正交试验优化硫酸长春新碱脂质体的制备工艺

目的制备性质稳定的硫酸长春新碱脂质体。方法采用单因素试验考察磷脂与胆固醇比例、药脂比、脂质浓度、载药温度、载药时间、外水相p H值对硫酸长春新碱脂质体包封率的影响。以包封率为指标,分别以氢化磷脂(SPC-3)和二硬脂酰磷脂酰胆碱(DSPC)为磷脂材料,通过正交试验考察载药温度、药脂比和载药时间对制备工艺的影响,优化出硫酸长春新碱脂质体的最佳制备工艺。结果硫酸长春新碱脂质体的最佳制备工艺为:将药物溶液(按照药物含量计)和空白脂质体溶液(按照脂质含量计)按照1∶20的比例混合,用Na2HPO4直接调节外水相p H值至7.2。SPC-3脂质体在65℃条件下载药,载药时间30 min。DSPC脂质体在60℃条件下载药,载药时间10 min。结论优选出的硫酸长春新碱脂质体的处方工艺稳定可行。     

硫酸长春新碱脂质体的质量评价研究

目的评价硫酸长春新碱脂质体的质量。方法采用p H梯度法制备硫酸长春新碱脂质体。透射电镜观察脂质体的外观形态,阳离子交换树脂柱法测定包封率,并考察其p H值、粒径、Zeta电位、稳定性及体外释放规律。结果形态学观察结果显示,脂质体均匀圆整度良好。硫酸长春新碱脂质体粒径为120 nm左右,Zeta电位约为10 m V,包封率均在90%以上。光照、4℃、18℃、25℃条件下,脂质体各项指标无显著变化。40℃条件下,包封率明显降低。结论本法准确,操作简便,可用于硫酸长春新碱脂质体的质量评价。     

长春新碱抗肿瘤新剂型的研究进展

长春新碱作为临床一线广谱化疗药物广泛用于实体瘤的治疗,由于存在药物半衰期短、神经系统和胃肠道毒性强等缺点,使其临床应用受到限制。因此,提高长春新碱的肿瘤靶向性、延长体内滞留时间,将其制备成新型给药系统具有重要意义。近十年来国内外关于长春新碱的新剂型研究主要有纳米粒、脂质体、微泡、微球等,这些新剂型提高了长春新碱生物利用度,使其具有良好的缓控释能力或肿瘤靶向能力。针对长春新碱抗肿瘤新型给药系统的研究做一综述,为合理开发长春新碱新剂型提供理论依据。     

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。     

脂质体制备方法的研究进展

目的论述脂质体制备方法的研究进展。方法检索近年来有关制备脂质体的文献,主要介绍了几种常用的脂质体制备方法,并比较制备出的脂质体的结构及包封性能和各自的优缺点。结果以脂质体作药物载体,可以提高药物的溶出度和稳定性,增加药物对靶区的指向性,降低对正常细胞的毒性,提高药物的生物利用度。结论这几种方法制备的脂质体都不能完全满足药用脂质体要求,因此通常将这些方法联合起来应用。     

主动载药法制备硫酸卷曲霉素脂质体及其质量评价

目的制备硫酸卷曲霉素脂质体,建立含量和包封率的测定方法,初步考察其体外释放规律。方法采用pH梯度法制备硫酸卷曲霉素脂质体,超滤法分离脂质体与游离药物,RP-HPLC测定脂质体的含量和包封率,透析法考察脂质体的体外释放行为。结果超滤法能很好地将脂质体与游离药物分离,测定硫酸卷曲霉素脂质体的含量为10.27mg/ml,包封率为47.8%,脂质体的体外释放规律符合一级动力学过程。结论pH梯度法适于制备硫酸卷曲霉素脂质体,超滤法可用于硫酸卷曲霉素脂质体包封率的测定,制备的脂质体具有一定的缓释效果。     

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。     

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 ,…     

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。     

硫酸奈替米星脂质体的制备及性质研究

 目的：制备硫酸奈替米星脂质体并对其体内外性质进行研究。方法：采用复乳-超声法制备硫酸奈替米脂质体,采用透析法测定其包封率,并研究其渗漏率和肾组织分布。结果：制得的脂质体粒径大小均匀,包封率最高可达82.7%,最低可达53%;脂质体在4 ℃储存90 d渗漏率小于6%;制备成脂质体剂型可降低肾组织分布。结论：复乳-超声法可用于制备硫酸奈替米星脂质体;透析法可用于其包封率的测定;所制备的脂质体较稳定,可降低肾毒性。     

