Corneal Critical Barrier against the Penetration of Dexamethasone and Lomefloxacin Hydrochloride: Evaluation by the Activation Energy for Drug Partition and Diffusion in Cornea

The cornea is a solid barrier against drug permeation. We searched the critical barrier of corneal drug permeation using a hydrophobic drug, dexamethasone (DM), and a hydrophilic drug, lomefloxacin hydrochloride (LFLX). The activation energies for permeability of DM and LFLX across the intact cornea were 88.0 and 42.1 kJ/mol, respectively. Their activation energies for permeability across the cornea without epithelium decreased to 33.1 and 16.6 kJ/mol, respectively. The results show that epithelium is the critical barrier on the cornea against the permeation of a hydrophobic drug of DM as well as a hydrophilic drug of LFLX. The activation energy of partition for DM (66.8 kJ/mol) was approximately 3-fold larger than that of diffusion (21.2 kJ/mol). The results indicate that the partition for the hydrophobic drug of DM to the corneal epithelium is the primary barrier. Thermodynamic evaluation of activation energy for the drug permeation parameters is a good approch to investigate the mechanism of drug permeability.     

The skin permeation mechanism of ketotifen: evaluation of permeation pathways and barrier components in the stratum corneum

To evaluate the pathways and barrier components in the stratum corneum (SC) for the permeation of ketotifen, the effect of delipidization on the permeation and partition was examined under several donor pHs. Assuming that ionized ketotifen (KTH+) and un-ionized ketotifen (KT) contribute independently in both permeation and partition, the intrinsic permeability coefficients and SC/water partition coefficients of both species were estimated. Delipidization enlarged the permeability of KTH+ 100 times. This suggested that the lipid phase functions as the barrier against KTH+. KT has an intrinsic permeability 100 times larger than that of KTH+. Delipidization did not result in a significant change in permeability of KT. This suggested that the permeability of KT through the lipid phase is comparable to that through the aqueous phase in delipidized SC; that is, the lipid phase functions as a highly permeable pathway for KT. On the other hand, the permeability coefficient of KTthrough delipidized SC was 1/34 of that through the pure aqueous layer, which had a thickness equivalent to SC. Since this suggests that the permeability of KT through the proteinaceous phase is much lower than that through the aqueous phase, the proteinaceous phase can be assumed to function as a barrier against the permeation of KT. From these results, it is concluded that the predominant permeation pathway for KT is through the lipid phase. The SC/water partition coefficient of KT was cut in half by delipidization, but the value was still more than 100. These results show that the proteinaceous phase functions not only as the barrier, but also as the depot for KT. The knowledge obtained here will be useful for formulation design and for the selection of enhancers in a transdermal therapeutic system of ketotifen.     

Long-Term Skin Permeation Kinetics of Estradiol (I): Effect of Drug Solubilizer-Polyethylene Glycol 400

Abstract

A skin permeation cell was recently developed to overcome the deficiencies noted in the currently available in vitro diffusion cells, and to provide a cell design which is suitable for studying the long-term drug permeation kinetics through the skin and is also sensitive enough for assessing the mechanisms of skin permeation by a high performance liquid chromatography.

To evaluate the rote of drug reservoir concentration in the kinetics of skin permeation as well as to maintain a sink condition in the receptor solution, the water-miscible polyethylene glycol (PEG) 400 was incorporated into the saline solution to act as a solubilizer to enhance the aqueous solubility of the relative water-insoluble estradiol. The equilibrium solubility of estradiol at 37°C was observed to in crease exponentially as increasing the volume fraction of PEG 400 added.

The rates o f permeation of estradiol across the male and female hairless mouse, whole and stripped skins excised freshly from the abdominal region, were measured a t various PEG concentrations and the permeability coefficients were determined. The permeability co-efficients were found t o decrease as increasing the PEG concentration. A linear relationship was established between th e permeability co-efficients and the skin /solution partition coefficients and the steady-stated if fusivity was calculated. Effect of sex was assessed.

