异维A酸固体脂质纳米粒的制备和稳定性考察

目的采用固体脂质纳米粒作为异维A酸载体,以提高其稳定性。方法采用纳米乳法制备异维A酸固体脂质纳米粒。结果制得的固体脂质纳米粒为球形粒子,平均粒径为53．23nm,包封率〉97％。25℃和40℃避光贮存6个月,含量和包封率均无明显变化。     

Trehalose is not a universal solution for solid lipid nanoparticles freeze-drying

Abstract

Objective: To prepare stable and easy to handle formulation of solid lipid nanoparticles (SLNs) by freeze-drying with or without cryoprotectants, as appropriate.

Materials and methods: SLNs were freeze-dried without cryoprotectants or with cryoprotectants in quantities selected by freeze–thaw test (sucrose, glucose) or literature search (trehalose, maltose). Appearance, re-dispersability and size distribution of re-dispersed samples were evaluated.

Results: SLN could be freeze-dried using 10% sucrose, trehalose or maltose. Trehalose was effective in protecting one of presented formulations that was already very stable on its own; its efficiency in protecting other two formulations was limited.

Discussion: Our results are in line with various reports of successful freeze-drying of SLN, but considering the stability of original dispersions, no improvement was achieved.

Conclusion: We confirmed that trehalose is among the most suitable cryoprotectant for SLN, however it did not improve shelf-life of the most stable formulation.     

Short- and long-term stability study of lyophilized solid lipid nanoparticles for gene therapy

Most studies in gene therapy are focused on developing more efficient non-viral vectors, ignoring their stability, even though physically and chemically stable vectors are necessary to achieve large easily shipped and stored batches. In the present work, the effect of lyophilization on the morphological characteristics and transfection capacity of solid lipid nanoparticles (LyoSLN) and SLN-DNA vectors (Lyo(SLN-DNA)) has been evaluated. The lyophilized preparations were stored under three different sets of temperature and humidity ICH conditions: 25 °C/60%RH, 30 °C/65%RH and 40 °C/75%RH. After lyophilization we found an increase in particle size which did not imply a reduction of “in vitro” transfection capacity. Stability studies of formulations lyophilized with trehalose showed that SLNs were physically stable during 9 months at 25 °C/60%RH and 6 months at 30 °C/65%RH. This stability was lost when harder conditions were employed (40 °C/75%RH). LyoSLNs maintained or increased the transfection efficacy (from 19% to approximately 40% EGFP positive cells) over time only at 25 °C/60%RH and 30 °C/65%RH. Lyo(SLN-DNA) resulted in almost no transfection under all conditions. LyoSLNs showed less DNA condensation capacity, whereas in Lyo(SLN-DNA) the plasmid became strongly bound, hampering the transfection. Furthermore, the storage of lyophilized lipoplexes stabilized with the disaccharide trehalose did not affect cell viability.     

The effects of cryoprotectants on the freeze-drying of ibuprofen-loaded solid lipid microparticles (SLM)

The effects of cryoprotectants on the diameter and the entrapment efficiency of ibuprofen-loaded solid lipid microparticles (SLM) during the freeze-drying process were investigated extensively. The SLM were prepared by the emulsion-congealing technique in which a glycerol behenate was used as the lipid matrix for the SLM and a soybean lecithin/bile salt used as the stabilizer. Also, trehalose, glucose, mannitol, and sucrose were chosen as the cryoprotectants. Trehalose and glucose proved to be the most effective in preventing particles aggregation and in inhibiting leakage from drug-loaded particles during the SLM freeze-drying process. The most suitable concentrations were proved to be 15% and 5% (wt), respectively.     

