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Fractional CO 2 laser treatment has been used in some clinical trials to promote topical drug delivery. Currently, there is no standard for laser settings to achieve a feasible therapy. The cutaneous recovery following laser treatment and its influence on drug absorption have not been well explored. This study evaluated the kinetics of laser-treated skin-barrier restoration and drug permeation in nude mice. The skin recovery and observation of the process were characterized by transdermal water loss (TEWL), erythema measurement, gross appearance, optical microscopy, and scanning electron microscopy (SEM). The skin absorption of a lipophilic small permeant (tretinoin), a hydrophilic small permeant (acyclovir), and a large molecule (fluorescein isothiocyanate dextran 4 kDa, FD4) was examined in vitro using Franz cell. TEWL suggested that the laser-treated skin restored its barrier function at 16 h after irradiation. The fractional laser produced microchannels of about 150 μm in diameter and 25 μm in depth that were surrounded with thermal coagulation. The bright-field imaging indicated that the micropores were progressively closed during the recovery period but had not completely closed even after a 16-h recovery. The laser treatment led to a rapid tretinoin penetration across the skin immediately after irradiation, with a 5-fold enhancement compared to intact skin. This enhancement was gradually reduced following the increase of recovery time. Conversely, the acyclovir and FD4 permeation peaked at 1-2 h post-irradiation. The FD4 flux was even elevated as the recovery time increased. The reasons for this could have been the subsequent inflammation after laser exposure and the deficient tight junction (TJ) barrier. The confocal imaging demonstrated the perpendicular diffusion of rhodamine B and FD4 through microchannels immediately after laser exposure. The lateral diffusion from the microchannels was observed at 2 h post-irradiation. Our results revealed a time-dependent recovery of skin permeation. The time frame for applying the drugs after laser irradiation was dependent upon the permeants and their various physicochemical properties., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Use of the ablative laser has been approved to enhance topical drug penetration. Investigation into the usefulness of the non-ablative laser for assisting drug delivery is very limited. In this study, we explored the safety and efficacy of the non-ablative fractional erbium:glass (Er:glass) laser as an enhancement approach to promote drug permeation. Both pig and nude mouse skins were employed as transport barriers. We histologically examined the skin structure after laser exposure. The permeants of 5-aminolevulinic acid (ALA), imiquimod, tretinoin, peptide, dextrans and quantum dots (QD) were used to evaluate in vitro and in vivo skin passage. The fractional laser selectively created an array of photothermal dots deep into the dermis with the preservation of the stratum corneum and epidermis. The barrier function of the skin could be recovered 8-60h post-irradiation depending on the laser spot densities. The application of the laser caused no local infection of Staphylococcus aureus and Pseudomonas aeruginosa. Compared to intact skin, ALA flux was enhanced up to 1200-fold after laser exposure. The penetration enhancement level by the laser was decreased following the increase of permeant lipophilicity. The skin accumulation of tretinoin, an extremely lipophilic drug, showed only a 2-fold elevation by laser irradiation. The laser promoted peptide penetration 10-fold compared to the control skin. Skin delivery of dextrans with a molecular weight (MW) of at least 40kDa could be achieved with the Er:glass laser. QD with a diameter of 20nm penetrated into the skin with the assistance of the non-ablative laser. The confocal microscopic images indicated the perpendicular and lateral diffusions of dextrans and nanoparticles via laser-created microscopic thermal zones. Controlled Er:glass laser irradiation offers a valid enhancement strategy to topically administer the permeants with a wide MW and lipophilicity range., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Psoriasis is a chronic inflammatory skin disease and topical therapy remains a key role for treatment. The aim of this study is to evaluate the influence of psoriasis-like lesions on the cutaneous permeation of anti-psoriatic drugs., Methods: We first set up imiquimod-induced dermatitis in mice that closely resembles human psoriasis lesions. The development of the lesions is based on the IL-23/IL17A axis for phenotypical and histological characteristics. Four drugs, 5-aminolevulinic acid (ALA), tacrolimus, calcipotriol, and retinoic acid, were used to evaluate percutaneous absorption., Results: The most hydrophilic molecule, ALA, revealed the greatest enhancement on skin absorption after imiquimod treatment. Imiquimod increased the skin deposition and flux of ALA by 5.6 to 14.4-fold, respectively, compared to normal skin. The follicular accumulation of ALA was also increased 3.8-fold. The extremely lipophilic drug retinoic acid showed a 1.7- and 3.8-fold increase in skin deposition and flux, respectively. Tacrolimus flux was enhanced from 2 to 21 μg/cm2/h by imiquimod intervention. However, imiquimod did not promote skin deposition of this macrolide. The lipophilicity, but not the molecular size, dominated drug permeation enhancement by psoriatic lesions. The in vivo percutaneous absorption of ALA and rhodamine B examined by confocal microscopy confirmed the deficient resistance of epidermal barrier for facilitating cutaneous delivery of drugs via psoriasis-like skin., Conclusion: We established the topical delivery profiles of anti-psoriatic drugs via imiquimod-treated psoriasis-like skin.

