Percutaneous Absorption Process Research Articles

Size-Dependent Absorption through Stratum Corneum by Drug-Loaded Liposomes

Topical treatment of various skin disorders requires drug absorption and penetration through the stratum corneum (SC) into the epidermis and dermis tissues. The use of nano-drug delivery systems including liposomes and lipid nanoparticles (SLNs) have been shown to facilitate SC penetration. The goal of this work was to study the impact of liposome sizes and the resulted drug distribution inside various skin tissue. All trans retinoic acid (ATRA) was used as the model drug and loaded into gel phase HSPC/CHOL/DSPE-PEG liposomes (lipo-ATRA) with sizes ranging from 80nm to more than 300nm. The percutaneous drug absorption process was monitored and analyzed. There were significant differences in percutaneous absorption and tissue distribution resulted from liposomes smaller than 100nm and those bigger than 200nm. Lipo-ATRA with a mean diameter of 83nm can deliver the content to epidermis and dermis. But for 200nm - 300nm liposomes, the resulted epidermis and dermis ATRA levels were less than about one third, suggesting bigger liposomes had poor penetration through the brick and mortar structure of SC. Gel phase liposomes with sizes under 100nm improved encapsulated drug absorption and distribution into the epidermis and dermis tissues. A size dependent mechanism for liposome penetration of the stratum corneum was proposed.

Probing the Role of Ion-Pair Strategy in Controlling Dexmedetomidine Penetrate Through Drug-in-Adhesive Patch: Mechanistic Insights Based on Release and Percutaneous Absorption Process.

The purpose of present study was to develop a controlled release drug-in-adhesive patch for transdermal delivery of dexmedetomidine (Dex) using ion-pair technique. Based on the in vitro transdermal experiment, the role of ion-pair on the Dex release behavior and percutaneous absorption process was also investigated. Fourier transform infrared spectroscopy (FTIR), molecular modeling, differential scanning calorimetry (DSC), and rheological test were conducted to probe the effect of ion-pair on the Dex release from patch. Besides, the tape stripping test, attenuated total reflectance Fourier transform infrared (ATR-FTIR), and molecular simulation were carried out to elaborate the action of ion-pair on the Dex percutaneous permeation process. Results showed that the optimized patch prepared with Dex-salicylic acid (SA) showed zero-order skin permeation profile within 24h; Dex-SA had greater hydrogen bonding formation potential with pressure sensitive adhesive (PSA) than Dex, which resulted in the decrease in the formation ability of free volume of PSA and the increase with the improvement of mechanical strength and chain stiffness of PSA and thus controlled the release rate of Dex from transdermal patch. Besides, the physicochemical properties of Dex such as molecular weight and octanol/water partition coefficient were changed after forming ion-pair with SA, which decreased the permeation ability of Dex. In conclusion, a controlled release drug-adhesive patch for Dex was developed and the mechanism study of ion-pair on the Dex release and percutaneous permeation process was proposed at molecular level.

Ethosomal Gel for Improving Transdermal Delivery of Thymosin β-4.

PurposeThymosin β-4(Tβ-4) is a macromolecular protein drug with potential for drug development in wound repair but is limited by the shortcomings of macromolecular protein, such as large volumes, poor membrane permeability, and unstable physicochemical characteristics. Ethosomes could enhance cell membrane fluidity and reduce epidermal membrane density to make macromolecular drugs through the stratum corneum into the deeper layers of the skin easily. Herein, we developed and characterized a novel transdermal delivery vehicle to load macromolecular protein peptides and use Tβ-4 as a model drug wrapped into ethosomes.MethodsWe used the orthogonal method to optimize the formulation of the ethosome preparation prepared by the ethonal infusion method. Ethosomal gels were characterized by using different analytical methods. Transdermal release rate in vitro have been demonstrated in Franz diffusion cells and the efficacy of drug-loaded nanocarriers in vivo was investigated in a mouse model.ResultsOptimized Tβ-4 ethosomal gels have good physicochemical properties. The drug amounts of the cumulative release in the ethosomal gel within 5 hours were 1.67 times that of the T-β4 gel in vitro release study, and the wound healing time of ethosomal gel group was only half of the T-β4 gel group in vivo pharmacokinetic study. Compared with the free drug group, the ethosome preparation not only promotes the percutaneous absorption process of the macromolecular protein drugs but also shortened wound recovery time.ConclusionHence, we provide a possible good design for ethosomal gel system that can load macromolecular protein peptide drugs to achieve transdermal drug administration, promoting the percutaneous absorption of the drug and improving the effect.

