Percutaneous Absorption Rate Research Articles

Evaluation of a compounding phospholipid base for the percutaneous absorption of high molecular weight drugs using the Franz finite dose model.

Permeation-enhancing compounding bases are aimed to facilitate the penetration of the active pharmaceutical ingredients (APIs) across the skin barrier. The purpose of this study was to evaluate the percutaneous absorption of radiolabeled human insulin (14 C-isototpe) when incorporated in a proprietary phospholipid base designed to deliver APIs with high molecular weights (HMW). The aim was not to claim the transdermal delivery of insulin with potential therapeutic applications in diabetes but, instead, to evaluate the ability of the compounding phospholipid base to deliver HMW drugs. The percutaneous absorption of 14 C-insulin was determined using human torso skin and the Franz skin finite dose model. Two topical test formulations were prepared for in vitro evaluation: insulin 1% in phospholipid base (standard) and insulin 1% in phospholipid base HMW. The rate of percutaneous absorption (mean flux) and the distribution of 14 C-insulin through the skin were evaluated for both topical test formulations. A two-way ANOVA was used to determine statistical differences. The 14 C-insulin was distributed into the stratum corneum, epidermis and dermis. Mean flux values showed a rapid penetration upon application and the maximum flux was achieved at 30 min, followed by a slow decline. Subsequently, a slower decline was observed for the topical test formulation including the phospholipid base HMW. The phospholipid base HMW facilitates the percutaneous absorption of HMW drugs across human cadaver skin and, therefore, it may potentially be a useful option for compounding pharmacists and practitioners when considering the skin for the percutaneous delivery of large drugs.

Design and evaluation of adapalene microemulsion for transfollicular drug delivery through guinea pig skin.

Acne vulgaris can be treated topically with adapalene, a synthetic derivative of naphthoic acid with retinoid activity. Adapalene has a very low rate of percutaneous absorption and is almost completely insoluble in water. To obviate this problem, microemulsion (ME) carrier is used. The study's goals were to create and characterize adapalene-loaded ME and assess the drug's transfollicular route of penetration to see if hair follicles can serve as a conduit for the drug to enter the skin. Adapalene microemulsions (MEs) are made by combining the right amounts of the cosurfactant (propylene glycol), surfactant (Tween 80 and Span 20), and oil phase (oleic acid-Transcutol P (10:1)). Physical and chemical characteristics of MEs, including droplet size, stability, viscosity, drug release, and in vitro skin permeability via guinea pigs' hairy and non-hairy skin, were assessed. The range of 13.86-56.16 nm was found to be the average droplet size of ME formulations. The range of viscosities was 117-240 cps. The drug release profile reveals that 95.374 percent of the drug was released within the experiment's first 24 h. Compared to the adapalene control (aqueous suspension), all MEs enhanced the adapalene flow through both hairy and non-hairy skin. The surfactant/cosurfactant ratio had an impact on the amount of drug that passed through both skins because a larger ratio enhanced the adapalene affinity in the follicular route. Furthermore, the proportions of the water and oil phases in formulations, as well as the S/C ratio, have a significant impact on the physicochemical characteristics and adapalene permeability across both pathways.

Validation of a quantitative liquid chromatography/hybrid quadrupole-linear ion trap MS/MS method for carfentanil and caffeine in a live human epidermis model.

