乳酸-羟基乙酸共聚物载药纳米粒的制备及体外释药性

背景：医用纳米粒作为药物传递的新型载体,目前已经成为医药领域研究的重点。目的：构建以生物可降解材料乳酸-羟基乙酸共聚物为载体,负载抗肿瘤药物5-氟尿嘧啶的载药纳米粒。方法：利用复乳-溶剂挥发法制备乳酸-羟基乙酸共聚物载药纳米粒。场发射扫描电子显微镜观察纳米粒表面形态;激光粒度分析仪测定粒径分布并计算成球率;紫外分光光度计测定5-氟尿嘧啶载药量、包封率,并对体外释药进行评估。结果与结论：纳米粒呈球性,平均粒径为（186±14）nm,成球率、载药量和包封率分别为70.8%、6.6%、28.1%,体外释药有突释现象,24h内5-氟尿嘧啶累积释药量达36.2%,10d达83.6%。提示成功制备乳酸-羟基乙酸共聚物载药纳米粒,其具有缓释效应。     

乳酸-羟基乙酸共聚物纳米粒的研究进展

乳酸-羟基乙酸共聚物是目前被认为最具发展前景的生物医用高分子可降解材料之一,对近年来乳酸-羟基乙酸共聚物纳米粒的制备方法和改性研究进行分析.目前制备乳酸-羟基乙酸共聚物纳米粒药物载体的方法主要有沉淀法、乳化溶剂挥发法、溶剂扩散法、喷雾干燥法等.乳酸-羟摹乙酸共聚物纳米粒的表面涂层、表面接枝、表面特异性配体修饰及与其他高聚物共聚、与无机物复合是改性研究的热点.乳酸-羟基乙酸共聚物纳米粒药物载体的制各技术和改性研究方法较多,但尚未完全解决临床应用上如何控制药物适量的突释,使血药浓度快速达到有效治疗浓度而不导致杀死正常细胞等一些问题,乳酸-羟基乙酸共聚物纳米粒系统有待进一步的完善.     

载异烟肼利福平聚乳酸纳米粒的制备及体外释药

背景:微载体药物因具有靶向性、控释性、稳定性、更好的安全性备受关注.目的:观察载异烟肼利福平两种抗结核药于同一聚乳酸纳米粒的给药系统及体外释放特性.方法:采用改良的自乳化二元溶剂扩散法制备载异烟肼和利福平纳米粒,亚微粒径分析仪测定纳米粒粒径及分布,透射电镜观察其形态;高效液相色谱仪建立测定异烟肼、利福平的载药量和包封率;以磷酸盐缓冲液为释放介质,观察载异烟肼和利福平纳米粒的体外释药特性.结果与结论:载利福平和异烟肼纳米粒表面完整光滑,无明显粘连现象,纳米粒均匀度好.亚微粒径分析仪测定纳米粒平均粒径80.4 nm.异烟肼载药量为(15.95±1.34)%,包封率为(5.01±0.17)%;利福平载药量为(4.66±0.97)%,包封率为(4.05±0.18)%.体外释药结果显示纳米粒的体外释药过程较平稳.突释期纳米粒中异烟肼释放度为15.22%,到3 d累积释放度可达95.6%;利福平释放度为9.26%,到3 d累积释放度可达90.3%.提示采用改良的自乳化二元溶剂扩散法制备载异烟肼和利福平纳米粒,所得载药纳米粒的粒径小且较均匀.纳米粒体外释药过程较平稳,无明显突释现象.     

正交优化聚乳酸-羟基乙酸纳米粒的制备

背景:聚乳酸-羟基乙酸纳米粒或纳米微球用于制备生物降解型缓释或定向给药体系已经研究了近30年,是国内外研究的热点.该体系能够控制粒径大小、延缓药物降解、延长药物释放时间、靶向释放、降低药物毒性和刺激性等.目的:以紫杉醇为模型药物、聚乳酸-羟基乙酸为包裹材料,探索载药纳米粒的制备条件对粒径、包封率等的影响,确定最佳制备工艺条件.方法:采用乳化-溶剂挥发法制备聚乳酸-羟基乙酸纳米粒,以粒径、包封率和载药量等为观察指标,通过正交设计法优化纳米粒制备工艺条件.结果与结论:通过正交实验设计,优化了制备工艺条件,其最佳条件是超声乳化时间为15 min,乳化剂浓度为1%,油水相比为1:25,合成温度为25℃.在此条件下进行实验,制备出的载药纳米粒粒径为217.6 nm,载药量1.79%,包封率85%.该制备工艺简单、稳定,优化制备条件,可制备出包封率高、粒径适宜的紫杉醇-聚乳酸-羟基乙酸纳米粒.     

