JP2013090808A - Microneedle device and manufacturing method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a high-quality microneedle device having a fluid conduit (through-hole), which can puncture a skin with small power without pain, and can smoothly perform the infusion of a drug or the suction of blood, a body fluid, etc. after the puncture.SOLUTION: The microneedle device 10 is a structure in which a plurality of needle-shaped projections 12 are formed on a flat base plate 11 so as to be integrated with the flat base plate 11 and aligned, wherein a distal end 17 side of the needle shape projection 12 from the boundary surface 13 is composed of a first material 14a that shows solubility in a body, and a flat base plate 11 side thereof is composed of a second material 14b that is insoluble, and has the fluid conduit 15 that is formed in the needle-shaped projections 12 and penetrates only a bottom surface side of the flat base plate 11.

Description

  The present invention relates to a microneedle device and a manufacturing method thereof.

  The microneedle device has a structure including a plurality of fine needle-like protrusions that transfer a chemical solution into the body through the skin of a human body or suck blood or body fluid from the body. For example, in Patent Documents 1 and 2, in a microneedle device in which a plurality of fine needle-like protrusions are formed on a substrate and a through-hole is provided in the needle-like protrusion, an opening on the needle side of the through-hole is provided. The thing of the structure provided in the most advanced part of the acicular protrusion is disclosed.

  In addition, a structure in which the needle side opening of the through-hole is provided on the inclined surface of the needle-like protrusion is often used for reasons such as improving the puncture property of the human skin and facilitating replication (for example, patents) References 3 and 4).

  Patent Documents 2 and 4 describe a method for duplicating and forming a microneedle device having the through hole. That is, the first duplication and molding method includes a first mold die having a reversal shape of needle-like projections, and a second mold die having struts having a reversal shape of through holes provided at the same pitch as the needle-like projections. The sheet-shaped resin material is sandwiched between the upper and lower half molds, and the resin material is melted by heat, while the gap between the upper and lower half molds is narrowed to press the material. This is a method of forming into a microneedle shape. The second replication and molding method is to form a microneedle device without a through-hole in advance by hot pressing or the like, heat a sword-shaped mold with a support having a reverse shape of the through-hole on the substrate, This is a method of providing a through hole by piercing from a bottom surface side of the microneedle having no through hole in a column of the type.

JP-T-2002-521222 Japanese translation of PCT publication No. 2003-501161 JP-T-2004-507371 Special table 2006-518675 gazette

  However, in the case of the microneedle device in which the opening of the through hole is provided at the most distal portion of the needle-like protrusion as in Patent Documents 1 and 2, the contact area with the skin is relatively large due to the structure. As a result, the resistance at the time of puncture increases, and a large force is required to reliably pierce the plurality of needle-like protrusions into the skin. In addition, an increase in puncture resistance is a factor that increases pain. Furthermore, part of the skin tissue enters the through-hole and becomes clogged, making it very difficult to inject a chemical solution or suck blood, body fluid, and the like.

  Moreover, when the opening part of a through-hole is provided in the inclined surface of a needle-like protrusion like patent document 3 and 4, since the initial contact area with skin can be made small, the puncture capability has an opening part in the front-end | tip Improvement can be expected compared to. However, since the skin tissue pushed away around the inside of the skin after puncture adheres to the surface of the needle-like projection, the opening of the through-hole is closed, and smooth drug injection or suction of blood, body fluid, etc. There is a problem that cannot be performed.

  Furthermore, there is a problem with the method of replicating and forming the microneedle device. For example, in the case of a duplication and molding method in which a final shape is obtained by pressing a material between molds divided into upper and lower parts as in Patent Documents 2 and 4, burrs (resin is not formed in the gap between the mating surfaces of the molds). In order to form a uniform through-hole without a phenomenon of flowing in), a depression pitch of the first mold die provided with a depression having a reversal shape of the needle-like projections and a plurality of reversal shapes of the through-holes It is necessary to match the column pitch of the second mold die having the elongated columns with high accuracy.

