丙二醇-肉豆蔻酸异丙酯系统中促透剂对来曲唑经皮透过性的影响

目的考察在丙二醇(propylene glycol,PG)-肉豆蔻酸异丙酯(isopropyl myristate,IPM)系统(简称PI系统)中经皮促透剂对来曲唑经皮透过性的影响。方法采用水平双室扩散池,以离体大鼠皮肤作为透过屏障进行体外透过实验。结果在不含经皮促透剂时,来曲唑的累积透过量随体系中PG浓度的增加而增大。在PI系统[m(PG)∶m(IPM)=20∶100]中,N-甲基-2-吡咯烷酮、月桂氮卓酮、乳酸对来曲唑的透过具有显著的促进作用,司盘-80和二乙二醇单乙基醚具有轻微抑制作用,而油酸和吐温-80则有显著的抑制作用。结论在PI系统中经皮促透剂对来曲唑的经皮透过性具有不同的促透作用,为开发来曲唑的透皮给药贴剂提供参考数据。     

三乙醇胺复合物促进氟比洛芬体外经皮透过

目的合成氟比洛芬三乙醇胺复合物(Flu-TEA),考察氟比洛芬(Flu)及Flu-TEA的体外经皮透过性。方法采用双室水平扩散池,大鼠腹部全皮为渗透膜,分别以增塑剂柠檬酸三乙酯或经皮穿透促进剂为溶剂,测定药物的体外经皮透过性。结果Flu-TEA的体外经皮透过系数均高于Flu,氮酮、肉豆蔻酸异丙酯(IPM)、1,2-丙二醇3种经皮穿透促进剂中,氮酮与1,2-丙二醇联用对药物的促透效果最佳。结论Flu与三乙醇胺成复合物盐后可明显增加体外经皮透过性。     

乙醇-肉豆蔻酸异丙酯系统中有机胺对酮洛芬经皮渗透的促进作用

目的应用乙醇(E)-肉豆蔻酸异丙酯(IPM)2组分溶液系统,研究在EI系统中有机胺对酮洛芬(KP)的经皮渗透的影响,初步探讨其作用机理。方法用水平扩散池,以离体大鼠皮肤作为渗透屏障进行体外渗透实验。用HPLC测定样品中KP浓度。结果除二乙胺(DEtA)和三乙胺外,当EI系统[m(乙醇)∶m(肉豆蔻酸异丙酯)=90∶10]中加入乙醇胺、二乙醇胺、三乙醇胺、和N-(2-羟乙基)吡啶时,KP在溶液系统中溶解度均略有降低。所有加入有机胺的EI溶液系统均对KP产生明显的渗透促进作用。此外,在DEtA-EI系统中,KP的流量与DEtA的浓度成正比,而E的渗透流量恒定,与KP流量变化无关。结论结果表明,EI系统中有机胺对KP的经皮渗透有促进作用。这种渗透促进作用可能依赖于KP与胺之间所形成的离子对组成。     

马钱子碱与士的宁体外经皮渗透性质的考察

目的:考察马钱子碱、士的宁游离药物体外经皮渗透性质及相互影响.方法:测定马钱子碱及士的宁在pH值7.4的磷酸盐缓冲液(PBS)、含10%乙醇的PBS、含20%乙醇的PBS及含20%乙醇的生理氯化钠溶液中的溶解度.用改良的Franz扩散池法考察马钱子碱溶液、士的宁溶液以及混合溶液中马钱子碱与士的宁体外透皮渗透性质.结果:根据溶解度实验结果选择含20%乙醇的PBS作为溶剂;以含20%乙醇的生理氯化钠溶液为接受液.马钱子碱与士的宁混合溶液中马钱子碱的体外经皮渗透速率比单用马钱子碱显著提高了近1.5倍(P<0.05),累积透过百分率也明显提高(P<0.01);而士的宁没有显著变化.结论:士的宁可显著促进马钱子碱的体外经皮渗透速度和程度.     

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。...     

