以油包水型微乳为载体促进氟尿嘧啶的经皮渗透

以磺化琥珀酸二辛酯钠 (AOT) 为主要表面活性剂,制备氟尿嘧啶油包水型微乳制剂,以促进药物的经皮渗透。以伪三元相图为基础,依据微乳区域大小, 初步筛选微乳处方;用改进的Franz扩散池和离体小鼠皮肤研究氟尿嘧啶的透皮速率,以单位面积的透皮累积渗透量 (Q_n) 为指标, 考察微乳处方中助表面活性剂的种类、水相比例、混合表面活性剂比例、表面活性剂和助表面活性剂质量比和载药量对离体鼠皮透皮吸收的影响, 优化处方。结果表明,氟尿嘧啶微乳的优化处方为含药0.5%（w/v）,水30%,混合表面活性剂（AOT/Tween 85, K_m = 2）20%, 油相（IPM）49.5%,经皮渗透符合一级速率方程,12 h累积渗透量为（1 355.5 ± 41.1）μg·cm^-2, 分别为0.5%药物水溶液和2.5%（w/w）市售乳膏（O/W）的19.1和7倍。水/AOT/Tween 85/IPM微乳系统能促进5-氟尿嘧啶的透皮吸收, 可以作为氟尿嘧啶等亲水性但水溶性差和渗透性差的药物的新型经皮给药载体。

     

盐酸氟西汀微乳的制备及其离体大鼠透皮作用研究

目的:制备盐酸氟西汀(FLU)微乳并考察其对离体大鼠的透皮能力。方法:筛选空白微乳中表面活性剂、助表面活性剂、油相等的组成及质量比,制备FLU微乳并考察其粒径及分布等指标;用改进的Franz扩散池研究微乳的透皮速率,考察油相含量、混合表面活性剂含量及载药量对透皮吸收的影响以优化处方并进行验证试验。结果:空白微乳组成为肉豆蔻酸异丙酯(IPM)/聚乙二醇羟硬脂酸酯15(SolutolSH15)/聚乙二醇(PEG)400/水;样品平均粒径为44.6nm,呈正态分布,多分散系数为0.317;最优处方为FLU/IPM/SolutolSH15/PEG400/水(1∶9∶20∶20∶39),验证试验中3批样品稳态透皮速率平均值为(128.96±0.32)μg·cm-2·h-1。结论:所制FLU微乳有较强的透皮能力,可进一步开发为FLU的新型透皮给药制剂。     

吡罗昔康外用微乳的制备及其透皮吸收的研究

目的制备吡罗昔康微乳并考察其体外经皮渗透特性。方法采用Lauroglycol FCC为油相、Labrasol、Cremo-phor EL为表面活性剂、Transcutol P、乙醇为助表面活性剂,绘制伪三元相图,制备吡罗昔康O/W微乳。采用智能透皮实验仪,大鼠背部皮肤作为透皮模型,HPLC测定药物透皮浓度,研究吡罗昔康微乳的透皮特性。结果本实验中微乳较优处方含：吡罗昔康0.5%,Lauroglycol FCC10%,Labrasol、Cremophor EL、Transcutol P各13.3%及水50%,吡罗昔康渗透速率可达10.04±1.73μg/（cm2.h）。结论吡罗昔康微乳有很强的透皮能力,有望成为吡罗昔康的新型透皮给药制剂。     

微乳基质对苦参碱经皮渗透的影响

以小鼠离体皮肤为模型,采用双室渗透扩散装置考察了微乳中不同的油相、表面活性剂和助表面活性剂对苦参碱经皮渗透的影响.采用HPLC法,以Kromasil NH2为色谱柱、乙腈-无水乙醇-3%磷酸(80:10:10)为流动相测定苦参碱的经皮渗透量.结果表明,油酸对苦参碱有显著的阻碍渗透作用,故油酸不宜作为苦参碱微乳的油相.本试验优化所得的微乳处方为油酸乙酯.丁酸乙酯(4:1,w/w)4.5%,Cremophor EL35-乳化剂OP-10(1:1,w/w)23%,PEG40015%,苦参碱7.2%.     

