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WO2008010573A1 - Micro-dispositif, procédé de fabrication et procédé d'assemblage de partie de matériau de sucres - Google Patents

Micro-dispositif, procédé de fabrication et procédé d'assemblage de partie de matériau de sucres Download PDF

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Publication number
WO2008010573A1
WO2008010573A1 PCT/JP2007/064346 JP2007064346W WO2008010573A1 WO 2008010573 A1 WO2008010573 A1 WO 2008010573A1 JP 2007064346 W JP2007064346 W JP 2007064346W WO 2008010573 A1 WO2008010573 A1 WO 2008010573A1
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WO
WIPO (PCT)
Prior art keywords
cantilever
micro
substrate
skin
chip
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2007/064346
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English (en)
Japanese (ja)
Inventor
Yoshikazu Tobinaga
Tomoya Kitagawa
Kentaro Ohshima
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ELEGAPHY Inc
Maruho Co Ltd
Original Assignee
ELEGAPHY Inc
Maruho Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ELEGAPHY Inc, Maruho Co Ltd filed Critical ELEGAPHY Inc
Publication of WO2008010573A1 publication Critical patent/WO2008010573A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Definitions

  • the present invention relates to a technique for inserting a pharmaceutical agent for the purpose of treatment or health into a human skin surface, that is, a transdermal dosage technology, and a functional material for beauty in the human skin surface.
  • Technology for the introduction of skin care materials that is, transdermal nutritional supplements and supplemental administration technology, skin cosmetics and modification technology, and in-vivo information extraction and individual identification signals within the human skin surface.
  • TECHNICAL FIELD The present invention relates to a technique for inserting a functional chip for sensing, that is, a technique for mounting a functional chip in the skin surface, and relates to a micro-implement for insertion in the skin surface to be used for the technique and a manufacturing method thereof.
  • the present invention provides a sugar material for bringing a sugar material part into contact with each other or bringing a sugar material part into contact with each other or a substrate or a substrate sheet composed of pullulan or a composite sugar material of pullulan and maltose. It relates to the parts assembly method.
  • Patent Document 1 Japanese Patent Laid-Open No. 2003-238347
  • a micro-perforator including a needle based on a water-soluble polymer such as polybutyl alcohol (PVA) and sodium carboxymethylcellulose (CMC-Na) for example, see Patent Document 2
  • PVA polybutyl alcohol
  • CMC-Na sodium carboxymethylcellulose
  • Patent Document 2 Japanese Translation of Special Publication 2006—500973
  • the degree of freedom of nutrients, etc. is limited when it is in a liquid state, and when it is in a liquid state, its use is almost limited to a low-concentration water-soluble lysate. There was a problem. Furthermore, in the case of a technique for mounting a skin-embedded functional chip used for in-vivo information extraction or the like, the chip is pushed out of the body as the skin surface is healed, and the functional chip is removed from the skin in a stable state. There was a problem that it was difficult to keep it inside.
  • an injection molding method or the like has been used as a method for producing microneedles using sugar as a base material, but due to the characteristics of the production method and the properties of the sugar to be used, the processing accuracy is high.
  • the problem is that it is almost impossible to mold microneedles with high strength. It was a title.
  • the base material is a polymer material
  • the base material is a polymer material
  • the shape of the molding was shaped on the bottom of the mold.
  • the accuracy of the needle tip is limited to about 30 m due to limitations due to fluid phenomena during molding (not flowing into details, turbulence or vortex phenomenon, ie, vortex phenomenon), which was a problem.
  • injection molding and casting cannot be performed with fine protrusions due to mechanical blurring at the time of release, which is also a problem.
  • the present invention is a structure having a fine cantilever made of a soluble material in the skin at the upper end of the side surface of the substrate or the surface of the substrate sheet.
  • Micro-implement for insertion, micro-implement for insertion in skin surface with functional chip mounted on fine cantilever, and functional materials such as pharmaceutical agents, nutrients and their supplements, cosmetic materials, color materials, etc. It is an object of the present invention to provide a microimplement for penetration into the skin surface and a method for producing the same. It is another object of the present invention to provide a simple assembling method for sugar material parts such as micro-implements composed of these sugars as a base material.
  • the present invention provides a means for solving the problem to achieve the above-described object
  • the cantilever has a substantially truncated cone shape,
  • the long width of the fine tip of the cantilever is 0.1 m to 100 ⁇ m
  • a microimplement for insertion into the skin surface characterized in that the length from the tip to the end of the cantilever is 50 m to 5 mm, and
  • the length of the fine tip of the cantilever is 0.1 ⁇ m to 100 ⁇ m, and the length from the tip to the end of the cantilever is 50,1 m to 5 mm.
  • the base material of the substrate is one or more selected from saccharides, cellulose, solid starch, paper, wood, plastic, metal, force, etc. Kano's micro-implement for penetration into the skin surface,
  • the cantilever contains one or more selected from protein, DNA, pharmaceutical agent, nutritional agent, nutritional supplement, cosmetic material, color material, metal, metal oxide, microcapsule, force. (1) to (7) the microimplement for insertion into the skin surface, and
  • the microimplement for insertion into the skin surface according to any one of (1) to (8), wherein the cantilever has a structure in which a functional chip is mounted; and (11)
  • the functional chip is a semiconductor chip, integrated circuit chip, temperature sensor chip, protein chip, DNA-containing chip, pharmaceutical agent-containing chip, nutrient-containing chip, nutritional supplement-containing chip, cosmetic material-containing chip, color material (9) or (10) the micro-implement for insertion into the skin surface, characterized in that it is 1 or 2 or more selected from a containing chip, a metal-containing chip, a micro-power chip, a force, and the like, and
  • the surface of the functional chip is covered with a composite sugar material of maltose, maltose and pullulan, polyethylene, polypropylene, and one material of which force is also selected.
