Microprojections, microprojection arrays, and transdermal delivery systems

Abstract

To provide a micro-protrusion capable of preventing deterioration in penetration effects of substances such as a medicine and increasing penetration efficiency of the substances, a micro-protrusion array, and a percutaneous administration system.SOLUTION: A micro-protrusion is made of a porous body and includes a flow path 11 formed of void portions of the porous body. The flow path 11 is modified with a polymer and has a fixed charge, and a substance can be held in the flow path 11. When the micro-protrusion is pressed against a skin and a current or voltage is applied between itself and the skin, a stratum corneum 1 is pushed out and the substance can be administered to the stratum corneum 1, or to the stratum corneum 1 and a layer 2 under the stratum corneum 1 by an electroosmotic flow.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to microprojections, a microprojection array, and a transdermal administration system.

Background Art

[0002] Conventionally, microneedles and microneedle arrays have been used to efficiently perform transdermal drug administration, collection of subcutaneous tissue fluid, etc. by penetrating the stratum corneum with relatively low molecular permeability using so-called sharp microneedles with sharp tips. In particular, in the field of drug administration, rapid practical application has been progressing (see, for example, Non-Patent Documents 1 to 3). As such sharp microneedles, for example, as shown in FIG. 8(a), general microneedles 51 in which the surface of the needle or the needle itself dissolves and drugs are released into the stratum corneum 1 and the layer 2 thereunder, and hollow microneedles and porous microneedles 52 that are insoluble themselves and function as passages for drugs (see, for example, Patent Document 1 or Non-Patent Document 4) have been developed. In addition, the present inventors have also developed a device that greatly improves the efficiency of drug penetration by utilizing the electroosmotic flow generated by energization (see, for example, Patent Document 2, Non-Patent Documents 5 or 6).

[0003] However, such sharp microneedles have problems of damaging the skin because they penetrate the skin and the risk of breaking when penetrating the skin. Therefore, as something that does not damage the skin and does not break, for example, a conical frustum-shaped soluble microprojection with a non-sharp tip has been developed to perform drug penetration into the stratum corneum (see, for example, Patent Document 3). As shown in FIG. 8(b), when this microprojection 53 is pressed against the skin, it can sink into the stratum corneum 1 and stretch the stratum corneum 1, facilitating molecular permeation, and thus is considered effective for drug penetration into the stratum corneum 1.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

[0005] [Patent Document 1] Japanese Patent Publication No. 2017-724 [Patent Document 2] International Publication No. WO2020 / 179850 [Patent Document 3] Japanese Patent Publication No. 2015-231466 [Overview of the project] [Problems that the invention aims to solve]

[0006] However, conventional non-sharp micro-protrusions have a drawback: because they dissolve themselves, as dissolution progresses, the elongation of the stratum corneum decreases, and the penetration effect of drugs and other substances into the stratum corneum diminishes. In addition, since penetration into the stratum corneum relies solely on the penetration power of the drug or other substance itself, there is also the problem of poor penetration efficiency.

[0007] This invention has been made in view of these problems, and aims to provide micro-protrusions, micro-protrusion arrays, and transdermal administration systems that can prevent a decrease in the penetration effect of substances such as drugs and can improve the penetration efficiency of substances. [Means for solving the problem]

[0008] To achieve the above objective, the micro-protrusions according to the present invention are capable of holding a substance and, when pressed against the skin and an electric current or voltage is applied between them and the skin, they expand the stratum corneum and are configured to allow the substance to be administered to the stratum corneum or to the stratum corneum and the layer beneath it by electroosmotic flow.

[0009] The micro-protrusions according to the present invention are used to administer substances such as drugs to the stratum corneum. When pressed against the skin, the micro-protrusions according to the present invention can expand the stratum corneum, thereby facilitating molecular permeability and allowing the held substances such as drugs to penetrate the stratum corneum. Furthermore, by applying an electric current or voltage between the micro-protrusions and the skin at this time, an electroosmotic flow can be generated, thereby increasing the efficiency of substance penetration into the stratum corneum.

[0010] The micro-protrusions according to the present invention are made insoluble and do not dissolve themselves when pressed against the skin, thereby maintaining a state of expanding the stratum corneum and preventing a decrease in the penetration effect of substances such as drugs. Furthermore, since the micro-protrusions according to the present invention do not penetrate the skin but only expand the stratum corneum, they do not cause wounds to the skin and there is no risk of breakage. The micro-protrusions according to the present invention may also be capable of administering substances such as drugs not only to the stratum corneum but also to the layer beneath the stratum corneum. The substance held by the micro-protrusions according to the present invention can be any substance that can be administered to the stratum corneum, and is particularly preferably an electrolyte solution containing drugs or cosmetic agents.

