Cutaneous Absorption Research Articles

Enhanced transdermal delivery of evodiamine and rutaecarpine using microemulsion

ObjectiveThe purpose of this study was to improve skin permeation of evodiamine and rutaecarpine for transdermal delivery with microemulsion as vehicle and investigate real-time cutaneous absorption of the drugs via in vivo microdialysis.MethodsPseudoternary phase diagrams were constructed to evaluate microemulsion regions with various surfactants and cosurfactants. Nine formulations of oil in water microemulsions were selected as vehicles for assessing skin permeation of evodiamine and rutaecarpine in ex vivo transdermal experiments. With a microdialysis hollow fiber membrane implanted in the skin beneath the site of topical drug administration, dialysis sampling was maintained for 10 hours and the samples were detected directly by high performance liquid chromatography. Real-time concentrations of the drugs in rat skin were investigated and compared with those of conventional formulations, such as ointment and tincture. Furthermore, the drugs were applied to various regions of the skin using microemulsion as vehicle.ResultsIn ex vivo transdermal experiments, cutaneous fluxes of evodiamine and rutaecarpine microemulsions were 2.55-fold to 11.36-fold and 1.17-fold to 6.33-fold higher, respectively, than those of aqueous suspensions. Different drug loadings, microemulsion water content, and transdermal enhancers markedly influenced the permeation of evodiamine and rutaecarpine. In microemulsion application with in vivo microdialysis, the maximum concentration of the drugs (evodiamine: 18.23 ± 1.54 ng/mL; rutaecarpine: 16.04 ± 0.69 ng/mL) were the highest, and the area under the curve0–t of evodiamine and rutaecarpine was 1.52-fold and 2.27-fold higher than ointment and 3.06-fold and 4.23-fold higher than tincture, respectively. A greater amount of drugs penetrated through and was absorbed by rat abdominal skin than shoulder and chest, and a reservoir in the skin was found to supply drugs even after the microemulsion was withdrawn.ConclusionCompared to conventional formulations, higher cutaneous fluxes of evodiamine and rutaecarpine were achieved with microemulsion. Based on this novel transdermal delivery, the transdermal route was effective for the administration of the two active alkaloids.

The effects of air pollution on vitamin D status in healthy women: A cross sectional study

BackgroundInadequate radiation or insufficient cutaneous absorption of UVB is one of the cardinal causes of vitamin D deficiency. The aim of this study is to determine whether air pollution and low ground level of ultra-violet B light (UVB; 290-315) can deteriorate the body vitamin D status in healthy women.MethodsIn this cross sectional study 200, free-living, housewives, aged between 20 to 55 years, from Tehran (high polluted area) and Ghazvin (low polluted area) were included. The Tehranian women were selected randomly from participants of the Tehran Lipid and Glucose Study (TLGS) and the Ghazvinian females from patients who came to public health centers. Participants were excluded for disease and drugs which affect vitamin D status and also if they were pregnant or breast feeding. We measured the ground level of UVB using a Haze meter as a surrogate of air pollution. In order to calculate the adjusted mean difference of 25-OH-D, ANCOVA analysis was used. Moreover, Binary logistic regression model was developed to determine the odds of living in Tehran for having serum 25-OH-D less than 20 ng/ml.ResultsThe mean ± SD of serum 25-OH-D was significantly higher in Ghazvinian women ((18 ± 11 vs. 13 ± 7), P-value < 001). The prevalence of 25-OH-D less than 10 ng/ml, and 25-OH-D between 10 and 20 ng/ml were higher in Tehranian group (36% and 54% vs. 31% and 32% in respectively). Secondary hyperparathyroidism was also significantly higher in Tehranian women (47% vs. 32%). In ANCOVA analysis, after adjustment, the mean of 25-OH-D in the Ghazvinian group was still statistically significantly higher than Tehranians (13 vs. 17 ng/ml P-value = 0.04). In addition, in binary logistic model, the odd of living in Tehran for having serum 25-OH-D less than 20 ng/ml was 5.22 (95% confidence interval 2.2-12.2, P-value < 0.001).ConclusionWe found that living in a polluted area plays a significant independent role in vitamin D deficiency and hence, residence can be one of the main reasons of vitamin D status of the women.

