肝动脉注射阿霉素温度敏感脂质体的靶行为和治疗应用的研究

Yatvin成功地用温度敏感脂质体进一步提高了脂质体在靶治疗中的中靶功能。本文还根据荷瘤肝脏的血流分布特性,将研制成功的阿霉素(adriamycin)温度敏感脂质体注入肝动脉,并与热疗相结合,对阿霉素温度敏感脂质体的体内行为和疗效进行研究,证明有提高抗肝癌疗效的可能。     

替加氟磁性长循环脂质体在大鼠体内的药代动力学和靶向性

目的研究替加氟磁性长循环脂质体经肝动脉给药的药代动力学和组织靶向性。方法采用高效液相色谱仪检测大鼠生物样品中替加氟的浓度。结果磁控并加热的替加氟磁性长循环脂质体组的肝内8h药时曲线下面积(AUC)是游离替加氟组的17.4倍,是替加氟长循环脂质体组的3.9倍;其肝外组织血浆和肾的AUC比游离替加氟组低。其肝靶向效率达到73.9%。结论替加氟磁性长循环脂质体经肝动脉给药能显著增加药物的肝脏靶向性,可能降低其肾毒性。     

脂质体作为抗肿瘤药物载体的应用研究

目前，应用脂质体作为抗肿瘤药物载体已成为趋势。脂质体可明显提高抗肿瘤药物的靶向性，延长药物的作用时间，降低药物毒性。作者对国内外普通脂质体和修饰脂质体（包括长循环脂质体、免疫脂质体、温度敏感脂质体和pH敏感脂质体）的相关文献进行了综述。结果表明，脂质体是抗肿瘤药物的理想载体，在肿瘤治疗中有着广阔的应用前景。     

新型脂质体的研究进展

［摘要］脂质体作为药物载体具有很多优点,但是其主动靶向性和稳定性较差,为了克服上述缺点,近年来国内外研制出许多新型脂质体。通过检索近20 a来国内外有关新型脂质体的相关文献,对新型脂质体如长循环脂质体、pH敏感脂质体、温度敏感脂质体、前体脂质体、磁性脂质体、免疫脂质体、膜融合脂质体、柔性脂质体等的研究及应用做一综述,并展望了新型脂质体的发展前景。     

反义核酸药物脂质体肝靶向性的研究

目的研究反义核酸药物脂质体给药系统的肝主动靶向性。方法采用薄膜分散法制备脂质体,以花青染料荧光标记脂质体,以荧光分光光度法定量分析;利用肝组织的体内冷冻切片和小鼠体内组织分布研究肝靶向性;检测大鼠肝非实质细胞与肝实质细胞的荧光强度(INPC和IPC)。结果主动靶向脂质体在肝脏中的荧光强度明显强于非主动靶向脂质体,相对摄取率(re)为5.64;非主动靶向脂质体的荧光值比(IPC/INPC)为1.16±0.89,主动靶向脂质体的IPC/INPC为8.24±1.37。结论主动靶向脂质体具有良好的肝实质细胞靶向性和肝靶向性。     

复方地塞米松霜的研制及临床应用

脂质体是由磷脂双分于层定向排列成的几毫微米至几微米的超细粒子.自从60年代问世后,70年代初便开始作为药物载体应用.最成功的便是1977年国外有人用脂质体包封抗肝利什曼原虫药物锑剂,结果药物在肝脏浓集200～700倍,治疗指数提高35～40倍.但随着脂质体应用、研究的深入,人们发现一般脂质体作为药物载体,其阿靶分布并不理想,贮存中稳定性也较差.近几年来为提高其靶向性和疗效,逐步开发、利用一些新型脂质体.现将温度敏感脂质体、pH敏感脂质体、免疫脂质体、聚合膜脂质体、前体脂质体等新型脂质体的研究概况介绍如下:     

阿霉素脂质体犬肝动脉栓塞后的体内分布与药代动力学研究

用阿霉素脂质体与碘油混合后对犬经导管肝动脉栓塞，用反相高效液相色谱法研究了阿霉素在犬体内的分布及药代动力学。结果显示，阿霉素脂质体－碘油栓塞组犬血浆阿霉素浓度显著低于阿霉素灌注组（ｐ〈０．０１）和阿霉素－碘油栓塞组（ｐ〈０．０１），而其血浆阿霉素消除半衰期和肝组织中阿霉素浓度与后两组相比则显著增加（ｐ〈０．０１及ｐ〈０．０５）。说明阿霉素脂质体与碘油混合肝动脉栓塞后可显著提高阿霉素对肝脏的靶向性，     

