酮洛芬凝胶的制备及体外透皮试验

目的 :为避免酮洛芬口服制剂对胃肠道的刺激作用 ,制备酮洛芬凝胶替代其口服制剂。方法 :以乙醇为溶媒 ,用三乙醇胺中和成中性 ,分散于凝胶基质 ,制成凝胶剂。并对该制剂进行含量测定、动物刺激性试验和体外透皮试验。结果 :表明酮洛芬凝胶处方设计合理 ,无刺激性 ,体外透皮效果良好。结论 :初步认为本制剂可替代口服制剂 ,临床效果有待进一步考察。     

Percutaneous absorption of ketoprofen. I. In vitro release and percutaneous absorption of ketoprofen from different ointment bases

Ketoprofen (KP) is a potent non-steroidal anti-inflammatory drug which is used for the treatment of rheumatoid arthritis. The oral administration of KP can cause gastric irritation and renal adverse effects. Topical application of the drug can bypass gastrointestinal disturbances and provide relatively consistent drug levels at the site of action. Since the efficacy of an ointment depends on the type of ointment base and the concentration of the drug, four different bases (white petrolatum, cold cream, hydrophilic ointment and Carbopol 940 gel) were used at 1, 3, 5, 7 and 10% concentrations of KP to evaluate the effect of ointment base and concentration. The general rank order of the drug release was found to be: Carbopol gel > hydrophilic ointment > cold cream > white petrolatum. There was a positive correlation between the concentration of KP and release rate for all bases except Carbopol gel. The in vivo percutaneous absorption of KP from different ointment bases at 3% concentration was studied by carrageenan-induced paw edema in mice. The rank order of the percent edema inhibition was as follows: Carbopol gel ≥ hydrophilic ointment > cold cream > white petrolatum. There was a good correlation between the in vitro and in vivo results.     

薄荷醇和氮酮对吲哚美辛体外促透作用的比较

目的：以吲哚美辛为模型药物，对薄荷醇和氮酮的促透特性进行比较，并探讨两种促透剂合用时的促透效果。方法：在离体透皮实验装置上进行透皮试验，由浓度计算累计透过量，透皮速率，稳态流量，滞后时间等指标。结果：用促透剂后，吲哚美辛的透皮速率均极显增加，分别比对照组增加6．21，4．91和6．92倍，当两种促透剂联合应用时，透皮速率比单独应用时显增加（P＜0．01），促透剂可使吲哚美辛透皮吸收的时滞均明显缩短，薄荷醇组对时滞的缩短作用比薄荷醇和氮酮联用组更为显（P＜0．01），对吲哚美辛透皮吸收稳态流量的影响，氮酮单独应用不明显，而薄荷醇则表现为降低作用，但当两种促透剂联合应用时，则表现为明显的增强效应，比单独应用时分别增加2．78和1．38倍，结论：薄荷醇和氮酮对吲哚美辛的体外经皮吸收具有显的促进作用，联用效果更理想。     

Simultaneous optimization based on artificial neural networks in ketoprofen hydrogel formula containing O-ethyl-3-butylcyclohexanol as percutaneous absorption enhancer

The influence of the amounts of additives including 1-O-ethyl-3-n-butylcyclohexanol (OEBC), diisopropyl adipate (DIA), and isopropanol (IPA) on the penetration rate (R(p)) of ketoprofen from hydrogels through rat skin in vivo was investigated. Skin irritation evoked by the application of hydrogels was evaluated based on a microscopic observation of skin cross-sections. Both optimization techniques incorporating an artificial neural network (ANN) and a second-order polynomial regression analysis were applied to the optimization of ketoprofen hydrogel formulations. Findings indicated that the R(p) and total irritation score (TIS) of the skin were predicted quantitatively as a function of quantities of OEBC, DIA, and IPA, employing ANN. In contrast, the prediction ability of the polynomial regression equation was somewhat poorer compared with that of ANN. The observed results of R(p) and TIS in the optimal formulation coincided well with the predictions in the simultaneous optimization technique incorporating ANN.     

