JP2008279237A - Cusp type skin surface inserting micro-needle - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve the problem wherein when a skin surface inserting micro-needle intended for dermal administration of a medicine or a functional agent is made of industrial material such as metal and plastics, encountered is the problem of causing an accident such that the micro-needle breaks and remains in the body, and in administration of a medicine using the micro-needle, generally the medicine is applied to the needle surface, but dermal osmosis has limitation in quantity so that enough dose cannot be secured. <P>SOLUTION: This cusp type skin surface inserting micro-needle 4 uses material soluble in skin as a base material, so that it can be safely, surely and easily inserted in the skin surface, and also in the case of an intra-corporeal remaining accident, the advantage of dissolving the micro-needle in a living body can be obtained. Further, it is possible to obtain the advantage of giving various effects and functions to the inside of the skin surface at a high concentration by the dissolving action of the micro-needle containing a medicine or the like at a high concentration. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a technique for administering a functional agent such as a nutritional functional agent, a coloring agent, and a pharmaceutical agent under the surface of a living body for the purpose of health, beauty, treatment, and the like. Belongs to. The present invention also relates to a skin modification technique for administering a cosmetic agent into human skin, or administering a nutritional supplement such as a supplement or a skin nutritional supplement. Furthermore, the present invention relates to a technique for safely and reliably transdermally administering proteins, DNA, metals, metal oxides, microcapsules and the like.

  Conventionally, transdermal administration has been performed by applying a drug to the surface of a fine needle made of metal or plastic, inserting the fine needle into the skin, and allowing the applied drug to penetrate into the skin. However, in the case of fine needles using industrial materials such as metals and plastics that are difficult to adapt to the living body, accidents in which broken needles remain in the body are often reported, and this has been regarded as dangerous. .

  Conventionally, in the cosmetic technique, there are techniques such as application of the skin surface, ultrasonic penetration method for transdermal administration, electrophoresis, etc., but a sufficient amount of administration is possible because of a skin protective film corresponding to foreign substances. The current situation is not possible. And in the case of administration of nutrients such as supplements into the body, since it is limited to oral, it is limited to low-concentration water-soluble lysates.

  Furthermore, the production method of fine needles based on polysaccharides or protein water-soluble substances that are soluble in the skin is mostly molded by the injection molding method used for resin processing and the pulling method used for yarn production. Was impossible.

In view of the above, there has been provided a micropile in which fine needles for skin using only a carbohydrate such as maltose as a main component material and a method for producing the same are provided. For example, Patent Document 1 is cited. The purpose of this is to improve convenience and safety for skin function regeneration in a painless state when a function is imparted to the skin or skin stratum corneum as a fine needle for skin.
JP 2003-238347 A

  In the case of microneedles for transdermal administration, if the material is an industrial material such as metal or plastic, an accident in which the microneedle breaks and remains in the body, that is, a residual accident in the body is a problem, which may cause an extremely dangerous state for the body. Not a few.

  In addition, there is a method of using sugar, which is a representative material that is easily compatible with living bodies, for fine needles. There is a big problem of losing.

  Furthermore, in the administration of a pharmaceutical agent with a fine needle, a method of applying the pharmaceutical agent to the needle surface is usually employed, but there is a quantitative limit when percutaneously penetrating, which poses a problem in securing a sufficient dose.

  On the other hand, as described above, in the molding of fine needles made of polysaccharides, proteins, etc., which are soluble materials in the skin, the problem is how sharply the tip of the needle can be sharpened. The molding of was extremely difficult.

  Therefore, if there is a fine needle made of a soluble material in the skin such as hyaluronic acid or collagen, administration of other mixed medicines including administration of hyaluronic acid or collagen is possible, but micromolding is extremely difficult. Therefore, the realization of micron-sized fine needles has been a problem. Conventionally, in particular, hyaluronic acid has been used as a method of dissolving in a solution and pouring it onto the skin.