Background: Ambient particulate matters (PMs) are known as inducers that adversely affect a variety of human organs., Objectives: In this study, we aimed to evaluate the influence of PMs on the permeation of drugs and sunscreens via the skin. The role of skin-barrier properties such as the stratum corneum (SC) and tight junctions (TJs) during the delivery process was explored., Methods: This work was conducted using both in vitro and in vivo experiments in pigs to check the responses of the skin to PMs. PMs primarily containing heavy metals (1648a) and polycyclic aromatic hydrocarbons (PAHs, 1649b) were employed to treat the skin., Results: According to the transepidermal water loss (TEWL), 1649b but not 1648a significantly disrupted the SC integrity by 2-fold compared to the PBS control. The immunohistochemistry (IHC) of cytokeratin, filaggrin, and E-cadherin exhibited that 1649b mildly damaged TJs. The cytotoxicity of keratinocytes and skin fibroblasts caused by 1649b was stronger than that caused by 1648a. The 1649b elicited apoptosis via caspase-3 activation. The proteomic profiles showed that PMs upregulated Annexin A2 by >5-fold, which can be a biomarker of PM-induced barrier disruption. We found that the skin uptake of ascorbic acid, an extremely hydrophilic drug, was increased from 74 to 112 μg/g by 1649b treatment. The extremely lipophilic drug tretinoin also showed a 2.6-fold increase of skin accumulation. Oxybenzone and dextran absorption was not affected by PMs. The in vivo dye distribution visualized by fluorescence microscopy had indicated that 1649b intervention promoted permeant partitioning into SC., Conclusions: Caution should be taken in exposing the skin to airborne dust due to its ability to reduce barrier function and increase the risk of drug overabsorption, although this effect was not very marked., (Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

The objective of this study was to design an all-trans retinoic acid (RA) topical release system that modifies drug diffusion parameters in the vehicle and the skin in order to reduce systemic absorption and the side-effects associated with topical application of the drug to skin. Three cases of application of hydrogels containing RA either in free form or encapsulated in stratum corneum lipid liposomes (SCLLs) have been considered. For this purpose, we have evaluated the RA in formulations with combinations of Carbopol Ultrez 10 (U10) and hyaluronic acid (HA) for percutaneous absorption. In vitro permeability experiments with [3H]-t-RA were carried out using a Franz-type diffusion cell in abdominal rat skin samples. Accumulation of the drug in the surface and skin layers was evaluated by both the tape stripping method and a dissection technique, and subsequently, all the radiolabelled samples were analyzed by liquid scintillation counting. The results show that RA encapsulation not only prolongs drug release but also promotes drug retention by the viable skin. At the same time, interaction between RA and HA has an obstructive effect on diffusion, which contributes to the formation of a reservoir of the latter.

The influence of liposome composition, size, lamellarity and charge on the (trans)dermal delivery of tretinoin (TRA) was studied. For this purpose we studied both multilamellar (MLV) or unilamellar (UV) liposomes. Positively or negatively charged liposomes were obtained using either hydrogenated (Phospholipon90H) or non-hydrogenated soy phosphatidylcholine (Phospholipon90) and cholesterol, in combination with stearylamine or dicetylphosphate. Liposomal formulations were characterized by transmission electron microscopy (TEM) and optical and light polarized microscopy for vesicle formation and morphology, and by dynamic laser light scattering for size distribution. In order to obtain more information about the stability and the thermodynamic activity of the liposomal tretinoin, TRA diffusion through a lipophilic membrane was investigated. The effect of the vesicular incorporation of tretinoin on its accumulation into the newborn pig skin was also studied. The experiments were performed in vitro using Franz cells in occlusive conditions and were compared to three different controls. The tretinoin amount delivered through and accumulated in the several skin layers was detected by HPLC. Furthermore, TEM in combination with osmium tetroxide was used to visualize the skin structure after the liposomal administration. Overall obtained results showed that liposomes may be an interesting carrier for tretinoin in skin disease treatment, when appropriate formulations are used. In particular, negatively charged liposomes strongly improved newborn pig skin hydration and TRA retention, though no evidence of intact vesicle penetration was found.

