新型薄荷醇酯类衍生物经皮促透作用评价及其促透机理的初步研究
|
摘要
L-薄荷醇(MT)具有促透作用强、毒性低、刺激性小、对亲水性和亲脂性药物均有促透作用等优点,但MT易挥发,高浓度时味辛且具有一定的皮肤刺激性。为了提高MT的促透作用,降低挥发性、气味及刺激性,本论文设计合成新型薄荷醇酯类衍生物,并对该类化合物的经皮促透作用进行了系统的研究。
将MT与饱和直链脂肪酸(乙酸、丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十二酸、十四酸、十六酸、十八酸)及药用辅料有机酸(油酸、乳酸、水杨酸、肉桂酸)以酯键连接,合成了十七种薄荷醇酯类衍生物,并合成了文献报道促透能力较优的薄荷乙基醚(MET)作为参比促进剂。利用~1H-NMR、MS确证了目标产物的结构。对合成的薄荷醇酯类衍生物的基本化学特征参数进行计算,包括溶解度参数(SP)、油/水分配系数(K_(O/W))以及极化率(PLB)。
分别选定不同K_(O/W)值和酸碱性的模型药物包括利多卡因(LD,碱性)、硝酸异山梨酯(ISDN,中性)、酮洛芬(KP,酸性)和具有较大K_(O/W)的吲哚美辛(IM)及较小K_(O/W)的5—氟脲嘧啶(5-FU),以大鼠皮肤为透过屏障采用水平双室扩散池,供给池一侧以肉豆蔻酸异丙酯(IPM)为溶剂,接收池一侧以PBS为接收液评价薄荷醇酯类衍生物的促透作用,结果表明:药物在IPM中的通透系数与药物和介质溶解度参数的差值正相关,且药物的稳态流量与其熔点成反比;直链饱和脂肪酸薄荷醇酯疏水链的长度对其促透作用有显著影响,对于亲水性药物5-FU而言,碳链长度与促透作用呈抛物线关系,长度为C14时促透效果最佳;而对于亲脂性药物当碳链长度为C6～C10时促透作用最强。乳酸薄荷醇酯(M-LA)可使高水溶性药物(5-FU、LD)的累积透过量(Q)显著增加,累积透过量的促透比值(ER_Q)分别为3.74及4.19;肉桂酸薄荷醇(M-CA)对不同K_(O/W)值的模型药物均无促透作用;水杨酸薄荷醇酯(M-SA)及油酸薄荷醇酯(M-OA)对低水溶性药物ISDN、KP、IM的促透作用显著强于高水溶性药物;除LD外四种模型药物的logK_(O/W)值与辅料酸薄荷醇酯通透系数的促透比(ER_P)间均呈抛物线关系{M-LA:r=0.989,(P=0.144);M-CA:r=0.965,(P=0.216);M-SA:r=0.786,(P=0.630):M-OA:r=0.996,(P=0.088)}。
以双氯芬酸(DA)为模型药物引入烷胺或烷醇胺(二乙胺、乙醇胺、二乙醇胺、三乙醇胺及N-羟乙基哌啶)制备双氯芬酸有机胺盐,并以DSC及FT-IR确证目标产物的形成,考察离子对存在时对薄荷醇酯类衍生物的促透作用的影响。DA与二乙胺(DETA)形成离子对可以改变DA的脂溶性从而显著增加其经皮透过量,其ER_Q值为为4.51;但结构中含有羟基的烷醇胺阳离子对DA的经皮透过均有抑制作用;M-TET对双氯芬酸二乙胺(D-DETA)有着最为显著的促透作用,M-TET与二乙胺的联合应用可使DA的累积透过量与对照组相比增加9.74倍。
以托特罗定(TOL)为模型药物寻找在压敏胶分散型(DIA)贴剂中有显著促透作用的薄荷醇酯,结果表明,M-OA在IPM溶液及DIA贴剂中均有显著促透作用;大鼠单剂量尾静脉注射酒石酸TOL溶液,经DAS(?)2.0计算后该药—时曲线符合双隔室模型(r=0.993),TOL的中央室分布容积(V_d)及总清除率(CL)分别为3.57 L/kg和0.51L/h,药物代谢较快,6 h后血药浓度低于检测限。
进行TOL贴剂的大鼠体内药动学实验,比较含有M-OA与MT及无促进剂贴剂在大鼠体内的稳态血药浓度(C_(SS))的差异并考察促进剂对药物在皮肤内储库作用的影响,并以贴剂体外稳态流量及静脉注射的CL值预测体内稳态血药浓度(C_(SS)~P)。经皮给药三种TOL贴剂后采用DAS(?)2.0以非隔室模型计算TOL的药动学参数,M-OA组的C_(max)、C_(SS)、AUC_(0-24)以及AUC_(0-∞)均显著高于MT组及无促进剂组(P<0.05);MT组及无促进剂组的C_(max)、T_(max)、AUC_(0-24)间无显著性差异(P>0.05),但二者的AUC_(0-∞)间有显著性差异(P<0.05)。停止给药后,三组贴剂TOL的血药浓度迅速消除,但消除速度均显著低于静脉注射(P<0.01);无促进剂组的消除速度常数明显大于M-OA及MT组(P<0.05),表明应用促进剂后可增强皮肤对TOL的储库作用。实验中测得无促进剂组、MT组及M-OA组贴剂的大鼠C_(SS)值分别为0.89、0.84、1.47μg/mL;计算得到的对应的0～24 h的C_(SS)~P尸值分别为0.95、1.04和1.44μg/mL,实测值与预测值非常接近表明TOL贴剂具有良好的体内外相关性,体外评价可以在一定程度上代替体内评价用于TOL经皮给药系统开发研究。采用SPSS(?)相关分析的结果表明,当以M-OA及MT作为促进剂时,TOL在IPM中的Q_8与贴剂中的Q_8、贴剂的体外Q_(48)与大鼠体内的AUC_(0-48)间有良好的促透相关性,相关系数分别为0.941及0.993。
应用扫描电镜(SEM)及衰减全反射红外(ATR-FTIR)技术,以猪耳背皮肤为模型初步探讨M-OA的促透作用机理。SEM观察经M-OA处理的皮肤发现,M-OA可抽提角质层中的脂质,造成皮表光滑度下降且皮肤表面角质间距离增大;ATR-FTIR结果显示,v_SCH_2及v_(as)CH_2均向高波数移动,分别从2849.5 cm~(-1)及2919.4 cm~(-1)移动到2851.1 cm~(-1)及2920.9 cm~(-1);角蛋白的酰胺吸收峰Ⅱ带从1540.6 cm~(-1)向低波数位移到1539.1 cm~(-1)。M-OA促进药物经皮吸收的机理推测有以下两个方面的作用。1)M-OA可提取皮肤表面角质层中的脂质;2)可增加角质层中酰胺及亚甲基的自由度。
L-menthol(MT) may offer advantages over many enhancers because of its high enhancing activity,low toxicity and irritancy,high promoting activity both on lipophilic and hydrophilic drugs.However,its low melting point,pungent flavor and irritancy at high concentration restricts its application in clinical situations.In this study,l-menthol was selected as a lead compound to synthesize new types of O-acylmenthol derivatives as candidates for percutaneous absorption enhancers which presumably could overcome above defects of MT.
To develop more effective compounds as penetration enhancers,two types of O-acylmenthol derivatives were synthesized,one type was synthesized by MT and saturated fatty acid,including acetic acid,propanoic acid,butyric acid,pentanoic acid,hexanoic acid, heptanoic acid,octanoic acid,nonylic acid,decanoic acid,dodecanic acid,tetradeconic acid, palmitic acid and stearic acid;the other type of O-acylmenthol was synthesized by MT and pharmaceutical excipient acids(lactic acid,cinnamic acid,salicylic acid and oleic acid), O-ethylmenthol(MET) was also synthesized as a reference penetration enhancer.The structures of final products were confirmed by ~1HNMR and MS.The physicochemical parameters of the O-acylmenthol derivatives such as solubilty parameter(SP),n-octanol/water partition coefficient(K_(O/W)) and polarizability(PLB) were calculated by MARVIN(?) or by the approaches of Hoftyzer/Van Krevelen.
Their promoting activity on the percutaneous absorption of five penetrants having different physicochemical properties,5-fluorouracil(5-FU,base),isosorbide dinitrate(ISDN, neutrality),lidocaine(LD,base),ketoprofen(KP,acid),indomethacin(IM,acid),which were selected based on their lipophilicity represented by logK_(O/W),were tested in vitro across full thickness rat skin with each of the evaluated drugs in isopropyl myristate(IPM) solution,the PBS buffer solutions were added in the receive side.In the case of the IPM as vehicle,we can conclude that for drugs of a similar size,the greater the difference in the SP values between drug and solvent,the larger the permeation coefficients(P) that can be obtained from the vehicle,interestingly,a reverse relationship between the melting point and flux was observed in IPM solution.The structure-activity relationships of O-acylmenthol derivatives synthesized by MT and saturated fatty acids as percutaneous absorption enhancers are summarized as follows:Tail chain length(C2-C18) has important effects on the enhancing activity,C6-C10 seems to be favorable for lipophilic drugs.A parabolic relationship between the carbon chain length of O-acylmenthol and skin permeation enhancement has been observed for hydrophilic drug(5-FU),2-isopropyl-5-methylcyclohexyl tetradecanoate(M-TET) with C14 alkyl chain is most effective.
2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate(M-LA) provided the highest increase of accumulation of 5-FU(3.74-fold) and LD(4.19-fold) in the receptor phase while 2-isopropyl-5-methylcyclohexyl cinnamate(M-CA) was ineffective for most of the drugs; Both 2-isopropyl-5-methylcyclohexyl 2-hydroxybenzoate(M-SA)and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate(M-OA) had better promoting effects on the drugs with low water-solubility.The four O-acylmenthol enhancers produced parabolic relationship between the lipophilicity(log K_(O/W)) of the model drugs(5-FU,ISDN,KP,IM) and their enhancement ratio of the permeation coefficient(ER_P),indicating that the lipophilicity of the penetrants has significant effect on the permeation results,r = 0.989,(P = 0.144) for M-LA,r = 0.965,(P = 0.216) for M-CA,r = 0.786,(P = 0.630) for M-SA,and r = 0.996,(P = 0.088) for M-OA.
We selected alkylamine or alkanolamines(diethylamine,ethanolamine,diethanolamine, triethanolamine and N-(hydroxylethyl) piperidine) to react with diclofenac acid(DA) to prepare DA salts,differential scanning calorimetry(DSC) and fourier transform infrared spectroscopy(FT-IR) analyses have been used to identify the formation of DA salts.We investigated the effects of five organic amines upon the penetration of DA by O-acylmenthol in the solutions of IPM.A 4.51-fold increase in the accumulative amount of DA was observed by ion-pair formation with diethylamine for the improvement of lipophilicity,however,the alkanolamines with hydroxyl groups had negative effects on the transdermal delivery of diclofenac.M-TET was effective on the penetration of diclofenac diethylamine(D-DETA), also,it is exciting to note that combined use of diethylamine with M-TET produced a 9.74-fold increase in accumulation amount(Q) of diclofenac compared with DA in IPM.
