Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations (original) (raw)
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Journal of controlled release : official journal of the Controlled Release Society, 2016
Skin is attractive for drug therapy because it offers an easily accessible route without first-pass metabolism. Transdermal drug delivery is also associated with high patient compliance and through the site of application, the drug delivery can be locally directed. However, to succeed with transdermal drug delivery it is often required to overcome the low permeability of the upper layer of the skin, the stratum corneum (SC). One common strategy is to employ so-called penetration enhancers that supposedly act to increase the drug passage across SC. Still, there is a lack of understanding of the molecular effects of so-called penetration enhancers on the skin barrier membrane, the SC. In this study, we provide a molecular characterization of how different classes of compounds, suggested as penetration enhancers, influence lipid and protein components in SC. The compounds investigated include monoterpenes, fatty acids, osmolytes, surfactant, and Azone. We employ natural abundance (13)C...
Pharmaceutics, 2012
The stratum corneum is a major barrier of drug penetration across the skin in transdermal delivery. For effective transdermal drug delivery, skin penetration enhancers are used to overcome this barrier. In the past decades, a number of research studies were conducted to understand the mechanisms of skin penetration enhancers and to develop a structure enhancement relationship. Such understanding allows effective prediction of the effects of skin penetration enhancers, assists topical and transdermal formulation development, and avoids extensive enhancer screening in the transdermal delivery industry. In the past two decades, several hypotheses on chemical enhancer-induced penetration enhancement for transport across the skin lipoidal pathway have been examined based on a systematic approach. Particularly, a hypothesis that skin penetration enhancement is directly related to the concentration of the enhancers in the stratum corneum lipid domain was examined. A direct relationship bet...
Journal of Pharmaceutical Sciences, 2003
Studies were previously conducted in our laboratory on the influence of n-alkanols, 1-alkyl-2-pyrrolidones, N,N-dimethlyalkanamides, and 1,2-alkanediols as skin permeation enhancers on the transport of a model permeant, corticosterone (CS). The experiments were conducted with hairless mouse skin (HMS) in a side-by-side, twochamber diffusion cell, with enhancer present in an aqueous buffer in both chambers. The purpose of the present study was to extend these studies and investigate in greater detail the hypothesis that a suitable semipolar organic phase may mimic the microenvironment of the site of enhancer action, and that the enhancer partitioning tendency into this organic phase may be used to predict the enhancer potency. CS flux enhancement along the lipoidal pathway of HMS stratum corneum was determined with the 1-alkyl-2-azacycloheptanones, 1-alkyl-2-piperidinones, 1,2-dihydroxypropyl decanoate, 1,2dihydroxypropyl octanoate, n-alkyl-b-D-glucopyranosides, 2-(1-alkyl)-2-methyl-1,3-dioxolanes, 1,2,3-nonanetriol, and trans-hydroxyproline-N-decanamide-C-ethylamide as enhancers. Enhancement factors (E values) were calculated from the permeability coefficient and solubility data over a range of E values. Comparisons of the enhancer potencies for all studied homologous series and the carbon number of the n-alkyl group revealed a nearly semilogarithmic linear relationship with a slope of $0.55, which is consistent with the hydrophobic effect. Moreover, comparisons of the enhancer potencies of all the enhancers with the n-hexanol-phosphate buffered saline (PBS), n-octanol-PBS, n-decanol-PBS, and n-hexane-PBS partition coefficients showed very good correlations for the n-alkanol solvents but not for n-hexane. This result supports the interpretation that the enhancer potency is directly related to the ability of the enhancer molecule to translocate to a site of action via its free energy of transfer from the bulk aqueous phase to a semipolar microenvironment in the stratum corneum lipid lamella that is well mimicked by water-saturated n-alkanols. ß
Mode of action of penetration enhancers in human skin
Journal of Controlled Release, 1987
Skin penetration enhancers are molecules which reversibly remove the barrier resistance of the stratum corneum. They allow drugs to penetrate more readily to the viable tissues and thus enter the systemic circulation. This paper presents a general theory for enhancer activity based on possible alterations at the molecular level of the stratum corneum. Within the intercellular route, accelerants may interact at the polar head groups of the lipids, within aqueous regions between lipid head groups, and between the hydrophobic tails of the bilayer. Within the corneocyte the keratin fibrils and their associated waterprovide the target. High concentrations of solvents may also alter partitioning phenomena. The theory has been applied specifically to water, Azone, dimethylsulfoxide, dimethylformamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, oleic acid, decylmethylsulfoxide, sodium lauryl sulfate andpropyleneglycol. The main techniques which supplied experimental support for the theory were permeation studies through human skin, the vasoconstrictor assay and differential scanning calorimetry; the results from DSC are mainly considered here. PERMEABILITY BARRIER OF HUMAN SKIN The importance of the stratum corneum in the barrier function of skin is well established, with the entire horny layer providing the major rate-limiting barrier. There are some exceptions to this-for instance for very lipophilic drugs the aqueous epidermal and dermal layers may provide a significant hindrance because of the clearance effect. Also, the appendage route may be important for ionic molecules or large polar compounds. However for most penetrants, permeation through the bulk of the stratum corneum provides the rate-limiting step at
Molecules, 2018
The skin permeability (Kp) defines the rate of a chemical penetrating across the stratum corneum. This value is widely used to quantitatively describe the transport of molecules in the outermost layer of epidermal skin and indicate the significance of skin absorption. This study defined a Kp quantitative structure-activity relationship (QSAR) based on 106 chemical substances of Kp measured using human skin and interpreted the molecular interactions underlying transport behavior of small molecules in the stratum corneum. The Kp QSAR developed in this study identified four molecular descriptors that described the molecular cyclicity in the molecule reflecting local geometrical environments, topological distances between pairs of oxygen and chlorine atoms, lipophilicity, and similarity to antineoplastics in molecular properties. This Kp QSAR considered the octanol-water partition coefficient to be a direct influence on transdermal movement of molecules. Moreover, the Kp QSAR identified a sub-domain of molecular properties initially defined to describe the antineoplastic resemblance of a compound as a significant factor in affecting transdermal permeation of solutes. This finding suggests that the influence of molecular size on the chemical's skin-permeating capability should be interpreted with other relevant physicochemical properties rather than being represented by molecular weight alone.
