利多卡因微乳凝胶剂的制备及初步药效学研究

目的制备利多卡因微乳凝胶剂,并对其药效学及皮肤刺激性进行初步研究。方法以油酸乙酯为油相,聚山梨酯-80为表面活性剂,无水乙醇为助表面活性剂,用水滴定的方法制备利多卡因微乳。以卡波姆940为凝胶骨架,采用直接溶胀法制备利多卡因微乳凝胶。采用Zetasizer Nano-ZS90马尔文激光粒度仪测定微乳的粒径。采用日立H-7650透射电子显微镜观察微乳的形态。采用热板法观察该药对小鼠的镇痛作用。采用连续给药的方法,考察该药对家兔正常皮肤与破损皮肤的刺激性。结果利多卡因微乳凝胶外观为白色透明凝胶态,微乳呈圆球形,微乳粒径<100 nm。利多卡因微乳凝胶剂能延长热板致痛的潜伏期,对家兔皮肤无刺激性。结论利多卡因微乳凝胶剂具有较好的局麻镇痛作用和安全性。     

蛇床子素微乳的制备及其透皮能力的研究

目的:制备蛇床子素微乳,并考察其对离体小鼠皮肤的透皮能力。方法:通过测定蛇床子素在不同油相、乳化剂和助乳化剂中的溶解度,结合伪三元相图筛选空白微乳的处方。考察蛇床子素微乳的黏度、电导率和粒径;用药物渗透扩散仪测定蛇床子素微乳的透皮速率。结果:制得的蛇床子素微乳的黏度为8.07mpa·s,电导率为123μS·cm-1,平均粒径为58.0nm。微乳中药物经小鼠皮肤的稳态渗透速率为(33.042±3.1)μg·cm-2·h-1(r=0.9950),是蛇床子素饱和溶液稳态渗透速率的25.5倍。结论:蛇床子素微乳有很强的透皮能力,有望成为蛇床子素的新型透皮给药制剂。     

氢溴酸东莨菪碱微乳的组成对其制备的影响

通过绘制伪三元相图考察体系各组分对空白微乳形成及其粒径和黏度的影响.结果表明,以Cremophor RH-40为表面活性剂,无水乙醇为助表面活性剂,Labrafil M 1944 CS为油相可得稳定的微乳体系.该体系中水溶性药物氢溴酸东莨菪碱的加入量对微乳的粒径和黏度无显著影响.     

来那度胺纳米水凝胶的制备及其体外透皮吸收研究

目的:制备性质稳定、质量可控的来那度胺纳米水凝胶,评价其理化性质并考察其体外透皮吸收情况。方法:通过对药物溶解度的增加程度初步筛选用于制备来那度胺纳米乳的油相、表面活性剂和助表面活性剂;通过表面活性剂对油相的乳化效果进一步筛选油相;绘制伪三元相图,优化表面活性剂与助表面活性剂的质量比(K_m)。用激光粒度测定仪测定来那度胺纳米乳的粒径。将来那度胺纳米乳分散于卡波姆940中制备来那度胺纳米水凝胶,考察来那度胺纳米乳的外观、形态、pH值、Zeta电位、稳定性以及体外透皮性能。结果:来那度胺纳米乳的最优处方为辛癸酸甘油酯/RH40/1,2-丙二醇/水=1∶4.5∶4.5∶6.95(m/m)。以此处方制备的来那度胺纳米乳澄清透明,外观透亮,pH值为5.20±0.14,平均粒径为(24.76±0.82)nm,多分散指数为0.256±0.088,粒径分布均一,Zeta电位为-47.33 mV,高速离心后无分层现象,耐寒耐热试验前后无明显差异,稳定性良好。来那度胺水凝胶的累积透过量显著高于原料药,透皮性能良好。结论:该研究制备的来那度胺纳米水凝胶处方组成合理、性质稳定、透皮性能良...     

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.     

