A Hollow Microneedle Equipped with a Micropillar for Improved Needle Insertion and Injection of Drug Solution.

PURPOSE: Hollow-type microneedles (hMNs) are a promising device for the effective administration of drugs into intradermal sites. Complete insertion of the needle into the skin and administration of the drug solution without leakage must be achieved to obtain bioavailability or a constant effect. In the present study, several types of hMN with or without a rounded blunt tip micropillar, which suppresses skin deformation, around a hollow needle, and the effect on successful needle insertion and administration of a drug solution was investigated. Six different types of hMNs with needle lengths of 1000, 1300, and 1500 µm with or without a micropillar were used. METHODS: Needle insertion and the disposition of a drug in rat skin were investigated. In addition, the displacement-force profile during application of hMNs was also investigated using a texture analyzer with an artificial membrane to examine needle factors affecting successful insertion and administration of a drug solution by comparing with in vivo results. RESULTS: According to the results with the drug distribution of iodine, hMN1300 with a micropillar was able to successfully inject drug solution into an intradermal site with a high success rate. In addition, the results of displacement-force profiles with an artificial membrane showed that a micropillar can be effective for depth control of the injected solution as well as the prevention of contact between the hMN pedestal and the deformed membrane. CONCLUSION: In the present study, hMN1300S showed effective solution delivery into an intradermal site. In particular, a micropillar can be effective for depth control of the injected solution as well as preventing contact between the hMN pedestal and the deformed membrane. The obtained results will help in the design and development of hMNs that ensure successful injection of an administered drug.

Development of an Auraptene-Loaded Transdermal Formulation Using Non-ionic Sugar Ester Surfactants.

Auraptene (Aur) is a naturally occurring monoterpene coumarin ether that exhibits numerous therapeutic properties. Its high lipophilicity and low skin penetration, however, limit its potential application for local and transdermal delivery. Biocompatible non-ionic sugar esters (SEs) possess beneficial properties for the development of transdermal formulations in delivering pharmaceutically challenging molecules such as graphene and Aur. In the present study, we conducted a series of experiments to demonstrate the effect of several previously unstudied SEs on the skin permeation and distribution of Aur by preparing gel- and dispersion-type formulations. Skin permeation and deposition experiments were conducted using a Franz diffusion cell with rat skin as the membrane. The dispersion-type formulations prepared using SEs had higher entrapment efficiency, as well as better skin permeation and retention profiles. The dispersion-type formulation containing sucrose palmitate (sSP) exhibited the highest skin permeation over 8 h. Notably, the enhancement effects on Aur concentration in full-thickness skin after the application of the dispersion-type formulation was higher than those of the control formulation. These results indicated that the prepared formulation has potential for use in the transdermal delivery of Aur in pharmaceutical and cosmetic products.

Enhanced Physical Stability of L-Ascorbic Acid in an Ionic Liquid.

Ionic liquid (IL) technology was used to enhance the stability of L-ascorbic acid (AA). Pyridoxine was selected as the counter cation for anionic AA in IL. After AA was dissolved in water at 40 °C, its ratio decreased to 3.2% after 7 d. In contrast, the IL formulation showed negligible degradation, with almost no loss of AA even after 28 d. These results suggest that the use of IL enhances the stability of AA.

Design of Ionic Liquid Formulations with Azone-Mimic Structures for Enhanced Drug Skin Permeation.

Although laurocapram (Azone) significantly enhances the skin permeation of drugs, its development was hindered by its skin irritation. We then developed an Azone-mimic ionic liquid (IL-Azone), composed of less irritating cationic ε-caprolactam and anionic myristic acid. IL-Azone dissociates to the original cation and anion in the presence of water in the formulation. We tried to select a formulation suitable for IL-Azone in the present study. Each formulation contained 5 % of either Azone or IL-Azone along with the model drug antipyrine, and skin permeation experiments of the drug were conducted. The results revealed that IL-Azone did not enhance skin permeation when combined with most formulations tested. However, a notable and rapid enhancement in skin permeation was observed when combined with white petrolatum. This effect could be attributed to the minimal water content in white petrolatum, which prevented IL-Azone degradation. Furthermore, its permeation-enhancing effects from IL-Azone in white petrolatum were more pronounced and rapid than Azone. The rapid onset observed with IL-Azone can be attributed to its degradation into its original components at the interface between the stratum corneum and the living epidermis, which results in a shorter lag time before achieving a steady-state concentration in the SC compared to Azone.