  • micro-implement which consists of a cantilever micro mold head having one or two or more fine cantilever inversion-shaped recesses on the upper surface end and a substrate mold having a substrate inversion-shaped recess
  • the micro-implement mold has a temperature control mechanism, and the micro-mold head for the cantilever and the mechanism for allowing the substrate mold to move independently.
  • the micro mold head for a cantilever having a reversal-shaped concave portion of one or more fine cantilevers at an upper end, the micro mold head has a temperature control mechanism and is on the surface of the substrate sheet.
  • the method for producing a microimplement for insertion into the skin surface wherein the microimplement head is manufactured using a micro mold head having a vertically movable mechanism, and
  • the sugar material component is a substrate or a substrate sheet, and the other sugar material component is brought into contact with and welded to the upper end of the side surface of the substrate or the surface of the substrate sheet.
  • the other sugar material part is the cantilever of (3), and the soluble material in the skin of the cantilever is anhydrous amorphous maltose or a complex sugar material of anhydrous amorphous maltose and pullulan (16) Sugar material parts assembly method,
  • the fine cantilever inserted into the skin surface is based on the soluble material in the skin, it is dissolved quickly within the skin surface. Is painless, easy to use, and can contain functional materials such as pharmaceutical agents, beauty agents, nutritional supplements and adjuvants, and color materials in a fine cantilever. There are few kind restrictions and quantitative limits in these agents and materials, and the cantilever has a constricted shape part, so that when the microimplement is inserted into the skin surface, the cantilever easily breaks in the constricted shape part. It has the characteristic effect that it is possible to easily and safely insert the microimplement into the skin surface.
  • the functional chip can be easily and painlessly attached to the skin surface in a stable state, and the skin solubilizer, which is the base material of the cantilever, is anhydrous and amorphous.
  • the skin solubilizer which is the base material of the cantilever, is anhydrous and amorphous.
  • the safety of the human body is high, the strength as a structure without crystal grain boundaries is high, the processing accuracy is high, and the stability is high.
  • the substrate of the substrate or the substrate sheet into saccharides the water-solubility of the substrate can be used to reduce the environmental impact due to the waste treatment! /, And! / Has a positive effect.
  • the cantilever since the cantilever has a substantially pyramid-shaped split shape, it is easy to mount a functional chip on a split surface that forms a horizontal plane at room temperature. Furthermore, the heat resistance of the functional chip is not so required because it is mounted at room temperature, and further, the functional chip is covered with a composite sugar material of maltose, maltose and pullulan, polyethylene, etc. This has the effect of strengthening the adhesion between the cantilever and the one-sided surface of the cantilever (the mounting surface of the functional chip).
  • the cantilever is encapsulated with a functional chip, thereby It is possible to reduce the penetration resistance of the chiller into the skin surface.
  • the heat resistance of the functional chip is required, the surface of the functional chip described above is combined with maltose, maltose and pullulan. Heat protection is possible by coating with sugar material, polyethylene, etc.
  • the functional chip since the functional chip is contained in the cantilever, it has a characteristic effect that it is hardly damaged.
  • the microimplement mold constituted by the micromold head for cantilever and the substrate mold having the concave portion having the inverted shape of the substrate, Has a temperature control mechanism, and has a mechanism that allows the parenthesis micro mold head and substrate mold to move independently, making it easy to manufacture substrate-type micro-implements with high processing accuracy and high structural strength.
  • the micro mold head for cantilever having a temperature control mechanism has a mechanism that can move vertically with respect to the surface of the substrate sheet, so that the processing accuracy is high and the substrate sheet has high structural strength. This has the effect that the micro-implement of the mold can be easily manufactured.
  • the bottom of the casting mold is not used, the limit of the fluid is avoided, and the protrusion is opened using the end (surface part) of the mold so that the fluid can flow.
  • the projection (needle part) and the base part are separated, the mechanical mold is eliminated, the fine part is formed in advance (release), and the separation mold is used to release the base part.
  • the sugar material part is composed of at least one of the two sugar material parts, or a complex sugar material of pullulan and maltose, and therefore uses the adhesiveness of pullulan.
  • these sugar material parts can be brought into contact with each other and welded, and the sugar material parts having a high structural strength can be easily assembled.
  • the sugar material component is a substrate or a substrate sheet made of pullulan or the like, so that the other sugar material component is brought into contact with the upper end portion of the substrate side surface or the substrate sheet surface. It has the effect that it can be welded and a sugar material part having a high structural strength can be easily assembled.
  • the other sugar material part is a cantilever
  • the soluble material in the skin of this cantilever is anhydrous amorphous maltose.
  • a complex sugar material of anhydrous amorphous maltose and pullulan it is possible to easily assemble a microimplement for insertion into the skin surface with high structural accuracy and high processing accuracy! It also has a characteristic effect.
  • FIG. 6 Schematic diagram showing a cross section of a substrate type micro-implement having a constricted portion. 7] Schematic diagram showing a cross section of a substrate type micro implement having a functional chip. 8] Functional chip mounting type.
  • FIG. 3 is a schematic diagram when the microimplement is inserted into the skin surface.
  • FIG. 13 is a schematic diagram showing a combination of a micro mold head for a cantilever and a mold for a substrate.
  • FIG. 14 is a schematic diagram showing a driving micro mold head and a cantilever on a substrate sheet. Explanation of symbols
  • the cantilever means structurally a cantilever, and the tip of the cantilever is a free end, and the end where the cantilever is in contact with the substrate or the substrate sheet is a fixed end.
  • the shape of the cantilever is a half of a pyramid that is close to a quadrangular pyramid, polygonal pyramid, cone, etc. (that is, a substantially pyramid) cut by a plane that passes through a perpendicular extending from the apex of the cone to the bottom of the cone. It is in the form of a single-sided crack, which is referred to as a substantially conical piece in the present invention.
