细菌触发型结肠靶向释药系统的研究进展

细菌触发型靶向释药系统是依据人体结肠独特的菌群分布，利用细菌具有的偶氮还原酶、糖苷酶及糖苷酸酶等多种酶，能生物降解药物载体，使药物在结肠定位释放。按释药机制和给药方式，细菌触发型结肠释药系统可分为4类：前体药物释药系统、多糖载体释药系统、联合pH依赖型或时滞型的复合释药系统、偶氮芳香族水性凝胶释药系统。它们需采用独特的溶出性试验评价药物的体外释放和γ-闪烁照相法观察药物的体内行为，本文对该领域的研究进展作一综述。     

庆大霉素聚氰基丙烯酸丁酯毫微球冻干注射剂的制备及其特性

用乳化聚合法制备庆大霉素聚氰基丙烯酸丁酯毫微球，经冷冻干燥制成冻干型注射剂。用一阶导数分光光度法测定药物的结合率和载药量；以浊度作为评价冻干毫微球重分散性能的指标，筛选配方和工艺；用透射电镜测定了冻干前后粒度分布的变化；对体外释药进行了考察；还对毫微球的其他理化特性进行了测定。     

吲哚美辛-果胶钙片结肠定位释药初探

目的：考察吲哚美辛-果胶钙片是否符合结肠定位释药的要求。方法：对吲哚美辛-果胶钙片进行体内、体外以及稳定性实验。结果：该药片在胃内不崩解，在小肠处少量释药，在结肠定位释药，定位效果可靠。结论：果胶钙可作为结肠定位释药系统的药物载体。     

5-氟尿嘧啶-聚α,β(2-羟乙基)-DL-天冬酰胺的合成及体内释放的研究

以5-氟尿嘧啶为模型药物,将药物以共价键的形式键合于生物降解型高分子材料聚-α,β(2-羟乙基)-DL-天冬酰胺上制成高分子载体药物,药物接入率达37.1%(w/w)。用红外和差热分析法对载体药物进行了表征。以纯种大白兔为实验动物,把载体药物制成混悬型和棒状型两种剂型,进行药物体内释放实验。结果表明:以棒状型药物给药在一定程度上可以降低释药初期的“爆释”现象,为进一步临床应用提供了重要依据。     

冻干rIFNα2a—PBCA—NS对小鼠抗流感病毒的作用

目的：考察冻干基因重组人干扰素α2a聚氰基丙烯酸丁酯纳米球（rIFNα2a-PBCA-NS)ig,sc给药对小鼠抗流感病毒的作用。方法：采用流感病毒FM1M12E11鼠肺适应株攻击用可致小鼠死亡的肺炎建立的强毒模型，研究抗小鼠流感病毒的作用。结果：ig,sc相同剂最后，小鼠延长生存率为：冻干rIFNα2a-PBCA-NS优于原药rIFNα2a,前者所含白蛋白不影响其体内作用。结论：冻干rIFNα2a-PBCA-NS能增强rIFNα2a的体内抗病毒作用。     

聚苹果酸在药物载体研究中的应用进展

聚苹果酸是一类具备生物可降解性,生物可吸收性及相容性的高分子,可作为生物医用材料广泛应用于药物释放系统和组织工程等领域。聚苹果酸作为药物载体可以控制药物释放,延长药物作用时间,降低药物的毒副作用,还可以加强制剂的靶向给药能力。此文对聚苹果酸的靶向给药机理,药物与载体的结合方式,载体药物的相容性以及释药分布等进行了综述,评价了该载体应用中存在的不足,展望了其应用前景。     

rIFNα2a聚氰基丙烯酸丁酯纳米囊制备工艺条件的优选

目的：优选制备ｒＩＦＮα２ａ聚氰基丙烯酸丁酯纳米囊的工艺条件。方法：采用均匀设计与正交试验法，以外观评分和包封率评分为指标，综合分析试验结果来确定制备工艺条件。结果：优选出的制备工艺条件为ｐＨ２．９的盐酸溶液，ＰｌｕｒｏｎｉｃＦ６８用量０．５％，ＢＣＡ用量０．６％，ｒＩＦＮα２ａ加入量０．８％。结论：所确定的制备ｒＩＦＮα２ａ聚氰基丙烯酸丁酯纳米囊的工艺条件稳定、可行。     

