Human Skin Permeation Research Articles

Towards the understanding of the IVPT results variability—Development, verification and validation of the PBPK model of caffeine in vitro human skin permeation

In the context of evaluating the safety and efficacy of dermal products, pharmacokinetic (PK) studies face considerable challenges, particularly concerning topically applied formulations. This underscores the necessity for alternative methods, such as in vitro permeation tests (IVPT) and physiologically based pharmacokinetic (PBPK) modelling, to better understand the dermal pharmacokinetics of a product. The purpose of this study was to modify, verify, and validate the PBPK model of caffeine permeation through human skin previously developed by Patel et al. (2022), and compare simulation results with experimental data from IVPT studies. Moreover, the study aimed to analyse the IVPT data variability and explore the potential of using the PBPK model to understand the influence of biological and drug-related factors on the IVPT results. In total, eight manuscripts describing nine experiments were included. The overall shapes of the permeation curves were considered acceptable based on visual checks for all analysed experiments. Five out of nine experiments met the predefined standard 2-fold difference criterion for comparison of the cumulative amount of caffeine in the receptor solution.. Our investigation highlights challenges in validating PBPK models for IVPT experiments, as the quality and consistency of experimental results pose significant hurdles. Despite access to data on caffeine permeation in scientific literature, reliable model validation is currently infeasible. Inter-laboratory variation suggests that alternative validation methods may be needed. Further studies should focus on issues with other compounds, especially lipophilic ones.

Impact of solvent dry down, phase change, vehicle pH and slowly reversible keratin binding on skin penetration of cosmetic relevant compounds: II. Solids

We extended a mechanistic, physics-based framework of the dry down process, previously developed for liquids and electrolytes, to solids and coded it into the latest UB/UC/P&G skin permeation model, herein renamed DigiSkin. The framework accounts for the phase change of the permeant from dissolved in a solvent (liquid) to precipitated on the skin surface (solid). The evaporation rate for the solid is reduced due to lower vapor pressure for the solid state versus subcooled liquid. These vapor pressures may differ by two orders of magnitude. The solid may gradually redissolve and penetrate the skin. The framework was tested by simulating the in vitro human skin permeation of the 38 cosmetically relevant solid compounds reported by Hewitt et al., J. Appl. Toxicol. 2019, 1–13. The more detailed handling of the evaporation process greatly improved DigiSkin evaporation predictions (r2 = 0.89). Further, we developed a model reliability prediction score classification using diverse protein reactivity data and identified that 15 of 38 compounds are out of model scope. Dermal delivery predictions for the remaining chemicals have excellent agreement with experimental data. The analysis highlighted the sensitivity of water solubility and equilibrium vapor pressure values on the DigiSkin predictions outcomes influencing agreement with the experimental observations.

Human skin absorption of three phthalates

Population studies reveal widespread exposure to phthalates. Understanding their absorption, distribution, metabolism, and excretion is vital to reduce exposure. However, data on skin absorption remain limited. We thus aim to characterize the skin permeation of three phthalates in a mixture, neat or in emulsion; di(2-ethylhexyl) phthalate (d4-DEHP), dibutyl phthalate (d4-DBP), and diethyl phthalate (d4-DEP), by comparing in vitro human skin (800 µm) permeation (24 hours) results using flow-through diffusion cells with urine results obtained from volunteers exposed to the same mixture applied to a forearm (40 cm2). Metabolites were analyzed in receptor fluids and urine. Phthalates crossed the skin barrier and metabolized into monoesters before elimination. Increased permeation was observed for phthalates in emulsion compared to neat substances, with polyethylene glycol (PEG) in the receptor fluid enhancing emulsion permeation, but not affecting neat substances. In vitro results mirrored in vivo findings: DEP showed rapid permeation (J: ∼2 ug/cm2/h) and urinary excretion peaking at six hours post-application, whereas DBP exhibited slower kinetics (J: ∼0.1 ug/cm2/h), with a urinary peak at 15–17 hours post-application. DEHP had minimal permeation (J: ∼0.0002 ug/cm2/h) with no observable urinary peak. These findings underscore the importance of comprehending phthalate skin absorption for effective exposure mitigation strategies.

