天然药物聚乳酸或聚乳酸-羟基乙酸共聚物微球的研究进展

通过查阅相关文献,综述天然药物聚乳酸、聚乳酸-羟基乙酸共聚物微球的特点、制备方法及给药途径,展望天然药物微球的发展前景.     

大黄素-聚乳酸-羟基乙酸共聚物纳米粒的制备

目的 制备大黄素-聚乳酸-羟基乙酸( emodin-polylactic-co-glycolic acid,EMD-PLGA NPs)共聚物纳米粒,观察其电镜形态、稳定性,测定粒径、包封率、载药量.方法 采用乳化-溶剂挥发法( emulsion solvent evaporation method)按照正交设计制备EMD-PLGA NPs并优化处方,透射电镜下观察纳米粒的外观形态,激光粒度仪检测纳米粒的大小、分布及zeta电位,沉降法观察稳定性,用紫外分光光度计测定大黄素纳米粒的吸光度以计算包封率、载药量.结果 得到最佳优化处方工艺条件,在最佳条件下制得大黄素纳米粒呈圆球状或椭圆状;粒径约( 100±50 )nm;分散体系的颗粒由上而下呈逐渐变淡的弥散分布,无明显的沉积物;包封率为(24.5±1.9)％,载药量为(18.5±3.7)％.结论 采用乳化-溶剂挥发法制备大黄素-PLGA纳米粒,该方法材料简单,便于操作,优于以往的固体脂质纳米粒法;制备的大黄素纳米粒粒径小、分布均匀、载药率较高,药物吸光度及稳定性等均符合要求,为进一步制备组织靶向药物的研究奠定了基础.     

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.     

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。     

利福平聚乳酸-羟基乙酸共聚物纳米粒的成型工艺及制剂学性质分析

目的优化利福平聚乳酸-羟基乙酸共聚物纳米粒(RFP-PLGA-NPs)的制备工艺,并分析其制剂学性质。方法以PLGA为载体,采用改良的自乳化溶剂蒸发法(M-SESD)制备RFP-PLGA-NPs。以粒径、包封率、载药量为指标,采用正交设计法优化处方和制备工艺。结果制备RFP-PLGA-NPs的优化条件为PLGA 100 mg,poloxsmer 188质量分数1.0%,丙酮与乙醇体积比3:1,有机相体积15 mL。按优化条件所制备的RFP-PLGA-NPs的粒径为(128.73±4.07)nm,多分散系数(PDI)为0.046～0.105,包封率(65.84±0.69)%,载药量(3.78±0.14)%。结论该工艺简单、稳定性好,为后续RFP-PLGA-NPs的体内研究奠定了基础。     

羟基喜树碱磷脂复合物的溶解性考察与表征

目的:制备羟基喜树碱磷脂复合物,进行溶解度考察和表征,推测其形成机理并为下一步的制剂制备提供参考。方法:以四氢呋喃为复合溶剂制备羟基喜树碱磷脂复合物,考察磷脂复合物在正辛醇与氯仿2种溶剂中的溶解性能,并采用紫外(UV)、红外(IR)与差示扫描量热法(DSC)对复合物进行表征。结果:羟基喜树碱磷脂复合物在氯仿中的溶解度显著提高但不稳定。紫外、红外图谱与DSC结果验证了复合物的形成。结论:羟基喜树碱可能与磷脂的极性端复合形成复合物,药物的脂溶性与溶出速率得以提高。     

盐酸表柔比星-聚乳酸-羟基乙酸共聚物纳米粒的制备

摘要目的制备盐酸表柔比星 聚乳酸 羟基乙酸（PLGA）共聚物纳米粒,对其进行质量评价。方法采用乳化 溶剂挥发法制备盐酸表柔比星纳米粒;对主要处方因素如PLGA用量、外水相中聚山梨酯 80用量、泊洛沙姆188和聚山梨酯 80比例进行正交设计,以药物的包封率、载药量和药物利用率等为考察指标。结果采用优化后处方制得的纳米粒药物包封率为（32.6±1.2）%,载药量为（7.2±0.5）%,药物利用率为（51.6±3.4）%,纳米粒平均粒径166.6 nm,药物可持续160 h释放。结论该方法制备盐酸表柔比星纳米粒工艺简单,无需使用聚乙烯醇,药物释放缓慢。     