聚乳酸-羟基乙酸纳米粒的制备

背景：聚乳酸-羟基乙酸是一种生物相容性良好的可降解材料,确定其最佳制备工艺条件,有利于聚乳酸-羟基乙酸后续药物载体研究与工业化生产条件的确立。目的：以聚乳酸-羟基乙酸为包裹材料,探索纳米粒的制备条件对粒径、表面形态等的影响,确定最佳制备工艺条件。方法：采用乳化-溶剂挥发法制备聚乳酸-羟基乙酸纳米粒,以粒径为观察指标,探讨乳化剂种类、乳化剂含量、油相种类、超声时间、挥发时间、油相与水相体积比（W∶O）以及聚合物质量浓度等制备条件对纳米粒粒径的影响,确定制备聚乳酸-羟基乙酸纳米粒的最佳工艺条件。结果与结论：优化后的制备工艺条件是在室温下,以一定的搅拌速度和滴加速度,选择常用无毒的乳化剂,浓度在0.3%~1.0%,丙酮为有机相,超声时间8~15min、挥发时间6~10h、水油相比（W∶O）〉25∶1,聚合物质量浓度〈60g/L。提示该制备工艺简单、稳定,优化制备条件,可制备出表面形态规整、粒径适宜的聚乳酸-羟基乙酸纳米粒。     

聚乳酸-羟基乙酸纳米粒的制备

背景:聚乳酸-羟基乙酸是一种生物相容性良好的可降解材料,确定其最佳制备工艺条件,有利于聚乳酸-羟基乙酸后续药物载体研究与工业化生产条件的确立。目的:以聚乳酸-羟基乙酸为包裹材料,探索纳米粒的制备条件对粒径、表面形态等的影响,确定最佳制备工艺条件。方法:采用乳化-溶剂挥发法制备聚乳酸-羟基乙酸纳米粒,以粒径为观察指标,探讨乳化剂种类、乳化剂含量、油相种类、超声时间、挥发时间、油相与水相体积比(W∶O)以及聚合物质量浓度等制备条件对纳米粒粒径的影响,确定制备聚乳酸-羟基乙酸纳米粒的最佳工艺条件。结果与结论:优化后的制备工艺条件是在室温下,以一定的搅拌速度和滴加速度,选择常用无毒的乳化剂,浓度在0.3%~1.0%,丙酮为有机相,超声时间8~15min、挥发时间6~10h、水油相比(W∶O)>25∶1,聚合物质量浓度<60g/L。提示该制备工艺简单、稳定,优化制备条件,可制备出表面形态规整、粒径适宜的聚乳酸-羟基乙酸纳米粒。     

乳酸-羟基乙酸共聚物缓释微球的制备、性能及应用

用于制备乳酸-羟基乙酸共聚物缓释微球的方法很多,可根据聚合物和药物的性质进行选择,其中乳化-固化法是目前制备乳酸-羟基乙酸共聚物缓释微球中最常用的方法,适用于在连续相中不溶或难溶的药物,缺点在于使用有机溶剂,不利于保持药物的活性,复乳化时工艺也比较复杂,不适宜进行工业化生产;喷雾干燥技术是一种快速的一步微囊化过程,其条件温和,制得的微球具有粒度分布窄、包封率高等特点,其用于不稳定药物微囊化的大规模生产极具潜力.由于给药初期的突释有可能导致血药浓度接近或超过中毒水平,产生明显的毒副作用.乳酸-羟基乙酸共聚物的分子质量、乳酸-羟基乙酸共聚物的纯度、主药理化性质、微球制备方法及制备参数、微球载药量等均是影响突释程度的具体因素.目前防止突释或降低突释程度的方法主要有改变载体材料结构、适当的微球制备以及萃取、洗涤或加入附加剂等.乳酸-羟基乙酸共聚物微球控释系统具有延长药物释放时间、靶向释放、降低药物毒性和刺激性等特点,存在多种给药途径可肌肉注射、皮下注射、玻璃体内注射、关节腔内给药、植入给药、黏膜给药等.     

