脂质体物理稳定性和包封率的影响因素

脂质体制备的难点在于改善物理稳定性和提高包封率.现从脂质体的常用制备方法、投料和投料比、制备过程中的条件控制及贮存条件等方面考察其对脂质体的物理稳定性和包封率的影响.     

载药脂质体的稳定性

脂质体(Liposome)是磷脂依靠疏水缔合作用在水中自发形成的一种分子有序组合体,为多层囊泡结构,每层均为类脂双分子膜,层间和脂质体内核为水相,双分子膜间为油相,膜厚度约为4nm。根据其结构所包含的双分子膜层数,分为单室脂质体和多室脂质体(MLV,粒径1μm～5μm)。粒径小于200nm的单室脂质体称为小单室脂质体(SUV),粒径在200nm～1000nm的称为大单室脂质体(LUV)。脂质体应用十分广泛,可用于模拟膜研究、在体内外将基因或其它物质向细胞内传递,还可用于临床检验和诊断、纳米粒子的制备、催化反应的控制等。70年代脂质体开始被用于药物释放…     

脂质体物理化学稳定性研究进展

目的了解影响脂质体稳定性的作用机制,从根本上控制脂质体的稳定性。方法综述了物理、化学两个方面影响脂质体稳定性的因素。结果与结论以脂质体的粒径、渗漏率、载药量等为指标评价其稳定性,并通过改变脂质体组成、改进制备方式、制备新型脂质体等方法提高脂质体的稳定性。     

鬼臼毒素脂质体的稳定性研究

目的预测鬼臼毒素脂质体的稳定性。方法采用离心-分光光度法测定稳定性参数(KE)值。采用经典恒温加速试验法分别在25,30,40℃恒温条件下,在不同间隔时间用高效液相色谱法测定鬼臼毒素脂质体中药物浓度,预测鬼臼毒素脂质体在4℃下的有效期t0.9。结果在光照条件下放置10 d的KE值较0 d增加的最多,增加了12.21倍,而在4,25,30,40℃放置10 d的KE值较0 d分别增加了3.88,5.85,6.96,8.12倍;鬼臼毒素脂质体在4℃下的有效期t0.9为5 d,t0.5为60 d。结论鬼臼毒素脂质体的稳定性与温度有关,温度越高,稳定性越差,应低温保存。     

提高脂质体稳定性研究进展

脂质体是人工制备的由磷脂双分子定向排列而成的微球。脂质体自20世纪70年代开始作为药物载体应用以来 ,由于具有制备简单 ,对人体无害 ,无免疫原性反应 ,易实现靶向性 ,可提高和延长药物疗效 ,缓和毒性 ,避免耐药性和改变给药途径等优点备受重视。但脂质体的应用范围受到其稳定性的限制。脂质体在储存过程中 ,由于药物渗漏、粒子的聚集以及磷脂在液态下的氧化水解等原因易被破坏 ;进入体内后 ,由于血中的白蛋白、调理素、抗体等各种物质的作用 ,脂质体可能发生破裂 ,致使包封药物快速渗漏 ,很快被网状内皮系统识别、吸收 ,从体循环中清除 ,…     

氨甲喋呤(MTX)脂质体的制备及其稳定性

本文探讨了提高MTX脂质体包裹率、影响它对热稳定性的因素,并自行设计了简便、迅速、重现性好的测定MTX脂质体的方法。结果表明:采用二次乳化蒸发法制备MTX脂质体,在控制乳化温度及有机相比例的条件下,可获得50%左右较高的包裹率。另外提示,脂质体分散溶媒的离子强度和脂质体中胆固醇的含量是影响MTX脂质体对热稳定性的重要因素。以选用50mM的磷酸盐缓冲液为分散溶媒和PC/CHOL/SA的脂质体组成,则100℃加热30分钟灭菌,所包MTX可滞留90%。且灭菌前后的脂质体经电镜观察形态无明显变化。     

