Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules

Zhang, Qian; Grice, Jeffrey E.; Li, Peng; Jepps, Owen G.; Wang, Guangji; Roberts, Michael S.

doi:10.1007/s11095-009-9912-4

Cited by 79 publications

(64 citation statements)

References 57 publications

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“…Compounds with molecular weights less than 500 Da or with a log P of approximately 1 to 4 are most likely to be absorbed through the skin. [1][2][3] Thus, most of the drugs used in transdermal therapeutic systems are designed in accordance with these physicochemical parameters. 4) Many trials have investigated methods that might enhance the skin penetration of poorly absorbed compounds.…”

mentioning

confidence: 99%

Effects of Oils and Emulsifiers on the Skin Penetration of Stearyl Glycyrrhetinate in Oil-in-Water Emulsions

Sakata

Fujii

Koizumi

et al. 2014

Biological & Pharmaceutical Bulletin

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We investigated whether an emulsifier or an emulsified oil affects the skin penetration of stearyl glycyrrhetinate (SG) when it is applied in an oil-in-water (O/W)-type emulsion under finite dose conditions in vitro. SG has a high molecular weight (MW: 723) and high lipophilicity (log P: 15.6). Skin penetration of SG applied with O/W emulsions was evaluated using 6 types of emulsifiers that are commonly used in cosmetics; however, no significant differences were observed between these emulsifiers. When applied with liquid paraffins in oil phase, SG skin penetration increased significantly as the molecular weight of the liquid paraffin decreased. The skin penetration of the fluorescent dye 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI; MW: 834, log P: 23.2) also increased with O/W-type emulsions containing liquid paraffins of lower molecular weights. These results indicate that use of O/W-type emulsions with an appropriate oil phase can improve SG skin penetration.

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mentioning

confidence: 99%

Effects of Oils and Emulsifiers on the Skin Penetration of Stearyl Glycyrrhetinate in Oil-in-Water Emulsions

Sakata

Fujii

Koizumi

et al. 2014

Biological & Pharmaceutical Bulletin

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“…Other (multiparametric) models have incorporated additional descriptors, typically describing molecular shape, solubility, polarity, and hydrogen-bonding capacity. In addition to simple and multiple linear regression approaches, non-linear modelling has also been applied, including relatively simple approaches, such as parabolic models (e.g., Lien and Gao, 1995 99 ) and bilinear models (e.g., Zhang et al, 2009 100 ) to more complex ones, such as artificial neural networks (e.g., Fatemi and Malekzadeh, 1995 101 ). Most QSARs are published in the scientific literature, although some are implemented in freely available software, such as Episuite, or commercial tools, such as Schrodinger's QikProp.…”

Section: In Silico Methodsmentioning

confidence: 99%

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

DumontCoralie

PrietoPilar

AsturiolDavid

et al. 2015

Applied In Vitro Toxicology

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The exposure of the skin to consumer products, drugs, and environmental chemicals can result in their penetrating the skin barrier and entering systemic circulation, potentially resulting in adverse effects in the skin and other organs. The assessment of dermal penetration and bioavailability (including penetration, metabolism, and entry into the systemic circulation) is therefore an important consideration in the risk assessment of chemicals. The skin is a heterogeneous organ with a multilayer structure. Based on its architecture and physiology, substances can penetrate through three major ways but can also be blocked in the different skin layers and in the skin appendages, which act as reservoir. In addition to that, as the skin is a metabolically competent organ, substances can undergo metabolism. After a brief description of the skin architecture, this review will focus on the skin penetration mechanisms and skin metabolic capacities. The skin absorption has traditionally been tested in vivo on animals. However, with the new legislation (i.e., Registration, Evaluation, Authorisation, and Restriction of Chemicals Regulation or Cosmetics Regulation), alternatives to animal testing have to be implemented. In a second part, this review will provide a description of the main in vitro and in silico or computational models available to study skin absorption and skin metabolism (i.e., ex vivo skin models, artificial membrane barriers, primary cells and cell lines, Quantitative Structure-Activity Relationship [QSAR], simulators for the prediction of skin metabolism).

