Transepidermal Penetration Research Articles

Hybrid systems based on avobenzone–wrinkled mesoporous silica as ingredients of sunscreen formulations

Excessive exposure to solar radiation causes skin reddening, and sunburn, may accelerate photoaging processes, and lead to neoplastic changes. Therefore, it is recommended to apply cosmetic formulations containing UV protection filters. In recent years, doubts have arisen regarding the safety of certain chemical sunscreen agents that can penetrate the deeper layers of the skin, undergo photodegradation, generate allergies, and affect the endocrine system. The aim of this study was to develop a strategy to limit the permeation of avobenzone from emulsions. Wrinkled mesoporous silicas modified with zinc oxide and/or aminosilane were synthesized, characterized, and next applied as the carriers for the selected UV filter – avobenzone. The introduction of organic groups and ZnO did not disturb the wrinkled morphology of materials, but it changed the textural parameters due to the blocking of micropores. The modification of the wrinkled mesoporous silica had a positive effect on reducing avobenzone rate of desorption. The smallest amount of avobenzone was released from wrinkled mesoporous silica modified with zinc oxide. The release of avobenzone from nanocarriers followed the Korsmeyer-Peppas model, while the diffusion from emulsion was based on the Higuchi model. It was proved that the introduction of avobenzone to functionalized wrinkled mesoporous silica materials reduced the diffusion process of avobenzone from cosmetic emulsions. Nanoporous carriers may help solve the problems related to transepidermal penetration and the potential impact of UV filters on the endocrine system.

Feline cutaneous atopic syndrome: Case Report

Atopic dermatitis (AD) is an inflammatory, itchy and chronic disease and is characterized by a predisposition to develop signs of hypersensitivity after repeated exposure to allergens that in most cases are aeroallergens (pollen and mites). Its development is related to the interaction between genetic and environmental factors that promote changes in the skin barrier. This facilitates the transepidermal penetration of allergens, which come into contact with immune cells present in the skin, triggering an immune response by Th2 lymphocytes. These, in turn, stimulate a high production of IgE, which activates mast cells, stimulating the release of chemical mediators, culminating in the inflammatory process characteristic of AD. In this case, a 7-year-old castrated, spayed female cat weighing 3,900 kg was seen. The animal had intense itching and skin lesions since the age of 1.5 years, which were responsive to the steroid, but when weaning was performed, the lesions returned. On physical examination, the animal presented plaque lesions in the abdominal and axillary region and abrasions in the left ear. The animal was initially treated with cyclosporine and prednisolone, which showed good improvement of the symptoms presented, but had some side effects such as diarrhea, sneezing and nasal and ocular secretion and gingival hyperplasia, which were treated with Fanciclovir and azithromycin-based paste. The animal improved its symptoms after the treatment and even after weaning from cyclosporine it remained well and with a good response to the treatment

Nanovesicles delivery approach for targeting steroid mediated mechanism of antipsoriatic therapeutics

Psoriasis is a most devastating autoimmune condition of anomalously differentiating keratinocytes modifying the barrier function of skin for topical medication. A recurring supply of antiinflammatory therapeutics at a viable epidermal layer is needed to regulate the skin pathology in psoriasis. To meet these treatment targets, traditional modules such as creams, lotions, and gels have been found to be relatively ineffective. Vesicular delivery carriers such as first-generation vesicular structures like liposomes and their modified forms are being utilized for effectual topical delivery of numerous therapeutics for about centuries but remain a realm to be explored with innovation. To provide a controlled release and therapeutic retention at the desired site, the nanovesicular approach is most effective. Apart from that, nanovesicles have numerous advantages such as substantial penetration through the stratum corneum (SC), ease of production, stability, biocompatibility, and inertness. Therefore, in the current investigation, the Triamcinolone acetonide-loaded transfersomes (TA-TFS) have been developed and optimized for the delivery of corticosteroids. The nanovesicles were tested for different in vitro and ex vivo characterization criteria and optimized carriers were subsequently incorporated into a gel as the final formulation. Further, the psoriatic animal model was developed and preclinical studies were performed to evaluate permeation, histopathological evaluation, and cytokine level. The permeation study showed the significant transepidermal penetration and distribution of TA-TFS at viable epidermal layer with controlled drug release. The therapeutic efficacy tested against histological characters and cytokine levels were also evident in providing the anti-inflammatory activity and improvement in other symptoms. The overall investigation suggests that the currently developed formulation can efficiently target the steroid-mediated mechanism of antipsoriatic therapeutics for the effective management of skin conditions in the psoriatic animal model.