Photodynamic Therapy in the Dermatological Field and Enhanced Cutaneous Absorption of Photosensitizer

The combination of light and chemicals to treat skin diseases is widely practiced in the fleld of dermatology, and has led to the concept of photodynamic therapy in recent years. In PDT for skin cancer, 5-aminolevulinic acid is applied topically to the afiected area to be absorbed percutaneously through passive difiusion, and typically requires 4{6h before performing PDT. In this study, we attempted to reduce the absorption period in PDT by ionizing ALA using direct current pulsed iontophoresis and Bowen's disease. In all subjects, protoporphyrin IX production was conflrmed after iontophoresis, and its production levels were comparable to the conventional occlusive dressing technique. Skin biopsies from the treated lesion showed the disappearance of tumour cells. 1. INTRODUCTION In recent years, the application of optical technology to clinical medicine has been thriving. Many apparati applying optical technology have been developed and are widely used in clinical settings; e.g., lasers have produced revolutionary results in surgery, most cases of chemical tests on specimens have been conducted using optical techniques, and automated assays have been developed, resulting in tremendous advances in patient diagnostics and medical examinations. Furthermore, a non- invasive treatment method has been recently developed, in which certain drugs given to the body are activated by light to exert their efiects, and the therapeutic efiects of this modality have drawn close attention. The modality is referred to as photodynamic therapy, and is based on the combined use of photosensitizers and photoradiation. That method administers a photosensitizer with a-nity for the tumor cells, followed by light irradiation which results in the selective disruption of only the tumor cells in the body. Since photodynamic therapy (PDT) is less invasive than surgical therapy, it can be used in patients with serious complications and also in elderly patients, and it is being increasingly applied in many clinical flelds, especially dermatology (1). In the fleld of dermatology, it is widely recognized that PDT, in which an excitation light is applied to externally applied 5-aminolevulinic acid (5-ALA), a porphyrin precursor, is efiective for the treatment of superflcial malignant tumors of the skin. However, since the percutaneous absorption of photosensitizers is extremely low, treatment using these substances requires a long time, making it di-cult to establish this method as a standard treatment modality and to apply it on an outpatient basis. In this study, PDT was optimized by introducing the photosensitizer into the skin within a short time by iontophoresis, which involves the application of a microelectric current to the skin to increase the percutaneous absorption of ionic drugs. The results of this study conflrm that iontophoresis indeed enhances the percutaneous absorption of the photosensitizer within a short time, which dramatically reduces the time required for treatment. The flndings of this study are reported herein. Since 5-ALA has an extremely low percutaneous absorbency, there are several methods to improve its absorption such as liposomal 5-ALA, and iontophoresis may dramatically enhance its absorption (2{4).

Topical Clobetasol Propionate in the Treatment of Psoriasis

Ultrapotent topical corticosteroids are the mainstay of psoriasis treatment, used either alone or in combination with a topical vitamin D analog. Traditionally used in an ointment vehicle for psoriasis, clobetasol propionate 0.05% is also available in spray, foam, lotion, and shampoo formulations, which may provide for improved convenience and acceptance in many patients with similar efficacy, safety, and tolerability as the traditional ointment and cream formulations. To compare newer formulations with traditional ointment and cream formulations, we performed a systematic review of the literature. Search terms included 'clobetasol propionate,' in combination with 'psoriasis,' 'vasoconstriction,' 'vasoconstrictor,' or 'absorption' for each of the four vehicles ('spray,' 'foam,' 'lotion,' and 'shampoo'). While there are very few direct comparison studies between clobetasol propionate in different vehicles, the efficacy rates (with success defined as clear or almost clear of psoriasis) for more recent formulations are high, with most patients achieving success after 2-4 weeks of treatment in well controlled clinical trials, with response rates that are similar to those with the traditional clobetasol propionate ointment. Small differences in vasoconstrictor potency or cutaneous absorption have been noted among the formulations, but the clinical significance of these observations is difficult to discern. Recent research has emphasized the importance of treatment adherence in the management of psoriasis. Adherence to treatment is likely to be a far more important determinant of success than are small differences in drug delivery, especially in actual clinical use as opposed to the well controlled environment of clinical trials. For patients who prefer a less messy vehicle, adherence and outcomes are likely to be better with the more recent formulations compared with the traditionally recommended ointment.

