壳寡糖－聚乳酸阿霉素胶团体外缓释性能考察

目的：考察阿霉素壳寡糖-聚乳酸嫁接物胶团的缓释性能。方法以超声分散法制备嫁接物胶团;以阿霉素为模型药物,透析法制备载药胶团。进行载药胶团体外释放实验,考察壳寡糖-聚乳酸共聚物胶团的缓释性能。结果在壳寡糖-聚乳酸嫁接物中,聚乳酸分子量为5000的两种壳寡糖-聚乳酸嫁接物载药胶团体外释放缓释效果明显。结论壳寡糖-聚乳酸聚合物胶团具有显著的缓释特征。其中聚乳酸分子量为5000的壳寡糖-聚乳酸嫁接物,缓释效果更明显。     

氟尿嘧啶/左旋聚乳酸生物可降解纤维支架载药体系构建与缓释效应

目的 研发一种可供机体埋植的长效的氟尿嘧啶载药纤维支架.方法 有机相分离法制备纤维,扫描电镜（SEM）观察纤维形态,光学显微镜测定纤维直径,红外光谱分析（FTIR）和差示扫描热分析（DSC）鉴定药物载体结合状态并测定纤维中PLLA的结晶度,紫外分光光度法（UV）测定纤维的载药量以及体外释放.结果 制备出微米级的载药纤维,载药量与载药效率均较高;药物与聚乳酸属于简单物理混合;相对应两种结构模式载药纤维呈现两种释放模式.结论 b型结构纤维适合于开发成长效的在位埋植载药纤维支架.     

聚乳酸/聚乙二醇琥珀酸酯-姜黄素纳米粒的制备及体外评价*

背景：聚乳酸及其共聚物是一类具有良好生物相容性的可降解高分子材料,已被广泛用于可生物降解型药物缓释或靶向给药系统中。 目的：探索载药纳米粒制备条件对包封率和载药量的影响,确定最佳制备工艺条件。 方法：以维生素E1000聚乙二醇琥珀酸酯(TPGS)为乳化剂、姜黄素为模型药物、聚乳酸为载体材料,采用O/W型乳化-溶剂挥发法制备聚乳酸-姜黄素纳米粒,以包封率和载药量为主要指标,单因素实验探索影响两指标的主要因素,再正交试验设计优化制备工艺。 结果与结论：通过正交试验设计制备聚乳酸-姜黄素纳米粒的最佳工艺为：水油相比10∶1,聚合物浓度15 g/L,药物浓度3 g/L,乳化剂TPGS浓度0.03%。以此工艺制备的载药纳米粒外形圆整光滑,粒度分布较为均匀,平均粒径为167.5 nm,包封率为89.52%,载药量为13.72%,纳米粒前期突释不明显具有良好的缓释作用。该工艺稳定、简单可行,优化制备工艺得到的聚乳酸-姜黄素纳米粒粒径适中、包封率和载药量较高。     

膜乳化法制备单分散性载羟基喜树碱缓释微球

目的 研究利用微孔膜乳化法制备载抗癌药10-羟基喜树碱（IqCPT）缓释微球的可行性。方法 以HCPT为模型药物,聚乳酸（PEA）为载体,以膜乳化法制备载药微球,并研究制剂的表面形态、载药率、包封率和缓释效果等性质。结果 膜乳化法制备的载HCPT聚乳酸微球,粒径可控制在1-10μm之间。表面圆整,稳定性、单分散性良好,载药率和包封率最高分别可达32．7％和81．7％,24h体外累积释放量为17．3％。结论 膜乳化法制备的载HCPT微球制剂均匀分散,具有明显缓释效果,是制备缓释微球制剂的较好方法。     

生物可降解载药纤维的制备、特征表征及释药特性的研究

为了研发一种可供脂溶性药物上载的长效释放植入生物可降解纤维载体,采用有机相分离法制备左旋聚乳酸(PLLA)纤维,扫描电镜(SEM)观察结构,差示扫描热分析(DSC)以及红外光谱分析(FTIR)分析药物载体状态,高效液相(HPLC)方法测定载药纤维的载药量,紫外分光光度法(UV)测定药物释放情况.结果表明制备出了成形性良好的空白PLLA纤维及载药纤维,药物包合入纤维中;药物与载体的结合形式为微晶分散与非晶态分散相结合,该纤维制剂在体外可以长效可调地释放.有机相分离法可以用来成功制备作为缓释植入药物载体的微米级别的左旋聚乳酸载药(PLLA)纤维.     

