微乳液相色谱法及其研究进展

微乳是由表面活性剂、油相、助表面活性剂、水相在适当比例下自发形成的一种透明或半透明的、低黏度的、各向同性且热力学稳定的水油混合系统。油相液滴（droplets）包裹于表面活性剂和助表面活性剂层并均匀分散在水相中,形成O／W型微乳;表面活性剂包裹水性液滴并分散在油相体系中形成W／O型微乳。微乳的研究主要集中在药剂学方面,用于药物分析方面的研究还比较少。微乳的粒径通常小于100nm,用于色谱流动相的微乳粒径可以小于10nm。微乳可以作为薄层色谱的展开剂和毛细管电泳的分离介质,也可以作为高效液相色谱的流动相,通常我们将以微乳为流动相的高效液相色谱法称为微乳液相色谱法（microemulsion liquid chromatography,MELC）。     

微乳作为经皮给药和其他给药载体的优势与局限性分析

<正>微乳(microemulsion,ME)是由水、油相、表面活性剂和助表面活性剂按适当的比例自发形成的一种透明或半透明的、低黏度、各向同性且热力学稳定的溶液系统。微乳属于胶体分散系统,其乳滴多为球形,大小均匀,外观透明或近似透明,经热压灭菌或离心也不能使之分层,按结构可分为油包水(W/O)型、水包油(O/W)型和双相连续型微乳。     

含电解质的W/O型微乳作为氟尿嘧啶透皮给药载体的研究

通过电解质氯化钠(NaCl)的加入,制备含水量高、载药量高且透过能力强的氟尿嘧啶(5-Fu)W/O型微乳,并研究其体外透皮特性及皮肤刺激性。以肉豆蔻酸异丙酯(IPM)为油相,磺化琥珀酸二辛酯钠(AOT)为表面活性剂,Tween 85为助表面活性剂,在室温下采用磁力搅拌法滴加NaCl溶液至油相中,形成空白微乳后直接加入5-Fu粉末,即形成5-Fu微乳。以伪三元相图为基础、单位面积的透皮累积透过量(Qn)为指标,用改进的Franz扩散池和离体小鼠皮肤考察微乳处方中含水量和载药量对离体鼠皮透过量的影响,优化处方。以表面张力、黏度和电导率为指标,研究NaCl/AOT-Tween 85/IPM微乳的理化性质,并对最优处方的皮肤刺激性进行初步评价。结果表明,5-Fu微乳的优化处方为含药0.7%(w/v),0.05 mol·L-1 NaCl溶液50%,混合表面活性剂(AOT/Tween 85,Km=2)20%,油相29.3%。12 h累积透过量为(2 013.4±41.6)μg.cm-2,分别为0.7%药物水溶液和2.5%(w/w)市售乳膏(O/W)的20.23倍和10.38倍。该微乳具有一定的刺激性,但停药后可迅速恢复。...     

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。

     

辅助表面活性剂对微乳相行为的影响

目的考察辅助表面活性剂对微乳相行为的影响，指导微乳制剂的研究和开发。方法采用滴水法制备微乳相图，以O／W微乳区面积和最大载油量为指标，考察辅助表面活性剂种类和性质对微乳形成的影响。结果短链醇（2～3个碳）的微乳区显著大于长链醇（大于5个碳），而CLogP在1附近的正丁醇和苯甲醇辅助乳化效果亦较好；弱碱性助表（酰胺类）可促进采用弱酸性油相（如油酸）的微乳形成。结论与油水两相间均有良好互溶性的助表更有利于微乳的形成。     

棕榈氯霉素卵磷脂O/W型微乳制剂的研究

目的棕榈氯霉素卵磷脂O/W型微乳制剂的制备与含量检测。方法用十六酸异丙酯溶解棕榈氯霉素作油相,卵磷脂和吐温80混合作为表面活性剂,乙醇为助表面活性剂,制备O/W型微乳制剂;用高效液相色谱法进行棕榈氯霉素含量的测定。色谱条件:C18柱(250 mm×4.60 mm,5μm),流动相为甲醇液,柱温25℃,流量为1.0 ml.min-1,检测波长为271 nm,进样体积20μl。结果取得了较好的棕榈氯霉素卵磷脂O/W型微乳制剂及较好的含量检测方法。讨论棕榈氯霉素可以制成卵磷脂O/W型微乳制剂,用高效液相色谱法进行含量测定。     

脂溶性药物在O/W型微乳中的分配行为

以亮菌甲素和氧氟沙星为模型药物，采用荧光光谱法考察微乳中各组分对药物荧光光谱的影响，以研究脂溶性小分子药物在O/W型微乳中的分配行为。结果显示在分别采用苯甲醇和PEG 400为助表面活性剂的微乳体系中，亮菌甲素主要存在于表面活性剂组成的界面膜中；氧氟沙星在油酸/橄榄油(1∶1)的微乳体系中的主要分布部位为油核，而在Gradamol GTCC为油相的微乳体系中主要存在于界面膜中；在各体系中药物均倾向于增溶在对药物溶解能力最强的组分所处的微环境中，具体的存在位置与该组分的用量有关。由此可见脂溶性药物在O/W型微乳中的存在部位可能取决于各组分对药物的溶解能力。     

不同助表面活性剂对o/w型微乳形成的影响

在微乳配方开发过程中,通常选用短链醇作为助表面活性剂,然而有些药物在这些助表面活性剂中的溶解度或相容性并不理想.因此,选用非醇类物质(Plurol(R) Oleique CC 497、CapyrolTM 90或Transcutol(R))为助表面活性剂,并以Labrasol(R)为表面活性剂,Labrafil(R) M 1944为油相,分别绘制了空白微乳的伪三元相图.结果表明,这些助表面活性剂的种类和表面活性剂/助表面活性剂比例(Km)对o/w型微乳的形成有影响.     

