JP6606939B2 - Transdermal administration device and method for producing transdermal administration device - Google Patents

Description

  The present invention relates to a transdermal administration device used for drug administration and a method for producing the same.

  The transdermal administration device includes an administration unit for administering a drug from the skin to a drug administration target. A microneedle, which is an example of an administration unit, includes a plurality of protrusions having a fine needle shape and a plate-like base, and the plurality of protrusions are arranged on the surface of the base. In the method of administering a drug using a microneedle, first, the base is pressed against the skin of the administration target to cause the protrusion to perforate the skin, and then the drug is injected into the body of the administration target from the hole formed by the protrusion. It is sent. In one example of such a microneedle, the drug is held on the surface of the protrusion. And a chemical | medical agent enters into the skin of an administration object with a projection part, and diffuses in a body (for example, refer patent document 1).

International Publication No. 2011/105496

  In the above-described step of holding the drug on the microneedle, the drug is applied to the surface of the protrusion in a liquid state and then solidified to be held on the surface of the protrusion. Therefore, since the amount of the drug that can be held by the microneedle, that is, the amount of the drug that can be administered by the microneedle is limited to the amount according to the surface area of the protrusion, the amount of the drug that can be administered is increased. There is a need for transdermal administration devices that can. In addition, the request | requirement which increases the quantity of the chemical | medical agent which can be administered is common in a transdermal administration device irrespective of the holding | maintenance form of a chemical | medical agent.

  An object of the present invention is to provide a transdermal administration device capable of increasing the amount of a drug that can be administered, and a method for producing the transdermal administration device.

  A transdermal administration device that solves the above problems includes a base having a first surface, a second surface that is the surface opposite to the first surface, and a protrusion protruding from the first surface. The surface of the protrusion has irregularities, and the irregularities include a plurality of irregular elements that are convex parts or concave parts, and the plural irregular elements include the streaky irregular elements extending in the first direction, and the first And the stripe-shaped concavo-convex element extending in a second direction intersecting with one direction.

  According to the above configuration, since the surface of the protrusion has unevenness, and the unevenness is configured by the stripe-shaped unevenness elements extending in different directions, the protrusion is compared with the configuration in which the surface of the protrusion is flat. The surface area of the part increases. As a result, the amount of drug that can be administered to the protrusion can be increased.

The said structure WHEREIN: The whole surface of the said projection part may have the said unevenness | corrugation.
According to the said structure, compared with the structure by which an unevenness | corrugation is arrange | positioned at a part of surface of a projection part, the quantity of the chemical | medical agent which can administer a projection part can be increased.

  A transdermal administration device that solves the above-described problem is a master comprising a base and a protrusion protruding from the base, the surface of the protrusion having a step, and a master preparation step for preparing the master, , A step of making an intaglio by copying and reversing the irregularities of the original plate, and having a shape following the shape of the protrusion and a first recess that has a shape following the shape of the base An intaglio plate producing step for producing the intaglio plate having a second depression that is a depression, a surface treatment step for forming streak-like irregularities on the inner surface of the second depression, and a processed plate that is an intaglio plate that has undergone the surface treatment step And a molding step of filling a material for forming a transdermal administration device to form a molded product, and a mold releasing step of separating the molded product from the processed plate to obtain a transdermal administration device.

  According to the said manufacturing method, the transdermal administration device in which the surface of a projection part has an unevenness | corrugation is manufactured. In such a transdermal administration device, the surface area of the protrusion is increased as compared with a configuration in which the surface of the protrusion is flat. Therefore, the amount of the drug that can be administered to the protrusion can be increased.

  In the manufacturing method, the surface treatment step includes a step of expanding a portion including the inner side surface of the second recess in the intaglio, a step of oxidizing the expanding inner side surface, and the oxidized inner side surface. Shrinking the portion to be included.

  According to the above manufacturing method, since unevenness is formed due to the difference in shrinkage between the oxidized inner surface and the unoxidized intaglio, complicated machining that processes the recesses and protrusions one by one Irrespective of this, it is possible to form irregularities on the inner surface of the second recess. Further, since the inner side surface has a level difference in which the surface step of the projection of the original plate is inverted, each of the flat regions on the inner side surface is compared with the configuration in which the inner side surface is flat. small. Accordingly, the extending direction and length of the stripe-shaped convex portions and concave portions constituting the concave and convex portions are limited, and thus the variation in the structural characteristics of the concave and convex portions is reduced. As a result, it is possible to suppress the occurrence of bias in the structural characteristics of the unevenness of the surface of the protrusion in the manufactured transdermal administration device. Moreover, since the unevenness | corrugation formed in an inner surface becomes fine compared with the structure where an inner surface is a plane, the peelability of the molded product from a processed plate is improved.

In the said manufacturing method, in the said intaglio preparation process, the part containing the said inner surface of the said 2nd recessed part in the said intaglio may be formed from a silicone resin.
According to the said manufacturing method, a stripe-shaped unevenness | corrugation can be suitably formed in an inner surface by a surface treatment process.

  ADVANTAGE OF THE INVENTION According to this invention, the quantity of the medicine which can be administered in a transdermal administration device can be increased.

