Transdermal Transport Research Articles

Construction and evaluation of transdermal delivery system of terbinafine-loaded plant exosomes for the treatment of cutaneous fungal infections

Local transdermal of antifungal agents is a problem that limits the effectiveness of clinical treatment of dermatomycosis. In this study, cucumber-derived plant extracellular vesicles (PEV) were extracted and loaded with the antifungal drug terbinafine (TBF) to form TBF-PEV, which was applied locally to the site of skin fungal infection to improve the transdermal transport capacity of TBF and the antifungal effect in vitro and in vivo. Chemical enhancer and physical enhancer methods were replaced by low immunogenicity and non-irritating PEV. TBF-PEV caused obvious curling and wrinkling in the skin, induced changes in the distribution of skin lipids, and changed the structure and content of skin lipids and proteins, thereby increasing the transdermal efficiency of TBF. The local drug concentration was increased, and the antifungal effect was improved in vitro and in vivo. It was first found that PEV inhibited the growth of Candida albicans with high efflux pump expression. In general, this paper has certain significance in local transdermal treatment of fungal skin infections and reversal of fungal resistance.

A wearable iontophoresis enables dual-responsive transdermal delivery for atopic dermatitis treatment

Atopic dermatitis is a chronic, inflammation skin disease that remains a major public health challenge. The current drug-loading hydrogel dressings offer numerous benefits with enhanced loading capacity and a moist-rich environment. However, their development is still limited by the accessibility of a suitable driven source outside the clinical environment for precise control over transdermal delivery kinetics. Here, we prepare a sulfonated poly(3,4-ethylenedioxythiophene) (PEDOT) polyelectrolyte hydrogel drug reservoir that responds to different stimuli-both endogenous cue (body temperature) and exogenous cue (electrical stimulation), for wearable on-demand transdermal delivery with enhanced efficacy. Functioned as both the drug reservoir and cathode in a Zn battery-powered iontophoresis patch, this dual-responsive hydrogel achieves high drug release efficiency (68.4 %) at 37 °C. Evaluation in hairless mouse skin demonstrates the efficacy of this technology by facilitating transdermal transport of 12.2 μg cm−2 dexamethasone phosphate when discharged with a 103 Ω external resistor for 3 h. The Zn battery-driven iontophoresis results in an effective treatment of atopic dermatitis, displaying reductions in epidermal thickness, mast cell infiltration inhibition, and a decrease in IgE levels. This work provides a new treatment modality for chronic epidermal diseases that require precise drug delivery in a non-invasive way.

Flexible surface acoustic wave technology for enhancing transdermal drug delivery.

Transdermal drug delivery provides therapeutic benefits over enteric or injection delivery because its transdermal routes provide more consistent concentrations of drug and avoid issues of drugs affecting kidneys and liver functions. Many technologies have been evaluated to enhance drug delivery through the relatively impervious epidermal layer of the skin. However, precise delivery of large hydrophilic molecules is still a great challenge even though microneedles or other energized (such as electrical, thermal, or ultrasonic) patches have been used, which are often difficult to be integrated into small wearable devices. This study developed a flexible surface acoustic wave (SAW) patch platform to facilitate transdermal delivery of macromolecules with fluorescein isothiocyanates up to 2000kDa. Two surrogates of human skin were used to evaluate SAW based energized devices, i.e., delivering dextran through agarose gels and across stratum corneum of pig skin into the epidermis. Results showed that the 2000kDa fluorescent molecules have been delivered up to 1.1mm in agarose gel, and the fluorescent molecules from 4 to 2000kDa have been delivered up to 100µm and 25µm in porcine skin tissue, respectively. Mechanical agitation, localised streaming, and acousto-thermal effect generated on the skin surface were identified as the main mechanisms for promoting drug transdermal transportation, although micro/nanoscale acoustic cavitation induced by SAWs could also have its contribution. SAW enhanced transdermal drug delivery is dependent on the combined effects of wave frequency and intensity, duration of applied acoustic waves, temperature, and drug molecules molecular weights.

Synergistic Strategies of Biomolecular Transport Technologies in Transdermal Healthcare Systems.