[0011] The micro-protrusions according to the present invention are made of a porous material and are provided with a channel formed by the void portion of the porous material, wherein the channel has a fixed charge and is capable of holding the substance in the channel. In this case, a substance such as a drug can be administered through the channel. Furthermore, when pressed against the skin and an electric current or voltage is applied between the skin and the micro-protrusions, an ionic current flows, and the fixed charge in the channel can generate electroosmotic flow in the channel. This can increase the penetration efficiency of substances such as drugs. The porous material may be made of, for example, a hydrogel material, a porous resin, an oxide, a metal, or a biodegradable material.

[0012] When the microprotrusions according to the present invention are made of a porous material, the channel may be modified with a polymer. This can promote the movement of relatively large molecules and particles, such as molecules with a molecular weight of 500 to 10,000, and increase the penetration efficiency of these molecules and particles. In this case, the polymer may have a fixed charge, and the fixed charge may be present on the surface of the channel. When the polymer has a fixed charge, it is preferable that the polymer is modified on the surface of the channel by covalent bonds in order to maintain the polymer content. As for modification by covalent bonds, for example, the polymer may be modified via functional groups introduced on the surface of the channel by surface treatment agents such as silane coupling agents and phosphonic acid derivatives, or by surface treatments such as oxygen plasma treatment, gamma ray irradiation, acid / alkali treatment, and electroless plating.

[0013] The micro-projections according to the present invention preferably have a flat or smooth curved tip to prevent penetration into the skin. In this case, the micro-projections according to the present invention preferably have a frustum shape such as a truncated cone or truncated pyramid, a columnar shape such as a cylinder or prism, or a shape in which the tip of the same is dome-shaped.

[0014] The micro-protrusion array according to the present invention is characterized by having a plurality of micro-protrusions according to the present invention, and each micro-protrusion is arranged in a row.

[0015] The microprotrusion array according to the present invention has a plurality of microprotrusions according to the present invention arranged side by side. Therefore, for example, administration of a linear or planar drug or the like can be efficiently performed. The microprotrusion array according to the present invention may arrange each microprotrusion in any configuration. For example, each microprotrusion may be arranged side by side on the surface of a hard substrate or a flexible substrate, or each microprotrusion may be connected and arranged side by side. Further, each microprotrusion may be arranged so as to protrude from the adhesive surface of an adhesive sheet capable of being attached to the skin for use by being attached to the skin.

[0016] The transdermal administration system according to the present invention is characterized by having the microprotrusion according to the present invention, or the microprotrusion array according to the present invention, and current / voltage application means provided so as to be able to generate the electroosmotic flow and apply a current or voltage between the microprotrusion and the skin.

[0017] In the transdermal administration system according to the present invention, an electroosmotic flow can be generated by applying a current or voltage between the microprotrusion and the skin with the current / voltage application means in a state where the microprotrusion is pressed against the skin, and the penetration efficiency of substances into the stratum corneum can be increased.

Effects of the Invention

[0018] According to the present invention, it is possible to provide a microprotrusion, a microprotrusion array, and a transdermal administration system that can prevent a decrease in the penetration effect of substances such as drugs and increase the penetration efficiency of substances.

Brief Description of the Drawings

[0019] [Figure 1] It is a cross-sectional view showing the usage state of the microprotrusion of the embodiment of the present invention. [Figure 2] It is a (a) perspective view and (b) enlarged side view showing the microprotrusion array of the embodiment of the present invention. [Figure 3] It is a front view showing the experimental method of the experiment for confirming the effect of spreading the stratum corneum of the microprotrusion array shown in FIG. 2. [Figure 4] Figure 2 shows a resistance-load curve graph illustrating the experimental results confirming the effect of the micro-protrusion array on expanding the stratum corneum. [Figure 5] Figure 2 is a front view illustrating the experimental method for drug transport experiments using the microprotrusion array shown in Figure 2. [Figure 6] Figure 2 shows the transport experiment results using rhodamine B as a drug model for the microprotrusion array, illustrating the penetration of rhodamine B: (a) electron microscope image for passive diffusion, (b) fluorescence microscope image for passive diffusion, (c) electron microscope image for current application, and (d) fluorescence microscope image for current application. [Figure 7] Figure 2 shows the results of transport experiments using FITC dextran as a drug model with the microprotrusion array, illustrating the penetration of FITC dextran: (a) when current is applied using the microprotrusion array, (b) when current is applied using a porous plate without microprotrusions, (c) in the case of passive diffusion using the microprotrusion array, and (d) in the case of passive diffusion using the porous plate (scale bar is 500 μm). [Figure 8] (a) A cross-sectional view showing conventional microneedles and porous microneedles, and (b) a cross-sectional view showing the usage state of conventional microprotrusions. [Modes for carrying out the invention]

[0020] The embodiments of the present invention will be described below based on the drawings and examples. Figures 1 to 7 show micro-protrusions, a micro-protrusion array, and a transdermal administration system according to embodiments of the present invention.