The nature of the receptor solution plays an important role in in vitro percutaneous absorption of highly lipophilic compounds having limited solubility. In vitro permeation studies of a lipophilic compound, all-trans retinoic acid (RA), through the rat dorsal skin were performed with the presence of glycerol (0-20% v/v) in the receptor solution, and the results were compared with those with the presence of albumin (4%). The results showed that an addition of glycerol (20%) into the receptor solution significantly increased the permeation rate of RA through the rat dorsal skin (0.0068 +/- 0.0041 vs. 0.0014 +/- 0.0010 microg/cm2/hr). It was also found that RA tends to accumulate in the lipophilic layer, and its log P value between the epidermis and the receptor solution significantly decreased with the presence of glycerol (20%) (1.48 +/- 0.14 vs. 2.45 +/- 0.21). An addition of glycerol, an osmotherapeutic agent, in the physiological receptor solution seemed to enhance the percutaneous absorption of RA by affecting the partition coefficient of RA.

Background: Apart from oral drug treatment, drug therapy in acne vulgaris comprises topical treatment with agents with a primarily keratolytic action (e.g. tretinoin and benzoylperoxide), and with antibiotics (clindamycin, erythromycin, and erythromycin-zinc complex). The acne grade in the particular patient usually determines the selection of the preferred route of administration, viz. topical or oral, or a combination of both, and topical treatment is usually preferred in mild to moderate acne. The fact that a topically applied compound may also become systemically available to a quantifiable extent, is not generally considered., Aim: The present paper reviews the clinical data on transdermal uptake of anti-acne agents in man, also with respect to their relevance for daily clinical practice., Outcome: The majority of published data on transdermal penetration of topical anti-acne agents focuses on the retinoid tretinoin, and on the antimicrobial agent clindamycin. This interest emerges from the fact that these agents have been associated with embryotoxicity/teratogenicity, and pseudomembranous colitis, respectively. For both compounds the extent of systemic availability after topical application is low, viz. 5-7% and 8%, respectively, at its highest. The height and variability in endogenous retinoid levels is very likely to outweigh any contribution of exogenously applied tretinoin, but a full consensus on the safe use of topical tretinoin in pregnancy is still lacking. With respect to clindamycin, the suggested association between its topical use and the occurrence of pseudomembranous colitis appears not to be of clinical relevance. In order to reduce systemic exposure to clindamycin as much as possible, topical application of clindamycin phosphate is to be preferred over clindamycin hydrochloride salt. Regarding other topical anti-acne agents, it has been suggested that topical zinc-erythromycin is to be preferred over erythromycin, both from clinical efficacy and safety viewpoints. With respect to the currently used compounds like benzoylperoxide, azelaic acid, and adapalene, available clinical pharmacokinetic data are scarce, and significant safety concerns did not emerge as yet., Conclusion: The limited transdermal uptake of topical anti-acne agents underpins their safe use in daily clinical practice. With respect to topical retinoids, formal consensus is lacking regarding their use in pregnancy.

Background: The percutaneous absorption of topically applied tretinoin cream and emollient cream formulations has not been comprehensively studied., Objective: To assess tretinoin absorption and plasma levels of tretinoin and its metabolites after single and repeated topical tretinoin doses., Methods: In study 1, 28 subjects were equally divided into four treatment groups that received a single dose of tritiated tretinoin in a 0.05% formulation of emollient cream (Renova, Retinova) or cream (Retin-A) alone or after 28 days of repeated nonradioactive doses. In study 2, subjects received single topical doses of tritiated tretinoin cream alone (n = 5) or after 1 year of nonradioactive applications (n = 4). Plasma, urine, and fecal samples were analyzed to determine absorption; plasma samples in study 1 were also analyzed for concentrations of tretinoin and its metabolites., Results: Percutaneous absorption of tretinoin was approximately 2% after a single dose and after 28 days of daily application. In patients receiving long-term therapy (i.e., > 1 year), absorption averaged 1.1%. Mean plasma concentrations of tretinoin after 28 days of treatment with either tretinoin emollient cream or tretinoin cream were not significantly changed when compared with the corresponding endogenous concentrations before treatment., Conclusion: Minimal percutaneous absorption of tretinoin was obtained after its topical application in cream formulations. Neither single-dose nor long-term treatment with topical tretinoin formulations appeared to affect the endogenous levels of tretinoin or its metabolites.

