多糖(BSP)为骨架材料制备糖尿病溃疡用多孔生物载药微球(Ms)，并对其进行质量评价。方法 采用乳化-交联法制备载黄连素(BBR)的白及多糖微球(BBR-BSP-Ms)，观察其外观形态、结构特点，评价粒径、载药量与体外释药行为等药剂学性质。结果 BBR-BSP-Ms处方和工艺：当BSP浓度为0.05%、BBR浓度为12%时，乳化时间为130min、交联温度为40℃、交联剂体积分数为11%、交联时间为70min、搅拌速度为960r·min^-1时，BBR-BSP-Ms粉末流动性好、互不粘连、分散性好，呈圆形、大小均匀，粒径分布为20～30μm，包封率为(86.92±0.03)%，载药量为(19.78±0.08)%；体外释药实验表明，BBR在48h内的累积释放率达82.12%，缓释效果良好。结论 以BSP为骨架材料载药微球工艺稳定可行，缓释效果明显，在糖尿病溃疡方面具有较好应用开发前景。     

牛白蛋白包裹复合磁性微球的制备及性能表征

首先在反相(W/O)微乳液体系中制备出Fe3O4/PAM(聚丙烯酰胺)磁性微球;然后在牛白蛋白的磷酸氢二钠-柠檬酸缓冲溶液中,以戊二醛为交联剂,加入Fe3O4/PAM微球,使蛋白质特异性吸附在微球上。采用电子衍射、透射电镜、差热、热重、红外光谱等方法对复合微球的粒径、结构等性质进行了表征与分析。并考察了牛白蛋白的浓度、pH以及保温时间对蛋白质吸附程度的影响。结果显示,微球粒径20 nm左右,粒径均匀;微球具有较大吸附量;pH增大使蛋白质的吸附量减小;在一定范围内,增大蛋白质初始浓度和延长保温时间均有利于增加蛋白质的吸附量。     

聚乳酸/纳米Fe3O4载多柔比星缓释剂的研究

采用乳化-溶剂挥发法,使用医药级可生物降解高分子材料聚乳酸为载体,在其中加入医药级多柔比星与纳米Fe_3O_4,制备了聚乳酸/纳米Fe_3O_4载多柔比星缓释微球,并通过正交实验确定最佳工艺条件。确定最佳工艺条件为多柔比星用量40mg、PLA浓度0.05mg·m L~(-1)、乳化温度20℃、吐温80用量0.5g。结果表明,制备的聚乳酸/纳米Fe_3O_4载多柔比星缓释微球释药百分数随时间平缓增加、释药时间延长,说明包覆效果增加,可使药物缓慢释放,药效温和而持久,缓释微球在外加电场时具有强磁性能。     

载穿心莲内酯核-壳型Ca-Alg/pNIPAM微球的制备及性能

针对穿心莲内酯(AND)口服给药存在药物苦极问题,拟制备一种有效掩蔽药物苦味且能实现药物控释的微球载体。以海藻酸钠(Na-Alg)和N-异丙基丙烯酰胺(NIPAM)为制备材料,采用静电液滴偶联单体聚合工艺制备了核-壳型AND/Ca-Alg/pNIPAM微球。采用扫描电微观测、红外光谱分析、溶胀实验和体外释药实验等表征微球结构与性能。结果表明:与Ca-Alg微球相比,Ca-Alg/pNIPAM微球具有清晰的核-壳结构;微球平衡溶胀率在32—36℃突降14.6%;微球在模拟胃液中2 h内药物累积释放率低于10%,而在模拟肠液中6—8 h即达到释放平衡且释药动力学符合Reter-Peppas模型。核-壳结构使Ca-Alg/pNIPAM微球在高效负载药物的同时掩蔽了药物苦味,并赋予微球温度/pH双重响应特性,实现了药物肠靶向释放。     