脂质体降低尼美舒利肝脏毒性的初步研究

目的考察尼美舒利脂质体对肝脏的影响作用。方法小鼠随机分为生理盐水对照组、尼美舒利溶液组及尼美舒利脂质体组,各组分别灌胃相应药物,21 d后处死并检测小鼠肝脏中ALT和AST活性,同时观察肝组织病理变化。结果 NIM溶液组小鼠与对照组小鼠相比,谷草转氨酶和谷丙转氨酶均明显升高,分别为(250.11±31.64),(234.01±29.59),P<0.01;脂质体组小鼠与溶液组相比,谷草转氨酶和谷丙转氨酶均降低,分别为(207.33±25.77),(198.44±24.70),P<0.05;小鼠肝脏病理切片显示脂质体组小鼠肝损伤程度明显低于溶液组小鼠。结论脂质体能显著降低尼美舒利的肝脏毒性。     

阿霉素脂质体犬肝动脉栓塞后的体内分布与药代动力学研究

用阿霉素脂质体与碘油混合后对大经导管肝动脉栓塞，用反相高效液相色谱法研究了阿霉素在犬体内的分布及药代动力学。结果显示，阿霉素脂质体－碘油栓塞组大血浆阿霉素浓度显著低于阿霉素灌注组（P＜0.01）和阿霉素－碘油栓塞组（P＜0．05），而其血浆阿霉素消除半衰期和肝组织中阿霉素浓度与后两组相比则显著增加（p＜0．01及p＜0．05）。说明阿霉素脂质体与碘油混合肝动脉栓塞后可显著提高阿霉素对肝脏的靶向性，延长阿霉素消除半衰期．     

脂质体作为药物载体研究进展

脂质体是由磷脂分散在水中形成的具有双分子层的直径仅有几十纳米至数微米的超微球状粒子.1965年Bangham等[1]发现脂质体,20世纪70年代Gregoriadis等[2]首先将脂质体作为药物载体应用.由于脂质体具有独特的作用特点,而受到越来越多的关注.靶向性是脂质体作为药物载体的主要目标之一,脂质体是治疗肝寄生虫病、利什曼病等网状内皮系统疾病理想的药物载体,在肿瘤治疗方面,利用脂质体的靶向作用,将脂质体作为抗肿瘤药物的有效载体而得到广泛应用.另外,药物被包埋在脂质体中缓慢释放,在血循环中脂质体药物要比游离药物有更长的滞留时间,因而延长了药物的作用时间,起到长效作用[3].药物由于有脂质体包封将提高被包封药物的稳定性,还能保护定向至某些需治疗的靶器官或组织中释放,使这些靶器官或组织药物浓度提高,提高了药物的疗效,以此同时,另外一些器官或组织药物浓度分布很少,避免药物对这些器官或组织的影响,从而降低了药物的毒性[4].近年来脂质体用作基因转移的有效载体[5,6],较病毒类载体有更大的优势,受到广泛的关注.     

Antimicrobial activity of liposome encapsulated cyclo(L-tyrosyl-L-prolyl)

Various studies have shown the potentially beneficial biological activities of cyclic dipeptides and in particular, cyclo(L-tyrosyl-L-prolyl) (cyclo(Tyr-Pro)) has shown fair antibacterial activity in vitro. This study aimed to determine if liposome encapsulation would have any significant effects on the antibacterial activity of this compound. The thin-film hydration method with extrusion was used to produce small unilamellar vesicles containing cyclo(Tyr-Pro) that were shown to have an average encapsulation of 9.4% with a mean particle size of 160.4 nm. Minimum inhibitory concentrations tested against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Bacillus subtillis were shown to be lower in liposome encapsulated cyclo(Tyr-Pro) than for the free form, while no antimicrobial activity was noted for either encapsulated nor non-encapsulated drug against the fungus Candida albicans or two methicillin-resistant strains of Staphylococcus aureus (MRSA). A positive control of liposome encapsulated amoxicillin was shown to be extremely active against both MRSA strains. The results confirm that liposome encapsulation has the potential to enhance activity as well as to overcome bacterial resistance towards current antibacterial agents.     