Carfentanil, an opioid 10K times more potent than morphine, has no licit clinical use. A powerful CNS depressant, it has been identified increasingly as the cause of overdose death in the United States. Because it is highly lipophilic, the law enforcement and medical communities have been concerned that responding personnel could be percutaneously exposed and that exposure could be enhanced with the use of alcohol-containing hand sanitizers. An LC-MS/MS method was developed to evaluate solvent effects on percutaneous absorption of carfentanil in a live human epidermal model. In this study, a quantitative liquid chromatography/hybrid triple quadrupole-linear ion trap method was developed for carfentanil and for caffeine, a molecule routinely used to monitor epidermal cell culture viability. The method employed reverse-phase liquid chromatography coupled with positive electrospray ionization and multiple reaction monitoring (MRM) to quantify carfentanil and caffeine against calibration curves formulated from authentic standards. Limits of detection (LOD) for the two compounds were determined using 10:1 signal-to-noise requirements for all product ions with relative peak areas within ±20% of those observed for a mid-level calibrator. Precision and accuracy were determined by analyzing positive controls formulated in quintuplicate, by a different analyst, at three concentrations bracketing the method dynamic range. Inter-day precision was evaluated using data collected from three separate days of analyses. Calibration curves for seven formulated replicates of the two compounds met linearity requirements over at least four orders of magnitude concentration range. The accuracy of measured concentration results was within ±20% of the actual, precision across results (%CV) was ≤15%, curve coefficients of determination (r) were ≥0.980 (correlation coefficient r > 0.990), and relative ion ratios of all qualifier ions were within ±20% of those for a mid-level standard. Limits of quantification (LOQs) for carfentanil and caffeine were 230 pg/ml and 12 ng/ml, respectively. Intra-day accuracies (mean concentrations) for carfentanil and caffeine ranged from 90.1% to 100.8% and from 87.1% to 108.9%, respectively; inter-day accuracies ranged from 98.7% to 100.4% and from 97.5% to 101.7%, respectively. Intra-day precision (%CV) over the dynamic range ranged from 1.31 to 8.88 and from 1.49 to 6.72 for carfentanil and caffeine, respectively. Inter-day precision ranged from 4.7 to 9.9 %CV for carfentanil and 7.6-121 %CV for caffeine. The method was used to evaluate the percutaneous absorption kinetics of carfentanil in solution as a function of solvent composition using an in vitro, live human epidermis model. Counterintuitively, as previously reported, the addition of organic solvents to the formulations decreased rather than increased the percutaneous absorption rate of the ultra-potent opioid, carfentanil.

POS0478 TOPICAL CALCIUM CHELATORS FOR TARGETING CUTANEOUS CALCIFICATION: PRECLINICAL EVIDENCE OF EFFICACY

BackgroundCutis calcinosis, defined as sub-epidermal deposition of calcium salts, is a painful, disabling, disfiguring, problem in 20-40% of patients with systemic sclerosis. Its pathogenesis remains poorly understood and currently there is no effective disease-modifying pharmacotherapy. One potential strategy is topical application of calcium chelating agents, able to penetrate the epidermal barrier and dissolve subcutaneous calcinotic deposits in situ. To date, the only compound reported for this application has been sodium thiosulfate (STS), with often-contradictory results.ObjectivesTo test the hypothesis, in pre-clinical studies, that polycarboxylic acids can induce calcium dissolution without skin toxicity, with the long-term aim of developing an effective topical treatment for cutis calcinosis.MethodsWe compared the metal ion-chelating agents citric acid (CA) and ethylenediaminetetraacetic acid (EDTA) - polycarboxylic acids with well-characterised chelation profiles – to STS for their ability to chelate calcium, without inducing cytotoxicity or inflammation (pro-inflammatory cytokine expression and release), using in vitro 2D (keratinocyte [HaCaT]; fibroblast ([HCA2]) and recombinant human epidermal (RHE) models. The resultant data was subsequently used to predict therapeutic concentrations for assessment in a validated skin irritation model (SkinEthicTM; Episkin SA) and to assay maximal percutaneous absorption. At relative dermal concentrations, the dissolution performance of each chelator was further assessed using two different models of calcinosis: 1) pharmaceutical dissolution of a hydroxyapatite (HAp) tablet (1) and; 2) dissolution of a calcified extracellular matrix laid down by mineralising SaOS2 in vitro monolayer culture (2).ResultsIncubation with CA, EDTA and STS induced cytotoxicity in both in vitro cell lines studied at concentrations of >10 mM; only EDTA (10 mM) resulted in inflammatory cytokine release (IL8) from cells at these higher concentrations (cf positive control, Lipopolysaccharide 10 mg/mL). When applied topically to RHE models as near-saturated solutions, none of the chelators were categorised as skin irritants. Due to differences in their relative aqueous solubility, higher concentrations of CA (1600 mM) and STS (1200 mM) could be delivered through the RHE model than EDTA (200 mM). Using a simple linear regression model, the rate of compound absorption was: CA, 0.43 ± 0.05; STS, 0.26 ± 0.03 and; EDTA, 0.05 ± 0.01 g/L/hr. At each time-point, the cumulative concentration of compound in the receptor media was CA > STS > EDTA. Incubation with chelators had no effect on the integrity of the RHE by standard histology. Based on the rate of percutaneous absorption, the dissolution performance of each chelator was tested at relative dermal concentrations for phosphate dissolution (nmoles) of HAp (CA, 9.61 ±0.97; EDTA, 5.38 ± 0.28; 3.78 ± 0.58) and in the calcified in vitro model (Figure 1; CA, 3285 ± 105, STS, 947 ± 95, EDTA, 1174 ± 89), showing the superiority of CA in both model systems.Figure 1.Dissolution of a calcified extracellular matrix by citric acidConclusionOverall, this study highlights the promise of polycarboxylic acids, particularly CA, to target subcutaneous calcification, which are neither toxic nor inflammatory to the skin. Specifically, we have identified CA as a potentially more efficacious alternative to STS for the topical treatment of cutis calcinosis.