It is a perspective view which shows the perspective structure of the transdermal administration device of one Embodiment. (A) is a perspective view which shows the perspective structure of the protrusion part of the transdermal administration device of one Embodiment, (b) is a figure which expands and shows a part of surface of the protrusion part shown by (a) (C) is a figure which shows the cross section of the convex part shown by (b). It is sectional drawing which shows the cross-section of the transdermal administration device of one Embodiment. It is a side view which shows the side structure of the negative | original plate protrusion part with which the negative | original plate used for manufacture of the transdermal administration device of one Embodiment is provided. It is a top view which shows the planar structure of the negative | original plate protrusion part with which the negative | original plate used for manufacture of the transdermal administration device of one Embodiment is provided. It is a top view which shows the other example of the planar structure of the negative | original plate protrusion part with which the negative | original plate used for manufacture of the transdermal administration device of one Embodiment is provided. It is a top view which shows the other example of the planar structure of the negative | original plate protrusion part with which the negative | original plate used for manufacture of the transdermal administration device of one Embodiment is provided. It is a figure which shows the manufacturing method of the transdermal administration device of one Embodiment typically, Comprising: It is a figure which shows the intaglio preparation process. It is a figure which shows typically the manufacturing method of the transdermal administration device of one Embodiment, Comprising: It is a figure which shows a part of intaglio plate produced in the intaglio plate preparation process. It is a figure which shows typically the manufacturing method of the transdermal administration device of one Embodiment, Comprising: It is a figure which shows the intaglio manufactured by the intaglio preparation process. It is a figure which shows typically the manufacturing method of the transdermal administration device of one Embodiment, Comprising: It is a figure which shows the processed plate produced in the surface treatment process. It is a figure which shows typically the change by the surface treatment process of the part containing the inner surface of a 2nd recessed part about the intaglio used for manufacture of the transdermal administration device of one Embodiment, (a) is the intaglio in a normal state (B) shows the intaglio which expanded by the expansion process, (c) shows the intaglio in which the inner surface was oxidized by the oxidation process, and (d) shows the intaglio which contracted by the contraction process. It is a figure which shows the manufacturing method of the transdermal administration device of one Embodiment typically, Comprising: It is a figure which shows a filling process. It is a figure which shows the manufacturing method of the transdermal administration device of one Embodiment typically, Comprising: It is a figure which shows the molded article released in the mold release process. It is a figure which shows the image which image | photographed the surface of the projection part in the transdermal administration device of Example 2 with the scanning electron microscope. It is a figure which shows the image which image | photographed the surface of the projection part in the transdermal administration device of the comparative example 2 with the scanning electron microscope.

With reference to FIGS. 1-14, one Embodiment of the manufacturing method of a transdermal administration device and a transdermal administration device is described.
[Configuration of transdermal administration device]
With reference to FIGS. 1-3, the structure of the microneedle which is an example of the administration part which comprises a transdermal administration device is demonstrated.

  As shown in FIG. 1, the microneedle 10 includes a base 11 having a plate shape and a protrusion 12 protruding from the base 11. The base body 11 has a first surface 11S that is a surface on which the protrusions 12 are disposed, and a second surface 11T that is a surface opposite to the first surface 11S. The first surface 11S is the surface of the protrusions 12. Supports the proximal end.

The outer shape of the base body 11 viewed from the direction facing the first surface 11S is not particularly limited, and the outer shape of the base body 11 may be circular, elliptical, or rectangular.
Although the shape of the projection part 12 is not specifically limited, When the surface of the projection part 12 is considered as a virtual plane, it is preferable that it is the cone shape enclosed by the plane. A cone defines a closed area on a plane and a specified point that is one point outside this plane, and the area is enlarged from the plane toward the specified point while maintaining a similar shape. It is a solid composed of a portion through which the region passes when it is deformed until it has a shape that matches the specified point. The cone includes a cone in a so-called mathematical meaning such as a triangular pyramid and a quadrangular pyramid. In this case, the closed region on the plane is the bottom surface, and the specified point is the vertex. The vertex here is not a point in the mathematical sense but a range having a certain spread. The cone shape surrounded by a plane includes, for example, a cone shape such as a triangular pyramid or a quadrangular pyramid whose bottom surface is a polygon.

  The number of protrusions 12 is not particularly limited as long as it is 1 or more. When the microneedle 10 has a plurality of protrusions 12, each of the plurality of protrusions 12 may be arranged regularly or irregularly when viewed from the direction facing the first surface 11S of the base body 11. You may line up. For example, the plurality of protrusions 12 are arranged in a lattice shape or a concentric shape.

As shown in FIG. 2A, the surface 12S of the protrusion 12 has irregularities that are structures including streak-like irregular elements. The unevenness is disposed on the entire surface 12S of the protrusion 12.
FIG. 2B is an enlarged view showing a part of the surface 12S of the protrusion 12 shown in FIG. 2A, and schematically showing the unevenness of the surface 12S. As shown in FIG. 2B, the unevenness includes a plurality of protrusions 13 that are raised on the surface 12S of the protrusion 12 and a plurality of recesses 14 that are recessed on the surface 12S of the protrusion 12. It consists of. A portion sandwiched between the convex portions 13 adjacent to each other is a concave portion 14, and each of the convex portion 13 and the concave portion 14 is an example of an uneven element.

  The convex portion 13 has a stripe shape, that is, a shape extending linearly. The plurality of convex portions 13 include a stripe-shaped convex portion 13a extending in a first direction which is an arbitrary direction, and a stripe-shaped convex portion 13b extending in a second direction intersecting the first direction. The plurality of convex portions 13 may include stripe-shaped convex portions 13 extending in a direction different from both the convex portions 13a and the convex portions 13b.

  If the convex part 13 is extended in one direction as a whole, it may not have a perfect linear shape and may have a part extended while curving. For example, the convex portion 13 may be gently curved or wavy.

  Each convex portion 13 may or may not intersect with another convex portion 13, but for each of the plurality of convex portions 13, another convex portion 13 that intersects with one convex portion 13. The number is approximately 5 or less.

In the above configuration, the recess 14 also has a shape extending in a stripe shape. That is, the streak-like unevenness is composed of a large number of streaky convex portions 13 and a large number of streaky concave portions 14.
The length Lt of the convex portion 13 is the length of the maximum portion of each convex portion 13 in the extending direction of each convex portion 13, and is preferably 1 μm or more and 50 μm or less. If the length Lt of the convex portion 13 is 1 μm or more, it is easy to obtain reproducibility of the length Lt of the convex portion 13, and if the length Lt of the convex portion 13 is 50 μm or less, the rigidity of the protruding portion 12 is increased. Large fluctuations due to the convex portion 13 are suppressed.

