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Percutaneous delivery is explored as alternative pathway for addressing the drawbacks associated with the oral administration of otherwise efficacious drugs. Short of breaching the skin by physical means, the preference goes to formulation strategies that augment passive diffusion across the skin. One such strategy lies in the use of skin penetration and permeation enhancers notably of hydroxylated solvents like propylene glycol (PG), ethanol (EtOH), and diethylene glycol monoethyl ether (Transcutol®, TRC). In a previous publication, we focused on the role of Transcutol® as enhancer in neat or diluted systems. Herein, we explore its' role in complex formulation systems, including patches, emulsions, vesicles, solid lipid nanoparticles, and micro or nanoemulsions. This review discusses enhancement mechanisms associated with hydroalcoholic solvents in general and TRC in particular, as manifested in multi-component formulation settings alongside other solvents and enhancers. The principles that govern skin penetration and permeation, notably the importance of drug diffusion due to solubilization and thermodynamic activity in the vehicle (formulation), drug solubilization and partitioning in the stratum corneum (SC), and/or solvent drag across the skin into deeper tissue for systemic absorption are discussed. Emphasized also are the interplay between the drug properties, the skin barrier function and the formulation parameters that are key to successful (trans)dermal delivery. [ABSTRACT FROM AUTHOR]

Compared with oral or injection administration, percutaneous immunotherapy presents a promising treatment modality for food allergies, providing low invasiveness and safety. This study investigated the efficacy of percutaneous immunotherapy using hen egg lysozyme (HEL)-loaded PLGA-PEG-PLGA nanoparticles (NPs), as an antigen model protein derived from egg white, compared with that of HEL-loaded chitosan hydroxypropyltrimonium chloride (CS)-modified PLGA NPs used in previous research. The intradermal retention of HEL in excised mouse skin was measured using Franz cells, which revealed a 2.1-fold higher retention with PLGA-PEG-PLGA NPs than that with CS-modified PLGA NPs. Observation of skin penetration pathways using fluorescein-4-isothiocyanate (FITC)-labeled HEL demonstrated successful delivery of HEL deep into the hair follicles with PLGA-PEG-PLGA NPs. These findings suggest that after NPs delivery into the skin, PEG prevents protein adhesion and NPs aggregation, facilitating stable delivery deep into the skin. Subsequently, in vivo percutaneous administration experiments in mice, with concurrent iontophoresis, demonstrated a significant increase in serum IgG1 antibody production with PLGA-PEG-PLGA NPs compared with that with CS-PLGA NPs after eight weeks of administration. Furthermore, serum IgE production in each NP administration group significantly decreased compared with that by subcutaneous administration of HEL solution. These results suggest that the combination of PLGA-PEG-PLGA NPs and iontophoresis is an effective percutaneous immunotherapy for food allergies. [ABSTRACT FROM AUTHOR]

Skin is a detailed, organized, and intricate niche in the human body. Topical and transdermal drugs are unique, in that their absorption is quite different from other routes of administration (oral, intramuscular, intravenous, etc.,.). A robust amount of research is required to approve the use of a drug-in vivo, in vitro, and ex vivo studies collectively help manufacturers and government agencies with approval of various compounds. Use of human and animal studies poses ethical and financial concerns, making samples difficult to use. In vitro and ex vivo methods have improved over the past several decades-results show relevance when compared to in vivo methods. The history of testing is discussed, followed by a detailed account of known complexities of skin and the current state of percutaneous penetration.

• Solvent deposition of dissolved solutes on human skin shows that spreading and evaporation rates and (possibly) osmosis govern dermal delivery. • At low doses, aqueous ethanol or dilute nonionic surfactants improve delivery versus water or ethanol alone without impacting the stratum corneum lipid barrier. • Authors recommend these excipients for finite dose testing of pharmaceutical and cosmetic ingredients. This study probes the mechanisms by which volatile solvents (water, ethanol) and a nonionic surfactant (Triton X-100) influence the skin permeation of dissolved solutes following deposition of small doses onto unoccluded human skin. A secondary objective was to sharpen guidelines for the use of these and other simple solvent systems for dermal safety testing of cosmetic ingredients at finite doses. Four solutes were studied – niacinamide, caffeine, testosterone and geraniol – at doses close to that estimated to saturate the upper layers of the stratum corneum. Methods included tensiometry, visualization of spreading on skin, polarized light microscopy and in vitro permeation testing using radiolabeled solutes. Ethanol, aqueous ethanol and dilute aqueous Triton solutions all yielded surface tensions below 36 mN/m, allowing them to spread easily on the skin, unlike water (72.4 mN/m) which did not spread. Deposition onto skin of niacinamide (32 μg·cm−2) or caffeine (3.2 μg·cm−2) from water and ethanol led to crystalline deposits on the skin surface, whereas the same amounts applied from aqueous ethanol and 2 % Triton did not. Skin permeation of these compounds was inversely correlated to the extent of crystallization. A separate study with caffeine showed the absence of a dose-related skin permeability increase with Triton. Permeation of testosterone (8.2 μg·cm−2) was modestly increased when dosed from aqueous ethanol versus ethanol. Permeation of geraniol (2.9 μg·cm−2) followed the order aqueous ethanol > water ∼ 2 % Triton >> ethanol and was inversely correlated with evaporative loss. We conclude that, under the conditions tested, aqueous ethanol and Triton serve primarily as deposition aids and do not substantially disrupt stratum corneum lipids. Implications for the design of in vitro skin permeability tests are discussed. [ABSTRACT FROM AUTHOR]

