Topical delivery of Idebenone using nanostructured lipid carriers: evaluations of sun-protection and anti-oxidant effects

The objective of present study was to develop nanostructured lipid carriers (NLC) for topical delivery of antioxidant drug and evaluation of its sun protection efficacy. In the present study attempts have been made to formulate Idebenone loaded nanostructured lipid carriers (INLC) by using solvent precipitation method. Preformulation study evidenced for selection of Captex 500 P as an oil phase in which Idebenone has saturation solubility of 0.266 ± 0.032 g/ml. Compritol 888 ATO and ethanol were selected as solid lipid and solvent respectively. Surfactant and co-surfactant as Labrasol and Transcutol P have given stable formulations on the basis of HLB required for stabilization, respect to oil phase. INLC has particle size of 605 ± 4.01 nm and %EE of 82.58 ± 2.20 %. Optimized batches were subjected for crystallographic investigation, in vitro skin permeation study, drug deposition study, SPF determination and antioxidant activity. XRD, DSC studies illustrated that partial amorphization of Idebenone by molecularly dispersion within lipid blend leads for entrapment of drug. Permeation data showed that optimized INLC has flux value (Jss) of 7.87 μg cm^?2 h^?1. High significance (P < 0.001) of drug deposition in skin was observed between INLC and plain Idebenone gel. SPF value for INLC has 23 which represents that lipid nanocarriers have standards of blocking of 94–96 % of UVB rays. Such high skin deposition and SPF leads to more antioxidant effect of formulations. Hence lipid nanocarriers such as NLC have potential as an antioxidant and sun protection for topical drug delivery.     

新型纳米结构脂质载体系统的研究进展

目的介绍新型的纳米结构脂质载体系统的研究进展,为其研究和应用提供参考。方法查阅相关文献33篇,进行整理和归纳。结果新型的纳米结构脂质载体能够克服固体脂质纳米粒的一些不足,并具有独特的结构特征,药物的包封机理和释放特征。结论纳米结构脂质载体作为药物传递系统的一种新剂型,具有广阔的发展前景。     

星点设计效应面法优化氟比洛芬纳米结构脂质载体的处方

目的采用星点设计法以总评"归一值"为指标优化氟比洛芬纳米结构脂质载体的处方。方法以粒径、包封率、载药量、Zeta电位等为评价指标,考察了氟比洛芬(flurbiprofen,FP)加入量、卵磷脂用量、吐温-80和泊洛沙姆188的总量以及去氧胆酸钠的用量对FP-NLC性质的影响。用多元线性方程和二次多项式描述各指标及总评"归一值"和3个影响因素之间的数学关系,根据总评"归一值"的最佳数学模型描绘效应面,选择最佳处方,并进行预测分析。结果 4个影响因素和4个评价指标及总评"归一值"之间存在定量关系。优选的最佳处方为氟比洛芬0.222 g,卵磷脂0.300 g,吐温-80和泊洛沙姆188总质量2.000 g,去氧胆酸钠0.100 g。优化处方各指标的预测值和目标值接近。结论所建立的模型预测性良好,可用于预测和优化氟比洛芬纳米结构脂质载体处方。     

星点设计效应面法优化氟比洛芬纳米结构脂质载体凝胶剂的处方

目的采用星点设计法以经皮累计渗透量为指标优化氟比洛芬纳米结构脂质载体凝胶剂的处方。方法以经皮累积渗透量为评价指标,考察了凝胶基质量(x1)、氮酮用量(x2)和丙二醇用量(x3)对氟比洛芬纳米结构脂质载体凝胶剂性质的影响。用多元线性方程和二次多项式描述经皮累积渗透量和3个影响因素之间的数学关系,根据经皮累积渗透量的最佳数学模型描绘效应面,选择最佳处方,并进行预测分析。结果三个影响因素和经皮累积渗透量之间存在定量关系。优选的最佳处方:卡波姆940为0.15 g、氮酮为0.70 g,丙二醇为1.50 g。优化处方各指标的预测值和目标值接近。结论所建立的模型预测性良好,可用于预测和优化氟比洛芬纳米结构脂质载体凝胶剂处方。     

