Mechanism for the enhancement effect of fatty acids on the percutaneous absorption of propranolol

The effects of a series of fatty acids on the percutaneous absorption of propranolol (PL) through rabbit skin and the mechanism by which fatty acids facilitate the skin penetration of PL were examined in vitro and in vivo using a gel base. Lauric and myristic acids, at the fatty acid:PL molar ratio of 1:1 were the most potent agents in increasing the skin penetration, giving the largest penetration rate (Js) and penetration coefficient (Kp) of PL. The molar ratio of 2:1 also exerted a large enhancing effect, comparable to that with a molar ratio of 1:1. When the enhancing effects of lauric acid, its amide, and its methyl ester were compared, the free acid gave the highest Js and Kp values. The plasma PL concentrations were significantly higher and more sustained after a single percutaneous application of the formulation with lauric acid than those after the formulation without the acid. The mechanism for the enhancing effect was examined by measuring IR and 13C NMR spectra, the solubility in buffer, and the apparent partition coefficient of PL. Additionally, the penetration of PL and lauric acid, as co-penetrants, through rabbit skin and shed snake skin were evaluated. The IR spectra of the mixture of PL with lauric acid (molar ratio, 1:1) was characterized by an extreme shift of the CO peak. Comparison of the NMR spectra of PL, lauric acid, and the mixture suggested that the carbonyl group of lauric acid interacted with the amino and hydroxyl groups of PL, probably by charge interaction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism for enhancement effect of lipid disperse system on percutaneous absorption: Part II

To further clarify the mechanism involved in the enhancement effect of lipid disperse systems (LDS) on percutaneous absorption, the effect of particle size of LDSs on percutaneous absorption of betahistine (BH), the comparison of the enhancement effect of LDS with the lipid mixtures or the plain LDS, the effect of pretreatment of skin with gel formulation on penetration of LDS-BH and the fluidising effect of LDSs on the stratum corneum (SC) lipids were estimated using Wistar and hairless rats. No major differences in BH absorption were seen between the gel formulations containing LDS with three different particle size (128±4, 336±15, 596±37 nm), prepared using egg phosphatidylcholine (EPC), cholesterol and dicetylphosphate. The percutaneous absorbability of BH from the formulations containing the lipid mixtures or plain LDS did not reach to the extent from EPC–LDS formulation. Following pretreatment with gel formulation containing enhancer (d-limonene or n-octyl-β-d-thioglucoside), BH absorption significantly decreased at the initial stage after application compared with that from LDS formulation, suggesting the additive enhancement effect of LDS and enhancer on the absorption. The treatment of the SC of hairless rat with LDSs significantly decreased the rotational correlation time (τ_c) and shifted downwards the slope of curves (τ_c versus temperature) at temperatures ranging from 25 to 60°C, compared with that of untreated SC. However, the significant differences in the fluidising effect between LDSs with different particle size were not observed     

The effect of aging on percutaneous absorption in man

Despite much research into the mechanisms of cutaneous aging and the identification of significant age-associated biological and biophysical changes within the skin, the question "How does aging affect percutaneous absorption (PA) in vivo?" remains unanswered. We have made in vivo measurements of PA in young (18-40 years) and old (greater than 65 years) subjects. Standard radiotracer methodology was employed and PA was quantified from the urinary excretion profiles of 14C radiolabel (corrected for incomplete renal elimination). Testosterone (TST), estradiol (EST), hydrocortisone (HC), benzoic acid (BA), acetylsalicylic acid (ASA), and caffeine (CAFF) have been studied. Permeation of HC, BA, ASA, and CAFF was significantly (p less than 0.01, 0.01, 0.01, and 0.05, respectively) lower in aged subjects, whereas the absorption of TST and EST was similar in the two groups. Thus it appears that aging can affect PA in vivo and that relatively hydrophilic compounds are particularly sensitive. The diminished surface lipid content of "old" skin implies a diminished dissolution medium for compounds administered topically. It is reasonable to speculate that this physiologic change will impact most severely upon those permeants whose lipid solubility is lowest (that is, HC, BA, ASA, CAFF). Furthermore, the typically reduced hydration of aged stratum corneum will compound this effect for these chemicals. Conversely, highly lipid-soluble chemicals (TST and EST) may still be able to dissolve readily into the stratum corneum even when the available lipid medium is reduced.     

