快速膜乳化法制备胸腺法新长效缓释微球

采用快速膜乳化技术结合溶剂蒸发法制备以生物可降解聚乳酸-羟基乙酸(PLGA)为载体的胸腺法新载药微球,考察了PLGA分子量、油相中PLGA和乳化剂浓度、外水相pH值和内水相体积等对微球包埋率和粒径的影响. 结果表明,制备粒径均一的PLGA载药微球的优化条件为：PLGA分子量51 kDa,油相中PLGA和乳化剂浓度为100和10 g/L,内水相体积0.5 mL,外水相pH值为3.5. 该条件下所制载药微球粒径均一性好(Span<0.7),药物包埋率高达80%以上,突释率24 h内低于20%,线性持续稳定释药时间长达30 d.     

快速膜乳化法制备载生长激素释放肽-6的PLGA微球

采用快速膜乳化法制备了聚(乳酸-羟基乙酸)(PLGA)微球,得到制备PLGA微球的优化条件为：过膜压力5 kPa,水相中PVA浓度19 g/L,油/水相体积比1:10,该条件下所制空白微球的平均粒径约为24 mm,粒径分布系数Span<0.7. 在此基础上制备载生长激素释放肽-6(GHRP-6)微球,油相乳化剂浓度2.5 g/L、外水相中NaCl浓度10 g/L条件下所制载GHRP-6微球包埋率最高可达85%,初乳制备方式对药物包埋率及体外释放行为均有较大影响,超声法制备的初乳所得微球内部结构紧密,药物包埋率较高(85%),但释药缓慢;而均质法制备的初乳所得微球内部结构疏松,药物包埋率较低(76.8%),但在体外释放更完全.     

Development of tunable biodegradable polyhydroxyalkanoates microspheres for controlled delivery of tetracycline for treating periodontal disease

This article was aimed at preparation and characterization of drug delivery carriers made from biodegradable polyhydroxyalkanoates (PHAs) for slow release of tetracycline (TC) for periodontal treatment. Four PHA variants; polyhydroxybutyrate (PHB), poly(hydroxybutyrate‐co‐hydroxyvalerate) with 5, 12, and 50% hydroxyvalerate were used to formulate TC‐loaded PHA microspheres by double emulsion‐solvent evaporation method. We also compared the effect of different molecular weight (M_w) of polyvinyl alcohol (PVA) acting as surface stabilizer on particle size, drug loading, encapsulation efficiency, and drug release profile. The TC‐loaded PHA microspheres exhibited microscale and nanoscale spherical morphology under scanning electron microscopy. Among formulations, TC‐loaded PHB:low M_w PVA demonstrated the highest TC loading with slow release behavior. Our results showed that the release rate from PHA microspheres was influenced by both the type of PHA and M_w of PVA stabilizer. Lastly, TC‐loaded PHB microspheres showed efficient killing activity against periodontitis‐causing bacteria, suggesting its potential application for treating periodontal disease. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44128.     

快速膜乳化与热固化法制备粒径均一的pH敏感壳聚糖季铵盐凝胶微球

以具有升温自固化特性的壳聚糖季铵盐/甘油磷酸钠混合溶液为水相,利用快速膜乳化与热固化法制备了粒径均一、pH敏感的壳聚糖季铵盐凝胶微球,考察了跨膜压力、水油相组成、水油相体积比及微孔膜孔径等对微球粒径、结构和药物包埋率的影响. 结果表明,得到粒径698±57.33, 1145±71.48, 2021±53.63及3984±191.72 nm、粒径分布窄(多分散系数<0.1)、药物包埋率高达75.49%±2.62%的凝胶微球. 所制微球生物相容性好,有明显的pH敏感性,中性和碱性环境下结构稳定,药物缓释,pH=7.4时24 h内药物累计释放率为34.6%;酸性环境下微球崩解,药物快速释放,pH=5.5时1 h内药物累计释放率高达79.6%.     