  In addition, it is important that not only the pitch but also the tip end of the support is in close contact with the recessed portion having the inverted shape of the needle-shaped protrusion of the first mold die without any gap. That is, the height position of the mating surface between the upper surface of the second mold post and the first mold is required to have very high accuracy.

  The present invention provides a microneedle device having a fluid conduit (through hole) that can be punctured without pain with a small force on the skin, and after puncture, can smoothly inject a drug or suck blood, body fluid, etc. An object is to provide a possible high quality microneedle device.

  It is another object of the present invention to provide a method for manufacturing a high-quality microneedle device with less burrs and the like without requiring high accuracy at the mating portion of the divided mold dies.

According to a first aspect of the present invention, there is a structure in which a plurality of conical or polygonal fine needle-like projections are integrally aligned with the substrate on the upper surface of a flat substrate,
The acicular protrusion has a fluid conduit that is perpendicular or substantially perpendicular to the substrate, and the fluid conduit is slightly closer to the tip side of the acicular protrusion from the boundary surface. The needle-like protrusions are made of different materials in two layers, upper and lower, with a boundary surface that is horizontal or at least smaller than 90 ° as the boundary, It is a soluble material that dissolves when the first material in the tip side portion from the boundary surface comes into contact with the human skin, and does not dissolve even when the second material in the substrate side portion from the boundary surface comes into contact with the human skin. A microneedle device is provided that is an insoluble material.

According to the second aspect of the present invention, the soluble material that dissolves when it comes into contact with the skin of the human body in each hollow portion of the first mold mold having the inverted shape of a plurality of conical or polygonal fine needle-like projections A first step of filling a certain amount of the first material comprising:
A second mold die comprising a plurality of elongated struts corresponding to the inverted shape of the plurality of needle-like protrusions on the first mold die filled with a predetermined amount of the first material in the first step. The second step of forming a cavity space having the shape of the target molded product on the mating surface portion of the mold, and facing and closely contacting so that the recess and the column are in the same position;
A third step of curing the first material in the cavity space formed by the second step;
After the third step, a fourth step of injecting and filling a second material made of an insoluble material that does not dissolve even when contacting the human skin into the cavity space;
After the fourth step, the second mold die and the first mold die are separated from each other, and are made of the first and second materials that are cured and integrated with each other, and according to the first aspect. A fifth step of taking out a molded product which is a structure in which a plurality of conical or polygonal fine needle-like projections are aligned with the substrate on the upper surface of a flat substrate;
A method for manufacturing a microneedle device is provided.

  According to the present invention, in a microneedle device having a fluid conduit (through hole), it is possible to puncture the skin without pain with a small force, and after the puncture, a drug injection or a suction of blood, body fluid, etc. is smoothly performed. It is possible to provide a high-quality microneedle device that can be used.

  In addition, according to the present invention, it is possible to provide a method of manufacturing a high-quality microneedle device with few burrs and the like without requiring high accuracy at the divided mold die mating portion.

1 is a longitudinal side view schematically showing a microneedle device according to an embodiment of the present invention. It is a perspective view which shows roughly the external appearance example of a microneedle device. It is a vertical side view which shows the manufacturing method of a microneedle device in order of a process. It is a vertical side view which shows roughly the mounting | wearing form to the applicator of a microneedle device. It is a perspective view which shows roughly the mounting form to the applicator of a microneedle device. It is a vertical side view which shows the procedure of the puncture to the skin of a microneedle device, and a chemical | medical solution administration.

  Embodiments of the present invention will be described below with reference to the drawings.

  FIG. 1 is a schematic cross-sectional view showing a microneedle device according to an embodiment of the present invention.

  As shown in FIG. 1, the microneedle device 10 according to the embodiment has a structure in which a plurality of needle-like protrusions 12 are integrally formed on a flat substrate 11.

  The acicular protrusion 12 is composed of first and second materials 14a and 14b having two different upper and lower layers with a boundary surface 13 that is horizontal or at least smaller than 90 ° with respect to the substrate 11. . A fluid conduit 15 that is perpendicular or substantially perpendicular to the substrate 11 is formed inside the needle-like protrusion 12. Note that “substantially perpendicular” means a state in which the inclination is within a range of ± 20 ° with respect to the vertical. One end of the fluid conduit 15 opens to the bottom surface of the substrate 11 to form an opening 16, and the other end does not open to the surface on the distal end side of the needle-like protrusion 12, but slightly distal to the boundary surface 13. A blind hole is formed at a position closer to the portion 17.

