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.     

9-硝基喜树碱纳米胶束的制备及体外释药研究

利用溶剂挥发成膜法制备了负载9-硝基喜树碱(9-NC)的两亲性共聚物载药胶束.通过对制备温度、加入蒸馏水体积、搅拌速率和投药量的单因素分析,深入探讨了各因素对胶束粒径和载药量的影响.结果表明在水浴温度为60℃、加入蒸馏水体积为16 ml、搅拌速率为 6 500 r/min、投药量为1.2 mg时制备得到具有良好分散状态的球状载药胶束,载药量为4.9%,粒径为50～70 nm.载药胶束的体外释放研究表明,9-NC从胶束中释放包括初期爆释和随后缓释两个阶段,释放速率随载药量的增加而降低.     

长效避孕皮下埋植剂体外缓释行为研究

本文对以加成型硅橡胶为基质的左旋18—甲基炔诺酮长效避孕埋植剂的体外释放行为及对可能影响其释放量的诸因素,进行了观察与研究,结果表明:此长效避孕皮下埋植剂的体外释药行为,符合零级释药动力学规律。释药量受控释膜厚度,控释膜交联密度及释药面积的影响。体外释放药物曲线无明显爆破峰。     

利福平-异烟肼-控释型载药人工骨的实验研究

开发研究一种能承载多药并有控释特性的载药人工骨。利用三维打印技术,制备具有多层同心圆柱体结构的载药人工骨,并将利福平和异烟肼由内到外按特定顺序加载,观察微观结构、孔隙率、体外药物释放特性和体外细胞生物相容性。所制备的载药人工骨呈多孔结构,孔隙率(61.76±2.53)%、微孔孔径50~100μm,体外药物呈现序贯释放,双药释放峰值依次交替出现,持续释放时间超过50 d,MTT检测示细胞毒性0级,电镜观察细胞生长分化良好,并有大量细胞黏附于载药人工骨表面;三维打印技术可以精确地制备具有复杂结构的载药人工骨,制备的多药控释型载药人工骨具有药物缓释和序贯控释的特性,同时具有良好的孔隙率和细胞相容性,为骨结核治疗提供一种新型有效的手段。     

乳酸-乙醇酸共聚物载药复合纤维制备及其释药行为研究

乳酸-乙醇酸共聚物(PLGA)复合纤维具有良好的生物相容性和生物可降解性,且降解速率可由相对分子质量和共聚物组成来调控.采用同轴静电纺丝法制备以PLGA为壳层材料、聚乙烯基吡咯烷酮(PVP)为内芯材料的复合纤维,研究两种模型药物(5-氟尿嘧啶和硝苯地平)在同轴复合纤维载体中的药物释放行为,并用扫描、透射电镜观察复合纤维的形貌与结构,用紫外分光光度计测量载药量和累积释放率.实验结果表明,通过改变芯、壳纺丝液浓度、PLGA相对分子质量以及共聚物中LA和GA的组成比,可制得具有芯-壳结构且直径大小不同的复合纤维.采用相同电纺丝条件,可以将不同药物以相同载药量包覆于复合纤维中,但药物的释放行为不相同.     

聚己内酯埋植剂的制备及药物通透性研究

目的制备聚己内酯（PCL）长效药物缓释制剂,优化药物缓释效果,并研究PCL埋植剂的药物通透性.方法 合成分子质量为（8～16）×104 u含有普朗尼克F68的PCL,用挤出法制备不同壁厚的PCL长效缓释埋植剂.将左炔诺孕酮（LNG）装入PCL管封装,制成LNG药囊.通过高效液相色谱法测定LNG的释放效果,考察PCL的分子质量及PCL管壁厚度对LNG通透性的影响.结果 当PCL分子质量为（8～16）×104u时,对LNG通透性无显著影响.PCL管壁厚在0.20～0.40 mm时,对LNG通透性亦无显著影响;当壁厚小于0.15 mm时,LNG通透性显著提高.结论 PCL埋植剂对LNG具有通透性,可通过改变PCL管壁厚度增加药物通透性.     

体外研究聚合物P（DLLA—co—TMC）的降解性能与释药行为

目的 研究P（DLLA—CO-TMC）聚合物的体外降解性能与释药行为,且探讨该聚合物作为长效避孕释放载体的可行性。方法以PBS溶液为溶媒研究P（DLLA-CO-TMC）的降解性能;以P（DLLA—CO—TMC）聚合物为载体制备含孕二烯酮的载药片,并通过蒸馏水浸泡载药片研究载药体系的体外释药行为。结果P（DLLA-CO-TMc）聚合物前期降解较慢,第30天和第90天失重率分别为10．0％和12．3％,后期降解速率较快,第120天的失重率为59．3％;P（DLLA-CO-TMC）的载药片前期释药速率较大,出现“暴释现象”,后期释药速率减缓并逐渐趋于平稳,第100天时累计释放率为5．64％。结论P（DLLA-co-TMC）聚合物降解性能良好、释药效果明显,有望通过体内研究使含孕二烯酮的P（DLLA—CO—TMC）聚合物载药系统应用于长效埋植避孕。     