토끼 혈장 중 피록시캄의 HPLC 분석 및 패취제 투여 후 경피흡수

A rapid and sensitive reversed-phase high performance liquid chromatography (HPLC) method was developed for the determination of piroxicam in the rabbit plasma. After a treatment of plasma sample by liquid-liquid extraction, the drug was analyzed on an HPLC system with ultraviolet detection at 330 nm. HPLC was carried out using reversed-phase isocratic elution with a C18 column, a mobile phase of a mixture of acetonitril, doubly deionized water and acetic acid 43.74:56.00:0.26 v/v%) at a flow rate of 1.1 mL/min. The chromatograms showed good resolution and sensitivity and no interference of plasma. The calibration curve for the drug in plasma sample was linear over the concentration range of 0.01-2.0 g/mL. The intra- and inter-day assay accuracies of this method ranged from 86.82% to 108.33% of normal values and the precision did not exceed 13% of relative standard deviation. The plasma concentration of piroxicam decreased to below the quantifiable limit at 12 hr after the i.v. bolus administration to rabbits following dose of 0.375 mg/kg yielding a apparen t plasma half life of 1.38 hr. The transdermal route prolongs plasma levels of piroxicam. The bioavailability, calculated from the dose-adjusted ratio of the to the , was 7.44%. The plasma concentration of piroxicam was detected by 48 hr after the transdermal administration of patch at a dose of 32 mg/kg. This method was suitable for cutaneous absorption studies of piroxicam in the rabbit after transdermal administration of different types of dosages of the drug.

Formulation effects of topical emulsions on transdermal and dermal delivery

It has been recognized that the vehicle in which a permeant is applied to the skin has a distinctive effect on the dermal and transdermal delivery of active ingredients. The cutaneous and percutaneous absorptions can be enhanced, e.g. by an increase in thermodynamic activity, supersaturation and penetration modifiers. Furthermore, dermal and transdermal delivery can be influenced by the interactions that may occur between the vehicle and the skin on the one hand, and interactions between the active ingredient and the skin on the other hand. Emulsions are widely used as cosmetic and pharmaceutical formulations because of their excellent solubilizing capacities for lipophilic and hydrophilic active ingredients and application acceptability. This review focuses, in particular, on the effect of emulsions on the dermal and transdermal delivery of active ingredients. It is shown that the type of emulsion (w/o vs. o/w emulsion), the droplet size, the emollient, the emulsifier as well as the surfactant organization (micelles, lyotropic liquid crystals) in the emulsion may affect the cutaneous and percutaneous absorption. Examples substantiate the fact that emulsion constituents such as emollients and emulsifiers should be selected carefully for optimal efficiency of the formulation. Moreover, to understand the influence of emulsion on dermal and transdermal delivery, the physicochemical properties of the formulation after application are considered.

Cutaneous absorption of Oleander: Fact or fiction

Cardiac conduction disorders following oral ingestion of Oleander plant materials were documented earlier. Transcutaneous absorption of yellow oleander (Thevetia peruviana) leaf extract applied over non intact skin (raw wound) resulting in reversible cardiac conduction disorder observed in four healthy males who were free from any other systemic or electrolyte or metabolic disorders or exposure to pesticide or toxins is reported for the first time. Their hematological, biochemical, clinical, and echocardiogram status were within normal limits and free of any abnormalities. One among the four, presented for weakness and breathlessness (class II). He had bradycardia with Mobitz II block and hypotension without any other demonstrable localizing signs. The other three were identified in the community and without any symptoms. However, their ECG revealed bradycardia with Mobitz I block in two and complete heart block in the other. All of the four recovered well without any untoward events. Hence, it is suggested that physicians and practitioners have to elicit history and route of administration of unconventional therapy, whenever they are confronted with clinical challenges and during medical emergencies before embarking final decision.

