JP6330342B2 - Manufacturing method of microneedle - Google Patents

Description

  The technology of the present disclosure relates to a method for manufacturing a microneedle.

  A method using a microneedle is known as a method for administering a delivery product such as a drug from the skin into the body. The microneedle has a plurality of protrusions having a needle shape on the surface of the substrate. In the administration method using microneedles, the protrusions perforate the skin when the substrate is pressed against the skin, and the delivery product is fed into the body from the holes formed by the protrusions.

  In such a microneedle manufacturing process, first, an original plate having a desired microneedle shape is formed. Then, an intaglio plate in which the unevenness of the original plate is inverted is formed from the original plate. The intaglio is filled with a microneedle forming material and hardened, and the molded product is detached from the intaglio to obtain a microneedle.

  The original microneedle is formed by processing a metal material, a crystal material, or the like by, for example, machining such as cutting or grinding, or various etching methods (see, for example, Patent Documents 1 and 2). .

International Publication No. 2008/013282 International Publication No. 2008/004597

In the microneedle manufactured from one intaglio plate through the manufacturing process described above, the size in the surface direction, which is the direction along the surface of the substrate, is determined by the size in the surface direction of the original plate. However, for example, when forming an original plate by machining, if the size of the original plate to be formed is too large, the tool is worn during the processing of the original plate, and the original plate cannot be formed efficiently. Further, when forming an original by etching, if the size of the original to be formed is too large, the progress of the etching becomes non-uniform depending on the position of the original in the surface direction, and the shape of the protrusion tends to vary. . In addition, whether it is machining or etching, and even when a processing method different from these processing methods is used, the size of the processing target that can be processed by the processing apparatus is not limited. There is a limit.
As described above, as a result of restrictions on the size of the original plate in the surface direction, there is a limit to the size in the surface direction of the microneedle that can be manufactured from one intaglio plate.
The technique of this indication aims at providing the manufacturing method which can expand the magnitude | size of the surface direction of the microneedle which can be manufactured from one intaglio.

  A method of manufacturing a microneedle that solves the above-described problem has a step of forming one or more original plates having protrusions protruding from the surface of the substrate, and a shape in which patterns in which the irregularities of the original plate are reversed are arranged. A step of forming one intaglio plate using the original plate, a step of filling the intaglio plate with a material for forming a microneedle, and forming a molded product; and separating the molded product from the intaglio plate and the size of two or more original plates Obtaining a microneedle corresponding to the above.

  According to the above method, microneedles having a larger size in the surface direction than the original can be produced from one intaglio. Therefore, even if the size of the original plate in the surface direction is limited, the size in the surface direction of the microneedle that can be manufactured from one intaglio can be increased.

  In the above method, the step of forming the intaglio comprises: a step of arranging a plurality of the original plates in a direction along the surface of the substrate to form one relief plate; and the intaglio having a shape obtained by inverting the relief of the relief plate. A method including a step of forming from the relief plate, or a step of forming the intaglio plate, wherein the surface of the base has a transferred surface and has a shape obtained by inverting the irregularities of the original plate. And a step of forming a second intaglio, which is the intaglio, by arranging a plurality of the first intaglio along the surface of the first intaglio. The size in the surface direction of the microneedles that can be manufactured from can be increased.

In the above method, the relief printing plate may include a stage and a plurality of the original plates placed on the stage. Alternatively, in the above method, the original plates adjacent to each other may be fixed to each other in the relief plate.
According to these methods, the relief can be easily formed.

In the above method, the second intaglio may include a stage and a plurality of the first intaglios placed on the stage. Alternatively, in the above method, the first intaglio plates adjacent to each other may be fixed to each other with the second intaglio plate.
According to these methods, the second intaglio can be easily formed.

  According to the technology of the present disclosure, the size of the microneedles that can be manufactured from one intaglio can be increased.