Modeling the Percutaneous Absorption of Solvent-deposited Solids Over a Wide Dose Range

The transient absorption of two skin care agents, niacinamide (nicotinamide, NA) and methyl nicotinate (MN), solvent-deposited on ex vivo human skin mounted in Franz diffusion cells has been analyzed according to a new variation on a recently published mechanistic skin permeability model (Yu et al. 2020. J Pharm Sci 110:2149-56). The model follows the absorption and evaporation of two components, solute and solvent, and it includes both a follicular transport component and a dissolution rate limitation for high melting, hydrophilic solids deposited on the skin. Explicit algorithms for improving the simulation of transient diffusion of solvent-deposited solids are introduced. The simulations can account for the ex vivo skin permeation time course of both NA and MN over a dose range exceeding 4.5 orders of magnitude. The model allows one to describe on a mechanistic basis why the percutaneous absorption rate of NA is approximately 60-fold lower than that of its lower melting, more lipophilic analog, MN. It furthermore suggests that MN perturbs stratum corneum barrier lipids and increases their permeability while NA does not, presenting a challenge to molecular modelers engaged in simulating biological lipid barriers.

Percutaneous permeability of 1-phenoxy-2-propanol, a preservative in cosmetics

1-Phenoxy-2-propanol (PP) is used as a preservative in cosmetics. PP is currently permitted to be used to up to 1% in cosmetic formulations in Korea and Europe. For risk assessment, percutaneous absorption is a crucial factor, but dermal absorption of PP has not yet been reported. In this study, Franz diffusion method was used to determine the percutaneous penetration of PP using the dorsal skin of rats. Each formulation of shampoo or cream, 113.6 mg/cm2, was applied to a donor compartment of Franz diffusion cell for 24 h. Receptor fluid was collected at 0, 1, 2, 4, 8, 12, and 24 h following dermal application. Remaining formulation was removed with a cotton swab after last sampling. Using tape stripping method, stratum corneum was removed. PP in epidermis and dermis was extracted in PBS for 24 h. The concentration of PP from the swab, stratum corneum, and epidermis and dermis samples was determined using high performance liquid chromatography. Total percutaneous absorption rates of PP for shampoo and cream were 50.0 ± 6.0% and 33.0 ± 3.2%, respectively. In vitro skin permeability was calculated as 1,377.2 ± 240.1 mg/cm2 for shampoo and 1,038.0 ± 72.2 mg/cm2 for cream for 24 h

Skin Penetration and Permeation Properties of Transcutol\xae\u2014Neat or Diluted Mixtures

A heightened interest in (trans)dermal delivery is in part driven by the need to improve the existing skin therapies and also the demand for alternative routes of administration, notably for pharmaceutical actives with undesirable oral absorption characteristics. The premise of delivering difficult actives to the skin or via the skin however is weighed down by the barrier function properties of the stratum corneum. Short of disrupting the skin by physical means, scientists have resorted to formulation with excipients known to enhance the skin penetration and permeation of drugs. A vehicle that has emerged over the years as a safe solubilizer and enhancer for a broad range of drug actives is the highly purified NF/EP grade of diethylene glycol monoethyl ether (DEGEE) commercially known as Transcutol®. Whereas numerous studies affirm its enhancing effect on drug solubilization, percutaneous absorption rate, and/or drug retention in the skin, there are few publications that unite the body of the published literature in describing the precise role and mechanisms of action for Transcutol®. In view of the current mechanistic understanding of skin barrier properties, this paper takes on a retrospective review of the published works and critically evaluates the data for potential misses due to experimental variables such as formulation design, skin model, skin hydration levels, and drug properties. The goal of this review is to mitigate the incongruence of the published works and to construct a unified, comprehensive understanding of how Transcutol® influences skin penetration and permeation.Graphical Transcutol has affinity for the hydrophilic head groups of the stratum corneum structures

