顺铂聚乳酸微球的药物释放特性及肝动脉栓塞研究

对顺铂聚乳酸微球进行了体外药物释放和家犬肝动脉栓塞研究。该微球粒径范围为50～200μm,平均粒径为115.76±35.94μm,顺铂含量为37.16%(W/W);体外药物释放机制符合Higuchi方程;肝动脉栓塞后8h,肝组织顺铂浓度高达21.55±12.18μg/g,明显高于肝动脉灌注顺铂组:3.16±0.09μg/g(P<0.05);肝动脉栓塞组的顺铂血浓峰值、各取血点浓度及曲线下面积AUC皆低于肝动脉灌注顺铂组。可望达到提高栓塞部位的药物疗效,降低全身毒副反应的作用。     

关节腔内注射用氟比洛芬明胶微球

目的:制备关节腔注射用氟比洛芬明胶微球。方法:按均匀设计法筛选乳化冻凝法制备氟比洛芬明胶微球(FP GMS)的最佳制备工艺。结果:微球粒径范围为2.5～12.3μm,平均粒径为7.53μm,氟比洛芬含量为5.02%(w/w)。其体外释药符合Higuchi方程,稳定性实验表明,FP-GMS的稳定性良好,兔关节腔内注射后,与溶液剂对照组相比氟比洛芬体内平均驻留时间(MRT)显著延长(P<0.01),峰时比对照组延长2.03倍,峰浓度比对照组减小5.57倍。体内外相关性研究表明,FP-GMS体外累积溶出百分率与兔体内药物吸收分数呈显著相关(P<0.01)。结论:本法制备的氟比洛芬明胶微球粒径分布集中,粒径大小符合设计要求,体内外释药结果表明氟比洛芬明胶微球具有明显的缓释作用。     

肺靶向利福平聚乳酸微球的研究

在单因素考察的基础上进行正交试验设计,筛选出肺靶向利福平聚乳酸微球的最佳制备工艺条件;利用桨板法研究了微球的体外释药规律;考察了微球在不同温度下的稳定性;用新西兰兔为实验对象,研究了利福平聚乳酸微球的体内药动学及组织药物分布。结果制得的微球形态圆整,粒径在5～15μm范围内的占总体积的86.54%,微球平均粒径为9.00±4.08μm;包封率为31.9%;载药量为16.0%;体外释药方程为Q=20.77+10.12T_1/2(γ=0.9892);微球在冰箱4℃和室温(20～25℃)条件下性质稳定;体内实验表明微球具有长效和肺靶向双重作用。     

肺靶向卡铂明胶微球的研究

目的:为提高卡铂的疗效,降低毒副作用,制备了该药的明胶微球。方法:用乳化法制备卡铂明胶微球,紫外分光光度法测定药物的含量,二阶导数法测定体外释药情况;用静脉注射肿瘤细胞建立了肺肿瘤模型,计算瘤结节数来考察疗效。结果:卡铂明胶微球平均粒径为13-20 μm ,粒径范围5-0～28-6 μm 的微球数占总数的91-8% 。微球平均载药量为23-76%(n=3) 。冰箱、室温和37℃,RH75% 考察3个月,几乎无变化,体外释药符合一级动力学规律,释药T_1/2 比原药延长约10倍。药效学实验表明,卡铂明胶微球对小鼠肺部S180肿瘤生长有明显的抑制作用,抑瘤作用较原药卡铂大大提高。结论:卡铂明胶微球在体内有良好的肺靶向性,对提高药物的疗效,降低药物毒副作用等方面有重大意义。     

盐酸川芎嗪肺靶向微球的研究

用乳化法制备盐酸川芎嗪明肢微球,优化了工艺。对微球的外观、粒径与其分布、含量、体外释药、稳定性及体内分布等进行研究。结果表明平均粒径为12.65μm,粒径范围5.0～24.9μm占总数的87.5%,球内含药量平均为16.49%±0.49%(n=3),冰箱或室温放置稳定,体外释药符合一级动力学规律,释药t_1/2比原药延长约5倍。小鼠静注微球后20 min,在肺内的相对分布百分率明显高于其它组织与血液,与溶液对照组相比,提高近6倍。     

