Skin Pharmacokinetics Research Articles

Composition, Skin Pharmacokinetics, and Pharmacological Effects of the Sanfu Herbal Patch

The Sanfu herbal patch (SHP) is a traditional Chinese medicine external therapy consisting of Sinapis semen, Asari Radix et Rhizoma, Kansui Radix, and Corydalis Rhizoma. The review involved searching for SHP-related keywords in various databases including Web of Science, PubMed, and China National Knowledge Infrastructure, etc Relevant literature was then selected and findings were summarized. The SHP encompasses a diverse array of bioactive constituents, such as fatty acids, thioglycosides, essential oils, terpenes, alkaloids, and additional chemical compounds. The parent constituents of the SHP that enter skin circulation mainly include sinapine thiocyanate from Sinapis semen, asarinin from Asari Radix et Rhizoma, and tetrahydropalmatine from Corydalis Rhizoma. The SHP exhibits anti-inflammatory, antitussive, analgesic, and antitumor properties, making it a valuable pharmacological agent. Moreover, the SHP is frequently employed in clinical settings to address various ailments including asthma, rhinitis, chronic bronchitis, chronic obstructive pulmonary disease, chronic degenerative joint disease, and chronic gastritis. This review focuses on the main components, skin pharmacokinetics, and pharmacological research progress of the SHP, offering valuable insights for further understanding its mechanism of action and enhancing its clinical application.

Highly efficient prevention of radiation dermatitis using a PEGylated superoxide dismutase dissolving microneedle patch

PEGylated superoxide dismutase (PEG-SOD) is commonly used as a cytoprotective agent in radiotherapy. However, its effectiveness in preventing radiation dermatitis is limited owing to its poor skin permeability. To address this issue, a PEG-SOD-loaded dissolving microneedle (PSMN) patch was developed to effectively prevent radiation dermatitis. Initially, PSMN patches were fabricated using a template mold method with polyvinylpyrrolidone K90 as the matrix material. PSMNs exhibited a conical shape with adequate mechanical strength to penetrate the stratum corneum. More than 90 % of PEG-SOD was released from the PSMN patches within 30 min. Notably, the PSMN patches showed a significantly higher drug skin permeation than the PEG-SOD solutions, with a 500-fold increase. In silico simulations and experiments on skin pharmacokinetics confirmed that PSMN patches enhanced drug permeation and skin absorption, in contrast to PEG-SOD solutions. More importantly, PSMN patches efficiently mitigated ionizing radiation-induced skin damage, accelerated the healing process of radiation-affected skin tissues, and exhibited highly effective radioprotective activity for DNA in the skin tissue. Therefore, PSMN patches are promising topical remedy for the prevention of radiation dermatitis.

Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia.

Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20 mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73 µg/g (IQR: 21.94-60.65 µg/g) in skin and 33.29 µg/mL (IQR: 25.9-42.58 µg/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6 mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.

A skin pharmacokinetics study of permeation enhancers: The root cause of dynamic enhancement effect on in vivo drug permeation

Skin pharmacokinetics (SPK) of permeation enhancers can answer the question of why enhancement effects different at the kinetic level. Herein, SPK of permeation enhancers were classified into two categories, namely, lateral elimination (elimination to surrounding stratum corneum (SC)) and longitudinal elimination (elimination to deep epidermal (EP)). They were evaluated with a specific parameter for permeation enhancers, diffusion ratio (DRSC-EP), according to results of tissue-distribution test, molecular dynamic (MD) simulation, and confocal laser scanning microscopy (CLSM). The linear relationship between ke-enahcer and Δ Cmax-drug (R2 = 0.92), MRTenhancer and Δ Tmax-drug (R2 = 0.97), AUCt-enhancer and Δ AUCt-drug (R2 = 0.90) suggesting that SPK of permeation enhancers precisely controlled dynamic process of drug permeation in vivo. The molecular mechanisms of the dynamic effect of SPK process on drug transdermal behaviors were characterized by modulated-temperature differential scanning calorimetry (MTDSC), dielectric spectroscopy, small-angle X-ray scattering (SAXS), solid-state NMR. Permeation enhancers with high molecular weight (M.W.) and high polar surface area (P.S.A.) had good compatibility and strong interaction strength with SC, leading their lateral-elimination behavior, causing their low DRSC-EP and resulting in low ke-enhancer, long MRTenhancer, and large AUCt-enhancer. Consequently, skin barrier can be rapidly opened fast and to a great extent. In summary, compared with SPK of permeation enhancers with longitudinal elimination, SPK of permeation enhancers with lateral elimination can enable more sustainable and greater drug permeation. The information about SPK of permeation enhancers offered a criterion to estimate its permeation-enhancement effect on the drug and its subsequent application in transdermal formulations.