The effect of aging on percutaneous absorption in man

Despite much research into the mechanisms of cutaneous aging and the identification of significant age-associated biological and biophysical changes within the skin, the question “How does aging affect percutaneous absorption (PA) in vivo?” remains unanswered. We have made in vivo measurements of PA in young (18–40 years) and old (>65 years) subjects. Standard radiotracer methodology was employed and PA was quantified from the urinary excretion profiles of¹⁴C radiolabel (corrected for incomplete renal elimination). Testosterone (TST), estradiol (EST), hydrocortisone (HC), benzoic acid (BA), acetylsalicylic acid (ASA), and caffeine (CAFF) have been studied. Permeation of HC, BA, ASA, and CAFF was significantly (p <0.01, 0.01, 0.01, and 0.05, respectively) lower in aged subjects, whereas the absorption of TST and EST was similar in the two groups. Thus it appears that aging can affect PA in vivo and that relatively hydrophilic compounds are particularly sensitive. The diminished surface lipid content of “old” skin implies a diminished dissolution medium for compounds administered topically. It is reasonable to speculate that this physiologic change will impact most severely upon those permeants whose lipid solubility is lowest (that is, HC, BA, ASA, CAFF). Furthermore, the typically reduced hydration of aged stratum corneum will compound this effect for these chemicals. Conversely, highly lipid-soluble chemicals (TST and EST) may still be able to dissolve readily into the stratum corneum even when the available lipid medium is reduced.     

The effect of terpenes on percutaneous absorption of tiaprofenic acid gel

Tiaprofenic acid is a potent analgesic and nonsteroidal anti-inflammatory drug (NSAID) and like any other nonsteroidal anti-inflammatory drug, oral administration of the conventional dosage forms of tiaprofenic acid invariably causes gastrointestinal side effects. In an effort to eliminate these side effects while enhancing the drug concentration at the target tissue, an epidermal application of tiaprofenic acid seems to be an effective alternative drug delivery modality. This study attempts to demonstrate the influence of different terpenes (d-limonene, menthol and nerolidol) in various combinations of preparations on the percutaneous penetration of tiaprofenic acid from Carbopol® 940 based gel formulations (1%) in an ex vivo experiment using Franz-type diffusion cells. The enhancement effect of terpenes on skin absorption of tiaprofenic acid was further evaluated by an in vivo method in rats. Amongst the terpenes used, d-limonene was the most outstanding penetration enhancer that was reference to penetration of tiaprofenic acid through rat skin ex vivo. In vivo penetration study shows that the AUC_0–48h was increased by about 10 fold by the addition of 5% d-limonene to the formulation. Histological studies show that d-limonene causes disruption on the skin surface and is responsible for enhanced penetration of tiaprofenic acid. Since tiaprofenic acid is known to cause gastrointestinal disturbances following systemic administration, topical formulations of tiaprofenic acid in gel form including 5% d-limonene could be suggested as an alternative.     

The effect of ultrasound on the percutaneous absorption of lignocaine.

The influence of ultrasound on the percutaneous absorption of lignocaine from a cream base was investigated in a double-blind cross-over trial in healthy volunteers. Mean data indicated that there was a slightly faster onset time for local anaesthesia when ultrasound was administered when compared with control values (no ultrasound). However, the differences were not statistically significant. Further controlled clinical studies are required into the effect of ultrasound on percutaneous absorption since the technique (phonophoresis) has been alleged to enhance percutaneous penetration of a number of drugs.     

混合透皮促进剂对替硝唑凝胶透皮吸收作用的研究

目的：考察混合促进剂月桂氮苷卓酮和薄荷脑对替硝唑透皮吸收作用的影响。方法：采用改良 Ｆｒａｎｚ 直立式释放池,以离体小白鼠皮肤为透皮屏障,使用不同浓度的混合月桂氮苷卓酮和薄荷脑,测量替硝唑的透皮吸收量。结果：含０ ．５ ％ ,１ ．５ ％ ,２ ％ ,２ ．５ ％ 月桂氮苷卓酮和薄荷脑的替硝唑凝胶与不含月桂氮苷卓酮和薄荷脑的替硝唑凝胶间,其透皮吸收在２４ ｈ 后有显著差异（ Ｐ＜ ０ ．０５） 。含１ ％ 月桂氮苷卓酮和薄荷脑的替硝唑凝胶与不含月桂氮苷卓酮和薄荷脑的替硝唑凝胶间,其透皮吸收在２ ｈ 后则呈极显著差异（ Ｐ＜ ０ ．０１） 。结论：不同浓度的混合促进剂均可不同程度地促进替硝唑的透皮吸收效果,其中以１ ％ 月桂氮苷卓酮加１ ％ 薄荷脑组成的混合促进剂作用最显著。     

