新型抗脑卒中化合物TID-101自微乳制剂大鼠体内生物利用度研究

目的：建立测定大鼠血浆中防治缺血性脑卒中化合物TID-101的LC-MS/MS方法,并研究其自微乳制剂大鼠体内生物利用度及药代动力学特征。方法血浆样品用甲醇沉淀蛋白处理,以乙腈-水为流动相,采用ESI源以多反应监测方式进行负离子检测,用于定量分析的离子反应为m/z 353.4→323.2（TID-101）和433.4→353.4（醋酸地塞米松,内标）。将建立的方法应用于大鼠口服TID-101自微乳的生物利用度及药代动力学研究。结果 TID-101在10～95000 ng/ml内呈良好的线性关系（r=0.9998）,日内、日间精密度（RSD）均＜15%,回收率在83.4%～87.0%之间。应用此法测试大鼠静脉注射TID-101脂肪乳和口服原料药及自微乳制剂后的血药浓度,计算出原料药混悬液和自微乳的口服绝对生物利用度分别为2.8%和14.9%。结论本法操作简单、准确、灵敏度高,可用于TID-101大鼠体内药动学研究;自乳化释药系统能有效提高TID-101大鼠口服生物利用度。     

赤芍总苷自微乳化给药系统的研究

目的 制备赤芍总苷自微乳化给药系统（TGP-SMEDDS）,优选其最佳处方,并对其进行初步的质量评价。方法 采用伪三元相图法优化自微乳化处方,并对最佳处方进行粒径、乳滴形态、Zeta电位、表面张力、自乳化时间、溶出度及稳定性评价。结果 由油酸乙酯、Cremophor RH40和Transcutol P组成的TGP-SMEDDS遇水可自发形成粒径为（47.26±0.08）nm的稳定微乳液,透射电镜下观察TGP-SMEDDS形态为均匀的球形,Zeta电位为（?22.80±0.42）mV。结论 制备的TGP-SMEDDS外观及稳定性良好,为赤芍总苷新剂型的进一步研究奠定了基础。     

Investigation of self-microemulsifying and microemulsion systems for protection of prednisolone from gamma radiation

Radiation is efficient for terminal sterilization. Unfortunately, its use for liquid pharmaceuticals is difficult. This work investigated the potential radioprotective effect of self-microemulsifying (SMEDDS), microemulsions and their phase transition systems which were reported to enhance ocular drug delivery. Prednisolone solutions were prepared in SMEDDS, W/O microemulsions containing, 5% w/w (ME 5%) or 10% w/w (ME 10%) water, liquid crystalline system with 25% water (LC) and coarse emulsion containing 80% water (EM). These were subjected to gamma irradiation with aqueous solution and suspension being used as control. The physical properties of the formulations were monitored and the chemical potency of the drug was determined using a stability indicating HPLC method. The phase behavior of the formulations was not affected by irradiation but the viscosity of LC was significantly reduced. The SMEDDS, ME 5% and ME 10% showed excellent radiation protection as indicated by no change in the chemical potency. The LC retained 84% and the EM retained 39.8% of the chemical potency after exposure to 20 KGy. The aqueous solution was extensively degraded with the suspension retaining only 73.5% of the potency at 20 KGy. SMEDDS and W/O microemulsion can thus protect prednisolone from degradation by ionizing radiation.     