基于D-最优混料设计法的塞来昔布微乳凝胶处方优化与评价

目的 制备塞来昔布微乳凝胶，并考察其体外透皮性能。方法 测定塞来昔布在不同油、乳化剂、助乳化剂中的溶解度，通过绘制伪三元相图确定塞来昔布微乳的处方组成；以油相、混合乳化剂、水为考察因素，微乳的载药量和粒径为评价指标，利用D-最优混料设计法优化塞来昔布微乳的处方；以卡波姆980为基质制备塞来昔布微乳凝胶，并测定粒径、粒度分布、Zeta电位、透光率及黏度，透射电镜观察塞来昔布微乳的外观形态；采用Franz扩散池法考察塞来昔布微乳凝胶的体外释放性能。结果 优化的塞来昔布微乳处方组成为油相4%、混合乳化剂20%、水76%；塞来昔布微乳凝胶的平均粒径为（59.65±1.09）nm，PDI为0.106，Zeta电位为（-25.76±0.92）mV；透射电镜观察微乳凝胶呈圆整、规则球形，分布较为均匀；与微乳相比，塞来昔布微乳凝胶黏度增大，便于涂布和经皮给药；塞来昔布微乳凝胶24 h累积透皮释放量为（80.12±3.37）μg·cm^-2，显著高于塞来昔布混悬液。结论 塞来昔布微乳凝胶可以显著增加药物的累积透皮量，有望成为新型局部给药制剂。     

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。     

夫西地酸微乳凝胶的制备与体外抗菌活性研究

目的 制备夫西地酸微乳凝胶并评价其体外抗菌活性。方法 通过考察夫西地酸在不同油相、表面活性剂和助表面活性剂中的平衡溶解度，确定夫西地酸微乳的处方组成，并进一步通过伪三元相图获得其处方用量；以卡波姆941作为凝胶基质制备夫西地酸微乳凝胶。使用激光粒度仪在25℃测定微乳的粒径分布以及Zeta电位；透射电子显微镜下观察微乳的形貌；使用黏度计和pH计在25℃测定微乳凝胶的黏度及pH值；透析法测定夫西地酸微乳和夫西地酸微乳凝胶的体外药物溶出速率；以外观、黏度和pH值作为指标，考察夫西地酸微乳凝胶在4、25℃下3个月内的物理稳定性； Mueller-Hinton肉汤稀释法测定夫西地酸微乳凝胶和夫西地酸原料药对金黄色葡萄球菌的最小抑菌浓度（MIC）；通过抑菌圈实验比较夫西地酸原料药和夫西地酸微乳凝胶的体外抗菌活性。结果 根据各辅料对夫西地酸溶解性，选择油酸乙酯、聚山梨酯80和异丙醇分别作为夫西地酸微乳的油相、表面活性剂和助表面活性剂，配比为6∶2∶2；夫西地酸微乳外观为淡蓝色半透明状溶液，在透射电镜下可观察到其呈规则球型，粒径分布均匀，平均粒径为（105.4±2.9）nm，Zeta电位为（-16.9±0.6） mV；夫西地酸微乳的黏度为（0.027 7±0.000 5）Pa·s，黏度过低，而夫西地酸微乳凝胶的黏度为（5.614 5±0.036 1） Pa·s；夫西地酸微乳中的药物在15 min内已完全溶出，而夫西地酸微乳凝胶中的药物溶出速度明显减慢，在240 min时溶出达到90%左右；夫西地酸微乳凝胶3个月内物理性质稳定。夫西地酸微乳凝胶、原料药对金黄色葡萄球菌的MIC分别为0.12、0.40 μg·mL^-1 ，抑菌圈直径分别为（33.7±0.6）、（27.5±0.7） mm。结论 制备的夫西地酸微乳凝胶理化性质较好，体外抗菌活性显著，有潜力成为夫西地酸局部外用给药新剂型。     

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。

     

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）。     

Viscoelastic Properties of Carbopol 940 Gels and Their Relationships to Piroxicam Diffusion Coefficients in Gel Bases

