Transdermal iontophoresis of 5-fluorouracil combined with electroporation and laser treatment

The influence of iontophoresis and other physical enhancement methods such as electroporation and erbium:yttrium-aluminum-garnet (YAG) laser on the skin permeation of 5-fluorouracil (5-FU) was examined. Iontophoresis increased the in vitro transdermal transport of both the anionic and non-ionic forms of 5-FU. A combination of electroporation pretreatment and subsequent iontophoresis resulted in a higher permeation of 5-FU than either technique alone. It appeared that electroporation treatment exerted a disruptive influence on the stratum corneum (SC). The SC layers in the skin were partly ablated by the laser, resulting in a great enhancement effect on the skin permeation of 5-FU. Application of iontophoresis further increased the drug permeation across laser-pretreated skin. The laser was consistently the most potent technique to enhance 5-FU delivery among the physical enhancement methods examined in this study.     

Noninvasive delivery of siRNA and plasmid DNA into skin by fractional ablation: Erbium:YAG laser versus CO2 laser

The present study was conducted to evaluate the impacts of fractional erbium (Er):YAG and CO₂ lasers on skin permeation of small interfering (si)RNA and plasmid (p)DNA vectors. In vitro skin delivery was determined with a Franz diffusion cell. In vivo absorption was investigated by observing fluorescence and confocal microscopic imaging. Fractional laser-mediated ablation of the skin resulted in significant enhancement of dextran and siRNA penetration. Respective fluxes of dextran (10 kDa) and siRNA, which had similar molecular size, with Er:YAG laser irradiation at 5 J/cm² were 56- and 11-fold superior to that of intact skin. The respective permeation extents of dextran and siRNA by the CO₂ laser at 4 mJ/400 spots were 42- and 12-fold greater than that of untreated skin. Fluorescence and confocal images showed increased fluorescence intensities and penetration depths of siRNA and pDNA delivery. According to an examination of the follicular permeant amount and fluorescence microscopy, hair follicles were important deposition areas for fractional laser-assisted delivery, with the Er:YAG modality revealing higher follicular siRNA selectivity than the CO₂ modality. This is the first report of siRNA and pDNA penetrating the skin with a sufficient amount and depth with the assistance of fractional lasers.     

Transdermal iontophoresis of sodium nonivamide acetate. V. Combined effect of physical enhancement methods

The effect of iontophoresis combined with treatment of other physical enhancement methods such as electroporation, low frequency ultrasound, and erbium:YAG (yttrium-aluminum-garnet) laser on the transdermal delivery of sodium nonivamide acetate (SNA) was examined in this present study. Iontophoresis increased the transdermal flux of SNA in vitro as compared to the passive diffusion without any enhancement. Furthermore, iontophoresis was always the most potent enhancement method for SNA permeation among the physical enhancement methods tested. Pulsing of high voltages (electroporation) followed by iontophoresis did not result in increased transport over iontophoresis alone. However, electroporation shortened the onset of transdermal iontophoretic delivery of SNA. Pretreatment of low frequency ultrasound (sonophoresis) alone on skin did not increase the skin permeation of SNA. The combination of iontophoresis and sonophoresis increased transdermal SNA transport more than each method by itself. The enhancement of drug transport across shunt routes and reduction of the threshold voltage in the presence of an electric field may contribute to this synergistic effect. Use of an erbium:YAG laser was a good method for enhancing transdermal absorption of SNA because it allows precise control of stratum corneum (SC) removal, and this ablation of SC could be reversible to the original normal status. The combination of laser treatment and iontophoresis also synergized the skin permeation of SNA, possibly due to a gradual drop in the electric resistance of the skin. The results in this present study point out that the choice of certain conditions with suitable physical enhancement methods can induce a synergistic effect on transdermal delivery of SNA during iontophoresis.     