聚乙二醇-聚乳酸-羟基乙酸嵌段共聚物载药纳米粒制备方法的研究进展

目的:为聚乙二醇-聚乳酸-羟基乙酸(PEG-PLGA)嵌段共聚物载药纳米粒制备方法的进一步研究提供参考。方法:以"聚乙二醇-聚乳酸-羟基乙酸""嵌段共聚物""载药纳米粒制备方法""PEG""PLGA""PEG-PLGA"等为关键词,组合查询1998年1月-2017年1月在Pub Med、Springer Link、Science Direct、中国知网、万方、维普等数据库中的相关文献,对溶剂挥发法、沉淀法、自乳化溶剂扩散法、盐析法等制备方法进行综述。结果与结论:共检索到相关文献246篇,其中有效文献28篇。虽然载药纳米粒制备方法已经解决了操作、耗能及环境污染上的一些难题,但仍然存在常使用毒性较大含氯有机溶剂和难以工业化大生产等问题。前者可通过寻找毒性较小的有机溶剂(如丙酮、乙酸乙酯)来代替和通过对PLGA结构修饰基团或合成方法的改进使其可溶于毒性较小的有机溶剂加以解决;后者可通过研发新型辅料,或是改进制备工艺(如冻干)来改善纳米粒的稳定性和研发新型生产设备来解决。     

载塞来昔布-聚乳酸/羟基乙酸共聚物纳米粒的制备及表征

目的:制备载塞来昔布-聚乳酸/羟基乙酸共聚物(PLGA)纳米粒,并对其进行表征。方法:采用乳化-溶剂蒸发法制备塞来昔布-PLGA纳米粒,以包封率、粒径为指标,首选Plackett-Burman试验设计筛选出对纳米粒性质影响显著的处方和工艺变量,然后对筛选出的变量(PLGA质量分数、超声功率、超声时间)应用Box-Behnken效应面法进一步优化,并进行验证。采用粒度分析仪测定最优处方工艺所制纳米粒的粒径分布和Zeta电位,采用透射电镜考察其形态,并考察纳米粒的体外释药行为和稳定性(25、5℃)。结果:最优处方工艺为PLGA质量分数30.0%、超声功率180 W、超声时间8 min;所制纳米粒的包封率和粒径分别为(85.7±4.1)%、(226.1±36.1)nm(n=3),粒径分布为(176.2±41.2)nm,多分散系数为0.211±0.021,Zeta电位为(-37.3±1.6)m V;电镜下微乳粒径均一,呈球状或椭圆形,24 h累积释放度为52.4%;纳米粒在5℃条件下放置3个月内稳定。结论:成功制得塞来昔布-PLGA纳米粒。     

利福平聚乳酸-羟基乙酸共聚物纳米粒雾化吸入给药肺靶向性研究

目的研究利福平聚乳酸-羟基乙酸共聚物纳米粒雾化吸入给药的肺靶向性。方法分别将利福平聚乳酸-羟基乙酸共聚物纳米粒混悬液(RFP-PLGA-NPs)和利福平注射液(RFP-Sol)以雾化吸入方式给予SD大鼠,在不同时间点测定利福平在大鼠肺组织中的浓度,计算相应药动学参数,比较2种制剂在肺组织中药动学过程,并评价靶向性。结果 RFP-Sol和RFP-PLGA-NPs的Tmax分别为(1.50±0.01)h和(2.00±0.08)h,Cmax分别为(0.83±0.07)mg.L 1和(5.02±0.05)mg.L 1,AUC0→∞分别为(6.24±0.24)mg.h.L 1和(35.80±6.34)mg.h.L 1,CL分别为(4.801±0.18)L.h 1.kg 1和(0.85±0.15)L.h 1.kg 1。通过对re和Ce等靶向性指标进行分析,RFP-PLGA-NPs在肺组织中的re和Ce均>1。结论与RFP-Sol相比,RFP-PLGA-NPs经雾化吸入给药后,明显提高了肺组织中药物的分布并且延缓消除,有显著的缓释性,从而降低药物对全身的不良反应,提高对肺结核的治疗作用。     

Physicochemical and structural characterization of iron–sucrose formulations: a comparative study

Abstract

Intravenous polynuclear iron formulations are vital components in the treatment of iron deficiency anemia associated with chronic kidney disease as well as other diseases associated with gastro-intestinal and cardio-vascular system. Intravenous iron preparations consist of iron–carbohydrate nanoparticles with iron–oxyhydroxide as a core covered by carbohydrate shell. These preparations should be very well characterized in terms of their physicochemical properties and pharmacological profile in order to establish safety and efficacy. The present research work was aimed to physicochemically characterize a new generic iron–sucrose preparation (IS-Claris) and establish its equivalency with the reference product (Venofer®). Various analytical techniques including gel permeation chromatography (GPC), mass spectroscopy (MALDI-TOF), absorption spectroscopy, X-ray diffraction analysis (XRD), nuclear magnetic resonance spectroscopy (proton and ¹³C NMR), Fourier transform infrared spectroscopy (FTIR) and thermal gravimetric analysis (TGA) were employed. It was observed that the specifications of IS-Claris obtained through these analyses reflect those of Venofer® and hence the two formulations were considered comparable.     

