Deep eutectic solvent combined with permeation enhancer strategy to convert tandospirone from oral to transdermal formulations improving drug bioavailability.

Tandospirone(Tan) is a commonly used drug for anxiety treatment. However, it has a significant first-pass effect and needs to be taken three times a day. To increase the bioavailability of the drug and reduce the number of administrations, this work amid to prepare a Tan patch that can be administered once a day by using the strategy of therapeutic deep eutectic solvent(THEDES) in cooperation with chemical permeation enhancer(CPE). In this study, four organic acids and five permeation enhancers were selected, and the optimized formulation was obtained by single-factor investigation and Box-Behnken design. The optimized formulation could significantly enhance drug loading by 2.5-fold and skin permeation up to 586.6 ±â€¯17 µg/cm2 in rats. Based on pharmacokinetic results, compared to oral administration, the drug exhibited a substantially elevated bioavailability, registering a 17-fold increase(from 3.01 % to 52.17 %), alongside a 10-fold rise in the mean residence time(MRT). Meanwhile, the patch was not irritating. The results of the mechanistic study showed that levulinic acid(LeA) acted as a bridge to increase the interaction between the Tan and the matrix and inhibited the crystallization of the drug in the patch, and THEDES together with CPE improved the matrix fluidity and skin permeability. This study provides a reference for the joint application of THEDES and CPEs in patch development.

Development of 3D-Printed Two-Compartment Capsular Devices for Pulsatile Release of Peptide and Permeation Enhancer.

OBJECTIVE: The oral absorption of a peptide is driven by a high local concentration of a permeation enhancer (PE) in the gastrointestinal tract. We hypothesized that a controlled release of both PE and peptide from a solid formulation, capable of maintaining an effective co-localized concentration of PE and peptide could enhance oral peptide absorption. In this study, we aimed to develop a 3D-printed two-compartment capsular device with controlled pulsatile release of peptide and sodium caprate (C10). METHODS: 3D-printed two-compartment capsular device was fabricated using a fused deposition modeling method. This device was then filled with LY peptide and C10. The release profile was modulated by changing the thickness and polymer type of the capsular device. USP apparatus II dissolution test was used to evaluate the impacts of device thickness and polymer selection on release profile in vitro. An optimal device was then enteric coated with HPMCAS. RESULTS: A strong linear relationship between the thickness of capsular devices and the delay in the release onset time was observed. An increase in the device thickness or the use of PLA decreased the release rate. The capsular device with compartment 1, compartment 2 and fence thickness of 0.4; 0.95 and 0.5 mm, respectively, and the use of PVA achieved desired pulsatile release profiles of both peptide and C10. Furthermore, enteric-coated capsular devices with HPMCAS had similar pulsatile release profiles compared to non-enteric coated devices. CONCLUSION: These findings suggest potential application of 3D-printing techniques in the formulation development for complex modified drug release products.

FREE FATTY ACIDS INHIBIT AN ION-COUPLED MEMBRANE TRANSPORTER BY DISSIPATING THE ION GRADIENT.

Glutamate is the main excitatory transmitter in the mammalian central nervous system; glutamate transporters keep the synaptic glutamate concentrations at bay for normal brain function. Arachidonic acid (AA), docosahexaenoic acid (DHA), and other unsaturated fatty acids modulate glutamate transporters in cell- and tissue slices-based studies. Here, we investigated their effect and mechanism using a purified archaeal glutamate transporter homolog reconstituted into the lipid membranes. AA, DHA, and related fatty acids irreversibly inhibited the sodium-dependent concentrative substrate uptake into lipid vesicles within the physiologically relevant concentration range. In contrast, AA did not inhibit amino acid exchange across the membrane. The length and unsaturation of the aliphatic tail affect inhibition, and the free carboxylic headgroup is necessary. The inhibition potency did not correlate with the fatty acid effects on the bilayer deformation energies. AA does not affect the conformational dynamics of the protein, suggesting it does not inhibit structural transitions necessary for transport. Single-transporter and membrane voltage assays showed that AA and related fatty acids mediate cation leak, dissipating the driving sodium gradient. Thus, such fatty acids can act as cation ionophores, suggesting a general modulatory mechanism of membrane channels and ion-coupled transporters.