Tolterodine(TOL) was selected as a model drug to screen the most promising enhancer among O-acylmenthol derivatives which were applied in the dug in adhesive(DIA) patches. The in vitro permeation studies indicated that M-OA was the most promising enhancer both in IPM solution and DIA patch for transdermal delivery.The pharmacokinetic analysis of the TOL plasma concentration-time profiles after single-dose intravenous bolus administration was carried out by fitting the data to a two-compartment model(r = 0.993).The steady-state volume of distribution(V_d) and clearance(CL) of TOL were 10.93 L/kg and 0.51 L/h, respectively.The concentration of TOL was too low to be detected in rat plasma up to 6 h of sampling.
The in vivo studies in rats were conducted in order to examine the ability of the TDDS of TOL to provide a steady-state plasma concentration of the drug as well to investigate the effects of enhancers on the skin reservoir and to predict the steady-state plasma concentrations (C_(SS)~P) of TOL from in vivo permeability data.Following topical administration of patches with M-OA,MT as enhancer or without enhancer,pharmacokinetic parameters were analyzed by non-compartment analysis.The pharmacokinetic parameters,including C_(max),C_(SS),AUC_(0-24) and AUC_(0-∞) of M-OA group were significantly larger than those of MT group and Control group (P<0.05);there were no significant difference between C_(max),C_(SS),AUC_(0-24) values of Control and MT group(P>0.05),however,AUC_(0-∞) of MT group was significantly different from that of Control group(P<0.05).The plasma level of TOL declined after the removal of the patches, and it is noteworthy that the TOL of the Control group was eliminated much faster than in the MT group,significant skin reservoir effects were observed,especially for the patches with MT and M-OA as enhancers,as the rate constants for terminal phase after removal of the patches were much smaller than the rate constant for the elimination phase after i.v bolus.
The observed steady-state plasma concentrations(C_(SS)) of TOL after the application of patches without enhancer(0.89±0.11μg/mL),with MT(0.84±0.14μg/mL) and M-OA (1.47±0.08μg/mL) as enhancers in rats were comparable with the respective predicted C_(SS)~P (0.95,1.04 and 1.44μg/mL) obtained over the period 0 and 24 h from the in vitro permeation data.This indicates that in vitro experiments with rat skin may be used for further transdermal drug delivery studies with TOL.The correlation analysis using the SPSS(?) program indicated there was a good enhancing activity correlation between the Q_8 from IPM and the Q_8 from patches,especially between the Q_(48) from patches in vitro and the AUC_(0-48) in vivo when TOL was in the Control patch or using MT and M-OA as enhancers,the r is 0.941(P<0.05) and 0.993(p<0.05) respectively.
To investigate the permeation mechanism of M-OA,morphological changes in the stratum corneum(SC) were observed by a scanning electron microscope(SEM),and the stretching vibration peak shifts of C-H and amide were estimated by attenuated total reflectance Fourier transform infared(ATR-FTIR).The wrinkles were increased and numerous concavities were observed on the skin surface,moreover,the intercellular space of the SC in the skin surface was enlarged after M-OA treatment.The ATR-FTIR results revealed that the stretching vibrations of v_SCH_2 andv_(as)CH_2 were shifted from 2849.5 cm~(-1) to 2851.1 cm~(-1) and from 2919.4 cm~(-1) to 2920.9 cm~(-1),respectively.AmideⅡstretching vibrations in the SC lipids were shifted from 1540.6 cm~(-1) to 1539.1 cm~(-1).There might be two reasons responsible for the penetration activity of M-OA,one is M-OA could extract the SC lipids,the other is to disorder the arrangement of lipids and increase the degree of freedom of C-H and amide.
将MT与饱和直链脂肪酸(乙酸、丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十二酸、十四酸、十六酸、十八酸)及药用辅料有机酸(油酸、乳酸、水杨酸、肉桂酸)以酯键连接,合成了十七种薄荷醇酯类衍生物,并合成了文献报道促透能力较优的薄荷乙基醚(MET)作为参比促进剂。利用~1H-NMR、MS确证了目标产物的结构。对合成的薄荷醇酯类衍生物的基本化学特征参数进行计算,包括溶解度参数(SP)、油/水分配系数(K_(O/W))以及极化率(PLB)。
分别选定不同K_(O/W)值和酸碱性的模型药物包括利多卡因(LD,碱性)、硝酸异山梨酯(ISDN,中性)、酮洛芬(KP,酸性)和具有较大K_(O/W)的吲哚美辛(IM)及较小K_(O/W)的5—氟脲嘧啶(5-FU),以大鼠皮肤为透过屏障采用水平双室扩散池,供给池一侧以肉豆蔻酸异丙酯(IPM)为溶剂,接收池一侧以PBS为接收液评价薄荷醇酯类衍生物的促透作用,结果表明:药物在IPM中的通透系数与药物和介质溶解度参数的差值正相关,且药物的稳态流量与其熔点成反比;直链饱和脂肪酸薄荷醇酯疏水链的长度对其促透作用有显著影响,对于亲水性药物5-FU而言,碳链长度与促透作用呈抛物线关系,长度为C14时促透效果最佳;而对于亲脂性药物当碳链长度为C6～C10时促透作用最强。乳酸薄荷醇酯(M-LA)可使高水溶性药物(5-FU、LD)的累积透过量(Q)显著增加,累积透过量的促透比值(ER_Q)分别为3.74及4.19;肉桂酸薄荷醇(M-CA)对不同K_(O/W)值的模型药物均无促透作用;水杨酸薄荷醇酯(M-SA)及油酸薄荷醇酯(M-OA)对低水溶性药物ISDN、KP、IM的促透作用显著强于高水溶性药物;除LD外四种模型药物的logK_(O/W)值与辅料酸薄荷醇酯通透系数的促透比(ER_P)间均呈抛物线关系{M-LA:r=0.989,(P=0.144);M-CA:r=0.965,(P=0.216);M-SA:r=0.786,(P=0.630):M-OA:r=0.996,(P=0.088)}。
以双氯芬酸(DA)为模型药物引入烷胺或烷醇胺(二乙胺、乙醇胺、二乙醇胺、三乙醇胺及N-羟乙基哌啶)制备双氯芬酸有机胺盐,并以DSC及FT-IR确证目标产物的形成,考察离子对存在时对薄荷醇酯类衍生物的促透作用的影响。DA与二乙胺(DETA)形成离子对可以改变DA的脂溶性从而显著增加其经皮透过量,其ER_Q值为为4.51;但结构中含有羟基的烷醇胺阳离子对DA的经皮透过均有抑制作用;M-TET对双氯芬酸二乙胺(D-DETA)有着最为显著的促透作用,M-TET与二乙胺的联合应用可使DA的累积透过量与对照组相比增加9.74倍。
以托特罗定(TOL)为模型药物寻找在压敏胶分散型(DIA)贴剂中有显著促透作用的薄荷醇酯,结果表明,M-OA在IPM溶液及DIA贴剂中均有显著促透作用;大鼠单剂量尾静脉注射酒石酸TOL溶液,经DAS(?)2.0计算后该药—时曲线符合双隔室模型(r=0.993),TOL的中央室分布容积(V_d)及总清除率(CL)分别为3.57 L/kg和0.51L/h,药物代谢较快,6 h后血药浓度低于检测限。
进行TOL贴剂的大鼠体内药动学实验,比较含有M-OA与MT及无促进剂贴剂在大鼠体内的稳态血药浓度(C_(SS))的差异并考察促进剂对药物在皮肤内储库作用的影响,并以贴剂体外稳态流量及静脉注射的CL值预测体内稳态血药浓度(C_(SS)~P)。经皮给药三种TOL贴剂后采用DAS(?)2.0以非隔室模型计算TOL的药动学参数,M-OA组的C_(max)、C_(SS)、AUC_(0-24)以及AUC_(0-∞)均显著高于MT组及无促进剂组(P<0.05);MT组及无促进剂组的C_(max)、T_(max)、AUC_(0-24)间无显著性差异(P>0.05),但二者的AUC_(0-∞)间有显著性差异(P<0.05)。停止给药后,三组贴剂TOL的血药浓度迅速消除,但消除速度均显著低于静脉注射(P<0.01);无促进剂组的消除速度常数明显大于M-OA及MT组(P<0.05),表明应用促进剂后可增强皮肤对TOL的储库作用。实验中测得无促进剂组、MT组及M-OA组贴剂的大鼠C_(SS)值分别为0.89、0.84、1.47μg/mL;计算得到的对应的0～24 h的C_(SS)~P尸值分别为0.95、1.04和1.44μg/mL,实测值与预测值非常接近表明TOL贴剂具有良好的体内外相关性,体外评价可以在一定程度上代替体内评价用于TOL经皮给药系统开发研究。采用SPSS(?)相关分析的结果表明,当以M-OA及MT作为促进剂时,TOL在IPM中的Q_8与贴剂中的Q_8、贴剂的体外Q_(48)与大鼠体内的AUC_(0-48)间有良好的促透相关性,相关系数分别为0.941及0.993。
应用扫描电镜(SEM)及衰减全反射红外(ATR-FTIR)技术,以猪耳背皮肤为模型初步探讨M-OA的促透作用机理。SEM观察经M-OA处理的皮肤发现,M-OA可抽提角质层中的脂质,造成皮表光滑度下降且皮肤表面角质间距离增大;ATR-FTIR结果显示,v_SCH_2及v_(as)CH_2均向高波数移动,分别从2849.5 cm~(-1)及2919.4 cm~(-1)移动到2851.1 cm~(-1)及2920.9 cm~(-1);角蛋白的酰胺吸收峰Ⅱ带从1540.6 cm~(-1)向低波数位移到1539.1 cm~(-1)。M-OA促进药物经皮吸收的机理推测有以下两个方面的作用。1)M-OA可提取皮肤表面角质层中的脂质;2)可增加角质层中酰胺及亚甲基的自由度。
L-menthol(MT) may offer advantages over many enhancers because of its high enhancing activity,low toxicity and irritancy,high promoting activity both on lipophilic and hydrophilic drugs.However,its low melting point,pungent flavor and irritancy at high concentration restricts its application in clinical situations.In this study,l-menthol was selected as a lead compound to synthesize new types of O-acylmenthol derivatives as candidates for percutaneous absorption enhancers which presumably could overcome above defects of MT.
To develop more effective compounds as penetration enhancers,two types of O-acylmenthol derivatives were synthesized,one type was synthesized by MT and saturated fatty acid,including acetic acid,propanoic acid,butyric acid,pentanoic acid,hexanoic acid, heptanoic acid,octanoic acid,nonylic acid,decanoic acid,dodecanic acid,tetradeconic acid, palmitic acid and stearic acid;the other type of O-acylmenthol was synthesized by MT and pharmaceutical excipient acids(lactic acid,cinnamic acid,salicylic acid and oleic acid), O-ethylmenthol(MET) was also synthesized as a reference penetration enhancer.The structures of final products were confirmed by ~1HNMR and MS.The physicochemical parameters of the O-acylmenthol derivatives such as solubilty parameter(SP),n-octanol/water partition coefficient(K_(O/W)) and polarizability(PLB) were calculated by MARVIN(?) or by the approaches of Hoftyzer/Van Krevelen.
