曲马多缓释多囊泡脂质体的制备和释放度影响因素研究

目的 制备包封率高和缓释作用好的PGE修饰的曲马多缓释缓释多囊泡脂质体,并与逆相蒸发法制备的曲马多普通脂质体比较其体外释药性能.方法 用复乳法制备曲马多缓释多囊泡脂质体;非火焰原子吸收分光光度法测定曲马多含量;磷脂酶试剂法测定脂质体中磷脂的浓度;测定包封率和体外释药性.结果 曲马多缓释多囊泡脂质体平均粒径为31.3μm,跨距为1.0;曲马多包封率可高达80%以上;曲马多缓释缓释多囊泡脂质体的体外释药符合一级释药规律,释药时间为72h,比逆相蒸发法制备的曲马多普通脂质体延长16.95（由原来为释药时间37.7h延长8.4倍推出）倍;经差示热分析发现辅助膜稳定剂有明显的膜稳定作用.结论 曲马多缓释多囊泡脂质体包封率高,并具有良好的缓释作用.     

盐酸利多卡因多囊脂质体的制备和质量评价

目的:制备具有缓释特性的盐酸利多卡因多囊脂质体,考察其理化性质。方法:以卵磷脂和胆固醇为膜材,采用复乳法制备盐酸利多卡因多囊脂质体,用透射电镜观察其外观形态,用激光粒度分析仪测定粒径,检测包封率和体外释药特性。结果:盐酸利多卡因多囊脂质体的外观形态圆整、规则,粒径分布在300～700nm及1～6μm两区域,包封率为(27.10±0.66)%。多囊脂质体在pH 7.4的磷酸盐缓冲液中,24h的累积释药百分率为(92.7±3.6)%。结论:盐酸利多卡因多囊脂质体具有一定的缓释特性。     

柔红霉素长循环脂质体的药剂学性质及大鼠体内药代动力学研究

目的研究柔红霉素长循环脂质体的药剂学性质及大鼠体内药代动力学。方法考察柔红霉素长循环脂质体的形态和粒径分布、包封率和加速实验稳定性;建立脂质体中柔红霉素含量测定的可见分光光度法和HPLC方法;考察脂质体在Hepes缓冲液(pH 7.5)和大鼠血清中的体外释放行为。考察脂质体在大鼠体内的药代动力学行为。结果制备的柔红霉素长循环脂质体包封率高(>85%)、稳定性好,平均粒径为56.3 nm,体外释放慢;长循环脂质体的T_1/2α和AUC分别是注射剂的17.6和96倍。结论制备的长循环脂质体包封率较高,药剂学性质稳定,在大鼠体内的药代动力学参数优于注射剂,能达到长循环目的。     

月桂酸二乙醇酰胺修饰利福喷丁脂质体的制备、性质及肺部给药

目的制备表面活性剂修饰利福喷丁(RIF)脂质体，进行该脂质体水化性能、载药量、释药速度和肺部给药研究。方法采用薄膜超声法制备利福喷丁脂质体，比较月桂酸二乙醇酰胺(LDEA)，Tween 80和azone修饰利福喷丁脂质体的形态、包封率、释药速度和离体猪肺膜透过性，通过纤支镜进行肺部给药研究。结果RIF-LDEA脂质体粒径在15～50 nm，包封率为83.0%，表观透膜系数Kp为44.29；LD₅₀为675 mg·kg^-1。结论LDEA修饰使利福喷丁脂质体的载药量增加1倍、释药速度的可调性强及安全性好。经纤支镜介导灌注给药治疗肺内膜结核的效果显著。     