Background: Permeation‐enhancing compounding bases are aimed to facilitate the penetration of the active pharmaceutical ingredients (APIs) across the skin barrier. Objectives: The purpose of this study was to evaluate the percutaneous absorption of radiolabeled human insulin (14C‐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. Methods: The percutaneous absorption of 14C‐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 14C‐insulin through the skin were evaluated for both topical test formulations. A two‐way ANOVA was used to determine statistical differences. Results: The 14C‐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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

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Dermal absorption of weak electrolytes applied to skin from pharmaceutical and cosmetic compositions is an important consideration for both their efficacy and skin safety. We developed a mechanistic, physics-based framework that simulates this process for leave on applications following solvent deposition. We incorporated this framework into our finite dose computational skin permeation model previously tested with nonelectrolytes to generate quantitative predictions for weak electrolytes. To test the model, we analyzed experimental data from an in vitro human skin permeation study of a weak acid (benzoic acid) and a weak base (propranolol) and their sodium and hydrochloride salts from simple, ethanol/water vehicles as a function of dose and ionization state. Key factors controlling absorption are the pH and buffer capacity of the dose solution, the dissolution rate of precipitated solids into a lipid boundary layer and the rate of conversion of the deposited solid to its conjugate form as the nonionized component permeates and (sometimes) evaporates from the skin surface. The resulting framework not only describes the current test data but has the potential to predict the absorption of other weak electrolytes following topical application. [Display omitted] • Weak electrolytes precipitated on skin as solids redissolve and penetrate the skin. • We model absorption as a function of dissolution rate, skin load and ionization state. • Skin pH recovers exponentially post-dose with a t 1/2 related to dose buffer capacity. • The model is calibrated based on in vitro permeation data for a weak acid and base. • The framework has potential to predict absorption of a wide range of electrolytes. [ABSTRACT FROM AUTHOR]

Objectives: Mefenamic acid (MA) is a strong non-steroidal anti-inflammatory drug, but because of its limited oral bioavailability and the side effects that come with taking it systemically, it is better to apply it topically. The major goal of this study was to see how certain permeation enhancers affected MA is in vitro skin permeability. In manufactured Franz diffusion cells, MA permeability tests using rat skin pretreatment with several permeation enhancers such as corn oil, olive oil, clove oil, eucalyptus oil, and menthol were conducted and compared to hydrate rat skin as a control. Materials and Methods: The steady-state flux (Jss), permeability coefficient (Kp), and diffusion coefficient are among the permeability metrics studied. The permeability enhancement mechanisms of the penetration enhancer were investigated using fourier transform infrared spectroscopy (FTIR) to compare changes in peak position and intensities of asymmetric and symmetric C-H stretching, C=O stretching, C=O stretching (amide I), and C-N stretching of keratin (amide II) absorbance, as well as differential scanning calorimetry (DSC) to compare mean transition temperature and their enthalpies. Results: Clove oil, olive oil, and eucalyptus oil were the most effective enhancers, increasing flux by 7.91, 3.32, and 2.6 times, as well as diffusion coefficient by 3.25, 1.34, and 1.25, respectively, when compared to moist skin. FTIR and DSC data show that permeation enhancers caused lipid fluidization, extraction, disruption of lipid structures in the SC layer of skin, and long-term dehydration of proteins in this area of the skin. Conclusion: According to the findings, the permeation enhancers used improved drug permeability through excised rat skin. The most plausible mechanisms for greater ERflux, ERD, and ERP ratios were lipid fluidization, disruption of the lipid structure, and intracellular keratin irreversible denaturation in the SC by eucalyptus oil, menthol, corn oil, olive oil, and clove oil. [ABSTRACT FROM AUTHOR]

