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。     

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。     

肺靶向卡铂泡囊的药代动力学和体内分布研究

目的：对肺靶向抗癌药卡铂泡囊和游离药卡铂的药代动力学、体内分布行为和肺靶向性进行比较研究。方法：采用原子吸收分光光度法测定静脉给药后,不同时刻小鼠血浆和各脏器组织中卡铂的浓度。结果：卡铂泡囊和游离卡铂药物动力学模型均为三室模型。具有明显的肺靶向性。结论：卡铂泡囊在体内具有良好的肺靶向性。卡铂泡囊对提高药物的疗效。降低药物毒副作用等方面有重大意义。     

左炔诺孕酮-聚3-羟基丁酸酯缓释微球的研究

目的：优化制备工艺,用可生物降解的成球材料制备缓释并有优良抗生育效果的左炔诺孕酮-聚3-羟基丁酸酯微球。方法：以均匀设计优化微球的液中干燥法制备工艺,用DTA确证含药微球的形成,对微球的外观、粒径、载药量、体外释药、稳定性及小鼠体内抗生育等进行了研究。结果：微球平均粒径为64 μm,(28.7～85.8) μm的微球占总数90％以上,微球中氯仿残留量低于0.001％,体外释药符合Higuchi方程,释药T_1/2比原药延长约1.8倍,4,25及40℃(RH 75%)放置3个月稳定。对小鼠具有抗生育效果。结论：微球的制备工艺满意,与原药相比,微球对小鼠有明显的缓释、延长抗生育时间和降低毒性的作用。     

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。     

N-(2-羟丙基)甲基丙烯酰胺聚合物-5-氟尿嘧啶接合物的体外释药规律、体内分布及抗肿瘤活性研究

考察本实验室合成的N-(2-羟丙基)甲基丙烯酰胺［N-(2-hydroxypropyl) methacrylamide，HPMA］聚合物-5-氟尿嘧啶(5-flurouracil，5-FU)接合物(P-FU)的体外释药、体内分布及抗肿瘤活性。以小鼠血浆为介质，考察P-FU中5-FU的释放规律；以小鼠H22肝癌实体瘤模型(皮下型)为肿瘤模型，考察接合物在荷瘤小鼠体内的分布情况、药代动力学规律及抑瘤活性。结果表明，37 ℃时P-FU在小鼠血浆中具有一定的稳定性，半衰期(t_1/2)为32.4 h。与5-FU相比，P-FU在荷瘤小鼠体内的循环时间明显延长(血浆中t_1/2为原药的166倍)，在肿瘤中的沉积量(AUC为5-FU的3.3倍)及滞留时间(t_1/2为5-FU的2.3倍)均有明显增加。体内药效学研究表明，P-FU组对荷瘤小鼠的肿瘤生长抑制率(69.09%)显著高于5-FU组(56.49%，P<0.05)，瘤块组织病理学观察结果也显示P-FU组小鼠肿瘤组织中细胞凋亡程度大于5-FU组。HPMA聚合物可被用于为5-FU构建一种新型实体瘤高分子给药系统。     

肝动脉栓塞用顺铂白蛋白微球的研究

按正交设计筛选乳化热固化法制备顺铂白蛋白微球的最佳工艺,并对影响微球粒径大小和体外释药速率的诸多因素进行了研究。该微球粒径范围为50.8～256μm。平均粒径为148.46μm,药物含量为51.16%(W/W)。兔肝动脉栓塞后,与对照组相比铂的分布半衰期延长336%,消除半衰期延长123%,体内最高血浓仅为对照组的30%。肝组织顺铂量显著增加(P<0.01),肾组织药物量明显降低(P<0.05),体内外相关性研究表明顺铂白蛋白微球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)。     

肺靶向顺铂隐形泡囊的研制及其体外生物学性质

目的 研制具有肺部靶向作用的隐形泡囊并进行体外抗癌细胞的实验评价.方法 将亲水聚合物与胆固醇相连,考察含不同种类亲水链及含不同密度亲水链的隐形泡囊的包封率、稳定性和巨噬细胞吞噬作用,以最佳泡囊处方进行癌细胞生长抑制实验.结果 用PluronieF68合成的胆固醇结合物所制隐形泡囊的包封率和固有水化层厚度较高,粒径合适;当胆固醇/Chol-PluronicF68的重鼍比为1:2.52时,泡囊的包封率、稳定性和体外规避巨噬细胞摄取等均较好,并具有和顺铂相似的抑制癌细胞生长的作用,粒径平均为8.432±O.043μm,有71.30%以上在被动肺靶向要求的7-25μm范围内,抑制癌细胞生长的结果与原料药顺铂相同.结论 隐形泡囊制备简单,具有一定的隐形效果,能保持原药的抗癌活性,粒径范围符合被动肺靶向的要求.     

