可降解聚乙交酯-丙交酯缓释微球用于甲状旁腺相关肽的持续释放

采用水包油包水(W1/O/W2)复乳溶剂挥发法制备了包载甲状旁腺激素相关肽(PTHrP)的聚乙交酯-丙交酯(PLGA)微球,通过核磁,红外,GPC,扫描电子显微镜等观察PLGA载药微球的结构,表明载药微球具有良好的球形结构,其平均粒径约为8μm.而体外模拟释放表明,此PLGA载药微球能实现PTHrP1-34长达25天的持续释放.并通过MTT法、碱性磷酸酶活性测定等检测负载PTHrP1-34的PLGA微球缓释系统对小鼠成骨细胞MC3T3-E1增殖及分化的影响,结果表明PTHrP1-34浓度为1×10-9mol/L时对MC3T3-E1增殖促进效应最大,且随着药物作用时间的延长,缓释系统促进细胞增殖、分化的作用越明显.     

PHBV纳米纤维的静电纺丝及在生物医用领域的研究进展

聚(3-羟基丁酸酯-3-羟基戊酸酯)(PHBV)纳米纤维具有高比表面积、高孔隙率、生物相容性、生物降解性等优点,可用作生物医用材料。本文综述了基于静电纺丝法制备的PHBV纳米纤维及其在生物医用领域的研究进展,讨论了PHBV纺丝溶液的溶剂、浓度、外加盐类以及聚合物等对PHBV纳米纤维形貌、结构及性能的影响规律,结合目前PHBV纳米纤维在组织工程和药物运输载体的研究现状,重点概述了其亲水改性、力学性能改善、功能化改性的研究进展。最后,对静电纺丝法制备PHBV纳米纤维存在的一些问题进行分析,并对其未来发展趋势和前景进行展望。     

静电纺丝法制备水中氨氮快速检测试纸

利用静电纺丝法制备了纳米聚乳酸-乙醇酸膜作为氨氮快速检测试纸的纸基,采用国标GB7479-87水中氨氮测定标准的纳氏试剂显色法原理制成试纸并对试纸的制备条件和显色条件进行了研究.通过扫描电子显微镜、红外光谱仪进行了表征.扫描电镜观察材料的微观结构表明,PLGA静电纺丝材料纤维直径在纳米级别,其表面光滑,粗细较均匀,交织成网状.所制得的试纸氨氮检测限为0~50mg/L;浸渍液的最佳配比为1.5g氨试剂加入20mL无氨水,滴加2滴620g/L的氢氧化钾溶液;其中氨试剂（碘化钾∶碘化汞∶酒石酸钾钠∶氯化钠）的配比为0.5∶1∶0.5∶30;检测实体水样时,试纸显色深浅随氨氮浓度由低至高呈明显梯度加深,色阶明显.试纸的检测结果与国标法测定结果吻合度高,并且数据重现性好.     

核-壳结构壳聚糖/聚乙烯醇-聚碳酸亚丙酯超细纤维的制备

利用同轴电纺丝技术制备出具有核-壳结构的壳聚糖/聚乙烯醇-聚碳酸亚丙酯电纺丝纤维,考察了溶剂复配对成纤的影响,采用扫描电镜和透射电镜对纤维的形貌、结构、直径分布等进行了探索,并在优化的工艺条件下,将羟基磷灰石负载在内层结构中.研究表明,采用氯仿/N,N-二甲基甲酰胺(1/1)复配溶剂可有效避免聚合物溶液在喷丝口处的凝结现象.同单纺纤维相比,核壳结构的纤维直径分布较宽,纤维壳层和核层界限清晰;红外谱图分析证明羟基磷灰石可负载在纤维的核结构中.     

