Comparison of wax and glyceride solid lipid nanoparticles (SLN)

The present study compares solid lipid nanoparticles (SLN) formulated with either wax or glyceride bulk material. While most published data deal with glyceride SLN, little knowledge is reported on wax carriers. The two types were compared with respect to drug encapsulation efficacy, particle size distribution after production and storage, and crystal packing. The inclusion of retinol as a model drug was investigated. Retinol is chemically unstable in water and rather stable in lipid phases. Thus, rapid degradation of retinol indicates rapid drug expulsion from the carrier. Good stability indicates an effective drug encapsulation in the lipid phase of the nanoparticles. Particle size distribution was measured by laser diffractometry. Subcell packing and assignment of polymorphic forms was investigated by WAXS measurements. Glyceride SLN showed good drug encapsulation, while physical stability was poor. In contrast, wax SLN possessed good physical stability but lacked sufficient drug encapsulation in the solidified state. These differences were attributed in part to different crystal packing. Less ordered crystal lattices favour successful drug inclusion, as in the case of glyceryl monosterate and glyceryl behenate SLN. The highly ordered crystal packing of wax SLN comprised of beeswax or cetyl palmitate, for instance, leads to drug expulsion, but also to superior physical stability.     

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。     

Preparation and characterization of nitrendipine solid lipid nanoparticles

Nitrendipine, a dihydropyridine calcium channel blocker, has very poor oral bioavailability (10-20%) due to first pass effect. Solid lipid nanoparticle (SLN) delivery systems of nitrendipine have been developed using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers stearylamine and dicetyl phosphate. SLNs were prepared by hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperatures above the melting point of lipids. Optimization studies of process and formulation variables were carried out. Particle size and zeta potential were measured by photon correlation spectroscopy (PCS) using Malvern zetasizer. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies were performed to characterize state of drug and lipid modification. In vitro release studies were performed in phosphate buffer pH 6.8 using modified Franz diffusion cell. Stable nitrendipine SLNs of mean size range 79 to 213 nm and zeta potential -38.2 to +34.6 mV were developed. About 99% nitrendipine was entrapped in SLNs and were stable on storage at 4 and 25 degrees C. DSC and PXRD analyses revealed that nitrendipine is dispersed in SLNs in an amorphous state. The release pattern of drug is analyzed and found to follow Weibull distribution rather than first order and Higuchi equation.     

注射用葫芦素B固体脂质纳米粒的制备

目的为提高葫芦素B的疗效,降低毒性及不良反应,,制备了葫芦素B固体脂质纳米粒。方法采用高压匀质法制备葫芦素B固体脂质纳米粒。以单因素轮换法考察影响制备葫芦素B固体脂质纳米粒的处方和工艺因素,通过正交设计优化处方。结果制备的纳米粒为类球形纳米粒子,包封率质量分数为90.67%,平均粒径为135 nm。结论高压匀质法可用于制备葫芦素B固体脂质纳米粒。     

Formulation and characterization of curcuminoids loaded solid lipid nanoparticles

Curcuminoids loaded solid lipid nanoparticles (SLNs) have been successfully developed using a microemulsion technique at approximately 75 degrees C. It was found that variation in the amount of ingredients had profound effects on the curcuminoid loading capacity, the mean particle size, and size distribution. At optimized process conditions, lyophilized curcuminoids loaded SLNs showed spherical particles with a mean particle size of approximately 450nm and a polydispersity index of 0.4. Up to 70% (w/w) curcuminoids incorporation efficacy was achieved. In vitro release studies showed a prolonged release of the curcuminoids from the solid lipid nanoparticles up to 12h following the Higuchi's square root model. After 6-month storage at room temperature in the absence of sunlight, the physical and chemical stabilities of the lyophilized curcuminoids loaded SLNs could be maintained, i.e. the mean particle size and the amount of curcuminoids showed no significant changes (P>0.05) compared to the freshly prepared SLNs. In addition, the chemical stability of curcuminoids incorporated into SLNs was further investigated by dispersing them into a model cream base. The results revealed that after storage in the absence of sunlight for 6 months, the percentages of the remaining curcumin, bisdemethoxycurcumin and demethoxycurcumin were 91, 96 and 88, respectively.     