胰岛素固体脂质纳米粒的制备及其包封率的测定

目的 制备胰岛素固体脂质纳米粒(Ins-SLNs),考察其理化性质,并建立测定包封率的方法.方法 通过复乳/溶剂扩散法制备Ins-SLNs,考察其形态、粒径分布、Zeta电位;通过改变pH,调节Zeta电位后,采用冷冻高速离心分离纳米粒与游离Ins的方法,测定Ins-SLNs的包封率.结果 复乳法制备的Ins-SLNs在扫描电镜下均呈球形,分布均匀,平均粒径为114.7±4.68 nm,Zeta电位为-54.36±2.04 mV;包封率测定方法的线性范围为1.047～100.47μg·ml-1,平均回收率为98.37%,RSD=1.02%;测得3批Ins-SLNs样品的平均包封率为97.78%.结论 所用制备工艺简单,制得的纳米粒包封率较高;包封率的测定方法方便、灵敏、准确.     

环巴胺固体脂质纳米粒的研究

目的 制备环巴胺固体脂质纳米粒(Cyc-SLNs),并考察其理化性质和对Hedgehog信号通路的抑制作用.方法 采用薄膜超声法制备Cyc-SLNs,并考察其对B16F10黑色素瘤细胞增殖、细胞周期、凋亡和Hedgehog信号通路靶基因Gli1表达的影响.结果 制得的Cyc-SLNs呈平整的球形,平均粒径、多分散指数(PDI)、Zeta电位和平均包封率分别为126.5 ±2.1 nm、0.198±0.007、23.5±0.7 mV、91.59％±0.37％;Cyc-SLNs对B16F10细胞增殖分裂的抑制、凋亡的促进和Gli1表达的下调均强于环巴胺.结论 成功制备了抗肿瘤细胞效果强于环巴胺的固体脂质纳米粒Cyc-SLNs.     

HPLC法测定多西他赛固体脂质纳米粒的药物含量

目的建立多西他赛固体脂质纳米粒的含量测定方法。方法采用Hypersil ODS C18柱(4.6 mm×200mm,5μm),流动相为乙腈-水(60∶40,V/V),检测波长:228 nm,流速:1 mL.min-1。结果多西他赛在0.50～50.00μg.mL-1的浓度范围内,峰面积对浓度有良好的线性关系(R2=0.999 9,n=7),方法的日内与日间精密度RSD均<2%,回收率分别为98.81%、99.22%、101.5%。结论该方法具有简便、快速、准确的特点,可用于多西他赛固体脂质纳米粒的含量测定。     

蓝萼甲素固体脂质纳米粒的制备工艺研究

目的以固体脂质纳米粒作为蓝萼甲素新型缓释给药系统,进行蓝萼甲素固体脂质纳米粒的制备工艺研究。方法采用乳化蒸发-低温固化法,均匀设计优化处方,按照优化工艺条件,以硬脂酸作为蓝萼甲素模型药物载体,制备得到蓝萼甲素固体脂质纳米粒,并对其包封率进行考察。结果本研究制得的蓝萼甲素固体脂质纳米粒的包封率达到80.4%。结论本研究方法可以作为蓝萼甲素固体脂质纳米粒的制备方法。     

Lung-targeting delivery of dexamethasone acetate loaded solid lipid nanoparticles

The objective of the present study was to develop a novel solid lipid nanoparticle (SLN) for the lung-targeting delivery of dexamethasone acetate (DXM) by intravenous administration. DXM loaded SLN colloidal suspensions were prepared by the high pressure homogenization method. The mean particle size, drug loading capacity and drug entrapment efficiency (EE%) of SLNs were investigated. In vitro drug release was also determined. The biodistribution and lung-targeting efficiency of DXM-SLNs and DXM-solutions (DXM-sol) in mice after intravenous administration were studied using reversed-phase high-performance liquid chromatography (HPLC). The results (expressed as mean +/- SD) showed that the DXM-SLNs had an average diameter of 552 +/- 6.5 nm with a drug loading capacity of 8.79 +/- 0.04% and an entrapment efficiency of 92.1 +/- 0.41%. The in vitro drug release profile showed that the initial burst release of DXM from DXM-SLNs was about 68% during the first 2 h, and then the remaining drug was released gradually over the following 48 hours. The biodistribution of DXM-SLNs in mice was significantly different from that of DXM-sol. The concentration of DXM in the lung reached a maximum level at 0.5 h post DXM-SLNs injection. A 17.8-fold larger area under the curve of DXM-SLNs was achieved compared to that of DXM-sol. These results indicate that SLN may be promising lung-targeting drug carrier for lipophilic drugs such as DXM.     