微流控法可控制备放射性壳聚糖栓塞微球

以壳聚糖(CS)为基材原料，京尼平为交联剂，采用液滴微流控法制备了粒径在20～90μm范围内精确可调的可用于内放射介入治疗的栓塞微球。首先，通过在CS微球上接枝螯合剂1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)进行改性，制备DOTA-CS微球，使微球具有稳定的负载放射性核素镥-177(¹⁷⁷Lu)的能力。然后，通过DOTA与¹⁷⁷Lu稳定的螯合作用，制备了DOTA-CS-¹⁷⁷Lu微球。探究了制备过程中乳液模板和CS微球之间大小变化的规律，实现了对微球尺寸的精确预测和调控。所制备CS微球的直径变异系数均低于5%，尺寸均一，单分散性好，具有良好的溶胀性能与弹性。通过分析傅里叶变换红外光谱(FT-IR)、紫外可见吸收光谱(UV-Vis)与电感耦合等离子体质谱(ICP-MS)结果，得出1∶1(质量比)为DOTA与微球的最佳改性比例。扫描电子显微镜(SEM)结果表明DOTA改性对微球的形貌与结构无影响。血液相容性实验与细胞毒性实验的评价结果表明，DOTA改性前后的CS微球均表现出良好的生物相容性。模拟体...     

载皂苷聚合物微球制备及其性能

以皂苷提取物为模型药物，PCL-PEG-PCL(聚己内酯-聚乙二醇-聚己内酯共聚物)为网络框架，采用溶剂挥发法制备载皂苷PCL-PEG-PCL微球，通过FT-IR(红外光谱)和SEM(扫描电镜)表征微球的组成和结构，并评价其体外释药性和抗氧化活性。FT-IR结果表明微球成功包载皂苷提取物；SEM结果表明微球为类球形，表面有微孔；体外释药实验结果表明微球对皂苷具有缓释性能，释药机理符合Higuchi模型；微球对ABTS⁺·、DPPH·、·OH清除能力随质量浓度增大而增强。微球体外释药结果为微囊释药机理提供理论基础，微球体外抗氧化活性结果有助于岗梅总皂苷抗氧化剂的开发利用。     

种子聚合法制备PS/PAA核壳微球的研究

设计制备了以疏水性聚苯乙烯(PS)为核、以亲水性聚丙烯酸(PAA)为壳的PS/PAA核壳结构复合微球。首先利用无皂乳液聚合法制备了亚微米级的PS微球,再以其为种子,利用种子无皂乳液聚合法制备PS/PAA核壳微球。在种子聚合阶段,选用AIBN当引发剂,经过红外光谱(IR)表征,表明当使用油溶性引发剂偶氮二异丁腈(AIBN),使其最终形成PS/PAA核壳结构微球。这种方法解决了亲水性较强的单体在以水为介质时在PS微球溶于少量的苯乙烯(St),并在引发聚合之前经过充分的吸附溶胀,可使亲水性单体AAc在PS种子微球表面聚合生成壳层,解决表面不容易直接聚合生成壳层的问题。     

Fe_3O_4/羧甲基壳聚糖磁性载药微球的制备及释药性能

通过乳化交联法制备了负载有抗癌药物5-氟尿嘧啶的Fe3O4/羧甲基壳聚糖磁性载药微球。利用红外光谱(IR)和扫描电镜(SEM)对载药微球的结构与形貌进行了表征,研究了影响载药微球载药和释药性能的因素。IR测试显示载药微球中含有磁性Fe3O4;SEM照片显示载药微球尺寸均一,表面光滑。确定制备磁性载药微球的最佳条件为:5-氟尿嘧啶0.5g、磁性Fe3O40.2g、戊二醛8mL;磁性载药微球在温度为35~40℃、pH值为5.2的缓冲溶液中释药量达到峰值,适用于人体十二指肠肿瘤的治疗。     