Development of Gentamicin Bilosomes Laden In Situ Gel for Topical Ocular Delivery: Optimization, In Vitro Characterization, Toxicity, and Anti-microbial Evaluation.

Purpose: The eye drops are the prominent preparation used to treat surface eye disease (bacterial conjunctivitis). However, they have some limitations i.e., short corneal residence, resulting in low ocular bioavailability and necessitating frequent dose administration. The present study developed gentamicin (GE) bilosomes (BM)- laden in situ gel to improve therapeutic activity. The in situ gel system is initially in sol form before administration and converted into gel form in physiological eye conditions. Methods: The GE-BM was developed using the thin film hydration technique and optimized by D-optimal design. GE-BM was characterized for vesicle size, entrapment efficiency, zeta potential, morphology, and Fourier transform electron microscope (FTIR). The optimized GE-BM (GE-BMopt) was incorporated into an in situ gel and assessed for physicochemical characteristics. GE-BMopt in situ gel was evaluated for in vitro release, ex vivo permeation, toxicity, and antimicrobial study. Results: GE-BMopt has a vesicle size of 185.1±4.8nm, PDI of 0.254, zeta potential of 27.6 mV, entrapment efficiency of 81.86±1.29 %, and spherical morphology. The FTIR study presented no chemical interactions between GE and excipients. GE-BMopt in situ gel (GE-BMoptIG4) showed excellent viscosity, gelling strength, and ex-vivo bio-adhesion. GE-BMopt-IG4 showed significant high and sustained release of GE (78.08±4.73% in 12h). GE-BMopt-IG4 displayed 3.27-fold higher ex-vivo goat corneal permeation than a pure GE solution. GE-BMopt-IG4 showed good corneal tolerance without any damage or irritation. GE-BMopt-IG4 showed significantly (P<0.05) higher anti-bacterial activity (ZOI) against Staphylococcus aureus and Escherichia coli than pure GE solution. Conclusion: The study determined that the BM in situ gel system can serve as a substitute carrier for GE to enhance its therapeutic effectiveness, and further preclinical studies are required.

Tailored Permeation Through ≈1 nm Thick Carbon Nanomembranes by Subtle Changes in Their Molecular Design.

Due to their nanoscale thickness (≈1 nm) and exceptional selectivity for permeation of gases, nanomembranes made of 2D materials possess high potential for energy-efficient nanofiltration applications. In this respect, organic carbon nanomembranes (CNMs), synthesized via electron irradiation-induced crosslinking of aromatic self-assembled monolayers (SAMs), are particularly attractive, as their structure can be flexibly tuned by choice of molecular precursors. However, tailored permeation of CNMs, defined by their molecular design, has not been yet demonstrated. In this work, it is shown that the permeation of helium (He), deuterium (D2) and heavy water (D2O) for CNMs synthesized from biphenyl-based SAMs on silver (C6H5-C6H4-(CH2)n-COO/Ag, n = 2-6) can be tuned by orders of magnitude by changing the structure of the molecular precursors by just a single methylene unit. The selectivity in permeation of D2O/D2 with an unprecedented value of 200 000 can be achieved in this way. The temperature-dependent study reveals a clear correlation between the molecular design and the permeation mechanisms facilitating therewith tailored synthesis of molecular 2D materials for separation technologies.

Effects of Titanium Dioxide (TiO2) on Physico-Chemical Properties of Low-Density Polyethylene.