425 A superfacial ulcer on the scrotum

A 54-year-old man presented to the dermatology clinic with an itchy red papule on the right scrotum for 2 years, which gradually expanded to a yellow central ulcerated plaque and the crust was not easy to be removed. Topical mupirocin and corticosteroids were not effective. Fluorescent microscopy for fungus was negative, as well as antibodies to syphilis and HIV. There was no similar history in his family, and he had hypertension for 14 years, type 2 diabetes for a year with normal renal function. Biopsy revealed epidermal necrosis and crust with transepidermal penetration and elimination of collagen. Therefore, the diagnosis was acquired reactive penetrating collagenosis (ARPC). Follow-up for 3 months after resection without recurrence. Reactive perforating collagenosis is a rare skin disease that includes both inherited and acquired forms. ARPC is associated with diabetes, chronic renal failure, hyperuricemia and hypertension. It usually occurs on the trunk and limbs, characterized by multiple umbilicated hyperkeratotic papules or nodules with Koebner's phenomenon clinically, but no scrotal lesions have been reported.

Efficacy of topical Miltefosine formulations in an experimental model of cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in ~90 countries, with an increasing incidence. Presently available pharmacotherapy implies the systemic administration of moderately/very toxic drugs. Miltefosine (Milt) is the only FDA-approved drug to treat CL via the oral route (Impavido®). It produces side effects; in particular, teratogenic effects are of concern. A topical treatment would have the great advantage of minimising the systemic circulation of the drug, preventing side effects. We prepared dispersions containing Milt and liposomes of different compositions to enhance/modulate trans-epidermal penetration and evaluated in vitro and in vivo efficacy and toxicity, in vitro release rate of the drug and particles size stability with time. Treatments were topically administered to BALB/c mice infected with Leishmania (Leishmania) amazonensis. The dispersions containing 0.5% Milt eliminated 99% of the parasites and cured the lesions with a complete re-epithelisation, no visible scar and re-growth of hair. Fluid liposomes decreased the time to heal the lesion and the time needed to eliminate viable amastigotes from the lesion site. Relapse of the infection was not found 1 month after treatment in any case. Ultraflexible liposomes on the other hand had no significant in vitro effect but decreased in vivo efficacy. A topical Milt formulation including fluid liposomes seems a promising treatment against CL.

Proteomic analysis of a filaggrin-deficient skin organoid model shows evidence of increased transcriptional-translational activity, keratinocyte-immune crosstalk and disordered axon guidance.

