微乳化技术制备固体脂质纳米粒微乳化技术制备固体脂质纳米粒

目的采用微乳化技术制备固体脂质纳米粒（SLN）。方法以硬脂酸为油相，卵磷脂为乳化剂，乙醇为助乳化剂，蒸馏水为水相，按不同比例混合制备微乳。通过改变卵磷脂与乙醇的配比（K_m），绘制出不同K_m值下的三元相图。从中选择适宜的微乳，将其分散于冷水中制备SLN。考察了工艺因素和处方因素对SLN制备和SLN质量的影响。在单因素考察的基础上，采用正交设计优化工艺，并对优化所得的工艺进行重现性考察。结果水相温度（T_w）、微乳的温度（T_i）、微乳注入速度（r_d）均直接影响SLN的制备，其中水相温度是影响SLN质量的重要因素；微乳各组分的配比、微乳与水相的比例也对SLN的质量有一定影响。结论微乳化技术制备固体脂质纳米粒是可行的。     

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。

     

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。     

三七总皂苷油包水微乳的处方筛选及体内外评价

筛选口服油包水(W/O)微乳处方以提高三七总皂苷(panax notoginsenoside，PNS)中人参皂苷Rb₁的体内肠吸收，分别采用大鼠体内肠吸收、脂质体和平行人工膜(parallel artificial membrane permeability assay，PAMPA)等模型分别研究微乳的体内药代动力学及体外对膜流动性和药物膜转运性质的影响。主要以磷脂/乙醇(SP/EtOH)为表面活性剂，与PNS水溶液(400 mg·mL^-1)和不同油相分别制备11个W/O微乳处方。多数微乳处方可提高药物的大鼠体内肠吸收，其吸收促进作用除与所含表面活性剂有关外，不同油相的选用也会产生一定影响，其吸收促进作用大小为月桂酸甘油酯≈肉蔻豆酸异丙脂>棕榈酸异丙脂>棕榈酸异辛酯。长链(>C₁₄)脂肪酸酯的吸收促进作用低于中链脂肪酸酯(C₈~C₁₄)。多数微乳处方可不同程度的提高脂质体的膜流动性。PAMPA研究中，稀释后微乳(D-ME)中药物的有效透过系数(P_e)多数高于PNS对照溶液，表明微乳中的组分可以提高药物的膜透过能力，稀释前微乳(ME)的P_e与大鼠体内肠吸收具有相对较好的直线相关性(r=0.774 0)。W/O微乳可以促进人参皂苷Rb₁的肠吸收，吸收促进作用与其提高生物膜流动性有一定关系。PAMPA可以尝试引入制剂处方研究(如吸收促进剂等)的某些领域中。     

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。     

用三角相图法研究药用微乳的形成条件

目的　用建立的改良三角相图法制备低毒药用微乳。方法　选磷脂和聚氧乙烯辛基苯基醚(OP)为乳化剂,乙醇和正辛醇为助乳化剂,油酸乙酯和橄榄油为油相,以改良三角相图法即固定水相和助乳化剂的比值(W/A)或油相和助乳化剂的比值(O/A),对比经典三角相图法即固定乳化剂和助乳化剂的比值(K_m)制备的微乳所需乳化剂和助乳化剂的量及相体积比的大小。结果　对磷脂为乳化剂形成的微乳系统,改良三角相图法所需乳化剂的量为6%-28%,而经典三角相图法所需乳化剂的量为28%-29.6%。对OP为乳化剂形成的微乳系统,改良三角相图法所需乳化剂为23%-40%;而经典三角相图法所需乳化剂为27.6%-49.8%,以上两种系统,前者均较后者用量小。结论　用改良三角相图代替经典三角相图研究形成药用微乳的理论,对寻找低毒性的微乳有积极的指导意义。     