渗透促进剂对醋氯芬酸经皮渗透性的影响

目的研究醋氯芬酸溶液经离体鼠皮的透过特性,寻找能有效增加醋氯芬酸渗透的促渗剂,用以开发醋氯芬酸经皮给药传递系统。方法测定醋氯芬酸在pH 2.5、3.6、5.0、6.8、7.4 PBS缓冲液中的饱和溶解度;采用水平扩散装置进行醋氯芬酸在pH 2.5、3.6、5.0、6.8、7.4条件下及在乙醇、丙二醇、卡必醇、桉叶油醇、松节油、油酸、氮酮等促渗剂作用下的经皮渗透实验;用HPLC法分析样品。结果随着pH值的增加,醋氯芬酸的溶解度增加,经皮渗透量也呈上升趋势;氮酮、油酸和松节油均可显著增加醋氯芬酸的经皮渗透,促渗顺序为氮酮>油酸>松节油,且主要通过增加表皮基质间的分配系数实现促渗效果。结论醋氯芬酸具有一定的经皮透过性,宜制成经皮给药剂型;油酸、油溶性氮酮可作为其有效的渗透促进剂。     

乙醇和丙二醇单用与联用对曲安奈德喷雾溶液透皮性能的影响

目的 对曲安奈德喷雾溶液进行体外透皮试验,考察乙醇和丙二醇单用与联用时对曲安奈德喷雾溶液体外透皮功能的影响。方法 选取新西兰白兔腹部皮肤,用Franz扩散池法对曲安奈德喷雾溶液进行体外透皮试验,用高效液相色谱法（HPLC）测定曲安奈德含量,用单因素方差分析法对各组间的透皮吸收速率进行对比分析。结果 乙醇和丙二醇联用时的透皮吸收速率均显著高于单用时的透皮吸收速率（P<0.05）,且乙醇和丙二醇联用时对曲安奈德喷雾溶液的促透作用顺序为10%乙醇+25%丙二醇>10%乙醇+20%丙二醇>15%乙醇+25%丙二醇>15%乙醇+20%丙二醇。结论 10%乙醇和25%丙二醇联用时可使曲安奈德喷雾溶液的透皮功能达到最佳化。     

乙醇对肠上皮细胞紧密连接蛋白ZO-1表达的影响

目的探讨乙醇引起肠黏膜屏障的破坏以及这种破坏机制是否与紧密连接蛋白ZO-1相关。方法培养人结肠腺癌细胞株Caco-2,分别设正常对照组:不加刺激物及干预因素;实验组:加入不同体积分数(1%、2.5%、5%、7.5%、10%)乙醇分别刺激不同时间(0～3h),四甲基偶氮唑盐(MTT)比色法检测细胞生存率;测定跨上皮电阻(TEER)和荧光黄的透过量反映肠上皮细胞单层通透性;选定体积分数5%乙醇作为实验浓度,应用蛋白印迹法检测紧密连接蛋白ZO-1表达的动态变化。结果体积分数为5%的乙醇未影响到细胞的生存率。不同浓度乙醇作用20min后,细胞单层通透性增加,60min达高峰,TEER下降,荧光黄透过增加,以体积分数5%乙醇最明显。蛋白印迹法检测体积分数5%乙醇在1h内致Caco-2细胞表达ZO-1减少。结论乙醇可引起肠上皮黏膜屏障破坏,其机制可能和紧密连接蛋白ZO-1的破坏相关。     

异搏定凝胶的透皮吸收

本文制备透皮吸收起全身作用的异搏定凝胶,通过大鼠皮肤的吸收试验,测定了异搏定的血浆及皮肤浓度,并探讨了Azone和肉豆蔻酸异丙酯(IPM)对药物透皮吸收的促进作用。制备方法:异搏定凝胶的基本处方为异搏定盐酸盐0.216 g、Carbopol 934 0.4g、EtOH-PG(2∶1)11.5ml、水8.0 ml、1NNaOH0.5 ml、10%三乙醇胺适量。将异搏定盐酸盐溶于乙醇-丙二醇混合液(2∶1,v/v),用1 NNaOH中和,加至Carbopo1934溶液中,加入2%Azone或IPM,再加三乙醇胺使成粘稠凝胶。凝胶中异搏定的体外释放试验:对含不     

Azone对安定的体外透皮促进作用

本文研究了含乙醇及丙二醇的水溶液系统中的Azone 对安定的体外透皮促进作用。发现不同浓度的Azone 溶液均可促进安定的透皮吸收,但以其0.8%的溶液作用最强,且有统计学意义。     