Background: Atopic eczema is an itchy inflammatory disorder characterised by skin barrier dysfunction. Loss-of-function mutations in the gene encoding filaggrin ( FLG) are a major risk factor, but the mechanisms by which filaggrin haploinsufficiency leads to atopic inflammation remain incompletely understood. Skin as an organ that can be modelled using primary cells in vitro provides the opportunity for selected genetic effects to be investigated in detail. Methods: Primary human keratinocytes and donor-matched primary fibroblasts from healthy individuals were used to create skin organoid models with and without siRNA-mediated knockdown of FLG. Biological replicate sets of organoids were assessed using histological, functional and biochemical measurements. Results: FLG knockdown leads to subtle changes in histology and ultrastructure including a reduction in thickness of the stratum corneum and smaller, less numerous keratohyalin granules. Immature organoids showed evidence of barrier impairment with FLG knockdown, but the mature organoids showed no difference in transepidermal water loss, water content or dye penetration. There was no difference in epidermal ceramide content. Mass spectrometry proteomic analysis detected >8000 proteins per sample. Gene ontology and pathway analyses identified an increase in transcriptional and translational activity but a reduction in proteins contributing to terminal differentiation, including caspase 14, dermokine, AKT1 and TGF-beta-1. Aspects of innate and adaptive immunity were represented in both the up-regulated and down-regulated protein groups, as was the term 'axon guidance'. Conclusions: This work provides further evidence for keratinocyte-specific mechanisms contributing to immune and neurological, as well as structural, aspects of skin barrier dysfunction. Individuals with filaggrin deficiency may derive benefit from future therapies targeting keratinocyte-immune crosstalk and neurogenic pruritus.

Evaluation of the Transepidermal Penetration of a Carnosine Complex in Gel Formulation by 3D Skin Models

Carnosine has several physiological roles, from intracellular pH buffering to antioxidant activities, which all depend on bioavailability. This study was conducted in a human skin 3D model and focuses on the effects of the topical delivery of carnosine, from a dermo-cosmetic gel, through the stratum corneum in the presence of a magnesium ion as a complexing agent. To evaluate possible enhancement for small peptide delivery to the skin from simple cosmetic formulations, we discovered that complexation was able to improve the delivery of carnosine into human skin 3D models by application in gel formulation. The concentrations of carnosine released in the underlying media and those that remained in the reconstructed human epidermis (RHE) tissues after 24 and 48 h exposure were measured. Moreover, the influence of magnesium ions was also evaluated comparing the same formulation with and without the salt. The results obtained in this study support hypothesis that magnesium can influence the delivery of small peptides and that the gel formulation based on the carnosine-magnesium complex allows for superior delivery of carnosine in the lower skin layer at a concentration up to 60% more than carnosine alone.

Urinary excretion of phenols, parabens and benzophenones in young men: Associations to reproductive hormones and semen quality are modified by mutations in the Filaggrin gene

BackgroundThe filaggrin gene (FLG) encodes an epidermal protein, filaggrin, which is important for normal skin barrier functions. We previously showed that FLG loss-of-function mutation carriers have a higher internal exposure to some non-persistent chemicals such as certain phthalates and parabens, suggesting increased trans-epidermal penetration. Several groups of non-persistent chemicals are suspected endocrine disrupters with potential to affect testicular function. ObjectivesTo investigate associations between exposure to non-persistent chemicals and testicular function in young Danish men with and without FLG mutations. MethodsWe measured urinary concentrations of bisphenol A (BPA) and other simple phenols, parabens, and UV filters including benzophenones (BP-1, BP-3 and 4-HBP) in men genotyped for FLG R501X, 2282del4, and R2447X loss-of-function mutations; in total 65 mutation carriers and 130 non-carriers (controls) were included. Outcomes were markers of testicular function, assessed by serum reproductive hormones and semen quality. ResultsWe found that associations between urinary chemical concentrations and outcomes were different in cases and controls. Within the group of FLG mutation carriers, higher urinary concentrations of BPA, BP-1 and BP-3 were associated with higher testosterone and estradiol serum levels and lower FSH. Similar trends in hormone levels were observed for FLG mutation carriers with measurable levels of 4-HBP compared to those who had no detectable levels of urinary 4-HBP. Furthermore, those in the highest urinary BPA quartile had lower sperm motility than those in the lower quartiles. None of these associations were evident in the control group. In the control group, however, lower sperm motility and sperm concentration were observed in the men with detectable urinary 4-HBP compared to the men non-detectable urinary 4-HBP. We found no association between any parabens and outcomes, nor for the other measured phenols or UV filters. ConclusionsAssociations between male reproductive health parameters and urinary levels of BPA and benzophenones such as BP-3, BP-1 and 4-HBP were observed in FLG mutation carriers but not in controls from the same study population. This difference between FLG mutation carriers and non-carriers is not explained solely by differences in exposure levels of the examined compounds as e.g. BPA and 4-HBP urinary levels did not differ between the two groups. We hypothesise that effects of exposure to these compounds may be modulated in FLG mutation carriers by either different levels of co-exposures or by route of uptake, with a higher fraction of the uptake by dermal uptake.