以油酸为油相的空白O/W微乳体系研究

目的 研究以油酸为油相的不同组成微乳体系的相行为特点,考察常见乳化剂和助乳化剂增溶特性,获得水增溶及油酸增溶量均较大的O/W微乳体系。方法 采用伪三元相图法,以微乳区域面积（A_T）、最大增溶水量（W_m）及对应的乳化剂用量（S_m）为水增溶参数,O/W结构能容纳的最大油酸量（O_m）为油酸增溶参数,通过比较筛选出最适乳化剂、助乳化剂及两者质量比,并通过体系电导率随含水量变化及相转变点绘出O/W微乳区域。结果 多元醇为助乳化剂时水增溶量有限且易形成凝胶;吐温类乳化剂中吐温20水增溶量最大,吐温80油酸增溶量最大,其油水增溶量与HLB值并不完全成正比;选用吐温80/无水乙醇为混合乳化剂,随着吐温80比例下降,最大油酸增溶量逐步下降,水增溶量先上升再下降,两者比例在1∶1时,所绘制三元相图的微乳区域面积最大,但形成的O/W微乳区域亦有限。结论 以油酸为油相,可采用质量比1∶1的吐温80/无水乙醇为混合乳化剂,其水增溶和油酸增溶量均较大,可形成一定区域的O/W微乳。     

药物脂水分配系数测定的微乳液电动色谱新方法研究

目的建立一种测定药物脂水分配系数的微乳液电动色谱(MEEKC)新方法，以避免测定时必须使用微乳相标记物，以及减小和评价测量误差。方法以系列化合物在MEEKC中的迁移时间t_m值与其脂水分配系数之间的关系，进行非线性拟合得出微乳相的虚拟迁移时间t_me，再建立标准曲线以测定所选取药物的脂水分配系数；从理论上评价测定结果准确度与t_m相关性，并以此评价测定结果的准确度。结果所选取的4种药物脂水分配系数的MEEKC测定值与摇瓶法测定值基本吻合，其平均差值为0.15，其测定准确度与t_m的相关性符合理论模型的分析。结论无微乳相标记物的MEEKC新方法简单、快速、可靠、重现性好，测定脂水分配系数的准确度较高，可用作药物脂水分配系数的测定。     

利多卡因——卵磷脂微乳处方的初步研究

目的 :以卵磷脂微乳为载体 ,制备利多卡因透皮给药系统。方法 :伪三元相图考察油包水型微乳形成区域 ;测定微乳黏度 ,正交分析法筛选微乳处方 ;紫外分光光度法直接测定微乳中盐酸利多卡因浓度。结果 :助表面活性剂的种类和Km(表面活性剂 /助表面活性剂用量比 )对微乳形成区域有显著性影响 ,正丙醇和异丙醇所形成的微乳区较大 ;低纯卵磷脂微乳形成区域较高纯卵磷脂大 ;醇的种类对微乳的黏度均有显著的影响 ,Km 对微乳的黏度有较大影响。选定紫外检测波长为 2 6 2nm ,盐酸利多卡因浓度在 0 .0 2～ 0 .5mg/mL范围内线性关系良好 (R =0 .9999)。平均回收率 ( 10 0 .17± 0 .16 ) %。日内差与日间差分别为 0 0 137±0 0 12 1,0 0 119± 0 0 115。结论 :选择混合表面活性剂利于制备微乳 ,醇的种类与用量对于利多卡因透皮微乳体系处方的选择具有重要意义。     

新型抗血吸虫药物QH917自微乳化释药系统的优化和评价

筛选新型抗血吸虫药物QH917自微乳化释药系统的处方。以油相的用量(%)和表面活性剂与助表面活性剂的质量比(K_m)作为自变量，自乳化时间(t)、平均粒径(PS)和多分散系数(PI)作为因变量，采用星点设计——效应面法进行处方优化，模拟体内环境，考察了离子强度、食物、pH值、转速和介质体积对优化处方释放的影响，并采用大鼠在体小肠吸收试验评价了优化处方的吸收情况。结果表明，优化处方为：油相中链甘油三酸酯(MCT)的质量分数为30%～34%，表面活性剂聚氧乙烯40氢化蓖麻油(Cremophor RH40)与助表面活性剂乙醇的质量比为4.8～5.2。优化处方的释放行为基本不受介质环境的影响。大鼠在体小肠吸收试验表明胆管结扎与未结扎对吸收率无显著影响，个体间吸收行为差异性较小。以星点设计——效应面法对自微乳化释药系统的处方进行优化，预测性良好，优化处方体外释放和大鼠小肠吸收行为均比较稳定。     

