可降解长效抗生育埋植剂的研究

本文介绍了用我们合成的可降解聚己内酯[Poly(ε-Caprolactone),PCL]和F68固体增释剂为原料经热塑挤管制成2.5mm外径和2.3mm内径的圆管,截取所需长度,内装一定剂量的左炔诺孕酮(Levonorgestrel,LNG)制成可降解的长效抗生育埋植剂(CaproF),经体外和大鼠体内药物释放量的测定,表明CaproF在设定时间内可保持恒定的药物释放速率;埋植体内两年,药囊形状完好,无破碎,未发现对狗有长期毒性反应,放免法测定大鼠血清中的LNG结果稳定,无明显波动,抗生育实验表明,对每只大鼠皮下埋植2.3cm,装LNG 20mg的胶囊两根,可保持两年100％抗生育效果,Ⅰ期临床实验,9名育龄妇女均未受孕,除个别受试者有轻微的点滴出血外,无其它副作用,两年内有确切的抗生育作用。     

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     

长效抗生育埋植剂CaproF体内药物释放的研究

目的对可降解长效抗生育埋植剂CaproF的体内药物释放动力学进行评价。方法将CaproF植入Wister大鼠皮下。每隔一定时间处死动物,取出埋植剂,用紫外分光光度法测药物残留量,计算单位长度埋植剂平均每日药物释放量。放射免疫法测定左炔诺孕酮(LNG)血药浓度。结果CaproF埋植剂在60、120、180、360、720d药物平均释放速率分别为(11.0±3.0)、(11.7±3.7)、(8.0±1.2)、(7.3±0.4)、(9.3±0.9)μg/(d·cm),并可维持基本恒定的血药浓度。结论左炔诺孕酮CaproF埋植剂植入体内后,平均药物释放速率达到7.6μg/(d·cm),并可维持2年的基本稳定释放。     

大白鼠皮下植入米非司酮埋植剂血药浓度和抑制异位子宫内膜效果的观察

目的观察大鼠皮下植入米非司酮埋植剂后的血药浓度变化及抑制大鼠子宫内膜异位症的效果。方法取体质量170～190g Wister雌性正常大鼠，分别在正常大鼠和动物模型大鼠（实验组5组和对照组）皮下埋植单根0．75cm、1．5cm、3．0cm和2根、3根3cm长米非司酮埋植剂（外径2．5mm），对照组植入2根3．0cm不含药的埋植剂。正常大鼠给药1个月．定期取血用HPLC法测血药浓度。动物模型大鼠给药3个月．用MRI测定异位子宫内膜体积并计算抑制率。结果不同剂量的米非司酮皮下埋植剂皆在植入体内7d时，血药浓度达到最高：随着给药剂量加大，血药浓度峰值也趋向增高，但7d后血药浓度逐渐下降，14d后除3根剂量组的血药浓度显著较高外（约0．18～0．20μg／ml），其他较低剂量组之间的血药浓度差异无统计学意义（约0．10～0．13μg/ml）。大鼠皮下植入埋植剂的剂量与血药浓度峰值呈线性关系。动物模型皮下植入1根1．5cm、3．0cm或2根3．0cm长埋植剂1个月时，异位内膜抑制率分别为18．6％±17．3％、31．5％±12．7％、72．2％±12．3％，与对照组比较差异有统计学意义，并且不再随剂量加大而显著提高抑制效果。结论 米非司酮皮下埋植剂作为治疗子宫内膜异位症的长效制剂是可行的．     

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.     