It is a perspective view which shows a part of perspective structure of the microneedle manufactured by the 1st-3rd embodiment in the technique of this indication. It is sectional drawing which shows a part of sectional structure of the microneedle manufactured by the 1st-3rd embodiment. It is sectional drawing which shows the cross-sectional structure of the original plate formed at the formation process of the original plate in the manufacturing method of the microneedle in 1st Embodiment. It is a figure explaining the formation process of the relief plate in the manufacturing method of the microneedle in 1st Embodiment using the cross-section of an original plate. It is a figure explaining the formation process of the intaglio in the manufacturing method of the microneedle in 1st Embodiment using the cross-sectional structure of a letterpress. It is sectional drawing which shows the cross-section of the intaglio formed by the intaglio formation process in the manufacturing method of the microneedle in 1st Embodiment. It is a figure explaining the filling process in the manufacturing method of the microneedle in a 1st embodiment using the section structure of an intaglio. It is sectional drawing which shows the cross-section of the microneedle which is the molded product release | released in the manufacturing method of the microneedle in 1st Embodiment. It is sectional drawing which shows the cross-section of the negative | original plate formed at the formation process of the negative | original plate in the manufacturing method of the microneedle in 2nd Embodiment. It is a figure explaining the formation process of the small intaglio in the manufacturing method of the microneedle in 2nd Embodiment using the cross-sectional structure of an original plate. It is sectional drawing which shows the cross-sectional structure of the small intaglio formed by the formation process of the small intaglio in the manufacturing method of the microneedle in 2nd Embodiment. It is a figure explaining the formation process of the large intaglio in the manufacturing method of the microneedle in 2nd Embodiment using the cross-sectional structure of a small intaglio. It is a figure which shows the filling process in the manufacturing method of the microneedle in 2nd Embodiment using the cross-section of a large intaglio. It is sectional drawing which shows the cross-sectional structure of the microneedle which is the molded product release | released in the manufacturing method of the microneedle in 2nd Embodiment. It is sectional drawing which shows the cross-section of the negative | original plate formed in the formation process of the negative | original plate in the manufacturing method of the microneedle in 3rd Embodiment. It is a figure explaining the formation process of the small intaglio in the manufacturing method of the microneedle in 3rd Embodiment using the cross-section of an original plate. It is sectional drawing which shows the cross-sectional structure of the small intaglio formed by the formation process of the small intaglio in the manufacturing method of the microneedle in 3rd Embodiment. It is a figure explaining the formation process of the 1st large intaglio in the manufacturing method of the microneedle in a 3rd embodiment using the section structure of a small intaglio. It is a figure explaining the formation process of the relief plate in the manufacturing method of the microneedle in 3rd Embodiment using the cross-section of a 1st large intaglio. It is a figure which shows the cross-sectional structure of the relief printing formed by the formation process of the relief printing in the manufacturing method of the microneedle in 3rd Embodiment. It is a figure explaining the formation process of the 2nd large intaglio in the manufacturing method of the microneedle in a 3rd embodiment using the section structure of a letterpress. It is a figure which shows the cross-section of the 2nd large intaglio formed by the formation process of the 2nd large intaglio in the manufacturing method of the microneedle in 3rd Embodiment. It is a figure which shows the filling process in the manufacturing method of the microneedle in 3rd Embodiment using the cross-section of a 2nd large intaglio. It is sectional drawing which shows the cross-sectional structure of the microneedle which is the molded product release | released in the manufacturing method of the microneedle in 3rd Embodiment. It is sectional drawing which shows the cross-section of the division | segmentation piece formed by dividing | segmenting the microneedle manufactured by the manufacturing method of the microneedle in 3rd Embodiment.

(First embodiment)
With reference to FIGS. 1-8, 1st Embodiment of the manufacturing method of a microneedle is described.

[Configuration of microneedle]
With reference to FIG. 1 and FIG. 2, the structure of the microneedle manufactured by the manufacturing method of 1st Embodiment is demonstrated. 1 and 2 show a part of the microneedle, and the microneedle has a shape in which the shape shown in FIGS. 1 and 2 is repeated.

  As shown in FIG. 1, the microneedle 10 includes a base body 11 and a plurality of protrusions 12 protruding from the surface of the base body 11. The bottom surface of the protrusion 12 is formed integrally with the surface of the base 11, and the base 11 supports the base ends of the plurality of protrusions 12.

  The shape of the substrate 11 may be a flat plate shape, a curved plate shape, or a rectangular parallelepiped shape. The surface of the base body 11, which is the surface from which the protrusions 12 protrude, may be flat or may have a step. The level difference is formed in, for example, a streak shape that divides a plurality of protrusions 12.

  The shape of the protrusion 12 may be a pyramid shape or a conical shape. Further, the protruding portion 12 may have a shape in which the tip is not pointed, such as a columnar shape or a prismatic shape. Further, the protruding portion 12 may have a shape in which two or more solids are combined, such as a shape in which cones are stacked on a cylinder. In short, the protrusion 12 may have any shape that can pierce the skin. In addition, the number of the projection parts 12 is arbitrary.

  The delivery object intended to be delivered to the inside of the perforation target is contained in the microneedle 10, and the delivery part diffuses inside the perforation target by the protrusion 12 being dissolved inside the perforation target. The delivery material may be supplied from the outside of the microneedle 10. Whether the delivery product is contained in the microneedle 10 or supplied from the outside of the microneedle 10 differs depending on the mode of use of the microneedle 10.

  When the delivery product is supplied from the outside of the microneedle 10, the protrusion 12 may be formed with a hole through which the delivery product is passed toward the inside of the perforation target. The hole formed in the protruding portion 12 may be a hole that penetrates from the tip of the protruding portion 12 to the back surface of the base body 11, or may be a hole that does not penetrate. Regardless of whether or not there is a hole, a groove that allows the delivery article to pass toward the inside of the object to be perforated may be formed around the protrusion 12. In addition, a hole through which the delivery material supplied from the outside of the microneedle 10 is directed toward the protrusion 12 may also be formed in the base body 11. The hole formed in the base 11 may be a hole penetrating from the surface of the base 11 to the back surface of the base 11 or may be a hole that does not penetrate.

Each of the plurality of protrusions 12 may be regularly arranged on the surface of the base 11 or may be irregularly arranged. In addition, the plurality of protrusions 12 may be arranged at a plurality of locations on the surface of the base body 11 in a biased manner. For example, the plurality of protrusions 12 are arranged in a lattice shape or a concentric shape.
A support layer made of a material different from that of the base body 11 may be laminated on the back surface of the base body 11.