磁性聚乙烯醇缩丁醛微球固定化α-淀粉酶

制备出磁性聚乙烯醇缩丁醛微球,并用该微球做载体,采用共价交联法固定α 淀粉酶。最佳固定化工艺条件为:pH=6 07,激活和交联时戊二醛的质量分数分别为4%和0 025%。在最佳固定化条件下所制磁性固定化酶的活力为25426 3U/g微球,蛋白载量为187 2mg/g微球,比活为135 8U/mg蛋白,活性回收率为36 9%。磁性固定化酶的理化性质为:磁性固定化酶的最适温度(60℃)比自由酶(50℃)高,最适pH(6 97)与自由酶相同,磁性固定化酶Km(米氏常数)值(5 7×10-4kg/L)较自由酶Km值(5 0×10-4kg/L)大,热稳定性、pH稳定性及操作稳定性均比自由酶有所提高。     

Enhanced gastric retention and drug release via development of novel floating microspheres based on Eudragit E100 and polycaprolactone: synthesis and in vitro evaluation

Eudragit E 100 and polycaprolactone (PCL) floating microspheres for enhanced gastric retention and drug release were successfully prepared by oil in water solvent evaporation method. Metronidazole benzoate, an anti-protozoal drug, was used as a model drug. Polyvinyl alcohol was used as an emulsifier. The prepared microspheres were observed for % recovery, % degree of hydration, % water uptake, % drug loading, % buoyancy and % drug release. The physico-chemical properties of the microspheres were studied by calculating encapsulation efficiency of microspheres and drug release kinetics. Drug release characteristics of microspheres were studied in simulated gastric fluid and simulated intestinal fluid i.e., at pH 1.2 and 7.4 respectively. Fourier transform infrared spectroscopy was used to reveal the chemical interaction between drug and polymers. Scanning electron microscopy was conducted to study the morphology of the synthesized microspheres.     

In vitro evaluation of spray‐dried chitosan microspheres crosslinked with pyromellitic dianhydride for oral colon‐specific delivery of protein drugs

Chitosan microspheres have been prepared using a spray‐drying method, and crosslinked with pyromellitic dianhydride. The chemical structure of the modified chitosan was characterized by FTIR spectroscopy and solid state 13C NMR analysis. The particle size and morphology of the crosslinked chitosan were investigated. These microspheres were evaluated for colon‐specific delivery of bovine serum albumin (BSA) as a model protein drug. The results indicate that the drug was released as follows: 37.1 ± 2.8% after 2 h in SGF, 73.1 ± 4.8% after 8 h (2 h in SGF+ 6 h in SIF), and 80.9 ± 4.1% after 12 h in SCF. The effect of β‐glucosidase on the drug release was also examined. The encapsulation efficiency was decreased from 88.4 ± 3.1% to 62.8 ± 2.9%, with increasing BSA concentration. Loading capacity was significantly increased from 6.3 ± 0.3% to 41.8 ± 4.1% by increasing the initial BSA concentration. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40514.     

Effect of the GLP-1 Analog Exendin-4 and Oxaliplatin on Intrahepatic Cholangiocarcinoma Cell Line and Mouse Model

The influence of Glucagon-like peptide-1 (GLP-1) and Exendin-4 on development of intrahepatic cholangiocarcinoma (ICC) is evaluated in the study. In vitro tests, including acute toxicity test, cell colony formation assays, cells proliferation and apoptosis, transwell assay, were performed. An ICC in situ tumor animal model was established. Then, animals were randomly divided into four groups (n = 6): control, Exendin-4 treatment, oxaliplatin treatment and Exendin-4-oxaliplatin treatment. Animals in the Exendin-4 treatment and Exendin-4-oxaliplatin treatment groups received a subcutaneous injection of Exendin-4 (100 μg/kg/day) for 1 week, and then received oxaliplatin (10 mg/kg/week) by tail vein injection. Animals in the control group received PBS. Immunohistochemistry tests were used for PCNA, Ki67, Caspase 3 expression in tumor tissue. Results show that that, after incubation of human cholangiocarcinoma cell lines, HuCCTI and GLP-1, or HuCCTI and Exendin-4, colony formation number was sharply decreased. However, GLP-1, HuCCTI or Exendin-4 did not affect the colony of normal cells. Combination treatment with oxaliplatin and Exendin-4 can significantly inhibit tumor cells’ proliferation and promote apoptosis. The combined effect is stronger than that of oxaliplatin or Exendin-4. Combination treatment with oxaliplatin and Exendin4 can significantly decrease Ki67 and PCNA proteins’ expression in subcutaneous tumors of nude mice. The inhibitory effect of Combination treatment with oxaliplatin and Exendin4 is clearly stronger than that of oxaliplatin. In addition, Combination treatment with oxaliplatin and Exendin4 can significantly increase Caspase3 protein positive expression. In short, these results show that combination treatment with oxaliplatin and Exendin4 can inhibit tumor cells’ proliferation, and promote apoptosis.     

