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The effects of ethanol on the transport of ??-estradiol and other permeants in hairless mouse skin. II. A new quantitative approach
Abstract
The influence of ethanol on the transport behavior of β-estradiol and other permeants in hairless mouse skin was investigated over a 0–100% ethanol/saline concentration range. At high ethanol levels (> 50%), there were significant increases in new pore formation in the stratum corneum component of the skin. With pure ethanol, pore pathway transport dominated the permeation for all solutes, irrespective of polarity. At low ethanol levels (<25%), ethanol had little or no effect on the pore pathway. However, the transport of β-estradiol and hydrocortisone via the lipid pathway of the stratum corneum was greatly enhanced. The enhancement factor, E, for β-estradiol and for hydrocortison was calculated from the experimental permeation data by correcting for the dermis /epidermis permeability coefficient, the stratum corneum pore pathway permeability coefficient, and by using solubility data to correct for chemical potential changes with solvent composition. The E-values for β-estradiol and for hydrocortisone were found to be of the same magnitude (7 to 9 at 25% ethanol and of the order of 100 at 50% ethanol). It is proposed that the ethanol enhancement effects at low ethanol levels may be interpreted in terms of fluidity increases in the transport rate-limiting lipid domains.
... The mathematical description of the transient behavior of a composite membrane and, in particular, bi-layer composite membranes, has important implications in drug release devices from planar matrix devices (Cabrera et al., 2006;Cabrera and Grau, 2007), in drug delivery through the skin (Ghanem et al., 1987;Couto et al., 2014), in the study of the cornea (Cooper and Kasting, 1987;Couto et al., 2014), studying the role of membranes in keeping compounds from contaminating the surroundings (Kalbe et al., 2002;Edil, 2003), in vacuum insulation panels that creates high performance thermal insulation (Garnier et al., 2011), mass diffusion of neutral species in the fabrication of multi-layer thin-film (Goldner et al., 1992), metallic thermal protection system (Gu et al., 2016), semiconductor composite in bi-layer organic solar cells (Hatton et al., 2007), biodegradable bi-layer film barrier using gelatin and chitosan (Rivero et al., 2009), gas transport in inorganic/organic hybrid structures (Jang and Han, 2009), and gas barrier of organic-inorganic hybrid coatings (Minelli et al., 2010), When modeling the phenomena of heat conduction or gas permeation, the exchange of heat or chemical at the surfaces contacting with the medium are often assumed to occur "infinitely" fast. Mathematically, this translates into the assumption that the temperature (for heat conduction) or concentration (for mass transfer) of the bi-layer at the surface equates that of the contacting medium, simplifying greatly the calculations necessary to find an analytical solution. ...
Exact analytical and closed-form solutions to the transient diffusion in bi-layer composites with external mass transfer resistance are reported. Expressions for the concentrations and the mass permeated are derived in both the Laplace and time domains through the use of the Laplace transform Inversion Theorem. The lead and lag times, which are often of importance in the characterization of membranes and arise from the analysis of the asymptotic behavior of the mass permeated through the bi-layer composite, were also derived. The presented solutions are also compared to previously derived limiting cases of the diffusion in a bi-layer with an impermeable wall and constant concentrations at the upstream and downstream boundaries. Analysis of the time lag shows that this membrane property is independent of the direction of flow. Finally, an outline is provided of how these transient solutions in response to a step function increase in concentration can be used to derive more complex input conditions. The importance of adequately handling boundary layer effects has a wide array of applications such as the study of bi-layers undergoing phenomena of heat convection, gas film resistance, and absorption/desorption.
... Cosurfactant can likewise influence the conduct of medication transport on the skin. For instance, ethanol, it can increment lipophilic transport of the stratum corneum through the arrangement of pores in the stratum corneum [31,32]. ...
Objective: White mulberry (Morus alba) root extract has terpenoid, flavonoid, and stilbene compounds. The stilbenes, oxyresveratrol and resveratrol, have antioxidant and antityrosinase activities. Nanocarriers can help active ingredients to be delivered in a more efficient manner. The advantages of nanoemulsion on products include increased penetration, biocompatibility, and low toxicity due to its non-ionic properties and have the ability to combine the properties of lipophilic and hydrophilic active ingredients. The objective of this study was to prepare, characterize, and evaluate the in vitro skin penetration of M. alba root extract nanoemulsion. Methods: The M. alba root extract was prepared by ionic liquid-based microwave-assisted extraction method. Nanoemulsion was optimized and prepared using virgin coconut oil (VCO), Tween 80, and polyethylene glycol 400 (PEG 400) by aqueous phase-titration method to construct pseudoternary phase diagram. M. alba root extract nanoemulsion was characterized for droplet size, viscosity, zeta potential, and physical stability tests for 12 weeks. In vitro skin penetration of oxyresveratrol from nanoemulsion was determined by the Franz diffusion cell and was compared by macroemulsion preparation, then analyzed by high-performance liquid chromatography method. Results: Based on pseudoternary phase diagram, nanoemulsion of white mulberry root extract contained of 2% VCO and 18% mixture of surfactant Tween 80 and PEG 400 (1:1) was chosen. Nanoemulsion has average globule size of 81.61 nm, with polydispersity index 0.22, and potential zeta −1.56 mV. The cumulative penetration of oxyresveratrol from nanoemulsion was 55.86 μg/cm2 with flux of 6.53 μg/cm2/h, while regular emulsion was 32.45 μg/cm2 with flux of 3.5501 μg/cm2/h. Conclusion: Nanoemulsion of white mulberry root extract was penetrated deeper than regular emulsion.
... Cosurfactant can likewise influence the conduct of medication transport on the skin. For instance, ethanol, it can increment lipophilic transport of the stratum corneum through the arrangement of pores in the stratum corneum [31,32]. ...
Objective: White mulberry (Morus alba) root extract has terpenoid, flavonoid, and stilbene compounds. The stilbenes, oxyresveratrol and resveratrol, have antioxidant and antityrosinase activities. Nanocarriers can help active ingredients to be delivered in a more efficient manner. The advantages of nanoemulsion on products include increased penetration, biocompatibility, and low toxicity due to its non-ionic properties and have the ability to combine the properties of lipophilic and hydrophilic active ingredients. The objective of this study was to prepare, characterize, and evaluate the in vitro skin penetration of M. alba root extract nanoemulsion. Methods: The M. alba root extract was prepared by ionic liquid-based microwave-assisted extraction method. Nanoemulsion was optimized and prepared using virgin coconut oil (VCO), Tween 80, and polyethylene glycol 400 (PEG 400) by aqueous phase-titration method to construct pseudoternary phase diagram. M. alba root extract nanoemulsion was characterized for droplet size, viscosity, zeta potential, and physical stability tests for 12 weeks. In vitro skin penetration of oxyresveratrol from nanoemulsion was determined by the Franz diffusion cell and was compared by macroemulsion preparation, then analyzed by high-performance liquid chromatography method. Results: Based on pseudoternary phase diagram, nanoemulsion of white mulberry root extract contained of 2% VCO and 18% mixture of surfactant Tween 80 and PEG 400 (1:1) was chosen. Nanoemulsion has average globule size of 81.61 nm, with polydispersity index 0.22, and potential zeta −1.56 mV. The cumulative penetration of oxyresveratrol from nanoemulsion was 55.86 μg/cm 2 with flux of 6.53 μg/cm 2 /h, while regular emulsion was 32.45 μg/cm 2 with flux of 3.5501 μg/cm 2 /h. Conclusion: Nanoemulsion of white mulberry root extract was penetrated deeper than regular emulsion.
... At low levels (<25%), ethanol has little or no effect on the pore pathway. It has been proposed that the ethanol enhancement effect at low levels may be interpreted in terms of increasing fluidity in the transport rate-limiting lipid domains [80]. In other words, low ethanol content (<50%) may be effective in fluidizing the SC lipid bilayer at or near the polar head plane, but not in the bilayer hydrocarbon interiors. ...
Nanoemulsions (NEs) are colloidal dispersions of two immiscible liquids, oil and water, in which one is dispersed in the other with the aid of a surfactant/co-surfactant mixture, either forming oil-in-water (o/w) or water-in-oil (w/o) nanodroplets systems, with droplets 20–200 nm in size. NEs are easy to prepare and upscale, and they show high variability in their components. They have proven to be very viable, non-invasive, and cost-effective nanocarriers for the enhanced transdermal delivery of a wide range of active compounds that tend to metabolize heavily or suffer from undesirable side effects when taken orally. In addition, the anti-microbial and anti-viral properties of NE components, leading to preservative-free formulations, make NE a very attractive approach for transdermal drug delivery. This review focuses on how NEs mechanistically deliver both lipophilic and hydrophilic drugs through skin layers to reach the blood stream, exerting the desired therapeutic effect. It highlights the mechanisms and strategies executed to effectively deliver drugs, both with o/w and w/o NE types, through the transdermal way. However, the mechanisms reported in the literature are highly diverse, to the extent that a definite mechanism is not conclusive.