月桂氮芯卓酮对青藤碱凝胶剂的透皮吸收作用

目的:考察不同浓度月桂氮(艹卓)酮(azone)对青藤碱凝胶透皮作用的影响,为青藤碱凝胶剂的处方筛选提供依据。方法:采用改良Franz扩散池,以离体大白鼠皮肤为透皮屏障,配制含不同浓度月桂氮(廿卓)酮的青藤碱凝胶,用HPLC法测定青藤碱的透皮吸收量,结果:青藤碱凝胶含2％azone时透皮吸收最好,其体外累积渗透量及促造速率最大。青藤碱凝胶剂的体外渗透药动学符合Higuchi方程。结论:选择2％azone作为青藤碱凝胶剂的促透剂。     

Mechanism of in vitro percutaneous absorption enhancement of carvedilol by penetration enhancers

The effect of penetration enhancers like tulsi (basil) oil, eucalyptus oil, clove oil, black cumin oil, oleic acid and Tween 80 on the percutaneous absorption of model lipophilic drug-carvedilol was investigated using excised rat abdominal skin. Transdermal flux, permeability coefficient and enhancement factor were calculated for each penetration enhancer. Black cumin oil (5% v/v) was selected on the basis of its highest enhancement in permeation and was evaluated further for its mode of action using DSC, FTIR and histological studies. The results indicated that the oil shows its action by extraction of lipids from stratum corneum as well as by loosening the hydrogen bonds between ceramides subsequently leading to fluidization of the lipid bilayer.     

The effect of meloxicam/ethanolamine salt formation on percutaneous absorption of meloxicam

This study was undertaken to prepare meloxicam-ethanolamine salts (MX-EAs) that enhance the transdermal delivery of meloxicam. The physicochemical properties of MX-EAs were investigated by solubility measurements, Differential Scanning Calorimetry (DSC), and Infrared Spectroscopy (FT-IR). The DSC thermogram and FTIR spectra indicated that meloxicam formed salts with ethanolamines. The effects of various vehicles on the percutaneous absorption of meloxicam and of its salts across hairless mouse skin were evaluated using a flow-through diffusion cell system at 37°C. Salt formation lowered the melting point of meloxicam and slightly reduced its octanol/water partition coefficient. Meloxicam-monoethanolamine salt (MX-MEA) and meloxicam-diethanolamine salt (MX-DEA) had greater solubilities and trans-dermal permeation rates across hairless mouse skin than meloxicam alone in various vehicles. Moreover, although the solubility of meloxicam-triethanolamine salt (MX-TEA) was generally lower than that of meloxicam, its permeation rate across the skin was higher. The fluxes of meloxicam and its salts were generally lower than those of piroxicam.     

Enhancing effect of terpenes on the in vitro percutaneous absorption of diclofenac sodium

The enhancing effect of naturally occurring terpenes on the in vitro percutaneous absorption of diclofenac sodium (DFS) from carbopol gels containing propylene glycol was investigated. Permeation experiments were performed on excised abdominal rat skin. Terpenes varied in their activities: the alcohol terpenes were effective accelerants for the drug whereas the ketones were much less efficient, providing only a 2-to-3-fold increase in DFS diffusion; limonene showed mild accelerant activity and 1,8-cineole was a poor accelerant. Acyclic alcohols were found to be the best enhancers for DFS, being geraniol, with an almost 20-fold increase, the most outstanding penetration enhancer. However, although the addition of terpenes increased DFS flux, diffusional lag times were longer than for the control gel.     

Combined effect of cyclic monoterpenes and ethanol on percutaneous absorption of diclofenac sodium.

The combined effect of cyclic monoterpenes and ethanol on the percutaneous absorption of diclofenac sodium (DFS) from gel ointments was investigated in vivo in rats. The enhancing activity of terpenes was significantly affected by the concentration of ethanol formulated in the gel ointments. At a lower concentration of ethanol (20%), 1,8-cineole was observed to be the most effective. On the other hand, d-limonene showed strong activity when the large amount of ethanol was formulated (40%). A synergistic effect between terpenes and ethanol on the percutaneous absorption of DFS was significantly observed in cases of 1,8-cineole and l-menthol using an analysis of variance (ANOVA). When the diclofenac (DF) free form was formulated in gel ointment, the percutaneous absorption was significantly reduced. The reduction of the percutaneous absorption was closely related to the decrease in pH of the gel ointment owing to the free form of DF which was formulated.     

