Patent Application
20220331572
The present invention relates to a microneedle, a microneedle array, and a production method of microneedle.
A microneedle, which refers to a micro-sized needle having a length of approx. several hundreds of micrometers, is capable of accessing the inside of the skin with low invasion while suppressing pain to the minimum. Therefore, such a microneedle has been applied as a tool for transdermal drug delivery or intradermal substance sensing by breaking the barrier of the surface layer of the skin (refer to, for example, Non-Patent Literature 1 or 2).
As a basic microneedle, a hollow microneedle 51 shown in
There is a porous microneedle 52 shown in
Moreover, along with the advancement of fine processing technology, a microneedle array in which a plurality of microneedles are arranged side by side on a single substrate has been developed (refer to, for example, Patent Literature 3 or 4).
The porous microneedles described in Patent Literatures 1, 2, and Non-Patent Literatures 4 to 6 have low resistance in drug delivery and allow a liquid drug to flow smoothly, and are thus suitably applicable as a tool for drug delivery or for diagnosis. However, the needle main bodies have the openings of the flow paths on the entire surfaces, and thus the needle main bodies are not capable of accessing a target portion on the surface of the skin or under the skin in a pinpoint manner. Therefore, in the use for drug delivery, there is a risk of causing a loss of drug.
The present invention has been made focusing on those problems. It is an object of the present invention to provide a porous microneedle capable of accessing a target portion on the surface of the skin or under the skin in a pinpoint manner, a microneedle array of the same, and a production method of the microneedle.
To attain the above object, the microneedle according to the present invention is characterized in that a part of the surface of a porous needle main body thereof is coated with a coating member.
The microneedle according to the present invention has a porous needle main body with a part of the surface thereof other than a desired part coated with a coating member, and is capable of accessing a target portion on the surface of the skin or under the skin in a pinpoint manner by using openings of the desired part. Accordingly, in an example, in the use for drug delivery under the skin by use of the flow path formed from opened voids, the microneedle enables efficient drug delivery to a target portion, thereby enabling to provide more efficient drug administration and to reduce drug loss. In another example, in the use for sensing of intradermal information as a tool for diagnosis, the microneedle is capable of efficiently obtaining the information at a desired position. The skin is configured with various tissues, and the depth of the boundary between the epidermal tissue corresponding to the outermost skin and the dermal tissue formed under the epidermal tissue is approx. 0.1 mm under the surface of the skin. For this reason, for example, the microneedle with an opened part in the length covering the both tissues is capable of collecting interstitial fluid from a target portion or measuring potential for use as an index of a skin health condition.
In the microneedle according to the present invention, the needle main body may include a flow path inside formed to extend in a net shape. The needle main body may be formed of a porous body, and may include a flow path formed from void parts of the porous body. In these cases, the needle main body may be configured of hydrogel having the structure of high polymer network with high definition, xerogel obtained by drying the hydrogel, hydrogel material, resin, oxide, metal, or biodegradable material.
In the microneedle according to the present invention, the needle main body may preferably have, on the surface thereof, a plurality of openings communicating with the flow path, and the coating member may be preferably disposed so as to coat some openings out of the plurality of openings. In the microneedle, a plurality of the flow paths may be preferably formed, and each of the openings may preferably communicate with at least one of the flow paths. In these cases, the microneedle is capable of accessing a target portion on the surface of the skin or under the skin by use of openings other than the openings coated with the coating member.
In the microneedle according to the present invention, the coating member may be disposed so as to coat any part of the surface of the needle main body. In an example, the coating member may coat the part of the surface other than the tip part of the needle main body, so that the tip part of the needle main body is opened. In another example, the coating member may coat only the surface of the flange part arranged around the rear end part of the needle main body, so that the area from the rear end part to the tip part of the needle main body is opened. In further another example, the coating member may coat the rear end part and the tip part of the needle main body, so that the middle part of the needle main body is opened. In the microneedle according to the present invention with any part coated with a coating member, the sharpness of the tip part of the needle main body is prevented from decreasing.
The coating member may be made of any material as long as the material blocks the openings of the surface of the needle main body, and may be a protective film made of resist material, as an example. It is preferable that the material of the coating member is properly selected according to the use. In the use for electrical measurement, the coating member may be preferably made of an insulating material that is electrically nonconductive, for example, parylene. The coating member is not limited to a solid, but may be liquid or gel.
The microneedle array according to the present invention has a plurality of the microneedles according to the present invention, and the microneedles are arranged side by side.
The microneedle array according to the present invention, in which the plurality of microneedles according to the present invention are arranged side by side, is capable of, for example, efficiently measuring swelling by measuring resistance of the epithelium of the skin, or efficiently administering a drug in a line manner or a plane manner. In the microneedle array according to the present invention, the microneedles may be arranged in any configuration. In an example, the microneedles may be arranged side by side on a surface of a hard substrate or a flexible substrate. In another example, the microneedles may be arranged to be connected mutually.
