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。     

角质层与活性皮肤层对硝酸异山梨酯透皮吸收的影响

目的:评价皮肤角质层和真皮层对药物经皮吸收的影响。方法:以硝酸异山梨酯(ISDN)为模型药物,采用Franz吸收池法,考察药物单独或与吸收促进剂肉豆蔻酸异丙酯(IPM)合用时,经完整皮肤和角质层剥离皮肤的透皮能力。结果:IS-DN经剥离角质层皮肤的表观透皮系数的Kp是经完整皮肤的1.68倍,IPM能分布在活性皮肤层,并可明显增加ISDN在角质层或真皮层的分布量及经皮累积透皮吸收百分率。结论:本实验为研究皮肤病态条件下(如皮肤受伤或溃疡等),药物透皮吸收规律,提供了一种新的方法。     

Effect of pH on skin permeation enhancement of acidic drugs by l-menthol-ethanol system

The effect of pH on the skin permeation enhancement of three acidic drugs by the l-menthol-ethanol system was investigated. The total flux of acidic drugs from the system remarkably varied over the pH range 3.0-8.0, and the permeation enhancement factor depended on the system pH and drug. A skin permeation model, which consists of two permeant (unionized and ionized) species, two system (oily and aqueous) phases, and two permeation (lipid and pore) pathways, was developed. The assumptions were made that only the unionized species can distribute to the oily phase and transport via the lipid pathway. The model explained the relationship between the concentration of drug in the aqueous phase and system pH. The skin permeability data were also described by the model and permeability coefficients corresponding to the physicochemical properties of permeant were calculated for the lipid and pore pathways. The model simulation showed that the permeation of acidic drugs occurred from the aqueous phase and the oily phase acted as a reservoir. Whether the total flux increased with increase of pH was dependent on the lipophilicity of drug. These results suggest that the pH of l-menthol-ethanol system should be given attention to elicit the maximum permeation enhancement.     

Effect of permeation enhancers on the in vitro percutaneous absorption of pentazocine

The effect of permeation enhancers on the percutaneous absorption of pentazocine (PTZ) was investigated in excised hairless mice using Franz diffusion cells in vitro. The enhancing effect on the percutaneous absorption of PTZ from the isopropyl myristate (IPM) solution system was improved with glyceryl monocaprylate (GEFA-C(8)), which is a kind of glycerol ester of fatty acid (GEFA). The flux of PTZ through the skin was ca. 4 times higher compared with IPM alone, while a less enhancing effect of glyceryl dicaprylate (GEFA-DiC(8)) and glyceryl tricaprylate (GEFA-TriC(8)) on the skin permeation of PTZ was found. Moreover, maximum enhancement of PTZ flux was observed with glyceryl monocaproate (GEFA-C(6)) among various alkyl chains (C(2)-C(18)) of monoglycerides. These results indicated that the IPM solution system combination with GEFA may be used to develop a transdermal formulation with improved skin permeation of PTZ.     

硝酸异山梨醇透皮给药系统的研制

硝酸异山梨醇透皮给药系统(ISDN—TDS)由背衬层、药库、乙烯—醋酸乙烯共聚物(EVA)控释膜、压敏胶及防粘层组成。采用Keshary—Chien体外释药装置,研究了药库组分、基质溶剂、控释膜、压敏胶粘度及透皮给药促进剂氮酮等对药物释放的影响。以释异丁烯、矿物油、EVA控释膜为主要材料制成的ISDN—TDS体外能持续释药72h,0～48h药物按零级动力学经皮透过。平均释药速率为13.76μg·h^-1/cm²,而国外类似产品Frandol tape-s按Higuchi模型释药仅24h。     

Effect of vehicle properties on skin penetration of emedastine

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

Effect of some penetration enhancers on the permeation of glibenclamide and glipizide through mouse skin