Percutaneous absorption and brain distribution facilitation of borneol on tetramethylpyrazine in a microemulsion-based transdermal therapeutic system

In this study, we show that the percutaneous absorption and brain distribution of tetramethylpyrazine (TMP) is enhanced when combined with borneol (BN) in a microemulsion-based transdermal therapeutic system (ME-TTS). The formulation of the TMP and BN microemulsion (TEM-BN-ME) was optimized in skin permeation studies in vitro following a uniform experimental design. Male Sprague-Dawley rats were used for the in vivo pharmacokinetic and tissue distribution studies of TMP-BN-ME-TTS. In the pharmacokinetic study, the TMP-BN-ME-TTS treated rats had significantly higher (P < 0.05) Cmax and AUC of TMP than the TMP-ME-TTS treated rats, indicating that BN improves the rate and extent of TMP percutaneous absorption. In the tissue distribution study, the AUC of TMP in brain was significantly higher in the TMP-BN-ME-TTS group (P < 0.05), indicating that BN facilitates the distribution of TMP in brain. In summary, BN enhanced the percutaneous absorption and brain distribution of TMP in a microemulsion-based transdermal therapeutic system.

Benzophenone-UV filters in personal care products and urine of schoolchildren from Shenzhen, China: Exposure assessment and possible source

The use of benzophenone (BP)-type UV filters in personal care products (PCPs) has rapidly increased in China over the past decade, leading to growing concerns on the potential adverse effects associated with the usage. Urine analysis is an ideal non-invasive approach for human biomonitoring of xenobiotics that are excreted mainly through urinary system. To investigate human exposure of PCPs to children from South China, we determined BP-type UV filters in a total of 156 commercial PCP goods covering 11 categories, as well as 280 urine samples collected from elementary school students in Shenzhen, China. Five BP analogues (i.e., BP1, BP2, BP3, BP8, and 4HB) were frequently detected in both PCPs and urine, among which BP3 was the dominant analogue, accounting for 96.3% of the total BPs in PCPs and 53.2% in urine, respectively. Sunscreens contained the highest BP concentrations (mean: 2.15 × 104 ng g−1) among all PCP goods. Girls exhibited higher urinary BP concentrations than boys, and body mass index positively influenced BP concentrations. However, no regional difference in urinary BP concentration was observed. The estimated dermal uptake of BPs from PCPs after considering the percutaneous absorption rates was much lower than the estimated dermal intake. The total daily excretion doses estimated from urinary BPs were 74.4 and 47.4 ng·kg−1bw day−1 for girls and boys, respectively. The higher usage of body lotions, hand lotions, and sunscreens by girls than boys (1.49 vs. 1.03 times week−1) might play an important role.

Pharmacological action and clinical outcome of newly developed NSAIDs patch, "LOQOA® tape"

Topical non-steroidal anti-inflammatory drugs (NSAIDs) patches are indispensable for the treatment of musculoskeletal diseases, while they are considered less effective than oral NSAIDs. LOQOA® tape is a tape-type patch containing esflurbiprofen (SFP) as a major active ingredient with potent cyclooxygenase inhibition and sufficient skin permeability. SFP patch (SFPP) showed higher percutaneous absorption rate, rapid pain relief, and potent anti-inflammatory efficacy comparing with existing NSAIDs patches in rat. SFPP showed dramatically higher synovial fluid and tissue concentration on SFP than that of flurbiprofen (FP) patch after single application to knee osteoarthritis (OA) patients. On the other hand, clinical dosage of SFPP was determined as not more than two patches a day from the estimation of systemic exposure to SFP of SFPP and oral FP. SFPP showed statistically significant differences in pain relief and all the other efficacy end points compared to inactive placebo or FP patch in knee OA patients. Efficacy on OA other than knee joint was also observed. In long-term study of SFPP, using up to two patches a day, a total of 201 patients was included and 161 patients achieved 52-week application. Among drug-related side effects, skin reaction at the application sites was observed in 46.8% and discontinued in 4.3%. Although gastro-intestinal reaction and abnormal changes in laboratory tests related to kidney function were observed as systemic drug-related side effects, most of them were mild in severity. SFPP, the new generation NSAIDs patch, would be one of effective options for the treatment of symptomatic OA patients.