氟比洛芬脂质体的制备及其理化特性

目的:制备氟比洛芬乙醇脂质体并对其理化特性进行评价。方法:采用注入法工艺制备氟比洛芬乙醇脂质体,正交设计法筛 选处方;用粒度分析仪测定粒径大小与分布;用HPLC法测定乙醇脂质体中氟比洛芬的含量及其包封率。结果:制备的脂质体粒径分 布集中,平均粒径为153nm,最大粒径1.3μm,300nm以下占78.1%;包封率为36.28%,25℃条件下贮存3个月,粒径分布无显著变 化,渗漏率小于5%,表明本品稳定性良好。结论:注入法制备乙醇脂质体简便可行,质量控制方法简便、快速、准确、重现性好。     

Reconsideration of drug release from temperature-sensitive liposomes

The liposomal phase transition temperature was monitored in unstirred suspensions using a differential scanning calorimeter. The main and pre-transition temperatures under conditions of stirring were measured by the change in 90 degrees light scattering using a fluorescence spectrophotometer. Both methods show the same main transition temperature either with or without stirring. Temperature sensitive liposomes were made of DPPC (dipalmitoylphosphatidylcholine), DMPC (dimylisitoylphosphatidylcholine) or DSPC (distearoylphosphatidylcholine). The calcein release profile from the liposomes depends on the stirring time of the liposome suspension at the main transition temperature. For 1 h incubation, the leakage profile with and without stirring is similar. It had been hypothesized that temperature sensitive liposomes released drug at the main-transition temperature. However, calcein leakage from liposomes is observed also at the pre-transition temperature. Thus, a liposomal encapsulated drug will likely leak from DPPC liposomes at body temperature (37 degrees C), even if the liposomes were designed to have a higher main transition temperature.     

Enhanced transdermal delivery and optimization of nano-liposome preparation using hydrophilic drug

The aim of this study is the appropriate manufacture of nano-liposome and evaluation of transdermal drug delivery after drug was loaded in liposome for topical site especially nose. To make small, stable, uniform and highly encapsulated nano-liposome, many factors including solvent, stabilizer, pH balance, homogenization speed, sonication time and filtration are critical. Especially, stearate series surfactants have positive effects on liposome size and long-term stability. In this experiment, unsaturated lecithin and Pseudoephedrine HCl (PSE) were selected for the surfactant and model drug, respectively. The unsaturated lecithin, one of the surfactants used to make the liposome, has excellent skin affinity and penetration. Tween 20 and Tween 80, support emulsifying agents, propylene glycol, a lecithin solvent?and triethanolamine as stabilizer were also used as materials for liposome. Nano-liposome was made with a high shear homogenizer and pulverized by ultrasonicator to reduce the size and increase uniformity. After that, a transdermal experiment was conducted with Franz-cells on hairless mouse skin and PSE was determined by HPLC. Based on the results of the experiments, when the appropriate concentrations of support emulsifying agent and stabilizer were added, the average size of the liposome was about 300?nm and the encapsulation rate was close up to 40%. Moreover, with faster mixing speed and longer sonication time, more uniform and smaller particles tended to be manufactured. In the skin permeation test, PSE entrapped in liposome had 20 times higher permeability than PSE raw material.     

苯丁酸氮芥脂质体的制备及处方因素考察

目的 制备苯丁酸氮芥脂质体并优化其处方。方法 薄膜超声分散法制备苯丁酸氮芥脂质体,采用微柱离心-HPLC法测定其包封率,以包封率为考察指标,研究膜材比、药脂比、水相介质pH值以及磷脂浓度等因素对脂质体包封率的影响;通过正交试验对处方进行优化,并进行质量评价。结果 苯丁酸氮芥脂质体优化后的制备处方为胆固醇与磷脂质量比1∶3、药脂比1∶10、水相介质pH值为7.4、磷脂浓度为0.3%。按该处方制得的苯丁酸氮芥脂质体包封率>87%,平均粒径为84.71 nm,PDI为0.167。结论 优选处方稳定可行,制备的苯丁酸氮芥脂质体包封率高、粒径小且均匀。     

青蒿素脂质体的制备及质量评价

目的通过对青蒿素脂质体的处方和制备工艺研究,研制高包封率和稳定的脂质体。方法采用乙醇注入法制备脂质体,以正交实验优化处方。测定了脂质体中药物的包封率;并初步考察了脂质体的稳定性。结果优化处方与工艺所得脂质体形态均匀,包封率〉85％,载药量达27．22％,粒径约为90nm,Zeta电位约为一68．4mV,具有良好的稳定性。结论乙醇注入法制备脂质体工艺简便,包封率高,制备的脂质体稳定性好。     