Effects of the process parameters on the initial burst release of poly(lactide‐co‐glycolide) microspheres containing bovine serum albumin by the double‐emulsion solvent evaporation/extraction method

The effects of fabrication parameters on the morphology, drug loading, and initial burst release of poly(lactide‐co‐glycolide) microspheres loaded with bovine serum albumin were investigated to establish an optimal process and system for the in vivo delivery of therapeutic proteins. Through the addition of salts or sugars to induce an osmotic pressure in the external water phase, large microspheres were seen to have their morphology, drug loading, and initial burst release significantly affected. However, the effect was not observed for compact microspheres less than 10 μm in diameter. The presence of poly(vinyl alcohol), Pluronic F127, and Tween 80 in the internal water phase had detrimental effects on the drug loading because of the depressed stability of the primary emulsion and competitive interactions of surface‐active substances with the polymer. However, the simultaneous addition of salts to the external water phase resulted in enhanced drug loading and decreased initial burst. The polymer concentration and volume of the internal water phase were important factors influencing the characteristics of the microspheres. These parameters were optimized for achieving the maximal drug loading and a low initial burst. The solvent extraction method yielded microspheres with a higher drug loading and a lower initial burst in comparison with the solvent evaporation method. Different ranges of protein encapsulation efficiencies were obtained with blends of poly(lactide‐co‐glycolide) and poly(ethylene glycol), depending on the molecular weight and content of poly(ethylene glycol). © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Novel blend microspheres of poly(3‐hydroxybutyrate) and Pluronic F68/127 for controlled release of 6‐mercaptopurine

The objective of this article is to investigate the controlled release characteristics of 6‐mercaptopurine (6‐MP) loaded microspheres prepared from the blends of poly(3‐hydroxybutyrate) (PHB) and Pluronic F68/127 by the oil‐in‐water emulsion‐solvent evaporation technique. Formulations were prepared by taking different ratios of individual polymer components to achieve a maximum 79% encapsulation and extending the release time up to 24 h. Differential scanning calorimetry (DSC) suggested reduction in crystallanity of PHB after blending with Pluronic F127. The absence of chemical interactions between 6‐MP and the blend matrix was confirmed by Fourier transform infrared (FTIR) spectroscopy, while the size of microspheres measured by optical microscopy ranged between 30 and 47 μm. X‐ray diffraction (XRD) confirmed the crystalline nature of 6‐MP even after encapsulation and surface morphology of the microspheres was investigated by scanning electron microscopy (SEM). In vitro release of 6‐MP at 37°C in pH 7.4 phosphate buffer media indicated a dependence on the composition of Pluronic in the blend. The release data have been fitted to empirical equations to understand the release profile of 6‐MP. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40196.     

5-FU-PLGA复乳微球的制备及体外释放

采用乳化溶剂挥发法制备W/O/W型5-FU-PLGA复乳微球,采用单因素设计考察了第一相体积比(内水相与油相)、第二相体积比(初乳与外水相)对复乳稳定性的影响,采用正交设计考察了搅拌温度、搅拌时间、辅料浓度和有机相中载体材料浓度对微球质量的影响,并对制备条件进行优化。最适宜制备条件为:第一相体积比为1:2,第二相体积比为1:1,搅拌温度为10 ℃、搅拌时间为6 h、辅料浓度为0.5%、有机相中载体材料浓度为15%。依据最适宜条件制备的微球圆整度良好、粒径范围窄,平均粒径5.20 μm,载药量为5.34%,包封率为77.22%。体外释放试验表明微球具有明显的缓释效果,释放行为符合Higuchi模型。     

复相乳化法制备海藻酸钙微球及其释放行为

采用复相乳化法制备了载牛血清白蛋白(BSA)的海藻酸钙微球,通过正交实验和单因素分析,以BSA包埋率、微球的载药率和平均粒径为考察指标,优化了该方法的制备参数,使最终制备的微球平均粒径小于10 mm,球形度较好,包埋率约70%,载药率达4%. 随着海藻酸钠质量分数的降低和BSA质量的增大,微球的包埋率下降、载药率升高、平均粒径减小. 微囊化BSA的体外释放曲线表明,该系统存在pH响应特性,尤其在磷酸缓冲液中,被包埋BSA的释放速率较快. 电泳结果表明,BSA的分子结构并未受制备过程的影响. 因此,该微囊化方法有望用于蛋白类药物的控释制剂,使其免受胃酸等的破坏,达到肠部释药的目的.     

快速膜乳化法制备载醋酸曲普瑞林PLGA微球

以生物可降解聚合物聚(乳酸?羟基乙酸)(PLGA)为载体,以160 g/L明胶水溶液为内水相、含500 g/L PLGA的二氯甲烷为油相,采用快速膜乳化和溶剂蒸发法制备了粒径均一的载醋酸曲普瑞林PLGA微球,微球粒径约30 mm,粒径分布系数Span<0.8,醋酸曲普瑞林包埋率达80.12%,药物在磷酸盐缓冲液中释放36 d的释放率为72.60%,体外释放行为良好.     