氨甲喋呤(MTX)脂质体的制备及其稳定性

本文探讨了提高MTX脂质体包裹率、影响它对热稳定性的因素,并自行设计了简便、迅速、重现性好的测定MTX脂质体的方法。结果表明:采用二次乳化蒸发法制备MTX脂质体,在控制乳化温度及有机相比例的条件下,可获得50％左右较高的包裹率。另外提示,脂质体分散溶媒的离子强度和脂质体中胆固醇的含量是影响MTX脂质体对热稳定性的重要因素。以选用50mM的磷酸盐缓冲液为分散溶媒和PC/CHOL/SA的脂质体组成,则100℃加热30分钟灭菌,所包MTX可滞留90％。且灭菌前后的脂质体经电镜观察形态无明显变化。     

冷冻干燥对提高脂质体稳定性的研究概况

讨论了脂质体在冷冻干燥、复水化及贮存过程中的稳定性,并介绍了冻干保护剂的作用机理.     

The Influence of Sodium Glycocholate and Other Additives on the in vivo Transfection of Plasmid DNA in the Lungs

Purpose. A plasmid containing the luciferase marker cDNA was constructed to test non viral gene delivery formulations in vivo. Methods. A scale up procedure was devised to produce up to gram quantities of plasmid. Sufficient quantities were generated to process and test the DNA with various additives and to generate a spray-dried powder formulation of the plasmid. Male Sprague-Dawley rats (250 g) were intratracheally instilled with 200–250 µl of solution containing 200 µg plasmid ± lipid [DC Chol:DOPE 1:1 molar (2mg/kg)] growth factors [KGF (10 mg/kg), EGF (5 mg/kg)], permeation enhancers [sodium glycocholate (0.01 to 10% w/v)), sodium deoxycholate (1% w/v), beta-cyclodextrin (1% w/v)], surfactant [Tween 80 (1% w/v)], a mucolytic [N-acetylcysteine (10% w/v)] and positively charged synthetic polymers [PVAVAM 6 and 14%]. Animals were sacrificed 24 hr post-dose and the lungs were assayed for luciferase using a chemiluminescent assay. Results. The relative ability of the materials to promote luciferase production in the lungs was permeation enhancer >> DNA alone lipid, mucolytic, surfactant, growth factor > polymer. Protein production in the lungs ranged from 10 times below the DNA control (16 pg) using the polymers (1.5 pg) to 125 times greater than the control using the permeation enhancer (2050 pg). The transfection capabilities of the majority of additives was low. The enhancing effects of sodium glycocholate were dose-dependent and perhaps associated with the critical micelle concentration. Although the bile salt was the most successful of the tested compounds, it resulted in significant mortality when used at concentrations greater than 1 % w/v. Conclusions. The results suggest that transfection can be significantly enhanced by additives such as NaGC but some toxicity may be unavoidable.     

叶绿素铜钠稳定性影响因素研究

目的 探讨影响叶绿素铜钠稳定性的主要因素.方法 采用分光光度法测定叶绿素铜钠的含量,研究酸性环境、温度、氧化还原剂、金属离子、光照、叶绿素铜钠颗粒中含水量对叶绿素铜钠含量稳定性的影响.结果 叶绿素铜钠在酸性环境下,尤其pH小于4时稳定性明显下降;温度在850℃以下时有较好的稳定性,当温度达85℃以上时叶绿素铜钠降解很快;叶绿素铜钠的稳定性受金属离子Mg2+,Zn2+.Al3+以及氧化还原剂H2O2,Na2S2O3的影响;而光照对叶绿素铜钠的影响不明显;颗粒含水量较高时,对叶绿素铜钠的稳定性影响显著.结论 叶绿素铜钠的稳定性受酸性环境,高温,氧化还原剂及二价、三价金属离子的影响.此外,压片前颗粒中水分的含量对叶绿素铜钠的稳定性有明显影响.     

助乳化剂对多囊脂质体影响的初步考察

以拓扑替康为模型药物,采用复乳法制备多囊脂质体,考察了分别以L-赖氨酸、聚乙烯醇和海藻酸钠为助乳化剂对脂质体粒径和包封率的影响.结果表明,三者均能作为助乳化剂得到多囊脂质体,但种类和用量对制品粒径和包封率均有显著影响.     