[0021] As shown in Figure 1, the micro-protrusions 10 are made of a porous material. The micro-protrusions 10 are porous and have a frustoconical shape so as not to penetrate the skin when pressed against it. The micro-protrusions 10 have a channel 11 inside and a plurality of openings on their surface that communicate with the channel 11. The channel 11 may extend in a network inside the micro-protrusion 10, or it may be formed by the voids of the porous material of the micro-protrusion 10. Preferably, the channel 11 consists of multiple channels, and each opening communicates with at least one channel 11.

[0022] The micro-protrusions 10 are insoluble and do not dissolve when pressed against the skin. Furthermore, the micro-protrusions 10 are configured such that the channels 11 are modified with polymers and possess fixed charges, allowing them to hold substances such as drugs. The polymers in the micro-protrusions 10 may have fixed charges, or the fixed charges may be present on the surface of the channels 11. In a specific example, the micro-protrusions 10 are composed of hydrogels with a fine polymer network structure, xerogels obtained by drying hydrogels, hydrogel materials, resins, oxides, metals, biodegradable materials, etc.

[0023] Here, the modification of the channel 11 may be, for example, by which the polymer is modified by interactions such as hydrogen bonding or intermolecular forces, through adhesion, bonding, adsorption, or support, or by covalent bonding via a coupling agent. As for modification by covalent bonding, for example, the polymer may be modified via functional groups introduced to the surface of the channel 11 by surface treatment agents such as silane coupling agents and phosphonic acid derivatives, or by surface treatments such as oxygen plasma treatment, gamma ray irradiation, acid / alkali treatment, or electroless plating. Preferred silane coupling agents are those that have a structure that can serve as a polymerization initiation site, such as 3-(trimethoxysilyl)propyl acrylate and 3-(trimethoxysilyl)propyl methacrylate. Examples of structures that can serve as a polymerization initiation site include acrylic structures, methacrylic structures, styryl structures, vinyl structures, halogen structures, etc.

[0024] Among the materials capable of forming the micro-protrusions 10, hydrogel materials are materials that form a hydrogel when dispersed in water (dispersion medium). Examples of hydrogel materials include agar, gelatin, agarose, xanthan gum, gellan gum, sclerotium gum, arabic gum, tragacanth gum, karaya gum, cellulose gum, tamarind gum, guar gum, locust bean gum, glucomannan, chitosan, carrageenan, quince seed, galactan, mannan, starch, dextrin, curdlan, casein, pectin, collagen, fibrin, peptides, chondroitin sulfate such as sodium chondroitin sulfate, hyaluronic acid (mucopolysaccharide), and hyaluronic acid. Natural polymers such as hyaluronic acid salts including sodium aluronate, alginic acid, sodium alginate, and calcium alginate, and their derivatives; cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose, and their salts; poly(meth)acrylic acids such as polyacrylic acid, polymethacrylic acid, and acrylic acid-methacrylate alkyl copolymers, and their salts;Synthetic polymers such as polyvinyl alcohol, polyethylene glycol di(meth)acrylate polymers (PPEGDA, PPEGDM), homopolymers or copolymers containing constituent units derived from hydroxyethyl methacrylate such as polyhydroxyethyl methacrylate, polyacrylamide, poly(N-isopropylacrylamide), poly2-acrylamide-2-methylpropanesulfonic acid, poly(N-isopropylacrylamide), homopolymers or copolymers containing constituent units derived from dimethylacrylamide, homopolymers or copolymers containing constituent units derived from vinylpyrrolidone, copolymers containing constituent units derived from dimethylacrylamide, polystyrene sulfonic acid, polyethylene glycol, carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, maleic anhydride copolymer, polyalkylene oxide resins, crosslinked products of poly(methylvinyl ether-alt-maleic anhydride) and polyethylene glycol, polyethylene glycol crosslinked products, N-vinylacetamide crosslinked products, acrylamide crosslinked products, starch-acrylate graft copolymer crosslinked products, etc.; silicones; interpenetrating network hydrogels and semi-interpenetrating network hydrogels (DN hydrogels); and mixtures of two or more of these. ;

[0025] Furthermore, the hydrogel material may contain monomer units having polymerizable ethylenically unsaturated groups at both ends, from the viewpoint that the resulting polymer has a polymeric crosslinking structure and excellent physical strength. The monomers having polymerizable ethylenically unsaturated groups at both ends may be monomers to which a structure derived from a hydrophilic polymer has been added. Examples of structures derived from hydrophilic polymers include polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, poly(meth)acrylic acid, poly(meth)acrylic acid salt, poly(2-hydroxyethyl(meth)acrylate), polytetrahydrofuran, polyoxetane, polyoxazoline, polydimethylacrylamide, polydiethylacrylamide, and poly(2-methacryloyloxyethyl phosphorylcholine).