are molecules that interact with the constituents of skin's outermost and rate limiting layer stratum corneum (SC), and increase its permeability. Designing and testing of new CPEs is a resource intensive task, thus limiting the rate of discovery of new CPEs. In-silico screening of CPEs in a rigorous skin model could speed up the design of CPEs. In this study, we performed coarse grained (CG) molecule dynamics (MD) simulations of a multilayer skin lipid matrix in the presence of CPEs. The CPEs are chosen from different chemical functionalities including fatty acids, esters, and alcohols. A multi-layer in-silico skin model was developed. The CG parameters of permeation enhancers were also developed. Interactions of CPEs with SC lipids was studied in silico at three different CPE concentrations namely, 1% w/v, 3% w/v and 5% w/v. The partitioning and diffusion coefficients of CPEs in the SC lipids were found to be highly size-and structure-dependent and these dependencies are explained in terms of structural properties such as radial distribution function, area per lipid and order parameter. Finally, experimentally reported effects of CPEs on skin from the literature are compared with the simulation results. The trends obtained using simulations are in good agreement with the experimental measurements. The studies presented here validate the utility of in-silico models for designing, screening and testing of novel and effective CPEs.
International Journal of Pharmaceutics, 1997
It is widely accepted that the intercellular lipid domain of the stratum corneum (SC) is the main barrier to transdermal permeation of most drugs. Previously, we reported a lamellar lipid matrix capable of modelling the structural properties of the SC intercellular lipids and its barrier performance toward oestradiol (OE) and 5-fluorouracil (5-FU). To investigate the ability of the matrix in modelling the effects of terpene penetration enhancers on the barrier performance of the SC, permeation of model drugs (OE and 5-FU) through cineole or limonene treated matrices were investigated here. Results revealed that the matrix is able to model the effects of cineole and limonene on the permeability coefficients of OE through the SC. The effects of cineole on the permeability coefficient of 5-FU through the SC seem to be underestimated by the model matrix; the difference was attributed to the effects of cineole on the SC intracellular proteins or to differences in the hydrophilicities of the SC lipids and the matrix. The matrix failed to model the enhancement effect of limonene toward permeation of 5-FU through the SC which might indicate that limonene increases the permeation of 5-FU in part through interactions with SC proteins which are not modelled in the matrix.
The role of percutaneous penetration enhancers
Advanced drug delivery reviews, 1996
It is clear that scientists are now only beginning to comprehend the complexity of transdermal drug delivery. Elucidation of the biochemical composition and functioning of the intrinsic diffusional barrier of the stratum corneum has prompted investigation of chemical and physical means of enhancing the percutaneous penetration of poorly absorbed drugs. Chemical enhancers that aid absorption of co-administered moieties are currently believed to improve solubility within the stratum corneum or increase lipid fluidity of the intracellular bilayers. Alternatively, the use of ionto-or phonophoresis may facilitate the absorption of some drug molecules by physical alteration of the barrier. The role of penetration enhancer inclusion in topical formulations has been well documented and will undoubtedly, in the future, permit the delivery of broader classes of drugs through the stratum corneum.
Skin Deep: The Basics of Human Skin Structure and Drug Penetration
Drug penetration and permeation through the skin are greatly influenced by the structural properties of the skin and the physicochemical properties of the drug. As such, penetration enhancement techniques largely focus on manipulating these two key factors. A great deal of research has focused on the stratum corneum, the primary skin barrier. In this chapter, we describe the structural properties of human skin, its functions, and the basic principles of drug penetration. The lipid composition and structural organisation of the stratum corneum, as well as the pathways of drug permeation, are highlighted. This chapter should provide a basic understanding of these topics and prepare the reader for advanced discussions in the specialist chapters that follow.