Microneedle-Assisted Percutaneous Delivery of a Tetramethylpyrazine-Loaded Microemulsion.

This study examined the efficacy of the percutaneous delivery of a tetramethylpyrazine-loaded microemulsion (TMP-ME) on skin pretreated with microneedles (MN). The TMP-ME formulation was optimized in vitro with skin permeation experiments, using a uniform experimental design, guided by a pseudo-ternary phase diagram, in which the TMP skin permeation level and mean particle size were indices. The effects of MN pretreatment on skin permeation by TMP-ME were assessed using in vitro skin permeation, in vivo skin microdialysis, and pharmacokinetic studies in rats. The influence of MN pretreatment on the skin barrier function was evaluated by measuring the electrical resistance of rat skin before and after MN insertion. In the optimal formulation of TMP-ME, the weight percentages of Maisine® 35-1 (oil phase), Labrasol® (surfactant), and Transcutol® P (co-surfactant) were 7%, 30% and 10%, respectively, with 1.5% TMP loading. In the in vitro skin permeation study, MN-assisted TMP-ME exhibited a two-fold increase in a 24-h cumulative TMP permeation compared with TMP-ME alone (p < 0.05). In the skin microdialysis study, TMP in MN-assisted TMP-ME exhibited a 1.25-fold increase in Cmax, a 0.93-fold decrease in Tmax, and a 0.88-fold increase in AUC0–t (p < 0.05). Similarly, in the pharmacokinetic study, TMP in MN-assisted TMP-ME exhibited a 2.11-fold increase in Cmax, a 0.67-fold decrease in Tmax, and a 1.07-fold increase in AUC0–t (p < 0.05). The percutaneous electrical resistance of rat skin before and after MN insertion was 850 ± 50 Ω/cm2 and 283 ± 104 Ω/cm2 respectively, indicating that MN dramatically compromises the skin barrier. These results suggest that MN assistance increases the skin permeation rate and the extent of percutaneous absorption of TMP-ME, and that the mechanism may involve the reversible barrier perturbation effect. The rate and extent of percutaneous absorption of TMP-ME can be significantly enhanced by MN assistance, possibly because MN causes a reversible barrier perturbation effect on skin.

In Vitro Methods for Predicting Chemical Leukoderma Caused by Quasi-Drug Cosmetics

Skin care cosmetics frequently contain whitening or lightening agents. The present study aimed to establish in vitro methods for predicting chemical leukoderma caused by whitening agents in cosmetics. The risks of chemical leukoderma were predicted based on percutaneous absorption rates, toxic concentrations, and toxicity mechanisms. Thus, in vitro skin permeation rate and cytotoxic concentrations of whitening agents were studied using excised skin and cultured B16 melanoma cells. Pigment cell toxicity was observed using transmission electron microscopy (TEM). The levels of hydroxyl radical (∙OH) were measured and the location of ∙OH generation sites were determined in cultured B16 melanoma cells. Pigment cells cultured under conditions with high tyrosinase activity developed cytotoxicity when exposed to compounds known to cause leukoderma, while those cultured under conditions with low tyrosinase activity did not. Phenolic compounds that cause leukoderma were applied to the pigment cells at the concentration absorbed percutaneously under conditions with high tyrosinase activity. Cells that were observed using TEM demonstrated a large number of vacuolar degenerations in intracellular melanosomes after treatment with phenolic compounds that are known to cause leukoderma. Hydroxyl radical generation during the tyrosinase reaction was examined, as the whitening agents that inhibit tyrosinase activity serve as tyrosinase substrates. Only phenolic compounds that cause leukoderma generated high amounts of hydroxyl radicals. Thus, the hydroxyl radical is a melanocyte-specific toxin that disrupts tyrosinase-containing melanosomes. Whitening agents that generate high amounts of hydroxyl radicals may cause leukoderma. The in vitro method being reported here can predict the potential of a drug to cause leukoderma and whether the use of a specific whitening agent poses a risk.