Development and evaluation of Chrysin-Phospholipid complex loaded solid lipid nanoparticles - storage stability and in vitro anti-cancer activity

Abstract

Context: Flavonoids show promising anticancer potential but it is limited due to poor solubility. Objective: The present investigation was to prepare Chrysin-Phospholipid complex loaded solid lipid nanoparticles (Ch-PC-SLNs) for improving its encapsulation as compared to that of Chrysin loaded SLNs (Ch-SLNs) and evaluated for potential increase in the anti-cancer activity against MCF-7 cell line. Methods: The physiochemical characteristics and release kinetics for Ch-SLNs and Ch-PC-SLNs were evaluated and compared. Storage stability of Ch-PC-SLNs was evaluated up to 3?months. Solid state properties (DSC, XRD) and morphology (AFM) of Ch-PC-SLNs were also studied. In-vitro anticancer activity was investigated by using MTT assay. Results and Discussion: Ch-PC-SLNs exhibited higher encapsulation efficiency than Ch-SLNs and zero order release kinetics. Ch-PC-SLNs were found to be stable upto 3?months upon lyophilisation with mannitol as cryoprotectant. DSC and XRD study revealed the loss of highly crystalline nature of Chrysin in Ch-PC-SLNs. The Ch-PC-SLNs lead to significantly higher in-vitro anticancer activity than that of bulk Chrysin. Conclusion: The study concludes that phospholipids complex with Chrysin lead to improve encapsulation, storage stability of SLNs and in vitro anticancer activity.     

Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization,pharmacokinetic and pharmacodynamic evaluation

Abstract

Candesartan cilexetil (CC) is used in the treatment of hypertension and heart failure. It has poor aqueous solubility and low oral bioavailability. In this work, CC loaded solid lipid nanoparticles (CC-SLNs) were developed to improve the oral bioavailability. Components of the SLNs include either of trimyristin/tripalmitin/tristearin, and surfactants (Poloxamer 188 and egg lecithin E80). The CC loaded nanoparticles were prepared by hot homogenization followed by ultrasonication method. The physicochemical properties, morphology of CC-SLNs were characterized, the pharmacokinetic and pharmacodynamic behaviour of CC-SLNs were evaluated in rats. Stable CC-SLNs having a mean particle size of 180–220?nm with entrapment efficiency varying in between 91–96% were developed. The physical stability of optimized formulation was studied at refrigerated and room temperature for 3 months. Further, freeze drying was tried for improving the physical stability. DSC and XRD analyses indicated that the drug incorporated into SLN was in amorphous form but not in crystalline state. The SLN-morphology was found to be nearly spherical by electron microscopic studies. Pharmacokinetic results indicated that the oral bioavailability of CC was improved over 2.75-fold after incorporation into SLNs. Pharmacodynamic study of SLNs in hypertensive rats showed a decrease in systolic blood pressure for 48?h, while suspension showed a decrease in systolic blood pressure for only 2?h. Taken together, these effects are due to enhanced bioavailability coupled with sustained action of CC in SLN formulation. Thus, the results conclusively demonstrated the role of CC-SLNs for a significant enhancement in oral bioavailability along with improved pharmacodynamic effect.     

Absorption, disposition and pharmacokinetics of solid lipid nanoparticles

Solid lipid nanoparticles (SLNs) are primarily composed of solid lipids, which thus impart to them some of the fundamental properties of these lipids, including biocompatibility, biodegradability and low-toxicity. SLNs represent a unique class of colloidal drug delivery systems that possess the advantages of both the "soft" drug carriers such as emulsions and liposomes and polymeric nanoparticles. In this review, we will provide an overview on the absorption, disposition and pharmacokinetics of SLNs. The lipidic nature, as well as the relatively small particle size, of SLNs ensures sufficient affinity with the biomembranes, and results in improved absorption by either of the oral, transdermal, pulmonary, nasal, ocular, rectal or buccal route. One special aspect of oral SLNs is the enhanced lymphatic absorption by either the chylomicron-association pathway or the M cell uptaking pathway. Intravenous SLNs are predominantly uptaken by the liver or spleen following opsonization by the complementary system. Modification of SLN surface with PEGs chains will mask the hydrophobic surface and divert SLNs to non-hepatic and non-splenic organs, while ligand-modification will achieve active targeting to specific tissues or organs. Degradation of SLNs is primarily based on the degradation of the lipids themselves by lipase. Pharmacokinetics reflects the effect of the lipidic vehicles of SLNs on in vivo disposition of the loaded drugs.     