Abnormal scar identification with spherical-nucleic-acid technology.

The accurate diagnosis of scar type and severity relies on histopathology of biopsied tissue, which is invasive and time-consuming, causes discomfort and may exacerbate scarring. Here, we show that imaging nanoprobes for the live-cell detection of intracellular messenger RNA (mRNA) (also known as NanoFlares) enable measurements of the expression of connective tissue growth factor (CTGF) as a visual indicator of hypertrophic scars and keloids. During cell culture, NanoFlares enabled the distinction of hypertrophic and keloidal fibroblasts from normal fibroblasts, and the detection of changes in CTGF expression resulting from the regulatory effects of transforming growth factor-β (TGF-β) agonists and TGF-β antagonists. We also applied the NanoFlares topically to the skin of live mice and rabbits, and to ex vivo human skin models. Transepidermal penetration of the NanoFlares enabled the visual and spectroscopic quantification of underlying abnormal fibroblasts on the basis of CTGF mRNA expression. Our proof-of-concept studies of topically applied NanoFlare technology as a means of biopsy-free scar diagnosis may eventually inform therapeutic decisions on the basis of the mRNA-expression patterns of skin disorders.

Exposure to phenols, parabens and UV filters: Associations with loss-of-function mutations in the filaggrin gene in men from the general population

BackgroundFilaggrin is an epidermal protein that is important for normal skin barrier functions. Up to 10% of Europeans and Asians carry filaggrin gene (FLG) loss-of function mutations that appear to facilitate trans-epidermal penetration of certain chemicals. We previously showed that mutation carriers have higher internal exposure to certain phthalates, compared to controls, and hypothesized that they could have increased trans-epidermal penetration of other chemicals. ObjectivesWe investigated exposure to non-persistent chemicals in young Danish men with and without FLG mutations. MethodsConcentrations of eight simple phenols, six parabens and nine UV filters were analysed in urine from 65 FLG loss-of-function mutation carriers and 130 non-carriers (controls). Regression analyses, controlling for urinary dilution and confounders, were performed to estimate associations between FLG mutation status and chemical concentrations in urine. ResultsFLG mutation carriers had 80% (13–180%) higher urinary concentrations of methyl paraben (MeP) and 91% (13–219%) higher concentrations of n-propyl paraben (n-PrP) than controls. For 13 compounds, levels were higher in FLG mutation carriers, although differences were only statistically significant for MeP and n-PrP. Combined statistical analysis of concentrations of all the 18 compounds that were detectable in >10% of subjects, suggested that concentrations were generally higher in mutation carriers (p=0.03). ConclusionFLG loss-of-function mutation carriers have a higher internal exposure to some non-persistent chemicals, independently of atopic dermatitis. This may be due to increased trans-epidermal absorption and/or higher exposure, and mutation carriers may constitute a group susceptible to increased absorption of chemicals and topical medication.