Transdermal healthcare systems have gained significant attention for their painless and convenient drug administration, as well as their ability to detect biomarkers promptly. However, the skin barrier limits the candidates of biomolecules that can be transported, and reliance on simple diffusion poses a bottleneck for personalized diagnosis and treatment. Consequently, recent advancements in transdermal transport technologies have evolved toward active methods based on external energy sources. Multiple combinations of these technologies have also shown promise for increasing therapeutic effectiveness and diagnostic accuracy as delivery efficiency is maximized. Furthermore, wearable healthcare platforms are being developed in diverse aspects for patient convenience, safety, and on-demand treatment. Herein, a comprehensive overview of active transdermal delivery technologies is provided, highlighting the combination-based diagnostics, therapeutics, and theragnostics, along with the latest trends in platform advancements. This offers insights into the potential applications of next-generation wearable transdermal medical devices for personalized autonomous healthcare.

Ambient Moisture-Driven Self-Powered Iontophoresis Patch for Enhanced Transdermal Drug Delivery.

Iontophoretic transdermal drug delivery (TDD) devices are known to enhance the transdermal transport of drugs. However, conventional transdermal iontophoretic devices require external power sources, wired connections, or mechanical parts, which reduce the comfort level for patients during extended use. In this work, a self-powered, wearable transdermal iontophoretic patch (TIP) is proposed by harvesting ambient humidity for energy generation, enabling controlled TDD. This patch primarily uses moist-electric generators (MEGs) as its power source, thus obviating the need for complex power management modules and mechanical components. A single MEG unit can produce an open-circuit voltage of 0.80V and a short-circuit current of 11.65µA under the condition of 80% relative humidity. Amplification of the electrical output is feasible by connecting multiple generator units in series and parallel, facilitating the powering of certain commercial electronic devices. Subsequently, the MEG array is integrated with the TDD circuit to create the wearable TIP. After 20 min of application, the depth of drug penetration through the skin is observed to increase threefold. The effective promotion effect of TIP on the transdermal delivery of ionized drugs is corroborated by simulations and experiments. This wearable TIP offers a simple, noninvasive solution for TDD.

Microneedles Based on a Biodegradable Polymer-Hyaluronic Acid.

Transdermal transport can be challenging due to the difficulty in diffusing active substances through the outermost layer of the epidermis, as the primary function of the skin is to protect against the entry of exogenous compounds into the body. In addition, penetration of the epidermis for substances hydrophilic in nature and particles larger than 500 Da is highly limited due to the physiological properties and non-polar nature of its outermost layer, namely the stratum corneum. A solution to this problem can be the use of microneedles, which "bypass" the problematic epidermal layer by dispensing the active substance directly into the deeper layers of the skin. Microneedles can be obtained with various materials and come in different types. Of special interest are carriers based on biodegradable and biocompatible polymers, such as polysaccharides. Therefore, this paper reviews the latest literature on methods to obtain hyaluronic acid-based microneedles. It focuses on the current advancements in this field and consequently provides an opportunity to guide future research in this area.

Transdermal drug delivery mediated by acoustic vortex beam

Ultrasound-mediated transdermal drug delivery exhibits various advantages such as biocompatibility, controllability and safety, which attracts plenty of interests within biomedical field. Current researches mostly emphasizes the acoustic cavitation generated by planar or focused waves while neglecting other physics that occur during transportation. Our experimental study illustrates the presence of an acoustic vortex (AV) beam that exhibits a lower acoustic intensity and typically means a lower dose of inertial cavitation, yet achieves a more efficient delivery. Such a result calls for the fundamental mechanism of ultrasound-mediated transdermal transfer using the AV beam. In this work, according to our knowledge, the AV beam is firstly introduced to ultrasound-mediated transdermal medication delivery. The transversal acoustic radiation force (T-ARF), which is the primary characteristic carried by the acoustic vortex beam, and its contribution to the transport enhancement are investigated. It is shown that a focused AV (FAV) beam with a maximal acoustic pressure of 200 kPa induces a pN-level T-ARF, which promotes the enlargement of pores on the stratum corneum and thereby enhances the permeability, as compared with a zero-order (non-vortex) counterpart. This contribution of the T-ARF is validated by the experimental transport on the cellulose membrane, which exhibits a significantly increased membrane porosity and delivery efficiency. The favorable results introduce the new degree of freedom into the ultrasound-mediated transdermal drug transport based on AV beam, and thereby promotes the development of a combined control strategy for more precise and efficient transdermal drug delivery in conjunction with the administration of acoustic cavitation.

