JP5402069B2 - Manufacturing method of needle-like structure - Google Patents

Description

  The present invention relates to a method for manufacturing a needle-like structure used as a jig for injecting a drug into a specific layer of skin.

Human skin is roughly divided into three layers from the surface: epidermis, dermis and subcutaneous fat. The epidermis has an average thickness of about 100 μm excluding palms and wrinkles, and has 500 to 600 Langerhans cells per 1 mm ² . Langerhans cells take in and activate antigens that have entered the skin, move to lymph nodes, stimulate T cells to differentiate into cytotoxic cells, and stimulate B cells via T cells Is produced. From this action, it can be said that the Langerhans cells have a role of protecting the living body from infection and cancer.

  As a means to make vaccines and drugs reach the Langerhans cells of the epidermis, administration with an injection needle has been performed conventionally, but if the needle tip reaches the dermis with an injection needle, it will not be efficiently taken up by Langerhans cells There are defects and pain for the patient, and there is a risk of bleeding and secondary infection.

  Therefore, instead of an injection needle, a technology has been developed in which a plurality of needle-like structures are formed on a base material, a drug is applied to the needle tip, and the needle is punctured to the epidermis of the skin to inject the drug. (Patent Documents 1 to 4).

  Conventionally, as a method for producing a needle-like structure, a nanoimprint method (Patent Document 1), in which a stamper having a desired uneven shape is brought into contact with a previously melted resin material and pressed, or Patent Document 2 is used. 4 is mainly produced by an injection molding method in which a molten resin material is injected into a mold having a desired three-dimensional shape and molded and solidified.

  Further, in Patent Document 1, in order to obtain a convex shape with a high aspect ratio, the resin is injected and cured repeatedly until a desired height is obtained using a photocurable resin. Further, according to Patent Documents 2 to 4, after the convex array is formed by injection molding, the mold frame and the resin material are easily peeled as a configuration in which the convex array is superimposed on the base sheet. In any case, an apparatus for injection molding or a similar apparatus is required as an apparatus, and there is a problem that both the apparatus and the process have a large structure.

  The material constituting the needle-like structure is preferably a biodegradable resin that is safe even if it remains in the body. However, since the injection molding method injects the resin material into the mold, it is necessary to wait for the resin material to be heated in a certain temperature range in advance. Therefore, it is not suitable for a biodegradable resin that is easily decomposed under the influence of heat.

JP 2006-320986 A JP 2008-6178 A JP 2008-245955 A JP 2008-29710 A

Therefore, as a method of manufacturing a needle-shaped structure having a high aspect ratio made of a biodegradable resin, a biodegradable resin material is loaded on a transfer plate having a needle-like recess formed on the bottom surface and kept at an appropriate temperature. After holding and softening, a method of pressing for a predetermined time to allow the biodegradable resin to permeate into the needle-like concave portion, and then gradually cooling and peeling off is promising. However, with a simple application of this method, the softened biodegradable resin cannot reach the tip of the needle-like concave portion of the transfer plate, and it is difficult to obtain a predetermined shape as a needle-like structure. There was a problem.
Therefore, the present invention has an object of providing means for causing the resin to reach the end of the most distal portion of the needle-like recess formed in the transfer plate in the above method.

The invention according to claim 1 of the present invention includes a resin material loading step of loading a resin material on a transfer plate on which a needle shape of a needle-like structure is transferred,
A resin material heating step of heating and melting the resin material on the transfer plate;
A pressing step of pressing the melted resin material and embedding and molding the needle-shaped portion of the transfer plate; and
A cooling step of cooling and curing the molded resin material,
The method for manufacturing a needle-like structure is characterized in that the resin material heating step and the pressing step are repeated twice or more in this order .
The invention according to claim 2 is characterized in that the needle-shaped portions of the needle-like structure are arranged in a lattice shape or a concentric circle shape. It is.
According to a third aspect of the present invention, in the method for producing a needle-like structure according to the first or second aspect, the resin material loaded on the transfer plate is made of a biodegradable resin. It is.
According to a fourth aspect of the present invention, in the manufacture of the acicular structure according to any one of the first to third aspects, the resin material loaded on the transfer plate is solid or granular. Is the method .
The invention according to claim 5 is characterized in that the needle-like structure has a plurality of microneedles formed on one side of a flat substrate. This is a method for manufacturing the needle-like structure.