Lasers as an approach for promoting drug delivery via skin

Introduction: Using lasers can be an effective drug permeation-enhancement approach for facilitating drug delivery into or across the skin. The controlled disruption and ablation of the stratum corneum (SC), the predominant barrier for drug delivery, is achieved by the use of lasers. The possible mechanisms of laser-assisted drug permeation are the direct ablation of the skin barrier, optical breakdown by a photomechanical wave and a photothermal effect. It has been demonstrated that ablative approaches for enhancing drug transport provide some advantages, including increased bioavailability, fast treatment time, quick recovery of SC integrity and the fact that skin surface contact is not needed. In recent years, the concept of using laser techniques to treat the skin has attracted increasing attention.

Areas covered: This review describes recent developments in using nonablative and ablative lasers for drug absorption enhancement. This review systematically introduces the concepts and enhancement mechanisms of lasers, highlighting the potential of this technique for greatly increasing drug absorption via the skin. Lasers with different wavelengths and types are employed to increase drug permeation. These include the ruby laser, the erbium:yttrium-gallium-garnet laser, the neodymium-doped yttrium-aluminum-garnet laser and the CO₂ laser. Fractional modality is a novel concept for promoting topical/transdermal drug delivery. The laser is useful in enhancing the permeation of a wide variety of permeants, such as small-molecule drugs, macromolecules and nanoparticles.

Expert opinion: This potential use of the laser affords a new treatment for topical/transdermal application with significant efficacy. Further studies using a large group of humans or patients are needed to confirm and clarify the findings in animal studies. Although the laser fluence or output energy used for enhancing drug absorption is much lower than for treatment of skin disorders and rejuvenation, the safety of using lasers is still an issue. Caution should be used in optimizing the feasible conditions of the lasers in balancing the effectiveness of permeation enhancement and skin damage.     

Skin Laser Treatments Enhancing Transdermal Delivery of ALA

Drug delivery across skin has been limited due to barrier properties of the skin, especially those of the stratum corneum (SC). Use of the laser radiation has been suggested for the controlled removal of the SC. The purpose of this study was to study in vitro the influence of infrared radiation from the erbium:yttrium–aluminum–garnet (Er:YAG) laser (λ = 2940 nm), and visible from the 2nd harmonic of a neodymium:yttrium–aluminum–garnet (Nd:YAG) laser (λ = 532 nm) on transdermal delivery of 5-aminolevulinic acid (ALA). Pinna skin of the inner side of rabbit ear was used for skin permeation. The light sources were an Er:YAG laser (Key III Plus KaVo) and a Q-switched Nd:YAG laser (Lotis TII SL-2132). Permeation study, morphological and structural skin examination by histology and differential scanning calorimetry (DSC) were carried out. Permeation profiles and histological observations obtained after irradiation with infrared and visible laser radiation differed due to different biophysical effects on irradiated skin. Wavelength of 2940 nm required lower energy contribution to produce the same level of permeation than visible radiation at 532 nm. Structural analysis by DSC shows a selective impact on the lipidic structure. Laser pretreatment enhanced the delivery of ALA trough the skin by SC ablation.     

Is the Fractional Laser Still Effective in Assisting Cutaneous Macromolecule Delivery in Barrier-Deficient Skin? Psoriasis and Atopic Dermatitis as the Disease Models

Purpose

Most of the investigations into laser-assisted skin permeation have used the intact skin as the permeation barrier. Whether the laser is effective in improving cutaneous delivery via barrier-defective skin is still unclear.

Methods

In this study, ablative (Er:YAG) and non-ablative (Er:glass) lasers were examined for the penetration of peptide and siRNA upon topical application on in vitro skin with a healthy or disrupted barrier.

Results

An enhanced peptide flux (6.9 fold) was detected after tape stripping of the pig stratum corneum (SC). A further increase of flux to 11.7 fold was obtained after Er:YAG laser irradiation of the SC-stripped skin. However, the application of Er:glass modality did not further raise the flux via the SC-stripped skin. A similar trend was observed in the case of psoriasiform skin. Conversely, the flux was enhanced 3.7 and 2.6 fold after treatment with the Er:YAG and the Er:glass laser on the atopic dermatitis (AD)-like skin. The 3-D skin structure captured by confocal microscopy proved the distribution of peptide and siRNA through the microchannels and into the surrounding tissue.

