综述——纳米材料与药物输递：脂质纳米粒在口服给药系统中的应用

脂质纳米粒是由固体脂肪酸或其酯类制成的一类纳米制剂,其生物相容性好、安全性好,所以在药物递送领域受到广泛关注．难溶性药物、多肽及蛋白质药物由于溶解度、跨膜能力以及稳定性等问题,导致口服生物利用度低,而利用脂质纳米粒作为其载体,口服给药后能显著改善药物的生物利用度,这使得脂质纳米粒在口服给药系统中得到了广泛的应用与研究．本文从口服脂质纳米粒的处方、制备工艺、吸收机制以及应用四个方面对其进行了详细的综述．     

固体脂质纳米粒制备方法的研究进展

固体脂质纳米粒是近年来备受关注的一种新型给药系统,本文对近年来固体脂质纳米粒的新型制备方法:薄膜接触器法、超声-挤压过滤法、微通道法、纳米反应嚣法的制备原理,方法及特点进行了讨论,并对现阶段存在的问题及今后的研究方向进行了展望.     

固体脂质纳米粒的制备及应用研究进展

固体脂质纳米粒自1991年出现以来引起了广泛的关注,它综合了传统胶体给药系统如乳剂、脂质体及聚合物纳米粒等的优点,同时避免了它们的许多缺点。本文综述了纳米粒的制备方法及适合工业大生产的方法,介绍了固体脂质纳米粒的理化性质及其研究方法,并讨论了适合于固体脂质纳米粒的不同的给药途径。     

多西他赛固体脂质纳米粒抗乳腺癌效果及机制研究

目的:探讨多西他赛固体脂质纳米粒抗乳腺癌效果及机制研究。方法:本实验采用MTT法考察了多西他赛固体脂质纳米粒对人乳腺癌MCF-7细胞增殖的抑制作用,采用流式细胞术检测多西他赛固体脂质纳米粒对MCF-7肿瘤细胞凋亡作用,并进一步应用Western-Blot印迹法观察多西他赛固体脂质纳米粒对MCF-7细胞中Src、E-cadherin、β-catenin蛋白表达的影响,探索了其抗乳腺肿瘤的作用机制。结果:多西他赛固体脂质纳米粒能够显著抑制人乳腺癌MCF-7肿瘤细胞的增殖,且浓度越高,抑制率越大(P0.05)。经25、50、100μg/m L多西他赛固体脂质纳米粒制剂作用24 h后,人乳腺癌细胞MCF-7的凋亡率分别为14.56%、21.21%、29.94%,细胞凋亡率随着药物浓度的增加而增加,且各实验组间比较有显著性差异(P0.05)。人乳腺癌MCF-7肿瘤细胞经不同浓度的多西他赛固体脂质纳米粒处理后,细胞中E-cadherin蛋白表达显著升高,Src、β-catenin蛋白表达显著降低,且呈现出明显的剂量依赖性。结论:多西他赛固体脂质纳米粒能够抑制人乳腺癌MCF-7细胞增殖,促进其凋亡,可能与下调β-catenin蛋白的表达,上调E-cadherin蛋白表达以及抑制Src激酶活性有关。     

长春新碱阳离子纳米结构脂质载体及其小肠吸收的研究

目的:硫酸长春新碱作为一种细胞毒型抗肿瘤药物,临床上多用其注射剂,虽应用广泛,但存在较多缺点,如药物半衰期短,代谢速率快以及毒副作用明显。本文目的是制备包载长春新碱和十二烷基磺酸钠的阳离子纳米结构脂质载体,并对其进行评价。方法:用复乳挥发法制备出目标脂质纳米粒;利用激光粒度仪对其粒径及zeta电位进行检测;利用高效液相色谱法对其包封率和载药量进行测定;透析法检测纳米粒的体外释放行为;用小肠吸收法评价纳米粒的促进吸收作用。结果:制得的纳米粒的平均粒径为(192.4±4.14)nm,多分散系数(PDI)为0.184±0.015,包封率为32.28%,Zeta电位为(30.6±4.09)m V,载药量为(1.56±0.10)%;体外释放实验显示在pH=7.4的中性释放介质中,硫酸长春新碱脂质纳米粒表现出缓释特性;小肠吸收实验表明十二烷基磺酸钠的加入和阳离子纳米粒的修饰可提高小肠对药物的吸收。结论:阳离子硫酸长春新碱纳米结构脂质载体具有缓释效果,并可以促进小肠对药物的吸收。     