The rate of permeation and the permeability coefficient across the stratum corneum were determined, using t h e multi-laminated dif-fusional resistance model. Results demonstrated that the stratum corneum acts as the rate-limiting barrier in the skin permeation of estradiol and the incorporation of upto 40% v/v PEG 400 does not in-fluence the barrier propertiesof stratum corneum, even though PEG 400 has been found to affect the aqueous solubility, permeability co-efficient, and skin /solution partition coefficient of estradiol.     

Controlled Transdermal Mucolytic Delivery System

Bromhexine a mucolytic agent was studied to explore for dermal route of administration. The formulations were based on commercial eudragit polymers and polyvinyl pyrrolidone.

Two systems i.e., Matrix and Pseudolatex were studied for their comparative performance evaluation in in vitro. The various combinations of hydrophobic (Eudragit RL-100) and hydrophilic (PVP 40,000) polymers were used to prepare the both matrix and pseudolatex topical systems. The prepared systems were studied for in vitro diffusion using a Franz diffusion cell. Study revealed that the relative concentration of hydrophobic to hydrophilic polymers determines the drug diffusion and across the skin permeation of the drug. Both the systems were noted to be stable, however, the drug release and across the skin permeability of drug from pseudolatex system recorded to be better and uniform. Preliminary studies on bromhexine are indicative of its potentiality for transdermal preparation and establish the need for in vivo evaluation.     

Long-Term Skin Permeation Kinetics of Estradiol (I): Effect of Drug Solubilizer-Polyethylene Glycol 400

A skin permeation cell was recently developed to overcome the deficiencies noted in the currently available in vitro diffusion cells, and to provide a cell design which is suitable for studying the long-term drug permeation kinetics through the skin and is also sensitive enough for assessing the mechanisms of skin permeation by a high performance liquid chromatography.

To evaluate the rote of drug reservoir concentration in the kinetics of skin permeation as well as to maintain a sink condition in the receptor solution, the water-miscible polyethylene glycol (PEG) 400 was incorporated into the saline solution to act as a solubilizer to enhance the aqueous solubility of the relative water-insoluble estradiol. The equilibrium solubility of estradiol at 37°C was observed to in crease exponentially as increasing the volume fraction of PEG 400 added.

The rates o f permeation of estradiol across the male and female hairless mouse, whole and stripped skins excised freshly from the abdominal region, were measured a t various PEG concentrations and the permeability coefficients were determined. The permeability co-efficients were found t o decrease as increasing the PEG concentration. A linear relationship was established between th e permeability co-efficients and the skin /solution partition coefficients and the steady-stated if fusivity was calculated. Effect of sex was assessed.

The rate of permeation and the permeability coefficient across the stratum corneum were determined, using t h e multi-laminated dif-fusional resistance model. Results demonstrated that the stratum corneum acts as the rate-limiting barrier in the skin permeation of estradiol and the incorporation of upto 40% v/v PEG 400 does not in-fluence the barrier propertiesof stratum corneum, even though PEG 400 has been found to affect the aqueous solubility, permeability co-efficient, and skin /solution partition coefficient of estradiol.     

Hydrogen transport through thin palladium-copper alloy composite membranes at low temperatures

Hydrogen permeation performance of three thin palladium-copper composite membranes with different thicknesses had been studied between 398 K and 753 K. Hydrogen permeance was obtained up to 2.7 × 10^− 6 mol/(m² s Pa) with an ideal selectivity over 1000 at 753 K. The hydrogen permeation exhibited two different activation energies over the temperature range: lower activation energy of about 9.8 kJ/mol above 548 K, while higher activation energy of about 26.4 kJ/mol below 548 K. After permeation tests, the alloy membranes were characterized by X-ray photoelectron spectroscopy, scanning electron microscopy, energy dispersive X-ray analysis and in situ X-ray diffraction. Palladium segregation on the surface of these palladium-copper alloys may induce changes of hydrogen permeation performance and thus influence the activation energies.     