  Furthermore, the administration of supplements into the body is limited to oral administration, and there is a problem that the administration is limited to low-concentration water-soluble lysates.

In order to achieve the above object, the present invention provides means for solving the problems.
(1) In a cusp type microneedle made of a soluble material in the skin, which is arranged on the upper surface or side surface of a substrate and has one or more pointed ends and opposing flat portions, the long width of the fine pointed portion 0.1 μm to 100 μm, the width of the end along the upper or lower surface of the substrate is 20 μm to 2 mm, and the length from the tip to the end is 50 μm to 5 mm. As well as
(2) The cusp-type microneedle has a sharp pointed portion by chamfering from the end or the middle position of the end and the tip on one side or both sides of the both planes toward the tip. (1) the cusp-type fine needle for insertion into the skin surface, and
(3) In the cusp type fine needle, the cusp type fine needle has a sharp pointed end by chamfering one or two side surfaces, and the insertion into the cusp type skin surface according to (1) or (2) Fine needles, and
(4) The cusp-type fine needle for insertion into a cusp-type skin surface according to any one of (1) to (3), wherein the cusp-type fine needle has one or more constricted portions, and
(5) The fine needle for insertion into a cusp-type skin surface according to any one of (1) to (4) above, wherein the base material of the substrate is a skin soluble material, and
(6) Any of (1) to (4) above, wherein the base material of the substrate is one or a mixture of two or more selected from sugar, cellulose, solid starch, paper, wood, plastic, and metal Cusp-type fine needle for insertion into the skin surface, and
(7) The fine needle for insertion into a cusp-type skin surface according to (6) above, wherein the saccharide as a base material of the substrate is pullulan or a complex sugar material of pullulan and maltose, and
(8) The (1) to (7), wherein the soluble material in the skin is one or a mixture of two or more selected from pullulan, chitosan, hyaluronic acid, cellulose, keratin, gelatin, collagen, and casein. Any of the cusp-type fine needles for insertion into the skin surface, and
(9) The said cusp type fine needle contains 1 or 2 or more chosen from protein, DNA, a pharmaceutical agent, a nutrient, a nutritional supplement, a cosmetic material, a color material, a metal, a metal oxide, and a microcapsule. (1) to (8) characterized in that the cusp type fine needle for insertion into the skin surface,
It is what.

  In the cusp-type fine needle of the present invention, if the fine needle is formed into a cusp shape by cutting the substrate, the tip can be sufficiently sharpened. That is, a fine needle having a structure having one or more V-shaped cusp shapes having both flat surfaces facing like leaves of a bamboo leaf and having a sharp tip, and in the cusp-type fine needle, If the length of the fine tip is 0.1 μm to 100 μm, the width of the end along the upper or lower surface of the substrate is 20 μm to 2 mm, and the length from the tip to the end of the cusp-type microneedle is 50 μm to 5 mm It becomes possible to insert a fine needle safely, reliably and easily for the skin of a living body. That is, when the long width is 0.1 μm or less, the needle strength is weak and cannot be produced, and when the long width is 100 μm or more, the resistance during insertion into the skin surface is large, and during insertion, Since it becomes easy to feel pain, it is not preferable. Further, in order to keep the needle strength moderately, the width of the end is preferably in the range of 20 μm to 2 mm. Furthermore, the length is preferably in the range of 50 μm to 5 mm for effective insertion into the skin surface.