优化地塞米松类脂纳米粒的制备工艺

目的筛选地塞米松类脂纳米粒(DSLN)的制备工艺。方法根据文献和单因素实验初选DSLN的制备工艺,按球面对称设计表设计实验,优化制备工艺并进行结果预测及验证。结果投药量为60 mg,三硬脂酸甘油酯用量110 mg,F68浓度2%。按优化条件制备的DSLN的体积径为198 nm,载药量为9%。结论按照球面对称设计优选的条件制备DSLN,其目标值在预测值范围内。     

固体脂质纳米粒的研究进展

目的综述固体脂质纳米粒的最新研究进展。方法以国内外大量有代表性的论文为依据,将固体脂质纳米粒的制备方法、特性分析、药物载入、药物释放及应用情况进行了概括,指出了发展前景和尚待解决的问题。结果固体脂质纳米粒的多种制备方法各有优、缺点,调整制备参数可调整药物的包封率和释药曲线。结论固体脂质纳米粒可供多途径给药,是极有发展前景的新型给药系统。     

VitD3-loaded solid lipid nanoparticles: stability,cytotoxicity and cytokine levels

Vitamin D3 (VitD3) has several beneficial effects on many metabolic pathways such as immunity system, bone development. The aim of the study, encapsulation of VitD3 with solid lipids, determine encapsulation efficiency and biocompatibility of nanoparticles. Therefore, VitD3-loaded solid lipid nanoparticles (SLNPs) were developed by optimising ratios of VitD3, stearic acid, beeswax and sodium dodecyl sulphate (SDS). Thermal stability, degradation profile, crystallinity rate, encapsulation efficiency and release profile of SLNPs were determined. Cytotoxicity of SLNPs on HaCaT, L929 and HUVEC cells were investigated. Negatively charged and VitD3-loaded nanoparticles with diameters between 30 and 60?nm were obtained. SLNPs containing up to 5.1?mg VitD3 per 10?mg powder samples were obtained. Cell proliferations were stimulated after exposure with VitD3-loaded SLNPs. Besides, inflammatory response after exposure to VitD3-loaded SLNPs was evaluated via determining IL10 and TNF-alpha levels on THP-1 cells. According to the results, no inflammatory response was observed.     

淫羊藿苷固体脂质纳米粒的大鼠体内药动学研究

目的:考察淫羊藿苷固体脂质纳米粒(ICA-SLN)在大鼠体内的药动学行为,以及利用固体脂质纳米粒技术提高ICA口服生物利用度的可行性。方法:对2组大鼠分别灌胃ICA混悬液和ICA-SLN混悬液后,采用HPLC-MS/MS法测定大鼠体内ICA的血药浓度,比较ICA混悬液和ICA-SLN混悬液在大鼠体内的吸收情况。结果:ICA在体内的药-时曲线呈现双峰,tmax为1 h,t1/2为3 h。载药纳米粒组与对照组的AUC0-∞分别为(233.6±71.2)ng.h.mL-1和(107.4±15.7)ng.h.mL-(1P<0.05)。结论:与单纯口服ICA相比较,ICA-SLN在大鼠体内的生物利用度更高。     

Metal ion-assisted drug-loading model for novel delivery system of cisplatin solid lipid nanoparticles with improving loading efficiency and sustained release

Metal ion-assisted drug loading model, in which metal ion was used to modify the microstructure of lipid layer, has been developed to improve drug loading efficiency of solid lipid nanoparticles (SLNs). The microstructure and properties of metal ion-assisted cisplatin-loading SLNs were investigated by infra-red spectroscopy, fluorescence spectroscopy and zetasizer. The reactions of hydrogenated soybean lecithin with Zn²⁺, Cu²⁺, Mn^2+?and Mg^2+?have been detected; the mechanism for higher drug encapsulation efficiency (EE) has been investigated. In metal ion introduction SLNs, the compact degree of the lipid molecules was increased due to the electrostatic interaction between metal ions and phospholipid acyl and choline polarity groups, which result in increasing of drug EE. Meanwhile, these electrostatic interactions slowed the releasing rate of encapsulated drug. The study of cytotoxic activity in vitro indicated that the cell cytotoxicity of metal ions introduction SLNs depended on both cell uptake of SLNs and drug releasing from SLNs.     

Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA

In this study, we formulated cationic solid lipid nanoparticles (cSLN) for co-delivery of paclitaxel (PTX) and siRNA. 1,2-Dioleoyl-sn-glycero-3-ethylphosphocholine-based cSLN were prepared by emulsification solidification methods. PTX-loaded cSLN (PcSLN) were characterized by zeta potential and gel retardation of complexes with small interfering RNA (siRNA). The sizes of PcSLN did not significantly differ from those of empty cSLN without PTX (EcSLN). The use of cSLN increased the cellular uptake of fluorescent dsRNA in human epithelial carcinoma KB cells, with PcSLN complexed to fluorescence-labeled dsRNA promoting the greatest uptake. For co-delivery of therapeutic siRNA, human MCL1-specific siRNA (siMCL1) was complexed with PcSLN; luciferase-specific siRNA (siGL2) complexed to EcSLN or PcSLN was used as a control. MCL1 mRNA levels were significantly reduced in KB cells treated with siMCL1 complexed to PcSLN, but not in groups treated with siMCL alone or siGL2 complexed to PcSLN. siMCL1 complexed to PcSLN exerted the greatest in vitro anticancer effects in KB cells, followed by siMCL1 complexed to EcSLN, siGL2 complexed to PcSLN, PTX alone, and siMCL1 alone. In KB cell-xenografted mice, intratumoral injection of PcSLN complexed to siMCL1 significantly reduced the growth of tumors. Taken together, our results demonstrate the potential of cSLN for the development of co-delivery systems of various lipophilic anticancer drugs and therapeutic siRNAs.     

Pharmacokinetics,tissue distribution and bioavailability of nitrendipine solid lipid nanoparticles after intravenous and intraduodenal administration

Purpose: The aim of this research was to study whether the bioavailability of nitrendipine (NDP) could be improved by administering nitrendipine solid lipid nanoparticles (SLN) duodenally to rats.

Methods: Nitrendipine was incorporated into SLN prepared by hot homogenization followed by ultrasonication method. SLN were produced using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers (dicetyl phosphate, DCP and stearylamine, SA). Particle size and charge measurements were made with a Malvern Zetasizer. Pharmacokinetics of nitrendipine SLNs (NDP-SLNs) after intravenous (i.v.) and intraduodenal (i.d.) administration to conscious male Wistar rats were studied. Tissue distribution studies of NDP-SLNs were carried out in Swiss albino mice after i.v. administration and compared to nitrendipine suspension (NDP-Susp).

Results: Average size and zeta potential of SLNs of different lipids, with and without charge modifiers ranged from 101.9 ± 3.0 to 123.5 ± 3.0 nm and ? 35.1 ± 0.5 to +34.6 ± 2.3 mV, respectively. AUC_(0–∞) was increased (up to 4.51-folds) and clearance was decreased (up to 4.54-folds) after i.v. administration of NDP-SLNs with and without charge modifiers compared to NDP-Susp. Effective bioavailability of NDP-SLNs were 2.81–5.35-folds greater after i.d. administration in comparison with that of NDP-Susp. In tested organs, the AUC and MRT of NDP-SLNs were higher than those of NDP-Susp especially in brain, heart and reticuloendothelial cells containing organs.

Conclusions: SLN are suitable drug delivery systems for the improvement of bioavailability of nitrendipine. Negatively and positively charged SLN were better taken up by the liver and brain, respectively.     