Phonophoresis in Physiotherapy: Mechanisms, Applications, and Emerging Trends for Enhanced Drug Delivery and Therapeutic Efficacy

Phonophoresis, a widely utilized treatment in physiotherapy, combines topically applied gel or cream-based medications with ultrasonic therapy to enhance percutaneous absorption of pharmacological agents. The procedure employs ultrasound frequencies of 0.7 to 1.1 MHz with intensities ranging from 0.0 to 3.0 Watts per cm². Indications for phonophoresis span various inflammatory, deformative, dermatological, and rheumatic/neurological conditions. Recent studies suggest its clinical efficacy in pain relief and improved function, especially in conditions like lateral epicondylitis and osteoarthritis. The mechanism of action involves both thermal and non-thermal effects, with cavitation playing a key role in enhancing transdermal transport. Phonophoresis offers a non-invasive alternative for drug delivery, bypassing hepatic metabolism and minimizing systemic side effects. Various medicinal gels, particularly diclofenac, are used for transdermal drug delivery through phonophoresis. Low frequency phonophoresis has gained attention for enhancing transdermal transport, especially for macromolecules. Its applications extend beyond physiotherapy to include ocular drug delivery, nail therapy, gene therapy, and sports sciences. Clinical studies demonstrate the effectiveness of phonophoresis in conditions like anterior knee pain, tuberculous lymphadenitis, acute low back pain, and latent myofascial trigger points. Dosage considerations emphasize optimizing thermal effects without causing tissue damage. Studies highlight the potential of phonophoresis in relieving pain and improving function, particularly in knee osteoarthritis. Additionally, phonophoresis with Phyllanthus amarus nanoparticle gel shows promise in reducing pain and enhancing functional capacity in symptomatic knee osteoarthritis. In summary, phonophoresis stands as a valuable modality in physiotherapy, showcasing diverse applications and demonstrating clinical efficacy in various musculoskeletal and inflammatory conditions. Further research is warranted to explore its full potential and optimize treatment protocols.

A novel anti-pruritic: Topical co-administration of high molecular weight hyaluronan (HMWH) with protamine, a transdermal transport enhancer.

Pruritis, the sensation of itch, is produced by multiple substances, exogenous and endogenous, that sensitizes specialized sensory neurons (pruriceptors and pruri-nociceptors). Unfortunately, many patients with acute and chronic pruritis obtain only partial relief when treated with currently available treatment modalities. We recently demonstrated that the topical application of high molecular weight hyaluronan (HMWH), when combined with vehicles containing transdermal transport enhancers, produce potent long-lasting reversal of nociceptor sensitization associated with inflammatory and neuropathic pain. In the present experiments we tested the hypothesis that the topical formulation of HMWH with protamine, a transdermal transport enhancer, can also attenuate pruritis. We report that this topical formulation of HMWH markedly attenuates scratching behavior at the nape of the neck induced by serotonin (5-hydroxytryptamine, 5-HT), in male and female rats. Our results support the hypothesis that topical HMWH in a transdermal transport enhancer vehicle is a strong anti-pruritic.

Assessing the Influence of a Rotating Magnetic Field on Ibuprofen Permeability from Diverse Pharmaceutical Formulations

This study introduces a novel approach for enhancing the transdermal permeability of ibuprofen through the skin by utilising a rotating magnetic field (RMF). The core objective is to systematically evaluate the influence of a 50 Hz RMF on ibuprofen’s skin permeability across various formulation types, each employing distinct physical forms and excipients. The experimental setup involved Franz cells with skin as the membrane, exposed to a 50 Hz RMF in conjunction with specific formulations. Subsequent comprehensive analysis revealed a notable increase in the transdermal transport of ibuprofen, irrespective of the formulation employed. Notably, the differences in the initial 30 min of permeation were particularly pronounced. Crucially, this investigation establishes that the application of a 50 Hz RMF resulted in a remarkable over-sevenfold increase in ibuprofen permeability compared to the control group without RMF exposure. It is noteworthy that in all semi-solid pharmaceutical formulations tested, RMF effectively reduced the delay time to zero, underscoring the efficiency of RMF in overcoming barriers to transdermal drug delivery. This research positions the application of RMF as a highly promising and innovative technology, significantly enhancing the transdermal penetration of anti-inflammatory and analgesic drugs through the skin. The demonstrated effectiveness of RMF across diverse formulations suggests its potential in transdermal drug delivery, offering a novel and efficient strategy for improving therapeutic outcomes in the administration of ibuprofen and potentially other pharmaceutical agents.