依托泊苷微乳相图的研究

目的确定o／w型依托泊苷微乳处方。方法选用油酸、十四酸异丙酯和十六酸异丙酯作为油相，Tween80、Cremophor EL和Cremophor RH40作为表面活性剂，乙醇、1，2-丙二醇、异丙醇、甘油和PEG400为助表面活性剂，通过滴定法绘制伪三元相图，以o／w型微乳区大小为指标筛选处方。结果确定了最终空白微乳处方为Cremophor RH40：乙醇：PEG 400：水：十四酸异丙酯=19．0：19．0：19．0：38．2：4．8（w／w）。结论所选择的微乳处方可以满足依托泊苷载药量的要求。     

酮康唑微乳的制备及其质量评价

目的制备酮康唑微乳并进行质量评价。方法以肉豆蔻酸异丙酯(isopropyl myristate,IPM),中链甘油三酯(medium chain triglycerides,MCT)为油相,以聚氧乙烯蓖麻油(polyoxyethylenated castor oil,EL-40)或Tween80为乳化剂,分别以乙醇、1,2-丙二醇、聚乙二醇400(polyethylene glycol400,PEG400)、甘油为助乳化剂,采用加水滴定法,绘制伪三元相图,以所形成的微乳区域大小为评价指标,筛选出酮康唑微乳的最佳处方。考察所制微乳的形态、粒径及其分布、稳定性和体外经皮透过性。结果最优处方为:按质量分数取IPM 12.0%、EL-40 27.0%、PEG400 9.0%、水50.5%、酮康唑1.5%。所制备的酮康唑微乳澄清透明,透射电子显微镜下呈圆整的球形,平均粒径为36.7nm、黏度为141 mPa·s、pH值为6.66,对热、光照稳定;其透皮速率显著大于酮康他索乳膏。结论酮康唑微乳质量稳定,此微乳体系对酮康唑的透皮具有促渗作用。     

遗传算法在经皮给药微乳载体处方优化中的应用

以萘普生为模型药物，用遗传算法优化经皮给药微乳载体的处方。用伪三元相图法确定由Tween 80、IPM、乙醇和水组成的微乳区域。用3因素3水平的中心设计法制备载药量为1.12%的萘普生模型微乳，并进行离体兔皮的体外渗透实验。以稳态渗透速率的二次回归模型为目标函数，用遗传算法对中心设计结果进行优化，筛选出具有最大透皮速率的萘普生微乳载体处方。所得优化处方的组成为：21.41% Tween 80、15.17%乙醇、4.14% IPM和59.28%水，预计的稳态渗透速率为183.57 μg·cm^-2·h^-1。回代试验表明，以优化处方制备的萘普生微乳，其稳态渗透速率的平均值为189.43 μg·cm^-2·h^-1，高于预测值。结果表明，用遗传算法筛选微乳经皮给药载体处方，方法可行，结果合理、可靠。     

辣椒碱纳米乳的制备及大鼠透皮实验研究

目的:制备辣椒碱纳米乳并评价其透皮作用。方法:以具有两亲性的苯甲醇作油相,分别以乙醇、1,2-丙二醇和正丁醇作助表面活性剂,以三元相图确定微乳区域,以辣椒碱透皮速率为指标,用单纯形法优化处方。比较优化处方所得辣椒碱纳米乳与其乳膏和水凝胶制剂经大鼠皮肤的稳态透皮速率(Js)。结果:以乙醇和1,2-丙二醇作助表面活性剂的纳米区域面积相当,均大于正丁醇的纳米乳面积。单纯形法可较准确地优化处方,优选处方辣椒碱纳米乳及乳膏和水凝胶的Js分别为17.54、2.78、7.35μg·cm-2·h-1(P<0.01)。结论:所制备的辣椒碱纳米乳具有良好透皮作用。     