[0026] Furthermore, the hydrogel material may contain hydrophilic monomer units. Examples of hydrophilic monomers include (meth)acrylamide; hydroxyalkyl (meth)acrylates such as 2-hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, and hydroxybutyl (meth)acrylate; (alkyl)aminoalkyl (meth)acrylates such as 2-dimethylaminoethyl (meth)acrylate and 2-butylaminoethyl (meth)acrylate; alkylene glycol mono(meth)acrylates such as ethylene glycol mono(meth)acrylate and propylene glycol mono(meth)acrylate; and polyethylene glycol. Polyalkylene glycol mono(meth)acrylates such as polypropylene glycol mono(meth)acrylate; ethylene glycol allyl ether; ethylene glycol vinyl ether; (meth)acrylic acid; aminostyrene; hydroxystyrene; vinyl acetate; glycidyl(meth)acrylate; allyl glycidyl ether; vinyl propionate; N,N-dimethylmethacrylamide, N,N-diethylmethacrylamide, N-(2-hydroxyethyl)methacrylamide, N-isopropylmethacrylamide, methacryloylmorpholine;N-vinyl-2-pyrrolidone, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-6-methyl-2-pyrrolidone, N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-2-piperidone, N-vinyl-3-methyl-2-piperidone, N-vinyl-4-methyl-2-piperidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-6-methyl-2-piperidone, N-vinyl-6-ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4 Examples include N-vinyllactams such as -dimethyl-2-piperidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-caprolactam, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, and N-vinyl-3,5,7-trimethyl-2-caprolactam; and N-vinylamides such as N-vinylformamide, N-vinyl-N-methylformamide, N-vinyl-N-ethylformamide, N-vinylacetamide, N-vinyl-N-methylacetamide, N-vinyl-N-ethylacetamide, and N-vinylphthalimide.

[0027] Examples of hydrogel materials having a fixed charge include gel materials obtained by introducing functional groups having a fixed charge into hydrogel materials that do not have a fixed charge, and gel materials that are polymers containing monomer units having a fixed charge. Among these, gel materials that are polymers containing monomer units having a fixed charge are preferred, and copolymers of uncharged monomers and monomers having a fixed charge are more preferred. The fixed charge may be either a positive charge or a negative charge, as long as the amount of one of the charges is greater, but it is preferable that it be either a positive charge or a negative charge.

[0028] The monomeric unit having a fixed charge is preferably a monomeric unit having at least one selected from the group consisting of a sulfonic acid group, a carboxyl group, a phosphate group, and an amino group, more preferably a monomeric unit having a sulfonic acid group or a carboxyl group, and even more preferably a monomeric unit having a carboxyl group.

[0029] Examples of non-charged monomers include hydroxyethyl methacrylate, ethylene glycol diacrylate, methyl methacrylate, N-vinylpyrrolidone, dimethylacrylamide, glycerol methacrylate, and vinyl alcohol. One or more non-charged monomers may be used.

[0030] Examples of monomers having a fixed charge include carboxyl group-containing monomers such as acrylic acid, methacrylic acid, itaconic acid, 1-(2-methacryloyloxyethyl) succinate, β-carboxyethyl acrylate, itaconic acid, maleic acid, fumaric acid, crotonic acid, and isocrotonic acid; sulfonic acid group-containing monomers such as 2-acrylamido-2-methyl-propanesulfonic acid, styrenesulfonic acid, vinylsulfonic acid, (meth)acrylicsulfonic acid, (meth)acrylamidopropanesulfonic acid, sulfopropyl (meth)acrylate, and (meth)acryloyloxynaphthalenesulfonic acid; phosphate group-containing monomers such as 2-hydroxyethyl acryloyl phosphate; amino group-containing monomers such as (alkyl)aminoalkyl (meth)acrylates such as 2-dimethylaminoethyl (meth)acrylate, 2-butylaminoethyl (meth)acrylate, and (meth)aminoethyl acrylate, and aminostyrene; and salts thereof. Monomers with a fixed charge may be used individually or in a mixture of two or more types.

[0031] Polymers in hydrogel materials can be obtained, for example, by adding polymerization initiators, crosslinking agents, polymerization accelerators, etc., to a monomer mixture containing monomers that constitute the hydrogel material, monomers with a fixed charge, etc., and then polymerizing it.

[0032] Examples of polymerization initiators include common radical polymerization initiators such as peroxides like lauroyl peroxide, cumene hydroperoxide, and benzoyl peroxide, as well as azobisvaleronitriles such as 2,2'-azobis(2,4-dimethylvaleronitrile) (V-65) and azobisisobutyronitrile (AIBN).