Conclusions

The fractional laser was valid for ameliorating macromolecule permeation into barrier-disrupted skin although the enhancement level was lower than that of normal skin.

     

Erbium:YAG laser resurfacing increases skin permeability and the risk of excessive absorption of antibiotics and sunscreens: the influence of skin recovery on drug absorption

While laser skin resurfacing is expected to result in reduced barrier function and increased risk of drug absorption, the extent of the increment has not yet been systematically investigated. We aimed to establish the skin permeation profiles of tetracycline and sunscreens after exposure to the erbium:yttrium-aluminum-garnet (Er:YAG) laser during postoperative periods. Physiological and histopathological examinations were carried out for 5 days after laser treatment on nude mice. Percutaneous absorption of the permeants was determined by an in vitro Franz cell. Ablation depths varied in reaching the stratum corneum (10 μm, 2.5 J/cm2) to approach the epidermis (25 μm, 6.25 J/cm2) and upper dermis (40 μm, 10 J/cm2). Reepithelialization evaluated by transepidermal water loss was complete within 2-4 days and depended on the ablation depth. Epidermal hyperplasia was observed in the 40-μm-treated group. The laser was sufficient to disrupt the skin barrier and allow the transport of the permeants into and across the skin. The laser fluence was found to play an important role in modulating skin absorption. A 25-μm ablation depth increased tetracycline flux 84-fold. A much smaller enhancement (3.3-fold) was detected for tetracycline accumulation within the skin. The laser with different fluences produced enhancement of oxybenzone skin deposition of 3.4-6.4-fold relative to the untreated group. No penetration across the skin was shown regardless of whether titanium dioxide was applied to intact or laser-treated skin. However, laser resurfacing increased the skin deposition of titanium dioxide from 46 to 109-188 ng/g. Tetracycline absorption had recovered to the level of intact skin after 5 days, while more time was required for oxybenzone absorption. The in vivo skin accumulation and plasma concentration revealed that the laser could increase tetracycline absorption 2-3-fold. The experimental results indicated that clinicians should be cautious when determining the dose for postoperative treatment.     

Enhanced transdermal delivery of low molecular weight heparin by barrier perturbation

The purpose of this work was to investigate the in vitro transdermal delivery of low molecular weight heparin (LMWH). Hairless rat skin was mounted on Franz diffusion cells and treated with various enhancement strategies. Passive flux was essentially zero and remained low even after iontophoresis (0.065 U cm(-2) h(-1)) or application of ultrasound (0.058 U cm(-2) h(-1)). A significant increase in flux across tape stripped skin (4.0 U cm(-2) h(-1)) suggests the interaction of stratum corneum (SC) with LMWH which was confirmed using Differential Scanning Calorimetry and Fourier Transform-Infrared spectrophotometry. Maltose microneedles were then employed as a means to locally disrupt and bypass the SC. Transepidermal water loss (TEWL) and transcutaneous electrical resistance (TER) were measured to confirm the barrier disruption. Microneedles breached the SC resulting in increased TEWL, decreased TER and enhanced LMWH permeability (0.175 U cm(-2) h(-1)). Microneedles when used in conjunction with iontophoresis had a synergistic effect on LMWH delivery resulting in enhancement of flux by 14.7-fold as compared to iontophoresis used alone. Confocal laser scanning microscopy substantiated the evidence about LMWH interaction with SC. In conclusion, LMWH was shown to interact with SC and therefore tape stripping or microneedles dramatically increased its delivery due to disruption of the SC skin barrier.     