Transcutaneous Immunotherapy for RNAi: A Cascade-Responsive Decomposable Nanocomplex Based on Polyphenol-Mediated Framework Nucleic Acid in Psoriasis.

Skin is the first barrier against external threats, and skin immune dysfunction leads to multiple diseases. Psoriasis is an inflammatory, chronic, common, immune-related skin disease that affects more than 125 million people worldwide. RNA interference (RNAi) therapy is superior to traditional therapies, but rapid degradation and poor cell uptake are the greatest obstacles to its clinical transformation. The transdermal delivery of siRNA and controllable assembly/disassembly of nanodrug delivery systems can maximize the therapeutic effect. Tetrahedral framework nucleic acid (tFNA) is undoubtedly the best carrier for the transdermal transport of genes due to its excellent noninvasive transdermal effect and editability. The authors combine acid-responsive tannic acid (TA), RNase H-responsive sequences, siRNA, and tFNA into a novel transdermal RNAi drug with controllable assembly and disassembly: STT. STT has heightened resistance to enzyme, serum, and lysosomal degradation, and its size is similar to that of tFNA, enabling easy transdermal transport. After transdermal administration, STT can specifically silence nuclear factor kappa-B (NF-κB) p65, thereby maintaining the stability of the skin's microenvironment and reshaping normal skin immune defense. This work demonstrates the advantages of STT in RNAi therapy and the potential for future treatment of skin-related diseases.

Uncertainty Quantification in Estimating Blood Alcohol Concentration From Transdermal Alcohol Level With Physics-Informed Neural Networks.

We develop an approach to estimate a blood alcohol signal from a transdermal alcohol signal using physics-informed neural networks (PINNs). Specifically, we use a generative adversarial network (GAN) with a residual-augmented loss function to estimate the distribution of unknown parameters in a diffusion equation model for transdermal transport of alcohol in the human body. We design another PINN for the deconvolution of the blood alcohol signal from the transdermal alcohol signal. Based on the distribution of the unknown parameters, this network is able to estimate the blood alcohol signal and quantify the uncertainty in the form of conservative error bands. Finally, we show how a posterior latent variable can be used to sharpen these conservative error bands. We apply the techniques to an extensive dataset of drinking episodes and demonstrate the advantages and shortcomings of this approach.

Bioderived Mesoporous Carbon@Tungsten Oxide Nanocomposite as a Drug Carrier Vehicle of Doxorubicin for Potent Cancer Therapy.

Scientists have investigated the possibility of employing nanomaterials as drug carriers. These nanomaterials can preserve their content and transport it to the target region in the body. In this investigation, we proposed a simple method for developing distinctive, bioderived nanostructures with mesoporous carbon nanoparticles impregnated with tungsten oxide (WO3). Prior to characterizing and encapsulating WO3 with bioderived mesoporous carbon, the anticancer drug doxorubicin (DOX) was added to the nanoparticles and examined loading and release study. The approaches for both nanoparticle production and characterization are discussed in detail. Colloidal qualities of the nanomaterial can be effectively preserved while also allowing transdermal transportation of nanoparticles into the body by forming them into green, reusable, and porous nanostructures. Although the theories of nanoparticles and bioderived carbon each have been studied separately, the combination presents a new route to applications connected to nanomedicine. Furthermore, this sample was used to study exotic biomedical applications, such as antioxidant, antimicrobial, and anticancer activities. The W-3 sample had lower antioxidant activity (44.01%) than the C@W sample (56.34%), which was the most potent. A high DOX entrapment effectiveness of 97% was eventually achieved by the C@W sample, compared to a pure WO3 entrapment efficiency of 91%. It was observed that the Carbon/WO3 composite (C@W) sample showed more efficacy because the mesoporous carbon composition with WO3 increases the average surface area and surface-active locations.

Understanding Drug Skin Permeation Enhancers Using Molecular Dynamics Simulations.

