以茶皂素为天然乳化剂制备水飞蓟素纳米乳及其理化性质考察

目的 以茶皂素为天然乳化剂制备水飞蓟素纳米乳（silymarin nanoemulsion,SM-NE）。方法 使用高速剪切联合高压均质法制备SM-NE,以平均粒径、粒度多分散系数（polydispersity index,PDI）、分层指数和外观为主要评价指标,采用单因素试验对处方和制备工艺进行优化;以摩尔增溶比（molar solubilization ratio,MSR）和胶束-水分配系数（K_m）作为评价指标探究了茶皂素对水飞蓟素的增溶能力;对最佳处方和工艺制备的SM-NE进行了理化性质和稳定性考察。结果 SM-NE的最佳处方为水飞蓟素用量0.15%,茶皂素用量为0.3%,油相用量为5%,最佳制备工艺为剪切速率16 000 r/min,剪切时间3 min,均质压力为100 MPa,均质次数为8次;茶皂素对水飞蓟素增溶参数值MSR和K_m分别为0.011 1和2.31;制得的SM-NE的平均粒径为（204.1±2.8）nm,PDI为0.058±0.007,电导率为（117.8±0.9）μs/cm,pH值为7.31±0.10,浊度为（59.75±1.10）cm^-1,水飞蓟素溶解度为（1.22±0.05）mg/mL;稳定性结果显示,SM-NE具有良好的离心稳定性和储存稳定性。结论 以茶皂素为天然乳化剂成功制备了稳定的SM-NE,茶皂素是一种潜在的用于水飞蓟素新型绿色纳米制剂生产的天然增溶剂。     

Solubilization of flurbiprofen into aptamer-modified PEG–PLA micelles for targeted delivery to brain-derived endothelial cells in vitro

Abstract

Novel aptamer-functionalized polyethylene glycol–polylactic acid (PEG–PLA) (APP) micelles were developed with the objective to target the transferrin receptor on brain endothelial cells. Flurbiprofen, a potential drug for therapeutic management of Alzheimer’s disease (AD), was loaded into the APP micelles using the co-solvent evaporation method. Results indicated that 9.03% (w/w) of flurbiprofen was entrapped in APP with good retention capacity in vitro. Targeting potential of APPs was investigated using the transferring receptor-expressing murine brain endothelial bEND5 cell line. APPs significantly enhanced surface association of micelles to bEND5 cells as quantified by fluorescence spectroscopy. Most importantly, APPs significantly enhanced intracellular flurbiprofen delivery when compared to unmodified micelles. These results suggest that APP micelles may offer an effective strategy to deliver therapeutically effective flurbiprofen concentrations into the brain for AD patients.     

A Simulated Stomach Duodenum Model Predicting the Effect of Fluid Volume and Prandial Gastric Flow Patterns on Nifedipine Pharmacokinetics From Cosolvent-Based Capsules

Nifedipine is a Biopharmaceutics Classification System class II drug displaying large variability in absorption even when administered as immediate-release soft gelatin capsules of a cosolvent formulation. This in vitro study sought to understand the reasons behind variability in nifedipine absorption, how it can be minimized, and if it can be predicted using in vitro models. A dynamic in vitro simulated stomach duodenum model was used to explore drug concentration–time profiles of nifedipine soft gelatin capsules under conditions simulating how patients take their medicines. Specifically, the effect of prandial gastric emptying patterns and fluid volume administration (250 mL vs. 50 mL water) were investigated. Significant supersaturation of nifedipine was observed. While administration of large and small water volumes gave rise to a similar C_max and area under the curve (AUC_∞), the coefficient of variation in AUC was 4.8% and 49%, respectively, which can be attributed to differences in precipitation kinetics. Fasting and fed gastric emptying patterns also gave rise to a similar AUC; however, C_max was significantly lower in the fed state. These trends are consistent with previously published in vivo results in healthy volunteers. The simulated stomach duodenum provides a good discriminative screening tool for predicting trends in drug concentration profiles of Biopharmaceutics Classification System class II drugs.     

Cyclodextrin Reduces Intravenous Toxicity of a Model Compound

Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-β-CD were determined. Blood compatibility and potential for hemolysis were assessed in vitro. Local tolerability was assessed after intravenous and subcutaneous injections in rats. A pharmacokinetic study was conducted in rats after intravenous bolus administration.GDC-0152 exhibited pH-dependent solubility that was influenced by self-association. The presence of succinic acid increased solubility in a concentration-dependent manner. HP-β-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-β-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by ～20-fold in vitro, and increased the maximum tolerated dose to 80 mg/kg.     

