聚乳酸微球生物降解机制和生物相容性研究进展

介绍了人工合成高分子材料聚乳酸（PLA）的性质，综述了PLA和乳酸／羟基乙酸共聚物（PLGA）微球的生物降解性和生物相容性。其生物降解为均匀降解，材料相对分子质量及其分布对降解行为有很大影响。注射微球的组织反应分为3个阶段，做组织相容性考察时应注意药物或生物活性物质的细胞毒性、抗原性和愈合作用对组织反应的影响。     

聚乳酸/乳酸-乙醇酸共聚物微球制剂研究的新进展

简要介绍了PLA／PLGA及其制剂的原理,并叙述近年来国内PLA／PLGA在新型微球基材、蛋白质和多肽类药物微球、疫苗佐剂类微球和化学合成药物微球的进展情况。     

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、药物的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     

聚乳酸、聚乳酸乙醇酸共聚物微球的制备及影响其质量因素的研究进展

本文综述了近年来以聚乳酸、聚乳酸乙醇酸共聚物为载体的微示的研究进展,并介绍此类微球的制备方法及影响其质量的主要因素。研究表明,载体和药物的性质及微球的制备工艺等对微球的质量和体外释放等均有重要的影响。     

聚乳酸乙醇酸的生物降解和安全性研究进展

聚乳酸乙醇酸(PLGA)的降解主要是通过酯键水解,自催化作用和巨噬细胞吞噬;水解产物为乳酸和乙醇酸,均可代谢分解生成二氧化碳和水,分别通过肺和肾排出体外,仅有微量的原型聚合物经尿液排出,体内没有蓄积现象.PLGA具有良好的生物相容性和可生物降解性,作为组织工程支架和药物控释系统材料是安全的.美国食品药品管理局(FDA)已经批准将PLGA作为组织工程细胞支架和药物载体,在美国、日本市场应用多年,未见严重的不良反应报道.目前国产PLGA的质量和控释微球药品的开发研究仍需要提高,尤其是制剂的载药量、控释技术以及稳定性技术.介绍PLGA的生物降解与安全性研究进展,为开发PLGA控释系统提供参考.     

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。     

一种聚乳酸聚乙醇酸缓释微球的制备工艺

目的:研究一种制备聚乳酸聚乙醇酸(PLGA)微球的新工艺,即将海藻酸钠与钙离子螯合形成缓释凝胶的原理与复乳法制备微球的工艺相结合。方法:以牛血清白蛋白(BSA)为模型药,以包封率、载药量、产率作为评价指标,研究PLGA黏度、海藻酸钠浓度及外水相1中氯化钙浓度对微球性质的影响,并通过L9(34)正交试验设计优选微球制备的工艺条件。结果:优选的制备工艺重现性好,微球形态圆整,结构致密,平均粒径为67.5μm,载药量、包封率和产率分别为0.669%、53.38%和80.08%。结论:本研究获得了较为满意的制备PLGA微球的新工艺,微球的理化性质良好。     

长春西汀聚乳酸-聚乙醇酸缓释微球的研制

目的:制备长春西汀聚乳酸-聚乙醇酸(PLGA)缓释微球,并研究其药剂学性质。方法:采用改良O/W乳化-溶剂挥发法制备微球,以PLGA浓度、理论载药量、有机相与分散介质的比例和分散介质中明胶的浓度为4因素,每个因素选定3个水平,按L9(34)的正交设计方案,以载药量、包封率和粒径分布为指标,优化处方。用扫描电镜观察微球的形态,用光学显微镜观察并计算微球的粒径分布,用差示扫描量热(DSC)法研究药物在载体中的分散状态,用紫外分光光度法检测微球中长春西汀含量并计算载药量和包封率,用动态透析释药法进行微球的体外释放研究。结果:最佳处方为PLGA浓度16%,理论载药量20%,有机相与分散介质的比例1:10,分散介质中明胶的浓度1%;制备的长春西汀PLGA缓释微球的形态圆整、光滑,粒径分布均匀,平均粒径为(10.0±0.18)μm(n=500),DSC法分析药物确已被包裹于微球中,载药量为(18.46±0.26)%,包封率为(91.30±0.98)%(n=3),24h累积释药率约为18%。结论:长春西汀PLGA缓释微球制备工艺稳定,质量符合药剂学要求,缓释性好。     

卡氮芥-聚乳酸缓释剂生物相容性研究

目的：研究卡氮芥(BCNU)-聚乳酸缓释剂生物相容性。方法：将BCNU-聚乳酸缓释膜片(BCNU—PLA组)及聚乳酸缓释膜片(PLA组)分别植入2组Wistar大鼠的额叶脑组织内，观察其对脑、心、肝、脾、肺、肾及血液系统的影响。结果：BCNU—PLA组缓释膜片植入后造成的局部脑水肿持续7d以上，术后14d仍有2只鼠轻度脑水肿，但与PLA组比较差别无统计学意义。其他器官及血液系统未见明显异常。聚乳酸缓释膜片植入后，除早期手术造成的轻微脑水肿外，其他器官与系统无异常。结论：BCNU-聚乳酸缓释剂安全、可靠，生物相容性良好。     

