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.     

Preparation and characteristics of oridonin-loaded nanostructured lipid carriers as a controlled-release delivery system

In order to improve drug entrapment efficiency and loading capacity, nanostructured lipid carriers consisting of solid lipid and liquid lipid as a new type of colloidal drug delivery system were prepared. The dispersions of oridonin-loaded solid lipid nanoparticles and nanostructured lipid carriers were successfully prepared by the emulsion-evaporation and low temperature-solidification technique using monostearin as the solid lipid, caprylic/capric triglycerides as the liquid lipid and oridonin as the model drug. Their physicochemical properties of oridonin-loaded nanostructured lipid carriers and release behaviours were investigated and compared with those of solid lipid nanoparticles. As a result, the mean particle size was ～200 nm with narrow polydispersity index lower than 0.4 for all developed formulations. Zeta potential values were in the range ?35 mV ～ ?50 mV, providing good physical stability of all formulations. The differential scanning calorimetry and X-ray diffraction analysis results demonstrated lipid nanoparticles exhibited crystal order disturbance and thus left more space to accommodate drug molecules. The improved drug entrapment efficiency and loading capacity were observed for nanostructured lipid carriers and they enhanced with increasing the caprylic/capric triglycerides content. In vitro drug release experiments exhibited biphasic drug release patterns with burst release initially and prolonged release afterwards. These results indicated that nanostructured lipid carriers could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release.     

Passive and active strategies for transdermal delivery using co-encapsulating nanostructured lipid carriers: In vitro vs. in vivo studies

This work aimed at designing a formulation based on nanostructured lipid carriers (NLC) for transdermal co-administration of olanzapine and simvastatin, using passive and active strategies in a combined in vitro/in vivo development approach. NLC were prepared by two distinct methods, namely solvent emulsification–evaporation (SE/E) and high pressure homogenization (HPH). HPH was selected on the basis of a better performance in terms of drug loading and in vitro permeation rate. Several mathematical models were used to elucidate the release mechanisms from lipid nanoparticles. In vitro release kinetics was shown to be driven by diffusion, but other mechanisms were also present, and supported the feasibility of using NLC for sustained drug delivery. The in vitro skin studies showed that the chemical penetration enhancers, limonene and ethanol, added to the NLC formulations, promoted a synergistic permeation enhancement of both drugs, with olanzapine exhibiting a higher permeation than simvastatin. Transdermal administration to rats resulted in steady-state levels reached at around 10 h and maintained for 48 h, again with olanzapine exhibiting a better permeation rate. The pharmacokinetic parameters indicated that the NLC dispersion displayed a better in vivo performance than the gel, which was consistent with the in vitro results. These differences were, however, negligible in the flux values, supporting the use of gel as a final, more convenient, formulation. The in vivo experiments in rats correlated well with in vitro findings and revealed that the combined use of ethanol and limonene, incorporated in the NLC formulation, provided the main driving force for drug permeation. The Dermaroller® pretreatment did not significantly enhance drug permeation, supporting the use of passive methods as suitable for a transdermal delivery system. Furthermore, this work may provide a promising proof-of-concept for further clinical application in the treatment of schizophrenia and associated disorders, combined with dyslipidemia.     

The effect of surfactant composition on the chemical and structural properties of nanostructured lipid carriers

Abstract

Fine-tuning the nanoscale structure and morphology of nanostructured lipid carriers (NLCs) is central to improving drug loading and stability of the particles. The role of surfactant charge on controlling the structure, the physicochemical properties and the stability of NLCs has been investigated using three surfactant types (cationic, anionic, non-ionic), and mixed surfactants. Either one, a mixture of two, or a mixture of three surfactants were used to coat the NLCs, with these classified as one, two and three surfactant systems, respectively. The mixed (two and three) surfactant systems produced smaller NLC particles and yielded NLCs with lower crystallinity than the one surfactant system. The combined effects of the ionic and the non-ionic surfactants may play a key role in assisting the lipid-oil mixing, as well as maintaining colloidal repulsion between NLC particles. In contrast, for the three surfactant system, the lipid–oil mixture in the NLCs appeared less homogenous. This was also reflected in the results of the stability study, which indicated that NLC particle sizes in two surfactant systems appeared to be retained over longer periods than for other surfactant systems.     