Lattice Boltzmann model of percutaneous drug absorption

A lattice Boltzmann numerical modeling method was developed to predict skin concentration after topical application of a drug on the skin. The method is based on D2Q9 lattice spaces associated with the Bhatnagar-Gross-Krook (BGK) collision term to solve the convection-diffusion equation (CDE). A simulation was carried out in different ranges of the value of bound γ, which is related to skin capillary clearance and the volume of diffusion during a percutaneous absorption process. When a typical drug is used on the skin, the value of γ corresponds to the amount of drug absorbed by the blood and the absorption of the drug added to the skin. The effect of γ was studied for when the region of skin contact is a line segment on the skin surface.

Mechanistic insights of the enhancement effect of sorbitan monooleate on olanzapine transdermal patch both in release and percutaneous absorption processes

In this paper, based on the optimized formulation of olanzapine (OLN) transdermal patch, the role of sorbitan monooleate (SP) in OLN release and percutaneous absorption processes was probed in vitro and in vivo. Rheological test, DSC, FT-IR and molecular modeling were conducted to elucidate the effect of SP on the release process of OLN from transdermal patch. Additionally, the action of SP on the percutaneous absorption process was probed using tape stripping transdermal experiment, confocal laser scanning microscopy (CLSM), ATR-FTIR and molecular docking. The results showed that the hydrogen bonding interaction between OLN and pressure sensitive adhesive (PSA) was weakened by SP, which resulted in a decrease in the cohesive interaction between polymer chains and an increase in the formation of free volume of PSA, thus, the release of OLN from patch was promoted. Meanwhile, the OH groups of SP interacted with the polar head groups of the ceramides, which increased the fluidity of the skin lipids, thereby improved the ability of OLN percutaneous absorption. In summary, this study demonstrated that not only the release but also the percutaneous absorption processes were promoted by SP. This study provided comprehensive molecular level understanding on the effect of penetration enhancer on transdermal patch and strategies for rationally selection of chemical enhancer for transdermal drug delivery systems.

LC-ESI-MS method for the determination of dexamethasone acetate in skin of nude mouse

A high-performance liquid chromatography-positive electrospray ionization single quadrupole mass spectrometric (LC-ESI-MS) method for the determination of dexamethasone acetate in skin of nude mouse using triamcinolone acetonide acetate as the internal standard (I.S.) was developed and fully validated. Both compounds were precipitated from skin homogenate with methanol and were separated by HPLC on a Shimadzu Shim-pack VP-ODS C18 column (150mm×2.0mm, 5μm) with a mobile phase of methanol-water (80:20, v/v) at a flow rate of 0.2mL/min. Calibration curves were linear over the range of 0.05-5μg/mL. The intra-run relative standard deviations were less than 9.59%. The inter-run relative standard deviations were less than 7.82%. The mean recovery was in the ranges of 89.95-95.97%, respectively. The method was successfully applied to determinate the concentration of dexamethasone acetate in skin and study the percutaneous absorption process in skin of nude mouse.

Determination of benzophenone-3 and its main metabolites in human serum by dispersive liquid–liquid microextraction followed by liquid chromatography tandem mass spectrometry

