纳米乳的皮肤刺激性研究

通过透射电镜和扫描电镜观察空白纳米乳作用于小鼠皮肤2h和6h时皮肤角质层和超微结构的变化，并与生理盐水对照组和空白对照组比较。分别测定纳米乳、Labrasol、Plurol Oleique、十二烷基硫酸钠对HaCat细胞的半数抑制率IC50＋结果表明，纳米乳粒子的平均粒径为28．8nm，其中99．3％的粒子粒径介于18．9～39．7nm，0．7％介于124．8～176．1nm。与生理盐水对照组相比，纳米乳组小鼠皮肤角质层明显变薄且出现角质剥脱现象，表皮棘细胞胞间连丝出现断裂，棘细胞间间距显著增宽。纳米乳的IC50值显著高于十二烷基硫酸钠（P〈0．01），推断Labrasol是产生皮肤刺激性的主要原因。     

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。     

雷公藤多苷纳米乳的制备及其理化性质评价

目的:研制雷公藤多苷纳米乳并对其理化性能、稳定性等进行评价。方法:结合雷公藤多苷在不同的油和表面活性剂中的溶解度以及伪三元相图的绘制,研制雷公藤多苷纳米乳,并对其类型、形态、粒径、理化参数及稳定性进行考察。结果:雷公藤多苷在聚氧乙烯氢化蓖麻油(RH-40)和肉豆蔻酸异丙酯(IPM)中溶解度较大,且以RH-40为表面活性剂,IPM为油相时纳米乳形成区域最大,最终纳米乳配方确定为RH-40∶IPM∶水,重量比为27∶3.3∶69.7,其中可添加浓度小于5%的透皮促渗剂氮酮;制备的雷公藤多苷纳米乳为棕黄色,澄清透明,流动性良好的O/W型纳米乳,该纳米乳粒子形态主要为圆球形,平均粒径为23.6nm,稳定性良好。结论:研制的雷公藤多苷纳米乳是质量稳定的新制剂。     

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...     

氨甲环酸纳米乳膏的制备及体外透皮效果评价

目的设计制备氨甲环酸纳米乳膏(TA-NC),并观察其体外透皮效果。方法采用高压均质法制备氨甲环酸纳米乳,并进一步制得TA-NC,检测TA-NC粒径、微观结构及包封率。以裸鼠皮肤为模型,通过体外透皮吸收实验、离体皮肤组织滞留实验考察TA-NC的体外透皮效果;以尼罗红为荧光探针制备荧光标记TA-NC,共聚焦显微镜观察其促透进入真皮层的效果。并考察TA-NC的6个月加速稳定性。结果制备的TA-NC粒径为(109.9±7.4)nm,形态圆整,分布均匀;包封率为(90.13±2.90)%。体外透皮吸收实验中,TA-NC组给药6 h药物皮肤中的累积滞留量达饱和状态,24 h累积透过量达(163.9±7.4)μg·cm-2;TA水溶液组皮肤的滞留量在20μg·cm-2以下,24 h累积透过量为(15.9±0.8)μg·cm-2,组间差异非常显著(P<0.01)。共聚焦显微镜下,荧光素TA水溶液组仅表皮角质层有荧光,荧光标记的TA-NC经皮吸收后可透过角质层和表皮层到达真皮层,且TA-NC粒径越小透皮能力越强。6个月内TA-NC制剂外观性状、有关物质、含量、粒度等均未发生明显改变。结论 TA-NC制备简单,透皮效果显著,稳定性好。     