The percutaneous bioavailability of naproxen is low and several technologies have been utilized to overcome the problem. Although, some studies have reported the permeation‐enhancing properties of natural essential oils, no research has reflected the effectiveness of Lavandula angustifolia essential oil (LAEO) on increasing the percutaneous absorption of naproxen sodium from a topical gel. Therefore, the present study was designed to investigate whether LAEO increased the percutaneous absorption and the analgesic effects of naproxen sodium topical gel. In the present study, naproxen topical gel was formulated using carbopol 940 (a gelling agent) and several vehicles such as PEG 400, ethanol, and water and the properties of gels were measured. Percutaneous absorption‐enhancing properties of LAEO were measured too. Based on our data, the essential oil‐containing formulation of naproxen represented greater penetration into (222.19 ± 24.87 vs. 107.65 ± 6.38 μg/cm2), and also across (22.07 ± 4.42 vs. 13.14 ± 2.87 μg/cm2) skin layers compared to the naproxen gel. Additionally, a significant analgesic property was observed in the naproxen topical gel containing 0.5% essential oil during both first and late phases of formalin test, as well as the late phase of tail‐flick test. It could be concluded that LAEO significantly enhanced naproxen percutaneous absorption and also its analgesic effects. [ABSTRACT FROM AUTHOR]

Skin is a detailed, organized, and intricate niche in the human body. Topical and transdermal drugs are unique, in that their absorption is quite different from other routes of administration (oral, intramuscular, intravenous, etc.,.). A robust amount of research is required to approve the use of a drug—in vivo, in vitro, and ex vivo studies collectively help manufacturers and government agencies with approval of various compounds. Use of human and animal studies poses ethical and financial concerns, making samples difficult to use. In vitro and ex vivo methods have improved over the past several decades—results show relevance when compared to in vivo methods. The history of testing is discussed, followed by a detailed account of known complexities of skin and the current state of percutaneous penetration.

[Display omitted] • Skin absorption of nanoparticles and their toxicity. • Understanding of the different pathways of nanoparticles to travel through the skin. • Overview of the different absorption assays for nanoparticles. • Trends and selected applications reported in the literature regarding nanoparticles dermal absorption. The role of inorganic nanoparticles in our society is increasing every day, from its use in sunscreens to their introduction in analytical laboratories, pharmacy, medicine, agricultural and other uses. Therefore, in order to establish precautions as well as correct handling of this type of material by operators, it is important to determine the ability of these compounds to travel through the different layers of the skin and to study their possible toxicological effects. In this sense, several authors have studied the ability of inorganic nanoparticles to penetrate the skin barrier by diverse methodologies in in vivo and in vitro modes. In the first case, most of the studies have been performed with animal skins that can imitate the human one (porcine, mouse and guinea pigs, among others), although human skin from surgery have been also explored. However, the use of animals is a common model that should be avoided in the following years due to ethical issues. In this sense, the use of in vitro methodologies is also usually selected to study the dermal absorption of nanoparticles through the skin. Nevertheless, most of the studies are performed with authentic animal skins, instead of the use of synthetic skins that imitate the permeability of our skin system, which has been scarcely studied. In addition, most of the literature is focused in achieving high-transdermal uptake to use nanoparticles (not only inorganic) as carriers for drugs, but little efforts have been done in the study of their inherent percutaneous absorption and toxicity. For these reasons, this review covers the current state-of-the-art of dermal absorption of inorganic nanoparticles in skin and their possible toxicity taking into account that people can be in contact with these nanomaterials in daily life, work or other places. In this sense, the observed results showed that the nanoparticles rarely reach the blood circulatory system, and no big toxicological effects were commonly found when in vivo and actual skin was used. In addition, similar results were found when synthetic skins were used, demonstrating the possibility of avoiding animals in these studies. In any case, more studies covering the dermal absorption of nanoparticles should be performed to have a better understanding of how nanoparticles can affect our health. [ABSTRACT FROM AUTHOR]