The purpose of this investigation was to study the effect of some penetration enhancers on in vitro permeation of glibenclamide and glipizide through mouse skin. Ethanol in various concentrations, N-methyl-2-pyrrolidinone, transcutol, propylene glycol and terpenes like citral, geraniol and eugenol were used as penetration enhancers. The in vitro skin permeation experiments were conducted by both simultaneous application of drug and enhancer solution and by pretreatment of the skin with neat enhancer. At the end of the experiment drug retained in the skin was estimated. The flux values (microg/cm2/h) of both drugs significantly (p < 0.05) increased in the presence of penetration enhancers, except transcutol and propylene glycol. The glibenclamide flux values ranged from 1.42 +/- 0.09 without enhancer, to 18.25 +/- 1.21 in a combination of 50% ethanol and 5% eugenol. Glipizide flux values ranged from 3.21 +/- 0.51 without enhancer, to 57.21 +/- 5.25 in a combination of 50% ethanol and 5% eugenol. Skin retention and solubility of both drugs increased with all penetration enhancers compared to control (except propylene glycol). As the target permeation rates for glibenclamide and glipizide were calculated to be 193.8 and 184.8 microg/h respectively, the present study showed that the required permeation rates for both drugs could be achieved with the aid of enhancers by increasing the area of application in an appreciable range.     

Effect of ethanol pretreatment on skin permeation of drugs

It has been demonstrated that ethanol (EtOH) can enhance skin permeation of drugs when simultaneously applied with drugs. However, only a few studies have reported on the pretreatment effect of EtOH on skin permeations. In this study, the pretreatment effects of EtOH on skin permeation of drugs were investigated by measuring changes in skin permeation and electrical skin resistance. Permeabilities of deuterium oxide (D2O), isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), calcein sodium (CA-Na), and fluorescein isothiocyanate-dextran 4?kDa (FD-4, 3.3-4.4?kDa) were evaluated through Yucatan micropig skin pretreated with different concentrations of EtOH solution. From the results, almost constant skin permeabilities of D2O and ISDN were observed independent of EtOH concentration. Skin permeabilities of ISMN, CA, and FD-4 increased with low concentrations of EtOH, but decreased with high concentrations of EtOH. At 99.5% EtOH pretreatment, skin permeabilities of hydrophilic compounds (ISMN, CA, and FD-4) decreased to non-detectable levels. In addition, low molecular ion transports were almost constant at any EtOH concentration. Since molecular (ion) sizes of ISMN, CA, and FD-4 are larger than Na⁺, Cl^－, and D2O, permeation pathway sizes for hydrophilic compounds in the skin barrier may be remarkably decreased by pretreatment with high concentrations of EtOH. However, the permeability coefficient of ISDN was not influenced by any EtOH concentration, since ISDN is a lipophilic, low-molecular compound that permeated through the lipophilic stratum corneum pathway. The present results show useful information for repeatedly and topically applied formulations containing EtOH, and also contribute to the effective use of alcohol formulations.     

Effect of penetration enhancers on skin permeation of trazodone hydrochloride from matrix type transdermal formulation through mouse and human cadaver epidermis

A transdermal dosage form of trazodone hydrochloride (TZN) may be useful in the treatment of moderate to severe depression in schizophrenic patients by providing prolonged duration of action. It will also improve patient compliance and bioavailability. Controlled input of TZN would attenuate fluctuating plasma level of TZN resulting from oral therapy. The aim of the current investigation was to evaluate its flux and the effects of various penetration enhancers, viz., isopropyl myristate (IPM), isopropyl palmitate (IPP), butanol and octanol on transdermal permeation from matrix-based formulations through the skin. The enhancing effect on the permeation of TZN was determined using the mouse and human cadaver epidermis. In vitro permeation data were collected at 37 degrees C using Keshary-Chien diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation flux of TZN, enhancement ratio and the diffusion parameter. The highest enhancing effect was obtained with IPM followed by butanol, octanol and IPP. In general, higher fluxes were observed through mouse epidermis as compared with the human cadaver epidermis. The skin retention of TZN for both the species in the presence of different enhancers was nearly 3 times higher than for the control formulation. Based on the observed results, a transdermal patch of about 70 cm2 consisting of 10 % IPM should be able to attain and maintain therapeutic plasma concentration of TZN at 0.75 mg/mL over a period of 24 h.     