... These results revealed that the selected ME can cross the skin barrier because the microstructure of the stratum corneum was disrupted. Lipid is extracted at ethanol concentrations of at least 50%, 33) but the ethanol concentration in the selected ME was 7.5%. Therefore, the selected ME can improve the skin permeability and is simultaneously safe for the skin. ...
The aim of this study was to develop novel microemulsions (MEs) for the transdermal delivery of capsaicin. Microemulsion-based nonionic surfactants consisting of isopropyl myristate as the oil phase, various nonionic surfactants as the surfactant (S), various glycols or alcohol as the co-surfactant (CoS), and reverse osmosis water as the aqueous phase were formulated. Based on the optimal ME obtained from Design Expert®, MEs containing a fixed concentration of oil, water or surfactant were prepared while varying the amounts of the other two fractions. The results indicated that the skin permeation flux of low dose capsaicin (0.15% (w/w)) was significantly higher for the selected ME than the commercial product and capsaicin in ethanol (control) by approximately two- and four-fold, respectively. We successfully demonstrated the feasibility of the transdermal delivery of capsaicin-loaded ME using a low concentration of nonionic surfactant and ethanol. Moreover, the optimization using computer program helped to simplify the development of a pharmaceutical product.
... However, a considerable increase in drug uptake and flux was observed if the receiver solution contains higher than 20% of ethanol. This might be due to conformational changes and formation of new pores in the skin with the use of higher percentage of ethanol [37,38]. These reports support the use of 20% ethanol in the receiver solution which would not compromise skin integrity or enhance drug permeation through the skin. ...
The objective of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for drug-in-adhesive (DIA) type estradiol transdermal drug delivery systems (TDDS). In vitro drug permeation studies across human skin were carried out to obtain the percent of estradiol permeation from marketed products. The in vivo time versus plasma concentration data of three estradiol TDDS at drug loadings of 2.0, 3.8 and 7.6mg (delivery rates of 25, 50 and 100μg/day, respectively) was deconvoluted using Wagner-Nelson method to obtain percent of in vivo drug absorption in postmenopausal women. The IVIVC between the in vitro percent of drug permeation (X) and in vivo percent of drug absorption (Y) for these three estradiol TDDS was constructed using GastroPlus® software. There was a high correlation (R(2)=1.0) with a polynomial regression of Y=-0.227X(2)+0.331X - 0.001. These three estradiol TDDS were used for internal validation whereas another two products of the same formulation design (with delivery rates of 60 and 100μg/day) were used for external validation. The predicted estradiol serum concentrations (convoluted from in vitro skin permeation data) were compared with the observed serum concentrations for the respective products. The developed IVIVC model passed both the internal and external validations as the prediction errors (%PE) for Cmax and AUC were less than 15%. When another marketed estradiol TDDS with a delivery rate of 100μg/day but with a slight variation in formulation design was chosen, it did not pass external validation indicating the product-specific nature of IVIVC model. Results suggest that the IVIVC model developed in this study can be used to successfully predict the in vivo performance of the same estradiol TDDS with in vivo delivery rates ranging from 25 to 100μg/day.
Copyright © 2015. Published by Elsevier B.V.
... The white circle represents gel formulation and the fill circle represents optimal ME. extraction in hairless mouse skin was obvious at 50% of ethanol or higher. 37) In the present study, the ethanol used was approximately 30%; therefore, the extraction effect was not pronounced. These results indicated that the effect of ethanol in the ME was not the extraction of lipid (thus this was safe for skin) but the disruption of the organization of lipid structure for improving skin permeability; thus, the disruption of the organization of lipid structure may be affected by the other components of the ME. ...
Microemulsions (ME) have gained attention as an alternative pharmaceutical formulation for transdermal delivery systems. However, the complicated relationships between various ME compositions (causal factors) and their characteristics (response variable) have not been fully comprehended. To overcome this problem, the design and development of ME for transdermal delivery was performed in our study using Design Expert® Software. The model formulations of ME were prepared according to the ME region obtained from pseudo-ternary phase diagrams using the simplex lattice design as an optimization technique. In this study, ketoprofen-loaded ME composed of oleic acid, Cremophor® RH40, ethanol and water were prepared, and their characteristics (e.g., size, charge, conductivity, pH, viscosity, drug content, loading capacity and skin permeation flux) were evaluated. The ME having an appropriate skin permeation flux was used as the basis for optimization. The skin permeation flux of the experimental ME was very close to the flux predicted by Design Expert® Software and was significantly greater than that for the commercial product. Possible mechanisms for the enhancement of the skin permeation of the ME were also investigated using Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). This finding provided an understanding of the relationship between the causal factors and response variables, as shown in the response surfaces. Moreover, these results indicated that the simple lattice design was beneficial for the pharmaceutical development of ME for transdermal delivery.
Objective:
Prototype cosmetic formulations containing short-chain acids and alcohols intended to be applied in the proximity of the eyes are sometimes evaluated for ocular irritation potential using the validated Bovine Corneal Opacity and Permeability Assay (OECD TG 437). We evaluated the eye irritation potential of nine experimental cosmetic formulations designed and prepared by Avon Global Reserach and Development to differ only in the concentrations of Ethanol, Glycolic Acid and Salicylic Acid.
Methods:
We analysed the data generated using the BCOP assay. The opacity and permeability values obtained following the exposure of bovine corneas to experimental cosmetic formulations were combined into a single In Vitro Irritancy Score used to rank eye irritation potential. Histopathological examination of treated corneas was used to provide additional information about the depth and degree of the injury and to support the prediction of eye irritation potential of each experimental cosmetic formulation.
Results:
The In Vitro Irritancy Scores and histopathological analysis showed that experimental formulations containing only Ethanol, Glycolic Acid, or Salicylic Acid alone had, at most, a mild ocular irritation potential. The experimental formulations containing both Ethanol and Glycolic Acid had a mild ocular irritation potential, while the experimental formulations containing both Ethanol and Salicylic Acid had a moderate ocular irritation potential. Severe ocular irritation potential was induced by an experimental formulation containing a combination of Glycolic Acid and Salicylic Acid and it was further accentuated by the addition of Ethanol to the formulation. Our data indicate a possible synergistic effect on eye irritation potential of Ethanol, Glycolic Acid and Salicylic Acid in at least some experimental cosmetic formulations. Further, our results provide insight on an apparent concentration-dependent ocular irritation potential effect of combinations of Glycolic Acid, Salicylic Acid and Ethanol in at least one experimental cosmetic formulation.
Conclusions:
The results presented herein emphasise the need to consider in vitro testing of prototype cosmetic formulations containing combinations of Ethanol, Glycolic Acid and Salicylic Acid rather than relying on any predicted additive effect on ocular irritation based solely on previously generated results of similar formulations containing Ethanol, Glycolic Acid or Salicylic Acid alone. Further work is required to understand the significance of these observations and to elucidate the mechanisms responsible for the apparent synergistic effects of Glycolic Acid, Salicylic Acid and Ethanol and eye irritation potential suggested by our results.
p>This thesis investigates the technique of cutaneous microdialysis as a means of exploring the factors that affect the absorption of topically applied drugs. Following a description of the factors affecting percutaneous absorption and methods used for studying percutaneous absorption the technique of microdialysis is described. The main advantage of cutaneous microdialysis is that it continuously samples from the dermal extracellular space in vivo and so enables a detailed pharmacokinetic profile to be built up of the drug under investigation under both normal and abnormal conditions. Using microdialysis to measure the dermal concentrations of the antiherpes drugs penciclovir (PCV) and acyclovir (ACV) following topical application, it was found that in their commercial preparations they are very poorly absorbed through normal skin. Therefore they represent suitable probes for investigating the different aspects of percutaneous absorption both in terms of the ‘penetrant’ and the barrier it has to cross.
The role of the stratum corneum barrier was investigated using tape stripping with transepidermal water loss measurement used as a measure of barrier impairment. PCV and ACV absorption were measured through different degrees of barrier impairment. Cutaneous blood flow was manipulated using noradrenaline as a vasoconstrictor and glyceryl trinitrate as a vasodilator to assess the effect of cutaneous blood flow on washing away percutaneously absorbed drug. Dermal levels of systemically absorbed PCV were compared with topically applied PCV. Finally microdialysis fibres have been uniquely used to continuously deliver muscarinic agonists to sweat glands to both clarify the physiology and pharmacology of eccrine sweat glands, and to investigate the absorption of PCV via skin appendages.</p
Studies on the effectiveness of substances such as drugs and cosmetics that act on the skin require structural evidence at the molecular level in the stratum corneum to clarify their interaction with intercellular lipid and soft keratin. For this purpose, when applying the substances to the stratum corneum X-ray diffraction experiment is one of the powerful tools. To detect minute structural changes in a stratum corneum sample, using a “solution cell”, dynamic synchrotron X-ray diffraction measurements were performed when applying aqueous solution of the substances to the stratum corneum: (1) It was found that a surfactant, sodium dodecyl sulfate, significantly disrupted the long-period lamellar structure. (2) To study the effects of water, structural modifications of the short-period lamellar structure and the soft keratin in corneocytes were measured as a function of time. At the initial water content of 15 wt%, the spacings of the short-period lamellar structure and the soft keratin increased toward those at the water content of 25 wt%, that is a key water content in the stratum corneum. (3) Nanoparticles composed of assembly of amphiphilic molecules are one of the leading pharmaceutical formulations. When the nanoparticles were applied, a new assembly of amphiphilic molecules originated from the nanoparticle appeared. This phenomenon suggests that the formation of the new assembly at the surface of skin is concerned with the release of the drug from the nanoparticles. (4) When ethanol was applied to the stratum corneum, only the liquid state in the intercellular lipid matrix was dissolved. After the removal of ethanol from this stratum corneum, the ordered hydrocarbon-chain packing structures appeared. From this fact we would propose that the liquid state region is the main pathway for hydrophobic drugs with a small molecular weight in connection with the so-called 500 Da rule. Here, not only the technique but also the background to these studies and the characteristic results obtained from these studies are explained.