  The 1st material 14a which comprises the acicular protrusion 12 is located in the front-end | tip part 17 side rather than the boundary surface 13, and is comprised with the soluble material which melt | dissolves with the body temperature, if it contacts human skin. The second material 14b is located on the substrate 11 side with respect to the boundary surface 13, and is made of an insoluble material that does not dissolve at the body temperature even when it contacts the human skin. The material of the substrate 11 is preferably the same as the second material (insoluble material) 14b under the needle-like protrusions 12, but is limited to this if it is insoluble when in contact with the human skin. It is not a thing.

  The length of the needle-like protrusion 12 from the upper surface of the substrate 11 is preferably 100 to 2000 μm, and more preferably 1500 to 1800 μm. It is preferable that the length of the part comprised by the 1st material (soluble material) 14a of the acicular protrusion 12 is 100-300 micrometers.

  The inner diameter at the blind hole position of the fluid conduit 15 is preferably 10 to 50 μm. In order to reduce the flow resistance, the inner diameter of the opening 16 of the fluid conduit 15 is more preferably as large as possible at least equal to the inner diameter of the blind hole position or less than the pitch interval between the adjacent fluid conduits 15. Further, it is preferable that the inner diameter of the fluid pipe line 15 itself gradually increases in a stepped or tapered manner from the blind hole position to the opening 16.

  The first material (soluble material) 14a constituting the tip side of the needle-like projection 12 is melted in a relatively short time with moisture in the skin of the human body, and is compatible with a living body and has high safety. Since it is necessary, for example, chitosan, pectin, alginate and the like can be mentioned.

  The second material (insoluble material) 14b constituting the substrate 11 side portion and the substrate 11 with respect to the boundary surface 13 of the needle-like protrusion 12 is, for example, polypropylene resin (PP), polyethylene resin (PE), polycarbonate resin (PC). General-purpose resin such as In consideration of compatibility with living bodies, biodegradable thermoplastics such as polyglycolic acid (PGA) and polylactic acid (PLA) are also suitable.

  The microneedle device 10 which concerns on embodiment is not limited to the structure shown in FIG. 1 mentioned above, For example, the structure shown to (a)-(c) of FIG. 2 demonstrated below may be sufficient.

  That is, FIG. 2A shows an example of a microneedle device 10 in which the substrate 11 has a circular shape and the needle-like protrusions 12 have a conical shape. A step 18 is formed in the portion.

  FIG. 2B similarly shows an example in which the substrate 11 is circular and the needle-like projections 12 have a quadrangular pyramid shape. FIG. 2C shows an example in which the substrate 11 has a quadrangular shape and the needle-like protrusions 12 have a quadrangular pyramid shape.

  In each example, the needle-like projection 11 is composed of two layers of different first and second materials 14a and 14b, and includes a fluid conduit 15 therein. Since the fluid conduit 15 is not open on the surface of the needle-like protrusion 12, it is difficult to distinguish the appearance from the solid structure of a sharp cone or pyramid with a sharp tip. Therefore, in FIG. 2, the fluid conduit 15 is represented by a broken line.

  Next, a method for manufacturing the microneedle device 10 according to the embodiment will be described with reference to FIGS. The basic process of this manufacturing method employs a method of taking and replicating a material using two mold dies having the inverted shape of the microneedle device 10. In addition, the manufacturing method of the microneedle device 10 which concerns on the following embodiment is a suitable example, and is not limited only to this method, Other manufacturing methods can also be applied suitably.

  In the first step, as shown in FIG. 3A, a first mold 20 having a plurality of indented portions 21 of the inverted shape of the needle-like projections 12 is prepared. Subsequently, a predetermined amount of the first material (soluble material) 14 a is filled in the hollow portions 21 of the first mold 20 by the micro discharge means 22. The minute discharge means 22 is preferably a minute discharge dispenser such as a piezo method or an electromagnetic piston method.