3种大黄酚制剂在兔血浆中的药动学研究

目的研究大黄酚脂质体(chrysophanol liposomes)、大黄酚聚氰基丙烯酸丁酯纳米囊(chrysophanol loaded polybu-tylcyanoacrylate,Chry-PBCA-NC)、大黄酚羟丙基-β-环糊精包合物(chrysophanol-hydroxypropyl-β-cyclodextrin inclusion com-plex,Chry-HP-β-CD)在兔血浆内的药动学特征,为优选最佳的大黄酚制剂提供依据。方法将3种制剂各分为高、中、低(9、3、1 mg.kg-1)3个剂量组,分别静脉注射于家兔体内,采用高效液相色谱法测定给药后不同时间点血浆中大黄酚的浓度并计算药动学参数。结果 3种大黄酚制剂的药时曲线下面积随着剂量的增加而增加。在中、高剂量下,大黄酚聚氰基丙烯酸丁酯纳米囊相对于另两种制剂其消除相半衰期差异有显著性。结论 3种大黄酚制剂静注后的血药浓度-时间曲线均符合二室模型,在血浆中消除过程较快,大黄酚聚氰基丙烯酸丁酯纳米囊的消除最为缓慢。     

阿苯达唑聚氰基丙烯酸正丁酯纳米粒的制备、性质及其组织靶向性研究阿苯达唑聚氰基丙烯酸正丁酯纳米粒的制备、性质及其组织靶向性研究

目的制备阿苯达唑聚氰基丙烯酸正丁酯纳米粒（albendazole polybutycyanocrylate nanoparticles，ABZ-PBCA-NP）TDDS给药系统，并考察相关特性及组织分布靶向性。方法种子乳化聚合法制备阿苯达唑纳米粒；等温吸附法考察纳米粒载药特性；动态透析法研究4种制剂的体外释药动力学；同位素标记阿苯达唑纳米粒在小鼠脏器组织分布和生物利用度。结果ABZ-PBCA-NP体外释药遵循Higuchi方程，加入PVP制成的载药纳米粒符合双指数函数。纳米粒的载药方式遵循Langmuir吸附方程。小鼠ig ³H-ABZ-PBCA-NP后, 药物的肝、脾中的靶向指数分别为11.4和3.9，阿苯达唑纳米粒和混悬剂相对生物利用度分别为76.0%和36.9%。结论制备纳米粒加入PVP可使药物具吸附性和分散性，纳米粒载体可降低药物与血浆蛋白结合率，增强药物的肝、脾脏器靶向性和延缓释药。     

注射用胰岛素缓释纳米囊的研究

以聚氰基丙烯酸丁酯纳米囊为载体制备注射用胰岛素纳米囊。通过均匀设计优选实验,以乳化聚合法得到了包封率为９３．７５％,平均粒径１０１ｎｍ,跨距为１．１４的胰岛素纳米囊。初步实验表明,注射用胰岛素纳米囊在４￣２５℃较稳定,含量,包封率,平均粒径等无明显变化;体外释药符合双指数模型;单次给药表明大鼠经皮下注射后,其降糖作用可持续一周,在药物的吸收相具良好的量效关系,药效优于相同剂量的胰岛素注射剂（Ｐ〈０     

Polysorbate-stabilized solid lipid nanoparticles as colloidal carriers for intravenous targeting of drugs to the brain: comparison of plasma protein adsorption patterns

Plasma proteins enriched on the surface of drug-delivery-purpose nanoparticles are regarded as key factors for determination of in vivo organ distribution after intravenous injection. Polysorbate 80-coated polybutylcyanoacrylate (PBCA) nanoparticles, preferentially adsorbing apolipoprotein E (apoE) on their surface, have previously been considered to deliver various drugs to the brain. In the present study, in vivo well tolerable solid lipid nanoparticles (SLN) using different types of polysorbates as stabilizers were produced. The influence of the different surfactants on in vitro adsorption of human plasma proteins was investigated using two-dimensional polyacrylamide gel electrophoresis (2-DE). Possible correlations of different amounts of adsorbed apoE to the hydrophilic-lipophilic balance (HLB) of the polysorbates are shown and discussed. Apolipoprotein C-II, albumin and immunoglobulin G, which are also decisive plasma proteins with regard to site-specific drug delivery of intravenously injected carriers to the brain, are compared with regard to adsorption. Moreover, certain similarities to the plasma protein adsorption patterns of previously analysed brain-specific PBCA nanoparticles could be detected. Despite some differences in adsorption behavior of proteins on the surface of polysorbate-stabilized SLN and PBCA nanoparticles, we conclude that in both cases polysorbate 80 might have the highest potential to deliver drugs to the brain.     