  As shown in FIG. 2, the height H of the protrusion 12 is preferably 10 μm or more and 1000 μm or less. The height H of the protrusion 12 is the length from the surface of the base 11 to the tip of the protrusion 12. The height H of the protrusion 12 is determined according to the depth of the hole required for the drilling target. When the target of perforation is human skin and the bottom of the hole is set in the stratum corneum, the height H is preferably 10 μm or more and 300 μm or less, and more preferably 30 μm or more and 200 μm or less. When the bottom of the hole is set to a depth that penetrates the stratum corneum and does not reach the nerve layer, the height H is preferably 200 μm or more and 700 μm or less, more preferably 200 μm or more and 500 μm or less, More preferably, it is 200 μm or more and 300 μm or less. When the depth is set so that the bottom of the hole reaches the dermis, the height H is preferably 200 μm or more and 500 μm or less. When the depth of the hole is set to a depth that reaches the epidermis, the height H is preferably 200 μm or more and 300 μm or less.

The width D of the protrusion 12 is the maximum value of the length of the protrusion 12 in the direction parallel to the surface of the base body 11. The width D of the protrusion 12 is preferably 1 μm or more and 300 μm or less. For example, when the protrusion 12 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 12 on the surface of the base 11 is the width D of the protrusion 12. For example, when the protrusion 12 has a conical shape or a cylindrical shape, the diameter of a circle defined by the bottom of the protrusion 12 is the width D of the protrusion 12.
The aspect ratio A (A = H / D), which is the ratio of the height H to the width D of the protrusion 12, is preferably 1 or more and 10 or less.

  When the tip of the projection 12 is formed in a sharp shape and a hole having a depth penetrating the stratum corneum is formed by perforation, the tip angle θ of the projection 12 is preferably 5 ° or more and 30 ° or less. More preferably, the angle is 10 ° or more and 20 ° or less. The tip angle θ is the maximum value of the angle formed by the tip of the protrusion 12 in the cross section orthogonal to the surface of the base 11. For example, when the projecting portion 12 has a regular quadrangular pyramid shape, the tip angle θ of the projecting portion 12 is the apex angle of a triangle having a square diagonal line defined by the bottom of the projecting portion 12 as a base and a vertex of the regular pyramid as a vertex. is there.

The width D, the aspect ratio A, and the tip angle θ of the protrusion 12 are determined according to the volume required by the hole. If the height H, the width D, the aspect ratio A, and the tip angle θ are within the above ranges, the shape of the protrusion 12 is a shape suitable for forming a hole in the skin.
When the microneedle 10 is used for a human body, the microneedle 10 is preferably formed from a biocompatible material.

  For example, the microneedle 10 is formed from a material including a water-soluble polymer and a delivery product. The delivery product is contained in the microneedle 10 in a state of being held in a water-soluble polymer that functions as a base material. When the microneedle 10 is used for a human body, the delivery product has a protrusion 12 of the skin. It is diffused in the body by dissolving with water.

Examples of the water-soluble polymer having biocompatibility include alginate, curdlan, chitin, chitosan, chitosan succinamide, glucomannan, polymalic acid, collagen, collagen peptide, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, Or pullulan etc. are mentioned.
As a delivery product, a pharmacologically active substance or a cosmetic composition can be used. The type of delivery is selected according to the purpose.

  Examples of the pharmacologically active substance include vaccines such as influenza, pain relieving drugs for cancer patients and the like, biologics, gene therapy drugs, injections, oral preparations, and skin application preparations. In transdermal administration using the microneedle 10, a drug is administered to a hole formed in the skin. Therefore, transdermal administration using the microneedle 10 can be used for administration of pharmacologically active substances that require subcutaneous injection, in addition to the pharmacologically active substances used for conventional transdermal administration. In particular, transdermal administration using the microneedle 10 is suitable for administration of injections such as vaccines to children because it does not cause pain during administration. In addition, transdermal administration using the microneedle 10 is suitable for administration of oral preparations for children who are difficult to take oral preparations, since it is not necessary to drink the drugs at the time of administration.

  A cosmetic composition is a composition used as a cosmetic or a cosmetic. Examples of the cosmetic composition include a moisturizer, a colorant, a fragrance, or a physiologically active substance that exhibits a beauty effect such as an improvement effect on wrinkles, acne, pregnancy lines, and an improvement effect on hair loss. When a material having a fragrance is used as a delivery product, a scent can be imparted to the microneedles 10, so that the microneedles 10 suitable for cosmetics can be obtained.

  The ratio between the delivery product and the water-soluble polymer contained in the microneedle 10 is determined in consideration of the amount of the delivery product that needs to be administered into the body and the amount of the water-soluble polymer that is necessary for forming the microneedle 10. Is done. In addition, the microneedle 10 may not include the delivery product separately from the water-soluble polymer as long as the water-soluble polymer functions as a delivery product or the delivery product is supplied from the outside of the microneedle 10. .

  Moreover, the microneedle 10 may be formed from resin. Examples of the biocompatible resin include medical silicone, polylactic acid, polyglycolic acid, polycarbonate, or cyclic olefin copolymer.

  In short, any material that can be applied to the manufacturing method for forming the microneedles 10 by filling the intaglio with the material can be used as a material for forming the microneedles 10.

[Manufacturing method of microneedle]
With reference to FIGS. 3-8, the manufacturing method of a microneedle is demonstrated. 3 to 8, the number of protrusions included in the microneedle and its original plate is simplified.

