The state-of-the-art of atmospheric pressure plasma for transdermal drug delivery

Plasma-enhanced transdermal drug delivery(TDD) presents advantages over traditional methods,including painless application, minimal skin damage, and rapid recovery of permeability. To harness its clinical potential, factors related to plasma’s unique properties, such as reactive species and electric fields, must be carefully considered.This review provides a concise summary of conventional TDD methods and subsequently offers a comprehensive examination of the current state-of-the-art in plasma-enhanced TDD. This includes an analysis of the impact of plasma on HaCaT human keratinocyte cells, ex vivo/in vivo studies, and clinical research on plasma-assisted TDD. Moreover, the review explores the effects of plasma on skin physical characteristics such as microhole formation, transepidermal water loss(TEWL), molecular structure of the stratum corneum(SC), and skin resistance. Additionally, it discusses the involvement of various reactive agents in plasma-enhanced TDD, encompassing electric fields,charged particles, UV/VUV radiation, heat, and reactive species. Lastly, the review briefly addresses the temporal behavior of the skin after plasma treatment, safety considerations, and potential risks associated with plasma-enhanced TDD.

Ionic liquids as the effective technology for enhancing transdermal drug delivery: Design principles, roles, mechanisms, and future challenges

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs;as novel solvents for improving the solubility of drugs in carriers;as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs;and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structure-activity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs.

Advances in Transdermal Drug Delivery for Cancer Therapy

Transdermal drug delivery offers a promising alternative to traditional cancer therapies by providing a non-invasive,controlled,and targeted delivery of therapeutic agents.This paper explores the advancements,benefits,and challenges associated with transdermal drug delivery systems(TDDS)in cancer treatment.It highlights the mechanisms of action,key technologies,and the potential impact on patient outcomes.By examining recent studies and clinical trials,this paper aims to provide a comprehensive overview of the efficacy,safety,and prospects of transdermal drug delivery in oncology.

Characteristics and Transdermal Drug Delivery of Triamcinolone-Acetonide-Acetate-Loaded Solid Lipid Nanoparticles Carbomer Gel

Aim To prepare triamcinolone-acetonide-acetate (TAA)-loaded solid lipidnanoparticles (SLN) carbomer gel with tripalmitin glyceride (TPG), and investigate theircharacteristics and transdermal drug delivery. Methods SLN suspension was prepared by high-pressurehomogenization technique, and then mixed with carbomer gel matrix to get SLN gel. The morphology,particle size with polydispersi-ty index (PI) and zeta potential were examined by atomic forcemicroscopy (AFM) and photon correlation spectroscopy (PCS). The entrapment efficiency, stability andin vitro drug release were also studied. The transdermal drug delivery through porcine ear skin wasevaluated using modified Franz diffusion cells. Results The SLN had a spherical shape with theaverage size of (95.5 - 186.2) nm, the zeta potential of (-26.3- -15.7) mV and the entrapmentefficiency of 67.4%-90.3% for different TAA encapsulated compounds. TAA-SLN carbomer gel had goodstability, the release profile in vitro fitted Higuchi equation. In comparison with conventionalhydrogels, TAA-SLN carbomer gel resulted in higher drug permeation amount and drug deposition withinporcine ear skin after 24 h penetration experiment. Conclusion TAA-SLN carbomer gel is preparedwith stable physicochemical properties. The release profile and improved drug permeation into skinmake it be a promising vehicle for transdermal drug delivery.

Investigation of Microemulsion System for Transdermal Drug Delivery of Amphotericin B

In order to solve the drawback of poor bioavailability by the oral route and infusion-related side effect for Amphotericin B（AmB）, microemulsion vehicles composed of isopropyl myristate（IPM）, Tween 80, isopropyl alcohol and water for transdermal delivery of AraB were designed. The pseudo-ternary phase diagrams were constructed by the H2O titration method and the structures of the microemulsion were determined by measuring electrical conductivities（σ）. The diffusion studies of AmB microemulsion were performed via excised rabbit skin on a drug diffusion apparatus. To obtain a high solubization of AmB, three different methods were tested to incorporate AmB into microemulsion. The result suggests adding AmB in the shape of NaOH solution to the O/W blank microemulsion over the phase inversion temperature（PIT） of the emulsifier obtains the maximum drug content（2.96 mg/mL）. The pH value of the system could be adjusted to pH〉8.5 or pH〈5.2, in this range AraB molecules converts from aqueous to the hydrophilic shell of the microemulsion droplets, drug precipitate is no more than 5%, and the formulations were corresponding to the characterizations of microemulsion. At pH 5.14, AmB microemulsion with Km 1：1, O/SC 1：9（mass ratio of oil phase to surfactant/cosurfactant blend）, water content 64.6%, drug content （2.93±0.08） mg/mL, showed the maximum permeation rate （3.255 ±0.64） μg·cm^-2.h^-1 which is stable for a long time.