In vitro studies into establishing therapeutic bioequivalence of complex topical products: Weight of evidence

Over the past decade, topically applied drug products have experienced extraordinary price increases, due to the shortage of multisource generic drug products. This occurrence is mainly related to the underlying challenges evolved in topical bioequivalence documentation. Although there has been continuing regulatory efforts to present surrogate in vitro methods to clinical endpoint studies, there is still a continued need for cost- and time-efficient alternatives that account for product specificities. Hence, this work intended to expose bioequivalence assessment issues for complex topical formulations, and more specifically those related with product efficacy guidance. As a model drug and product, a bifonazole 10 mg/g cream formulation was selected and two different batches of the commercially available Reference Product (RP) were used: RP1 that displayed lower viscosity and RP4 which presented high, but not the highest, viscosity. In vitro human skin permeation testing (IVPT) was carried out and the results were evaluated by means of the traditional bioequivalence assessment approach proposed by the EMA, as well as by the Scaled Average Bioequivalence assessment approach proposed by the FDA. Based on previous experience, there was an expectation of a high level of variability in the results, thus alternative methods to evaluate local drug skin availability were developed. More specifically, an infected skin disease model, where ex vivo human skin was infected and ATP levels were used as a biological marker for monitoring antifungal activity after product application. The results showed that permeation equivalence could not be supported between the different RP batches. In contrast, this statistical difference between the formulation batches was not indicated in the disease model. Nevertheless, in pivotal IVPT studies, the lowest permeant formulation (RP4) evidenced a higher antifungal in vitro activity as reported by the lower levels of ATP. A critical appraisal of the results is likewise presented, focusing on an outlook of the real applicability of the regulatory guidances on this subject.

New graphene-containing pharmaceutical formulations for infrared lamps-based phototherapy of skin cancer: In vitro validation and ex-vivo human skin permeation

Basal cell carcinoma (BCC) is the most common form of human cancer, and treatment usually involves surgery, with alternative strategies being needed. We propose the use of carbopol hydrogels (HG) for topical administration of nanographene oxide (GOn) and partially-reduced nanographene oxide (p-rGOn) for photothermal therapy (PTT) of BCC. GOn and p-rGOn incorporated into the HG present lateral sizes ∼200 nm, being stable for 8 months. After 20 min irradiation with an infrared (IR) photothermal therapy lamp (15.70 mW cm−2), GOn-HG increased temperature to 44.7 °C, while p-rGOn-HG reached 47.0 °C. Human skin fibroblasts (HFF-1) cultured with both hydrogels (250 μg mL−1) maintained their morphology and viability. After 20 min IR irradiation, p-rGOn HG (250 μg mL−1) completely eradicated skin cancer cells (A-431). Ex vivo human skin permeability tests showed that the materials can successfully achieve therapeutic concentrations (250 μg mL−1) inside the skin, in 2.0 h for GO HG or 0.5 h for p-rGOn HG.

Modeling the percutaneous absorption of solvent-deposited solids over a wide dose range: II. Weak electrolytes

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.

Fragment contribution models for predicting skin permeability using HuskinDB

Mathematical models to predict skin permeation tend to be based on animal derived experimental data as well as knowing physicochemical properties of the compound under investigation, such as molecular volume, polarity and lipophilicity. This paper presents a strikingly contrasting model to predict permeability, formed entirely from simple chemical fragment (functional group) data and a recently released, freely accessible human (i.e. non-animal) skin permeation database, known as the ‘Human Skin Database – HuskinDB’. Data from within the database allowed development of several fragment-based models, each including a calculable effect for all of the most commonly encountered functional groups present in compounds within the database. The developed models can be applied to predict human skin permeability (logKp) for any compound containing one or more of the functional groups analysed from the dataset with no need to know any other physicochemical properties, solely the type and number of each functional group within the chemical structure itself. This approach simplifies mathematical prediction of permeability for compounds with similar properties to those used in this study.

Poroelastic behavior and water permeability of human skin at the nanoscale.

Topical skin care products and hydrating compositions (moisturizers or injectable fillers) have been used for years to improve the appearance of, for example facial wrinkles, or to increase "plumpness". Most of the studies have addressed these changes based on the overall mechanical changes associated with an increase in hydration state. However, little is known about the water mobility contribution to these changes as well as the consequences to the specific skin layers. This is important as the biophysical properties and the biochemical composition of normal stratum corneum, epithelium, and dermis vary tremendously from one another. Our current studies and results reported here have focused on a novel approach (dynamic atomic force microscopy-based nanoindentation) to quantify biophysical characteristics of individual layers of ex vivo human skin. We have discovered that our new methods are highly sensitive to the mechanical properties of individual skin layers, as well as their hydration properties. Furthermore, our methods can assess the ability of these individual layers to respond to both compressive and shear deformations. In addition, since human skin is mechanically loaded over a wide range of deformation rates (frequencies), we studied the biophysical properties of skin over a wide frequency range. The poroelasticity model used helps to quantify the hydraulic permeability of the skin layers, providing an innovative method to evaluate and interpret the impact of hydrating compositions on water mobility of these different skin layers.