  In the second step, as shown in FIG. 3B, a plurality of elongated shapes having the inverted shape of the fluid conduit 15 and arranged at the same number and at the same intervals as the recesses 21 of the first mold die 20 are used. A second mold 30 provided with a support 31 is prepared. Next, the second mold die 30 is disposed above the first mold die 20. By this clamping, the indented portion 21 of the first mold 20 and the support 31 of the second mold 30 are positioned so as to be fitted one-on-one, and the inclined surface of the indented portion 21 It fixes in the state which maintained the slight space | interval, without contacting the front-end | tip part of the support | pillar 31. FIG. For this reason, the cavity space 40 which has the shape of the microneedle device 10 which is the target molded product is formed in the joint part of the first and second mold dies 20 and 30.

  In addition, the filling amount of the first material 14a in the second step shown in FIG. 3B is adjusted in advance so as not to fall below the tip end portion of the column 31 in the contracted state after drying and curing.

  In the third step, as shown in FIG. 3C, the first material 14a in the cavity space 40 is cured. That is, the first material 14a is a solution of a soluble material that dissolves when it comes into contact with the human skin. The first material 14a is formed into a cavity by a decompression means (not shown) through a gate 32 provided in the first mold 20 or a vent path (not shown). By depressurizing the space 40, the first material 14a is deaerated, and further, the first material 14a is heated and dried and cured by heating means (not shown).

  In the fourth step, as shown in FIG. 3D, the cavity material 40 is injected and filled with the second material 14b. That is, the cavity material 40 is high-pressure filled with the second material 14 b melted by the injection means (not shown) through the gate 32 provided in the first mold 20. In this filling process, the injected second material 14 b flows from the gate 32 to the end of the cavity space 40, and passes through the gap between the column 31 and the recess 21 having the inverted shape of the needle-like protrusion 12. The position of the first material 14a that has already hardened is reached, and finally the entire cavity space 40 is filled with the first and second materials 14a and 14b.

  In the fifth step, the microneedle device 10 as a molded product is taken out from the first and second mold dies 20 and 30 as shown in FIG. That is, after the second material 14b is cooled and hardened, the second mold die 30 is first separated upward from the first mold die 20, and the support column 31 is removed from the molded product. Subsequently, the molded product remaining on the second mold die 30 side is discharged by the discharge pins 25 incorporated in the second mold die 30. In the molded product taken out, the peripheral runner portion 19 is removed to form a plurality of needle-like projections 12 made of two different layers on the flat substrate 11 which is the final form. The microneedle device 10 having the structure shown is obtained.

  Next, a mounting form on the applicator used at the time of puncturing the actual skin of the microneedle device 10 of the embodiment will be described.

  FIG. 4 shows a state where the microneedle device 10 is mounted on the applicator 50. The applicator 50 includes a holder 51 that directly fixes the microneedle device 10 and a syringe 52 that actually injects a chemical solution and sucks blood and body fluid.

  The holder 51 includes a support base 56 having a flange structure with different inner diameters that substantially couples the microneedle device 10 and the syringe 52, and a sleeve 55 for tightly fixing the microneedle device 10 to the support base 56. The

  The outer diameter of the opening on the larger side of the support base 56 is set according to the substrate size of the microneedle 10. The microneedle device 10 is fixed by the sleeve 55 in a state where the back surface thereof is in close contact with the opening base of the support base 56. The reservoir space 59 surrounded by the microneedle device 10 and the support base 56 is secured by the fixed pressure.

  A lock portion 57 is provided outside the cylindrical portion on the small side of the support base 56. By this lock portion 57, the support base 56 including the microneedle device 10 and the syringe 52 are securely and securely fixed without leakage.

  According to the configuration shown in FIG. 4, the chemical solution 58 inside the syringe 52 can be injected into the human skin through the reservoir space 59 and the fluid conduit 15 of the microneedle device 10.