莪术油明胶微球用于肝动脉栓塞

目的　制备符合肝动脉栓塞要求的莪术油明胶微球(ZT-GMS)。方法　用正交设计优化了微球的制备工艺,对微球的制备工艺、粉体学性质、体外释药、初步稳定性和初步药效进行了研究。结果　球径在40～160 μm的微球占97.16%,平均产率为89.73%,平均含药量为2.13%,平均包封率为19.36%(均以莪术醇计)。体外释药12 h达80%,符合一级动力学模型,释药机理为溶蚀加扩散。稳定性考察实验结果表明其稳定性较好。肝动脉栓塞荷瘤大鼠实验结果表明大鼠平均生存率显著延长(P<0.01),肿瘤体积显著减小(P<0.01)。结论　微球的制备工艺及粒径分布较好,体外释药有明显的缓释作用,有一定疗效。     

肝靶向米托蒽醌白蛋白微球的研究

用乳化—热固化法制备了米托蒽醌白蛋白微球,并对其形态、大小及其分布、微粉学性质、载药性能、体外释药、稳定性和体内分布进行了研究。结果表明,该载药微球的平均算术径为0.99μm,平均表面径为1.24μm,平均容积径为1.44μm;表观载药量为2.558%±0.101%;有效载药量为1.503%±0.127%;包封率为92.82%±4.60%;体外释药符合双相动力学规律,释药方程为1-Q=0.6428e^-0.2132t+0.3988e^-000150t(γ₁=-0.9951,γ₂=-0.9982);T_1/2α=3.250h,T_1/2β=461.7h;室温放置3个月,微球形态、药物含量等均无明显变化。HPLC测定表明,小鼠尾iv该微球20min内即有77.6%±1.38%的药物浓集于肝脏,具有明显的肝靶向性。提示米托蒽醌白蛋白微球有可能提高米托蒽醌的抗肝癌效果和降低其全身毒副作用。     

褪黑激素明胶微球的鼻腔给药

目的　制备经鼻粘膜给药的褪黑激素明胶微球,以提高其生物利用度。方法　用乳化交联技术制备褪黑激素明胶微球,用放射性核素^99mTc标记,用γ射线闪烁显像技术考察微球在鼻粘膜滞留时间,用HPLC法测定药物的体内吸收。结果　褪黑激素明胶微球粒径在30～70 μm,平均粒径为50.2 μm,褪黑激素含量为13.48%。与滴鼻液相比,明胶微球在鼻粘膜滞留时间明显延长。褪黑激素明胶微球的绝对生物利用度为87.47%。结论　鼻粘膜给药明胶微球,能避免肝脏首过作用,延长药物在鼻粘膜滞留时间,提高药物吸收,有很好的应用前景。     

顺铂壳聚糖微球的制备及特性研究

对顺铂壳聚糖微球的制备、载药量、大小及分布、形态及表面状态、体外释放及降解性进行了研究。微球用乳化-化学交联技术制备,平均粒径为74.80μm,顺铂含量为20.83%±0.36%。电镜扫描显示,微球球形圆整,表面粗糙。生理盐水中放置1h微球轻微溶胀,其体外释药符合一级方程,微球经⁶⁰Co辐射灭菌达到无菌要求。犬肝动脉栓塞后一个月,病理切片可见栓塞区仍有壳聚糖微球存在。     

