利巴韦林脂质体在大鼠体内的药物动力学及其生物利用度

应用高效液相色谱法 ,以市售利巴韦林口服液为对照 ,测定了利巴韦林脂质体灌胃给药后大鼠血清中的药物浓度 ,按非隔室模型计算利巴韦林脂质体的药物动力学参数 ,AUC值为1 1 1 2 6μg·h/mL,MRT值为 2 1 6h ,K值为 0 0 61 /h ,其相对生物利用度为 1 2 1 3 %     

Preparation and evaluation of a chitosan-coated antioxidant liposome containing vitamin C and folic acid

Vitamin C (VC) and folic acid (FA) are the important nutrient and antioxidant in human body. In order to improve their stability, their co-loaded liposomes (VCFA-Lip) and chitosan-coated liposomes (CS-VCFA-Lip) are prepared and characterised. The mean particle size of VCFA-Lip and CS-VCFA-Lip is 138?nm and 249?nm, respectively. The encapsulation efficiencies of both drugs for CS-VCFA-Lip are much higher than those for VCFA-Lip. Furthermore, the experimental results show that the antioxidant activity of CS-VCFA-Lip is higher than that of VCFA-Lip. Moreover, the storage stability study reveals that the chitosan coating can efficiently improve the physical stability of VCFA-Lip. These results indicate that stability of VC and FA can be greatly improved after being wrapped by liposomes. In addition, the performance of CS-VCFA-Lip is better than VCFA-Lip, indicating CS-VCFA-Lip can be applied as a promising delivery system for the antioxidant defence system to the food industry and cosmetic industry.     

Formulation and Evaluation of a Folic Acid Receptor-Targeted Oral Vancomycin Liposomal Dosage Form

Purpose. To demonstrate utility of folic acid-coated liposomes for enhancing the delivery of a poorly absorbed glycopeptide, vancomycin, via the oral route. Methods. Liposomes prepared as dehydration-rehydration vesicles (DRVs) containing vancomycin were optimized for encapsulation efficiency and stability. A folic acid-poly(ethylene oxide)-cholesterol construct was synthesized for adsorption at DRV surfaces. Liposomes were characterized by differential scanning calorimetry (DSC) and assessed in vitroin the Caco-2 cell model and in vivoin male Sprague-Dawley rats. Non-compartmental pharmacokinetic analysis of vancomycin was conducted after intravenous and oral administration of solution or liposome-encapsulated vancomycin with or without 0.05 mole ratio FA-PEO-Chol adsorbed at liposome surfaces. Results. Optimal loading of vancomycin (32%) was achieved in DRVs of DSPC:Chol:DCP, 3:1:0.25 mole ratio (m.r.) after liposome extrusion. Liposomes released less than 40% of the entrapped drug after 2 hours incubation in simulated gastrointestinal (GI) fluid and simulated intestinal fluid containing a 10 mM bile salt cocktail. Incorporation of FA-PEO-Chol in liposomes increased drug leakage by 20% but resulted in a 5.7-fold increase in Caco-2 cell uptake of vancomycin. Liposomal delivery significantly increased the area under the curve of oral vancomycin resulting in a mean 3.9-fold and 12.5-fold increase in relative bioavailability for uncoated and FA-PEO-Chol-coated liposomes, respectively, compared with an oral solution. Conclusions. The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the rat compared with uncoated liposomes or oral solution. It is speculated that the cause of the observed effect was due to binding of liposome-surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.     