叶酸修饰乳酸-羟基乙酸共聚物纳米粒的制备及性能表征

以聚乙二醇二氨为偶联剂,通过叶酸活性酪和聚合物端基活性酯与聚乙二醇二氨反应,制得叶酸修饰的大分子,再通过乳化法合成载紫杉醇纳米粒,制备叶酸修饰的乳酸-羟基乙酸共聚物纳米粒子.紫外光谱、红外光谱、核磁光谱显示叶酸成功连接在高聚物分子上.所制得的纳米粒粒径(276±12)nm,扫描电镜观察其形态为规整的球形.该方法可成功制备叶酸修饰的乳酸-羟基乙酸共聚物载药纳米粒.     

乳酸-羟基乙酸共聚物缓释微球的制备工艺与生物学性能

微球(microspheres)是一种生物物理靶向载药制剂,粒径为1～300μm.微球的载体材料按其来源可分为天然高分子材料、半合成高分子材料及合成高分子材料.在合成高分子材料中,通过采用合适的制备工艺和处方,制得的载药微球可在几周或几个月时间内以一定速率释放药物,减少给药次数,增加患者顺应性.对蛋白和多肽类药物,微球是相当理想的载药系统.微球制剂是近年来缓释剂型的研究热点,根据临床需要很多药物正被研究成微球制剂.乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid),PLGA]有着优良的安全性、生物相容性和可变的生物降解性,是制备微球的常用基本材料.PLGA缓释微球制剂的制备方法基本上可分为3种:溶剂挥发法、喷雾干燥法、相分离法.溶剂挥发法是常用的制备方法之一,目前PLGA微球作为多肽、蛋白类药物的载体已广泛应用于免疫学、基因治疗、肿瘤治疗、骨缺损修复、眼科等众多医学领域中.     

聚乳酸羟基乙酸CXCR4-miRNA纳米微粒的制备及其特征

背景：有关研究表明聚乳酸羟基乙酸能够有效包裹反义寡核苷酸、小的干扰 RNA、微小RNA等,可以较好地保护其在体内不受各种酶的破坏,并可以起到缓慢释放药物的作用,从而可以减少药物的给药次数,达到长期、有效的治疗效果。 目的：制备聚乳酸羟基乙酸CXCR4-miRNA纳米微粒,并研究纳米微粒的特性。 方法：运用二次超声乳化溶剂挥发法制备聚乳酸羟基乙酸CXCR4-miRNA纳米微粒,采用紫外分光光度法测定纳米微粒的载药量及包封率,透射电镜观察微粒形态,激光粒径仪测定纳米微粒的大小和分布;将纳米微粒悬浮于磷酸盐缓冲液中观察其缓释特性。 结果与结论：制备的纳米微粒形态呈圆形,表面光滑,分散性好,不粘连,其粒径分布在143-502 nm,平均粒径为280 nm,平均载药量为（0.515±0.023）%,平均包封率为50.2%,批间差异小。纳米微球在体外可以缓慢释放,经过前几天的快速释放后,在第14天进入平台期。结果充分表明运用二次超声乳化溶剂挥发法制备聚乳酸-羟基乙酸CXCR4-miRNA纳米微粒的工艺过程简单,粒子性状符合要求且具有缓释性。     