Response to the Letter to the Editor

Dear Sir, A number of cosmetic ingredients need to be more evaluated in terms of skin penetration. The cutaneous passage of parabens in respect to their lipophilicity and the number of applications was studied during our experiments. The passage of paraben esters had been shown: it was depending on their polarity: the less lipophilic molecules cross the skin more easily than the most lipophilic ones. Our investigation showed that the penetration of these molecules depends also on the number of applications, the passage of paraben esters being increased after each deposit. The aim of our inquiry was to imitate the current usage of cosmetics in daily life (applying many cosmetic products a day, and usually for a long period). Our results are leading to a suggestion that ‘increasing the permeation could provoke, in a long period, an accumulation within fatty tissues’. Thus, our study was an investigation on the cutaneous absorption of paraben esters but not on paraben’s toxicity. According to the comments of Mr Godfrey we would like to clarify some points. Indeed, we agree with Mr Godfrey that our experiments did not demonstrate the accumulation of parabens even after repeated applications, but just an increased permeation. We only suggested that such an increased permeation could lead to an accumulation. The role of metabolic processes and excretion must been taken, in fact, into consideration. Mr Godfrey reminds that parabens are hydrolyzed by esterases present in the skin and refers to the mentioned reference in our paper (1). Indeed, we do not know what occurs in terms of esterases activities in the skin placed within Franz cells. Nevertheless, only a part (and not the totality) of parabens seems to be metabolized (1). In our conclusion, we only indicated that there is a possibility of accumulation. In the second group of experiments (three applications of the lotion), it was done intentionally to imitate the usual usage of cosmetics as it was explained in our paper. Concerning skin integrity after 36 h, a number of studies assessed the cutaneous passage of molecules for more than 24 h: 48 h of investigation (2,3) and 36 h of investigation (4). The aim of our work was to evoke the suspected side effects of parabens and our introduction quoted some references showing the necessity for parabens to be more studied in order to draw conclusions about their toxicity or their innocuity. We understand that Mr Godfrey develops his own analysis about the relationships between parabens and breast cancer. It was absolutely not the aim of our study to explicate such aspect of parabens. Finally, we can understand the position of Mr Godfrey by defending the paraben’s usage in cosmetic formulations. We are grateful to Mr Godfrey for developing some comments about parabens, and this long development shows that the analysis of parabens penetration remains an important issue.

Effects of hypertonic stimuli and arginine vasotocin (AVT) on water absorption response in Japanese treefrog, Hyla japonica

Anuran amphibians do not drink orally but absorb water osmotically through the highly permeable ventral skin. In this cutaneous water absorption, roles of the putative cerebral osmoreceptors and functions of arginine vasotocin (AVT) were examined in the central nervous system of the Japanese treefrog, Hyla japonica. Intracerebroventricular (ICV) or intralymphatic sac (ILS) administration of various hypertonic solutions (NaCl, mannitol and urea) significantly extended the residence time in water in a dose-dependent manner, suggesting facilitation of water absorption in frogs. ICV injection of AVT also increased significantly the residence time in a dose-dependent manner. The water absorption effect of AVT was significantly inhibited by pretreatment of ICV OPC-21268, a vasopressin V 1 receptor antagonist. But pre-ICV injection of OPC-31260, a vasopressin V 2 receptor antagonist, did not block the water absorption effect of AVT. Extension of the residence time induced by hyperosmotic NaCl (1000 mOsm) ICV injection was significantly inhibited by pretreatment of ICV OPC-21268. The present results showed that increases of osmotic pressure in plasma and/or cerebrospinal fluid stimulate water absorption response, suggesting that osmoreceptors are certainly present in the central nervous system and AVT may directly stimulate water absorption in the treefrog. It is also suggested that AVT activates cellular mechanisms via V 1-like but not V 2-like receptors in the central nervous system and facilitates water absorption response in the treefrog.