Purpose This study was conducted to determine the effect of formula compositions on viscoelastic properties of piroxicam gels using Carbopol 940 as a gelling agent and to determine the relationships between viscoelastic properties of Carbopol 940 gel bases and diffusion coefficients of piroxicam in gel bases. Methods Piroxicam gels (1.0% w/w) were prepared by using Carbopol 940 as a gelling agent and varying Carbopol 940 concentrations, glycerin, and sodium chloride contents. The in vitro release of piroxicam from gel bases to the receiving media, isotonic phosphate buffer solution (pH 7.4), were carried out using Franz-modified cell. The piroxicam diffusion coefficients were obtained by Higuchi's equation. Rheological property measurements of gel samples were performed via a cone and plate fluid rheometer. Relationships between viscoelastic properties of gel samples and piroxicam diffusion in gel bases were analyzed by Pearson's test at a p value of less than 0.05. Results All piroxicam gels exhibited predominantly elastic solid behavior whose magnitude depended on Carbopol 940 concentration. Preparations containing good solvent exhibited more elastic solid characters. In contrast, the piroxicam gels containing higher sodium chloride contents possessed more viscous fluid behavior. Analyzed by Pearson's test at a p value of less than 0.05, piroxicam diffusion coefficients were directly proportional to loss tangent, but were inversely proportional to storage modulus, loss modulus, complex modulus, and viscosity. Conclusions There is a potential for predicting drug diffusion coefficients from their correlations to rheological parameters. This could be beneficial to the formulation design of transdermal drug delivery systems including mucoadhesive drug delivery systems.     

Formulation design of microemulsion for dermal delivery of penciclovir

The purpose of the present study was to evaluate the potential application of microemulsions as a dermal drug delivery loading penciclovir. The pseudo-ternary phase diagrams were developed for various microemulsion formulations composed of oleic acid (oil phase), Cremorphor EL (surfactant) and ethanol (cosurfactant). Composition of microemulsion systems was optimized using simplex lattice mixture design including the concentrations of surfactant, cosurfactant and water (independent variables) and the solubility and the cumulative amount of penciclovir permeated through excised mouse skins per unit area (response variables). The physicochemical properties of the optimized microemulsion and the permeating ability of penciclovir from microemulsions were also investigated. The results showed that the optimized microemusion formulation was composed of oleic acid (5%, w/w), Cremorphor EL (20%, w/w), ethanol (30%, w/w) and water (45%, w/w). The mean particle diameter was 36.5nm and solubility of penciclovir in the emulsion was 7.41 mg g(-1). The cumulative amount of penciclovir permeated through excised mouse skins from microemulsion was about 3.5 times that of the commercial cream. The conclusion was that the permeating ability of penciclovir was significantly increased from the microemulsion formulation compared with commercial cream.     

Vehicle effects on in vitro release of tiaprofenic acid from different topical formulations

The aim of the present study was to investigate the in vitro release properties of tiaprofenic acid (TA) from different topical vehicles. Carbopol 940 gel, chitosan gel, two types of emulsion-based ointment formulations (o/w and w/o) and hydrophilic petrolatum USP were prepared with 2% drug content. Drug release from all vehicles through a standard cellophane membrane was evaluated by using Franz-type diffusion cells. In vitro release study results showed that the diffusion coefficients of the drug from vehicles rank according to the following order: Carbopol 940 gel (D = 3.11 x 10(-7) +/- 0.54 cm(2)/s) > chitosan gel (D = 0.27 x 10(-7) +/- 0.08 cm(2)/s) > emulsion-based ointment (o/w) (D = 0.18 x 10(-7) +/- 0.05 cm(2)/s) > emulsion-based ointment (w/o) (D = 0.13 x 10(-7) +/- 0.02 cm(2)/s) > hydrophilic petrolatum USP (D = 0.02 x 10(-7) +/- 0.01 cm(2)/s). Carbopol 940 gel base showed significantly higher drug release than other vehicles (P < 0.001). These results indicated that Carbopol 940 gel base is a good candidate for the topical delivery of TA, giving significantly higher drug release than the other vehicles.     