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。     

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。     

利多卡因纳米乳的制备及质量控制

目的制备利多卡因纳米乳并建立其质量控制的方法.方法伪三元相图法结合origin 7.0软件分析确定制备5%利多卡因纳米乳的最佳Km值(表面活性剂/助表面活性剂)及各组分的比例;对利多卡因纳米乳的外观及稳定性进行考察;马尔文Zeta粒径分析仪测定利多卡因纳米乳粒径大小及分布范围;透射电镜观察利多卡因纳米乳的形态及体系类型;HPLC法对利多卡因纳米乳进行质量控制考察.结果Km=3时利多卡因纳米乳形成区域的面积值最大,利多卡因纳米乳的平均粒径为36.4 nm,其中98%的粒径范围介于17.1～57.5 nm之间,2%介于77.9～261.3 nm之间;其分布体系为大小不均的球形多分散体系;利多卡因进药量与色谱峰面积在10～200 mg·L-1范围内线性关系良好(r=0.999 4),平均回收率为99.45%,RSD为1.08%.结论伪三元相图法结合origin 7.0软件分析并确定利多卡因纳米乳各组分比例的方法简便、准确;马尔文粒径测定结合透射电镜观察测定利多卡因纳米乳的粒径、分布、形态及体系类型的方法较为全面;利多卡因纳米乳样品的处理和HPLC测定方法简便、快速、准确,可作为利多卡因纳米乳的质量控制考察.     

尼莫地平脂质体的制备及体外透皮研究

目的:采用2种方法制备尼莫地平脂质体,并考察其包封率与体外透皮性。方法:用薄膜法和乙醇注入法制备尼莫地平脂质体,考察2种方法所制脂质体的粒径分布及包封率;采用Franz扩散装置对脂质体进行体外透皮试验,并与尼莫地平溶液比较。结果:薄膜法和乙醇注入法制备的脂质体平均粒径分别为(768.7±190.6)、(1 742±270)nm,平均包封率均高达97%以上。与尼莫地平溶液比较,脂质体中药物透皮缓慢,其中以薄膜法制备的脂质体在48h以后其单位面积累积透皮量显著更高。结论:2种制备方法中以薄膜法更优。     

苦参碱微乳的制备及透皮研究

目的：制备苦参碱微乳透皮给药系统，对其理化性质及透皮行为进行考察。方法：以苦参碱、磷脂、聚氧乙烯辛基苯基醚、肉豆蔻酸异丙酯和去离子水为主要成分，水相溶液逐滴加入油相的方法，制备苦参碱微乳，考察其外观形态、粒径大小及分布，采用Valia-Chien扩散池考察苦参碱微乳的体外透皮过程。结果：制得的苦参碱微乳为淡黄色透明液体，平均粒径120nm，外观圆整均匀，24h的累积释放量为（1056．1±74．9）μg／cm^2。结论：苦参碱微乳具有良好的透皮效果，为苦参碱的临床应用提供了一种新型制剂。     

Stability and self-nanoemulsification efficiency of ramipril nanoemulsion containing labrasol and plurol oleique

The aim of the present investigations was to evaluate the capacity of a combination of Labrasol and Plurol oleique as surfactant and cosurfactant on self-nanoemulsification efficiency of ramipril nanoemulsion. Sefsol-218, Labrasol, Plurol oleique, and standard buffer solution (pH 5.0) were selected as oil phase, surfactant, cosurfactant, and aqueous phase, respectively. Nanoemulsion formulations of ramipril were developed by a spontaneous emulsification method. Pseudoternary phase diagrams were constructed to identify nanoemulsion zones of ramipril. Selected formulations were evaluated in terms of thermodynamic stability tests using centrifugation, heating–cooling cycles, and freeze–thaw stress test. Some formulations were found stable and other formulations were unstable upon thermodynamic stability tests. Thermodynamically stable formulations were taken for self-nanoemulsification efficiency test. All the selected formulations passed self-nanoemulsification test in grade E only but not in grades A and B. Because none of the formulations passed the self-nanoemulsification efficiency test in grades A and B, it was concluded that a combination of Labrasol and Plurol is not suitable as surfactant and cosurfactant, respectively, for oral or self-nanoemulsifying drug delivery system of ramipril.     

薄荷素油纳米乳的制备

目的：研究探索制备薄荷素油纳米乳的处方。方法：采用转向法制备薄荷素油纳米乳,通过滴定法绘制伪三元相图,以纳米乳区域的面积、稳定性为考察指标,筛选薄荷素油纳米乳最佳处方。通过稀释法鉴定薄荷素油纳米乳类型、透射电子显微镜观察其外观形态、激光粒度测定仪测定其粒径分布、电位。结果：薄荷素油纳米乳优选处方结果为：表面活性剂为蓖麻油聚氧乙烯醚（EL-40）、助表面活性剂为聚乙二醇400（PEG-400）,K_m为3：1,薄荷素油、复表面活性剂、蒸馏水含量为56.62%：23.67%：19.72%;所制得薄荷素油纳米乳为澄清透明,平均粒径为19.55 nm,PDI为0.183,呈正态分布,Zeta电位为3.10 mV。结论：薄荷素油纳米乳制备工艺简单,采用优选处方制备的薄荷素油纳米乳粒径小、大小均匀。     