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We studied the effect that three alcohols, ethanol (EA), propanol (PA), and isopropanol (IPA), have on the skin permeation of p-hydroxy benzoic acid methyl ester (HBM), a model ester-type prodrug. HBM was applied to Yucatan micropig skin in a saturated phosphate buffered solution with or without 10% alcohol, and HBM and related materials in receptor fluid and skin were determined with HPLC. In the absence of alcohol, p-hydroxy benzoic acid (HBA), a metabolite of HBM, permeated the skin the most. The three alcohols enhanced the penetration of HBM at almost the same extent. The addition of 10% EA or PA to the HBM solution led to trans-esterification into the ethyl ester or propyl ester of HBA, and these esters permeated skin as well as HBA and HBM did. In contrast, the addition of 10% IPA promoted very little trans-esterification. Both hydrolysis and trans-esterification in the skin S9 fraction were inhibited by BNPP, an inhibitor of carboxylesterase (CES). Western blot and native PAGE showed the abundant expression of CES in micropig skin. Both hydrolysis and trans-esterification was simultaneously catalyzed by CES during skin permeation. Our data indicate that the alcohol used in dermal drug preparations should be selected not only for its ability to enhance the solubility and permeation of the drug, but also for the effect on metabolism of the drug in the skin.
Study objective was to assess skin-to-skin drug transfer potential that may occur due to drug retention in human epidermis (DRE) pretreated with application of estradiol transdermal drug delivery systems (TDDS) and other estradiol transdermal dosage forms (gels and sprays). TDDS (products-A, B, and C) with varying formulation design and composition, and other estradiol transdermal products (gel and spray) were applied to heat separated human epidermis (HSE) and subjected to in vitro drug permeation study. Amounts of DRE were quantified after 24 h. The DRE with product-B was significantly (P < 0.001) higher than that with product-C, product-A, gel, and spray. However, products-A and C, gel, and spray showed almost the same (P > 0.05) amounts of DRE. A separate in vitro permeation study was carried out to determine amounts of drug transferred from drug-retaining epidermis to untreated HSE. The amounts of drug transferred, due to DRE after 8 h, with product-C were significantly (P < 0.001) higher than those with products-A and B, gel, and spray. The in vitro study results indicate a high potential of skin-to-skin drug transfer due to the DRE after labeled period of using estradiol TDDS, though the clinical relevance of these findings is yet to be determined.
Mathematical models of epidermal and dermal transport, which includes transport of a solute through vehicle and various layers of the skin, metabolism in the skin and its subsequent distribution and clearance into systemic circulation from underlying tissues, play an essential role in development of topical and transdermal drug products and are reviewed in this chapter.
A number of mathematical models have been used to describe percutaneous absorption kinetics. In general, most of these models have used either diffusion-based or compartmental equations. The object of any mathematical model is to a) be able to represent the processes associated with absorption accurately, b) be able to describe/summarize experimental data with parametric equations or moments, and c) predict kinetics under varying conditions. However, in describing the processes involved, some developed models often suffer from being of too complex a form to be practically useful. In this chapter, we attempt to approach the issue of mathematical modeling in percutaneous absorption from four perspectives. These are to a) describe simple practical models, b) provide an overview of the more complex models, c) summarize some of the more important/useful models used to date, and d) examine sonic practical applications of the models. The range of processes involved in percutaneous absorption and considered in developing the mathematical models in this chapter is shown in Fig. 1. We initially address in vitro skin diffusion models and consider a) constant donor concentration and receptor conditions, b) the corresponding flux, donor, skin, and receptor amount-time profiles for solutions, and c) amount- and flux-time profiles when the donor phase is removed. More complex issues, such as finite-volume donor phase, finite-volume receptor phase, the presence of an efflux. rate constant at the membrane-receptor interphase, and two-layer diffusion, are then considered. We then look at specific models and issues concerned with a) release from topical products, b) use of compartmental models as alternatives to diffusion models, c) concentration-dependent absorption, d) modeling of skin metabolism, e) role of solute-skin-vehicle interactions, f) effects of vehicle loss, a) shunt transport, and h) in vivo diffusion, compartmental, physiological, and deconvolution models. We conclude by examining topics such as a) deep tissue penetration, b) pharmacodynamics, c) iontophoresis, d) sonophoresis, and e) pitfalls in modeling.
Betamethasone-17-valerate (BM-17-V) is a corticosteroid commonly administered in semisolid preparations for cutaneous use. In this study, an ointment and a cream from the German Pharmacopoeia, i.e. wool fat alcohol ointment (WS) and basis cream DAC were loaded separately with BM-17-V. Two conventional penetration enhancers, namely isopropyl alcohol (IPA) and isopropyl myristate (IPM) as sole additives, as well as a mixture of both, IPA-IPM 1:1 (w/w) were also incorporated into the different semisolid formulations and in vitro permeation experiments of BM-17-V were carried out in Franz diffusion cells using excised human stratum corneum (SC). The effect of the additives on the thermal behavior of the SC lipid matrix was evaluated by differential scanning calorimetry (DSC). The saturation concentrations of BM-17-V within the formulations were estimated based on microscopical characterization. BM-17-V is transformed into its hydrolization product, betamethasone (BM), during the permeation experiments by the effect of the SC using the BM-21-V pathway. Furthermore the microstructure of the lipids and protein complexes located at the membrane of the corneocytes was altered by the use of the enhancers. The combination of IPA and IPM resulted in a synergetic enhancement of the BM flux. The BM permeation was augmented by approximately 12 times when a combination of IPA-IPM 1:1 (w/w) was used in wool fat alcohol ointment.
The objective of this work is to study transdermal delivery of calcitonin using iontophoresis and to evaluate various factors which affect the transdermal transport. We have studied the effect of polarity, current density, drug concentration, penetration enhancers (isopropyl myristate [IPM] and ethanol) and laser treatment on transdermal flux and the results were compared. We also investigated the iontophoretic flux from microemulsions containing calcitonin together with oleic acid (OA) or IPM. In vitro flux study was performed at 33^{\circ}C, using side-by-side diffusion cell and full thickness hairless mouse skin. Anodal delivery at pH 3.0 was much larger than cathodal and passive delivery, due to the positive charge of calcitonin. Cumulative amount delivered (CUM) by cathodal or passive delivery was close to zero for 10 hours. The pretreatment of skin by neat IPM markedly increased the CUM anodically. CUM increased as the current density, drug concentration or the duration of IPM treatment increased. Microemulsion containing IPM or oleic acid was prepared and the phase diagram was constructed. CUM also increased when IPM was incorporated into a microemulsion. OA microemulsion showed similar enhancing effect to IPM microemulsion. The delivery of calcitonin from 70% (v/v) ethanol aqueous solution showed a large increase in flux. Laser treatment of skin before flux experiment exhibited about 2 fold increase in total calcitonin amount transported for 12 hours, when compared to that delivered by IPM microemulsion. Based on these results, we have evaluated the possibility of delivering enough amount of calcitonin to reach the therapeutic level. The data suggest that it is highly possible to deliver clinically effective amount of calcitonin using iontophoresis patch with small area ().
We show that ethanol can induce the formation of water-permeable defects in model membranes of skin, providing a fresh perspective on ethanol as a membrane modulator. We rationalise our findings in terms of the chemical nature of ethanol, i.e., a combination of its hydrogen bonding propensity and amphiphilic character.
The permeation enhancing property of 5% oleic acid in ethanol on -estradiol was investigated in vitro and in vivo using symmetrical and asymmetrical side-by-side diffusion cells and the human skin sandwich flap, respectively. -Estradiol permeability in vitro and in vivo was similar in 75% ethanol (ETOH). Oleic acid (5%) did not alter -estradiol permeability in vivo but increased permeability sixfold in vitro in symmetrical diffusion cells. -Estradiol permeability in oleic acid was not different from that in ETOH, however, using asymmetrical diffusion cells. Stratum corneum-to-vehicle partition coefficients of -estradiol in the vehicles were similar, yet fourfold more steroid was detected in skin biopsies from the in vitro symmetrical diffusion cells. Thus, oleic acid increased -estradiol permeability in vitro only when skin was equilibrated with fatty acid. Attention to in vitro diffusion cell design and its relevance in vivo is critical to defining the mechanisms of enhanced solute permeation.