The Effect of Jet-Milling on Lyophilized Liposomes

Pharmaceutical Research -     

维生素C注射液对注射用头孢地嗪钠稳定性的影响

目的考察维生素C注射液在5％葡萄糖注射液中对注射用头孢地嗪钠稳定性的影响。方法观察配伍液的外观、pH值变化，采用高效液相色谱法测定头孢地嗪钠含量。结果室温下配伍液6h内外观、pH值、含量无明显变化。结论维生素C注射液在室温下6h内对头孢地嗪钠稳定性无影响。     

注射用头孢唑林钠与丹皮酚磺酸钠注射液配伍稳定性研究

目的：观察注射用头孢唑林钠与丹皮酚磺酸钠注射液在0.9%氯化钠注射液中的配伍稳定性。方法模拟临床使用条件,用高效液相色谱法测定头孢唑林钠与丹皮酚磺酸钠配伍后6 h内的相对百分含量,并观察其外观、不溶性微粒数及pH变化。结果头孢唑林钠与丹皮酚磺酸钠配伍后,在室温下放置6 h,配伍液的外观、不溶性微粒数、pH及含量均无明显变化。结论注射用头孢唑林钠与丹皮酚磺酸钠注射液在0.9%氯化钠注射液中配伍后,室温下6 h内可使用。     

注射用硝普钠在氯化钠注射液中稳定性研究

目的考察注射用硝普钠与氯化钠注射液配伍的稳定性。方法将注射用硝普钠,根据临床应用需要配制成溶液,考察在不同环境下,不同放置时间硝普钠溶液的稳定性,包括溶液性状、pH、不溶微粒、紫外-可见吸收光谱、硝普钠含量等。结果避光套避光,在20℃或35℃时,注射用硝普钠与氯化钠注射液混合后26h内是稳定的;不避光任何条件下溶液均不稳定;溶液的稳定性与浓度及温度无关,与光照和强度与时间密切相关。结论在避光条件下,注射用硝普钠与氯化钠注射液配伍26h内稳定。     

Immunotargeting of Liposomes Containing Lipophilic Antitumor Prodrugs

Potential therapeutic applications of recently developed liposomes with a reduced affinity to the reticuloendothelial systems and a prolonged circulation time as targeting systems for lipophilic prodrugs were examined. In these studies, liposomes composed of phosphatidylcholine and cholesterol, additionally containing monosialoganglioside (G_M1) or polyethylene glycol conjugated to phosphatidyl-ethanolamine (PEG-PE), were used. Three antitumor lipophilic prodrugs, N-trifluoroacetyl-adriamycin-14-valerate (AD32), araC-diphosphate-diglyceride (araCdPdG), and 3,5-o-dipalmitoyl-5-fluoro-2-deoxyuridine (dpFUdR), were used to examine the effect of lipophilic prodrug incorporation into long-circulating liposomes and immunoliposomes on their biodistribution in mouse. Biodistribution studies with antibody-free liposomes containing lipophilic prodrugs showed that the activities of G_M1 or PEG2000-PE in prolonging the circulation time of liposomes appeared to be preserved in the presence of each of the three lipophilic prodrugs at a drug/lipid molar ratio of 3:97. The effect of lipophilic prodrug incorporation on target binding of immunoliposomes was then examined using a mouse model. Incorporation of AD32 or dpFUdR into immunoliposomes, directed to the normal endothelium, did not affect the targetability of immunoliposomes, suggesting a potential effectiveness of these lipophilic prodrug-containing immunoliposomes in therapy for lung tumors. On the contrary, incorporation of araCdPdG resulted in significantly reduced target binding of immunoliposomes by yet unknown mechanism(s).     

硫酸长春新碱空白脂质体的稳定性研究

目的考察三瓶装硫酸长春新碱脂质体中空白脂质体的物理、化学稳定性。方法采用高效液相色谱-蒸发光散射检测器(HPLC-ELSD)测定空白脂质体中氢化大豆磷脂(HSPC)的含量;采用粒度仪测定脂质体粒径;用阳离子树脂分离脂质体与游离药物,测定包封率。结果在4℃下,空白脂质体的理化性质未见明显变化,稳定性较好。结论硫酸长春新碱脂质体适合制成三瓶分装制剂,有利于提高药物稳定性。