Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The skin is involved in body temperature regulation by the storage of fat and water. It is an interesting tissue in regard to the local and transdermal application of active ingredients for prevention or treatment of pathological conditions. Topical and transdermal delivery is an emerging route of drug and cosmetic administration. It is beneficial for avoiding side effects and rapid metabolism. Many pharmaceutical, technological and cosmetic innovations have been described and patented recently in the field. In this review, the main features of skin morphology and physiology are presented and are being followed by the description of classical and novel nanoparticulate dermal and transdermal drug formulations. The biophysical aspects of the penetration of drugs and cosmetics into or across the dermal barrier and their investigation in diffusion chambers, skin-on-a-chip devices, high-throughput measuring systems or with advanced analytical techniques are also shown. The current knowledge about mathematical modeling of skin penetration and the future perspectives are briefly discussed in the end, all also involving nanoparticulated systems.

Gallic acid (GA) is a phenolic compound known as 3,4,5-trihydroxybenzoic acid. GA is used as a hair dye ingredient. It is limited to be below 4.0% in Korea. Dermal absorption rate of GA has not been reported yet. In this study, an analytical method for GA was developed and validated using high-performance liquid chromatography (HPLC) in various matrices of swab, stratum corneum (SC), skin (dermis + epidermis), and receptor fluid (RF). HPLC analysis showed acceptable linearity (r2 = 0.999-0.9998), accuracy (90.3-112.8%), and precision (0.7-13.6%) in accordance with validation guidelines by Korea Ministry of Food and Drug Safety (MFDS). The dermal absorption rate of GA was determined using Franz diffuse cells. GA (4.0%) was applied to mini pig skin of 10 μl/cm2. After 30 min application, the GA was wiped out and receptor fluid sampling was continued until 24 h. After 24 h, skin was wiped off with swab and SC was collected using tape stripping. All samples were extracted with ethanol and analyzed using the validated method. The total dermal absorption rate of GA was determined to be 2.6 ± 1.3% (24 h).

OBJECTIVE: The permeability of triamcinolone acetonide (TA), from bilayer mucoadhesive buccal films, through a biomimetic membrane, Permeapad™, was investigated employing Franz diffusion cell. The delivery systems composition and ethyl cellulose (EC) backing layer, on drug permeability, were assessed.
METHODS: Three TA-loaded films were tested; hydroxypropyl methylcellulose (HPMC K4M; bilayer [F1] and monolayer), HPMC K4M/Polyvinylpyrrolidone (PVP): 90/10 [F2], and HPMC K15M film [F3]. All films contained propylene glycol (PG-plasticiser). TA solution alone was used as a control. TA permeability via a Permeapad™ barrier, simulating buccal mucosa, was assessed over 8 h using a Franz diffusion cell. TA permeated into the receptor compartment, released in the donor compartment, and located on/within the Permeapad™ barrier were analysed using UV-spectrophotometer.
RESULTS: 45.7 % drug retention within the Permeapad™ barrier was delivered from F1 (highest). F1, F2, and F3 significantly improved the TA\'s permeability through Permeapad™, compared to TA solution alone (e.g., 8.5 % TA-solution, 21.5 %-F1), attributed to the synergy effect of HPMC and propylene glycol acting as penetration enhancers. F1 displayed a significant increase in drug permeability (receptor compartment; 21.5 %) compared to F3 (17.0 %). PVP significantly enhanced drug permeability (27.5 %). Impermeable EC backing layer controlled unidirectional drug release and reduced drug loss into the donor compartment (e.g., ∼28 % for monolayer film to ∼10 % for bilayer film, F1).
CONCLUSIONS: The mucoadhesive films demonstrated improved TA permeability via Permeapad™. The findings suggest that these bilayer mucoadhesive films, particularly F1, hold promise for the effective topical treatment of oral mucosa disorders, such as recurrent aphthous stomatitis and oral lichen planus.

Valsartan (Val) is an important antihypertensive medication with poor absorption and low oral bioavailability. These constraints are due to its poor solubility and dissolution rate. The purpose of this study was to optimize a mixed micelle system for the transdermal delivery of Val in order to improve its therapeutic performance by providing prolonged uniform drug levels while minimizing drug side effects. Thin-film hydration and micro-phase separation were used to produce Val-loaded mixed micelle systems. A variety of factors, including the surfactant type and drug-to-surfactant ratio, were optimized to produce micelles with a low size and high Val entrapment efficiency (EE). The size, polydispersity index (PDI), zeta potential, and drug EE of the prepared micelles were all measured. The in vitro drug release profiles were assessed using dialysis bags, and the permeation through abdominal rat skin was assessed using a Franz diffusion cell. All formulations had high EE levels exceeding 90% and low particle charges. The micellar sizes ranged from 107.6 to 191.7 nm, with average PDI values of 0.3. The in vitro release demonstrated a uniform slow rate that lasted one week with varying extents. F7 demonstrated a significant (p < 0.01) transdermal efflux of 68.84 ± 3.96 µg/cm2/h through rat skin when compared to the control. As a result, the enhancement factor was 16.57. In summary, Val-loaded mixed micelles were successfully prepared using two simple methods with high reproducibility, and extensive transdermal delivery was demonstrated in the absence of any aggressive skin-modifying enhancers.

