JP2019170795A - Production method of microneedle and microneedle - Google Patents

Abstract

To provide a production method of an inexpensive microneedle.SOLUTION: A production method of a microneedle is a production method of a microneedle comprising protrusion parts on one surface of a substrate, and comprises: a step for preparing an intaglio plate which comprises recesses corresponding to the protrusion parts of the microneedle; a heating/compression step for arranging on the intaglio plate, a thermoplastic resin and a sheet in an order from the intaglio plate side, then heating and compressing the thermoplastic resin and the sheet to the intaglio plate; a cooling step for cooling the sheet and the thermoplastic resin on the intaglio plate; and a peeling step for moving at least a part of the sheet in a state in which the sheet and the thermoplastic resin are adhered, thereby peeling the sheet and the thermoplastic resin from the intaglio plate.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a microneedle used for medical treatment, a MEMS (Micro Electro Mechanical Systems) device, an optical member, drug discovery, cosmetics, cosmetic use, and the like.

  As a method of administering the drug to the human body, oral administration, puncture of the dermal layer or vein with a syringe, administration to the local dermis layer by applying an ointment to the skin surface, local dermis layer by applying to the skin surface And the like (see Patent Document 1).

  Among these, in recent years, development of microneedles having protrusions that are a plurality of minute needles has been promoted as a device for administering a drug into the body by a method of attaching or puncturing using an applicator. As the material of the microneedle, a material that is harmless even if dissolved or remains in the living body is selected so that even if a part of the needle-shaped body is broken by puncture and remains in the body, it is harmless.

International Publication No. 2005/058162 JP 2006-334419 A

  An object of this invention is to provide the manufacturing method of an inexpensive microneedle.

  One aspect of the present invention for solving the above problem is a method of manufacturing a microneedle having a protrusion on one surface of a substrate, the step of preparing an intaglio having a recess corresponding to the protrusion of the microneedle, The thermoplastic resin and the sheet are arranged on the intaglio in order from the intaglio side, the heating and pressurizing step for heating and pressurizing the thermoplastic resin and the sheet toward the intaglio, and the sheet on the intaglio and the thermoplastic resin are cooled. A method for producing microneedles, including a cooling step to perform, and a peeling step of peeling the sheet and the thermoplastic resin from the intaglio by moving at least a part of the sheet in a state where the sheet and the thermoplastic resin are bonded. .

  Further, the sheet may be arranged so that a part thereof protrudes from the intaglio.

  Another aspect of the present invention is a method of manufacturing a microneedle having a protrusion on one surface of a substrate, the step of preparing an intaglio plate having a plurality of recesses corresponding to the protrusions of the plurality of microneedles, A thermoplastic resin and a sheet are arranged on the intaglio in order from the intaglio side, and a heating and pressurizing step for heating and pressurizing the thermoplastic resin and the sheet toward the intaglio, and the sheet on the intaglio and the thermoplastic resin are cooled. A microneedle manufacturing method comprising: a cooling step; and a peeling step of peeling the sheet and the thermoplastic resin from the intaglio by moving at least a part of the sheet in a state where the sheet and the thermoplastic resin are bonded. .

  Further, the sheet may be arranged so that a part thereof protrudes from the intaglio.

  Another aspect of the present invention is a microneedle including a substrate and a protrusion formed on one surface of the substrate, the microneedle including a thermoplastic resin, and the thickness of the substrate is 50 μm or more and 2 mm or less. It is the microneedle which is in the range.

  The sheet may be provided on the surface opposite to the surface on which the protrusions of the substrate are formed, and the thickness of the sheet may be in the range of 50 μm to 500 μm.

  In the manufacturing method of the microneedle of the present invention, since it is possible to reduce the possibility of damage to the intaglio and the deformability of the microneedle by using a peeling step that performs peeling using a sheet, it is inexpensive. It is possible to provide a method for manufacturing a microneedle.

The perspective view of the microneedle which concerns on one Embodiment of this invention Sectional drawing of the microneedle which concerns on one Embodiment of this invention The perspective view of the microneedle which concerns on a modification Explanatory drawing of the manufacturing method of the microneedle which concerns on the 1st Embodiment of this invention. Explanatory drawing of the manufacturing method of the microneedle which concerns on the 2nd Embodiment of this invention. Explanatory drawing of the manufacturing method of the microneedle which concerns on the 3rd Embodiment of this invention. Explanatory drawing of the manufacturing method of the microneedle which concerns on the 4th Embodiment of this invention.