Spray drying of fenofibrate loaded nanostructured lipid carriers

The conversion of aqueous dispersion of nanostructured lipid carriers (NLCs) into dry powder by spray drying could be a useful approach to render NLCs with better physical chemical stability than the aqueous dispersion. In this study, aqueous NLC dispersion containing fenofibrate was converted into dry, easily reconstitutable powder using spray drying. A central composite face centered design (CCFD) was used to investigate the influence of the ratio of lipid to protectant (mannitol and trehalose) and crystallinity of spray-dried powder on the particle size, yield and residual moisture content of the dried powder. A linear relationship (R² = 0.9915) was established between the crystalline content of the spray-dried powders against the ratio of mannitol to trehalose from 3:7 to 10:0 (w/w). Spray drying of NLC aqueous dispersion using a mannitol and trehalose mixture resulted in an increase in particle size of the NLCs after reconstitution in water as compared to that in the initial aqueous dispersion. The decrease in crystallinity of the dry powder by reducing the ratio of mannitol to trehalose could improve the reconstitution of the NLCs in water. However the yield and residual moisture content of dry powder decreased with an increase in the ratio of mannitol to trehalose. Lipid nanoparticles were able to retain the drug incorporation and the prolonged drug release profile after spray drying. The experimental model was robust, and suggested that spray drying is a viable technique for the conversion of NLCs into dry powder.     

Long circulation nanostructured lipid carriers for gambogenic acid: formulation design,characterization, and pharmacokinetic

1.?GNA-PEG-NLC and GNA-NLC were prepared by emulsification and low-temperature solidification methods. The optimized GNA-PEG-NLC and GNA-NLC were not only found to have small mean size (146.33?±?2.11 and 144.07?±?1.44) nm, high Zeta potential (?25.10?±?1.35 and ?28.03?±?0.29) mV, but also great entrapment efficiency (79.07?±?1.11 and 84.65?±?0.98%). TEM proved that particles were nearly spherical with smooth surface shape. Furthermore, in vitro release revealed a burst release initially, followed by a sustained profiles up to 48?h, and the cumulative drug release of GNA-PEG-NLC and GNA-NLC was 65.90?±?2.34% and 69.25?±?1.77%, respectively.

2.?In pharmacokinetic, GNA-PEG-NLC exhibited prolonged MRT and higher AUC values compared with GNA-NLC and GNA solution. Moreover, the tissue distribution demonstrated a high uptake of GNA-PEG-NLC in stomach.

3.?These results indicated that PEG-NLC is a promising delivery system for GNA, which could prolong drug circulation time in body and thus improved its bioavailability.     

Preparation and characteristics of monostearin nanostructured lipid carriers

Nanostuctured lipid carriers (NLC) consisted of solid lipid and liquid lipid are a new type of lipid nanoparticles, which offer the advantage of improved drug loading capacity and release properties. In this study, solvent diffusion method was employed to produce NLC. Monostearin (MS) and caprylic/capric triglycerides (CT) were chosen as the solid lipid and liquid lipid. Clobetasol propionate used as a model drug was incorporated into the NLC. The influences of preparation temperature and CT content on physicochemical properties of the NLC were characterized. As a result, monostearin solid lipid nanoparticles (without CT content, SLN) obtained at higher temperature (70 degrees C) exhibited slightly higher drug loading capacity than that of 0 degrees C (P < 0.05). In contrast, the production temperature made little effect on NLC drug loading capacity (P > 0.05). The improved drug loading capacity was observed for NLC and it enhanced with increasing the CT content in NLC. The results were explained by differential scanning calorimetry (DSC) measurement for NLC. The incorporation of CT to NLC led to crystal order disturbance and thus left more space to accommodate drug molecules. NLC displayed a good ability to reduce the drug expulsion in storage compared to SLN. The in vitro release behaviors of NLC were dependent on the production temperature and CT content. NLC obtained at 70 degrees C exhibited biphasic drug release pattern with burst release at the initial 8h and prolonged release afterwards, whereas NLC obtained at 0 degrees C showed basically sustained drug release throughout the release time. The drug release rates were increased with increasing the CT content. These results indicated that the NLC produced by solvent diffusion method could potentially be exploited as a carrier with improved drug loading capacity and controlled drug release.     

Solid lipid nanoparticles and nanostructured lipid carriers--innovative generations of solid lipid carriers

The first generation of solid lipid carrier systems in nanometer range, Solid Lipid Nanoparticles (SLN), was introduced as an alternative to liposomes. SLN are aqueous colloidal dispersions, the matrix of which comprises of solid biodegradable lipids. SLN are manufactured by techniques like high pressure homogenization, solvent diffusion method etc. They exhibit major advantages such as modulated release, improved bioavailability, protection of chemically labile molecules like retinol, peptides from degradation, cost effective excipients, improved drug incorporation and wide application spectrum. However there are certain limitations associated with SLN, like limited drug loading capacity and drug expulsion during storage, which can be minimized by the next generation of solid lipids, Nanostructured lipid carriers (NLC). NLC are lipid particles with a controlled nanostructure that improves drug loading and firmly incorporates the drug during storage. Owing to their properties and advantages, SLN and NLC may find extensive application in topical drug delivery, oral and parenteral administration of cosmetic and pharmaceutical actives. Cosmeceuticals is emerging as the biggest application target of these carriers. Carrier systems like SLN and NLC were developed with a perspective to meet industrial needs like scale up, qualification and validation, simple technology, low cost etc. This paper reviews present status of SLN and NLC as carrier systems with special emphasis on their application in Cosmeceuticals; it also gives an overview about various manufacturing techniques of SLN and NLC.     