Their promoting activity on the percutaneous absorption of five penetrants having different physicochemical properties,5-fluorouracil(5-FU,base),isosorbide dinitrate(ISDN, neutrality),lidocaine(LD,base),ketoprofen(KP,acid),indomethacin(IM,acid),which were selected based on their lipophilicity represented by logK_(O/W),were tested in vitro across full thickness rat skin with each of the evaluated drugs in isopropyl myristate(IPM) solution,the PBS buffer solutions were added in the receive side.In the case of the IPM as vehicle,we can conclude that for drugs of a similar size,the greater the difference in the SP values between drug and solvent,the larger the permeation coefficients(P) that can be obtained from the vehicle,interestingly,a reverse relationship between the melting point and flux was observed in IPM solution.The structure-activity relationships of O-acylmenthol derivatives synthesized by MT and saturated fatty acids as percutaneous absorption enhancers are summarized as follows:Tail chain length(C2-C18) has important effects on the enhancing activity,C6-C10 seems to be favorable for lipophilic drugs.A parabolic relationship between the carbon chain length of O-acylmenthol and skin permeation enhancement has been observed for hydrophilic drug(5-FU),2-isopropyl-5-methylcyclohexyl tetradecanoate(M-TET) with C14 alkyl chain is most effective.
2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate(M-LA) provided the highest increase of accumulation of 5-FU(3.74-fold) and LD(4.19-fold) in the receptor phase while 2-isopropyl-5-methylcyclohexyl cinnamate(M-CA) was ineffective for most of the drugs; Both 2-isopropyl-5-methylcyclohexyl 2-hydroxybenzoate(M-SA)and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate(M-OA) had better promoting effects on the drugs with low water-solubility.The four O-acylmenthol enhancers produced parabolic relationship between the lipophilicity(log K_(O/W)) of the model drugs(5-FU,ISDN,KP,IM) and their enhancement ratio of the permeation coefficient(ER_P),indicating that the lipophilicity of the penetrants has significant effect on the permeation results,r = 0.989,(P = 0.144) for M-LA,r = 0.965,(P = 0.216) for M-CA,r = 0.786,(P = 0.630) for M-SA,and r = 0.996,(P = 0.088) for M-OA.
We selected alkylamine or alkanolamines(diethylamine,ethanolamine,diethanolamine, triethanolamine and N-(hydroxylethyl) piperidine) to react with diclofenac acid(DA) to prepare DA salts,differential scanning calorimetry(DSC) and fourier transform infrared spectroscopy(FT-IR) analyses have been used to identify the formation of DA salts.We investigated the effects of five organic amines upon the penetration of DA by O-acylmenthol in the solutions of IPM.A 4.51-fold increase in the accumulative amount of DA was observed by ion-pair formation with diethylamine for the improvement of lipophilicity,however,the alkanolamines with hydroxyl groups had negative effects on the transdermal delivery of diclofenac.M-TET was effective on the penetration of diclofenac diethylamine(D-DETA), also,it is exciting to note that combined use of diethylamine with M-TET produced a 9.74-fold increase in accumulation amount(Q) of diclofenac compared with DA in IPM.
Tolterodine(TOL) was selected as a model drug to screen the most promising enhancer among O-acylmenthol derivatives which were applied in the dug in adhesive(DIA) patches. The in vitro permeation studies indicated that M-OA was the most promising enhancer both in IPM solution and DIA patch for transdermal delivery.The pharmacokinetic analysis of the TOL plasma concentration-time profiles after single-dose intravenous bolus administration was carried out by fitting the data to a two-compartment model(r = 0.993).The steady-state volume of distribution(V_d) and clearance(CL) of TOL were 10.93 L/kg and 0.51 L/h, respectively.The concentration of TOL was too low to be detected in rat plasma up to 6 h of sampling.
The in vivo studies in rats were conducted in order to examine the ability of the TDDS of TOL to provide a steady-state plasma concentration of the drug as well to investigate the effects of enhancers on the skin reservoir and to predict the steady-state plasma concentrations (C_(SS)~P) of TOL from in vivo permeability data.Following topical administration of patches with M-OA,MT as enhancer or without enhancer,pharmacokinetic parameters were analyzed by non-compartment analysis.The pharmacokinetic parameters,including C_(max),C_(SS),AUC_(0-24) and AUC_(0-∞) of M-OA group were significantly larger than those of MT group and Control group (P<0.05);there were no significant difference between C_(max),C_(SS),AUC_(0-24) values of Control and MT group(P>0.05),however,AUC_(0-∞) of MT group was significantly different from that of Control group(P<0.05).The plasma level of TOL declined after the removal of the patches, and it is noteworthy that the TOL of the Control group was eliminated much faster than in the MT group,significant skin reservoir effects were observed,especially for the patches with MT and M-OA as enhancers,as the rate constants for terminal phase after removal of the patches were much smaller than the rate constant for the elimination phase after i.v bolus.
The observed steady-state plasma concentrations(C_(SS)) of TOL after the application of patches without enhancer(0.89±0.11μg/mL),with MT(0.84±0.14μg/mL) and M-OA (1.47±0.08μg/mL) as enhancers in rats were comparable with the respective predicted C_(SS)~P (0.95,1.04 and 1.44μg/mL) obtained over the period 0 and 24 h from the in vitro permeation data.This indicates that in vitro experiments with rat skin may be used for further transdermal drug delivery studies with TOL.The correlation analysis using the SPSS(?) program indicated there was a good enhancing activity correlation between the Q_8 from IPM and the Q_8 from patches,especially between the Q_(48) from patches in vitro and the AUC_(0-48) in vivo when TOL was in the Control patch or using MT and M-OA as enhancers,the r is 0.941(P<0.05) and 0.993(p<0.05) respectively.
To investigate the permeation mechanism of M-OA,morphological changes in the stratum corneum(SC) were observed by a scanning electron microscope(SEM),and the stretching vibration peak shifts of C-H and amide were estimated by attenuated total reflectance Fourier transform infared(ATR-FTIR).The wrinkles were increased and numerous concavities were observed on the skin surface,moreover,the intercellular space of the SC in the skin surface was enlarged after M-OA treatment.The ATR-FTIR results revealed that the stretching vibrations of v_SCH_2 andv_(as)CH_2 were shifted from 2849.5 cm~(-1) to 2851.1 cm~(-1) and from 2919.4 cm~(-1) to 2920.9 cm~(-1),respectively.AmideⅡstretching vibrations in the SC lipids were shifted from 1540.6 cm~(-1) to 1539.1 cm~(-1).There might be two reasons responsible for the penetration activity of M-OA,one is M-OA could extract the SC lipids,the other is to disorder the arrangement of lipids and increase the degree of freedom of C-H and amide.
引文
[1]郑俊民,丁平田,方亮,等.经皮给药新剂型[M].北京:人民卫生出版社,2006:12.
[2]Barry BW.Novel mechanisms and devices to enable suc-cessful transdermal drug delivery.Eur J Pharm Sci,2001,14:101-114.
[3]Williams AC,Barry B W.Penetration enhancers.Adv Drug Dev Rev,2004,56:603-618.
[4]Valiveti S,Dana CH,Paudel KS,et al.In vivo evaluation of 3-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs.J Control Release,2005,102:509-520
[5]Knoblauch P,Moll F,In vitro pulsatile and continuous transdermal delivery of buserelin by iontophoresis.J Control Release,1993,26:203-211.
[6]Vanbever R,Lecouturier N,Preat V.Transdermal delivery of metoprool by electroporation.Pharm Res,1994,11:1657-1662.
[7]Mitragotri S,Blankschtein D,Langer R.Ultrasound-mediated transdermal protein delivery.Science,1995,269:850-853.
[8]Henry S,Mcallister,DV,Allen MG,et al.Microfabricated microneedles:a novel approach to transdermal drug delivery.J Pharm Sci,1998,87:922-928.
[9]Mezei M,Gulusekharam V.Liposomes--a selective drug delivery system for the topical route of administration,lotion dosage form.Life Sci,1980,26:1473-1477.
[10]Tu JB,Yang ZQ,He XJ,et al.Effect of ethosomal minoxidil on dermal delivery and hair cycle of C57BL/6 mice.J Dermatol Sci,2007,45:135-137.
[11]Moreno MA,Ballesteros MP,Frutos P.Lecithin-based oil-in-water microemulsion for parenteral use:pseudoternary phase diagrams,characterization and toxicity studies.J Pharm Sci,2003,92:1428-1437.
[12]de Jaron EG,Blanco-Prieto MJ,Ygartua P,et al.PLGA microparticles:possible vehicles for topical drug delivery.Int J Pharm,2001,226:181-184.
[13]Thakur RA,Wang Y,Michniak BB.Essential oils and terpenes,In:Smith EW,Maibach HI(Eds),Percutaneous Penetration Enhancers,CRC Press,Boca Raton,2006,pp.159-173.
[14]Gao S,Singh J.In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes.J Control Release,1998,51:193-199.
[15]Thomas S,Narishetty K,Panchagnula R.Transdermal delivery of zidovudine:effect of terpenes and their mechanism of action.J Control Release,2004,95:367-379.
[16]Morimoto Y,Wada Y,Seki T.In vitro permeation of morphine hydrochloride during the finite application of penetration-enhancing system containing water,ethanol and l-menthol.Biol Pharm Bull,2002,25:134-136.
[17]殷立新,刘宝库．薄荷醇的促透皮吸收作用．中国医药工业杂志,1999,2：15-19．
[18]Williams AC,Barry BW.Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement.Pharm Res,1991,8:17-24.
[19]Walters KA,Roberts MS.Veterinary applications of skin penetration enhancers.In:Walters KA,Hadgraft J (Eds),Pharmaceutical Skin Penetration Enhancement,Marcel Dekker,New York,1993,pp.113-143.
[20]Chan TCK.Percutaneous penetration enhancers:An update.The proceedings of the 9th Biennial International Conference of Perspectives in Percutaneous Penetration,2004,La Grand Motte,France.
[21]Yamane MA,Williams AC,Barry BW.Effects of terpenes and oleic acid as skin penetration enhancers towards 5-fluorouracil as assessed with time;permeation,partitioning and differential scanning calorimetry.Int J Pharm,1995,116:237-51.
[22]Cornwell PA,Barry B W.The routes of penetration of ions and 5-fluorouracil across human skin and the mechanisms of action of terpene skin penetration enhancers.Int J Pharm,1993,94:189-194
[23]Kitagawa S,Hosokai,Kaseda Y,et al.Permeability of benzoic acid derivatives in excised guinea pig dorsal skin and effects of 1-menthol.Int J Pharm,161:115-122.
[24]Narishetty ST,Panchagnula R.Transdermal delivery of zidovudine:effect of terpenes and their mechanism of action.J Control Release,2004,95:367-79.
[25]Negishi J,Takayama K,Higashlyama K,et al.Promoting effect of O-alkylmenthol and O-acylmenthol derivatives on the percutaneous absorption of ketoprofen in rats.STP Pharm Sci,1995,5:156-161.
[26]Nakamura Y,Takayama K,Higashiyama K,et al.Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen.Int J Pharm,1996,145:29-36.
[27]Obata Y,Sato H,Li CJ,et al.Effect of synthesized cyclohexanol derivatives using L-menthol as a lead compound on the pecutaneous absorption of ketoprofen.Int J Pharm,2000,198:191-2000.
[28]Obata Y,Li CJ,Fujikawa M,et al.Evaluation and structure-activity relationship of synthesized cyclohexanol derivatives on percutaneous absorption of ketoprofen using artificial neural network.Int J Pharm,2001,212:223-231.
[29]Takanashi Y,Higashiyama K,Komiya H,et al.Thiomenthol derivatives as novel percutaneous absorption enhancers.Drug Devel Ind Pharm,1999,25:89-94.