Design and in vivo pharmacodynamic evaluation of nanostructured lipid carriers for parenteral delivery of artemether: Nanoject

The objective of the present investigation was to explore the potential of nanostructured lipid carriers (NLC) for the intravenous delivery of artemether (ARM), a poorly water-soluble antimalarial agent. The NLC of ARM (Nanoject) were formulated by employing a microemulsion template technique. The NLC were evaluated for particle size, encapsulation efficiency, in vitro drug release and in vitro hemolysis. The antimalarial activity of the Nanoject and conventional ARM injectable formulation was evaluated in Plasmodium berghei infected mice. The average particle size of Nanoject was 63+/-28 nm and the encapsulation efficiency was found to be 30+/-2%. The Nanoject released ARM in a sustained manner. In vitro haemolytic studies showed that Nanoject had lower haemolytic potential (approximately 13%) as compared to all the components when studied individually. Nanoject showed significantly higher (P<0.005) antimalarial activity as compared to the marketed injectable formulation. The antimalarial activity of Nanoject lasted for a longer duration (more than 20 days) indicating that Nanoject may be long-circulating in vivo. Nanoject showed significantly higher survival rate (60%) even after 31 days as compared to marketed formulation which showed 0% survival (100% mortality). This clearly indicates that Nanoject offers several advantages over the currently marketed oily intramuscular formulation (Larither).     

Preparation of the nanostructured lipid carriers of artemisinin and its pharmacokinetic evaluation

Artemisinin (ART) is a widely used active drug for malaria, including severe and cerebral malaria. However, its therapeutic efficacy is affected by its lower bioavailability. In the present study, nanostructured lipid carriers (NLCs) were proposed as carrier of ART to improve pharmacokinetic properties of the drug. ART-NLC was prepared by high-pressure homogenization based on orthogonal design. The particle size, zeta potential, encapsulation efficiency (EE) and percentage of drug loading (DL) of ART-NLC were (53.06±2.11) nm, (–28.7±3.59) mV, 73.9%±0.5% and 11.23%±0.37%, respectively. ART-NLC showed the sustained release characteristics and scarcely the hemolysis effect on human red blood cells. The pharmacokinetics of ART-NLC for rats after tail intravenous injection (i.v) or intraperitoneal injection (i.p) were investigated by liquid chromatography-tandem mass spectroscopy (LC-MS/MS). And ART solution was designed as control preparation. For rats of i.v groups, the AUC0–∞ ((707.45±145.65) ng·h/mL) of ART-NLC were significantly bigger than that of ART ((368.98±139.58) ng·h/mL). The MRT ((3.38±0.46) h) of ART-NLC was longer than that of ART ((1.39±0.61) h). And similar results were observed for rats of i.p groups. The AUC0–∞ ((1233.06±235.57) ng·h/mL) and MRT ((4.97±0.69) h) of ART-NLC were both bigger than those of ART, which were (871.17±234.03) ng·h/mL) and (1.75±0.31) h), respectively. Compared with ART, ART-NLC showed a significant increase in AUC0–∞ (P<0.05) and MRT (P<0.001) for both i.p and tail i.v administrations.     