聚乳酸乙醇酸在微球控释制剂中的研究进展

聚乳酸乙醇酸(PLGA)是生物可降解的聚合物,已取得了美国FDA的批准,用于组织工程支架和药物载体。由于其具有良好的生物相容性和生物可降解性,近20年来成为小分子药物、蛋白质和其他大分子(DNA、RNA或多肽类)化合物的缓释控释制剂研究的热点。对于PLGA微球制剂的研究主要集中在疫苗类、激素类、抗生素类、抗肿瘤类、神经营养物质类等药物控释制剂。主要介绍近5年来这些药物微球的研究情况,为进一步开发利用PLGA作为药物载体提供参考。     

PLGA microspheres for the delivery of a novel subunit TB vaccine

Biodegradable poly(dl-lactide-co-glycolide) microspheres were prepared using a modified double emulsion solvent evaporation method for the delivery of the subunit tuberculosis vaccine (Ag85B-ESAT-6), a fusion protein of the immunodominant antigens 6-kDa early secretory antigenic target (ESAT-6) and antigen 85B (Ag85B). Addition of the cationic lipid dimethyl dioctadecylammonium bromide (DDA) and the immunostimulatory trehalose 6,6′-dibehenate (TDB), either separately or in combination, was investigated for the effect on particle size and distribution, antigen entrapment efficiency, in vitro release profiles and in vivo performance. Optimised formulation parameters yielded microspheres within the desired sub-10 μm range (1.50 ± 0.13 μm), whilst exhibiting a high antigen entrapment efficiency (95 ± 1.2%) and prolonged release profiles. Although the microsphere formulations induced a cell-mediated immune response and raised specific antibodies after immunisation, this was inferior to the levels achieved with liposomes composed of the same adjuvants (DDA–TDB), demonstrating that liposomes are more effective vaccine delivery systems compared with microspheres.     

PLGA microspheres containing bee venom proteins for preventive immunotherapy

Bee venom (BV) allergy is potentially dangerous for allergic individuals because a single bee sting may induce an anaphylactic reaction, eventually leading to death. Currently, venom immunotherapy (VIT) is the only treatment with long-lasting effect for this kind of allergy and its efficiency has been recognized worldwide. This therapy consists of subcutaneous injections of gradually increasing doses of the allergen. This causes patient lack of compliance due to a long time of treatment with a total of 30-80 injections administered over years. In this article we deal with the characterization of different MS-PLGA formulations containing BV proteins for VIT. The PLGA microspheres containing BV represent a strategy to replace the multiple injections, because they can control the solute release. Physical and biochemical methods were used to analyze and characterize their preparation. Microspheres with encapsulation efficiencies of 49-75% were obtained with a BV triphasic release profile. Among them, the MS-PLGA 34 kDa-COOH showed to be best for VIT because they presented a low initial burst (20%) and a slow BV release during lag phase. Furthermore, few conformational changes were observed in the released BV. Above all, the BV remained immunologically recognizable, which means that they could continuously stimulate the immune system. Those microspheres containing BV could replace sequential injections of traditional VIT with the remarkable advantage of reduced number of injections.     

Development of new reverse micellar microencapsulation technique to load water-soluble drug into PLGA microspheres

The objective of this study was to develop a new reverse micelle-based microencapsulation technique to load tetracycline hydrochloride into PLGA microspheres. To do so, a reverse micellar system was formulated to dissolve tetracycline hydrochloride and water in ethyl formate with the aid of cetyltrimethylammonium bromide. The resultant micellar solution was used to dissolve 0.3 to 0.75 g of PLGA, and microspheres were prepared following a modified solvent quenching technique. As a control experiment, the drug was encapsulated into PLGA microspheres via a conventional methylene chloride-based emulsion procedure. The microspheres were then characterized with regard to drug loading efficiency, their size distribution and morphology. The reverse micellar procedure led to the formation of free-flowing, spherical microspheres with the size mode of 88 microm. When PLGA microspheres were prepared following the conventional methylene chloride-based procedure, most of tetracycline hydrochloride leached to the aqueous external phase: A maximal loading efficiency observed our experimental conditions was below 5%. Their surfaces had numerous pores, while their internal architecture was honey-combed. In sharp contrast, the new reverse micellar encapsulation technique permitted the attainment of a maximal loading efficiency of 63.19 +/- 0.64%. Also, the microspheres had smooth and pore-free surfaces, and hollow cavities were absent from their internal matrices. The results of this study demonstrated that PLGA microspheres could be successfully prepared following the new reverse micellar encapsulation technique.     