Transdermal delivery of low molecular weight heparin loaded in flexible liposomes with bioavailability enhancement: comparison with ethosomes

Low molecular weight heparin (LMWH)-loaded flexible liposomes (flexosomes) were formulated for transdermal delivery, and their physicochemical and pharmacokinetic parameters were compared with LMWH-loaded ethosomes. Flexosomes had similar particle size compared with ethosomes, but their deformability was higher than that of ethosomes (76.7% vs. 46.8%). In vitro, flexosomes demonstrated 2.6-fold higher permeability coefficient than ethosomes. In comparison to LMWH aqueous solution, skin deposition of flexosome increased 3.2-fold, while that of ethosome increased only 2.0-fold. In vivo, after the topical application of flexosome to hairless mouse, [anti-Xa]_max was 1.11?IU/mL, while ethosomes showed only 0.32?IU/mL. Moreover, AUC_0–24?h of flexosomes was 2.5-fold higher than ethosomes. In conclusion, the enhanced skin permeation and bioavailability of LMWH can be achieved with flexosomes in comparison with ethosomes. The LMWH transdermal delivery via flexosomes has the potential to replace the parenteral dosage forms for the treatment of venous thromboembolism, pulmonary embolism and cardiovascular events.     

Influence of green and black tea on folic acid pharmacokinetics in healthy volunteers: potential risk of diminished folic acid bioavailability

Previous in vitro studies using Caco-2 cell monolayers suggested a possible interaction between green and black tea and folic acid at the level of intestinal absorption. The main purpose of the present study was to investigate a possible pharmacokinetic interaction between tea and folic acid in healthy volunteers. In an open-labeled randomized cross-over study, the pharmacokinetic interaction between tea and folic acid (0.4 mg and 5 mg) was investigated in healthy volunteers. Water was used as the reference drink. Subjects ingested 0.4 mg folic acid tablets with water, green or black tea (0.3 g extract/250 ml) or 5 mg folic acid tablets with water or green tea (0.3 g extract/250 ml). Blood samples were collected over a period of 8 h. Serum folate analysis was carried out by a competitive immunoassay which uses direct chemiluminescent technology. At the 0.4 mg folic acid dose, green and black tea reduced the mean C(max) of serum folate by 39.2% and 38.6%, and the mean AUC(0 --> infinity) by 26.6% and 17.9%, respectively. At the 5 mg folic acid dose, the mean C(max) of serum folate was reduced by 27.4% and the mean AUC(0 --> infinity) was decreased significantly by 39.9% by the co-application of green tea. The present results suggest an in vivo interaction between tea and folic acid with even low concentrations of green and black tea extracts yielding decreased bioavailabilities of folic acid. Copyright (c) 2008 John Wiley & Sons, Ltd.     

Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil

Diseases and disorders of the brain are extremely difficult to treat pharmacologically because most drugs are unable to pass across the blood–brain barriers. Complex multi-strand tight junctions between adjacent cerebral endothelial cells and between choroid plexus epithelial cells form a physical barrier and prevent the passage of water soluble drugs from the blood into the brain, whereas the inward passage of lipid soluble drugs is restricted by drug efflux pumps which act as a functional barrier. In the present work, a transferrin-coupled liposomal system for brain delivery of 5-florouracil has been investigated.

5-florouracil and ^99mTc-DTPA bearing non-coupled liposomes were prepared by cast film method, which were coupled with the transferrin by incubating these liposomes with transferrin in the presence of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in saline phosphate buffer (pH 7.4). These liposomal systems were characterized for vesicle size, percent drug entrapment, and in vitro drug release. The size of the liposomes was increased on coupling with transferrin while percent drug entrapment reduced. The results of the in vitro release profile demonstrated that non-coupled liposomal formulation releases a comparatively higher percent (i.e. 74.8±3.21%) of drug than coupled liposomes. Results of in vivo study suggested a selective uptake of the transferrin-coupled liposomes from the brain capillary endothelial cells. In case of coupled liposomes, the level of radioactivity was 17-fold more as compared to the free radioactive agent and 13 times more with the non-coupled liposomes. Therefore, it could be concluded that using transferrin coupled liposomes the brain uptake of the drug could be enhanced.     