A new analytical method for the determination of benzophenone-3 (2-hydroxy-4-methoxybenzophenone), and its main metabolites (2,4-dihydroxybenzophenone and 2,2’-dihydroxy-4-methoxybenzophenone) in human serum is presented. The method is based on dispersive liquid–liquid microextraction (DLLME) as preconcentration and clean-up technique, followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Acidic hydrolysis and protein precipitation with HCl 6M (1:1) (100°C, 1h) were carried out before extraction. The variables involved in the DLLME process were studied. Under the optimized conditions, 70µL of acetone (disperser solvent) and 30µL of chloroform (extraction solvent) were mixed and rapidly injected into 800µL of hydrolyzed serum sample. Sample pH or ionic strength adjustment were not necessary. The method was validated by analyzing spiked human serum samples. No satisfactory recoveries were obtained when aqueous standards or standards prepared in synthetic serum were used, but excellent recoveries were achieved by using matrix-matched calibration standards. Moreover, limits of detection in the low µgL−1 level and good repeatability were obtained. In order to show the applicability of the proposed method in the study of percutaneous absorption processes, it was applied to the analysis of serum samples from two volunteers after topical application of a sunscreen cosmetic product containing 2-hydroxy-4-methoxybenzophenone.

Comparative in vitro characterization of moxidectin and doramectin percutaneous absorption through bovine skin

Topical formulations have achieved worldwide acceptance in veterinary medicine because their administration is an easy, less labor-intensive and nonstressing form. Any chemical compound that comes in contact with the skin has the potential to be locally and/or systemically absorbed. However, many factors related to the features of animal skin, composition of the topical formulation and to the drug itself can determine marked differences in the percutaneous absorption process. The aim of the current work was to characterize the pattern of in vitro percutaneous absorption for moxidectin (MXD) and doramectin (DRM), two of the most worldwide used topical macrocyclic lactone antiparasitic compounds in cattle. The work included the development of a simple and inexpensive in vitro assay useful to predict in vivo drug percutaneous absorption in cattle. Both drugs were administered as the commercial formulations intended for their topical administration to cattle. The in vitro studies were carried out using modified Franz-type vertical diffusion cells. Cattle skin slices of 500 μm thickness were prepared using a dermatome to separate the stratum corneum and upper epidermis from dermis and subcutaneous tissue. The receptor medium was sampled up to 72 h postadministration and drug concentrations were measured by HPLC. The parameters used to estimate the comparative in vitro skin permeation showed marked differences between DRM and MXD. A 5.29-fold longer lag time (T(lag)) was observed for DRM. Similarly, the flux (J) (2.93-fold) and the permeation coefficients (K(p) ) (2.95-fold) in cattle skin were significantly higher (P < 0.05) for DRM compared to those obtained for MXD. Additionally, the data obtained from the in vitro permeation studies was correlated with the plasma concentrations of both compounds achieved in vivo in cattle treated with the same topical formulations. Correlation coefficients between percentage of drug permeated in vitro vs. percentage of drug absorbed in vivo (up to 48 h post-treatment) were 0.856-0.887 (MXD) and 0.976-0.990 (DRM). However, the highest in vitro-in vivo correlations for both molecules were observed up to 24 h post-treatment A rapid screening method for testing different topical formulations can be achieved with the simple in vitro cattle skin permeation technique described here, which has been successfully adapted to test the comparative percutaneous absorption of MXD and DRM.

Rapid evaluation and quantitative analysis of eugenol derivatives in essential oils and cosmetic formulations on human skin using attenuated total reflectance–infrared spectroscopy

We studied the fragrances 4-allylbenzenes (eugenol, methyl eugenol, acetyl eugenol) as well as 4-propenylbenzenes (isoeugenol) in commercial essential oils using a fast and nondestructive attenuated total reflectance–infrared (ATR–IR) spectroscopy method. The method was based on ATR–IR utilizing partial least square regression. The calibrations were modeled in the characteristic region for eugenol (1430–1432 cm−1), isoeugenol (960–970 cm−1) and methyl eugenol (803–807 cm−1). The models were then applied to predict the percutaneous absorption process yield and to monitor the concentrations of eugenol derivatives on human skin.

Rapid evaluation and quantitative analysis of eugenol derivatives in essential oils and cosmetic formulations on human skin using attenuated total reflectance–infrared spectroscopy

We studied the fragrances 4-allylbenzenes (eugenol, methyl eugenol, acetyl eugenol) as well as 4-propenylbenzenes (isoeugenol) in commercial essential oils using a fast and nondestructive attenuated total reflectance–infrared (ATR–IR) spectroscopy method. The method was based on ATR–IR utilizing partial least square regression. The calibrations were modeled in the characteristic region for eugenol (1430–1432 cm−1), isoeugenol (960–970 cm−1) and methyl eugenol (803–807 cm−1). The models were then applied to predict the percutaneous absorption process yield and to monitor the concentrations of eugenol derivatives on human skin.