In vitro characterization and growth inhibition effect of nanostructured lipid carriers for controlled delivery of methotrexate

The present study describes the design and characterization of nanostructured lipid carriers (NLCs) for controlled delivery of methotrexate (MTX). A series of NLCs with or without MTX were prepared using different ratios of liquid–lipid to solid–lipid and type and concentration of surfactants. The effect of different formulation parameters on the physical properties of NLCs, entrapment efficiency of MTX and in vitro drug release was evaluated. In addition, the in vitro delivery and cytotoxicity of MTX-loaded NLCs against human prostate cancer DU-145 cells and ovarian human cancer A2780 cells were investigated. Drug loading capacity, particle size and surface charge of the prepared NLCs and the in vitro MTX release were affected by the formulation parameters. In vitro growth inhibition assay using DU-145 and A2780 cancer cell lines showed that drug-free NLCs maintained cell viability while MTX-loaded NLCs inhibited the growth of both cell lines. In addition, MTX-loaded NLCs showed superior inhibitory effect on cell growth over the free drug especially in A2780 cell lines and a higher cytotoxic effect on DU-145 at higher drug concentration. The results of the current study warrant further exploration for the use NLCs as a controlled delivery system for chemotherapeutic agents.     

UPLC-MS/MS法考察多西他赛纳米脂质载体的大鼠体内药代动力学研究

目的以多西他赛注射液为参比制剂,研究多西他赛纳米脂质载体在大鼠体内的药代动力学。方法采用平行对照试验法,12只大鼠随机分成2组,每组6只,分别静脉注射多西他赛纳米脂质载体和多西他赛注射液10 mg/kg,建立UPLC-MS/MS法测定血浆中不同时间多西他赛的浓度,并计算药代动力学参数。结果大鼠静脉注射多西他赛纳米脂质载体和多西他赛注射液后,t_(1/2)分别为(3.12±0.66)、(2.22±0.51)h,C_(max)为(21 731.57±2 751.01)、(7 062.30±681.62)ng/m L,Vss为(4.92±1.75)、(9.34±2.36)L/kg,CL为(1.07±0.20)、(2.91±0.39)L/(h·kg),AUC_(0-t)为(9 591.32±1 855.55)、(3 448.45±495.88)ng·h/m L,AUC_(0-∞)为(9 647.89±1 845.93)、(3 488.34±492.14)ng·h/m L,各项药动学参数比较差异均有统计学意义。结论本方法简单快速,准确可靠,与多西他赛注射液比较,多西他赛纳米脂质载体具有一定的缓释和长循环特征。     

Budesonide-loaded nanostructured lipid carriers reduce inflammation in murine DSS-induced colitis

The challenge for the treatment of inflammatory bowel disease (IBD) is the delivery of the drug to the site of inflammation. Because nanoparticles have the ability to accumulate in inflamed regions, the aim of the present study was to evaluate nanostructured lipid carriers (NLCs) as nanoparticulate drug delivery systems for the treatment of IBD. Budesonide (BDS) was chosen as a candidate anti-inflammatory drug. BDS-loaded NLCs (BDS-NLC) produced by high-pressure homogenization had a size of 200 nm and a negative zeta potential. BDS-NLCs reduced the TNF-α secretion by activated macrophages (J774 cells). BDS-NLCs were more active in a murine model of dextran sulfate-induced colitis when compared with Blank-NLCs or a BDS suspension: BDS-NLCs decreased neutrophil infiltration, decreased the levels of the pro-inflammatory cytokines IL-1β and TNF-α in the colon and improved the histological scores of the colons. These data suggest that NLCs could be a promising alternative to polymeric nanoparticles as a targeted drug delivery system for IBD treatment.     

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。     

Clinical cosmeceutical repurposing of melatonin in androgenic alopecia using nanostructured lipid carriers prepared with antioxidant oils

Background: The present work aims to formulate nanostructured lipid carriers (NLCs) exhibiting high skin deposition and high inherent antioxidant potential to repurpose the use of melatonin hormone and some antioxidant oils in the treatment of androgenic alopecia (AGA).

Research design and methods: NLCs were characterized for their size, charge, drug entrapment, anti-oxidant potential, physical stability, in vitro release, surface morphology, and ex-vivo skin deposition. Their merits were clinically tested on patients suffering from AGA by calculating the degree of improvement, conduction of hair pull test, histometric assessment, and dermoscopic evaluation.

