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.     

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.     

丹皮酚聚乳酸羟基乙酸微球的制备及体外释药考察

目的:制备丹皮酚聚乳酸羟基乙酸(PLGA)微球,考察其体外释药过程。方法:以丹皮酚为芯材,以PLGA为载体,采用乳化溶剂挥发法制备丹皮酚PLGA微球;以聚乙烯醇质量分数、PLGA质量浓度、药物与PLGA质量比及水油相体积比为考察因素,以包封率和载药量的综合评分为评价指标,采用正交试验优选制备工艺;扫描电镜和光学显微镜观察微球的外观和粒径,并测定其体外释药过程。结果:优选的工艺为聚乙烯醇质量分数0.9%、PLGA质量浓度60g/L、药物与PLGA质量比1∶3、水油相体积比1∶10。制得的微球球型规则,表面平滑,平均粒径为(31.75±0.13)μm。微球的载药量为(21.16±0.51)%,包封率为(66.91±1.62)%,8h体外累积释药量为37%。结论:所选工艺可用于制备丹皮酚PLGA微球,可为缓释药物传递系统的开发提供参考。     

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。     

紫杉醇-索拉非尼-聚乳酸-羟基乙酸载药栓塞微球的制备及体外释药特性研究

目的:制备紫杉醇-索拉非尼-聚乳酸-羟基乙酸(PLGA)载药栓塞微球,建立其含量的测定方法,并考察其体外释药特性。方法:采用乳化-溶剂挥发法制备紫杉醇-索拉非尼-PLGA载药栓塞微球。采用高效液相色谱法测定微球中紫杉醇、索拉非尼的含量并计算载药量及包封率,色谱柱为Agilent TC-C_(18),流动相为水-乙腈(40∶60,V/V),流速为1.0 mL/min,检测波长为228 nm,柱温为28℃,进样量为10μL。采用光学显微镜、扫描电镜观察微球的形态,采用激光粒度仪测定微球的粒径;采用高效液相色谱法测定生理温度(37℃)下紫杉醇、索拉非尼的释放度;采用阿伦尼乌斯方程预测37℃下的反应速率常数,并与实测(37℃)值进行比较。结果:紫杉醇、索拉非尼的检测质量浓度线性范围均为2.0～400.0μg/mL(r均为0.999 6);定量限分别为1.902 6、1.890 2μg/mL,检测限分别为0.985 5、1.264 5μg/mL;精密度、稳定性、重复性试验的RSD均小于2%;回收率分别为99.00%～102.91%(RSD=1.12%,n=9)、98.39%～102.96%(RSD=1.94%,n=9)。所得微球形态圆整,表面光滑无粘连、无突起,平均粒径为(139±1.16)μm;紫杉醇、索拉非尼的载药量分别为1.12%、0.85%,包封率分别为73.11%、58.65%;在37℃下,41 d内累积释放度分别为(71.83±3.96)%、(81.44±6.02)%;紫杉醇、索拉非尼预测反应速率常数与实测值相对标准偏差的RSD<10%,相似因子分别为83.53、73.95。结论:成功制得紫杉醇-索拉非尼-PLGA载药栓塞微球,其形态较好,且具有较好的缓释作用;预测释放度曲线与实测释放度曲线相关性较好;所建含量测定方法操作简便、稳定性较好。     

聚乳酸-羟基乙酸载药微球控制体外释放因素的研究进展

体外释放行为研究是为了能够更好地反映微球在体内的释药状况,有利于筛选出更理想的处方及工艺.体外释放度试验是微球制剂释药速度的体外评价方法,可以了解制剂的生物药剂学特点和预测药物在体内的释放和吸收,使体外释放获得的数据能与体内数据具有相关性.体外释放度实验是常用的微球制剂体外释药速度的评价方法.建立体内外相关性后就能以体外实验代替体内实验来测定生物利用度和生物等效性.根据药物的性质、给药途径和释药时间,选用不同的聚乳酸-羟基乙酸(PLGA)采用相应的制备工艺;通过调整PLGA的组成、分子量、载药量及粒径的大小等因素,能控制药物达到不同的释放速度或程度.     

聚乳酸羟基乙酸载药微球的研究进展

综述聚乳酸羟基乙酸(PLGA)载药微球的制备方法及其微球中药物释放的研究。     

青风藤总生物碱聚乳酸微球的制备

聚乳酸(PLA)及其共聚物具有良好的生物相容性和生物降解性,在人体内无积聚,最终可完全降解为二氧化碳和水.PLA微球可用于制备生物降解型缓释或定向给药体系[1,3],具有广泛的应用前景.     