[0033] Crosslinking agents include allyl methacrylate, vinyl methacrylate, 4-vinylbenzyl methacrylate, 3-vinylbenzyl methacrylate, methacryloyloxyethyl acrylate, ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, diethylene glycol diallyl ether, triethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, propylene glycol dimethacrylate, dipropylene glycol dimethacrylate, butanediol dimethacrylate, trimethylolpropane trimethacrylate, 2,2-bis(p-methacryloyloxyphenyl)hexafluoropropane, 2,2-bis(m-methacryloyloxyphenyl)hexafluoropropane, 2,2- Examples include bis(o-methacryloyloxyphenyl)hexafluoropropane, 2,2-bis(p-methacryloyloxyphenyl)propane, 2,2-bis(m-methacryloyloxyphenyl)propane, 2,2-bis(o-methacryloyloxyphenyl)propane, 1,4-bis(2-methacryloyloxyhexafluoroisopropyl)benzene, 1,3-bis(2-methacryloyloxyhexafluoroisopropyl)benzene, 1,2-bis(2-methacryloyloxyhexafluoroisopropyl)benzene, 1,4-bis(2-methacryloyloxyisopropyl)benzene, 1,3-bis(2-methacryloyloxyisopropyl)benzene, and 1,2-bis(2-methacryloyloxyisopropyl)benzene. The amount of crosslinking agent is preferably 1 part by mass or less, more preferably 0.8 parts by mass or less, and more preferably 0.05 parts by mass or more, and more preferably 0.1 parts by mass or more, per 100 parts by mass of the total amount of monomers used in polymerization.

[0034] Hydrogel materials can be obtained, for example, by solidifying a gel solution, or by placing a monomer mixture into a mold made of metal, glass, plastic, etc., sealing it, and gradually or continuously raising the temperature in a constant temperature bath in the range of 25 to 120°C for 5 to 120 hours to polymerize it. Ultraviolet light, electron beams, gamma rays, etc. may be used during polymerization. Alternatively, water or an organic solvent may be added to the monomer mixture and solution polymerization may be applied.

[0035] After polymerization is complete, the material is cooled to room temperature, the resulting molded piece is removed from the mold, and then cut and polished as needed. The resulting molded piece may be hydrated and swollen to form a hydrogel. As for the liquid used for hydration and swelling (swelling solution), for example, an aqueous solution containing ions with a charge opposite to the fixed charge can be used, from the viewpoint of generating electroosmotic flow. The swelling solution can be heated to 60-100°C and immersed for a certain period of time to quickly achieve a hydrated and swollen state. Furthermore, the swelling treatment can also remove unreacted monomers contained in the polymer.

[0036] Examples of anionic ions contained in the swollen aqueous solution include amino acid ions (natural amino acid ions, unnatural amino acid ions), chloride ions, citrate ions, lactate ions, succinate ions, phosphate ions, malate ions, pyrrolidone carboxylate ions, sulfocarbonate ions, sulfate ions, nitrate ions, phosphate ions, carbonate ions, and perchlorate ions. Examples of natural amino acids include glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, threonine, serine, proline, tryptophan, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, and histidine. Examples of unnatural amino acids include hydroxyproline, cystine, and thyroxine. Examples of cationic ions contained in the aqueous solution include K+, Na+, Ca2+, and Mg2+.

[0037] Furthermore, among the materials that can constitute the micro-protrusions 10, materials other than hydrogels include, as resins, urethane resin, polycarbonate, acrylonitrile-butadiene-styrene (ABS) resin, phenolic resin, acrylic resin, methacrylic resin (polyglycidyl methacrylate resin, etc.). As oxides, inorganic oxides and their derivatives are included, where inorganic oxides include silicon dioxide, tin oxide, zirconia oxide, titanium dioxide, niobium oxide, tantalum oxide, aluminum oxide, tungsten oxide, hafnium oxide, zinc oxide, etc. As metals, nickel, iron, and alloys thereof are included. In addition, as biodegradable materials, polylactic acid-glycolic acid copolymer (PLGA) and mixed materials mainly composed of PLGA, β-tricalcium phosphate, calcium carbonate, polycaprolactone, polydioxanone, hydroxyapatite, polyethylene glycol, magnesium alloy, etc. The micro-protrusions 10 may consist of a combination of two or more of the substances listed here.

[0038] As shown in Figure 1, the micro-projections 10 are configured to spread the stratum corneum 1 without penetrating the skin when pressed against it. Furthermore, the micro-projections 10 are configured to generate electroosmotic flow when pressed against the skin and an electric current or voltage is applied between them and the skin. This allows the substance held in the channel 11 to be administered to the stratum corneum 1. The micro-projections 10 are also configured to administer the substance held in the channel 11 to the layer 2 beneath the stratum corneum 1.

[0039] Although the micro-projections 10 are frustoconical in shape, they may take any shape as long as their tips are formed with a flat or smooth curved surface to prevent penetration into the skin. For example, they may be frustoconical, cylindrical or prism-like, or have dome-shaped tips.

[0040] Next, I will explain the mechanism of action. The micro-protrusions 10 are used to administer substances such as drugs to the stratum corneum 1. When pressed against the skin, the micro-protrusions 10 can spread the stratum corneum 1, facilitating molecular permeability and allowing substances such as drugs held in the channel 11 to penetrate the stratum corneum 1. The micro-protrusions 10 can also allow substances such as drugs to penetrate the layer 2 below the stratum corneum 1. Furthermore, when pressed against the skin and an electric current or voltage is applied between the skin and the micro-protrusions, an ionic current flows, and the fixed charges in the channel 11 can generate electroosmotic flow in the channel 11. This can increase the penetration efficiency of substances such as drugs. In addition, because the channel 11 is modified with polymers, it can promote the movement of relatively large molecules and particles, for example, with a molecular weight of about 500 to 10000, thereby increasing the penetration efficiency of those molecules and particles.

