肝靶向氟尿嘧啶类脂纳米粒的研究

目的　为了提高氟尿嘧啶(5-Fu)的疗效,降低其毒副作用,制备具肝靶向的5-Fu类脂纳米粒。方法　利用氟尿嘧啶与硬脂酰氯进行反应,制备了5-Fu前体药物N₁-硬脂酰-5-Fu,通过红外光谱及核磁共振谱对合成的目标化合物进行结构确认。同时研究了前体药物的性质及稳定性。采用物理凝聚法制备类脂纳米粒,并研究其形态、粒径及粒径分布、载药量、体外释药特征、动物体内分布与药代动力学参数等。结果　平均粒径d_av=240.19 nm,载药量为20.53%。体外释药速率符合一级动力学模型。与5-Fu水针剂比较,类脂纳米粒组在肝脏中药物含量平均增加了一倍以上。家兔体内主要药动学参数为：V_c=0.04336 L.kg^-1,T_1/2β=1.2834 h,CL=0.1632 L.h^-1。结论　利用前体药物可提高药物的脂溶性,首次以物理凝聚法制备类脂纳米粒,小鼠体内分布研究表明类脂纳米粒有明显的肝靶向,有一定的优越性和参考价值。     

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。     

肝靶向万乃洛韦毫微粒的研究

为提高核苷类药物对乙型肝炎的疗效并降低其毒性,用乳化聚合法制备了万乃洛韦聚氰基丙烯酸正丁酯毫微粒,对其形态、大小及其分布、体外释药特性、载药量、初步稳定性、动物体内的分布和体外肝细胞的摄取情况进行了研究。结果表明,该毫微粒粒径d_av=104.77±11.78nm;载药量11.20%;包封率84.85%;体外释药符合双相动力学规律;对肝细胞具有通透性;静注后15min有74.49%集中在肝脏。提示,万乃洛韦毫微粒对于提高万乃洛韦对病毒性乙型肝炎的治疗效果和降低其对肾脏的毒性有意义。     

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。     

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。     

载羟基喜树碱聚乳酸微球的制备与体外释药研究

目的:研究载羟基喜树碱的聚乳酸微球的制备方法并考察其体外释药性质。方法:以PLA为成膜材料,采用改良乳化-溶剂挥发法,制备载羟基喜树碱的聚乳酸微球并优化制备工艺;对载药微球进行表征;超声介导下进行载药微球的体外释药试验。结果:微球粒径在1～7μm,大小均一;羟基喜树碱浓度在10mg.mL-1下,载药微球包封率为62.2%,载药量为1.69%;药物体外释药符合Higuchi方程。结论:采用乳化-溶剂挥发法,以PLA为成膜材料可制得具有较高包封率的羟基喜树碱微球,有望实现降低羟基喜树碱给药量、减少不良反应,提高靶向性的目标。     

盐酸阿霉素聚乳酸纳米粒的制备及大鼠体内药动学研究

目的 优化盐酸阿霉素聚乳酸纳米粒（DOX-PLA-NPs）的制备工艺,并对其理化性质、体外释放及大鼠体内药动学进行研究。方法 采用改良的复乳-溶剂挥发法制备DOX-PLA-NPs,正交设计优化其处方工艺,对其纳米粒形态、粒径、Zeta电位、包封率与载药量进行测定。以DOX原药为对照组,考察DOX-PLA-NPs的体外释药特性及大鼠尾静脉给药后的体内药动学参数。结果 DOX-PLA-NPs外观圆整,平均粒径为（125.67±3.80） nm、Zeta电位为（-35.97±1.58） mV、包封率和载药量分别为（81.23±1.46）%,（10.29±0.63）%。体外释放结果显示,DOX经纳米粒包裹后,具明显的缓释作用。DOX原药和纳米粒的体内药动学过程均符合开放式二室模型,t_1/2β分别为（1.15±0.175） h、（6.43±2.12） h,CL分别为（174.76±47.22） h·L^-1、（30.68±11.86） h·L^-1,AUC_0→t分别为（6.01±1.61）μg·h·L^-1、（36.04±13.72）μg·h·L^-1。结论 制备的盐酸阿霉素聚乳酸纳米粒粒径较小、包封率较高,具明显的缓释作用,并能提高药物的生物利用度。     