Surface characterization by atomic force microscopy of sterilized PLGA microspheres

Atomic force microscopy (AFM) is recognized a suitable and powerful technique for surface and morphological analysis. Even if until now this technique has not been frequently used in the pharmaceutical field, it can contribute to an accurate morphologic characterization of microspheres and nanospheres. In this work, atomic force microscopy has been used to perform the surface characterization of sterilized microspheres. The aim is to investigate the morphologic modifications induced by gamma irradiation on poly(lactide-co-glycolide) microspheres loaded with ovalbumin and to compare the results obtained by AFM to those obtained by scanning electron microscopy (SEM). The results obtained show that, with respect to SEM, AFM can give some additional information regarding the modifications induced by γ-irradiation on microspheres surface morphology. The significant changes in surface roughness after irradiation are indicative of damage due to γ-irradiation. The unchanged surface roughness values calculated for microspheres containing PEG in their matrix, suggest that this polymer exerts a protective effect towards γ-irradiation.     

Development and validation of a reverse phase liquid chromatography method for the quantification of rasagiline mesylate in biodegradable PLGA microspheres

In the present study, a reverse phase high performance liquid chromatographic method was developed and validated for the determination of rasagiline mesylate in biodegradable microspheres. Chromatographic separation was carried out on a RP-18 column using a mobile phase consisting of acetonitrile:water (5:95, v/v) adjusted at pH 3.1. Flow rate was 1.0 ml min⁻¹ and UV detection at 290 nm. Acyclovir was used as the internal standard. The calibration curve was linear over the range 0.5–20.0 μg ml⁻¹. R.S.D. for precision was <1.8%. Accuracy ranged between 99.01% and 102.55% with a R.S.D. lower than 1.3%. LOD and LOQ were 0.07 μg ml⁻¹ and 0.23 μg ml⁻¹, respectively. The method was simple, rapid, and easy to apply, making it very suitable for routine analysis of rasagiline mesylate in biodegradable PLGA microspheres. It could be also used with reliability for the determination of the drug in other pharmaceutical dosage forms.     

PLGA微球控释系统的突释及其控制

针对目前限制PLGA微球控释系统临床应用的突释问题，重点介绍了近年来国内外有关的研究进展，包括突释现象、突释原因、影响因素和控制突释的方法和技术。     

乳酸羟乙醇酸共聚物微球中蛋白包封率的测定

目的:寻求一种合适的方法测定蛋白在乳酸羟乙醇酸共聚物(PLGA)微球中的包封率。方法:采用复乳 溶剂挥发法制备 BSA的PLGA微球,应用考马斯亮蓝法测定总蛋白浓度,根据文献报道的7种不同方法进行包封率测定。结果:不同的测定方法对 PLGA微球中真实的药物包封率的反映程度不同,相互间差异很大。结论:以水解法测定BSA在PLGA微球中包封率的方法提取 最完全。水解法中,又以乙腈作溶剂、再用氢氧化钠水解两步提取法最为简便、快速、准确。     

胸腺五肽聚乳酸-羟基乙酸共聚物长效微球在大鼠体内的药动学研究

目的:研究胸腺五肽(TP5)聚乳酸-羟基乙酸共聚物(PLGA)长效微球(简称"TP5长效微球")在大鼠体内的药动学特征。方法:取8只大鼠均分为普通注射液组(以TP5计1.5 mg/kg)和长效微球组(以TP5计40 mg/kg),单剂量肌肉注射相应的异硫氰酸荧光素标记TP5(FITC-TP5),以酶标仪测定普通注射液组(给药后0、5、10、15、30 min和1、2、4、6、10、24 h)和长效微球组(给药后0、0.5、1、2、4、10、24 h和4、7、14、21、28、35、42、49 d)大鼠体内FITC-TP5的荧光强度,计算血药浓度,采用DAS 2.0软件计算药动学参数和长效微球的累积释药情况。结果:普通注射液组和长效微球组大鼠体内FITC-TP5的药动学参数分别为t1/2z:0.031、9.292d,tmax:0.021、0.042 d,MRT0-∞:0.064、11.351 d,cmax:0.706、0.909 mg/L,AUC0-∞:0.078、2.554 mg·d/L;与普通注射液相比,长效微球中FITC-TP5的t1/2延长了299.7倍、MRT延长了177.3倍,缓释特征符合Higuchi方程,相对生物利用度为123%。结论:TP5长效微球可在大鼠体内缓慢释放,释药周期达42⁴9d。     

Biodegradation and biocompatibility of PLA and PLGA microspheres

A fundamental understanding of the in vivo biodegradation phenomenon as well as an appreciation of cellular and tissue responses which determine the biocompatibility of biodegradable PLA and PLGA microspheres are important components in the design and development of biodegradable microspheres containing bioactive agents for therapeutic application. This chapter is a critical review of biodegradation, biocompatibility and tissue/material interactions, and selected examples of PLA and PLGA microsphere controlled release systems. Emphasis is placed on polymer and microsphere characteristics which modulate the degradation behaviour and the foreign body reaction to the microspheres. Selected examples presented in the chapter include microspheres incorporating bone morphogenetic protein (BMP) and leuprorelin acetate as well as applications or interactions with the eye, central nervous system, and lymphoid tissue and their relevance to vaccine development. A subsection on nanoparticles and nanospheres is also included. The chapter emphasizes biodegradation and biocompatibility; bioactive agent release characteristics of various systems have not been included except where significant biodegradation and biocompatibility information have been provided.