Viscoelasticity of Liposomal Dispersions.

Janus-faced viscoelastic gelling agents-possessing both elastic and viscous characteristics-provide materials with unique features including strengthening ability under stress and a liquid-like character with lower viscosities under relaxed conditions. The mentioned multifunctional character is manifested in several body fluids such as human tears, synovial liquids, skin tissues and mucins, endowing the fluids with a special physical resistance property that can be analyzed by dynamic oscillatory rheology. Therefore, during the development of pharmaceutical or cosmetical formulations-with the intention of mimicking the physiological conditions-rheological studies on viscoelasticity are strongly recommended and the selection of viscoelastic preparations is highlighted. In our study, we aimed to determine the viscoelasticity of various liposomal dispersions. We intended to evaluate the impact of lipid concentration, the presence of cholesterol or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the gelling agents polyvinyl alcohol (PVA) and hydroxyethylcellulose (HEC) on the viscoelasticity of vesicular systems. Furthermore, the effect of two model drugs (phenyl salicylate and caffeine) on the viscoelastic behavior of liposomal systems was studied. Based on our measurements, the oscillation rheological properties of the liposomal formulations were influenced both by the composition and the lamellarity/size of the lipid vesicles.

Effects of Intradermal Administration Volume Using a Hollow Microneedle on the Pharmacokinetics of Fluorescein Isothiocyanate Dextran (M.W. 4,000).

PURPOSE: Hollow microneedles (hMNs) have been gaining attention as a tool to enable the intradermal (i.d.) administration of pharmaceutical products. However, few reports have examined the effect of administration volume on distribution in the skin and pharmacokinetics parameters after i.d. injection. In the present study, a model middle molecular weight compound, fluorescein isothiocyanate dextran (M.W. 4,000, FD-4), was selected, and blood concentration-time profiles after i.d. and subcutaneous (s.c.) injections with different administration volumes were compared. METHODS: FD-4 solution was injected i.d. using a hMN or injected s.c. with a 27 G needle. Pharmacokinetics and dermatokinetics of FD-4 were analyzed using a compartment model. The skin distribution of iodine, as an X ray tracer, was used to evaluate drug disposition. RESULTS: With the administered drug assumed to be absorbed from the broad injection site into blood vessels in the upper and lower dermis by rapid (krapid) and slow (kslow) first-order absorption rate constants, respectively, better agreement of observed and theoretical values was obtained. Furthermore, the fraction, F, of the administered dose absorbed with krapid decreased with the increase in injection volume after i.d. injection, although the pharmacokinetics parameters were almost the same regardless of administration volume after s.c. injection. CONCLUSION: The drug distribution in the skin may be related to the obtained pharmacokinetics parameters suggested that the number of needles in the MN system and the total administration volume should be considered in designing hMN systems. The present results provide useful information that may support effective drug delivery with hMNs.

Prediction of Critical Quality Attributes Based on the Numerical Simulation of Stress and Strain Distributions in Pharmaceutical Tablets.

Various stresses and strains are generated on the surface and inside of pharmaceutical tablets when an external force is applied. In addition, stresses in various directions can remain on the surface and inside the tablets because they are generally prepared by compaction of pharmaceutical powders using dies and punches. As it is difficult to measure the stress and strain generation in the tablets experimentally, a numerical simulation was applied by employing a finite element method (FEM). An elastic model is often used to represent stress and strain generation after loading an external force to tablets, and the Drucker-Prager cap (DPC) model has been widely recognized for representing the remaining stress distributions during the compaction of powder to tablet form. Firstly, this article describes an FEM simulation of the stress generation on the surface of the scored tablets after loading the bending force from the back side of the tablets. Next, the FEM simulation was introduced to determine the effect of diametrical compression on the stress and strain generation in the tablets by comparing the results measured experimentally. Furthermore, the residual stresses remaining inside the tablets were simulated using FEM, in which powder compaction was represented as the DPC model. A clear difference was observed in the residual stress distributions between the flat and convex tablets. This indicates that FEM simulation is useful for achieving a science-based understanding of critical quality attributes in various types of tablets.

Design of an Ante-enhancer with an Azone-Mimic Structure using Ionic Liquid.