Characterisation of fenofibrate dissolution delivered by a self-microemulsifying drug-delivery system

Objectives This study attempted to characterise the in‐vitro release profiles of fenofibrate (FFB) from a self‐microemulsifying drug‐delivery system (SMEDDS) for optimising formulation factors and dissolution conditions for in‐vivo absorption. Methods The study was conducted by profiling the release of FFB formulated with either a complete solution or a micronised dispersion system (MDS) in a SMEDDS composed of medium‐chain triglyceride (MCT) oil and surfactant mixtures (S_mix) of TPGS and Tweens at different ratios (K_m = TPGS/Tweens), with and without adding water. Optimised FFB SMEDDS formulations were then selected for in‐vivo bioavailability study. Key findings The release rates of FFB from TPGS/Tween 20 systems were faster than those from TPGS/Tween 80 systems at the same K_m value. In both systems, the release rates of FFB increased with a decrease in the K_m value. Furthermore, both the release rates and the amounts of FFB from MDS in the water medium decreased with an increasing percentage of S_mix added to both water contents. However, the release rates and amounts of FFB from MDSs increased with an increasing percentage of S_mix in a 0.025 M sodium lauryl sulfate (SLS) solution. It was further illustrated that the release of FFB from SMEDDSs was complete within 30 min in both the 0.025 M SLS solution and water medium, but the release of FFB from Tricor® or MDSs was limited in water medium. An optimised FFB SMEDDS with either Tween 20(E5(20)) or Tween 80(E5(80)) and one MDS were selected for a pharmacokinetic study to compare with Tricor^®. The results demonstrated that the area under the receiver operating curve and C_max values were in the order of Tricor^® > E5(80) ? E5(20) > MDS and Tricor^® ? E5(80) > E5(20) > MDS, respectively. Conclusions The absorption of drug carried by SMEDDS might not be enhanced as a result of the smaller volume of water taken with oral administration of SMEDDSs and the agitation rate of the gastrointestinal tract not being strong enough to efficiently promote the self‐microemulsification process to facilitate the in‐vivo dissolution rate.     

辛伐他汀自微乳化胶囊的制备与质量控制

目的建立辛伐他汀自微乳化胶囊的制备工艺及其质量控制方法.方法取辛伐他汀与辅料制成加热溶解均匀后定量制成胶囊剂;采用380 ZLS Nicomp Particle Sizer测定自乳化后的乳滴粒径;以甲醇-水(80∶20)为流动相,采用高效液相色谱法测定辛伐他汀的有关物质及含量.结果所得制剂内容物为类白色的固体或半固体;自乳化溶液的平均粒径为(18.8±2.6)nm;辛伐他汀检测浓度线性范围为10～100μg/ml(r=0.9999),平均回收率为98.4 %(RSD=1.22%,n=9) .结论该制剂制备工艺简单,有关物质和含量测定方法简便、准确,质量可控.     

Preparation and in vivo evaluation of SMEDDS (self-microemulsifying drug delivery system) containing fenofibrate

The present work was aimed at formulating a SMEDDS (self-microemulsifying drug delivery system) of fenofibrate and evaluating its in vitro and in vivo potential. The solubility of fenofibrate was determined in various vehicles. Pseudoternary phase diagrams were used to evaluate the microemulsification existence area, and the release rate of fenofibrate was investigated using an in vitro dissolution test. SMEDDS formulations were tested for microemulsifying properties, and the resultant microemulsions were evaluated for clarity, precipitation, and particle size distribution. Formulation development and screening was done based on results obtained from phase diagrams and characteristics of resultant microemulsions. The optimized formulation for in vitro dissolution and pharmacodynamic studies was composed of Labrafac CM10 (31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%). The SMEDDS formulation showed complete release in 15 minutes as compared with the plain drug, which showed a limited dissolution rate. Comparative pharmacodynamic evaluation was investigated in terms of lipid-lowering efficacy, using a Triton-induced hypercholesterolemia model in rats. The SMEDDS formulation significantly reduced serum lipid levels in phases I and II of the Triton test, as compared with plain fenofibrate. The optimized formulation was then subjected to stability studies as per International Conference on Harmonization (ICH) guidelines and was found to be stable over 12 months. Thus, the study confirmed that the SMEDDS formulation can be used as a possible alternative to traditional oral formulations of fenofibrate to improve its bioavailability.     