The microneedle and the microneedle array according to the present invention may be produced in any method. The production method of microneedle according to the present invention for producing the microneedle and the microneedle array according to the present invention may include, for example, a needle forming process of producing the needle main body with the flow path blocked with a soluble material dissolvable in a predetermined solution, a coating process of first masking a part of the surface of the needle main body with a protective member, and subsequently applying the coating member on the surface of the needle main body, and a flow path forming process of first removing the protective member, and subsequently dissolving the soluble material in the predetermined solution.
In the use of the protective member, the needle forming process may be performed by any method as long as the method enables to produce the needle main body with the flow path blocked with a soluble material, for example, a well-known method disclosed in any of Non-Patent Literatures 4 to 6 and Patent Literatures 1 to 4. In the use of such a well-known method, the needle forming process may include the step of producing the porous microneedle in such a well-known method, and the step of blocking the flow path with a soluble material, or may be performed by use of the needle main body with the flow path blocked with a soluble material, which is obtained during the production of the porous microneedle by a well-known method. In the needle forming process, the entire flow path may be blocked with a soluble material, or alternatively only the openings of the flow path on the surface of the needle main body may be blocked.
In the use of the protective member, the soluble material may be made of any material as long as the material is different from the material of the needle main body. The predetermined solution for dissolving the soluble material is preferably the solution that dissolves only the soluble material but does not dissolve the needle main body, and may be made of any material of such characteristics.
In another example of the production method of microneedle according to the present invention, the production method of microneedle may include the steps of, without using the soluble material, preparing the needle main body with the flow path thereof not blocked, that is, the needle main body with the flow path formed, masking a part of the surface of the needle main body with a protective member, coating the surface of the needle main body with the coating member, and subsequently removing the protective member. In further another example, the method may include the steps of, without using the protective member or the soluble material, preparing the needle main body with the flow path thereof not blocked, that is, the needle main body with the flow path formed, and coating a part of the surface of the needle main body with the coating member so as not to block the openings of other part. In further another example, the method may include the step of producing the needle main body with all the openings of the flow path thereof blocked with the soluble coating member, and before use or during use, only the part of the soluble coating member blocking the openings of a desired position may be dissolved.
The present invention provides a porous microneedle capable of accessing a target portion on the surface of the skin or under the skin in a pinpoint manner, a microneedle array of the same, and a production method of the microneedle.
Embodiments of the present invention will be described with reference to the drawings, hereinafter.
As shown in
The needle main body 11 is a porous member formed in a conical shape, and has a flange part 21 around the rear end part in the bottom side of the cone. The needle main body 11 has a flow path inside, and has a plurality of openings communicating with the flow path, on the surface. The flow path may be formed to extend in a net shape inside the needle main body 11, or may be formed from void parts of the needle main body 11 formed of a porous body. It is preferable that a plurality of the flow paths are formed, and each of the openings communicates with at least one of the flow paths. In an example, the needle main body 11 is configured of hydrogel having a structure of high polymer network with high definition, xerogel obtained by drying the hydrogel, hydrogel material, resin, oxide, metal, or biodegradable material.
The hydrogel material herein refers to the material that forms hydrogel by being dispersed in water (dispersion medium). Examples of the hydrogel material include natural polymers of agar, gelatin, agarose, xanthan gum, gellan gum, sclerotium gum, gum arabic, gum tragacanth, gum karaya, cellulose gum, tamarind gum, guar gum, locust bean gum, glucomannan, chitosan, carrageenan, quince seed, galactan, mannan, starch, dextrin, curdlan, casein, pectin, collagen, fibrin, peptide, chondroitin sulfate such as chondroitin sulfate sodium salt, hyaluronate such as hyaluronic acid (mucopolysaccharide) and sodium hyaluronate, alginate such as alginic acid, sodium alginate and calcium alginate, and their derivatives; cellulose derivatives of methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and their salts; poly (meth) acrylic acids of polyacrylic acid, polymethacrylic acid, sodium polymethacrylate, and acrylic acid-alkyl methacrylic acid copolymer, and their salts; synthetic polymers of polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylamide, poly (N-isopropyl acrylamide), polyvinylpyrrolidone, polystyrene sulfonate, polyethylene glycol, carboxyvinyl polymer, alkyl modified carboxyvinyl polymer, maleic anhydride copolymer, polyalkylene oxide resin, crosslinked product of poly (methyl vinyl ether-alt-maleic anhydride) and polyethylene glycol, polyethylene glycol crosslinked product, N-vinyl acetamide crosslinked product, acrylamide crosslinked product, and crosslinked product of starch-acrylate graft copolymer; silicone; interpenetrating network hydrogel and semi-interpenetrating network hydrogel; poly 2-hydroxyethyl methacrylic acid, and poly 2-acrylamide-2-methyl propane sulfonic acid; and mixtures of two or more materials among these. Preferable hydrogel materials among these materials, from the viewpoint of withstand load and bioaffinity, are collagen, and glucomannan; carboxymethyl cellulose, and sodium carboxymethyl cellulose; polyacrylic acid, and sodium polyacrylate; and interpenetrating network hydrogel, and semi-interpenetrating network hydrogel. A preferable hydrogel material, from the viewpoint of excellent mechanical strength and excellent biocompatibility, is a crosslinked product of poly (methyl vinyl ether-alt-maleic anhydride) and polyethylene glycol. A preferable hydrogel material, from the viewpoint of ensuring electrical neutrality in hydrogel, is crosslinked polyethylene glycol.