国产皮下埋植剂埋植5年妇女血液流变学变化的观察

目的了解国产长效皮下埋植剂避孕妇女血液流变学的变化。方法对４６例国产皮下埋植避孕满５年的妇女进行血液流变学检测、结果发现４０Ｓ~(－１)全血粘度、血浆粘度（ηｐ）、还原粘度（ηｒ）、血球压积（ＨＣＴ）、血栓长度（Ｌ）等与对照组比较明显升高，有非常显著差异。结论应埋剂置入５年后可造成部分妇女血液流变学某些指标的升高。当皮埋剂取出一段时间后，这些改变可随外源性药物作用的消失而恢复。     

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。     

缓释管组成结构对药物缓释速率的影响因素研究

为探究药物本身及缓释管组成结构等因素对药物缓释速率的影响,以孕酮、睾酮和雌二醇作为缓释试验药物,对硅胶缓释管的封堵方式、管长、管壁厚度以及所填充药物的方式等因素对药物缓释速率的影响进行了检测。实验结果表明,药物的结构对其本身的缓释速率具有决定性作用。硅胶缓释管的封堵方式、管长、管壁厚度及所填充药物的方式都对药物的缓释速率具有显著的调节作用,且调节作用的大小与药物本身缓释性能的大小成正比。另外,我们新研制的玻璃-硅胶缓释管释放面积小,药物储存能力大,特别适用于释放速率较快的药物在体内的长期缓释。     

具有三层管壁结构组织工程血管支架的生物力学性能

目的针对组织工程血管的体内培养技术路线，对所制备的具有三层管壁结构的组织工程血管支架的生物力学性能进行测试，并研究了壁厚对支架力学性能的影响，以保证后续的动物体内移植实验能顺利进行。方法采用涂敷，喷涂．滤沥的方法制备了具有三层管壁结构（多孔PLGA层．致密PU层．多孔PLGA层）的可降解组织工程血管支架，用自制的设备测试了其爆破强度和径向顺应性，并对血管支架进行了缝合强度的测试。结果所制备的厚度为0．295mm-0．432mm的三层结构血管支架的径向顺应性为3．80％／100mmHg-0．57％／100mmHg，爆破强度为160kPa～183kPa，缝合强度为0．63N／针～1．52N／针。结论支架的管壁厚度，尤其是中间层厚度，对支架的力学性能有重要影响。增大壁厚可导致径向顺应性急剧下降，爆破强度和缝合强度线性提高。在所制备的样品中，管壁厚度为0．295mm的支架其综合力学性能最优，可满足血管组织工程体内植入的力学性能要求。     

医用聚己内酯埋植剂体内降解的研究

目的 对医用聚己内酯埋植剂材料合成及体内降解进行研究,了解埋植剂材料的性能. 方法 Pluronic F68经乙酰封端处理后与己内酯单体（CL）混合,加入催化剂于N2保护的聚合釜中,在140 ℃～170 ℃条件下聚合48 h,用挤出机制成管材.研究致孔剂的工艺、微孔的形成.用核磁共振和扫描电镜等方法观察聚己内酯埋植剂材料的结构.用氚标记的低相对分子量的聚己内酯胶囊植入大鼠皮下,测定其体内降解、吸收和排泄. 结果 含有F68的医用聚己内酯埋植剂材料（PCL/F68）在亲水介质中F68很快溶出,可形成多微孔结构.该材料起始相对分子量为66 000时,在体内可完整存在2年,2年后降解为低相对分子量碎片,可被机体吸收、排泄,不在体内积蓄. 结论 聚己内酯/F68埋植剂材料在体内可降解并主要通过粪便排出体外,不在体内积蓄,脏器中放射性极少.     