[0041] Since the micro-protrusions 10 are insoluble and do not dissolve themselves when pressed against the skin, they can maintain a state of being stretched open in the stratum corneum 1, thus preventing a decrease in the penetration effect of substances such as drugs. Furthermore, since the micro-protrusions 10 do not penetrate the skin but only stretch open the stratum corneum 1, they do not cause wounds to the skin and there is no risk of breakage. In this way, the micro-protrusions 10, through the synergistic effect of stretching the stratum corneum 1 and electroosmotic flow, can penetrate drugs and other substances into the stratum corneum 1 and the layer 2 below it, and even large molecules with a molecular weight of about 10,000 can penetrate without damaging the stratum corneum 1.

[0042] The micro-protrusions 10 can be used not only for administering drugs but also for administering cosmetic agents and other substances. Furthermore, by holding an electrolyte solution containing drugs, etc., in the channel 11, the micro-protrusions 10 facilitate electrical conduction and make it easier to generate electroosmotic flow, thereby further increasing the penetration efficiency of drugs, etc.

[0043] In the embodiment of the present invention, the micro-protrusion array has multiple micro-protrusions 10 arranged side by side. This allows for efficient administration of linear or planar drugs, for example. The micro-protrusion array in the embodiment of the present invention may be arranged in any configuration, for example, by arranging the micro-protrusions 10 side by side on the surface of a rigid or flexible substrate, or by connecting the micro-protrusions 10 together. Furthermore, for use by being attached to the skin, each micro-protrusion 10 may be arranged to protrude from the adhesive surface of an adhesive sheet that can be attached to the skin.

[0044] Furthermore, the transdermal administration system according to the embodiment of the present invention comprises micro-protrusions 10 or a micro-protrusion array and a current-voltage application means. The current-voltage application means is provided to apply current or voltage between the micro-protrusions 10 and the skin in a manner that can generate electroosmotic flow.

[0045] In the transdermal administration system of the embodiment of the present invention, by applying an electric current or voltage between the micro-protrusions 10 and the skin using an electric current / voltage application means while the micro-protrusions 10 are pressed against the skin, electroosmotic flow can be generated, thereby increasing the penetration efficiency of substances into the stratum corneum 1 and the layer 2 below it. [Examples]

[0046] A micro-protrusion array according to an embodiment of the present invention, having multiple micro-protrusions 10, was manufactured, and various evaluation experiments were conducted. The reagents, materials, and equipment used for manufacturing and experiments are as follows.

[0047] • Glycidyl methacrylate (GMA, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Trimethylolpropane trimethacrylate (TRIM, manufactured by Sigma-Aldrich) • Polyethylene glycol (PEG 10 kDa, manufactured by Sigma-Aldrich) • Diethylene glycol (DEG, manufactured by Tokyo Chemical Industry Co., Ltd.) • Irgacure 184 (manufactured by BASF SE) • Polydimethylsiloxane (PDMS, SILPOT 184, manufactured by DuPont-Toray Specialty Materials Co., Ltd.) • 3-(Trimethoxysilyl)propyl methacrylate (TMSPMA, manufactured by Nacalai Tesque Co., Ltd.) 2-acrylamide-2-methylpropanesulfonic acid (AMPS) N,N,N',N'-tetramethylethylenediamine (TEMED) • Ammonium peroxodisulfate solution (APS, 10 w / v%) • Methanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Fluorescein isothiocyanate-dextran (FITC dextran, molecular weight 10,000, manufactured by Sigma-Aldrich) • Ethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Ringer's solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) • Acrylic sheet (manufactured by AcrySunday Co., Ltd.) • Cutting machine (manufactured by Modia Systems Co., Ltd.) • Source meter (Multi-channel source measuring unit "GS820", manufactured by Yokogawa Electric Corporation) • Electrochemical analyzer (ALS 7082E, manufactured by BAS Corporation) • Fluorescence microscope (manufactured by Olympus Corporation) • NSC electrode (NM-31, manufactured by Nihon Kohden Corporation)

[0048] [Manufacturing of microprotrusions and microprotrusion arrays] First, a female mold of a micro-protrusion array having multiple frustoconical micro-protrusions 10 was fabricated by drilling holes in an acrylic plate using a cutting machine. This was then transferred in two steps using PDMS to produce a female mold made of PDMS.