莲子心总碱缓释片体外释放度试验

目的 考察莲子心总碱缓释片体外释放度。方法 模拟人体体内环境,用紫外分光光度法测定莲子心总碱的体外释放度。结果 莲子心总碱释药方程:log(100-R_n)=2.112-0.128t(F=219.310,P<0.001),r=-0.982(P<0.001),T₅₀=3.233h,T_d=4.274h,K_r=0.128h^-1。结论 莲子心总碱缓释片体外释药符合一级释药模式,具有缓释特点。     

米托蒽醌聚氰基丙烯酸正丁酯毫微粒的研究

用乳化聚合法制备了米托蒽醌聚氰基丙烯酸正丁酯毫微粒,并对其表面荷电特性、形态、大小及其分布、体外释药性质、载药量、初步稳定性和在动物体内的分布进行了研究。结果表明,粒径d_av=55.23nm,载药量为46.77%,包封率为84.89%,表面带负电荷。体外释药符合双相动力学规律。其胶体溶液能经受煮沸30min灭菌。经氚标记液闪计数技术测定证实其iv后主要集中于肝脏,并有一定的肝肿瘤和肝细胞的靶向性。提示其对于提高米托蒽醌抗肝癌的效果和降低其全身毒副作用有重要意义。     

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。     

Sustained-release hydroxycamptothecin polybutylcyanoacrylate nanoparticles as a liver targeting drug delivery system

Sustained release hydroxycamptothecin polybutylcyanoacrylate nanoparticles (HCPT-PBCA-NP) associated with polybutylpyrolidone (PVP) for liver targeting were prepared by the adsorption-entrapping method. The morphology, sizes, drug loading efficiencies, release characteristics in vitro, distribution and pharmacokinetic parameters in vivo of the HCPT-PBCA-NP associated with PVP were studied. The median diameter of the particles was 81 nm and the drug loading was 1.2%. The release characteristics in vitro were in accordance with the Higuchi equation: Q = 0.0615 + 0.0940 mean square root t. 64.5% of the HCPT were concentrated in the liver at 15 min after i.v. administration of HCPT-PBCA-NP associated with PVP. The plasma drug concentration-time curve of the HCPT in rabbits was fitted to a two-compartment open model. The Vc, T 1/2 and CL were 3.5L; 147h; 0.18L x h(-1), respectively. The method of preparation presented in this paper seems to bean alternative for the preparation of PBCA-NP of poorly soluble drugs both in water and in lipid.     

Preparation, characterization and biodistribution of the lactone form of 10-hydroxycamptothecin (HCPT)-loaded bovine serum albumin (BSA) nanoparticles

10-Hydroxycamptothecin (HCPT) is insoluble in both water and physiological acceptable organic solvents and tends to change into its carboxylate form, which shows minimal anticancer activity and several unpredictable side effects. The goal of this study is to exploit an appropriate delivery system for HCPT to improve the stability of its lactone form. Bovine serum albumin (BSA) nanoparticles entrapping HCPT were prepared by reformative emulsion-heat stabilization technique. During this process, HCPT transformed from lactone to carboxylate and finally back to lactone form successfully. A simple reversed-phased HPLC method was developed to analyze both lactone and carboxylate forms of HCPT synchronously. Mean particle size and the ratio of lactone and carboxylate forms of HCPT were evaluated to investigate the effects of the formulations and preparation conditions. It was indicated the percentage of lactone form of HCPT in resultant BSA nanoparticles could be improved over 95% through adjusting the concentration of NaOH solution and the stirring time after high-speed emulsification. This drug delivery system was also characterized by dynamic light scattering (DLS) and light microscopy. The investigations on drug loading, in vitro release and body distribution in rats after intravenous (i.v.) administration were also carried out. It was found that the obtained nanoparticles showed spherical shape with the mean particle size of around 600 nm, and drug loading content, encapsulation efficiency and yield achieved 2.21%, 57.5% and 90.5% with the optimal preparation conditions, respectively. The in vitro release behavior exhibited a sustaining release manner and was affected by the trypsin in medium. HCPT could release more than 90% within 20 h in the medium of pH 7.4 PBS containing 750 U/ml trypsin, but only 25% within 40 h in the pure pH 7.4 PBS. The results of body distribution study in rats showed the liver targeting potential of HCPT–BSA nanoparticles that 59.6%, 52.9% and 55.3% of the examined amount of lactone HCPT accumulated in livers at 1, 4 and 24 h after injection, respectively. These results suggest that the HCPT–BSA nanoparticles seem to be a stable delivery system for poorly soluble HCPT or its derivatives.     