  Here, FIG. 1 is a schematic three-dimensional view of a cusp-type fine needle arranged on the side surface of a substrate made of hyaluronic acid which is a soluble material in the skin, and shows two fine needles made of hyaluronic acid. Is obtained by cutting a hyaluronic acid substrate. In the figure, the fine needle 4 is arranged on the side surface 3 of the substrate, the tip of the fine needle 4 is a pointed portion, and the width of the end along the upper surface of the substrate 1 is the fine needle viewed from directly above. It means the base of a fine needle that sometimes forms a triangle. Therefore, the length from the tip to the end means the length of a line segment perpendicular to the top of the triangle from the top to the bottom, and the length of the fine tip is the plane of the fine needle (upper surface). ) The length of the line segment obtained by dropping a perpendicular line from the apex of the fine needle tip 5 to the same plane (lower surface), that is, in the drawing, the thickness of the substrate. FIG. 2 is a schematic three-dimensional view of a plurality of cusp type fine needles arranged on the upper surface of the substrate made of pullulan which is a soluble material in the skin, and shows 20 cusp type fine needles made of pullulan. This is done by cutting the cusp-type microneedles obtained by cutting the pullulan board at the end to produce a plurality of the same parts as microneedle parts, and bonding them to the upper surface of the pullulan board using the pullulan adhesive properties. It is obtained.

  In the cusp-type fine needle of the present invention, chamfering is performed from one end or both ends of the two planes toward the tip from the end or the middle position of the end and the tip to form a sharper tip. It becomes possible. FIG. 3 shows a cusp type microneedle arranged on the side surface of the hyaluronic acid substrate shown in FIG. 1, and further, a predetermined chamfer from the middle of the end of one side (upper surface) and the tip of both planes toward the tip. It is a schematic three-dimensional view of the cusp type fine needle which processed and became a sharper tip part. In the figure, the surface cut by the chamfering process shows a case where it passes through a line segment parallel to the end and the tip of the fine needle at the intermediate position.

  In the cusp-type fine needle of the present invention, the both side surfaces can be subjected to a predetermined chamfering process to form a sharper tip. FIG. 4 is a schematic three-dimensional view of a cusp-type microneedle arranged on the side surface of the hyaluronic acid substrate shown in FIG. 1 and further chamfered on both side surfaces to form a sharper tip. FIG. FIG. 5 is a schematic three-dimensional view of the fine needle shown in FIG. 4 turned upside down. In the drawing, a microcapsule or the like can be mounted on a plane above the fine needle.

  In the cusp type fine needle of the present invention, the cusp type fine needle disposed on the substrate surface or the side surface of the substrate can be cut to obtain the cusp type fine needle having the constricted portion. Thereby, the fine needle inserted into the skin surface is easily broken in the skin surface, and the soluble material in the skin, the protein, the DNA, the pharmaceutical agent, the nutrient agent, the nutritional supplement, the cosmetic material, the color material, the metal It becomes possible to insert a fine needle containing one or more selected from metal oxides and microcapsules into the skin surface safely, reliably and easily. FIG. 6 is a schematic plan view of a cusp-type microneedle arranged on the side surface of the substrate made of hyaluronic acid shown in FIG. 1 and further subjected to predetermined cutting on both side surfaces to form a constricted portion. It is a figure (viewed from right above the substrate plane (upper surface)).

  The cusp-type microneedle of the present invention is composed of a soluble material in the skin that is a mixture of one or more selected from pullulan, chitosan, hyaluronic acid, cellulose, keratin, gelatin, collagen, and casein. The problem can be solved even if an accident that leaves the material occurs because the material dissolves in vivo.

  The cusp-type fine needle of the present invention comprises a soluble material in the skin which is a mixture of one or more selected from pullulan, chitosan, hyaluronic acid, cellulose, keratin, gelatin, collagen, and casein, and is a pharmaceutical agent at room temperature. Or since a cosmetic agent can be mixed, the problem which impairs the characteristic of a mixed functional agent can be solved.

  The cusp-type fine needle of the present invention comprises a soluble material in the skin which is a mixture of one or more selected from pullulan, chitosan, hyaluronic acid, cellulose, keratin, gelatin, collagen, and casein. Since a pharmaceutical agent, a cosmetic agent, or the like can be mixed in the melt, the problem of insufficient dose can be solved.