SDS-PAGE analysis of protein and lipopolysaccharide of extracellular vesicules and Sarkosyl-insoluble membranes from Bacteroides gingivalis

We have compared outer membranes (OM) of Bacteroides gingivalis ATCC 33277 isolated by the following 3 techniques: 1) high speed centrifugation after mechanical cell shearing; 2) sonication of the bacteria, followed by solubilization of the cytoplasmic membrane with N-Laurylsarconsinate (Sarkosyl), after which the Sarkosyl-insoluble membranes were recovered by centrifugation; 3) ammonium sulfate precipitation of extracellular vesicules from culture supernatant, followed by centrifugation and dialysis. Electron microscopy showed that the 3 preparations consisted of closed vesicules. Analysis by SDS-PAGE revealed that all 3 contained up to 28 polypeptides, most of which were common to each extract. The extracellular vesicules and Sarkosyl-insoluble preparation yielded similar protein patterns, although quantitative differences were observed. The sheared-cell preparation contained 8 additional proteins. The level of contamination of OM material by peptidoglycan and cytosol components was 1.8% in the sheared-cell preparation, and was null or lower than 0.8% in the other preparations. All 3 preparations showed the presence of LPS with a multiple banding pattern typical of smooth LPS. The sheared-cell preparation had a slightly lower LPS content than the other 2 preparations. Since extracellular vesicules are naturally released during bacterial growth, and are relatively simple to obtain, such native entities seem an appropriate source of OM components for use in studying the immunobiology of B. gingivalis surface antigens.     

Cosolvency of Dimethyl Isosorbide for Steroid Solubility

Dimethyl isosorbide (DMI), which is currently under investigation for its potential use as a pharmaceutical vehicle and drug permeation enhancer, is a water-miscible liquid with relatively low viscosity. The solubilization behavior of DMI as a cosolvent for nonpolar drugs was characterized via dielectric constant measurements of binary solvent systems containing DMI and either water, propylene glycol (PG), or polyethylene glycol (PEG). Evidence from the dielectric constant profiles and NMR studies suggest that DMI undergoes complexation with water and PG, but not with PEG, through hydrogen bonding interactions. The solvent complexation exhibited a major effect on the solubilities of prednisone, dexamethasone, and prednisolone in the mixed solvent systems. Maximum solubility of each drug was found to occur near a DMI/water or DMI/PG concentration ratio of 1:2. In the DMI–PEG mixed system, while there is no apparent interaction between DMI and PEG molecules, the solubility of prednisone was found to increase with decreasing dielectric constant.     

重组阿片肽包涵体的溶解工艺

通过SDS PAGE凝胶电泳确定了目的重组阿片肽存在于包涵体中,系统研究了影响大肠杆菌表达的重组阿片肽包涵体溶解的因素,确定了重组阿片肽包涵体制备溶解的最佳工艺条件,即菌体超声破碎5min,间隔时间6s,破碎效果最好;包涵体洗涤温度为4℃,尿素洗涤液的浓度为2mol/L,洗涤时间7～8h,8mol/L的尿素溶液对包涵体进行溶解,蛋白质质量浓度约为600μg/mL,其效果最佳.     

Controlled Release of Steroids Through Microporous Membranes with Sodium Dodecyl Sulfate Micelles

The effect of solubilization by sodium dodecyl sulfate (SDS) micelles on the transport of steroids across synthetic microporous membranes has been studied experimentally in a diffusion cell and compared with theoretical calculations. The model used for calculations accounted for the fluxes of free and micelle-solubilized drug. Since the pores of the microporous membranes were only 10 times larger than the micelle, hindered diffusion effects for the micelles were taken into account. The compounds of interest (hydrocortisone, testosterone, and progesterone) had a wide range of aqueous solubilities and distribution coefficients between the aqueous and the micellar phases. In general, the theoretical predictions of drug diffusion agreed with the data to within approximately 10%.     

水溶性聚合物和两亲聚合物23.两亲聚合物PAMC_(16)S对螺口恶嗪化学和物理行为的影响

研究了两亲聚合物聚 (2 -丙烯酰胺基十六烷磺酸 ) (PAMC16S)存在下 1 -乙基 -3 ,3 -二甲基螺 [吲哚啉 -萘并口恶嗪 ](SO -E)在水溶液中的增溶作用及PAMC16S对SO -E化学和光化学性质的影响。PAMC16S明显增加了SO -E在水相的溶解性 ,SO -E的最大增溶浓度随PAMC16S浓度增加呈线性增加规律。在PAMC16S存在下 ,新配制的SO -E溶液显示可逆的光致变色性 ,显色体呈红色 ,最大吸收峰位于 5 2 0nm ,在室温下的消色反应速度明显慢于无PAMC16S存在下的兰色显色体。SO -E/PAMC16S溶液是不稳定的 ,配制后较长时间即失去SO -E的正常光致变色性质。盐酸具有与PAMC16S相似的作用 ,SO -E/PAMC16S体系的不稳定性可用氨水中和的方法解决。1H -NMR结果表明SO -E在酸性介质中发生了不可逆的化学反应。     

聚氧乙烯山梨糖醇酐单油酸酯增溶冰片的研究

目的:研究聚氧乙烯山梨糖醇酐单油酸酯(吐温-80)增溶冰片的最佳配比。方法:相同量的吐温-80中分别加入不同量的冰片,以澄清度为指标,筛选出冰片、吐温-80增溶最佳配比。结论及结果:吐温-80与冰片质量比为15∶1时,溶液稳定且可稀释百倍而不析出冰片晶体。