薄荷脑促进扑热息痛透皮吸收作用研究

本文对扑热息痛的透皮吸收作用作了初步的观察并对其助渗剂作了一些探讨,用裸鼠皮肤制作透皮吸收的实验模型,于给药后2、4、8、12、24h于接受池中取样测定扑热息痛的透过量。实验表明扑热息痛可以透过皮肤,给药后2h起则可在接受池中检测到扑热息痛的存在,随时间延长透过量逐渐增多。实验还观察到薄荷脑和月桂氮(艹卓)酮(即氮酮)对扑热息痛的透皮吸收有显著的促进作用。薄荷脑的助渗作用在给药后2h有显著的促进作用(P<0.01),并随时间的推移继续增加,月桂氮(艹卓)酮的助渗作用在8h后才具显著性(p<0.01),随后继续增加,两种助渗剂在24h内助渗作用之间没有显著性差别(p>0.05),说明薄荷脑与月桂氮(艹卓)酮均是扑热息痛的良好助渗剂,但薄荷脑的助渗作用比月桂氮(艹卓)酮出现得更早。     

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。     

Effect of synthesized cyclohexanol derivatives using L-menthol as a lead compound on the percutaneous absorption of ketoprofen

L-Menthol was selected as a lead compound to synthesize new candidates for percutaneous absorption enhancers. In a previous study, O-ethylmenthol (MET) was the most effective compound and caused relatively little skin irritation. To develop more effective compounds, mono- or disubstitute groups of cyclohexane with an O-ethyl group were synthesized. Some 35 compounds were synthesized and evaluated for their promoting activity and effect on skin. An in vivo percutaneous absorption study was performed using rats with hydrogel containing ketoprofen and each of the synthesized compounds. The plasma concentration of ketoprofen was determined after the application of hydrogel to the abdominal area of rats. The apparent penetration rate (R(p)) was estimated based on the pharmacokinetic model with a constant rate of penetration through the skin after the lag time. The 2-compartment model was applied to the data obtained from the iv administration. As an index to evaluate the promoting activity of each enhancer, an enhancement factor (E(f)) was defined as follows: E(f) = R(p) (with enhancer)/R(p) (without enhancer). Irritation to skin was pathologically evaluated. The treated area of rat abdominal skin was excised after the in vivo experiment using total irritation score (TIS). The compound having a C-3 positioned iso-butyl group on the chemical structure was the most effective and caused relatively little irritation among mono-substituted compounds. In the case of di-substituted compounds, all had the same effect as or a stronger effect than MET. Furthermore, the promoting activity almost corresponded to irritation. To estimate log P, one of the physicochemical properties of molecules, a computer program 'CAChe' was employed. The log P was calculated using the atom typing scheme. Multiple regression analysis revealed that the relations between E(f) or TIS and log P were parabolic. It was suggested that the optimum logP value reflects the promoting activity to enhance percutaneous absorption of ketoprofen.     

蛇床子挥发油、薄荷醇及冰片对甲硝唑促透作用的比较

目的对蛇床子挥发油、薄荷醇、冰片促透作用进行比较，为蛇床子挥发油的应用提供理论依据。方法在离体透皮实验装置上进行透皮吸收实验和储库效应的研究。结果蛇床子挥发油、冰片、薄荷醇单独应用时对甲硝唑经皮渗透均有促进作用，增渗倍数分别为2．21、2．19和2．66；当蛇床子挥发油与冰片或薄荷醇合用时，促透效应比单用蛇床子挥发油时显著增强（P〈0．01）。蛇床子挥发油和冰片合用时储库效应显著增加。结论蛇床子挥发油对甲硝唑的皮肤吸收有促透作用，与冰片、薄荷醇合用时效果明显增强。     

Effect of 1-O-ethyl-3-butylcyclohexanol on the skin permeation of drugs with different physicochemical characteristics

The effects of 1-O-ethyl-3-butylcyclohexanol (OEBC) on the in vitro skin permeation of ten model drugs with different physicochemical properties across excised rat skin were evaluated. The results showed that the addition of OEBC significantly improved the in vitro skin permeation of the model drugs compared with the control (without OEBC). To clarify the promoting mechanism of OEBC, a multiple regression analysis was employed. When the permeation study was performed without OEBC, the permeability coefficient was quantitatively predicted as a linear function of molecular weight (log MW) and their lipophilicity (partition coefficient of drugs between octanol and water (log K(o/w)) with a sufficiently high correlation coefficient (r=0.842). It was suggested that skin permeation of drugs without OEBC was explained as a function of diffusion of drugs through the skin and partitioning of drugs to the skin. Although OEBC was administered, the permeability coefficient of drugs cannot be predicted as a linear function of log MW and log K(o/w) (r=0.572).     