A Compartment Model for Percutaneous Drug Absorption

In recent years, compartment models have been advocated for percutaneous drug absorption.- However, in vitro percutaneous permeation processes where steady-state is eventually attained have long been described using Fick's Law of Diffusion. Fick's Law is also sometimes applied to in vitro and in vivo percutaneous absorption pharmacokinetics where a finite dose is given. Although both compartment and diffusion models are currently employed to describe percutaneous absorption pharmacokinetics, it is not well known whether a compartment model can substitute for a diffusion model. This communication indicates that a compartment model is roughly interchangeable with a diffusion model so that finite dose percutaneous absorption processes, including those after the removal of vehicle and repeated dosing, can be approximated by a compartment model.

Pharmacodynamic measurements of methyl nicotinate percutaneous absorption: the effect of aging on microcirculation

The penetration of drugs through aged skin is important both in terms of transdermal delivery to elicit systemic pharmacological effects, and for topical treatment. Cutaneous microcirculation efficiency, an integral parameter in the overall process of percutaneous absorption, was studied in young (20-34 years) and old (64-86 years) individuals. Cutaneous erythema as induced by topical administration of methyl nicotinate to the ventral forearm, was monitored non-invasively using laser-Doppler flowmetry. Dose-response behaviour was characterized by five parameters: (i) the time of onset of action; (ii) the time to reach maximum response; (iii) the magnitude of the maximum response; (iv) the area under the response-time curve; and (v) the time to decay to 75% of the maximum response. Additionally, the sensitivity and efficiency of the cutaneous microcirculation in both age groups was evaluated using a pharmacokinetic-pharmacodynamic model. Statistical analysis of all data showed no significant differences between the age groups for the same concentrations. The results indicate that microvessel reactivity to the applied stimulus is comparable in the ventral forearm of both young and old populations.

In Vitro Evaluation of Skin Absorption and Metabolism

AbstractIn vitro methods using human and animal skin have frequently been used to measure the absorption/diffusion of chemicals through skin. Since some compounds have recently been shown to be metabolized during the percutaneous absorption process, we are examining the importance and feasibility of determining metabolic activity in skin when making absorption measurements. The viability of skin can be readily maintained for at least 24 hr in flow-through diffusion cells. A Hepes-buffered Hank's balanced salt solution is, in some cases, superior as a receptor fluid to minimum essential medium containing 10% fetal bovine serum. The balanced salt solution is sufficient to maintain viability as assessed by glucose metabolism and electron microscopy and it does not interfere with quantitation of metabolites. We have found enzyme activity in skin to be 10-100 times less than that in liver and insufficient for detectable metabolism of caffeine, salicylic acid, or chlorophenothane (DDT) during absorption studies...

A diffusion-diffusion model for percutaneous drug absorption.

Several theories describing percutaneous drug absorption have been proposed, incorporating the mathematical solutions of differential equations describing percutaneous drug absorption processes where the vehicle and skin are regarded as simple diffusion membranes. By a solution derived from Laplace transforms, the mean residence time MRT and the variance of the residence time VRT in the vehicle are expressed as simple elementary functions of the following five pharmacokinetic parameters characterizing the percutaneous drug absorption: kd, which is defined as the normalized diffusion coefficient of the skin, kc, which is defined as the normalized skin-capillary boundary clearance, the apparent length of diffusion of the skin 1d, the effective length of the vehicle lv, and the diffusion coefficient of the vehicle Dv. All five parameters can be obtained by the methods proposed here. Results of numerical computation indicate that: concentration-distance curves in the vehicle and skin approximate two curves which are simply expressed using trigonometric functions when sufficient time elapses after an ointment application; the most suitable condition for the assumption that the concentration of a drug in the uppermost epidermis can be considered unchanged is the case where the partition coefficient between vehicle and skin is small, and the constancy of drug concentration is even more valid when the effective length of the vehicle is large; and the amount of a drug in the vehicle or skin and the flow rate of the drug from vehicle into skin or from skin into blood becomes linear on a semilogarithmic scale, and the slopes of those lines are small when Dv is small, when the partition coefficient between vehicle and skin is small, when lv is large, or when kc is small. A simple simulation method is also proposed using a biexponential for the concentration-time curve for the skin near the skin-capillary boundary, that is, the flow rate-time curve for drug passing from skin into blood.