  FIG. 5 shows the substance of the applicator 50. The microneedle device 10 is provided so as to be attachable to the syringe 52 via the holder 51. In such an applicator 50, since only the needle-like protrusion 12 portion of the microneedle device 10 protrudes toward the cylindrical cross section of the sleeve 55 of the holder 51, the needle is compared with a normal injection needle. It becomes possible to puncture skilllessly without paying close attention to the depth and angle of inserting.

  Next, a situation where the skin is actually punctured using the microneedle device 10 and a drug solution is administered into the body will be described with reference to FIGS.

  First, as shown in FIG. 6A, the microneedle device 10 attached to the holder 51 is punctured into the skin 60. The skin 60 includes an epidermis 61 (thickness of about 0.2 mm) including a stratum corneum on the surface, a dermis 62 (thickness of about 1.5 to 2.0 mm) having capillaries, nerves, sweat glands, and the like, and a lower part thereof. It is composed of a subcutaneous tissue 63 mainly composed of fat or the like. The tip 17 of the needle-like protrusion 12 made of the first material (soluble material) 14a is not yet melted at this point and maintains an acute state, so that it easily penetrates the relatively hard skin 61. It is possible.

  Next, as shown in FIG. 6B, the needle-like protrusion 12 of the microneedle device 10 penetrates the epidermis 60 and reaches the upper surface of the dermis 62 or the subcutaneous tissue 63. By maintaining this state for a short time, the tip 17 of the needle-like protrusion 12 made of the first material 14a starts to melt into the skin.

  Next, as shown in FIG. 6C, almost the entire tip 17 of the needle-like projection 12 made of the first material 14a is melted, and the fluid conduit 15 in the needle-like projection 12 is inside the skin 60. Exposed to. As a result, the body and the reservoir space 59 are directly conducted through the fluid conduit 15 of the microneedle device 10. By pressurizing a syringe (not shown) in this state, the chemical solution 58 filled in the reservoir space 59 can be easily injected into the body with a small force.

  Next, the microneedle device 10 is pulled out from the skin 60 as shown in FIG. Immediately after the extraction, a fine hole remains as a puncture mark 65 in the skin 60. Normally, the hole is closed in a short time, and the injected drug solution 58 hardly flows out.

  As described above, the microneedle device 10 according to the embodiment is a structure in which a plurality of needle-like protrusions 12 are integrally formed on a flat substrate 11 and includes a human body. By puncturing the needle-like protrusion 12 into the skin of a living body, it becomes possible to transfer a chemical solution into the body through a fluid conduit 15 provided inside, and a microneedle capable of sucking blood, body fluid, etc. from the body A device 10 can be provided.

  In addition, the needle-like protrusion 12 is composed of first and second materials 14a and 14b having two different upper and lower layers on the boundary surface 13 which is horizontal with respect to the substrate 11 or at an angle smaller than at least 90 °. It is a soluble material that dissolves when the first material 14a on the tip side from the surface 13 contacts the human skin, and dissolves even when the second material 14b on the substrate 11 side from the boundary surface 13 contacts the human skin. Further, the fluid conduit 15 inside the needle-like projection 12 penetrates from the boundary surface 13 to a position slightly close to the tip side of the needle-like projection 12 to the bottom surface of the substrate 11. Thus, the needle-like protrusion 12 can be formed into a conical or polygonal cone-shaped sharp needle shape whose surface is covered with a smooth continuous surface. As a result, the puncture into the skin can be performed smoothly with a small force, and the pain associated with the puncture can be greatly reduced.

  Further, after the puncture, the tip of the needle-like protrusion 12 is melted in the skin, and the fluid conduit 15 is opened and exposed in the skin, so that the back surface of the substrate 11, that is, the fluid conduit from the outside of the skin to the inside of the skin. Therefore, it is possible to transfer the drug solution into the body and to suck blood and body fluid from the body very smoothly and efficiently.

  Furthermore, according to the manufacturing method of the microneedle device 10 according to the embodiment, a plurality of needles are formed on the substrate 11 in order to include the first to fifth steps shown in (a) to (e) of FIG. The microneedle device 10 on which the protrusions 12 are formed can be easily manufactured.