  The cusp-type fine needle of the present invention contains one or more selected from proteins, DNA, pharmaceutical agents, nutrients, nutritional supplements, cosmetic materials, color materials, metals, metal oxides, and microcapsules. Thus, various effects and functions can be imparted to the skin and the living body. Note that the microcapsules containing the functional agent and the material may be mounted on the upper surface of the cusp-type microneedle, and the middle of the cusp-type microneedle positioned from the end to the tip on both planes. A hole may be made in the abdomen, and the microcapsule may be inserted therein, and further, a hollow may be formed in the middle abdomen of the cusp-type fine needle, and the microcapsule may be inserted therein. FIG. 8 shows a schematic three-dimensional view of a hemispherical microcapsule mounted on the upper surface (plane) of a cusp-type fine needle, and FIG. 9 shows a hole (insertion hole) for inserting the microcapsule. FIG. 2 is a schematic plan view of a cusp type microneedle composed of three microneedles provided in the middle abdomen (viewed from directly above the substrate plane). Moreover, about the microcapsule containing a functional agent and material, the shape may be a chip shape, and in this case, a chip-shaped microcapsule will be used. Furthermore, in the present invention, there is an aspect in which the microchip is mounted on the upper surface of the cusp-type fine needle. However, including this case, it is referred to as a “cusp-type microneedle containing a microchip”. Included in the content of

  The cusp-type skin surface insertion microneedle of the present invention can contain drugs and the like at a high concentration, so that various effects and functions can be achieved in the skin surface at a high concentration by the dissolving action of the soluble material in the skin. It becomes possible to give. Further, even if the fine needle made of the soluble material in the skin surface is broken in the skin surface, the fine needle is dissolved, so there is no problem.

  Furthermore, the cusp-type microneedle of the present invention is composed of a soluble material in the skin that is a mixture of one or more selected from pullulan, chitosan, hyaluronic acid, cellulose, keratin, gelatin, collagen, and casein. It contains at least one selected from protein, DNA, pharmaceutical agent, nutrient agent, nutritional supplement, cosmetic material, color material, metal, metal oxide, and microcapsule. Thus, various effects and functions can be imparted to the skin and the living body.

  Hereinafter, embodiments of the cusp-type skin surface insertion microneedle according to the present invention will be described, but the present invention is not limited to the following embodiments.

  By cutting a planar substrate made of hyaluronic acid having a thickness of 100 μm, the length of the fine tip portion is 15 μm, the width of the end along the top surface of the substrate is 200 μm, the length from the tip to the end is 600 μm, A predetermined chamfering process is performed toward the tip from a position away from the end of one side (upper surface) of both planes of the substrate to the tip of 200 μm so as to have a sharp pointed portion 2 as shown in FIG. Cusp-type fine needles were obtained.

  By inserting the above cusp-type fine needle made of hyaluronic acid into the skin, it was possible to administer high-concentration hyaluronic acid and give the skin a feeling of swelling. FIG. 7 is a schematic view showing a cross-section when the above-mentioned cusp-type microneedle is inserted into the skin surface. The sharp pointed portion made of hyaluronic acid makes it safe, reliable and easy. A fine needle could be inserted.

  When a cusp-type fine needle made of hyaluronic acid was inserted into the skin and a hole with a diameter of less than 100 μm was made on the skin surface in order to measure the blood glucose level, blood could be collected without pain and several mg.

  Vitamin C, which is easily decomposable by heating such as sodium ascorbate phosphate, has a number of holes on the skin surface by the cusp-type fine needle made of hyaluronic acid, and 1% by weight aqueous sodium ascorbate solution from there. Can be applied to the skin surface and effectively penetrated into the skin.

  When a cusp-type fine needle made of hyaluronic acid is mixed with 1% by weight of magnesium C ascorbate as a whitening cosmetic material and administered to the skin shallowly within 200 μm from the surface, about 1 month So I was able to reduce the brown stain on my face.