PURPOSE: Laurocapram (Azone) was broadly examined as a representative enhancer of skin penetration in the 1980s. However, it was not approved for treatment because it caused skin irritation following its penetration into the epidermis through the stratum corneum. In the present study, a so-called ante-enhancer with an Azone-mimic structure was designed based on an ante-drug with negligible systemic toxic effects following its permeation through the skin. METHODS: The ante-enhancer was designed using ionic liquid technology: an ionic liquid-type ante-enhancer (IL-Azone) with an Azone-mimic structure was prepared from ε-caprolactam and myristic acid as cationic and anionic substances, respectively. The enhancing effects of IL-Azone on the permeation by the following model drugs through pig skin were examined: isosorbide 5-mononitrate (ISMN), antipyrine (ANP), and fluorescein isothiocyanate dextran (FD-4). Skin irritation by IL-Azone was assessed using the Draize method. RESULTS: The primary irritation index (P.I.I.) of IL-Azone by the Draize method was markedly lower than that of Azone (6.9). Although the ability of IL-Azone to enhance skin penetration was not as high as Azone, IL-Azone moderately increased skin permeation by the model compounds tested (ISMN: 4.7 fold, ANP: 4.5 fold, FD-4: 4.0 fold). CONCLUSIONS: These results suggest the usefulness of designing a skin penetration enhancer using ionic liquid technology. Further trials on the ionic liquid design with an Azone-mimic structure using other cations and anions may lead to the development of better ante-enhancers.

Gene knockdown in HaCaT cells by small interfering RNAs entrapped in grapefruit-derived extracellular vesicles using a microfluidic device.

Small interfering RNAs (siRNAs) knockdown the expression of target genes by causing mRNA degradation and are a promising therapeutic modality. In clinical practice, lipid nanoparticles (LNPs) are used to deliver RNAs, such as siRNA and mRNA, into cells. However, these artificial nanoparticles are toxic and immunogenic. Thus, we focused on extracellular vesicles (EVs), natural drug delivery systems, for the delivery of nucleic acids. EVs deliver RNAs and proteins to specific tissues to regulate various physiological phenomena in vivo. Here, we propose a novel method for the preparation siRNAs encapsulated in EVs using a microfluidic device (MD). MDs can be used to generate nanoparticles, such as LNPs, by controlling flow rate to the device, but the loading of siRNAs into EVs using MDs has not been reported previously. In this study, we demonstrated a method for loading siRNAs into grapefruit-derived EVs (GEVs), which have gained attention in recent years for being plant-derived EVs developed using an MD. GEVs were collected from grapefruit juice using the one-step sucrose cushion method, and then GEVs-siRNA-GEVs were prepared using an MD device. The morphology of GEVs and siRNA-GEVs was observed using a cryogenic transmission electron microscope. Cellular uptake and intracellular trafficking of GEVs or siRNA-GEVs to human keratinocytes were evaluated by microscopy using HaCaT cells. The prepared siRNA-GEVs encapsulated 11% of siRNAs. Moreover, intracellular delivery of siRNA and gene suppression effects in HaCaT cells were achieved using these siRNA-GEVs. Our findings suggested that MDs can be used to prepare siRNA-EV formulations.

Remote-controllable dosage management through a wearable iontophoretic patch utilizing a cell phone.

With regard to medical treatment through operations, remote control is possible, however, the area of remote-controllable drug treatment is yet to be established. In this study, a prototyped remote-controllable dosage management system that allows patients and caregivers to administer therapeutic drugs via an internet line without touching the dosage device or formulation was developed. This system consists of a transmitter (System A) located away from the patient, and a dosage device (System B) equipped with a receiver (B1), dosage management unit (B2), and a drug treatment unit (B3) that can be installed on the patient. Additionally, Bluetooth® is adopted to communicate from System A to System B. In the present study, System A was incorporated into a cell phone, and System B was a constant-current iontophoresis (IP) device, which was applied on excised pig skin. Sodium salt of betamethasone phosphate (BP-Na+) was selected as a model drug, and the in vitro skin permeation of BP- was evaluated. As a result, by transmitting the administration information incorporated in System A through B1 to B2, the optimal current was passed between the IP electrodes in B3, and the skin permeation of BP- was obtained by remote control. That is, the skin permeation of BP- was obtained by the current flowing from the IP device. The permeation amount decreased when the voltage load was stopped. These results suggested that remote control from System A enables dosing management of bioactive substances from dosage devices applied on the skin, intracutaneously, or subcutaneously without being near the patient. Although various trials are still required to complete the remote-controlled system, the patient does not have to go to the hospital except to take injections. Such drug administrations would lead to decreased medical expenses and increased quality of life for patients.

[Transdermal Drug Delivery Systems: From the Dawn and Early Stage to the Development and Maturity Stage, and the Future].