Erbium–Yttrium–Aluminum–Garnet Laser Irradiation Ameliorates Skin Permeation and Follicular Delivery of Antialopecia Drugs

Alopecia usually cannot be cured because of the available drug therapy being unsatisfactory. To improve the efficiency of treatment, erbium–yttrium–aluminum–garnet (Er–YAG) laser treatment was conducted to facilitate skin permeation of antialopecia drugs such as minoxidil (MXD), diphencyprone (DPCP), and peptide. In vitro and in vivo percutaneous absorption experiments were carried out by using nude mouse skin and porcine skin as permeation barriers. Fluorescence and confocal microscopies were used to visualize distribution of permeants within the skin. Laser ablation at a depth of 6 and 10 μm enhanced MXD skin accumulation twofold to ninefold depending on the skin barriers selected. DPCP absorption showed less enhancement by laser irradiation as compared with MXD. An ablation depth of 10 μm could increase the peptide flux from zero to 4.99 and 0.33 μg cm⁻² h⁻¹ for nude mouse skin and porcine skin, respectively. The laser treatment also promoted drug uptake in the hair follicles, with DPCP demonstrating the greatest enhancement (sixfold compared with the control). The imaging of skin examined by microscopies provided evidence of follicular and intercellular delivery assisted by the Er–YAG laser. Besides the ablative effect of removing the stratum corneum, the laser may interact with sebum to break up the barrier function, increasing the skin delivery of antialopecia drugs. The minimally invasive, well‐controlled approach of laser‐mediated drug permeation offers a potential way to treat alopecia. This study's findings provide the basis for the first report on laser‐assisted delivery of antialopecia drugs.     

Impact of Different Vehicles for Laser-Assisted Drug Permeation via Skin: Full-Surface versus Fractional Ablation

Purpose

This study aimed to assess impact of different vehicles for laser-assisted skin drug delivery. We also tried to uncover the mechanisms by which different vehicles affect laser-aided skin permeation.

Methods

Full-surface ablative (conventional) and fractional lasers were used to irradiate nude mouse skin. Imiquimod and 5-aminolevulinic acid (ALA) were used as lipophilic and hydrophilic permeants. Vehicles employed included water with 40% polyethylene glycol 400 (PEG 400), propylene glycol (PG), and ethanol. Lipid nanoparticles were also utilized as carriers.

Results

In vitro permeation profiles showed improvement in imiquimod flux with conventional laser (2.5 J/cm²) producing a 12-, 9-, and 5-fold increase when loading imiquimod in 40% PEG400, PG, and ethanol, respectively, as compared with intact skin. Nanoparticulate delivery by laser produced a 6-fold enhancement in permeation. Fractional laser produced less enhancement of imiquimod delivery than conventional laser. Laser exposure increased follicular imiquimod accumulation from 0.80 to 5.81 μg/cm². ALA permeation from aqueous buffer, PEG 400, and PG with conventional laser treatment was 641-, 445-, and 104-fold superior to passive control. In vivo skin deposition of topically applied ALA examined by confocal microscopy indicated the same trend as the in vitro experiment, with aqueous buffer showing the greatest proporphyllin IX signaling. Diffusion of cosolvent molecules into ablated skin and drug partitioning from vehicle to skin are two predominant factors controlling laser-assisted delivery. In contrast to conventional laser, lateral drug diffusion was anticipated for fractional laser.

Conclusions

Our results suggest that different drug delivery vehicles substantially influence drug penetration enhanced by lasers.     

Investigating the potential of essential oils as penetration enhancer for transdermal losartan delivery: Effectiveness and mechanism of action

The effect of tea tree oil (TTO), cumin oil (CO), rose oil (RO) and aloe vera oil (AVO) on the skin permeation of losartan potassium (LP) was investigated. In vitro skin permeation studies were carried out using rat skin. The mechanism of skin permeation enhancement of LP by essential oils treatment was evaluated by FTIR, DSC, activation energy measurement and histopathological examination. Both concurrent ethanol/enhancer treatment and neat enhancer pretreatment of rat SC with all the oils produced significance increase in the LP flux over the control. The effectiveness of the oils as the penetration enhancers was found to be in the following descending order: AVO > RO > CO > TTO. However, only AVO was the only enhancer to provide target flux required to deliver the therapeutic transdermal dose of LP. FTIR and DSC spectra of the enhancer treated SC indicated that TTO, CO, RO and AVO increased the LP permeation by extraction of SC lipids. The results of thermodynamic studies and histopathological examination of AVO treated SC suggested additional mechanisms for AVO facilitated permeation i.e. transient reduction in barrier resistance of SC and intracellular transport by dekeratinization of corneocytes which may be attributed to the presence of triglycerides as constituents of AVO. It is feasible to deliver therapeutically effective dose of LP via transdermal route using AVO as penetration enhancer.     