  By cutting a planar substrate made of pullulan having a thickness of 120 μm, the length of the fine tip is 75 μm, the width of the end along the substrate is 75 μm, the length from the tip to the end is 250 μm, and Two cusps having a rough shape as shown in Fig. 3 by giving a predetermined chamfering process toward the tip from a position away from the end of one side (upper surface) of both planes to the tip of 80µm A mold fine needle was obtained. As a whitening cosmetic material, α-arbutin is mixed in a cusp-type fine needle made of pullulan in the amount of 0.3% by weight and administered to the skin shallowly within 100 μm from the surface. Was able to be diluted.

  Lidocaine, a kind of local anesthetic material, was previously contained in a cusp-type fine needle made of pullulan at a weight ratio of 1% and administered to the skin of a rat. Lidocaine was present in plasma. Thus, penetration of lidocaine into the whole rat body was confirmed.

  When iron particles containing a diameter of 25 μm or less are mixed in the cusp-type fine needle made of pullulan and the microcantilever is inserted into the skin, the iron particles can be counted by a high-sensitivity timing sensor, and number correspondence can be obtained. It was confirmed that it could be used for inpatient numbering.

  Human IgG antibody is mixed in a chip-shaped microcapsule of a mixed material of maltose and pullulan (weight ratio 50:50) by a weight ratio of 0.25%, and the chip is mounted on the upper surface of a cusp-type fine needle made of the above pullulan. Then, using the cusp-type fine needle, In-Vivo. As a result of experiments, it was confirmed that human IgG could be administered into the skin.

  A part of DNA is mixed in a chip-like microcapsule of a mixed material (weight ratio 50:50) of pullulan and non-crystalline pure maltose, and mixed in the cusp-type fine needle made of the pullulan. When the needle was inserted into the skin, it was confirmed that the DNA remained in the stratum corneum.

  Albumin, which is a kind of protein, is mixed in a chip-shaped microcapsule of a mixed material of pullulan and non-crystalline pure maltose (weight ratio 50:50) by 3% by weight to form a cusp-type microneedle composed of the above pullulan. When mixed and the cusp-type fine needle was inserted into the skin, it was confirmed that albumin remained in the stratum corneum.

  When the skin tone standard cosmetic material standard mixture of titanium oxide and oxidative iron (weight ratio 30:70) was mixed into the cusp-type fine needle made of pullulan at a weight ratio of 5% and inserted into the skin, The above-mentioned mixed material could be left in the stratum corneum, and the stain formed on a part of the face could be diluted and covered with skin color.

  When the red pigment was mixed with the above-mentioned pullulan cusp-type microneedles at a weight ratio of 5% and inserted into the skin, the pigment could be left in the skin stratum corneum, making simple and safe tattooing impossible. In addition, pigments can be used to mark any shape in the skin.

  When a cusp-type fine needle made of pullulan was mixed with a osmotic orange pigment, tartardin at a weight ratio of 1% and inserted into the rat skin, the skin was cut out and the cross section was observed. As a result, the tartardin color penetrated deeply into the skin. It was confirmed that

  A blue pigment with a strong adhesion to protein, Coomassie Brilliant Blue (CBB), was mixed in the cusp-type fine needle made of pullulan at a weight ratio of 1% and inserted into the rat skin. , CBB color could project the cross-sectional shape of the insertion part of the cusp fine needle.

  A chip-shaped microcapsule is prepared by mixing a carotenoid of vitamin A with a mixture of pullulan and amorphous maltose (weight ratio 40:60) by a weight ratio of 1%, and the chip is a cusp-type fine needle made of the above pullulan. And mixed on the skin surface. When this was inserted into the skin surface, carotenoids could remain in the skin stratum corneum.

  When insulin was mixed in the cusp-type fine needle made of pullulan at a weight ratio of 1% and inserted into the skin surface, insulin could remain in the skin stratum corneum without decomposing.

  With the cusp-type fine needle made of pullulan, a large number of holes are made by hitting the skin surface several times, and a 1% by weight aqueous solution of hydroquinone, which is a relatively unstable chemical substance, is imprinted on the skin. Hydroquinone could be infiltrated.