<Microneedle>
A microneedle 10 according to an embodiment of the present invention will be described with reference to FIGS. 1 and 2. FIG. 1 is a perspective view of a microneedle according to an embodiment of the present invention, and FIG. 2 is a cross-sectional view of the microneedle according to an embodiment of the present invention. The microneedle 10 can be manufactured by a microneedle manufacturing method according to an embodiment of the present invention described later.

  The microneedle 10 includes a plate-like substrate having a first surface 12A, a second surface 12B, and a side surface 12C, and a plurality of protrusions 11 formed on the first surface 12A. The outer shape of the substrate 12 (planar shape of the substrate 12) viewed from the direction facing the first surface 12A of the substrate is not particularly limited, and may be a circle, an ellipse, or a rectangle.

  The protrusion 11 is an area that is punctured into the skin. The shape of the protrusion 11 is not limited as long as it can be punctured, and may be a pyramid shape or a cone shape. Further, the protruding portion 11 may have a shape in which the tip is not sharp, for example, a cylindrical shape or a prismatic shape. Further, the protruding portion 11 may have a shape in which two or more solids are combined, such as a shape in which cones are stacked on a cylinder. Further, a constriction or a step may be formed on the side wall of the protruding portion 11, or a groove or a hole may be formed.

  The number of the protrusions 11 is not particularly limited as long as it is plural. The plurality of protrusions 11 may be regularly arranged on the first surface 12A of the substrate 12 or may be irregularly arranged. For example, the plurality of protrusions 11 are arranged in a lattice shape or a concentric shape.

  As shown in FIG. 2, the length H of the protrusion 11 is the length from the first surface 12A to the tip of the protrusion 11 in the thickness direction of the substrate 12, that is, in the direction orthogonal to the first surface 12A. That's it. The height H of the protrusion 11 is preferably 10 μm or more and 2000 μm or less, and is determined in accordance with the depth required for the hole formed in the puncture target by the protrusion 11 within this range.

  The width D of the protrusion 11 is the maximum value of the length of the protrusion 11 in the direction along the first surface 12A of the substrate 12, that is, in the direction parallel to the first surface 212A. For example, when the protrusion 11 has a regular quadrangular pyramid shape or a regular quadrangular prism shape, the length of the diagonal line in the square defined by the bottom of the protrusion 11 on the first surface 12A of the substrate 12 is the width of the protrusion 11. D. For example, when the protrusion 11 has a conical shape or a cylindrical shape, the diameter of a circle defined by the bottom of the protrusion 11 is the width D of the protrusion 11. The width D of the protrusion 11 is preferably 1 μm or more and 300 μm or less. The aspect ratio A (A = H / D), which is the ratio of the height H to the width D of the protrusion 11, is preferably 1 or more and 10 or less.

  In addition, the thickness L of the substrate of the microneedle of the present invention is preferably in the range of 50 μm to 2 mm.

  As the material of the microneedle 10, a thermoplastic resin can be used. Examples of the thermoplastic resin include polyglycolic acid, polylactic acid, polylactic acid-polyglycolic acid copolymer, polyethylene, polypropylene, polystyrene, polyamide, polycarbonate, polyacrylonitrile, cyclic polyolefin, polycaprolactone, acrylic, urethane resin, aromatic Group polyetherketone and epoxy resin. However, the forming material of the microneedle 1 is not limited to these.

  Next, a microneedle 20 that is a modification of the microneedle 10 will be described. FIG. 3 is a perspective view of the microneedle 20. The microneedle 20 can also be manufactured by the manufacturing method mentioned later. In the following description, the difference between the microneedle 10 and the microneedle 20 will be mainly described.

  The difference between the microneedle 10 and the microneedle 20 is the presence or absence of the sheet S. As shown in FIG. 3, the microneedle 20 is provided with a sheet S on the surface of the microneedle 10 opposite to the surface on which the protrusions 11 of the substrate 12 are formed. The thickness of the sheet S is preferably in the range of 50 μm to 500 μm.

  The sheet S may be formed so as to protrude from the outer edge of the substrate 12 as shown in FIG. 3A, or the outer edge coincides with the outer edge of the substrate 12 as shown in FIG. It may be formed as follows.

<Microneedle manufacturing method>
Next, the manufacturing method of the microneedle which concerns on this invention is demonstrated.