新型可降解聚酯材料地西泮缓释微球的研制

目的　优化制备工艺,用新型的生物可降解材料聚羟基丁酸酯—羟基戊酸酯共聚物（PHBV）与D,L-聚乳酸（PLA）共混物为基材制备以地西泮（diazepam,DZP）为模型药物的缓释微球（MS）。方法　用正交设计优化微球制备工艺,用扫描电镜（SEM）观察微球表面形态。对微球粒径及其分布、体外释药、稳定性及在动物体内药动学进行了测定。结果　微球平均粒径为(20.45±4.50) μm,粒径在15.5～35.2 μm占总数88%以上。载药量为(16.95±0.80)%,包封率为(69.68±1.13)%;体外释药方程为Q=2.7027t+13.50(γ=0.9827),动物体内实验表明,微球的血药浓度-时间曲线下面积AUC是溶液对照组的2.35倍,平均驻留时间MRT是对照组的3.62倍。微球在冰箱4℃与室温（20～25℃）条件下性质稳定。结论　微球制备工艺稳定,与DZP针剂相比,具有明显缓释作用。     

Preparation and evaluation of biodegradable flubiprofen gelatin micro-spheres for intra-articular administration

Purpose: A controlled release delivery system that localizes flurbiprofen (FP) in synovial joint is prefered to treat inflammation in rheumatoid arthritis (RA). The purpose of this study is to develop and characterize FP-loaded gelatin microspheres and evaluate FP plasma concentrations following intra-articular injection into healthy rabbits.

Methods: Flurbiprofen gelatin microspheres (FP-GMS) were prepared by a emulsion-congealing method. The RP-HPLC method was established to determine the FP concentraion in plasma. The particle size of FP-GMS with optimized formulation was 2.5?～?12.3?µm with a mean size of gelatin microspheres of 7.53?µm. The drug loading efficiency was 5.02% (w/w). The dissolution profile of the FP-GMS was depicted by Higuchi kinetics.

Results: The half time for 50% release of FP from FP-GMS (t₅₀) was 5.58?h. A total of 96% original FP was remained in the microspheres after being stored under 75% humidity and 37°C for 3 months. The pharmacokinetics study demonstrated that the mean resident time (MRT) of FP in the FP-GMS group was prolonged vs. the injection group significantly (p?<?0.01) after intra-articular administration into healthy rabbit hind joints. The T_p of FP-GMS group was prolonged by 2.03-times and the C_max was decreased by 5.57-times vs. that of the injection group, respectively. The FP plasma concentration in FP-GMS was 8-fold higher than that of the FP injection group at 8?h. In addition, FP was rapidly cleared from blood circulation within 8?h with the injection group while FP was retained for more than 24?h with the FP-GMS group.

Conclusions: These data indicate that the simple emulsion-congealing method can be used to encapsulate water soluble drugs such as FP for the treatment of inflammatory disease within the joint cavity.     

芬太尼透皮贴剂联合吗啡皮下注射治疗晚期肝癌介入治疗后疼痛的护理观察

目的 观察芬太尼透皮贴剂联合吗啡皮下注射在晚期肝癌介入术后疼痛护理应用中的优势。方法 回顾性分析166例晚期肝癌介入治疗后疼痛治疗护理的临床资料,对89例芬太尼联合吗啡治疗组和77例吗啡治疗组在疼痛评分、缓解率两方面数据进行比较,并进行统计学分析;同时记录各组治疗中的副反应。结果 与吗啡治疗组比较,芬太尼联合组疼痛评分,在12 h（1.97±0.56 vs 3.23±1.49,P<0.05）以及24 h（1.63±0.44 vs 4.19±1.68,P<0.01）均有显著降低。与吗啡治疗组比较,芬太尼联合组介入治疗后疼痛总缓解率,在介入后12 h（92.1% vs 76.6%,P<0.05）以及24 h（97.8% vs 70.1%,P<0.05）均有显著缓解。结论 晚期肝癌介入治疗后联合使用吗啡皮下注射+芬太尼透皮贴剂外贴治疗,可以显著提高患者介入术后72 h内的疼痛缓解率。     

Effects of formulation parameters on encapsulation efficiency and release behavior of thienorphine loaded PLGA microspheres