[0049] Next, precursor solutions for forming porous bodies were prepared. The precursor solutions were prepared by mixing solutions A and B with a photopolymerization initiator. Solution A was prepared by mixing PEG (4 g), a soluble material for elution to form pores in the structure, with the solvent DEG (20 mL) at 60°C. DEG has a molecular structure closer to that of the solute PEG, thus preventing solute precipitation during the preparation process. Alternatively, 2-methoxyethanol may be used instead of DEG. Solution B was prepared by mixing the monomer GMA (10 mL) with the crosslinking agents Trim (5.23 mL) and TEGDMA (15.7 mL). Solution A (450 μL), solution B (550 μL), and the photopolymerization initiator Irgacure 184 (1.8 mg) were mixed at 40°C to obtain the precursor solution.

[0050] Next, the precursor solution was poured into a PDMS mold and degassed under reduced pressure of -0.096 MPa at 25°C for 80 minutes. This degassing process prevents defects in the protrusion shape due to air bubbles. After degassing, the monomer and crosslinking agent were polymerized and solidified by irradiation with 365 nm ultraviolet light at 25°C for 1 hour. The solidified molded body was then removed from the mold. The resulting molded body had a frustoconical shape, with the voids of the porous body sealed with pologen PEG. The molded body was immersed overnight in a mixed solution of distilled water and methanol (volume ratio 1:1) to dissolve the PEG. In this way, a micro-protrusion array 20 having 37 porous micro-protrusions 10 was manufactured, as shown in Figure 2(a). In one example shown in Figure 2(b), the dimensions of the manufactured frustoconical micro-protrusion 10 were as follows: the diameter of the top surface was 157.18 μm, the diameter of the bottom surface was 290.94 μm, and the height was 295.10 μm.

[0051] The prepared micro-protrusion array 20 was immersed in a silane coupling agent solution (2 mL; 0.6 mL TMSPMA, 1.4 mL ethanol) at room temperature for 1 hour to modify the surface, including the inner walls of the pores, with the silane coupling agent. Subsequently, the micro-protrusion array 20 was rinsed twice for 15 minutes each time in distilled water using a shaker to remove excess TMSPMA and ethanol that did not react. After thoroughly wiping off the moisture, the micro-protrusion array 20 was immersed in an AMPS solution (2 mL; 0.5-10 mmol AMPS, 1 vol% APS, 0.1 vol% TEMED) at 4°C for more than 8 hours to uniformly impregnate the inside of the pores. Then, polymerization was carried out in an oven at 70°C for 1 hour with the immersion liquid to obtain AMPS-modified micro-protrusion array 20.

[0052] [Experiment to confirm the effect of expanding the stratum corneum] Using the micro-protrusion array 20 shown in Figure 2, an experiment was conducted to confirm that when the micro-protrusions 10 are pressed against the skin, the stratum corneum 1 is stretched due to skin elongation, thereby reducing its barrier function. In this experiment, the change in transcutaneous resistance when the micro-protrusions 10 are pressed was measured using pig skin. For comparison, the change in resistance was also measured without using the micro-protrusion array 20.

[0053] In the experiment, the micro-protrusion array 20 shown in Figure 2 was used after being immersed in Ringer's solution for 1 hour. As shown in Figure 3, first, pig skin 31 was stretched to 1.1 times its original size and fixed onto a PDMS stage 32. NSC electrodes (adhesive electrodes for electromyography) 33 were attached to the stratum corneum 1 side and the back side of the pig skin 31, respectively, and a load of up to 30 N was applied using a force gauge 34 from above the NSC electrode 33 on the stratum corneum 1 side to create a resistance-load curve. Next, as shown in Figure 3, the NSC electrode 33 on the stratum corneum 1 side was attached to the side opposite the micro-protrusions 10 of the micro-protrusion array 20, and the micro-protrusion array 20 was placed on the stratum corneum 1 with the micro-protrusions 10 facing the stratum corneum 1 side. In this state, a load of up to 30 N was applied in the same manner to create a resistance-load curve.

[0054] The obtained resistance-load curve is shown in Figure 4. As shown in Figure 4, it was confirmed that even without the micro-protrusions 10, pressing the NSC electrode 33 deformed the skin and reduced the resistance to about 300 kΩ. In contrast, when the micro-protrusions 10 were pressed into the skin, the resistance decreased further, to about 25 kΩ. This is thought to be because the stratum corneum 1 was stretched out by the micro-protrusions 10. From these results, it can be said that by using the micro-protrusions 10 and the micro-protrusion array 20, transdermal current can be applied at a low voltage, thereby increasing safety.

[0055] [Transportation experiments using drug models] An experiment was conducted to confirm that drug penetration is promoted by pressing the microprotrusions 10 against the skin using the microprotrusion array 20 shown in Figure 2. In the experiment, first, 5 mg / ml PBS solutions of rhodamine B (molecular weight 479) and FITC dextran were prepared as drug models, and the microprotrusion array 20 shown in Figure 2 was immersed in each solution overnight to hold each drug inside the pores. Next, as shown in Figure 5, pig skin 37 was placed on cotton 36 soaked in PBS solution, and the microprotrusion array 20 was placed near the center of the skin with the microprotrusions 10 facing the pig skin 37. Cotton 36 was placed on the opposite side of the microprotrusion array 20 from the microprotrusions 10, and a load of about 10 N was applied from above using a salt bridge 38 to press down. This salt bridge 38 was used as the anode, and the cathode side salt bridge 39 was connected to cotton 40 placed under the pig skin 37.

