The effect of glycyrrhizin on the release rate and skin penetration of diclofenac sodium from topical formulations

The influence of glycyrrhizin extracted from Glycyrrhiza glabra var. glandulifera (licorice roots) on the percutaneous absorption of diclofenac sodium from sodium carboxymethylcellulose (NaCMC) gels or oil-in-water (o/w) emulsion was investigated. Skin permeation experiments were carried out using excised abdominal rat skin. The results showed that the efficiency of glycyrrhizin as an enhancer agent is greater in gel formulations than it is in the emulsions. The enhancer with the concentration of 0.1% w/w in gel increased diclofenac sodium flux value to tenfold compared with the control gel.     

The effect of surfactants on the skin penetration of diazepam

The percutaneous permeation of diazepam was investigated in rat skin after application of a water-propylene glycol (50:50% v/v) using a diffusion cell technique. The effect of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on skin permeability were evaluated. Flux, K(p), lag time and enhancement ratios (ERs) of diazepam were measured over 10 h and compared with control sample (containing no surfactant). Furthermore, diazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of diazepam. Benzalkonium chloride which possessed the highest lipophilicity (logP=1.9) among cationic surfactants provided the greatest enhancement for diazepam flux (7.98-fold over control). CTAB (logP<1) at a concentration of 1% w/w exhibited no significant increase in flux of diazepam compared to control (1.16-fold over control). The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant to form micelles and is normally observed only if interaction between micelle and the drug occurs. The results showed that the nature of enhancer greatly influences cutaneous barrier impairment.     

Enhancing effect of surfactants on fexofenadine.HCl transport across the human nasal epithelial cell monolayer

The effect of various surfactants (sodium cholate, sodium taurocholate, Tween 80 and Poloxamer F68) on enhancing the transepithelial permeability of fexofenadine·HCl was evaluated in a human nasal epithelial cell monolayer model. The cytotoxicity of the surfactants on the human nasal epithelial cells was evaluated by the MTT assay. A dose-dependent reduction of cell viability was observed at higher than critical micelle concentration (CMC) of the surfactants, and the IC₅₀ of non-ionic surfactants (Tween 80 and Poloxamer F68) was higher than that of ionic surfactants (sodium cholate and sodium taurocholate). The TEER values significantly decreased after 2 h incubation with the ionic surfactants, but were recovered after 24 h in the fresh culture media. Ionic surfactants significantly increased the transepithelial permeability (P_app) of fexofenadine·HCl compared to the non-ionic surfactants. The reduction of TEER values upon exposing the cell monolayer to the surfactants for 2 h correlated well with the P_app of fexofenadine·HCl, which suggests that the permeation-enhancing mechanism of the ionic surfactants is by altering the tight junction property of the paracellular pathway. F-actin staining showed that the effect of ionic surfactants on the tight junction is temporary and reversible, which is consistent with the TEER value recovery within 24 h. These results imply that ionic surfactants are potentially useful permeation enhancers for nasal delivery of hydrophilic compounds, such as fexofenadine·HCl. This study also indicated the usefulness of the human nasal epithelial cell monolayer model not only for evaluating the in vitro nasal drug transport but also for studying the mechanism and toxicity of enhancers.     

Evaluation of penetration enhancement of lidocaine by nonionic surfactants through hairless mouse skin in vitro

The effect of two nonionic surfactants (polyoxyethylene sorbitan monoesters) on percutaneous absorption of lidocaine in the presence of various concentrations of propylene glycol is reported. Comparisons were made in vitro using excised hairless mouse skin as the barrier membrane. Under infinite dose conditions, steady-state flux was enhanced by surfactants at high propylene glycol concentrations. The same trend was observed following application of a thin layer of formulation to the skin (finite-dose conditions). However, penetration behavior was complex due to: (a) changes in vehicle composition following application, (b) temperature changes resulting from evaporation or moisture uptake, and (c) depletion of lidocaine as a result of penetration with compositions that lost water by evaporation. Two peaks in the flux versus time curve were observed. Surfactant monomer concentration in the vehicles was increased in the presence of propylene glycol.     