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.     

Preparation and characterization of solid lipid nanoparticles loaded with alpha-Asarone

This work investigated the potential of solid lipid nanoparticles (SLNs) to improve oral bioavailablity and tissue uptake of a poorly soluble drug, alpha-Asarone. Ultrasonic homogenization method was employed to prepare alpha-Asarone-loaded SLNs (alpha-Asarone-SLNs). Particle size and distribution, pH, viscosity, drug incorporation and zeta potential of the SLNs were investigated. Pharmacokinetic study of oral administration to male rats at 10 mg/Kg suggested that the relative bioavailability of alpha-Asarone was significantly improved in alpha-Asarone-SLN group compared to alpha-Asarone solution group. Comparison of alpha-Asarone-SLN to alpha-Asarone control solution for alpha-Asarone concentrations in rat tissue showed an increased uptake of alpha-Asarone in brain and lung for the ARE-SLN group. These results indicate that alpha-Asarone-SLNs significantly enhance the absorption and tissue distribution of alpha-Asarone. SLNs offer a new approach to improve the oral bioavailability of poorly soluble drugs.     

左旋多巴固体脂质纳米粒的制备及包封率测定

目的:用微乳法制备左旋多巴固体脂质纳米粒(LDP-SLN),并建立包封率的测定方法。方法:通过绘制三元相图,采用微乳法制备LDP-SLN,用TEM和激光粒度仪进行了颗粒形貌和粒径分布的研究,用葡聚糖凝胶层析法分离测定包封率。对其粒径、形态、包封率等理化性质进行研究,并考察其稳定性。结果:实验制得LDP-SLN为稳定的略泛蓝色乳光的纳米混悬液,在透射电镜下显示为较为均匀的球体,激光粒度测定平均粒径为108nm,多分散系数1.153;4℃放置2个月,粒径、包封率无显著变化。包封率测定的线性范围为2～100mg·mL-1,线性良好(r=0.9999),精密度符合要求,LDP-SLN上柱洗脱后分离度和回收率均符合要求。结论:该研究中制备了物理性质较为稳定的LDP-SLN,建立了合适的包封率测定方法,并考查初步稳定性较好。     

Emodin loaded solid lipid nanoparticles: preparation, characterization and antitumor activity studies

The objective of the present study was to prepare and characterize emodin (EMO)-loaded solid lipid nanoparticles (E-SLNs) and evaluate their antitumor activity in vitro. EMO and pharmaceutical lipid material were used to prepare E-SLNs by high pressure homogenization (HPH). Poloxamer 188 and Tween 80 were used as surfactants. The physicochemical properties of the E-SLNs were investigated by particle size analysis, zeta potential measurement, drug entrapment efficiency (EE), stability and in vitro drug release behavior. The E-SLNs showed stable particle size at 28.6 ± 3.1 nm, ideal drug EE and relative long-term physical stability after being stored for 4 months. The drug release of E-SLNs could last 72 h and exhibited a sustained profile, which made it a promising vehicle for oral drug delivery. MTT assay showed that E-SLNs could significantly enhance the in vitro cytotoxicity against human breast cancer cell line MCF-7 and MDA-MB-231 cells compared to the EMO solution, while free EMO, blank SLNs (B-SLNs) and E-SLNs all showed no significant toxicity to human mammary epithelial line MCF-10A cells. Flow cytometric analysis demonstrated that E-SLNs also showed more significant cell cycle arrest effect in MCF-7 cells compared to bulk EMO solution. Hoechst 33342 staining and Annexin V-FITC/PI double staining further confirmed that E-SLNs induced higher apoptotic rates in MCF-7 cells, indicating that cell cycle arrest and apoptosis maybe the underlying mechanism of the enhanced cytotoxicity. Taken together, it seems that HPH was a simple, available and effective method for preparing high quality E-SLNs to enhance its aqueous solubility. Moreover, these results suggest that the delivery of EMO as lipid nanoparticles maybe a promising approach for cancer therapy.     