Introduction: Heparin is a commonly used anti-coagulant administered either by intravenous or subcutaneous injection for a systemic effect or topically for the treatment of peripheral vascular disorders. Objective: This study aimed to formulate heparin in non-ionic colloidal carrier systems (CCSs) having enhanced percutaneous absorption for systemic and topical administration. Methods: Five CCSs were developed and characterized for their rheological properties, droplet size, and drug loading. The percutaneous absorption of heparin was evaluated in vitro using Franz diffusion cells with rats' skin and with the aid of a developed high-pressure chromatography method. Furthermore, the efficacy of two developed heparin CCSs was tested percutaneously in rats by measuring the response against the time in comparison to subcutaneous administration. Results: The rheograms and droplet size measurements showed that the developed drug delivery systems have Newtonian properties with a droplet size between 109 and 460 nm. As much as 500 mg of heparin could be loaded in around 5 mL of CCS. Furthermore, using Franz diffusion cells, a diffusion rate of 19.216 ± 2.01 USP U/cm2.h could be achieved for heparin-loaded CCSs. Moreover, the estimated percutaneous in vivo relative bioavailability in comparison to subcutaneous administration could reflect that at least more than 50% of the drug passed through the skin. Conclusion: The developed novel non-toxic CCSs containing heparin can be good candidates for percutaneous administration as alternative delivery systems for subcutaneous and intravenous invasive administration. [ABSTRACT FROM AUTHOR]

Background: Flutamide is a non-steroidal anti-androgenic agent which is not only used in treating prostate cancer but also can be effective in some disorders such as androgenic alopecia and male pattern baldness. Several serious side effects for systemic administration of flutamide can be overcome by emulgel dosage form. Absorption enhancers can promote permeation of flutamide through skin. Percutaneous absorption of Flutamide emulgels with different concentrations of Transcutol P and Precirol ATO5 was studied. Methods: Various emulgel formulations using different concentration of Transcutol P and Precirol ATO5 with 0.5 to 5 % w/w were prepared. Percutaneous absorption was tested with standard Franz Diffusion Cell equipment using full thickness rat skin. Drug concentrations in the samples were analyzed by High-Performance Liquid Chromatography (HPLC) equipped with UV-Vis detector at 305 nm. Results: The percutaneous absorption of flutamide emulgels formulated with enhancers was higher than control formulations. Enhancement ratio increased from 1.218 to 3.670 and 1.346 to3.900 for Precirol ATO5 and Transcutol P, respectively. Area under the Curve (AUC) increased by increase the enhancers’ concentration and a significant upsurge was seen in the concentration 1% for both enhancers. Conclusion: The flutamide emulgel containing 1% Transcutol P showed more appropriate percutaneous absorption through the skin compared to others.

Nanoformulation have been widely used in skin and transdermal drug delivery. However, the differences in integral nanoparticles absorption in healthy and diseased skin have not yet fully analyzed. The present study attempted to explore the percutaneous absorption of drugs via lesional skin by using atopic dermatitis (AD) as a model, dinitrochlorobenzene (DNCB) induced AD-like skin. In here, the small molecules of insoluble Licoricchalcone A (LA) and macromolecules glycyrrhizin polysaccharide were used to prepare LA-polysaccharide self-assembled nanoparticles (GPA-SANs) by micro-precipitation. An environment-responsive dye, P4, was loaded into SAN to track the transdermal translocation of the nanoparticles, while the drug marked with coumarin 6 (C6). Compared to healthy skin, the permeability of GPA-SANs on AD-like skin is stronger, which may be due to damage to the stratum corneum of the AD-like skin and increased intercellular spaces, resulting in an increased permeability coefficient. Therefore, the storage of nanoparticles and their diffusion at the lesion site also increased accordingly. CLSM shown that the fluorescence of P4 and C6 is observed to concentrate around the hair follicles and disseminate in the surrounding area in both AD-affected and healthy skin. It can be clearly seen that fluorescence signal of C6 in the intercellular spaces of the dermis and epidermis of AD-like skin, indicating that nano-drug on the disease skin can penetrate through the intercellular pathway to achieve therapeutic. The focus of the present study is to assess the permeability of healthy and disease skin, discuss their characteristics and discrepancy, aiming to provide a reference for the further study of nano-formulations in transdermal delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (kout) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the kout determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the kout parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously. [ABSTRACT FROM AUTHOR]