<Formation process of original plate>
As shown in FIG. 3, a plurality of original plates 20 are formed in the original forming process. Each of the plurality of original plates 20 includes a base 21 and a plurality of protrusions 22 protruding from the surface of the base 21.

  The original plate 20 has substantially the same shape as the protrusions 12 included in the microneedle 10 and has protrusions 22 that are arranged at the same interval as the interval between the adjacent protrusions 12. The size of the original plate 20 in the surface direction that is the direction along the surface of the substrate 21 is smaller than the size of the microneedles 10 in the surface direction that is the direction along the surface of the substrate 11 in the microneedles 10.

  When the surface of the base body 11 of the microneedle 10 is virtually divided into a plurality of regions, one original 20 has a shape corresponding to one divided part. The different masters 20 have shapes corresponding to different parts of the plurality of divided parts. Each of the plurality of original plates 20 may have a different shape from each other, or may have the same shape.

  The method for forming the original 20 is not particularly limited. For example, the original 20 is formed by processing the forming material of the original 20 using a fine processing technique. Examples of the fine processing technique include a lithography method, a wet etching method, a dry etching method, a sand blasting method, a laser processing method, and a precision machining method including a cutting process and a grinding process.

  The material for forming the original plate 20 may be any material that can be processed by the above processing techniques, such as metal materials such as aluminum, nickel, and stainless steel, crystal materials such as silicon, silicon carbide, and quartz, polycarbonate, polystyrene, and polyacetal. Synthetic resins such as acrylic resin and fluororesin, ceramics such as alumina and aluminum nitride, glass, and the like are used.

<Letterpress forming process>
As shown in FIG. 4, in the relief forming process, a relief 30 in which a plurality of original plates 20 are combined is formed. The plurality of original plates 20 are arranged along the surface direction of the original plate 20 to constitute one relief plate 30.

  The relief plate 30 includes, for example, a stage 31 having a recess 32 in which the original plate 20 is disposed, and a plurality of original plates 20 that are fitted in the recess 32 of the stage 31 and placed on the stage 31. In the stage 31, the depression 32 is formed for each original 20, and the adjacent originals 20 may not be in contact with each other. In the stage 31, one depression 32 may be formed so as to be common to the plurality of original plates 20, and the adjacent original plates 20 may be in contact with each other. One relief plate 30 has a shape corresponding to one microneedle 10, and the shape of one relief plate 30 determines the shape of one microneedle 10.

In addition, the relief plate 30 should just be comprised from the some original plate 20, for example, is formed by the mutually adjacent original plate 20 being fixed by adhesion | attachment, joining, fastening, etc. in the state in which the some original plate 20 was arranged. May be. Alternatively, each of the original plates 20 is formed with a fitting structure, and in a state where a plurality of original plates 20 are arranged, the original plates 20 are fixed to each other by fitting the fitting structures of the adjacent original plates 20 together. 30 may be formed.
The surface of the base 21 in the plurality of masters 20 is preferably arranged on the same plane, but a step may be formed between the bases 21 of the masters 20 adjacent to each other.

<Intaglio forming process>
As shown in FIG. 5, the intaglio 40 is formed from the relief 30 in the intaglio forming process. The intaglio 40 is formed by a known shape transfer method. Examples of the shape transfer method include a method of forming an Ni intaglio 40 by Ni electroforming, a method of performing transfer molding using a resin such as a molten thermosetting silicone resin, and the like. Thereby, as shown in FIG. 6, an intaglio 40 having a shape obtained by inverting the unevenness of the relief 30 is formed.

<Filling process>
As shown in FIG. 7, in the filling process, the forming material is formed by filling the intaglio 40 with the forming material of the microneedles 10.
For example, when the forming material of the microneedle 10 has a water-soluble polymer as a main component, a solution in which the forming material is dissolved is filled in the intaglio 40, and the filled solution is dried to form a molded product. The For example, when the forming material of the microneedle 10 is a resin, the molded product is molded by a molding method using the intaglio 40 such as injection molding, extrusion molding, imprinting, hot embossing, or casting. Thus, in the filling process, a known molding technique corresponding to the forming material of the microneedle 10 is used to mold the molded product.

<Release process>
As shown in FIG. 8, in the mold release step, the molded product is released from the intaglio plate 40. The molded product released from the intaglio plate 40 is the microneedle 10. The microneedle 10 has a size in the surface direction corresponding to two or more original plates 20. As a method for releasing the molded product, for example, a method of peeling the molded product from the intaglio plate 40 with a physical force, a method of selectively dissolving the intaglio plate 40 using chemical properties, or the like is used. it can.

  In the relief plate 30, when a gap or a step is formed between the adjacent masters 20, a plurality of protrusions 12 are provided at positions corresponding to the gap or step on the surface of the base 11 of the microneedle 10. A streak-shaped step is defined.

In addition, a part of the microneedle 10 which is a molded product that has been released may be punched to adjust the outer shape. In this case, the size of the relief plate 30 in the surface direction is formed larger in the surface direction than the divided piece of the microneedle 10 which is a product finally formed. By adjusting the shape by punching, it is possible to easily manufacture a divided piece having a complicated outer shape in the surface direction and a divided piece in which the protrusion 12 is formed up to the end in the surface direction. Moreover, compared with the case where the division piece of one microneedle 10 is manufactured from one intaglio, the division piece of a microneedle can be manufactured in large quantities.
The microneedle 10 is manufactured by the above process.