酸敏阿霉素脂质纳米粒的制备及其体外抗肿瘤活性研究

目的:本研究旨在制备具有被动靶向和酸敏特性的脂质混合纳米粒,以期提高阿霉素(doxorubicin,DOX)的靶向递药效率,降低DOX的毒副作用,提高抗肿瘤活性。方法:采用微乳法制备磷酸钙纳米粒核,薄膜分散法制备脂质混合纳米粒,硫酸铵梯度法包封DOX。采用透射电镜观察外观形态,用zeta电位及纳米粒度分析仪测定纳米粒的粒径及zeta电位,透析法评价阿霉素脂质纳米粒体外释药特征。用MTT方法研究阿霉素脂质混合纳米粒对A549细胞的细胞毒性。采用流式细胞仪和激光共聚焦显微镜观察A549细胞对阿霉素脂质纳米粒的摄取。结果:体外释药结果显示阿霉素脂质纳米粒具有酸敏特性。流式结果说明A549细胞对阿霉素脂质纳米粒的摄取具有明显的时间依赖性,激光共聚焦显示阿霉素脂质纳米粒能将阿霉素递送至细胞核中。结论:阿霉素脂质体对A549细胞有明显的细胞毒性,为进一步进行体内实验提供了基础。     

高乌甲素磷脂复合物纳米粒的制备、表征及药动学研究

采用溶剂挥发法制备高乌甲素磷脂复合物,薄膜超声法制备高乌甲素磷脂复合物固体脂质纳米粒,并考察基本理化性质。SD大鼠分别灌胃给予高乌甲素及其磷脂复合物固体脂质纳米粒,比较药动学特征及生物利用度。结果表明,高乌甲素磷脂复合物固体脂质纳米粒平均粒径为(224.37±1.93)nm,Zeta电位为(-6.14±0.09)m V,包封率为(85.08±1.84)%。体外释药符合Weibull模型。药动学结果显示,Tmax,Cmax,AUC0~t和AUC0~?均具有统计学意义(P0.05或P0.01),口服吸收生物利用度提高了2.58倍。因此,高乌甲素磷脂复合物固体脂质纳米粒可有效提高高乌甲素的口服吸收生物利用度。     

凝聚法制备川芎嗪固体脂质纳米粒

目的:制备川芎嗪固体脂质纳米粒.方法:采用凝聚法制备,并以包封率和载药量为指标采用正交设计法优化川芎嗪固体脂质纳米粒的制备工艺,并利用透射电镜、激光粒度分析仪、Zeta电位测定仪表征了其药剂学性质结果:所得川芎嗪固体脂质纳米粒的最佳制备处方是川芎嗪45mg,卵磷脂600mg,硬脂酸450mg,0.4%的泊洛沙姆60ml 结论:该处方可用于川芎嗪固体脂质纳米粒的制备,工艺简单、可行.     

壳聚糖和帕米膦酸双修饰的固体脂质纳米粒的制备

目的:制备壳聚糖和帕米膦酸双修饰的固体脂质纳米粒。方法:首先利用课题组发表的专利合成帕米膦酸修饰Brij78的新型非离子表面活性剂(Pa-Brij78),然后以壳聚糖(CS)溶液为水相,Pa-Brij78为乳化剂,E-Wax为油相,采用微乳法,利用修饰的帕米膦酸基团与壳聚糖分子链中质子化的氨基交联反应原理,通过一系列实验条件的探索,确定了最佳实验工艺条件,成功制备了壳聚糖和帕米膦酸双修饰的固体脂质纳米粒。通过动态光散射(DLS)粒径仪测定了纳米粒的粒径大小和Zeta电位;透射电子显微镜(TEM)对CS-Pa-Brij78-SLNs的形貌结构进行了表征。结果:实验结果显示,制备壳聚糖和帕米膦酸双修饰的固体脂质纳米粒的最佳条件为:p H=6.0,壳聚糖浓度分别为0.1%,0.2%;反应温度65℃,反应时间40 min,在该条件下,制备的壳聚糖和帕米膦酸双修饰的固体脂质纳米粒(CS-Pa-Brij78-SLNs)粒径分别为97.9±6.6 nm和182.4±62.2 nm,表面电位分别为(+5.21±1.4m V);(+7.94±0.80 m V),装载姜黄素时,载药量为10%,包封率在90%以上,透射电镜下观察其形态圆整,清晰可见壳聚糖包裹的电晕。结论:本文以壳聚糖(CS)溶液为水相,合成的新型非离子表面活性剂Pa-Brij78为乳化剂,E-Wax为油相,采用微乳化法,经过最佳实验条件的探索,通过一步法成功制备了稳定的壳聚糖和帕米膦酸双修饰的固体脂质纳米粒(CS-Pa-Brij78-SLNs)。     