可控核/壳结构聚合物电纺纤维的制备与应用

核/壳结构纳米纤维是一种兼具核层与壳层优异性能的功能化复合纤维, 通常具有优于核层和壳层自身的性能, 如可控的机械强度和较好的热传导系数等。其特殊的结构极大地提高了纤维的使用价值, 拓宽了纤维的应用领域, 因此, 核/壳结构纳米纤维成为纤维领域的研究热点之一。静电纺丝技术因其简单有效的特点, 近些年来在众多纳米纤维制备技术中一直备受关注, 制备结构和形貌可控的核/壳结构纤维的方法对于指导其在实际中的应用尤为重要。本文系统介绍了以静电纺丝技术制备核/壳结构纳米纤维的方法, 主要包括单喷头相分离法、同轴静电纺丝法、乳液静电纺丝法以及模板法, 重点讨论了影响核/壳结构的主要因素以及核/壳结构对纤维性能的影响。综述了近几年来国内外关于可控核/壳结构电纺纤维制备的研究新进展及其在药物缓释体系、组织工程支架、多功能敷料、污水处理材料、疏水性材料等领域的潜在应用价值。     

三层同轴电喷-去模板法制备核壳纳米颗粒用于蛋白质药物输送

分别以聚乙二醇(PEG)、聚(丙交酯-乙交酯)(PLGA)和牛血清白蛋白(BSA)为冠、壳和核层材料,采用三层同轴电喷技术制备得到微米颗粒.激光共聚焦显微镜(LSCM)显示,该方法制备得到的微米颗粒呈现核-壳-冠结构.通过脱去该微米颗粒的PEG冠层(模板),得到包载有BSA的纳米颗粒.研究发现,随着壳层PLGA溶液进样速度的减慢,去模板后纳米颗粒的粒径从约146 nm减小到68 nm.BSA在纳米颗粒中的包埋率可高达78.3%,并且其释放没有显著的药物暴释现象.圆二色谱结果表明,同轴电喷过程对BSA二级结构影响很小.因此,利用三层同轴电喷-去模板法可制备得到粒径可调控的蛋白质纳米载体系统,并且该过程中蛋白质的结构基本维持不变.     

星形聚乳酸

星形聚乳酸以其独特的结构与性能引起了人们的广泛兴趣,通常使用“先核后臂”法进行合成。本文根据不同类型的“核”进行分类,如小分子多羟基醇（天然糖醇）、无机（杂环）化合物的衍生物、金属有机化合物、多元酚的衍生物和星形高分子等,综述了星形聚乳酸近年来合成（尤其是丙交酯开环聚合法合成）、性能与应用等方面的研究进展,指出星形聚乳酸高分子量、低黏度、良好溶解性和热稳定性等优点有利于其在药物缓释等生物医用材料中的加工应用。     

n-Ag/AD/PLGA功能性材料的制备及生物学性能

利用静电纺丝技术制备了纳米银(n-Ag)/山莨菪碱(AD)/聚乳酸-乙醇酸(PLGA)功能性材料.通过场发射扫描电子显微镜(ESEM)和傅里叶变换红外光谱(FTIR)研究了材料的微观结构及组成,评价了材料的体外药物释放、抑菌性、细胞相容性及细胞毒性.FTIR结果表明,山莨菪碱已担载到n-Ag/AD/PLGA材料中,且随着山莨菪碱含量的增加,n-Ag/AD/PLGA材料内纤维的平均直径逐渐增大.药物释放试验结果证明,山莨菪碱可以逐渐释放.当山莨菪碱的质量分数为1%~5%时,n-Ag/AD/PLGA材料无毒性,且有助于小鼠L929成纤维细胞的生长和增殖.研究结果表明,n-Ag/AD/PLGA材料具有良好的抗菌性能和细胞相容性,担载的山莨菪碱可有效释放,为糖尿病足部感染的临床治疗提供新的人工敷料.     