As described above, according to the first embodiment, the following effects can be obtained.
(1) The microneedle 10 having a larger size in the surface direction than the original 20 can be manufactured. Therefore, the size of the microneedles 10 in the surface direction is less restricted from the size of the original plate 20 in the surface direction. Therefore, even if the size of the original plate 20 in the surface direction is limited, the size of the microneedle 10 that can be manufactured from one intaglio plate 40 can be increased.

  In addition, since the relief plate 30 that determines the shape of the microneedle 10 to be manufactured is formed by the combination of the original plate 20, the relief plate 30 corresponding to the microneedle 10 having a complicated outer shape can be easily formed.

  (2) Since the relief plate 30 includes the stage 31 and the original plate 20 placed on the stage 31, the relief plate 30 can be easily assembled. Further, if the relief plate 30 is formed by fixing a plurality of original plates 20, the relief plate 30 can be easily formed, and the stage 31 is omitted, thereby reducing the burden required for the production of the stage 31 and the production process. The number of necessary parts can be reduced.

(Second Embodiment)
With reference to FIGS. 9-14, 2nd Embodiment of the manufacturing method of a microneedle is described. The second embodiment is a method of manufacturing a microneedle having the same configuration as the microneedle manufactured in the first embodiment, and an intaglio is manufactured as compared with the first embodiment. The procedure is different. Below, it demonstrates centering on difference with 1st Embodiment, about the structure similar to 1st Embodiment, the same code | symbol is attached | subjected and the description is abbreviate | omitted.

<Formation process of original plate>
As shown in FIG. 9, in the original forming process, the original 20 is formed. The original plate 20 includes a base body 21 and a plurality of protrusions 22 protruding from the surface of the base body 21. The original plate 20 has substantially the same shape as the protrusions 12 included in the microneedle 10 and has protrusions 22 that are arranged at the same interval as the interval between the adjacent protrusions 12. On the other hand, the size of the original plate 20 in the surface direction is smaller than the size of the microneedles 10 in the surface direction.

When the surface of the substrate 11 of the microneedle 10 is virtually divided into a plurality of regions, if the regions can be divided so that the shapes of the divided portions are the same, the master 20 to be formed is 1 There may be one, or a plurality of original plates 20 having the same shape may be formed. In this case, the original plate 20 has a shape corresponding to the divided portion. When the shapes of the plurality of divided parts are different from each other, the original plate 20 is formed for each part having a different shape, and has a shape corresponding to each part.
As the forming method and forming material of the original plate 20, the forming method and forming material exemplified in the first embodiment are used.

<First Intaglio Forming Step>
As shown in FIG. 10, in the first intaglio forming process, a small intaglio 41 that is a first intaglio having a shape obtained by inverting the irregularities of the original 20 is formed from the original 20. The small intaglio 41 has a surface onto which the surface of the base 21 of the original 20 is transferred.

  A plurality of small intaglio plates 41 may be formed from one original plate 20, and when there are a plurality of original plates 20, one small intaglio plate 41 may be formed from each original plate 20. As a result, when the surface of the base body 11 of the microneedle 10 is virtually divided into a plurality of regions, a small intaglio 41 having a shape obtained by inverting the unevenness of the shape of each divided portion may be formed. .

  As a method for forming the small intaglio 41, the method for forming the intaglio 40 exemplified in the first embodiment is used. As a result, as shown in FIG. 11, a plurality of small intaglio plates 41 are formed.

<Second Intaglio Forming Step>
As shown in FIG. 12, in the second intaglio forming process, a plurality of small intaglio plates 41 are combined to form a large intaglio plate 42 that is the second intaglio plate. The plurality of small intaglios 41 are arranged in a direction along the surface to which the surface of the base 21 of the original 20 is transferred.

  The large intaglio 42 includes, for example, a stage 43 having a depression 44 in which the small intaglio 41 is disposed, and a plurality of small intaglios 41 that are fitted in the depression 44 of the stage 43 and placed on the stage 43. . In the stage 43, the depression 44 is formed for each small intaglio 41, and the adjacent small intaglios 41 do not have to be in contact with each other. Further, in the stage 43, one recess 44 is formed so as to be common to the plurality of small intaglio plates 41, and the adjacent small intaglio plates 41 may be in contact with each other. One large intaglio 42 has a shape obtained by inverting the irregularities of the shape of one microneedle 10.

  The large intaglio 42 may be composed of a plurality of small intaglios 41. For example, in a state where the plurality of small intaglios 41 are arranged, the adjacent small intaglios 41 are fixed by adhesion, bonding, fastening, or the like. May be formed. Alternatively, each of the small intaglios 41 is formed with a fitting structure, and in a state where a plurality of small intaglios 41 are arranged, the small intaglios 41 are fixed to each other by fitting the fitting structures of the small intaglios 41 adjacent to each other. Thereby, the large intaglio 42 may be formed.

In the plurality of small intaglio plates 41, the surface to which the surface of the base 21 of the original 20 is transferred is preferably arranged on the same plane, but a step is formed between the surfaces of the small intaglio plates 41 adjacent to each other. It may be.
<Filling process>
As shown in FIG. 13, in the filling step, the forming material is formed by filling the large intaglio 42 with the forming material of the microneedles 10.
The molding technique illustrated in the first embodiment is used as a molding method of the molded product.