  In particular, in the second step shown in FIG. 3B, the first mold 14a sinks at least slightly into the first material 14a filled with the tip of the support 31 of the second mold die 30, and the first mold is used. Since it is kept at a position that does not contact the side wall of the recessed portion 21 of the mold 20, the high alignment accuracy between the recessed portion 21 of the first mold 20 and the support 31 of the second mold 30 is high. It becomes unnecessary, and it can prevent that the burr | flash etc. generate | occur | produce in the acicular protrusion 12 and the internal fluid conduit 15.

  Furthermore, in the third step shown in FIG. 3C, the depressurization and heating of the first material 14a can be promoted by depressurizing and heating the inside of the cavity space 40. A high-quality microneedle device 10 having a plurality of needle-like protrusions 12 formed on 11 can be manufactured inexpensively and easily.

  DESCRIPTION OF SYMBOLS 10 ... Microneedle device, 11 ... Board | substrate, 12 ... Needle-like protrusion, 13 ... Interface, 14a ... 1st material (soluble material), 14b ... 2nd material (insoluble material), 15 ... Fluid pipe line, DESCRIPTION OF SYMBOLS 16 ... Opening part, 17 ... Tip part, 18 ... Step part, 20 ... 1st mold type | mold, 21 ... Recessed part, 30 ... 2nd mold type | mold, 31 ... Support | pillar, 40 ... Cavity space, 50 ... Applicator, DESCRIPTION OF SYMBOLS 51 ... Holder, 52 ... Syringe, 55 ... Sleeve, 56 ... Support base, 57 ... Lock part, 58 ... Chemical solution, 59 ... Reservoir space.

Claims (6)

A structure in which a plurality of conical or polygonal fine needle-like protrusions are integrally aligned with the substrate on the upper surface of a flat substrate,
The acicular protrusion has a fluid conduit that is perpendicular or substantially perpendicular to the substrate, and the fluid conduit is slightly closer to the tip side of the acicular protrusion from the boundary surface. The needle-like protrusions are made of different materials in two layers, upper and lower, with a boundary surface that is horizontal or at least smaller than 90 ° as the boundary, It is a soluble material that dissolves when the first material in the tip side portion from the boundary surface comes into contact with the human skin, and does not dissolve even when the second material in the substrate side portion from the boundary surface comes into contact with the human skin. A microneedle device, which is an insoluble material.   The microneedle device according to claim 1, wherein the first material is selected from chitosan, pectin, and alginate.   The microneedle device according to claim 1 or 2, wherein the second material is selected from general-purpose resins, polyglycolic acid (PGA), and polylactic acid. A fixed amount of a first material made of a soluble material that dissolves when it comes into contact with the skin of a human body is filled in each depression of the first mold mold having a reverse shape of a plurality of conical or polygonal fine needle-like protrusions. A first step of:
A second mold die comprising a plurality of elongated struts corresponding to the inverted shape of the plurality of needle-like protrusions on the first mold die filled with a predetermined amount of the first material in the first step. The second step of forming a cavity space having the shape of the target molded product on the mating surface portion of the mold, and facing and closely contacting so that the recess and the column are in the same position;
A third step of curing the first material in the cavity space formed by the second step;
After the third step, a fourth step of injecting and filling a second material made of an insoluble material that does not dissolve even when contacting the human skin into the cavity space;
After the fourth step, the second mold die and the first mold die are separated from each other, and the first and second fluid pipes that are perpendicularly or substantially perpendicular to the substrate are cured and integrated with each other. A molded article, which is a structure made of two materials and having a plurality of conical or polygonal fine needle-like protrusions integrally aligned with the substrate on the upper surface of the flat substrate according to claim 1, is taken out. 5 steps,
A method for producing a microneedle device, comprising:   In the second step, at least slightly bites into the first material filled with the tip end portion of the column of the second mold, and on the side wall of the hollow portion of the first mold 5. The method of manufacturing a microneedle device according to claim 4, wherein the microneedle device is maintained at a position where it does not contact.   6. The method of manufacturing a microneedle device according to claim 4, wherein in the third step, the inside of the cavity space is depressurized and heated to degas and dry-harden the first material.

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