抗癌复方硫酸长春新碱脂质体的体外释药特性及小鼠体内的组织分布

目的研究复方硫酸长春新碱脂质体的制备方法并考察其体外释放规律以及在小鼠体内的组织分布。方法采用pH梯度法合并逆相蒸发制备同时包载硫酸长春新碱(VCR)和盐酸米托蒽醌(MTO)的复方脂质体，实验考察脂质体的体外释药特性；采用反相高效液相法测定小鼠组织中的VCR和MTO浓度。结果体外释放结果表明，复方脂质体中VCR在24 h释放完全，对照溶液中VCR在6 h释放完全，脂质体中MTO在288 h仅释放了0.05%，对照溶液中MTO在12 h释放完全；体内药动学结果表明复方脂质体在血浆中VCR的AUC是对照溶液的1.70倍，T_1/2(Ke)为对照溶液的1.14倍；MTO的AUC是对照溶液的40.62倍，T_1/2(Ke)为对照溶液的432倍。结论 与对照液比较，体外释放实验证实复方脂质体具有缓释特性，体内实验结果表明复方脂质体可延长药物在血液中的循环时间并且提高了药物在血液中浓度，改善了原药的体内分布特性。     

奥沙利铂脂质体的制备及体外释药研究

目的：制备一种包封率较高的奥沙利铂脂质体,并考察该脂质体的体外性质。方法采用多种方法制备奥沙利铂脂质体,通过单因素试验和正交试验最终确定脂质体处方。采用高效液相色谱法检测脂质体包封率, ZetaPlus 激光粒度分析仪测定脂质体粒径。同时,采用高效液相色谱法、原子吸收光谱法两种方法考察了该脂质体的体外释放情况。结果与薄膜分散法和 pH 梯度法相比,通过逆相蒸发法制备得到的了奥沙利铂脂质体包封率更高;在此基础上进行的处方筛选试验确定了最优处方工艺为药脂比1∶7.5,胆磷比1∶2,超声功率195 W,超声时间3 min;体外释放试验结果表明,通过高效液相色谱法和原子吸收光谱法测定的奥沙利铂脂质体24 h 的累计释放率分别为25.0%和33.6%。结论通过逆相蒸发法制备得到的奥沙利铂脂质体包封率高,且具有较高的稳定性和一定的缓释作用。     

酪丝亮肽多囊脂质体的制备和体外释放研究

目的:制备酪丝亮肽多囊脂质体,并考察其体外释药性能。方法:采用复乳法制备酪丝亮肽多囊脂质体,RP-HPLC法测定酪丝亮肽含量,以稳定性、包封率和体外释放为指标,正交试验设计法对酪丝亮肽多囊脂质体处方工艺进行优化。结果:酪丝亮肽多囊脂质体粒径均一,有80%的粒径分布在20~30μm,包封率达92.43%。酪丝亮肽多囊脂质体体外释放符合Korsmeyer-Peppas模型,37℃条件下在PBS介质中释药t1/2达111.5 h。结论:酪丝亮肽多囊脂质体稳定性好,包封率高,具有良好的缓释效果。     

肺靶向卡铂囊泡的研究

目的制备卡铂非离子型表面活性剂囊泡,以提高卡铂对肺癌的疗效并降低其毒副作用。方法用薄膜分散法制备卡铂囊泡,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。小鼠体内分布试验,用iv.S-180肿瘤细胞建立了肺肿瘤模型,计算瘤结节数。结果卡铂囊泡平均粒径为3.72μm,最小粒径为2.0μm,最大粒径为10.0μm,跨距为0.66。卡铂囊泡包封率为29.2%。体外释药符合双指数方程的规律,释药T_1/2比原药延长9.14倍。体内分布研究表明,卡铂囊泡与原药相比,有明显的肺靶向性。卡铂泡囊对小鼠肺脏S-180肿瘤生长较原药的抑瘤作用有明显提高。结论卡铂囊泡在体内有良好的肺靶向性。     