Combined use of phospholipid complexes and self-emulsifying microemulsions for improving the oral absorption of a BCS class IV compound,baicalin

The aim of this study was to develop a formulation to improve the oral absorption of baicalin (BA) by combining a phospholipid complex (PC) and self-emulsifying microemulsion drug delivery system (SMEDDS), termed BA–PC–SMEDDS. BA–PC was prepared by a solvent evaporation method and evaluated by complexation percentage (CP). The physicochemical properties of BA–PC were determined. The synergistic effect of PC and SMEDDS on permeation of BA was studied in vitro with Caco-2 cells and in situ with a single pass intestinal perfusion model. The improved bioavailability of BA in BA–PC–SMEDDS was confirmed in an in vivo rat model. The CP of BA–PC reached 100% when the molar ratio of drug to phospholipid (PP) was ≥1:1. The solubility of BA–PC increased in both water and octanol, and the log P_o/w of BA–PC was increased significantly. BA–PC–SMEDDS could be dispersed more evenly in water, compared to BA and BA–PC. Both the Caco-2 cell uptake and single-pass intestinal perfusion models illustrated that transport of BA in BA–PC was lower than that of free BA, while improved significantly in BA–PC–SMEDDS. The relative bioavailability of BA–PC(1:2)–SMEDDS was 220.37%. The combination system of PC and SMEDDS had a synergistic effect on improving the oral absorption of BA.KEY WORDS: Baicalin, SMEDDS, Phospholipid complex, Caco-2 cell, Single-pass intestinal perfusion, Bioavailability     

水飞蓟宾过饱和自微乳给药系统在大鼠体内的药动学研究

目的 研究水飞蓟宾过饱和自微乳给药系统（S-SMEDDS）在大鼠体内的药动学特征。方法 12只雄性SD大鼠随机分为对照组和实验组,每组6只,对照组大鼠ig给予水飞蓟宾自微乳（SMEDDS）533 mg/kg,实验组大鼠ig给予水飞蓟宾-S-SMEDDS 533 mg/kg。采用Accusampler清醒动物自动采血装置于不同时间点采血,HPLC法测定大鼠ig水飞蓟宾- S-SMEDDS后水飞蓟宾的血药浓度,非房室模型的统计矩分析方法计算药动学参数。结果 对照组和实验组的t_max分别为（1.00±0.40）、（1.50±0.84）h,C_max分别为（5.68±0.52）、（16.10±4.06）μg/mL,AUC_0→t分别为（27.30±3.29）、（82.64±12.36）μg?h?mL^?1。结论 将水飞蓟宾制成S-SMEDDS可进一步提高其口服生物利用度。     

银杏叶总黄酮自微乳化口腔速溶膜的制备及其性质研究

目的研制银杏叶总黄酮的自微乳化口腔速溶膜,并考察其体外性质。方法采用溶解度法和伪三元相图法筛选确定银杏叶总黄酮自微乳化给药系统处方;在此基础上,以成膜性和体外崩解时间为指标筛选固体载体,制备能在口腔中迅速自微乳化的固体膜剂。考察其自微乳化性能、崩解时间、体外释放度等体外性质,采用差示扫描量热法和扫描电子显微镜表征药物晶型和膜的表面形态。结果光子相关光谱法测得本制剂微乳液的平均粒径为(48.1±5.45)nm,与银杏叶总黄酮自微乳化给药系统的微乳粒径无差异;崩解时间为(9.94±0.26)s;体外释放度在5 min时即可达到(70.98±0.31)%,显著快于市售片。结论银杏叶总黄酮自微乳化口腔速溶膜结合了自微乳化给药系统和口腔速溶膜的双重优点,是具有应用前景的新剂型。     

自微乳化释药系统在药物制剂中的应用

很多新活性药物在生物体内溶解度很小,如何增加药物溶解度,提高其生物利用度是药物制剂工作中的一大难题.本文介绍了自微乳化释药系统的基本概述,并对其在难溶性西药制剂中的应用进行综述.