Results: Results revealed that melatonin NLCs showed nanometer size, negatively charged surface, high entrapment efficiency, and high anti-oxidant potential, in addition to sustained release for 6 h. Furthermore, NLCs displayed good storage stability and they were able to increase the skin deposition of melatonin 4.5-folds in stratum corneum, 7-folds in epidermis, and 6.8-folds in the dermis compared to melatonin solution. Melatonin NLCs displayed more clinically desirable results compared to the melatonin solution in AGA patients, manifested by increased hair density and thickness and decreased hair loss.

Conclusions: The aforementioned system was shown to be a very promising treatment modality for AGA, which is worthy of futuristic experimentation.     

葛根素纳米结构脂质载体大鼠体内药动学与组织分布

目的:制备葛根素纳米结构脂质载体(葛根素-NLCs),并考察其在大鼠体内的药动学及组织分布特性。方法:采用热熔乳化超声-低温固化法制备葛根素-NLCs,考察了葛根素-NLCs的粒径分布、Zeta电位和形态学性质;研究了葛根素-NLCs在大鼠体内的药动学与组织分布特征。结果:葛根素-NLCs平均粒径为(116.2±34.5)nm,多聚分散系数为0.217±0.024,Zeta电位为(-37.2±3.6)mV,包封率为(87.4±4.3)%。葛根素-NLCs在大鼠体内的AUC_0-t和MRT_0-t分别为葛根素注射剂的3.69和2.13倍;组织分布结果表明葛根素-NLCs在大鼠肝、脾、脑内的相对摄取率分别为葛根素注射液的3.95,3.41和2.30倍。结论:葛根素-NLCs延长了药物在血浆中的滞留时间,在体内具有良好的肝、脾和脑靶向性,可提高药物疗效。     

Physicochemical characterization and in vitro release studies of ascorbyl palmitate-loaded semi-solid nanostructured lipid carriers (NLC gels)

The aim of this study was to characterize the physicochemical properties and to study in vitro release of ascorbyl palmitate from semi-solid lipid nanoparticles based on nanostructured lipid carriers (NLC gels) systems with the desired viscosity for dermal delivery. NLC gels were obtained by a one-step production procedure employing a high pressure homogenization technique using different solid lipid matrices. Ascorbyl palmitate (AP) was selected as a lipophilic active ingredient due to its range of cosmetic applications. After the production, particles within the size range 170–250 nm having polydispersity index lower than 0.3 were obtained from all formulations. After the AP incorporation into the NLC gels, the zeta potential increased to values higher than |30 mV|. Almost 100% encapsulation efficiency was observed. The obtained SEM and AFM data revealed non-spherical shaped nanoparticles. From DSC and X-ray diffraction studies, it was shown that the lipid recrystallized in the solid state possessing a less ordered structure as compared to the bulk material. The release study of active-loaded NLC gel formulations using Franz diffusion cells revealed that the type of lipid matrix affects both the rate and the release pattern. The viscoelastic measurements revealed a more elastic than viscous behaviour of NLC formulations indicating a typical gel-like structure.     

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。     

Development of ionic-complex-based nanostructured lipid carriers to improve the pharmacokinetic profiles of breviscapine

Aim:

Breviscapine isolated from the Chinese herb Erigeron breviscapus (Vant) Hand-Mazz is widely used to treat cardiovascular and cerebrovascular diseases. The aim of this study was to improve the pharmacokinetic profiles of breviscapine using nanostructured lipid carrier based on an ionic complex formation.

Methods:

Breviscapine nanostructured lipid carrier (Bre-NLC) was prepared using the thin film homogenization method. The morphology of Bre-NLCs was determined using transmission electron microscopy. The mean particle size, polydispersity index, zeta-potential analysis and entrapment efficiency were analized. In vitro release was studied using the dialysis method. In vitro stability was studied in fresh plasma and liver slurry of rats. In vivo pharmacokinetics was analyzed in rats after intravenous injection of a dose equivalent to breviscapine (10 mg/kg).