Estimation of the percutaneous absorption is essential for the safety assessment of cosmetic and dermopharmaceutical products. Currently, an artificial membrane, Strat-M®, has been focused on as the tool which could obtain the permeation parameters close to the skin-derived values. Nevertheless, few practical methodologies using the permeation parameters for assessing percutaneous absorption under in-use conditions are available. In the present study, based on Fick's first law of diffusion, a novel mathematical model incorporating the permeation parameters as well as considering the water evaporation (Teva) was constructed. Then, to evaluate the applicability domain of our model in the case where Strat-M®-derived parameters were used, the permeation parameters were compared between the skin from edible porcine and Strat-M®. Regarding chemicals (−0.2 ≤ Log Kow ≤ 2.0), their permeation profiles were equivalent between Strat-M® and porcine skin. Therefore, for these chemicals, the percutaneous absorption was calculated using our model with the permeation parameters obtained using Strat-M® and the Teva determined by measuring the solution weight. The calculated values revealed a good correlation to the values obtained using porcine skin in finite dose experiments, suggesting that our mathematical approach with Strat-M® would be useful for the future safety assessment of cosmetic and dermopharmaceutical products. [ABSTRACT FROM AUTHOR]

The dataset represented in this article is referred to by the review article entitled “Topical drug delivery: history, percutaneous absorption, and product development” (MS Roberts et al., 2021) [1]. The dataset contains maximal flux (Jmax), and permeability coefficient (kp) values collated from In Vitro human skin Permeation Test (IVPT) reports published to date for various drugs, xenobiotics, and other solutes applied to human epidermis from aqueous solutions. Also included are each solute's physicochemical properties and the experimental conditions, such as temperature, skin thickness, and skin integrity, under which the data was generated. This database is limited to diluted or saturated aqueous solutions of solutes applied on human epidermal membranes or isolated stratum corneum in large volumes so that there was minimal change in the donor phase concentration. Included in this paper are univariate Quantitative Structure-epidermal Permeability Relationships (QSPR) in which the solute epidermal permeation parameters (kp, and Jmax) are related to potential individual solute physicochemical properties, such as molecular weight (MW), log octanol-water partition coefficient (log P), melting point (MP), hydrogen bonding (acceptor - Ha, donor – Hd), by scatter plots. This data was used in the associated review article to externally validate existing QSPR regression equations used to forecast the kp and Jmax for new therapeutic agents and chemicals. The data may also be useful in developing new QSPRs that may aid in: (1) drug choice and (2) product design for both topical and transdermal delivery, as well as (3) characterizing the potential skin exposure of hazardous substances.

Percutaneous absorption is of importance given its role in topical medicaments, transdermal drug systems, and dermatotoxicology. Many factors influence percutaneous penetration, including anatomical region, although little is currently known regarding this parameter. Hence, the aim of this study was to summarize existing data on regional variation in percutaneous penetration in in vitro human models. PubMed, Embase, Web of Science, and US patent literature were explored, and relevant data collected. Eight eligible articles were identified, which together, explored 15 anatomical locations. Four investigations compared percutaneous penetration between scalp and abdominal skin, and all concluded that the former was more permeable. Within those four studies, 10 penetrants of varying physical/chemical properties were tested indicating that in those particular study conditions, anatomical location exerted a greater effect on percutaneous absorption than the physicochemical properties of the penetrants. In addition, torso area was less absorptive than scrotum in both studies in which these sites were compared. In conclusion, the scrotum and scalp appear to be highly susceptible to percutaneous absorption compared to other locations such as the abdomen. This is postulated to be largely due to the high density of hair follicles in these areas, enabling greater penetration via the appendageal pathway. However, there is a paucity of conclusive data regarding the penetrability of other anatomical locations. Investigations testing and ranking the susceptibility of different anatomical regions is of vital importance given the importance of (1) transdermal drug delivery and decontamination protocols and (2) understanding the underlying mechanisms and degree of these variances might aid our pharmacologic/toxicologic judgments. [ABSTRACT FROM AUTHOR]

Lead (Pb) exposure continues to be a significant public health issue in both occupational and non-occupational settings. The vast majority of exposure and toxicological studies have focused on effects related to inhalation and gastrointestinal exposure routes. Exposure to inorganic Pb compounds through dermal absorption has been less well studied, perhaps due to the assumption that the dermal pathway is a minor contributor to aggregate exposures to Pb compounds. The aim of this rapid review was to identify and evaluate published literature on dermal exposures to support the estimation of key percutaneous absorption parameters (K p, flux, diffusion rate) for use in occupational risk assessment. Eleven articles were identified containing information from both in vitro and in vivo systems relevant to percutaneous absorption kinetics. These articles provided 24 individual study summaries and information for seven inorganic Pb compounds. The vast majority of study summaries evaluated (n = 22, 92%) reported detectable amounts of dermal absorption of inorganic Pb. Data were identified for four Pb compounds (Pb acetate, Pb nitrate, Pb oxide, and Pb metal) that may be sufficient to use in evaluating physiologically based pharmacokinetic models. Average calculated diffusion rates for the pool of animal and human skin data ranged from 10−7 to 10−4 mg cm−2 h−1, and K p values ranged from 10−7 to 10−5 cm h−1. Study design and documentation were highly variable, and only one of the studies identified was conducted using standard test guideline-compliant methodologies. Two studies provided quality estimates on the impacts of dermal absorption from water-insoluble Pb compounds on blood Pb levels. These two studies reported that exposures via dermal routes could elevate blood Pb by over 6 µg dl−1. This estimation could represent over 100% of 5 µg dl−1, the blood Pb associated with adverse health effects in adults. The utility of these estimates to occupational dermal exposures is limited, because the confidence in the estimates is not high. The literature, while of limited quality, overall strongly suggests inorganic Pb has the potential for dermal uptake in meaningful amounts associated with negative health outcomes based on upper bound diffusion rate estimates. Future standard test guideline-compliant studies are needed to provide high-confidence estimates of dermal uptake. Such data are needed to allow for improved evaluation of Pb exposures in an occupational risk assessment context. [ABSTRACT FROM AUTHOR]