Release of drugs from liposomes varies with particle size

The efficacy of many drugs is improved by liposomal formulations. The greatest improvements in therapeutic benefits are achieved if the drug is retained in the liposomes for several hours after administration. Many basic drugs can be concentrated efficiently into liposomes in response to a transmembrane pH gradient. However, the rate of release from liposomal formulations is drug-dependent; for example, doxorubicin is released slowly from liposomes whereas vincristine leaks out rapidly. The aim of this study was to identify the causes of the rapid release of drugs from liposomes and then to apply this knowledge to the development of more stable formulations. Our initial focus was to explore the influence of liposomal size on the rate of release of drugs. The retention of doxorubicin within liposomes was independent of the particle size as far as this experimental condition was concerned. However, the rate of release of vincristine varied in relation to the particle size of the liposomes; vincristine was retained more effectively in larger liposomes. Experimental data generated using (31)P-NMR analysis and trap volume measurements, indicated that the number of lipid bilayers in liposomes increased as the particle size was increased. Additional lipid bilayers are likely to present a more effective barrier thereby slowing the release of drugs.     

The effect of lipid composition of small unilamellar liposomes containing melphalan and vincristine on drug clearance after injection into mice

Melphalan and vincristine together with their radiolabelled derivatives were entrapped in small unilamellar liposomes of varying choleresterol content and phospholipid composition. After intravenous injection of drug-containing egg phosphatidylcholine liposomes into mice, drug clearance rates from the blood were reduced with increasing cholesterol content. Circulating drugs were partially associated with the carrier and partly free, mostly bound to plasma proteins. The ratio of drug associated with liposomes to that circulating as free was dependent on the type of liposomes used and highest when these were cholesterol-rich. Drug clearance rates were reduced and entrapped:free drug ratios increased further when egg phosphatidylcholine in cholesterol-rich liposomes was replaced by sphingomyelin. Drug-containing cholesterol-rich liposomes injected intraperitoneally were found capable of entering the periphery intact and quantitatively to assume clearance rates similar to those observed after intravenous treatment. Such manipulations in liposomal lipid composition can alter pharmacokinetics in ways that could provide optimal conditions for drug distribution into tumours and a therapeutic effect.     

Development of Pegylated Liposomal Vincristine Using Novel Sulfobutyl Ether Cyclodextrin Gradient: Is Improved Drug Retention Sufficient to Surpass DSPE–PEG-Induced Drug Leakage?

The purpose of this study is to develop novel stable PEGylated liposome vincristine formulations with optimal antitumor efficacy. Vincristine could interact with negatively charged distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), leading to rapid drug release from vesicles. To improve drug retention, vincristine was loaded into vesicles using sulfobutyl ether cyclodextrin (sbe-CD) as trapping agent. Despite that, vincristine could not form a precipitate with sbe-CD; the aggregation status of vincristine/sbe-CD inside vesicles must be complicated because drug retention was considerably improved in vivo. Theoretical consideration revealed that the release constant K equals to pA(m)k(1)k(2)/([H(+)](i)[sbe(-)](i)V(i) ), which can be used to expound why increasing drug/lipid ratio induced decreased vincristine circulation half-life. The stabilization effect afforded by sbe-CD was sufficient to surpass DSPE-PEG-induced drug leakage, so PEGylated liposomal vincristine formulations with prolonged circulation half-life (t(1/2): from 43.6 to 70.0 h) could be achieved, of which the formulation pLV-c-2.9-3 exhibited optimal antitumor effects and reduced toxicity. The strategy might be used to load other vinca alkaloids into PEGylated liposomes and improve their retention inside vesicles.     