鸦胆子油微乳的制备及稳定性研究

目的研究鸦胆子油微乳的制备、稳定性及微乳中药物含量的测定方法。方法选用MCT(辛葵酸甘油三脂)为油相,大豆卵磷脂为表面活性剂,乙醇为助表面活性剂,在制备三元相图的基础上,考察微乳的组分对微乳形成的影响。结果大豆卵磷脂为乳化剂形成微乳系统所需表面活性剂的量为20%～30%。结论采用微乳作为药物载体制备口服鸦胆子油微乳是一种很好的药物传递系统。     

光学异构20（R）-人参皂苷Rg3微乳的相图研究

目的:筛选人参皂苷Rg3空白微乳处方组成.方法:通过滴定法绘制伪三元相图,以微乳区面积大小为指标,考察各系统的相图行为及各因素对微乳区形成的影响.结果:不同的表面活性剂、助表面活性剂、Km值、油相物质的种类、温度等对微乳形成均有较大影响.结论:Km=2,25℃时形成的曲拉通X-100/异丙醇/油酸乙酯/水微乳体系为最优的微乳体系.     

Transdermal delivery of hydrocortisone from eucalyptus oil microemulsion: effects of cosurfactants

This study investigated the effects of cosurfactants on the transdermal delivery of hydrocortisone (model drug) from eucalyptus oil microemulsion. Eucalyptus oil which was successfully employed for steroidal drugs was used as the oil. Tween 80 which was readily miscible with eucalyptus oil was used as surfactant. Ethanol, isopropanol and propylene glycol which are relatively tolerable by the skin were employed as cosurfactants. Pseudo-ternary phase diagrams were constructed in the presence and absence of cosurfactants. Microemulsion formulations containing 20% oil, 20% water and 60% of either Tween 80 or 1:1 surfactant/cosurfactant mixture were compared. Incorporation of cosurfactants expanded the microemulsion zone. The cosurfactant free microemulsion was viscous showing pseudo-plastic flow. The cosurfactant containing preparations were less viscous with Newtonian flow. The drug loading and release rate were increased in the presence of cosurfactants with the release depending on the viscosity. Incorporation of hydrocortisone in microemulsion increased the transdermal flux compared to saturated aqueous solution. The presence of cosurfactants increased the transdermal drug flux compared to the cosurfactant free formulation. Ethanol produced the greatest effect followed by propylene glycol and isopropanol. The presence of cosurfactant and its type can thus affect both the phase behavior and the transdermal delivery potential of microemulsion.     

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。     

Novel dithranol phospholipid microemulsion for topical application: development, characterization and percutaneous absorption studies

The objective of this study was to develop and characterize a novel dithranol-containing phospholipid microemulsion systems for enhanced skin permeation and retention. Based on the solubility of dithranol, the selected oils were isopropyl myristate (IPM) and tocopherol acetate (TA), and the surfactants were Tween 80 (T80) and Tween 20 (T20). The ratios of cosurfactants comprising of phospholipids and ethanol (1?:?10) and surfactant to co-surfactant (1?:?1 and 2.75?:?1) were fixed for the phase diagram construction. Selected microemulsions were evaluated for globule size, zeta potential, viscosity, refractive index, per cent transmittance, stability (freeze thaw and centrifugation), ex vivo skin permeation and retention. The microemulsion systems composed of IPM and T80 with mean particle diameter of 72.8?nm showed maximum skin permeation (82.23%), skin permeation flux (0.281?mg/cm2/h) along with skin retention (8.31%) vis-à-vis systems containing TA and T20. The results suggest that the developed novel lecithinized microemulsion systems have a promising potential for the improved topical delivery of dithranol.     