Omadacycline Oral Dosing and Pharmacokinetics in Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infection.

Omadacycline, a first-in-class aminomethylcycline antibiotic, is approved in the USA as intravenous (IV) and/or oral therapy for treatment of adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI). Phase 1 and 3 studies indicate that omadacycline dose adjustments are not required for any patient group based on age, sex, race, weight, renal impairment, end-stage renal disease, or hepatic impairment. Equivalency of exposure has also been demonstrated for 300 mg oral and 100 mg IV doses. Using an oral loading-dose regimen results in drug exposures exceeding established efficacy targets against the most common CABP and ABSSSI pathogens by Day 2 of treatment, and omadacycline has demonstrated clinical efficacy and is well tolerated. The oral-only dosing regimens provide the potential for treatment of CABP and ABSSSI either within a hospital setting or in the community, which could support earlier hospital discharge and reduced treatment costs.

Skin pharmacokinetics of diclofenac and co-delivered functional excipients

An important question in the development of a dermatological drug product is whether a target concentration has been achieved in, for example, the viable epidermis following topical administration. When attempting to address this challenge, it is essential to consider the role of excipients in the formulation that may influence drug partitioning and diffusion in the different layers of the skin. The objective, therefore, was to correlate, in human subjects, the skin pharmacokinetics of diclofenac (specifically, its uptake into and clearance from the stratum corneum (SC)) from an approved drug product (Voltaren® medicated plaster) with the in vivo co-uptake of two key excipients, namely propylene glycol and butylene glycol. SC sampling was used to assess diclofenac input into the skin during patch application, and its subsequent clearance post-removal of the delivery system. In parallel the uptake of the two glycol excipients was also measured. Drug and excipient amounts in the SC increased with time of application up to 6 h and, for diclofenac, no further increase was observed when the administration was prolonged to 12 h. When the plaster was removed after 6 h of wear, diclofenac cleared relatively slowly from the SC suggesting that drug binding with a slow off-rate had occurred. The results indicate that the optimisation of drug delivery from a topical formulation must take into account the disposition of key excipients and their impact on dermato-pharmacokinetics in general.

Skin Pharmacokinetics of Transdermal Scopolamine: Measurements and Modeling.

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post application of topical drug products. Commercially available transdermal patches, such as Scopoderm (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data are available with which to validate a predictive model. The long-term research aim, therefore, is to develop a physiologically based pharmacokinetic model (PBPK) to predict the dermal absorption and disposition of actives included in complex dermatological products. This work explored whether in vitro release and skin permeation tests (IVRT and IVPT, respectively), and in vitro and in vivo stratum corneum (SC) and viable tissue (VT) sampling data, can provide a satisfactory description of drug "input rate" into the skin and subsequently into the systemic circulation. In vitro release and skin permeation results for scopolamine were consistent with the previously reported performance of the commercial patch investigated. New skin sampling data on the dermatopharmacokinetics (DPK) of scopolamine also accurately reflected the rapid delivery of a "priming" dose from the patch adhesive, superimposed on a slower, rate-controlled input from the drug reservoir. The scopolamine concentration versus time profiles in SC and VT skin compartments, in vitro and in vivo, taken together with IVRT release and IVPT penetration kinetics, reflect the input rate and drug delivery specifications of the Scopoderm transdermal patch and reveal the importance of skin binding with respect to local drug disposition. Further data analysis and skin PK modeling are indicated to further refine and develop the approach outlined.