Hazardous chemicals are transported on rail and road networks. In the case of accidental spillage or terror attack, civilian and military first responders must approach the scene equipped with appropriate personal protective equipment. The plausible manufacturing of chemical protective polymer material, from photocatalyst anatase titanium dioxide (TiO2) doped low-density polyethylene (LDPE), for cost-effective durable lightweight protective garments against toxic chemicals such as 2-chloroethyl ethyl sulphide (CEES) was investigated. The photocatalytic effects on the physico-chemical properties, before and after ultraviolet (UV) light exposure were evaluated. TiO2 (0, 5, 10, 15% wt) doped LDPE films were extruded and characterized by SEM-EDX, TEM, tensile tester, DSC-TGA and permeation studies before and after exposure to UV light, respectively. Results revealed that tensile strength and thermal analysis showed an increasing shift, whilst CEES permeation times responded oppositely with a significant decrease from 127 min to 84 min due to the degradation of the polymer matrix for neat LDPE, before and after UV exposure. The TiO2-doped films showed an increasing shift in results obtained for physical properties as the doping concentration increased, before and after UV exposure. Relating to chemical properties, the trend was the inverse of the physical properties. The 15% TiO2-doped film showed improved permeation times only when the photocatalytic TiO2 was activated. However, 5% TiO2-doped film exceptionally maintained better permeation times before and after UV exposure demonstrating better resistance against CEES permeation.

The effect of mucoadhesive polymers on ocular permeation of thermoresponsive in situ gel containing dexamethasone-cyclodextrin complex.

Dexamethasone (DXM) is a commonly used corticosteroid in the treatment of ocular inflammatory conditions that affect more and more people. The aim of this study was to evaluate the effect of the combination of hydroxypropyl-ß-cyclodextrin (HPBCD), in situ gelling formulations, and other mucoadhesive polymers, i.e., hydroxypropyl methylcellulose (HPMC) and zinc-hyaluronate (ZnHA), on permeation by applying in vitro and ex vivo ophthalmic permeation models. Additionally, gelling properties, in vitro drug release, and mucoadhesion were measured to determine the impact of these factors on permeation and ultimately on bioavailability. The results showed that GEL1 and GEL2 had an optimal gelling temperature, 36.3 ℃ and 34.6 ℃, respectively. Moreover, the combination of Poloxamer 407 (P407) with other polymers improved the mucoadhesion (GEL1: 1333.7 mN) compared with formulations containing only P407 (P12: 721.8 mN). Both HPBCD and the gel matrix had a considerable influence on the drug release and permeability of DXM, and the combination could facilitate the permeation into the aqueous humor. After 30 min of treatment, the DXM concentration in the aqueous humor was 1.16-1.37 µg∕mL in case of the gels, whereas DXM could not be detected when treated with the DXM suspension. The results of the experiments using an in vitro cell line indicated that the formulations could be considered safe for topical treatment of the eye. In conclusion, with application of a small amount of HPMC (0.2 % w∕w), the concentration of P407 could be reduced to 12 % w/w while maintaining the ideal gelling properties and gel structure without negatively affecting permeability compared with the formulation containing a higher amount of P407. Furthermore, the gel matrix may also provide programmed and elongated drug release.

Electrospun fiber patches for inflammatory skin diseases - Correlating in vitro drug release with ex vivo permeation.

In this proof-of-concept study, we aimed to develop an anti-inflammatory patch that in contrast to the semi-solid standard therapy is dry and non-greasy, and only needs to be changed once a day due to continuous release of the active ingredient over 24 h. While fiber materials for the treatment of inflammatory skin diseases have been reported in the literature, the majority of studies focuses solely on material characterization including in vitro release studies; however, there is a lack of ex vivo permeation studies as well as comparison with standard therapy. However, such experiments are crucial to deduct the potential efficacy of the drug delivery system, as skin absorption of the drug may be the rate-limiting step and not the drug release. Therefore, we set out to investigate different types of electrospun fiber systems based on polycaprolactone, a polymer with a well-established safety profile widely used for fabricating electrospun patches. The electrospun fiber patches were loaded with the anti-inflammatory drug hydrocortisone and characterized not only for their drug release properties, but for the first time also for their skin permeation and retention as well as their cytocompatibility and anti-inflammatory properties on human skin. While in the release studies, the layer-by-layer fiber system proved to be best suited for an application time of 24 h, this was not reflected in the permeation studies, where all fiber systems showed a similar skin permeation and retention of the drug. In our study set-up, a comparison with standard cream formulations revealed that electrospun fibers offer an advantage in terms of the permeated amount of hydrocortisone. Overall, this study supports the importance of conducting comparisons with standard therapies and, additionally, confirms that electrospun fibers are a promising dosage form for the controlled release of anti-inflammatory drugs for the treatment of inflammatory skin diseases.