新型纳米粒给药系统——纳米结构的脂质载体

固体脂质纳米粒（SLN）已被公认是一种新型的纳米粒给药系统，但SLN有不同程度的潜在问题。作为新一代的纳米粒给药系统——纳米结构的脂质载体（Nanostructured lipid carriers，NLC）可减小或者避免SLN有限载药能力及储藏过程包封药物泄漏的问题，而且能调整SLN的释放曲线。NLC以固体脂质与物态上相异的液体脂质混合制备得到，形成3种类型特殊结构的脂质骨架：结晶不完全态、无定形态、复合态。现介绍一种特殊的制备方法，不仅适合于制备NLC，而且也可作为制备高粒子浓度（30％～95％）SLN分散液的方法。描述了NLC作为给药系统潜在的应用前景。     

正交设计联用星点设计-效应面法优化蒿甲醚长循环纳米结构脂质载体处方

目的采用正交设计联用星点设计-效应面法优化蒿甲醚长循环纳米结构脂质载体处方。方法先采用正交设计进行蒿甲醚长循环纳米结构脂质载体处方主要影响因素的初步筛选,再采用星点设计-效应面法进一步优化处方,以固液脂质质量比、PEG占脂质的质量分数、药物占脂质的质量分数为考察因素,以包封率、平均粒径、zeta电位、总评"归一化"值为考察指标,对结果进行多元线性回归、多元非线性拟合,经效应面法预测最佳处方。结果优化处方制备的蒿甲醚长循环纳米结构脂质载体的包封率为99.3%,平均粒径为29.2 nm,zeta电位为-37.2 m V。结论采用正交设计联用星点设计-效应面法建立的数学模型,较好地预测了蒿甲醚长循环纳米结构脂质载体的处方优化,根据优化处方制得的蒿甲醚长循环纳米结构脂质载体的包封率、粒度及zeta电位等达到预期目标。     

奥扎格雷纳米结构脂质载体包封率的测定方法

目的:建立奥扎格雷纳米结构脂质载体(ozagrel-loaded nanostructured lipid carriers,OZ-NLC)包封率的测定方法。方法:分别采用超滤法、葡聚糖凝胶柱层析法、超速离心法分离游离药物,以紫外分光光度法测定奥扎格雷的含量,计算包封率。结果:超滤法和葡聚糖凝胶柱层析法可有效分离OZ-NLC与游离药物,两种方法的平均回收率分别为98.31%和97.15%,平均包封率为59.21%和61.11%。结论:葡聚糖凝胶柱层析法操作简便,结果可靠,重现性好,故选择该方法测定OZ-NLC的包封率。     

Anti-inflammatory activity of injectable dexamethasone acetate-loaded nanostructured lipid carriers

This work studied the intravenous injection formulation of nanostructured lipid carriers (NLCs) loaded with dexamethasone acetate (DA), a poorly water-soluble drug. The goal of this study was to design nanoparticles which could improve therapeutic efficacy of DA on inflammations. Based on the optimized results of single-factor screening experiment, DA-loaded NLCs (DA-NLCs) prepared by an emulsification-ultrasound method were found to be relatively uniform in size (178?±?4?nm) with a negative zeta potential (-38?±?4 mV). The average drug entrapment efficiency was 91?±?3 %. In vitro release tests indicated DA-NLCs possessed a sustained release characteristic and the accumulative release percentage was near 80 % at 23?h. DA-NLCs exhibited an average peak concentration of DA (7.6 μg/ml) in the pleural exudate after intravenous administration to an experimental model of γ-carrageenan-induced pleuritis rats, which was 8.3 times higher than that of free DA (0.9 μg/ml). The γ-carrageenan-induced edema test showed that the anti-acute inflammatory activity of DA-NLCs was stronger than that of free drug at the same drug concentration (P<0.05). In addition, biodistribution results clearly indicated that DA-NLCs preferentially accumulated in mice livers and lungs after intravenous injection. These results revealed that injectable NLCs may serve as a promising carrier for DA, greatly enhancing the selective effect on inflammatory sites, reducing systematic side effects and may be a potential carrier to increase therapeutic efficacy on inflammatory diseases.     