Hydrogel Containing Silibinin-Loaded Pomegranate Oil-Based Nanocapsules for Cutaneous Application: In Vitro Safety Investigation and Human Skin Biometry and Permeation Studies.

In previous studies, we developed a hydrogel formulation containing silibinin-loaded pomegranate oil nanocapsules (HG-NCSB) that had improved in vivo anti-inflammatory action in comparison to non-encapsulated silibinin. To determine skin safety and whether the nanoencapsulation influences silibinin skin permeation, NCSB skin cytotoxicity, HG-NCSB permeation in human skin, and a biometric study with healthy volunteers were conducted. The formulation of nanocapsules was prepared by the preformed polymer method while the HG-NCSB was obtained by thickening the suspension of nanocarriers with gellan gum. The cytotoxicity and phototoxicity of nanocapsules were assessed in Keratinocytes (HaCaT) and fibroblast (HFF-1) using the MTT assay. The hydrogels were characterized regarding the rheological, occlusive, and bioadhesive properties, and silibinin permeation profile in human skin. The clinical safety of HG-NCSB was determined by cutaneous biometry in healthy human volunteers. NCSB yielded better cytotoxicity results than the blank nanocapsules (NCPO). NCSB did not cause photocytotoxicity, while NCPO and the non-encapsulated substances (SB and pomegranate oil) were phototoxic. The semisolids presented non-Newtonian pseudoplastic flow, adequate bioadhesiveness, and low occlusive potential. The skin permeation demonstrated that HG-NCSB retained a higher SB amount in the outermost layers than HG-SB. In addition, HG-SB reached the receptor medium and had a superior concentration of SB in the dermis layer. In the biometry assay, there was no significant cutaneous alteration after the administration of any of the HGs. Nanoencapsulation promoted greater SB retention in the skin, averted percutaneous absorption, and made the topical use of SB and pomegranate oil safer.

Cosmeceutical formulations of pro-vitamin E phosphate: In-vitro release testing and dermal penetration into excised human skin

Long-term exposure to solar radiation can lead to skin damage such as photoageing, and photocarcinogenesis. This can be prevented by topically applying α-tocopherol phosphate (α-TP). The major challenge is that a significant amount of α-TP needs to reach viable skin layers for effective photoprotection. This study aims to develop candidate formulations of α-TP (gel-like, solution, lotion, and gel), and investigate formulation characteristics’ effect on membrane diffusion and human skin permeation. All the formulations developed in the study had an appealing appearance and no signs of separation. All formulations had low viscosity and high spreadability except the gel. The flux of α-TP through the polyethersulfone membrane was the highest for lotion (6.63 ± 0.86 mg/cm2/h), followed by control gel-like (6.14 ± 1.76 mg/cm2/h), solution (4.65 ± 0.86 mg/cm2/h), and gel (1.02 ± 0.22 mg/cm2/h). The flux of α-TP through the human skin membrane was numerically higher for lotion compared to the gel-like (328.6 vs.175.2 µg/cm2/h). The lotion delivered 3-fold and 5-fold higher α-TP in viable skin layers at 3 h and 24 h, respectively, compared to that of the gel-like. The low skin membrane penetration rate and deposition of α-TP in viable skin layers were observed for the solution and gel. Our study demonstrated that dermal penetration of α-TP was influenced by characteristics of formulation such as formulation type, pH, and viscosity. The α-TP in the lotion scavenged higher DPPH free radicals compared to that of gel-like (almost 73% vs. 46%). The IC50 of α-TP in lotion was significantly lower than that of gel-like (397.2 vs. 626.0 µg/mL). The preservative challenge test specifications were fulfilled by Geogard 221 and suggested that the combination of benzyl alcohol and Dehydroacetic Acid effectively preserved 2% α-TP lotion. This result confirms the suitability of the α-TP cosmeceutical lotion formulation employed in the present work for effective photoprotection.