Recent in vivo investigations have shown that pretreatment with topical all-trans retinoic acid (RA) may diminish the skin response to sodium lauryl sulphate (SLS). This study evaluated the permeation of SLS through human skin after pretreatment with RA, and vice versa, by in vitro methods. The permeability coefficient of SLS (3.24 +/- 0.21 x 10(3) cm/h) and the 24-h cumulative amount of SLS (3.41 +/- 0.6% of dose applied) permeating RA-pretreated skin did not differ significantly from those across untreated skin (control) (P > 0.05). In contrast, the permeability coefficient of RA (0.23 +/- 0.05 x 10(3) cm/h) and its 24-h cumulative amount (0.37 +/- 0.05% of dose applied) penetrating SLS-pretreated skin were significantly greater than those permeating untreated skin (P < 0.05). Thus, an increase in RA penetration was induced by SLS pretreatment; however, pretreating the skin with RA did not inhibit the percutaneous permeation of SLS. Based on previous in vivo findings where RA reduced skin reactions to SLS, one would speculate that RA pretreatment may decrease SLS penetration. However, these penetration data do not necessarily uphold this presumption. Perhaps, other interactions between the substances and the skin, e.g. at cellular levels, may be responsible for the differing skin responses.

The purpose of these studies was to compare directly the percutaneous absorption,excretion and metabolism of all-trans-retinoyl beta-glucuronide (RAG), a nontoxic retinoid, with all-trans-retinoic acid (RA) in the rat. Previously, it was demonstrated that topical treatment of human acne with either RAG or RA in cream resulted in a significant reduction of lesions. Whereas 0.1% RA showed adverse effects, concentrations of RAG up to 2.4% did not cause any adverse reactions. In the present studies, radiolabeled RAG or RA, dispersed in a water-based cream, was applied to the shaved dorsal skin of vitamin A-sufficient rats. Both RAG and RA were absorbed from the skin in a similar way. In both cases, radioactivity peaked in the plasma within 2-4 h and within the liver at 4-12 h. During a 7-day period, the overall excretion of radioactivity derived from RA and RAG in the feces and urine were similar, e.g. 17 and 12%, respectively. it is concluded that: (1) the transport, metabolism and excretion of topically applied radioactive RA and RAG are similar, although not identical, in the rat and (2) the toxic skin manifestations induced by RA but not by RAG cannot be attributed to major differences in their overall absorption, metabolism and excretion.

The aromatic synthetic retinoid acid derivative, acitretin, is efficacious in several cutaneous diseases. Its toxicological profile makes a topical form with no or reduced systemic adverse effects desirable. Direct application of a topical acitretin formulation might result in therapeutic skin concentrations at the site of the disease while minimizing systemic exposure. The present studies define the percutaneous absorption characteristics of acitretin from an isopropylmyristate formulation. We investigated, in-vitro, (1) the role of receptor solution variations, (2) the role of skin modifications, (3) the influence of skin from three different species on the absorption of topically applied acitretin and (4) the drug distribution within the skin. Addition of solubilizers (Polyethylenglycol-20 and albumin) to the receptor solutions improved the flux of acitretin through monkey skin, whereas the acitretin concentration in the skin was not affected by the various receptor solutions used. Acitretin flux through tape-stripped monkey skin and dermis was only slightly higher than through intact skin. Acitretin concentration in human skin was significantly higher than in rhesus monkey or guinea-pig skin. Topical application of acitretin can produce dermal concentrations in excess of those achieved by therapeutic oral doses.