Water/oil type microemulsion systems containing lidocaine hydrochloride: in vitro and in vivo evaluation

Abstract

The purpose of this study was to develop a water/oil microemulsion containing lidocaine hydrochloride (4%) and to compare its local anaesthetic efficacy with commercial products. A pseudoternary diagram (K_m:1/1 or 1/2) was constructed using lecithin/ethanol/oil/water. The droplet size, viscosity and release of the microemulsions were evaluated. Tail flick tests were conducted for in vivo effectiveness; the initiation time of effect, maximum effect, time to reach maximum effect, and relative efficacy were evaluated. The drug caused a significant increase in droplet size. The use of olive oil resulted in a decrease in the solubilisation parameter, as well as a reduction in the release. The droplet size and viscosity of the microemulsion composed of Miglyol/lecithin/ethanol/water/drug (K_m:1/2) was lower than other microemulsions (8.38?nm, 6.9 mPa), and its release rate (1.61?mg/h) was higher. This system had a faster and more efficient anaesthetic effect than the other microemulsions and commercial products. Results indicate that a water/oil type microemulsion (Miglyol/lecithin/ethanol/water) has promising potential to increase the local anaesthetic effect.     

Particle size analysis of concentrated phospholipid microemulsions: II. Photon correlation spectroscopy

The solvated droplet size of concentrated water-in-oil (w/o) microemulsions prepared frome egg and soy lecithin/water/isopropyl myristate and containing short-chain alcohol cosurfactants has been determined using photon correlation spectroscopy (PCS). The effect of increasing the water volume fraction (from 0.04 to 0.26) on the solvated size of the w/o droplets at 298 K has been investigated at 4 different surfactant/cosurfactant weight ratios (K _m of 1∶1, 1.5∶1, 1.77∶1, and 1.94∶1); in all cases the total surfactant/cosurfactant concentration was kept constant at 25% w/w. In the case of the microemulsions prepared from egg lecthin, the diffusion coefficients obtained from PCS measurements were corrected for interparticulate interactions using a hard-sphere model that necessitated estimation of the droplet volume fractions, which in the present study were obtained from earlier total intensity light-scattering (TILS) studies performed on the same systems. Once corrected for hard-sphere interactions, the diffusion coefficients were converted to solvated radii using the Stokes-Einstein equation assuming spherical microemulsion droplets. For both egg and soy lecithin systems, no microemulsion droplets were detected at water concentrations less than 9 wt% regardless of the alcohol and K _m used, suggesting that at low concentrations of added water, cosolvent systems were formed. At higher water concentrations, however, microemulsion droplets were observed. The changes in droplet size followed the expected trend in that for a fixed K _m the size of the microemulsion droplets increased with increasing volume fraction of water. At constant water concentration, droplet size decreased slightly upon increasing K _m. Interestingly, only small differences in size were seen upon changing the type of alcohol used. The application of the hard-sphere model to account for interparticulate interactions for the egg lecithin systems indicated that the uncorrected diffusion coefficients underestimated particle size by a factor of slightly less than 2. Reassuringly, the corrected droplet sizes agreed very well with those obtained from our earlier TILS study.     

Investigations into the formation and characterization of phospholipid microemulsions. IV. Pseudo-ternary phase diagrams of systems containing water-lecithin-alcohol and oil; The influence of oil

Phase studies have been performed for quaternary systems composed of egg lecithin, cosurfactant, water and oil. The lecithin used was the commercially available egg lecithin Ovothin 200 (which comprises ≥ 92% phosphatidylcholine). The cosurfactants employed were propanol and butanol, and these were used at lecithin/cosurfactant mixing ratios (K_m) of 1:1 and 1.94:1 (weight basis). Six polar oils were investigated, including the alkanoic acids, octanoic and oleic, their corresponding ethyl esters and the medium and long chain triglycerides, Miglyol 812 and soybean oil. All oils, irrespective of the alcohol and the K_m used, gave rise to systems that produced a stable isotropic region along the surfactant/oil axis (designated as a reverse microemulsion system). In addition, the systems incorporating propanol at both K_m and butanol at a K_m of 1.94: 1, generally gave rise to a liquid crystalline region and, in some cases, a second isotropic non-birefingent area (designated as a normal microemulsion system). The phase behaviour observed was largely dependent upon the alcohol and K_m used and the size and the polarity of the oil present.     