Chemosensory function of amphibian skin epithelium: Amiloride inhibition of basolateral membrane depolarization in response to increased bath osmolality correlates with afferent neural activity and behavior.

In dehydrated toads cutaneous water absorption is associated with initiation a behavior, the water absorption response (WR), in which the toads press the skin to a rehydration surface. WR initiation is suppressed in toads given a hyperosmotic (250 mM) NaCl solution. Associated with WR suppression the activity of spinal nerve #6 increased when the skin was exposed to this solution and the basolateral membrane potential (Vb) of principal cells in the isolated skin depolarized. These results support our hypothesis that the chemosensory properties of the skin are analogous to taste cells of the mammalian tongue where depolarization of Vb also stimulates neural activity. Here we show the frequency of WR initiation increased from 21% to 50% of trials in toads given 250 mM NaCl with 10 μM amiloride, that the time toads allow ventral skin contact is greater in the presence of amiloride, and that the depolarization of Vb is greatly reduced, relative to NaCl alone. The frequency of WR initiation was also greater with 250 mM Na gluconate as the rehydration solution (40% vs 21% with NaCl) and was increased to 80% of trials when 10 μM amiloride was added to the Na gluconate solution. Inhibition of the transcellular pathway with amiloride and the paracellular pathway with gluconate have similar behavioral responses, and variability in the behavioral responses correspond with variability in Vb and paracellular conductance.

Chemosensory function of amphibian skin epithelium: Amiloride inhibition of basolateral membrane depolarization in response to increased bath osmolality correlates with afferent neural activity and behavior.

Cutaneous water absorption by dehydrated toads is associated with initiation of water absorption response behavior (WR) in which the toads press the skin to a rehydration surface. WR initiation is suppressed in toads given a hyperosmotic (250 mM) NaCl solution. The activity of spinal nerve 6 increased when the skin was exposed to this solution and the basolateral membrane potential (Vb) of principal cells in the isolated skin depolarized. These results support our hypothesis that the chemosensory properties of the skin are analogous to taste cells of the mammalian tongue where depolarization of Vb also stimulates neural activity. The frequency of WR initiation increased from 21% to 50% of trials in toads given 250 mM NaCl with 10 μM amiloride, the time toads allowed ventral skin contact was greater in the presence of amiloride, and the depolarization of Vb was greatly reduced, relative to NaCl alone. The frequency of WR initiation was also greater with 250 mM Na gluconate as the rehydration solution (40% vs 21% with NaCl) and was increased to 80% of trials when 10 μM amiloride was added to the Na gluconate solution. Inhibition of the transcellular pathway with amiloride and the paracellular pathway with gluconate have similar behavioral responses, and variability in the behavioral responses corresponds with variability in Vb and paracellular conductance.

Thermoregulatory responses to environmental toxicants: The interaction of thermal stress and toxicant exposure

Thermal stress can have a profound impact on the physiological responses that are elicited following environmental toxicant exposure. The efficacy by which toxicants enter the body is directly influenced by thermoregulatory effector responses that are evoked in response to high ambient temperatures. In mammals, the thermoregulatory response to heat stress consists of an increase in skin blood flow and moistening of the skin surface to dissipate core heat to the environment. These physiological responses may exacerbate chemical toxicity due to increased permeability of the skin, which facilitates the cutaneous absorption of many environmental toxicants. The core temperature responses that are elicited in response to high ambient temperatures, toxicant exposure or both can also have a profound impact on the ability of an organism to survive the insult. In small rodents, the thermoregulatory response to thermal stress and many environmental toxicants (such as organophosphate compounds) is often biphasic in nature, consisting initially of a regulated reduction in core temperature (i.e., hypothermia) followed by fever. Hypothermia is an important thermoregulatory survival strategy that is used by small rodents to diminish the effect of severe environmental insults on tissue homeostasis. The protective effect of hypothermia is realized by its effects on chemical toxicity as molecular and cellular processes, such as lipid peroxidation and the formation of reactive oxygen species, are minimized at reduced core temperatures. The beneficial effects of fever are unknown under these conditions. Perspective is provided on the applicability of data obtained in rodent models to the human condition.