生物可降解聚合物纳米粒给药载体

生物可降解聚合物纳米粒用于给药载体具有广阔的前景。本文综述了生物可降解聚合物纳米粒给药载体领域的最新进展 :包括纳米粒表面修饰特性、药物释放、载多肽和蛋白质等生物大分子药物传输中的潜在应用。     

Design and Characterization of Metformin-Loaded Solid Lipid Nanoparticles for Colon Cancer

Colorectal cancer is a global concern, and its treatment is fraught with non-selective effects including adverse side effects requiring hospital visits and palliative care. A relatively safe drug formulated in a bioavailability enhancing and targeting delivery platform will be of significance. Metformin-loaded solid lipid nanoparticles (SLN) were designed, optimized, and characterized for particle size, zeta potential, drug entrapment, structure, crystallinity, thermal behavior, morphology, and drug release. Optimized SLN were 195.01?±?6.03 nm in size, ?17.08?±?0.95 mV with regard to surface charge, fibrous in shape, largely amorphous, and release of metformin was controlled. The optimized size, charge, and shape suggest the solid lipid nanoparticles will migrate and accumulate in the colon tumor preventing its proliferation and subsequently leading to tumor shrinkage and cell death.     

Recent Advances in Lipid Nanoparticle Formulations with Solid Matrix for Oral Drug Delivery

Lipid nanoparticles based on solid matrix have emerged as potential drug carriers to improve gastrointestinal (GI) absorption and oral bioavailability of several drugs, especially lipophilic compounds. These formulations may also be used for sustained drug release. Solid lipid nanoparticle (SLN) and the newer generation lipid nanoparticle, nanostructured lipid carrier (NLC), have been studied for their capability as oral drug carriers. Biodegradable, biocompatible, and physiological lipids are generally used to prepare these nanoparticles. Hence, toxicity problems related with the polymeric nanoparticles can be minimized. Furthermore, stability of the formulations might increase than other liquid nano-carriers due to the solid matrix of these lipid nanoparticles. These nanoparticles can be produced by different formulation techniques. Scaling up of the production process from lab scale to industrial scale can be easily achieved. Reasonably high drug encapsulation efficiency of the nanoparticles was documented. Oral absorption and bioavailability of several drugs were improved after oral administration of the drug-loaded SLNs or NLCs. In this review, pros and cons, different formulation and characterization techniques, drug incorporation models, GI absorption and oral bioavailability enhancement mechanisms, stability and storage condition of the formulations, and recent advances in oral delivery of the lipid nanoparticles based on solid matrix will be discussed.     

Challenges and solutions for the delivery of biotech drugs--a review of drug nanocrystal technology and lipid nanoparticles

Biotechnology allows tailor-made production of biopharmaceuticals and biotechnological drugs; however, many of them require special formulation technologies to overcome drug-associated problems. Such potential challenges to solve are: poor solubility, limited chemical stability in vitro and in vivo after administration (i.e. short half-life), poor bioavailability and potentially strong side effects requiring drug enrichment at the site of action (targeting). This review describes the use of nanoparticulate carriers, developed in our research group, as one solution to overcome such delivery problems, i.e. drug nanocrystals, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and lipid-drug conjugate (LDC) nanoparticles, examples of drugs are given. As a recently developed targeting principle, the concept of differential protein adsorption is described (PathFinder Technology) using as example delivery to the brain.     

