Oral Delivery of Highly Lipophilic,Poorly Water-Soluble Drugs: Self-Emulsifying Drug Delivery Systems to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a Cholesteryl Ester Transfer Protein Inhibitor in Preclinical Species

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.     

黄连素自乳化微球的制备及其包封率影响因素研究

目的制备黄连素自乳化微球,并对影响包封率的处方因素进行研究。方法采用膜乳化法制备黄连素自乳化微球,分别考察3种主要处方因素即自乳化成分、海藻酸钠的含量、氯化钙浓度对黄连素自乳化微球的包封率的影响。结果随着自微乳化成分的增加,包封率逐渐增加;随着海藻酸钠的含量增加,微球的包封率先增加后减少;随着氯化钙浓度的增加,包封率逐渐增加。结论海藻酸钠的含量、氯化钙的浓度、自微乳化成分对黄连素自乳化微球的包封率均有影响,这为进一步优化自乳化微球的处方奠定基础。     

尼莫地平自微乳化液的处方研究

 目的　研究尼莫地平自微乳化液的处方。方法　考察了尼莫地平在不同的油及乳化剂中的平衡溶解度;以自微乳化效率为指标对不同的油和乳化剂进行配伍选择。同时进行了空白自微乳化药物传递系统 (SMEDDS)假三元相图研究以及含药SMEDDS在水和0.1mol·L^-1盐酸溶液中的自微乳化效率的考察,确定了乳化剂和辅助乳化剂的最佳比例。结果　制得了安全稳定的尼莫地平自微乳化液。结论　通过处方研究确定了最终的处方。     

自乳化莪术油软胶囊中莪术油的含量测定研究

目的:建立自乳化莪术油软胶囊中莪术油含量测定方法。方法:采用可见光分光光度法,将胶囊中内容物用无水乙醇稀释后,采用香草醛硫酸溶液显色,于(520±2)nm检测,测定其吸收度。结果:莪术醇浓度在40～320μg·ml~(-1)范围内,线性关系良好(r=0.9979),回收率96.59％,RSD为1.03％。结论:本方法准确,可靠,适合用于自乳化莪术油软胶囊制剂的含量测定。     

茴拉西坦自乳化给药系统与片剂的药代动力学及体内外相关性的研究

目的：研究茴拉西坦自乳化制剂和普通片剂的体内外相关关系;评价其大鼠口服给药的体内药代动力学。方法：通过测定自乳化制剂和普通片剂的体外溶出度考察其释药特性,采用RP-HPLC法测定活性代谢产物对氨基甲氧基丁酸的浓度血浆中,通过Wagner-Nelson法计算体内吸收分数（f）,研究两制剂的吸收分数（f）与体外累积溶出度（Q%）的相关性。结果：自乳化微乳体外15min的溶出度为（80±4）%,比片剂的溶出度（50%）明显提高;体内代谢产物的回收率为90%,日内日间精密度分别小于4%和6%,该方法灵敏度高、准确可靠。自乳化微乳的AUC0-∞为（11168±2395）ng·mL^-1·h,是普通片剂的3倍。自乳化微乳和片剂的MRT0-∞分别为（2.7±0.6）h和（1.7±0.5）h,具有统计学差异（P〈0.05）。体内外相关性结果表明,片剂的体内吸收与体外溶出度呈线性相关,线性方程的斜率为0.7765,截距为-2.9527;自乳化微乳的体内外相关性符合二次模型,其拟合系数为0.972。结论：茴拉西坦自乳化给药系统可显著提高药物体内的生物利用度。自乳化制剂处方中含有促吸收的复合表面活性剂和油相,其体外药物呈快速释放的特性,而体内自发与胃肠液形成o/w型微乳后可通过淋巴转运的吸收途径。     