Idebenone loaded solid lipid nanoparticles interact with biomembrane models: calorimetric evidence

The knowledge of the interactions between solid lipid nanoparticles (SLN) and cell membranes is important to develop effective carrier systems for drug delivery applications. Loading idebenone (IDE), an antioxidant drug useful in the treatment of neurodegenerative diseases, into SLN improves IDE antioxidant activity in in vitro biological studies, but the mechanism by which IDE permeation through the blood-brain barrier (BBB) occurs are still unclear. Therefore, in this research, unloaded and IDE loaded SLN interaction with biomembrane models, consisting of dimyristoylphosphatidylcholine multilamellar vesicles (MLV), were studied by differential scanning calorimetry (DSC). In the experiments performed, unloaded and IDE loaded SLN where incubated with the biomembrane models and their interactions were evaluated through the variations in their calorimetric curves. The results of our DSC studies indicated that the SLN under investigation were able to go inside the phospholipid bilayers with a likely localization in the outer bilayers of the MLV from where they moved toward the inner layers by increasing the contact time between SLN and MLV. Furthermore, IDE loaded SLN were able to release IDE into the biomembrane model, thus facilitating IDE penetration into the bilayers while free IDE showed only a low ability to interact with this model of biomembranes. Our results suggest that these SLN could be regarded as a promising drug delivery system to improve IDE bioavailability and antioxidant activity.     

Formulation and evaluation of verapamil hydrochloride loaded solid lipid microparticles

The present study aimed to produce verapamil hydrochloride-loaded solid lipid microparticles (SLM) by the w/o/w emulsion solvent evaporation technique, using diethyl ether as solvent phase, glyceryl monostearate as biodegradable polymer and Span 60 as surfactant. SLM of spherical shape were prepared by simple dilution of the emulsion with water. To increase the lipid load the process was conducted at 50 degrees C, and in order to reach sub-micron size, a high-shear homogenizer was used. The encapsulation efficiency of prepared SLM reached 74.29 +/- 0.76%. Particle size (98.55 +/- 1.42 microm), surface morphology (spherical) and drug loading efficiency (18.57 +/- 1.25% w/w) were investigated. And optimization of drug polymer ratio (3:1), nature and concentration of emulsion stabilizer in the external aqueous (0.1%), phase viscosity of external aqueous phase (0.5%), volume of external aqueous phase and stirring rate (1000 rpm) were detected. Analysis of microsphere content after processing showed that verapamil did not undergo any chemical modification within the micro-particles. The in-vitro release of verapamil from the microparticles was very low and an initial burst effect of 17% of the dose was observed. The slow release may help to avoid a high frequency of administration. The prepared solid lipid microparticles appear to have interesting perspectives as delivery systems for the oral administration of verapamil hydrochloride with improved half-life, improved bioavailability, and minimized local and systemic gastrointestinal disturbances of the drug.     

环孢素A纳米粒-凝胶制剂的制备及兔泪液药动学

目的制备环孢素A固体脂质纳米粒-原位凝胶复合制剂并考察其在家兔泪液中消除情况。方法采用乳化-超声法制备环孢素固体脂质纳米粒,用带正电的十八胺包衣以调节纳米粒表面的电性,用Cou lter LS 230测定纳米粒粒径,用电泳光散射法测定纳米粒的动电电位,将包衣纳米粒载于F127形成的原位凝胶中,考察制剂在家兔泪液中不同时间点药物浓度,以环孢素橄榄油滴眼液作对照,计算药物动力学参数。结果纳米粒粒径121 nm,动电电位+23 mv,纳米粒-凝胶制剂在家兔眼部经3 h的泪液代谢动力学参数AUC、MRT分别为蓖麻油制剂的3.4和4.0倍,包衣纳米粒的AUC和MRT也均比未包衣纳米粒有显著提高。结论环孢素A固体脂质纳米粒-原位凝胶制剂可显著提高环孢素在泪液中的浓度,延长作用时间,减少刺激性。     

Formulation and in vitro characterization of domperidone loaded solid lipid nanoparticles and nanostructured lipid carriers

Background and the purpose of the study

Domperidone (DOM) is a dopamine- receptor (D₂) antagonist, widely used in the treatment of motion-sickness. The pharmacokinetic parameters of DOM make it a suitable candidate for development of Solid Lipid Nanoparticle (SLN) and Nanostructured Lipide Carrier (NLC). The purpose of the present investigation was to prepare and evaluate DOM loaded solid lipid nanoparticles (DOM-SLN) and DOM loaded nanostructured lipid carriers (DOM-NLC).