In vitro absorption through human skin is a critical component in the safety assessment of chemicals, crop protection products, consumer healthcare products and cosmetics. A barrier integrity assay is used to identify skin samples which are potentially damaged. A retrospective analysis of 9978 electrical resistance (ER) measurements generated in a single laboratory (DTL) over a 15-year period was performed. Skin absorption experiments were performed using two model penetrants, testosterone and sucrose, utilising no ER acceptance criteria, and the results assessed. Using a barrier integrity test, to remove potentially damaged samples, was offset against one that can be used to remove intact skin samples with a poorer barrier function (i.e. false positives). The previously identified barrier integrity limit (10 kΩ for a 2.54 cm2 diffusion cell; Davies et al., 2004) was demonstrated to identify half of all samples tested, many of which would be false positive samples. This retrospective analysis identified 5.0 kΩ (17.5th percentile) as an acceptance criterion for a 2.54 cm2 diffusion cell, whilst not considerably changing results generated in skin absorption studies. This was confirmed from the cumulative absorption of the model penetrants tested. Using this limit would, therefore, provide suitable skin samples for regulatory skin absorption studies.

Tacrolimus (TAC) is a drug from natural origin that can be used for topical application to control autoimmune skin diseases such as atopic dermatitis, psoriasis, and vitiligo. Computational simulation based on quantum mechanics theory by solving Schrödinger Equation for n-body problem may allow the theoretical calculation of drug geometry, charge distribution and dipole moment, electronic levels and molecular orbitals, electronic transitions, and vibrational transitions. Additionally, the development of novel nanotechnology-based delivery systems containing TAC can be an approach for reducing the dose applied topically, increasing dermal retention, and reducing the reported side effects due to the controlled release pattern. Firstly, this paper was devoted to obtaining the molecular, electronic, and vibrational data for TAC by using five semi-empirical (SE) methods and one Density Functional Theory (DFT) method in order to expand the knowledge about the drug properties by computational simulation. Then, this study was carried out to prepare TAC-loaded poly(ԑ-caprolactone) nanocapsules by interfacial polymer deposition following solvent displacement and investigate the in vitro drug permeation using the Franz diffusion cell and the photoacoustic spectroscopy. Computational simulations were compared in the three schemes SE/SE, SE/DFT, and DFT/DFT, where the first method represented the procedure used for geometry optimization and the second one was performed to extract electronic and vibrational properties. Computational data showed correspondence with TAC geometry description and electronic properties, with few differences in HOMO - LUMO gap (Δ) and dipole values. The SE/DFT and DFT/DFT methods presented a better drug description for the UV-Vis, Infrared, and Raman spectra with low deviation from experimental values. Franz cell model demonstrated that TAC was more delivered across the Strat-M® membrane from the solution than the drug-loaded poly(ԑ-caprolactone) nanocapsules. Photoacoustic spectroscopy assay revealed that these nanocapsules remained more retained into the Strat-M® membranes, which is desirable for the topical application.

In this study, a new approach to pesticide permeation through the apple peel into the pulp is discussed. The tested compounds can be classified, based on mode of action, as systemic (boscalid, cyprodinil, pirimicarb, propiconazole and tebuconazole) or contact (captan, cypermethrin and fludioxonil) pesticides. The barrier effect was assessed using a Franz flow-type vertical diffusion cell system. A residue analysis was performed using a modified quick, easy, cheap, efficient, rugged and safe (QuEChERS) extraction method coupled to gas chromatography with tandem mass spectrometry (GC-MS/MS). The limits of detection (LODs) ranged between 2.6 µg kg-1 (pirimicarb) and 17 µg kg-1 (captan), with the coefficient of variability (CV) lower than 6%, while recoveries ranged from 85% (boscalid) to 112% (captan) at 0.1 and 1 mg kg-1 spiked levels. The highest peel penetration was observed for pirimicarb, captan and cyprodinil, with cumulative permeations of 90, 19 and 17 µg cm-2, respectively. The total absorption was in the range from 0.32% (tebuconazole) to 32% (pirimicarb). Only cypermethrin was not quantitatively detected in the pulp, and its use can be recommended in crop protection techniques. The obtained results indicate that molecular weight, octanol-water partition coefficient and water solubility are important parameters determining the process of pesticide absorption.