Controlled release of drugs from multi-component biomaterials

In order to control their release, drugs are encapsulated into systems which are expected to provide a certain site with a predetermined amount of drug over a well-defined period of time. Here we report on a multi-component drug delivery biomaterial that consists of a hydrogel matrix in which drug-loaded biodegradable microcarriers are dispersed, and whose potential applications could be found in the design of implantable devices with long-term activity, as required by contraceptive and hormone replacement treatments. The release profile of the drug can actually be tuned by the complex interplay of several release mechanisms, including the permeability and eventually the degradation rate of the microcarriers and the diffusion through the hydrogel. The hydrogel consisted of 2-hydroxyethyl methacrylate cross-linked by ethylene glycol dimethacrylate. The microcarriers were biodegradable poly-epsilon-caprolactone (PCL) microspheres in which active molecules, such as levonorgestrel (LNG), were encapsulated. The hydrogels were characterized by water swelling, thermal properties, LNG diffusion through drug-free and drug-depleted hydrogel membranes and LNG release from devices with drug dispersed in the hydrogel. The PCL microspheres were observed by scanning electron microscopy; their size distribution, LNG loading and release were also investigated. The hydrogel-microsphere assemblies were characterized in terms of the distribution of the microspheres within the hydrogel, water swelling and the release of the encapsulated molecules. The developed device, due to its composite structure, has the ability to combine several release mechanisms, leading to drug release obeying zero-order kinetics for most of the time.     

盐酸多柔比星缓释植入剂体外释药与体外降解的研究

以聚（乳酸-羟基乙酸）共聚物（PLGA）为载体制备盐酸多柔比星缓释植入剂,测定植入剂的释放度和PLGA失重率,结果表明PLGA体外降解曲线呈＂S＂形,起初的迟缓期后降解速率加快,5周时失重率达80%。植入剂表现出趋于零级的药物释放模式（r=0.9880）,在0~25 d日均释放度达3.26%,35 d时累积释放度达90%以上。植入剂可持续释药1个月,释药速率主要取决于PLGA降解速率,通过调节PLGA降解速率可以很好地控制药物的释放度。     

紫杉醇聚己内酯／泊洛沙姆188载药纳米粒及其抗肿瘤活性

目的利用聚己内酯（PCL）与亲水性添加剂泊洛沙姆188（F68）共混物作为载体材料与抗癌药物紫杉醇组成纳米粒缓释载药系统,并评价其在裸鼠人乳腺癌B37实体瘤模型中的抗肿瘤效果。方法采用超声乳化／溶剂挥发法制备紫杉醇PCL/F68载药纳米粒：对紫杉醇PCI／F68载药纳米粒进行表征及高压液相色谱法（HPLC）测定包封率和体外释放度：利用差示扫描热分析（DSC）法分析紫杉醇在PCL／F68载药纳米粒中的分散状态;评价紫杉醇PCL／F68载药纳米粒在裸鼠人乳腺癌B37实体瘤模型中的抗肿瘤活性．结果紫杉醇PCL/F68载药纳米粒呈现规整的球形：平均粒径为150．50nm（标准差25．41nm）．多分散系数为O．18。紫杉醇PCI仃68纳米粒的载药量为18％,药物包封率为84-36％。紫杉醇PCIJF68载药纳米粒体外药物释放研究表明在50d的释放周期内累计释放量约为49％,接近零级释放（R=0．998）。体内抗肿瘤活性实验研究表明．紫杉醇PCL/F68载药纳米粒对裸鼠人乳腺癌B37实体瘤生长具有明显抑制作用。结论肿瘤局部注射紫杉醇PCL/F68载药纳米粒能够有效地抑制肿瘤的生长,     

Gravity spun polycaprolactone fibres: controlling release of a hydrophilic macromolecule (ovalbumin) and a lipophilic drug (progesterone)

A hydrophilic macromolecule (ovalbumin (OVA)) and a lipophilic drug (progesterone) were incorporated in polycaprolactone (PCL) fibres by gravity spinning using particulate dispersions and co-solutions of PCL and steroid, respectively. PCL fibres loaded with 1% (w/w) OVA powder displayed a pronounced burst release phase (60% of the protein load) over 2 days in PBS at 37 degrees C. The release profile then tended to plateau. In contrast, OVA nanoparticle-loaded fibres exhibited delayed protein release initially and then a major increase at day 14. This behaviour may be useful for sequential release of polypeptide growth factors which are influential at specific time points in the wound healing process. SDS-PAGE analysis revealed that the protein molecular weight was conserved during fibre spinning. The amount of progesterone release from PCL fibres in PBS increased with drug loading but the cumulative release profiles (% w/w) were little affected by the initial drug loading of the fibres (1.5 and 3.5% w/w) or the concentration of the PCL spinning solution (12.5 and 20% w/v). Steroid delivery was rapid due to the high fibre surface area and high permeability of PCL resulting in complete drug loss over 24h. Released progesterone inhibited the growth of MCF-7 breast epithelial cells in culture, demonstrating retention of bioactivity. Gravity spinning shows potential for producing PCL fibre-based platforms for programmed delivery of bioactive molecules of utility for tissue engineering and drug delivery.     