The effect of a lipophilic chemical enhancer system on the skin permeation of ketotifen fumarate (KF) was investigated in vitro using excised hairless rat skin. Organic acids, alcohols and oleaginous solvents were selected as fundamental components of the system. Among the several lipophilic systems, a ternary component vehicle consisting of L-lactic acid, ethanol and isopropyl myristate (IPM) (3:10:87) exhibited a significant skin penetration-enhancing effect. The rank order of the effect on KF skin permeation for oleaginous components containing ethanol or L-lactic acid/ethanol was IPM > ethyl oleate > diisobutyl adipate > oleic acid. This order was similar to that on ethanol flux. The KF permeation was thus enhanced and regulated by the ethanol permeation. The KF flux from various alcohol/IPM systems was increased, with an increase in the solubility parameter of alcohols. L-Lactic acid in the alcohol/IPM systems did not have a marked effect on the alcohol flux, whereas it increased the KF flux. Addition of several organic acids into the ethanol/IPM system (1:10:89) shortened the lag time of KF permeation, and the effect may be related to these chain lengths and functional groups.
A new polymeric membrane, designated as a ‘one-way’ membrane, was designed to be permeable to ethanol with minimal flux of drug or water. A trilaminate membrane consisting of Silastic Q7-4840, methylhydrodimethylsiloxane and cellulose acetate was designed as the one-way membrane. Membrane permeation characteristics were determined from solvent and drug diffusion experiments. The one-way membrane, which provided optimum and constant ethanol activity, may contribute a new concept in the design of transdermal delivery systems as a rate-limiting membrane.
Attempts were made to visualise intact liposomes in the human skin by fluoromicrography. To this end the aqueous compartment of the liposomes as well as the lipid bilayer were followed by labelling with hydrophilic and lipophilic fluorophores, respectively. Micrographs at various times after external application suggested that intact liposomes do not penetrate deeper than the horny layer.
Based on Siegel's theory, the permeability (P) and the downstream time lag (tL) for absorptive unidirectional permeation, accompanying a first-order reaction, across a membrane composed of two parallel laminae in series with another lamina, have been calculated from the transmission matrix of the whole membrane. This matrix can be constructed from the transmission matrix of each component lamina. The transmission matrix of the whole membrane is first calculated from the matrices of the component laminae in the Laplace domain. P and tL are then derived from the first row and second column of the transmission matrix of the whole membrane according to Siegel's theory. Thus, P and tL can be represented in terms of the elements of the transmission matrix, and hence the diffusion parameters, of each component lamina. The directional symmetry of tL is also proven, based on the unity value of the determinant of the transmission matrix. The advantage of the matrix method is also discussed.
Complex impedance measurements have been used to study changes in electrical properties of human stratum corneum related to transdermal drug delivery. A careful determination of the effect of temperature revealed an activated process associated with the transport of charged species up to ca. 338 K. Above this temperature a drastic and irreversible decrease was observed in the resistance of the stratum corneum. This temperature, which has been identified by permeability studies and by a variety of biophysical measurements including differential scanning calorimetry (DSC), IR and EPR, corresponds to a transition caused by lipid melting. The changes in electrical properties occurring when stratum corneum was treated with chemical penetration enhancers also correlated well with results obtained using other techniques. Our measurements suggest that iontophoretically assisted transdermal drug delivery may cause less lipid structural alteration within the skin than would the use of such chemical penetration enhancers.
The time dependence of the skin permeation enhancing effect of ethanol was investigated quantitatively. Ethanol enhanced the skin permeability of drugs in a manner dependent on the polarity of drugs and pretreatment time with ethanol. The skin permeation data were analyzed based on the parallel permeation pathway model, and the change in several permeation parameters by ethanol pretreatment was estimated. Further, the change was related mathematically with the delipidizing effect of ethanol on the skin, which is an index of ethanol concentration in the stratum corneum. The time-dependent percutaneous absorption enhancing effect of ethanol could be described by the change of permeation parameters dependent on ethanol concentration in the stratum comcum.
Peroral administration of tacrine, a drug approved for the treatment of Alzheimer's disease, is associated with low bioavailability (due to first-pass effect), short elimination half-life and reversible hepatotoxicity. Transdermal administration may reduce the degree of these problems. In this investigation the influence of three commonly used solvents (water, propylene glycol and ethanol), and their mixtures, on the in vitro permeation of tacrine through rat and human skin were evaluated. Maximum flux and permeability were observed from ethanol-propylene glycol and water-ethanol binary mixtures, respectively. The permeability of tacrine through rat skin was about 2.5 times higher than that through human skin. Excellent correlation between the rat and human skin data was observed. The flux from the ethanol-propylene glycol binary mixture was 98 μg/cm² per h through rat skin and was selected for in vivo transdermal administration. The observed in vivo tacrine plasma concentrations were in good agreement with the concentration-time profile simulated using in vitro flux and tacrine clearance in rat. Preliminary short-term (24 h) irritation studies did not indicate any irritation. The results from this investigation indicate that transdermal delivery of tacrine may be feasible and that the ethanol-propylene glycol (1:1) mixture appears to be a promising solvent system.
The effect of ethanol on the skin permeation of diclofenac (DF) was investigated using excised hairless rat abdominal skin in vitro. The steady-state flux of DF increased with increase in the pH of DF-suspended donor solution; this phenomenon demonstrated a close correspondence with enhancement in the solubility of DF in the donor solution. In constrast, the steady-state permeability coefficient (P) of DF was inversely proportional to the change in pH of the donor solution, suggesting that the pattern of skin permeation of DF apparently obeyed the pH-partition theory, although the contribution of the ionized form of DF cannot be taken as being negligible. In order to determine the contribution of either the nonionized or ionized form on the skin permeation of DF, the permeability coefficients for each form (nonionized and ionized molecules) were calculated using the P values and the degree of ionization of DF in the donor solution. Addition of ethanol in the donor solution led to a marked decrease in the Pvalue of nonionized DF, whereas theP value of ionized DF was not greatly affected by ethanol. A large amount of ethanol might increase the extent of permeation of DF through the lipid pathway by affecting the dense barrier structure of the skin. The flux of the ionized form of DF was particularly enhanced due to the increase in solubility as a result of the addition of ethanol, since the partition coefficient (skin/donor solution) of the ionized form was not greatly decreased compared with that of the nonionized form.
The feasibility of achieving transdermal delivery of the opioid analgesic kelobemidone was assessed in human skin penetration studies in vitro using both ketobemidone itself and three carbonate ester prodrugs formed at the phenolic hydroxyl group. Whereas ketobemidone itself only showed a limited ability to permeate the skin from either polar or apolar vehicles the ester prodrugs very readily penetrated through the skin from solutions in isopropyi myristate and, in particular, from ethanol and ethanol-water solutions. Thus. steady-state fluxes in the range of 40–140 μg ketobemidone per h were observed for the ketobemidone esters from 20% w/v solutions in ethanol and ethanol-water (3:1 and 1: 1 v/v) vehicles. The esters were rapidly hydrolyzed to the parent drug in the presence of skin enzymes and only free ketobemidone was detected in the receptor phase. The study demonstrates the feasibility of achieving transdermal delivery of ketohemidone based on the ready enzymatic conversion and the favourable skin penetration properties of the ester prodrugs which in turn are attributed to their high solubilities in both polar and apolar solvents.
Link: http://www.sciencedirect.com/science/article/pii/037851739290163V
A novel theoretical model/method has been developed to predict permeant transport across skin for the ‘asymmetric’ case, i.e., for situations in which there is significant cotransport of an enhancer solvent along with the principal permeant. The method has successfully predicted effects of the simultaneous transport of ethanol on the simultaneous diffusion and metabolism of ß-estradiol (E2ß) at steady state in hairless mouse skin using parameter values deduced from experiments conducted under symmetric conditions (i.e., the same ethanol concentration on both sides of the skin membrane). The studies have involved the determination of (a) effective ethanol concentration gradients and (b) skin position-depedent permeability coefficients and partition coefficients, concentration (activity) gradients, and fluxes for E2ß and its transdermal metabolite, estrone (E1), with stripped skin and with full thickness skin. As this approach is quite general and as the asymmetric situation is the practical situation in vivo, it is believed that the outcomes of this study are important in transdermal/dermal formulations research.
A diffusion system is considered in which transport occurs along two parallel paths which, in turn, are in series with another path. Relations for the steady-state permeability and lag time are obtained in terms of the cross-sectional areas and lengths of diffusion, diffusivities and interfacial partition coefficients. The relations are derived from the slope and intercept (on the time axis) of the linear asymptote for the total amount of diffusant released into the receiver. The asymptote is calculated by repeated integration rather than a complete solution to the coupled diffusion equations. Equivalence relations are given for the transformation of the parallel paths into a single path, thus allowing for a treatment of the whole system in the form of two homogeneous paths in series. These equivalence relations include an effective partition coefficient as an average of its component's partition coefficient weighted by the corresponding fraction of cross-sectional area, and an effective diffusivity as an average of individual diffusivities weighted by the corresponding fraction of the product of cross-sectional area and partition coefficient.