紫杉醇脂质体的制备及其表征

目的制备紫杉醇脂质体并观察其表征。方法采用薄膜分散法制备紫杉醇脂质体,高效液相色谱法测定脂质体中紫杉醇的含量,透射电镜观察脂质体的形貌,激光粒度仪测量粒径和电位。结果制备的脂质体包封率约为（97．95±1．32）％,呈圆形或类圆形,平均粒径在54．6nm左右,电位-40．9mV,体外释放曲线符合Higuchi方程。结论薄膜分散法能制备出粒径小、包封率高稳定性较好的紫衫醇脂质体。     

Encapsulation of drugs and excipients in liposomes — measurements with drug-specific electrodes

In this study, the degree of encapsulation of benzalkonium chloride in liposomes was quantitatively measured using a potentiometric membrane electrode specific for benzalkonium chloride. The encapsulation of lidocaine hydrochloride was examined with another ion-selective electrode for comparison. Liposomes were prepared from a commercially available liposome concentrate (Phosal 75 SA). Photon correlation spectroscopy was used to detect the formation of liposomes in the size range of 200 nm.The measurements with the membrane electrode enabled the activity of the free drug to be quantitatively determined in the presence of liposomes. The investigations showed that, in the concentration range examined, up to 97% of the amphiphilic benzalkonium chloride is encapsulated in the liposomes. In the case of the hydrophilic lidocaine hydrochloride, virtually no liposomal encapsulation occurs.     

Effect of Neutral Liposomes on Corneal and Conjunctival Transport of Didanosine

The objective of this study is to determine the effect of various neutral liposomes on corneal and conjunctival permeability of didanosine (ddI), an antiviral drug. Multi-lamellar vesicles (MLVs), large unilamellar vesicles (LUVs), and sonicated multi-lamellar vesicles (SMLVs) encapsulating ddI (with trace quantities of 3HddI) were prepared using distearoyl phosphatidylcholine (DSPC), a neutral lipid. The liposomes contained 14C-cholesteryl oleate as a lipid tracer. Liposome formulations containing free and encapsulated drug (f + e) and those containing only encapsulated drug (e) of an equal quantity were compared with free drug in this study. The permeability studies were conducted in the mucosal to serosal direction across excised rabbit cornea and conjunctiva. The percent encapsulation of ddI in MLVs, LUVs, and SMLVs was 25.66 0.30, 26.56 0.57, and 19.41 0.30, respectively. The mean particle size of MLVs, LUVs, and SMLVs containingfree and encapsulated drug was 3058, 774, and 270 nm, respectively. With all liposome formulations tested, the percent uptake of lipid by tissues was higher compared to ddI uptake. While ddI permeated across the tissues, the lipid tracer did not permeate in detectable quantities.The SMLV(e) formulation was better than the SMLV(f + e) formulation with respect to initial flux and tissue uptake in both tissues and permeability across conjunctiva. In general, the permeability coefficient, initial flux, and tissue levels of ddI at the end of the transport study were lower in the presence of all liposome formulations compared to free drug. Thus, neutral liposomal encapsulation is not a suitable approach to enhance the corneal or conjunctival transport or uptake of ddI.     

头孢匹胺钠脂质体的制备及其理化性质研究

目的：制备头孢匹胺钠脂质体并进行质量评价。方法：采用逆相蒸发法制备头孢匹胺钠脂质体,在单因素考察基础上,以药脂比（A）、磷脂与胆固醇质量比（B）、有机相（乙醚）与水相体积比（C）、超声时间（D）为因素,以包封率为考察指标,按Lq（3‘）正交试验设计表优化最佳处方和工艺,并进行处方验证;考察脂质体的形态,测定其粒径、Zeta电位、包封率、栽药量和72h体外累积释放度并进行模型拟合。结果：正交试验设计优化的A为1：6、B为5：1、C为4：1、D为5min,验证试验证明处方合理;所得的脂质体为封闭的多层囊状或圆球体,大小均匀,平均粒径为（7．146±O．29）gm,Zeta电位为一11．75mV,包封率为（82．10±4．21）％,载药量为（愠42±O．67）％;72h体外累积释放度为76．84％,体外释药行为符合We~bull模型（r=0．9910）。结论：采用逆相蒸发法制备的头孢匹胺钠脂质体,包封率较高,体外释药有明显的缓释效果。