叶酸受体介导多西他赛长循环脂质体与肿瘤细胞结合机理的研究

目的研究叶酸受体介导多西他赛长循环脂质体与肿瘤细胞的结合机理。方法采用薄膜分散法制备脂质体,采用荧光法、流式细胞仪和荧光显微镜检测脂质体与MCF-7细胞、Hela细胞的结合。结果叶酸受体介导多西他赛长循环脂质体与MCF-7细胞的结合量大于Hela细胞;游离叶酸可竞争抑制叶酸受体介导多西他赛长循环脂质体与MCF-7细胞的结合;荧光显微镜下,MCF-7细胞可见明亮绿色荧光,而Hela细胞中只有微弱绿色荧光。结论叶酸受体介导多西他赛长循环脂质体是通过叶酸介导的细胞内化而进入细胞。     

Protective effects of folic acid on PM2.5‐induced cardiac developmental toxicity in zebrafish embryos by targeting AhR and Wnt/β‐catenin signal pathways

Our previous observations indicated that extractable organic matter (EOM) from PM2.5 induced malformations in the heart of zebrafish embryos by activating AhR and inhibiting canonical Wnt/β‐catenin signal pathway. As a nutritional factor, folic acid (FA) is reported to prevent cardiac defects during embryo development. Hence, we hypothesize that FA may prevent PM2.5‐induced heart defects by interfering with AhR and Wnt/β‐catenin signaling pathways. Our results showed that FA supplementation alleviated the EOM‐induced heart defects in zebrafish embryos, and both AhR inhibitor CH223191 and Wnt activator CHIR99021 enhanced the protective efficiency of FA. Furthermore, FA supplementation attenuated the EOM‐induced upregulation of AhR and its target genes including Cyp1a1, Cyp1b1, Ahrra, and Ahrrb. EROD assay confirmed that the EOM agonized Cyp1a1 activity was diminished by FA. The EOM‐induced downregulation of β‐catenin and its target genes including Nkx2.5, Axin2, Sox9b, and Cox2b were recovered or even overexpressed in embryos exposed to EOM plus FA. In conclusion, our study suggested that FA supplementation protected against PM2.5 cardiac development toxicity by targeting AhR and Wnt/β‐catenin signal pathways.     

盐酸吡硫醇脂质体在大鼠体内药动学研究

目的 研究盐酸吡硫醇脂质体注射液在大鼠体内的药动学行为,并与盐酸吡硫醇注射液进行比较,评价盐酸吡硫醇脂质体药动学特征。方法 采用大鼠股静脉给药,眼眶取血,UPLC/MS/MS法测定大鼠血浆中盐酸吡硫醇的浓度,运用MasslynxTM NT4.1软件进行数据采集;运用QuanLynxTM program进行数据分析。结果 脂质体及溶液剂的AUC0-t分别为（1817.093±197.832）、（2592.349±303.194）μg/(L?h);Cmax分别为（6080.502±549.12）、（9525.987±531.813）μg/L;t1/2分别（1.512±0.387）、（0.732±0.388）h。两制剂的药时过程均符合三隔室模型,两者药动学行为相似。结论 运用DAS2.0进行生物等效性评价,脂质体组与溶液剂组药动学参数均在等效置信区间内,两制剂生物等效。     

Preparation of paraoxonase‐1 liposomes and studies on their in vivo pharmacokinetics in rats

A liposome formulation of the enzyme paraoxonase‐1 (PON1) was prepared for purposes of prolonging and maintaining its activity in vivo. Following purification of PON1 from rabbit serum, liposomes containing PON1 (L‐PON1) were prepared using a film‐dispersion method with a soybean phospholipid–cholesterol mixture (5 : 1, w/w). The pharmacokinetic behaviour of conventional injectable PON1 and L‐PON1 was compared following a single intravenous injection in rats. The enzyme activity of PON1 and its pharmacokinetic parameters were calculated based on a two‐compartment model following conventional injection. The level of PON1 encapsulation in L‐PON1 was 86.20 ± 3.12%. The particle size distribution of L‐PON1 was a narrow unimodal form, with an average diameter of 126 nm. The results suggest that compared with conventional injectable PON1, L‐PON1 has an improved half‐life and enhanced enzyme activity in rats. In conclusion, PON1 can be encapsulated into a lipid bilayer for enhanced stability.     