Transdermal Drug Delivery by Electroporation： The Effects of Surfactants on Pathway Lifetime and Drug Transport

Electroporation creates aqueous pathways by short high-voltage pulses resulting in a transient perme- abilization of stratum corneum and an increase in the transdermal delivery rate.However the aqueous pathways will reseal after pulsing,which leads to the rapid drop of transdermal flux.In the present study,the surfactants were added to the donor solution to hinder the shrinkage and resealing of the electropore,and to prolong the lifetime of the aqueous pathways with the consideration that the surfactants could reduce the surface energy of the electropore. These effects of surfactants were demonstrated by the dynamic electrical resistance of the skin and the fluorescent imaging of the local transport regions.Piroxicam(PIX)was transported percutaneously in the presence of surfac- tants in vitro.Owing to the longer lifetime of aqueous pathways,together with the promotion of PIX availability at the barrier exterior and the improvement in the partition of PIX into the aqueous pathways,the presence of surfac- tants led to a remarkable increase in the transdermal delivery rate during electroporation and a significant growth of the accumulative transdermal amount of PIX.

Ethosomes-Silk Fibroin/Polyvinyl Alcohol Composite Hydrogel Transdermal Drug Delivery System : Preparation and Characterization

One key of constructing ideal transdermal drug delivery system(TDDS)is enhancing the percutaneous rate of drugs without sacrificing compatibility.Ethosomes(Eths)have excellent transdermal performance as well as good biocompatibility,and thus been widely used as drug carrier.Hydrogel has good 3-dimensional mesh structure which is convenience for drugs release and storage.In this study,Eths were introduced into silk fibroin(SF)/polyvinyl alcohol(PVA)composite hydrogel to construct a novel TDDS through a green process.The Ethsomes(Eths)-SF/PVA composite hydrogel TDDS showed good mechanical properties(stress:(0.236±0.032)MPa;strain:(65.74±2.45)%).Also,skin fibroblasts can grow and proliferate well on this TDDS,indicating that this material has a good cytocompatibility.Furthermore,with doxorubicin hydrochloride(Dox)as a model drug loaded in ethosomes,in vitro studies showed that this TDDS was able to transdermally release Dox efficiently.Our data suggested this novel system had a good potential for application in TDD,though further evaluative study still needed to carry out.

Research progress on the application of microneedle transdermal drug delivery system in dermatology

Transdermal drug delivery systems(TDDs)have the advantages on good local targeting,controlled and sustainable drug delivery.Hoewever,the stratum corneum,as the main skin barrier,severely limits the transdermal penetration of drugs and reduces bioavailability,which also limits their application.Microneedles(MNS)penetrate the stratum corneum and create several reversible microchannels in a minimally invasive manner to significantly improve the penetration of therapeutic agents,and are considered a milestone for effective transdermal drug delivery.As an emerging drug delivery modality,microneedle transdermal drug delivery systems have the advantages of being minimally invasive,safe,efficient,economical and convenient.In addition to the extensive research on microneedles for improving transdermal drug delivery,there is a growing interest in using them to manage and treat dermatological conditions.Being the largest organ in the human body,the skin acts as a barrier between the body and the external environment,while having an immense influence on appearance and self-confidence.Indeed,there is now a considerable body of evidence on how dermatological conditions can lead to psychological problems and a reduced quality of life.The utilisation of microneedle transdermal drug delivery systems for the management and treatment of dermatological conditions is of great therapeutic and commercial value.The principleof microneedle transdermal drug delivery systems and the progress of its clinical application in dermatology are reviewed here.

Enhancement of Transdermal Drug Delivery by ns Q-swithed Nd:YAG Laser-induced Pressure Wave

A non-invasive laser enhancing transdermal drug delivery technique has been investigated. The second harmonic wavelength of 532 nm of a Q-Switched Nd:YAG laser with pulse duration of 15 ns was used to irradiate on a black polyethylene sheet covering on the surface of the drug solution, and hence produced pressure waves in the solution. Porcine skin and Rhodamine B were used as skin model and reagent respectively. Fluorescence microscope was employed to examine the mechanisms of drug delivery via the skin samples after laser treatment. The experiment revealed that the penetration depth of Rhodamine B under the illumination of laser increased with the energy density of the laser beam. After 20 laser shots at laser energy density of 70 mJ/cm2, the penetration depth reached 440 μm in 30 minutes, which was about three times as that without laser illumination. One possible explanation was that laser-induced pressure waves formed microchannels in the stratum corneum of the skin tissue. These microchannels provided much more effective paths for infiltration of Rhodamine B through the SC than follicular and intercellular paths. The drug solution diffused into the SC under the concentration gradient through the channels.