Preparation and in vitro release behavior of urapidil hydrochloride loading into microspheres based on poly(L‐lactide)

Microencapsulation of the antihypertensive drug urapidil hydrochloride was investigated as a means of controlling drug release and minimizing or eliminating local side effects. Poly(L ‐lactide) (PLLA) microspheres were prepared using an alternative oil‐in‐water (O/W) solvent‐evaporation method such as the O/W cosolvent solvent‐evaporation method and O/W with various electrolytes added to the aqueous phase method. The surface morphology and the size of the microspheres were observed by scanning electron microscope. Meanwhile, the drug loading efficiency of microspheres and the in vitro release of urapidil hydrochloride from microspheres were performed. The release study indicated that the urapidil hydrochloride‐PLLA microspheres exhibited better sustained release capacity, and the kinetics of urapidil hydrochloride‐PLLA microspheres in vitro release could be described by the Higuchi equation. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

静电喷雾法制备聚乳酸/布洛芬微球及其性能研究

采用静电喷雾技术,以聚乳酸（PLA）为骨架载体材料,布洛芬（IBU）为模型药物,成功制备出PLA载IBU微球,利用扫描电子显微镜（SEM）、X射线衍射仪（XRD）、差示扫描量热仪（DSC）、傅里叶变换红外光谱仪（FTIR）、热失重分析仪（TG）和紫外可见分光光度计分析了微球形貌、结构和性能。结果表明,PLA/IBU微球呈表面多孔的无定形结构,分散性较好,IBU以分子或无规则状态负载在PLA中,化学结构未有变化,稳定性较纯IBU有所提高。在体外缓释测试中,PLA/IBU微球相比较纯IBU具有良好的缓释效果,随着投药量的增加,IBU的释放速率和累计释放量逐渐提高,含16 %IBU的PLA微球在48 h内累计释放量可达52 %。静电喷雾法制备的PLA/IBU微球有望提高IBU的生物利用度和溶出率,在生物医药领域具有潜在的应用前景。     

井冈霉素载药二氧化硅空心微球的原位制备及缓释性能评价

利用正硅酸乙酯在W/O乳液中的原位水解聚合,成功制备了包埋井冈霉素的二氧化硅载药空心微球. 对所得产品进行了SEM, XRD, FT-IR和粒径分布等分析,结果表明,载药空心微球粒径分布窄,范围在7.5~15 mm,球状形貌良好,具有空心结构,呈无定型态. 热重分析表明载药空心微球的药物负载量约为31.9%(w),缓释溶出实验显示载药空心微球药物释放持续时间约240 min,最终释放量达总载药量的90%以上.     

