Dermal Patches Research Articles

Preparation and Evaluation of Gene-transfected Cultured Skin as a Novel Drug Delivery System for Severely Burned Skin

The purpose of this study is to prepare and evaluate gene-transfected cultured skin to establish a dermal patch consisting of cultured skin as a new and novel delivery system for severely burned skin. Plasmid DNA encoding the green fluorescent protein (GFP) gene was used as a model gene and transfected to rat and human cultured dermis models (CDMs) using the hemagglutinating virus of Japan envelope vector (HVJ-E) to prepare gene-transfected CDM and evaluate GFP expression in the CDM. Two kinds of transfection methods were evaluated. In pre-transfection, the gene was first transfected into fibroblasts and then CDM was prepared using these gene-transfected cells. In post-transfection, the gene was transfected directly into CDM. GFP expression was observed in both the pre- and post-transfected CDMs. The post-transfection method showed higher GFP expression in the CDM than pre-transfection, although no statistically significant difference was observed. The cell viability of these transfected CDMs was also examined with MTT assay. Slight decrease in viability was observed in these transfected CDMs. These methods could be useful in preparing gene-transfected cultured skins with low cell damage. Gene transfection to cultured skin may produce several dermal patches that release potent endogenous bioactive peptides.

Risk Assessment of Human Exposure to Cypermethrin During Treatment of Mandarin Fields

The potential dermal and respiratory exposure assessment and risk assessment for applicator were performed with cypermethrin EC. The pesticide was applied on a mandarin field using a power sprayer. Gloves were used for the hand exposure assessment, mask for face, and dermal patches for the other parts of the body. Personal air monitor equipped with a XAD-2 resin was used for the respiratory exposure assessment. During the application of cypermethrin in the field, the rate of potential dermal exposure ranged from 28.1 to 58.8 mg/h. The major exposure parts were upper-arms (22.1-24.6%) and legs (thigh and shin, 28.3-29.2%) for females and thigh (21.0-46.9%) and hand (14.9-19.3%) for males. Females were exposed more than males. No exposure was detected from the respiratory monitoring. For risk assessment, the potential dermal exposure (PDE), the absorbable quantity of exposure (AQE), and the margin of safety (MOS) were calculated. Among those four risk assessments, MOS was < 1 in only trial I, which indicated any possibility of risk. However, in the others, the possibility of risk was little. Moreover, the safe work time ranged from 3.61 h to 9.69 h.

Assessment of dermal exposure to benzene and toluene in shoe manufacturing by activated carbon cloth patches

The aim of this investigation was to use activated carbon cloth (ACC) patches to study the probability and extent of dermal exposure to benzene and toluene in a shoe factory. Inhalation and dermal exposure loading were measured simultaneously in 70 subjects on multiple days resulting in 113 observations. Dermal exposure loading was assessed by ACC patches attached to likely exposed skin areas (e.g. the palm of the hand and abdomen). A control patch at the chest and an organic vapor monitor (OVM) were used to adjust the hand and abdomen patches for the contribution from the air through passive absorption of benzene and toluene on the ACC patches. Systemic exposure was assessed by quantification of unmetabolized benzene (UBz) and toluene (UTol) in urine. Mean air concentrations for the study population were 1.5 and 7.5 ppm for benzene and toluene, respectively. Iterative regression analyses between the control patch, OVM and the dermal patches showed that only a small proportion of the ACC patches at the hand had likely benzene (n = 4; mean 133 microg cm(-2) h(-1)) or toluene (n = 5; mean 256 microg cm(-2) h(-1)) contamination. Positive patches were exclusively observed among subjects performing the task of gluing. Significant dermal exposure loading to the abdomen was detected only for toluene (n = 2; mean 235 microg cm(-2) h(-1)). No relation was found between having a positive hand or abdomen ACC patch and UBz or UTol levels. In contrast a strong association was found between air levels of benzene (p = 0.0016) and toluene (p < 0.0001) and their respective urinary levels. ACC patches are shown to be a useful technique for quantifying the probability of dermal exposure to organic solvents and to provide estimates of the potential contribution of the dermal pathway to systemic exposure. Using ACC patches we show that dermal exposure to benzene and toluene in a shoe manufacturing factory is probably rare, and when it occurred exposures were relatively low and did not significantly contribute to systemic exposure.