Transport of stavudine, delavirdine, and saquinavir across the blood-brain barrier by polybutylcyanoacrylate, methylmethacrylate-sulfopropylmethacrylate, and solid lipid nanoparticles

Permeability of the anti-human immunodeficiency virus (HIV) agents, including stavudine (D4T), delavirdine (DLV), and saquinavir (SQV), across the in vitro blood–brain barrier (BBB) was studied. Here, the anti-HIV agents were incorporated with polybutylcyanoacrylate (PBCA) nanoparticles (NPs), methylmethacrylate-sulfopropylmethacrylate (MMA-SPM) NPs, and solid lipid nanoparticles (SLNs). Transport of the anti-HIV agents across BBB is a key factor in their applications to the therapy of the acquired immunodeficiency syndrome (AIDS). Experimental results revealed that the drug order of the loading efficiency (LE) on PBCA and MMA-SPM was D4T > DLV > SQV. For the entrapment efficiency (EE) in SLNs, this order was reversed. Also, LE of D4T on MMA-SPM was larger than that on PBCA; however, the reverse was true for DLV and SQV. As the particle size increased, LE decreased and EE increased. For a fixed drug carrier, an increase in the particle size yielded a decrease in the BBB permeability coefficient of the anti-HIV agents. Moreover, enhancement in the BBB permeability was on the carrier order of PBCA > MMA-SPM > SLNs for D4T, and for DLV and SQV, the order became PBCA > SLNs > MMA-SPM. PBCA, MMA-SPM, and SLNs were efficacious carriers of D4T, DLV, and SQV to meliorate BBB permeability by 3–16 folds, indicating the clinical potential of the present NP formulations for the AIDS treatment.     

Stability and ocular tolerance of cyclophosphamide-loaded nanospheres

The physical and chemical stabilities of several formulations of cyclophosphamide-loaded polybutylcyanoacrylate (PBCA) nanospheres developed for an ophthalmic application as an immunosuppressive agent were studied over 6 months of storage at 4, 25 and 40 degrees C in different experimental conditions. The physical stability of nanospheres was followed by the study of morphological (visual appearance) and morphometrical properties (mean particle size and polydispersity). The pH and tonicity of the suspensions and the association efficiency of the drug to polymeric system were also analysed to evaluate their chemical stability. The behaviour of colloidal suspensions with storage conditions was also followed by differential scanning calorimetry. The degradation of PBCA was affected by temperature and pH. The average particle size of all nanospheres remained practically unchanged throughout the study, with the polydispersity index being less than 0.1, corresponding to a monodisperse system. At 40 degrees C, a loss of 25.9% of the initial association efficiency, especially in non-buffered pH 7.2 medium, was observed. The type of polymer degradation (surface erosion) was also determined by photon correlation spectroscopy. The results obtained from in vivo study of ocular tolerance indicate a good ocular tolerance for drug loaded to nanospheres.     

Indirect Evidence that Drug Brain Targeting Using Polysorbate 80-Coated Polybutylcyanoacrylate Nanoparticles Is Related to Toxicity

Purpose. To investigate the mechanism underlying the entry of the analgesic peptide dalargin into brain using biodegradable polybutylcyanoacrylate (PBCA) nanoparticles (NP) overcoated with polysorbate 80. Methods. The investigations were carried out with PBCA NP and with non biodegradable polystyrene (PS) NP (200 nm diameter). Dalargin adsorption was assessed by HPLC. Its entry into the CNS in mice was evaluated using the tail-flick procedure. Locomotor activity measurements were performed to compare NP toxicities. BBB permeabilization by PBCA NP was studied in vitro using a coculture of bovine brain capillary endothelial cells and rat astrocytes. Results. Dalargin loading was 11.7 µg/mg on PBCA NP and 16.5µg/ mg on PS NP. Adding polysorbate 80 to NP led to a complete desorption. Nevertheless, dalargin associated with PBCA NP and polysorbate 80 induced a potent and prolonged analgesia, which could not be obtained using PS NP in place of PBCA NP. Locomotor activity dramatically decreased in mice dosed with PBCA NP, but not with PS NP. PBCA NP also caused occasional mortality. In vitro, PBCA NP (10 µg/ml) induced a permeabilization of the BBB model. Conclusions. A non specific permeabilization of the BBB, probably related to the toxicity of the carrier, may account for the CNS penetration of dalargin associated with PBCA NP and polysorbate 80.     

眼用诺氟沙星毫微粒制备工艺的初选及优化

目的:寻找眼用诺氟沙星毫微粒最佳的处方和制备工艺。方法:选择氰基丙烯酸正丁酯为载体材料,用乳化聚合法制备NFLXPBCANP,通过单因素试验初选、均匀设计优化处方和制备工艺。结果:在优化条件下制备的NFLXPBCANP为乳白色胶体溶液,毫微粒外形圆整光滑、分布均匀、不粘连,平均粒径553nm,包封率90.14%,载药量22.70%。结论:该优化条件可作为眼用诺氟沙星毫微粒最佳的处方和制备工艺。     

Preparation and evaluation of biodegradable polymeric systems for the intra-articular delivery of drugs

Colloidal suspensions of four biodegradable polymers, polylactic acid (PLA), polybutylcyanoacrylate (PBCA), gelatin (PG) and albumin (PA) were prepared within the size range 1-10 micron. In-vivo biocompatibility tests with synovial tissues were carried out to assess the irritancy of the polymers following intra-articular injection into rabbit knee joints. PLA, PBCA and PG were found to cause joint inflammation whereas PA was well tolerated by the tissues. PA microspheres may provide a means of sustaining the release and reducing the rate of clearance of drugs from the knee joint.     