Influence of lipophilic counter-ions in combination with phloretin and 6-ketocholestanol on the skin permeation of 5-aminolevulinic acid

In this study, the effect of lipophilic counter-ions on the permeation of 5-aminolevulinic acid (ALA) in combination with skin impregnation by phloretin and 6-ketocholestanol was evaluated. Standard in vitro permeation experiments with porcine skin were performed analysing the ALA content by HPLC and fluorescent detection after ALA derivatisation. The shake flask method in combination with a trinitrobenzensulfonic acid test for ALA analysis was performed to calculate the apparent partition coefficient (logP(Oct)). The permeation of ALA was enhanced by cetylpyridinium chloride and benzalkonium chloride at pH 7.0 and by sodium-1-octanesulfonic acid, sodium-1-heptanesulfonic acid and sodium-1-pentanesulfonic acid monohydrate at pH 4.0. Corresponding effects of these additives were observed on the partitioning of ALA. Pre-impregnation of porcine skin with phloretin and 6-ketocholestanol increased the ALA diffusion about 1.7-fold at pH 7.0. Moreover, this transport enhancement by 6-ketocholestanol was 3.5-fold higher when a combination of ALA and cetylpyridinium chloride was used as donor.     

Topical delivery of 5-fluorouracil (5-FU) by 1,3-bisalkylcarbonyl-5-FU prodrugs.

The solubilities in isopropyl myristate (S(IPM)) and pH 4.0 buffer (S(AQ)) and the partition coefficients between IPM and pH 4.0 buffer (K(IPM:AQ)) have been measured for a series of 1,3-bisalkylcarbonyl-5-fluorouracil prodrugs (1,3-AC-5-FU). The 1,3-AC-5-FU prodrugs were each over 500 times more soluble in IPM, but all members of the series, whose solubilities could be estimated, were much less soluble in pH 4.0 buffer than 5-FU. The abilities of the 1,3-AC-5-FU prodrugs to deliver total 5-FU species through hairless mouse skin from IPM suspensions (J(i)) were also measured. The 1,3-diacetyl derivative 2, which exhibited the highest S(AQ) in the series, gave the highest J(i) value. Although the series of 1,3-AC-5-FU prodrugs was generally effective at increasing J(i) (three to ten times), the best 1,3-AC-5-FU prodrug was not as effective as the best 1- or 3-alkylcarbonyl-5-FU prodrug (1- or 3-AC-5-FU) at increasing J(i) and their ability to increase the concentration of total 5-FU species in the skin was generally less than that of the 1-AC-5-FU prodrugs, but greater than that of the 3-AC-5-FU prodrugs. Thus, the 1-AC-5-FU prodrugs remain the best prodrugs with which to enhance the topical delivery of 5-FU.     

Phospholipid polymer, 2-methacryloyloxyethyl phosphorylcholine and its skin barrier function