Cultured skin loaded with tetracycline HCl and chloramphenicol as dermal delivery system: Mathematical evaluation of the cultured skin containing antibiotics

Dermal patches consisting of cultured human skin with antibiotics, which have a protective effect on wound skin as well as a preventative effect on second infection of the skin, were prepared and mathematically analyzed as a new drug delivery system (DDS) that can be applied to serious skin defects such as severe burns. In the present study, a three-dimensional cultured human skin model (living skin equivalent-high, LSE-high) was used as a cultured skin membrane and tetracycline HCl (TC-HCl) and chloramphenicol (CP) were used as antibiotics. At first, antibiotics were entrapped in the LSE-high from the dermal side through culture medium in order to obtain a drug-loaded LSE-high. The antibiotic release from the drug-loaded LSE-high was then examined and the resulting release data were used to calculate the effective diffusion coefficient of the antibiotics (DLSE) and initial loading concentration of the antibiotics (C0) in the LSE-high. The release profile of TC-HCl was represented by general diffusion-limited kinetics, whereas an initial burst effect was found in the release profile of CP. Therefore, the burst effect was taken into account for analyzing the release profile of CP. Stripped skin excised from hairless rats was used as a wound model, and the antibiotic permeation through the skin from aqueous solution was examined and evaluated using differential equations for Fick's second law of diffusion to obtain the effective diffusion coefficient of the antibiotics in the wound skin (Dskin). Furthermore, the antibiotic permeation profile through the excised stripped skin from the drug-loaded LSE-high was measured and theoretically evaluated by Fick's second law of diffusion with previously obtained parameters (C0, DLSE, Dskin) using a newly constructed two- or three-layered diffusion model. The calculated concentrations of TC-HCl and CP in the upper epidermis of the model wound skin were over their minimum inhibitory concentration (MIC) for several hours against various bacteria, suggesting that this dosage system is useful for the treatment of severe burns. In addition, the present analytical method and diffusion model, with the drug-loaded LSE-high and stripped rat skin, are useful tools for evaluating this new DDS.

Development of a Biologically Relevant Dermal Sampler

There are currently no appropriate methods for measuring dermal exposure to volatile agents. To address this we have produced a prototype Institute of Occupational Medicine (IOM) dermal sampler consisting of an adsorbent sandwiched between a permeable membrane and an impervious backing. The concentration of solvent on the membrane surface may be estimated from the mass collected on the adsorbent and the known permeation rate through the membrane. We have developed the prototype IOM dermal sampler for measurement of toluene exposures. Evaluation of the prototype sampler was undertaken in two stages: laboratory performance in controlled exposure situations and two short-field evaluations, which included simultaneous measurement of inhalation exposure. In all cases we compared the prototype IOM dermal sampler with activated charcoal cloth (ACC). Laboratory trials were split into spray, pour and immersion tests. The data from these suggest that the sampler responds to concentration rather than the mass on the surface of the sampler. The field study showed that the prototype sampler was suitable for measuring dermal exposure. However, the mean permeation rate of the best membrane was 78 000 mug cm(-2) h(-1), which is higher than the permeation rate through skin. This high permeation rate created difficulties throughout the study, particularly as it allowed the adsorbent to become rapidly saturated. The prototype IOM dermal sampler is the first practical dermal exposure sampler to mimic uptake through the skin. The sampler gave reproducible results in the laboratory and field trials. Future work is required to identify a less permeable membrane, which has characteristics closer to that of human skin. Additionally, a higher capacity adsorbent would be desirable. We have demonstrated a major difference when calculating the total contribution to body burden via the dermal exposure pathway using the prototype IOM dermal sampler and ACC patches, 1.5% of the total body burden compared with 95%. The prototype IOM dermal sampler provides a more biologically relevant exposure metric than the alternatives.