盐酸表阿霉素纳米靶向制剂的缓释效应

背景：盐酸表阿霉素是一种广谱抗生素,目前临床使用的不足多为药物释放快、目标组织药物浓度低,静脉给药后广泛分布于体内各种组织器官,不良反应明显。 目的：针对盐酸表阿霉素临床应用的不足,制备盐酸表阿霉素纳米靶向注射制剂。 方法：以叶酸偶联牛血清白蛋白为载体,采用乳化-高压匀质法,制备盐酸表阿霉素纳米靶向注射制剂,以激光粒度分析仪测定纳米颗粒的粒径大小、粒径分布及Zeta电位,扫描电镜观察纳米颗粒的表面形态,高效液相色谱法分析白蛋白负载盐酸表阿霉素纳米制剂的包封率、载药量和释药性能。 结果与结论：制备的盐酸表阿霉素纳米粒外观呈均匀球型,粒径分布较窄,平均粒径为(157.73±     0.40) nm,平均 Zeta 电位为(-30.85±0.43) mV,载药量 22.78%,包封率可达96.24%。体外模拟释药结果表明药物释放曲线分为两个阶段,突释阶段微球释药量在24 h内达42.6%,缓释阶段纳米粒释药持续时间长,在112 h 时释药量达 84.1%,载药纳米粒的药物释放速率持续稳定。结果表明乳化结合高压匀质法制备的盐酸表阿霉素纳米靶向制剂粒径均匀,粒径范围分布窄,载药量和包封率高,具有一定的缓释作用。     

左炔诺孕酮长效缓释埋植剂Ⅰ.结构特征的研究和体内外药物释放的长期观察

用生物降解性聚己内酯（ＰＣＬ）为载体制备女性抗生育药物左炔诺孕酮（ＬＮＧ）的长效皮下埋植胶囊。除可降解外,该胶囊具有微孔结构,重要技术特征是在ＰＣＬ中加入固体水溶性大分子ＰｌｕｒｏｎｉｃＦ６８（Ｆ６８）作为致孔剂,研究了加入致孔剂的工艺和微孔形成的原理,用核磁共振和扫描电镜等方法证明在亲水介质中Ｆ６８很快溶出,形成多微孔结构。体外和动物体内药物释放的研究证明该埋植剂具有零级释放动力学,可在体内长期维持稳定的药物释放量,每根３ｃｍ长的埋植剂在体内每天释放约２１微克ＬＮＧ,预期一次植入两根可有效地避孕两年     

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。关键词：聚乳酸;异烟肼;利福平;纳米粒;体外释药 doi:10.3969/j.issn.1673-8225.2012.16.014     

生物可降解载药纤维的成形特性的研究

为了开发一种用于治疗肿瘤的局部定位缓释给药系统，本研究在室温条件制备了生物可降解的聚乳酸（PLLA）纤维，并且详细研究了制备过程中的处方工艺条件（聚合物分子量、聚合物浓度、注射速度、出口口径以及固化液的种类）对聚乳酸纤维的成形特性（纤维直径、纤维的表面与内部结构以及纤维的结晶度）的影响。此外，还在聚乳酸纤维上上载了一种脂溶性模型药物（尼莫地平），并对载药纤维的体外释放性质进行了研究。结果表明，这类载药纤维可以成为一种有开发前景的局部定位给药缓释系统。     

Dexamethasone-releasing biodegradable polymer scaffolds fabricated by a gas-foaming/salt-leaching method

Dexamethasone, a steroidal anti-inflammatory drug, was incorporated into porous biodegradable polymer scaffolds for sustained release. The slowly released dexamethasone from the degrading scaffolds was hypothesized to locally modulate the proliferation and differentiation of various cells. Dexamethasone containing porous poly(D,L-lactic-co-glycolic acid) (PLGA) scaffolds were fabricated by a gas-foaming/salt-leaching method. Dexamethasone was loaded within the polymer phase of the PLGA scaffold in a molecularly dissolved state. The loading efficiency of dexamethasone varied from 57% to 65% depending on the initial loading amount. Dexamethasone was slowly released out in a controlled manner for over 30 days without showing an initial burst release. Release amount and duration could be adjusted by controlling the initial loading amount within the scaffolds. Released dexamethasone from the scaffolds drastically suppressed the proliferations of lymphocytes and smooth muscle cells in vitro. This study suggests that dexamethasone-releasing PLGA scaffolds could be potentially used either as an anti-inflammatory porous prosthetic device or as a temporal biodegradable stent for reducing intimal hyperplasia in restenosis.     