Preparation and Evaluation of Miconazole Nitrate-Loaded Solid Lipid Nanoparticles for Topical Delivery

The purpose of this study was to prepare miconazole nitrate (MN) loaded solid lipid nanoparticles (MN-SLN) effective for topical delivery of miconazole nitrate. Compritol 888 ATO as lipid, propylene glycol (PG) to increase drug solubility in lipid, tween 80, and glyceryl monostearate were used as the surfactants to stabilize SLN dispersion in the SLN preparation using hot homogenization method. SLN dispersions exhibited average size between 244 and 766 nm. All the dispersions had high entrapment efficiency ranging from 80% to 100%. The MN-SLN dispersion which showed good stability for a period of 1 month was selected. This MN-SLN was characterized for particle size, entrapment efficiency, and X-ray diffraction. The penetration of miconazole nitrate from the gel formulated using selected MN-SLN dispersion as into cadaver skins was evaluated ex-vivo using franz diffusion cell. The results of differential scanning calorimetry (DSC) showed that MN was dispersed in SLN in an amorphous state. The MN-SLN formulations could significantly increase the accumulative uptake of MN in skin over the marketed gel and showed a significantly enhanced skin targeting effect. These results indicate that the studied MN-SLN formulation with skin targeting may be a promising carrier for topical delivery of miconazole nitrate.     

The use of solid lipid nanoparticles to target a lipophilic molecule to the liver after intravenous administration to mice

Taspine solid lipid nanoparticles (Ta-SLN) and taspine solid lipid nanoparticles modified by galactoside (Ta-G(2)SLN) were prepared by the film evaporation-extrusion method. The nanoparticles were spherical or near-spherical particles with smooth surface, small size and high encapsulation efficiency. Ta-G(2)SLN and Ta-SLN showed significant inhibition on 7721 cell growth. Intravenous injection of either Ta-SLN or Ta-G(2)SLN resulted in a higher plasma and liver concentration and a longer retention time in mice compared with the administration of Ta. These results suggested that SLN tended to be preferentially delivered to the liver and Ta-G(2)SLN may further enhance liver targeting.     

Characterization and Evaluation of 5-Fluorouracil-Loaded Solid Lipid Nanoparticles Prepared via a Temperature-Modulated Solidification Technique

The aim of this research was to advance solid lipid nanoparticle (SLN) preparation methodology by preparing glyceryl monostearate (GMS) nanoparticles using a temperature-modulated solidification process. The technique was reproducible and prepared nanoparticles without the need of organic solvents. An anticancer agent, 5-fluorouracil (5-FU), was incorporated in the SLNs. The SLNs were characterized by particle size analysis, zeta potential analysis, differential scanning calorimetry (DSC), infrared spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), drug encapsulation efficiency, in vitro drug release, and in vitro cell viability studies. Particle size of the SLN dispersion was below 100 nm, and that of redispersed lyophilizates was ~500 nm. DSC and infrared spectroscopy suggested that the degree of crystallinity did not decrease appreciably when compared to GMS. TEM and AFM images showed well-defined spherical to oval particles. The drug encapsulation efficiency was found to be approximately 46%. In vitro drug release studies showed that 80% of the encapsulated drug was released within 1 h. In vitro cell cultures were biocompatible with blank SLNs but demonstrated concentration-dependent changes in cell viability to 5-FU-loaded SLNs. The 5-FU-loaded SLNs can potentially be utilized in an anticancer drug delivery system.KEY WORDS: atomic force microscopy, calorimetry (DSC), FTIR, particle size, solid lipid nanoparticles     

Drug Targeting to Macrophages With Solid Lipid Nanoparticles Harboring Paromomycin: an <Emphasis Type="Italic">In Vitro</Emphasis> Evaluation Against <Emphasis Type="Italic">L. major</Emphasis> and <Emphasis Type="Italic">L. tropica</Emphasis>

Leishmaniasis is a worldwide disease that leads to high mortality and morbidity in human populations. Today, leishmaniasis is managed via drug therapy. The drugs that are already in clinical use are limited to a number of toxic chemical compounds and their parasite drug resistance is increasing. It is therefore essential, in order to circumvent the current difficulties, to design a new anti-leishmanial drug treatment strategy. Besides producing new, active anti-leishmanial entities, another promising strategy could be developing novel delivery systems and formulations of the existing pharmaceutical ingredients to improve drug efficacy. In the present study, paromomycin sulfate (PM), as one of the promising anti-leishmanial drugs, was formulated in solid lipid nanoparticles (SLN), and its in vitro efficacy was investigated against different strains of Leishmania using a MTT test, Parasite-Rescue-Transformation-Assay, SYTO Green staining, and fluorescent microscope imaging. The results show that PM-loaded SLN is significantly more effective than PM in inhibiting parasite propagation (P?<?0.05) and that cytotoxicity of PM-SLN formulations is size dependent. According to our results, delivery of the drugs to the macrophages via nanoparticle utilization seems to be an accessible and practical approach.     