新型镇痛药AF-353的合成

以1-（2-羟基-5-甲氧基）乙-1-酮为反应原料,经6步反应制得关键中间体2-（5-碘-2-异丙基-4-甲氧基苯氧）乙腈（8）,再与Bredereck试剂、盐酸苯胺和碳酸胍经“一锅法”合成新型镇痛药AF-353,总收率55%,其结构经¹H NMR和MS确证。     

尼达尼布的合成新方法

以N-甲基-4-硝基苯胺作为起始原料,依次经氯乙酰化、取代及氢化还原反应制得关键中间体N-(4-氨基苯基)-甲基-2-(4-甲基-1-哌嗪基)乙酰胺（4）;以4-氯-3-硝基苯甲酸为原料,依次经酯化、取代、氢化还原及环合反应制得6-甲氧羰基-2-吲哚酮（8）; 8与原苯甲酸三乙酯和乙酸酐经“一锅煮”反应制得中间体1-乙酰基-3-甲氧基(苯基)亚甲烯基-2-氧代吲哚环-6-羧酸甲酯（9）; 4和9进行取代反应的同时脱除保护,经“一锅煮”反应合成尼达尼布,总收率57.2%,其结构经¹H NMR,¹³C NMR和MS(ESI)确证。     

Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanosphere. Part 2: Simultaneous release of a drug and a prodrug (clindamycin and clindamycin phosphate)

The novel concept of a simultaneous, controlled release of a drug and a prodrug with different physico-chemical properties was applied in order to prolong the release period of antibiotics and estimate their high local concentrations, which are the necessary preconditions for the treatment of some chronic infection diseases. For this purpose poly(D,L-lactide-co-glycolide)/hydroxyapatite (PLGA/HAp) core-shell nanostructures were used as the carrier of clindamycin-base, as a drug, and clindamycin-2-phosphate, as a prodrug model. As a result, a two-step release was observed: the controlled release of the more soluble phosphate form and the sustained release of the less-soluble base form of clindamycin, resulting in a high overall concentration of the released drug during the period of 30 days in vitro. The HAp phase within the PLGA core-shells, applied as a drug carrier, delayed the process of the degradation of the polymer; however, the presence of the drug affected the process of degradation and this influence was the dominant factor in the control over the degradation of the polymer phase of PLGA/HAp and the consequent kinetics of the drug release.     

Core-shell lipid-polymer nanoparticles as a promising ocular drug delivery system to treat glaucoma

Nowadays,tremendous researches have been focused on the core-shell lipid-polymer nanoparticles(LPNs) due to the advantages of both liposomes and polymer nanoparticles.In this work,LPNs were applied to encapsulate brinzolamide(Brz-LPNs) for achieving sustained drug release,improving drug corneal permeation and enhancing drug topical therapeutic effect.The structure of Brz-LPNs was composed of poly(lactic-co-glycolic) acid(PLGA) nanocore which encapsulated Brz(Brz-NPs) and lipid shell around the core.Brz-LPNs were prepared by a modified thin-film dispersion method.With the parameters optimization of Brz-LPNs,optimal Brz-LPNs showed an average particle size of151.23±1.64 nm with a high encapsulation efficiency(EE) of 86.7%±2.28%.The core-shell structure of Brz-LPNs were confirmed by transmission electronic microscopy(TEM).Fourier transformed infrared spectra(FTIR) analysis proved that Brz was successfully entrapped into Brz-LPNs.Brz-LPNs exhibited obvious sustained release of Brz,compared with AZOPT^■ and Brz-LPs.Furthermore,the corneal accumulative permeability of Brz-LPNs significantly increased compared to the commercial available formulation(AZOPT^■) in vitro.Moreover,Brz-LPNs(1 mg/mL Brz) showed a more sustained and effective intraocular pressure(IOP) reduction than Brz-LPs(1 mg/mL) and AZOPT^■(10 mg/mL Brz) in vivo.In conclusion,Brz-LPNs,as promising ocular drug delivery systems,are well worth developing in the future for glaucoma treatment.     