乳酸-羟基乙酸共聚物(PLGA)微球控释系统的突释

目的介绍近年来国内外对乳酸-羟基乙酸共聚物(PLGA)微球控释系统的突释的研究。方法分析有关文献资料,对产生突释的原因、影响突释的因素以及减少突释的方法进行详细介绍。结果和结论突释通常是不受欢迎的,随着对突释原因的深入了解,突释问题应能得到解决和控制。     

微球中聚乳酸羟基乙酸共聚物浓度与微球结构、释药、降解的关系研究

目的:研究微球中聚乳酸羟基乙酸共聚物(PLGA)浓度与微球结构、释药、降解的关系。方法:以牛血清白蛋白(BSA)为药物,采用复乳法制备PLGA浓度分别为10%、15%、20%的BSA-PLGA微球,以包封率、载药量、粒径为指标考察PLGA浓度对3种微球性质的影响;采用扫描电子显微镜观察3种微球和降解40 d内的外观和内部形态;使用荧光蛋白-异硫氰酸荧光素牛血清白蛋白代替BSA作为模型药物制备PLGA微球,并采用激光共聚焦显微镜观察荧光蛋白在微球骨架内的分布情况;采用BCA法考察3种微球的体外释药情况;采用压汞仪考察降解28 d内20%PLGA所制微球的孔径、孔隙率、截面孔隙率的变化;采用凝胶渗透色谱法检测10%、20%PLGA所制微球降解28 d内分子质量及其降解模型拟合。结果:与10%、15%PLGA所制微球比较,20%PLGA所制微球的包封率[(81.96±1.84)%]和粒径[(139.50±0.21)μm]最大,载药量[(7.28±0.45)%]最低,截面孔隙率[(32.35±1.98)%]和孔径[(12.43±0.14)μm]最小,释药突释率最低,40 d内的释放速率相对较慢,降解后截面孔隙率最大,降解均遵循假一级模式(r2=0.065 3)。结论:在考察范围内,随着PLGA浓度的增加,微球的结构更致密,释药更平稳,降解更易形成中空结构。     

Stabilization of Vinca Alkaloids Encapsulated in Poly(lactide-co-glycolide) Microspheres

Purpose. The purpose of this study was to stabilize the vinca alkaloids,vincristine sulfate (VCR) and vinblastine sulfate (VBL), inpoly(lactide-co-glycolide) (PLGA) microspheres and to release the drugs in asustained manner for more than a month. Methods. An oil-in-oil emulsion-solvent extraction method was usedto encapsulate VCR and VBL in PLGA50/50 microspheres. Stabilityand release kinetics of the drugs during the incubation at 37°C inPBS/Tween 80 were assessed by HPLC. Degradation products wereidentified with HPLC-MS. Results. VCR and VBL were encapsulated in PLGA microspheresunchanged. During the microsphere incubation, however, VCRdegraded inside the particles with a t_1/2 7.5 days. The degradationproduct was identified by LC-MS as the deformyl derivative, commonlyformed at acidic pH. VBL, which differs only by a stable methyl groupin place of the N-formyl group in VCR, was completely stable in thePLGA microclimate. The neutralization of acidic PLGA microclimateby addition of 3–10% Mg(OH)₂ completely inhibited deformylationof VCR during release, but introduced a new degradation productformed under the more alkaline conditions used during the preparation.The substitution of Mg(OH)₂ with a weaker base, ZnCO₃, inhibitedthe formation of both degradation products resulting in VCRstabilization of >92% for 4 weeks. The optimal formulations of VCR(containing ZnCO₃) and VBL (no additives) slowly and continuouslyreleased stable drugs for over a month. Conclusions. VCR and VBL were successfully stabilized and releasedin a sustained manner from PLGA microspheres. Co-encapsulation ofZnCO₃ stabilizes VCR against acid-catalyzed degradation duringrelease from the polymer and minimizes VCR decomposition duringencapsulation.     