Ultrasound-mediated transdermal drug delivery of fluorescent nanoparticles and hyaluronic acid into porcine skin in vitro

Transdermal drug delivery （TDD） can effectively bypass the first-pass effect. In this paper, ultrasound-facilitated TDD on fresh porcine skin was studied under various acoustic parameters, including frequency, amplitude, and exposure time. The delivery of yellow-green fluorescent nanoparticles and high molecular weight hyaluronic acid （HA） in the skin samples was observed by laser confocal microscopy and ultraviolet spectrometry, respectively. The results showed that, with the application of ultrasound exposures, the permeability of the skin to these markers （e.g., their penetration depth and concentration） could be raised above its passive diffusion permeability. Moreover, ultrasound-facilitated TDD was also tested with/without the presence of ultrasound contrast agents （UCAs）. When the ultrasound was applied without UCAs, low ultrasound frequency will give a better drug delivery effect than high frequency, but the penetration depth was less likely to exceed 200 p.m. However, with the help of the ultrasound-induced microbubble cavitation effect, both the penetration depth and concentration in the skin were significantly enhanced even more. The best ultrasound-facilitated TDD could be achieved with a drug penetration depth of over 600 p.m, and the penetration concentrations of fluorescent nanoparticles and HA increased up to about 4-5 folds. In order to get better understanding of ultrasound-facilitated TDD, scanning electron microscopy was used to examine the surface morphology of skin samples, which showed that the skin structure changed greatly under the treatment of ultrasound and UCA. The present work suggests that, for TDD applications （e.g., nanoparticle drug carriers, transdermal patches and cosmetics）, protocols and methods presented in this paper are potentially useful.

Unlocking the potential of transdermal drug delivery

Transdermal drug delivery(TDD)has gained clinical approval over several decades,with extensive research dedicated to novel drug and device development.Despite notable research progress,the mar-ket adoption of TDD devices has not met anticipated levels,with oral administration and injection remaining predominant delivery meth-ods.To maximize the potential of TDD,we identify bottlenecks hinder-ing its widespread clinical application and propose promising research avenues.We begin by analyzing stringent demands necessary to truly benefit patients,addressing significant challenges in biomechanics,nanomedicine,and flexible electronics.Subsequently,we delve into skin anatomy,enhancement strategies,nano-carriers,and their under-lining mechanisms,highlighting the importance and framework of quantitative modeling.Based on these discussions,we highlight the core strength of TDD,such as automatic precise administration based on feedback and high delivery efficiencies,especially applicable to localized conditions(e.g.,central nervous system diseases,tumors).Finally,we envision the future of intelligent TDD device and its opera-tion scenario,aiming to steer research efforts toward faster translation of laboratory innovations into widely used products for sufferers.

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic,systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate.Several drugs have been used for the treatment of rheumatoid arthritis,but their use is limited by suboptimal bioavailability,serious adverse effects,and nonnegligible first-pass effects.In contrast,transdermal drug delivery systems(TDDSs)can avoid these drawbacks and improve patient compliance,making them a promising option for the treatment of rheumatoid arthritis(RA).Of course,TDDSs also face unique challenges,as the physiological barrier of the skin makes drug delivery somewhat limited.To overcome this barrier and maximize drug delivery efficiency,TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology,and different generations of TDDSs have been derived,which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery.In this review,we summarize the different generations of transdermal drug delivery systems,the corresponding transdermal strategies,and their applications in the treatment of RA.

Nano-formulations for transdermal drug delivery:A review

Transdermal drug delivery refers to a means of delivering drugs through the surface of the skin for local or systemic treatment. The drug functions after absorption through the skin into the systemic circulation via capillary action at a certain rate. Use of traditional physical and chemical enhancers to improve the transdermal permeation rate by increasing drug solubility, diffusion coefficient, and reservoir effect is not feasible owing to the toxic side effects of the overuse of chemical penetration enhancers. Nanoformulations generally vary in size and range from 10 nm to 100 nm. The smaller particle size leads to increased drug permeability, stability, retention, and targeting, making nano-formulations suitable for transdermal drug delivery. The different applications of nano-formulations(vesicles or nanoparticles and nanoemulsions) have been widely studied. Here, the classification, characteristics, transdermal mechanism, and application of the most popular nano-formulations in transdermal drug delivery system are reviewed.