The effect of poly[2-methacryloyloxyethyl phosphorylcholine] (pMPC) on the skin permeation property was investigated by performing in vitro skin permeation study of a model drug, nicotinic acid (NA). Effect of pMPC polymer in donor solution on skin permeation rates was evaluated using side-by-side diffusion cells. Also, the structural alterations in the stratum corneum (SC), inter-lamellar bilayer (ILB) and dermis layers in pMPC-treated and -untreated skin sections were investigated with transmission electron microscopy (TEM). The permeation profile of NA without pMPC in donor solution showed biphasic mode: initial 1st phase and 2nd hydration phase. The sudden, more than 10-fold increase in flux from the initial steady state (43.5 microg/cm2/hr) to the 2nd hydration phase (457.3 microg/cm2/h) suggests the disruption of skin barrier function due to extensive hydration. The permeation profile of NA with 3% pMPC in the donor solution showed monophasic pattern: the steady state flux (10.9 microg/cm2/h) without abrupt increase of the flux. The degree of NA permeation rate decreased in a concentration-dependent manner of pMPC. TEM of skin equilibrated with water or 2% pMPC for 12 h showed that corneocytes are still cohesive and epidermis is tightly bound to dermis in 2% pMPC-treated skin, while wider separation between corneocytes and focal dilations in inter-cellular spaces were observed in water-treated skin. This result suggests that pMPC could protect the barrier property of the stratum corneum by preventing the disruption of ILB structure caused by extensive skin hydration during skin permeation study.     

In vitro percutaneous absorption and in vivo protoporphyrin IX accumulation in skin and tumors after topical 5-aminolevulinic acid application with enhancement using an erbium:YAG laser

5-aminolevulinic acid (ALA) is used as a precursor of protoporphyrin IX (PpIX) for photodynamic therapy (PDT) of superficial skin cancers and subcutaneous metastases of internal malignancies. The permeability of ALA across intact skin is always low, making it difficult to achieve the desired therapeutic benefits. Hence new methods for enhancing ALA permeation are urgently needed. The aim of this study was to determine the in vivo kinetics of PpIX generation in mouse tissues after topical ALA application enhanced by an erbium (Er):yttrium-aluminum-garnet (YAG) laser. The in vitro permeation of ALA was also used to screen the optimal method for the in vivo study. The efficacy of the improved drug delivery was determined as a function of various laser fluences and cancer models. ALA applied to laser-treated skin produced a higher accumulations of PpIX within superficial skin and subcutaneous tumors as compared to those of the non-treated group (t-test, p < 0.05). The enhancement ratios (ER) of laser-treated skin ranged from 1.7 to 4.9 times as compared to the control depending to the fluences used. The enhanced PpIX level of laser-treated skin was generally more pronounced in normal and lesional skin than in subcutaneous nodular tumors. Confocal laser scanning microscopy (CLSM) of laser-treated skin revealed intense red fluorescence within the epidermis and upper dermis, and a much-weaker fluorescence within the bottom layers of the skin. On the other hand, the fluorescence intensity of the control group was much lower than that of laser-treated group. The barrier properties of the skin irradiated by the laser had completely recovered within 3 days. Pretreatment of skin using an Er:YAG laser was useful in increasing the amount of Pp IX within skin tumors.     

薄荷醇及其二组分系统对5-氟脲嘧啶经皮渗透和贮库效应的影响

目的：探讨薄荷醇及其二组分系统对氟脲嘧啶(5—Fu)经皮渗透和贮库效应的影响。方法：在离体透皮吸收装置上，测定不同时间5—FU的透过量，计算累积透过量、渗透系数和增渗倍数，并考察其贮库效应。结果：不同浓度薄荷醇对5—FU经皮渗透均有明显的促进作用，其增渗倍数分别为1．25、1.45和1．37倍。其中含2％浓度的薄荷醇组作用最强；含2％和4％薄荷醇的组有显的贮库效应。几种促透剂单独应用或与薄荷醇联合应用时，5—FU的经皮渗透均有显或极显的增加。结论：薄荷醇及其二组分系统能显增强5—FU经皮渗透，加强其贮库效应。     