Even if dermal exposure to metal(loid)s from contaminated soils has received less attention than oral and inhalation exposure, the human health risk can be significant for some contaminants and exposure scenarios. The purpose of this study was to assess the influence of sebum proportion (1% v/v and 3% v/v) in two synthetic sweat formulations (EN 1811, pH 6.5 (sweat A) and NIHS 96-10, pH 4.7 (sweat B)) on As, Cr, Cu, Ni, Pb, and Zn dermal bioaccessibility and on subsequent diffusion through synthetic skin. A Franz cell with a Strat-M® membrane was used to quantify permeation parameters of bioaccessible metal(loid)s. Sebum\'s presence in synthetic sweat formulations significantly modified bioaccessibility percentages for As, Cr, and Cu. However, sebum proportion in both sweats did not influence the bioaccessibility of Pb and Zn. Some metal(loid)s, namely As and Cu, permeated the synthetic skin membrane during permeation tests when sebum was added to sweat while no permeation was observed without sebum in sweat formulations. Depending on sweat formulation, the addition of sebum (1% v/v) increased or decreased the Cr permeation coefficients (Kp). In all cases, bioaccessible Cr was no longer permeable when extracted with 3% sebum. Ni transdermal permeation was not influenced by the presence of sebum, and no permeation was observed for Pb and Zn. Further studies on the speciation of metal(loid)s in bioaccessible extracts in the presence of sebum are recommended.

BACKGROUND: Effective topical drug delivery is the essence of dermatologic treatment. The drug must be applied to the skin surface, be released from the vehicle, enter the stratum corneum, traverse the epidermis, and enter the dermis pharmacologically intact. New advances have improved emulsion-type formulation and drug delivery technology by encapsulating dispersed oil droplets in a robust multimolecular aqueous film of surfactants, oil, and water, enabling a multifold decrease in surfactant concentration compared to conventional creams. In the research reported here, we studied this new concept, termed polyaphron dispersion (PAD) technology, by comparing skin delivery of betamethasone dipropionate from a novel oil-in-water emulsion system of calcipotriene and betamethasone dipropionate (CAL/BDP) cream to that from a traditional topical suspension (CAL/BDP TS) utilizing in vitro and in vivo detection methods.
METHODS: The amount of BDP released from the CAL/BDP cream and CAL/BDP TS was evaluated using both in vitro Franz cell analysis and in vivo human tape stripping from ten female human volunteers after a single application of CAL/BDP cream or CAL/BDP TS. For the tape stripping analysis, 20 circular tape strips were taken from forearm application sites at 1, 2, 4, and 8 h after application and analyzed for the amount of BDP in the tape strip using liquid chromatography-mass spectrometry (LC-MS).
RESULTS: The in vitro Franz cell analysis demonstrated that the cumulative amount of BDP that diffused through the epidermis was statistically significantly greater for the CAL/BDP cream compared to the CAL/BDP TS at all time points. In addition, consistently higher amounts of BDP were recovered following CAL/BDP cream application than following CAL/BDP TS application at 1, 2, 4, and 8 h following application utilizing the in vivo tape stripping technique.
CONCLUSIONS: The novel PAD technology-based cream formulation delivered more BDP into the upper stratum corneum and lower epidermis than a traditional topical suspension.

In the treatment of pain, especially chronic pain, the rule of multimodal therapy applies, based on various painkillers mechanisms of action. The aim of the conducted study was to evaluate the in vitro penetration of ketoprofen (KET) and lidocaine hydrochloride (LH) through the human skin from a vehicle with transdermal properties. The results obtained with the use of the Franz chamber showed statistically significantly higher penetration of KET from the transdermal vehicle as compared to commercial preparations. It was also shown that the addition of LH to the transdermal vehicle did not change the amount of KET permeated. The study also compared the penetration of KET and LH by adding various excipients to the transdermal vehicle. Comparing the cumulative mass of KET that penetrated after the 24-h study, it was observed that the significantly highest permeation was found for the vehicle containing additionally Tinctura capsici, then for that containing camphor and ethanol, and the vehicle containing menthol and ethanol as compared to that containing Pentravan® alone. A similar tendency was observed in the case of LH, where the addition of Tinctura capsici, menthol and camphor led to a statistically significant higher penetration. Adding certain drugs such as KET and LH to Pentravan®, and substances such as menthol, camphor or capsaicin, can be an interesting alternative to administered enteral drugs especially in the group of patients with multiple diseases and polypragmasy.