In vitro determination of transdermal permeation of synthetic musks and estimated dermal uptake through usage of personal care products

Synthetic musks, chemical constituents of personal care products, enter the human body through dermal contact. Elucidation of the mechanisms underlying transdermal permeation of synthetic musks should enhance our understanding of their uptake and distribution in human skin and allow accurate evaluation of associated human exposure. Here, the transdermal permeation dynamics and distribution of galaxolide (HHCB) and tonalide (AHTN) were investigated using an in vitro skin diffusion model. The transdermal permeation amounts of HHCB and AHTN increased rapidly during the first 6 h. The applied HHCB and AHTN amounts did not affect percutaneous absorption rates. HHCB and AHTN remained primarily in the stratum corneum, accounting for 70.0% and 70.3% of the totals during the 24-h period, respectively. The percutaneous absorption rate of both chemicals was ∼11%. HHCB, AHTN, musk ketone, musk xylene, and Musk-T were detected in 29 personal care products. The average total concentrations of the musks were 3990, 54.0, 17.7, and 9.8 μg g−1 in perfume, shampoo, lotion, and shower gel, respectively. Among the four product categories, HHCB was dominant (57.4%–99.6%), followed by AHTN. The data clearly indicate that polycyclic and nitro musks are most commonly used in personal care products. The total estimated dermal intake (51.6 μg kg−1bw day−1) was markedly higher than total dermal uptake (5.9 μg kg−1bw day−1) when percutaneous absorption rates of the chemicals were added into the calculation. Uptake of HHCB and AHTN via dermal contact of personal care products was significantly higher than that from dust inhalation calculated according to earlier literature data.

Evaluation of the in vitro Human Skin Percutaneous Absorption of Progesterone in Versabase® Using the Franz Skin Finite Dose Model

Women may benefit from hormone replacement therapy to alleviate undesirable menopausal symptoms such as hot flashes, disruption of sleep and fatigue. Transdermal hormone replacement therapy consists in the delivery of hormones through the skin and into the blood stream, avoiding gastrointestinal drug absorption difficulties and the first pass effect. Transdermal compounded medications may be customized to meet the individual needs of women by changing the hormones used, the respective concentrations and the medicine’s formulation. Two compounded medications were prepared for progesterone 50 mg/g, as follows: Progesterone in VersaBase® Cream and progesterone in VersaBase® Cream Gel. The purpose of this study is to determine the in vitro human skin percutaneous absorption of progesterone for both test formulations. The Franz Skin Finite Dose Model was the methodology used to evaluate the total absorption, the rate of absorption and the skin content of progesterone applied to the outer surface of ex vivo skin. This model has proven to be a valuable tool for the study of percutaneous absorption of topically applied drugs and to accurately predict in vivo permeation kinetics. The skin samples were obtained within 24 h to 48 h of death from three adult Caucasian donors and a total of 17 Franz diffusion chambers were prepared for testing. Results are presented as the mean ± standard error per parameter, for each test formulation. The rate of percutaneous absorption, presented as mean flux, was similar for the two test formulations and characterized by 2 peaks at approximately 6 hours and 28 hours after dose application, followed by a decline in flux over time. The total absorption and the skin content of progesterone were also similar: 21.6% and 21.8% of the applied doses for the test formulations 1 and 2, respectively. Although in vitro, these results suggest that progesterone in VersaBase® is likely to be delivered through the skin and into the general circulation for systemic effects. Practitioners may then consider transdermal progesterone as a viable route of drug administration for menopausal women.