[30]Fuji M,Takeda Y,Yoshida M,et al.Comparison of skin permeation enhancement by 3-1-menthoxypropane-1,2-diol and l-menthol:The permeation of indomethacin and antipyrine through Yucatan micropig skin and changes in infrared spectra and X-ray diffraction patterns of stratum corneum.Int J Pharm,2003,258:217-233.
[31]Montagna,WJ.Histology and cytochemistry of human skin.Ⅸ.The distribution of non-specific esterases.Biophys Biochem Cytol,1995,1:13-16.
[32]Wong O,Huntington J,Konishi R,et al.Unsaturated cyclic ureas as new nontoxic biodegradable transdermal penetration enhancers Ⅰ:Synthesis.J Pharm Sci,1988,77:967-971.
[33]Wong O,Tsuzuki N,Nghiem B,et al.Unsaturated cyclic ureas as new non-toxic biodegradable transdermal penetration enhancers.Ⅱ.Evaluation study.Int J Pharm,1989,52:191-202.
[34]Wong O,Huntington J,Nishihaa T,et al.New alkyl N,N-dialkyl-substituted amino acetates as transdermal penetration enhancers.Pharm Res,1989,6,286-295.
[35]Michniak BB,Chapman JM,Seyda KL.Facilitated transport of two model steroids by esters and amides of clofibric acid.J Pharm Sci,1993,82:214-219.
[36]Wertz PW.The nature of the epidermal barrier:biochemical aspects.Adv Drug Deliv Rev,1996,18:283-294.
[37]V(?)vrov(?) K,Hrab(?)lek A,Dole(?)al P,et al.L-Serine and Glycine based ceramide analogues as transdermal permeation enhancers:Polar head sized and hydrogen bonding.Bioorg Med Chem Lett,2003,13:2351-2353.
[38]V(?)vrov(?) K,Hrab(?)lek A,Dole(?)al P,et al.Biodegradable derivatives of tranexamic acid as transdermal permeation enhancers.J Control Release,2005,104:41-49.
[39]Klimentov(?) J,Hrab(?)lek A,V(?)vrov(?) K,et al.Synthesis and transdermal penetration-enhancing activity of carbonic and carbamic acid esers-Comparison with transkarbam 12.Bioorg Med Chem Lett,2006,16:1981-1984.
[40]Hrab(?)lek A,Dole(?)al P,V(?)vrov(?) K,et al.Synthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline,clotrimazole,flobufen,and griseofulvin.Pharm Res,2006,23:912-919.
[41]Holas T,Vavrov(?) K,(?)ima M,et al.Synthesis and transdermal permeation-enhancing activity of carbonate and carbamate analogs of transkarbam 12.Bioorg Med Chem,2006,14:7671-7680.
[42]Slepushkin VA,Simoes S,Dazin P,et al.Sterically stabilized pH-sensitive liposomes,Intracellular delivery of aqueous contents and prolonged circulation in vivo.J Biol Chem,1997,272:2382-2388.
[43]Funke AP,Schiller R,Motzkus HW,et al.Transdermal delivery of highly lipophilic drugs:in vitro fluxes of antiestrogens,permeation enhancers,and solvents from liquid formulations.Pharm Res,2002,19:661-668.
[44]Sebastiani P,Nicoli S,Santi P.Effect of latic acid and iontophoresis on drug permeation across rabbit ear skin.Int J Pharm,2005,292:119-126.
[45]Copovi A,Diez-Sales O,Herr(?)ez-Dom(?)nguez,JV,et al.Enhancing effect of alpha-hydroxyacids on “in vitro” permeation across the human skin of compounds with different lipophilicity.Int J Pharm,2006,314:31-36.
[46]Zhang C,Yang Z,Luo J,et al.Effect of cinnamene enhancers on transdermal delivery of ligustrazine hydrochloride.Eur J Pharm Biopharm,2007,67:413-419.
[47]Loden M.Keratolytics.In:Gabard B,Eisner P,Surber C,et al (Eds),Dermatopharmacology of Topical Preparations,Springer,Berlin,pp.2000,225-280.
[48]Barry B W,Bennett SL.Effect of penetration enhancers on the permeation of mannitol,hydrocortisone and progesterone through human skin.J Pharm Pharmacol,1987,39:535-546.
[49]Panchagnula R,Salve PS,Thomas NS,et al.Transdermal delivery of naloxone:effect of water,propylene glycol,ethanol and their binary combinations on permeation through rat skin.Int J Pharm,2001,219:95-105.
[50]Fang L,Numajiri S,Kobayashi D,et al.The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid.Int J Pharm,2003,262:13-22.
[1]Krevelen V,Krevelen DW.Properties of Polymers,Elsevier,Sci.Publ.Co.,Amsterdam,1990.
[2]李俊山,孙军,张大龙.估算橡胶助剂溶解度参数用集团贡献值的研究.橡胶工业,1995,42:393-395.
[3]Obata Y,Li CJ,Fujikawa M,et al.Evaluation and structure-activity relationship of synthesized cyclohexanol derivatives on percutaneous absorption of ketoprofen using artificial neural network.Int J Pharm,2001,212:223-231.
[4]国永敏,李宝宗.链烷烃计算极化率与沸点的关系.苏州大学学报,2000,16:82-85.
[5]Vavrova K,Hrabalek A,Dolezal P,et al.L-Serine and Glycine based ceramide analogues as transdermal permeation enhancers:Polar head sized and hydrogen bonding.Bioorg Med Chem Lett,2003,13:2351-2353.
[6]Negishi J,Takayama K,Higashlyama K,et al.Promoting effect of O-alkylmenthol and Oacylmenthol derivatives on the percutaneous absorption of ketoprofen in rats.STP Pharm Sci,1995,5:156-161.
[7]Fuji M,Takeda Y,Yoshida M,et al.Comparison of skin permeation enhancement by 3-1-menthoxypropane-1,2-diol and l-menthol:The permeation of indomethacin and antipyrine through Yucatan micropig skin and changes in infrared spectra and X-ray diffraction patterns of stratum corneum.Int J Pharm,2003,258:217-233.
[1]Kirschbaum J.High-pressure liquid chromatography of triamcinolone acetonide:effect of different octadecylsilane columns on mobility.J Pharm Sci,1980,69:481-482.
[2]Li GF,Quan YS,Fumio KY.Influence of different layers of skin on the percutaneous absorption of drugs with different lipophilicity.Chin Pharm J,2002,37:833-836.
[3]Strichartz GR.Fundamental properties of local anesthetic Ⅱ Measured octanol:buffer partition coefficients and pka values of clinical used drugs.AneshAnalg,1990,71:58-70.
[4]Morimoto Y.Prediction of skin permeability of drugs:comparison of human and hairless rat skin.J Pharm Pharmacol,1992,44:634-639.
[5]Deppeler HP.Hydrochlorothiazide.In:Florey K(Ed),Analytical Profiles of Drug Substances,Academic press,New York,1981,pp.443-469.
[6]Brodin A,Nyqvist-mayer A,Wadsten T,et al.Phase diagram and aqueous solubility of lidocaine-prilocaine binary system.J Pharm Sci,1984,73:481-484.
[7]Alvalez C,Torrado JJ,Cadorhigna R.Stereoselective drug release from ketoprofen and ricobendazole matrix tablets.Chirality,1999,11:611-615.
[8]HO H,Chen L,Lin H,et al.Penetration enhancement by menthol combined with a solubilization effect in a mixed solvent system.J Control Release,1998,51:301-311.[9]Krevelen V,Krevelen DW.Properties of Polymers,Elsevier,Sci.Publ.Co.,Amsterdam,1990.
[10]李俊山,孙军,张大龙.估算橡胶助剂溶解度参数用集团贡献值的研究.橡胶工业,1995,42:393-395.
[11]彭书泉,刘晓华,崔慧萍.HPLC法测定5-氟尿嘧啶氯化钠注射液的含量.山东医药工业,2002,21:16-17.
[12]邢玉仁,马洁.HPLC法测定硝酸异山梨酯气雾剂的含量及每揿含量.药物分析杂志,1998,5:338-339.
[13]柯光明,王丽,杜洪光,等.高效液相色谱法测定盐酸利多卡因贴剂含量.北京化工大学学报,2004,31:110-112.
[14]张仲元,岳莉,张青萍,等.高效液相色谱法测定酮洛芬贴片的含量及其稳定性研究.沈阳药科大学学报,2000,17:188-190.
[15]杨金荣,韩蕊,董伟林,等.HPLC法测定吲哚美辛巴布剂的含量.天津药学,2006,18:62-64.
[16]Sheth NV,Freeman DJ,Higuchi WI,et al.The influence of Azone,propylene glycol and polyethylene glycol on in vitro skin penetration of trifluorothymidine.Int J Pharm,1986,28:201-209.
[17]Nakamura Y,Takayama K,Higashiyama K,et al.Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen.Int J Pharm,1996,145:29-36.
[18]Lee PJ,Ahmad N,Langer R,et al.Evaluation of chemical enhancers in the transdermal delivery of lidocaine.Int J Pharm,2006,308:33-39.
[19]Leichtnam ML,Rolland H,Wüthrich P,et al.Identification of penetration enhancers for testosterone transdermal delivery from spray formulations.J Control Release,2006,113:57-62.
[20]Guy RH,Hadgraft J.Transdermal drug delivery:a simplified pharmacokinetic approach.Int J Pharm,1985,24:267-274.
[21]Fang L,Numajiri S,Kobayashi D,et al.The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid.Int J Pharm,2003,262:13-22.
[22]Izumoto T,Aioi A,Uenoyama S,et al.Relationship between the transference of a drug from a transdermal patch and the physicochemical properties.Chem Pharm Bull,1992,40:456-458.
[23]Monene LM,Goosen C,Breytenbach JC,et al.Percutaneous absorption of cyclizine and its alkyl analogues,Eur J Pharm Sci,2005,24:239-244.
[24]Hori M,Satoh S,Maibach HI,et al.Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro:effect of enhancer lipophilicity.J Pharm Sci,1991,80:32-35.
[25]Wenkers BP,Lippold BC.Skin pernetration of non-steroidal anti-inflammatory drugs out of a lipophilic vehicle:influence of the viable epidermis.J Pharm Sci,1999,88:1326-1331.
[26]Williams AC,Barry BW.Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement.Pharm Res,1991,8:17-24.
[27]Dias M,Hadgraft J,Lane ME.Influence of membrane-solvent-solute interactions on solute permeation in skin.Int J Pharm,2007,340:65-70
[28]Brodin A,Nyqvist-mayer A,Wadsten T.Phase diagram and aqueous solubility of lidocaine-prilocaine binary system.J Pharm Sci,1984,73:481-484.
[29]Gao S,Singh J.Mechanism of transdermal transport of 5-fluorouracil by terpenes:Carvone,1,8-cineole and thymol.Int J Pharm,1997,154:67-77.
[30]Cornwell PA,Barry BW.Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil.J Pharm Pharmacol,1994,46:261-269.
[31]Okamoto H,Ohyabu M,Hashida M,et al.Enhanced penetration of mitomycin C through hairless mouse and rat skin by enhancers with terpene moieties.J Pharm Pharmacol,1987,39:531-534.
[32]Sekura DL,James S.The percutaneous absorption of alkyl methyl sulfoxides.Adv Biol Skin,1972,12:257-269.
[33]Cooper ER.Increased skin permeability for lipophilic molecules.J Pharm Sci,1984,73:1153-1156.