316L不锈钢基体氧化铝涂层的氢渗透性能

在316L不锈钢上采用金属有机化学气相沉积(MOCVD)法沉积了氧化铝涂层。使用XRD、SEM分析氧化铝涂层的物相和微观形貌, 采用气相氢渗透装置对涂层氢渗透行为进行表征。结果表明, 973 K退火处理后涂层为非晶氧化铝, 涂层均匀、完整, 厚度为190 nm。氧化铝涂层的氢渗透压力指数为0.56~0.78, 说明氢渗透过程机制为表面过程和体扩散过程共同控制。氧化铝涂层的表观氢渗透率为P = 1.99×10^-6 exp(-117×10³/RT) mol/(m·s·Pa^1/2)。氧化铝涂层的氢渗透激活能为117 kJ/mol, 远高于316L不锈钢的66.6 kJ/mol, 涂层对氢的渗透具有明显的阻挡作用。此外, 在873~973 K氧化铝涂层对316L不锈钢的氢渗透阻挡因子(PRF)为59~119, 涂层氢渗透阻挡性能优异。     

Basil oil is a promising skin penetration enhancer for transdermal delivery of labetolol hydrochloride

The present work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER = 46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.     

Basil Oil is a Promising Skin Penetration Enhancer for Transdermal Delivery of Labetolol Hydrochloride

Thepresent work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER?=?46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.     

Computer simulation of the adsorption and diffusion of benzene in silicalite,theta-1, and a new zeolite,EU-1

The diffusion of benzene in three zeolites, silicalite, theta-1, and EU-1, is studied using the method of atom-atom potentials. Activation energies of diffusion for benzene were predicted to be about 25 kJ/mol in the silicalite straight channel and 3 kJ/mol in theta-1. Two modes of diffusion are suggested for benzene in EU-1: (a) solely along the straight channel with an activation energy of 22 kJ/mol and (b) diffusion along the straight channel into the side pocket with an activation energy of 28 kJ/mol. Limitations of the minimization routine employed are discussed.     

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

The Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability. Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds.     

Charge dependent catalytic activity of gasborne nanoparticles

It is shown experimentally that the electric charge of unsupported catalyst particles has a major influence on the methanation of CO with nano-sized Ni particles as catalyst at temperatures between 680 K and 720 K. Neutral particles showed an apparent activation energy of 148 kJ/mol, significantly higher than the apparent activation energies of 43 kJ/mol and 60 kJ/mol for negatively and positively charged particles, respectively. The obtained activation energies are comparable to energies obtained for different sites on alumina supported nickel catalysts. The change in activation energy can be qualitatively explained by different electron interchange between the chemisorbed species and the catalyst. We suggest that the observed effect of electron enhancement or depletion on catalysis is also a governing effect in strong metal support interaction (SMSI), where the displacement of electrons is related to the contact potential between catalyst and substrate.     

近临界水中聚甲基丙烯酸甲酯水解反应动力学

系统测定了近临界水中210℃～290℃下聚甲基丙烯酸甲酯的无催化和醋酸催化下水解反应动力学数据,并采用傅立叶变换红外光谱仪、凝胶色谱仪、热重分析仪对水解产物进行了表征。结果表明,近临界水中聚甲基丙烯酸甲酯水解改性是可行的,通过改变水解工艺条件可获得一系列不同酯基及羧基含量的水解产物;以自催化反应动力学模型对实验数据进行拟合,得到了无催化和1 mol/L醋酸催化条件下聚甲基丙烯酸甲酯水解反应活化能分别为47.3 kJ/mol和34.2 kJ/mol。     