植入型表阿霉素缓释药膜的制备及体内抑瘤活性

制备用于实体肿瘤局部治疗的植入型表阿霉素缓释药膜.采用复乳.溶剂挥发法制备聚乳酸载表阿霉素缓释微球,用交联复合法制备含载药微球的植入型胶原药膜;用扫描、透射电镜、共聚焦及粒度仪等考察微球和药膜的形貌、结构、粒径及体外释放;用H22肝癌荷瘤动物模型评价其体内抑瘤效果.结果:载药微球粒径分布均匀,外观圆整,平均粒径为5.8μm;微球的载药量4.39%,包裹率为37.2%;10h内载药微球在模拟体液中的累积释放率为35%;腹腔注射载药微球与瘤体局部植入胶原药膜对H22肝癌均有明显的抑瘤效果;微球注射与药膜植入两种不同给药方式对H22肝癌抑瘤效果也存在显著性差异(P<0.05).植入型载表阿霉素缓释胶原膜具有良好的药物局部缓释特性,在肿瘤的术后局部治疗方面具有良好的临床应用前景.     

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15min,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217.6nm,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-羟基乙酸共聚物吗啡微球的制备及其镇痛作用

背景:药物微球因其对特定器官和组织的靶向性及微粒中药物释放的缓释性而成为一种新的给药系统。国内外学者对局麻药缓释给药系统进行了一系列研究,但麻醉性镇痛药的微球制剂未见报道。目的:制备以聚乳酸-羟基乙酸共聚物为载体的吗啡生物可降解缓释微球制剂,并检测其镇痛作用。方法:采用溶剂挥发法制备吗啡聚乳酸-羟基乙酸共聚物微球,并计算其载药量及包封率。将雄性健康SD大鼠以数字表法随机分为3组:空白对照组(皮下注射生理盐水),阳性对照组(皮下注射盐酸吗啡注射剂)和吗啡微球组(皮下注射吗啡聚乳酸-羟基乙酸共聚物微球),利用CO2激光为热刺激进行痛阈测定。结果与结论:制成的吗啡聚乳酸-羟基乙酸共聚物微球为白色粉末,载药量为11.86%,药物包封产率为33%,微球可较明显延长吗啡作用时间至6h以上。结果说明吗啡聚乳酸-羟基乙酸共聚物微球明显地延长了吗啡释放时间,缓释性好,但未达到预期的理想时间,仍然需要进行改进。     

紫杉醇聚合物胶束及其抗肿瘤活性研究

目的 以聚己内酯-聚乙二醇-聚己内酯（PCL-PEG-PCL）为载体材料,制备载紫杉醇聚合物胶束,并评价其对EMT-6乳腺癌的抗肿瘤效果.方法 采用薄膜-超声法制备载紫杉醇聚合物胶束并对其进行表征;采用差示扫描热分析法（DSC）分析紫杉醇在载药聚合物胶束中的分散状态;采用MTT法研究紫杉醇聚合物胶束对EMT-6乳腺癌细胞的细胞毒性;建立荷EMT-6乳腺癌小鼠模型,以市售紫杉醇注射液为对照,研究紫杉醇聚合物胶束的体内抗肿瘤活性.结果 紫杉醇聚合物胶束为表面粗糙的球形,具有明显核壳结构,平均粒径为93nm;DSC研究结果表明,将紫杉醇制成缓释纳米粒后其结晶状态发生了变化,以无定型状态存在于聚合物胶束中;MTT研究表明,在相同紫杉醇含量下,紫杉醇聚合物胶束的细胞毒性低于市售紫杉醇／聚氧乙烯蓖麻油注射剂;体内抗肿瘤活性研究表明,紫杉醇聚合物胶束对小鼠EMT-6乳腺癌具有明显抑制作用,相同给药剂量下其抑瘤效果优于紫杉醇注射剂（肿瘤抑制率：85.79％ vs 63.37％,P＜0.05）.结论 制备的载紫杉醇聚合物胶束高效低毒,是一种有潜力的可用于肿瘤治疗的纳米载药体系.     