包载雷帕霉素聚乳酸-聚乙醇酸纳米粒子的制备、表征及体外释放试验

背景：新型可生物降解多聚物纳米控释载药制剂能显著改善药物穿透组织能力、再分布时程和滞留时间,可能克服载药基质对血管修复的负性影响,有望避免药物洗脱支架晚期支架内血栓。目的：制备雷帕霉素-聚乳酸-聚乙醇酸纳米粒子（rapamycin poly（lactic-co-glycolic）acid nanoparticles,RPM-PLGA-NPs）并观察其表征及体外控释性能。设计、时间及地点：单一样本实验于2003-03/09在中国医学科学院,中国协和医科大学,生物医学工程研究所生物医学材料重点实验室完成。材料：聚乳酸-聚乙烯醇酸共聚物50∶50由美国Birmingham Polymers公司提供。方法：以可生物降解高分子材料聚乳酸-聚乙醇酸共聚物作载药基质,超声乳化-溶剂挥发法制备RPM-PLGA-NPs,采用双室扩散池行体外药物释放试验。主要观察指标：测定平均载药量、平均包封率;激光光散射实验测定纳米粒子的粒径及分布;扫描电镜观察纳米粒子的表面形态;高效液相色谱法计算体外药物释放量、绘制累积释放曲线。结果：成功制备了平均粒径为246.8nm的RPM-PLGA-NPs,平均粒径246.8nm,粒径分布集中在208～294nm,呈窄分布;包封率大于77%,平均载药量为19.42%。体外释放近似于零级过程,至2周释放75%的药物。结论：超声乳化-溶剂挥发法制备RPM-PLGA-NPs稳定可靠,包封效率高,载药量控制稳定,粒径小、范围窄,体外释放药物恒定、具有良好的控释效能。     

装载油酸修饰氧化铁的聚乳酸/羟基乙酸纳米粒的制备、表征及体外MR显像

目的制备装载油酸修饰氧化铁的聚乳酸/羟基乙酸(PLGA)纳米粒(磁性PLGA纳米粒),并对其理化性质进行表征,观察其体外MR显像效果。方法以油酸修饰氧化铁和PLGA-COOH为原料,采用单乳化法制备磁性PLGA纳米粒。以激光共聚焦扫描显微镜及透射电镜观察其表面及内部结构;Malvern激光分析仪测量其粒径大小、分布及表面电位;X射线粉末衍射仪分析其内部物象结构;原子吸收光谱法测量样品中Fe的浓度;热重分析法分析其内装载的Fe3O4的量。将稀释到不同浓度的磁性PLGA纳米粒分别置于Eppendof管中,行MR扫描。结果所得样品为棕色混悬液,大小均匀,粒径为(292.70±77.07)nm,多分散指数为0.009,粒径分布较窄;Zeta电位为(-10.20±4.34)mV;透射电镜和X射线粉末衍射法证实其内包裹大量Fe3O4颗粒;原子吸收光谱法计算得Fe3O4的包封率为39.6%,Fe3O4的负载量为1.036%。体外MR显像显示,所得样品能使T2*信号强度降低,且样本中Fe浓度越大,其信号强度越低。结论制备所得磁性PLGA纳米粒粒径小,分布窄,能有效降低T2*信号强度,为构建潜在多功能MRI分子探针奠定了基础。     

Polymer degradation and in vitro release of a model protein from poly(D,L-lactide-co-glycolide) nano- and microparticles.

The objective of the study was to investigate the effect of particle size of nano- and microparticles formulated from poly(D,L-lactide-co-glycolide) (50:50 PLGA) on polymer degradation and protein release. Since the surface area to volume ratio is inversely proportional to the particle size, it is hypothesized that the particle size would influence the polymer degradation as well as the release of the encapsulated protein. PLGA nano- and microparticles of approximate mean diameters of 0.1, 1 and 10 microm, containing bovine serum albumin as a model protein, were formulated using a multiple water-in-oil-in-water emulsion solvent evaporation technique. These particles were incubated at 37 degrees C in phosphate-buffered saline (pH 7.4, 154 mM) and the particles were characterized at various time points for molecular weight of polymer, surface-associated polyvinyl alcohol content (PVA), and the particle surface topology using scanning electron microscopy. The supernatants from the above study were analyzed for the released protein and PVA content. Polymer degradation was found to be biphasic in both nano- and microparticles, with an initial rapid degradation for 20-30 days followed by a slower degradation phase. The 0.1 microm diameter nanoparticles demonstrated relatively higher polymer degradation rate (P<0.05) during the initial phase as compared to the larger size microparticles (first order degradation rate constants of 0.028 day(-1), 0.011 day(-1) and 0.018 day(-1) for 0.1, 1 and 10 microm particles, respectively), however the degradation rates were almost similar (0.008 to 0.009 day(-1)) for all size particles during the later phase. All size particles maintained their structural integrity during the initial degradation phase; however, this was followed by pore formation, deformation and fusion of particles during the slow degradation phase. Protein release from 0.1 and 1 microm particles was greater than that from 10 microm size particles. In conclusion, the polymer degradation rates in vitro were not substantially different for different size particles despite a 10- and 100-fold greater surface area to volume ratio for 0.1 microm size nanoparticles as compared to 1 and 10 microm size microparticles, respectively. Relatively higher amounts of the surface-associated PVA found in the smaller-size nanoparticles (0.1 microm) as compared to the larger-size microparticles could explain some of the observed degradation results with different size particles.     