The goal of this research is the localization of hydroquinone (HQ) to the epidermis for the treatment of hyperpigmentation in rat skin. For this purpose, nanostructured lipid carrier (NLC) was selected for the dermal delivery of HQ. A 23 factorial design was used in this study, and eight NLCs were prepared with a cold homogenization technique. HQ entrapment efficiency (EE %), particle size, morphology, thermal behavior of NLCs, and permeability parameters through rat skin with NLC in comparison with HQ aqueous solution (HQ-S) with Franz diffusion cells were evaluated. Based on the optimization technique, the best NLC was selected and in the in vivo experiment, the depigmentation effect of optimized NLC in comparison with that of HQ-S was evaluated. The results showed that the main problem for HQ permeability was fast permeation and low concentration in the site of action. Partitioning from aqueous donor phase into skin rate was the limiting step for drug flux, and this can be solved using NLC. The decrease in maximum flux obtained by NLC was according to formulation 8. Regression analysis suggested a significant and direct effect of the S/L ratio and the percentage of liquid lipids on the drug loading. NLC decreased drug permeation through rat skin basically due to sustained release properties. [ABSTRACT FROM AUTHOR]

Purpose: To predict the percutaneous absorption of olmesartan medoxomil using dermal parameters obtained under pH control. Methods: Partition coefficient of olmesartan medoxomil was determined in a chloroform-buffer system by shake flask method at room temperature. The test was carried out under different pH conditions. Established mathematical equations were utilized to calculate percutaneous absorption parameters, including the permeability coefficient of the drug through the skin, maximum flux through the skin, activation energy involved in the partitioning of the drug in the chloroform-buffer system, and diffusion coefficient of the drug through skin. Results: At pH 2.0, the drug gave the highest logarithm partition coefficient when compared to other pH values investigated as well as distilled water (control). The mean logarithm partition coefficient of the drug (4.36 ± 0.06) at pH 2.0 compared well to the mean logarithm partition coefficient of the drug (4.15 ± 0.07) in distilled water at 95 % level. Statistical analysis indicated that null hypothesis was rejected at this confidence level. Test of significance was not carried out on the other parameters including maximum flux, activation energy and diffusion coefficient data because they were estimated from the experimental partition coefficient. Conclusion: Percutaneous absorption of olmesartan medoxomil using dermal parameters obtained under pH control can be predicted. As the rate of penetration into the skin is quantitatively assessed by the use of permeability coefficient, the results predict significant percutaneous absorption of olmesartan medoxomil. [ABSTRACT FROM AUTHOR]

The aim of the present study was to develop a topical liposomal formulation as a transdermal delivery of rivastigmine for the treatment of Alzheimer's disease as an alternative to the oral dosage form and to achieve smooth continuous drug delivery and maintain plasma levels within the therapeutic window. Rivastigmine-loaded liposomes were prepared by a thin layer hydration technique that was applied in ex vivo–in vivo correlation study. Permeability parameters through rat skin in ex vivo study and pharmacokinetic parameters in the in vivo study were evaluated. The ex vivo permeation study showed that liposomes provided steady-state flux 0.11 ± 0.01 mg/cm.h that were more than 2-fold the aqueous control. In the in vivo experiments, after topical application of optimized rivastigmine liposomes, the Cmax 208 ng/ml and AUC0–24 3605 (ng.h/ml) were also significantly higher than the control group (both p < 0.01). A point-to-point significant linear correlation was found between ex vivo and in vivo parameters, meaning in vivo pharmacokinetic parameters can be predicted by ex vivo permeation parameters. These data suggest that a liposomal formulation could be an effective carrier to enhance rivastigmine permeation through the skin and maintain plasma levels within the therapeutic window. [ABSTRACT FROM AUTHOR]

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (kout) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the kout determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the kout parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously.