新型抗肝损伤化合物XXH-32脂质体的制备及其药剂学性质研究

目的 制备新型抗肝损伤化合物XXH-32脂质体,并对其药剂学性质进行研究。方法 采用薄膜分散法制备脂质体,正交试验设计考察影响制备工艺的因素,用扫描电镜观察脂质体表面形态,对制备的XXH-32脂质体的粒径、载药量、包封率等性质及体外释放特性进行了研究。结果 XXH-32脂质体的最佳制备工艺稳定,脂质体形态圆整,粒径分布适宜。优化工艺制得的脂质体平均粒径为（175.2±2.55）nm,多分散系数为0.262±0.01,载药量为（2.60±0.12）%,包封率为（95.05±1.06）%,体外释放符合一级动力学方程,ln（100-Q）=-0.06t+4.79（R²=0.979 4）。结论 本实验获得了较理想的新型抗肝损伤化合物XXH-32脂质体,其体外释药特性符合缓释制剂特征。     

紫杉醇脂质体的制备及质量考察

目的:制备紫杉醇脂质体并考察其质量。方法:以薄膜分散法制备脂质体;采用高效液相色谱法测定其中主药的含量并计算包封率及体外释放度。结果:所制脂质体粒径为70～150nm;紫杉醇检测浓度的线性范围为0.3～75μg·mL-1(r=0.9998),平均回收率为100.3%(RSD=1.16%,n=3);包封率约为96.46%;体外释药符合Higuchi方程,具有缓释性。结论:薄膜分散法适于制备紫杉醇脂质体;离心法能够准确快速测定脂质体包封率;该制剂体外缓慢释药。     

硫酸阿米卡星多囊脂质体的制备及评价

目的 制备硫酸阿米卡星多囊脂质体(amikacin sulfate multivesicular liposomes, AMK-MVLs),对其进行质量评 价,并考察了其体外抗菌活性。方法 采用复乳法制备AMK-MVLs混悬液Ⅰ,Box-Behnken效应面法优化筛选最佳处方,采 用生理盐水洗涤后调整药物浓度得AMK-MVLs混悬液。采用光学显微镜、激光粒度仪、差示扫描量热(differential scanning calorimeter,DSC)考察制剂的理化性质,采用透析法考察其体外释放规律,通过微量稀释法初步考察其体外抗菌活性。结 果 优化得到AMK-MVLs混悬液Ⅰ的最佳处方为：大豆磷脂与胆固醇质量比为1.91:1,三油酸甘油酯用量为1.02%,PVA用量为 0.62%。AMK-MVLs呈堆叠有无数囊泡的非同心球状,AMK-MVLs混悬液包封率(87.12±1.55)%,平均粒径为11.93 μm。DSC 结果表明,AMK以无定型状态存在于脂质体内。体外释放结果显示AMK-MVLs混悬液在72 h时释药约80%。体外溶血实验表 明,AMK-MVLs脂质体粒子浓度低于400 μg/mL时无溶血风险。体外抗菌实验结果显示,相较于AMK溶液,AMK-MVLs混悬液对E. coli、 P. aeruginosa、S. aureus 3种细菌具有更好的抗菌效果。结论 成功制备了一种硫酸阿米卡星多囊脂质体,其粒径分布均匀、包 封率高,释药规律符合Higuchi动力学模型,具有增强的抗菌活性。     

Multivesicular liposomes bearing celecoxib-beta-cyclodextrin complex for transdermal delivery