Optimization and characterization of a sphingomyelin/cholesterol liposome formulation of vinorelbine with promising antitumor activity

Vinorelbine (VRL) is a particularly lipophilic member of the vinca alkaloids which, as a class of drugs, exhibit improved cytotoxicity and therapeutic activity through increased duration of exposure. Here, we describe and optimize a sphingomyelin/cholesterol (SM/Chol) liposome formulation of VRL to maximize in vivo drug retention, plasma circulation time, and therapeutic activity. VRL was efficiently encapsulated (>90%) into 100 nm liposomes using an ionophore-mediated loading method. VRL retention in SM/Chol liposomes after intravenous injection in mice was dependent on drug-to-lipid ratio (D/L), with higher D/L ratios exhibiting increased drug retention (0.3 > 0.2 > 0.1, wt/wt) and improved pharmacokinetics. Cryo-electron microscopic examination of a high D/L ratio formulation indicated that the intravesicular regions of these liposomes were electron dense compared with empty liposomes. The optimized, high D/L ratio SM/Chol VRL formulation showed promising activity against subcutaneous B16 melanoma tumors compared with VRL or SM/Chol formulations of vincristine or vinblastine. Finally, the stability of the formulation was excellent (<5% drug leakage, >99% intact VRL, no changes in liposome size after 1 year at 2-8 degrees C). The optimized drug retention properties of the SM/Chol formulation of VRL, combined with its promising antitumor activity and pharmaceutical stability, make this formulation an excellent candidate for future clinical development.     

Targeted thermosensitive liposomes: an attractive novel approach for increased drug delivery to solid tumors

Introduction: Currently available chemotherapy is hampered by a lack in tumor specificity and resulting toxicity. Small and long-circulating liposomes can preferentially deliver chemotherapeutic drugs to tumors upon extravasation from tumor vasculature. Although clinically used liposomal formulations demonstrated significant reduction in toxicity, enhancement of therapeutic activity has not fully met expectations.

Areas covered: Low drug bioavailability from liposomal formulations and limited tumor accumulation remain major challenges to further improve therapeutic activity of liposomal chemotherapy. The aim of this review is to highlight strategies addressing these challenges. A first strategy uses hyperthermia and thermosensitive liposomes to improve tumor accumulation and trigger liposomal drug bioavailability. Image-guidance can aid online monitoring of heat and drug delivery and further personalize the treatment. A second strategy involves tumor-specific targeting to enhance drug delivery specificity and drug internalization. In addition, we review the potential of combinations of the two in one targeted thermosensitive-triggered drug delivery system.

Expert opinion: Heat-triggered drug delivery using thermosensitive liposomes as well as the use of tumor vasculature or tumor cell-targeted liposomes are both promising strategies to improve liposomal chemotherapy. Preclinical evidence has been encouraging and both strategies are currently undergoing clinical evaluation. A combination of both strategies rendering targeted thermosensitive liposomes (TTSL) may appear as a new and attractive approach promoting tumor drug delivery.     

Liposomes and liposome-like nanoparticles: From anti-fungal infection to the COVID-19 pandemic treatment

The liposome is the first nanomedicine transformed into the market and applied to human patients. Since then, such phospholipid bilayer vesicles have undergone technological advancements in delivering small molecular-weight compounds and biological drugs.Numerous investigations about liposome uses were conducted in different treatment fields,including anti-tumor, anti-fungal, anti-bacterial, and clinical analgesia, owing to liposome’s ability to reduce drug cytotoxicity and improve the therapeut...     

新型脂质体在经皮给药系统中的应用

摘 要 药物经皮传递系统的角质层屏障等问题日益受到关注,而新型脂质体作为药物传递载体,可以有效解决这一问题。新型脂质体能明显提高药物经皮渗透,从而增强疗效,具有广阔的应用价值和开发前景。本文结合国内外研究现状,对在经皮给药系统中作为载体应用的新型脂质体的分类、促渗机制及其应用进展做一综述。     

Liposomal drug formulations in the treatment of rheumatoid arthritis

Liposomes have been extensively investigated as drug delivery systems in the treatment of rheumatoid arthritis (RA). Low bioavailability, high clearance rates and limited selectivity of several important drugs used for RA treatment require high and frequent dosing to achieve sufficient therapeutic efficacy. However, high doses also increase the risk for systemic side effects. The use of liposomes as drug carriers may increase the therapeutic index of these antirheumatic drugs. Liposomal physicochemical properties can be changed to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to nontarget tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells in RA. This review gives an overview of liposomal drug formulations studied in a preclinical setting as well as in clinical practice. It covers the use of liposomes for existing antirheumatic drugs as well as for new possible treatment strategies for RA. Both local administration of liposomal depot formulations and intravenous administration of passively and actively targeted liposomes are reviewed.