The dermal delivery of lignocaine: influence of ion pairing

The purpose of the present study was to determine the significance of ion pairing on the permeation of lignocaine. Results of diffusion studies through polydimethylsiloxane (PDMS) at different pH values 4. 0, 6.0, 7.0, 8.0 indicated that lignocaine hydrochloride (L-HCl) flux significantly increased with the amount of unionized base. In order to see if similar results could be obtained using human skin, permeation runs were performed with human skin at pH of 4.0, 5.5 and 7.0. These values were chosen to simulate an appropriate range of physiological conditions. Results of the experiments with human epidermis showed increasing L-HCl flux with increasing pH, confirming the trends seen with PDMS membranes. A linear relationship was found between the apparent partition coefficient and the steady state flux. Further experiments were conducted at donor pH 4.0 to minimise the contribution of the unionized species. Although an excess of different ions such as nitrate, mesylate and bromide increased the apparent partition coefficient, the steady state flux was not significantly increased. The steady state lignocaine flux was increased up to 2.45-fold using different counter ions. The highest flux was measured from lignocaine morpholinopropane sulfonate (L-mps). It is possible to enhance the flux of salts across lipophilic membranes by using an ion pair approach. The degree to which this is possible depends on the lipophilicity of the counter ion, the medium in which the ion pair forms, and the ionic strength.     

The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

Topical 5-fluorouracil (5-FU) is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter). In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5%) was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy.KEY WORDS: Microneedles, 5-Fluorouracil, Cytotoxicity, Melanoma, Immunohistochemistry, Flux, Transdermal, Antitumor activity, Skin permeability     

Treatment of photoaging with a very superficial Er:YAG laser in combination with a broadband light source

BACKGROUND AND OBJECTIVE: Studies documenting improvement following combined laser and light-based devices are needed. The objective of this study was to evaluate clinical, histological, and ultrastructural changes in photodamaged facial skin following sequential treatment with ablative superficial erbium:YAG (Er:YAG) laser peels and nonablative intense pulsed light, or broadband light (BBL), treatments. STUDY DESIGN/MATERIALS AND METHODS: Fifteen subjects with photodamaged facial skin and Fitzpatrick skin types I to III underwent 3 monthly treatments with the Profile system (Sciton, Inc, Palo Alto, CA) utilizing very superficial MicroLaserPeel settings of 2.5 to 5.0 J/cm2 and BBL settings of 515-, 560-, or 590-nm filters, 10-msec pulse duration, and fluences of 12 J/cm2. Five subjects underwent pre- and post-treatment postauricular skin biopsies for evaluation of treatment-induced light and electron microscopic changes. RESULTS: Twelve subjects completed the study. Both blinded evaluator and subject assessment of clinical changes documented significant improvement in photodamaged skin, with the greatest improvement achieved in overall appearance and epidermal dyspigmentation. These results were largely maintained at 3 months following the last treatment. Light microscopy showed changes in the epidermis, collagen, and elastic fibers consistent with a wound repair mechanism to the depth of 250 to 350 microns. Electron microscopy revealed a slight decrease in the average collagen fiber thickness, pointing to an increase in type III collagen. CONCLUSION: A protocol utilizing multiple combined superficial Er:YAG ablative treatments and nonablative BBL treatments lead to a significant improvement in the clinical signs of photodamaged skin, with histological and ultrastructural evidence of new collagen formation.     

Structure-permeability relationship analysis of the permeation barrier properties of the stratum corneum and viable epidermis/dermis of rat skin

The purpose of this study was to evaluate structure-permeability relationships for chemicals through stratum corneum (SC) and viable epidermis/dermis (VED). In vitro skin permeation of ten compounds through excised rat skin was analyzed based on a two-layer diffusion model and the diffusion coefficients in SC (D(SC)) and VED (D(VED)) were determined. The relationships between the permeation parameters and the physicochemical parameters (octanol-water partition coefficient (log K(o/w)), and hydrogen bond donor number (HBD)) of the compounds were analyzed. D(SC) increased as lipophilicity increased, whereas D(VED) decreased for log K(o/w) > 2. Increases in log K(o/w) caused a decrease in the permeability coefficient from SC through VED (P(VED/SC)) for log K(o/w) > 1. The simulation study suggests that the in vitro skin permeation of a highly lipophilic compound is strongly controlled by skin thickness due to low diffusivity in VED. The present study suggests that VED act as a considerable permeation barrier for highly lipophilic compounds due to low diffusivity.