Green Electrospun Silk Fibroin Nanofibers Loaded with Cationic Ethosomes for Transdermal Drug Delivery

Transdermal drug delivery system(TDDS)facilitates the controlled release of active ingredients penetrating through the skin,avoiding the liver first pass effect.Electrospinning is a simple process to fabricate ultrafine fibers with a higher specific surface area,making them excellent candidates for drug delivery.In current work,a novel silk fibroin(SF)nanofiber loaded with cationic ethosomes(CEs)was prepared via green electrospinning.The data of Fourier transform infrared spectroscopy(FTIR)and laser scanning confocal microscopy(LSCM)confirmed the existence of CEs in the SF nanofibers.The morphology of the nanofibers was not significantly affected by the incorporation of CEs as shown by scanning electron microscopy(SEM)images.The CEs-loaded SF nanofibrous patch(CEs-SFnP)showed good cytocompatibility as proved by both cell counting Kit-8(CCK-8)assay and SEM.Using doxorubicin hydrochloride(Dox)as a model drug,the transdermal performance of CEs-SFnP was evaluated through Franz diffusion cell against mouse skin.The results indicated that CEs-SFnP can effectively deliver drug into the skin,with a much higher permeation rate than the normal nanofibers without CEs.The as-spun CEs-SFnP in this study could find promising applications in TDDS.

Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery

Parenteral sustained release drug formulations, acting as preferable platforms for longterm exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.

Transdermal delivery of fluorescein isothiocyanate-dextrans using the combination of microneedles and low-frequency sonophoresis

This study aimed to evaluate the patient-friendly methods that are used in the delivery of hydrophilic macromolecules into deep skin layers,in particular,the combination of microneedles patch(MNs patch)and low-frequency sonophoresis(SN).The hydrophilic macromolecule drug fluorescein isothiocyanate(FITC)-dextrans(FD-4:MW 4.4 kDa)was used as the model drug in our experimental design.In this study,excised porcine skin was used to investigate and optimize the key parameters that determine effective MNs-and SNfacilitated FD-4 delivery.In vitro skin permeation experiments revealed that the combination of MNs patch with SN had a superior enhancing effect of skin permeation for FD-4 compared to MNs alone,SN alone or untreated skin,respectively.The optimal parameters for the combination of MNs and SN included the following:10 N insertion force of MNs,4 W/cm^(2)SN intensity,6 mm radiation diameter of the SN probe,2 min application time,and the continuous mode duty cycle of SN.In addition,vertical sections of skin,clearly observed under a confocal microscope,confirmed that the combination of MNs and SN enhanced permeation of FD-4 into the deep skin layers.These studies suggest that the combination of MNs and SN techniques could have great potential in the delivery of hydrophilic macromolecules into deep skin.

Characteristics and pharmacokinetics of tripterygium glycosides nano-carries transdermal delivery systems:skin-blood synchronous microdialysis and numerical simulation

The traditional Chinese medicine tripterygium glycosides(TPG)is used clinically to treat some Rheumatism,Eczema,immunosuppression and tumor,with the activities of hypnosis,antipyretic,analgesic,antiinflammatory,allergy and antitumor.However TPG has low water solubility and low skin permeability,so its clinical use is limited.Transdermal delivery systems can provide a controlled drug release rate that can keep constant concentrations of drug in the plasma for up to multiple days,improved patient compliance,and the possibility ofreducing the rate and severity of side effects.In this study,a fast and sensitive technique skin-blood two sites synchronous microdialysis coupled with LC-MS was used to study the pharmacokinetic parameter of three different formulations(TPG nanoemulsion,TPG nanoemulsion based gels and TPG gel).Creating a multilayer model,use the model to simulate the three formulations dynamics in transdermal-drug delivery system.The experiment results showed that the TPG nanoemulsion,TPG nanoemulsion based gels can significantly raise the drug concentrations in skin more than that of TPG gels.The numerical simulation results indicating that TPG gel and TPG nanoemulsion are close to practical measurements,only in the concentration increase phase the numerical simulation result has some difference with the experimental results.TPG nanoemulsion based gels have significant difference with the experimental results,both in concentration increase stage and concentration decreasing stage,but its trend was same.The study shows that the skin-blood synchronous microdialysis technique provided a new method for the pharmacokinetics study of nanocarriers transdermal delivery systems.In addition,the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery system.