纳米结构脂质载体肺部给药研究进展

传统吸入疗法不能使药物靶向到肺的特定部位,而纳米载体药物的肺部给药系统可克服传统吸入药物的不足。其中纳米结构脂质载体是固体和液体脂质的混合物经表面活性剂乳化后形成的纳米粒,具有更好的胶体稳定性和持续的药物释放行为。其组成成分具有无毒、生理惰性和生物相容性的特点,还具有良好的雾化特性,特别适用于肺部应用,并且生产过程简单（高压均质）,适合大规模生产。本文介绍了常见肺部给药纳米载体,概述了纳米结构脂质载体应用于肺部的优势,为其在肺部给药领域中的深度开发提供参考。     

Anti-inflammatory activity of injectable dexamethasone acetate-loaded nanostructured lipid carriers

This work studied the intravenous injection formulation of nanostructured lipid carriers (NLCs) loaded with dexamethasone acetate (DA), a poorly water-soluble drug. The goal of this study was to design nanoparticles which could improve therapeutic efficacy of DA on inflammations. Based on the optimized results of single-factor screening experiment, DA-loaded NLCs (DA-NLCs) prepared by an emulsification-ultrasound method were found to be relatively uniform in size (178?±?4?nm) with a negative zeta potential (-38?±?4 mV). The average drug entrapment efficiency was 91?±?3 %. In vitro release tests indicated DA-NLCs possessed a sustained release characteristic and the accumulative release percentage was near 80 % at 23?h. DA-NLCs exhibited an average peak concentration of DA (7.6 μg/ml) in the pleural exudate after intravenous administration to an experimental model of γ-carrageenan-induced pleuritis rats, which was 8.3 times higher than that of free DA (0.9 μg/ml). The γ-carrageenan-induced edema test showed that the anti-acute inflammatory activity of DA-NLCs was stronger than that of free drug at the same drug concentration (P<0.05). In addition, biodistribution results clearly indicated that DA-NLCs preferentially accumulated in mice livers and lungs after intravenous injection. These results revealed that injectable NLCs may serve as a promising carrier for DA, greatly enhancing the selective effect on inflammatory sites, reducing systematic side effects and may be a potential carrier to increase therapeutic efficacy on inflammatory diseases.     

托伐普坦纳米结构脂质载体的制备与药动学研究

目的 制备托伐普坦纳米结构脂质载体（Tol-NLCs）,以提高托伐普坦（Tol）的口服生物利用度。方法 根据溶解度对辅料进行筛选,包括固体脂质（双硬脂酸甘油酯、山嵛酸甘油酯、聚乙二醇-8山嵛酸甘油酯、单硬脂酸甘油酯和单亚油酸甘油酯）、液体脂质（油酸聚乙二醇甘油酯、单油酸甘油酯、月桂酸聚乙二醇甘油酯和单辛酸丙二醇酯）和表面活性剂（聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇-15羟基硬脂酸酯和泊洛沙姆188）,采用乳化超声-低温固化法制备TolNLCs,并使用Box-Behankn效应面法优化处方;分别采用电镜（TEM）观察、粒径分布及Zeta电位测定、差示扫描量热法（DSC）对制备的Tol-NLCs进行表征,同时比较Tol原料药和Tol-NLCs体外药物释放特点、跨膜转运特征;比较Tol混悬液和Tol-NLCs经大鼠ig给药后的体内药动学特征。结果 根据溶解度确定以山嵛酸甘油酯作为固体脂质,单油酸甘油酯作为液体脂质,聚乙二醇-15羟基硬脂酸酯作为表面活性剂,通过优化得到Tol-NLCs的最佳处方：总脂质质量浓度为40.0 mg·mL^-1,表面活性剂质量浓度为25.0 mg·mL^-1,超声时间为6 min。在透射电镜下可观察到制备的Tol-NLCs呈类球状,分布均匀;Tol-NLCs的平均粒径为（106.2±14.7）nm,PDI为（0.196±0.004）,Zeta电位为（-26.6±0.6）mV;药物在Tol-NLCs中以非结晶形式存在。Tol-NLCs在pH 6.8磷酸盐缓冲液中表现为前期药物释放较快,后期药物释放平缓。Caco-2细胞跨膜转运结果显示,Tol-NLCs的P_{app（AP→BL）}值为（11.16±0.58）×10^-6 cm·s^-1,P_{app（BL→AP）}值为（4.51±0.46）×10^-6 cm·s^-1,与Tol溶液相比,P_{app（AP→BL）}表现出明显增加趋势,P_{app（BL→AP）}表现出明显降低趋势,说明Tol包裹在NLCs中促进了药物吸收,抑制了P-糖蛋白（P-gp）的外排作用。与Tol混悬液相比,大鼠ig Tol-NLCs后,Tol生物利用度提高了2.5倍。结论 按优化处方制备的Tol-NLCs,能够显著提高药物的生物利用度。     