Rheology and stability of water-in-oil-in-water multiple emulsions containing Span 83 and Tween 80

Multiple emulsions are often stabilized using a combination of hydrophilic and hydrophobic surfactants. The ratio of these surfactants is important in achieving stable multiple emulsions. The objective of this study was to evaluate the long-term stability of water-in-oil-in-water (W/O/W) multiple emulsions with respect to the concentrations of Span 83 and Tween 80. In addition, the effect of surfactant and electrolyte concentration on emulsion bulk rheological properties was investigated. Light microscopy, creaming volume, and rheological properties were used to assess emulsion stability. It was observed that the optimal surfactant concentrations for W/O/W emulsion long-term stability were 20% wt/vol Span 83 in the oil phase and 0.1% wt/vol Tween 80 in the continuous phase. Higher concentrations of Tween 80 had a destructive effect on W/O/W emulsion stability, which correlated with the observation that interfacial film strength at the oil/water interface decreased as the Tween 80 concentration increased. High Span 83 concentrations increased the storage modulus G′ (solidlike) values and hence enhanced multiple emulsion stability. However, when 30% wt/vol Span 83 was incorporated, the viscosity of the primary W/O emulsion increased considerably and the emulsion droplets lost their shape. Salt added to the inner aqueous phase exerted an osmotic pressure that caused diffusion of water into the inner aqueous phase and increased W/O/W emulsion viscosity through an increase in the volume fraction of the primary W/O emulsion. This type of viscosity increase imposed a destabilizing effect because of the likelihood of rupture of the inner and multiple droplets.     

Physicochemical characterization and evaluation of a microemulsion system for antimicrobial activity of glycerol monolaurate

The purpose of this study was to improve the depression, enhance the bioavailability, hence strengthen the antimicrobial ability of poorly water-soluble glycerol monolaurate (GML) by loading it in microemulsion system. Microemulsions were prepared with GML as oil, tweens as surfactant, and medium-and-short chain alcohols at different ratio as cosurfactants. The effect of the ratio of surfactant to cosurfactant on the stability of microemulsion was tested. And the effect of the composition and ratio of cosurfactant and the effect of potassium sorbate dissolved in water at different concentration on the area of O/W microemulsion region in pseudo-ternary phase diagrams were also investigated. The results showed that the microemulsion is most stable when the ratio of surfactant to cosurfactant was 3:2, the suitable cosurfactant is pentanol to dodecane at 2:1, the area of O/W microemulsion region in pseudo-ternary phase diagram increased with increasing content of potassium sorbate. The conclusion of this study was that GML loaded in microemulsion had much higher anti-microbial activity than GML alone.     

The use of some ingredients for microemulsion preparation containing retinol and its esters

A study of microemulsions with retinol and its esters. Physical properties of w/o and o/w microemulsions containing Tween 60, Tween 80, Epicurone 135 (soy bean lecithin) as surfactants, n-butanol, triacetin, propylene glycol as cosurfactants were examined. The drug-containing systems were characterised in regard to their ophthalmic parameters. Physiologically well-tolerated and physically stable multiple-components were developed. The concentrations of surfactants and cosurfactants which are necessary to form stable systems were evaluated. The values of the following parameters--refractive index, viscosity, pH value, osmotic tension, obtained in the study, proved suitable for the purpose and the preparations were physiologically tolerated, the use of microemulsions as potential drug delivery systems for ocular administration has been discussed. The influence of retinol and its esters on the physical parameters the preparation was investigated. Microemulsion stored at 20 degrees C up to 6 months showed no significant physical changes.     

Novel dithranol phospholipid microemulsion for topical application: development,characterization and percutaneous absorption studies

The objective of this study was to develop and characterize a novel dithranol-containing phospholipid microemulsion systems for enhanced skin permeation and retention. Based on the solubility of dithranol, the selected oils were isopropyl myristate (IPM) and tocopherol acetate (TA), and the surfactants were Tween 80 (T80) and Tween 20 (T20). The ratios of cosurfactants comprising of phospholipids and ethanol (1?:?10) and surfactant to co-surfactant (1?:?1 and 2.75?:?1) were fixed for the phase diagram construction. Selected microemulsions were evaluated for globule size, zeta potential, viscosity, refractive index, per cent transmittance, stability (freeze thaw and centrifugation), ex vivo skin permeation and retention. The microemulsion systems composed of IPM and T80 with mean particle diameter of 72.8?nm showed maximum skin permeation (82.23%), skin permeation flux (0.281?mg/cm²/h) along with skin retention (8.31%) vis-à-vis systems containing TA and T20. The results suggest that the developed novel lecithinized microemulsion systems have a promising potential for the improved topical delivery of dithranol.     

Structural characterisation of water-Tween 40/Imwitor 308-isopropyl myristate microemulsions using different experimental methods

Pharmaceutically usable microemulsion systems were prepared from water and isopropyl myristate with a constant amount of Tween 40 and Imwitor 308 at a mass ratio of 1. Their type and structure were examined by measuring density and surface tension, and by viscometry, electric conductivity, differential scanning calorimetry (DSC) and small-angle X-ray scattering (SAXS), and the degree of agreement between the techniques was assessed. A model based on monodisperse hard spheres adequately fits the SAXS data in W/O microemulsions predicting, depending on composition, elongated or spherical droplets. It also suggests the involvement of strong attractive interactions in O/W systems. Results of conductivity, viscosity, density and surface tension measurements confirm the prediction of a percolation transition to a bicontinuous structure. DSC detects the degree of water interaction with surfactants thus identifying the type of microemulsion. The conclusions from all the techniques agree well and indicate that such studies could also be carried out on more complex systems. In future, the ability to determine type and structure of such microemulsion systems could enable partitioning and release rates of drugs from microemulsions to be predicted.