  According to the present invention, by providing a plurality of pressing steps and reheating and remelting steps, it is possible to distribute the resin material to the needle-shaped concave portions formed on the transfer plate, and in particular, the needle shape in one cycle of the manufacturing process. It is possible to form a fine shape with a very small amount of resin, which is equivalent to one structure.

  Further, the molding apparatus of the present invention does not require an apparatus for heating (melting) the resin material in a predetermined temperature range, which is required in the injection molding apparatus. Further, since molding can be performed without increasing the pressing pressure required in the pressing process, a high-output pressing means is not required. Therefore, the molding apparatus of the present invention has advantages in that the equipment is not large and the installation space can be reduced.

(A)-(b) is the schematic explaining the structure of the shaping | molding apparatus used by this invention. (A) is the schematic of a front view, (b) is the schematic of a side view. The process process drawing explaining the acicular structure shaping | molding process which becomes this invention. (C)-(k) is process drawing which illustrates typically an example of the manufacturing method of the acicular structure of this invention. The external view of the acicular structure which this invention makes the object of manufacture.

  Hereinafter, an example of the manufacturing method of the acicular structure which becomes this invention is demonstrated based on drawing.

  1A and 1B are schematic diagrams for explaining the configuration of the molding apparatus of the present invention. FIG. 1A is a schematic view of the molding apparatus viewed from the front, and FIG. 1B is a schematic view of the molding apparatus viewed from the side. 1 to 4 are air cylinders, 5 is a forming frame, 6 is a punch, 7 is a heater, and 8 is a cooling nozzle. FIG. 2 is a process step diagram for forming a needle-like structure according to the present invention. 3 (c) to 3 (k) are process diagrams showing a series of flows according to the molding of the present invention. In addition, 9 is a transfer plate and 10 is a resin material.

  In the molding apparatus of the present invention, as shown in FIG. 1, an air cylinder 1 and an air cylinder 2 are provided above the molding frame 5 and the punch 6 so that the molding frame 5 and the punch 6 can move up and down. In addition, a heater 7 that is a heating body is installed below the air cylinder 3 so as to move up and down.

  FIG. 2 shows a process of molding a needle-like structure from a resin using the molding apparatus of FIG. 1, and FIGS. 3 (c) to 3 (k) show a flow of the resin molding process. .

  In step S1, as shown in FIG. 3C, after the solid or granular resin material 10 is loaded on the transfer plate 9, the heating process of step S2 is started. In the heating step, the heater 7 comes into contact with the lower surface of the transfer plate 9 by the air cylinder 3, and the first heating is started. Thereafter, when the melting temperature of the resin material is reached, the resin material 10 starts to melt and the resin material 10 starts to expand as shown in FIG.

  When the entire resin material 10 is melted, as shown in FIG. 3 (d), first, the molding frame 5 that forms the outer shape of the needle-like structure is lowered onto the transfer plate 9. Thereafter, as step S3, the resin material 10 melted by the punch 6 is pressed as shown in FIG. This first press is a preliminary press for spreading the resin material 10 to the outermost peripheral portion where the concave portion for the needle-like structure of the transfer plate 9 is formed. At this time, the time for which the punch 6 contacts the resin material 10 is 1 second or more. However, depending on the type of resin used as the resin material 10, decomposition and curing may occur when a high temperature state continues for a predetermined time or longer, so the time during which the punch 6 is in contact with the resin material 10 is a resin. It is desirable to make the time as short as possible in consideration of the material of the material 10.

After the first press, the molding frame 5 and the punch 6 are moved upward as shown in FIG. 3 (f), the second heating in Step S4 is performed, and the resin material 10 once cured in Step S3.
Thaw again.

  When the resin material 10 is remelted, the molding frame 5 is lowered onto the transfer plate 9 as shown in FIG. Thereafter, as step S5, the resin material 10 melted by the punch 6 is re-pressed as shown in FIG. This second press is for pushing the resin to the most distal end of the needle-like recess to form the final shape of the needle-like structure.

  In step S <b> 6, the heating by the heater 7 is finished, and the heater 7 and the cooling nozzle 8 are switched by the air cylinder 4.

  In the cooling step of step S7, as shown in FIG. 3I, air is discharged from the cooling nozzle 8, and the resin material 10 is cooled and cured from the lower surface of the transfer plate 9. At this time, cooling is performed to a temperature below the freezing point of the resin material 10.