Our skin constitutes an effective permeability barrier that protects the body from exogenous substances but concomitantly severely limits the number of pharmaceutical drugs that can be delivered transdermally. In topical formulation design, chemical permeation enhancers (PEs) are used to increase drug skin permeability. In vitro skin permeability experiments can measure net effects of PEs on transdermal drug transport, but they cannot explain the molecular mechanisms of interactions between drugs, permeation enhancers, and skin structure, which limits the possibility to rationally design better new drug formulations. Here we investigate the effect of the PEs water, lauric acid, geraniol, stearic acid, thymol, ethanol, oleic acid, and eucalyptol on the transdermal transport of metronidazole, caffeine, and naproxen. We use atomistic molecular dynamics (MD) simulations in combination with developed molecular models to calculate the free energy difference between 11 PE-containing formulations and the skin's barrier structure. We then utilize the results to calculate the final concentration of PEs in skin. We obtain an RMSE of 0.58 log units for calculated partition coefficients from water into the barrier structure. We then use the modified PE-containing barrier structure to calculate the PEs' permeability enhancement ratios (ERs) on transdermal metronidazole, caffeine, and naproxen transport and compare with the results obtained from in vitro experiments. We show that MD simulations are able to reproduce rankings based on ERs. However, strict quantitative correlation with experimental data needs further refinement, which is complicated by significant deviations between different measurements. Finally, we propose a model for how to use calculations of the potential of mean force of drugs across the skin's barrier structure in a topical formulation design.

Estimation of the Controlled Release of Antioxidants from β-Cyclodextrin/Chamomile (Matricaria chamomilla L.) or Milk Thistle (Silybum marianum L.), Asteraceae, Hydrophilic Extract Complexes through the Fast and Cheap Spectrophotometric Technique.

This is the first study on the modeling of the controlled release of the estimated antioxidants (flavonoids or flavonolignans) from β-cyclodextrin (β-CD)/hydrophilic vegetable extract complexes and the modeling of transdermal pharmaceutical formulations based on these complexes using an overall estimation by the spectrophotometric method. The Korsmeyer-Peppas model was chosen for evaluating the release mechanisms. β-CD/chamomile (Matricaria chamomilla L., Asteraceae) ethanolic extract and β-CD/milk thistle (Silybum marianum L., Asteraceae) ethanolic extract complexes were obtained by the co-crystallization method with good recovering yields of 55-76%, slightly lower than for β-CD/silibinin or silymarin complexes (~87%). According to differential scanning calorimetry (DSC) and Karl Fischer water titration (KFT), the thermal stability of complexes is similar to β-CD hydrate while the hydration water content is lower, revealing the formation of molecular inclusion complexes. In the Korsmeyer-Peppas model, β-CD/M. chamomilla flower extract complexes reveal Case II transport mechanisms, while the corresponding complexes with leaf extracts indicate non-Fickian diffusion for the controlled release of antioxidants in ethanol 60 and 96%. The same non-Fickian diffusion was revealed by β-CD/S. marianum extract and β-CD/silibinin complexes. On the contrary, almost all model transdermal pharmaceutical formulations based on β-CD/M. chamomilla extract complexes and all those based on β-CD/S. marianum extract complexes revealed non-Fickian diffusion for the antioxidant release. These results indicate that H-bonding is mainly involved in the diffusion of antioxidants into a β-CD based matrix, while the controlled release of antioxidants in model formulations is mainly due to hydrophobic interactions. Results obtained in this study can be further used for studying the particular antioxidants (namely rutin or silibinin, quantified, for example, by liquid chromatographic techniques) for their transdermal transport and biological effects in innovatively designed pharmaceutical formulations that can be obtained using "green" methods and materials.

Mathematical modeling of anomalous diffusive behavior in transdermal drug-delivery including time-delayed flux concept

Molecular transport through a composite multilayer membrane is a central process in transdermal drug delivery (TDD). Classical Fickean approach treats skin as a pseudo-homogenous membrane, while in reality skin is highly heterogeneous system as shown in basic physiological research. Particle transport across such systems shows anomalous diffusive behavior that is described by fractional models. These models don't consider experimentally observed dependence of particle transport nature on time scale. The possible way of inclusion of that observation in model of transdermal transport is presented in this paper. The generalized fractional models of the spectral functions of the concentration profile and the cumulative amount of the drug absorbed through the bloodstream are derived. The derived model predicts resonances in concentration profile and larger cumulative amount of the drug in both the short-time limit and the long-time limit, which can have significant physiological implications.