Effect of lateral diffusion on the percutaneous absorption of micro-particles

ABSTRACTThe rate of percutaneous absorption of micro-particles is very important due to its effects on human health. In this study, a new approach is proposed to investigate both the lateral and the longitudinal diffusions during the absorption of a micro-particle. The results of the current 2D model are compared with the results of a previous 1D model. According to the results, the influence of lateral diffusion on the rate of percutaneous absorption is important, especially for the lipohilic materials. On the other words, the difference between the results of the two models is more significant, at lower values of the ratio of viable-epidermis-diffusivity to the stratum-corneum-diffusivity (DVE/DSC), or at lower values of the viable epidermis to the stratum corneum partition-coefficient (kVE/kSC). For instance, when DVE/DSC equals to 1 and kVE/kSC is 0.33, for a particle with a radius of 10 µm, the steady-state-molar-flux estimated by the 2D model is 2.37 times greater than that estimated by the 1D model. Hence, the lateral diffusion should be taken into account in the percutaneous absorption of micro-particles.

Mechanistic Evaluation of Hydration Effects on the Human Epidermal Permeation of Salicylate Esters.

We sought to understand when and how hydration enhances the percutaneous absorption of salicylate esters. Human epidermal membrane fluxes and stratum corneum solubilities of neat and diluted solutions of three esters were determined under hydrated and dehydrated conditions. Hydration doubled the human epidermal flux seen for methyl and ethyl salicylate under dehydrated conditions and increased the flux of neat glycol salicylate 10-fold. Mechanistic analyses showed that this hydration-induced enhancement arises mainly from an increase in the stratum corneum diffusivity of the three esters. Further, we showed that unlike methyl and ethyl salicylate, glycol salicylate is hygroscopic and the ∼10-fold hydration-induced flux enhancement seen with neat glycol salicylate may be due to its ability to hydrate the stratum corneum to a greater extent. The hydration-induced enhancements in in vitro epidermal flux seen here for glycol and ethyl salicylate were similar to those reported for their percutaneous absorption rates in a comparable in vivo study, whilst somewhat higher enhancement was seen for methyl salicylate in vivo. This may be explained by a physiologically induced self enhancement of neat methyl salicylate absorption in vivo which is not applicable in vitro.

The application of Gaussian processes in the predictions of permeability across mammalian and polydimethylsiloxane membranes

The problem of predicting the rate of percutaneous absorption of a drug is an important issue, particular with the increasing use of the skin as a means of moderating and controlling drug delivery. One key feature of this problem domain is that human skin permeability to penetrants (often characterised by Kp, the permeability coefficient) has been shown to be inherently non-linear when mathematically related to the key physicochemical parameters of penetrants. The aims of the current study were to apply and validate Gaussian process regression methods to datasets for membranes other than human skin, and to explore how the nature of the dataset may influence its analysis. Permeability data for absorption across rodent and pig skin, and polydimethylsiloxane Silastic® membranes was collected from the literature. Two QSPR methods were applied to compare to the Gaussian process models. The results demonstrated that Gaussian process models with different covariance functions outperform the QSPR model for human, pig and rodent datasets, but in general are not good for Silastic® membranes. These results suggest that the physicochemical parameters employed in this study might not be appropriate for developing models that represent this membrane. In addition, the results show the size of the datasets, in both absolute and comparative senses, appears to influence model quality.

Influence of Skin Thickness on the in Vitro Permeabilities of Drugs through Sprague-Dawley Rat or Yucatan Micropig Skin

The purpose of this study was to clarify the influence of skin thickness on the in vitro permeabilities of 3 model drugs with different physicochemical properties (nicorandil (NR), isosorbide dinitrate (ISDN) and flurbiprofen (FP)) through Sprague-Dawley rat (rat) or Yucatan micropig (YMP) skin. Intact, dermis-split, stratum corneum-stripped or stratum corneum-stripped and dermis-split rat or YMP skin (rat skin thickness: approximately 0.4, 0.9 or 1.2 mm; YMP skin thickness: approximately 0.4, 0.9, 1.8 or 2.8 mm) were set in Franz-type diffusion cells to determine the permeation rate, lag time and resistance ratio of the viable epidermis and dermis against whole skin (R(ved)/R(tot)) of the drugs. The YMP skin permeabilities of the drugs decreased with an increase in the skin thickness, and significant differences were observed in the permeation rates and lag times between intact and dermis-split (0.4 mm) YMP skins. The decreases in the permeabilities of the drugs through the YMP skin were larger than those through the rat skin. The influence of resistances of ISDN and FP through the dermis-split rat or YMP skin was greater at 0.9 mm skin thickness than 0.4 mm skin thickness. The R(ved)/R(tot) values for the YMP skins were relatively large for lipophilic drugs (ISDN and FP), and these ratios increased with an increase in the dermis thickness. These results suggest that in vitro skin permeation studies must be done using dermis-split (0.4 mm) skin with the thinnest dermis for predicting in vivo human percutaneous absorption rate.