  With the above-mentioned cusp-type fine needle made of pullulan, many holes are made by hitting the skin surface several times, and a 1% by weight aqueous solution of sodium or magnesium ascorbate, which is a relatively unstable chemical substance, is applied to the skin. By imprinting, it was possible to penetrate the skin stratum corneum with sodium ascorbate phosphate or magnesium into the skin.

  When a hemispherical microcapsule having a diameter of 50 μm encapsulating lidocaine was mounted on the upper surface of the cusp-type fine needle made of pullulan as described above and inserted into the skin surface, it was confirmed that lidocaine was present in the body.

  The cusp-type skin insertion microneedle of the present invention is made of a soluble material in the skin that is safe in the living body, and the structure of the cusp-type microneedle is simple so that it can be industrially mass-produced. It is what has.

  It is a schematic three-dimensional view of the cusp type fine needle arranged on the side surface of the hyaluronic acid substrate.   It is a schematic three-dimensional view of a plurality of cusp type fine needles arranged on the upper surface of the pullulan substrate.   It is a schematic three-dimensional view of the cusp type fine needle by which the upper surface of the fine needle was chamfered.   It is a schematic three-dimensional view of a cusp type fine needle in which both side surfaces of the fine needle are chamfered.   FIG. 5 is a schematic three-dimensional view of the cusp-type fine needle shown in FIG. 4 turned upside down.   It is a schematic plan view of a cusp type fine needle having a constricted shape portion.   It is a cross-sectional schematic diagram when a cusp-type fine needle is inserted into the skin surface.   It is a schematic three-dimensional view of the cusp type fine needle carrying a microcapsule.   It is a schematic plan view of a cusp type fine needle having a microcapsule insertion hole.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Substrate 2 Upper surface of substrate 3 Side surface of substrate 4 Fine needle 5 Plane (upper surface) of fine needle
6 Side surface of fine needle 7 Chamfered surface 8 Constricted part 9 Skin surface 10 Skin surface 11 Hemispherical microcapsule 12 Microcapsule insertion hole

Claims (9)

  In a cusp-type microneedle made of a soluble material in the skin, which is arranged on the upper surface or the side surface of a substrate and has one or two or more apex portions and opposing flat portions, the long width of the micro apex portion is 0. A fine needle for insertion into a cusp-type skin surface, characterized in that 1 μm to 100 μm, the width of the end along the upper or lower surface of the substrate is 20 μm to 2 mm, and the length from the tip to the end is 50 μm to 5 mm.   The cusp-type microneedle has a sharp pointed portion by chamfering from the end or the middle of the end and the tip on one side or both sides of the both planes toward the tip. The fine needle for insertion into a cusp-type skin surface according to claim 1.   The cusp-type microneedle for insertion into a cusp-type skin surface according to claim 1 or 2, wherein the cusp-type microneedle has a sharp pointed end by chamfering one or two side surfaces.   The cusp-type microneedle for insertion into a cusp-type skin surface according to any one of claims 1 to 3, wherein the cusp-type microneedle has one or more constricted portions.   The cusp-type skin surface insertion microneedle according to any one of claims 1 to 4, wherein the base material of the substrate is a soluble material in the skin.   5. The cusp mold according to claim 1, wherein the base material of the substrate is one or a mixture of two or more selected from saccharides, cellulose, solid starch, paper, wood, plastic, and metal. Fine needle for insertion into the skin surface.   7. The fine needle for insertion into a cusp-type skin surface according to claim 6, wherein the saccharide as a base material of the substrate is pullulan or a complex sugar material of pullulan and maltose.   8. The skin soluble material is one or a mixture of two or more selected from pullulan, chitosan, hyaluronic acid, cellulose, keratin, gelatin, collagen, and casein. Cusp type fine needle for insertion into the skin surface.   The cusp-type fine needle contains one or more selected from protein, DNA, pharmaceutical agent, nutrient, nutritional supplement, cosmetic material, color material, metal, metal oxide, and microcapsule. A cusp-type fine needle for insertion into a skin surface according to any one of claims 1 to 8.

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