Feasibility studies of dermal delivery of paclitaxel with binary combinations of ethanol and isopropyl myristate: role of solubility, partitioning and lipid bilayer perturbation

In the current investigation, paclitaxel (PCL) delivery into the different layers of skin, vehicle optimization and relationship between vehicle composition and the relative contribution of solubility, partition and diffusion towards drug transport has been outlined. Saturation solubility of PCL was determined in ethanol (EtOH), isopropyl myristate (IPM) and their binary combinations, and partition studies performed to study the probability of skin depot formation. Epidermal and dermal partitioning was carried from PCL saturated vehicles. Skin permeation of PCL was studied using the rat skin. FT-IR has been utilized to study the skin barrier perturbation, and the localization of PCL and isopropyl myristate (IPM) in epidermis. High K(app) value in mineral oil/buffer indicated the tendency of PCL to form a reservoir in skin, and an inverse relationship between PCL solubility in different solvent systems and partitioning into epidermis was found. Maximum K(epidermis) for PCL was observed with IPM, while PCL in EtOH/IPM (1:1) showed high partitioning into dermis. Maximum flux of PCL was observed with EtOH/IPM (1:1). For lipophilic drug like PCL modulation of vehicle seems to be effective approach to increase the permeability across the skin. With a binary combination of EtOH/IPM (1:1) higher concentration of PCL can be delivered to deeper layer of skin whereas with IPM higher concentration of PCL could be localized in the epidermis. While engineering the delivery vehicle selection of solvents should be such that one of them is miscible in both hydrophilic and lipophilic phase like ethanol and another should be lipophilic in nature (IPM in this case) so that an optimum balance between 'push-pull' and 'blending' effect can be achieved.     

皮肤条件影响茶碱经皮吸收的观察

目的　考察不同皮肤组织对药物经皮吸收的影响。方法　选择茶碱 (TP)为模型药物 ,以体外Franz吸收池法 ,评价TP经完整皮肤和剥离角质层皮肤的体外透皮能力Kp ,以及吸收促进剂肉豆蔻酸异丙酯 (IPM)对Kp的影响。结果　TP经剥离角质层皮肤的Kp是经完整皮肤的 2 1倍 ,加入IPM后TP的Kp分别提高到原来的 8 9倍 (经完整皮肤 )和 15 1倍 (经剥离角质层皮肤 )。结论　IPM非常显著地增加TP经不同皮肤层的经皮吸收。本文也为皮肤病态条件 ,如皮肤受损或溃疡等时的药物经皮吸收规律研究提供一种新的方法     

Penetration‐Enhancing Effect of Ethanol–Water Solvent System and Ethanolic Solution of Carvone on Transdermal Permeability of Nimodipine from HPMC Gel Across Rat Abdominal Skin

The aim of this investigation was to find the effect of the ethanol–water solvent system and the ethanolic solution of carvone on the permeation of nimodipine across rat abdominal skin in order to select a suitable solvent system and optimal concentration of carvone for the development of membrane‐moderated transdermal therapeutic system of nimodipine. The solubility of nimodipine in water, ethanol, and ethanol–water cosolvent systems, or the selected concentration of carvone [2% (w/w) to 12% (w/w)] in 60:40 (v/v) ethanol–water were determined. The effect of these solvents or cosolvent systems on the transdermal permeation of nimodipine was also studied using in vitro permeability studies across the rat abdominal skin. The cosolvent system containing 60:40 (v/v) of ethanol–water showed highest permeability across the rat abdominal skin. Further, the effect of ethanolic solution [60% (v/v) ethanol–water] of carvone [2% (w/w) to 12% (w/w)] on the in vitro permeation of nimodipine across the rat abdominal skin from 2% (w/w) hydroxypropyl methylcellulose (HPMC) gel was also investigated. The transdermal permeability of nimodipine across rat abdominal skin was enhanced further by the addition of carvone to HPMC gel prepared with 60% (v/v) of ethanol. There was a steady effect on the flux of nimodipine (161.02 ± 4.14 µg/cm²/hr) with an enhancement ratio of 4.56 when carvone was incorporated at a concentration of 10% (w/w) in HPMC gels prepared with 60% (v/v) ethanol. The Fourier transform infrared data indicated that ethanolic solution of carvone increased the transdermal permeability of nimodipine across the rat abdominal skin by partial extraction of lipids in the stratum corneum. The results suggest that 10% (w/w) of carvone in 60% (v/v) ethanol–water, along with HPMC as antinucleating agent may be useful for enhancing the skin permeability of nimodipine from the membrane‐moderated transdermal therapeutic system.     