  • the cutting of the substantially cone in the plane is cut so that its volume is almost halved, in other words, the plane is divided so that the bottom of the cone is divided almost in half of its bottom area.
  • the bottom of the cone is almost circular.
  • its half-cracked shape (the cantilever shape at this time is shown in Fig. 3). (Shown) is about half the volume of the cone.
  • the substantially pyramid is a substantially quadrangular pyramid
  • the bottom surface of the cone is almost rectangular, and if the above plane passes through the diagonal of the square, its half-broken shape (the cantilever shape at this time is shown in FIG.
  • the volume is almost half that of the pyramid. However, if the cone bottom area and cone volume are halved, the above plane can pass through any line other than the diagonal line of the cone base. Good. Therefore, since the one-side crack surface of the one-sided shape of the substantially pyramid is horizontal, it is possible to easily mount a functional chip on the one-side crack surface.
  • the size of the cantilever in the present invention is the longest diameter in the shape (substantially polygonal or substantially circular) of the long width of the fine tip of the cantilever, that is, when the apex of the approximate cone is viewed directly in front. However, it is preferably in the range of 0.1 ⁇ 111 to 100 ⁇ 111, but this is physically impossible at less than 0.1 l ⁇ m, and physically into the skin surface at more than 100 in. This is because there is a great deal of resistance and a stinging sensation. Also, the length from the tip to the end of the cantilever ( In other words, the length of the above normal line) is preferably in the range of 50 mm to 5 mm.
  • the insertion of the micro-implement into the skin surface substantially means that the cantilever is inserted into the skin from the skin surface, and the skin (keratin) located on the surface of the skin is called the skin. Layer)), the underlying dermis, and the underlying subcutaneous tissue.
  • the insertion site in the skin is identified according to the insertion purpose, and the cantilever tip force is adjusted accordingly. If you decide the length of
  • the substrate and the substrate sheet refer to a force that is necessary for the above-mentioned cantilever to fix the end portion thereof.
  • the cantilever fixes the end portion to the upper end portion of the side surface of the substrate, (Shown in Fig. 1) and the cantilever that fixes the end of the substrate sheet surface (shown in Fig. 2).
  • This is called a micro-implement for penetration into the skin surface.
  • Fig. 3 shows an enlarged perspective view of a part of the cantilever in the substrate type micro-implement shown in Fig. 1. This is a case where the cantilever is almost in the shape of a half piece of a cone, and its bottom surface is almost the same. Shows a semicircle.
  • FIG. 4 shows an enlarged perspective view of a part of the cantilever in the substrate sheet type micro-implement shown in Fig. 2. This is a case where the cantilever has a substantially half-pyramidal shape, and its bottom surface. Indicates a triangle.
  • the cross-section of the cantilever shown in FIG. 3 is the force S shown in FIG. 5, particularly in the case of a substrate type microimplement, the cantilever's half-break surface 7 and the substrate top surface 8 are connected with almost no step as shown in FIG.
  • the surface is normally parallel. By tilting this parallel contact surface with respect to the substrate sheet surface, it is possible to make the one-side crack surface of the cantilever stand at an angle other than perpendicular to the substrate sheet surface.
  • the shape and size of the substrate and the substrate sheet are not particularly limited, and the shape and size may be specified according to the intended use of the micro-implement for insertion into the skin surface. Further, the micro-implement of the present invention can be mounted on the cantilever according to the purpose of use.
  • the term “implement” is used to mean mounting and mounting in the design field of a semiconductor integrated circuit, but in the present invention, a tool (that is, a tool used for mounting a cantilever on a skin surface) In other words, it means wearing equipment).
  • the cantilever according to the present invention preferably has a constriction-shaped portion between its distal end portion and the distal end portion.
  • the constricted part between the tip and the end of the cantilever This is to make the cantilever easy to break at this shape.
  • This constriction shape has a stepped constriction or a curved constriction. The constriction shape is not particularly limited.
  • the substrate sheet in the present invention refers to a substrate in the form of a sheet, and therefore the base material which is the material thereof is the same as the substrate.
  • the substrate in the present invention and the substrate in the substrate sheet are preferably one or more selected from saccharides, cellulose, solid starch, paper, wood, plastic, metal, force and the like.
  • saccharide include glucose, fructose, galactose for monosaccharides, and maltose, sucrose, ratatoose, cellobiose, trehalose for disaccharides, and other oligosaccharides such as trisaccharides and tetrasaccharides.
  • the substrate sheet is preferably composed of pullulan or a complex sugar material of pullulan and maltose among saccharides! /, But it is preferable to use the adhesiveness of pullulan. This is because the cantilever can be firmly fixed. The reason for using maltose is that it is easy to make a complex sugar material by mixing with pullulan, and it is cheap and easily available. In this case, the mixing ratio of pullulan and maltose is not particularly limited.
  • the skin-soluble material in the present invention literally means a material that can be dissolved in the skin.
  • biocompatible materials such as saccharides, chitin and chitosan, and biodegradation of polylactic acid and the like.
  • saccharides having the highest dissolution rate in vivo are preferable.
  • anhydrous amorphous maltose or a complex sugar material of anhydrous amorphous maltose and pullulan is preferred in terms of safety to the human body and immediate solubility in the skin, and there is no grain boundary. Therefore, it is preferable because a cantilever with high processing accuracy can be obtained.
  • anhydrous amorphous maltose refers to maltose from which water of crystallization has been removed and it is amorphous (amorphous), but this anhydrous amorphous maltose is low molecular weight and anhydrous. It is easy to mix with polysaccharide aqueous solutions such as pullulan, that is, when anhydrous amorphous maltose and pullulan aqueous solution are mixed, pullulan hydrated molecules are easily taken into maltose, and a complex sugar material with a good mixing state is obtained. It is easy to be done.