To develop a long-acting injectable thienorphine biodegradable poly (d, l-lactide-co-glycolide) (PLGA) microsphere for the therapy of opioid addiction, the effects of formulation parameters on encapsulation efficiency and release behavior were studied. The thienorphine loaded PLGA microspheres were prepared by o/w solvent evaporation method and characterized by HPLC, SEM, laser particle size analysis, residual solvent content and sterility testing. The microspheres were sterilized by gamma irradiation (2.5 kGy). The results indicated that the morphology of the thienorphine PLGA microspheres presented a spherical shape with smooth surface, the particle size was distributed from 30.19?±?1.17 to 59.15?±?0.67μm and the drug encapsulation efficiency was influenced by drug/polymer ratio, homogeneous rotation speed, PVA concentration in the water phase and the polymer concentration in the oil phase. These changes were also reflected in drug release. The plasma drug concentration vs. time profiles were relatively smooth for about 25 days after injection of the thienorphine loaded PLGA microspheres to beagle dogs. In vitro and in vivo correlation was established.     

西黄丸联合紫杉醇和铂类新辅助化疗对晚期宫颈癌患者术后疗效的影响

目的 探讨西黄丸联合紫杉醇和铂类新辅助化疗对晚期宫颈癌患者术后疗效的影响。方法 选取2014年1月-2017年1月安阳市第三人民医院收治的晚期宫颈癌患者80例为研究对象,采用随机数字表法分为观察组和对照组各40例,均择期行根治性子宫切除术,术后对照组予以紫杉醇+顺铂新辅助化疗方案,3周为1个疗程,治疗2个疗程;观察组在对照组基础上予以西黄丸2次/d,治疗6周。比较两组化疗有效率、生存率及复发率,测定两组化疗前后T淋巴细胞亚群（CD3⁺、CD4⁺、CD8⁺）及免疫球蛋白（IgA、IgG、IgM）水平,应用卡氏评分表（KPS）、数字评分法（NRS）评价生活质量及癌痛度,记录不良反应。结果 观察组化疗有效率（87.50%）与对照组（77.50%）比较略高,但差异无统计学意义;观察组化疗后3、6个月生存率、复发率与对照组对比均无统计学差异;化疗后观察组CD3⁺（72.39±1.47）%、CD4⁺（37.62±1.17）%、IgA （11.11±1.34） g/L、IgG （1.23±0.45） g/L、IgM （2.60±0.46） g/L较对照组明显增加,差异有统计学意义（P<0.05）;观察组CD8⁺（20.32±1.39）%低于对照组,差异有统计学意义（P<0.05）。治疗后观察组KPS评分（78.49±1.45）分较对照组显著增加,而其NRS评分（1.20±0.11）较对照组明显降低,差异有统计学意义（P<0.05）。观察组不良反应发生率（7.50%）明显低于对照组（25.00%）,差异有统计学意义（P<0.05）。结论 西黄丸西黄丸联合紫杉醇和铂类新辅助化疗对晚期宫颈癌患者术后疗效较好,可改善其免疫功能、生活质量、疼痛度,减少不良反应,近期不会明显改善生存率及复发率,远期疗效需进一步研究。     

Self-Emulsifying Drug Delivery Systems: Formulation and Biopharmaceutic Evaluation of an Investigational Lipophilic Compound

Self-emulsifying drug delivery systems (SEDDSs) represent a possible alternative to traditional oral formulations of lipophilic compounds. In the present study, a lipophilic compound, WIN 54954, was formulated in a medium chain triglyceride oil/nonionic surfactant mixture which exhibited self-emulsification under conditions of gentle agitation in an aqueous medium. The efficiency of emulsifi-cation was studied using a laser diffraction sizer to determine particle size distributions of the resultant emulsions. An optimized formulation which consisted of 25% (w/w) surfactant, 40% (w/w) oil, and 35% (w/w) WIN 54954 emulsified rapidly with gentle agitation in 0.1 N HCl (37°C), producing dispersions with mean droplet diameters of less than 3 µm. The self-emulsifying preparation was compared to a polyethylene glycol 600 (PEG 600) solution formulation by administering each as prefilled soft gelatin capsules to fasted beagle dogs in a parallel crossover study. Pharmacokinetic parameters were determined and the absolute bioavailability of the drug was calculated by comparison to an i.v. injection. The SEDDS improved the reproducibility of the plasma profile in terms of the maximum plasma concentration (C _max) and the time to reach the maximum concentration (t _max). There was no significant difference in the absolute bioavailability of WIN 54954 from either the SEDDS or the PEG formulations.     