The influence of irritant contact dermatitis on percutaneous penetration was investigated for four 14C-labeled compounds with diverse physicochemical properties: hydrocortisone (HC), indomethacin (IM), ibuprofen (IB), and acitretin (AC). Hairless guinea pigs were pretreated in vivo for 24 h with either 0.5% sodium lauryl sulfate (SLS) to induce irritant contact dermatitis or with water (controls). Twenty-four hours after pretreatment animals were sacrificed. Percutaneous penetration was then measured using in vitro diffusion cells and the removed (pretreated) skin. The following parameters were determined: cumulative amount of compound penetrated, steady state flux, lag time, and permeability coefficient, skin concentration per unit area, and the relative amount of drug remaining in the skin (as a percentage of the cumulative amount of compound penetrated through the skin). SLS pretreatment resulted in moderate irritant dermatitis in all animals and increased in vivo transepidermal water loss 4.5 times. Flux was increased in SLS-pretreated skin as compared with controls for all four compounds, with the greatest enhancement for hydrocortisone (HC) (5.9 times), followed by indomethacin (IM) (4.6 times), ibuprofen (IB) (3.9 times), and acitretin (AC) (3.4 times). Skin concentrations increased to a smaller degree from 1.6 times (IB) and 2.6 times (HC) to 3.4 times (IM). However, AC skin concentrations were not different between the two groups. Thus, percutaneous penetration parameters were equivocally influenced by SLS-induced irritation. Increased skin concentrations were paralleled by even higher increases in flux.

A single application of 17 micrograms/kg or 8.7 mg/kg all-trans-[10,11-3H2]-retinoic acid dissolved in acetone to shaved dorsal hamster skin resulted in rapid absorption and dose-dependent rates of elimination. An equation describing a two-compartment open model with a very brief lag time and first-order uptake and elimination was used to describe the central plasma compartment kinetics. Unchanged all-trans-retinoic acid represented less than or equal to 4% of the total circulating radio-activity. Peak circulating concentrations of parent all-trans-retinoic acid were less than those observed after an equivalent oral dose, but prolonged absorption from the skin appears to contribute to high total bioavailability of topical retinoid. Topical administration to intact skin of up to three consecutive doses of 10.5 mg/kg/d all-trans-retinoic acid or a single 5 mg/kg dose of etretinate (Ro 10-9359) during a critical stage of embryogenesis in hamsters caused erythema and/or dose-dependent epidermal hyperplasia at the site of application, but failed to induce a significant teratogenic response. Topical application of 0.01-1.0 mg/kg arotinoid Ro 13-6298 resulted in dose-dependent mucocutaneous toxicity and an increase in the numbers of dead embryos and malformed offspring. The marked skin toxicity and attenuated concentrations in maternal blood, compared to the oral route, limit the amounts of retinoid that can reach the hamster embryo. It is thus more important to compare the retinoid systemic values (absorbed dose) than it is to compare the oral or topical (applied) dose, when interpreting the results of conventional teratogenicity bioassays. The data suggest that in the human it is skin toxicity that limits the amounts of retinoid that can be applied and subsequently reach the embryo. In the rodent, overt skin toxicity under continued dosing could increase the amounts of retinoid penetrating the skin and reaching the embryo.

It is well known that urea can considerably increase the release of drugs from ointment bases and that it is one of the most effective penetration promoters for topically applied drugs. In our present study, therefore, we investigated the influence of urea on the penetration kinetics of vitamin A acid (VAA) into the various layers of human skin. When a vehicle containing urea was applied to the skin, we found increased VAA concentrations depending on the penetration of urea. We discuss the significance of the synergistic properties of VAA and urea in the topical treatment of various skin disease.

Five choline esters, lauroylcholine, myristoylcholine, palmitoylcholine, stearoylcholine and oleoylcholine, were evaluated as skin penetration enhancers by testing their effects on the penetration of six drugs, acyclovir, 17 beta-estradiol, hydrocortisone, nitroglycerin, all-trans-retinoic acid and trifluorothymidine, across hairless mouse skin in vitro and comparing the results to those obtained with oleic acid. The results show that the transdermal delivery of the drugs tested from propylene glycol vehicle systems, can be significantly increased by adding small amounts of choline esters and/or oleic acid to the vehicle. Lauroylcholine was a better enhancer than oleic acid for the transdermal delivery of 17 beta-estradiol and, in mixtures, lauroylcholine and oleic acid acted as synergists giving larger enhancement of the transdermal delivery of nitroglycerin and acyclovir than when used separately.