酪丝亮肽多囊脂质体的制备和体外释放研究

目的:制备酪丝亮肽多囊脂质体,并考察其体外释药性能。方法:采用复乳法制备酪丝亮肽多囊脂质体,RP-HPLC法测定酪丝亮肽含量,以稳定性、包封率和体外释放为指标,正交试验设计法对酪丝亮肽多囊脂质体处方工艺进行优化。结果:酪丝亮肽多囊脂质体粒径均一,有80%的粒径分布在20~30μm,包封率达92.43%。酪丝亮肽多囊脂质体体外释放符合Korsmeyer-Peppas模型,37℃条件下在PBS介质中释药t1/2达111.5 h。结论:酪丝亮肽多囊脂质体稳定性好,包封率高,具有良好的缓释效果。     

靶向递药系统长循环脂质体的研究进展

长循环脂质体作为一种新型的纳米载药系统,因其能实现血液中长滞留、高浓度靶向富集于病灶部位,在肿瘤的治疗中显示了独特的优势。通过查阅国内外相关文献并进行归纳总结,现就长循环脂质体及其制备方法、质量评价、药动学及药效学等进行综述。     

Preparation and physicochemical characterization of atovaquone‐containing liposomes

This work describes the preparation and the physicochemical properties of atovaquone‐loaded liposomes. It also describes drug release from the liposomes. As many factors can influence liposome stability, we studied several formulations, including different concentrations of atovaquone, phospholipids, and cholesterol. The effect of atovaquone (ATV) concentration was also evaluated. The highest binding percentage (100±2.5%) was obtained under alkaline conditions for a 2 mg/ml concentration of ATV. The percentage of encapsulation decreased significantly when drug concentrations increased. Drug uptake (expressed per unit mass of phospholipids) was nonlinearly related to equilibrium ATV concentration. A Langmuir‐type sorption was suggested (r = 0.978). In acidic or neutral buffer, the binding percentage reached 42.1 ± 0.02%. The increase of phospholipids and cholesterol concentrations did not significantly improve the ATV binding yield for the lowest ATV concentration. Conversely, ATV binding was significantly increased for the highest ATV concentration. All the formulations tested gave monodispersed liposomes with a mean diameter around 260 nm. The dilution (1/5–1/20) of liposomes in alkaline conditions induced a significant release of ATV (74% release). In acidic or neutral buffer no release was observed, suggesting an encapsulation process. Drug Dev. Res. 47:155–161, 1999. © 1999 Wiley‐Liss, Inc.     

Pharmacokinetics of paclitaxel-containing liposomes in rats

In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1±3.32 μg-h/mL; Cre-pac: 34.5±0.994 μg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (K_p) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, K_p was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.     

紫杉醇纳米脂质体的制备与大鼠体内药动学

目的:制备紫杉醇新型纳米脂质体并研究其在大鼠体内的药动学。方法:采用薄膜分散超声结合冷冻干燥制备紫杉醇纳米脂质体。大鼠尾静脉注射紫杉醇脂质体及市售紫杉醇注射液Anzatax,血浆样品经乙醚提取后用反相高效液相色谱法(RP-HPLC)检测血浆紫杉醇浓度,并用3P87软件包估算药动学参数。色谱条件如下:色谱柱为Gemini ODS(150 mm×4.6 mm,5μm),流动相为0．035mol·L-1乙酸铵缓冲液(pH 5．0)-乙腈(45:50),流速1．0 mL·min,检测波长230 nm,地西泮为内标。结果:制备的紫杉醇纳米脂质体的体积权重粒径为(54.1±26．0)nm,包封率大于80％,符合药典规定,且24 h内与葡萄糖注射液配伍稳定。紫杉醇脂质体及市售紫杉醇注射液Anzatax经大鼠尾静脉注射后均符合二室模型,脂质体组的消除半衰期(t1/2β)显著长于Anzatax组[(3．38±0．39)vs．(2．49±0．63)h,P<0．05];其他药动学参数经方差分析均无显著性差异。紫杉醇脂质体与Anzatax的AUC0-8h比值为88．13％。结论:制备的紫杉醇纳米脂质体在大鼠体内的药动物参数与市售紫杉醇注射液Anzatax比较,t1/2β稍有延长,AUC0-8h值相近。     