  The width Wt of the convex portion 13 is the length of the maximum portion of each convex portion 13 in the direction orthogonal to the extending direction of each convex portion 13, and is preferably 0.1 μm or more and 5.0 μm or less. If the width Wt of the convex portion 13 is 0.1 μm or more, it is easy to prevent the convex portion 13 from falling, and if the width Wt of the convex portion 13 is 5.0 μm or less, the rigidity of the protruding portion 12 is the convex portion 13. Can be prevented from fluctuating greatly.

  The interval Pt between the protrusions 13 is the maximum length between two adjacent protrusions 13 that extend in substantially the same direction, that is, the recesses between these protrusions 13 in the direction in which these protrusions 13 are arranged. The maximum length of 14 is preferably 0.1 μm or more and 5.0 μm or less. If the spacing Pt between the convex portions 13 is 0.1 μm or more, it is easy to prevent the adjacent convex portions 13 from being united in the process of forming them, and the spacing Pt between the convex portions 13 is 5.0 μm or less. Thus, the effect of increasing the dose of the drug can be sufficiently obtained.

  FIG.2 (c) is a schematic diagram which shows typically the cross-section of the convex part 13 which FIG.2 (b) shows. As shown in FIG. 2C, the height Ht of the convex portion 13 is the length of the maximum portion of the convex portion 13 in the direction orthogonal to the direction in which the surface 12S of the protruding portion 12 spreads, that is, the base portion of the convex portion 13. To the top of the convex portion 13, and preferably 0.1 μm or more and 5.0 μm or less. If the height Ht of the convex portion 13 is 0.1 μm or more, the effect of increasing the dose of the drug is sufficiently obtained, and if the height Ht of the convex portion 13 is 5.0 μm or less, the protrusion 12 Can be suppressed from greatly fluctuating due to the convex portion 13.

  In the plurality of convex portions 13, the length Lt, the width Wt, the interval Pt, and the height Ht of the convex portion 13 are not constant. On the surface 12S of the protruding portion 12, the plurality of convex portions 13 are arranged such that the extending direction, the length Lt, the width Wt, the interval Pt, and the height Ht vary irregularly.

  However, the extending direction of the plurality of convex portions 13 is roughly divided into two directions of a first extending direction and a second extending direction. The first extending direction is a direction along the direction in which the surface 12S of the projecting portion 12 spreads, and is a direction from the base of the projecting portion 12 toward the tip of the projecting portion 12. The second extending direction is the projecting portion. 12 is a direction along the direction in which the surface 12S spreads, and is a direction orthogonal to the first extending direction. For the majority of the protrusions 13 included in the plurality of protrusions 13, the direction in which the protrusions 13 extend is such that the inclination from the first extending direction is 10 degrees or less, or the inclination from the second extending direction is The direction is 10 degrees or less.

  As shown in FIG. 3, the height Hp of the protrusion 12 is the tip of the protrusion 12 from the first surface 11S in the thickness direction of the base 11, that is, the direction orthogonal to the direction in which the first surface 11S of the base 11 spreads. Is the length. The height Hp of the protrusion 12 is determined based on the depth of the hole that needs to be formed by the perforation of the protrusion 12 according to the purpose of the perforation by the protrusion 12 and the type of medicine to be administered. The height Hp of the protrusion 12 is preferably 20 μm or more and 1000 μm or less.

  The width Wp of the protruding portion 12 is the maximum length of the protruding portion 12 in a direction parallel to the direction in which the first surface 11S of the base 11 spreads. For example, when the protrusion 12 has a regular quadrangular pyramid shape, a square diagonal line that is the bottom surface of the protrusion 12 partitioned in the first surface 11S of the base body 11 is the width Wp of the protrusion 12. The width Wp of the protrusion 12 is determined according to the required aspect ratio of the protrusion 12, the volume of the hole that needs to be formed by perforation of the protrusion 12, and the like. The width Wp of the protrusion 12 is preferably 1 μm or more and 300 μm or less.

  When the protrusion 12 has a sharp tip, the tip angle θ of the protrusion 12 is preferably 5 ° or greater and 45 ° or less. The tip angle θ of the protrusion 12 is the maximum value of the angle formed by the tip of the protrusion 12 in the cross section in the thickness direction of the base body 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 the square diagonal of the bottom surface of the projecting portion 12 as the base and the apex of the regular pyramid as the apex.

In addition, when the microneedle 10 has the some projection part 12, the several projection part 12 may contain the projection part 12 of a mutually different shape.
[Method of manufacturing transdermal administration device]
With reference to FIGS. 4-14, the manufacturing method of the microneedle 10 mentioned above is demonstrated as an example of a transdermal administration device.

<Original plate making process>
As shown in FIG. 4, first, in the original production process, the original 20 of the microneedle 10 is produced. The original 20 includes an original substrate 21 and an original projection 22 protruding from the original substrate 21. The original substrate 21 has substantially the same shape as the substrate 11 of the microneedle 10 to be produced, and is a surface opposite to the formation surface 21S and the formation surface 21S on which the original protrusions 22 are arranged. And a forming surface 21T. The original projection 22 has substantially the same shape as the projection 12 of the microneedle 10 to be manufactured, except for the surface shape. For example, when the projection 12 has a quadrangular pyramid shape, the original plate projection 22 also has the same quadrangular pyramid shape as the projection 12.

  Here, the surface 22S of the original projection 22 has a step. The step is formed in a staircase shape and includes a plurality of steps 23. Each step 23 has a surface parallel to the forming surface 21S of the original substrate 21 and a surface orthogonal to this surface. In other words, the original projection 22 has a shape in which flat layers are stacked. The cross-sectional area of each step 23 in the direction parallel to the direction in which the forming surface 21S spreads gradually decreases from step to step toward the tip of the original projection 22.