Enhancing effects of medium chain aliphatic alcohols and esters on the permeation of 6-carboxyfluorescein and indomethacin through rat skin

Medium chain aliphatic alcohols (C8-C12) and methyl or propyl esters of medium chain fatty acids (C8-C12) enhanced the permeation of 6-carboxyfluorescein (6-CF) and indomethacin (IND) through excised rat skin. The enhancing effects of the aliphatic alcohols for 6-CF and IND decreased with the increase in carbon chain length. The dependence on the carbon chain length was different from that exhibited by medium-chain fatty acids previously reported. In the case of fatty acid esters, the enhancing effects were lower than those of aliphatic alcohols and fatty acids. The relationship between the enhancing effects and the total number of carbon atoms in the esters was different for 6-CF and IND. The dependence on the total number of carbon atoms was similar to that in the aliphatic alcohols for 6-CF, and greater effects were observed in the shorter esters. On the other hand, no definite trends were observed for IND. Although the relationships between the structure and skin permeation-enhancing effect of the aliphatic alcohols and fatty acid esters used in this study are not yet fully understood, they are possible candidates as permeation enhancers for hydrophilic and lipophilic drugs. Further experiments, including examination of the location and environment of the lipophilic carbon chain and hydrophilic groups of such enhancers in the stratum corneum, are needed to optimize transdermal delivery systems containing them.     

The percutaneous absorption of hydroquinone (HQ) through rat and human skin in vitro

Because of the potential for human contact with photographic developer solutions containing hydroquinone (HQ), the rates of percutaneous absorption of HQ through human stratum corneum and full-thickness rat skin have been measured in vitro using 5% aqueous solutions of HQ as the donor solutions. The studies were performed using infinite doses of aqueous solutions containing ¹⁴C-labeled HQ in Franz-type diffusion cells. The measured absorption rate (mean ± S.D.) of HQ through human stratum corneum was 0.52 ± 0.13 μg/cm²/h, while that for full-thickness rat skin was 1.1 ± 0.65 μg/cm²/h. The ratio (rat/human) of the permeability constants (K_p) was 2.4. Using the definitions suggested by Marzulli et al. (1969) Toxicol. Appl. Pharmacol. Suppl. 3, 76–83, HQ would be classified as ‘slow’ with respect to its absorption through human stratum corneum.     

桉油对川芎嗪透过离体大鼠皮肤的促进作用

目的研究桉油对川芎嗪透皮吸收的促进作用及其最佳浓度。方法采用V-C水平扩散池,以流通量为指标,观察桉油及其在真空条件下分馏得到的各馏分和不同浓度的桉树脑对川芎嗪透过离体大鼠皮肤的促进作用。结果各馏分中以2%浓度的69.5~70℃馏分的促透效果最好,与1%、2%桉树脑的促透效果相当。结论桉油主成分桉树脑对川芎嗪透皮起主要促进作用,并以(1.45±0.04)%的浓度最佳。     

Assessment of the percutaneous penetration of cisplatin: The effect of monoolein and the drug skin penetration pathway

It was intended to examine the in vitro penetration of cisplatin (CIS) through porcine skin in the presence of different concentrations of monoolein (MO) as well as to verify the main barrier for CIS skin penetration. In vitro skin penetration of CIS was studied from propylene glycol (PG) solutions containing 0%, 5%, 10%, and 20% of MO using Franz-type diffusion cell and porcine ear skin. Pretreatment experiments with MO and experiments with skin without stratum corneum (SC) were also carried out. Skin penetration studies of CIS showed that the presence of MO doubled the drug permeation through the intact skin. However, permeation studies through the skin without SC caused only a small enhancement of CIS permeation compared to intact skin. Moreover, pretreatment of skin with MO formulations did not show any significant increase in the flux of the drug. In conclusion, MO did not act as a real penetration enhancer for CIS, but it increased the drug partition to the receptor solution improving CIS transdermal permeation. The absence of improvement in drug permeation by MO pretreatment and by the removal of SC indicates that the SC is not the main barrier for the permeation of the metal coordination compound.     