  • the pullulan adhesiveness makes it extremely easy to bond the bottom surface of the cantilever to the side surface of the substrate or the surface of the substrate sheet.
  • the mixing ratio of anhydrous amorphous maltose and pullulan is not particularly limited, but 1: 0 to; 1: 9 is preferred, and in order to emphasize the characteristics of pullulan, 1: 1 or more is preferable.
  • the immediate solubility in the skin means that the dissolution in the skin is extremely fast. From the viewpoint of safety and convenience after inserting a cantilever made of a soluble material in the skin into the skin surface, The cantilever is preferably dissolved in about 60 seconds at the latest, and more preferably in about 30 seconds at the latest.
  • the cantilever in the present invention preferably contains one or more selected from protein, DNA, pharmaceutical agent, nutrient, nutritional supplement, cosmetic material, color material, metal, metal oxide, and microcapsule.
  • proteins there are general proteins such as albumin, actin, and myosin, and pharmaceutical proteins for treatment, etc.
  • DNA there are cells that are not encapsulated! /, Pure DNA, etc.
  • transdermal administration! / An effective analgesic agent, insulin effective in treating diabetes, lidocaine as a local anesthetic, chlorhexine dalconate effective in periodontal disease, etc.
  • a force that is not particularly limited.
  • FIG. 10 is a schematic diagram showing a state in which a normal cantilever 18 and a cantilever 19 having a constricted portion are inserted into the skin surface of a substrate-type microimplement containing a functional material.
  • the direction force of the cantilever 19 having the constricted portion is easier to penetrate into the skin surface than the normal cantilever 18 because the resistance of the constricted portion is less.
  • FIG. 11 is a schematic diagram showing the state after insertion of both cantilevers.
  • a cantilever having a constricted portion is naturally used.
  • the cantilever remains deeper in the skin surface than when a normal cantilever is used, that is, the cantilever 21 remains deeper in the skin surface than the cantilever 20.
  • the functional material diffuses and permeates, but the area is naturally proportional to the insertion position of the cantilever, and the diffusion permeation area 23 is more than the diffusion permeation area 22.
  • There are two types of cantilevers according to the present invention which have a structure in which a functional chip is mounted on the surface (see FIG. 7) and a structure in which a functional chip is mounted inside.
  • the functional chip In the case of the former, it is easy to mount the functional chip on one side that forms a horizontal plane at room temperature, and the thermal resistance of the functional chip is not so required for mounting at normal temperature.
  • the heat resistance of the functional chip is required, it is possible to take heat countermeasures by coating the surface of the functional chip with maltose, maltose and pullulan complex sugar material, polyethylene, etc.
  • the functional chip in the present invention includes a semiconductor chip, an integrated circuit chip, a temperature sensor chip, a protein chip, a DNA-containing chip, a medicine-containing chip, a nutrient-containing chip, a nutritional supplement-containing chip, a cosmetic material-containing chip, and a color material-containing chip.
  • a chip, a metal-containing chip, a microcapsule-containing chip, or one or more functional chips selected is preferable.
  • the surface force of the functional chip is preferably coated with one material selected from maltose, maltose and pullulan complex sugar materials, polyethylene, polypropylene, and force.
  • the base material of the above chip is not particularly limited, but from the viewpoint of the affinity of the base material used in the present invention, a saccharide is used as a base and it contains a pharmaceutical agent, a functional material and the like.
  • a saccharide is used as a base and it contains a pharmaceutical agent, a functional material and the like.
  • sugars that can be used for example, maltose, anhydrous amorphous maltose, and complex sugar materials thereof with pullulan can be used.
  • FIG. 8 is a schematic diagram showing a state in which a normal force cantilever 12 and a cantilever 13 having a constricted portion are inserted into the skin surface of a substrate-type microimplement. A cantilever 13 having a force constricted portion 13 is shown.
  • FIG. 9 is a schematic diagram showing the state after insertion of both cantilevers. Both cantilevers dissolve and disappear in the skin, and then leave their chips. Of these tips, when a cantilever having a constricted part is used, the tip remains naturally at a deeper position in the skin surface than when a normal cantilever is used. Also remains deep within the skin surface.
  • a micro mold head for a cantilever having a concave portion of a fine cantilever at the upper surface end in a micro cantilever manufacturing method is an anhydrous amorphous maltose or a composite of anhydrous amorphous maltose and pullulan.
  • a substrate mold having a concave portion with an inverted shape of the substrate is a substrate mold that can be formed into a substrate that can support a cantilever and can be incorporated into a micro mold head.
  • the temperature control mechanism of the micro-implement mold is a temperature control mechanism capable of rapidly heating and melting the above-mentioned base material formed by the micro-mold head and cooling and solidifying it.
  • the micro-mold head for cantilever and the substrate The mechanism that can move the mold independently can prioritize the molding of the fine cantilever shape and drive only the micro mold head in advance. After the cantilever is released and molded, the substrate can be released by separate drive. This is the mechanism. As a result, the substrate type micro-implement can be manufactured.
  • the mechanism that the micro mold head for cantilevers can move vertically with respect to the surface of the substrate sheet means that one or more cantilevers are provided perpendicularly to the surface of the substrate sheet.
  • the method of moving to the formation of the next cantilever is a mechanism in which the micro mold head is once retracted in the direction perpendicular to the sheet and then moved to the position of the next cantilever.
  • FIG. 14 shows a schematic diagram of a micro mold head and a substrate sheet.
  • a temperature control heater is used as the temperature control mechanism
  • a drive stage is used as the movable mechanism.
  • the substrate sheet type micro-implement can be manufactured.
  • the temperature control mechanism in the present invention is not particularly limited, any temperature control mechanism can be used as long as it can control the temperature from 50 ° C. to about 200 ° C. and can maintain a constant temperature, for example. it can.