  The size and number of the step 23 are not particularly limited, but the height Hd of the step 23, which is the length of the step 23 in the direction orthogonal to the direction in which the formation surface 21S spreads, is 0.1 μm or more and 5.0 μm or less. preferable. The width D of the surface parallel to the formation surface 21S of the step 23 is preferably 0.001 μm or more and 0.5 μm or less. That is, the width D of the step 23 is the length between the ends of the step 23 and the step 23 immediately above the step 23 in a direction parallel to the direction in which the formation surface 21S extends. In the plurality of steps 23, the height Hd and the width D of each step 23 are preferably constant. Further, the surface 22S of the original projection 22 preferably has a number of steps 23 equal to or greater than 100 steps.

  As shown in FIG. 5, each step 23 has a shape similar to the bottom surface of the original projection 22 when viewed from the direction facing the forming surface 21 </ b> S of the original substrate 21, and the outer shape of each step 23 is the original projection. 22 gradually decreases from the base portion toward the tip.

  FIG. 5 shows an example in which the original projection 22 has a triangular pyramid shape, and the bottom surface of the original projection 22 and the outer shape of each step 23 viewed from the direction facing the forming surface 21S are triangular. Instead, for example, as shown in FIG. 6, when the original projection 22 has a quadrangular pyramid shape and the bottom of the original projection 22 is a square, each step viewed from the direction facing the forming surface 21 </ b> S. The outer shape of 23 is a quadrangle having a similar shape to the bottom surface. Further, for example, as shown in FIG. 7, when the original projection 22 has an octagonal pyramid shape and the bottom of the original projection 22 is an octagon, the outer shape of each step 23 viewed from the direction facing the forming surface 21S. Is an octagon similar in shape to the bottom.

  The material for forming the original 20 is not particularly limited, and a material that can be processed by a known fine processing technique may be used. Examples of the material for forming the master 20 include metal materials such as stainless steel, aluminum, and titanium, ceramics such as alumina, aluminum nitride, and machinable ceramics, hard and brittle materials such as silicon and glass, and organic materials such as acrylic and polyacetal. Is mentioned. The material for forming the original 20 is preferably selected in consideration of processability, material availability, and the like.

  For forming the original 20, a known fine processing technique such as a machining technique or a processing technique used for manufacturing a semiconductor device is used. Examples of the fine processing technique include dicing, sandblasting, laser processing, lithography, wet etching, and dry etching.

  A well-known fine processing technique may be used for forming the step 23, and it is particularly preferable that the step 23 is formed using a micro drill. If a micro drill is used, it is possible to form fine grooves extending in various directions with respect to an object to be processed by grinding. Therefore, the use of a micro drill is suitable for forming a fine step 23.

The original plate 20 may be subjected to processing or modification for facilitating the release of the intaglio plate from the original plate 20 in producing the intaglio plate to which the shape of the original plate 20 is transferred.
<Intaglio production process>
Subsequently, in the intaglio plate making process, an intaglio plate having a recess having a shape obtained by inverting the unevenness of the original plate 20 is made.

  As a material for forming the intaglio, a silicone resin is preferably used from the viewpoint of moldability, followability of a fine shape in a molded product, and high mold releasability, and the silicone resin is made of polydimethylsiloxane. It is particularly preferable that the silicone resin is contained. As such a silicone resin, for example, a silicone resin obtained by adding a curing agent to polydimethylsiloxane (PDMS) (manufactured by Dow Corning Toray Co., Ltd., SYLGARD 184, etc.) can be used. By using a silicone resin that is excellent in releasability as a material for forming the intaglio plate 30, the mold releasability of the molded product is improved, so that damage to the mold during mold release can be suppressed.

  As shown in FIG. 8, when producing the intaglio, first, the unevenness of the original 20 is filled with a liquid containing the intaglio forming material, and the liquid is cured. Then, as shown in FIG. 9, the intaglio plate 30 is formed by peeling the cured product from the original plate 20. That is, the intaglio plate 30 is formed by copying and inverting the unevenness of the original plate 20.

  As shown in FIG. 10, the recess 31 of the intaglio plate 30 includes a first recess 32 that is recessed in a shape that follows the shape of the original substrate 21, and a second recess 33 that is recessed in a shape that follows the shape of the original projection 22. It consists of. The first recess 32 and the second recess 33 communicate with each other, and the second recess 33 is positioned closer to the bottom of the intaglio plate 30 than the first recess 32. The second recess 33 is arranged in such a direction that a portion corresponding to the tip of the original projection 22 is directed to the bottom of the intaglio 30 and a portion corresponding to the base end of the original projection 22 is directed to the first recess 32. .

  The inner side surface 33S of the second recess 33 has a step that is the reverse of the step on the surface 22S of the original projection 22. That is, the step provided on the inner side surface 33S of the second recess 33 is formed in a stepped shape composed of a plurality of steps 34, and the inner diameter of the second recess 33 in the direction perpendicular to the extending direction of the second recess 33 is , And gradually decreases from the opening of the second recess 33 toward the bottom.

<Surface treatment process>
Subsequently, in the surface treatment step, a processing plate is manufactured by performing a process on the inner side surface 33S of the second concave portion 33 of the intaglio plate 30. Specifically, the surface treatment step includes an expansion step of expanding a portion including the inner side surface 33S of the second concave portion 33 in the intaglio plate 30, an oxidation step of oxidizing the expanded inner side surface 33S, and an oxidized inner side surface 33S. A shrinking step of shrinking a portion including Through these steps, streaky irregularities are formed on the inner side surface 33S.

  As shown in FIG. 11, the intaglio plate 30 that has undergone the surface treatment process is a processed plate 40. That is, the processing plate 40 has a recess 31 composed of a first recess 32 and a second recess 33, and the processing surface 43S, which is the inner surface of the second recess 33, has a large number of stripe-shaped protrusions It has unevenness composed of a large number of stripe-shaped recesses, which are regions between adjacent protrusions.

Here, a process in which irregularities are formed on the inner side surface 33S of the second concave portion 33 in the intaglio 30 in the surface treatment step will be described.
FIGS. 12A to 12D are diagrams schematically showing a portion including the inner side surface 33 </ b> S of the second concave portion 33 in the intaglio plate 30.