Percutaneous Penetration of Acyclovir Through Excised Hairless Mouse and Rat Skin: Effect of Vehicle and Percutaneous Penetration Enhancer

The effects of vehicle and percutaneous penetration enhancer on the penetration of acyclovir through excised hairless mouse and rat skin were investigated. Four solvents, propylene glycol (PG), ethanol (ET), isopropanol (IPA), and isopropyl myristate (IPM), were employed as vehicles, in combination with four enhancers, l-farnesylazacycloheptan-2-one (7FU), l-geranylazacycloheptan-2-one (7GU), l-geranylazacyclopentan-2-one (5GU), and l-dodecylazacycloheptan-2-one (Azone). Acyclovir was suspended in vehicles to avoid the effect of the thermodynamic activity of acyclovir in the vehicle. The penetration of acyclovir through hairless mouse skin from IPA was enhanced by 7GU, whereas that from IPM was not affected. All combinations of vehicle and penetration enhancer were examined using rat skin. No effect of the enhancers was observed in the IPM vehicle. The estimated solubility parameters of vehicles and enhancers indicated that the polarities of IPM and the enhancers are similar, which prevents effective penetration of the enhancers from IPM. However, the penetration of acyclovir from the other vehicles was increased by the enhancers. The combination of hydrophilic vehicle and hydrophobic enhancer resulted in a large enhancing effect. The disappearance of the enhancers from the vehicle correlated with their enhancing activity, but other factors also seemed to affect the penetration enhancement of acyclovir.     

Formulation and in vitro evaluation of pentazocine transdermal delivery system

The aim of this study was to prepare a pentazocine (PTZ) matrix-type transdermal drug delivery system (TDDS) using acrylic pressure-sensitive adhesives. Among the five Duro-Tak adhesive polymers tested (87-9301, 87-2677, 87-201A, 87-2196, 87-2852), in vitro dissolution studies demonstrated the highest PTZ release flux from the Duro-Tak 87-9301 matrix. In addition, the effects of permeation enhancers, isopropyl myristate (IPM) and glyceryl monocaprylate (GEFA-C(8)), and drug content on PTZ skin permeation from prepared patches were evaluated using Franz diffusion cells fitted with hairless mouse skin. IPM and GEFA-C(8) were found to produce effective flux of PTZ at a patch concentration of 10% w/w and 5% w/w, respectively. The PTZ flux increased linearly as the loading dose increased up to 30%, whereas no further increase in flux was observed at loading doses of 40% and 50% due to drug crystallization in the matrix. Thus, the highest skin permeation rate (24.2 microg/cm(2)/h) was achieved when 30% of PTZ was loaded in Duro-Tak 87-9301 with 10% IPM and 5% GEFA-C(8). These results demonstrate the feasibility of a novel narcotic-antagonist analgesic matrix-type TDDS for PTZ.     

Penetration-enhancing effect of ethanol-water solvent system and ethanolic solution of carvone on transdermal permeability of nimodipine from HPMC gel across rat abdominal skin

The aim of this investigation was to find the effect of the ethanol-water solvent system and the ethanolic solution of carvone on the permeation of nimodipine across rat abdominal skin in order to select a suitable solvent system and optimal concentration of carvone for the development of membrane-moderated transdermal therapeutic system of nimodipine. The solubility of nimodipine in water, ethanol, and ethanol-water cosolvent systems, or the selected concentration of carvone [2% (w/w) to 12% (w/w)] in 60:40 (v/v) ethanol-water were determined. The effect of these solvents or cosolvent systems on the transdermal permeation of nimodipine was also studied using in vitro permeability studies across the rat abdominal skin. The co-solvent system containing 60:40 (v/v) of ethanol-water showed highest permeability across the rat abdominal skin. Further, the effect of ethanolic solution [60% (v/v) ethanol-water] of carvone [2% (w/w) to 12% (w/w)] on the in vitro permeation of nimodipine across the rat abdominal skin from 2% (w/w) hydroxypropyl methylcellulose (HPMC) gel was also investigated. The transdermal permeability of nimodipine across rat abdominal skin was enhanced further by the addition of carvone to HPMC gel prepared with 60% (v/v) of ethanol. There was a steady effect on the flux of nimodipine (161.02 +/- 4.14 microg/cm2/hr) with an enhancement ratio of 4.56 when carvone was incorporated at a concentration of 10% (w/w) in HPMC gels prepared with 60% (v/v) ethanol. The Fourier transform infrared data indicated that ethanolic solution of carvone increased the transdermal permeability of nimodipine across the rat abdominal skin by partial extraction of lipids in the stratum corneum. The results suggest that 10% (w/w) of carvone in 60% (v/v) ethanol-water, along with HPMC as antinucleating agent may be useful for enhancing the skin permeability of nimodipine from the membrane-moderated transdermal therapeutic system.     