This review describes the analytical methods for percutaneous absorption and skin permeation of chemical substances and the transdermal drug delivery system (TDDS) that I have been researching for about half a century. This period coincides with that of the dawn and early stage of TDDS through its development to the maturity stage. First, as an introduction, the skin structure, definitions of scientific terms such as percutaneous absorption, skin permeation, skin penetration, types of chemical substances that make contact with the skin, and the skin permeation pathway of chemical substances are outlined. Next, the experimental methods established for percutaneous absorption and skin permeation of chemical substances are described. Then, analytical methods for the percutaneous absorption rate are outlined: i.e., partition to skin barrier and diffusion in the stratum corneum of chemical substances, the meaning of the permeability coefficient, and Fick's 1st and 2nd laws of diffusion. Furthermore, after showing the modeling of the skin barrier as a diffusion layer, the analytical method of skin concentration is also explained. In addition, after explaining the concept of thermodynamic activity of chemical substances for percutaneous absorption, the usefulness of skin-penetration enhancers and physical means to increase skin permeation is reviewed. Finally, I introduce my dream of an installable DDS on or in the skin in future therapeutic modalities.

A Pilot Study of Transdermal Application of Diphenhydramine to the Nasal Ala in Patients with Allergic Rhinitis and Asthma.

BACKGROUND: To date, topical allergic rhinitis drugs must be applied intranasally. We studied the efficacy, safety, and impact on co-existing asthma symptoms of transdermal delivery of diphenhydramine through the nasal ala. METHODS: We enrolled outpatients with symptomatic allergic rhinitis and asthma who were on stable medication for at least 4 weeks. Patients applied diphenhydramine ointment, 0.07 g measured with weighing spoon (0.7 mg diphenhydramine), to the nasal ala twice a day for 2 weeks, followed by 2 weeks' washout. Effects were assessed with the Japanese Allergic Rhinitis Standard Quality of Life Questionnaire (JRQLQ) and Self-assessment of Allergic Rhinitis and Asthma (SACRA) and Asthma Control Test (ACT) questionnaires. RESULTS: Ten patients participated in the study. Two patients experienced acute exacerbation of asthma during the intervention phase, but no other adverse effects occurred. Self-assessments indicated efficacy in treating nasal symptoms in 5 patients. No significant changes in scores were seen, although mean total JRQLQ score showed a numerical improvement (from 34.3 [21.0] to 14.4 [8.8]; P = 0.0547). Asthma symptoms improved subjectively in 2 patients. CONCLUSIONS: The efficacy of transdermal application of diphenhydramine on the nasal ala for treating allergic rhinitis was not conclusive, but appears to be effective in certain patients.

Self-Assembled Structure of α-Isostearyl Glyceryl Ether Affects Skin Permeability-a Lamellar with 70-nm Spaces and L3 Phase Enhanced the Transdermal Delivery of a Hydrophilic Model Drug.

Self-assembled surfactant structures, such as liquid crystals, have the potential to enhance transdermal drug delivery. In the present study, the pseudo-ternary system of GET (composed of α-Isostearyl glyceryl ether (GEIS) and polysorbate 60)/1,3 butanediol (BG)/water) was shown to exhibit a complex phase diagram. Small- and wide-angle X-ray scattering (SWAXS) and freeze-fracture transmission electron microscopy (FF-TEM) revealed that GET6BG60 (6%GET/60%BG/34%Water) formed a lamellar phase with a repeated distance of approximately 72 nm. Such a long-repeated distance of the lamellar phase was unique in the surfactant system. Moreover, the various structures, such as multilamellar vesicles and branched-like layers, were observed, which suggested that they might be deformable. On the other hand, only core-shell particles were observed in GET6BG20, the core of which was an L3 phase. GET6BG20 and GET6BG60 significantly enhanced the skin permeation of the hydrophilic model drug, antipyrine (ANP) (log Ko/w, - 1.51). However, their permeation profiles were distinct. Liquid chromatography-tandem mass spectrometry revealed that epidermal accumulation of GEIS was significantly higher with GET6BG60 than GET6BG20 after 1.5 h of permeation, which might be attributed to differences in their deformable properties. Furthermore, GEIS was reported to affect intercellular lipids. Accumulated GEIS in the epidermis may have interacted with intercellular lipids and enhanced the transdermal delivery of ANP. The difference in the permeation profiles of ANP may be attributed to the penetration process of GEIS in the epidermis. This study suggests that GET6BG20 and GET6BG60 are unique carriers to enhance the permeation of hydrophilic drugs, such as ANP.

