This study examined the effect of self-microemulsiflying drug delivery system (SMEDDS) containing Cremophor RH40 or Tween 80 at various dilutions on cytochrome P450 3A (CYP3A) enzymes in rat hepatocytes, with midazola...This study examined the effect of self-microemulsiflying drug delivery system (SMEDDS) containing Cremophor RH40 or Tween 80 at various dilutions on cytochrome P450 3A (CYP3A) enzymes in rat hepatocytes, with midazolam serving as a CYP3A substrate.The particle size and zeta potential of microemulsions were evaluated upon dilution with aqueous medium.In vitro release was detected by a dialysis method in reverse.The effects of SMEDDS at different dilutions and surfactants at different concentrations on the metabolism of MDZ were investigated in murine hepatocytes.The cytotoxicity of SMEDDS at different dilutions was measured by LDH release and MTT technique.The effects of SMEDDS on the CYP3A enzymes activity were determined by Western blotting.Our results showed that dilution had less effect on the particle size and zeta potential in the range from 1:25 to 1:500.The MDZ was completely released in 10 h.A significant decrease in the formation of 1’-OH-MDZ in rat hepatocytes was observed after treatment with both SMEDDS at dilutions ranging from 1:50 to 1:250 and Cremophor RH 40 or Tween 80 at concentrations ranging from 0.1% to 1% (w/v), with no cytotoxicity observed.A significant decrease in CYP3A protein expression was observed in cells by Western blotting in the presence of either Cremophor RH40 or Tween 80-based SMEDDS at the dilutions ranging from 1:50 to 1:250.This study suggested that the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates.展开更多
The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be in...The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil(Kolliphor ~? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80(LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides(40% to 75%), Kolliphor ~? RH40(5% to 55%), LPC(0 to 40%) and ethanol(0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor~? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor~? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor ~? RH40 as a reference for formulation developers.展开更多
目的:考察乙醇-油酸聚乙二醇甘油酯(labrafil M 1944 CS)和聚氧乙烯氢化蓖麻油40(cremophor RH40)的鼻黏膜毒性,探讨其在鼻腔给药系统中应用的可行性。方法:以山梨糖醇酐油酸酯(span-80)和聚山梨酯-80(tween-80)为参比,采用在体蟾蜍上...目的:考察乙醇-油酸聚乙二醇甘油酯(labrafil M 1944 CS)和聚氧乙烯氢化蓖麻油40(cremophor RH40)的鼻黏膜毒性,探讨其在鼻腔给药系统中应用的可行性。方法:以山梨糖醇酐油酸酯(span-80)和聚山梨酯-80(tween-80)为参比,采用在体蟾蜍上腭模型,光学显微镜下观察纤毛持续运动时间,考察cremophor RH40和labrafil M 1944 CS的纤毛毒性作用;运用家兔血细胞溶血试验,考察cremophor RH40和labrafil M 1944 CS对细胞膜完整性的影响。结果:体积分数为1%时,4种表面活性剂对纤毛运动的影响顺序为cremophor RH40<labrafil M 1944 CS<tween-80<span-80;cremophor RH40的细胞膜毒性最小,tween-80和span-80次之,而labrafil M 1944 CS的影响最大;cremophor RH40对细胞膜完整性无影响用量为tween-80和span-80的15倍。结论:在一定体积分数下cremophor RH40的鼻黏膜毒性作用较小,可应用于鼻腔给药制剂的研制。展开更多
In view of two consecutive failures of Siemens 3RH1122-2KF40 relay on DKZ15 electric bus of Beijing metro line 10, it is found that Siemens 3RH1122-2KF40 relay has the defects of unreliable contact mechanical structur...In view of two consecutive failures of Siemens 3RH1122-2KF40 relay on DKZ15 electric bus of Beijing metro line 10, it is found that Siemens 3RH1122-2KF40 relay has the defects of unreliable contact mechanical structure and degraded contact electrical performance. In order to further improve the reliability of the key circuits of the train of line 10, eliminate the hidden dangers of vehicle faults, and reduce the failure rate and the cost of use and maintenance, it is decided to replace this type of relay. In the early stage of the transformation, the failure cause analysis, relay selection, comparative test and life accounting were carried out, and the transformation scheme was finally formed. The replacement relay effectively makes up for the deficiencies in the mechanical and electrical performance of Siemens 3RH1122-2KF40 relay, and is more in line with the actual needs of urban rail transit operation under the balanced repair mode in the future. At present, the transformation of DKZ15 electric buses of line 10 has been completed. After the transformation, the vehicle operation is in good condition, and the maximum operation mileage has exceeded 600000 km. Through relay transformation, the reliability of key circuits of the train is effectively improved, the maintenance and replacement free in the whole life cycle of the train are achieved, and the labor and material costs are reduced, which lays a solid quality guarantee for promoting the balanced maintenance mode of metro vehicles in the future.展开更多