5-Fu/PLGA 微球的制备

以可生物降解高分子材料乳酸—羟乙酸共聚物(PLGA)为载体,以5—氟脲嘧啶(5-Fu)为活性药物,用相分离—凝聚法制备了可供肿瘤动脉栓塞化疗用微球,并进行了初步的微球体外药物释放试验。     

Dose and Load Studies for Subcutaneous and Oral Delivery of Poly(lactide-co-glycolide) Microspheres Containing Ovalbumin

Poly(lactide-co-glycolide) microspheres containing different loads of OVA (0.05, 0.1, 0.5 and 1.0% w/w) were manufactured by a w/o/w emulsion/solvent evaporation method. Low load efficiencies of less than 20% were observed. Normal size distributions with mean volume diameters ranging from 3.7 to 4.7 µm were obtained for different batches. The in vitro release of OVA from different loaded microspheres showed an expected burst release with all batches. The in vivo dose study (1, 10, 25, 50 µg of OVA) was performed by subcutaneous and oral inoculation in mice by single (0 week) or double (0 and 3 weeks) administration of PLGA 50/50 microspheres containing 0.1% OVA. Subcutaneous administration showed an immune response (serum Ig levels by ELISA) statistically (Fishers paired t-test; P < 0.05) above OVA saline negative controls at 3, 6 and 12 weeks after administration. Oral administration of microspheres produced statistically higher systemic immune responses at the higher doses. Single and double inoculation orally and subcutaneously produced similar serum antibody levels. The in vivo load study was performed by subcutaneous and oral administration to mice of 25 µg OVA contained in various loaded (0.05, 0.1, 0.5 and 1.0% w/w) microspheres. Serum immune responses at 3, 6, and 12 weeks after inoculation were statistically above OVA saline controls and were inversely proportional to the OVA load using either route. This observation suggested a relationship between the number of microspheres delivered and the in vivo serum response. Single subcutaneous administration of 0.05 or 0.1% OVA loaded PLGA 50/50 microspheres induced larger immune responses compared with complete Freunds adjuvant.     

Particle Size Studies for Subcutaneous Delivery of Poly(lactide-co-glycolide) Microspheres Containing Ovalbumin as Vaccine Formulation

The primary objectives of the present study were to produce poly(lactide-co-glycolide) (PLGA) microspheres with different diameters, to characterize these microspheres which were loaded with a model antigen, ovalbumin and to evaluate the effect of microsphere particle size on the serum antibody levels following administration to mice. Four kinds of ovalbumin-loaded PLGA microspheres with different diameters (1·2, 3·5, 7·0 and 14·3 μm as mean volume diameter) were manufactured by a w/o/w emulsion/solvent evaporation method. Low loading percent (0·08%-0·25%w/w) and efficiencies (8–25% w/w) were observed. Examination using scanning electron photomicrographs showed smooth spherical particles. The in-vitro release of ovalbumin from microspheres showed an expected burst release with all batches and the extent of the burst release increased with decreasing diameters of spheres; PLGA microspheres with the smallest diameter (1·2/μm) showed an 80% burst release within one day. Approximately 10–60% of ovalbumin remained unreleased 30 days later. The single subcutaneous administrations of ovalbumin-loaded PLGA microspheres with different diameters to mice induced good antibody responses above ovalbumin saline negative controls at 3, 6, 9, and 12 weeks after inoculation. Especially, 0·16% ovalbumin-loaded PLGA microspheres having mean volume diameter of 3·5 /μm exhibited the best immune responses with values greater than those obtained after inoculation with adjuvants such as complete Freund's adjuvant or alum as positive control. The strong adjuvant activity of PLGA microspheres as vaccine formulation was suggested.     

Release of Human Serum Albumin from Poly(lactide-co-glycolide) Microspheres

Human serum albumin (HSA) was encapsulated in a 50:50 copolymer of DL-lactide/glycolide in the form of microspheres. These microspheres were used as a model formulation to study the feasibility of controlling the release of large proteins over a 20- to 30-day period. We show that HSA can be successfully incorporated into microspheres and released intact from these microspheres into various buffer systems at 37°C. A continuous release of the protein could be achieved in physiological buffers at 37°C over a 20- to 30-day period from microspheres with high protein loadings (11.6%). These results demonstrate the potential of poly(DL-lactide-co-glycolide) microspheres for continuous delivery of large proteins.     