药用缓释材料聚乳酸-乙醇酸共聚物的研制

目的：合成药用聚乳酸-乙醇酸高分子缓释材料，用于某些生物药物缓、控释剂型的制备；同时探讨聚合反应条件的影响因素以及优化工艺。方法：在一定的温度和压力下，采用配位-插入聚合法通过交酯开环合成聚乳酸-乙醇酸共聚物缓释材料。结果：本研制合成的聚乳酸-乙醇酸共聚物（PLGA75／25和PLGA50／50）经采用多种鉴定手段表征化学结构正确，力学性能良好，玻璃转化温度为33．7℃，分子量为27000～70000，分子量分布为1．4～1．6，产品最终产率可达70％以上。结论：通过制备工艺条件的控制和优化，在一定范围内，不仅可以得到分子量大小不等和单体比例不同的聚乳酸-乙醇酸缓释材料，而且每批次之间所得分子量重现性良好，合成工艺稳定、可靠。     

The structure of the antimicrobial peptide Ac‐RRWWRF‐NH2 bound to micelles and its interactions with phospholipid bilayers

Abstract: The hexapeptide Ac‐RRWWRF‐NH₂ has earlier been identified as a potent antimicrobial peptide by screening synthetic combinatorial hexapeptide libraries. In this study, it was found that this peptide had a large influence on the thermotropic phase behavior of model membranes containing the negatively charged headgroup phosphatidylglycerol, a major component of bacterial membranes. In contrast, differential scanning calorimetry showed that it had little effect on model membranes containing the zwitterionic phosphatidylcholine headgroup, the main component of erythrocyte membranes. This behavior is consistent with its biological activity and with its affinity to these membranes as determined by titration calorimetry, implying that peptide–lipid interactions play an important role in this process. The structure of this peptide bound to membrane‐mimetic sodium dodecyl sulfate (SDS) and dodecylphosphocholine micelles has been determined using conventional two‐dimensional nuclear magnetic resonance methods. It forms a marked amphipathic structure in SDS with its hydrophobic residues on one side of the structure and with the positively charged residues on the other side. This amphipathic structure may allow this peptide to penetrate deeper into the interfacial region of negatively charged membranes, leading to local membrane destabilization. Knowledge about the importance of electrostatic interactions of Arg and the role of Trp residues as a membrane interface anchor will provide insight into the future design of potent antimicrobial peptidomimetics.     

Novel,dynamic on-line analytical separation system for dissolution of drugs from poly(lactic acid) nanoparticles

A novel method for investigating drug release in a dynamic manner from nanoparticles including, but not limited to, biodegradable poly(lactic acid) (PLA) is reported. The PLA nanoparticles were prepared by the nanoprecipitation method. Two poorly soluble drugs, beclomethasone dipropionate (BDP) and indomethacin, were encapsulated into PLA nanoparticles, and their dissolution from the nanoparticles were followed in a dynamic way. The on-line method comprised a short column (vessel) packed with the PLA nanoparticles, on-line connected to an analytical liquid chromatographic column via a multiport switching valve equipped with two loops. The system allowed monitoring of the drug release profiles in real time, and the conditions for the drug release could be precisely controlled and easily changed. The effects of solvent composition and temperature on the rate of dissolution of the drugs from the PLA nanoparticles were investigated. The system proved to be linear for the drugs tested over the concentration range 10–3000 ng (n = 6, R² = 0.999 and 0.997 for indomethacin and beclomethasone, respectively) and repeatable (RSD of peak areas <0.5%). The recoveries of the dissolution study were quantitative (120 and 103% for indomethacin and beclomethasone, respectively).     

脱氧胆酸对胰岛素聚乳酸纳米粒在大鼠小肠吸收的影响

目的 :探讨脱氧胆酸 (DOC)对胰岛素聚乳酸纳米粒 (Ins PLA NP)在小肠吸收的影响。方法 :在正常大鼠小肠分别给予含与不含吸收促进剂DOC的Ins PLA NP后 ,观察降血糖效果。结果 :Ins PLA NP小肠直接给药表现出和缓持久的降血糖效果 ,而DOC在小肠给药中能明显加快Ins PLA NP的吸收并增强药效 ,给药后 0 5h血糖下降至用药前的 (35 49± 6 6 4) % ,显著的降血糖作用可维持 2h左右。结论 :DOC对于Ins PLA NP在小肠部位的吸收具有促进作用     

Evaluation of poly(lactic acid) as a biodegradable drug delivery system for parenteral administration

Poly(lactic acid) (PLA) microspheres of 1–10 μm diameter prepared by emulsion deposition and containing entrapped prednisolone released the drug rapidly into an aqueous medium. Similarly sized microparticles prepared by a fusion process exhibited a more prolonged drug release profile and may have potential as a long-acting parenteral delivery system. Both methods of fabricating the polymer produced material which was cytotoxic when phagocytosed by mouse peritoneal macrophages. The intracellular toxicity and hence potential irritancy in vivo was only partially overcome by incorporating anti-inflammatory drug. Compressed implants of the same polymers containing prednisolone 10% w/w (100 mg·cm⁻³) and weighing 12 mg were readily administered and sustained the delivery of the drug for over 30 days without complications at the implantation site.     