  Finally, step S8 is a step of releasing the cured resin and the transfer plate. First, as shown in FIG. 3 (j), the molding frame 5 that forms the outer shape of the sufficiently cooled and solidified resin material 10 is raised to a height higher than the thickness of the needle-like structure to separate the outer portion. . Thereafter, the punch 6 is also raised from the resin material 10, and only the molded resin material 10 remains on the transfer plate 9. Finally, by removing the molded resin material 10 from the transfer plate 9 with a jig or the like having tweezers or a gripping function, it is possible to obtain a needle-like structure having microneedles.

  In this specification, the heater and the cooling nozzle are driven by an air cylinder. However, the motor and the like may be driven without being limited thereto.

  Examples of the present embodiment are shown below.

  A solid resin material 10 is loaded on a transfer plate 9 in which a needle-like concave portion having a shape obtained by inverting the shape of a microneedle of a needle-like structure is formed. Next, the heater 7 installed below the transfer plate 9 is brought into contact with the lower surface of the transfer plate 9, and the temperature of the transfer plate 9 is raised to melt the resin material 10.

  When the resin material 10 is melted as a whole, a first press is performed by the punch 6 in order to spread the resin material 10 to the outer peripheral portion of the transfer plate 9. The pressing time at this time may be about 1 second.

  Since the resin material 10 melted in the first pressing step is deprived of heat by the punch 6 and the surface is solidified, the resin material 10 is remelted by reheating. When the resin material 10 is melted again, a second press is performed with the molding frame 5 and the punch 6. The second press is a press for adjusting the outer shape of the fine needle of the needle-like structure by causing the resin to completely reach the tip of the needle-like recess.

  After a predetermined time for forming the shape has elapsed, the heater 7 is separated from the transfer plate 9 and air is discharged from the cooling nozzle 8 instead, and the resin material 10 is cooled from the lower surface of the transfer plate 9 to solidify the resin material. . The time at this time shall be performed until the resin material falls below the solidification temperature.

  After the resin material 10 is solidified, the molding frame 5 and the punch 6 are separated from the resin material 10 and the molding process of the needle-like structure is completed. For example, the transfer plate 9 and the resin material 10 are released using a jig such as tweezers.

By the manufacturing process as described above, a needle-like structure in which a plurality of microneedles 12 are formed on one surface of a flat substrate 11 as shown in FIG. 4 can be obtained. In FIG. 4, a flat substrate 11
Indicates a rectangular shape, but other shapes (for example, a disk shape or an elliptical plate shape) may be used. In addition, the arrangement of the microneedles 12 may be a rectangular lattice arrangement, a triangular lattice arrangement, a hexagonal lattice arrangement, a concentric arrangement, or any other appropriate arrangement.

  The present invention is not limited to the needle-like structures used for medical purposes described above, but can be applied to those that form fine protrusions on a substrate, such as the formation of an antireflection film or a dot-type optical waveguide. .

1 ... Air cylinder 1
2 ... Air cylinder 2
3 ... Air cylinder 3
4 ... Air cylinder 4
5 ... Molding frame 6 ... Punch 7 ... Heater 8 ... Cooling nozzle 9 ... Transfer plate 10 ... Resin material 11 ... Base material 12 ... Micro needle

Claims (5)

A resin material loading step of loading a resin material on a transfer plate to which the needle shape of the needle-like structure is transferred;
A resin material heating step of heating and melting the resin material on the transfer plate;
A pressing step of pressing the melted resin material and embedding and molding the needle-shaped portion of the transfer plate; and
A cooling step of cooling and curing the molded resin material,
The method for producing a needle-like structure, wherein the resin material heating step and the pressing step are repeated twice or more in this order. The method for manufacturing a needle-shaped structure according to claim 1, wherein the needle-shaped portions of the needle-shaped structure are arranged in a lattice shape or a concentric shape. The method for producing a needle-like structure according to claim 1 or 2, wherein the resin material loaded on the transfer plate is made of a biodegradable resin. 4. The method for manufacturing a needle-shaped structure according to claim 1, wherein the resin material loaded on the transfer plate is solid or granular. The method for manufacturing a needle-like structure according to any one of claims 1 to 4, wherein the needle-like structure has a plurality of microneedles formed on one side of a flat substrate.

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