  • the cantilever can be manufactured and assembled separately from the substrate or the substrate sheet, the tip can be sharp! /,
  • the cantilever can be manufactured with high accuracy, and the shape of the sword mountain shape. It becomes possible to easily manufacture a micro implement having a large number of cantilevers within a certain area. Also, the material of the cantilever and the material of the substrate or the substrate sheet can be different.
  • the materials of the substrate and the fine needle are always the same, and even when a plurality of fine needles are provided, the drug that can be mixed with the fine needles is monolithic, which is limited to a single item.
  • fine needles cannot be formed on the surface of the sheet-like base material, and a very large restriction is imposed on the shape of the microimplement.
  • the method of the present invention it is possible to introduce an assembly method in which the substrate is manufactured in advance and only the cantilever-shaped microneedles can be manufactured later, which is different from the case where the substrate and the microneedles are integrally formed.
  • the needle tip accuracy can be maintained without being affected by the substrate. This makes it possible to manufacture cantilevers with a fine tip of less than 10 m, and it is possible to accurately manufacture even cantilevers with a fine tip length of 2 to 3 m. For this reason, it was possible to reduce the pressure applied when the cantilever was inserted into the skin, and to achieve sufficient pain-freeness.
  • a mechanism which is adapted to drive the mold cantilever as Heddode device enables ideal sword mountain shape fabrication as shown in FIG. 2, a high density of needle (cantilever such 1 cm 2 per 100 or more Even a micro-implement with) can be manufactured. Furthermore, since the cantilever can be formed regardless of the shape of the substrate, it is possible to use a sheet-like substrate or the like that is only a plate-like substrate, and the degree of freedom of the shape of the micro-implement is increased. In addition, since the cantilever is assembled on the substrate, the base material and the fine needle material can be made different, and different cantilevers can be incorporated in each cantilever.
  • the sugar material part assembling method of the present invention comprises at least one of the two sugar material parts, S, pullulan, or a composite sugar material of pullulan and maltose. Force to contact and weld S is suitable. Further, the sugar material component composed of pullulan, or a composite sugar material of pullulan and manoletose is a substrate or a substrate sheet, and the other sugar material component is brought into contact with the upper end of the side surface of the substrate or the surface of the substrate sheet for welding. It is preferable to let this occur.
  • the other sugar material component is a fine cantilever
  • the soluble material in the skin of the cantilever is anhydrous amorphous maltose, or anhydrous amorphous maltose and pullulan. of A complex sugar material is preferred.
  • the bottom surface has a diameter of 200 ⁇ m, and the perpendicular length from the apex to the bottom surface is 550 ⁇ m.
  • a stainless steel plate vertical length: 15 mm, horizontal length: 5 mm, thickness: 1 mm
  • the four inverted concavities of the above-mentioned substantially conical cracked shape are dug by machining so that the shape of the fine tip of the cantilever is almost circular (diameter 0.
  • a mold head for a cantilever was produced.
  • a substrate mold having a concave portion having a reverse shape of the above-mentioned substrate is manufactured.
  • a combination of cantilever mold head and substrate mold having the shape shown in Fig. 13 was produced. If you look directly at the substrate mold with the mold head removed, you will see a U-shape.
  • this U-shaped mold substrate was combined with the above-mentioned cantilever mold head to form a concave-shaped substrate mold.
  • the substrate material a mixture of saccharide maltose and pullulan (50% by weight maltose and 50% by weight pullulan dissolved in 105 ° C) was used, and the above-mentioned mouth shape maintained at 105 ° C.
  • the substrate raw material was poured into a substrate mold until the substrate had a thickness force of S lmm, and was slowly cooled to 80 ° C. to produce a substrate.
  • anhydrous amorphous maltose dissolved at 105 ° C was poured into the recess of the mold head to produce a cantilever, and then slowly cooled to room temperature to produce the microimplement shown in FIG.
  • the length of the vertical line from the apex to the bottom is 550 m at the top of the side of the substrate, which is 10 mm long, 50 mm wide, and 1 mm thick, at the top of the side of the substrate, with a bottom diameter of 200 m.
  • a cantilever with a roughly conical piece (its bottom is a semicircle with a diameter of 200 m), and its fine tip A cantilever force S having a substantially circular shape (diameter 0.3 m), and four substrate-type micro-implements arranged in the longitudinal direction of the substrate were assembled and manufactured.
  • FIG. 1 is a schematic diagram, the size of the cantilever and the substrate are not relatively matched.
  • the force used by dissolving the substrate and the cantilever raw material at 105 ° C was put into the mold and die head held at 105 ° C in the above-mentioned state in the state of particles. It's okay.
  • the cantilever mold head and substrate mold having the shape shown in FIG. 13 are used, and these are held at 105 ° C., and the raw material is poured into the cantilever mold and substrate.
  • the cantilever and the substrate are made of the same material.
  • the substrate sheet type micro-implement with the shape shown in Fig. 2, first, 30% by weight of pullulan and 30% by weight of maltose were mixed together, and then 40% of water was added to create a viscous state. Furthermore, it is stretched into a sheet shape and dried. A substrate sheet of 10 mm in length, 10 mm in width, and 0.5 mm in thickness (with a composition ratio of 50% by weight of pullulan and 50% by weight of maltose, the substrate sheet is square when viewed from directly above. ) was produced. Next, it is a rhombus that is a combination of two equilateral triangles with a bottom of 150 m on one side, and the vertical length from the apex to the bottom is 500 m.