Examples of the resin include polycarbonate, acrylonitrile butadiene styrene (ABS) resin, phenolic resin, acrylic resin, methacrylic resin (such as, polyglycidyl methacrylate resin). Examples of the oxide include inorganic oxide and its derivative. Examples of the inorganic oxide herein include silicon oxide, tin oxide, zirconia oxide, titanium oxide, niobium oxide, tantalum oxide, aluminum oxide, tungsten oxide, hafnium oxide, and zinc oxide. Examples of the metal include nickel, iron, and these alloy. Examples of the biodegradable material include poly lactic-co-glycolic acid (PLGA) and mixed material mainly made of PLGA, β-tricalcium phosphate, calcium carbonate, polycaprolactone, polydioxanone, hydroxyapatite, polyethylene glycol, and magnesium alloy. The needle main body 11 may be made of combination of two or more of the substances indicated above.
The coating member 12 is disposed so as to coat a part of the surface of the needle main body 11. The coating member 12 is disposed so as to coat some openings out of the plurality of openings of the surface of the needle main body 11. The coating member 12 may coat any part of the surface of the needle main body 11. In an example, as shown in
The coating member 12 may be made of any material as long as the material blocks the openings of the surface of the needle main body 11, and may be a protective film made of resist material, as an example. It is preferable that the material of the coating member 12 is properly selected according to the use. In the use for electrical measurement, the coating member 12 may be preferably made of an insulating material that is electrically nonconductive, for example, parylene. The coating member 12 is not limited to a solid, but may be liquid or gel.
The microneedle 10 and the microneedle array according to the embodiment of the present invention are able to be produced by the production method of microneedle according to the embodiment of the present invention to be described below. In other words, the production method of microneedle according to the embodiment of the present invention includes the step of, in a needle forming process, first producing the needle main body 11 with its flow path blocked with a soluble material that is dissolvable in a predetermined solution. In the needle forming process, a well-known method of producing a microneedle may be used. In an example, after the production of a microneedle by a well-known method, the flow path may be blocked with a soluble material. Alternatively, the needle main body with its flow path blocked with a soluble material that is obtained in the process of producing the microneedle by a well-known method may be used. The soluble material herein may be made of any material as long as the material is different from the material of the needle main body 11. The predetermined solution that dissolves the soluble material may be any solution that does not dissolve the needle main body 11 but dissolves the soluble material.
After the needle forming process, a part of the surface of the needle main body 11 is masked with a protective member, and subsequently the coating member 12 is disposed on the surface of the needle main body 11 (coating process). Thereafter, the protective member is removed, and the soluble material is dissolved in a predetermined solution (flow path forming process). With these processes, the microneedle 10 and the microneedle array according to the embodiment of the present invention are able to be produced.
The microneedle 10 having the porous needle main body 11 with a part of the surface thereof other than a desired part coated with the coating member 12 is capable of accessing a target portion on the surface of the skin or under the skin in a pinpoint manner by using the openings of the desired part. Accordingly, for example, in the use for drug delivery under the skin, the microneedle 10 is capable of efficiently delivering a drug to a target portion, thereby enabling to provide more efficient drug administration and to reduce drug loss. In the use for sensing of intradermal information or the like as a tool for diagnosis, the microneedle 10 is capable of efficiently obtaining the information at a desired position. In an example, the microneedle 10 with an opened part in the length covering the both tissues of an epidermal tissue and a dermal tissue is capable of collecting interstitial fluid from a target portion or measuring potential for use as an index of a skin health condition.
In the microneedle 10 with any part coated with the coating member 12, the sharpness of the tip part of the needle main body 11 is prevented from decreasing. The microneedle array, in which the plurality of microneedles 10 are arranged side by side, is capable of efficiently measuring swelling by measuring resistance of the epithelium of the skin, or efficiently administering a drug in a line manner or a plane manner.