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.     

Microemulsion: a novel transdermal delivery system to facilitate skin penetration of indomethacin

In this study, we aimed to develop thermodynamically stable microemulsion formulations of indomethacin with lower surfactant and cosurfactant contents, to improve drug permeability. Formulations were based on the oil/water microemulsion region of pseudo-ternary phase diagrams. The characteristic parameters (viscosity, diameter, and polydispersity) of the microemulsion formulations were then determined. In vitro permeation studies were performed using Franz diffusion cells. Permeation through mouse skin and skin retention of indomethacin microemulsions and ointment were tested. The cumulative amount of permeated indomethacin and its skin retention were significantly higher in microemulsion formulations compared with ointment. Drug flux and skin retention improved with decreasing droplet diameter of the microemulsions. On the basis of these results, we suggest some possible mechanisms for the enhanced transdermal permeation of drugs in microemulsions, including high drug-loading capacity, permeation enhancement by surfactants and cosurfactants, and smaller droplet diameter. In conclusion, microemulsions represent a novel transdermal delivery vehicle for increasing the solubility and permeability of indomethacin.     

The effect of component of microemulsions on transdermal delivery of buspirone hydrochloride

The aim of this study was to evaluate the influence of components such as type, level, and hydrophilic-lipophilic balance (HLB) value of surfactant, type and amount of cosurfactant, and drug concentration on the permeability of buspirone hydrochloride microemulsions through rat skin. The cumulative amount at 24 h ranged from 502.2 ± 57.8 to 1754.3 ± 616.6 μg/cm(2), flux ranged from 23.03 ± 1.84 to 83.36 ± 25.08 μg/(cm(2)/h), and lag time ranged from 3.0 to 4.7 h, indicating that the permeation parameters of buspirone from microemulsions were markedly influenced by the composition of microemulsions. In comparison with the effect of composition of microemulsions on the buspirone permeation capacity, it was found that microemulsions containing surfactant with HLB value of 11.16 possessed higher flux. The viscosity of microemulsions increased, flux decreased, and lag time was prolonged when amount of surfactant in microemulsions increased. The various cosurfactants can also influence the microemulsion formation and drug permeability. The microemulsion with ethanol as cosurfactant had higher permeation rate. However, the buspirone microemulsion with higher flux can provide the therapeutic minimum effective concentration, at workable administrated area about 3.3-5.8 cm(2), demonstrating microemulsions could be a promising drug carrier for transdermal delivery systems.     

Formulation and ex vivo evaluation of rofecoxib gel for topical application

The potential gastrointestinal disorders associated with oral administration of rofecoxib can be avoided by delivering the drug to the inflammation site at a sustained, concentrated level over an extended period of time. Hydroxypropylmethylcellulose (HPMC), sodium alginate and Carbopol 940 were used in an attempt to develop topical gel formulations of rofecoxib. The effects of polymer composition on the rate of drug release from the gel formulations were examined through cellulose membrane mounting on a Keshary-Chien diffusion cell. The effects of initial drug concentration and viscosity on the permeation rate of rofecoxib from the gel formulations were evaluated using rat epidermis at 37 +/- 0.5 degrees C. The anti-inflammatory activity of the rofecoxib gel formulation was evaluated using the rat hind paw edema model. The gel formulation consisting of 4% w/w sodium alginate-Carbopol 940 at 3:1 ratio was found to be suitable for topical application based on in vitro evaluation and ex vivo permeation studies. The drug permeation rate increased with an increase of the initial drug concentration in gels up to 25% w/w. An inverse relationship was observed between the in vitro drug release rate/ex vivo permeation rate and viscosity of the gel formulations. The anti-inflammatory activity of 4% w/w sodium alginate-Carbopol 940 gel containing 25% w/w rofecoxib in the rat hind paw edema model reveals that the drug was delivered to the inflammation site at a controlled level over a period of 6 h. These results suggest the feasibility of the topical gel formulation of rofecoxib.