  In the expansion process, the intaglio 30 in the normal state shown in FIG. 12A is expanded as shown in FIG. The expansion is preferably thermal expansion. For example, when the intaglio 30 is heated by a heat source such as a heater, the intaglio 30 expands. The inflating step may be a step for expanding the inner side surface 33S. For example, the intaglio 30 may be inflated by a chemical action by immersing the intaglio 30 in an organic solvent or the like. By pulling the end portion, the inner side surface 33S may be expanded by a physical action.

  Subsequently, as shown in FIG. 12C, the expanded inner surface 33S is oxidized in the oxidation step. When the intaglio 30 is formed from a silicone resin, the inner side surface 33S is vitrified by oxidation. The inner side surface 33S is preferably oxidized by plasma treatment. A plasma processing apparatus used for manufacturing a semiconductor device may be used for the plasma processing. In place of the plasma treatment, the inner side surface 33S may be oxidized by ultraviolet irradiation.

  Subsequently, as shown in FIG. 12D, the expanding intaglio 30 is contracted in the contraction step. In the expansion process, when the intaglio 30 is expanded by heating, in the contraction process, for example, the intaglio 30 is contracted by cooling to room temperature. The inner side surface 33S vitrified by oxidation is harder than the portion below the inner side surface 33S in the intaglio plate 30, that is, the portion not vitrified, and hardly contracts. Therefore, while the lower layer of the inner side surface 33S contracts to the normal state, the inner side surface 33S is pulled by the contraction of the lower layer while the area of the inner side surface 33S is expanded from the normal state. As a result, wrinkles approach the inner side surface 33S, and streaky irregularities are formed on the inner side surface 33S. Since the step width at the step on the inner side surface 33S is fine, the step almost disappears due to the formation of the unevenness, but the step on the inner side surface 33S has such a width that it remains even after the formation of the unevenness. May be. When the step on the inner side surface 33S remains, the stripe-shaped unevenness is sufficiently finer than such a step.

  In the surface treatment step, at least the inner side surface 33S of the second concave portion 33 in the intaglio plate 30 and its vicinity need only expand and contract. That is, in the surface treatment process, the entire intaglio 30 may expand and contract, or a part of the intaglio 30 including the inner side surface 33S may expand and contract.

  The material for forming the intaglio 30 is not limited to silicone resin. The intaglio forming material is preferably selected in consideration of the shape following ability to transfer the shape of the original plate 20 well, transferability in transfer molding, durability, and mold releasability. As such a material, it is preferable to use a resin having high releasability. Specifically, in addition to the silicone resin, a thermoplastic resin such as urethane rubber, norbornene resin, polycarbonate, polyethylene terephthalate, polystyrene, acrylic, Examples of the resin composition include methyl methacrylate and liquid crystal polymer. As a material for forming the intaglio 30, a material that can be used to form irregularities on the surface by the surface treatment described above may be used.

<Filling process>
As shown in FIG. 13, subsequently, in the filling step, the concave material 31 of the work plate 40 is filled with the forming material of the microneedle 10 to form a molded product.

The material for forming the microneedles 10 is not particularly limited as long as it is a material that can be molded by filling the working plate 40, but is preferably a biodegradable material.
Examples of the biodegradable resin include polylactic acid, a copolymer of lactic acid and glycolic acid, polyethylene succinate, polybutylene succinate adipate, polybutylene succinate carbonate, polycaprolactone, polyesteramide, polyester carbonate, And mixtures thereof. In particular, polylactic acid or a copolymer of lactic acid and glycolic acid is preferably used.

  A water-soluble polymer may be used as a material for forming the microneedle 10. Examples of the water-soluble polymer include starch, carboxymethylcellulose (CMC), chitosan, methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid polymer, One or more compounds selected from the group consisting of polyacrylamide (PAM) and polyethylene oxide (PEO) are used. Among these water-soluble polymers, it is preferable that at least one of carboxymethyl cellulose and chitosan is used as a material for forming the microneedle 10. This is because carboxymethylcellulose and chitosan have high biological safety.

Note that the forming material of the protrusions 12 and the forming material of the base body 11 may have different compositions.
The method for filling the processing plate 40 with the forming material of the microneedle 10 is not particularly limited. When a thermoplastic resin is used as a material for forming the microneedles 10, from the viewpoint of improving productivity, an imprint method, a hot embossing method, an injection molding method, an extrusion molding method, or a casting method is used. The forming material is preferably filled into the processing plate 40 to form a molded product.

  Further, when a water-soluble polymer is used as a material for forming the microneedle 10, the working plate 40 may be filled with a solution in which the water-soluble polymer is dissolved. A molded object is formed when a filling solidifies by drying.

<Release process>
As shown in FIG. 14, in the mold release step, the molded product is released from the work plate 40. A molded product released from the processing plate 40 is the microneedle 10.

  In addition, the microneedle 10 may be formed by punching a molded product after mold release by machining. That is, the outer shape of the base body 11 of the microneedle 10 may be adjusted by punching the molded product, or a plurality of microneedles 10 may be formed from one molded product.

As a result, the microneedle 10 having streak-like irregularities on the surface 12S of the protrusion 12 is formed.
In addition, since the surface 12S of the projection part 12 has an unevenness | corrugation, compared with the case where the surface 12S does not have an unevenness | corrugation, a molded product becomes difficult to leave | separate from the processed plate 40. FIG. In order to improve the peelability of the molded product from the working plate 40, that is, in order to facilitate separation of the molded product from the working plate 40, the processing plate 40 is filled before the forming material of the microneedle 10 is filled in the working plate 40. A release layer having a function of improving the mold release property of the molded product may be formed on the inner side surface. For example, the release layer is made of a fluorine resin. The release layer can be suitably formed by using a thin film forming method such as a CVD method, a spin coating method, or a dip coating method.

  The liquid drug is applied to the surface 12S of the protrusion 12 of the microneedle 10 manufactured as described above and solidified, whereby the drug is held on the surface 12S of the protrusion 12. The drug is not particularly limited as long as it is a substance that functions by being administered intradermally. Examples of the drug include physiologically active substances and cosmetic compositions having a cosmetic effect.