Estimation of the percutaneous absorption is essential for the safety assessment of cosmetic and dermopharmaceutical products. Currently, an artificial membrane, Strat-M®, has been focused on as the tool which could obtain the permeation parameters close to the skin-derived values. Nevertheless, few practical methodologies using the permeation parameters for assessing percutaneous absorption under in-use conditions are available. In the present study, based on Fick’s first law of diffusion, a novel mathematical model incorporating the permeation parameters as well as considering the water evaporation (Teva) was constructed. Then, to evaluate the applicability domain of our model in the case where Strat-M®-derived parameters were used, the permeation parameters were compared between the skin from edible porcine and Strat-M®. Regarding chemicals (−0.2 ≤ Log Kow ≤ 2.0), their permeation profiles were equivalent between Strat-M® and porcine skin. Therefore, for these chemicals, the percutaneous absorption was calculated using our model with the permeation parameters obtained using Strat-M® and the Teva determined by measuring the solution weight. The calculated values revealed a good correlation to the values obtained using porcine skin in finite dose experiments, suggesting that our mathematical approach with Strat-M® would be useful for the future safety assessment of cosmetic and dermopharmaceutical products.

Background: Skin being the largest organ of the human body plays a very important role in the permeation and penetration of the drug. In addition, the transdermal drug delivery system (TDDS) plays a major role in managing dermal infections and attaining sustained plasma drug concentration. Thus, evaluation of percutaneous penetration of the drug through the skin is important in developing TDDS for human use. Material and methods: Various techniques are used for getting the desired drug penetration, permeation, and absorption through the skin in managing these dermal disorders. The development of novel pharmaceutical dosage forms for dermal use is much explored in the current era. However, it is very important to evaluate these methods to determine the bioequivalence and risk of these topically applied drugs, which ultimately penetrate and are absorbed through the skin. Results: Currently, numerous skin permeation models are being developed and persuasively used in studying dermatopharmacokinetic (DPK) profile and various models have been developed, to evaluate the TDD which include ex vivo human skin, ex vivo animal skin, and artificial or reconstructed skin models. Conclusion: This review discusses the general physiology of the skin, the physiochemical characteristics affecting particle penetration, understand the models used for human skin permeation studies and understanding their advantages, and disadvantages. [ABSTRACT FROM AUTHOR]

Percutaneous penetration of chemicals from clothing can result in both acute and chronic toxicities. Although personal protective equipment composed of nonwoven material can provide thorough protection, it is often uncomfortable under normal occupational conditions. Certain everyday textiles are often utilized as protective clothing due to their cost, comfort, and convenience. Although common textiles may cover most skin, certain regions remain exposed by such outfits. The body areas covered by the fabric are at risk for fabric permeation and percutaneous penetration of chemical, either immediately or over time, dependent on the fabric composition and the characteristics of the chemical used. in vitro and in vivo publications studied percutaneous penetration of chemicals from contaminated fabric and show that everyday textiles are superior to bare skin. The increased protection offered can be attributed to properties of the fabric such as weave, thickness, fabric finish, absorbency, and the overall barrier provided. Although common textiles do offer some protection, they remain inferior to nonwoven personal protective equipment. Much remains unknown regarding percutaneous penetration and protection offered by everyday textiles. Although common clothing fabrics do offer some protection from chemicals for occupational workers, there is still risk for percutaneous penetration of chemical, either immediately or over time. Here, we review in vitro and in vivo studies quantifying percutaneous penetration of chemicals from contaminated fabric through an extensive literature search, resulting in 22 relevant publications. The degree of percutaneous penetration from fabric varied, dependent upon fabric composition and chemical characteristics. [ABSTRACT FROM AUTHOR]