Preparation and release behavior of carboxymethylated chitosan/alginate microspheres encapsulating bovine serum albumin

Microspheres were prepared from carboxymethylated chitosan (CM‐chitosan) and alginate by emulsion phase separation. Their structure and morphology were characterized with IR spectroscopy and scanning electron microscopy. Bovine serum albumin (BSA) was encapsulated in the microspheres to test the release behavior. The swelling behavior, encapsulation efficiency, and release behavior of BSA from the microspheres at different pHs and with a pH‐gradient condition were investigated. The BSA encapsulation efficiency was calculated to be 80%. The degree of swelling of the microspheres without BSA loaded at pH 7.2 was much higher than that at pH 1.0. The encapsulated BSA was quickly released in a Tris–HCl buffer (pH 7.2), whereas a small amount of BSA was released under acid conditions (pH 1.0) because of the strong electrostatic interaction between ? NH₂ groups of CM‐chitosan and ? COOH groups of alginic acid and a dense structure caused by a Ca²⁺ crosslinked bridge. For the simulation of the processing of the drug under the conditions of the intestine, the microspheres were tested in a pH‐gradient medium, in which an acceleration of the release occurred at pH 7.4 after a lag time at a low pH (5.8–6.8). At pH 7.4, a large amount of BSA was released from the microspheres in a short time because of the rapid swelling of the microspheres. However, the release only depended on the diffusion of BSA at relatively low pHs, this resulted in a relatively low release. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 878–882, 2004     

Synthesis of collagen‐modified polylactide and its application in drug delivery

In this article, collagen modified polylactide (CPLA) was synthesized by means of graft modification, and its structure was confirmed by FTIR and FITC‐labeled fluorescence spectra. Subsequently, the performance of CPLA was characterized with hydrophilicity test and degradability test. After that, the aspirin sustained release microspheres of the synthetic copolymers were prepared via the emulsion‐solvent evaporation technique, followed with its measurements of morphology, size, and encapsulation efficiency. Finally, the controlled release properties of the obtained microspheres were investigated. The results showed that the aspirin sustained release microspheres exhibited well‐defined morphology with smooth spherical surface, with average size of 3.990 μm and encapsulation efficiency of 51.83%. Furthermore, compared with aspirin‐loaded PLA microspheres, at the initial 32 h, the drug release was faster for aspirin‐loaded CPLA microspheres favored by its increased hydrophilicity, and then the drug release was slower than that of PLA microspheres because the ? NH₂ group on the introduced collagen inhibited acidic autocatalytic degradation. The results suggested that CPLA showed a great potential as particles for drug delivery. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Controlled release of recombinant human nerve growth factor (rhNGF) from poly[(lactic acid)‐co‐(glycolic acid)] microspheres for the treatment of neurodegenerative disorders

Recombinant human nerve growth factor (rhNGF)/bovine serum albumin‐loaded microspheres were prepared by a water/oil/water emulsion and solvent evaporation technique with some modifications. The microspheres were characterized with respect to encapsulation efficiency, morphological properties and drug release. Using higher protein/polymer ratios in the primary emulsion resulted in higher protein content in the microspheres. The protein encapsulation efficiency increased from 89.1% to 97.5% on adding poly(ethylene glycol) to the inner aqueous phase. The in vitro rhNGF release lasted for more than 5 weeks. The biological activity of released rhNGF was confirmed by PC12 cell culture. The microspheres maintained a sustained release of rhNGF for at least 4 weeks in the basal forebrain as detected by fluorescence‐labeled and indirect immunofluorescent techniques. These results demonstrated the rhNGF‐containing microspheres are an effective means for delivering this molecule into the brain and their use may be a promising strategy in the treatment of neurodegenerative disorders such as Alzheimer's disease. Copyright © 2007 Society of Chemical Industry     

Alkylated pectin hydrogels as potential protein drug carriers

Pectin has been used in the development of safe and effective drug delivery systems because of its unique physicochemical and biological characteristics. However, it still needs to be modified to overcome some inherent drawbacks. In the present study, pectin was alkylated by bromododecane. The C₁₂‐alkylated pectin (PC₁₂) can form strong hydrogels in the presence of Ca²⁺. Such hydrogels were explored to prepare bovine serum albumin (BSA)‐loaded microspheres (PC₁₂‐MS). The BSA encapsulation yield of PC₁₂‐MS was significantly higher than that of microspheres prepared with the original pectin (PC‐MS). Differential scanning calorimetry analysis indicated that interactions existed between BSA and pectin during the preparation of microspheres. Release tests showed that PC₁₂‐MS almost avoided BSA release in simulated gastric fluids, which was verified by environmental scanning electron microscopy analysis, and exhibited an effective controlled release throughout the simulated gastrointestinal tract compared to PC‐MS. In addition, an MTT assay showed the biocompatibility of C₁₂‐alkylated pectin. Thus alkylated pectin may serve as a potential protein drug carrier. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45344.     