羟基喜树碱微球的制备及其小鼠体内分布研究

目的:制备肺靶向性羟基喜树碱(HCPT)微球,评价其体外释药特性及其在小鼠体内的肺靶向性。方法:以聚乳酸为主要辅料,采用溶剂挥发法制备微球,考察其粒径、包封率、载药量,比较微球及原料药的体外释药性;取12只小鼠分别尾静脉注射HCPT微球及原料药,30min后分别测定血浆及各组织的药物浓度并计算相对分布率。结果:所制微球粒径在7～30μm者达81.6%,平均粒径为(14.2±3.1)μm,包封率为72.36%,载药量为(40.6±3.6)%,微球及原料药体外释药参数T50分别为85、18min。微球给药组在肺中的药物浓度最高(32.2±2.48)μg.mL-1,相对分布率58.1%;原料药给药组在血浆中的药物浓度最高(13.52±2.58)μg.mL-1,相对分布率25.24%。结论:所制HCPT微球具有明显的缓释性及肺靶向性。     

Preparation, pharmacokinetics and tissue distribution of micelles made of reverse thermo-responsive polymers

New reverse thermo-responsive polymers, poly(ethylene oxide)–poly(propylene oxide) multiblock copolymers (poly(ether-carbonate)s) were synthesized. The micelles made of new reverse thermo-responsive polymers were also prepared loaded with the poorly soluble anticancer drug, hydroxycamptothecin (HCPT). The structure characterization of poly(ether-carbonate)s was determined by ¹H NMR and FT-IR analysis. The critical micelle concentration (CMC), critical micelle temperature (CMT), size distribution and drug release in vitro were determined. The pharmacokinetics and tissue distribution in vivo for novel copolymer micelles were studied. The experimental results showed that the micelles was spherical in appearance and dispersed well. The process of HCPT release from micelles in vitro was composed of two steps, abrupt release and sustained release. After i.v. administration (2 h), the drug concentration of poly(ether-carbonate) micelles group in liver in mice was 3.46 μg/g, while that of HCPT injection group was 0.401 μg/g. Compared with HCPT injection, the elimination half-life of poly(ether-carbonate) micelles group was prolonged remarkably from 1.3 to 12.5 h. The poly(ether-carbonate) micelles showed a combination of liver targeting and sustained drug release in experiments on animals.     

星点设计-效应面法优化羟基喜树碱/mPEG-S-S-C18纳米粒的制备工艺

目的 制备载羟基喜树碱（hydroxycamptothecin,HCPT）还原响应mPEG-S-S-C18纳米粒,采用星点设计-效应面法筛选优化制备工艺。方法 采用乳化-溶剂挥发法制备HCPT/mPEG-S-S-C18纳米粒,应用单因素法考察投药量、水相/油相体积比、超声功率以及超声时间对载药纳米粒包封率和载药量的影响。在此基础上,以包封率和载药量作为评价指标,采用Design-Expert V8.0.6软件进行星点设计,优化载药纳米粒的制备工艺。结果 优化获得的HCPT/mPEG-S-S-C18纳米粒制备工艺投药量为1.0 mg,水相/油相体积比为4.56∶1,超声功率为562.5 W。该工艺制备的载药纳米粒包封率为（58.14±1.04）%,载药量为（3.46±0.22）%,平均粒径为（322.9±9.52） nm,多分散性指数为0.195±0.05,Zeta电位为（-17.5±2.11） mV。结论 乳化-溶剂挥发法适用于制备HCPT/mPEG-S-S-C18纳米粒,星点设计-效应面法可优化获得载药纳米粒的最佳制备工艺,所得的载药纳米粒包封率和载药量较高,所建立的数学模型预测性良好。     