Pharmacokinetic and toxicological in silco profiling of pluchine from the medicinal plant – Pluchea lanceolata

Background: Pluchea lanceolata belongs to the genus Pluchea (family: Asteraceae). The medicinal herb has been used for various ailments to prevent joint swelling in arthritic disorders, rheumatism, and other neurological-inflammatory disorders. Pluchine, which in our review was found to be a compound from P. Lanceolata, is explored for possible pharmacokinetic and toxicological properties by in silico computational predictive tools. Aims and Objectives: The aim of the study is to profile the pharmacokinetic, toxicological, and drug likeness scores of pluchine’s active principle using computational analysis and prediction tools. Materials and Methods: The authenticated and validated chemical structure of pluchine with its chemical formula will be extracted from standard web-based tools PubChem and ChemSpider. The two-dimensional to three-dimensional (3D) structure conversion will be processed with ChemSketchonline software; the 3D structure output will be processed further to be screened for molecular and pharmacokinetic properties for absorption, distribution, metabolism, and elimination, followed by toxicity profiling through AdmetSAR software. Results: Pluchine active principle from P. lanceolata had a predictive pharmacokinetic profile of human intestinal absorption of <30%, Human skin permeability coefficients (log k p) of pluchine were −6.75 cm/s, and the blood–brain barrier were predicted to be positive with a probability score of 0.65. Drug likeness lipinskiscore is positive with -0- violations. Acute oral toxicity testing for pluchine predicts it to be placed in category III with LD50 values >500 mg/kg but <5000 mg/kg. Conclusion: The pluchineactive principle from P. lanceolata is predicted to have a favorable pharmacokinetic and drug-like property profile for lead compound development.

Development of silymarin topical formulation: In vitro and ex vivo dermal kinetics of silymarin

Silymarin constituents are extensively investigated in the treatment of skin disorders. The main constituents of silymarin include taxifolin (TX), silychristin (ST), silydianin (SDN), silybin A (SA), silybin B (SB), isosilybin A (ISA) and isosilybin B (ISB). The objective of the present study was to determine in-vitro dermal kinetics of individual silymarin constituents in human skin models and to develop a silymarin topical formulation. In-vitro studies indicate human skin binding of silymarin was in the range of 2.09 to 12.3% and half-life of silymarin constituents was > 15.5 h in epidermal and dermal cells. Topical silymarin cream was prepared using sulfobutylether-β-cyclodextrins as solubilizer and propylene glycol as permeation enhancer. The cream was subjected to ex-vivo human skin permeation studies. In ex-vivo studies, cumulative amount of TX, ST, SDN, SA, SB, ISA and ISB permeated across human cadaver skin at 24 h was 921 ± 13.5, 1992 ± 67.6, 345 ± 39.2, 1089 ± 45.0, 1770 ± 100, 1469 ± 81.5 and 1285 ± 33.1 ng/cm2, respectively. The amount TX, ST, SDN, SA, SB, ISA and ISB retained after 24 h was 60.7 ± 8.2, 376 ± 45.5, 72.3 ± 6.9, 66.4 ± 8.0, 208 ± 31.3, 154 ± 12.4 and 102 ± 6.3 ng/mg of human cadaver skin, respectively. The study results demonstrate silymarin topical formulation could deliver significant amount of silymarin constituents into skin. The developed silymarin formulation could be beneficial for treatment or management of a broad spectrum of dermatological disorders.

Predicting skin permeability using HuskinDB

A freely accessible database has recently been released that provides measurements available in the literature on human skin permeation data, known as the ‘Human Skin Database – HuskinDB’. Although this database is extremely useful for sourcing permeation data to help with toxicity and efficacy determination, it cannot be beneficial when wishing to consider unlisted, or novel compounds. This study undertakes analysis of the data from within HuskinDB to create a model that predicts permeation for any compound (within the range of properties used to create the model). Using permeability coefficient (Kp) data from within this resource, several models were established for Kp values for compounds of interest by varying the experimental parameters chosen and using standard physicochemical data. Multiple regression analysis facilitated creation of one particularly successful model to predict Kp through human skin based only on three chemical properties. The model transforms the dataset from simply a resource of information to a more beneficial model that can be used to replace permeation testing for a wide range of compounds.

Mechanisms of ultrasound-microbubble cavitation for inducing the permeability of human skin.