Methods

DOM loaded SLN and NLC were prepared by hot homogenization followed by ultrasonication technique, using trimyristin as solid lipid, cetyl recinoleate as liquid lipid and a mixture of soy phosphatidylcholine (99%) and tween 80 as surfactant. SLN and NLC were characterized for particle size, polydispersity index (PDI), zeta potential and entrapment efficiency. The effects of composition of lipid materials and surfactant mixture on the particle size, PDI, zeta potential, drug entrapment efficiency, and in vitro drug release behavior were investigated. DSC analysis was performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by transmission electron microscopy (TEM). SLN and NLC formulations were subjected to stability study over a period of 40 days.

Results

The mean particle size, PDI, zeta potential and entrapment efficiency of optimized SLN (SLN1) and NLC were found to be 30.45 nm, 0.156, 12.40 mV, 87.84% and 32.23 nm, 0.160, 10.47 mV, 90.49% respectively. DSC studies revealed that DOM was in an amorphous state and triglycerides were in the β prime form in SLN and NLC. Shape and surface morphology was determined by TEM revealed fairly spherical shape of nanoparticles. In vitro release studies demonstrated that both the SLN and NLC formulations possessed a controlled release over a period of 24 hrs. SLN and NLC formulations were subjected to stability over a period of 40 days. There was no significant (P<0.05) change in particle size, zeta potential, PDI and entrapment efficiency indicating the developed SLN and NLC were fairly stable.

Conclusion

Fairly spherical shaped, stable and controlled release DOM-SLN and DOM-NLC could be prepared by hot homogenization followed by ultrasonication technique.     

盐酸雷洛昔芬固体脂质纳米粒的制备与体内药动学研究

目的 制备盐酸雷洛昔芬固体脂质纳米粒(raloxifene hydrochloride solid lipid nanoparticles, RLX-SLNs),并研究其在大鼠体内的药动学。方法 采用热熔乳化-高压均质法制备RLX-SLNs,通过测定包封率、粒径分布、Zeta电位、微观形态并用差示扫描量热法(differential scanning calorimetry, DSC)对其进行表征;考察了RLX-SLNs的体外释药特性和稀释稳定性;比较了RLX混悬剂与RLX-SLNs经大鼠口服给药后的体内药动学。结果 制备的RLX-SLNs外观呈乳白色溶液状,包封率为97.8%±1.6%,粒径为(194.5±8.5) nm,多聚分散指数(polydispersity index, PDI)为0.183±0.08,Zeta电位为(-34.3±1.5) mV;在透射电镜下观察到RLX-SLNs呈球状分布,无聚集;DSC测定结果显示RLX-SLNs中的药物吸热峰消失;RLX-SLNs在4种释放介质中均表现为双相释药特征;大鼠口服RLX-SLNs后,其药物达峰质量浓度和口服生物利用度均显著高于RLX混悬剂。结论 将盐酸雷洛昔芬制备成固体脂质纳米粒,制备工艺可控,生物利用度显著提高,为盐酸雷洛昔芬的二次开发奠定了实验基础。     

Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles

Docetaxel is used in the treatment of many types of cancer, but its entry into the brain is restricted by p-glycoprotein (p-gp) efflux. A potential drug–drug interaction exists between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system, and ketoconazole can inhibit p-gp efflux of docetaxel at blood brain barrier. Hence, these two drugs were loaded in solid lipid nanoparticles (SLNPs) and surface of these NPs were modified with folic acid for brain targeting. These NPs were characterized for particle size, zeta potential, entrapment efficiency, in vitro drug release, cytotoxicity, and cell uptake in brain endothelial cell lines. Plasma and brain pharmacokinetics have shown increased brain uptake of docetaxel with surface-modified dual drug-loaded SLNPs. Brain permeation coefficient (K_in) of folate-grafted docetaxel and ketoconazole loaded SLNPs was 44 times higher than that of Taxotere. Hence, these NPs were suitable for the delivery of lipophilic anticancer drugs to the brain.From the Clinical EditorIn this paper, successful delivery of docetaxel and ketoconazole is reported using solid lipid nanoparticles surface modified with folic acid for brain targeting, which may pave the way to optimized clinical applications of lipophilic anticancer drugs to the brain.