Diffusion and permeation of vapors in composite polymer thin films

The moisture barrier properties of polyimide (PI) thin films used for passivation in microelectronic devices are poorer than those of many other polymers. The enhancement of the barrier properties of PI films obtainable by coating them with polymers of lower permeability to form multilayer composite membranes was investigated. In this paper we report a study of the diffusion and permeation of water vapor in four composite PI/polymer thin films: PI/polyethylene, PI/polyethylene-acrylic acid, PI/polyvinylidene fluoride and PI/poly(chloro-p-xylylene). The temperature-dependent permeability coefficient of single-layer and composite thin films was measured and found to follow the Arrhenius relation with low activation energies (lower than 6 kcal mol^?1). Enhancement in the barrier properties by a factor of 4–6 at 30°C is attained when 2–3 μm PI films are coated with 2 μm films of the four polymers investigated.     

Effects of some hydrophilic permeation enhancers on the absorption of bepridil through excised human skin

The permeation of Bepridil through excised human skin was measured from vehicles composed of various mixtures of aqueous buffer and the permeation enhancers ethanol, DMSO or DMF. Only DMSO was found to act as a true permeation enhancer for the drug, the magnitude of its action depending on its concentration in the vehicle. At concentrations greater than 50% DMSO the permeability coefficient of the drug was increased over and above that which could be accounted for by changes in partitioning of the drug between vehicle and skin. The effects of ethanol could be related to changes in the measured skin/vehicle partition coefficients of the drug. DMF showed a complicated, concentration dependent influence on permeation.     

Effects of some hydrophilic permeation enhancers on the absorption of bepridil through excised human skin

Abstract

The permeation of Bepridil through excised human skin was measured from vehicles composed of various mixtures of aqueous buffer and the permeation enhancers ethanol, DMSO or DMF. Only DMSO was found to act as a true permeation enhancer for the drug, the magnitude of its action depending on its concentration in the vehicle. At concentrations greater than 50% DMSO the permeability coefficient of the drug was increased over and above that which could be accounted for by changes in partitioning of the drug between vehicle and skin. The effects of ethanol could be related to changes in the measured skin/vehicle partition coefficients of the drug. DMF showed a complicated, concentration dependent influence on permeation.     

Design and Evaluation of Transdermal Drug Delivery System for Curcumin as an Anti-Inflammatory Drug

The purpose of this research was to develop a matrix-type transdermal therapeutic system containing herbal drug, curcumin (CUR), with different ratios of hydrophilic (hydroxyl propyl methyl cellulose K4M [HPMC K4M]) and hydrophobic (ethyl cellulose [EC]) polymeric systems by the solvent evaporation technique. Different concentrations of oleic acid (OA) were used to enhance the transdermal permeation of CUR. The physicochemical compatibility of the drug and the polymers was also studied by differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results suggested no physicochemical incompatibility between the drug and the polymers. Formulated transdermal films were physically evaluated with regard to drug content, tensile strength, folding endurance, thickness, and weight variation. All prepared formulations indicated good physical stability. In vitro permeation studies of formulations were performed by using Franz diffusion cells. The results followed Higuchi kinetics, and the mechanism of release was diffusion-mediated. Formulation prepared with hydrophilic polymer containing permeation enhancer showed best in vitro skin permeation through rat skin as compared with all other formulations. This formulation demonstrated good anti-inflammatory activity against carrageenan-induced oedema in Wistar albino rats similar to standard formulation.     

Design and evaluation of transdermal drug delivery system for curcumin as an anti-inflammatory drug

The purpose of this research was to develop a matrix-type transdermal therapeutic system containing herbal drug, curcumin (CUR), with different ratios of hydrophilic (hydroxyl propyl methyl cellulose K4M [HPMC K4M]) and hydrophobic (ethyl cellulose [EC]) polymeric systems by the solvent evaporation technique. Different concentrations of oleic acid (OA) were used to enhance the transdermal permeation of CUR. The physicochemical compatibility of the drug and the polymers was also studied by differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results suggested no physicochemical incompatibility between the drug and the polymers. Formulated transdermal films were physically evaluated with regard to drug content, tensile strength, folding endurance, thickness, and weight variation. All prepared formulations indicated good physical stability. In vitro permeation studies of formulations were performed by using Franz diffusion cells. The results followed Higuchi kinetics, and the mechanism of release was diffusion-mediated. Formulation prepared with hydrophilic polymer containing permeation enhancer showed best in vitro skin permeation through rat skin as compared with all other formulations. This formulation demonstrated good anti-inflammatory activity against carrageenan-induced oedema in Wistar albino rats similar to standard formulation.     