Percutaneous absorption of piroxicam from ointment bases in rabbits

In order to investigate the process of percutaneous absorption from various ointment bases, the blood levels of piroxicam were determined at optimal intervals after the ointment application in rabbits. After the oral and intravenous administrations, the plasma levels of piroxicam were described by the two-compartment model. A pharmacokinetic model similar to the percutaneous absorption of indomethacin was developed to test the concepts regarding the percutaneous absorption of piroxicam from topical ointment bases. A reasonably good fit between experimental and calculated values was obtained by taking into account identical absorption rate constant (K a) and the changes in drug release constant (K r) and the fraction of drug absorbed (F). We found that piroxicam in the o/w ointment base (UCH ointment containing 12% propylene glycol) had a better percutaneous absorption effect than the other three different kinds of ointment bases which were a simple ointment, PEG ointment and petrolatum rosewater ointment. The pH value of the water phase in UCH ointment containing 12% propylene glycol was adjusted to pH 9.2 by the sodium bicarbonate-buffered solution, then the percutaneous absorption of piroxicam could be increased. The effect of the amount of piroxicam on the percutaneous absorption was also investigated. The optimal effect with the additives in the ointment was finally attained with an addition of 5% urea.

A theoretical consideration of percutaneous drug absorption.

The percutaneous drug absorption process and its clinical significance are not fully known. In this article we propose a theoretical method to obtain two parameters (kd and kc) of percutaneous drug absorption from in vivo data. These parameters are related to diffusion of a drug through the skin and removal process at the skin-capillary boundary, respectively, characterizing several pharmacokinetic aspects of the drug applied to the skin. Moreover, by employing these two kinetic constants, a simulation of percutaneous drug absorption can be theoretically generated. On the basis of our theoretical considerations on the percutaneous drug absorption process described herein, we conclude that the percutaneous drug absorption process is better understood by employing two kinetic constants in a mathematical model and that its clinical application would be highly possible.

Influence of vehicle composition on the penetration of indomethacin through guinea-pig skin.

In order to investigate the process of percutaneous absorption of indomethacin (IND) from aqueous ethanol solution, the flux of IND was determined under various conditions by using a specially designed diffusion cell which was attached to the back of a guinea-pig. It was found that the flux of IND was governed by the initial concentration of IND, pH, the amount of ethanol in the vehicle and the amount of additive ester : the flux increased with increase in the concentrations of IND and added ester, but decreased with increase in pH and the amount of ethanol. The interactions of the components of the vehicle with IND and the skin appeared to influence the process of the percutaneous absorption of IND very strongly.

Percutaneous Absorption After Twenty-five Years: Or “Old Wine in New Wineskins”

Two developments have greatly added to our knowledge of percutaneous absorption over the past quarter century: (1) proof that the entire stratum corneum is the effective barrier layer of the skin, and (2) the advent of highly sensitive analytical techniques. The first enabled us to measure permeation rates on excised skin and the second greatly extended the kinds of substances that could be studied in vivo and in vitro. The process of percutaneous absorption is beginning to be understood more quantitatively. New light has been shed on the elementary mechanisms of permeation, the site of diffusional resistance at the molecular level, the effect of specific functional groups on solute permeation, the role of skin appendages, and the effects of vehicles.

Factors Influencing Percutaneous Absorption II: Absorption of Methyl Ethyl Ketone

A method is described for following the percutaneous absorption process with a vapor-phase chromatography technique. Data showing the absorption of methyl ethyl ketone (MEK) from a forearm surface of 91.5cm.² under both normal and hydrous conditions of the stratum corneum are presented. Hydration of the stratum corneum enhanced the percutaneous absorption rate of methyl ethyl ketone, but this penetrant subsequently partially dehydrated the stratum corneum. The resulting steady-state concentration of MEK in expired air, however, was still higher than that obtained with normal skin.