<Release process>
As shown in FIG. 14, in the mold release step, the molded product is released from the large intaglio 42. A molded product released from the large intaglio 42 is the microneedle 10. As a method for releasing the molded product, the method exemplified in the first embodiment is used.

  In the large intaglio plate 42, when a gap or a step is formed between the adjacent small intaglio plates 41, the protrusion 12 is provided at a position corresponding to the gap or the step on the surface of the base 11 of the microneedle 10. A streak-shaped step that divides a plurality is formed.

In addition, a part of the microneedle 10 which is a molded product that has been released may be punched to adjust the outer shape. In this case, the large intaglio 42 is formed to have a larger size in the surface direction than the divided piece of the microneedle 10, which is a finally formed product.
The microneedle 10 is manufactured by the above process.

As described above, according to the second embodiment, the following effects can be obtained.
(3) The microneedle 10 having a larger size in the surface direction than the original 20 can be manufactured. Therefore, the size of the microneedles 10 in the surface direction is less restricted from the size of the original plate 20 in the surface direction. Therefore, even if the size in the surface direction of the original plate 20 is limited, the size in the surface direction of the microneedle 10 that can be manufactured from the large intaglio plate 42 that is one intaglio plate can be increased.

  Further, since the large intaglio 42 corresponding to the shape of the microneedle 10 to be manufactured is formed by the combination of the small intaglio 41, it is easy to form the large intaglio 42 corresponding to the microneedle 10 having a complicated outer shape in the surface direction. Become.

  Further, when a plurality of small intaglio plates 41 are formed from one original plate 20, the number of original plates 20 required in the manufacturing process can be reduced as compared with the first embodiment. The burden can be reduced and the number of parts required for the manufacturing process can be reduced.

  (4) Since the large intaglio 42 includes the stage 43 and the small intaglio 41 placed on the stage 43, the large intaglio 42 can be easily assembled. In addition, if the large intaglio 42 is formed by fixing a plurality of small intaglios 41, the large intaglio 42 can be easily formed, and the stage 43 is omitted, thereby reducing the burden required for manufacturing the stage 43. The number of parts required for the manufacturing process can be reduced.

(Third embodiment)
With reference to FIGS. 15-25, 3rd Embodiment of the manufacturing method of microneedle is described. The third embodiment is a method of manufacturing a microneedle having the same configuration as the microneedle manufactured in the first embodiment, and an intaglio is manufactured as compared with the first embodiment. The procedure is different. Below, it demonstrates centering on difference with 1st Embodiment, about the structure similar to 1st and 2nd embodiment, the same code | symbol is attached | subjected and the description is abbreviate | omitted.

<Formation process of original plate>
As shown in FIG. 15, in the original forming process, the original 20 is formed. The original plate 20 includes a base body 21 and a plurality of protrusions 22 protruding from the surface of the base body 21. The original plate 20 has substantially the same shape as the protrusions 12 included in the microneedle 10 and has protrusions 22 that are arranged at the same interval as the interval between the adjacent protrusions 12. On the other hand, the size of the original plate 20 in the surface direction is smaller than the size of the microneedles 10 in the surface direction.

When the surface of the substrate 11 of the microneedle 10 is virtually divided into a plurality of regions, if the regions can be divided so that the shapes of the divided portions are the same, the master 20 to be formed is 1 There may be one, or a plurality of original plates 20 having the same shape may be formed. In this case, the original plate 20 has a shape corresponding to the divided portion. When the shapes of the plurality of divided parts are different from each other, the original plate 20 is formed for each part having a different shape, and has a shape corresponding to each part.
As the forming method and forming material of the original plate 20, the forming method and forming material exemplified in the first embodiment are used.

<First Intaglio Forming Step>
As shown in FIG. 16, in the first intaglio forming process, a small intaglio 41 that is a first intaglio having a shape obtained by inverting the unevenness of the original 20 is formed from the original 20. The small intaglio 41 has a surface onto which the surface of the base 21 of the original 20 is transferred.

  A plurality of small intaglio plates 41 may be formed from one original plate 20, and when there are a plurality of original plates 20, one small intaglio plate 41 may be formed from each original plate 20. As a result, when the surface of the base body 11 of the microneedle 10 is virtually divided into a plurality of regions, a small intaglio 41 having a shape obtained by inverting the unevenness of the shape of each divided portion may be formed. .

  As a method for forming the small intaglio 41, the method for forming the intaglio 40 exemplified in the first embodiment is used. Thereby, as shown in FIG. 17, a plurality of small intaglio plates 41 are formed.

<Second Intaglio Forming Step>
As shown in FIG. 18, in the second intaglio forming process, a plurality of small intaglio plates 41 are combined to form a first large intaglio plate 45 that is a second intaglio plate. The plurality of small intaglios 41 are arranged in a direction along the surface to which the surface of the base 21 of the original 20 is transferred.

  The first large intaglio 45 includes, for example, a stage 46 having a recess 47 in which the small intaglio 41 is disposed, and a plurality of small intaglios 41 that are fitted in the recess 47 of the stage 46 and placed on the stage 46. Is done. In the stage 46, the depression 47 is formed for each small intaglio 41, and the adjacent small intaglios 41 may not be in contact with each other. Further, in the stage 46, one recess 47 is formed so as to be common to the plurality of small intaglio plates 41, and the adjacent small intaglio plates 41 may be in contact with each other. In the first large intaglio 45 shown in FIG. 18, the small intaglios 41 adjacent to each other on the stage 46 are in contact with each other.