RP-HPLC法测定黄金搭档组合维生素片中叶酸的含量

目的建立黄金搭档组合维生素片中叶酸含量测定方法。方法用反相高效液相色谱法进行分析。色谱柱为L ichro-spher-C18柱,ODS(5μm,250 mm×4.6 mm),流动相为水-甲醇-0.25 mol.L-1庚烷磺酸钠溶液-乙酸-7%氨水(70∶30∶1.5∶1∶0.25),检测波长280 nm。结果峰面积与含量有良好的线性(r=0.9997);重复性好(RSD=1.26%);回收率高(X=97.6%,RSD=1.95%)。结论方法稳定,简便易行,快速准确,可作为此片剂质量检测方法。     

Ameliorative effects of riboflavin on acetic acid‐induced colonic injury in rats

Riboflavin (RF) has been found to be a promising antioxidant and/or anti‐inflammatory agent in several studies. However, the effect of RF against acetic acid (AA)‐induced colonic injury is currently unknown. This study aimed to investigate the potential antioxidant and protective effects of RF in a rat model of ulcerative colitis. Starting immediately after the colitis induction (AA+RF group) or 1 week before the colitis induction (RF+AA+RF group), the rats were treated with RF (25 mg/kg per day; p.o.) for 3 days. The control and AA groups received saline (1 mL; p.o.) whereas AA+SS group (positive control) received sulfasalazine (100 mg/kg per day; p.o.) for 3 days. Colonic samples were taken for the biochemical and histological assessments on the third day. High damage scores, elevated tissue wet weight index (WI), tissue myeloperoxidase (MPO) activity, 8‐hydroxy‐2′‐deoxyguanosine levels and chemiluminescence values, and a pronounced decrease in antioxidant glutathione (GSH) levels of the AA group were all reversed by RF pretreatment (RF+AA+RF group) and SS treatment (AA+SS group) (P < .05‐.001). Tissue WI, MPO activity and GSH levels were not statistically changed in the AA+RF group. Western blot analysis revealed that the decreased protein expressions of tissue collagen (COL) 1A1, COL3A1 and transforming growth factor‐β1 in the AA group were elevated in all the treatment groups (P < .05‐.001). In conclusion, RF exerts both the antioxidant and anti‐inflammatory effects against AA‐induced colonic inflammation by suppressing neutrophil accumulation, inhibiting reactive oxidant generation, preserving endogenous glutathione, improving oxidative DNA damage and regulating inflammatory mediators, suggesting a future potential role in the treatment and prevention of ulcerative colitis.     

超氧化物歧化酶脂质体在大鼠体内的药代动力学和组织分布

目的考察3种超氧化物歧化酶(SOD)脂质体静脉给药后在大鼠体内的药代动力学和组织分布。方法 用反相蒸发法制备SOD脂质体，采用黄嘌呤氧化酶法检测SOD活力，静脉注射给药后，测定大鼠血中SOD含量变化和不同组织中SOD含量变化。结果在血浆中，SOD水溶液、SOD普通脂质体、用DSPE-PEG2000修饰的SOD脂质体、用Tween 80修饰的SOD脂质体的半衰期分别为0.25，0.34，0.66和0.41 h；AUC分别为12.48，24.66，41.16和33.02 μg·h·mL^-1。与普通脂质体比较，经过DSPE-PEG和Tween 80修饰后的脂质体，使肝、脾中SOD的含量有不同程度的降低，脑中含量有所提高。结论3种SOD脂质体均可不同程度地延长SOD的血浆半衰期，并以用DSPE-PEG2000修饰的SOD脂质体效果最好。与普通脂质体相比，用Tween 80修饰的SOD脂质体可以提高进入脑中的SOD量，用DSPE-PEG2000修饰的SOD脂质体可以减少肝脾对SOD的摄取。