  • the mold head held at 80 ° C was brought into contact with the substrate sheet surface, and anhydrous amorphous maltose dissolved at 105 ° C and A composite sugar material with pullulan (anhydrous amorphous 50% by weight, pullulan 50% by weight composition ratio) is poured into the mold head, and after forming the cantilever, the mold head is retracted in a direction perpendicular to the substrate sheet surface. Then, a cantilever was fabricated on the surface of the substrate sheet as shown in FIG. Next, the mold head is moved laterally at a pitch interval of 250 ⁇ m, and this mold head is placed on the substrate sheet surface.
  • the mold head is moved forward and brought into contact, the above complex sugar material dissolved at 105 ° C is poured into the mold head, and after the cantilever is formed, the mold head is moved backward in a direction perpendicular to the substrate sheet surface, A second cantilever was fabricated on the substrate sheet surface.
  • the cantilever for a total of 30 on the surface of the substrate sheet with a total pitch of 5 and 6 with a pitch interval of 250 m (having the above-mentioned substantially quadrangular pyramid piece shape)
  • a substrate sheet type micro-implement having the structure shown in Fig. 2 and a structure in which cantilevers were arranged was assembled and manufactured. However, since FIG.
  • FIG. 2 is a schematic diagram, the size of the cantilever and the substrate sheet are not relatively matched.
  • the force S that required the above-mentioned repetitive operation 30 times using a die head for producing one cantilever was used, and six cantilevers for the die head in the vertical direction.
  • an inversion-shaped concave part it is only necessary to repeat the operation five times, and it is possible to produce a micro-implement very efficiently.
  • Example 1 When the substrate-type microimplement of Example 1 was inserted into the skin surface of the back of the hand, it was painless, and it was confirmed by observation with a microscope that the cantilever melted and disappeared in about 1 minute. Furthermore, when the surface of the skin was observed with a microscope, it was confirmed that four almost semicircular holes with a diameter of about 150 m were opened in the skin surface. When a finger was pressed near the hole, a small amount of blood came out of the hole, so it was possible to measure the blood glucose level by collecting a few mg of the blood.
  • Example 2 When the substrate sheet type microimplement of Example 2 was inserted into the skin surface of the back of the hand, it was confirmed that the cantilever melted and disappeared in about 1 minute by observation with a microscope. Furthermore, when the skin surface was observed with a microscope, it was confirmed that approximately ellipsoidal holes with a diameter of about 100 m were opened at 30 locations on the skin surface. After pressing these points with your finger and wiping the blood that has come out with absorbent cotton, applying an aqueous solution of sodium ascorbate phosphate 1% to the skin surface of those locations, the aqueous solution quickly spills into those holes. Was able to penetrate the aqueous solution into the skin surface.
  • the cantilever The force used for opening this is because vitamin C, which is easily decomposed by heating, such as sodium ascorbate phosphate, cannot be included in cantilevers formed by overheating. As a result, vitamin C was able to penetrate into the skin more effectively.
  • a substrate-type microimplement was produced in the same manner as in Example 1 using anhydrous amorphous maltose containing 1% by weight of lidocaine, which is a kind of local anesthetic, as a base material of the cantilever.
  • This microimplement was inserted into the skin surface of the abdomen of the rat, and as a result of plasma analysis, it was found that lidocaine was present in the plasma, which confirmed the penetration of lidocaine into the whole body of the rat.
  • a substrate sheet type micro-implement was prepared in the same manner as in Example 2 using a composite sugar material with anhydrous amorphous maltose containing 0.3% by weight of ⁇ -arbutin as a whitening cosmetic material and pullulan as a base material. Produced. However, each of the 30 cantilevers has a constricted portion at a position 150 m from the fine tip, and the cantilever is easily broken at the constricted portion. This micro-implementation was conducted once a day in a series of experiments in which the skin surface with brown spots on the face (within 200 m from the skin surface) was inserted. It was confirmed by visual observation that the thickness was thin.
  • Example 8 The complex sugar material with whitening cosmetic material in which vitamin C kind Asukorubin magnesium phosphate 1wt 0/0 containing anhydrous amorphous maltose and pullulan as a substrate material, in the same manner as in Example 2, A substrate sheet type micro-implement was produced. However, each of the 30 cantilevers has a constricted portion at a position 150 inches from the fine tip, and the cantilever is easily broken at the constricted portion. As a result of conducting an experiment in which the microimpregnation was inserted into the skin surface (within 200 m from the skin surface) with brown spots on the face once a day, about one month passed as in Example 7. As a result, the brownish stain on the face faded and was confirmed.
  • Example 11 As a result of lightly applying the substrate sheet type microimplement of Example 2 to the skin surface of the back of the hand five times, it was confirmed by observation with a microscope that a large number of holes were opened on the skin surface. At a place open these holes have a whitening effect, a relatively unstable chemicals aqueous solution containing 1 weight 0/0 Asukorubin magnesium phosphate is more applied to the glass rod, using a glass rod By imprinting the liquid onto the skin, ascorbic acid magnesium phosphate was able to penetrate into the stratum corneum as in Example 9.
  • Example 11 Example 11
  • Example 12 Using anhydrous amorphous maltose containing 5% by weight of a mixture of titanium oxide and oxidative iron (1: 1 composition ratio), which is a skin-colored cosmetic material, as a base material, in the same manner as in Example 2, A substrate sheet type micro-implement was produced. However, each of the 30 cantilevers has a constricted portion at a position 150 m from the fine tip, and the cantilever is easily broken at the constricted portion. This micro-implement is brown on the face As a result of experiments conducted within the surface of the skin where there was a stain (within 200 m from the surface of the skin), it was confirmed by visual observation that the brown stain on the face had faded and the skin color was strengthened.
  • Example 12
  • a substrate-type microimplement was produced in the same manner as in Example 1 using anhydrous amorphous maltose containing 5% by weight of a natural gardenia red pigment, which is a pigment specified in the body.
  • each of the four cantilevers similarly has a constricted portion at a location 100 inches from the fine tip, and the cantilever is easily bent at the constricted portion.