Abstract A transdermal therapeutic system can be developed by promoting the skin permeability of drugs with some materials. In this study, the promoting effect of terpenes present in essential oils on the percutaneous absorption of indomethacin from alcoholic hydrogels was investigated in rats in vivo. The enhancing activity of terpenes was expressed quantitatively as a quadratic function of lipophilicities of the terpenes, measured as a lipophilic index. Further increase in the significant level was observed when the molecular weight of terpenes was included in this function as the second factor. The synergism of ethanol with d-limonene, selected from among the other terpenes, on the promoting activity was statistically investigated. It was evident that both d-limonene and ethanol were important factors for promoting the percutaneous absorption of indomethacin. A significant synergism of d-limonene with ethanol was also observed. As a possible mechanism for enhancement action of d-limonene and ethanol, it was considered that, at first, d-limonene penetrates into the skin under coexistence with ethanol and may change the barrier structure of the stratum corneum. The transfer of ethanol to the skin is thereby enhanced under the coexistence with d-limonene in the skin. Thus, the permeation of indomethacin can be promoted due to its affinity with ethanol.
This paper describes a systematic experimental and theoretical study of the simultaneous diffusion and metabolism of β-estradiol (E2β) in hairless mouse skin (in vitro). The strategy involved (a) considering a general three-layer skin model (stratum corneum, epidermis, and dermis), (b) considering three possible enzyme distributions (Model A: homogeneous enzyme distribution across both epidermis and dermis; Model B: homogeneous enzyme distribution in the epidermis; and Model C: homogeneous enzyme distribution in the ‘basal cell layer’ only of the epidermis), and (c) carrying out a wide range of independent diffusion experiments so that a ‘best’ model may be deduced in which all of the experimental data are consistent with the model and a single set of transport and metabolism parameters. The various diffusion/metabolism experiments included using three skin membranes (dermis, stripped skin, and full-thickness skin), two membrane configurations (transport of permeants in the direction: stratum corneum → epidermis → dermis, and in the reverse direction), two permeants (E2β and estrone, E1, the principal metabolite), and measuring three fluxes (forward fluxes of E2β and E1 and the back flux of E1). Analysis of all of the experimental data demonstrated that Model C was superior to Models B and A; within the uncertainties of the experiments and model fitting, Model C agreed well with the data in all instances while the predictions of Models B and A exhibited significant deviations from the experimental data.
The penetration of the dopaminergic D2 agonist S(−)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923) was evaluated in vitro on full-thickness rat skin, using the Franz diffusion cell. The drug was tested as the N-0923 · HCl salt as well as the N-0923 base. The penetration-enhancing effect of Azone was studied in a vehicle concentration of 5%, or after pretreating shaven rat skin in vivo, at several time intervals before the in vitro experiment, with a solution containing 1 or 5% Azone. From the vehicle containing 60% ethanol, 20% propylene glycol and 20% water, the extent of penetration through rat skin was relatively low for the base and even lower for the salt. The introduction of Azone into the vehicle in a final concentration of 5% resulted in a 6-fold decrease in penetration for the free base. Nevertheless, penetration of the salt increased about 12-fold in extent during the first 12 h, after which it declined to almost zero. The lag time was reduced from 13 to 5 h. Pretreatment of rat skin in vivo with an ethanol-propylene glycol-water solution containing 5% Azone resulted in a 12-fold increase in flux for the salt, a 2-fold increase in flux for the base and a decrease in lag time to about the same values for both N-0923 · HCl and N-0923 base. In vivo pretreatment of rat skin with a solution containing 1% Azone had no significant effect on the flux and lag time vs controls. This study indicates that Azone may have potential in facilitating the transdermal application of N-0923, principally through pretreatment of the skin to enhance absorption. This may allow it to circumvent its considerable oral first-pass metabolism.
An in vitro method was developed to investigate the enhancement of hydrocortisone transport across human stratum corneum (SC) by a model enhancer, lauric acid, in aqueous solutions under equilibrium conditions with respect to the enhancer. In contrast to classical (i.e., nonequilibrium) loading techniques, in which the enhancer is applied only to the donor side of SC either in pure form or in an organic solvent while enhancer-free aqueous buffers are placed in the receptor phase, this method allowed the investigation of pH effects, concentration effects, and reversibility of both enhancer uptake and enhancement of drug transport under thermodynamically well-defined conditions. The SC–buffer partition coefficients for lauric acid were linear with concentration and sigmoidal with pH, suggesting that both the neutral species and laurate anion partition into SC. Comparisons of partition coefficients in delipidized and untreated SC as a function of pH indicated that the uptake of lauric acid in neutral form is governed primarily by the lipid domain, whereas the protein domain accounts for anion uptake. The effects of lauric acid on skin permeability were >80% reversible upon extraction of the enhancer from the membrane. However, the degree of enhancement of hydrocortisone permeability was nonlinearly dependent on the equilibrium concentration of lauric acid in either the aqueous buffer or the membrane, exhibiting thresholds in the appearance of enhancement with concentration. The enhancer concentration necessary to achieve isoenhancement of about 6-fold varied from ∼1 × 10−5 M at pH < pKa to ∼1 × 10−2 M at high pH (pH > 8) demonstrating the higher influence of the free acid species. Maximum enhancement, however, occurred at high pH, reflecting the significantly higher solution concentration of laurate anion attainable in saturated solutions at high pH.
Trimethylpsoralen (TMP) is often used to treat skin diseases (i.e., psoriasis, vitiligo, etc.). This drug permeates moderately the skin barrier. In the present study, we investigated the effect of formulation on the improvement of TMP skin bioavailability. Three formulations were performed. Each form (liposomes, nanospheres, and EtOH solution) contained 0.05% of TMP. For each preparation, the quantity deposited on the skin surface was 250 µg (Q0). The TMP percutaneous penetration through ex-vivo human skin was processed by Franz® cells (n=4) using a human albumin solution (1.4% w/v) as receiver medium. The percentages of the extracted TMP that permeated through the skin and that were retained in the skin over 24 h, were calculated with respect to Q0. The values obtained were reported, respectively, as follows: EtOH solution (1.33 vs. 0.08%), liposomes (0.93 vs. 0.93%), and PLG-nanospheres (0.79 vs. 3.01%). So, considering the correlation between the cumulated amounts of TMP permeated through the skin and the TMP stocked in the skin, the nanosphere form showed the higher quantity of TMP accumulated in the skin structures. On the other hand, the maximum value of the flux (ng/cm2/h) in the steady state of TMP incorporated in each formulation was at 6 h for all formulations: 173.5±1.06 (EtOH solution) > 120.4±1.06 (liposomes) > 93.82±0.88 (PLG-nanospheres). These results indicate that the controlled release of TMP by incorporation in PLG-nanospheres may increase drug content in the skin, while maintaining a minimal percutaneous absorption. Finally, this work shows that the PLG-nanospheres could constitute a promising approach for controlling TMP release in order to maintain its topical activity. Drug Dev. Res. 61:86–94, 2004. © 2004 Wiley-Liss, Inc.
We have previously established that the relative concentrations of propylene glycol and ethanol as a binary solvent system have a significant effect on the skin penetration of 2% solutions of minoxidil at 50 μL/cm2. The present work extends these studies and investigates the penetration of minoxidil from the different vehicle combinations as functions of application volume and occlusion. Decreasing the application volume has a variable effect which depends on vehicle composition. Penetration of minoxidil from 100% ethanol solutions decreased linearly with application volume. Generally, irrespective of the volume applied, the penetration of minoxidil increased with increasing ethanol fraction with a maximum penetration at 90% ethanol. Penetration from all the formulations was enhanced upon occluding the skin, with greatest increase evident in solutions with higher volatile fraction. Penetration of minoxidil in vivo showed trends similar to those seen in vitro.
Percutaneous absorption-enhancing effects of d-limonene and oleic acid were investigated using three model drugs with different lipophilicities in in vitro diffusion experiments with guinea pig skin. Pretreatment of the skin with d-limonene resulted in a large penetration enhancement for the lipophilic butylparaben (BP) and amphiphilic 6-mercaptopurine (6-MP) but had little effect on the hydrophilic mannitol (MT). Oleic acid caused a large effect only on 6-MP penetration. The penetration profiles were analyzed with a two-layer skin diffusion model consisting of stratum corneum with polar and nonpolar routes and viable epidermis plus dermis. Through curve-fitting, six parameters corresponding to drug diffusivity and partitioning in these three regions of the skin were obtained, and the mechanisms of enhancers were assessed in comparison with those of l-geranylazacycloheptan-2-one (GACH) reported previously. Increased penetration was caused mainly by modification of the barrier property of the nonpolar route in the stratum corneum in all cases. In the nonpolar route, d-limonene increased mainly drug diffusivity, while GACH enhanced predominately drug partitioning. On the other hand, oleic acid moderately increased both parameters.
Purpose. A theoretical design of percutaneous penetration enhancement in which prodrug derivation and enhancer application are combined is proposed based on the skin diffusion model and it is experimentally verified.