Effects of incorporated drugs on degradation of novel 2,2'-bis(2-oxazoline) linked poly(lactic acid) films

Earlier studies have indicated that the degradation rate of poly(lactic acid) (PDLLA) can be modified by using 2,2′-bis(2-oxazoline) as a chain extender in polymer synthesis to form a lactic acid-based poly(ester-amide) (PEA). In the present study, the effect of an incorporated drug on the degradation rate of the PEA was evaluated. The model drugs, neutral guaifenesin, acidic sodium salicylate (pK_a 3.0) and basic timolol (pK_a 9.2), were incorporated into solvent cast PDLLA and PEA films. The drug content in the films was 2% (w/w). The degradation studies were carried out in PBS (pH 7.4, 37 °C); the resulting decrease in molecular weight of polymers was determined by size exclusion chromatography and the weight loss of films was measured. In addition, the drug release from the films in PBS (pH 7.4, 37 °C) was studied. The model drugs were released from the PDLLA and PEA films in a biphasic or triphasic manner. The final fast release phase of the drugs from both PDLLA and PEA films started when the molecular weight (M_n) of the polymer had decreased close to 15,000 g/mol. The degradation rate of the PDLLA films was clearly enhanced by incorporated sodium salicylate or timolol. Whereas, the degradation rate of the PEA film was not enhanced by the incorporated drugs. The present results indicate that when compared to the PDLLA film, degradation rate of the PEA film in the presence of the drug is more predictable.     

113Cd Nuclear Magnetic Resonance (NMR) Study of the Inhibitory Effect of Methylvinylether/Maleic Acid (PVM/MA) Copolymer on the Alkaline Phosphatase of Escherichia coli

The inhibitory effect of PVM/MA copolymer on the alkaline phosphatase (AP) of E. coli was investigated. Kinetic studies indicated that enzyme inhibition was characterized by a reduction in both the Vmax and the Km. Addition of 1 mM zinc or magnesium ions to the reaction prevented inhibition of the enzyme by the copolymer. The inhibitory effect of the copolymer on alkaline phosphatase was also investigated using 113Cd NMR after exchange of the active center metal ions with 113Cd. The resulting Cd(II)6AP exhibited characteristic 113Cd resonances reflecting the environment of the A, B, and C metal binding sites of the enzyme's active center. Addition of copolymer resulted in a 113Cd NMR spectrum which indicated removal of 113Cd from the C site and formation of two distinct forms of the enzyme. Possible explanations for the 113Cd NMR results are discussed.     

In search of a novel antifungal agent: probing molecular interactions of fluconazole and its analogues with model membranes by NMR and DSC techniques

Objectives In search of a novel antifungal agent with high susceptibility and increased antifungal potency it is necessary to increase the overall lipophilicity of these agents. In view of that, we have synthesized different carboxylic acid ester analogues of fluconazole, such as fluconazole‐benzoate, fluconazole‐p‐nitrobenzoate, fluconazole‐p‐methoxybenzoate and fluconazole‐toluate, with varying degrees of lipophilicity. In order to probe molecular level interactions of these molecules with biomembrane, lipid bilayers prepared from l‐α‐dipalmitoyl phosphatidyl choline (DPPC) as the model membrane were used. Methods Multinuclear and multidimensional nuclear magnetic resonance, differential scanning calorimetry and transmission electron microscopy was used to investigate the changes in the thermotropic properties, organization of the membrane and intermolecular interactions. Key findings Fluconazole and its analogues show varying degrees of changes in the DPPC bilayer's architecture and physico‐chemical characteristics. This might influence important biological features of fungal biomembranes that could be responsible for their respective antifungal effects. Conclusions The study indicates that fluconazole‐p‐methoxybenzoate is the most active among all analogues and therefore could be the most promising antifungal candidate.     

Preparation, Characterization, and Antitumor Efficacy of Biodegradable Poly(lactic acid) Methotrexate Implantable Films

Implantable methotrexate films using poly(D,L-lactic acid) and poly(L-lactic acid) (PLA) of different molecular weights were prepared. The in vitro drug release was dependent on the drug loading and molecular weight of the PLA. By blending these polymers in different ratios, the drug release could be controlled and modified. The antitumor efficacy in Sarcoma-180 tumor-bearing mice revealed that the implantable film was more efficacious than subcutaneous injection of plain methotrexate.