[First Embodiment]
FIG. 4 shows an explanatory view of the method of manufacturing the microneedle according to the first embodiment of the present invention.

(Intaglio preparation process)
First, an intaglio 2 having a recess corresponding to the protrusion 12 of the microneedle 10 is prepared ((a) of FIG. 4). The intaglio 2 can be formed, for example, by taking a mold from a microneedle master. The microneedle master can be produced by, for example, cutting, grinding, wet etching, dry etching, or a combination of these. The material of the intaglio 2 is not particularly limited, and a material can be selected in consideration of the shape following ability to function as the intaglio 2 and transferability, durability, and releasability in transfer processing molding described later. For example, nickel, a thermosetting silicone resin, or the like can be used as the material of the intaglio 2. When nickel is selected, the intaglio 2 can be formed by plating, PVD, or CVD. When a thermosetting silicone resin is used, as a method for forming the intaglio 2, a method can be used in which a silicone resin before thermosetting is supplied to the microneedle original plate, heat-cured, and peeled off. Further, as the intaglio 2, the intaglio 2 may be formed directly from a plate-like member without producing an original plate.

(Heating and pressing process)
Next, the granular thermoplastic resin 3 and the sheet S, which are microneedle forming materials, are arranged on the intaglio 2 in order from the intaglio 2 side (FIGS. 4B and 4C), and the thermoplastic resin 3 and the sheet are arranged. S is heated and pressurized toward the intaglio plate 2 (pressurization with heating) ((d) in FIG. 4). In the peeling step described later, the sheet S and the thermoplastic resin 3 are peeled from the intaglio 2 by moving a part or all of the sheet S in a state where the sheet S and the thermoplastic resin 3 are bonded. Therefore, it is preferable that the thermoplastic resin 3 and the sheet S used as the microneedle material are made of a material that exhibits sufficient adhesive strength by heating and pressing. The sheet S is not limited to a sheet-like member, and may be a film-like member. The method of heating the thermoplastic resin 3 and the intaglio 2 can be performed by providing a heating mechanism such as a heater on the opposite side of the intaglio 2 from the concave surface. The pressurizing method can be performed by the press device 4 or the like. By the heating and pressurizing step, the concave portion is filled with the thermoplastic resin 3 and the microneedle 10 is molded.

  As an example of the material of the sheet S used in the method of manufacturing the microneedle of the present invention, a thermoplastic resin, a thermosetting resin, and a metal material can be used, but the material is not limited. The thermoplastic resin 3 and the sheet S used as the microneedle material must exhibit sufficient adhesive strength by heating and pressing. If a sufficient adhesive material cannot be obtained, an adhesive layer may be provided between the sheet S and the thermoplastic resin 3. For example, an adhesive layer can be formed on one surface of the sheet S. Further, the material of the sheet S and the thermoplastic resin 3 used as the microneedle material can be the same material.

  In addition, as thickness of the sheet | seat S used in the manufacturing method of the microneedle of this invention, it is preferable to exist in the range of 50 micrometers or more and 500 micrometers or less. When the thickness of the sheet S is less than 50 μm, handling may be difficult in the peeling step described later. On the other hand, when the thickness of the sheet S exceeds 500 μm, handling may be difficult in the peeling step, and the cost may be increased.

(Cooling process)
Next, the thermoplastic resin 3 filled in the concave portion of the intaglio 2 is cooled. Cooling may be performed by stopping heating or may be cooled by a blower mechanism or the like.

(Peeling process)
Next, the microneedles 10 formed on the intaglio 2 are peeled off. In the peeling, the sheet S and the thermoplastic resin 3 are peeled from the intaglio 2 by moving at least a part of the sheet S in a state where the sheet S and the thermoplastic resin 3 are bonded. Specifically, the sheet S and the thermoplastic resin 3 can be peeled from the intaglio 2 by fixing the edge of the sheet S with the supporting member 5 for peeling and peeling (FIG. 4 (e)). .

  In the microneedle manufacturing method according to the prior art, there is a case where at least a part of the side surface 12C of the microneedle 10 is supported and peeled in the peeling step of peeling the thermoplastic resin 3 from the intaglio 2. For this reason, there is a possibility that the support member 5 and the intaglio 2 come into contact with each other and the intaglio 2 is damaged, or the microneedle 10 is deformed. When the intaglio 2 is damaged, it may be necessary to replace the intaglio 2, and when the microneedle 10 is deformed, it may become a defective product. Improvement was difficult and manufacturing at low cost was difficult.