DGT, a novel heterocyclic diterpenoid, effectively suppresses psoriasis via inhibition of STAT3 phosphorylation.

Psoriasis is a chronic immune-mediated inflammatory skin disease that easily recurs and is difficult to cure. DGT is a novel synthetic heterocyclic diterpenoid, whose structure has not been previously reported. We have investigated the action of DGT against psoriasis, specifically the hyperproliferation of epidermal keratinocytes, angiogenesis and pathogenic inflammatory responses. We investigated its pharmacokinetics in skin after topical administration. We characterized its pharmacological actions in vitro and in vivo using cell proliferation assay, cell apoptosis assay, diethylstilbestrol-induced mouse vaginal epithelial cell mitosis model, tube formation assay, cell migration assay, chick embryonic chorioallantoic membrane (CAM) assay, histological, flow cytometric analysis and imiquimod (IMQ)-induced psoriasis-like model. DGT was found to be mainly distributed in the epidermis and dermis, which indicated that DGT was suitable as a topical treatment. DGT inhibited cell proliferation and induced apoptotic cell death of keratinocytes in vitro and in vivo. Moreover, DGT inhibited endothelial cell proliferation, tube formation and migration of in vitro angiogenesis, as well as in vivo CAM angiogenesis. In an IMQ-induced psoriasis-like skin inflammation murine model, topical application of DGT ameliorated keratinocyte proliferation and inflammatory response, especially in IL-17-related psoriasiform dermatitis. Furthermore, our results demonstrated that DGT prevented these pathological processes of psoriasis through suppression of STAT3 phosphorylation. DGT has great potential as a novel therapeutic agent for the treatment of psoriatic skin disease.

Finite Element Analysis for Predicting Skin Pharmacokinetics of Nano Transdermal Drug Delivery System Based on the Multilayer Geometry Model.

BackgroundSkin pharmacokinetics is an indispensable indication for studying the drug fate after administration of transdermal drug delivery systems (TDDS). However, the heterogeneity and complex skin structured with stratum corneum, viable epidermis, dermis, and subcutaneous tissue inevitably leads the drug diffusion coefficient (Kp) to vary depending on the skin depth, which seriously limits the development of TDDS pharmacokinetics in full thickness skin.MethodsA multilayer geometry skin model was established and the Kp of drug in SC, viable epidermis, and dermis was obtained using the technologies of molecular dynamics simulation, in vitro permeation experiments, and in vivo microdialysis, respectively. Besides, finite element analysis (FEA) based on drug Kps in different skin layers was applied to simulate the paeonol nanoemulsion (PAE-NEs) percutaneous dynamic penetration process in two and three dimensions. In addition, PAE-NEs skin pharmacokinetics profile obtained by the simulation was verified by in vivo experiment.ResultsCoarse-grained modeling of molecular dynamic simulation was successfully established and the Kp of PAE in SC was 2.00×10−6 cm2/h. The Kp of PAE-NE in viable epidermis and in dermis detected using penetration test and microdialysis probe technology, was 1.58×10−5 cm2/h and 3.20×10−5 cm2/h, respectively. In addition, the results of verification indicated that PAE-NEs skin pharmacokinetics profile obtained by the simulation was consistent with that by in vivo experiment.DiscussionThis study demonstrated that the FEA combined with the established multilayer geometry skin model could accurately predict the skin pharmacokinetics of TDDS.

Label-Free Quantification of Pharmacokinetics in Skin with Stimulated Raman Scattering Microscopy and Deep Learning

The treatment of inflammatory skin conditions relies on a deep understanding of how drugs and tissue behave and interact. Although numerous methods have been developed that aim to follow and quantify topical drug pharmacokinetics, these tools can come with limitations, assumptions, and trade-offs that do not allow for real-time tracking of drug flow and flux on the cellular level in situ. We have developed a quantitative imaging toolkit that makes use of stimulated Raman scattering microscopy and deep learning-based computational image analysis to quantify the uptake of specific drug molecules in skin without the need for labels. Analysis powered by trained convolutional neural networks precisely identified features such as cells, cell junctions, and cell types within skin to enable multifactorial analysis of skin pharmacokinetics. We imaged and quantified the flow and flux of small molecule drugs through the layers and structures of exvivo nude mouse ear skin and extracted pharmacokinetic parameters through convolutional neural network-based image processing, including relative area under the curve accumulation, time of maximum drug concentration, and in situ partition ratios. This approach, which facilitates the direct observation and quantification of pharmacokinetics, can be used to glean mechanistic insight into underlying phenomena in skin pharmacokinetics.