We have previously reported that ultrasound (US)-mediated microbubble (MB) cavitation (US-MB) changed the permeability of the skin and significantly enhanced transdermal drug delivery (TDD) without changing the structure of the skin. In this study we found that US-MB enhanced TDD via disruption of epidermal cell-cell junctions and increased matriptase activity. Matriptase is a membrane-bound serine protease regulated by its inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1), and it is expressed in most epithelial tissues under physiologic conditions. Matriptase is expressed in mice after chronic exposure to UV radiation. This study found that US-MB can be used to monitor active matriptase, which rapidly formed the canonical 120-kDa matriptase-HAI-1 complex. These processes were observed in HaCaT human keratinocytes when matriptase activation was induced by US-MB. The results of immunoblot analysis indicated that the matriptase-HAI-1 complex can be detected from 10min to 3h after US-MB. Immunohistochemistry (IHC) of human skin revealed that US-MB rapidly increased the activated matriptase, which was observed in the basal layer, with this elevation lasting 3h. After 3h, the activated matriptase extended from the basal layer to the granular layer, and then gradually decayed from 6 to 12h. Moreover, prostasin expression was observed in the epidermal granular layer to the spinous layer, and became more obvious in the granular layer after 3h. Prostasin was also detected in the cytoplasm or on the cell membrane after 6h. These results suggest that matriptase plays an important role in recovering from US-MB-induced epidermal cell-cell junction disruption within 6h. US-MB is therefore a potentially effective method for noninvasive TDD in humans.

Reconstructed Human Epidermis: An Alternative Approach for In Vitro Bioequivalence Testing of Topical Products.

The use of in vitro human skin permeation tests is of value when addressing the quality and equivalence of topical drug products in Europe and the US. Human skin is the membrane of choice for these studies. The use of human skin as a membrane is hindered by limited access, high variability of results, and limited applicability for drugs with low skin permeability. Reconstructed human epidermis (RhE) models are validated as skin surrogates for safety tests and have been explored for percutaneous absorption testing. Clotrimazole poorly permeates human skin and is widely available for topical treatments. In this study, clotrimazole creams were used to test the ability of RhE to be used as biological membrane for bioequivalence testing, based on the Draft Guideline on Quality and Equivalence of Topical Products (CHMP/QWP/708282/2018) using a discriminative and modified in vitro permeation test (IVPT). To fulfill the validation of a discriminatory method, Canesten® 10 mg/g cream was compared with a test product with the same drug strength, along with two “negative controls” dosed at a 50% and 200% drug strength. Products were compared in finite dose conditions, regarding maximal flux (Jmax) and the total amount of drug permeated (Atotal). The results showed the discriminatory power of the method among the three drug strengths with no interference of the placebo formulation. The study design and validation complied with the requirements established in the guideline for a valid IVPT. This new test system allowed for the equivalence comparison between test and comparator product. Higher permeability of the RhE compared to human skin could be observed. This arose as a strength of the model for this modified IVPT bioequivalence testing, since comparing permeation profiles among products is envisaged instead of drawing absolute conclusions on skin permeation extent. These results may support the acceptance of RhE as biological membranes for modified IVPT in bioequivalence testing of topical products.

Impact of solvent dry down, vehicle pH and slowly reversible keratin binding on skin penetration of cosmetic relevant compounds: I. Liquids

To measure progress and evaluate performance of the newest UB/UC/P&G skin penetration model we simulated an 18-compound subset of finite dose in vitro human skin permeation data taken from a solvent-deposition study of cosmetic-relevant compounds (Hewitt et al., J. Appl. Toxicol. 2019, 1–13). The recent model extension involved slowly reversible binding of solutes to stratum corneum keratins. The selected subset was compounds that are liquid at skin temperature. This set was chosen to distinguish between slow binding and slow dissolution effects that impact solid phase compounds. To adequately simulate the physical experiments there was a need to adjust the evaporation mass transfer coefficient to better represent the diffusion cell system employed in the study. After this adjustment the model successfully predicted both dermal delivery and skin surface distribution of 12 of the 18 compounds. Exceptions involved compounds that were cysteine-reactive, highly water-soluble or highly ionized in the dose solution. Slow binding to keratin, as presently parameterized, was shown to significantly modify the stratum corneum kinetics and diffusion lag times, but not the ultimate disposition, of the more lipophilic compounds in the dataset. Recommendations for further improvement of both modeling methods and experimental design are offered.