氟尿嘧啶隐形泡囊的制备及其体外性质的研究

目的制备氟尿嘧啶隐形泡囊并考察其理化性质和体外细胞毒性。方法用自制Plu-Chol,以改良注入法制备氟尿嘧啶隐形泡囊,考察泡囊的形态、粒径、电位、包封率和体外释放特性,通过MTT比色法比较泡囊与原药对Hela细胞的作用效应。结果氟尿嘧啶隐形泡囊在电镜下的外观为球形,平均粒径为904.87±0.45 nm,Zeta电位为-66.75 mV,包封率为30.93%±1.71%;体外释放符合Weibull distribution模型,且具有明显的缓释性(氟尿嘧啶隐形泡囊释药t1/2为游离氟尿嘧啶的3.75倍);细胞毒性试验表明泡囊对Hela细胞的杀伤作用明显优于原药(IC50降低了83.95%,P<0.01)。结论所制氟尿嘧啶隐形泡囊的操作简单,对肿瘤细胞的杀伤力显著强于原药。     

喜树碱固体脂质纳米粒的研究

目的：为提高喜树碱的疗效,降低毒副作用,制备了该药的固体脂质纳米粒。方法：采用热融分散技术制备了喜树碱固体脂质纳米粒,反相高效液相色谱—荧光检测法测定了体外和体内喜树碱的浓度。结果：纳米粒平均粒径为d_ln=196.8 nm,载药量为4.8%,包封率为99.5%,表面带有负电荷,在pH 7.4的磷酸缓冲溶液中体外释药符合Weibull方程。以喜树碱溶液为对照组,Poloxamer 188包衣的喜树碱固体脂质纳米粒静脉注射后药物在血液中的滞留时间显著延长,小鼠脑、心、肝、脾、血浆、肾和肺中的分布显著增加。结论：喜树碱固体脂质纳米粒在体内具有良好的靶向性,对提高药物的疗效,降低药物毒副作用等方面有重大意义。     

Cancer chemotherapy by liposomal 6-[12-(dimethylamino)ethyl]aminol-3-hydroxy-7H-indeno[2,1-clquinolin-7-one dihydrochloride (TAS-103), a novel anti-cancer agent

A novel anti-tumor agent, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103), effectively inhibits both topoisomerase I and II activities. To enhance anti-tumor efficacy and to reduce the side effects of the agent, liposomalization of TAS-103 was performed. TAS-103 was effectively entrapped in liposomes by a remote-loading method, and was stable at 4 degrees C and in the presence of 50% serum. To evaluate the anti-tumor efficacy of liposomal TAS-103, the growth inhibition against Lewis lung carcinoma cells in vitro and the therapeutic efficacy against solid tumor-bearing mice in vivo were examined. Liposomal TAS-103 showed strong cytotoxic effect against Lewis lung carcinoma cells in a dose dependent manner and effectively suppressed solid tumor growth accompanying longer survival time of tumor-bearing mice in comparison with the mice treated with free TAS-103. These results suggest that liposomal TAS-103 is useful for cancer therapy.     

Studies on a high encapsulation of colchicine by a niosome system

To prepare niosomes which have high encapsulation capacity for soluble drugs, starting from Span 60 and cholesterol, an improved method, evaporation-sonication method, was proposed. The corresponding niosomes show a good stability at least 40 days. Colchicine was chosen as a model drug for examining the capsulation capacity of these niosomes. To obtain the highest encapsulation efficiency, several factors including the structure of surfactant, level of lipid, content of drug and cholesterol were investigated and optimized. The inner cause was also discussed. The results indicate that the Span 60 is the most ideal surfactant among four kinds of Span. Furthermore, the release studies of colchicine and 5-fluorouracil (5-FU) in vitro from niosomes exhibited a prolonged release profile as studied over a period of 24 h. The results demonstrated that niosomes prepared in this way not only have high encapsulation capacity but also is expected that side effects of drugs may be reduced. It still suggests that this method may be used extensively in the field of encapsulation soluble drugs.     

Nonphospholipid vesicles of Carboplatin for lung targeting

Carboplatin (CPt) was incorporated into nonphospholipid vesicles (NPLV) by the method of membrane dispersion and its content determined spectrophotometrically. The particle size was between 2.0-10.0 microm with a mean value of 3.26 microm and a span of 0.55; and the drug content was 3.965 mg/ml. Dynamic dialysis was used for in vitro release of CPt and the results indicated that the drug release t(1/2) was increased eight times, compared with the original drug. These parameters had little change after lyophilization. When tested with mice, the body distribution parameters showed obviously lung targeting characteristics. The S-180 lung neoplasm models were established by intravenous cancer cells in mice and the number of pulmonary nodules examined for evaluation of the therapeutic efficacy. Antitumor effect was increased and differed significantly (p <.05) compared with the original drug of the same dose.     