Preparation, characterization, and in vitro and in vivo evaluation of lovastatin solid lipid nanoparticles

The purpose of this research was to study whether the bioavailability of lovastatin could be improved by administering lovastatin solid lipid nanoparticles (SLN) duodenally to rats. Lovastatin SLN were developed using triglycerides by hot homogenization followed by ultrasonication. Particle size and zeta potential were measured by photon correlation spectroscopy. The solid state of the drug in the SLN and lipid modification were characterized. Bioavailability studies were conducted in male Wistar rats after intraduodenal administration of lovastatin suspension and SLN. Stable lovastatin SLN having a mean size range of 60 to 119 nm and a zeta potential range of −16 to −21 mV were developed. More than 99% of the lovastatin was entrapped in the SLN. Lovastatin was dispersed in an amorphous state, and triglycerides were in {ieE162-1} form in the SLN. In vitro stability studies showed the slow release and stability of lovastatin SLN. The relative bioavailabilities of lovastatin and lovastatin hydroxy acid of SLN were increased by ∼173% and 324%, respectively, compared with the reference lovastatin suspension. Published: March 23, 2007     

Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin A

The purpose of this research was to investigate novel particulate carrier system such as solid lipid nanoparticles (SLN) for topical application of vitamin A palmitate and to study its beneficial effects on skin. Topical gels enriched with SLN of vitamin A were prepared. The solid lipid nanoparticulate dispersion was prepared using high-pressure homogenization technique and was incorporated into polymeric gels of Carbopol, Pemulen, Lutrol, and Xanthan gum for convenient application. The nanoparticulate dispersion and its gels were evaluated for various parameters such as particle size, in vitro drug release, in vitro penetration, in vivo skin hydration, and skin irritation. The solid lipid nanoparticulate dispersion showed mean particle size of 350 nm. Differential scanning calorimetry studies revealed no drugexcipient incompatibility. In vitro release profile of vitamin A palmitate from nanoparticulate dispersion and its gel showed prolonged drug release up to 24 hours, which could be owing to embedment of drug in the solid lipid core. In vitro penetration studies showed almost 2 times higher drug concentration in the skin with lipid nanoparticle-enriched gel as compared with conventional gel, thus indicating better localization of the drug in the skin. In vivo skin hydration studies in albino rats revealed increase in the thickness of the stratum corneum with improved skin hydration. The developed formulation was nonirritant to the skin with no erythema or edema and had primary irritation index of 0.00. Thus it can be concluded that SLN represents a promising particulate carrier having controlled drug release, improved skin hydration, and potential to localize the drug in the skin with no skin irritation.     

Artemisia arborescens L essential oil-loaded solid lipid nanoparticles for potential agricultural application: Preparation and characterization

The aim of this study was to formulate a new delivery system for ecological pesticides by the incorporation of Artemisia arborescens L essential oil into solid lipid nanoparticles (SLN). Two different SLN formulations were prepared following the high-pressure homogenization technique using Compritol 888 ATO as lipid and Poloxamer 188 or Miranol Ultra C32 as surfactants. The SLN formulation particle size was determined using Photon correlation spectroscopy (PCS) and laser diffraction analysis (LD). The change of particle charge was studied by zeta potential (ZP) measurements, while the melting and recrystallization behavior was studied using differential scanning calorimetry (DSC). In vitro release studies of the essential oil were performed at 35°C. Data showed a high physical stability for both formulations at various storage temperatures during 2 months of investigation. In particular, average diameter of Artemisia arborescens L essential oil-loaded SLN did not vary during storage and increased slightly after spraying the SLN dispersions. In vitro release experiments showed that SLN were able to reduce the rapid evaporation of essential oil if compared with the reference emulsions. Therefore, obtained results showed that the studied SLN formulations are suitable carriers in agriculture. Published: January 3, 2006