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Daniel Blankschtein

Publications and source records attributed to Daniel Blankschtein.

26 records · Page 2Linked to original sources
PubMed2002

Effects of low-frequency ultrasound on the transdermal permeation of mannitol: comparative studies with in vivo and in vitro skin.

The in vivo and the in vitro correlation of the effects of low-frequency ultrasound (low-frequency sonophoresis, LFS) on the percutaneous penetration of mannitol, a model hydrophilic permeant, was investigated using three in vitro skin models (including full-thickness and split-thickness pig skin, and heat-stripped human cadaver skin) and in vivo pig as the animal model. The central objective of this article was to identify the relevant in vitro skin models and ultrasound conditions that may be used in in vitro LFS studies to predict the effects of LFS in vivo on the transdermal delivery of hydrophilic permeants. In this article, by conducting comparative studies of the in vivo pig skin and of the three in vitro skin models under two LFS protocols (a constant ultrasound energy dose protocol, and a constant skin electrical resistance protocol), we demonstrated that: (1) under a constant ultrasound energy dose protocol (protocol A, 5 min LFS), no good correlation was observed between the in vivo skin and the in vitro skin models in terms of the measured skin permeabilities to mannitol. Moreover, the effects of LFS on the barrier functions of the in vivo pig skin, as measured by the enhancement ratio of the skin permeation rate of mannitol and by the reduction of the skin electrical resistance, are much more pronounced than those observed with the excised skin models in vitro; (2) under a constant skin electrical resistance protocol (protocol B) of LFS, a good correlation was found between the skin permeability to mannitol measured using the three in vitro skin models and that of the in vivo pig skin. This result indicates that by utilizing the skin electrical resistance as a quick indicator of the skin permeabilization state due to LFS, the three in vitro skin models can be utilized to predict the transport rate of mannitol across the in vivo skin during LFS; (3) by applying a recently developed skin porous-pathway theory, we demonstrated that within the range of LFS conditions examined, the three in vitro skin models exhibit similar transport properties to mannitol and similar skin effective pore radius values, and hence, represent equivalent skin models for the in vitro LFS studies in the case of hydrophilic permeants; (4) histological studies revealed that the LFS protocol that was shown to be efficacious in enhancing the skin penetration rate of mannitol across the in vivo pig skin, and was also utilized for the in vivo/in vitro skin comparative studies, is safe for the living skin; and (5) through measuring the skin concentration of mannitol in the presence and in the absence of the LFS treatment, we found that the LFS-induced flux enhancement outweighs the enhancement of the skin concentration of mannitol during the LFS studies both in vivo and in vitro. This result suggests that LFS represents a good method of enhancing the systemic absorption of hydrophilic permeants, while it does not significantly alter the vehicle-to-skin partition coefficient for the same class of permeants.

Administration, Cutaneous↗
PubMed2002

Prediction of steady-state skin permeabilities of polar and nonpolar permeants across excised pig skin based on measurements of transient diffusion: characterization of hydration effects on the skin porous pathway.

The applicability of a two-parameter Fickian diffusion model for predicting the skin steady-state permeability based on measurements of the transient transport of permeants across the skin was tested. Using five model permeants possessing different physicochemical properties and pig skin as the model membrane, the skin permeabilities predicted by the two-parameter Fickian diffusion model were compared with the measured skin permeabilities. Results show that the transient skin permeation profiles of the hydrophobic permeants, estradiol, testosterone, and dolichol, across split-thickness pig skin can be modeled adequately by the two-parameter Fickian diffusion model (with constant parameter values), and therefore, that this model can be utilized to shorten the experimental time required to determine the skin permeabilities of these compounds. However, the skin permeabilities of the highly hydrophilic permeants, mannitol and sucrose, predicted by the two-parameter Fickian diffusion model (with constant parameter values) were significantly lower than the experimentally determined values, indicating that the dominant skin pathway of polar permeants within the excised pig skin undergoes significant structural changes during the in vitro diffusion cell studies. Although the skin permeability values determined experimentally using the traditional steady-state method normally correspond to a highly hydrated skin sample, the two-parameter Fickian diffusion model enables an estimation of the skin permeability of the skin membrane at its less-hydrated state (a condition more representative of in vivo and clinical situations). Using the two-parameter Fickian diffusion model and a recently developed skin porous-pathway theory, the effects of skin hydration on the skin porous pathway within the excised pig skin were characterized. Specifically, we found that hydration leads to induction of new pores/reduction of the tortuosity of existing pores within the excised pig skin during the 48 h diffusion cell studies conducted, while the skin average pore radii remain relatively constant (approximately 26 A) for up to 48 h.