BBBper: A Machine Learning-based Online Tool for Blood-Brain Barrier (BBB) Permeability Prediction.

AIMS: Neuronal disorders have affected more than 15% of the world's population, signifying the importance of continued design and development of drugs that can cross the Blood-Brain Barrier (BBB). BACKGROUND: BBB limits the permeability of external compounds by 98% to maintain and regulate brain homeostasis. Hence, BBB permeability prediction is vital to predict the activity of a drug-like substance. OBJECTIVE: Here, we report about developing BBBper (Blood-Brain Barrier permeability prediction) using machine learning tool. METHOD: A supervised machine learning-based online tool, based on physicochemical parameters to predict the BBB permeability of given chemical compounds was developed. The user-end webpage was developed in HTML and linked with back-end server by a python script to run user queries and results. RESULT: BBBper uses a random forest algorithm at the back end, showing 97% accuracy on the external dataset, compared to 70-92% accuracy of currently available web-based BBB permeability prediction tools. CONCLUSION: The BBBper web tool is freely available at http://bbbper.mdu.ac.in.

Atorvastatin loaded glycerosomal patch as an effective transdermal drug delivery: optimization and evaluation.

Aim: The study explores glycerosomes as effective vesicular systems for transdermal delivery of atorvastatin (ATO) to overcome drawbacks related to its oral administration.Methodology: The objectives of this study were to formulate, by thin-film hydration method, optimize using definitive screening design and evaluate ATO-loaded glycerosomes (ATOG) which were then incorporated into patch followed by the evaluation of glycerosomes containing different concentration of glycerol.Results & discussion: Vesicle size, Polydispersity index (PDI), zeta potential, entrapment efficiency and loading capacity of spherical ATOG (0-30%w/w) showed 137.3-192d.nm, 0.292-0.403, -3.81 to-6.76mV, 80.03-92.77% and 5.80-6.40%, respectively. In-vitro release study showed sustained release, increased skin permeability and better cell viability than pure drug. ATOG patches showed greater skin permeability than pure drug and ATO-liposomal patches.Conclusion: The study concludes that ATOGs are promising for effective transdermal delivery.

[Box: see text].

Quantifying skin permeation of a novel metformin lotion using modified hydrophilic interaction liquid chromatography.

Aim: This study aimed to quantify the permeation of metformin (Met) lotion through pig ear skin using high-performance liquid chromatography, specifically hydrophilic interaction liquid chromatography (HILIC), to separate Met from biological contaminants and effectively measure its permeation through skin similar to human skin.Materials & methods: A Franz cell permeation assay was used to assess the permeation kinetics of 6% Met lotion through pig ear skin. Samples were collected at various time points and prepared for high-performance liquid chromatography analysis by removing large biological contaminants. The permeated Met was quantified by monitoring its retention time (RT) at 9 min using HILIC, with an acidic, polar mobile phase and a normal-phase column.Results: A distinct Met peak with a RT of approximately 9 min was observed in the 6% Met lotion, which was absent in the permeation samples from the 0% Met lotion. This peak (RT 9 min) was distinct from the 'biological-contaminants' peaks at RT 2-3 min and increased linearly over time, reaching 36.8% of the total applied Met at 24 h.Conclusion: These findings demonstrate that the HILIC method effectively separates Met from biological components in pig ear skin, allowing accurate quantification of Met despite the presence of skin lipids and proteins.

[Box: see text].

Strategies for transportation of peptides across the skin for treatment of multiple diseases.