Clinical relevance of tixocortol pivalate‐positive patch tests and questionable bioequivalence of different hydrocortisone preparations

Tixocortol-21-pivalate (tixocortol pivalate) is used as a surrogate marker for contact allergy to hydrocortisone and other corticosteroids. To review the results of repeated open application testing (ROAT) and patch testing with hydrocortisone creams and ointments in tixocortol pivalate patch test-positive patients. ROAT was performed when the history of hydrocortisone contact dermatitis was negative or equivocal. Hydrocortisone cream and/or ointment patch tests were performed in patients with and without histories of hydrocortisone contact dermatitis. Results were excluded in patients allergic to vehicle ingredients. ROAT was positive in 15 of 20 patients (75%) with hydrocortisone cream versus 6 of 16 (38%) with hydrocortisone ointment (p = 0.02). Patch testing was positive with hydrocortisone cream in 23 of 27 patients (85%) versus 1 of 14 (7%) with hydrocortisone ointment (p < 0.0001). Only 1 of 26 tixocortol pivalate patch test-negative patients had a positive patch test with hydrocortisone cream caused by a vehicle ingredient. Clinical relevance was shown in most patients with positive tixocortol pivalate patch tests. Hydrocortisone creams gave positive patch tests and positive repeated open application tests much more often than hydrocortisone ointments. There were also significant differences in patch test reactivity among different hydrocortisone creams. We hypothesize that these differences may be explained by differences in hydrocortisone transepidermal penetration in different vehicles.

Efficacy of Combined Peroxisome Proliferator-Activated Receptor-α Ligand and Glucocorticoid Therapy in a Murine Model of Atopic Dermatitis

Although topical glucocorticoids (GCs) display potent anti-inflammatory activity in inflamed skin, they also can exert numerous harmful effects on epidermal structure and function. In contrast, topical applications of ligands of peroxisome proliferator-activated receptor-α (PPARα) not only reduce inflammation, and also improve cutaneous barrier homeostasis. Therefore, we examined whether sequential topical GCs followed by topical Wy14643 (a ligand of PPARα) might be more effective than either alone for atopic dermatitis (AD) in a hapten (oxazolone)-induced, murine model with multiple features of AD (Ox-AD). Despite expected anti-inflammatory benefits, topical GC alone induced: i) epidermal thinning; ii) reduced expression of involucrin, loricrin and filaggrin; and iii) allowed outside-to-inside penetration of an epicutaneous tracer. While Wy14643 alone yielded significant therapeutic benefits in mice with mild or moderate Ox-AD, it was less effective in severe Ox-AD. Yet, topical applications of Wy14643 after GC was not only significantly effective comparable to GC alone, but it also prevented GC-induced structural and functional abnormalities in permeability barrier homeostasis. Moreover, rebound flares were largely absent after sequential treatment with GC and Wy14643. Together, these results show that GC and PPARα ligand therapy together is not only effective but also prevents development of GC-induced side effects, including rebound flares, in murine AD.

The skin barrier function: a micro‐PIXE study

AbstractHuman body is perpetually subjected to environmental exposures as sun, natural, urban or industrial pollutions and societal exposures. Skin is the main physiological barrier facing to these different stresses; however its response mechanisms are still not well understood. Skin models are thus necessary to understand skin physiology and behavior in normal conditions or under stress. Because of the large natural interindividual variability and of some difficulties in obtaining human skin biopsies, we have been developing and characterizing different skin models such as reconstructed epidermis in vitro, native pigskin and human keratinocyte cells. These models allow us to study the mechanisms involved in ion homeostasis in correlation with structural organization and biological responses. In the present study, we have characterized the pig ear skin model using micro‐particle induced x‐ray emission (PIXE) analysis with the aim of evaluating the distribution of inorganic ions under normal or stress conditions together with the transepidermal penetration of external agents, such as aluminum oxides. The nuclear microprobe analysis allowed us to validate the culture conditions of the tissue and we have shown an alteration of the inorganic ion patterns after exposure to a chemical compound (sodium dodecyl sulfate) known for its deleterious effects on the barrier function. Finally, we have shown no transepidermal penetration of aluminum oxides after different exposures to cosmetic formulations. Copyright © 2009 John Wiley &amp; Sons, Ltd.