[34]Kanikkannan N,Kandimalla K,Lamba SS,et al.Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery.Curr Med Chem,2000,7:593-608.
[35]Marjukka S.T,Bouwstra JA,Urtti A.Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations.J Control Release,1999,59:149-161.
[36]Cal K,Janicki S,Sznitowska M.In vitro studies on penetration of terpenes from matrix-type transdermal sytems through human skin.Int J Pharm,2001,224:81-88.
[37]Cornwell PA,Barry BW,Bouwstra JA,et al.Modes of action of terpene penetration enhancers in human skin;differential scanning calorimetry,small-angle X-ray diffraction and enhancer uptake studies.Int J Pharm,1996,127:9-26.
[38]Sebastiani P,Nicoli S,Santi P.Effect of latic acid and iontophoresis on drug permeation across rabbit ear skin.Int J Pharm,2005,292:119-126.
[39]Copoví A,Díez-Sales O,Herráez-Domínguez JV,et al.Enhancing effect of alpha-hydroxyacids on "in vitro" permeation across the human skin of compounds with different lipophilicity.Int J Pharm,2006,314:31-36.
[40]Zhang C,Yang Z,Luo J,et al.Effect of cinnamene enhancers on transdermal delivery of ligustrazine hydrochloride.Eur J Pharm Biopharm,2007,67:413-419.
[41]Loden M.Keratolytics.In:Gabard B,Eisner P,Surber C,et al(Eds),Dermatopharmacology of Topical Preparations,Springer,Berlin,2000,pp.225-280.
[42]Barry B W.Bennett SL.Effect of penetration enhancers on the permeation of mannitol,hydrocortisone and progesterone through human skin.J Pharm Pharmacol,1987,39:535-546.
[43]Vaddi HK,Ho PC,Chan SY.Terpenes in propylene glycol as skin-penetration enhancers:permeation and partition of haloperidol,Fourier transform infrared spectroscopy,and differential scanning calorimetry.J Pharm Sci,2002,91:1639-1651.
[44]Kang L,Ho PC,Chan SY.Interactions between a skin penetration enhancer and the main compoents of human stratum corneum lipids.Isothermal titration calorimetry study.J Therm Anal Calorimetry,2006,83:27-30.
[45]Kraeling MEK,Bronaugh RL.In vitro percutaneous absorption of alpha hydroxyl acids in human skin.J Soc Cosmet.Chem,1997,48:187-197.
[46]Hrab(?)lek A,V(?)vrov(?) K,Dole(?)al P,et al.Esters of 6-aminohexanoic acid as skin permeation enhancers:the effect of branching in the alkanol moiety.J Pharm Sci,2005,94:1494-1499.
[47]Narishetty ST,Panchagnula R.Transdermal delivery of zidovudine:effect of terpenes and their mechanism of action.J Control Release,2004,95,367-379.
[48]Jain AK,Thomas NS,Panchagnula R.Transdermal drug delivery of imipramine hydrochloride I.Effect of terpenes.J Control Release,2002,79:93-101.
[49]Song JF,Lau-cam CA,Kim KH.Monohydroxylation and esterification as determinants of the effects of cis- and trans-9-octadecenoic acids on the permeation of hydrocortisone and 5-fluororacil across hairless mouse skin in vitro.Int J Pharm,2001,212,153-160.
[50]Yamashita F,Bando M,Koyama Y,et al.In vitro and in vivo analysis of skin penetration enhancement based on a two-layer diffusion model with polar and nonpolar routes in the stratum corneum.Pharm Res,1994,11:185-191.
[51]Yamashita F,Koyama Y,Kitano M,et al.Analysis of in vivo skin penetration enhancement by oleic acid based on a two-layer diffusion model with polar and nonpolar routes in the stratum corneum.Int J Pharm,1995,117:173-179.
[52]Golden GM,Mckie JE,Potts RO,et al.Role of stratum corneum lipid fluidity in transdermal drug flux.J Pharm Sci,1987,76:25-28.
[53]Blank IH,Scheuplein RJ,MacFarlane DJ.Mechanism of percutaneous absorption.3.The effect of temperature on the transport of non-electrolytes across the skin.Invest Dermatol,1967,49:582-589.
[1]Kraus CA.The ion pair concept:Its evolution and some applications.J Phys Chem,1956,60:129-141.
[2]Hatanaka T,Kamon T,Morigaki S,et al.Ion pair skin transport of a zwitterionic drug,cephalexin.J Control Release,2000,66:63-71.
[3]Trotta M,Ugazio E,Peira E,et al.Influence of ion pairing on topical delivery of retinoic acid from microemulsions.J Control Release,2003,86:315-321.
[4]Megwa SA,Cross SE,Benson HAE,et al.Ion-pair formation as a strategy to enhance topical delivery of salicylic acid.J Pharm Pharmacol,2000,52:919-928.
[5]Megwa SA,Cross SE,Whitehouse MW,et al.Effect of ion pairing with alkylamines on the in-vitro
dermal penetration and local tissue disposition of salicylates.J Pharm Pharmacol,2000,52:929-940.
[6]Fang L,Kobayashi Y,Numajiri S,et al.The enhancing effect of a triethanolamine-ethanol-isopropyl myristate mixed system on the skin permeation of acidic drugs.Biol Pharm Bull,2002,25:1339-1344.
[7]Cavallari C,Rodriguez L,Albertini B,et al.Thermal and fractal analysis of diclofenac/gelucire 50/13microparticles obtained by ultransound-assisted atomization.J Pharm Sci,2005,94:1124-1134.
[8]Fini A,Fazio G,Benetti L,et al.Diclofenac Salts.IV.Thermal analysis of some diclofenac salts with alkyl and alkylhydroxy amines.Thermochimica Acta,2007,464,65-74.
[9]Fini A,Garuti M,Fazio G,et al.Diclofenac salts.I.fractal and thermal analysis of sodium and potassium diclofenac salts.J Pharm Sci,2001,90:2049-2057.
[10]O'Connor KM,Corrigan OI.Comparison of the physicochemical properties of the N-(2-hydroxyethyl) pyrrolidine,diethylamine and sodium salt forms of diclofenac.Int J Pharm,2001,222:281-293.
[11]郑凯.HPLC法测定双氯芬酸钠肠溶片的含量.西北药学杂志,2005,20:6-7.
[12]Sugibayashi K,Nakayama S,Seki T,et al.Mechanism of skin penetration enhancing effect by laurocapram.J Pharm Sci,1992,81:58-64.
[13]Aungst BJ,Rogers NJ,Shefter E.Enhancement of naloxone penetration through human skin in vitro using fatty acids,fatty alcohols,surfactants,sulfoxides and amides.Int J Pharm,1986,33:225-234.
[14]Roberts MS,Cross SE,Pellett MA.Skin transport in dermatological and transdermal fourmulations.In:Walters,K.A.(Ed),Dermatological and Transdermal Formulations.Marcel Dekker,New York,2002,pp.89-185.
[15]Plessis JD,Pugh WJ,Judefeind A,et al.The effect of hydrogen bonding on diffusion across model membranes:consideration of the number of H-bonding groups.Eur J Pharm Sci,2001,13,135-141.
[16]Wertz,PW.Epidermal lipids.Semin Dermatol,1992,11:106-113.
[17]Pugh Wj,Roberts MS,Hadgraft J.Epidermal permeability-penetrant structure relationships.3.The effect of hydrogen-bonding interactions and molecular-size on diffusion across the stratum-corneum.Int J Pharm,1996,138:149-165.
[18]Plessis JD,Pugh WJ,Judefeind A,et al.Physico-chemical determinants of dermal drug delivery:effects of the number and substitution pattern of polar groups.Eur J Pharm Sci,2002,16:107-112.
[19]Izumoto T,Aioi A,Uenoyama S,et al.Relationship between the transference of a drug from a transdermal patch and the physicochemical properties.Chem Pharm Bull,1992,40:456-458.
[20]Kaplun-Frischoff Y,Touitou E.Testosterone skin permeation enhancement by menthol through the formation of a eutectic with drug and interaction with skin lipids.J Pharm Sci,1997,86:1349-1399.
[21]Stott W,Williams AC,Barry BW.Transdermal delivery from eutectic systems:enhanced permeation of a model drug,ibuprofen.J Control Release,1997,50:297-308.
[22]Monene LM,Goosen C,Breytenbach JC,et al.Percutaneous absorption of cyclizine and its alkyl analogues.Eur J Pharm Sci,2005,24:239-244.
[1]Abrams P,Freeman R,Anderstrom C,et al.Tolterodine,a new antimuscarinic agent:as effective but better tolerated than oxybutynin in patients with an overactive bladder.Br J Urol,1998,81:801-810.
[2]Wefer J,Truss MC,Jonas U.Tolterodine:an overiew.Word J Urol,2001,19:312-318.
[3]周忠宏.HPLC法测定酒石酸托特罗定原料含量.齐鲁药事,2008,27:466-467.
[4]Tan HS,Pfister WR.Pressure-sensitive adhesives for transdermal drug delivery systems.Pharm Sci Technolo Today,1999,2:60-69.
[5]Guy RH,Hadgraft J.Rate control in transdermal delivery.Int J Pharm,1992,82:R1-R6
[6]Kubota K,Maibach HI.Significance of viable skin layers in percutaneous absorption and its implication in mathematical models:theoretical consideration based on parameters for betamethasone 17-valerate.J Pharm Sci,1994,83:1300-1306.
[7]Kemppainen B W,Reifenrath WG,Stafford RG,et al.Methods for in vitro skin absorption studies of a lipophilic toxin produced by red tide.Toxicology,1991,66:1-17.
[8]Bronaugh RL,Collier SW.Protocol for in vitro percutaneous absorption studies.In:Bronaugh RL,Maibach HI(Eds.),In Vitro Percutaneous Absorption:Principles,Fundamentals,and Applications,CRC Press,Boston,1991,pp.237-241.
[9]Hai NT,Kim J,Park ES,et al.Formulation and biopharmaceutical evaluation of transdermal patch containing benztropine.Int J Pharm,2008,357:55-60.
[10]Guyot M,Fawaz F.Design and in vitro evaluation of adhesive matrix for transdermal delivery of propranolol.Int J Pharm,2000,204:171-182.
[11]Cho YJ,Choi HK.Enhancement of percutaneous absorption of ketoprofen:effect of vehicles and adhesive matrix.Int J Pharm,1998,169:95-104.
[12]Kim JH,Cho YJ,Choi HK.Effect of vehicles and pressure sensitive adhesives on the permeation of tacrine across hairless mouse skin.Int J Pharm,2000,196:105-113.
[13]Cheong HA,Choi HK.Effect of ethanolamine salts and enhancers on the percutaneous absorption of piroxicam from a pressure sensitive adhesive matrix.Eur J Pharm Sci,2003,18:149-153.
[14]Zhang B,Zhang Z,Tian Y,et al.High performance liquid chromatography-electrospray ionization mass spectrometric determination of tolterodine tartrate in human plasma.J Chromatogr B,2005,824:92-98.
[15]Valiverti S,Hammell DC,Paudel IS,et al.In vivo evaluation of 3-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs.J Control Release,2005,102:509-520.
[1]Pilgram GS,VanPelt AM,Spies F,et al.Cryo-electron diffraction as a tool to study local variations in the lipidorganization of human stratum corneum.J Microsc,1998,189:71-78.