Preparation,optimization by 2<Superscript>3</Superscript> factorial design,characterization and in vitro release kinetics of lorazepam loaded PLGA nanoparticles

The aim of this work was to formulate the lorazepam loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles by optimization of different preparation variables using 2³ factorial design. The effect of three independent factors, the amount of polymer, concentration of the stabilizer and volume of organic solvent was investigated on two dependent responses, i.e., particle size and % drug entrapment efficiency. By using PLGA as polymer, PVA as a stabilizer and dimethyl sulfoxide as organic solvent lorazepam loaded PLGA nanoparticles were successfully developed through modified nanoprecipitation method. FTIR and DSC studies were carried out to examine the interaction between the excipients used and to explore the nature of the drug, the formulation and the nature of drug in the formulations. These nanoparticles were characterized for particle size, shape, zeta potential, % drug entrapment efficiency, % process yield and in vitro drug release behavior. In vitro evaluation showed particles size between 161.0 ± 5.4 and 231.9 ± 4.9 nm, % drug entrapment efficiency of formulations was in the range of 60.43 ± 5.8 to 75.40 ± 1.5, % process yield at 68.34 ± 2.3 to 81.55 ± 1.3 was achieved and in vitro drug release for these formulations was in the range of 49.2 to 54.6%. Different kinetics models, such as zero order, first order, Higuchi model, Hixson-Crowell model and Korsmeyer- Peppas model were used to analyze the in vitro drug release data. Preferred formulation showed particle size of 161.0 ± 5.4 nm, PDI as 0.367 ± 0.014,–25.2 mV zeta potential, drug entrapment efficiency as 64.58 ± 3.6% and 72.48 ± 2.5% process yield. TEM results showed that these nanoparticles were spherical in shape, and follow the Korsmeyer-Peppas model with a release exponent value of n = 0.658.     

Biodegradable PLGA microspheres as a sustained release system for a new luteinizing hormone-releasing hormone (LHRH) antagonist

A sustained release poly(DL-lactide-co-glycolide) (PLGA) microsphere delivery system to treat prostate cancer for a luteinizing hormone-releasing hormone (LHRH) antagonists, LXT-101 was prepared and evaluated in the paper. LXT-101 microspheres were prepared from PLGA by three methods: (1) double-emulsion solvent extraction/evaporation technique, (2) single-emulsion solvent extraction/evaporation technique, and (3) S/O/O (solid-in-oil-in-oil) method. The microspheres were investigated on drug loading, particle size, surface morphology and in vitro release profiles. An accelerated release approach was also established in order to expedite the evaluation periods. The in vivo evaluation of the microspheres was made by monitoring testosterone levels after subcutaneous administration to rats. The LXT-101 PLGA microspheres showed smooth and round surfaces according to a scanning electron microscopic investigation, and average particle size of ca. 30 mum according to laser diffractometry. The drug encapsulation efficiency of microspheres was influenced by LA/GA ratio of PLGA, salt concentrations, solvent mixture and preparation methods. Moreover, LA/GA ratio of PLGA, different preparation methods and different peptide stabilizers affected in vitro release of drugs. In vivo study, the testosterone levels were suppressed to castration up to 42 d as for the 7.5 mg/kg dose. And in vivo performance of LXT-101 microspheres was dose-dependent. The weights of rat sexual organs decreased and histopathological appearance of testes had little changes after 4-month microspheres therapy. This also testified that LXT-101 sustained release microspheres could exert the efficacy to suppress the testosterone level to castration with little toxicity. In conclusion, the PLGA microspheres could be a well sustained release system for LXT-101.     