In vitro human skin absorption of linalool: Effects of vehicle composition, evaporation and occlusion on permeation and distribution

In vitro human skin permeation and distribution of the fragrance material linalool (3,7-dimethyl-1,6-octadien-3-ol, CAS No. 78–70-6) following application in a range of single and mixed vehicles was determined, under unoccluded and occluded conditions, using human epidermal membranes. Vehicles were (70/30 v/v) ethanol[EtOH]/water, dipropyleneglycol [DPG], diethyl phthalate [DEP], (25/75 v/v) EtOH/DEP, (25/75 v/v) EtOH/DPG and petrolatum.Worst case absorbed dose values (% applied dose) for linalool under unoccluded conditions varied from 1.84% (DPG) to 4.08% (EtOH/water) and under occluded conditions from 5.9% (DEP) to 14.7% (EtOH/water). Occlusion always increased absorption but the magnitude of the effect varied with the vehicle from 2 to 6-fold.This study demonstrated that in vitro human skin permeation of linalool varied quite widely between test vehicles and that the magnitude of the effect of occlusion was also vehicle dependent. This was particularly significant in view of the reported variations in biological responses using different vehicles (Lalko et al., 2004; Politano et al., 2006).

In Silico Prediction of Skin Permeability Using a Two-QSAR Approach.

Topical and transdermal drug delivery is an effective, safe, and preferred route of drug administration. As such, skin permeability is one of the critical parameters that should be taken into consideration in the process of drug discovery and development. The ex vivo human skin model is considered as the best surrogate to evaluate in vivo skin permeability. This investigation adopted a novel two-QSAR scheme by collectively incorporating machine learning-based hierarchical support vector regression (HSVR) and classical partial least square (PLS) to predict the skin permeability coefficient and to uncover the intrinsic permeation mechanism, respectively, based on ex vivo excised human skin permeability data compiled from the literature. The derived HSVR model functioned better than PLS as represented by the predictive performance in the training set, test set, and outlier set in addition to various statistical estimations. HSVR also delivered consistent performance upon the application of a mock test, which purposely mimicked the real challenges. PLS, contrarily, uncovered the interpretable relevance between selected descriptors and skin permeability. Thus, the synergy between interpretable PLS and predictive HSVR models can be of great use for facilitating drug discovery and development by predicting skin permeability.

An advanced automation platform coupled with mass spectrometry for investigating in vitro human skin permeation of UV filters and excipients in sunscreen products.

Systemic absorption of UV-filtering chemicals following topical application of sunscreens may present a safety concern. The Food and Drug Administration (FDA) had recommended an in vitro skin permeation test (IVPT) to evaluate the potential of this safety risk for the evaluation of sunscreens prior to clinical studies. Therefore, a sensitive and robust bioanalytical method(s) were required for IVPT studies of different topical sunscreen products. An analytical procedure to quantitate sunscreen UV-filtering components and excipients in IVPT samples including avobenzone, octocrylene, oxybenzone, ecamsule, methylparaben and propylparaben was developed employing a RapidFire 360 robotic sample delivery system coupled with a triple quadrupole mass spectrometer. The analytical procedure was developed and validated according to the requirements of the FDA Bioanalytical Method Validation Guidance for Industry (2018). The analytical method provided a turnaround time of 12 seconds per sample and was determined to be accurate, precise, specific, and linear over the corresponding analytical ranges. The validated method was successfully applied for two IVPT studies for evaluating the skin permeation potential of UV-filtering chemicals and assisting with the selection of the sunscreen products for the clinical study conducted by the FDA. This work highlights the first analytical procedure that has applied a non-chromatographic-MS/MS automation platform to an in vitro biopharmaceutics study. The analytical platform simultaneously quantitated four UV filters and two excipients in complex media to evaluate their permeation in IVPT studies. The sample throughput and analytical performance of advanced automation platforms indicate their analytical procedure has the potential to significantly advance the efficiency of IVPT studies to evaluate permeation of a wide variety of UV chemical filters and excipients for topical OTC sunscreen products.

The development of an artificial skin membrane mimicking the lipid bilayer structure for in vitro permeation study

In vitro permeation test is an important method to predict permeability of transdermal formulation. We developed a liquid crystal artificial skin membrane (LC ASM) with the combination of hydrophobic polydimethylsiloxane, hydrophilic chitosan network and liquid crystal to mimic the lipid structure, for preliminary in vitro permeation test. The characterization results suggested that polydimethylsiloxane formed the main framework of the artificial skin membrane and it contained crystalline compartment. It has good thermal stability and mechanical strength, with elastic modulus about 0.2–6.2 MPa. The permeation study of model drugs with different polarity, aminopyrine and lidocaine, ketoprofen, flurbiprofen, through the synthetic LC ASMs were carried out. Results indicated that a good correlation of the permeability coefficients between the liquid crystal artificial skin and the human skin permeation tests was obtained. Therefore, it was suggesting that a synthetic artificial skin membrane could be an alternative option for preliminary in vitro permeation test to evaluate of the permeability of drug compounds.