Molecular basis of atopic dermatitis

Atopic dermatitis is a common chronic inflammatory skin disease and there are numerous publications on this topic. This review will focus on developments in understanding the molecular basis of atopic dermatitis while considering the genetic background, skin barrier impairment, immune system deviation and microbial superinfections. Atopic dermatitis is a complex genetic disease in which gene-gene and gene-environment interactions play a key role. Surprisingly some genetic regions of interest were found to be overlapping with loci identified to play a role in another very common inflammatory skin disease, psoriasis, while no overlap has so far been observed with asthma. Impairment of the skin barrier followed by antigens trespassing seems to play an important role, favouring sensitization via transepidermal penetration which is the focus of current investigations. Superinfections by pathogens such as Staphylococcus aureus due to a weak innate defence seem to be significant in atopic dermatitis as they elicit a strong inflammatory response. Atopic dermatitis is a chronic inflammatory skin disease with a high incidence in school children and adults. Disease pathogenesis is complex and the background is multifactorial, making the underlying predispositions elusive. Understanding new pathogenic pathways may lead to the development of new drugs with enhanced benefit for the patient.

The role of 3-dimethylaminopropylamine and amidoamine in contact allergy to cocamidopropylbetaine.

Since it has been found that all subjects with contact allergy to cocamidopropylbetaine (CAPB) have positive reactions to 3-dimethylaminopropylamine (DMAPA), and reports have appeared in literature of the sensitizing action of amidoamine in products containing CAPB, we aimed to verify the possibility that pure amidoamine may have a sensitizing role in subjects with positive reactions to CAPB. To this end, in 10 patients with contact allergy to a commercial CAPB, we tested DMAPA 1% aq. and a pure amidoamine in concentrations ranging from 0.5% aq. to 0.1% aq. The study showed that all patients with positive reactions to DMAPA reacted to amidoamine at 0.5% and 0.25% aq., while 4 of the 10 also had positive reactions to amidoamine at 0.1% aq. We consider that simultaneous allergic reaction to DMAPA and amidoamine represents cross-reactivity and hypothesize that DMAPA is in fact the true sensitizing substance, while amidoamine, which may in any case release DMAPA in vivo as a result of enzymatic hydrolysis, may favour the transepidermal penetration of the sensitizing agent. In addition, we advise that testing of CAPB be suspended, because, as suggested by chemico-structural analyses and demonstrated in vivo, when thoroughly purified, it no longer has a sensitizing action.

Liposome associated interferon-alpha-2b functions as an anti-fibrogenic factor in dermal wounds in the guinea pig.

We have previously reported that interferon-alpha-2b (IFN-alpha-2b) can be encapsulated in liposomes without compromising its anti-fibrogenic effects on dermal fibroblasts in vitro. This study was conducted to determine whether this preparation applied topically to guinea pig wounds can affect their healing. The rationale for this approach is that systemic administration of IFN-alpha-2b by injection for treatment of dermal fibrosis is uncomfortable, requires a large quantity of the cytokine and cannot be easily used in children. Liposomes are potentially useful vehicles for the topical delivery of drugs. Empty sonicated liposome vesicles were mixed with various concentrations of IFN-alpha-2b and then dried and rehydrated. An enzyme-linked immunosorbent assay (ELISA) was used to determine the efficiency of encapsulation and the stability of the preparation under experimental conditions. A total of 36 full thickness skin wounds (6/animal, 3 on each side) were made with an 8 mm disposable punch. Each wound on the right side received cream (100 mg/wound) containing 3000 units of liposome-encapsulated IFN-alpha-2b, while wounds on the left side received cream containing empty liposomes. There was a significant reduction in rate of contraction of wounds treated with IFN-alpha-2b as early as 5 days after wounding. This reduction remained significant up to 10 days. Northern analysis, used to evaluate the expression of mRNAs for type I and type III collagens in response to IFN-alpha-2b showed a marked reduction in abundance of the transcripts for the pro-alpha1(I) chain of type 1 collagen on days 11 and 14 after wounding. Similarly, the level of mRNA for type III procollagen was markedly reduced as early as day 7 and remained depressed up to day 14. These findings were consistent with results obtained for the total collagen content in tissue samples. Cellularity of the IFN-alpha-2b-treated wounds, assessed by vimentin content, was also markedly reduced at day 7 and remained depressed up to day 14. Liposome associated IFN-alpha-2b applied 5 days after completion of epithelialization reduced mRNA for the pro-alpha1(I) chain of type 1 collagen, confirming its transepidermal penetration and effectiveness. The activity of liposome-associated IFN-alpha-2b in vivo supports the concept of the topical use of this anti-fibrogenic agent for treatment of fibroproliferative disorders.