油酸微乳对利多卡因透皮吸收的影响

目的研究油酸微乳对利多卡因透皮吸收的影响。方法在制备相图的基础上，考察了微乳的组分对微乳形成的影响。选择适当的表面活性剂/助表面活性剂比例，制备利多卡因的油酸微乳处方，考察微乳、乳剂、胶束和饱和水溶液在透皮吸收方面的差异。结果以Labrasol为表面活性剂，吐温80为助表面活性剂所得油酸微乳的区域较大，微乳对利多卡因有明显的促透作用，透皮速率依次为微乳＞乳剂＞饱和水溶液＞胶束。结论油酸微乳可促进利多卡因的透皮吸收。     

乳剂类型对5-氟尿嘧啶释药的影响

抗癌药制成乳剂后具有淋巴趋向性,为研究乳剂的类型对抗癌药的有效性影响,制备含5-氟尿嘧啶(5-Fu)的两种复乳(w/o/w型、o/w/o型)及两种单乳(o/w型、w/o型)。油相用橄榄油,油相:水相=1∶1,乳化剂用聚氧乙烯氢化蓖麻油、司盘-85及单硬脂酸铝,表面活性剂总量为0.5%(w/v)。研究四     

Microemulsion-based gel of fluorouracil for transdermal delivery

This study is to prepare the microemulsion-based gel based on the W/O microemulsion and fluorouracil (5-Fu) as a model drug to study the transdermal characterization and observe its skin irritation of the microemulsion-based gel in vitro. IPM acted as oil phase, AOT as surfactant, Tween 85 as cosurfactant, water was added dropwise to the oil phase to prepare W/O microemulsion at room temperature using magnetic stirring, then 5-Fu powder was added. The gelatin was used as substrate to prepare 5-Fu microemulsion-based gel. The permeation flux of 5-Fu from 5-Fu microemulsion-based gel across excised mice skin was determined in vitro using Franz diffusion cell to study the influence of the amount of gelatin and the drug loading capacity. Refer to 5-Fu cream, the irritation of microemulsion and microemulsion-based gel on the rat skin was studied. Based on the water/AOT/Tween 85/IPM microemulsion, only the gelatin can form the microemulsion-based gel. At 25 degrees C, 32 degrees C and 40 degrees C, the amount of gelatin required for the formation of microemulsion-based gel were 7%, 14% and more than 17%, respectively. The 12 h transdermal cumulated permeation amount of 5-Fu from microemulsion-based gel containing 14% gelatin and 0.5% drug loading were (876.5 +/- 29.1) microg x cm(-2), 12.3 folds and 4.5 folds more than 0.5% 5-Fu aqueous solution and 2.5% (w/w) 5-Fu cream, respectively. Microemulsion-based gel exhibited some irritation, but could be subsided after drug withdrawal. Microemulsion-based gel may be a promising vehicle for transdermal delivery of 5-Fu and other hydrophilic drug.     

5-氟尿嘧啶口服微乳的制备及其大鼠肠吸收作用研究

目的:制备5-氟尿嘧啶(5-Fu)口服微乳,并考察其在大鼠肠吸收的作用。方法:以肉豆蔻酸异丙酯为油相、单辛/癸酸甘油酯为乳化剂,借助伪三元相图法对不同5-Fu微乳处方进行评价;用外翻肠囊法制备肠吸收离体模型,考察5-Fu微乳的吸收部位和促吸收效果。结果:选择肉豆蔻酸异丙酯-单辛/癸酸甘油酯-无水乙醇-水(Km=1∶2)体系作为5-Fu微乳的载药体系;与其溶液比较,5-Fu微乳可明显改善药物的肠吸收,小肠中后段是其最佳吸收部位,90min时累积吸收率微乳是溶液的3倍。结论:所制备的5-Fu微乳性质稳定、肠吸收效果良好。     