生物降解多功能缓释微球的制备与表征

通过羧甲基壳聚糖接枝二甲基十八烷基环氧丙基氯化铵, 合成水油两溶性的羧甲基壳聚糖十八烷基季铵盐(OQCMC); 并将其作为乳化剂与乳酸-羟基乙酸(PLGA)和羟乙基纤维素(HEC)复合, 利用溶剂挥发法, 构建一种多功能的药物载体缓释系统, 并尝试包裹脂溶性药物盐酸米诺环素. 利用Transmission electron microscopy, Quasielastic laser light scattering, Zeta电位仪, FTIR, 1H NMR等对OQCMC及载药微球进行表征, 并进行药物的体外释放实验. 结果表明: OQCMC可作为一种优良的乳化剂对PLGA微球进行修饰; 并可使复合微球体系带正电, 在提高微球载药率(9.4%)的同时减小微球粒径[(166.4±0.8) nm]; 复合微球体系对盐酸米诺环素具有较好的物理包裹能力, 并有长效缓释作用(PBS, pH＝7.9).     

Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanospheres. Part 1: A multifunctional system for controlled drug delivery

Biodegradable poly(d,l-lactide-co-glycolide) (PLGA) and bioactive hydroxyapatite (HAp) are selected for the formation of a multifunctional system with the specific core-shell structure to be applied as a carrier of a drug. As a result, both components of PLGA/HAp core-shells are able to capture one part of the drug. Polymeric shells consisting of small nanospheres up to 20nm in size act as a matrix in which one part of the drug is dispersed. In the same time, ceramic cores are formed of rod-like hydroxyapatite particles at the surface of which another part of the drug is adsorbed onto the interface between the polymer and the ceramics. The content of the loaded drug, as well as the selected solvent/non-solvent system, have a crucial influence on the resulting PLGA/HAp morphology and, finally, unimodal distribution of core-shells is obtained. The redistribution of the drug between the organic and inorganic parts of the material is expected to provide an interesting contribution to the kinetics of the drug release resulting in non-typical two-step drug release.     

Preparation of glucagon-like peptide-1 loaded PLGA microspheres: characterizations, release studies and bioactivities in vitro/in vivo

The gut hormone glucagon-like peptide-1 (GLP-1) is proposed for treatment of Type II diabetes mellitus. However, the short half life of GLP-1 in vivo is a major limitation for its application due to the frequent invasive administrations. To provide a optimal formulation to overcome this limitation, we developed a GLP-1 entrapped microspheres to achieve sustained release GLP-1 for 4-week. GLP-1 was stabilized by GLP-1-zinc complexation with zinc carbonate and encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) with S/O/O solvent extraction to obtain GLP-1 loaded PLGA microspheres (MS). The characteristics of MS were evaluated as follows: The surface morphology was assessed by scanning electron microscopy (SEM); The drug encapsulation efficiency and GLP-1 controlled release profile was tested by HPLC; The sustained release of GLP-1 MS in vivo and pharmacological efficacy were studied in normal mice and streptozotocin (STZ)-induced diabetic mice model after subcutaneous administration of GLP-1 MS. GLP-1-zinc complexation significantly reduced initial burst release from 37.2 to 7.5%. The controlled release bioactive GLP-1 in vitro was achieved for 4-week period by zinc complexation and addition of ZnCO(3). The optimal and complete cumulative release of GLP-1 from MS was increased from 23 to 63% in 28 d by using low MW PLGA (MW 14000). The in vivo testing in normal mice and diabetic mice suggest that this zinc-stabilized technique combined with S/O/O method in the presence of water insoluble antacid additive ZnCO(3) preserve the biological activity of GLP-1. GLP-1 MS formulation achieved controlled released in vivo for 28 d and exhibit sustained long term pharmacological efficacy to decrease blood glucose level in diabetic mice. This GLP-1 MS formulation provides a practical formulation for long-term sustained delivery of GLP-1 to treat Type II diabetes.     