影响宫腔内人工授精妊娠率的临床及精液因素分析

目的探讨促排卵方案、子宫内膜因素、处理后前向运动精子总数和活动率、受精次数对人工授精妊娠率的影响。方法回顾性分析本中心2009-2010年收治的677对病人促排卵方案,子宫内膜类型及厚度,受精次数,将前向运动精子总数分为7组,即A：（4～9）×106,B：（10～12）×106,C：（13～15）×106,D：（16～20）×106,E：（21～25）×106,F：（26～30）×106,G：〉30×106,分别比较各组患者年龄、不孕年限、活动率对临床妊娠率的影响。结果 677个周期共获得88例生化妊娠,79例临床妊娠,平均生化妊娠率为13.15%,临床妊娠率为11.81%。促排卵方案以HMG组最好,子宫内膜类型为三线征及内膜厚度大于8mm是妊娠达到10%以上的必要条件。双次人工授精妊娠率（15.27%）明显高于单次（7.57%）。各活动精子数量组妊娠率分别为0、14.37%、11.92%、15.09%、8.33%、20.34%、6.06%,A组临床妊娠率最低,与其余组比较差异有统计学意义,F组活动率和妊娠率最高,与其余组比较差异有统计学意义。结论促排卵方案以HMG组最好;三线征子宫内膜且厚度大于8mm、（26～30）×106精子密度和84%以上的活动率是获得高妊娠率的先决条件;双次人工授精优于单次。     

肺癌磁共振扩散加权成像与肿瘤细胞密度的相关性研究

目的利用表观扩散系数（ADC）来评价肺癌的组织学特征。方法28例肺癌患者，其中男性18例，女性10例，年龄25～79岁．平均年龄52岁。行扩散加权成像（DWI）检查并测量病灶的ADC，方差分析比较不同组织学类型肺癌ADC问的差别。对11例外科切除的肺癌病灶ADC与细胞密度进行相关性分析。结果鳞癌、腺癌、小细胞癌平均ADC分别为（1．67±020）×10^-3mm2／s、（2．08±0128）×10^-3mm2／s、（1．76±0.21）×10^-3mm2／s，腺癌的ADC明显高于鳞癌及小细胞癌（P〈Q05）。肺癌ADC与细胞密度呈显著负相关（r=-0．71，P=0．015）。结论腺癌的ADC明显高于其他类型肺癌；ADC似乎可以鉴别肺癌的组织学类型。     

Effect of biphasic calcium phosphates on drug release and biological and mechanical properties of poly(epsilon-caprolactone) composite membranes

Poly(epsilon-caprolactone) (PCL) and biphasic calcium phosphate (CaP) composite membranes were prepared for use in tissue regeneration by a novel solvent casting-pressing method. An antibiotic drug, tetracycline hydrochloride (TCH), was entrapped within the membranes to investigate the efficacy of the material as a drug delivery system. The CaP powders were varied in amount (0-50 wt %) and in powder characteristics by heat treating at different temperatures, and their effects on the mechanical and biological properties and drug release of the membranes were examined. With CaP addition up to 30 wt %, the elastic modulus of the membranes was enhanced much due to the rigidity of CaP. While the tensile strength and elongation rate decreased gradually with CaP addition because the CaP powders acted as a failure source. The osteoblast-like cells cultured on the CaP-PCL composite membranes exhibited significant improvements in proliferation and alkaline phosphatase (ALP) activity compared to pure PCL and culture plastic control, indicating excellent cell viability and functional activity. The TCH drugs were released from the PCL and CaP-PCL membranes in a similar fashion; an initial burst followed by a reduced release rate. The initial burst effect diminished much by the addition of CaP powders. The CaP addition increased the drug release rate after an initial period, and this was attributed to the high water uptake capacity and dissolution of the CaP containing membranes. Compared to the composite membranes containing heat-treated CaP powders, those with as-precipitated ones had higher dissolution and drug releases. These observations on mechanical properties and cellular responses as well as on drug release profiles suggested that the CaP-PCL composite membranes are potentially applicable to tissue regeneration and drug delivery system.     