Toxic serum levels of tacrolimus after topical administration in an infant with severe cutaneous graft-versus-host disease

Previous reports have been published of increased cutaneous absorption of tacrolimus in children with concomitant conditions associated with a skin-barrier dysfunction. Our case is the first report on toxic levels of tacrolimus after topical administration in a child with severe cutaneous acute GVHD. An 11-month-old boy who underwent unrelated umbilical cord blood stem cell transplantation for a SCID received topical tacrolimus for severe cutaneous GVHD. After only two applications restricted to the upper extremities, tacrolimus serum levels reached 23.4 ng/ml. Serum levels rapidly decreased following discontinuation of the topical tacrolimus. No adverse effects related to tacrolimus toxic levels were observed. This case report suggests that significant topical tacrolimus absorption may occur in some children with concomitant conditions displaying skin-barrier dysfunction. Drug monitoring of tacrolimus should be considered in children with extensive skin lesions treated with topical tacrolimus to adjust appropriately dosage.

Development of topical functionalized formulations added with propolis extract: Stability, cutaneous absorption and in vivo studies

Propolis, which is a natural product widely consumed in the folk medicine, is a serious candidate to be applied topically due to its outstanding antioxidant properties. So, the purpose of this study was to develop stable topical formulations added with propolis extract in an attempt to prevent and/or treat the diseases occurring in skin caused by UV radiation. The antioxidant activity using a chemiluminescent method was used to evaluate the functional stability and the permeation/retention in skin of these formulations. In the long-term stability study, the formulations were stored at 25 ± 2 °C/AH and at 40 ± 2 °C/70% RH for 360 days. It was found in this study, that the formulations prepared with Polawax ® showed functional and physical stability in the period of study. In addition, this formulation presented good results in the percutaneous study, allowing the antioxidant compounds present in the propolis extract to reach lower layers in pig ear skin and in the whole hairless mice skin (retention = 0.12 and 0.13 μL of propolis/g of skin, respectively). In the in vivo study, it was also suggested that this formulation may be effective in protecting skin from UVB photodamage, nevertheless other assays need to be done in order to have a complete understanding of the protective effect of formulations added with propolis extract.

Brûlure par acide chromique : prévention systématique de la toxicité systémique

Chromic acid burns can lead to systemic toxicity by cutaneous absorption of the chrome seen surfaces more than 1% of the total body surface area. In order to illustrate the necessity of anticipate systematically this toxicity by a specific treatment, we describe the case of a patient with systemic toxicity in the least severe situation of chromic acid burn: the chromic acid was diluted to 0,02%, the burn was superficial second degree, both thermic and chemical, on the forearm, and extended only to 1% of the total body surface area. In spite of the specific treatment, our patient had a blood transfer of the chrome, however without any consequences on the renal and hepatic functions. He cicatrised in 2 weeks, and his blood and urinary chromium levels were normalised in 3 weeks. Without this specific early treatment, what would have been the consequences of a systemic toxicity even more important?

Can Alcohol-Based Hand-Rub Solutions Cause You To Lose Your Driver's License? Comparative Cutaneous Absorption of Various Alcohols

We assessed cutaneous ethanol (ETOH) and isopropanol (ISOP) absorption after intensive (30 times per h) use of alcohol-based hand-rub solutions by healthcare workers (HCWs). ETOH was detectable in the breath of 6/20 HCWs (0.001 to 0.0025%) at 1 to 2 min postexposure and in the serum of 2/20 HCWs at 5 to 7 min postexposure. Serum ISOP levels were unrecordable at all time points.