Laboratory Evaluation of a Potential Diesel Fuel Interference in the Determination of Polycyclic Aromatic Compounds on Dermal Samplers

Road pavers are exposed to asphalt fumes through dermal contact, inhalation, or ingestion. These fumes contain polycyclic aromatic compounds (PACs), a class of compounds including polycyclic aromatic hydrocarbons (PAHs). The PAHs include compounds such as pyrene and benzo(a)pyrene and a large number of other compounds of known or suspected carcinogenicity. To estimate dermal deposition of asphalt fume particulate matter, polypropylene sampling patches can be worn on a worker's inside wrist. Diesel fuel used for cleaning can splash onto the dermal sampler. Exposed dermal patches were solvent extracted and PACs estimated in the extract using a modification of NIOSH Method 5800. The final solution was analyzed by high pressure liquid chromatography (HPLC) with a fluorescence detector using an excitation wavelength of 270 nanometers and an emission wavelength of 415 nanometers. The PACs were concentrated on a C-18 reverse phase guard column but not separated so that they could be measured expediently as a group. In this study we examined whether deposited diesel fuel interferes with the HPLC determination of PACs. We characterized the effect of diesel fuel contamination over broad ranges of both analyte and interferent. Two drops, or approximately 100 μL, of diesel fuel on the dermal samplers caused an overestimation of the concentration of polycyclic aromatic compounds (PACs). In the range of PACs determined in our field study (0 to 54 μg per sample), these errors could have exceeded 100%. Because 100 μL of deposited diesel fuel produced a clear visual “wetness,” this observation can serve as one of the criteria for sample rejection. Sampling media must be examined carefully for visible contamination to prevent bias in the measurement of PACs deposited from asphalt fume.

New contraceptive choices across reproductive life

The range of contraceptive options and consumer awareness of new contraceptive methods have both increased significantly over the past 10 years. New methods available in Australia include lower-dose oral contraceptive pills, new oral progestogens, progestogen implants, a progestogen-bearing intrauterine device and polyurethane female condoms. Contraceptive options which may soon be introduced in Australia include novel methods of administering combined (oestrogen-progestogen) contraception, such as dermal patches and vaginal rings.

Development of sampling and analytical methods for concerted determination of commonly used chloroacetanilide, chlorotriazine, and 2,4-D herbicides in hand-wash, dermal-patch, and air samples.

Sampling and analytical methods were developed for commonly used chloroacetanilide, chlorotriazine, and 2,4-D herbicides in hand washes, on dermal patches, and in air. Eight herbicides selected for study were alachlor, atrazine, cyanazine, 2,4-dichlorophenoxyacetic acid (2,4-D), metolachlor, simazine, and two esters of 2,4-D, the 2-butoxyethyl ester (2,4-D, BE) and the 2-ethylhexyl ester (2,4-D, EH). The hand-wash method consisted of shaking the worker's hand in 150 mL of isopropanol in a polyethylene bag for 30 seconds. The dermal-patch method entailed attaching a 10-cm x 10-cm x 0.6-cm polyurethane foam (PUF) patch to the worker for exposure; recovery of the herbicides was achieved by extraction with 40 mL of isopropanol. The air method involved sampling with an OVS-2 tube (which contained an 11-mm quartz fiber filter and two beds of XAD-2 resin) and recovery with 2 mL of 10:90 methanol:methyl t-butyl ether. Analysis of each of the three sample types was performed by gas chromatography with an electron-capture detector. Diazomethane in solution was employed to convert 2,4-D as the free acid to the methyl ester in each of the three methods for ease of gas chromatography. Silicic acid was added to sample solutions to quench excess diazomethane. Limits of detection for all eight herbicides were matrix-dependent and, generally, less than 1 microgram per sample for each matrix. Sampling and analytical methods met NIOSH evaluation criteria for all herbicides in hand-wash samples, for seven herbicides in air samples (all herbicides except cyanazine), and for six herbicides in dermal-patch samples (all herbicides except cyanazine and 2,4-D). Speciation of 2,4-D esters and simultaneous determination of 2,4-D acid were possible without losses of the esters or of other herbicides (acetanilides and triazines) being determined.