[2]Sweeny TM,Downing DT.The role of the lipids in the epidermal barrier to water diffusion.J Invest Dermato,1970,55:135-140.
[3]Moghimi HR,Williams AC,Barrry BW.A lamellar matrix model for stratum corneum intercellular lip ids.Ⅱ.Effect of geometry of the stratum corneum on permeation of model drugs 5-fluorouracil and oestradiol.IntJPharm,1996,131:117-129.
[4]Boddé HE,Van den Brìnk I,Koerten HK,et al.Visualization of in vitro percutaneous penetration of mercuric chloride transport through intercellular space versus cellular up take through desmosomes.J Control Release,1991,15:227-236.
[5]Tumbleson ME.In:Swine in Biomedical Research,Plenum Press,New York,1986,pp.641-655..
[6]Abdullah D,平其能,刘国杰.精油对5-Fu渗透大鼠皮肤的促进作用.药学学报,1996,31:214-221.
[7]Fang L,Numajiri S,Kobayshi D,et al.The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid.Int J Pharm,2003,262:13-22.
[8]Fang JY,Hwang TL,Leu YL.Effect of enhancers and retarders on percutaneous absorption of flurbiprofen from hydrogels.Int J Pharm,2003,250:313-325.
[9]Fang C,Liu Y,Ye X,et al.Synergistically enhanced transdermal permeation and topical analgesia of tetracaine gel containing menthol and ethanol in experimental and clinical studies.Eur J Pharm Biopharm,2008,68:735-740.
[10]Obata Y,Hatta I,Ohta N,et al.Combined effects of ethanol and L-menthol on hairless rat stratum corneum investigated by sunchrotron X-ray diffraction.J Control Release,2006,115:275-279.
[11]Krishnaiah YSR,Satyanarayana V,Karthikeyan RS.Effect of the solvent system on the in vitro permeability of nicardipine hydrochloride through excised rat epidermis.J Pharm Pharmaceut Sci,2002,5:124-130.
[12]张春凤,杨中林,罗佳波.D-柠檬烯和L-柠檬烯对盐酸川芎嗪透皮吸收的影响.药学学报,2006,41:772-777..
[13]Bhatia KS,Singh J.Mechanism of transport enhancement of LHRH through porcine epidermis by terpenes and iontophoresis:permeability and lipid extraction studies.Pharm Res,1998,15:1857-1862.
[14]Takahashi K,Sakano H,Yoshida M,et al.Characterization of the influence of polyol fatty acid esters on the permeation of diclofenac through rat skin.J Control Release,2001,73:351-358.
[15]Naik A,Pechtold LARM,Pottos RO,et al.Mechanism of oleic acid in duced skin penetration enhancement in vivo in humans.J Control Release,1995,37:299-306.
[16]Tanojo H,Junginger HE,Bodde HE.In vivo human skin permeability enhancement by oleic acid:transepidermal water loss and fourier-transform infrared spectroscopy studies.J Control Release,1997,47:31-39.
[17]Lin SY,Duan KJ,Lin TC.Microscopic FT-IR/DSC system used to simultaneously investigate the conversion process of protein structure in porcine stratum corneum after pretreatment with skin penetration enhancers.Methods Find Exp Clin Pharmacol,1996,18:175-181.
[2]Barry BW.Novel mechanisms and devices to enable suc-cessful transdermal drug delivery.Eur J Pharm Sci,2001,14:101-114.
[3]Williams AC,Barry B W.Penetration enhancers.Adv Drug Dev Rev,2004,56:603-618.
[4]Valiveti S,Dana CH,Paudel KS,et al.In vivo evaluation of 3-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs.J Control Release,2005,102:509-520
[5]Knoblauch P,Moll F,In vitro pulsatile and continuous transdermal delivery of buserelin by iontophoresis.J Control Release,1993,26:203-211.
[6]Vanbever R,Lecouturier N,Preat V.Transdermal delivery of metoprool by electroporation.Pharm Res,1994,11:1657-1662.
[7]Mitragotri S,Blankschtein D,Langer R.Ultrasound-mediated transdermal protein delivery.Science,1995,269:850-853.
[8]Henry S,Mcallister,DV,Allen MG,et al.Microfabricated microneedles:a novel approach to transdermal drug delivery.J Pharm Sci,1998,87:922-928.
[9]Mezei M,Gulusekharam V.Liposomes--a selective drug delivery system for the topical route of administration,lotion dosage form.Life Sci,1980,26:1473-1477.
[10]Tu JB,Yang ZQ,He XJ,et al.Effect of ethosomal minoxidil on dermal delivery and hair cycle of C57BL/6 mice.J Dermatol Sci,2007,45:135-137.
[11]Moreno MA,Ballesteros MP,Frutos P.Lecithin-based oil-in-water microemulsion for parenteral use:pseudoternary phase diagrams,characterization and toxicity studies.J Pharm Sci,2003,92:1428-1437.
[12]de Jaron EG,Blanco-Prieto MJ,Ygartua P,et al.PLGA microparticles:possible vehicles for topical drug delivery.Int J Pharm,2001,226:181-184.
[13]Thakur RA,Wang Y,Michniak BB.Essential oils and terpenes,In:Smith EW,Maibach HI(Eds),Percutaneous Penetration Enhancers,CRC Press,Boca Raton,2006,pp.159-173.
[14]Gao S,Singh J.In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes.J Control Release,1998,51:193-199.
[15]Thomas S,Narishetty K,Panchagnula R.Transdermal delivery of zidovudine:effect of terpenes and their mechanism of action.J Control Release,2004,95:367-379.
[16]Morimoto Y,Wada Y,Seki T.In vitro permeation of morphine hydrochloride during the finite application of penetration-enhancing system containing water,ethanol and l-menthol.Biol Pharm Bull,2002,25:134-136.
[17]殷立新,刘宝库．薄荷醇的促透皮吸收作用．中国医药工业杂志,1999,2：15-19．
[18]Williams AC,Barry BW.Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement.Pharm Res,1991,8:17-24.
[19]Walters KA,Roberts MS.Veterinary applications of skin penetration enhancers.In:Walters KA,Hadgraft J (Eds),Pharmaceutical Skin Penetration Enhancement,Marcel Dekker,New York,1993,pp.113-143.
[20]Chan TCK.Percutaneous penetration enhancers:An update.The proceedings of the 9th Biennial International Conference of Perspectives in Percutaneous Penetration,2004,La Grand Motte,France.
[21]Yamane MA,Williams AC,Barry BW.Effects of terpenes and oleic acid as skin penetration enhancers towards 5-fluorouracil as assessed with time;permeation,partitioning and differential scanning calorimetry.Int J Pharm,1995,116:237-51.
[22]Cornwell PA,Barry B W.The routes of penetration of ions and 5-fluorouracil across human skin and the mechanisms of action of terpene skin penetration enhancers.Int J Pharm,1993,94:189-194
[23]Kitagawa S,Hosokai,Kaseda Y,et al.Permeability of benzoic acid derivatives in excised guinea pig dorsal skin and effects of 1-menthol.Int J Pharm,161:115-122.
[24]Narishetty ST,Panchagnula R.Transdermal delivery of zidovudine:effect of terpenes and their mechanism of action.J Control Release,2004,95:367-79.
[25]Negishi J,Takayama K,Higashlyama K,et al.Promoting effect of O-alkylmenthol and O-acylmenthol derivatives on the percutaneous absorption of ketoprofen in rats.STP Pharm Sci,1995,5:156-161.
[26]Nakamura Y,Takayama K,Higashiyama K,et al.Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen.Int J Pharm,1996,145:29-36.
[27]Obata Y,Sato H,Li CJ,et al.Effect of synthesized cyclohexanol derivatives using L-menthol as a lead compound on the pecutaneous absorption of ketoprofen.Int J Pharm,2000,198:191-2000.
[28]Obata Y,Li CJ,Fujikawa M,et al.Evaluation and structure-activity relationship of synthesized cyclohexanol derivatives on percutaneous absorption of ketoprofen using artificial neural network.Int J Pharm,2001,212:223-231.
[29]Takanashi Y,Higashiyama K,Komiya H,et al.Thiomenthol derivatives as novel percutaneous absorption enhancers.Drug Devel Ind Pharm,1999,25:89-94.
[30]Fuji M,Takeda Y,Yoshida M,et al.Comparison of skin permeation enhancement by 3-1-menthoxypropane-1,2-diol and l-menthol:The permeation of indomethacin and antipyrine through Yucatan micropig skin and changes in infrared spectra and X-ray diffraction patterns of stratum corneum.Int J Pharm,2003,258:217-233.
[31]Montagna,WJ.Histology and cytochemistry of human skin.Ⅸ.The distribution of non-specific esterases.Biophys Biochem Cytol,1995,1:13-16.
[32]Wong O,Huntington J,Konishi R,et al.Unsaturated cyclic ureas as new nontoxic biodegradable transdermal penetration enhancers Ⅰ:Synthesis.J Pharm Sci,1988,77:967-971.
[33]Wong O,Tsuzuki N,Nghiem B,et al.Unsaturated cyclic ureas as new non-toxic biodegradable transdermal penetration enhancers.Ⅱ.Evaluation study.Int J Pharm,1989,52:191-202.
[34]Wong O,Huntington J,Nishihaa T,et al.New alkyl N,N-dialkyl-substituted amino acetates as transdermal penetration enhancers.Pharm Res,1989,6,286-295.
[35]Michniak BB,Chapman JM,Seyda KL.Facilitated transport of two model steroids by esters and amides of clofibric acid.J Pharm Sci,1993,82:214-219.
[36]Wertz PW.The nature of the epidermal barrier:biochemical aspects.Adv Drug Deliv Rev,1996,18:283-294.
[37]V(?)vrov(?) K,Hrab(?)lek A,Dole(?)al P,et al.L-Serine and Glycine based ceramide analogues as transdermal permeation enhancers:Polar head sized and hydrogen bonding.Bioorg Med Chem Lett,2003,13:2351-2353.
[38]V(?)vrov(?) K,Hrab(?)lek A,Dole(?)al P,et al.Biodegradable derivatives of tranexamic acid as transdermal permeation enhancers.J Control Release,2005,104:41-49.
[39]Klimentov(?) J,Hrab(?)lek A,V(?)vrov(?) K,et al.Synthesis and transdermal penetration-enhancing activity of carbonic and carbamic acid esers-Comparison with transkarbam 12.Bioorg Med Chem Lett,2006,16:1981-1984.
[40]Hrab(?)lek A,Dole(?)al P,V(?)vrov(?) K,et al.Synthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline,clotrimazole,flobufen,and griseofulvin.Pharm Res,2006,23:912-919.
[41]Holas T,Vavrov(?) K,(?)ima M,et al.Synthesis and transdermal permeation-enhancing activity of carbonate and carbamate analogs of transkarbam 12.Bioorg Med Chem,2006,14:7671-7680.
[42]Slepushkin VA,Simoes S,Dazin P,et al.Sterically stabilized pH-sensitive liposomes,Intracellular delivery of aqueous contents and prolonged circulation in vivo.J Biol Chem,1997,272:2382-2388.
[43]Funke AP,Schiller R,Motzkus HW,et al.Transdermal delivery of highly lipophilic drugs:in vitro fluxes of antiestrogens,permeation enhancers,and solvents from liquid formulations.Pharm Res,2002,19:661-668.