Percutaneous penetration in man is affected by several factors: chemical properties, skin anatomy variables, and environmental conditions can all modify the quantity of chemical that penetrates through the skin barrier. The amount of chemical or drug that penetrates the cutaneous barrier must be considered due to the local and systemic absorption that may occur. Regional variation in percutaneous absorption is an additional factor to recognize when analysing chemical percutaneous penetration. Although it has been studied that certain anatomic sites allow for increased absorption, there is limited literature regarding in vivo data in man. This overview catalogues and analyses studies performed in man to quantify chemical permeation at varying anatomical locations. We also review what is known about the pharmacokinetics of Food and Drug Administration approved medication patches and semisolids and the regional variation in absorption that they may display. This research work aims to create an updated, concise overview of the pertinent studies available regarding percutaneous penetration and regional variability. We searched PubMed, Web of Science, Google Scholar and the United States Food and Drug Administration's online database for approved transdermal delivery systems from January 1965 to March 2020, with the search words: percutaneous absorption, regional variation, anatomical location, along with extensive bibliographical review. We further utilized the prior listed search engines to search for published data pertaining to regional differences in percutaneous absorption for each of the FDA-approved medications. If no publication was found, we utilized the Summary Basis of Approval documents for each medication to determine patch application site pharmacokinetics. Several chemical containing gels and solutions were tested for regional variability. Chemical characteristics and body site location were determinants in absorption. In general, the head, neck and genitalia contamination resulted in greatest absorption, whereas trunk, back, and thighs resulted in less absorption. Most of the FDA-approved transdermal delivery patch medications are efficacious at more than one body location, allowing for greater patient convenience when choosing patch location. Regional variability in chemical and drug absorption is of clinical and pharmacological significance. More studies determining in vivo percutaneous absorption in man are necessary to further understand the role of regional variation, the mechanisms involved, and how to derive reliable formulas for extrapolating flux from one anatomic site to the next, often required for risk assessments. [ABSTRACT FROM AUTHOR]

Propylene glycol (PG) has been used in formulations as a co-solvent and/or to enhance drug permeation through the skin from topical preparations. Two skin in vitro permeation approaches are used to determine the effect of PG on drug penetration. The in vitro Skin-PAMPA was performed using 24 actives applied in aqueous buffer or PG. PG modulates permeability by increasing or diminishing it in the compounds with poor or high permeability, respectively. Percutaneous absorption using pigskin on Franz diffusion cells was performed on seven actives and their commercial formulations. The commercial formulations evaluated tend to have a lower permeability than their corresponding PG solutions but maintain the compound distribution in the different strata: stratum corneum, epidermis and dermis. The results indicate the enhancer properties of PG for all compounds, especially for the hydrophilic ones. Additionally, the Synchrotron-Based Fourier Transform Infrared microspectroscopy technique is applied to study the penetration of PG and the molecular changes that the vehicle may promote in the different skin layers. Results showed an increase of the areas under the curve indicating the higher amount of lipids in the deeper layers and altering the lipidic order of the bilayer structure to a more disordered lipid structure. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to use Gaussian process regression (GPR) methods to quantify the effect of experimental temperature (Texp) and choice of diffusion cell on model quality and performance. Methods: Data were collated from the literature. Static and flow‐through diffusion cell data were separated, and a series of GPR experiments was conducted. The effect of Texp was assessed by comparing a range of datasets where Texp either remained constant or was varied from 22 to 45 °C. Key findings: Using data from flow‐through diffusion cells results in poor model performance. Data from static diffusion cells resulted in significantly greater performance. Inclusion of data from flow‐through cell experiments reduces overall model quality. Consideration of Texp improves model quality when the dataset used exhibits a wide range of experimental temperatures. Conclusions: This study highlights the problem of collating literature data into datasets from which models are constructed without consideration of the nature of those data. In order to optimise model quality data from only static, Franz‐type, experiments should be used to construct the model and Texp should either be incorporated as a descriptor in the model if data are collated from a range of studies conducted at different temperatures. [ABSTRACT FROM AUTHOR]

The lipids mainly oils, fats, waxes and phospholipids are of substantial importance in the development and functioning of cosmetic products. The lipid nanoparticles-based cosmetic product is highly capable of protecting the skin against harmful radiations and is utilized for anti-aging therapy. Naturally derived antioxidants such as carotenoids, retinoids and tocopherols could be employed for their antioxidant properties as therapeutics and skincare active moieties in cosmetic products. Such a lipid nanoparticles-based cosmetic formulation consisting of antioxidants are very effective against irritated and inflamed skin and very promising for treating skin disorders such as atopic dermatitis and psoriasis. Therefore, the present review provides an insight into lipid nanoparticles based cosmetics and the mechanistic of their percutaneous absorption. The manuscript discussion highlights the role of lipid nanoparticles-based cosmetics/cosmeceuticals employing active ingredients of synthetic and natural origin in alleviating dermatological disorders and enhancing skin health and appeal. Furthermore, the manuscript also updates about contemporary research studies carried on the concept of lipid nanoparticles based formulation design of cosmetic preparation and significant outcome to alleviate skin disorders.