Synthesis and Characterization of Doxorubicin-Loaded Poly(Lactide-co-glycolide) Nanoparticles as a Sustained-Release Anticancer Drug Delivery System

The objective of the present study was to prepare a polymeric drug delivery system with no burst effect. To attain this goal, doxorubicin (Dox) as an effective anticancer drug was loaded into poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) to improve the drug performance and also maximize the release period. After the synthesis process, the freshly made PLGA NPs with two different lactide-to-glycolide ratios (75:25 and 50:50) were evaluated physically and chemically. To determine the encapsulation efficiency, a centrifugation method was applied. Also, the drug loading effect on particle size, polydispersity index, and zeta potential was examined. The results indicated that the NPs had nearly the same diameters around 360?nm, and the entrapment efficiencies for 75:25 PLGA and 50:50 PLGA were reported around 39 and 48?%, respectively. A slight increase in all parameters was observed due to the increase of the drug loading content. The primary release was 7.91?% (w/w) and 14.70?% (w/w) for 75:25 and 50:50 drug-loaded NPs, respectively; no burst effect was observed. After 20?days, the drug release was around 70.98 and 62.22?% of the total entrapped drug for 75:25 and 50:50 drug-loaded NPs, respectively. Finally, it was found that Dox was an appropriate anticancer agent with good capability to be encapsulated in polymeric NPs and could be released from the carriers with no burst effect and favor rate.     

Preparation, characterization, and pharmacodynamics of exenatide-loaded poly(DL-lactic-co-glycolic acid) microspheres

Exenatide (synthetic exendin-4), a 39-amino acid peptide, was encapsulated in poly(DL-lactic-co-glycolic acid) (PLGA) microspheres as a sustained release delivery system for the therapy of type 2 diabetes mellitus. The microspheres were prepared by a double-emulsion solvent evaporation method and the particle size, surface morphology, drug encapsulation efficiency, in vitro release profiles and in vivo hypoglycemic activity were evaluated. The results indicated that the morphology of the exenatide PLGA microspheres presented as a spherical shape with smooth surface, and the particle sizes distributed from 5.8 to 13.6 μm. The drug encapsulation efficiency tested by micro-bicinchoninic acid (BCA) assay was influenced by certain parameters such as inner and outer aqueous phase volume, PLGA concentration in oil phase, polyvinyl alcohol (PVA) concentrations in outer aqueous phase. Moreover, in vitro release behaviors were also affected by some parameters such as polymer type, PLGA molecular, internal aqueous phase volume, PLGA concentration. The pharmacodynamics in streptozotocin (STZ)-induced diabetic mice suggested that, exenatide microspheres have a significant hypoglycemic activity within one month, and its controlling of plasma glucose was similar to that of exenatide solution injected twice daily with identical exenatide amount. In conclusion, this microsphere could be a well sustained delivery system for exenatide to treat type 2 diabetes mellitus.     

Controlled release of doxorubicin from electrospun MWCNTs/PLGA hybrid nanofibers

In this study, multiwalled carbon nanotubes (MWCNTs) were used to encapsulate a model anticancer drug, doxorubicin (Dox). Then, the drug-loaded MWCNTs (Dox/MWCNTs) with an optimized drug encapsulation percentage were mixed with poly(lactide-co-glycolide) (PLGA) polymer solution for subsequent electrospinning to form drug-loaded composite nanofibrous mats. The structure, morphology, and mechanical properties of the formed electrospun Dox/PLGA, MWCNTs/PLGA, and Dox/MWCNTs/PLGA composite nanofibrous mats were characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, and tensile testing. In vitro viability assay and SEM morphology observation of mouse fibroblast cells cultured onto the MWCNTs/PLGA fibrous scaffolds demonstrate that the developed MWCNTs/PLGA composite nanofibers are cytocompatible. The incorporation of Dox-loaded MWCNTs within the PLGA nanofibers is able to improve the mechanical durability and maintain the three-dimensional structure of the nanofibrous mats. More importantly, our results indicate that this double-container drug delivery system (both PLGA polymer and MWCNTs are drug carriers) is beneficial to avoid the burst release of the drug and able to release the antitumor drug Dox in a sustained manner for 42 days. The developed composite electrospun nanofibrous drug delivery system may be used as therapeutic scaffold materials for post-operative local chemotherapy.