Oral Ionic Liquid for Transdermal Delivery and Obesity Treatment.

Obesity is currently a prerequisite for more than 70% of adults, including chronic obesity and long-term obesity. With the increase of diabetes patients in the world, it is urgent to develop effective oral drugs to replace insulin. However, the gastrointestinal tract is a main obstacle to oral drug preparations. Here, a highly effective oral drug was developed, mainly formulated as an ionic liquid (IL) prepared by l-(-)-carnitine and geranic acid. Density functional theory (DFT) calculations showed that l-(-)-carnitine and geranic acid can exist stably through hydrogen bonding. IL can significantly enhance the transdermal transport of drugs. In vitro study of intestinal permeability showed that particles formed by IL can prevent the absorption of intestinal fat. Compared with the control group, oral administration of IL (10 mL kg-1) significantly reduced blood glucose, white adipose tissue in the liver and epididymis, and the expression of SREBP-1c and ACC in IL. Therefore, these results and high-throughput sequencing analysis showed that IL can effectively reduce the intestinal absorption of adipose tissue to reduce blood glucose. IL has good biocompatibility and stability. Therefore, IL has a certain application value in the field of oral drug-delivery carriers, which provides an effective means for the treatment of diabetes and is a potential tool to solve the epidemic of obesity.

A Conformable Ultrasound Patch for Cavitation-Enhanced Transdermal Cosmeceutical Delivery.

Increased consumer interest in healthy-looking skin demands a safe and effective method to increase transdermal absorption of innovative therapeutic cosmeceuticals. However, permeation of small-molecule drugs is limited by the innate barrier function of the stratum corneum. Here, a conformable ultrasound patch (cUSP) that enhances transdermal transport of niacinamide by inducing intermediate-frequency sonophoresis in the fluid coupling medium between the patch and the skin is reported. The cUSP consists of piezoelectric transducers embedded in a soft elastomer to create localized cavitation pockets (0.8 cm2 , 1mm deep) over larger areas of conformal contact (20 cm2 ). Multiphysics simulation models, acoustic spectrum analysis, and high-speed videography are used to characterize transducer deflection, acoustic pressure fields, and resulting cavitation bubble dynamics in the coupling medium. The final system demonstrates a 26.2-fold enhancement in niacinamide transport in a porcine model in vitro with a 10 min ultrasound application, demonstrating the suitability of the device for short-exposure, large-area application of sonophoresis for patients and consumers suffering from skin conditions and premature skin aging.

Skin models of cutaneous toxicity, transdermal transport and wound repair.

Skin is widely used as a drug delivery route due to its easy access and the possibility of using relatively painless methods for the administration of bioactive molecules. However, the barrier properties of the skin, along with its multilayer structure, impose severe restrictions on drug transport and bioavailability. Thus, bioengineered models aimed at emulating the skin have been developed not only for optimizing the transdermal transport of different drugs and testing the safety and toxicity of substances but also for understanding the biological processes behind skin wounds. Even though in vivo research is often preferred to study biological processes involving the skin, in vitro and ex vivo strategies have been gaining increasing relevance in recent years. Indeed, there is a noticeably increasing adoption of in vitro and ex vivo methods by internationally accepted guidelines. Furthermore, microfluidic organ-on-a-chip devices are nowadays emerging as valuable tools for functional and behavioural skin emulation. Challenges in miniaturization, automation and reliability still need to be addressed in order to create skin models that can predict skin behaviour in a robust, high-throughput manner, while being compliant with regulatory issues, standards and guidelines. In this review, skin models for transdermal transport, wound repair and cutaneous toxicity will be discussed with a focus on high-throughput strategies. Novel microfluidic strategies driven by advancements in microfabrication technologies will also be revised as a way to improve the efficiency of existing models, both in terms of complexity and throughput.

The Impact of Water on Choline‐2‐Octenoic Ionic Liquid‐Facilitated Transdermal Transport (Adv. Therap. 1/2023)

The Impact of Water on Choline‐2‐Octenoic Ionic Liquid‐Facilitated Transdermal Transport (Adv. Therap. 1/2023)