Letter to the editor

Autoradiography and the technique of stripping/slicing were used in order to investigate the pathways and to quantify drug penetration into skin after iontophoresis of two model compounds: fentanyl, a lipophilic molecule and TRH, a hydrophilic molecule. Iontophoresis was performed for 1, 4 and 6 h at a mean current density of 0.33 mA/cm2 and was compared to passive diffusion. The quantification studies showed that iontophoresis increases the drug concentration in the part of the skin limiting molecule permeation: viable skin for fentanyl and stratum corneum for TRH. Even though, besides accumulation, autoradiography allows one to localize the route of passage, observations tend to confirm that transepidermal penetration can take place and that an important route of penetration is the transappendageal pathway.

Quantification and localization of fentanyl and trh delivered by iontophoresis in the skin

Autoradiography and the technique of stripping/slicing were used in order to investigate the pathways and to quantify drug penetration into skin after iontophoresis of two model compounds: fentanyl, a lipophilic molecule and TRH, a hydrophilic molecule. Iontophoresis was performed for 1, 4 and 6 h at a mean current density of 0.33 mA/cm 2 and was compared to passive diffusion. The quantification studies showed that iontophoresis increases the drug concentration in the part of the skin limiting molecule permeation: viable skin for fentanyl and stratum corneum for TRH. Even though, besides accumulation, autoradiography allows one to localize the route of passage, observations tend to confirm that transepidermal penetration can take place and that an important route of penetration is the transappendageal pathway.

Preparation and enhancing effect of 1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD) on the transepidermal penetration of clonidine, hydrocortisone, and indomethacin through shed snake skin

1-( N, N-Dimethylamino)-2-propanol dodecanoate (DAIPD), a new biodegradable penetration enhancer was prepared by condensing lauroyl chloride with 1-( N, N-dimethylamino)-2-propanol. The penetration enhancing effects of DAIPD on the transdermal delivery of clonidine, hydrocortisone, and indomethacin were evaluated using shed snake skin ( Elaphe obsoleta) as the model membrane. Azone was used as a typical enhancer for comparison. DAIPD showed a 1.2-2-times greater promoting effect than azone for the above-cited drugs. In vitro biodegradability of DAIPD was demonstrated in the presence of porcine esterase. The results indicate that DAIPD increases markedly the transdermal delivery of several types of drug substances.

Improvement of epidermal differentiation and barrier function in reconstructed human skin after grafting onto athymic nude mice.

To determine whether epidermis reconstructed in vitro at the air-liquid interface on de-epidermized dermis has the capacity to normalize the expression of differentiation-specific markers, its lipid composition and stratum corneum barrier properties, human skin equivalents were transplanted onto athymic nude mice and investigated at different stages ranging from 1 to 4 months after grafting. Indirect immunofluorescence with species- or non-species-specific antibodies revealed that as early as 1 month after transplantation keratinization, and involucrin, loricrin and transglutaminase patterns were normalized. Human melanocytes were observed in the basal layer of the pigmented graft. As revealed by high-performance thin-layer chromatography and transmission electron microscopy after ruthenium tetroxide fixation, the lipid profile and the intracellular lamellar organization were similar to those found in natural epidermis. Transepidermal water loss measurements and penetration studies showed that the barrier properties of the reconstructed epidermis after transplantation were comparable to those of normal human skin.