In vitro evaluation of quercetin cutaneous absorption from topical formulations and its functional stability by antioxidant activity

Recently, it was demonstrated that two different formulations containing quercetin inhibit the UVB-induced cutaneous oxidative stress and inflammation. Therefore, in the present study it was evaluated the functional stability of those formulations by the antioxidant activity, the release of quercetin from the formulations, and its skin retention using modified Franz diffusion cells. Both formulations tested ((1) non-ionic emulsion with high lipid content and (2) anionic emulsion with low lipid content) remained functionally (hydrogen-donating ability) stable during 180 days. Furthermore, quercetin was released from both formulations as determined using nitrocellulose membrane. In vitro antioxidant activity of retained quercetin into the skin was observed for both formulations as detected by the inhibition of malondialdehyde formation. The effect of quercetin retention was time-dependent for formulation 1. Concluding, this study demonstrates that quercetin remains functionally stable in formulations, and measuring the antioxidant activity is an efficient approach to evaluate quercetin skin retention with minimal interference of the tissue products. Furthermore, the present results on skin retention explain the previous study on quercetin in vivo activities, and together, these data suggest that formulations containing quercetin may be used as topical active products to control UVB-mediated oxidative damage of the skin.

Hypopigmenting agents: an updated review on biological, chemical and clinical aspects

An overview of agents causing hypopigmentation in human skin is presented. The review is organized to put forward groups of biological and chemical agents. Their mechanisms of action cover (i) tyrosinase inhibition, maturation and enhancement of its degradation; (ii) Mitf inhibition; (iii) downregulation of MC1R activity; (iv) interference with melanosome maturation and transfer; (v) melanocyte loss, desquamation and chemical peeling. Tyrosinase inhibition is the most common approach to achieve skin hypopigmentation as this enzyme catalyses the rate-limiting step of pigmentation. Despite the large number of tyrosinase inhibitors in vitro, only a few are able to induce effects in clinical trials. The gap between in-vitro and in-vivo studies suggests that innovative strategies are needed for validating their efficacy and safety. Successful treatments need the combination of two or more agents acting on different mechanisms to achieve a synergistic effect. In addition to tyrosinase inhibition, other parameters related to cytotoxicity, solubility, cutaneous absorption, penetration and stability of the agents should be considered. The screening test system is also very important as keratinocytes play an active role in modulating melanogenesis within melanocytes. Mammalian skin or at least keratinocytes/melanocytes co-cultures should be preferred rather than pure melanocyte cultures or soluble tyrosinase.

Application of sucrose fatty acid esters in transdermal therapeutic systems

Transdermal therapeutic systems (TTSs) were studied applying different sucrose fatty acid esters (SEs) as drug delivery agents. Matrix and membrane controlled TTSs were prepared and compared. Membrane was made from a methacrylic polymer (Eudragit® NE) of pH independent permeability which can achieve diffusion controlled drug liberation. Model drug was a water soluble β-blocker, metoprolol, which has short biological half-life, so applying it in a TTS, the duration of its action could be prolonged. Sucrose fatty acid esters of different fatty acid chain lengths and consequently different hydrophilic–lipophilic balance (HLB) values were studied considering their effect on the metoprolol release from TTSs. Different mathematical models were applied for the evaluation of the release process. The results of the in vitro studies indicated that SEs of shorter fatty acid chain length and higher HLB value increased the amount of released drug about 10 times. SEs could be promising agents in transdermal therapeutic systems to control the drug release and cutaneous absorption.

Percutaneous malathion absorption in the harvested perfused anuran pelvic limb

The objective of this study was to establish an accurate in vitro model for cutaneous absorption in anurans. The harvested perfused anuran pelvic limb (HPAPL) model maintains the anatomic and physiologic integrity of the skin from the pelvic limb, including the intact capillary network. Radiolabeled malathion was applied to the skin of the dorsal thigh, and perfusate was collected over a 6 h period. Residues from the skin surface, stratum externum, and dosed area beneath the stratum externum were analyzed. Kinetic parameters were calculated from these data. Absorption was significantly less for the HPAPL than previously reported for Teflon flow-through diffusion cells. However, partitioning effects were comparable. The HPAPL is an appropriate in vitro model for examining cutaneous absorption kinetics in the bullfrog.