  On the other hand, in the manufacturing method of the microneedle of the present invention, the possibility of damage to the intaglio 2 and the possibility of deformation of the microneedle 10 are reduced by adopting a peeling step for peeling using the sheet S. Therefore, the microneedles 10 and 20 can be manufactured at low cost. Further, according to the microneedle manufacturing method of the present invention, even if the substrate 12 is thin, the possibility of damage to the intaglio 2 and the deformability of the microneedle 10 can be reduced. The needles 10 and 20 can be manufactured.

  In the microneedle manufacturing method of the present invention, it is preferable that in the peeling step, a part of the sheet S is disposed so as to protrude from the intaglio plate 2 before peeling the thermoplastic resin 3 from the intaglio plate 2. Specifically, it is preferable to arrange the sheet S so that a part of the sheet S can protrude from the outer edge of the intaglio 2 during the heating and pressing step. By disposing the sheet S so that a part of the sheet S protrudes from the outer edge of the intaglio 2 before peeling, contact between the intaglio 2 and the support member 5 can be prevented when the support member 5 fixes a part of the sheet S. .

  The microneedle 20 of this invention is manufactured by the above ((f) of FIG. 3).

[Second Embodiment]
Next, the manufacturing method of the microneedle which concerns on 2nd Embodiment is demonstrated.
FIG. 5 shows an explanatory diagram of a method of manufacturing a microneedle according to the second embodiment. Note that a description of the same parts as those in the first embodiment is omitted.

  In the second embodiment, the shape of the intaglio 2a is different from that of the first embodiment. The intaglio 2 of the first embodiment is provided with a convex object (wall) on the periphery of the recess, whereas the intaglio 22 of the second embodiment is provided with a convex object (wall) on the periphery of the recess. ((A) of FIG. 5).

  Moreover, in 2nd Embodiment, the supply method of the thermoplastic resin 3 to the intaglio 2a differs. In the first embodiment, the granular thermoplastic resin 3 is arranged on the intaglio 2 whereas in the second embodiment, a lump of thermoplastic resin 3 is supplied on the intaglio 2a ( FIG. 5B).

  Furthermore, in the second embodiment, the process after peeling is different. In the second embodiment, after the peeling step of peeling the sheet S and the thermoplastic resin 3 (microneedle 10) from the intaglio 2a, a step of peeling the sheet S and the microneedle 10 is further provided (FIG. 5). (G)). Thus, it is possible to peel the sheet S and the microneedle 10 in a step after the peeling step. In addition, the outer shape of the microneedle 20 can be formed by punching out the microneedle 10 and the sheet S, the microneedle 10 or the sheet S in a step after the peeling step.

[Third Embodiment, Fourth Embodiment]
Next, the manufacturing method of the microneedle which concerns on 3rd and 4th embodiment is demonstrated. FIG. 6 shows an explanatory view of the method of manufacturing the microneedle according to the third embodiment. FIG. 7 shows an explanatory diagram of a method of manufacturing a microneedle according to the fourth embodiment. The third and fourth embodiments are methods for producing a plurality of microneedles 10 and 20 using a single sheet. Note that a description of the same parts as those in the first embodiment is omitted.

  In the third embodiment, an intaglio 2b capable of producing a plurality of microneedles is used ((a) of FIG. 6). The intaglio 2b may be a series of a plurality of intaglios 2 capable of producing one microneedle 10, or may be an intaglio 2b capable of producing a plurality of microneedles 10 by providing a plurality of recesses. It may be combined.

  In the third embodiment, one sheet S is disposed on the thermoplastic resin 3 on which the plurality of microneedles 10 are formed ((c) of FIG. 6).

  Also in 3rd Embodiment, the peeling process which peels the thermoplastic resin 3 in which the sheet | seat S and the several microneedle 10 are formed from the intaglio 2b using the supporting member 5 is provided ((e) of FIG. 6).

  In the third embodiment, the sheet S is punched out into individual microneedles 20 ((g) in FIG. 6).

  In the fourth embodiment, an intaglio 2c capable of producing a plurality of microneedles 10 is used. In 4th Embodiment, the lump thermoplastic resin 3 which can produce the several microneedle 10 is arrange | positioned on the intaglio 2c ((b) of FIG. 7).

  In the fourth embodiment, one sheet S is disposed on the thermoplastic resin 3 on which the plurality of microneedles 10 are formed ((c) of FIG. 7).