Expert consensus of the Chinese Association for the Study of Pain on pain treatment with the transdermal patch

Chronic pain lasting more than 3 mo,or even several years can lead to disability.Treating chronic pain safely and effectively is a critical challenge faced by clinicians.Because administration of analgesics through oral,intravenous or intramuscular routes is not satisfactory,research toward percutaneous delivery has gained interest.The transdermal patch is one such percutaneous delivery system that can deliver drugs through the skin and capillaries at a certain rate to achieve a systemic or local therapeutic effect in the affected area.It has many advantages including ease of administration and hepatic first pass metabolism avoidance as well as controlling drug delivery,which reduces the dose frequency and side effects.If not required,then the patch can be removed from the skin immediately.The scopolamine patch was the first transdermal patch to be approved for the treatment of motion sickness by the Food and Drug Administration in 1979.From then on,the transdermal patch has been widely used to treat many diseases.To date,no guidelines or consensus are available on the use of analgesic drugs through transdermal delivery.The pain branch of the Chinese Medical Association,after meeting and discussing with experts and based on clinical evidence,developed a consensus for promoting and regulating standard use of transdermal patches containing analgesic drugs.

The enhancing effect and promoting mechanisms of the stereoisomeric monoterpene alcohol esters as enhancers for drugs with different physicochemical properties

To explore the structure-activity connections of amphiphilic permeation enhancers containing the length of the hydrophobic chains as well as the properties of the polar head,O-acylgeraniol and O-acylnerol derivatives were synthesized from geraniol/nerol(cis-isomer of geraniol) and pharmaceutical excipient acids in this research. Their promotion of the percutaneous absorption of three drugs as the model, flurbiprofen(FP), isosorbide dinitrate(ISDN) and donepezil(DNP), which were selected based on their physicochemical properties,was tested by in vitro skin penetration and in vivo. Molecular simulation, ATR-FTIR, CLSM and histological observation were implement to evaluate the mode of action of the enhancers.The results indicated that(E)-3,7-dimethyl-2,6-octadien-1-yl tetradecanoate(GER-C14, trans-)achieved the highest enhancement ability for the three drugs;additionally, the in vivo results obtained were in good correlation with the in vitro data. Molecular docking results suggested that enhancers loosen the hydrogen bonds between ceramides, and the results of molecular simulation indicated that GER-C14, NER-C14 could insert into the middle of the lipid bilayer to form an independent phase. According to ATR-FTIR and histological evaluation, the enhancers extracted lipids and influenced the protein region, thereby disturbing the skin array. In addition, CLSM described the dynamic effects of enhancers on lipids between stratum corneum(SC) cells. In conclusion, GER-C14 had a better penetration promotion effect, which broadened our understanding of stereoisomeric penetration enhancers.

Systematic Review and Meta-Analysis on the Effect of Transdermal Preparations of Sinomenium Acutum on Rheumatoid Arthritis

Objective:We evaluated the efficacy and safety of transdermal preparations of Sinomenium acutum(SA)for rheumatoid arthritis(RA).Methods:Randomized controlled trials(RCTs)of SA transdermal preparations for RA were extracted from relevant databases and screened in accordance with the inclusion criteria.The Cochrane System Evaluation Manual(version 5.1.0)was used to assess the quality of the included trials.We used the Cochrane Review Manager(version 5.4)to conduct the meta-analysis.Results:Six trials comprising 436 patients(220 patients in the treatment group and 216 patients in the control group)were analyzed.The meta-analysis indicated that SA transdermal preparations in combination with disease-modifying antirheumatic drugs(DMARDs)enhanced the overall effect(odds ratio[OR]3.97,95%confidence interval[CI][2.25,7.00],P<0.00001),decreased visual analogue scale(VAS)results(mean difference[MD]-0.64,95%CI[-1.20,-0.09],P=0.02),decreased laboratory indexes including the erythrocyte sedimentation rate(ESR)(MD-4.36,95%CI[-5.63,-3.08],P<0.00001)and C-reactive protein(CRP)(MD-3.6,95%CI[-3.99,-3.21,P<0.00001]),and decreased the Disease Activity Score-28(DAS28)(MD-0.41,95%CI[-0.78,-0.03],P=0.03).The results suggest that combination therapy did not shorten the duration of morning stiffness(DMS;standardized MD[SMD]-6.13,95%CI[-17.33,5.06],P=0.28)or reduce rheumatoid factor(RF)laboratory indexes(SMD-0.85;95%CI[-2.19,0.49],P=0.21).Only one study reported adverse reactions,and thus,it was difficult to determine whether adverse drug reactions in the combination therapy group were significantly different from those in the control group.Conclusion:We found that SA transdermal preparations combined with DMARDs may have greater clinical efficacy than DMARDs for RA.More well-designed and high-quality RCTs are required to verify the findings and determine whether transder-mal preparations cause fewer adverse events.