Formulation and in vitro evaluation of pentazocine transdermal delivery system

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

Transdermal delivery of glibenclamide and glipizide: in vitro permeation studies through mouse skin

The purpose of this investigation was to study the feasibility of transdermal delivery of glibenclamide and glipizide. In vitro permeation of these drugs was studied through mouse skin using various penetration enhancers like Tween -20, polyethyleneglycol-400, ethanol and d-limonene by simultaneous application of drug and enhancer solution or by pretreatment of the skin with neat enhancer. The partition coefficient values indicated that both drugs partition well into the skin. Glipizide did not show any skin metabolism, while glibenclamide showed a minimal metabolism during in vitro skin metabolism studies. The flux values (microgram/cm2/h) of both drugs significantly (p < 0.05) increased in the presence of penetration enhancers. The glibenclamide flux values ranged from 1.39 +/- 0.13 without enhancer, to 19.01 +/- 2.14 in a combination of 50% ethanol and 5% d-limonene. Glipizide flux values ranged from 3.01 +/- 0.74 without enhancer, to 62.97 +/- 7.10 in a combination of 50% ethanol and 5% d-limonene. Skin retention and solubility of both drugs increased with all penetration enhancers compared to control. The target permeation rates for glibenclamide and glipizide were calculated to be 193.8 and 184.8 micrograms/h respectively. The present study showed that the target permeation rates for both drugs could be achieved with the aid of enhancers by increasing the area of application in an appreciable range.     

Effectiveness and Mode of Action of Isopropyl Myristate as a Permeation Enhancer for Naproxen through Shed Snake Skin

The effectiveness and mode of action of isopropyl myristate (IPM) as an enhancer for the permeation of naproxen through shed snake skin have been investigated. The highest naproxen permeability was afforded by IPM (36.2 × 10^?4 cm h^?1), followed by menthol (25.0 × 10^?4 cm h^?1), oleic acid (11.1 × 10^?4 cm h^?1), azone (7.3 × 10^?4 cm h^?1)_and control (1.4 × 10^?4 cm h^?1). Whereas the permeability of un-ionized naproxen (47.4 × 10^?5 cm h^?1) was much greater than that of ionized naproxen (1.11 × 10^?5 cm h^?1), IPM-treatment of the intact skin increased the flux of ionized naproxen significantly more (50?fold) than that of un-ionized naproxen (15?fold). The large effect of pH on the permeation of naproxen through the intact stratum corneum became insignificant after extraction of lipids from the skin. Similar permeation of naproxen through intact and delipidized skin after IPM treatment indicated that the lipid barrier of the skin was largely impaired by IPM. Direct application of IPM to skin yielded a 2.6?fold higher naproxen permeability than the application of IPM as a gel. A greater amount of naproxen was absorbed from 1% test gel (pH 5) containing IPM than from 10% commercial gel (pH 7) containing no IPM. These results show that use of IPM can significantly improve the bioavailability of naproxen in topical preparations.     

两种渗透促进剂对药物透皮吸收的作用

本文主要研究了两种渗透促进剂氮酮和卖泽对亲脂性药物硝苯吡啶、炎痛喜康和亲水性药物扑热息痛、苯呋心安通过小鼠皮肤渗透性的影响。将药物与促进剂一起制成油性软膏、选择适宜的释放液进行体外释放试验,从而计算出药物的稳定状态流量(J),以说明药物渗透性的大小。结果表明:两种促进剂都能增加药物的皮肤渗透性,促进剂浓度的选择由具体药物确定。     

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

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

The effect of penetration enhancers on permeation kinetics of nitrendipine in two different skin models

The purpose of this research was to evaluate the effect of penetration enhancers on permeation kinetics of nitrendipine (NTP) through two different skin models. The permeation profile and related kinetics parameters such as activity parameter, diffusion parameter, lag time, relative activity parameter and relative diffusion parameter of NTP was determined in presence of some novel and widely accepted permeation enhancers. Among all the more pronounced enhancing effect was obtained with oleic acid (OA) as it presented the highest permeability coefficient. The enhancement was found to be increased in the following order: Dimethyl sulphoxide (DMSO)相似文献   

Evaluation of chemical enhancers in the transdermal delivery of lidocaine

The effect of various classes of chemical enhancers was investigated for the transdermal delivery of the anesthetic lidocaine across pig and human skin in vitro. The lipid disrupting agents (LDA) oleic acid, oleyl alcohol, butenediol, and decanoic acid by themselves or in combination with isopropyl myristate (IPM) showed no significant flux enhancement. However, the binary system of IPM/n-methyl pyrrolidone (IPM/NMP) improved drug transport. At 2% lidocaine dose, this synergistic enhancement peaked at 25:75 (v/v) IPM:NMP with a steady state flux of 57.6 +/- 8.4 microg cm(-2) h(-1) through human skin. This observed flux corresponds to a four-fold enhancement over a 100% NMP solution and over 25-fold increase over 100% IPM at the same drug concentration (p < 0.001). NMP was also found to co-transport through human skin with lidocaine free base and improve enhancement due to LDA. These findings allow a more rational approach for designing oil-based formulations for the transdermal delivery of lidocaine free base and similar drugs.     