PCL/poloxamer 188 blend microsphere for paclitaxel delivery: Influence of poloxamer 188 on morphology and drug release

A novel controlled release system, paclitaxel‐loaded poly (ε‐caprolactone) (PCL)/poloxamer 188 (Pluronic F68, F68) blend microspheres is proposed in the present work. F68 was incorporated into PCL matrices as both a pore‐forming agent and a drug releasing enhancer. Paclitaxel‐loaded PCL/F68 blend microspheres with different amounts of F68 were prepared by the oil‐in water (O/W) emulsion/solvent evaporation method. Characterization of the microspheres followed to examine the particle size, the drug encapsulation efficiency, the surface morphology, and in vitro release behavior. The influences of F68 on microsphere morphology and paclitaxel release are discussed. The porosity of the surface of PCL/F68 blend microspheres and the release rate of paclitaxel from the PCL/F68 blend microspheres increased as the initial amount of blended F68 increased. Faster and controlled release was achieved in comparison with the PCL microspheres. Through this study, the developed microporous PCL/F68 blend microspheres could be used as a drug delivery system to enhance and control drug release in the future. © 2007 Wiley Periodicals, Inc. JAppl Polym Sci 104: 1895–1899, 2007     

载5-氟尿嘧啶壳聚糖/明胶微粒的制备及药物释放性能

壳聚糖及明胶是生物相容性良好的高分子药物载体,制备载5-氟尿嘧啶壳聚糖/明胶微粒,并进行体外释药研究。以石蜡油为外相,壳聚糖/明胶为内相,用乳化交联法制备微粒,以吸附药量为指标,采用正交设计实验优化获得最佳制备条件,用红外光谱、SEM对最佳条件下制备的微粒进行表征。结果表明壳聚糖/明胶微粒的最佳制备条件如下:水油比1:7,壳聚糖/明胶浓度比1:3,乳化剂100.7mmol/L,乳化5min,乳化温度60℃,交联剂戊二醛用量5.5mmol/L,交联时间1h。在此条件下,载药微粒的载药量为34.93%,包封率为38.36%。红外光谱图表明壳聚糖/明胶微粒已负载5-氟尿嘧啶,SEM表明微粒成球状,表面较光滑。模拟胃肠释放表明,微粒具有一定的缓释性能。采用乳化交联法制备载5-氟尿嘧啶壳聚糖/明胶微粒方法简单,重现性好,且其体外释放实验显示出明显的缓释作用。     

Preparation of magnetic poly(lactic‐co‐glycolic acid) microspheres with a controllable particle size based on a composite emulsion and their release properties for curcumin loading

Because of their unique magnetic features and good biocompatibility, magnetic poly(lactic‐co‐glycolic) acid (PLGA) microspheres have great application potential in magnetic targeted drug‐delivery systems. In this research, magnetic PLGA microspheres with controllable particle sizes were successfully prepared from a composite emulsion with a T‐shaped microchannel reactor. A water‐in‐oil‐in‐water composite emulsion was generated by the injection of a dichloromethane/gelatin water‐in‐oil initial emulsion into the microchannel together with a coating aqueous phase, that is, the aqueous solution of glucose and poly(vinyl alcohol). The mean particle size of the microspheres could be controlled by the manipulation of the osmotic pressure difference between the internal and external aqueous phases via changes in the glucose concentration. Curcumin, a drug with an inhibitory effect on tumor cells, was used to exemplify the release properties of the magnetic PLGA microspheres. We found that the mean particle size of the microspheres ranged from 16 to 207 μm with glucose concentrations from 0 to 20 wt %. The resulting microspheres showed a rapid magnetic response, good superparamagnetism, and a considerable magnetocaloric effect, with a maximum magnetic entropy of 0.061 J·kg^?1·K^?1 at 325 K. An encapsulation efficiency of up to 77.9% was achieved at a loading ratio of 3.2% curcumin. A release ratio of 72.4% curcumin from the magnetic PLGA microspheres was achieved within 120 h in a phosphate‐buffered solution. The magnetic PLGA microspheres showed potential to be used as drug carriers for magnetic targeted tumor therapy. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43317.     