[0056] Each salt bridge 38, 39 is connected to the source meter 43 via the PBS solution 41 and the carbon fabric electrode 42, and the reading is 0.5 mA / cm. 2 A direct current was applied for 2 hours. After the current was applied, the pig skin 37 was exposed to liquid nitrogen while the micro-protrusion array 20 was still pressed against it, and the pig skin 37 was frozen. Then, the frozen pig skin 37 was prepared into 40 μm thick frozen sections using a microtome, and the penetration of the drug model was confirmed by observing each section with a fluorescence microscope. For comparison, the same experiment was performed using a porous plate without micro-protrusions 10 instead of the micro-protrusion array 20. The same observations were also performed when the sample was left for 2 hours without current (hereinafter referred to as "passive diffusion").

[0057] Figure 6 shows the observation results for passive diffusion and current application when using rhodamine B. As shown in Figures 6(a) and (b), it was confirmed that penetration into the stratum corneum 1 occurs by passive diffusion when the micro-protrusions 10 are pressed against the skin. Furthermore, as shown in Figures 6(c) and (d), it was confirmed that penetration from the stratum corneum 1 to the layer below it 2 is further promoted when a current is applied. This can be attributed to the acceleration of molecular penetration into the skin by the downward electroosmotic flow (in the direction from the micro-protrusions 10 toward the interior of the skin) generated by the negatively charged micro-protrusion array 20.

[0058] Figure 7 shows the observation results when FITC dextran is used, when current is applied using the micro-protrusion array 20, when current is applied using a porous plate without micro-protrusions 10, in the case of passive diffusion using the micro-protrusion array 20, and in the case of passive diffusion using a porous plate. As shown in Figure 7(a), when current is applied using the micro-protrusion array 20, it was confirmed that dextran penetrates from the stratum corneum 1 to the layer below it 2. This result shows that dextran with a molecular weight of 10,000 penetrates to the layer below the stratum corneum 1 without destroying the stratum corneum 1, overturning the so-called 500Da rule (an empirical rule that molecules with a molecular weight of 500 or more cannot penetrate the stratum corneum).

[0059] Furthermore, as shown in Figure 7(b), when an electric current was applied using a porous plate, it was confirmed that the penetration of dextran remained within the stratum corneum 1. Also, as shown in Figures 7(c) and (d), in the case of passive diffusion where the micro-protrusion array 20 or porous plate was pressed against the surface without current, almost no penetration of dextran was observed. From these results, it can be said that the synergistic effect of the extension of the stratum corneum 1 by the micro-protrusions 10 and electroosmotic flow allows even high molecular weight drugs to penetrate from the stratum corneum 1 to the layer below it 2 without damaging the stratum corneum 1. [Explanation of Symbols]

[0060] 1 stratum corneum 2. The layer beneath the stratum corneum 10 micro-protrusions 11 channels 20 Micro-protrusion array 31. Pig skin 32 stages 33 NSC electrode 34 Force Gauge 36, 40 Cotton 37. Pig skin 38, 39 Shiobashi 41 PBS solution 42 Carbon Fabric Electrodes 43 Source Meter 51 (Conventional) Microneedles 52 (Conventional) Porous Microneedles 53 (Conventional) Micro-protrusions

Claims

1. A material comprising a porous body, comprising a channel formed by the void portion of the porous body, wherein the channel has a fixed charge, and the channel holds a substance containing molecules with a molecular weight of 500 to 10000. To prevent penetration into the skin, the tip is formed with a flat or smooth curved surface. A micro-protrusion characterized in that, when pressed against the skin and an electric current or voltage is applied between it and the skin, it expands the stratum corneum and, by electroosmotic flow, delivers the substance to the stratum corneum or to the stratum corneum and the layer beneath it.

2. The micro-protrusion according to claim 1, characterized in that the channel is modified with a polymer.

3. The micro-protrusions according to claim 2, characterized in that the polymer has the fixed charge.

4. The micro-protrusions according to claim 2 or 3, characterized in that the polymer is modified on the surface of the channel via a silane coupling agent.

5. The micro-projection according to any one of claims 1 to 4, characterized in that it is frustum-shaped or columnar.

6. Having a plurality of micro-protrusions as described in any one of claims 1 to 5, Each micro-protrusion is arranged in a line. A distinctive feature is the array of micro-protrusions.

7. A micro-protrusion according to any one of claims 1 to 5, or a micro-protrusion array according to claim 6, A current-voltage applying means is provided between the micro-protrusions and the skin so as to be able to generate the aforementioned electroosmotic flow, A transdermal administration system characterized by having [a certain feature].

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