Controlled release of plasmid DNA from biodegradable scaffolds fabricated using a thermally-induced phase-separation method

Highly porous poly(D,L-lactic-co-glycolic acid) (PLGA) scaffolds were fabricated by a thermally-induced phase-separation (TIPS) method to deliver plasmid DNA in a controlled manner. A variety of TIPS parameters directly affecting pore structures and their interconnectivities of the scaffold, such as polymer concentration, solvent/non-solvent ratio, quenching methods and annealing time, were systematically examined to explore their effects on sustained release behaviors of plasmid DNA. Plasmid DNA was directly loaded into the inner pore region of the scaffold during the TIPS process. By optimizing the parameters, PLGA scaffolds releasing plasmid DNA over 21 days were successfully fabricated. DNA release profiles were mainly affected by the pore structures and their interconnectivities of the scaffolds. Plasmid DNA released from the scaffolds fully maintained its structural integrity and showed comparable transfection efficiency to native plasmid DNA. These biodegradable polymeric scaffolds capable of sustained DNA release can be potentially applied for various tissue engineering purposes requiring a combined gene delivery strategy.     

Paclitaxel-eluting composite fibers: drug release and tensile mechanical properties

New core/shell fiber structures loaded with paclitaxel were developed and studied. These composite fibers are ideal for forming thin, delicate, biomedically important structures for various applications. Possible applications include fiber-based endovascular stents that mechanically support blood vessels while delivering drugs for preventing restenosis directly to the blood vesel wall, or drug delivery systems for treatment of cancer. The core/shell fiber structures were formed by "coating" dense core fibers with porous paclitaxel-containing poly(DL-lactic-co-glycolic acid) (PDLGA) structures. Shell preparation ("coating") was performed by freeze-drying water in oil emulsions. The present study focused on the effects of the emulsion's formulation (composition) and processing conditions on the paclitaxel release profile and on the fibers' tensile mechanical properties. In general, the porous PDLGA shell released approximately 40% of the paclitaxel, with most of the release occurring during the first 30 days. The main release mechanism during the tested period is diffusion, rather than polymer degradation. The release rate and quantity increased with increased drug content or decreased polymer content, whereas the organic:aqueous phase ratio had practically no effect on the release profile. These new composite fibers are strong and flexible enough to be used as basic elements for stents. We demonstrated that proper selection of processing conditions based on kinetic and thermodynamic considerations can yield polymer/drug systems with the desired drug release behavior and good mechanical properties.     

Bone regeneration on a collagen sponge self-assembled peptide-amphiphile nanofiber hybrid scaffold

The objective of this study was to create a novel approach to promote bone induction through sustained release of growth factor from a 3-dimensional (3D) hybrid scaffold. Peptide-amphiphile (PA) was synthesized by standard solid-phase chemistry that ends with the alkylation of the NH2 terminus of the peptide. Collagen sponge was reinforced by incorporation of poly(glycolic acid) (PGA) fiber. A 3D network of nanofibers was formed by mixing basic fibroblast growth factor (bFGF) suspensions with dilute aqueous solutions of PA. A hybrid scaffold was fabricated by combination of self-assembled PA nanofibers and collagen sponge reinforced with incorporation of PGA fibers. The in vitro release profile of bFGF from hybrid scaffold was investigated, and ectopic bone formation induced by the released bFGF was assessed after subcutaneous implantation of hybrid scaffold into the backs of rats. Homogeneous bone formation was histologically observed throughout the hybrid scaffolds, in marked contrast to collagen sponge-incorporated bFGF. The level of alkaline phosphatase activity and osteocalcin content at the implanted sites of hybrid scaffolds were significantly high compared with collagen sponge incorporated with bFGF. The combination of bFGF incorporated in a collagen sponge self-assembled PA nanofiber hybrid scaffold is a promising procedure to improve bone regeneration.     

Osteogenic Induction of Bone Marrow-Derived Stromal Cells on Simvastatin-Releasing,Biodegradable, Nano- to Microscale Fiber Scaffolds

Tissue engineering is an effective approach for the treatment of bone defects. Statins have been demonstrated to promote osteoblastic differentiation of bone marrow-derived stromal cells (BMSCs). Electrospun biodegradable fibers have also shown applicability to drug delivery in the form of bone tissue engineered scaffolds with nano- to microscale topography and high porosity similar to the natural extracellular matrix (ECM). The aim of this study was to investigate the feasibility of a simvastatin-releasing, biodegradable, nano- to microscale fiber scaffold (SRBFS) for bone tissue engineering with BMSCs. Simvastatin was released from SRBFS slowly. BMSCs were observed to spread actively and rigidly adhere to SRBFS. BMSCs on SRBFS showed an increase in alkaline phosphatase activity 2 weeks after cell culture. Furthermore, osteoclastogenesis was suppressed by SRBFS in vitro. The new bone formation and mineralization in the SRBFS group were significantly better than in the biodegradable fiber scaffold (BFS) without simvastatin 12 weeks after implantation of the cell-scaffold construct into an ectopic site on the murine back. These results suggest that SRBFS promoted osteoblastic differentiation of BMSCs in vitro and in vivo, and demonstrate feasibility as a bone engineering scaffold.     

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.