固体自乳化药物传递系统的研究概况

综述固体自乳化药物传递系统的定义与特点、处方组分、制备工艺、药物体外释放和体内吸收的影响因素及质量评价指标。固体自乳化药物传递系统为一种新型制剂，可以显著提高难溶性药物的口服生物利用度，还可以通过添加各种固体辅料或采用包衣技术制备缓控释产品。     

自乳化药物传递系统的研究进展

本文对近几年国内外有关自乳化药物传递系统的特点、吸收机制、组成、影响因素及其在药剂学方面的应用进行了归纳和分析。自乳化药物传递系统可显著地提高难溶性或亲脂性药物口服生物利用度，具有广阔的发展前景。     

酮洛芬自乳化制剂处方及化学稳定性研究

目的建立酮洛芬自乳化制剂处方 ,并考察其稳定性。方法通过溶解度实验和三元相图的建立 ,筛选酮洛芬自乳化制剂处方。用HPLC法测定处方经高低温循环和光照加速实验前后药物的含量 ,考察其化学稳定性。结果酮洛芬自乳化制剂处方中油相、表面活性剂和助表面活性剂分别为油酸乙酯、Tween 80和乙二醇单乙基醚 (Transcutol)。处方经高低温循环后酮洛芬平均含量由 99 8% (w)变为 99 0 % (w) ,光照 5d和 10d后 ,平均含量分别降为 85 7% (w )和 6 8 7%(w )。结论酮洛芬自乳化制剂处方比例为酮洛芬 油酸乙酯 Tween 80 Transcutol(w∶w∶w∶w =5 0∶4 0 0∶4 3 5 0∶11 5 )。制剂对热稳定 ,对光不稳定 ,需避光保存     

2种自乳化递送系统的制备及其对斑马鱼炎症损伤部位“引药”作用

目的 以橄榄油和芝麻油分别作为油相进行自乳化递送系统（self-emulsifying drug delivery system,SEDDS）载体构建,考察2种SEDDS载体的药剂学性能及对斑马鱼体内炎症损伤部位递送差异。初步阐明辅料的“引药”效应,拟为炎症损伤部位有效递送材料的选择和辅料“引药达所”提供实验参考。方法 结合相转变法和伪三元相图法筛选乳化剂、助乳化剂、乳化剂与助乳化剂质量比（Km）,星点设计-效应面法（central composite design-response surface methodology,CCDRSM）优化2种SEDDS载体处方;通过布鲁克海文纳米粒径仪测定2种SEDDS载体的中位径（D50）和ζ电位;利用立体荧光显微镜观察2种SEDDS载体在斑马鱼体内炎症损伤部位的递送差异。结果 2种SEDDS最佳乳化剂和助乳化剂均为聚山梨酯80-无水乙醇（2∶1）,最佳处方油相与Km值均为1∶1,滴加适量纯水后呈半透明略带蓝色乳光液体;橄榄油和芝麻油SEDDS最佳处方D50分别为（219.36±14.86）、（225.06±13.66）nm,ζ电位分别为（-3....     

Self-emulsifying drug delivery system and the applications in herbal drugs

Abstract

Herbal drugs have been used for thousands of years in the east and have had a recent resurgence in popularity among consumers in the west. However, most of herbal drug are poorly soluble and have hydrophobic properties and poor distribution, leading to reduced bioavailability and hence decreased treatment efficacy, requiring repeated administration or increased dose. In the past few decades, considerable attention has been focused on the development of self-emulsifying drug delivery system (SEDDS) for herbal drugs. SEDDS is isotropic and thermodynamically stable solutions consisting of oil, surfactant, co-surfactant and drug that can spontaneously form oil-in-water micro/nanoemulsion when mixed with water under gentle stirring. The formulation can be a viable alternative to classical formulations to take advantage of their lipophilic nature and to solve their problems of poor solubility, poor bioavailability, low oral absorption and instability. The mechanism of self-emulsification, solubility studies, construction of phase diagram, optimization and characterization of herbal drugs-loaded SEDDS formulation and in situ absorption evaluation of herbal drugs in rat intestine are presented in our article.