Methods. Employing acyclovir as a model drug, the hypothesis was tested by synthesis of its prodrugs and evaluation of their in vitro permeation in the rat skin, with or without a penetration enhancer, 1-geranylazacycloheptan-2-one(GACH).
Results. Among five acyclovir prodrugs, those with higher lipophilicit-ies (propionate, butyrate, valerate, and hexanoate prodrugs) showed greater skin penetration than those of hydrophilic prodrugs (acetate), when administered in combination with GACH. Furthermore, the observed enhancement ratios were in good agreement with those predicted by theoretical consideration.
Conclusions. Thus, skin permeation of prodrugs applied with an enhancer can be predicted and optimized by model analysis.
Purpose. To synthesize new naproxen (01) derivatives with amide or ester structures or with a combination of the two (02–15). To compare their physicochemical properties with naproxen esters (16–22) and their respective skin permeation behavior. To study structure–permeation relationships via partial least squares (PLS)–analysis.
Methods. Stability, aqueous, and octanol solubility were determined. Lipophilicity and further 53 chemical descriptors were computed. A suitable in–vitro skin permeation model was developed to compare maximal flux (Jmax) of derivatives. Based on these flux data, PLS–analysis was performed to derive structure–permeation relationships.
Results. None of the new derivatives showed an improved flux in comparison to naproxen. This result can be explained by PLS–analysis: skin permeation increases with the solubility both in water and in octanol. For a good permeation, an optimized molecule should exhibit a small volume with a spherical shape. The surface area should be large in relation to volume, as indicated by the rugosity parameter. A clear separation between the hydrophobic and the hydrophilic domain (= high amphiphilic moment) is favorable. Lipophilicity is inversely correlated with skin permeation.
Conclusions. PLS–analysis is a valuable tool to derive significant, internally predictive quantitative models for structure–permeation relationships of naproxen derivatives in the above described skin permeation assay.
Purpose. The aim of our study was to clarify the kinetic performance of a membrane controlled reservoir system (MCRS) for -estradiol (E2) under in vitroconditions by determination of the role of membrane and adhesive layer on E2flux control.
Methods. E2and ethanol fluxes across EVA membrane or membrane coated with adhesive from saturated solutions in defined ethanol/PBS mixtures were measured in the symmetric and asymmetric configuration. Physicochemical parameters of the EVA membrane were determined.
Results. The E2flux across the 9% EVA membrane steadily increased with increasing ethanol concentrations in both configurations, due to enhanced uptake of E2by the polymer and increasing membrane diffusivity. Permeation across the EVA membrane coated with an adhesive layer in the symmetric and asymmetric configuration increased up to maximum values of 0.80 0.14 (g cm–2 h–1and 0.37 0.02 g cm–2 h–1, respectively, at 62.5% (v/v) ethanol. The fluxes then decreased with further increase in the volume fraction of ethanol due to a dramatically reduced permeability of the adhesive layer. For the asymmetric case, a linear dependence of E2on ethanol fluxes was observed.
Conclusions. The E2flux from MCRS is strictly dependent on reservoir ethanol concentrations, whereas the adhesive layer represents the rate controlling barrier at high ethanol levels (>70% v/v).
Ethanol–water systems enhance permeation of ionic solutes through human stratum corneum. Optimum enhancement of salicylate ion permeation has been observed with ethanol volume fractions near 0.63. The mechanism of action of ethanol–water systems enhancing skin permeation was investigated by in vitro skin permeation studies combined with Fourier transform infrared spectroscopy experiments. The increased skin permeation of the ionic permeant by the ethanol–water systems may be associated with alterations involving the polar pathway. Polar pathway alterations may occur in either or both the lipid polar head and proteinaceous regions of the stratum corneum. Ion-pair formation may also contribute to increased permeation. However, the decreased permeation of salicylate ion observed at higher volume fractions of ethanol may be attributed to decreased uptake of permeant into the stratum corneum.
In vitro and in vivo skin penetration of three drugs with different lipophilicities and the enhancing effects of l-geranylazacycloheptan-2-one (GACH) were studied in rats. In vivo drug absorption profiles obtained by deconvolution of urinary excretion profiles were compared to the corresponding in vitro data obtained with a diffusion experiment. In vivo skin penetration of lipophilic butylparaben was considerably greater than that observed in vitro, while hydrophilic mannitol and acyclovir showed low penetration in both systems without GACH pretreatment. On the other hand, GACH enhanced mannitol and acyclovir penetration, especially in the in vivo system. Analysis of absorption profiles, using a two-layer skin model with polar and nonpolar routes in the stratum corneum, suggested that the diffusion length of a viable layer (viable epidermis and dermis) was shorter in vivo than in vitro and the effective area of the polar route in the stratum corneum was larger in vitro without GACH pretreatment. GACH increased the partitioning of acyclovir into the nonpolar route to the same extent in both systems. In addition, GACH increased the effective area of the polar route in vivo, probably because of enhanced water permeability; however, this effect was smaller in vitro since the stratum corneum was already hydrated even without GACH pretreatment.
The controlled release of ethanol from a reservoir in the transdermal system was studied in order to ensure continuous drug permeation across the skin. The permeation of ethanol through various polymeric membranes was evaluated. The release rate of ethanol was fairly controlled when the membrane was prepared from the ethylmethacrylate-hydroxyethylmethacrylate copolymer (EMA-HEMA). The transdermal system containing indomethacin (IMC) as a model drug, and d-limonene and ethanol as absorption enhancers was newly developed employing the EMA-HEMA membrane. In vitro permeation of IMC through the rat abdominal skin in the system was investigated. The constant flux of IMC was attained by the control of ethanol permeation from the system during the permeation experiment.
The effect of terpenes as penetration enhancers (e.g. carvone, 1,8-cineole and thymol) was studied on the in vitro percutaneous absorption of the model hydrophilic compound 5-fluorouracil through porcine epidermis. The above terpenes (5% w/v) significantly (P<0.01) increased the permeability coefficient of 5-fluorouracil in comparison to the control. Enhancement in the permeability of 5-fluorouracil by carvone, 1,8-cineole and thymol in comparison to the control was 91.62, 153.75 and 273.75, respectively. Fourier transform infrared (FT-IR) spectroscopy, and in vitro transepidermal water loss (TEWL) studies were undertaken to investigate the effect of enhancers on the biophysical properties of the stratum corneum and macroscopic barrier integrity of the epidermis, respectively, in order to understand the mechanism of percutaneous absorption enhancement of 5-fluorouracil by terpenes. The FT-IR spectrum of the stratum corneum treated with thymol produced a blue shift in the antisymmetric C–H stretching peak to higher wavenumbers, suggesting an increase in the disorder of the acyl chains of the stratum corneum lipids (i.e. increased lipid fluidity). Treatments of the epidermis with enhancers significantly (P<0.01) enhanced the in vitro TEWL in comparison to the control.
During the last few years the general interest in the percutaneous absorption of chemicals has increased. It is generally accepted that there is very few reliable quantitative and qualitative data on dermal exposure to chemicals in the general population and in occupationally exposed workers. In order to predict the systemic risk of dermally absorbed chemicals and to enable agencies to set safety standards, data is needed on the rates of percutaneous penetration of important chemicals. Standardization of in vitro tests and comparison of their results with the in vivo data could produce internationally accepted penetration rates and/or absorption percentages very useful for regulatory toxicology. The work of the Percutaneous Penetration Subgroup of EC Dermal Exposure Network has been focussed on the standardization and validation of in vitro experiments, necessary to obtain internationally accepted penetration rates for regulatory purposes. The members of the Subgroup analyzed the guidelines on percutaneous penetration in vitro studies presented by various organizations and suggested a standardization of in vitro models for percutaneous penetration taking into account their individual experiences, literature data and guidelines already in existence. During the meetings of Percutaneous Penetration Subgroup they presented a number of short papers of up to date information on the key issues. The objective was to focus the existing knowledge and the gaps in the knowledge in the field of percutaneous penetration. This paper is an outcome of the meetings of the Percutaneous Penetration Subgroup and reports the presentations on the key issues identified throughout the 3-year duration of the Dermal Exposure Network (1997–1999).
The stratum corneum is considered to be the diffusional barrier of mammalian skin for water and most solutes. The intercellular lipid multilayer domains of the stratum corneum are believed to be the diffusional pathway for most lipophilic solutes. Fluidization of the lipid multilayers in the presence of ethanol is frequently conceived to result in enhanced permeation. Current investigations address the effect of ethanol on the phase behavior in terms of stratum corneum lipid alkyl chain packing, mobility and conformational order as measured by Fourier transform infrared (FTIR) spectroscopy. Phospholipid multimellar vesicles were also studied as model systems. There appeared to be no effect of ethanol on either the solid-solid phase transition or the gel phase interchain coupling of the stratum corneum lipids. However, there was a reduction in the mobility of the alkyl chains in the presence of ethanol. Possible mechanistic relationships between the current FTIR spectroscopic results with available literature data of ethanol induced lipophilic solute penetration enhancement through the skin are discussed.