Cremophor RH40-PEG 400 microemulsions as transdermal drug delivery carrier for ketoprofen

The aim of this study was to prepare novel microemulsion for transdermal drug delivery of ketoprofen (KP). The microemulsion composed of ketoprofen as model drug, isopropyl myristate (IPM) as oil phase, surfactant mixture consisting of polyoxyl 40 hydrogenated castor oil (Cremophor RH40) as surfactant and polyethylene glycol 400 (PEG400) as co-surfactant at the ratio 1:1, and water were prepared. The viscosity, droplet size, pH, conductivity of microemulsions, and skin permeation of KP through shed snake skin were evaluated. The particle size, pH, viscosity and conductivity of microemulsions were in the range of 114-210 nm, 6.3-6.8, 124-799 cPs and 1-45 μS/cm, respectively. The ratio of IPM, and surfactant mixture played the important role in the skin permeation of KP microemulsions. As the amount of surfactant mixture and IPM increased, the skin permeation of KP decreased. The formulation composed of 30% IPM, 45% surfactant mixture and 25% water showed the highest skin permeation flux. The incorporation of terpenes in the 2.5% KP microemulsions resulted in significant enhancement in skin permeation of KP. The rank order of enhancement ratio for skin permeation enhancement of terpenes was α-pinene > limonene > menthone. The results suggested that the novel microemulsion system containing IPM, water, Cremophor RH40:PEG400 and terpenes can be applied for using as a transdermal drug delivery carrier.     

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.     

冰片鸦胆子油纳米乳的制备及对大鼠脑胶质瘤的抑瘤作用研究

目的 筛选和优化冰片鸦胆子油纳米乳处方,制备冰片鸦胆子油纳米乳,并初步考察其对大鼠脑胶质瘤的抑瘤作用。方法 通过柱前衍生化处理,建立GC测定鸦胆子油中油酸含量的分析方法;采用转相法制备冰片鸦胆子油纳米乳;绘制伪三元相图,筛选最佳处方;透射电子显微镜观察外观形态、激光粒度仪测定粒径分布和Zeta电位;构建大鼠脑胶质瘤模型,以瘤重和瘤体积变化为指标,初步考察冰片鸦胆子油纳米乳对大鼠脑胶肿瘤的抑瘤作用。结果 建立了GC测定鸦胆子油中油酸含量的分析方法,筛选冰片鸦胆子油纳米乳最佳处方为油相肉豆蔻酸异丙酯35%,鸦胆子油（含1%冰片）35%,乳化剂Cremopher RH40 18%,Labrasol 12%,纳米乳外观呈圆整球形,平均粒径（47.60±0.57）nm,PDI为（0.22±0.01）,Zeta电位为（1.06±0.12）mV,载药量（0.424 1±0.005 6）mg.mL 1。抑瘤实验显示,模型组、鸦胆子油注射剂组、鸦胆子油纳米乳组和冰片鸦胆子油纳米乳组的瘤重分别为（1.32±0.19）,（0.84±0.08）,（0.76±0.06）和（0.57±0.10）g,肿瘤体积分别为（72.2±9.4）,（44.2±5.1）,（42.3±4.9）和（27.9±2.5）mm3,鸦胆子油注射剂组、鸦胆子油纳米乳组和冰片鸦胆子油纳米组的肿瘤抑制率分别为36.49%,42.80%和56.94%。结论 所筛选的最佳处方采用转相法制备冰片鸦胆子油纳米乳,粒径分布均匀,油酸含量较高,稳定性较好。同时冰片鸦胆子油纳米乳对大鼠胶质瘤相对具有较强的抑瘤作用,初步推断冰片可能促进鸦胆子油跨过血脑屏障来提高抑瘤作用。     

Nanoemulsion system for the transdermal delivery of a poorly soluble cardiovascular drug