眼镜蛇毒细胞毒素缓释微球制备及体外性质研究

目的研究眼镜蛇毒细胞毒素(Cytotoxin,CTX)聚乳酸/羟基乙酸缓释微球的制备方法,考察其一般性质、体外释药特性及生物学活性。方法采用色谱方法纯化眼镜蛇CTX,MTT方法检测细胞毒活性,复乳-溶剂挥发法制备载药微球,考察微球表面形态、粒径、包封率、载药率、体外释药行为及释放眼镜蛇CTX细胞毒活性。结果纯化眼镜蛇CTX具有明显的细胞毒作用,对肝癌HepG2细胞12,24 h的IC50分别为1.43,1.12μg/mL,对L02肝细胞12,24 h的IC50分别为1.37,1.01μg/mL。微球表面光滑圆整,粒径2.1~7.8μm,包封率和载药率分别为(74.10±9.92)%和(0.72±0.09)%,30 d药物累积释放84.3%,释放眼镜蛇CTX保持较好的生物学活性。结论采用复乳-溶剂挥发法可制备具有较高包封率,良好缓释效果,保持完整生物学活性的眼镜蛇CTX缓释微球。     

PLA nanoparticles loaded with an active lactone form of hydroxycamptothecin: Development,optimization, and in vitro–in vivo evaluation in mice bearing H22 solid tumor

Hydroxycamptothecin (HCPT)‐loaded PLA nanoparticles were prepared by a one‐step method using the direct dialysis technique, and were examined for particle characteristics, in vitro drug release, and cytotoxicity, as well as antitumor efficiency. Three main influential factors based on the results of a single‐factor test, i.e., PLA concentration, ratio of HCPT to PLA (wt/wt), and dialysis bags with different molecule weight cutoffs, were evaluated using an orthogonal design, giving nanoparticles an average diameter of ～226.8 nm with smooth surface, modest drug entrapment efficiency (65.15%), and fine drug‐loading content (5.16%, w/w). HCPT was in a crystalline state within the particles. In vitro drug release studies exhibited a slow and prolonged release profile over a period of 30 days. The cytotoxicity test on BEL‐7402 cells indicated that the HCPT‐PLA nanoparticles were more cytotoxic than commercially available HCPT injection. When the antitumor effect was examined by i.v. administration to mice bearing H22 solid tumor, HCPT‐PLA nanoparticles showed a significant suppression of tumor growth without loss of body weight. These results suggest that HCPT‐PLA nanoparticles prepared by the dialysis technique present desirable characteristics for sustained drug delivery and are potentially useful to enhance the antitumor efficacy of HCPT. Drug Dev Res 72: 337–345, 2011. © 2011 Wiley‐Liss, Inc.     

Sustained release of cisplatin from multivesicular liposomes: potentiation of antitumor efficacy against S180 murine carcinoma

Cisplatin was encapsulated into multivesicular liposomes (MVLs) and the entrapment efficiency, size distribution, and in vitro drug release characteristics of the cisplatin-MVLs were studied. Pharmacokinetics, tissue distribution, and therapeutic efficacy of cisplatin-MVLs were compared against injection of cisplatin solution into mice inoculated with the murine carcinoma 180 (S180) tumor. The results showed that the cisplatin-MVLs were capable of high drug loading (0.148:1 mg cisplatin/mg lipid) and high encapsulation efficiency (>80%). The mean diameter of cisplatin-MVLs was 17 microm. In vitro studies of cisplatin-MVLs in saline solution showed that they sustained release of encapsulated drug for >7 days. Cisplatin-MVLs showed higher drug accumulation in the liver, spleen, and tumor regions than cisplatin solution, as well as higher plasma concentrations and a longer circulation time. The therapeutic efficacy of the cisplatin-MVL preparation against S180 tumor-bearing mice is significantly higher than that of cisplatin solution.     

Studies on the poly(lactic-co-glycolic) acid microspheres of cisplatin for lung-targeting

Lung-targeting cisplatin-loaded poly(lactic-co-glycolic) acid microspheres (CDDP-PLGA-MS) were prepared by a solvent evaporation method. The uniform design was used to optimize the technology of preparation, the appearance and size distribution were examined by scanning electron microscope, and the aspects such as in vitro release characteristics, stability, drug loading, loading efficiency, pharmacokinetics and tissue distribution in rabbit were studied. The experimental results showed that the microspheres were globular in appearance and dispersed well. The average particle size was 12.8 microm with 98% of the microspheres being in the range of 5-30 microm. The drug loading and loading efficiency were 17.68 and 53.2%, respectively. The in vitro release behavior could be expressed by the following equation: 1-Q=0.424e(-0.360t)+0.474e(-0.001t). After i.v. administration (15 min), the drug concentration of microspheres group in lung in rabbits was 212 microg/g, while that of controlled group was 1.37 microg/g. CDDP-PLGA-MS showed a combination of lung-targeting and sustained drug release in experiments on rabbits.