轻中度创伤性脑损伤患者记忆受损与血清Tau蛋白的关系

目的 探讨轻中度创伤性脑损伤（TBI）患者记忆受损与血清Tau蛋白的关系。方法 选取安徽医科大学第一附属医院2016年6月至2017年6月收治的TBI患者60例为研究对象,依据患者入院时格拉斯哥昏迷评分（GCS）分为轻度TBI组（30例）与中度TBI组（30例）。另选取20名志愿者为健康对照组。在入院时、伤后第72小时、2周、6周和3个月时,采用ELISA法检测受试对象的血清Tau蛋白浓度,同时运用神经心理学测试量表对受试对象记忆认知特点进行评估。结果 入院时,TBI组患者血清Tau蛋白浓度为（574.3±270.1） pg/mL、健康对照组为（79.9±36.3） pg/mL,两组差异有统计学意义（t=13.807,P<0.05）。伤后第72小时,中度TBI组患者血清Tau蛋白浓度为（1 051.2±333.9） pg/mL、轻度TBI组为（805.2±400.2） pg/mL,两组差异有统计学意义（t=2.585,P=0.012）。伤后3个月,TBI组患者血清Tau蛋白浓度为（100.8±35.6） pg/mL,与健康对照组相比,差异无统计学意义（t=2.001,P=0.051）。TBI组患者记忆受损明显,且伤后第72小时患者记忆认知水平处于最低,至伤后6周,TBI组患者记忆受损逐渐恢复至健康对照组水平,两组差异无统计学意义（P>0.05）。伤后第72小时和伤后2周,TBI组患者血清Tau蛋白浓度与神经心理学测试评分呈负相关（P<0.05）。结论 早期检测TBI患者的血清Tau蛋白浓度不仅可以评估患者的受伤程度,而且能够有效地反映患者记忆受损的程度。     

Effect of Particle Size and Polymer Loading on Dissolution Behavior of Amorphous Griseofulvin Powder

The effect of particle size on the dissolution behavior of the particles of amorphous solid dispersions (ASDs) of griseofulvin (GF), with 0%-50% Kollidon^® VA 64 as a crystallization inhibitor is investigated. Both the final dissolved GF concentration and the dissolution rate of GF ASDs were found to be inversely proportional to the particle size. The solution concentrations for the smallest (45-75 μm) size group with different polymer loadings were significantly higher than those for the largest (250-355 μm) group regardless of the initial GF amount. Specifically, the dissolution rate of GF ASDs with 50% polymer loading for the finest group was 2.7 times higher than for the largest group under supersaturating conditions. The rates of dissolution and recrystallization were assessed through surface concentration (C_s) and Avrami recrystallization rate kinetics, where the solid-state recrystallization was confirmed using Raman spectroscopy. Outcomes indicated that particle size reduction enhanced ASD drug loading by reducing the amount of polymer necessary as finest size ASDs initially dissolve faster, negating their higher recrystallization rate. Kollidon® VA 64 at 30% loading was sufficient to inhibit the GF recrystallization. Overall, the combination of particle size reduction and recrystallization inhibition is effective for improved dissolution behavior of GF ASDs.     