Chitosan-coated PLGA nanoparticles for transcutaneous immunization: Skin distribution in lysozyme-sensitized mice.

The effect of transcutaneous immunization was studied using a combined system of poly(DL-lactide-co-glycolide) (PLGA) nanoparticles and iontophoresis (IP). Both hen egg-white lysozyme (HEL)-loaded PLGA nanoparticles coated with chitosan hydroxypropyltrimonium chloride and their fluorescent nanoparticles were prepared using an antisolvent diffusion method. Their mean volume diameters were 87.6 ± 38.9 nm and 84.9 ± 27.6 nm, respectively. It was suggested from the results of the ex vivo skin accumulation study using fluorescent nanoparticles that the HEL released from the nanoparticles to the skin surface was efficiently delivered to antigen-presenting cells. HEL-specific IgG1 and IgG2a titers were determined in an in vivo percutaneous immunoreactivity study using lysozyme-sensitized mice. As results, the group using nanoparticles and IP showed 1.33 times higher HEL-specific IgG1 titer than a sham treatment group. The HEL-specific IgG2a titer was 1.36 times higher in the nanoparticles and IP group than in the HEL solution and IP group. It was suggested from the quantification results of total IgE in serum that the combined use of PLGA nanoparticles and IP reduced the total IgE concentration. The level of cytokines may have decreased due to Th1 cell activation and relative suppression of Th2 cells. The cytokine level is presumed to be reduced by activation of Th1 cells and relative suppression of Th2 cells. The histamine amount in plasma and rectal temperature after the induction of anaphylactic shock using lysozyme-sensitized mice were also studied, which indicates that the combined use of PLGA nanoparticles and IP may provide the same therapeutic effect as an injection.

Effects of Physicochemical Properties of Constituent Ions of Ionic Liquid on Its Permeation through a Silicone Membrane.

Ionic liquids (ILs), defined as liquid salts composed of anions and cations, have the advantage of allowing constituent ions to be stably absorbed through biological membranes, such as skin. However, limited information is currently available on the effects of the physicochemical properties of constituent ions on the membrane permeation of ILs. Therefore, we herein investigated the effects of the polarity of constituent cations on the membrane permeation of each constituent ion from IL. Various ILs were prepared by selecting lidocaine (LID) as a cation and a series of p-alkylbenzoic acids with different n-octanol/water partition coefficients (Ko/w) as anions. These ILs were applied to a skin model, a silicone membrane, and membrane permeability was investigated. The membrane permeabilities of p-alkylbenzoic acids from their single aqueous suspensions were also measured for comparison. The membrane permeability of p-alkylbenzoic acid from the aqueous suspension increased at higher Ko/w. However, the membrane permeability of ILs was similar regardless of the Ko/w of the constituent p-alkylbenzoic acid. Furthermore, the membrane permeability of the counterion LID remained unchanged regardless of the constituent p-alkylbenzoic acid. These results suggest that even when the Ko/w of IL constituents markedly differs, the resulting IL does not affect membrane permeability.

A Mathematical Approach Using Strat-M® to Predict the Percutaneous Absorption of Chemicals under Finite Dose Conditions.

Estimation of the percutaneous absorption is essential for the safety assessment of cosmetic and dermopharmaceutical products. Currently, an artificial membrane, Strat-M®, has been focused on as the tool which could obtain the permeation parameters close to the skin-derived values. Nevertheless, few practical methodologies using the permeation parameters for assessing percutaneous absorption under in-use conditions are available. In the present study, based on Fick's first law of diffusion, a novel mathematical model incorporating the permeation parameters as well as considering the water evaporation (Teva) was constructed. Then, to evaluate the applicability domain of our model in the case where Strat-M®-derived parameters were used, the permeation parameters were compared between the skin from edible porcine and Strat-M®. Regarding chemicals (-0.2 ≤ Log Kow ≤ 2.0), their permeation profiles were equivalent between Strat-M® and porcine skin. Therefore, for these chemicals, the percutaneous absorption was calculated using our model with the permeation parameters obtained using Strat-M® and the Teva determined by measuring the solution weight. The calculated values revealed a good correlation to the values obtained using porcine skin in finite dose experiments, suggesting that our mathematical approach with Strat-M® would be useful for the future safety assessment of cosmetic and dermopharmaceutical products.

Development of Self-Administered Formulation to Improve the Bioavailability of Leuprorelin Acetate.