Preparation,characterization, and release behavior of ceftiofur‐loaded gelatin‐based microspheres

Drug‐loaded microspheres prepared from biomacromolecules have received considerable interest. In this article, we report a facile method for preparing ceftiofur‐loaded gelatin‐based microspheres for controlled release. We investigated the effects of factors, including the rotational speed, concentration of surfactant, concentration of gelatin, and ratio of water to oil (W/O), on the morphologies of gelatin microspheres and obtained the optimized conditions; for a typical average diameter of about 15 μm, these were 1000 rpm, a concentration of span 80 of 2.0%, a gelatin concentration of 20%, and a W/O of 1:20. Gelatin microspheres loaded with ceftiofur, ceftiofur‐Na, and ceftiofur‐HCl were prepared and characterized by scanning electron microscopy and laser light scattering. In vitro release studies were carefully performed for microspheres prepared with different crosslinker contents, loaded with different drugs, and blended with chitosan. The loaded ceftiofur showed an obviously longer release time compared with pure ceftiofur powder. A higher content of crosslinker led to a longer release time, but when the content reached 5%, the microspheres had a significantly cracked surface. The results also indicate that the blending of a small amount of chitosan could greatly prolong the release time. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 2369–2376, 2013     

海藻酸钙/埃洛石载药微球的制备与缓释盐酸二甲双胍性能

缓释可提高药物利用率,降低其毒副作用。采用交联法制备了海藻酸钙/埃洛石载药微球,以载药微球对盐酸二甲双胍（MH）药物的包封率和缓释效果为考察对象,研究了载药微球的制备工艺和缓释性能,并通过SEM、FTIR和TGA对其结构进行了表征。结果表明：在交联温度为0℃、海藻酸钠用量为1g、埃洛石添加量为2g时,能得到较优的载药微球包封率（79.23%）。上述条件下制得的复合载药微球在pH=6.8的磷酸盐缓冲液中能有效缓释,且720min后缓释度可达85.83%,说明其具有较好的pH敏感性和缓释效果。SEM表明海藻酸钙颗粒与埃洛石在载药微球内部形成复合结构,FTIR表明MH主要以物理包埋的形式于载药微球中,TGA表明添加埃洛石可以提高复合材料在200℃以上的热稳定性。     

Docetaxel-Loaded Chitosan Microspheres as a Lung Targeted Drug Delivery System: In Vitro and in Vivo Evaluation

The aim of this study was to prepare docetaxel-loaded chitosan microspheres and to evaluate their in vitro and in vivo characteristics. Glutaraldehyde crosslinked microspheres were prepared using a water-in-oil emulsification method, and characterized in terms of the morphological examination, particle size distribution, encapsulation ratio, drug-loading coefficient and in vitro release. Pharmacokinetics and biodistribution studies were used to evaluate that microspheres have more advantage than the conventional formulations. The emulsion crosslinking method was simple to prepare microspheres and easy to scale up. The formed microspheres were spherical in shape, with a smooth surface and the size was uniform (9.6 ± 0.8 μm); the encapsulation efficiency and drug loading of prepared microspheres were 88.1% ± 3.5% and 18.7% ± 1.2%, respectively. In vitro release indicated that the DTX microspheres had a well-sustained release efficacy and in vivo studies showed that the microspheres were found to release the drug to a maximum extent in the target tissue (lung). The prepared microspheres were found to possess suitable physico-chemical properties and the particle size range. The sustained release of DTX from microspheres revealed its applicability as drug delivery system to minimize the exposure of healthy tissues while increasing the accumulation of therapeutic drug in target sites.     

超小尺寸碳载Mn3O4纳米催化剂制备及其催化性能

以MnCl₂为原料,聚乙烯醇(PVA)为稳定剂,利用PVA介导沉淀法制备Mn₃O₄纳米粒子(PVA/Mn₃O₄),进一步将冻干的PVA/Mn₃O₄复合物炭化制备了超小尺寸的Mn₃O₄-C催化剂。使用XRD、XPS、TEM、BET表征制备材料的结构和形貌,发现PVA能够有效减小Mn₃O₄在制备过程中的聚集和长大。无PVA介导沉淀法制备的Mn₃O₄-P平均粒径为(38.8±9.3)nm。加入PVA后,制备过程中PVA分子链间的Mn₃O₄纳米粒子平均粒径为(3.2±0.8)nm,经过Ar保护炭化处理后,平均粒径为(4.5±1.2)nm的Mn₃O₄纳米粒子被均匀固定在碳基底上。制备的Mn₃O_4<...