  When the microneedle 10 is used, the protrusion 12 is stuck into the skin when the microneedle 10 is pressed against the skin to be administered. That is, the base 11 is pressed against the skin until the tip of the protrusion 12 is directed to the skin and the first surface 11S of the base 11 contacts the skin. The drug enters the skin together with the protrusion 12 and diffuses into the body of the administration target.

[Action]
The operation of this embodiment will be described. Since the surface 12S of the protrusion 12 of the microneedle 10 has a large number of stripe-shaped irregularities, the surface area of the protrusion 12 is increased as compared with a configuration in which the surface of the protrusion 12 is flat. As a result, since the amount of the drug that can be held by the protrusion 12 increases, the amount of the drug that can be administered by the microneedle 10 increases. Moreover, since the unevenness | corrugation of the surface 12S of the projection part 12 contains the stripe-shaped convex part 13 extended in a mutually different direction, compared with the structure where the extending direction of a convex part is equal, in the case of application | coating of a chemical | medical agent The drug is easily caught on the projection 13 and stays on the surface 12S of the projection 12.

  Here, the unevenness of the surface 12S of the protrusion 12 is an unevenness formed based on the unevenness of the processing surface 43S of the second recess 33 in the processing plate 40. And the unevenness | corrugation of the process surface 43S is formed by performing surface treatment with respect to the inner surface 33S of the 2nd recessed part 33 in the intaglio 30. FIG. In order to form the intaglio 30, since the original plate 20 having a step 22 on the surface 22S of the original projection 22 is used, the inner side surface 33S of the intaglio 30 has a step, and the inner surface 33S having the step has a surface. By performing the processing, a processed surface 43S having irregularities is formed.

  Since the formation of irregularities by surface treatment uses a phenomenon that occurs due to the difference in shrinkage between the oxidized surface and the non-oxidized interior, when surface treatment is performed on a flat surface, the uneven structure It is difficult to control the specific characteristics, that is, the direction and length of the stripe-shaped convex portions and concave portions constituting the concaves and convexes in the plane. On the other hand, since the inner side surface 33S has a step composed of a plurality of steps 34, each of the flat regions on the inner side surface 33S is small, and the inner side surface 33S is partitioned in this way. The formed flat areas are regularly arranged. Therefore, compared to the case where the surface treatment is performed on one large plane, the extending direction and length of the formed protrusions and recesses are limited. The variation is reduced.

  As a result, variations in the structural characteristics of the irregularities on the surface 12S of the protrusion 12 are also reduced. In other words, the unevenness of the surface 12S of the protruding portion 12 is an unevenness composed of irregularly arranged streaky convex portions and concave portions, but the variation in structural characteristics thereof becomes excessively large. It can be suppressed. Therefore, it is possible to suppress the occurrence of unevenness in the amount of the medicine held in the surface 12S of the protrusion 12.

  Further, as compared with the case where the surface treatment is performed on one large plane, the length of the convex portion and the concave portion formed on the inner side surface 33S is shortened, and the unevenness formed on the inner side surface 33S is fine. Therefore, even if the peelability of the molded product from the work plate 40 is reduced due to the unevenness, the surface treatment is performed on the flat inner surface of the intaglio plate to form the unevenness as compared with the case where the unevenness is formed. The peelability of the molded product from the processed plate 40 is improved.

As described above, according to the present embodiment, the effects listed below can be obtained.
(1) Since the surface 12S of the projecting portion 12 of the microneedle 10 has a large number of stripe-shaped irregularities, the surface area of the projecting portion 12 is increased compared to a configuration in which the surface of the projecting portion 12 is flat. To do. As a result, it is possible to increase the amount of drug that can be held by the protrusions 12, and thus the amount of drug that can be administered.

  (2) Since the unevenness is arranged on the entire surface 12S of the protrusion 12, the drug that can be held by the protrusion 12 compared to a configuration in which the unevenness is arranged on a part of the surface 12S of the protrusion 12. The amount of can be increased.

  (3) The surface 22S of the original projection 22 in the original 20 has a step, and the intaglio 30 is formed by transferring the shape from the original 20, and streaks are formed on the inner surface 33S of the second recess 33 in the intaglio 30. As a result, the processed plate 40 is formed. Then, the molding material is formed by filling the concave portion 31 of the processing plate 40 with the forming material of the microneedle 10, and the molding product is released from the processing plate 40 to form the microneedle 10. According to such a manufacturing method, since the microneedles 10 having the irregularities on the surface 12S of the protrusion 12 are manufactured, it is possible to increase the amount of drug that can be held by the protrusion 12, and consequently the amount of drug that can be administered. it can.

  (4) A step of inflating a portion including the inner side surface 33S of the second recess 33 in the intaglio plate 30, a step of oxidizing the expanding inner side surface 33S, and a step of contracting a portion including the oxidized inner side surface 33S. As a result, streaky irregularities are formed on the inner side surface 33S. According to such a manufacturing method, fine irregularities can be formed without depending on complicated machining in which concave portions and convex portions are processed one by one.

  Further, since the inner side surface 33S has a level difference based on the level difference of the surface 22S of the original projection 22, the structural surface of the unevenness formed on the inner side surface 33S is compared with a configuration in which the inner side surface is flat. Variation in characteristics is reduced. Therefore, since the variation in the structural characteristics of the irregularities on the surface 12S of the protrusion 12 is reduced, it is possible to suppress the occurrence of unevenness in the amount of drug held in the surface 12S of the protrusion 12. Moreover, since the unevenness | corrugation formed in the inner surface 33S becomes fine compared with the structure where an inner surface is a plane, the peelability of the molded product from the processed plate 40 is improved.

  (5) When at least a portion of the intaglio plate 30 including the inner side surface 33S of the second concave portion 33 is formed of a silicone resin, the inner side surface 33S is subjected to a surface treatment step including an expansion step, an oxidation step, and a contraction step. In addition, streaky irregularities can be suitably formed.