Exposure of farmers to phosmet, a swine insecticide.

The goal of this study was to measure dermal and inhalation exposures to phosmet during application to animals and to identify what determinants of exposure influence the exposure levels. Ten farmers were monitored using dermal patches, gloves, and air sampling media during normal activities of applying phosmet to pigs for insect control. Exposures were measured on the clothing (outer), under the clothing (inner), on the hands, and in the air. Possible exposure determinants were identified, and a questionnaire on work practices was administered. The geometric mean of the outer exposure measurements was 79 microg/h, whereas the geometric mean of the inner exposure measurements was 6 microg/h. The geometric mean for hand exposure was 534 microg/h, and the mean air concentration was 0.2 microg/m3. Glove use was associated with the hand and total dermal exposure levels, but no other determinant was associated with any of the exposure measures. The average penetration through the clothing was 54%, which dropped to 8% when the farmers wearing short sleeves were excluded. The farmers reported an average of 40 hours a year performing insecticide-related tasks. Farmers who applied phosmet to animals had measurable exposures, but the levels were lower than what has been seen in other pesticide applications. Inhalation exposures were insignificant when compared with dermal exposures, which came primarily from the hands. Clothing, particularly gloves, provided substantial protection from exposures. No other exposure determinant was identified.

Dermal Patches for the Controlled Release of Miconazole: Influence of the Drug Concentration on the Technological Characteristics

The aim of this work was to evaluate the effect of different amounts of miconazole nitrate (MIC) on the technological characteristics (drug release profile, adhesiveness, and water vapor permeability) of a nonocclusive dermal therapeutic system (DTS) for the treatment of tinea unguium infection. Artificial silk was used as a backing layer. The self-adhesive matrix was made of a mixture of Plastoid® E 35 L (PL L), an adhesive hydrophilic polymer, and Eudragit® NE 40 D (EU NE), a nonadhesive hydrophobic polymer able to modify the drug release. Plastoid E 35 L is a copolymer of dimethylaminoethyl methacrylate and neutral methacrylic ester. Eudragit NE 40 D is a copolymer of ethylacrylate and methylmethacrylate. Formulations containing different amounts of MIC, ranging from 2% to 16% w/w of the dried matrix, were designed. Drug crystals were observed by polarizing light microscopy, proving the incomplete solubilization of MIC only in the matrices containing 8% w/w or more of this compound. All systems provided an in vitro control of drug release for at least 24 hr. The amount of the drug released increased with drug loading in all DTS. The percentage of the drug released was the same in all the DTS containing detectable crystals of MIC. When the MIC was completely dissolved in the matrix, the released percentage decreased when drug loading increased. The water vapor permeability and the adhesive properties of the DTS were excellent.

Absorption, metabolism, and disposition of [14C]SDZ ENA 713, an acetylcholinesterase inhibitor, in minipigs following oral, intravenous, and dermal administration.