  Also in 4th Embodiment, the peeling process which peels the thermoplastic resin 3 in which the sheet | seat S and the several microneedle 10 are formed from the intaglio 2c using the supporting member 5 is provided ((e) of FIG. 7).

  In 4th Embodiment, the microneedle 10 is separated into pieces after peeling from the intaglio 2c. Moreover, the microneedle 1 and the sheet | seat S are peeled ((g) of FIG. 7) After separating the microneedle 20 into pieces, the sheet S may be peeled off, or the sheet S and the plurality of microneedles 20 are peeled off. Later, the microneedles 10 may be separated.

(Example)
Examples are shown below. In Examples, microneedles were manufactured by the manufacturing method according to the third embodiment shown in FIG.

  A grinding process for forming a linear groove on the surface of the alumina substrate was performed, and the same grinding process was performed in a direction perpendicular to the linear groove to produce a microneedle master. Next, an intaglio was prepared from the microneedle master. The intaglio was produced by forming a nickel film on the surface of the microneedle original plate by plating and peeling the nickel film from the microneedle original plate.

  Four intaglio plates obtained were arranged in 2 rows × 2 columns, and polyglycolic acid was arranged on each intaglio plate. Furthermore, a polyethylene terephthalate film (PET film) having an adhesive layer formed on one surface was placed on polyglycolic acid, and heated and pressed from the PET film toward the intaglio.

  After the heat press, the film was cooled, and then the microneedles formed from polyglycolic acid and the PET film were peeled off in a state where the PET film and polyglycolic acid were adhered from the intaglio. At the time of peeling, the end of the PET film protruding from the intaglio was grasped with tweezers and peeled off by pulling up. At the time of peeling, the PET film and the molded microneedles could be peeled together without peeling. Further, the tweezers did not touch the intaglio during peeling. As a result, a molded article in which four microneedles were arranged on the PET film was obtained. Thereafter, four molded products in which polyglycolic acid microneedles were formed on the PET film were obtained by punching the PET film. The obtained microneedle has 36 protrusions of 6 rows × 6 columns formed in a lattice shape. Moreover, the height H of the protrusion part of the obtained microneedle was 200 μm, and the width D was 50 μm.

  The present invention can be used for the production of microneedles.

DESCRIPTION OF SYMBOLS 1 Microneedle 11 Protrusion part 12 Board | substrate 2, 2a, 2b, 2c Intaglio 3 Thermoplastic resin 4 Press apparatus 5 Support member S Sheet

Claims (6)

A method of manufacturing a microneedle having a protrusion on one surface of a substrate,
Preparing an intaglio with a recess corresponding to the protrusion of the microneedle;
On the intaglio, a thermoplastic resin and a sheet are arranged in order from the intaglio side, and a heating and pressing step of heating and pressurizing the thermoplastic resin and the sheet toward the intaglio,
A cooling step for cooling the sheet and the thermoplastic resin on the intaglio, and moving the at least part of the sheet in a state where the sheet and the thermoplastic resin are bonded, from the intaglio, the sheet and Including a peeling step of peeling the thermoplastic resin.
Manufacturing method of microneedle.   The microneedle manufacturing method according to claim 1, wherein the sheet is arranged so that a part thereof protrudes from the intaglio. A method of manufacturing a microneedle having a protrusion on one surface of a substrate,
Preparing an intaglio plate having a plurality of recesses corresponding to the protrusions of the plurality of microneedles;
On the intaglio, a thermoplastic resin and a sheet are arranged in order from the intaglio side, and a heating and pressing step of heating and pressurizing the thermoplastic resin and the sheet toward the intaglio,
A cooling step for cooling the sheet and the thermoplastic resin on the intaglio, and moving the at least part of the sheet in a state where the sheet and the thermoplastic resin are bonded to each other from the intaglio Including a peeling step of peeling the thermoplastic resin.
Manufacturing method of microneedle.   The method of manufacturing a microneedle according to claim 3, wherein the sheet is arranged so that a part thereof protrudes from the intaglio. A microneedle comprising a substrate and a protrusion formed on one surface of the substrate,
The microneedle includes a thermoplastic resin,
A microneedle having a thickness of the substrate in the range of 50 μm to 2 mm.   The microneedle according to claim 5, wherein a sheet is provided on a surface of the substrate opposite to the surface on which the protrusion is formed, and the thickness of the sheet is in a range of 50 μm to 500 μm.