阿霉素纳米囊的制备工艺及其毒性试验

目的对阿霉素纳米囊(adriamyc in nanocapsu les,ADM-NC)的制备工艺进行研究,优化最佳制备工艺,并对ADM-NC进行了急性毒性试验。方法以可生物降解的聚氰基丙烯酸正丁酯(polybutylcyanoacrylate,PBCA)为囊材,采用乳化聚合法(emu lsion polym erization m ethod)制备ADM-NC;以NC粒度和包封率为评价指标,通过正交试验设计(orthogonal design)优化制备工艺。以小鼠尾静脉注射方式分别测定空白纳米囊及载药纳米囊的半数致死量LD50。结果优化制备工艺后ADM-NC冻干前后的粒径分别为110nm和130nm;Zeta电位为114.6mV;以凝胶色谱法测得ADM-NC中药物的包封率达53.5%;测得空白纳米囊的LD50为(238.1±40.0)mg/kg,载药纳米囊ADM-NC的LD50为(36.6±6.2)mg/kg。结论利用乳化聚合法可制备具有较高包封率的ADM-NC;与ADM普通制剂的LD50(8.7±0.3)mg/kg相比,ADM-NC的毒性明显降低。     

Synthesis of high loading and encapsulation efficient paclitaxel-loaded poly(n-butyl cyanoacrylate) nanoparticles via miniemulsion

The manufacture of stable paclitaxel-loaded poly(n-butyl cyanoacrylate) (PBCA) nanoparticles containing high loading and encapsulation efficiency simultaneously were achieved in the presence of pluronic F127 via miniemulsion. It was found that both drug loading and encapsulation efficiencies of PBCA nanoparticles prepared by miniemulsion were higher (approximately three times) than those obtained by emulsion with similar paclitaxel content in the feed monomer (1%, w/w). Furthermore, the loading and encapsulation efficiencies increased concurrently (to a maximum of 4 and 80%, respectively) with increasing paclitaxel content and these nanoparticles were spherical in shape and with size near 100 nm. XRD patterns revealed that paclitaxel in particles was distributed in the molecular or amorphous state or in the form of small crystals. The in vitro drug release profile of drug-loaded PBCA nanoparticles prepared from miniemulsion exhibited a gradual release; more than 80% (w/w) of the paclitaxel was released after 96 h.     

Polysorbate-stabilized solid lipid nanoparticles as colloidal carriers for intravenous targeting of drugs to the brain: Comparison of plasma protein adsorption patterns

Plasma proteins enriched on the surface of drug-delivery-purpose nanoparticles are regarded as key factors for determination of in vivo organ distribution after intravenous injection. Polysorbate 80-coated polybutylcyanoacrylate (PBCA) nanoparticles, preferentially adsorbing apolipoprotein E (apoE) on their surface, have previously been considered to deliver various drugs to the brain. In the present study, in vivo well tolerable solid lipid nanoparticles (SLN) using different types of polysorbates as stabilizers were produced. The influence of the different surfactants on in vitro adsorption of human plasma proteins was investigated using two-dimensional polyacrylamide gel electrophoresis (2-DE). Possible correlations of different amounts of adsorbed apoE to the hydrophilic–lipophilic balance (HLB) of the polysorbates are shown and discussed. Apolipoprotein C-II, albumin and immunoglobulin G, which are also decisive plasma proteins with regard to site-specific drug delivery of intravenously injected carriers to the brain, are compared with regard to adsorption. Moreover, certain similarities to the plasma protein adsorption patterns of previously analysed brain-specific PBCA nanoparticles could be detected. Despite some differences in adsorption behavior of proteins on the surface of polysorbate-stabilized SLN and PBCA nanoparticles, we conclude that in both cases polysorbate 80 might have the highest potential to deliver drugs to the brain.     

静电纺丝载药微纳米纤维膜在经皮给药系统中的应用

静电纺丝技术构建的载药微纳米纤维膜由于具有高比表面积和高孔隙率等特点,在经皮给药系统中的应用成为研究的热点。不同药理活性的药物经不同纺丝(单轴、同轴、三轴等)工艺被负载于适宜的载体材料,这些载药体系适用于经皮给药。较多研究将载药微纳米纤维膜应用于皮肤,发挥局部和全身治疗作用,但研究多集中于药物体外经皮渗透性能的改善,体内药动学及药效学评价较少,静电纺丝载药微纳米纤维膜在经皮给药系统中的应用值得更加深入的研究。