Enhance transdermal delivery of flurbiprofen via microemulsions: Effects of different types of surfactants and cosurfactants

Background and the purpose of the study

Microemulsions are thermodynamically stable, clear dispersions of water, oil, surfactant, and cosurfactant. This study was aimed to develop flurbiprofen microemulsion for enhanced transdermal delivery and investigate the effects of different surfactants and cosurfactants on its delivery and phase behavior.

Method

Various surfactant-cosurfactant mixtures in ratio of 2:1 (Smix) along with oleic acid (oil) were selected and phase diagrams were constructed. Six microemulsions each containing 5% drug, 5% oil, 56% Smix and 34% water, were prepared and compared for their permeation and phase behaviors to determine the effects of the type of Smix.

Results

In vitro transdermal permeation through rabbit skin of all microemulsions was high than saturated aqueous drug solution. Tween 20 and ethanol as Smix produced the highest flux amongst all the Smix, and were used to prepare formulations with different values of oil and Smix. While the type of surfactant did not affect the droplet size, propylene glycol as cosurfactant produced the largest droplets and highest viscosity. Decrease in oil or Smix concentration resulted in decrease of the droplet size and increase in permeation flux while decrease in viscosity also increased the permeation flux of microemulsions. Finally the selected microemulsion formulation comprising 5% flurbiprofen, 5% oleic acid, 46% Tween 20:ethanol (2:1) and 44% water, showed the highest transdermal flux and caused no skin irritation.

Conclusion

Type of surfactant and cosurfactant affect both the phase behavior and transdermal drug delivery of microemulsion; and results of this study showed that they are promising vehicles for improved transdermal delivery and sustained action of flurbiprofen.     

Transdermal delivery of capsaicin derivative-sodium nonivamide acetate using microemulsions as vehicles

The objective of this study was to prepare sodium nonivamide acetate (SNA) microemulsion for topical administration. Microemulsions consisted of a mixed surfactant of Tween 80 and Span 20 as surfactant, ethanol as cosurfactant, isopropyl myristate (IPM) as an oil phase and water as an external phase. The effect of composition of microemulsion including the ratio of oil phase/surfactant/aqueous phase, various cosurfactant and polymer on the character and permeability of microemulsion were evaluated. The mean droplet size of SNA microemulsions ranged from 64 to 208 nm. Microemulsions showed potent enhancement effect for SNA transdermal delivery by a 3.7-7.1-fold increase when compared with the control group. Microemulsion containing ethanol as cosurfactant had the highest enhancement effect. With incorporated polymer, the viscosity of microemulsions increased resulting in the decrease in penetration rate of SNA. However, the permeability of SNA delivered from microemulsion was higher than SNA from volatile vehicles (pH 4.2 buffer containing 25% ethanol) reported in an earlier study, therefore microemulsions could be an effective vehicle for topical delivery of SNA.     

Sucrose esters/cosurfactant microemulsion systems for transdermal delivery: Assessment of bicontinuous structures

This research studies microemulsion systems containing minimal amounts of surfactant for topical use. Sucrose esters are not able to form microemulsions without a cosurfactant. Microemulsion areas were investigated for numerous systems including sucrose esters/cetearyl octanoate/alcohols/water at different surfactant/cosurfactant mass ratios, called K_m, and different HLB values. The pseudoternary isotherm diagrams were constructed by titration at 25°C. The long and unsaturated oleic chain of the surfactant improves the extent of the microemulsion zone and when K_m increases the domain becomes larger. A combination of laurates at HLB = 7 increases the water and oil solubilizing capacity. Cosurfactants affect the shape and the extent of microemulsion regions. Shorter alcohols which are expected to disorder the interfacial film gave extended microemulsion zones by destabilizing the liquid crystalline phases. Moreover, in short alcohol based diagrams, the microemulsion areas are single volume in which the percolation transition law can be applied. The electroconductive behaviour allows us to determine the percolation threshold and to identify quantitatively bicontinuous structures. These structures, owing to their very low interfacial tension, associated to their wetting properties, should be very interesting as new drug carrier systems for transdermal delivery.     