An established view in genetic engineering dictates an increase in the discovery of therapeutic peptides to enable the treatment of multiple diseases. The use of hypodermic needle for delivery of proteins and peptides occurs due to the hydrophilic nature, sensitivity toward proteolytic enzymes and high molecular weight. The non-invasive nature of the transdermal delivery technique offers multiple advantages over the invasive route to release drugs directly into the systemic circulation to enhance bioavailability, better patient compliance, reduced toxicity and local irritability. The transdermal route seems highly desirable from the pharmaco-therapeutic and patient compliance point of view, however, the lipophilic barrier of skin restricts the application. The use of several techniques like electrical methods (iontophoresis, sonophoresis etc.), chemical penetration enhancers (e.g. protease inhibitors, penetration enhancers, etc.) and nanocarriers (dendrimers, lipid nanocapsules, etc.) are utilized to improve the passage of drug molecules across the biomembranes. Additionally, such clinical interventions facilitate the physicochemical characteristics of peptides, to enable effective preservation, conveyance and release of therapeutic agents. Moreover, strategies ensure the attainment of the intended targets and enhance treatment outcomes for multiple diseases. This review article focuses on the techniques of peptide transportation across the skin to advance the delivery approaches and therapeutic efficiency.

[Box: see text].

Combining ion-pair strategy and percutaneous permeation enhancers to develop sustained-release paliperidone patch.

In this study, a sustained-release paliperidone (PAL) patch was developed using a combination of ion-pair strategy and percutaneous permeation enhancers (PPEs). The ion-pair strategy was used to improve drug-adhesive miscibility and control drug release. PPEs were used to break SC barrier function to facilitate drug skin permeation. The in vitro skin permeation experiments using single-factor experiments and Box-Behnken design gave the optimized formulation, a 55 µm adhesive thickness patch with 7 % (w/w) PAL-LA (Lauric acid), 9.7 % (w/w) Plurol® Oleique CC 497 (POCC). Moreover, the pharmacokinetic study confirmed its potential in sustained-release transdermal patch with longer MRT0-t (18.35 ± 3.11 h) and higher BA (63.14 %) than the gavage group (Cmax = 6.64 ± 2.61 µg/mL, MRT0-t = 2.88 ± 1.06 h, BA = 45.70 %) without significant increasing Cmax. The mechanism study revealed that forming ion-pairs effectively modulated drug's physicochemical properties and doubly ionic H-bond strength to improve drug miscibility in patches. To summarize, a sustained-release patch of PAL was successfully developed, which provided a strategy for sustained-release patches with good drug-polymer miscibility, drug controlled-release, and feasible drug utilization features.

Graphene Oxide and its Composites: Advanced Membranes for Selective Water Permeation.

Graphene oxide (GO) membranes have gained significant attention as a promising material for separation by selective permeation processes due to their advantageous structural and chemical properties, including high water permeability, chemical resistance, and mechanical strength. In this study, we explore the potential applications of GO membranes in pervaporation to separate liquid mixtures. The layered structure and hydrophilic nature of GO membrane facilitate rapid and selective water transport through angstrom-scale interlayer spacings, resulting in superior performance over conventional polymeric and inorganic membranes. The unique mass transport mechanisms - slip flow and molecular alignment - enable GO membranes to selectively permeate water over organic solvents. For chemical dehydration, GO membranes are the most potential candidates. Furthermore, advancements in composite GO membranes and cross-linking techniques that improve their stability and separation performance are discussed. This study highlights the advantages of GO membranes and their potential to replace or complement existing technologies, by emphasizing their role in advancing membrane-based separation and promoting environmental sustainability. Future research is expected to optimize the fabrication techniques for GO membranes and expand their application scope.

Alpha-Tocopherol-Infused Flexible Liposomal Nanocomposite Pressure-Sensitive Adhesive: Enhancing Skin Permeation of Retinaldehyde.