Enhanced transdermal delivery of atenolol from the ethylene-vinyl acetate matrix

To enhance transdermal delivery of atenolol, ethylene-vinyl acetate (EVA) matrix of drug containing penetration enhancer was fabricated. Effect of penetration enhancer on the permeation of atenolol through the excised rat skin was studied. Penetrating enhancers showed the increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene 2-oleyl ether showed the best enhancement. For the controlling transdermal delivery of atenolol, the application of EVA matrix containing permeation enhancer could be useful in the development of transdermal drug delivery system.     

Enhanced transdermal delivery of triprolidine from the ethylene-vinyl acetate matrix.

Triprolidine-containing matrix was fabricated with ethylene-vinyl acetate (EVA) copolymer to control the release of the drug. The permeation rate of triprolidine in the stripped skin was greatly larger than that in the whole skin. Thus it showed that the stratum corneum acts as a barrier of skin permeation. The effect of penetration enhancer and stripping of skin on the permeation of triprolidine through the excised mouse skin was studied. Penetrating enhancers showed increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene-2-oleyl ether showed the best enhancement. The permeability of triprolidine was markedly increased with stripping of the mouse skin to remove the stratum corneum that acts as a barrier of skin permeation. For the controlling transdermal delivery of triprolidine, the application of EVA membrane containing permeation enhancer could be useful in the development of transdermal drug delivery system.     

Novel dithranol phospholipid microemulsion for topical application: development, characterization and percutaneous absorption studies

The objective of this study was to develop and characterize a novel dithranol-containing phospholipid microemulsion systems for enhanced skin permeation and retention. Based on the solubility of dithranol, the selected oils were isopropyl myristate (IPM) and tocopherol acetate (TA), and the surfactants were Tween 80 (T80) and Tween 20 (T20). The ratios of cosurfactants comprising of phospholipids and ethanol (1?:?10) and surfactant to co-surfactant (1?:?1 and 2.75?:?1) were fixed for the phase diagram construction. Selected microemulsions were evaluated for globule size, zeta potential, viscosity, refractive index, per cent transmittance, stability (freeze thaw and centrifugation), ex vivo skin permeation and retention. The microemulsion systems composed of IPM and T80 with mean particle diameter of 72.8?nm showed maximum skin permeation (82.23%), skin permeation flux (0.281?mg/cm2/h) along with skin retention (8.31%) vis-à-vis systems containing TA and T20. The results suggest that the developed novel lecithinized microemulsion systems have a promising potential for the improved topical delivery of dithranol.     

Comparison of skin permeation enhancement by 3-l-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

3-l-Menthoxypropane-1,2-diol (MPD) is a derivative of l-menthol, which has an enhancement effect on drug permeation through skin. In this study, the effect of MPD on drug permeation through skin was compared with that of l-menthol. MPD or l-menthol at final concentrations of 3% in 40% ethanol was added to the drugs indomethacin or antipyrine and each mix then applied to Yucatan micropig skin in vitro. Drug concentrations in the skin were higher in the presence of either MPD or l-menthol, however, only l-menthol shortened the lag time of permeation. MPD enhanced the skin permeation of the drugs only by increasing the skin concentration of the drugs. In contrast, l-menthol enhanced the skin permeation of the drugs by increasing both the skin concentration and the diffusion rate in skin. The infrared (IR) spectra and X-ray diffraction patterns of stratum corneum after treatment with MPD did not differ from those of intact stratum corneum. A change in the IR spectra of stratum corneum after treatment with l-menthol was observed at the CH band, and the peaks representative of the lipid structure in the X-ray diffraction patterns decreased in intensity. These results suggest that l-menthol, but not MPD, disrupts the intercellular lipid structure of stratum corneum. Thus, MPD is expected to be a moderate skin permeation enhancer.