α-Bisabolol, an inflammatory-inhibiting sesquiterpene, was assessed for its ability to enhance transepidermal drug penetration, in vitro. Human skin samples pretreated with a 1:1 α-bisabolol-propylene glycol mixture were 17-fold more permeable to 5-fluorouracil (5-FU) and 73-fold more permeable to triamcinolone acetonide (TACA) with respect to untreated skin. Differential scanning calorimetry of treated stratum corneum samples showed a dramatic decrease in the lipid transition enthalpy, suggesting increased lipid fluidity. Determinations of drug distribution indicated that the stratum corneum-vehicle partition coefficient of 5-FU was unaffected by the enhancer. The solubility ratio of TACA between the enhancer and the vehicle was very low in comparison with the increase in skin permeability. Hence, for both drugs the enhanced penetration in the presence of a-bisabolol arose predominantly from an increase in their diffusivities across the modified skin barrier.
A predictive method for skin permeability of drugs from polyethylene glycol 400 (PEG)-water and ethanol (EtOH)-water binary solvents is proposed. The method is based on a permeation model, in which the stratum corneum is assumed to be a membrane having two parallel permeation pathways: lipid and pore pathways. Skin permeability of several drugs with a variety of physicochemical properties from various PEG-water and EtOH-water solvents was tested. In PEG-water solvents, almost the same skin permeation rate of lipophilic drugs was obtained independent of the solvent, whereas the permeability coefficient of hydrophilic drugs decreased with increasing PEG fraction. The solvent viscosity was increased and the skin permeability of solvents was decreased by addition of PEG, suggesting the decreased diffusion of the drugs in the pore pathway. EtOH, in contrast, markedly enhanced the skin permeation rate of lipophilic drugs, though no such effect was found on hydrophilic drugs. The enhancing ratio in permeation of lipophilic drugs was dependent not on the lipophilicity of the drug but on the EtOH fraction in the solvent. EtOH-water solvents increased the fluidity of skin lipids, although the extraction of lipids by EtOH-water solvents was relatively low. These results suggest that EtOH enhances diffusion in the lipid pathway. Equations for predicting the skin permeability of a drug from various PEG-water and EtOH-water binary solvents were then derived. The skin permeation behavior of a drug can be predicted by its solubility in octanol and vehicle based on the parallel skin permeation pathway model.
The intercellular lipid multilayers of stratum corneum, the outermost layer of mammalian skin, is generally accepted as the rate determining pathway of transmembrane diffusion for lipophilic solutes. The short chain alcohols, iso-propanol, n-propanol and n-butanol, are known to enhance permeation through the stratum corneum at low concentrations. The effects of these alcohols, at concentrations giving equivalent penetration enhancement, on the stratum corneum lipid alkyl chain packing, mobil- ity and conformational order as measured by Fourier transform infrared (FTIR) spectroscopy have been investigated. Reference is made to studies of model DSPC/DSPA phospholipid multilamellar vesicles in the presence of the alcohols. Iso-propanol and n-butanol do not alter the stratum corneum lipid interchain interactions and gel-gel phase transition. n-Butanol is shown to increase the lipid chain freedom of motion above 45 ° C. However, only n-propanol appears to alter the stratum corneum lipid gel to liquid-crystalline phase transition. In the densely packed gel state (below 45°C), n-butanol was demonstrated to decrease the alkyl chain freedom of motion.
l-Lactic acid-ethanol-isopropyl myristate (IPM) mixed system markedly increased in vitro permeation of ketotifen (KT) through excised hairless rat skin. The object of this study is to verify action site(s) of the mixed system for its enhancing effect on the skin permeation. In vitro permeations of KT through full-thickness skin and stratum corneum-stripped skin from the following vehicles were in the order; silicone fluid<IPM<1% l-lactic acid/IPM<10% ethanol/IPM<1% l-lactic acid-10% ethanol/IPM for both skins. Addition of l-lactic acid or ethanol increased the permeability coefficient of stratum corneum, whereas no change was evidenced for that of viable epidermis and dermis. KT permeabilities were also measured following application of these vehicles on the dermis side and concomitantly on the stratum corneum side. With IPM or 10% ethanol/IPM being used, the drug permeations from the stratum corneum side were higher than those from the dermis. KT permeations through silicone and porous polypropylene membranes, each comprising lipid and aqueous domains, were measured; ethanol exhibited an enhancing effect on permeations through both membranes. In contrast, l-lactic acid increased the KT permeation through the porous membrane only when ethanol was simultaneously used. From these findings, it was concluded as follows; (i) IPM mainly exerted effects on lipid domain of the stratum corneum; (ii) ethanol increased drug permeation through the entire region of the skin; and (iii) l-lactic acid had an effect on the aqueous domain of the stratum corneum and the layer beneath.
I am honored and grateful to the Organizing Committee to have been invited to participate in this Symposium honoring Tak. It may be especially so because my assignment is to talk about drug transport in skin and my first job after receiving my Ph.D. in 1956 was to study factors influencing drug transport across skin at the University of Wisconsin under a Defense Department contract directed by Tak and Dale Wurster.
The cutaneous permeation characteristics of estradiol were examined to evaluate the effect of 21 different organic solvents, some of which are commonly used in topical formulations. The steady-state permeation rate (Fss) through excised human abdominal skin mounted in open diffusion cells was compared to a reference consisting of estradiol applied in volatile solvent. Fss varied in the range of 0.001–0.215 μg cm-2 h-1 where dimethyl sulphoxide and glycols most effectively increased the permeation.Estradiol solubility was determined in all the vehicles and the magnitude of the vehicle effect on the skin was quantified in terms of relative apparent diffusion coefficient. Mainly the facilitating effect could be ascribed to a change in the nature of the skin barrier. It appeared that the estradiol flux from propylene glycol vehicles was unaffected by occlusion and smaller changes in the applied propylene glycol amount.
The effect of polyethylene glycol 400 on the penetration of drugs through human cadaver skin is reported. Polyethylene glycol 400 was used in various concentrations in the donor and the receptor compartments. It was observed that polyethylene glycol 400 had significant effects on the penetration rates of compounds, both when used in the donor as well as in the receptor solutions. These effects were barrier specific and are related to the alteration of the skin structure and the mass flow of water.
Topical formulations of the antiviral compound trifluorothymidine (TFT) were prepared with different proportions of Azone, propylene glycol (PG), polyethylene glycol (PEG-300) and/or water and evaluated by measuring in vitro diffusion of TFT through excised guinea pig skin. Azone dramatically increased drug flux. With 5% Azone in the vehicle, TFT flux values increased 3–4-fold as the ratio of PG: PEG-300 in the vehicle went from 0:100 to 100:0. In experiments without Azone, the TFT penetration rate in PG was 4-fold greater compared to water and 17-fold greater compared to PEG-300. In summary, Azone and PG both enhanced membrane permeability relative to water and acted synergistically on the penetration of the antiviral compound, while PEG-300 appeared to be less efficient than water as a vehicle.
The effect of the penetration enhancer, Azone, on drug transport across skin was investigated using an in vitro permeation technique involving diffusion cells, hairless rat skin and 5-fluorouracil. The permeability of 5-fluorouracil across full-thickness skin (stratum corneum to dermis transport) was enhanced by Azone about 100-fold although a lag time of approximately 10 h was observed. This long lag time was not found after in vitro and in vivo pretreatments with Azone. Azone had no effect on the epidermis-to-dermis transport (across stripped skin) or dermis-to-stratum corneum transport (across reversed full-thickness skin). These results suggest that the amount of Azone in the skin, especially in the stratum corneum, may be related to its penetration enhancing effect. The results also suggest that incorporation of Azone into transdermal dosage forms could be useful in enhancing the transport of drugs for which the rate-limiting step for percutaneous absorption is penetration of the stratum corneum.
The effects of ethanol on fluidity of reconstituted membranes formed from lipid extracts in tolerant and control mice synaptosomal membranes were assessed by fluorescence polarization techniques. Ethanol was less able to fluidize reconstituted membranes of ethanol-tolerant mice than controls. Acute in vivo administration of ethanol did not alter ethanol-induced fluidization of the reconstituted membranes. Since increased membrane cholesterol has been suggested to account for tolerance, the cholesterol and trace non-polar lipids from the lipid extracts were removed and then cholesterol was added back so as to equalize its level in all groups. Following removal of cholesterol, it was not possible to detect any differences between the tolerant and control groups. However, when the cholesterol was added back so that all groups had a cholesterol/phospholipid ratio of the control group level, it was possible to measure differences between tolerant and control lipid extracts. These results suggest that changes in the lipid composition of membranes can account in part for tissue adaptation to ethanol-induced membrane fluidization. The presence of cholesterol in the membranes appears to be unrelated to the expression of tolerance. The small changes in the cholesterol content of membranes observed following development of tolerance probably are not responsible for the attenuation of ethanol-induced membrane fluidization.