Rate and Extent of Percutaneous Absorption of Sertaconazole Nitrate after Topical Administration

The purpose of this open study was to evaluate the rate and extent of the penetration of sertaconazole nitrate (CAS 99592-32-2, Zalaïn) penetration into the stratum corneum/lucidum of the human skin. Selected areas of 9 cm2 each of the back skin of 12 healthy volunteers were exposed over 8 different time intervals (between 0 and 48 h) to 100 mg of a 2% cream preparation of the compound or to placebo. Using a HPLC-assay the relative amounts of the applied dose of sertaconazole nitrate were determined in the residual cream of the skin surface as well as in 3 layers of the epidermis obtained by the stripping technique. Sertaconazole nitrate was shown to penetrate into the stratum corneum shortly after application, disappearing from the application areas with a mean apparent half-life of approximately 60 h. Immediately after topical application the residual amount of the applied mean dose of 2103 +/- 146.3 microg on the skin's surface was 88.9 +/- 2.3%, decreasing steadily to 52.4 +/- 8.5% after 48 h. A relevant amount of the applied dose (5.3 +/- 3.0%) was recovered from the stratum corneum already 30 min after application, and 3 h after administration a plateau was reached (6.9 +/- 3.2) which could be maintained until 48 h. A gradient from the site of application to the epidermis was apparent since the amounts recovered in The estimated average level of sertaconazole nitrate for a volume of 1 mL of stratum corneum after application of 100 mg cream was 1409 microg immediately after application and reached a plateau at 3 h with 9029 microg. Although not directly measured, the results also gave information about the mean amount of sertaconazole nitrate that penetrated through the stratum corneum and deeper layers allowing an estimate of the total mean amount of compound penetrating into the skin. The relative portion of this amount steadily increased from 1.1% of the applied dose at 0 h to 24.1% at 12 h, 34.2% at 24 h and finally to 37.6% of dose after 48 h of exposure. In view of the high target organ levels of the compound maintained over days, its rapid appearance in the stratum corneum after application and the earlier finding that Sertaconazole nitrate is not distributed into blood in substantial quantities the pharmacokinetic properties of this antifungal preparation therapy can be regarded as favourable.

Developing Acceptable Surface Limits for Occupational Exposure to Pharmaceutical Substances

Abstract Acceptable surface limits (ASLs) are developed in order to establish a quantitative measure for the potential risk from exposure by dermal contact. In the pharmaceuticals industry, ASLs are used for protection against active pharmaceutical ingredients that are known to cause pharmacological or toxicological effects. An ASL can be used, together with appropriate analytical methods and industrial hygiene monitoring, to assess workplaces for potential dermal exposure and to protect the health and safety of individuals who might come in direct contact with contaminated surfaces in the workplace. ASLs are also used to evaluate the adequacy of housekeeping measures and the effectiveness of engineering containment approaches, or to determine whether a chemical is present on surfaces where it is not intended to be (e.g., in lunch rooms or offices, or on the outside surfaces of packaging materials). However, they should not be confused with cleaning limits for the surfaces of manufacturing devices that might come into contact with the drug product, which are set to minimize cross contamination between drug products and to protect end-users (e.g., patients taking drug products) as opposed to workers. A number of parameters must be evaluated in order to accurately develop appropriate and scientifically supportable limits. These include the dose or concentration that will cause the potential effect, the degree of chemical transfer from contaminated surfaces to the skin, and the rate or amount of percutaneous absorption. In practice, this information is usually limited or unavailable. Additionally, there has been very little regulatory guidance on the setting of ASLs. Consequently, in order to calculate an ASL, various assumptions must be made by health and safety professionals regarding how dermal exposures might occur. As quantitative data become available, the ASL can be adjusted accordingly. An overview of the setting of health-based and performance-based ASLs for pharmaceutical substances from animal and human toxicological data is provided.