In our work depot delivery systems of celecoxib were developed using multivesicular liposomes. Moreover, the solubility of celecoxib was enhanced by complexing drug with cyclodextrin to overcome the limitation of conventional therapy. The multivesicular liposomes (MVLs) bearing celecoxib-β -cyclodextrin inclusion complex were prepared by reverse phase evaporation method, and multilamellar vesicles (MLVs)-bearing drug complex was prepared by the cast film method. The formulations were characterized for vesicle size, encapsulation efficiency, and in vitro drug release. In vivo performance of multivesicular liposomes bearing celecoxib-β -cyclodextrin inclusion complex was evaluated by assessing anti-inflammatory activity using carrageenan-induced rat paw edema volume method. The results were compared with that of celecoxib-cyclodextrin complex and MLVs containing celecoxib-β -cyclodextrin inclusion complex in equal amounts. Phase solubility studies for the celecoxib-β -cyclodextrin inclusion complex clearly indicated an increase in aqueous solubility of celecoxib with an increase in β -CD concentration. The in vitro release studies reveal that MLVs release more than 80% drug within 48 hr whereas MVL formulations release nearly the same amount of drug in 120 hr. In vivo data reveal that reduction in paw volume with MVL formulation was not rapid and fast, but the effect was maintained for prolonged periods, and even after 24 hr there was 40.7 ± 3.40% reduction in paw volume. MVL formulation showed more sustained and prolonged anti-inflammatory effect compared with plain drug and MLVs. We concluded that multivesicular liposome can be successfully utilized for the sustained delivery of celecoxib.     

阿糖胞苷多囊脂质体的制备及体外释放度考察

目的制备阿糖胞苷多囊脂质体,并考察其体外释放特性。方法采用复乳法制备阿糖胞苷多囊脂质体;RP-HPLC法测定含量、包封率和体外释放特性;以包封率为指标,单因素及正交试验筛选、优化工艺和处方;光学显微镜下观察多囊脂质体形态;以激光粒度测定仪测定粒径。结果一次乳化时间为8 min、氮气流速为0.3 m3.h-1时包封率最高;优化处方中二油酰磷脂酰胆碱(DOPC)、二棕榈酰磷脂酰甘油(DPPG)、胆固醇(CH)、三油酸甘油酯(TO)的质量浓度分别为10、2、7.5、4 g.L-1,赖氨酸浓度为40 mmol.L-1,有机溶剂选择氯仿-乙醚(体积比1∶1)。阿糖胞苷多囊脂质体在400倍显微镜下形态光滑、圆整,内部呈蜂窝状,无磷酯碎片;平均粒径19.49μm,跨距0.91;包封率达70%以上;以人空白血浆为释放介质,两周释放药物约60%。结论制备的阿糖胞苷多囊脂质体外观良好,包封率较高,体外释放试验表明药物缓慢释放,无突释现象。     

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.     

Preparation of novel double liposomes using the glass-filter method

The glass-filter method, a newly developed preparative method for liposomes, was applied for preparation of novel double liposomes. Double liposomes were prepared by filtering a suspension of liposomes prepared using a G4 filter (pore size: 10-16 microm) into a G3 filter (pore size: 40-100 microm) coated with a similar lipid layer. The morphological structure of the double liposomes was confirmed using scanning electron microscopy by the freeze-fracture method to be multivesicular vesicles consisting of small liposomes enveloped in larger liposomes. The diameter of liposomes prepared using the G4 filter was 0.8-2 microm and that of liposomes prepared using the G3 filter or double liposomes was 5-10 microm. These results suggested that the particle size of liposomes is dependent on the pore size of the glass-filter. The encapsulation efficiencies of double liposomes for brilliant blue FCF (BB) and erythrosine (ER) were higher than those of liposomes prepared by the standard Bangham method. Double liposomes showed suppressed release of BB or ER compared with normal liposomes. In particular, no release of BB was observed from the double liposomes prepared with stearylamine. These findings implied that the outer lipid layer protects the inner liposomes. The glass-filter method is the only method that we can get the double liposomes in a short period, and double liposomes prepared by this novel method had adequate size and good stability in vitro.     