A comparison of the effect of lorazepam on memory in heavy and low social drinkers

The cognitive deficits, particularly memory impairment, observed in association with organic brain damage caused by chronic alcohol ingestion, are consistent with the profile of benzodiazepine-induced amnesia. This study examined the cognitive capabilities of a group of heavy social drinkers (n=11) and a group of low social drinkers (n=11) under the influence of a pharmacological challenge (lorazepam 2 mg) and a placebo treatment. Lorazepam impaired visual memory and verbal learning in both groups, but the effect of lorazepam was exacerbated in the heavy social drinkers for delayed recall of verbal material. Heavy social drinkers had lower verbal fluency scores and were less able to copy complex figures than low social drinkers whether or not the pharmacological challenge was present. Lorazepam induced deficits, in both groups, which conformed to the classic profile of those observed in benzodiazepine-induced amnesia. The deficits, both in the absence and presence of lorazepam, shown by heavy social drinkers suggest that changes may have occurred in their brain functioning.     

Effects of lorazepam on human contrast sensitivity

The anxiolytic lorazepam was studied for its effects on contrast sensitivity to gratings flickering in counterphase in normal volunteers. The drug significantly reduced contrast sensitivity at low spatial frequencies in a dose-related manner. The results are discussed with reference to possible GABA-mediated processes in the retina and lateral geniculate nucleus.     

The effect of sodium deoxycholate and other surfactants on the mucosal surface pH in proximal jejunum or rat

Summary The mucosal surface pH (acid microclimate) and nucleotide levels of rat proximal jejunum were measured in vivo under various conditions which included exposure to pharmacological agents and to surfactants. Mucosal surface pH was unaffected by sodium nitroprusside, A23187 and amiloride, as was mucosal cGMP content, although amiloride and A23187 reduced cAMP content. In contrast, surfactants elevated the pH of the mucosal surface significantly (P < 0.001): control value 6.23 ± 0.02 (n = 12); Lubrol PX 0.8% (v/v) 6.98 ± 0.02 (n = 5); sodium deoxycholate 2 mmol/l 6.67 ± 0.04 (n = 5); Triton X-100 0.5% (v/v) 7.41 ± 0.03 (n = 5). No significant changes in cGMP levels were noted after surfactant treatment, although DOC and Triton X-100 reduced cAMP levels. The ability of higher concentrations of surfactant to elevate the mucosal surface pH beyond neutrality to values similar to plasma pH contrasts with the action of Escherichia coli heat-stable (STa) enterotoxin which at high concentrations could not elevate the mucosal surface pH beyond neutrality. Consistent with the known effects on tight junction permeability, surfactants may act by allowing plasma-like subepithelial fluid to neutralise the microclimate. Send offprint requests to M. L. Lucas at the above address     

Human skin penetration of gold nanoparticles through intact and damaged skin

Abstract

Gold nanoparticles (AuNPs) are produced for many applications but there is a lack of available data on their skin absorption. Experiments were performed using the Franz diffusion cell method with intact and damaged human skin. A physiological solution was used as receiving phase and 0.5 mL (1st exp) and 1.5 mL (2nd exp) of a solution containing 100 mgL^-1 of AuNPs (15 and 45 μg cm^-2, respectively) was applied as donor phase to the outer surface of the skin for 24 h. Skin absorption was dose dependent. Mean gold content of 214.0 ± 43.7 ng cm^-2 and 187.7 ± 50.2 ng cm^-2 were found in the receiving solutions of cells where the AuNPs solution was applied in higher concentration on intact skin (8 Franz cells) and on damaged skin (8 Franz cells), respectively. Twenty-four hours gold flux permeation was 7.8 ± 2.0 ng cm^-2 h^-1 and 7.1 ± 2.5 ng cm^-2 h^-1 in intact and damaged skin, respectively, with a lag time less than 1 hour. Transmission Electron Microscope analysis on skin samples and chemical analysis using Inductively Coupled Plasma-Mass Spectrometry demonstrated the presence of AuNPs into epidermis and dermis. This study showed that AuNPs are able to penetrate the human skin in an in vitro diffusion cell system.     