In another example of the production method of microneedle according to the embodiment of the present invention, the method may include the steps of, without using the soluble material, preparing the needle main body 11 with the flow path thereof not blocked, that is, the needle main body 11 with the flow path formed, masking a part of the surface of the needle main body 11 with a protective member, coating the surface of the needle main body 11 with the coating member 12, and subsequently removing the protective member. In further another example, the method may include the steps of, without using the protective member or the soluble material, preparing the needle main body 11 with the flow path thereof not blocked, that is, the needle main body 11 with the flow path formed, and coating a part of the surface of the needle main body 11 with the coating member 12 so as not to block the openings of other part. In further another example, the method may include the step of producing the needle main body 11 with all the openings of the flow path thereof blocked with the soluble coating member 12, and before use or during use, only the part of the soluble coating member 12 blocking the openings of a desired position may be dissolved.
The microneedle 10 is produced by the production method of microneedle according to the embodiment of the present invention, and subjected to various types of evaluation experiments. The reagents, the materials and the instruments for use in the production and the experiments are as follows:
Glycidyl Methacrylate (GMA), made by FUJIFILM Wako Pure Chemical Corporation
Trimethylolpropane trimethacrylate (TRIM), made by Sigma Aldrich
Polyethylene glycol (PEG) 10 kDa, made by Sigma Aldrich
Diethylene glycol (DEG), made by Tokyo Chemical Industry Co., Ltd.
Irgacure 184, made by BASF SE
Parylene C, made by Daisan Kasei Co., Ltd.
Polydimethylsiloxane (PDMS), SILPOT 184, made by DuPont Toray Specialty Materials K.K.
Methanol, made by FUJIFILM Wako Pure Chemical Corporation
Rhodamine B, made by FUJIFILM Wako Pure Chemical Corporation
Gellan gum, made by FUJIFILM Wako Pure Chemical Corporation
Ethanol, made by FUJIFILM Wako Pure Chemical Corporation
Ringer solution, made by Otsuka Pharmaceutical Co., Ltd.
Acrylic board, made by Acrysunday Co., Ltd.
Cutting machine, made by Modia Systems Co., Ltd.
Scanning electron microscope (SEM) VE-9800, made by Keyence corporation
Energy dispersive X-ray spectroscopy system (SEM EDX), JSM-7400F, made by JEOL Ltd.
Electrochemical analyzer, ALS 7082E, made by BAS Inc.
The microneedle 10 is produced by any of the methods disclosed in Non-Patent Literatures 4 to 6. The microneedle array produced herein includes three of the microneedles 10 arranged side by side. First, the needle forming process shown in
Subsequently, a precursor solution for forming the porous needle main body 11 is prepared. The precursor solution is prepared by mixing photoinitiator in a solution A and a solution B. The solution A is prepared by mixing the PEG (4 g) of a soluble material and the DEG (20 mL) of a solvent at 60° C. The DEG, which has a molecular structure close to the PEG of a solute, is capable of preventing precipitation of the solute during the production process. Alternatively, 2-methoxyethanol may be used instead of the DEG The solution B is prepared by mixing the GMA (10 mL) of a monomer, and the TRIM (5.23 mL) and TEGDMA (15.7 mL) of cross-linking agents. The precursor solution is prepared by mixing the solution A (450 μL), the solution B (550 μL), and photoinitiator Irgacure 184 (1.8 mg) at 40° C. As shown in
As shown in
Subsequently, the coating process shown in
As shown in
The produced microneedle 10 is subjected to line scanning in the vicinity of the tip part of the needle main body 11 by the EDX.
Subsequently, the produced microneedle is subjected to a diffusion test of coloring matter. As shown in
Subsequently, the produced microneedle is subjected to the test for measuring a DC resistance. As shown in
The epidermal potential measurement is performed by use of the microneedle 10 (the present invention), in which a small part of the tip part of the needle main body 11 is exposed and the other part is coated with the coating member 12. Since an epidermal potential is generated in the thickness direction of the epidermal tissue corresponding to the outermost skin, the uncoated microneedle that is exposed entirely is not capable of measuring the potential difference between the inside and the outside of the epidermis, due to short circuit. On the other hand, in the microneedle 10 allowing pinpoint connection at the tip part, the tip part of the needle main body 11 is connected to the dermis in a pinpoint manner under the epidermal tissue. Accordingly, the microneedle 10 is capable of measuring the potential difference between the inside and the outside of the epidermis.
As shown in
As shown in
43: Electrolyte solution (Ringer solution)
| Number | Date | Country | Kind |
|---|---|---|---|
| 2021-070360 | Apr 2021 | JP | national |