Characterization of the Enhancing Effect of a Vehicle in a Transdermal System

Abstract

The percutaneous absorption of Morphine and Morphine hydrochloride is optimized using binary solvent systems as vehicle of the drugs. Release kinectics through hairless mouse skin are performed in vitro: variations of the flux, of the lagtime and of the cumulative released quantities as a function of the vehicle composition point out a synergistic effect of the two solvents (Labrafac hydrophile and Transcutol). Independant determinations of the skin/vehicle partition coefficient, of the solubility and of the diffusion coefficient are realized; the results allow us to explain the different enhancing effects of each solvent: the first one has an enhancing effect on the drug concentration in the skin, and the second one modifies the mobility of the drug in the skin

The rate of the drug release is usually optimized increasing the drug activity in the donor in relation with the solubility variation. With transdermal system (matrix, film) a more accurate approach is to increase the skin permeation of the drug (1) (2). This effect is commonly attempted with enhancers contained in the system, but a particular vehicle can act as an enhancer and as a solvent (3–7). In this case, we optimize the permeation coefficient, P = (K D/e), where K is the skin/vehicle partition coefficient, D is the diffusion coefficient and e is the skin thickness. The partition coefficient allows variation of the drug concentration in the skin, while the diffusion coefficient represents the mobility of the drug in the skin

The aim of this presentation is to analyze, on experimental data, the variation of the permeation to identifie, to localize, and to explain the role of a such vehicle. We studied the morphine permeation through hairless mouse skin with a binary solvents system. The solvents used are a diethylene glycol monoether (T) and a glycolysed ethoxylated glyceride (L). We propose to analyze the influence of the mixture composition on the partition and diffusion coefficient of morphine. We used an hydrophilic specie, morphine hydrochloride (MHCl), and a lipophilic specie, basic morphine (M), assuming that their routes of penetration are different: etheir hydrophilic inter or intra cellular route, or lipidic intercellular route. We suppose that each solvent can modifie the physical or chemical structure of these routes and consequently, the permeation of one particular specie of morphine     

In vitro models to estimate drug penetration through the compromised stratum corneum barrier

Objectives: The phospholipid vesicle-based permeation assay (PVPA) is a recently established in vitro stratum corneum model to estimate the permeability of intact and healthy skin. The aim here was to further evolve this model to mimic the stratum corneum in a compromised skin barrier by reducing the barrier functions in a controlled manner. Methods: To mimic compromised skin barriers, PVPA barriers were prepared with explicitly defined reduced barrier function and compared with literature data from both human and animal skin with compromised barrier properties. Caffeine, diclofenac sodium, chloramphenicol and the hydrophilic marker calcein were tested to compare the PVPA models with established models. Results and discussions: The established PVPA models mimicking the stratum corneum in healthy skin showed good correlation with biological barriers by ranking drugs similar to those ranked by the pig ear skin model and were comparable to literature data on permeation through healthy human skin. The PVPA models provided reproducible and consistent results with a distinction between the barriers mimicking compromised and healthy skin. The trends in increasing drug permeation with an increasing degree of compromised barriers for the model drugs were similar to the literature data from other in vivo and in vitro models. Conclusions: The PVPA models have the potential to provide permeation predictions when investigating drugs or cosmeceuticals intended for various compromised skin conditions and can thus possibly reduce the time and cost of testing as well as the use of animal testing in the early development of drug candidates, drugs and cosmeceuticals.