  • this microimplement was inserted into the skin surface of the back of the hand, it was confirmed by visual observation that a pigment was left in the skin stratum corneum.
  • simple and safe tattooing became possible. Arbitrary notation within the stratum corneum became possible.
  • a substrate type microimplement was produced in the same manner as in Example 1 using anhydrous amorphous maltose containing 1% by weight of orange dye tartardin as a base material. After inserting the microimplement into the skin surface of the abdomen of the rat, the cross section of the skin was observed with a microscope, and it was confirmed that the tartardin dye penetrated deep into the skin.
  • a substrate-type micro-implement was prepared in the same manner as in Example 1, using anhydrous amorphous maltose containing 1% by weight of Coomassie brilliant blue (CBB), a blue pigment with strong adhesiveness to proteins. did. After inserting this microimplement into the skin surface of the abdomen of the rat, the cross-section of the skin was observed with a microscope, and it was confirmed that the CBB color reflected the cross-sectional shape of the microcantilever insertion. .
  • CBB Coomassie brilliant blue
  • Albumin which is a kind of protein, is contained in 3% by weight of a disk-shaped chip (diameter 50 m, thickness 5 111) of pullulan and anhydrous amorphous maltose (1: 1 composition ratio).
  • Substrate type micro-implementation of Example 1 (however, three of the four cantilevers were removed A microchip with a functional chip mounted type was fabricated by bonding it at room temperature on the one side of the chip. When the microimplement was inserted into the skin surface of the back of the hand, as a result of microscopic observation and chemical analysis of the extracted corneocytes, albumin remained in the stratum corneum! .
  • Insulin effective in treating diabetes is contained in 1% by weight of a disk-shaped chip (diameter 50 m, thickness 5 111) of pullulan and anhydrous amorphous maltose (1: 1 composition ratio).
  • a disk-shaped chip (diameter 50 m, thickness 5 111) of pullulan and anhydrous amorphous maltose (1: 1 composition ratio).
  • Example 1 but three of the four cantilevers were removed) to produce a micro-implement with a functional chip.
  • the micro-implement was inserted into the skin surface of the back of the hand, it was confirmed that the insulin remained in the stratum corneum as a result of observation with a microscope and chemical analysis of the extracted corneocytes.
  • Carotenoid a type of vitamin A, a nutritional supplement
  • a disc-shaped chip (diameter 50 m, thickness 5 m) of pullulan and anhydrous amorphous maltose (1: 1 composition).
  • the chip is bonded to one side of the cracked surface of the substrate type micro-implement in Example 1 (however, three of the four cantilevers are removed) at room temperature, so that the functional chip mounted type A micro-implement was made.
  • the microimplement was inserted into the skin surface of the back of the hand, observations using a microscope and chemical analysis of the extracted corneocytes confirmed that the carotenoid remained in the stratum corneum.
  • Hyaluronic acid as a humectant is contained in 3% by weight of a disk-shaped chip (diameter 50 m, thickness 5 m) of pullulan and anhydrous amorphous maltose (1: 1 composition ratio).
  • a microchip (with a functional chip mounted type) in which the above chip is mounted inside the cantilever in the same manner as in Example 1 except that it is inserted into one recess of the mold head for the cantilever in Example 1. And only one cantilever).
  • hyaluronic acid which was decomposed by heating as a result of observation with a microscope and chemical analysis of the extracted corneocytes, was found. It was confirmed that it stayed in the stratum corneum and was able to administer hyaluronic acid easily into the skin surface.
  • Adhesive consisting of a composite sugar material (1: 1 composition ratio) of pullulan and anhydrous amorphous maltose on the back of a so-called IC tag, an IC chip with a side of 200 ⁇ m and a thickness of 10 ⁇ m Then, the back surface of the substrate-type microimplement of Example 1 was bonded to the one side of the substrate-type microimplement at room temperature to produce an IC tag-mounted microimplement. When the microimplement was inserted into the skin surface of the back of the hand, observation with a microscope confirmed that the IC chip remained in the stratum corneum 100 m below the skin surface.
  • a micro silicon substrate temperature sensor chip with a side of 150 ⁇ m and a thickness of 10 ⁇ m was covered with polyethylene and the lead wire was left on the substrate type micro-implementation of Example 1 (however, 4 (3 out of the cantilevers were removed) were bonded at room temperature to a micro-implement with a micro silicon substrate temperature sensor chip.
  • the microimplement was inserted into the skin surface of the back of the hand, as a result of observation with a microscope, it was confirmed that it remained in the stratum corneum 50 m below the skin surface, and the lead wire was externally exposed. In addition, the signal could be extracted through the lead wire, so that the temperature inside the body could be measured accurately.
  • Human IgG antibody a disk-shaped chip of pullulan and anhydrous amorphous maltose (1: 1 composition ratio) 0.25% by weight in a diameter of 50 111 and a thickness of 5 111), and the chip is divided into parts of the substrate type micro-implement of Example 1 (however, three of the four cantilevers are removed)
  • a human IgG antibody-containing micro-implement was fabricated by bonding it at room temperature. After conducting an in-vivo experiment in which the microimplement was administered to the skin of the abdomen of the rat, the cross-section of the rat skin was observed with a microscope, and the presence of human IgG in the rat skin was confirmed.
  • the DNA portion is contained in a disk-shaped chip (diameter 50 111, thickness 5 m) of pullulan and anhydrous amorphous maltose (1: 1 composition ratio), and the chip is used as the substrate type of Example 1
  • a micro-implement with a DNA-containing chip mounted was fabricated by bonding the micro-implant (however, three of the four cantilevers were removed) to one side of the cracked surface at room temperature. When the microimplement was inserted into the skin surface of the back of the hand, it was confirmed by observation with a microscope that the DNA part remained in the stratum corneum!