Algorithms↗
PubMed2002

An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport.

PURPOSE: Low-frequency ultrasound (20 kHz) has been shown to increase the skin permeability to drugs, a phenomenon referred to as low-frequency sonophoresis (LFS). Many previous studies of sonophoresis have proposed that ultrasound-induced cavitation plays the central role in enhancing transdermal drug transport. In this study, we sought to definitively test the role of cavitation during LFS, as well as to identify the critical type(s) and site(s) of cavitation that are responsible for skin permeabilization during LFS. METHODS: Pig full-thickness skin was treated by 20 kHz ultrasound and the effect of LFS on the skin permeability was monitored by measuring the increase in the skin electrical conductance. A high pressure LFS cell was constructed to completely suppress cavitation during LFS. An acoustic method, as well as chemical and physical dosimetry techniques, was utilized to monitor the cavitation activities during LFS. RESULTS: The study using the high-pressure LFS cell showed definitively that ultrasound-induced cavitation is the key mechanism via which LFS permeabilizes the skin. By selectively suppressing cavitation outside the skin using a high-viscosity coupling medium, we further demonstrated that cavitation occurring outside the skin is responsible for the skin permeabilization effect, while internal cavitation (cavitation inside the skin) was not detected using the acoustic measurement method under the ultrasound conditions examined. Acoustic measurement of the two types of cavitation activities (transient vs. stable) indicates that transient cavitation plays the major role in LFS-induced skin permeabilization. Through quantification of the transient cavitation activity at two specific locations of the LFS system, including comparing the dependence of these cavitation activities on ultrasound intensity with that of the skin permeabilization effect, we demonstrated that transient cavitation occurring on, or in the vicinity of, the skin membrane is the central mechanism that is responsible for the observed enhancement of skin permeability by LFS. CONCLUSIONS: LFS-induced skin permeabilization results primarily from the direct mechanical impact of gas bubbles collapsing on the skin surface (resulting in microjets and shock waves).

Acoustics↗
PubMed2002

Topographic heterogeneity in transdermal transport revealed by high-speed two-photon microscopy: determination of representative skin sample sizes.

A novel application of high-speed two-photon microscopy was utilized to determine the optimum number of skin sites required to accurately determine the changes in transdermal transport properties incurred globally, over a clinically relevant area of skin. In contrast to the four to six skin sites (100 microm by 100 mirom area per site) examined previously, this study accounted for the fluorescent probe distributions at 400 consecutive skin sites, covering a total skin area of 2 mm by 2 mm. The oleic-acid-induced changes in the transdermal transport properties of the model hydrophobic probe, rhodamine B hexyl ester, and of the model hydrophilic probe, sulforhodamine B, for this 400-skin-site study exhibited different dependencies on sample size for each probe. Whereas the examination of six skin sites captures the relative changes in the global transdermal transport properties of the hydrophobic probe, the valid assessment of these changes for the hydrophilic probe requires a significantly larger sample size of at least 24 skin sites.

Biological Transport↗
PubMed2000

Effects of Multisolute Steric Interactions on Membrane Partition Coefficients.