Transdermal delivery of ketoprofen using microemulsions

A transdermal preparation containing ketoprofen was developed using O/W microemulsion system. Of the oils tested, oleic acid was chosen as the oil phase of the microemulsion, as it showed a good solubilizing capacity and excellent skin permeation rate of the drug. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant and cosurfactant for microemulsion formation, and the effect of these additives on skin permeation of ketoprofen was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 3% ketoprofen, 6% oleic acid, 30% Labrasol/Cremophor RH 40 (1:1) and water. Terpenes were added to the microemulsion at the level of 5% and their effect on the skin permeation of ketoprofen from the microemulsion was evaluated. Of the four terpenes used, only limonene resulted in a powerful enhancing activity (3-fold increase over control).     

The novel formulation design of O/W microemulsion for improving the gastrointestinal absorption of poorly water soluble compounds

The design of the novel O/W microemulsion formulation, which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds was examined. Using medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), ethanol and PBS (pH 6.8) as an oil phase, a lipophilic surfactant, a hydrophilic surfactant, a solubilizer and an aqueous phase, at the mixture ratio of 5%/1%/9%/5%/80% (w/w), respectively, the O/W microemulsion with an average particle diameter of 20 nm or less was prepared. Moreover, for nine kinds of poorly water soluble compounds, such as Ibuprofen, Ketoprofen, Tamoxifen, Testosterone, Tolbutamide and other new compounds, the solubility to water was increased from 60 to 20,000 times by this O/W microemulsion formulation. The AUCs in plasma concentration of Ibuprofen and a new compound, ER-1039, following single oral administration of these compounds as the O/W microemulsion to fasted rats were equivalent to that of solution administration or increased by nine and two times that of suspension administration, respectively. Accordingly, this novel O/W microemulsion is a useful formulation, which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.     

应用电导率-含水量曲线法研究广东王不留行提取物为模型药物的O/W型微乳

目的:建立广东王不留行提取物为模型药物的O/W型微乳处方筛选及制备成型的一种方法。方法:选取文献及本实验室15个处方空白微乳建立电导率-含水量曲线,同时与目测法进行对比研究,选取其中4个稳定的微乳处方,分别建立以广东王不留行提取物为模型药物的O/W型微乳的电导率-含水量曲线,进行其方法学考察及微乳质量评价。结果:O/W型空白及含药微乳成型的临界点均是电导率-含水量曲线的顶点,进一步验证其值显著高于目测法测定的临界值,目测法所测定的O/W型微乳临界值在双连续区域内,通过电导率-含水量曲线确定的空白及含药O/W型微乳方法学实验RSD<1%,空白及含药微乳平均粒径均在10~100 nm之间。结论:电导率-含水量曲线法制备的O/W型微乳分布均匀、具备量化、准确、重复性好,应用于微乳处方筛选及制备工艺研究具有理论及实际可行性,能准确反应微乳的相行为及结构变化。     

草乌甲素微乳的制备及其理化性质的考察

目的 选择适宜比例的油相、表面活性剂、助表面活性剂和水相,制备草乌甲素微乳制剂,以增加药物的溶解度,优化处方,并研究其理化性质.方法 绘制伪三元相图,确定各相的比例,以微乳区域大小为指标,考察优化微乳的处方.测定草乌甲素微乳的粒度及其分布.结果 草乌甲素微乳制剂中药物的溶解度极大提高,乳液滴的平均粒径为53.6 nm.结论 制备了O/W型草乌甲素微乳,为开发草乌甲素透皮制剂提供了依据.     