Evaluation and structure-activity relationship of synthesized cyclohexanol derivatives on percutaneous absorption of ketoprofen using artificial neural network

The effect of 35 newly synthesized O-ethylmenthol (MET) derivatives on percutaneous absorption of ketoprofen was investigated in rats. In order to understand the relationship between the structure of compounds and promoting activity (structure-activity relationship), an artificial neural network (ANN) was employed. In the in vivo percutaneous absorption study, male Wistar rats, weighing 160-180 g, were used. The apparent penetration rate (Rp) was estimated based on a pharmacokinetic model with a constant rate of penetration through the skin after a lag time. As an index of the promoting activity of each compound, an enhancement factor (Ef), defined as follows, was used: Ef=Rp(with enhancer)/Rp(without enhancer). An irritation evoked on rat skin was microscopically judged at the end of the in vivo percutaneous absorption experiment and evaluated as a total irritation score (TIS). Ef and TIS were selected as output variables to determine the ANN structure. Calculated logP, molecular weight, steric energy (SE), van der Waals area, van der Waals volume, dipole moment, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were used as factors to determine the structural nature of cyclohexanol derivatives. Among these parameters, logP, SE and LUMO significantly affected the prediction of Ef and TIS. The predicted values of Ef and TIS coincided well with in vivo percutaneous absorption experimental values. However, results observed with a linear regression method were poor compared with the ANN approach. The contribution index of logP was approximately 50% in the prediction of Ef, suggesting that lipophilicity among physicochemical properties contributes most of the promoting activity of these compounds.     

Dermal absorption of camphor, menthol, and methyl salicylate in humans

Camphor, menthol, and methyl salicylate occur in numerous over-the-counter products. Although extensively used, there have been no estimates of human exposure following administration via dermal application. Furthermore, there is little information about the pharmacokinetics of those compounds. The authors report the plasma concentrations of the intact compounds as a function of dose following dermal patch application. Three groups of 8 subjects (4 male, 4 female) applied a different number of commercial patches (2, 4, or 8) to the skin for 8 hours. Plasma samples were assayed using sensitive and selective gas-chromatographic methods. For the 8-patch group, the average maximum plasma concentrations (Cmax +/- SD) were 41.0 +/- 5.8 ng/mL, 31.9 +/- 8.8 ng/mL, and 29.5 +/- 10.5 ng/mL for camphor, menthol, and methyl salicylate, respectively. The corresponding values for the 4-patch group were 26.8 +/- 7.2 ng/mL, 19.0 +/- 5.4 ng/mL, and 16.8 +/- 6.8 ng/mL. The harmonic mean terminal half-lives were 5.6 +/- 1.3 hours, 4.7 +/- 1.6 hours, and 3.0 +/- 1.2 hours for camphor, menthol, and methyl salicylate, respectively. The 2-patch group had measurable but low plasma concentrations of each compound. Low-dose dermal application for an extended time results in low plasma concentrations of all 3 compounds. Four and 8 patches, when applied for 8 hours, gave measurable and nearly proportional plasma concentrations. Although unable to determine the absolute dermal bioavailability of these compounds, there appears to be relatively low systemic exposure to these potentially toxic compounds, even when an unrealistically large number of patches are applied for an unusually long time.     

酮洛芬大鼠在体肠吸收药物动力学研究

目的考察酮洛芬在大鼠各肠段的吸收动力学特征。方法采用大鼠在体单向灌流法进行肠吸收实验,利用高效液相色谱法(HPLC)测定酮洛芬的含量,从药物浓度、吸收部位、灌流速度3个方面考察酮洛芬的各肠段吸收动力学特征,利用质量法计算动力学参数。结果酮洛芬浓度在1.4~9.8 mg/L范围内,吸收速率常数K_a和表观吸收系数P_(app)值差异无统计学意义(P>0.05);小肠段和结肠段的K_a和P_(app)值差异有统计学意义(P<0.05),结肠段的K_a和P_(app)值较小,但小肠各段(十二指肠、空肠、回肠)K_a和P_(app)值差异无统计学意义(P>0.05);不同灌流速度下,K_a和P_(app)值差异有统计学意义(P<0.05)。结论酮洛芬主要以被动扩散机制吸收进入体循环,在全肠道吸收均较好。随着灌流速度的增加,K_a和P_(app)值均明显增加。     

薄荷醇和氮酮对水杨酸体外透皮吸收的促进作用

目的 研究薄荷醇和氮酮单独使用及合用时对水杨酸的促透作用。方法 采用离体鼠皮作透皮吸收试验。结果 薄荷醇对水杨酸的促透作用强于氮酮,而两药合用时的促透作用并不比分别使用时的促透效果好,在合用浓度较高时,甚至表现促透作用降低。     

冰片及薄荷醇对尼群地平在家兔体内吸收的影响

目的：以冰片、薄荷醇分别与尼群地平合用,观察其对尼群地平在家兔体内吸收的影响。方法：15只家兔随机分成3组,灌胃口服给药,对照组：单用尼群地平4mg.kg^-1;冰片合用组：尼群地平4mg.kg^-1和冰片30mg.kg^-1;薄荷醇合用组;尼群地平4mg.kg^-1和薄荷醇30mg.kg^-1。采用Waters440高产液相色谱仪测定家兔体内尼群地平的血药浓度。结果：与对照组比较,冰片能使尼群地平在家兔体内吸收过程中C t AUC分别提高95%,增大887%;而薄荷醇则不明显,分别只提高14.6%,增大20.6%。结论：尼群地平与冰片合用能显著增加家兔体内的尼群地平的吸收,而与薄荷醇合用则增加不明显。     