The effect of ion pairing on the skin permeation of amlodipine

The purpose of the present study was to evaluate the effect of ion pairing on the skin permeation of amlodipine. Amlodipine base (AM) was first prepared from amlodipine besilate (AM-B), then amlodipine adipate (AM-A), amlodipine oxalate (AM-O) and amlodipine maleate (AM-M) were prepared using AM and the corresponding organic acids. Differential scanning calorimetry (DSC) thermogram studies demonstrated the formation of complexes between AM and the various acids. In vitro percutaneous absorption of AM and its complexes was evaluated through excised rat skin using 2-chamber diffusion cells. The results showed that AM had the greatest steady-state flux and lowest permeability coefficient of the five compounds from the El system (ethanol:isopropyl myristate (IPM)= 2:8), and its four complexes all exhibited a lower flux and higher permeability coefficient than AM.     

Effect of vehicle properties on skin penetration of emedastine

We investigated sorption and permeation of emedastine with 11 different vehicles, composed of single or binary solvents, in excised rat skin. In the sorption study, partition parameters of the drug with each vehicle were obtained by dividing the drug amount in skin at equilibrium by its donor concentration. When the logarithm of the partition parameters for the stratum corneum/vehicle partitioning (Ks') was plotted against the dielectric constants of the vehicles, a bi-linear relationship was obtained. The skin flux of emedastine largely differ among the vehicles. A quasi-steady-state flux of emedastine exhibited a good linear relationship with Ks', except for ethanol (EtOH)/isopropyl myristate (IPM) systems, indicating that the partitioning process is critical in determining the permeation rate. Delineation of the EtOH/IPM systems would be due to an increase in the diffusivity of the drug in the stratum corneum, as indicated by the analysis using a two-layer diffusion model. Thus, differential evaluation of partitioning and diffusion processes by both sorption and permeation studies would give further insights into the effects of vehicles on skin permeation of drugs.     

Comparative dermatotoxicology: I. Direct comparison of rabbit and human primary skin irritation responses to isopropylmyristate

The primary skin irritation properties of isopropylmyristate (IPM) have been determined for rabbit and human skin. In rabbit studies, an occluded patch procedure was used in which irritation due to a vehicle was eliminated. Known amounts of IPM were applied to patches with ethanol as a vehicle. A radiotracer study showed the ethanol could be evaporated to a nonirritating level prior to use of the patch. This procedure was used with an experimental design that improved the efficiency of the irritation test by allowing removal of animal-to-animal variability and permitting four different treatments on each animal at one time. Four consecutive 23-hr occluded exposures of rabbit skin to 6.3 mg IPM/cm² of patch produced moderate erythema according to the Draize scale while four exposures to 23 or 85 mg IPM/cm² of patch produced moderate to severe erythema with very slight edema. A single exposure at doses ranging from 1.7 to 85 mg IPM/cm² of patch produced responses ranging from no erythema to well-defined erythema. The responses to a single exposure were less with 1 or 4 hr of occlusion than with 23 hr. A statistical analysis showed substantial variation in irritation scores from skin site-to-skin site but no tendency for one site on the rabbits' backs to have systematically higher scores than another. Human studies were conducted with experimental conditions the same as for the rabbit. Four consecutive 23-hr occluded exposures of human back skin to 85 mg IPM/cm² of patch produced only very slight erythema with no edema. The results of these studies support the use of IPM as a model species-variable skin irritant to study the biological basis for the variability of skin irritation among species.