Retinaldehyde (RAL), or retinal, is a vitamin A derivative that is widely used for several skin conditions. However, it is light sensitive and has low water solubility, limiting its efficiency in transdermal delivery. This study developed a novel delivery system for retinal (RAL) using flexible liposomes (FLPs) infused with α-tocopherol succinate (α-TS) to improve stability, and enhance skin permeability. The RAL-FLPs were embedded in pressure-sensitive adhesive (PSA) hydrogels, creating a delivery platform that supports prolonged skin residence and efficient permeation of RAL. The stability and skin permeation as well as human skin irritation and adhesion capabilities were assessed to determine the formulation's safety and efficacy. Our findings suggested that the addition of α-TS could improve liposomal stability and RAL chemical stability. Moreover, the skin permeation and fluorescence microscopic-based studies suggested that the addition of α-TS could enhance skin permeability of RAL through hair follicles. The RAL-FLP was embedded in PSA hydrogels fabricated from 25% GantrezTM S-97 (GT) and 1% hyaluronic acid (Hya) with aluminum as a crosslinker. The PSA hydrogel exhibited desirable peeling and tacking strengths. The developed hydrogels also demonstrated greater skin deposition of RAL compared with its aqueous formulation. Additionally, the RAL-FLP-embedded PSA hydrogels showed no skin irritation and maintained better adhesion for up to 24 h compared to commercial patches. Hence, the developed hydrogels could serve as a beneficial platform for delivering RAL in treating skin conditions.

The Design Features, Quality by Design Approach, Characterization, Therapeutic Applications, and Clinical Considerations of Transdermal Drug Delivery Systems-A Comprehensive Review.

Transdermal drug delivery systems (TDDSs) are designed to administer a consistent and effective dose of an active pharmaceutical ingredient (API) through the patient's skin. These pharmaceutical preparations are self-contained, discrete dosage forms designed to be placed topically on intact skin to release the active component at a controlled rate by penetrating the skin barriers. The API provides the continuous and prolonged administration of a substance at a consistent rate. TDDSs, or transdermal drug delivery systems, have gained significant attention as a non-invasive method of administering APIs to vulnerable patient populations, such as pediatric and geriatric patients. This approach is considered easy to administer and helps overcome the bioavailability issues associated with conventional drug delivery, which can be hindered by poor absorption and metabolism. A TDDS has various advantages compared to conventional methods of drug administration. It is less intrusive, more patient-friendly, and can circumvent first pass metabolism, as well as the corrosive acidic environment of the stomach, that happens when drugs are taken orally. Various approaches have been developed to enhance the transdermal permeability of different medicinal compounds. Recent improvements in TDDSs have enabled the accurate administration of APIs to their target sites by enhancing their penetration through the stratum corneum (SC), hence boosting the bioavailability of drugs throughout the body. Popular physical penetration augmentation methods covered in this review article include thermophoresis, iontophoresis, magnetophoresis, sonophoresis, needle-free injections, and microneedles. This review seeks to provide a concise overview of several methods employed in the production of TDDSs, as well as their evaluation, therapeutic uses, clinical considerations, and the current advancements intended to enhance the transdermal administration of drugs. These advancements have resulted in the development of intelligent, biodegradable, and highly efficient TDDSs.

Tuning Barrier Properties of Low-Density Polyethylene: Impact of Amorphous Region Nanostructure on Gas Transmission Rate.

This work focused on determining the factors that are of key importance in the oxygen barrier properties of low-density polyethylene (LDPE). It has been shown that, depending on the type and amount of the low-molecular-weight compound (tetracosane, paraffin wax, paraffin oil) introduced into the LDPE matrix, it can contribute to the improvement or deterioration of barrier properties. Tetracosane and paraffin wax incorporated into the LDPE matrix caused a reduction in oxygen permeability parameters compared to neat polyethylene. As their content increased, the barrier properties of the samples towards oxygen also increased. A completely opposite effect was achieved with paraffin oil. The results of comprehensive studies provide evidence that in the case of LDPE blends, two mechanisms are responsible for changing/controlling their transport properties. The first mechanism is associated with changes in the molecular packing in the interlamellar amorphous regions, while the second is related to the crystallinity of the samples. In cases where there are no changes in crystallinity, the density of the amorphous phase becomes the decisive factor in barrier properties, as clearly shown by results assessing chain dynamics.

Concanavalin a Grafted Nanoemulsions for Nasal Delivery: Preliminary Studies with Fluorescently Labelled Formulations.