离子载体A23187介导pH梯度法制备重酒石酸长春瑞滨长循环脂质体

目的:采用A23187制备重酒石酸长春瑞滨长循环脂质体,优化了处方工艺,并考察了含量、包封率、药脂比和体外释放等检测指标。方法:采用A23187介导的pH梯度法制备了重酒石酸长春瑞滨脂质体;用HPLC法检测了脂质体中重酒石酸长春瑞滨的含量和脂质(HSPC)的含量,考察了药脂比;采用阳离子交换树脂分离脂质体和游离药物,HPLC法检测包封率;以4 mmol.L-1NH4Cl-PBS(pH 7.4)为体外释放介质考察了脂质体的体外释放行为。结果:重酒石酸长春瑞滨脂质体包封率为96.1%,药脂比为1∶5(w/w);高药脂比有利于延长药物体外释放的时间。结论:采用A23187介导的pH梯度法制备重酒石酸长春瑞滨脂质体工艺可行、载药量大、包封率高;所建立体外释放的检测方法快速、准确。     

Encapsulation enhancement and stabilization of insulin in cationic liposomes

The purpose of this study was to enhance encapsulation efficiency and sustained-release delivery for parenteral administration of a protein drug. To reduce the administration frequency of protein drugs, it is necessary to develop sustained delivery systems. In this study, protein drug-loaded cationic liposomes were formulated with dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), dioleoyl-3-trimethylammonium-propane (DOTAP), and cholesterol (CH) at a molar ratio of DOPE/DOTAP/CH of 2/1.5/2. Five mol% of distearoylphosphatidyl ethanolamine polyethylene glycol (DSPE-PEG) was added prior to encapsulation of the drug into liposomes. Insulin was chosen as a model protein drug and encapsulation efficiency was evaluated in various liposomes with and without DSPE-PEG. Scanning electron microscopy was used to examine the insulin-loaded cationic liposomes. Structural analysis was performed using spectropolarimetry. Additionally, the stability and cytotoxicity of insulin-loaded cationic liposomes were evaluated. Liposomes coated with DSPE-PEG showed higher insulin encapsulation efficiency than did those without DSPE-PEG, but not significantly. Moreover, among the liposomes coated with DSPE-PEG, those hydrated with 10% sucrose showed higher encapsulation efficiency than did liposomes hydrated in either phosphate-buffered saline or 5% dextrose. In vitro release of insulin was prolonged by cationic liposomes. Our findings suggest that cationic liposomes may be a potential sustained-release delivery system for parenteral administration of protein and peptide drugs to prolong efficacy and improve bioavailability.     

溴新斯的明多囊脂质体的制备及其体外释放行为的初步研究

目的:制备溴新斯的明多囊脂质体(NB-MVL),并对其体外药物释放行为进行考察。方法:采用复乳法制备载药多囊脂质体,并用单因素试验优化处方,以动态透析技术与ƒ₂相似因子评价法对NB-MVL与溴新斯的明在体外不同释放介质中的释放行为进行研究,计算其药物释放度与相似因子。结果:NB-MVL的包封率受投料比、药物浓度等因素影响;NB-MVL在不同的释放介质中所获得的释放模型均符合Weibull模型,同时与溴新斯的明溶液在不同释放介质中所得累积释放曲线间的相似因子小于50。结论:本试验制备所得NB-MVL包封率较高,且体外药物释放行为与溴新斯的明存在显著性差异,表现出良好的缓释作用。     

兰索拉唑脂质体的制备及性质考察

目的研究兰索拉唑阳离子脂质体的制备方法并考察其体外释放行为及稳定性等。方法采用正交设计筛选处方;采用乙醇注入法制备兰索拉唑脂质体;采用超滤法测定其包封率;采用透射电镜观察脂质体的外观形态;采用粒径分析仪和Zeta电位仪分别测定脂质体的粒径和Zeta电位;采用透析法考察脂质体的释放规律。结果制得的脂质体包封率约为(80±1.23)%(n=3);脂质体的形态为粒径均匀的球形和类球形;粒径为(184±21)nm(n=3),Zeta电位为(36.1±5)mV(n=3);脂质体的体外释放符合一级方程,具有较好的稳定性。结论优选得到的脂质体处方和制备工艺合理,制剂性质稳定,其体外释放具有缓释特点。