[Modification]
The above embodiment can be implemented with the following modifications.
If the surface 12S of the protrusion 12 of the transdermal administration device has irregularities, and the irregularities include a plurality of stripe-like irregular elements including a plurality of stripe-like irregular elements extending in different directions. The transdermal administration device may be manufactured by a manufacturing method different from the above-described manufacturing method. If the transdermal administration device has the above configuration, the effect (1) can be obtained. For example, an intaglio plate is produced using an original plate having an original plate projection having no steps, and a processed plate produced by subjecting the flat inner surface of the second concave portion of the intaglio plate to surface treatment, A skin administration device may be manufactured. Also by such a manufacturing method, since a stripe-shaped unevenness | corrugation is formed in the processed surface of a processed plate, the transdermal administration device in which the surface 12S of the projection part 12 has a stripe-shaped unevenness | corrugation is obtained.

  The protrusion 12 is preferably a shape surrounded by a plane when the surface of the protrusion 12 is regarded as a virtual plane, but is not limited to a cone shape, but a shape that can pierce the skin. I just need it. For example, the protrusion 12 may have a shape with no sharp tip, such as a prismatic shape, or a shape in which two or more solids are combined, such as a shape in which pyramids are stacked on a prism. Good. Further, a constriction or a step may be formed on the surface of the protrusion 12.

  Furthermore, the shape of the protrusion 12 constituting the administration portion of the transdermal administration device is not limited to the needle shape, that is, the shape extending along the thickness direction of the substrate 11. The shape of the protrusion 12 is blade-shaped, that is, the protrusion 12 extends along one surface direction that is a direction along the direction in which the first surface 11S of the base 11 spreads, and the tip of the protrusion 12 is the base 11. The shape formed in the linear form extended in the direction different from the thickness direction of this, for example, the direction along the said surface direction may be sufficient. For example, the protrusion 12 has a triangular prism shape extending along the surface direction, and one of the three rectangular side surfaces of the triangular prism is in contact with the base 11, and the side defining the two side surfaces is the protrusion. You may have the shape which functions as 12 front-end | tips.

  As long as the drug is a substance that functions by being administered into the skin, the drug may be held on the surface 12S, may be included in the projection 12 itself, or may be externally exposed when the skin is perforated by the projection 12 May be supplied from If the protrusion 12 includes a drug, the area of the surface 12S increases due to the unevenness, so that the dose of the drug can be increased. Even when the drug is supplied from the outside of the transdermal administration device, the amount of the drug that enters the skin through the surface 12S of the protrusion 12 is increased by the increase in the area of the surface 12S due to the unevenness. Since the increase is possible, the dose of the drug can be increased.

  The concave portion 14 may have a shape other than the stripe shape, and only the convex portion 13 may have the stripe shape. Further, the convex portion 13 may have a shape other than the stripe shape, and only the concave portion 14 may have the stripe shape. Of the convex portion 13 or the concave portion 14, the one having a streak-shaped shape is a concave-convex element, and when both the convex portion 13 and the concave portion 14 have a streaky shape, either the convex portion 13 or the concave portion 14 is What is necessary is just to handle as an uneven | corrugated element.

[Example]
The transdermal administration device and the manufacturing method thereof will be described using specific examples and comparative examples.

<Example 1>
In the original production process, silicon was used as a material for forming the original, and after forming the outer shape of the original projection and the original substrate by wet etching, a step was formed on the surface of the original projection by grinding using a dicing saw. In the intaglio plate making process, a silicone resin was used as a material for forming the intaglio plate, and the unevenness of the original plate was reversed and transferred by transfer molding to produce an intaglio plate having a first recess and a second recess.

In the surface treatment process, as an expansion process, the intaglio was left on a hot plate heated to 100 ° C. for 5 minutes. Thereafter, an intaglio was installed in the plasma processing apparatus, and as an oxidation process, plasma treatment with O ₂ plasma was performed on the inner surface of the second concave portion of the expanded intaglio under conditions of 250 W and 4 min. Subsequently, as a shrinking process, the intaglio was left in a room temperature environment and naturally cooled. As a result, a processed plate was produced.

  In the filling step, a polylactic acid resin was placed on the concave portion of the processed plate, and a molded product was molded by heat molding. As the mold release step, the transdermal administration device of Example 1 was obtained by peeling the molded product from the processed plate.

When the 2nd recessed part of the processed plate was observed using the stereomicroscope, the processed surface of the 2nd recessed part was cloudy. This suggests that fine irregularities are formed on the processed surface.
Moreover, when the surface of the protrusion part of the transdermal administration device was observed using a scanning electron microscope (SEM), the surface of the protrusion part was a streak-like convex part and a second extension extending in the first extension direction. It had the unevenness | corrugation comprised from many stripe-shaped convex parts including the stripe-shaped convex part extended in a direction, and many stripe-shaped recessed parts.
Also, the molded product was easily peeled from the processed plate.

<Example 2>
A transdermal administration device of Example 2 was produced by the same steps as in Example 1 except for the plasma treatment conditions in the oxidation step. In the oxidation step, a plasma treatment with O ₂ plasma was performed on the inner side surface of the second concave portion of the expanded intaglio under conditions of 250 W and 32 min. Compared to Example 1, since the plasma treatment was performed for a long time, the intaglio after the oxidation process was heated to such an extent that it could not be held with bare hands.

  When the 2nd recessed part of the processed plate was observed using the stereomicroscope, the processed surface of the 2nd recessed part was a little cloudy. This indicates that fine irregularities are formed on the processed surface, but suggests that the irregularities are rough as compared with Example 1.

Moreover, when the surface of the protrusion part of the transdermal administration device was observed using a scanning electron microscope (SEM), the surface of the protrusion part was a streak-like convex part and a second extension extending in the first extension direction. It had the unevenness | corrugation comprised from many stripe-shaped convex parts including the stripe-shaped convex part extended in a direction, and many stripe-shaped recessed parts. However, as compared with Example 1, the length, width, and interval of the protrusions were large, and the unevenness was rough. The image which image | photographed the surface of the protrusion part in the transdermal administration device of Example 2 with the scanning electron microscope is shown in FIG.
Also, the molded product was easily peeled from the processed plate.