  • a substrate-type microimplement was produced in the same manner as in Example 1 using anhydrous amorphous maltose containing 2 wt% of iron particles having a diameter of 25 Hm or less as a base material of the cantilever. After inserting this micro-implement into the skin surface of the back of the hand, the high-sensitivity time sensor can count the iron particles in the skin surface, and the number correspondence can be taken. Application of this method suggests the possibility of convenient use for inpatient numbering.
  • a micro-force psell (particle size: 1 ⁇ m) containing 1% by weight of lidocaine and the base material is anhydrous amorphous maltose, a disk of pullulan and anhydrous amorphous maltose (1: 1 composition ratio)
  • a chip-shaped chip (diameter 50 m, thickness 5 111) containing 5% by weight, and the chip is a single-sided surface of the board-type micro-implement of Example 1 (however, three of the four cantilevers are removed)
  • the microcapsule-mounted microimplement was fabricated by bonding it at room temperature. After the microimplement was inserted into the skin surface of the abdomen of the rat, the cross-section of the skin was observed with a microscope, and as a result, lidocaine was present on the skin surface. Was confirmed.
  • the skin surface microimplement and the method for producing the same of the present invention have the above-mentioned various characteristic effects.
  • the medical field the field of nutrients and supplements, the field of beauty, the field of cosmetics, the field of application of various functional materials. It can be used in application fields of microcapsules and functional chips.
  • the sugar material parts assembling method can easily and efficiently assemble sugar material parts, it can be used in the application fields of various sugar material parts.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Medical Informatics (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

L'invention concerne un micro-dispositif pour une introduction dans la surface de la peau qui assure une excellente sécurité, aucune douleur et une facilité d'utilisation, qui présente moins de limitations quantitatives ou de restrictions dans la variété du matériau fonctionnel, etc., et qui présente aussi une résistance de structure élevée, une stabilité élevée et une précision d'usinage élevée, et qui, à la mise au rebut de celui-ci, est très faible en charge environnementale ; l'invention concerne également un procédé de fabrication du micro-dispositif, et un procédé pertinent d'assemblage de parties de matériau de sucres. L'invention concerne un micro-dispositif pour une introduction dans la surface de la peau ayant de minuscules extensions d'un matériau soluble dans la peau, disposées sur une partie de bord supérieur de la face latérale du substrat ou sur la surface d'une feuille de substrat, chacune des extensions ayant approximativement une configuration de cône à moitié fendu et ayant une dimension donnée. En outre, l'invention concerne le procédé de fabrication du micro-dispositif ci-dessus et un procédé pertinent d'assemblage de parties de matériau de sucres.
PCT/JP2007/064346 2006-07-21 2007-07-20 Micro-dispositif, procédé de fabrication et procédé d'assemblage de partie de matériau de sucres Ceased WO2008010573A1 (fr)

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JP2009178531A (ja) * 2008-01-31 2009-08-13 Yoshiichi Tobinaga 微細糖質針、その製造方法及び製造装置
JP2010069270A (ja) * 2008-09-17 2010-04-02 Yoshiichi Tobinaga 機能剤投与デバイス、その製造方法及び製造装置
JP2010141278A (ja) * 2008-12-10 2010-06-24 Yoshiichi Tobinaga 多糖質配線基板及びその製造方法
JP2010142472A (ja) * 2008-12-19 2010-07-01 Toppan Printing Co Ltd 胴部に括れを有する突起部を具備する針状体およびその製造方法
JP2010240281A (ja) * 2009-04-09 2010-10-28 Toppan Printing Co Ltd マイクロニードルチップ、マイクロニードルチップ製造方法、履歴管理システム
EP2614854A1 (fr) * 2012-01-13 2013-07-17 Technische Universität Berlin Dispositif de piqûre répétée d'un tissu organique, module d'application et procédé
JP2014079557A (ja) * 2012-09-28 2014-05-08 Kosumedei Seiyaku Kk 段差に薬物を保持したマイクロニードル
JP2014147815A (ja) * 2014-04-07 2014-08-21 Toppan Printing Co Ltd マイクロニードルチップ履歴管理システム

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KR101610598B1 (ko) * 2015-09-21 2016-04-07 비엔엘바이오테크 주식회사 잇몸 굴곡에 맞게 유연하며 치과용 물질 전달을 위한 마이크로 니들 및 그 제작방법
JP7147289B2 (ja) * 2018-06-26 2022-10-05 凸版印刷株式会社 マイクロニードルデバイス
WO2025197082A1 (fr) * 2024-03-22 2025-09-25 合同会社マイクロコンプレックス Micro-outil et son procédé de production

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Publication number Priority date Publication date Assignee Title
JP2009178531A (ja) * 2008-01-31 2009-08-13 Yoshiichi Tobinaga 微細糖質針、その製造方法及び製造装置
JP2010069270A (ja) * 2008-09-17 2010-04-02 Yoshiichi Tobinaga 機能剤投与デバイス、その製造方法及び製造装置
JP2010141278A (ja) * 2008-12-10 2010-06-24 Yoshiichi Tobinaga 多糖質配線基板及びその製造方法
JP2010142472A (ja) * 2008-12-19 2010-07-01 Toppan Printing Co Ltd 胴部に括れを有する突起部を具備する針状体およびその製造方法
JP2010240281A (ja) * 2009-04-09 2010-10-28 Toppan Printing Co Ltd マイクロニードルチップ、マイクロニードルチップ製造方法、履歴管理システム
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JP2014079557A (ja) * 2012-09-28 2014-05-08 Kosumedei Seiyaku Kk 段差に薬物を保持したマイクロニードル
JP2014147815A (ja) * 2014-04-07 2014-08-21 Toppan Printing Co Ltd マイクロニードルチップ履歴管理システム

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