The Acidic Microclimate in Poly(lactide-co-glycolide) Microspheres Stabilizes Camptothecins

Purpose. The camptothecin (CPT) analogue, 10-hydroxycamptothecin (10-HCPT) has been shown previously to remain in its acid-stable (and active) lactone form when encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres (1). The purpose of this study was to determine the principal mechanism(s) of 10-HCPT stabilization. Methods. CPTs were encapsulated in PLGA 50:50 microspheres by standard solvent evaporation techniques. Microspheres were eroded in pH 7.4 buffer at 37°C. The ratio of encapsulated lactone to carboxylate was determined by HPLC as a function of time, initial form of drug encapsulated, fraction of co-encapsulated Mg(OH)₂, CPT lipophilicity, and drug loading. Two techniques were developed to assess the microclimate pH, including: i) measurement of H⁺ content of the dissolved microspheres in an 80:20 acetonitrile/H₂O mixture and ii) confocal microscopy of an encapsulated pH-sensitive dye, fluorescein. Results. The encapsulated carboxylate converted rapidly to the lactone after exposure to the release media, indicating the lactone is favored at equilibrium in the microspheres. Upon co-encapsulation of Mg(OH)₂, the trend was reversed, i.e., the lactone rapidly converted to the carboxylate form. Measurement of -log(hydronium ion activity) (pa*_H) of dissolved microspheres with pH-electrode and pH mapping with fluorescein revealed the presence of an acidic microclimate. From the measurements of H+ and water contents of particles hydrated for 3 days, a microclimate pH was estimated to be in the neighborhood of 1.8. The co-encapsulation of Mg(OH)₂ could both increase the pa*_H reading and neutralize pH in various regions of the microsphere interior. Varying the drug lipophilicity and loading revealed that the precipitation of the lactone could also stabilize CPT. Conclusions. PLGA microspheres prepared by the standard solvent evaporation techniques develop an acidic microclimate that stabilizes the lactone form of CPTs. This microclimate may be neutralized by co-encapsulating a base such as Mg(OH)₂, as suggested by previous work with poly(ortho esters) (2).     

盐酸恩丹西酮乳酸羟基乙酸共聚物微球中药物的含量测定

目的:建立测定盐酸恩丹西酮乳酸羟基乙酸共聚物微球含量的方法.方法:采用二氯甲烷溶解微球后,再以水提取主药,用紫外分光光度法测定药物的含量.结果:盐酸恩丹西酮在2～20μg·ml-1的范围内,浓度与吸收度的线性关系良好,平均回收率为98.76%±0.64%,RSD为1.82%.结论:该方法操作简单、可靠,可用于快速测定微球中药物的含量.     

紫杉醇聚丙交酯乙交酯共聚物纳米粒的制备与体外评价

目的采用聚丙交酯乙交酯共聚物（PLGA）载体制备紫杉醇（TAX）纳米粒,并进行体外评价。方法采用改良的溶剂扩散法制备TAX PLGA共聚物纳米粒,考察不同乳化剂类型和各工艺因素对纳米粒粒径的影响,通过动态激光粒度分析仪、透射电子显微镜（TEM）、扫描电子显微镜（SEM）、差示扫描量热法（DSC）及X线粉末衍射（XRD）初步研究其载药性质,并研究纳米粒冻干粉的体外释放特性。结果优选出制备工艺为：双十二烷基二甲基溴化铵（DMAB）作为乳化剂,浓度为1%（W/V）,聚合物浓度为1%（W/V）,水相与有机相的体积比例为20：10,均质机转速为16 000 r&#8226;min 1,药物浓度为0.1%（W/V）。所得纳米粒外观圆整,平均粒径为99.0 nm,Zeta电位58.3 mV,包封率为56.77%,载药量率为7.10%。TAX纳米粒具有缓释性,体外释放分为两相。DSC及XRD表明TAX被有效地包裹在纳米粒中。结论PLGA纳米粒可成为TAX的新型载体。     

多柔比星聚酯微球的制备

采用液中干燥法制备多柔比星聚酯微球,使用星点设计-效应面法优化制备工艺.以药物与药物和聚β-羟基丁酸酯(PHB)总量的重量比、有机相中PHB浓度和水相中聚乙烯醇(PVA)浓度为自变量,载药量、包封率、粒径和跨距为因变量,分别进行多元线性回归和二次多项式拟合.结果表明,4个方程均采用二次多项式拟合的效果较好.根据因变量效应面选择的较佳工艺条件为药物与药物和PHB总量之比6%、PHB浓度50mg/m1、PVA浓度6.5%,按优化工艺制得的微球形态圆整,载药量、包封率、平均粒径和跨距分别为1.0%、16.8%、43.1μm和1.45,体外释放60d累积释放65%.