Results:

The Bre-NLCs were spherical with a mean particle size of ∼170 nm, a zeta potential of ∼20 mV and a high entrapment efficiency of ∼89%. Compared with a commercially available solution, a substantial decrease in the cumulative release of breviscapine was found for the Bre-NLCs. The NLC has a significantly protective effect against the liver enzyme degradation of breviscapine. After intravenous administration in rats, the Bre-NLCs exhibited a 32 times increase in the AUC_0–t and a 12 times increase in T_1/2 as compared to the commercially available breviscapine solution.

Conclusion:

The results demonstrate that the NLC has great potential to use as a novel sustained release system for breviscapine.     

Baicalein loaded in tocol nanostructured lipid carriers (tocol NLCs) for enhanced stability and brain targeting

The objective of the present work was to investigate the specific brain targeting of baicalein by intravenous injection after incorporation into nanostructured lipid carriers (NLCs). The NLC system, composed of tripalmitin, Gelucires, vitamin E, phospholipids, and poloxamer 188 (referred to as tocol NLCs), was characterized in terms of its physicochemical properties, differential scanning calorimetry (DSC), stability, in vivo pharmacokinetics, and brain distribution. The lipid nanoparticles were spherical with an average size of ∼100 nm. The zeta potential of the nanoparticles was about −50 mV. DSC studies suggested that the majority of the inner cores of tocol NLCs had a slightly disordered crystal arrangement. The nanoparticulate dispersions demonstrated good physical stability during storage for 6 days. The incorporation of vitamin E in the formulations greatly reinforced baicalein's stability. The aqueous control and tocol NLCs were intravenously administered to rats. The plasma level of baicalein in NLCs was much higher and the half-life much longer than those in the free control. In the experiment on the brain distribution, NLCs respectively revealed 7.5- and 4.7-fold higher baicalein accumulations compared to the aqueous solution in the cerebral cortex and brain stem. Greater baicalein accumulations with NLCs were also detected in the hippocampus, striatum, thalamus, and olfactory tract. A 2-3-fold increase in baicalein amounts were achieved in these regions. Tocol NLCs improved baicalein's stability and the ability of baicalein to penetrate the brain; thus, this is a promising drug-targeting system for the treatment of central nervous system disorders.     

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。     

前列地尔纳米结构脂质载体的制备及含量测定

目的：制备前列地尔（PGE1）纳米结构脂质载体（NLC）并测定其含量。方法：以单硬脂酸甘油酯和miglyol812为脂质材料,采用超声分散法制得PGE1-NLC。采用C18柱（200mm×4.6mm,5μm）,流动相为0.0067mol/L磷酸盐缓冲液（pH6.3）-乙腈（3：1,V/V）,流速为1.2mL/min,柱后反应液为1mol/L氢氧化钾溶液,柱后反应管为聚四氟乙烯管（φ0.5mm×10m）,检测波长为278nm,进样量为20μL,柱温为60℃。结果：制得PGE1-NLC粒径为54.89±10.02nm,平均Zeta电位为-14.5mV,包封率为98.2%,含量为98.5%。结论：制备的PGE1-NLC纳米结构脂质载体粒径小,药物包封率高,含量测定方法简单易行。     

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。     

Preparation,characterization and biodistribution of nanostructured lipid carriers for parenteral delivery of bifendate

Nanostructured lipid carrier (NLC)-loaded bifendate (DDB) was prepared by melt-emulsification method to improve drug payloads and liver targeting. The particle size of the prepared formulation analysed by photon correlation spectroscopy (PCS) was 217.4?nm with a narrow polydispersity index (PI) lower than 0.2, meanwhile the loading capacity increased from 4.3% to 15.7% in comparison with DDB-loaded SLN reported in previous study. The zeta potential value was ?21.91?mV, and transmission electron microscopy studies revealed NLC of irregularly spherical shape. With respect to lipid polymorphism, a less ordered structure of NLC was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In addition, tissue distribution of DDB-loaded NLC and DDB solution were carried out in Kunming strain mice. In tested organs, the distribution of DDB-loaded NLC to liver was higher than that of free drug. These results support the potential applications of NLC for the delivery of DDB.