Analysis of chlorhexidine gluconate in skin using tape stripping and ultrahigh-performance liquid chromatography-tandem mass spectrometry

BackgroundTopical chlorhexidine gluconate (CHG) is used widely to reduce healthcare-associated infection. The optimal therapeutic dose for maximum efficacy and reduced toxicity is unclear, in part because of the lack of analytical methods to monitor CHG levels in skin. A novel method was developed to accurately measure CHG levels in skin after topical application with the goal of determining its pharmacokinetics in skin. MethodsUltrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used to develop a validated assay for measuring CHG levels in skin cells collected by a non-invasive adhesive tape-stripping method. CHG levels in the skin stratum corneum of healthy adult volunteers were measured at 0.5, 4, 8, and 24 h after its application. ResultsConditions for extraction of CHG were optimized and the assay was linear in the range 0.1–50 μg/mL (corresponding to 0.2–100 μg chlorhexidine/tape), with an intra-assay precision of 1.74–10.50 % and a relative error of ≤10 %. The inter-assay accuracy was in the range of 5.86–10.96 % with a relative error <9 %. CHG was stable on tapes stored at 4 °C and ambient temperature for 14 and 3 days, respectively. The recovery of CHG from the tape was quantitative and the matrix effect was determined as 2.1–14.8 %. CHG levels in healthy adult volunteer skin following topical application decreased rapidly over a 24 h period. ConclusionsA rapid, accurate and specific UHPLC-MS/MS method was developed for the measurement of CHG in the skin obtained by tape stripping that was linear over a large dynamic range. This assay afforded a simple and convenient non-invasive approach to monitor CHG levels in skin after topical application that can be applied to enable the optimal dose to prevent infection and minimize toxicity.

Interaction of Strychni Semen Combined with Paeoniae Radix Alba after Transdermal Administration: Skin Permeation and Pharmacokinetics

Interaction of Strychni Semen Combined with Paeoniae Radix Alba after Transdermal Administration: Skin Permeation and Pharmacokinetics

Regional variation in percutaneous absorption in the tree frog Litoria caerulea

Frog skin structure and physiology differs between skin regions, however little is known about how these differences affect transdermal absorption of chemicals. Further, no information is available regarding how the relative lipophilicity of a chemical influences its transdermal pharmacokinetics in frog skin. This study investigated the in vitro percutaneous absorption of three model chemicals - benzoic acid, caffeine, and ibuprofen - through dorsal and ventral skin of the tree frog Litoria caerulea. Flux was significantly higher through the ventral skin for all chemicals. Relative lipophilicity affected flux differently in different skin regions. These differences are likely due to significantly thicker dorsal skin increasing absorption path length, and also possibly owing to lipoid secretions on the dorsum providing an additional diffusional barrier. This knowledge can advise risk mitigation of xenobiotics in agricultural and industrial settings, and also guide selection of chemicals and doses when considering transdermal drug therapy in captive frogs.