基金supported by a grant from National Natural Sciences Foundation of China (No.30873171)
文摘This study examined the effect of self-microemulsiflying drug delivery system (SMEDDS) containing Cremophor RH40 or Tween 80 at various dilutions on cytochrome P450 3A (CYP3A) enzymes in rat hepatocytes, with midazolam serving as a CYP3A substrate.The particle size and zeta potential of microemulsions were evaluated upon dilution with aqueous medium.In vitro release was detected by a dialysis method in reverse.The effects of SMEDDS at different dilutions and surfactants at different concentrations on the metabolism of MDZ were investigated in murine hepatocytes.The cytotoxicity of SMEDDS at different dilutions was measured by LDH release and MTT technique.The effects of SMEDDS on the CYP3A enzymes activity were determined by Western blotting.Our results showed that dilution had less effect on the particle size and zeta potential in the range from 1:25 to 1:500.The MDZ was completely released in 10 h.A significant decrease in the formation of 1’-OH-MDZ in rat hepatocytes was observed after treatment with both SMEDDS at dilutions ranging from 1:50 to 1:250 and Cremophor RH 40 or Tween 80 at concentrations ranging from 0.1% to 1% (w/v), with no cytotoxicity observed.A significant decrease in CYP3A protein expression was observed in cells by Western blotting in the presence of either Cremophor RH40 or Tween 80-based SMEDDS at the dilutions ranging from 1:50 to 1:250.This study suggested that the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates.
基金Financial support from the University of Copenhagen and the Phospholipid Research Center(Heidelberg,Germany)is kindly acknowledged
文摘The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil(Kolliphor ~? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80(LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides(40% to 75%), Kolliphor ~? RH40(5% to 55%), LPC(0 to 40%) and ethanol(0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor~? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor~? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor ~? RH40 as a reference for formulation developers.
文摘目的:考察乙醇-油酸聚乙二醇甘油酯(labrafil M 1944 CS)和聚氧乙烯氢化蓖麻油40(cremophor RH40)的鼻黏膜毒性,探讨其在鼻腔给药系统中应用的可行性。方法:以山梨糖醇酐油酸酯(span-80)和聚山梨酯-80(tween-80)为参比,采用在体蟾蜍上腭模型,光学显微镜下观察纤毛持续运动时间,考察cremophor RH40和labrafil M 1944 CS的纤毛毒性作用;运用家兔血细胞溶血试验,考察cremophor RH40和labrafil M 1944 CS对细胞膜完整性的影响。结果:体积分数为1%时,4种表面活性剂对纤毛运动的影响顺序为cremophor RH40<labrafil M 1944 CS<tween-80<span-80;cremophor RH40的细胞膜毒性最小,tween-80和span-80次之,而labrafil M 1944 CS的影响最大;cremophor RH40对细胞膜完整性无影响用量为tween-80和span-80的15倍。结论:在一定体积分数下cremophor RH40的鼻黏膜毒性作用较小,可应用于鼻腔给药制剂的研制。
文摘In view of two consecutive failures of Siemens 3RH1122-2KF40 relay on DKZ15 electric bus of Beijing metro line 10, it is found that Siemens 3RH1122-2KF40 relay has the defects of unreliable contact mechanical structure and degraded contact electrical performance. In order to further improve the reliability of the key circuits of the train of line 10, eliminate the hidden dangers of vehicle faults, and reduce the failure rate and the cost of use and maintenance, it is decided to replace this type of relay. In the early stage of the transformation, the failure cause analysis, relay selection, comparative test and life accounting were carried out, and the transformation scheme was finally formed. The replacement relay effectively makes up for the deficiencies in the mechanical and electrical performance of Siemens 3RH1122-2KF40 relay, and is more in line with the actual needs of urban rail transit operation under the balanced repair mode in the future. At present, the transformation of DKZ15 electric buses of line 10 has been completed. After the transformation, the vehicle operation is in good condition, and the maximum operation mileage has exceeded 600000 km. Through relay transformation, the reliability of key circuits of the train is effectively improved, the maintenance and replacement free in the whole life cycle of the train are achieved, and the labor and material costs are reduced, which lays a solid quality guarantee for promoting the balanced maintenance mode of metro vehicles in the future.