双乳化-凝胶法制备单分散海藻酸钙微球及其载BSA研究

采用双乳化-凝胶法制备了单分散的海藻酸钙凝胶微球,并通过正交试验系统考察了海藻酸钠浓度、氯化钙浓度、表面活性剂浓度、搅拌速度和油水比对海藻酸钙凝胶微球粒径及形貌的影响。在优化的条件下,制备出了平均粒径为4μm、单分散和球形度好的海藻酸钙凝胶微球。包埋模型药物牛血清白蛋白(BSA)的过程中,以去离子水作为洗涤液洗涤海藻酸钙微球时,BSA的包封率仅为13%左右;当水洗液的pH值为3.2时,BSA的包封率提高到66%左右,载药率可达16%,这是海藻酸钙pH值响应溶胀和BSA与海藻酸盐之间静电作用的结果。微球中BSA的体外释放曲线表明,该系统具有在模拟胃液中释药速率慢、释药量低、模拟肠液中释药迅速的特性。因此,双乳化-凝胶法制备海藻酸钙微球有望成为制备蛋白类药物控释制剂的一种新方法,以达到靶向快速给药的目的。     

快速膜乳化法制备粒径均一的PLGA微球和微囊

以聚(乳酸-羟基乙酸)(PLGA)为膜材,采用快速膜乳化结合溶剂萃取法制备了胰高血糖素样肽-1(GLP-1)微囊,研究了PLGA分子量对药物装载率、药物活性和体外释放行为的影响. 制备均一微球的优化条件为过膜压力1000 kPa,过膜次数3次,外水相稳定剂聚乙烯醇浓度19 g/L,油水体积比1:5. 在此条件下,制备了粒径350 nm左右、多分散系数小于0.050的载GLP-1的PLGA微囊,GLP-1包埋率达65%以上,活性保留达85%以上,药物体外释药可达20 d.     

Temperature sensitive semi‐IPN microspheres from sodium alginate and N‐isopropylacrylamide for controlled release of 5‐fluorouracil

Semi‐interpenetrating network (IPN) of sodium alginate (NaAlg) and N‐isopropylacrylamide (NIPAAm) microspheres were prepared by water‐in‐oil (w/o) emulsification method. The microspheres were encapsulated with 5‐fluorouracil (5‐FU) and release patterns carried in 7.4 pH at temperatures of 25 and 37°C. The semi‐IPN microspheres were characterized by Fourier transform infrared spectroscopy (FTIR). Differential scanning calorimetry (DSC) and scanning electron microscopic studies were done on the drug‐loaded microspheres to confirm the polymorphism of 5‐FU and surface morphology of microspheres. These results indicated the molecular level dispersion of 5‐FU in the semi‐IPN microspheres. Particle size and size distribution were studied by laser light diffraction technique. Microspheres exhibited release of 5‐FU up to 12 h. The swelling studies were carried in 1.2 and 7.4 pH buffer media at 25 and 37°C. Drug release from NaAlg‐NIPAAm semi‐IPN microspheres at 25 and 37°C confirmed the thermosensitive nature by in vitro dissolution. The micro domains have released in a controlled manner due the presence of NIPAAm in the matrix. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Ethylenediamino bridged bis(β‐cyclodextrin)/ poly(DL‐lactic‐co‐glycolic acid) nanoparticles prepared by modified double emulsion method: Effect of polyvinyl alcohol on nanoparticle properties

This study continues long‐standing efforts to develop protein delivery systems based on cyclodextrin‐conjugated polyester in our laboratory. The crude products of ethylenediamino bridged bis(β‐cyclodextrin)‐conjugated poly(DL ‐lactic‐co‐glycolic acid) were used in this study to make full use of unreacted reactant. With bovine serum albumin (BSA) as a model protein, the encapsulation effects (the encapsulation efficiency and particle size) of nanoparticles were similar to those of using pure conjugated products. Besides, a water‐in‐oil‐in‐water emulsification technique was conveniently modified. By adding polyvinyl alcohol (PVA) in the internal aqueous phase, a more stabilized emulsion was formed. Consequently, less PVA (～ 0.05%) was needed in the outer aqueous phase and less PVA (0.14 g/g nanoparticles) remained in the nanoparticles. This modification resulted in improved encapsulation efficiency (～ 89–94%) of BSA and an enlarged particle size (340–390 nm). Furthermore, the burst release of BSA at the 1st day was less pronounced (7–12% of the encapsulated amount) than that of nanoparticles with no PVA added in the internal aqueous phase. Degradation studies using transmission electron microscope and gel permeation chromatography suggested that the mechanism for protein release was mainly through nanoparticles erosion. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008