Modulated release of IdUrd from poly (D,L-lactide-co-glycolide) microspheres by addition of poly (D,L-lactide) oligomers.

This paper reports the release characteristics of a radiosensitizer, 5-iodo-2'-deoxyuridine (IdUrd), from poly (D,L-lactide-co-glycolide) 50: 50 (PLGA) microparticles obtained by a phase separation technique. Poly (D,L-lactide) oligomers (D,L-PLA) were incorporated into the PLGA matrix in order to accelerate the overall drug release rate and regulate the triphasic release profile exhibited by the standard PLGA microparticles. For D,L-PLA (800), the burst effect was large and the IdUrd release was complete between 28 and 35 days. These results were attributed to rapid pore formation on the periphery of the microsphere in the early stages of incubation, due to hydrosolubility of the smallest oligomers (D,L-PLA (800)). In the case of D,L-PLA (1,100), drug release occurred over a six week period, the standard time course of conventional radiation therapy. The period during which the radiosensitizer was incorporated in human brain tumor cell nuclei after its entrapment in biodegradable microspheres was determined by using an organotypical tissue culture. The presence of radiosensitizer in the DNA of tumor cell nuclei was detected by immunohistochemical labelling of tumor fragments. IdUrd release from standard microspheres (7+/-0.5 weeks) was longer than from oligomer-containing batches. For D,L-PLA (800)-containing microspheres, the radiosensitizer was entirely released within 4. 5+/-0.5 weeks. The microspheres containing D,L-PLA (1,100) allowed an IdUrd release over a 5 to 6 week period. The ex vivo data were consistent with the in vitro findings in terms of release duration.     

Preparation and in vitro characterization of valsartan-loaded ethyl cellulose and poly(methyl methacrylate) nanoparticles

Valsartan is an antihypertensive drug used primarily orally, however, due to its hydrophobic nature it has got low bio-availability thus requiring higher dosage/frequency and causing more side effects. The aim of our work was to prepare valsartan-loaded nanoparticles by using ethyl cellulose and poly(methyl methacrylate) polymers which can be administered orally and to investigate the preparation conditions and their significance as potential drug carriers for valsartan delivery by in vitro release studies. Ethyl cellulose and poly(methyl methacrylate) polymers were used for the preparation of nanoparticles by single emulsion-solvent evaporation technique. The formation of drug-loaded nanoparticles was designed by experimental design for size and encapsulation efficiency, in addition the prepared nanosuspensions were nano spray dried in order to gain a powder form that is easy to handle and store. Both of the nano spray dried formulations had an amorphous structure in contrast to the pure drug according to differential scanning calorimetry and X-ray diffraction analysis, which can be advantageous in drug absorption. The originally processed ethyl cellulose-valsartan nanoparticles increased the solubility of the drug in the model intestinal medium, while poly(methyl methacrylate)-valsartan nanoparticles enabled substantially prolonged drug release. The release kinetics of both types of nanoparticles could be described by the Weibull model.

Valsartan-loaded ethyl cellulose and poly(methyl methacrylate) nanoparticles were prepared and nano spray-dried. The active agent was structurally changed in the nanoparticles, which could be advantageous in the intestinal absorption.     