经皮渗透促进剂卡必醇的应用和机制

目的　介绍卡必醇近年来国内外在经皮给药制剂中的研究和应用。方法　分析有关文献资料,对卡必醇的理化性质,以及卡必醇在经皮促渗方面的应用和机制进行总结归纳。结果和结论　卡必醇作为一种优良的渗透促进剂,具有广泛的应用前景。     

薄荷脑和冰片对长春西汀的促渗作用

目的：采用大鼠腹部皮肤研究薄荷脑及冰片在不同溶剂中对长春西汀体外经皮渗透的影响。方法：采用Valia-Chien水平扩散池，研究长春西汀经大鼠腹部皮肤的渗透性。半池有效扩散面积为1.91cm^2，按规定时间取样，采用高效液相色谱法进行测定，进样量为20μL，计算药物经皮渗透动力学参数。结果：薄荷脑与冰片均能促进长春西汀经皮渗透，在不同的溶剂中，其发挥的促渗作用也不同。丙二醇为溶煤时，它们的促渗作用不佳，而以乙醇为溶媒时，3％薄荷脑－40％乙醇－水与5％薄荷脑－40％乙醇－水复合系统均能显著地促进长春西汀经皮渗透，增渗比分别为7．05与7．18。结论：在不同溶媒系统中冰片与薄荷脑对长春西汀具有促渗作用。     

The use of second-order derivative UV spectroscopy to monitor the percutaneous absorption of naphazoline and oxprenolol

Derivative spectroscopy was used to measure the transfer of the cationic drugs, oxprenolol and naphazoline, across full-thickness human skin in vitro. Flow-through diffusion cells were employed. These allowed the receptor fluid to be pumped through a microprocessor-controlled UV spectrophotometer. Spectra were then recorded at preprogrammed intervals. From the second-order derivative curves it was possible to evaluate the concentration of each diffusant within the receptor phase. Confirmation of the technique was established using HPLC. The steady-state fluxes of both drugs were measured. The diffusion of naphazoline and to a lesser extent oxprenolol were enhanced in the presence of lauric acid. The use of derivative spectroscopy in this manner provides a rapid, labour-saving technique for the continuous monitoring of the absorption of various drugs across excised skin.     

The effect of magnesium hydroxide on the oral absorption of ibuprofen, ketoprofen and diclofenac.

1. The effect of magnesium hydroxide on the oral absorption of ibuprofen, ketoprofen and diclofenac was investigated in two randomized cross-over studies, both consisting of two phases. 2. Single doses of magnesium hydroxide (850 mg) or of water (150 ml) only were given to six healthy volunteers immediately after the ingestion of ibuprofen (400 mg, Study 1), ketoprofen (50 mg, Study 2) or diclofenac (50 mg, Study 2). Plasma drug concentrations were measured up to 24 h. 3. Magnesium hydroxide increased the area under the plasma ibuprofen concentration-time curve between 0 and 1 h by 65% (P less than 0.05) and the peak concentration of ibuprofen in plasma by 31% (P less than 0.01). The time to peak was shortened by about 0.5 h. The extent of bioavailability of ibuprofen was not increased by magnesium hydroxide. 4. Neither the rate nor the extent of absorption of ketoprofen or diclofenac was changed significantly by magnesium hydroxide. 5. When rapid onset of the analgesic effect of ibuprofen is required, concomitant ingestion of an antacid, which contains magnesium hydroxide without aluminium, is recommended.     

Effect of formulation variables on the percutaneous permeation of ketoprofen from gel formulations

The objectives of our study were to evaluate the effect of four terpene enhancers, enhancer lipophilicity, and ethanol concentration using hydroxypropyl cellulose (HPC) and two Pluronic F-127 (PF-127) gel formulations on the percutaneous permeation of ketoprofen. All experiments were conducted using hairless mouse skin in vitro. Data recorded over 24 hr was compared with that for control gels (containing no terpene) using Franz diffusion cells. In the three gel formulations, the highest increase in the ketoprofen permeation was observed using limonene followed by nerolidol, fenchone, and thymol. Relationships were established between terpene lipophilicity, enhancement ratios for ketoprofen flux (ER_flux), and the cumulative amount of ketoprofen after 24 hr (Q₂₄