Dermal pharmacokinetics of pyrazinamide determined by microdialysis sampling in rats

Studies have demonstrated the efficacy of pyrazinamide (PZA) against stages of the Leishmania parasite that causes cutaneous leishmaniasis. Although PZA is widely distributed in most body fluids and tissues, the amount of drug reaching the skin is unknown. This study aimed to investigate the pharmacokinetics of PZA in rat dermal tissue by dermal microdialysis. Skin pharmacokinetics was assessed by implanting a linear microdialysis probe in the dermis of ten rats. In addition, blood samples were collected to assess plasma pharmacokinetics. Unbound microdialysate (N = 280) and plasma (N = 120) concentrations following single intravenous doses of 25 mg/kg or 50 mg/kg PZA were quantified by a validated HPLC method. Probe calibration was performed by retrodialysis. Non-compartmental analysis and non-linear mixed-effects modelling were performed using WinNonlin and NONMEM v.7.3. PZA rapidly permeated into the dermis and reached high levels, with mean maximum concentrations (Cmax) of 22.4 ± 7.1 µg/mL and 48.6 ± 17.3 µg/mL for the two doses studied. PZA showed significant distribution to the skin (fAUCdermal/fAUCplasma = 0.82 ± 0.31 and 0.84 ± 0.25 for 25 mg/kg and 50 mg/kg doses, respectively). Active unbound concentrations in dermal tissue reached lower levels than free plasma concentrations, indicating that free PZA levels in plasma were in equilibrium with tissue levels. These results showed equivalent unbound drug tissue concentrations and corresponding unbound plasma levels. This study shows that PZA distributes rapidly into dermal interstitial fluid space in rats and therefore may be a potential agent in the treatment of cutaneous leishmaniasis.

Quantification of uptake and clearance of acyclovir in skin layers.

Quantification of drug uptake and clearance in the skin layers could provide better insight into the skin kinetics of dermatological formulations aimed for deeper skin tissues. This study assessed the skin kinetics of acyclovir in different skin layers following topical application on the abdominal region of Wistar rats. In vivo skin pharmacokinetics parameters were determined by two different protocols such as post drug load assessment and subsequent drug load assessment following topical application of 500 mg of cream formulation containing 5% (w/w) of acyclovir. Topical application of acyclovir exhibited concentration gradient between the skin layers (stratum corneum > viable epidermis > dermis) which were inconsistent over the time-course of the study. The rate and extent of drug reaching target site (basal epidermis) was relatively low. The drug uptake and clearance profiles were found to be distinct in all the three skin layers suggesting no drug concentration correlation (P<0.05) between skin layers. Drug concentration in the viable epidermis continued to increase even after termination of therapy (Tmax=4 h) and then declined rapidly. The availability of acyclovir in the target was comparatively low (approximately 0.4% of the applied dose) although an order of magnitude higher percentage was determined in the stratum corneum. The data observed in this study demonstrates low skin uptake and rapid clearance of acyclovir in the target site. Further, the methodology employed can be useful for studying other topical antiviral agents as well as for optimizing formulations for drugs (such as acyclovir) that may enhance their efficacy.

Quantitative transdermal behavior of pellitorine from Anacyclus pyrethrum extract

The plant Anacyclus pyrethrum (AP) consists of several N-alkylamides with pellitorine as main constituent. AP extracts are known to be biologically active and some products for topical administration containing AP plant extracts are already commercially available with functional cosmeceutical claims. However, no transdermal data for pellitorine are currently available. Therefore, our general goal was to investigate the local skin pharmacokinetics of the plant N-alkylamide pellitorine using a Franz diffusion cell set-up. Two different forms were applied on human skin: purified pellitorine and the AP extract. Our study demonstrated that pellitorine is able to cross the stratum corneum and the subsequent skin layers. A significantly higher permeability coefficient was observed when the AP extract (Kp=2.3×10−4cm/h) was administered, compared to purified pellitorine (Kp=1.1×10−4cm/h). With the obtained pellitorine concentrations in the skin layers and the receptor fluid, it is concluded that local and systemic effects can be expected after topical application. Due to these findings and as a regulatory consequence, products containing reasonable concentrations of pellitorine are recommended to be classified as a medicinal product.