华法林快速抗凝方案在脑梗死合并房颤患者中的应用价值

目的 探索华法林快速抗凝方案在中国急性脑梗死合并非瓣膜病性心房颤动患者中的应用价值。方法 2013年1月-2016年2月间急性脑梗死合并非瓣膜病性房颤患者101例,采用前瞻性开放研究,将其分为快速抗凝组和常规抗凝组。快速抗凝组的华法林初始剂量为3~4.5 mg,随后按流程每日调整剂量至INR稳定达标;常规抗凝组的初始剂量为1~3 mg,随后根据对患者的风险与获益评估调整华法林剂量。主要终点是比较2组间的INR稳定达标率、达标时间和安全性。结果 至1周、2周和1月时,快速抗凝组INR稳定达标率均显著高于常规抗凝组（48.2% vs 4.4%,P=0.000;91.1% vs 40.0%,P=0.000;96.4% vs 48.9%,P=0.000）、INR稳定达标时间分别为（8.3±2.9） d和（13.2±4.5） d（P=0.000）。随访至1年,快速抗凝组的INR稳定达标率为54.5%（30/55）,而常规抗凝组仅为31.8%（14/44）,2组具有显著性差异（P<0.05）。在安全性方面,快速抗凝组与常规抗凝组2周内INR ≥ 4的患者比例分别为5.4%（3/56）和6.7%（3/45）。结论 华法林快速抗凝治疗比常规抗凝不仅更安全有效,而且显著增加了患者的依从性,值得借鉴。     

Effects of combined procedure and devascularization alone on hyperdynamics of the portal venous system in patients with portal hypertension

Shunts and devascularizations have totally different effects on the hemodynamics of the portal venous system. The actual results of pericardial devascularization (PCDV) alone and conventional splenorenal shunt combined with pericardial devascularization (combined procedure, CP) should be determined by more clinical observations. This study aimed to evaluate effects on hemodynamics in the portal venous system after CP and PCDV only. In 20 patients who received CP and 18 who received PCDV, hemodynamic parameters of the portal venous system were studied by magnetic resonance angiography 1 week before and 2 weeks after operation. Free portal pressure (FPP) was continuously detected by a transducer during the operations. Compared to the preoperative data, a decreased flow in the portal vein (PVF) [(563.12 ± 206.42) mL/min vs (1080.63 ± 352.85) mL/min, P < 0.05], a decreased portal vein diameter (PVD) [(1.20 ± 0.11) cm vs (1.30 ± 0.16) cm, P < 0.01], a decreased FPP [(21.50 ± 2.67) mmHg vs (29.88 ± 2.30) mmHg, P < 0.01] and an increased flow in the superior mesenteric vein (SMVF) [(1105.45 ± 309.03) mL/min vs (569.13 ± 178.46) mL/min, P < 0.05] were found in the CP group after operation; a decreased PVD [(1.27 ± 0.16) cm vs (1.40 ± 0.23) cm, P < 0.05], a decreased PVF [(684.60 ± 165.73) mL/min vs (1175.64 ± 415.09) mL/min, P < 0.05], a decreased FPP [(24.40 ± 3.78) mmHg vs (28.80 ± 3.56) mmHg, P < 0.05] and an increased SMVF [(697.91 ± 121.83) mL/min vs (521.30 ± 115.82) mL/min, P < 0.05] were observed in the PCDV group. After operation, PVF in the CP group [(563.12 ± 206.42) mL/min vs (684.60 ± 165.73) mL/min, P > 0.05] had no significant decrease, while FPP [(21.50 ± 2.67) mmHg vs (24.40 ± 3.78) mmHg, P < 0.01] had a significant decrease as compared with that in the PCDV group. PVF and FPP could be decreased by both surgical procedures, but the effect of decreasing FPP was much better in the combined procedure than in PCDV alone. Further, there was no significant difference in PVF between the two groups. It is suggested that the combined surgical procedure could integrate the advantages of shunting with those of devascularization, as well as maintaining the normal anatomic structure of hepatic portal system, thus it should be one of the best choices for patients with portal hypertension when surgical interventions are considered.