电纺载盐酸四环素的聚乳酸-聚乙醇酸纳米纤维膜制备以及性能表征

背景:由于良好的疗效和较低的不良反应,局部药物控制释放系统防止感染正在引起越来越多的关注。而静电纺丝制得的高分子纳米纤维,是一种良好的载药材料。目的:使用静电纺丝技术制备载不同含量盐酸四环素的聚乳酸-聚乙醇酸载药纳米纤维膜,着重观察其抑菌性能和细胞相容性。方法:以15～20kV的电压,0.3～0.5mL/h的流速使用静电纺丝技术制备载不同含量盐酸四环素的聚乳酸-聚乙醇酸载药纳米纤维膜。通过扫描电镜观察纳米纤维膜的形貌。检测载药率,绘制药物释放曲线,并用改良的Kirby-Bauer实验来观察载药纳米纤维膜的体外抑菌性能。用MG-63细胞来检测纳米纤维膜的生物相容性。结果与结论:载不同含量盐酸四环素的聚乳酸-聚乙醇酸载药纳米纤维直径均在360～470nm之间。且载药率都可以达到80%以上。载药量为10%的纳米纤维突释最大。载药纳米纤维膜可以有效的抑制金黄色葡萄球菌的生长但是对于MG-63细胞的黏附和增殖没有明显的不良影响。相比较而言,载药量为3%和5%的载盐酸四环素纳米纤维膜对于防止引导组织再生术后感染而言是较好的选择。     

Peripheral nerve regeneration with sustained release of poly(phosphoester) microencapsulated nerve growth factor within nerve guide conduits

Prolonged delivery of neurotrophic proteins to the target tissue is valuable in the treatment of various disorders of the nervous system. We have tested in this study whether sustained release of nerve growth factor (NGF) within nerve guide conduits (NGCs), a device used to repair injured nerves, would augment peripheral nerve regeneration. NGF-containing polymeric microspheres fabricated from a biodegradable poly(phosphoester) (PPE) polymer were loaded into silicone or PPE conduits to provide for prolonged, site-specific delivery of NGF. The conduits were used to bridge a 10 mm gap in a rat sciatic nerve model. Three months after implantation, morphological analysis revealed higher values of fiber diameter, fiber population and fiber density and lower G-ratio at the distal end of regenerated nerve cables collected from NGF microsphere-loaded silicone conduits, as compared with those from control conduits loaded with either saline alone, BSA microspheres, or NGF protein without microencapsulation. Beneficial effects on fiber diameter, G-ratio and fiber density were also observed in the permeable PPE NGCs. Thus, the results confirm a long-term promoting effect of exogenous NGF on morphological regeneration of peripheral nerves. The tissue-engineering approach reported in this study of incorporation of a microsphere protein release system into NGCs holds potential for improved functional recovery in patients whose injured nerves are reconstructed by entubulation.     

Biodegradable microparticles and fiber fabrics for sustained delivery of cisplatin to treat C6 glioma in vitro