A physical model approach to the topical delivery of a vidarabine ester prodrug was investigated. It involved modeling, theoretical simulations, experimental method development for factoring and quantifying parameters, and, finally, employment of the deduced parameters to determine the steady-state species fluxes and concentration profiles in the target tissue. The present report describes the physical modeling and theoretical simulation aspects. The physical model for the simultaneous transport and bioconversion of a topically delivered prodrug was formulated assuming homogeneous enzyme distributions and constant diffusivities in the membrane. The mathematical problem was solved, and the solution yielded concentration profiles and fluxes of all species in the biomembrane. These results provided the prevailing levels of the prodrug, the drug, and the metabolite at the target site and the transport rates of all species into the bloodstream. Computations of concentration profiles and fluxes were carried out for a reasonable range of the parameters. The relative activities of the esterase and the deaminase enzymes, as well as the stratum corneum permeabilities, were important in influencing the concentration profiles and fluxes of all species.
The effects of ethanol on membrane fluidity at 37° have been assessed by a sensitive electron paramagnetic resonance technique. Erythrocyte and brain membranes from DBA/2J mice were spin-labeled with 5-doxylstearic acid (N-oxyl-4',4'-dimethyloxazolidine derivative of 5-ketostearic acid). The molecular motion of the spin label was measured from the EPR spectrum by determining the order parameter S, an index of membrane fluidity. The fluidity of both erythrocyte and synaptosomal membranes was greater than that of myelin but less than that of mitochondrial membranes. The addition of low concentrations (0.02 or 0.04 M) of ethanol in vitro increased fluidity in erythrocyte, mitochondrial, and synaptosomal membranes. This fluidizing effect of ethanol was dose-related up to 0.35 M in all the membranes except myelin. These data suggest that nonlethal concentrations of ethanol may increase membrane fluidity in vivo.
By first determining the thermodynamic activities and activity coefficients of methanol, 1-butanol and 1-octanol in binary dimethyl sulfoxide:water media, it has been possible to separate solubilizing (thermodynamic) effects of dimethyl sulfoxide from its kinetic (diffusive) influence as they relate to the skin permeation of these small, nonelectrolyte alkanols. This was done by normalizing the experimental permeability coefficients found with full-thickness hairless mouse skin membranes to unit activity in the vehicle. When the dimethyl sulfoxide media were placed on both sides of the skin sections in a two compartment diffusion cell, activity-adjusted permeability coefficients of the permeants were invariant to dimethyl sulfoxide concentrations of 50% strength. Thus, up to this concentration and in the absence of net solvent crosscurrents, the permeabilities of methanol, 1-butanol, and 1-octanol appear to be strictly determined by partitioning into the stratum corneum. However, when the dimethyl sulfoxide percentage strength was raised to greater than or equal to 75%, activity-adjusted permeability increased systematically and profoundly, indicating severe barrier impairment with increased diffusion across the horny layer (kinetic effect). When neat dimethyl sulfoxide was placed on both sides of the skin, the experimental permeability coefficients of the three alcohols were maximal and equal in magnitude, suggesting total functional impairment of the stratum corneum. When the dimethyl sulfoxide media were placed in contact with the stratum corneum surface of the skin membranes only, accelerating effects were noted at dimethyl sulfoxide concentrations less than 50%, further supporting the idea that solvent cross flows themselves disrupt the horny structure. The degree of impairment was quantified under all experimental circumstances.(ABSTRACT TRUNCATED AT 250 WORDS)
The solubilities of salicylic acid in, and the fluxes through, hairless mouse skin from isopropyl myristate, 1-octanol, 1-propanol, propylene glycol, and formamide have been determined experimentally. Values for permeability coefficients (Kp) corresponding to the respective fluxes were determined from: flux/solubility = Kp. These values were then compared with values for the respective partition coefficients (P) which were calculated from the known solubility parameters for the vehicles (delta v), salicylic acid (delta i), and skin (delta s). Two different delta i values were used to calculate theoretical P values, one based on the peak solubility method and the other based on calculation from group contributions (11 and 14.4 (cal/cm3)1/2, respectively). There was good correlation between the values for theoretical log P - 1.42 and experimental log Kp for the delivery of salicylic acid from vehicles exhibiting solubility parameters in the range of delta v = 10-18 (cal/cm3)1/2, when delta i was assumed to be 14.4 (cal/cm3)1/2. There was also a good correlation between the values for theoretical log P - 2.09 and experimental log Kp for vehicles exhibiting solubility parameters in the range of delta v = 7.6-10 (cal/cm3)1/2, when delta i was assumed to be 11 (cal/cm3)1/2. Two different delta i values were used because salicylic acid apparently behaves like a polar molecule in polar vehicles and a nonpolar molecule in nonpolar vehicles. Qualitatively, fluxes and permeability coefficients were found to be inversely dependent on drug solubility in the vehicles, with a minimum that corresponded approximately to the point where delta v = delta i, and the minimum within the theoretical P curve.(ABSTRACT TRUNCATED AT 250 WORDS)
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.
This study has established a correlation between the hypnotic potencies of aliphatic alcohols and their abilities to disrupt the structure of neuronal membranes in vitro. The hypnotic potency was determined in mice from the ED50 for loss of righting reflex. The alcohol-induced perturbation of mouse brain synaptosomal plasma membranes was measured by a sensitive electron paramagnetic resonance technique. The membrane disordering potency was determined from the slope of the concentration-dependent decrease in order parameter observed for each alcohol. Significant reductions in the order parameter were observed at nerve blocking concentrations. The following alcohols were investigated: ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3-methyl-1-butanol, 1-hexanol and 1-octanol. The disordering potency of each alcohol was closely related to its membrane solubility, based on published oil/water partition coefficients. Structural disorganization resulting from the incorporation of alcohols into neuronal membranes may be an integral step in the mechanism of alcohol intoxication. For a given degree of membrane disorder, intramembrane alcohol concentrations and intramembrane alcohol volumes were estimated from published partitioning and molecular volume data and compared for constancy. The data did not favor either the intramembrane drug concentration or the intramembrane drug volume as a more effectual determinant of disordering potency.
The permeation behavior of 3H-vidarabine (3H-9-beta-D-ara-binofuranosyladenine) and 14C-n-pentanol through different strata of hairless mouse skin was studied using a diffusion cell at 37 degrees under steady-state conditions. Partition coefficients for the skin components verus 0.9% aqueous NaCl solution also were obtained. Various skin preparations including full-thickness skin, cellophane-stripped skin, and dermis membranes of different thicknesses were employed. The dermis membranes were considered to be diffusionally homogenous, and the product of the permeability coefficient and the thickness was taken as the apparent diffusivity. The apparent diffusivities for both compounds investigated were independent of thickness. Therefore, it was concluded that the molecular diffusivity is constant throughout the dermis. Comparisons of permeability coefficients in various strata of the skin revealed that, while the stratum corneum is the major diffusional barrier, the epidermis appears to be significantly less permeable than the dermis.
1. Anesthetic alcohols (pentanol, hexanol and heptanol) were found to increase the fluidity of red cell membrane lipids as monitored by the fluorescence depolarization of diphenylhexatriene. The relative potency of the alcohols was found to be parallel to their relative membrane/water partition coefficients. 2. Hexanol had biphasic effect on erythritol uptake by simple diffusion by red cells. At concentrations less than 9 mM, there was an approximately linear increase in erythritol permeability with increasing alcohol concentration. 3. The facilitated transport of uridine was markedly inhibited by hexanol. Hexanol at 6 mM produced a 65% inhibition of uridine (4 mM) uptake. Hexanol decreased both the apparent Km and V values for the equilibrium exchange of uridine. 4. The facilitated transport of galactose was only slightly inhibited by hexanol. 5. Hexanol was without effect on the passive and active fluxes of Na+ and K+ in red cells with altered cation contents. Cells that were slightly depleted of K+ and cells that were highly K+ -depleted were both insensitive to hexanol.
Relative affinities of the protein and lipid domains on the stra-tum corneum for various functional groups, Abs. No. 155 Pharm
- P Raykar
- W I Higuchi
- B D Anderson
P. Raykar, W.I. Higuchi and B.D. Anderson, Relative affinities of the protein and lipid domains on the stra-tum corneum for various functional groups, Abs. No. 155 Pharm. Drug Delivery Sec., 1st National Meeting of AAPS, Washin~on, D.C., November 1986, p. 78 S. P. Ashton, J. Hadgraft and K.A. Wafters, Effect of surfactants in percutaneous absorption, Pharm. Acta
Relative affinities of the protein and lipid domains on the stratum corneum for various functional groups
- Raykar
dermal/transdermal metabolism of β-estradiol in hairless mouse skin in vitro
- Liu
The uptake of fluocinonide in propylene-glycol/water systems into human stratum corneum in vitro
- Raykar
Structural considerations of the stratum corneum barrier: A molecular level approach
- Knutson
The effect of ethanol on the transport oIf β-estradiol in hairless mouse skin: I. Comparison of experimental data with a pore model
- Higuchi
Mechanistic studies of stratum corneum permeability: II. Molecular level studies
- Knutson
Differential scanning calorimetry of stratum corneum and evaluation of heat of transitions: A novel approach for studying permeation enhancers or solvent interactions
- Govil