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。     

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.     

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 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.     

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.     

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。     

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。     

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。     

氯霉素透皮吸收作用研究

本文对氯霉素的透皮吸收作用作了进一步观察,用95%乙醇配制的含月桂氮酮溶液与不含月桂氮酮的溶液对氯霉素的透皮吸收作用没有显著性影响,24h 前者透过量虽较高,但经统计学检验没有显著性意义,而用50%乙醇配制的溶液在24h 则有显著的促进氯霉素透皮吸收作用(P<0.01),提示单用该浓度的乙醇有显著促进氯霉素的透皮吸收。     

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     

酮洛芬的脊髓镇痛作用及其机制

目的研究酮洛芬的脊髓镇痛作用及作用机制。方法采用温浴法、热板法观察动物痛阈变化。结果鞘内注射（ｉｔｈ）酮洛芬１．６～３．２ｍｇ·ｋｇ－１具有明显镇痛作用，全身用药需１６ｍｇ·ｋｇ－１才具有同等镇痛效应。ｉｔｈ与ｉｐ药物有效剂量比为１∶１０。ｉｔｈ用药，作用可被ｉｐ利血平、ｓｃ哌唑嗪、育亨宾阻滞。结论酮洛芬具有脊髓镇痛作用，其机制与ＮＥ－α受体系统介导的内源性镇痛系统密切相关     

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.     

Pharmacokinetics of ketoprofen in man after repeated percutaneous administration

A topical formulation of ketoprofen, a widely used nonsteroidal antiinflammatory drug, has recently been developed. Ten healthy young subjects (mean age 23.5 +/- 2.5 years) received daily 15 g of 2.5% ketoprofen gel, corresponding to 375 mg on the skin of the back over an area of 750 cm2. Plasma samples were collected after the first dose and after 10 days of chronic treatment. Urine was also collected. Ketoprofen was assayed by HPLC. The peak plasma concentration was 144 +/- 91 ng/ml after the first administration with apparent absorption and elimination half-lives of 3.2 +/- 2.4 h and 27.7 +/- 18.0 h, respectively. The total quantities of ketoprofen eliminated in the urine represented about 2.6% of the first dose applied. At the end of the study, the apparent half-life of unchanged ketoprofen was 17.1 +/- 9.1 h, and there was no accumulation. In this study, no sign of local intolerance was seen.     

薄荷醇和氮酮对促进甲硝唑透皮吸收作用的比较

通过薄荷醇和氮酮对甲硝唑透皮作用比较,进一步证明薄荷醇确实是一种很有价值的助渗剂,同时也证明甲硝唑在氮酮和薄荷醇助渗下,明显透过离体皮肤,对临床应用甲硝唑作为外用制剂提供依据。     

薄荷醇和氮酮对促进甲硝唑透皮吸收作用的比较

通过薄荷醇和氮酮对甲硝唑透皮作用比较,进一步证明薄荷醇确实是一种很有价值的助渗剂,同时也证明甲硝唑在氮酮和薄荷醇助渗下,明显透过离体皮肤,对临床应用甲硝唑作为外用制剂提供依据。     

The percutaneous absorption of phenolic compounds: the mechanism of diffusion across the stratum corneum

The effect of temperature on the permeation of phenolic compounds from aqueous solution through excised human skin has been examined. From a thermodynamic analysis of the data, a mechanism is postulated by which these solutes penetrate through human skin. For the more polar solutes it is suggested that the main resistance to penetration is the lipid barriers in the stratum corneum. Diffusion of these substances through the stratum corneum appears to depend on the breaking of hydrogen bonds in the desolvation of the solute during this penetration process and by the overall ‘viscosity’ of the stratum corneum. With non-polar solutes, the aqueous boundary layers appear to provide an additional barrier to the penetration of phenolic compounds.