The duration of cisplatin release from most of the drug delivery devices seemed to be shorter than 14 days except large microparticles. The objective of this study was to fabricate and characterize cisplatin-loaded PLA microparticles, PLA/PLGA (30/70) composite microparticles, and fibers as formulations for long-term sustained delivery of cisplatin to treat C6 glioma in vitro by electrospray and electrospinning techniques. Cisplatin-loaded biodegradable microparticles with particle size of around 5 microm and fiber fabrics with diameter of 0.5-1.7 microm were obtained using electrospray and electrospinning techniques. Encapsulation efficiency and in vitro release of formulations were measured by ICP-OES. The encapsulation efficiency for different samples of microparticles was approximately from 33% to 72% and the fiber fabrics had encapsulation efficiency greater than 90%. Cisplatin-loaded microparticles showed typical characteristics of cisplatin release profile: a large initial burst followed by a sustained slow release of 35 days. The composite PLA/PLGA (30/70) microparticles could reduce the initial burst release of cisplatin because of their core-shell structures. In contrast, more than 75 days sustained release could be achieved by fiber fabric formulations without large initial burst. MTT assay was used to quantify the cytotoxicity of different formulations against C6 glioma cells. Microparticle formulations had slightly higher cytotoxicity than free drug. In contrast, the cytotoxicity of fiber fabrics formulation was around 4 times higher than of the free drug based on the actual amount of drug released. The microparticle and fiber fabric formulations presented may be promising for the sustained delivery of cisplatin to eliminate the undesired side effects caused by direct injection of cisplatin solution in systemic administration.     

Bioresorbable nanofiber-based systems for wound healing and drug delivery: optimization of fabrication parameters

Wound healing is a complex process that often requires treatment with antibiotics. This article reports the initial development of a biodegradable polymeric nanofiber-based antibiotic delivery system. The functions of such a system would be (a) to serve as a biodegradable gauze, and (b) to serve as an antibiotic delivery system. The polymer used in this study was poly(lactide-co-glycolide) (PLAGA), and nanofibers of PLAGA were fabricated with the use of the electrospinning process. The objective of this study was to determine the effect of fabrication parameters: orifice diameter (needle gauge), polymer solution concentration, and voltage per unit length, on the morphology and diameter of electrospun nanofibers. The needle gauges studied were 16 (1.19 mm), 18 (0.84 mm), and 20 (0.58 mm), and the range of polymer solution concentration studied was from 0.10 g/mL to 0.30 g/mL. The effect of voltage was determined by varying the voltage per unit electrospinning distance, and the range studied was from 0.375 kV/cm to 1.5 kV/cm. In addition, the mass per unit area of the electrospun nanofibers as a function of time was determined and the feasibility of antibiotic (cefazolin) loading into the nanofibers was also studied. The results indicate that the diameter of nanofibers decreased with an increase in needle gauge (decrease in orifice diameter), and increased with an increase in the concentration of the polymer solution. The voltage study demonstrated that the average diameter of the nanofibers decreased with an increase in voltage. However, the effect of voltage on fiber diameter was less pronounced as compared to polymer solution concentration. The results of the areal density study indicated that the mass per unit area of the electrospun nanofibers increased linearly with time. Feasibility of drug incorporation into the nanofibers was demonstrated with the use of cefazolin, a broad-spectrum antibiotic. Overall, these studies demonstrated that PLAGA nanofibers can be tailored to desired diameters through modifications in processing parameters, and that antibiotics such as cefazolin can be incorporated into these nanofibers. Therefore, PLAGA nanofibers show potential as antibiotic delivery systems for the treatment of wounds.     

In vitro and in vivo release of gentamicin from biodegradable discs

Osteomyelitis is an infection of the bone and successful treatment involves the removal of the affected bone and the tissue by a surgical procedure following prolonged systemic and local antibiotic therapy for 4 to 6 weeks. The current local treatment is done by poly methyl methacrylate (PMMA) beads loaded with gentamicin and PMMA, being nondegradable, is to be removed by a second surgical procedure. The current study aims to develop a biodegradable composition that gives sustained release and hence reducing the need for a second surgery. Gentamicin-loaded discs were produced by compressing microparticle-gentamicin mixture obtained by spray drying a mixture of gentamicin in a solution of a biodegradable polymer. Different copolymers of poly (DL-lactic-co-glycolic acid) (PLGA) were used to study the effect of copolymer ratio and the hydrophilic-hydrophobic nature of the polymer. Theoretical drug loading up to 25% were studied and it was observed that 10% drug loading was optimum for gentamicin to be used as solid in spray drying. The results showed that about 60% of the drug is released in about 5 to 6 days and the remaining drug is released in about 30 days in total. An in vivo study was carried on rabbit femur and the local area and systemic concentration of gentamicin was monitored. It was observed that the local area concentration of gentamicin was above minimum inhibitory concentration for more than 20 days and this was also validated by computer simulations.     