芹菜素囊泡的制备及理化性质考察

目的筛选合适的非离子表面活性剂,制备芹菜素囊泡,并考察其体外理化性质和冻干工艺。方法采用Tween80和Myrij52为成囊材料,建立了乙醇注入法制备芹菜素囊泡的制备工艺;采用微柱离心法测定芹菜素囊泡的包封率,并考察不同处方因素对包封率的影响;经正交设计得到最优处方;对囊泡的粒径、外观、稳定性等理化性质及体外释放行为进行研究,分别以外观、粒径和渗漏率为指标对冻干工艺进行初步考察。结果乙醇注入法获得囊泡包封率为(69.48±2.5)%,平均粒径为(148±5.03)nm,透射电镜下观察显示呈类球形,4℃下密封保存3个月包封率为(54.25±3.7)%、渗漏率为21.9%,在pH值为7.4的磷酸盐缓冲液中体外释药行为符合一级动力学方程。以葡萄糖和甘露醇(质量比1∶1)为冻干保护剂,预冻时间为3 h,干燥时间为30 h。结论该制剂制备方法简单,制备的囊泡包封率较高,粒径较小,体外具有明显的缓释作用,冻干制剂外观饱满,粒径和包封率变化较小,可以明显提高囊泡的体外稳定性。     

Targeted delivery of levofloxacin-liposomes for the treatment of pulmonary inflammation

The present study systematically studied the intravenous injectable formulation of liposomes loaded with levofloxacin, an amphipathic antibiotic. The aim of the present study was to design passive targeting liposomes, which might improve the antibacterial activity by accumulating in lung and reduce side effects such as neurotoxicity and hematotoxicity associated with direct injection of the drug. Levofloxacin-loaded liposomes were prepared by the ammonium sulfate gradients method. The formulated liposomes were found to be relatively uniform in size (7.424 ± 0.689 μm) with a positive zeta potential (+13.11 ± 1.08 mV). The entrapment efficiency of levofloxacin-loaded liposomes ranged from 82.19% to 86.23%. The administered liposomes were composed of soybean phosphatides, cholesterol, levofloxacin, and sulfate which existed in inner liposomes. In vitro drug release was monitored for up to 3 days, and the release behavior was in accordance with the Weibull equation. The levofloxacin-loaded liposomes exhibited a longer elimination half-life (t_1/2β) in vivo compared with the levofloxacin solution after intravenous injection to New Zealand rabbits. The encapsulation of levofloxacin in liposomes also changed its biodistribution in mice after intravenous injection in caudal vein. Liposomal levofloxacin performed significant lung targeting efficiency with area under the concentration–time curve, targeting efficacy (Te), and The intake rate (Re) of lung, all showing obvious increase. In addition, liposomal formulations presented accumulative activity in spleen and liver. Conversely, the biodistribution of liposomal formulation in non-RES sites, such as kidney, brain, heart, and plasma, decreased with descending peak concentration ration (Ce) compared to levofloxacin injection, which potentially resulted in the reduction of the side effects of free drug. These results indicated that the levofloxacin-loaded liposomes were promising passive targeting to lung for pulmonary infection treatment.     

Preparation and evaluation of reverse-phase evaporation and multilamellar niosomes as ophthalmic carriers of acetazolamide

Niosomes have been reported as a possible approach to improve the low corneal penetration and bioavailability characteristics shown by conventional ophthalmic vehicles. Niosomes formed from Span 40 or Span 60 and cholesterol in the molar ratios of 7:4, 7:6 and 7:7 were prepared using reverse-phase evaporation and thin film hydration methods. The prepared systems were characterized for entrapment efficiency, size, shape and in vitro drug release. Stability studies were carried out to investigate the leaching of drug from niosomes during storage. The intraocular pressure (IOP) lowering activity of acetazolamide niosomal formulations in rabbits was measured using Shi?tz tonometer. Histological examination for the corneal tissues of rabbits receiving niosomal formulations was carried out for assessment of the ocular irritancy of niosomes. The results showed that the type of surfactant, cholesterol content and the method of preparation altered the entrapment efficiency and drug release rate from niosomes. Higher entrapment efficiency was obtained with multilamellar niosomes prepared from Span 60 and cholesterol in a 7:6 molar ratio. Niosomal formulations have shown a fairly high retention of acetazolamide inside the vesicles (approximately 75%) at a refrigerated temperature up to a period of 3 months. Each of the tested acetazolamide niosomes prepared by either method produced a significant decrease in IOP compared to the solution of free drug and plain niosomes. Multilamellar acetazolamide niosomes formulated with Span 60 and cholesterol in a 7:4 molar ratio were found to be the most effective and showed prolonged decrease in IOP. Histological examination of corneal tissues after instillation of niosomal formulation for 40 days showed slight irritation in the substantia propria of the eye which is reversible and no major changes in tissues were observed.