Ultrasound-triggered drug release and enhanced anticancer effect of doxorubicin-loaded poly(D,L-lactide-co-glycolide)-methoxy-poly(ethylene glycol) nanodroplets

A novel ultrasound-responsive doxorubicin (DOX)-loaded nanoparticulate system was prepared in this study. The DOX-loaded polymeric micelles were first prepared using poly(D,L-lactide-co-glycolide)-methoxy-poly(ethylene glycol) (PLGA-mPEG) with a high encapsulation efficiency of 89.2%. After filling with perfluoropentane (boiling point 29°C), the micelles were transformed into nanodroplets that were stable as a result of the PEG shell. The nanodroplets were transformed into nanobubbles at 37°C, and little drug was released if no ultrasound was exerted. Ultrasound-triggered drug release, with pH dependency, was shown. The DOX release percentage was 9.59% at pH 6.5 (also appeared in tumor) and only 2.22% at pH 7.4 after sonicating for 0.5 min at 37°C. The tumor inhibitory rate of Group III (DOX-loaded nanodroplets combined with ultrasound) was 84.3%, more than that of Group II (DOX-loaded nanodroplets), which was 60.4%. Moreover, the nanodroplets showed much lower toxicity than free drugs. The novel nanodroplets could be a promising anticancer drug delivery system.     

Stabilizing insulin-like growth factor-I in poly(D,L-lactide-co-glycolide) microspheres.

This study aimed at developing a controlled drug delivery system for recombinant human insulin-like growth factor-I (IGF-I) for localized delivery in bone healing. IGF-I was microencapsulated into an end-group uncapped 14 kDa poly(D,L-lactide-co-glycolide) 50:50 (PLGA 50:50) by solvent extraction from a W(1)/O/W(2) dispersion. Prior to encapsulation, IGF-I was exposed to ultrasonication in a water/dichloromethane dispersion, and its stability tested in the presence and absence of various excipients in the W(1) phase. HPLC and RIA were used for the assessment of IGF-I stability. Microencapsulated IGF-I was tested again for its structural intactness and also for in vitro release from various formulations containing appropriate co-encapsulated excipients. A specific fat cell assay was used to determine the biological activity of released IGF-I. Moderate ultrasonic treatment of aqueous IGF-I/dichloromethane mixtures caused approx. 50% IGF-I degradation. However, IGF-I was fully protected when bovine serum albumin, succinylated gelatin or poly(ethyleneglycol) were added to the aqueous IGF-I. Co-encapsulation of these excipients protected efficiently the protein upon microencapsulation. IGF-I release from microsphere formulations was sustained for up to 13 days featuring a moderately pulsatile pattern, depending on the microsphere composition. Typically, the amounts of IGF-I released within the first 24 h (burst) and during the second release pulse were in the order of 20 and 40%, respectively, of the total dose. The biological activity of released IGF-I was confirmed at selected time-points by the fat cell assay. In conclusion, the developed microspheres proved to be suitable to release biologically intact IGF-I over up to 13 days, a time-period considered to be relevant to promote bone fracture healing.     

载药型磷酸钙骨水泥的制备及体外释放性能

背景：磷酸钙骨水泥具有良好的生物相容性,可作为骨修复材料与药物载体。目的：制备载药磷酸三钙骨水泥,并分析其体外释放性能。方法：采用共沉淀法制备磷酸三钙前躯体,经高温煅烧研磨获得α-磷酸三钙粉体,测试含不同浓度（1.25%,2.5%,3.75%,5%）抗生素（头孢拉定或头孢氨苄或环丙沙星）骨水泥,浸泡不同时间后（6h、12h、24h、2d、3d、4d、5d、6d、7d、8d）的药物体外释放浓度。结果与结论：制备的磷酸三钙粉体粒度约2μm,结晶度良好。载不同抗生素的骨水泥体外释放都受自身物理性质的影响。载药骨水泥中环丙沙星能够满足长时间缓释,并能达到一个比较理想的缓释浓度,头孢类药物由于自身稳定性等原因,缓释效果并不理想。头孢氨苄的水解速率较低,环丙沙星的光降解条件比较苛刻,因此两者释放未受太大影响,与Higuchi模型基本吻合;头孢拉定的水解速率相对较高,对体系的释放驱动力产生较大影响,使得释放不再遵循Higuchi模型。