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“…Secondly (105), a vehicle or solute leads to increase in drug solubility in the SC. For example, a study by Kadir et al (106) suggested that addition of paraffin oil to propionic acid solutions increased the flux of either theophylline or adenosine by enhancing the flux of propionic acid into the skin and accelerating the partitioning of the solutes in the modified skin barrier. There are many agents which can enhance or retard skin penetration.…”

Section: Drug-vehicle-skin Interactionsmentioning

confidence: 99%

“…Topical administration products account for an increasingly significant percentage of solute delivery candidate compounds under clinical evaluation (106). To be useful, topical products must provide efficient delivery of actives to either the systemic circulation or to the skin, but for most substances, the uppermost layer of the skin, the stratum corneum presents a substantial barrier to their penetration.…”

Section: Introductionmentioning

confidence: 99%

“…The maximum or saturation flux (Jmax) is defined as that occurring when a solute is applied to the skin in a saturated solution. The important of Jmax is that for a given solute, it is an invariant in the thermodynamic description of the permeation process (106). By definition, if neither the vehicle nor the solute affect the membrane, the same maximum flux will be observed for the solute from a range of vehicles regardless of its concentration in them (138).…”

Section: Introductionmentioning

confidence: 99%

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Targeted skin delivery of topically applied drugs by optimised formulation design

Abd¹

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Early research concentrated on the relationship between a solute's physicochemical properties and its skin permeation, mostly from simple solutions. Relatively less is known about how vehicles, particularly complex ones, might also affect skin permeation by altering the properties of the skin, although this is an area that has attracted much interest. Key requirements for topical delivery is understanding the relationships between drug-vehicle, drug-skin or drug -vehicle -skin interaction. In this project, understanding this relationship was crucial to designing novel formulations able to deliver drugs with different lipophilicity topically or systemically. The first aim was to explore the impact of various solution compositions on skin permeation of some model drugs. I compared in vitro maximum penetration fluxes (Jmax) and solubilities of the vehicles (Sv) and of the stratum corneum (SSC) and derived diffusivities (D*) for four drugs (caffeine, minoxidil, lidocaine and naproxen) having a range of lipophilicities. I used a range of solvent vehicles that were hypothesised to affect the skin to differing degrees to evaluate vehicle effects on permeability parameters.If neither the vehicle nor the solute alters the properties of the skin, maximum (or saturated) solute flux is independent of both the vehicle composition and the solute's saturated solubility in that vehicle. These findings were confirmed in this study for all four drugs used.The permeation of caffeine, minoxidil, lidocaine and naproxen were found to be selectively enhanced by vehicles containing specific excipients that were hypothesised to alter the properties of the skin. The greatest effects were seen on flux and diffusivity by the eucalyptol (EU) and oleic acid (OA) vehicles on the more hydrophilic compounds, caffeine and minoxidil. We concluded that enhanced solute fluxes were mainly driven by increased diffusivity in the stratum corneum.I also examined the extent of skin permeation enhancement of the hydrophilic drug caffeine and lipophilic drug naproxen applied in nanoemulsions incorporating skin penetration enhancers. Infinite doses of fully characterised oil-in-water nanoemulsions containing the skin penetration enhancers oleic acid or eucalyptol as oil phases and caffeine (3%) or naproxen (2%) were applied to full-thickness skin and human epidermal membranes in Franz diffusion cells, along with aqueous control solutions. Caffeine and naproxen fluxes were determined over 8 h. Solute solubility in the formulations and in the stratum corneum, as well as the uptake of product components into the stratum corneum were measured.The nanoemulsions significantly enhanced the skin penetration of caffeine and naproxen compared to aqueous control solutions. The maximum flux enhancement of caffeine was III associated with a synergistic increase in both its solubility in the stratum corneum and skin diffusivity. Enhanced skin penetration in these systems is largely driven by uptake of formulation excipients containing the active compounds into th...

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Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules

Cited by 79 publications

References 57 publications

Effects of Oils and Emulsifiers on the Skin Penetration of Stearyl Glycyrrhetinate in Oil-in-Water Emulsions

Effects of Oils and Emulsifiers on the Skin Penetration of Stearyl Glycyrrhetinate in Oil-in-Water Emulsions

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

Targeted skin delivery of topically applied drugs by optimised formulation design

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