[44]Sebastiani P,Nicoli S,Santi P.Effect of latic acid and iontophoresis on drug permeation across rabbit ear skin.Int J Pharm,2005,292:119-126.
[45]Copovi A,Diez-Sales O,Herr(?)ez-Dom(?)nguez,JV,et al.Enhancing effect of alpha-hydroxyacids on “in vitro” permeation across the human skin of compounds with different lipophilicity.Int J Pharm,2006,314:31-36.
[46]Zhang C,Yang Z,Luo J,et al.Effect of cinnamene enhancers on transdermal delivery of ligustrazine hydrochloride.Eur J Pharm Biopharm,2007,67:413-419.
[47]Loden M.Keratolytics.In:Gabard B,Eisner P,Surber C,et al (Eds),Dermatopharmacology of Topical Preparations,Springer,Berlin,pp.2000,225-280.
[48]Barry B W,Bennett SL.Effect of penetration enhancers on the permeation of mannitol,hydrocortisone and progesterone through human skin.J Pharm Pharmacol,1987,39:535-546.
[49]Panchagnula R,Salve PS,Thomas NS,et al.Transdermal delivery of naloxone:effect of water,propylene glycol,ethanol and their binary combinations on permeation through rat skin.Int J Pharm,2001,219:95-105.
[50]Fang L,Numajiri S,Kobayashi D,et al.The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid.Int J Pharm,2003,262:13-22.
[1]Krevelen V,Krevelen DW.Properties of Polymers,Elsevier,Sci.Publ.Co.,Amsterdam,1990.
[2]李俊山,孙军,张大龙.估算橡胶助剂溶解度参数用集团贡献值的研究.橡胶工业,1995,42:393-395.
[3]Obata Y,Li CJ,Fujikawa M,et al.Evaluation and structure-activity relationship of synthesized cyclohexanol derivatives on percutaneous absorption of ketoprofen using artificial neural network.Int J Pharm,2001,212:223-231.
[4]国永敏,李宝宗.链烷烃计算极化率与沸点的关系.苏州大学学报,2000,16:82-85.
[5]Vavrova K,Hrabalek A,Dolezal P,et al.L-Serine and Glycine based ceramide analogues as transdermal permeation enhancers:Polar head sized and hydrogen bonding.Bioorg Med Chem Lett,2003,13:2351-2353.
[6]Negishi J,Takayama K,Higashlyama K,et al.Promoting effect of O-alkylmenthol and Oacylmenthol derivatives on the percutaneous absorption of ketoprofen in rats.STP Pharm Sci,1995,5:156-161.
[7]Fuji M,Takeda Y,Yoshida M,et al.Comparison of skin permeation enhancement by 3-1-menthoxypropane-1,2-diol and l-menthol:The permeation of indomethacin and antipyrine through Yucatan micropig skin and changes in infrared spectra and X-ray diffraction patterns of stratum corneum.Int J Pharm,2003,258:217-233.
[1]Kirschbaum J.High-pressure liquid chromatography of triamcinolone acetonide:effect of different octadecylsilane columns on mobility.J Pharm Sci,1980,69:481-482.
[2]Li GF,Quan YS,Fumio KY.Influence of different layers of skin on the percutaneous absorption of drugs with different lipophilicity.Chin Pharm J,2002,37:833-836.
[3]Strichartz GR.Fundamental properties of local anesthetic Ⅱ Measured octanol:buffer partition coefficients and pka values of clinical used drugs.AneshAnalg,1990,71:58-70.
[4]Morimoto Y.Prediction of skin permeability of drugs:comparison of human and hairless rat skin.J Pharm Pharmacol,1992,44:634-639.
[5]Deppeler HP.Hydrochlorothiazide.In:Florey K(Ed),Analytical Profiles of Drug Substances,Academic press,New York,1981,pp.443-469.
[6]Brodin A,Nyqvist-mayer A,Wadsten T,et al.Phase diagram and aqueous solubility of lidocaine-prilocaine binary system.J Pharm Sci,1984,73:481-484.
[7]Alvalez C,Torrado JJ,Cadorhigna R.Stereoselective drug release from ketoprofen and ricobendazole matrix tablets.Chirality,1999,11:611-615.
[8]HO H,Chen L,Lin H,et al.Penetration enhancement by menthol combined with a solubilization effect in a mixed solvent system.J Control Release,1998,51:301-311.[9]Krevelen V,Krevelen DW.Properties of Polymers,Elsevier,Sci.Publ.Co.,Amsterdam,1990.
[10]李俊山,孙军,张大龙.估算橡胶助剂溶解度参数用集团贡献值的研究.橡胶工业,1995,42:393-395.
[11]彭书泉,刘晓华,崔慧萍.HPLC法测定5-氟尿嘧啶氯化钠注射液的含量.山东医药工业,2002,21:16-17.
[12]邢玉仁,马洁.HPLC法测定硝酸异山梨酯气雾剂的含量及每揿含量.药物分析杂志,1998,5:338-339.
[13]柯光明,王丽,杜洪光,等.高效液相色谱法测定盐酸利多卡因贴剂含量.北京化工大学学报,2004,31:110-112.
[14]张仲元,岳莉,张青萍,等.高效液相色谱法测定酮洛芬贴片的含量及其稳定性研究.沈阳药科大学学报,2000,17:188-190.
[15]杨金荣,韩蕊,董伟林,等.HPLC法测定吲哚美辛巴布剂的含量.天津药学,2006,18:62-64.
[16]Sheth NV,Freeman DJ,Higuchi WI,et al.The influence of Azone,propylene glycol and polyethylene glycol on in vitro skin penetration of trifluorothymidine.Int J Pharm,1986,28:201-209.
[17]Nakamura Y,Takayama K,Higashiyama K,et al.Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen.Int J Pharm,1996,145:29-36.
[18]Lee PJ,Ahmad N,Langer R,et al.Evaluation of chemical enhancers in the transdermal delivery of lidocaine.Int J Pharm,2006,308:33-39.
[19]Leichtnam ML,Rolland H,Wüthrich P,et al.Identification of penetration enhancers for testosterone transdermal delivery from spray formulations.J Control Release,2006,113:57-62.
[20]Guy RH,Hadgraft J.Transdermal drug delivery:a simplified pharmacokinetic approach.Int J Pharm,1985,24:267-274.
[21]Fang L,Numajiri S,Kobayashi D,et al.The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid.Int J Pharm,2003,262:13-22.
[22]Izumoto T,Aioi A,Uenoyama S,et al.Relationship between the transference of a drug from a transdermal patch and the physicochemical properties.Chem Pharm Bull,1992,40:456-458.
[23]Monene LM,Goosen C,Breytenbach JC,et al.Percutaneous absorption of cyclizine and its alkyl analogues,Eur J Pharm Sci,2005,24:239-244.
[24]Hori M,Satoh S,Maibach HI,et al.Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro:effect of enhancer lipophilicity.J Pharm Sci,1991,80:32-35.
[25]Wenkers BP,Lippold BC.Skin pernetration of non-steroidal anti-inflammatory drugs out of a lipophilic vehicle:influence of the viable epidermis.J Pharm Sci,1999,88:1326-1331.
[26]Williams AC,Barry BW.Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement.Pharm Res,1991,8:17-24.
[27]Dias M,Hadgraft J,Lane ME.Influence of membrane-solvent-solute interactions on solute permeation in skin.Int J Pharm,2007,340:65-70
[28]Brodin A,Nyqvist-mayer A,Wadsten T.Phase diagram and aqueous solubility of lidocaine-prilocaine binary system.J Pharm Sci,1984,73:481-484.
[29]Gao S,Singh J.Mechanism of transdermal transport of 5-fluorouracil by terpenes:Carvone,1,8-cineole and thymol.Int J Pharm,1997,154:67-77.
[30]Cornwell PA,Barry BW.Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil.J Pharm Pharmacol,1994,46:261-269.
[31]Okamoto H,Ohyabu M,Hashida M,et al.Enhanced penetration of mitomycin C through hairless mouse and rat skin by enhancers with terpene moieties.J Pharm Pharmacol,1987,39:531-534.
[32]Sekura DL,James S.The percutaneous absorption of alkyl methyl sulfoxides.Adv Biol Skin,1972,12:257-269.
[33]Cooper ER.Increased skin permeability for lipophilic molecules.J Pharm Sci,1984,73:1153-1156.
[34]Kanikkannan N,Kandimalla K,Lamba SS,et al.Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery.Curr Med Chem,2000,7:593-608.
[35]Marjukka S.T,Bouwstra JA,Urtti A.Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations.J Control Release,1999,59:149-161.
[36]Cal K,Janicki S,Sznitowska M.In vitro studies on penetration of terpenes from matrix-type transdermal sytems through human skin.Int J Pharm,2001,224:81-88.
[37]Cornwell PA,Barry BW,Bouwstra JA,et al.Modes of action of terpene penetration enhancers in human skin;differential scanning calorimetry,small-angle X-ray diffraction and enhancer uptake studies.Int J Pharm,1996,127:9-26.
[38]Sebastiani P,Nicoli S,Santi P.Effect of latic acid and iontophoresis on drug permeation across rabbit ear skin.Int J Pharm,2005,292:119-126.
[39]Copoví A,Díez-Sales O,Herráez-Domínguez JV,et al.Enhancing effect of alpha-hydroxyacids on "in vitro" permeation across the human skin of compounds with different lipophilicity.Int J Pharm,2006,314:31-36.
[40]Zhang C,Yang Z,Luo J,et al.Effect of cinnamene enhancers on transdermal delivery of ligustrazine hydrochloride.Eur J Pharm Biopharm,2007,67:413-419.
[41]Loden M.Keratolytics.In:Gabard B,Eisner P,Surber C,et al(Eds),Dermatopharmacology of Topical Preparations,Springer,Berlin,2000,pp.225-280.
[42]Barry B W.Bennett SL.Effect of penetration enhancers on the permeation of mannitol,hydrocortisone and progesterone through human skin.J Pharm Pharmacol,1987,39:535-546.
[43]Vaddi HK,Ho PC,Chan SY.Terpenes in propylene glycol as skin-penetration enhancers:permeation and partition of haloperidol,Fourier transform infrared spectroscopy,and differential scanning calorimetry.J Pharm Sci,2002,91:1639-1651.
[44]Kang L,Ho PC,Chan SY.Interactions between a skin penetration enhancer and the main compoents of human stratum corneum lipids.Isothermal titration calorimetry study.J Therm Anal Calorimetry,2006,83:27-30.
[45]Kraeling MEK,Bronaugh RL.In vitro percutaneous absorption of alpha hydroxyl acids in human skin.J Soc Cosmet.Chem,1997,48:187-197.
[46]Hrab(?)lek A,V(?)vrov(?) K,Dole(?)al P,et al.Esters of 6-aminohexanoic acid as skin permeation enhancers:the effect of branching in the alkanol moiety.J Pharm Sci,2005,94:1494-1499.
[47]Narishetty ST,Panchagnula R.Transdermal delivery of zidovudine:effect of terpenes and their mechanism of action.J Control Release,2004,95,367-379.
[48]Jain AK,Thomas NS,Panchagnula R.Transdermal drug delivery of imipramine hydrochloride I.Effect of terpenes.J Control Release,2002,79:93-101.
[49]Song JF,Lau-cam CA,Kim KH.Monohydroxylation and esterification as determinants of the effects of cis- and trans-9-octadecenoic acids on the permeation of hydrocortisone and 5-fluororacil across hairless mouse skin in vitro.Int J Pharm,2001,212,153-160.