The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion I: enhancing effects on oral bioavailability of poorly water soluble compounds in rats and beagle dogs

We examined the design of the versatile novel self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds. Namely, seven kinds of poorly water soluble compounds such as disopyramide, ibuprofen, ketoprofen, tolbutamide, and other new compounds, as the model compounds were used to compare the plasma concentration profile of the compound following single oral administration of each compound to rats and beagle dogs as a solution, an oily solution, a suspension (or a powder), an O/W microemulsion, and a SEDDS type O/W microemulsion. And the enhancing effect of the SEDDS type O/W microemulsion on the gastrointestinal absorption of these compounds was evaluated. In the components of the SEDDS type O/W microemulsion, medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), and ethanol were used as an oil, a lipophilic surfactant, a hydrophilic surfactant, and a solubilizer, at the mixture ratio of 25/5/45/25 (w/w%), respectively. Thereby, to six kinds of the model compounds except disopyramide, the solubility was from 340 to 98,000 times that in water, and the AUCs in plasma concentration of the compound were equivalent to that of solution or O/W microemulsion administration, or was increased by 1.5 to 78 times that of suspension administration. Accordingly, this novel SEDDS type O/W microemulsion is the versatile, useful formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.     

水包油型微乳形成因素的考察

目的考察影响O/W型微乳形成的主要因素。方法选用丁酸乙酯、油酸乙酯和豆油作为油相 ,Tween 80、Tween 2 0和Labrasol作为表面活性剂 ,乙醇、1,2 -丙二醇和正丁醇为助表面活性剂 ,通过滴加法绘制假三元相图 ,以O/W型微乳区大小为指标考察各因素对微乳形成的影响。结果油相、表面活性剂、助表面活性剂、表面活性剂与助表面活性剂的质量比、离子强度、添加剂和温度对微乳的形成均有一定影响。结论O/W型微乳能够作为药用载体。     

长春西汀微乳的优化及其理化性质的考察

目的选择适宜比例的油相、表面活性剂、助表面活性剂和水相制备长春西汀微乳制剂以增加药物的溶解度和经皮渗透量，优化处方，并对其理化性质和刺激性进行研究。方法绘制伪三元相图，确定各相的比例，以经皮稳态渗透流量为指标，利用单纯形网格法优化处方，并考察优化微乳的pH、粘度、电导率、折光率、粒径分布等理化性质。采用MTT法考察微乳制剂对人体皮肤细胞系模型Hacat细胞的毒性。结果O/W微乳在相图中的区域随着表面活性剂和助表面活性剂比例的增加而增加；单纯形网格优化法预测的指标值与实测值相近，所得的优化微乳性质稳定，对Hacat细胞无刺激性，与阴性组无显著性差异。结论长春西汀微乳制剂中药物的溶解度极大提高，经皮稳态渗透流量显著增大，安全稳定，可作为经皮给药的新型载体。     

The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion II: stable gastrointestinal absorption of a poorly water soluble new compound, ER-1258 in bile-fistula rats

The stabilization effect of the novel self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion on the gastrointestinal absorption of a poorly water soluble new compound, ER-1258 was examined by bile-fistula model rats. In the components of this formulation, medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40) and ethanol were used as an oil, a lipophilic surfactant, a hydrophilic surfactant and a solubilizer at the mixture ratio of 25/5/45/25 w/w%, respectively. The ratios of AUC in the non-treated rats to that in the bile-fistula rats were 5.1, 12.1 and 3.0 for the suspension, the oily solution and the SEDDS type O/W microemulsion, respectively. The risk from which the difference between individuals of the compound absorption amounts resulting from the flow of the bile secretion serves as the maximum was high in order of oily solution>suspension>SEDDS type O/W microemulsion. Therefore, it was verified that the SEDDS type O/W microemulsion was able to reduce this risk, compared with the other formulations. When short chain fatty acid triglyceride (Triacetin) was used as an oil, the similar effect was demonstrated in the formulation composed of sorbitan sesquioleate (SO-15) as a lipophilic surfactant and polyoxyethylene hydrogenated castor oil 60 (HCO-60) or polyoxyethylene 20 sorbitan monooleate (TO-10M) as a hydrophilic surfactant.