Particle size analysis of concentrated phospholipid microemulsions: I. Total intensity light scattering

Water-in-oil phospholipid microemulsions prepared from a constant total surfactant/cosurfactant concentration of 25 wt% at four different lecithin/alcohol weight ratios (K _m of 1∶1, 1.5∶1, 1.77∶1, and 1.94∶1) and containing water concentrations (or volume fractions) ranging from 2.0 to 26 wt% (or 0.04 to 0.26) have been examined at 298 K using total intensity light scattering. The data obtained were analysed using the hard-sphere model of Percus-Yevick, modified to account for the partitioning of the alcohol between the various phases. The light-scattering results showed that, regardless of the K _m or the alcohol used, a minimum water concentration of at least 9 wt% was required for the formation of a microemulsion; although this value was reasonably constant for each of the alcohols investigated, there was a tendency for a slightly higher concentration of water to be required for microemulsion formation at higher K _m values. Simple calculations suggested that a microemulsion was formed only when sufficient water was present to satisfy the hydration of both the phospholipid head groups and the hydroxyl groups of the cosurfactant associated with the droplet. At water concentrations lower than this minimum value, a cosolvent system was observed. In all systems above this minimum concentration, as the concentration of water increased, the size of the microemulsion droplets also increased. Surprisingly, however, there was little difference in the size of the microemulsion droplets obtained with the different alcohols, regardless of the K _m, although for a particular alcohol there was some indication that the higher K _m systems produced the slightly smaller droplets for an equivalent water concentration. There was also a suggestion that the more hydrophobic alcohols produced slightly smaller droplets than the more polar alcohols at the same K _m.     

Transdermal delivery of diclofenac using microemulsions

A transdermal preparation containing diclofenac diethylammonium (DDA) was developed using an O/W microemulsion system. Of the oils tested, lauryl alcohol 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 DDA was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 1.16% of DDA, 5% of lauryl alcohol, 60% of water in combination with the 34.54% of Labrasol (surfactant)/ethanol (cosurfactant) (1:2). The efficiency of formulation in the percutaneous absorption of DDA was dependent upon the contents of water and lauryl alcohol as well as Labrasol:ethanol mixing ratio. It was concluded that the percutaneous absorption of DDA from microemulsions was enhanced with increasing the lauryl alcohol and water contents, and with decreasing the Labrasol:ethanol mixing ratio in the formulation.     

Investigating effect of microemulsion components: In vitro permeation of ketoconazole

The purpose of this study was to evaluate the effect of oil, surfactant/co-surfactant mixing ratios and water on the in vitro permeation of ketoconazole (KTZ) applied in O/W microemulsion vehicle through intact rat skin. Lauryl Alcohol (LA) was screened as the oil phase of microemulsions, due to a good solubilizing capacity of the microemulsion system. The pseudo-ternary phase diagrams for microemulsion regions were constructed using LA as the oil, Labrasol (Lab) as the surfactant (S) and ethanol (EtOH) as the cosurfactant (CoS). The formulation which showed a highest permeation rate of 54.65?±?1.72 µg/cm²/h¹ and appropriate physico-chemical properties was optimized as containing 2% KTZ, 10% LA, 20% Lab/EtOH (1:1) and 68% double distilled water (w/w). The efficiency of microemulsion formulation in the topical delivery of KTZ was dependent upon the contents of water and LA as well as Lab/EtOH mixing ratio. It was concluded that the percutaneous absorption of KTZ from microemulsions was enhanced with increasing the LA and water contents, and with decreasing the Lab/EtOH ratio in the formulation. Candida albicans was used as a model fungus to evaluate the antifungal activity of the best formula achieved, which showed the widest zone of inhibition as compared to KTZ reference. The studied microemulsion formulation showed a good stability for a period of three months. Histopathological investigation of rat skin revealed the safety of microemulsion formulations for topical use. These results indicate that the studied microemulsion formulation might be a promising vehicle for topical delivery of KTZ.     

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.