齐墩果酸固体脂质纳米粒口服给药系统的制备与表征(英文)

采用改良的乳化-溶剂挥发法制备齐墩果酸-固体脂质纳米粒(OA-SLNs)并对其性质进行评价。其粒径,zeta电位,包封率和载药率分别为(104.5±11.7)nm,(-25.5±1.8)mV,(94.2±3.9)%,和(4.71±0.15)%。透射电子显微镜下,可见球形实心纳米粒。X-粉末衍射和差示扫描量热(DSC)图谱证实药物分子均匀分散在脂质骨架中。体外释放实验表明,OA-SLNs以每小时4.88%速率缓慢释放药物,符合零级释放动力学模型。OA-SLNs在人工胃液和肠液中具有良好的稳定性。本文研究为OA-SLNs口服给药系统的应用进一步研究提供了可能。     

Production & stability of stavudine solid lipid nanoparticles—From lab to industrial scale

The production of stavudine-loaded solid lipid nanoparticles (SLN) for intravenous injection was scaled up from lab scale (40 g) to medium scale (10 kg) and large scale (20/60 kg). The SLN were produced by high pressure homogenization of stavudine lipid melt dispersed in hot surfactant solution (pre-emulsion) applying 800 bar pressure. Employed were piston-gap homogenizers with increasing capacity (APV Gaulin products LAB 40, LAB 60 and Gaulin 5.5, and Avestin C50), using them in the continuous (circulation) and discontinuous mode. Size analysis was performed by photon correlation spectroscopy (PCS), laser diffractometry and light microscopy. At lab scale a PCS size of 53 nm was obtained. At the same pressure, all homogenizers on larger scale yielded a size in the range of the lab scale product (35-70 nm). Differences were found in the size as a function of circulation time (size increase or size reduction with time) and the number of cycles required (1 or 5) for the optimal product. The stavudine SLN formulation (2% lipid content, high surfactant to lipid ratio) showed a different behavior to conventional higher concentrated SLN suspensions or nanoemulsions (10% or 20% lipid/oil, low surfactant to lipid ratio). In general, smallest sizes were obtained in the discontinuous mode after just one homogenization cycle. The continuous production mode was only efficient with a 10 kg batch size using the LAB 60. In addition, the long-term stability over 1 year was monitored at refrigeration, room temperature and at 40 °C to assess a potential effect of the homogenizer type on stability. All batches at room temperature and below were stable, only a negligible increase in size was observed.     

微乳法制备阿昔洛韦固体脂质纳米粒

目的:用微乳法制备眼用阿昔洛韦(aciclovir,ACV)固体脂质纳米粒(SLN).方法:分别以硬脂酸、单硬脂酸甘油酯为油相,以大豆磷脂和吐温80、吐温20为乳化剂,以乙醇、甘油、胆酸钠、十二烷基硫酸钠(SLS)为助乳化剂制备微乳,微乳分散于水中形成SLN.分别考察处方组成和制备工艺对SLN混浊度和稳定性的影响.用微乳法制备的ACV-SLN经冷冻干燥后,观察其重建效果.用原子力显微镜观察ACV-SLN表面的精细结构.结果:使用注射器滴入法和优选处方可以快速制得粒径<150 nm的含1.0%脂质的ACV-SLN混悬液,10 d内保持稳定.ACV-SLN混悬液经冷冻干燥后可重建.结论:微乳法制备ACV-SLN,简单快捷,不需使用有机溶剂(如二氯甲烷、氯仿等)和复杂设备,适合SLN的研究和小规模制备.     

盐酸氟桂利嗪固体脂质纳米粒包封率的测定

目的建立盐酸氟桂利嗪固体脂质纳米粒包封率的测定方法。方法分别采用透析法、离心法和葡聚糖凝胶法分离盐酸氟桂利嗪固体脂质纳米粒和游离药物,并计算盐酸氟桂利嗪固体脂质纳米粒的包封率。结果透析法包封率的测定结果为76．42％,RSD值为1．75％;离心法包封率为46．37％,RSD值为3．26％;葡聚糖凝胶法包封率为79．2％,RSD值为1．61％。结论通过比较三种方法的优缺点,葡聚糖凝胶法作为盐酸氟桂利嗪固体脂质纳米粒的包封率测定方法最为合适。