  The first large intaglio 45 only needs to be composed of a plurality of small intaglios 41. For example, in a state where the plurality of small intaglios 41 are arranged, the adjacent small intaglios 41 are fixed by bonding, joining, fastening, or the like. May be formed. Alternatively, each of the small intaglios 41 is formed with a fitting structure, and in a state where a plurality of small intaglios 41 are arranged, the small intaglios 41 are fixed to each other by fitting the fitting structures of the small intaglios 41 adjacent to each other. Thereby, the first large intaglio 45 may be formed.

  In the plurality of small intaglio plates 41, the surface to which the surface of the base 21 of the original 20 is transferred is preferably arranged on the same plane, but a step is formed between the surfaces of the small intaglio plates 41 adjacent to each other. It may be.

<Letterpress forming process>
As shown in FIG. 19, in the relief forming process, a relief 35 having a shape obtained by inverting the irregularities of the first large intaglio 45 is formed.
First, the material for forming the relief plate 35 is filled in the first large intaglio plate 45. As a material for forming the relief plate 35, for example, a thermoplastic resin such as polystyrene is used. The forming material of the relief plate 35 is filled into the first large intaglio plate 45 and molded by, for example, hot press molding. Then, when the molded product is released from the first large intaglio 45, the relief 35 is formed as shown in FIG.
As a method for forming the relief plate 35, a known forming technique can be used in addition to the above-described example.

<Third intaglio forming step>
As shown in FIG. 21, in the third intaglio forming process, the second large intaglio 48 that is the third intaglio is formed from the relief 35. The second large intaglio 48 is formed by a known shape transfer method. Examples of the shape transfer method include a method of forming the second large intaglio plate 48 made of Ni by the Ni electroforming method, a method of performing transfer molding using a resin such as a molten thermosetting silicone resin, and the like. Thereby, as shown in FIG. 22, the second large intaglio plate 48 having a shape obtained by inverting the unevenness of the relief plate 35 is formed.
<Filling process>
As shown in FIG. 23, in the filling step, the forming material is formed by filling the second large intaglio 48 with the forming material of the microneedles 10.
The molding technique illustrated in the first embodiment is used as a molding method of the molded product.

<Release process>
As shown in FIG. 24, in the mold release step, the molded product is released from the second large intaglio 48. The molded product released from the second large intaglio 48 is the microneedle 10. As a method for releasing the molded product, the method exemplified in the first embodiment is used.

In addition, as FIG. 25 shows, you may punch out a part of microneedle 10 which is a mold release product, and may form the division | segmentation piece 15 of the microneedle 10. FIG. Even in such a case, the second large intaglio plate 48 which is one intaglio plate having a shape in which patterns in which the unevenness of the original plate 20 is inverted is arranged has a size in the surface direction corresponding to two or more original plates 20. A microneedle 10 is formed. A case where the divided pieces 15 are formed from the respective small intaglio plates 41 by dividing the microneedle 10 having a large size in the surface direction formed from one intaglio and forming the divided pieces 15 having a small size in the surface direction; In comparison, the divided pieces 15 can be efficiently mass-produced.
The microneedle 10 is manufactured by the above process.

As described above, according to the third embodiment, the following effects can be obtained.
(5) The microneedle 10 having a larger size in the surface direction than the original 20 can be manufactured. Therefore, the size of the microneedles 10 in the surface direction is less restricted from the size of the original plate 20 in the surface direction. Therefore, even if the size in the surface direction of the original plate 20 is limited, the size in the surface direction of the microneedle 10 that can be manufactured from the second large intaglio plate 48 that is one intaglio plate can be increased.

(Modification)
Each of the above embodiments can be implemented with the following modifications.
An intaglio for forming the microneedle 10 as a molded product is a set of the intaglio 40 described in the first embodiment formed from a plurality of original plates 20 and a small intaglio 41 formed from one original plate 20. It may be a combination with the large intaglio plate 42 described in the second embodiment. In short, an intaglio for forming the microneedle 10 as a molded product is formed by transferring and reversing the shape directly from the original 20, or formed as a result of multiple times of transferring the shape of the original 20 using the original 20. Thus, it is only necessary to have one intaglio plate having a shape in which patterns in which the unevenness of the original plate 20 is inverted are arranged.

(Example)
The manufacturing method of the microneedle mentioned above is demonstrated using a specific Example.
[Example 1]
<Formation process of original plate>
A microneedle master was formed from a silicon substrate by precision machining. The shape of the protrusions was a regular quadrangular pyramid (height: 150 μm, bottom surface: 60 μm × 60 μm), and 36 protrusions were arranged in a grid of 6 columns and 6 rows at 1 mm intervals on the substrate. The size of the original plate was 30 mm square. The same process was repeated to form 16 original plates.
<Letterpress forming process>
Sixteen original plates were bonded with an adhesive to form a 120 mm square relief plate.

<Intaglio forming process>
A nickel film having a thickness of 500 μm was formed on the relief plate by plating. Then, using a 30% by weight potassium hydroxide aqueous solution heated to 90 ° C., the relief printing plate made of silicon was removed by wet etching to form a 120 mm square intaglio printing plate made of nickel.