Microparticles developed by electrohydrodynamic atomization for the local delivery of anticancer drug to treat C6 glioma in vitro

This study aims to fabricate biodegradable polymeric particles by electrohydrodynamic atomization (EHDA) for applications in sustained delivery of anticancer drug-paclitaxel to treat C6 glioma in vitro. Controllable morphologies such as spheres, doughnut shapes and corrugated shapes with sizes from several tens of microns to hundred nanometers of particles were observed by scanning electron microscopy (SEM) and field emission electron microscope (FSEM). The differential scanning calorimetry (DSC) study indicated that paclitaxel could be either in an amorphous or disordered-crystalline phase of a molecular dispersion or a solid solution state in the polymer matrix after fabrication. The X-ray photoelectron spectroscopy (XPS) result suggested that some amount of paclitaxel could exist on the surface layer of the microparticles. The encapsulation efficiency was around 80% and more than 30 days in vitro sustained release profile could be achieved. Cell cycling results suggested that paclitaxel after encapsulation by EHDA could keep its biological function and inhibit C6 glioma cells in G2/M phase. The cytotoxicity of paclitaxel-loaded biodegradable microparticles to C6 glioma cells could be higher than Taxol in the long-term in vitro tests evaluated by MTS assay. The drug delivery devices developed by EHDA in this study could be promising for the local drug delivery to treat malignant glioma.     

Biodegradable polyhydroxyalkanoate implants for osteomyelitis therapy: in vitro antibiotic release

Various random copolyesters of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV) and 3-hydroxybutyrate and 4-hydroxybutyrate P(3HB-4HB) were used in the construction of biodegradable, implantable rods for the local delivery of antibiotics (Sulperazone and Duocid) in chronic osteomyelitis therapy. Drug loading, type of active agent, and additional coating of the implant surface all have significant contributions to the in vitro release profile. The rate and duration of Sulperazone release from P(3HB-4HB) rods were controlled by the polymer/drug ratio (drug loading). The rate of drug dissolution was substantially higher than that of polymer degradation. Therefore, the release phenomenon was more dependent on drug dissolution rather than on polymer degradation or diffusion. Coating rods with the same type of polymer substantially reduced the initial burst effect observed with the uncoated rods, and significantly decreased the release rate so that the release kinetics became almost zero order. Antibiotic release from coated rods was sustained for over a period of 2 weeks at a constant rate, whereas uncoated rods released their contents in less than a week. Impregnation of Duocid into the hydrophobic polymer matrix yielded a rod with a smoother surface topography. The release from these rods was significantly higher than for rods loaded with Sulperazone and a zero order release could not be obtained with these samples.     

A novel non-toxic camptothecin formulation for cancer chemotherapy

The use of a novel injectable biocompatible and biodegradable camptothecin-polymer implant for sustained intra-tumoral release of high concentrations of camptothecin is described. The drug delivery vehicle is an in situ thermogelling formulation, which is based on the natural biopolymer chitosan. This formulation, containing homogeneously dispersed camptothecin, was implanted intra-tumorally into a sub-cutaneous mouse tumor model (RIF-l). The effectiveness of treatment was measured in terms of tumor growth delay (TGD). Animals treated with the polymer implants containing camptothecin had significantly longer TGDs compared to untreated animals as well as to animals treated systemically with camptothecin by intra-peritoneal injection with no evidence of toxicity in terms of loss of body weight. The results indicate that this novel biodegradable polymer implant is an effective vehicle for the sustained intra-tumoral delivery of camptothecin which might also be suitable to deliver other insoluble anti-cancer drugs such as taxol.