Fate of carbaryl in rat skin

Metabolism of carbaryl by rat liver and skin post-mitochondrial fraction has been measured in the presence and absence of cofactors to promote different metabolic pathways. The metabolic capacity was compared with the metabolism of carbaryl during percutaneous absorption in a static skin diffusion system using a variety of receptor fluids. Carbaryl was metabolised by hydrolysis, and ring hydroxylation followed by conjugation to the glucuronide or sulphate with liver post-mitochondrial fraction. Using skin post-mitochondrial fraction only hydrolysis and conjugation were detected. No metabolism was seen during percutaneous absorption in vitro even with receptor fluids which maintain the skin tissue viability. Studies using post-mitochondrial fraction indicate the metabolic capacity of the tissue, whereas during absorption, rates of absorption and accessibility of substrate to the metabolising enzymes must be considered.     

Effect of penetration enhancers on in vitro percutaneous penetration of nimesulide through rat skin

The influence of several penetration enhancers alone and/or in various combinations on the percutaneous penetration of nimesulide (NM) from Carbopol 934 based gel formulations was investigated. Skin permeation studies were performed using Franz-type diffusion cells and full-thickness abdominal rat skin. Various types of compounds such as ethanol, isopropyl alcohol, propylene glycol, Transcutol, Tween 80 and oleic acid were employed as penetration enhancers. The steady-state flux, the lag time and permeability coefficients of NM for each formulation were calculated. The results showed that the skin permeability of NM from gels tested was significantly increased (P < 0.05) by isopropyl alcohol (40%) and the combination of oleic acid (3%) with Transcutol (30%) when compared with the control formulation. In conclusion, these substances could be considered as penetration enhancers for NM topical formulations.     

Influence of membrane-solvent-solute interactions on solute permeation in skin

The relative importance of solubility parameters and other solvent properties on membrane diffusion processes has not been fully elucidated in the literature. Previously, we have studied the effect of different vehicles on the permeation of caffeine, benzoic acid (BA) and salicylic acid (SA) through silicone membranes. The present paper investigates diffusion of the selected permeants from different saturated solutions through human epidermis.

The permeation of caffeine was strongly affected by the vehicle chosen and the maximum enhancement observed for the permeation of caffeine was 288-fold. A maximum of 12-fold enhancement in the flux was observed for the permeation of SA and a maximum of 10-fold enhancement was observed for the permeation of BA. The diffusion profiles obtained for SA in the different solvents were very similar when compared with those obtained for BA but the permeation rates were higher for BA than for SA. This similarity results from the similar chemical structure and lipophilicity.     

不同浓度的月桂氮酮对双氯芬酸钠凝胶剂透皮吸收的影响

目的　通过动物离体透皮吸收试验 ,选择双氯芬酸钠凝胶剂中最佳浓度的月桂氮 艹卓 酮 (氮酮 ,Azone)作为渗透促进剂。方法　采用改良的Franz扩散装置 ,以离体鼠皮为屏障、生理盐水为接受介质 ,研究了不同浓度的月桂氮 艹卓 酮 (0 %、1%、2 %、3%、5 %Azone)对双氯芬酸钠凝胶剂透皮吸收的影响。结果　双氯芬酸钠凝胶剂 12h累积透皮释药百分率依次为 38.4 2 %、6 2 .35 %、72 .80 %、32 .10 %、5 5 .36 %。结论　Azone促进双氯芬酸钠凝胶剂透皮释药的最大浓度为 2 % ,筛选出 2 %月桂氮 艹卓 酮作为促进剂 ,制备了具有良好经皮吸收性能的双氯芬酸钠凝胶剂。     

Enhancing effect of alpha-monoisostearyl glyceryl ether on the percutaneous penetration of indomethacin through excised rat skin.