Gamithromycin plasma and skin pharmacokinetics in sheep

This study assessed the plasma kinetics and skin/plasma concentration ratio of the azalide antibiotic gamithromycin (ZACTRAN®, Merial) in sheep after a single subcutaneous administration at 6 mg/kg bodyweight. Gamithromycin concentrations in plasma samples collected at various intervals up to 21 days following treatment and metacarpal skin obtained from animals at two, five and ten days after treatment were determined by liquid chromatography–tandem mass spectrometry methods.After administration, gamithromycin was rapidly absorbed, and individual maximum plasma concentrations were observed within 6 hours post-dose. Plasma peak concentration was 573 ± 168 ng/ml. The mean area under the plasma concentration versus time curve extrapolated to infinity was 8.00 ± 1.41 µg · hr/ml, and the mean terminal half-life was 34.5 ± 5.4 hours. Gamithromycin skin concentrations were much higher than the plasma concentrations resulting in skin/plasma concentration ratios of approximately 21, 58, and 138 at two, five and ten days post-dose, respectively, demonstrating extensive distribution to skin tissue.

Topical Formulations Containing Finasteride. Part I: In Vitro Permeation/Penetration Study and In Vivo Pharmacokinetics in Hairless Rat

In hair follicle (Hf) cells, the type-2 5-α-reductase enzyme, implicated in androgenetic alopecia, is selectively inhibited by finasteride (FNS). Because an effective topical formulation to deliver FNS to Hf is currently unavailable, this investigation aimed at evaluating in vitro FNS skin permeation and retention through and into hairless rat and human abdominal skin. Four hydroxypropyl chitosan (HPCH)-based formulations (P-08-012, P-08-016, P-08-063, and P-08-064) and one anhydrous formulation without HPCH (P-10-008) were tested. The pharmacokinetics in plasma and skin after application of P-08-016 or P-10-008 on dorsal rat skin with single and repeated doses was investigated. P-08-016 performed the best in driving FNS to the reticular dermis without producing a high transdermal flux. Neither the in vivo single nor the repeated dose experiments produced plasma levels of FNS and no differences were found between formulations concerning skin retention. No increase in the amount of drug retained in the skin was obtained with the repeated dose experiment. In conclusion, the HPCH-based formulation P-08-016 might represent an alternative to systemic therapy for its ability to promote a cutaneous depot of FNS in the region of hair bulbs, minimizing systemic absorption even after repeated treatments.

Trials and tribulations of skin iontophoresis in therapeutics

Iontophoresis is a method of non-invasive transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current. Both local and systemic administration are possible; however, the skin pharmacokinetics of iontophoretically delivered drugs is complex and difficult to anticipate. The unquestionable theoretical advantages of the technique make it attractive in several potential applications. After a brief review of the factors influencing iontophoresis, we detail the current applications of iontophoresis in therapeutics and the main potential applications under investigation, including systemic and topical drugs and focusing on the treatment of scleroderma-related ulcerations. Finally, we address the issue of safety, which could be a limitation to the routine clinical use of iontophoresis.

Dermal Microdialysis Technique to Evaluate the Trafficking of Surface-Modified Lipid Nanoparticles upon Topical Application

To evaluate the skin pharmacokinetics and tissue distribution of cell penetrating peptides (CPP) modified nano-structured lipid carrier (NLC) using an in vivo dermal microdialysis (MD) technique. Celecoxib (Cxb) encapsulated NLCs (CXBN), CPP modified CXBN (CXBN-CPP) and Cxb-Solution (CXBS) formulations were prepared and tested for in vitro skin distribution. MD was used to assess pharmacokinetic parameters of Cxb after topical application of Cxb formulations. The effect of pre-treatment with Cxb formulations was evaluated for expression of prostaglandin-E2 (PGE(2)) and Interleukin-6 (IL-6) after exposure of xylene using MD. Allergic contact dermatitis (ACD) model was used to confirm in vivo therapeutic response of Cxb formulations. The cumulative permeation of Cxb in MD dialysate after 24h for CXBN-CPP was significantly higher (p < 0.001) than CXBN and CXBS. Further, pre-treatment with CXBN-CPP significantly inhibited PGE(2) and IL-6 expression compared to CXBS and CXBN (p < 0.001). In ACD model, CXBN-CPP showed significant reduction (p < 0.001) in ear thickness compared to controls. Surface modification of NLC with CPPs can enhance the skin permeation of Cxb and MD can be used to investigate pharmacokinetics of Cxb nanoparticles in the skin.