<Example 3>
In the original plate production process, no step is formed on the surface of the original plate projection, and in the intaglio plate production step, an intaglio plate is produced using an original plate having an original plate projection having no step, and the same as in Example 2. According to the process, the transdermal administration device of Example 3 was produced.

When the 2nd recessed part of the processed plate was observed using the stereomicroscope, the processed surface of the 2nd recessed part was transparent.
In addition, when the surface of the protrusion of the transdermal administration device was observed using a scanning electron microscope (SEM), the surface of the protrusion was a large number of stripe-shaped protrusions including a plurality of protrusions extending in different directions. It has the unevenness | corrugation comprised from a part and many stripe-shaped recessed parts. However, as compared with Example 2, the length, width, and interval of the protrusions were large, and the unevenness was rough. From these results, it is suggested that rougher irregularities are formed on the processed surface of the processed plate than in Example 2. Further, as compared with Example 1 and Example 2, the extending direction of the projections was non-uniform, and the structural characteristics of the irregularities were greatly varied.
Moreover, it had a bigger force than Example 1 and Example 2 in peeling of the molding from a processed plate, and the molding was difficult to peel.

<Comparative Example 1>
A transdermal administration device of Comparative Example 1 was produced in the same manner as in Example 1 except that plasma treatment with Ar plasma was performed under conditions of 250 W and 4 min instead of the oxidation step.

When the 2nd recessed part of the processed plate was observed using the stereomicroscope, the processed surface of the 2nd recessed part was transparent.
Moreover, when the surface of the protrusion part of the transdermal administration device was observed using the scanning electron microscope (SEM), the unevenness | corrugation containing a stripe-shaped convex part and a recessed part was not confirmed on the surface of the protrusion part. In addition, the unevenness | corrugation resulting from the level | step difference of the surface of an original-plate protrusion part was not confirmed on the surface of the protrusion part. Since the steps on the surface of the original projections are minute, it is considered that the steps are lost because the shapes of the steps are not accurately transferred when transferring the shape from the original to the intaglio and from the processed plate to the molded product.
Also, the molded product was easily peeled from the processed plate.

<Comparative Example 2>
A transdermal administration device of Comparative Example 2 was produced in the same manner as in Example 1 except that none of the expansion process, oxidation process, and contraction process in the surface treatment process was performed.

When the 2nd recessed part of the intaglio was observed using the stereomicroscope, the inner surface of the 2nd recessed part was transparent.
Moreover, when the surface of the protrusion part of the transdermal administration device was observed using the scanning electron microscope (SEM), the unevenness | corrugation containing a stripe-shaped convex part and a recessed part was not confirmed on the surface of the protrusion part. In addition, as in Comparative Example 1, no irregularities due to the steps on the surface of the original plate protrusion were observed on the surface of the protrusion. The image which image | photographed the surface of the protrusion part in the transdermal administration device of the comparative example 2 with the scanning electron microscope is shown in FIG.
Also, the molded product was easily peeled from the processed plate.

<Result>
Table 1 summarizes the manufacturing conditions and the above-described evaluation results for each of the examples and comparative examples.

  As shown in Table 1, in the transdermal administration devices of Examples 1 to 3 formed using a processing plate formed through a surface treatment process including an expansion process, an oxidation process, and a contraction process, the protrusions It was shown that the surface of this has streak-like unevenness. In addition, the transdermal administration device of Examples 1 and 2 manufactured using an original plate having a step on the surface of the original projection is an embodiment manufactured using an original plate on which the surface of the original protrusion has no step. Compared with the transdermal administration device of No. 3, it was shown that the molded product was easily peeled from the processed plate.

  DESCRIPTION OF SYMBOLS 10 ... Microneedle, 11 ... Base | substrate, 11S ... 1st surface, 11T ... 2nd surface, 12 ... Protrusion part, 12S ... Surface, 13 ... Convex part, 14 ... Recessed part, 20 ... Original plate, 21 ... Original substrate, 21S ... Forming surface, 21T ... non-forming surface, 22 ... original plate projection, 22S ... surface, 23 ... step, 30 ... intaglio, 31 ... concave, 32 ... first recess, 33 ... second recess, 33S ... inside surface, 34 ... Step, 40 ... machined plate, 43S ... machined surface.

Claims (4)

A base body having a first surface and a second surface opposite to the first surface;
A protrusion protruding from the first surface,
The surface of the protrusion has a bowl-shaped unevenness,
The unevenness is a streaky first convex portion extending in a first direction and a streaky convex portion extending in a second direction intersecting the first direction, and intersects the first convex portion and the first convex portion. The transdermal administration device containing the 2nd convex part connected with the 1 convex part . The transdermal administration device according to claim 1, wherein the entire surface of the protrusion has the unevenness. An original plate comprising a base and a protrusion protruding from the base, the surface of the protrusion having a step, an original plate manufacturing step for preparing the original, and
A step of producing an intaglio by copying and reversing the irregularities of the original plate, the first recess being a recess having a shape following the shape of the base, and a recess having a shape following the shape of the protrusion An intaglio plate making step for producing the intaglio plate having a second recess which is
A surface treatment step of forming streaky irregularities on the inner surface of the second recess;
A forming step of forming a molded product by filling a forming material for a transdermal administration device into a processing plate that is an intaglio plate that has undergone the surface treatment step;
Releasing the molded product from the processed plate to obtain a transdermal administration device ,
The surface treatment step includes
Inflating a portion including the inner surface of the second recess in the intaglio;
Oxidizing the expanding inner surface;
Shrinking the portion including the oxidized inner surface.
A method for producing a transdermal administration device. The method for manufacturing a transdermal administration device according to claim 3 , wherein, in the intaglio making step, a portion including the inner side surface of the second recess in the intaglio is formed from a silicone resin.