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。     

六白白疕巴布剂经皮吸收研究

目的根据活性成分的透皮吸收速率优化六白白疕巴布膏剂的处方.方法用高效液相色谱法测定方中主药甘草的有效成分甘草酸的体外透皮累积量,评估透皮吸收促进剂氮酮的影响.结果该巴布剂具有良好的透皮作用,加入3%氮酮作为透皮促进剂效果最佳.结论氮酮可以促进药物的透皮吸收.     

Transdermal absorption enhancing effect of the essential oil of Rosmarinus officinalis on percutaneous absorption of Na diclofenac from topical gel

Abstract

Context: Rosemary essential oil has been used topically for several purposes (analgesic, anti acne, and anti-inflammatory) in Iranian traditional medicine.

Objectives: This investigation aimed to study the effect of essential oil of Rosmarinus officinalis L. (Lamiaceae) on the transdermal absorption of Na diclofenac from topical gel.

Material and methods: Diclofenac sodium topical gel was prepared with HPMC K4M and Carbopol 934P as a gelling agent, and several vehicles. The most stable gel was chosen and enhancing effects of the essential oil with different concentrations (0.1, 0.5, and 1.0% w/w) on the permeation of diclofenac were evaluated. The anti-nociceptive effect of preparations was evaluated based on the formalin and tail flick tests in mice.

Results: The major constituents of the essential oil were 1,8-cineol (15.96%), α-pinene (13.38%), camphor (7.87%), bornyl acetate (6.54%), verbenone (5.82%), borneol (5.23%), camphene (4.96%), and (E)-caryophyllene (3.8%). Topical diclofenac containing 0.5% essential oil showed more analgesic effect after 25, 30, and 35?min (p?<?0.001) than the reference drug in the tail flick test. The analgesic effect of preparation containing 1% essential oil was more than reference gel after 15?min (p?<?0.05). This difference was observed after 20, 25, 30, 35, and 40?min (p?<?0.001) too. Rosemary essential oil 1% promoted analgesic effect of drug in comparison with diclofenac gel in the formalin early phase (p?<?0.05). The enhancing effect of rosemary was observed in 0.5 and 1% concentration (p?<?0.05 and p?<?0.001, respectively) in the late phase.

Conclusion: This study proved the enhancing effect of 0.5 and 1% of rosemary essential oil on diclofenac percutaneous absorption.     

Mechanism(s) of in vitro percutaneous absorption enhancement of tamoxifen by enhancers

The effects of enhancers (5% terpenes; i.e., eugenol, limonene, and menthone) in combination with 50% propylene glycol in water (50% PG) on the in vitro percutaneous absorption of tamoxifen through the porcine epidermis, on biophysical changes in the stratum corneum (SC) lipids, on macroscopic barrier properties, and on binding of the drug to the SC were investigated. These enhancers in combination with 50% PG significantly increased (p<0.05) the permeability coefficient of tamoxifen in comparison with that of the control (50% PG in water). Fourier transform infrared spectroscopy (FT-IR) was employed to investigate the biophysical changes in the SC lipids. The FT-IR results showed that treatment of the SC with 5% terpenes/50% PG did not shift the asymmetric and symmetric C-H stretching absorbances peak positions to higher wavenumbers but resulted in a decrease in the peak heights and areas in comparison with the untreated SC. Treatment with menthone and limonene in combination with 50% PG significantly increased (p<0.05) the partition coefficient of tamoxifen in comparison with treatment with 50% PG alone. Also, exposure of the SC to 5% terpenes in combination with 50% PG significantly increased (p < 0.05) the in vitro transepidermal water loss (TEWL) in comparison with 50% PG alone. Thus, an enhancement by menthone, eugenol, and limonene in the permeability of the SC to tamoxifen is due to lipid extraction and macroscopic barrier perturbation. Moreover, the effective diffusion coefficient of tamoxifen through the epidermis was enhanced following the treatment with either 5% eugenol/50%PG or 5% limonene/50%PG compared with 50%PG alone.