Preservative system development for argan oil-loaded nanostructured lipid carriers

Nanostructured lipid carriers (NLC) are used in many dermal cosmetic formulations. To prevent microbiological spoilage of NLC suspensions preservative systems must be used. Preservatives can impair the physical stability of NLC suspensions. Therefore, a systematic screening of preservative systems should be performed and the compatibility of these preservative systems with each NLC formulation has to be investigated. In this study three Argan oil-loaded NLC formulations were developed. Ethanol, propylene glycol and pentylene glycol were admixed to these formulations as preservative systems. The physical stability of the non-preserved and preserved formulations has been investigated. Upon admixing 20% w/w ethanol to the selected formulations, immediate particle aggregation could be detected using laser diffractometry and after 24 hours gelling occurred. This was accompanied with a lowering of Zeta potential value. Samples preserved with 10% w/w propylene glycol did not show any change in particle size or in Zeta potential, in comparison to the non-preserved formulation, when measured after one day and 120 days. Samples preserved with 5% pentylene glycol proved also to be stable after 120 days and did not show any change in particle size or Zeta potential.     

In vivo studies on the oridonin-loaded nanostructured lipid carriers

Oridonin (ORI)-loaded Nanostructured lipid carriers (NLC) were prepared by emulsion–evaporation and low temperature–solidification technique, and evaluated for morphological observation, particle size, zeta potential and in vitro drug release. Next, the characteristics of biodistribution and pharmacokinetics in vivo were examined. The average particle size of resultant NLC was 245.2?nm and the zeta potential was found to be -38.77 mV. The in vivo characteristics of ORI-loaded NLC were studied after intravenous administration using Kunming strain mice as experimental animals. An ORI control solution was studied parallelly. In tested organs, the distribution of ORI-loaded NLC to liver was higher than that of free drug. ORI-loaded NLC showed higher AUC (area under tissue concentration–time curve) values and circulated in the blood stream for a longer time compared with ORI solution. These results support the potential applications of NLC for the delivery of ORI.     

YSA肽修饰的纳米结构脂质载体的制备及表征

目的本研究作者旨在制备载siRNA的YSA肽修饰的纳米结构脂质载体(siRNA/YSA-NLC)并对其进行表征。方法通过YSA与DSPE-PEG_(2000)-Mal发生反应生成DSPE-PEG_(2000)-YSA;采用熔融-超声法制备NLC;以合成的DSPE-PEG_(2000)-YSA对NLC进行表面修饰,制得YSA-NLC,与siRNA复合,制备siRNA/YSA-NLC复合物。采用MCF-7细胞对DSPE-PEG_(2000)-YSA的用量进行筛选,并对优化后的siRNA/YSA-NLC进行表征。结果 DSPE-PEG_(2000)-YSA在NLC中的用量为6%;siRNA/YSA-NLC的粒径为(114.26±11.35)nm,多聚分散度(PDI)为(0.287±0.043),Zeta电位为(6.16±2.79)mV,包封率为(82.31±2.41)%;在4～8℃条件下放置30 d,粒径、PDI和Zeta电位无明显变化;YSA-NLC对siRNA具有良好的保护作用,在血浆中24 h内仍能保持稳定。结论选定和制备了具有良好体外理化性质和瘤靶向能力的YSA-NLC递送siRNA。     

In vivo studies on the oridonin-loaded nanostructured lipid carriers

Oridonin (ORI)-loaded Nanostructured lipid carriers (NLC) were prepared by emulsion-evaporation and low temperature-solidification technique, and evaluated for morphological observation, particle size, zeta potential and in vitro drug release. Next, the characteristics of biodistribution and pharmacokinetics in vivo were examined. The average particle size of resultant NLC was 245.2?nm and the zeta potential was found to be -38.77 mV. The in vivo characteristics of ORI-loaded NLC were studied after intravenous administration using Kunming strain mice as experimental animals. An ORI control solution was studied parallelly. In tested organs, the distribution of ORI-loaded NLC to liver was higher than that of free drug. ORI-loaded NLC showed higher AUC (area under tissue concentration-time curve) values and circulated in the blood stream for a longer time compared with ORI solution. These results support the potential applications of NLC for the delivery of ORI.