Nasal delivery is a non-invasive strategy for effective drug delivery. Nevertheless, in order to promote drug uptake by the nasal mucosa, it is fundamental to increase its residence time in the administration site. To this aim, nano-sized drug delivery systems are widely exploited. Within this context, the commercially available nanoemulsion for parenteral nutrition is a biocompatible, safe and clinically approved vehicle for drug delivery. Furthermore, the nanodroplet surface can be modified via a well-established protocol to graft Concavalin A, a lectin capable of improving the mucosal adhesion, by binding to the α-mannose and α-glucose residues of the mucosal glycocalyx. The obtained targeted formulation is able to induce haemagglutination, as opposite to non-modified nanoemulsion. Furthermore, the ConA grafting maintains the physicochemical properties of the nanodroplets (size~230 nm, Z < -35 mV) and does not interfere with the loading of the Rose Bengal fluorescent probe. Fluorescently labelled ConA grafted nanodroplets showed enhanced permeation and accumulation in ex vivo bovine nasal mucosa. This study is a proof of concept that Concanavalin A can be used to decorate the surface of nanodroplets, acting as a permeation promoter.

A Consideration on Infinite and Finite Dosing in Skin Permeation Using Reconstructed Models.

INTRODUCTION: When vitamin derivatives penetrate the epidermis, they release active compound such as ascorbic acids (AsA) and tocopherols via enzymatic digestion of chemical modifiers. To determine the transdermal penetration of the derivatives, the total permeation of both the derivatives and their active compounds that released from the derivatives should be considered. In this study, we established a skin penetration test method using a cultured, reconstructed skin model with active epidermal enzymes. And we analyzed two vitamin derivatives with different chemical properties: magnesium ascorbyl phosphate (APM) and sodium tocopheryl phosphate (TPNa), both of which has been confirmed their skin permeation in the reconstructed models and the digestion to AsA and α-tocopherol by the epidermal enzymes, respectively. METHODS: We prepared the 1% of water solution containing either APM or TPNa. Then, we tested the cumulative permeation of the derivatives at 2 application volumes, 25 µL/cm2 (finite dosing) and 85 µL/cm2 (infinite dosing), on cultured reconstructed skin and observed the permeation of the permeants every 2 h up to 24 h. RESULTS: When the applied formula was used to assess the evaporation rate to determine an end point of the test system, all the water evaporated in 6 h in finite model and in 8 h in infinite model. Both models showed that the cumulative permeation of the active compounds increased and a constant flux until 8 h after application; however, the flux decreased thereafter, indicating that the decreased flux depended on an end point of the test system. This indicated that our test system can analyze the permeation of the vitamin derivatives within 8 h before reaching the end point. CONCLUSION: Using an infinite model of this system, we assessed the cumulative permeation of vitamin derivatives within 8 h using a reconstructed skin model.

Retinol semisolid preparations in cosmetics: transcutaneous permeation mechanism and behaviour.

Retinol is widely used to treat skin ageing because of its effect on cell differentiation, proliferation and apoptosis. However, its potential benefits appear to be limited by its skin permeability. Herein, we investigated the transcutaneous behavior of retinol in semisolid cosmetics, in both in vitro and in vivo experiments. In vitro experiments used the modified Franz diffusion cell combined with Raman spectroscopy. In in vivo experiments, the content of retinol in rat skin and plasma was detected with HPLC. Retinol in semisolid cosmetics was mainly concentrated in the stratum corneum in the skin of the three animal models tested, and in any case did not cross the skin barrier after a 24 h dermatologic topical treatment in Franz diffusion cells tests. Similar results were obtained in live mice and rats, where retinol did not cross the skin barrier and did not enter the blood circulation. Raman spectroscopy was used to test the penetration depth of retinol in skin, which reached 16 µm out of 34 µm in pig skin, whereas the skin of mouse and rat showed too strong bakground interference. To explore epidermal transport mechanism and intradermal residence, skin transcriptomics was performed in rats, which identified 126 genes upregulated related to retinol transport and metabolism, relevant to the search terms "retinoid metabolic process" and "transporter activity". The identity of these upregulated genes suggests that the mechanism of retinol action is linked to epidermis, skin, tissue and epithelium development.