<Filling process>
A forming solution was prepared by dissolving chitosan having a molecular weight of 800,000 in an aqueous citric acid solution. Then, the forming solution was filled into the intaglio using a dispenser. The intaglio filled with the forming solution was placed on a hot plate set at 90 ° C. and heated for 10 minutes, and the forming solution was dried and cured to form a molded product.
<Release process>
The molded product was peeled from the intaglio to obtain the microneedle of Example 1.

[Example 2]
<Formation process of original plate>
A microneedle master was formed from a silicon substrate by precision machining. The shape of the protrusions was a regular quadrangular pyramid (height: 150 μm, bottom surface: 60 μm × 60 μm), and 36 protrusions were arranged in a grid of 6 columns and 6 rows at 1 mm intervals on the substrate. The size of the original plate was 30 mm square.

<Formation process of small intaglio>
A nickel film having a thickness of 500 μm was formed on the original microneedle by plating. Then, using a 30% by weight potassium hydroxide aqueous solution heated to 90 ° C., the original microneedle plate made of silicon was removed by wet etching to form a 30 mm square small intaglio plate made of nickel. The same process was repeated to form 16 small intaglio plates.
<Large intaglio forming process>
Sixteen small intaglio plates were bonded with an adhesive to form a 120 mm square large intaglio plate.

<Filling process>
A forming solution was prepared by dissolving chitosan having a molecular weight of 800,000 in an aqueous citric acid solution. Then, the forming solution was filled into the large intaglio using a dispenser. The large intaglio plate filled with the forming solution was placed on a hot plate set at 90 ° C. and heated for 10 minutes, and the forming solution was dried and cured to form a molded product.
<Release process>
The molded product was peeled from the large intaglio and the microneedle of Example 2 was obtained.

[Example 3]
<Formation process of original plate>
A microneedle master was formed from a silicon substrate by precision machining. The shape of the protrusions was a regular quadrangular pyramid (height: 150 μm, bottom surface: 60 μm × 60 μm), and 36 protrusions were arranged in a grid of 6 columns and 6 rows at 1 mm intervals on the substrate. The size of the original plate was 30 mm square.

<Formation process of small intaglio>
A 30 mm square small intaglio was formed by performing transfer molding from the original using a thermosetting silicone resin. The same process was repeated to form 16 small intaglio plates.
<Formation process of the first large intaglio>
Sixteen small intaglios were lined up on the stage without gaps to form a 120 mm square first large intaglio.
<Letterpress forming process>
A first large intaglio plate made of polystyrene was formed at 120 mm square by placing sheet-like polystyrene on the first large intaglio plate and performing hot press molding.
<Formation process of the second large intaglio>
By performing transfer molding from the first large intaglio plate using a thermosetting silicone resin, a 120 mm square second large intaglio plate was formed.

<Filling process>
Hydroxypropylcellulose was dissolved in water to prepare the forming solution. Then, the forming solution was filled in the second large intaglio using a dispenser. The large intaglio plate filled with the forming solution was placed on a hot plate set at 90 ° C. and heated for 10 minutes, and the forming solution was dried and cured to form a molded product.

<Release process>
The molded product was peeled from the large intaglio to obtain the microneedle of Example 3. Furthermore, the microneedle of Example 3 was divided by a punching method to produce a divided piece of microneedle.
According to Examples 1 to 3, microneedles having a larger size in the surface direction than the original plate were obtained.

  DESCRIPTION OF SYMBOLS 10 ... Microneedle, 11 ... Base | substrate, 12 ... Protruding part, 15 ... Divided piece, 20 ... Original plate, 21 ... Base | substrate, 22 ... Protruding part, 30, 35 ... Letterpress, 31 ... Stage, 32 ... Depression, 40 ... Intaglio, 41 ... small intaglio, 42 ... large intaglio, 45 ... first large intaglio, 43,46 ... stage, 44,47 ... concave, 48 ... second large intaglio.

Claims (2)

Forming a plurality of original plates having a shape with protruding portions protruding from the surface of the substrate;
Arranging a plurality of the original plates in a direction along the surface of the base to form one relief plate;
Forming one intaglio plate having a shape obtained by inverting the relief of the relief plate from the relief plate;
Filling the intaglio with a material for forming a microneedle and molding a molded article;
Separating the molded product from the intaglio plate to obtain microneedles corresponding to the size of two or more original plates;
Only including,
The letterpress is
A stage having a plurality of depressions;
A plurality of the original plates placed on the stage, and
On the stage, each original plate is fitted in the depression for each original plate, and the adjacent original plates are separated from each other.
Manufacturing method of microneedle. Forming one or more masters having a shape with protruding portions protruding from the surface of the substrate;
Forming a plurality of first intaglio plates having a surface on which the surface of the substrate is transferred and having the shape obtained by inverting the irregularities of the original plate;
Arranging a plurality of the first intaglios along the surface of the first intaglio to form a second intaglio that is one intaglio;
Filling the second intaglio with a microneedle forming material to form a molded article;
Separating the molded product from the second intaglio and obtaining microneedles corresponding to the size of two or more original plates;
Only including,
The second intaglio is
A stage having a plurality of depressions;
A plurality of the first intaglios placed on the stage,
On the stage, each first intaglio is fitted in the depression for each first intaglio, and the first intaglios adjacent to each other are separated from each other.
Manufacturing method of microneedle.

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