The purpose of the present study is to develop and evaluate the potential of nanoemulsions for increasing the solubility and the in vitro transdermal delivery of carvedilol. Pseudoternary phase diagrams were developed and various nanoemulsion formulations were prepared using oleic acid and isopropyl myristate (IPM) (1:1) as the oil, Tween 80 as surfactant, and Transcutol P as cosurfactant. The prepared nanoemulsions were subjected to physical stability tests. Transdermal permeation of carvedilol through rat abdominal skin was determined with Keshary-Chien diffusion cell. Significant increase (P < 0.05) in the steady state flux (Jss) and permeability coefficient (Kp) was observed in nanoemulsion formulations as compared to control or drug-loaded neat components. The highest value of these permeability parameters was obtained in optimized formulation B3, which consisted of 0.5% w/w of carvedilol, 6% w/w of oleic acid:IPM (1:1), 22.5% w/w of Tween 80, 22.5% w/w of Transcutol P, and 49% w/w of distilled water and in which the solubility of the drug was 4500-fold higher. The optimized nanoemulsion was characterized for pH, conductivity, viscosity, droplet size, droplet shape, and refractive index. Thermodynamic studies showed that there had been a significant decrease of 88% in activation energy (Eact) when the drug was incorporated in nanoemulsion. The irritation studies suggested that the optimized nanoemulsion was a non-irritant transdermal delivery system.     

Fabrication,in-vitro characterization,and enhanced in-vivo evaluation of carbopol-based nanoemulsion gel of apigenin for UV-induced skin carcinoma

The aim of this study was to develop a potential novel formulation of carbopol-based nanoemulsion gel containing apigenin using tamarind gum emulsifier which was having the smallest droplet size, the highest drug content, and a good physical stability for Skin delivery. Apigenin loaded nanoemulsion was prepared by high speed homogenization method and they were characterized with respect to morphology, zeta potential, differential scanning calorimeter study, and penetration studies. In-vitro release studies and skin permeation of apigenin loaded nanoemulsion by goat abdominal skin was determined using Franz diffusion cell and confocal laser scanning microscope (CLSM). The cytotoxicity of the reported formulation was evaluated in HaCaT Cells (A) and A431 cells (B) by MTT assay. The nanoemulsion formulation showed droplet size, polydispersity index, and zeta potential of 183.31?nm, 0.532, and 31.9?mV, respectively. The nanoemulsions were characterized by TEM demonstrated spherical droplets and FTIR to ensure the compatibility among its ingredients. CLSM showed uniform fluorescence intensity across the entire depth of skin in nanocarriers treatment, indicating high penetrability of nanoemulsion gel through goatskin. The nanoemulsion gel showed toxicity on melanoma (A341) in a concentration range of 0.4–2.0?mg/ml, but less toxicity toward HaCaT cells. The carbopol-based nanoemulsion gel formulation of apigenin possesses better penetrability across goatskin as compared to marketed formulation. Hence, the study postulates that the novel nanoemulsion gel of apigenin can be proved fruitful for the treatment of skin cancer in near future.     

Nanosuspension improves tretinoin photostability and delivery to the skin

The aims of this work were to improve cutaneous targeting and photostability of tretinoin by using nanosuspension formulation. Tretinoin is a drug widely used in the topical treatment of various dermatological diseases. The tretinoin nanosuspension was prepared by precipitation method and then characterized by photo correlation spectroscopy for mean size and size distribution, and by transmission electron microscopy for morphological studies. An oil in water tretinoin nanoemulsion was also prepared and used as a control. Dermal and transdermal delivery of both tretinoin nanosuspension and nanoemulsion were tested in vitro by using Franz diffusion cells and newborn pig skin. Photodegradation studies were carried out by UV irradiation (1 h, λ = 366 nm) of the tretinoin nanosuspension in comparison with the nanoemulsion and a methanolic solution of the drug. During 8 h percutaneous experiments, the nanosuspesion was able to localize the drug into the pig skin with a very low transdermal drug delivery, whereas the nanoemulsion greatly improved drug permeation. UV irradiation of the nanosuspension showed a great improvement of tretinoin stability in comparison with both controls. Overall results show that nanosuspension might be a useful formulation for improving tretinoin dermal delivery and stability.