[50]Yamashita F,Bando M,Koyama Y,et al.In vitro and in vivo analysis of skin penetration enhancement based on a two-layer diffusion model with polar and nonpolar routes in the stratum corneum.Pharm Res,1994,11:185-191.
[51]Yamashita F,Koyama Y,Kitano M,et al.Analysis of in vivo skin penetration enhancement by oleic acid based on a two-layer diffusion model with polar and nonpolar routes in the stratum corneum.Int J Pharm,1995,117:173-179.
[52]Golden GM,Mckie JE,Potts RO,et al.Role of stratum corneum lipid fluidity in transdermal drug flux.J Pharm Sci,1987,76:25-28.
[53]Blank IH,Scheuplein RJ,MacFarlane DJ.Mechanism of percutaneous absorption.3.The effect of temperature on the transport of non-electrolytes across the skin.Invest Dermatol,1967,49:582-589.
[1]Kraus CA.The ion pair concept:Its evolution and some applications.J Phys Chem,1956,60:129-141.
[2]Hatanaka T,Kamon T,Morigaki S,et al.Ion pair skin transport of a zwitterionic drug,cephalexin.J Control Release,2000,66:63-71.
[3]Trotta M,Ugazio E,Peira E,et al.Influence of ion pairing on topical delivery of retinoic acid from microemulsions.J Control Release,2003,86:315-321.
[4]Megwa SA,Cross SE,Benson HAE,et al.Ion-pair formation as a strategy to enhance topical delivery of salicylic acid.J Pharm Pharmacol,2000,52:919-928.
[5]Megwa SA,Cross SE,Whitehouse MW,et al.Effect of ion pairing with alkylamines on the in-vitro
dermal penetration and local tissue disposition of salicylates.J Pharm Pharmacol,2000,52:929-940.
[6]Fang L,Kobayashi Y,Numajiri S,et al.The enhancing effect of a triethanolamine-ethanol-isopropyl myristate mixed system on the skin permeation of acidic drugs.Biol Pharm Bull,2002,25:1339-1344.
[7]Cavallari C,Rodriguez L,Albertini B,et al.Thermal and fractal analysis of diclofenac/gelucire 50/13microparticles obtained by ultransound-assisted atomization.J Pharm Sci,2005,94:1124-1134.
[8]Fini A,Fazio G,Benetti L,et al.Diclofenac Salts.IV.Thermal analysis of some diclofenac salts with alkyl and alkylhydroxy amines.Thermochimica Acta,2007,464,65-74.
[9]Fini A,Garuti M,Fazio G,et al.Diclofenac salts.I.fractal and thermal analysis of sodium and potassium diclofenac salts.J Pharm Sci,2001,90:2049-2057.
[10]O'Connor KM,Corrigan OI.Comparison of the physicochemical properties of the N-(2-hydroxyethyl) pyrrolidine,diethylamine and sodium salt forms of diclofenac.Int J Pharm,2001,222:281-293.
[11]郑凯.HPLC法测定双氯芬酸钠肠溶片的含量.西北药学杂志,2005,20:6-7.
[12]Sugibayashi K,Nakayama S,Seki T,et al.Mechanism of skin penetration enhancing effect by laurocapram.J Pharm Sci,1992,81:58-64.
[13]Aungst BJ,Rogers NJ,Shefter E.Enhancement of naloxone penetration through human skin in vitro using fatty acids,fatty alcohols,surfactants,sulfoxides and amides.Int J Pharm,1986,33:225-234.
[14]Roberts MS,Cross SE,Pellett MA.Skin transport in dermatological and transdermal fourmulations.In:Walters,K.A.(Ed),Dermatological and Transdermal Formulations.Marcel Dekker,New York,2002,pp.89-185.
[15]Plessis JD,Pugh WJ,Judefeind A,et al.The effect of hydrogen bonding on diffusion across model membranes:consideration of the number of H-bonding groups.Eur J Pharm Sci,2001,13,135-141.
[16]Wertz,PW.Epidermal lipids.Semin Dermatol,1992,11:106-113.
[17]Pugh Wj,Roberts MS,Hadgraft J.Epidermal permeability-penetrant structure relationships.3.The effect of hydrogen-bonding interactions and molecular-size on diffusion across the stratum-corneum.Int J Pharm,1996,138:149-165.
[18]Plessis JD,Pugh WJ,Judefeind A,et al.Physico-chemical determinants of dermal drug delivery:effects of the number and substitution pattern of polar groups.Eur J Pharm Sci,2002,16:107-112.
[19]Izumoto T,Aioi A,Uenoyama S,et al.Relationship between the transference of a drug from a transdermal patch and the physicochemical properties.Chem Pharm Bull,1992,40:456-458.
[20]Kaplun-Frischoff Y,Touitou E.Testosterone skin permeation enhancement by menthol through the formation of a eutectic with drug and interaction with skin lipids.J Pharm Sci,1997,86:1349-1399.
[21]Stott W,Williams AC,Barry BW.Transdermal delivery from eutectic systems:enhanced permeation of a model drug,ibuprofen.J Control Release,1997,50:297-308.
[22]Monene LM,Goosen C,Breytenbach JC,et al.Percutaneous absorption of cyclizine and its alkyl analogues.Eur J Pharm Sci,2005,24:239-244.
[1]Abrams P,Freeman R,Anderstrom C,et al.Tolterodine,a new antimuscarinic agent:as effective but better tolerated than oxybutynin in patients with an overactive bladder.Br J Urol,1998,81:801-810.
[2]Wefer J,Truss MC,Jonas U.Tolterodine:an overiew.Word J Urol,2001,19:312-318.
[3]周忠宏.HPLC法测定酒石酸托特罗定原料含量.齐鲁药事,2008,27:466-467.
[4]Tan HS,Pfister WR.Pressure-sensitive adhesives for transdermal drug delivery systems.Pharm Sci Technolo Today,1999,2:60-69.
[5]Guy RH,Hadgraft J.Rate control in transdermal delivery.Int J Pharm,1992,82:R1-R6
[6]Kubota K,Maibach HI.Significance of viable skin layers in percutaneous absorption and its implication in mathematical models:theoretical consideration based on parameters for betamethasone 17-valerate.J Pharm Sci,1994,83:1300-1306.
[7]Kemppainen B W,Reifenrath WG,Stafford RG,et al.Methods for in vitro skin absorption studies of a lipophilic toxin produced by red tide.Toxicology,1991,66:1-17.
[8]Bronaugh RL,Collier SW.Protocol for in vitro percutaneous absorption studies.In:Bronaugh RL,Maibach HI(Eds.),In Vitro Percutaneous Absorption:Principles,Fundamentals,and Applications,CRC Press,Boston,1991,pp.237-241.
[9]Hai NT,Kim J,Park ES,et al.Formulation and biopharmaceutical evaluation of transdermal patch containing benztropine.Int J Pharm,2008,357:55-60.
[10]Guyot M,Fawaz F.Design and in vitro evaluation of adhesive matrix for transdermal delivery of propranolol.Int J Pharm,2000,204:171-182.
[11]Cho YJ,Choi HK.Enhancement of percutaneous absorption of ketoprofen:effect of vehicles and adhesive matrix.Int J Pharm,1998,169:95-104.
[12]Kim JH,Cho YJ,Choi HK.Effect of vehicles and pressure sensitive adhesives on the permeation of tacrine across hairless mouse skin.Int J Pharm,2000,196:105-113.
[13]Cheong HA,Choi HK.Effect of ethanolamine salts and enhancers on the percutaneous absorption of piroxicam from a pressure sensitive adhesive matrix.Eur J Pharm Sci,2003,18:149-153.
[14]Zhang B,Zhang Z,Tian Y,et al.High performance liquid chromatography-electrospray ionization mass spectrometric determination of tolterodine tartrate in human plasma.J Chromatogr B,2005,824:92-98.
[15]Valiverti S,Hammell DC,Paudel IS,et al.In vivo evaluation of 3-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs.J Control Release,2005,102:509-520.
[1]Pilgram GS,VanPelt AM,Spies F,et al.Cryo-electron diffraction as a tool to study local variations in the lipidorganization of human stratum corneum.J Microsc,1998,189:71-78.
[2]Sweeny TM,Downing DT.The role of the lipids in the epidermal barrier to water diffusion.J Invest Dermato,1970,55:135-140.
[3]Moghimi HR,Williams AC,Barrry BW.A lamellar matrix model for stratum corneum intercellular lip ids.Ⅱ.Effect of geometry of the stratum corneum on permeation of model drugs 5-fluorouracil and oestradiol.IntJPharm,1996,131:117-129.
[4]Boddé HE,Van den Brìnk I,Koerten HK,et al.Visualization of in vitro percutaneous penetration of mercuric chloride transport through intercellular space versus cellular up take through desmosomes.J Control Release,1991,15:227-236.
[5]Tumbleson ME.In:Swine in Biomedical Research,Plenum Press,New York,1986,pp.641-655..
[6]Abdullah D,平其能,刘国杰.精油对5-Fu渗透大鼠皮肤的促进作用.药学学报,1996,31:214-221.
[7]Fang L,Numajiri S,Kobayshi D,et al.The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid.Int J Pharm,2003,262:13-22.
[8]Fang JY,Hwang TL,Leu YL.Effect of enhancers and retarders on percutaneous absorption of flurbiprofen from hydrogels.Int J Pharm,2003,250:313-325.
[9]Fang C,Liu Y,Ye X,et al.Synergistically enhanced transdermal permeation and topical analgesia of tetracaine gel containing menthol and ethanol in experimental and clinical studies.Eur J Pharm Biopharm,2008,68:735-740.
[10]Obata Y,Hatta I,Ohta N,et al.Combined effects of ethanol and L-menthol on hairless rat stratum corneum investigated by sunchrotron X-ray diffraction.J Control Release,2006,115:275-279.
[11]Krishnaiah YSR,Satyanarayana V,Karthikeyan RS.Effect of the solvent system on the in vitro permeability of nicardipine hydrochloride through excised rat epidermis.J Pharm Pharmaceut Sci,2002,5:124-130.
[12]张春凤,杨中林,罗佳波.D-柠檬烯和L-柠檬烯对盐酸川芎嗪透皮吸收的影响.药学学报,2006,41:772-777..
[13]Bhatia KS,Singh J.Mechanism of transport enhancement of LHRH through porcine epidermis by terpenes and iontophoresis:permeability and lipid extraction studies.Pharm Res,1998,15:1857-1862.
[14]Takahashi K,Sakano H,Yoshida M,et al.Characterization of the influence of polyol fatty acid esters on the permeation of diclofenac through rat skin.J Control Release,2001,73:351-358.
[15]Naik A,Pechtold LARM,Pottos RO,et al.Mechanism of oleic acid in duced skin penetration enhancement in vivo in humans.J Control Release,1995,37:299-306.
[16]Tanojo H,Junginger HE,Bodde HE.In vivo human skin permeability enhancement by oleic acid:transepidermal water loss and fourier-transform infrared spectroscopy studies.J Control Release,1997,47:31-39.
[17]Lin SY,Duan KJ,Lin TC.Microscopic FT-IR/DSC system used to simultaneously investigate the conversion process of protein structure in porcine stratum corneum after pretreatment with skin penetration enhancers.Methods Find Exp Clin Pharmacol,1996,18:175-181.