Characterization of polymeric poly(epsilon-caprolactone) injectable implant delivery system for the controlled delivery of contraceptive steroids

Contraceptive steroids levonorgestrel (LNG) and ethinyl estradiol (EE) have been encapsulated with poly(epsilon-caprolactone) (PCL) microspheres using a w / o /w double emulsion method. The microspheres prepared were smooth and spherical, with a mean size from 8-25 microm. In vitro release profiles of microspheres showed a trend of increasing initially at the first week, and thereafter the release was sustained. At the end of the seventh week LNG/EE from 1:5 and 1:10 PCL microspheres were 60 and 48%, 52 and 46%, respectively. An in vitro degradation study shows that at the 20th week the microspheres maintained the surface integrity. The PCL microspheres showed a triphasic in vivo release profile with an initial burst effect due to the release of the steroid adsorbed on the microsphere surface, a second sustained release phase due to the steroid diffusion through the pores or channels formed in the polymer matrix, and third phase due to polymer bioerodible. Histological examination of PCL microspheres injected intramuscularly into thigh muscle of a rat showed a minimal inflammatory reaction demonstrating that contraceptive steroid-loaded microspheres were biocompatible. The level of inflammatory cytokines determined by immunostaining for IL-1alpha, the tissue response to formulations at the first week was considered mild, whereas at the end of the 20th week the inflammatory response ceased. Thus, this study helped us to evaluate the feasibility of using these microspheres as a long-acting biodegradable drug delivery system for contraceptive steroids.     

Curcumin- and natural extract-loaded nanofibres for potential treatment of lung and breast cancer: in vitro efficacy evaluation

Drug-eluting medical implants are more common, particularly for fighting against cancers. FDA and other drug regulatory bodies have approved many nanoformulated devices eluting active pharmaceutical ingredients and thus there is growing demand for further value- added devices. Nanofibre membranes are known for its versatility of drug incorporation and sustained drug release. We intend to fabricate natural ingredient or extract, and their combination loaded polycaprolactone (PCL) nanofibre for usage as drug-eluting stents or implants for anticancer activity against lung and breast cancers. The fabricated nanofibre membranes were characterised by scanning electron microscope for morphology, FT-IR for chemical nature and tensile testing for mechanical strengths. Release of curcumin was studied with time to find the applicability of the device as drug-eluting implant. The activity of the nanofibre membranes was tested against human breast cancer (MCF7) and lung cancer (A459) cell lines in vitro. In both the cell lines tested, 1% aloe vera and 5% curcumin-loaded PCL nanofibre exhibited 15% more cytotoxicity in comparison with the commercial drug 1% cis-Platin-loaded PCL nanofibre after 24?h incubation.     

高效凝胶色谱法测定多花黄精多糖分子量与分子量分布

目的：建立多花黄精多糖的分子量与分子量分布分析方法。方法：应用高效凝胶渗透色谱法，色谱柱为Shodex OHPak SB-803HQ（8mm×300mm），流动相为0．71％硫酸钠溶液（内含0．02％叠氮钠），柱温：35℃，示差折光检测器（检测器温度35℃），流速0．5ml·min^-1。结果：根据建立的方法测定，得到多糖的高效凝胶色谱图，计算出多花黄精多糖的重均分子量及其分布。结论：所用方法简便、快速、准确，可用于多花黄精多糖的质量控制。