In recent years, the development of self-injectable formulations has attracted much attention, and the development of formulations to control pharmacokinetics, as well as drug release and migration in the skin, has become an active research area. In the present study, the development of a lipid-based depot formulation containing leuprorelin acetate (LA) as an easily metabolizable drug in the skin was prepared with a novel non-lamellar liquid-crystal-forming lipid of mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE). Small-angle X-ray scattering, cryo-transmission electron microscopy, and nuclear magnetic resonance observations showed that the MGE-containing formulations had a face-centered cubic packed micellar structure. In addition, the bioavailability (BA) of LA after subcutaneous injection was significantly improved with the MGE-containing formulation compared with the administration of LA solution. Notably, higher Cmax and faster Tmax were obtained with the MGE-containing formulation, and the BA increased with increasing MGE content in the formulation, suggesting that LA migration into the systemic circulation and its stability might be enhanced by MGE. These results may support the development of self-administered formulations of peptide drugs as well as nucleic acids, which are easily metabolized in the skin.

The Effect of Iontophoresis with and without Electroporation on the Penetration of High Molecular Compounds into the Stratum Corneum.

Both iontophoresis (IP) and electroporation (EP) can be utilized to increase the penetration of relatively high molecular pharmaceutical and/or cosmeceutical compounds into the stratum corneum (SC), the uppermost layer of the skin. However, few reports exist on which molecular weights are capable of penetrating the SC, although low molecular compounds of less than 500 Da have been found to readily permeate the skin barrier. In our investigation, we applied fluorescein amine-labeled sodium hyaluronate to porcine aural skin after treatment by IP alone or EP + IP. Each layer of the SC was then tape stripped several times. The stripped SC sheets were observed using a confocal laser scanning microscope to determine the relative amounts of sodium hyaluronate present. The results confirmed that the molecular weight of sodium hyaluronate that penetrated the SC was higher with EP + IP than with IP alone. A high correlation was also established between the quantity of sodium hyaluronate that penetrated and its molecular weight following combined EP + IP treatment.

Magnetic Field-Responsive Pulsatile Drug Release Using A Magnetic Fluid.

Ferrofluids are colloidal liquids with fine magnetic particles. They change shape and fluidity depending on the magnitude and direction of the external magnetic field. The magnetic field-responsive pulsatile release of a model drug, lidocaine hydrochloride (LID·HCl), was determined using a depot-type injection containing white petrolatum and/or hydrophilic cream with a magnetic fluid in various proportions. Drug release was confirmed using a self-made diffusion cell and the application of a moving magnet at the bottom of the preparation. Magnetic field-responsive LID release was observed only when using the white petrolatum preparation and depended on the concentration of the magnetic fluid. Magnetic field responsiveness was not observed in the preparation with only the hydrophilic cream. A greater magnetic field-responsive release was observed with a combination of white petrolatum and hydrophilic cream than with white petrolatum alone. These results may lead to the development of an injectable formulation that enables pulsatile administration of macromolecular drugs.

Enhancement of skin permeation of fluorescein isothiocyanate-dextran 4 kDa (FD4) and insulin by thermalporation.

Thermalporation has gained attention as a physical means to enhance skin permeation by creating micropores in the primary skin barrier, stratum corneum, which allows much higher permeation of middle and high molecular weight biopharmaceuticals. In the present study, a PassPort® system (PS) was used as a thermalporation device, and the obtained change in permeation resistance of drugs was evaluated using a parallel skin permeation-resistance model. In addition, the blood concentration-time profile after topical application of insulin was also investigated with the PS treatment. Fluorescein isothiocyanate-dextran (FD-4) and insulin were used as model middle molecular weight drugs. Micropores created by the PS treatment were measured using an optical microscope. An in vitro skin permeation and an in vivo pharmacokinetics experiments were done with FD-4 and insulin, respectively. Barrier function recovery after the PS treatment was evaluated with changes in the electrical skin resistance. About 960-fold higher skin permeation of FD-4 was observed by PSs treatment (4 milliseconds (ms), 200 micropores/cm2). A gradually increased blood concentration of insulin was observed by the PSs treatment, and the relative bioavailability of insulin was 21.1% compared with subcutaneous injection. Skin resistance value was dramatically decreased immediately after the PS treatment, but its value was turned into the initial one by 12 h. The thermalporation is effective for improving skin permeation of FD-4 and transdermal absorption of insulin. These results suggested that the PS treatment may be utilized to increase the skin permeation of topically applied FD-4 and insulin.