SDZ ENA 713 (rivastigmine) is an acetylcholinesterase inhibitor intended for therapeutic use in Alzheimer's disease. The present study compared the pharmacokinetics of [14C]SDZ ENA 713 after intravenous, oral, and dermal administration to male minipigs, and also examined the effects of dose level and skin abrasion on transdermal absorption. Four groups of 3 minipigs each received a single intravenous (0.1 mg/kg), single oral (1.0 mg/kg), or topical doses of 18 mg or 54 mg of [14C]SDZ ENA 713. Topical doses were administered as dermal patches on two occasions 10 days apart. On Study Day 1, test patches were applied to a virgin skin site. Placebo patches were applied to a separate skin site and were replaced daily during Days 1-10. On Study Day 11, test patches were applied to the site on which the placebo patches had been previously applied. After each dose, serial blood and quantitative urine and feces were collected at designated intervals for 7 days. Concentrations of radioactivity, parent drug, and metabolite ZNS 114-666 were measured in whole blood. Radioactivity was also determined in excreta, skin application sites (at study termination), and on used dermal patches (at 24 hr after application). Oral doses of [14C]SDZ ENA 713 were rapidly (tmax = 0.83 hr) and efficiently (ca. 93%) absorbed, although the bioavailability of the parent drug was low, ca. 0.5%, apparently due to extensive first-pass metabolism. Radioactivity was excreted mainly in the urine (approximately 90%) with a half-life of 56 hr, slightly longer than that observed after an intravenous dose, 46 hr. After dermal administration of [14C]SDZ ENA 713 to a virgin skin site, absorption was 8% at both dose levels investigated. Following daily application of placebo patches for 10 days, absorption from a [14C]SDZ ENA 713 dermal patch increased by approximately twofold, 17% and 19% of the 18 mg and 54 mg doses, respectively. The increase is possibly due to hydration or abrasion of the skin as a result of repeated application and removal of the adhesive patches. Whereas total absorption from the dermal dose was smaller than that from the oral dose, essentially all of the absorbed drug via the dermal route reached the systemic circulation intact, thus yielding a SDZ ENA 713 bioavailability 20-40 times greater than that of the oral dose. Metabolite ZNS 114-666 was rapidly formed and accounted for <4% of total drug-related material in the systemic circulation. Dermal administration in minipigs provided a markedly greater bioavailability of SDZ ENA 713 than the oral route. The extent of absorption was independent of dose within the range tested, and appeared to be enhanced by hydration or abrasion of the skin application site.

The Use of Scopolamine in the Treatment of Detrusor Instability

Purpose A prospective randomized double-blind study was done to evaluate the efficiency of transdermal scopolamine in the treatment of detrusor instability. Materials and Methods A total of 20 female patients with detrusor instability was assigned randomly into 2 groups of 10 each. The study group received 4 transdermal scopolamine dermal patches postauricularly, while in the control group placebo patches were applied. Both groups were similar regarding patient age, parity, duration of symptoms and previous anti-incontinence surgery. Results The patients were reassessed after 14 days. Improvement in complaints of diurnal frequency (p less than 0.05), nocturia (p less than 0.005), urgency (p less than 0.05) and urge incontinence (p less than 0.05) was noted in the study group and not in the control group. A significantly (p less than 0.05) less pressure increase on filling and a decreased volume at which pressure exceeded 15 cm. water (p less than 0.05) were noted on cystometry in the study group only. No significant side effects were reported and no patient discontinued treatment. Conclusions Transdermal scopolamine was effective and safe in the treatment of female patients with detrusor instability.

Estimation of Pesticide Exposure to Greenhouse Application Using Video Imaging and Other Assessment Techniques

Pesticide exposure in greenhouse applicators was measured using the video imaging technique to assess exposure (VITAE) along with dermal patches, air monitoring, and biological assessment techniques. The exposure of five males to pesticides during high- and low-volume application methods in commercial greenhouse operations was evaluated. Failure to use precautionary handling methods when using low-volume applications resulted in the highest level of dermal tracer deposition. Results demonstrated nonuniform deposition of tracer/pesticide mixtures on various body regions, supporting earlier work that questioned the assumption of uniform deposition when assessing exposure with the dermal patch technique. By combining the tracer with an oil-based concentrate, it remained uniformly suspended in the spray solution, and deposition ratios remained constant. Estimates of pirimicarb exposure using the VITAE method were highly correlated with excretion of urinary metabolites (r2 = 0.93). The immediate visual results provided by the VITAE system to applicators proved to be a powerful educational tool in helping them adopt precautionary application techniques. The need to employ protective operating procedures when handling pesticides was demonstrated, no matter how brief the exposure period.