A key parameter in membrane and chromatographic separations is the partition coefficient, the equilibrium ratio of the solute concentration in a porous or fibrous material to that in bulk solution. The theoretical effects of solute size on partition coefficients in straight pores or randomly oriented fiber matrices have been investigated previously for very dilute solutions, where solute-solute interactions are negligible, and also for more concentrated solutions consisting of spherical solutes of uniform size. For concentrated solutions it has been found that steric and other repulsive interactions among solutes increase the partition coefficient above the dilute limit. To extend the results for porous or fibrous media to include concentrated mixtures of solutes with different sizes or shapes, we used an excluded volume approach. In this formulation, which describes steric interactions only, partition coefficients were computed by summing all volumes excluded to a solute molecule by virtue of its finite size, the finite size of other solutes, and the presence of fixed obstacles (pore walls or fibers). For a mixture of two spherical solutes, the addition of any second solute at finite concentration increased the partition coefficient of the first solute. That increase was sensitive to the size of the second solute; for a given volume fraction of the second solute, the smaller its radius, the larger the effect. When the total volume fraction of solutes was fixed, an increase in the amount of a second, smaller solute increased the partition coefficient of the first solute, whereas an increase in the amount of a second, larger solute had the opposite effect. Results were obtained also for oblate or prolate spheroidal solutes and for fibrous media containing fibers of different radii. For constant total fiber volume fraction, an increase in the amount of a second, smaller fiber decreased the partition coefficient of a spherical solute, whereas an increase in the amount of a second, larger fiber had the opposite effect. Overall, the theory suggests that the introduction of heterogeneities, whether as mixtures of solute sizes or mixtures of fiber sizes, may cause partition coefficients to differ markedly from those of uniform systems. Copyright 2000 Academic Press.

Journal Article↗
PubMedDate not supplied

Challenging the surfactant monomer skin penetration model: penetration of sodium dodecyl sulfate micelles into the epidermis.

The penetration of sodium dodecyl sulfate (SDS) into the epidermis was measured using (14)C-radiolabeled SDS. It was found that, at surfactant concentrations that exceed the critical micelle concentration (CMC) of SDS, the concentration of SDS measured in the epidermis increased as the total SDS concentration in the solution contacting the skin increased, thus demonstrating that micellar SDS contributes to the penetration of SDS into the epidermis. The observed SDS dose-dependent response contradicts the widely accepted view that only surfactant monomers penetrate into the skin, while surfactant in micellar form does not contribute to surfactant penetration into the skin. Nevertheless, this finding is consistent with previously unexplained observations of a dose-dependent damage to the skin induced by SDS at concentrations above the CMC. When poly(ethylene oxide) (PEO) was mixed with SDS, SDS micelles bound to PEO did not contribute to the concentration of SDS in the epidermis, while SDS in free SDS micelles did. Dynamic light-scattering measurements revealed an average hydrodynamic radius of 20 A for the SDS micelles, and a larger radius of 25 A for the PEO-bound SDS micelles. A comparison with typical aqueous pore radii in the stratum corneum measured in the literature (10-28 A) suggests that the SDS micelles may be able to penetrate into the skin, while the PEO-bound SDS micelles may be sterically hindered from penetrating into the skin.

Animals↗
PubMedDate not supplied

Penetration of mixed micelles into the epidermis: effect of mixing sodium dodecyl sulfate with dodecyl hexa(ethylene oxide).

The penetration of the anionic surfactant sodium dodecyl sulfate (SDS) into the epidermis from contacting solutions of SDS and the nonionic surfactant dodecyl hexa(ethylene oxide) (C(12)E(6)) was measured for three SDS concentrations (25 mM, 50 mM, and 100 mM) and three SDS solution compositions (1, 0.83, and 0.50). The addition of C(12)E(6) to the SDS solutions was found to decrease the amount of SDS penetrating into the epidermis. The observed decrease occurred via two plausible mechanisms: (i) the addition of C(12)E(6) decreased the SDS monomer concentration, thus reducing the driving force for the penetration of monomeric SDS into the epidermis, and (ii) the addition of C(12)E(6) reduced, or prevented, the penetration of micellar SDS into the epidermis. Using dynamic light scattering, the hydrodynamic radii of the SDS/C(12)E(6) micelles were determined to be 20 A, for the alpha(m) = 1 micelles, 24 A for the alpha(m) = 0.83 micelles, and 27 A for the alpha(m) = 0.50 micelles (where alpha(m) denotes the SDS micelle composition). A comparison with typical stratum corneum aqueous pore radii reported in the literature (10-28 A) suggests that the alpha(m) = 1 (pure SDS) micelles are able to penetrate into the epidermis, while the alpha(m) = 0.83 and the alpha(m) = 0.50 SDS/C(12)E(6) mixed micelles are sterically hindered from doing so due to their larger sizes. The observed reduced penetration of SDS into the epidermis upon the addition of C(12)E(6) could lead to a reduction in the skin irritation potential of SDS, provided that there is a relationship between the concentration of SDS in the epidermis and the skin irritation induced by SDS.

Animals↗