The enhancing effect of alpha-monoisostearyl glyseryl ether (GE-IS) on the percutaneous penetration of indomethacin (IM) from test solutions in propylene glycol (PG) was investigated using the excised abdominal skin of rats in vitro. The percutaneous penetration of IM into diffusion cells was significantly increased in the presence of 0.2% or 1% (w/w) GE-IS compared with enhancer-free PG solution. Permeation parameters of IM, such as lag time and permeability coefficient, revealed that GE-IS significantly augmented the percutaneous penetration of IM from PG. These results strongly suggested that GE-IS functions as a penetration enhancer of IM through rat skin. To elucidate the mode of action of GE-IS as a penetration enhancer, the solubility of IM in the test solution and the percutaneous penetration of IM through damaged skin from which the stratum corneum had been stripped were investigated. The results suggested that GE-IS acts directly on the stratum corneum and alters the permeability of the skin.     

Evaluation of nicotinamide microemulsion on the skin penetration enhancement

This study purposed to evaluate a microemulsion containing nicotinamide for its characteristics, stability, and skin penetration and retention comparing with a solution of nicotinamide in 2:1 mixture of water and isopropyl alcohol (IPA). The microemulsion system was composed of 1:1 mixture of Span80 and Tween80 as a surfactant mixture, isopropyl palmitate (IPP) as an oil phase, and 2:1 mixture of water and IPA as an aqueous phase. Nicotinamide microemulsion was prepared by dissolving the active in the aqueous phase before simply mixing with the other components. It was determined for its characteristics and stability under various conditions. The skin penetration and retention studies of nicotinamide microemulsion and solution were performed by modified Franz diffusion cells, using newborn pig skin as the membrane. The results showed that nicotinamide microemulsion could be obtained as clear yellowish liquid, was water-in-oil (w/o) type, possessed Newtonian flow, and exhibited physicochemical stability when kept at 4?°C and room temperature (≈30?±?2?°C) during 3 months. From the skin penetration data, the microemulsion could enhance the skin penetration of nicotinamide comparing with the solution. Additionally, nicotinamide microemulsion could provide much higher amount of skin retention than that of skin penetration, resulting in suitability for a cosmeceutical product.     

Differential effects of oxazepam and lorazepam on aggressive responding

Two doses of two very similar benzodiazepines (oxazepam 15 and 30 mg: lorazepam 1 and 2 mg) and placebo were compared 4 h post-administration on a competitive reaction time task designed to measure behavioural aggression. Forty-five subjects were assigned randomly to five independent drug groups. Subjective ratings of mood, anxiety and aggression were completed pre- and post-drug and post-task. Oxazepam and lorazepam had very similar subjective effects, but the higher dose of lorazepam increased aggressive responding on the task more than any other treatment. This may be related to the different ceiling efficacies of the two benzodiazepines.     

Effects of lorazepam on deductive reasoning

Rationale Benzodiazepines slow reasoning performance, but it is still unknown which phase of reasoning is affected and whether this effect is present for different types of relations between entities in reasoning problems. Objectives We investigated which phases of deductive reasoning are affected by lorazepam and whether this effect varies according to the type of relations in deductive reasoning problems. Methods This was a double-blind, crossover design study of acute oral doses of lorazepam (2 mg) and placebo, using young healthy volunteers. We focused on response delay of three separable phases of deductive reasoning and matched working memory tasks (that involved only maintenance of information) the premise processing phase, the premise integration phase, and the validation phase, in which reasoners decide whether a conclusion logically follows from the premises (reasoning task) or is identical to one of the premises (maintenance task). Type of relations in the premises was also manipulated. We employed material that was difficult to envisage visually and visuospatially (“subiconic”) and material easy to envisage visually or visuospatially. Results Lorazepam slowed response as memory load increased, irrespective of type of relations. It also specifically slowed validation in reasoning problems with visual relations, an effect that disappeared after subtraction of maintenance scores, and increased validation time in problems with subiconic relations, which remained after this subtraction. Conclusion Acute lorazepam administration affected reasoning in two ways: it slowed processing nonspecifically when working memory demands increased and augmented validation time depending on the difficulty in generating and/or manipulating mental representations by the central executive.