JP7202638B2 - Separate tip microneedle - Google Patents

Description

The present invention is a drug delivery system (DDS), particularly a transdermal therapeutic system (TTS, hereinafter sometimes abbreviated as TTS) that administers drugs into the body through the skin. More specifically, the shape of the microneedle is a pyramid, and the pyramidal microneedle that punctures the skin has a two-step structure of the support and the tip, and the tip that leaves only the tip in the body. More specifically, the separation type pyramidal microneedle has a two-stage structure in which the side edge (side edge) of the tip portion and the side edge (side edge) of the support portion are displaced around the apex of the pyramid as the center of rotation. Regarding microneedles.

Compared to injections, TTS is less painful and less invasive to the human body. There is convenience such as being able to deliver a constant concentration of drug into the body over a period of time.

A microneedle method is known as one of the TTSs, and is generally used in the form of a microneedle array in which a plurality of microneedles each having a conical or pyramidal shape and a height of several hundred μm are arranged. A needle whose surface is coated with a drug or a needle whose interior is impregnated with a drug penetrates the stratum corneum of the skin, thereby realizing delivery of the drug dissolved in the dermal tissue into the body. At that time, since the needle does not reach the nerve, there is an advantage that the pain is hardly felt.

At the beginning of the development of the microneedle method in medicine, microneedles were manufactured from metal materials such as titanium, but in recent years, three-dimensional microfabrication technology (micro electromechanical systems: MEMS) using ultraviolet or electron beam photolithography has been introduced. With the progress of the technology, research on a microneedle manufacturing method using single-crystal silicon as a raw material, as disclosed in Patent Document 1, for example, is underway.

Microneedles made of silicon have the excellent feature of being inexpensive and mass-producible, but there is also the risk of them remaining inside the skin due to breakage. discloses a method of puncturing and inserting a drug-containing biosoluble polymer into dermal tissue through a through-hole provided in a microneedle, but there is a problem that the structure of the microneedle becomes complicated. be.

As a method of puncturing and inserting a drug into the dermal tissue with a relatively simple microneedle structure, for example, Non-Patent Document 1 discloses a biosoluble polymer containing a drug in series with a support microneedle as a material. Disclosed is a microneedle structure for TTS in which a tip microneedle is provided, the microneedle has a two-story structure, and after the microneedle is punctured into the skin, only the tip microneedle remains in the dermal tissue. However, there is a problem that it is difficult to separate the tip portion from the support portion and place it in place when the tip portion is pulled out after puncturing the skin.

Japanese Patent No. 3521205 Japanese Patent No. 4913030

Mitsuhiro Shikida (2016), Microneedle fabrication method using Si-MEMS microfabrication, Journal of JSPE Vol.82, No.12, 1005-1009

In the drug administration method by TTS using the two-story microneedle described in Non-Patent Document 1, the tip microneedle made of biosoluble polymer containing the drug in series with the support microneedle A needle is provided and the microneedle has a two-story structure, and after puncturing the skin with this microneedle, only the microneedle at the tip remains in the dermal tissue, so the amount of drug remaining in the dermal tissue can be accurately adjusted. Moreover, it is characterized in that drug administration can be performed simply and in a short processing time.

However, in the microneedle with the double-decker structure described in Non-Patent Document 1, the bottom portion of the tip portion acting as a barb is small at the time of withdrawal after puncturing the skin, that is, the bottom portion of the tip portion protrudes outward from the side surface of the support portion. The portion is small, and as a result, the bottom surface of the tip portion is difficult to get caught on the skin, and there is a problem that it is difficult to separate and indwell the tip portion from the support portion.

In the course of various investigations against the background of the above circumstances, the present invention has found that the shape of the microneedle is a pyramid, and the pyramidal microneedle that punctures the skin has a two-step structure of a support portion and a tip portion, and the tip is placed in the body. Regarding the tip-separated pyramidal microneedle that leaves only the part, the side edge (side edge) of the tip part and the side edge (side edge) of the support part are displaced around the apex of the pyramid as the center of rotation. By using a microneedle having a microneedle, the bottom surface of the tip that acts as a barb when pulled out after puncturing the skin is large, that is, the portion that protrudes outward from the bottom surface of the tip with respect to the side surface of the support is large, and as a result, the tip It has been found that the bottom surface is easily caught on the skin, and the distal end portion can be easily separated from the support portion and retained. The present invention has been made based on such findings.

That is, the gist of the first invention is a microneedle used in a transdermal absorption system for administering a drug or the like into the body through the skin, wherein the microneedle has a pyramidal shape and a pyramidal shape that penetrates the skin. The microneedle has a two-step structure of a support part and a tip part, and the tip separation type pyramidal microneedle that leaves only the tip part in the body. ) is a microneedle having a two-stage structure with the apex of the pyramid as the center of rotation.

The gist of the second invention is that in the first invention, the microneedle has a two-stage structure consisting of the support part and the tip part of the pyramidal microneedle, and the pyramid shape is a polypyramid not less than a triangular pyramid. It is in being. From the standpoint of separation and retention, the pyramidal microneedle is preferably a triangular pyramid or a quadrangular pyramid.

The gist of the third invention is that in the first invention, the microneedle has a two-stage structure consisting of the support portion and the tip portion of the pyramidal microneedle, and the side ridge (side) of the tip portion side) and the side edge (side edge) of the support part are the microneedles having a two-stage structure in a state where the apex of the pyramid is the center of rotation, and the microneedle is viewed from above in a plan view, A two-step structure is provided in which the side edge (side edge) of the tip portion is positioned at the center of the bottom side of the support portion.

The gist of the fourth invention is the microneedle having a two-step structure consisting of the support part and the tip part according to any one of the first to third inventions, wherein the support part and the tip part and have similar pyramidal shapes.

The gist of the fifth invention is the microneedle having a two-stage structure consisting of the support part and the tip part according to any one of the first to third inventions, and the tip part is pyramid-shaped. and the supporting portion is in the shape of a truncated pyramid.

The gist of the sixth invention is the microneedle having a two-stage structure consisting of the support part and the tip part according to any one of the first to third inventions, wherein the support part and the tip part The metal mold used as the base for manufacturing is made of a silicon material, and the pyramidal shape is formed by etching.

The gist of the seventh invention is the microneedle having a two-step structure consisting of the support part and the tip part according to any one of the first to third inventions, wherein the material of the tip part is raw. It is a degradable material.

The gist of the eighth invention is the microneedle having a two-step structure consisting of the support part and the tip part according to any one of the first to third inventions, and the microneedle having the two-step structure The whole height of the needle is 0.1 mm to 2.0 mm.

The gist of the ninth invention is a microneedle array formed by arranging a plurality of the microneedles having a two-stage structure consisting of the support part and the tip part according to any one of the first to third inventions. It is in being.

According to the microneedle of the first invention, the shape of the microneedle is a pyramid, and the pyramidal microneedle that punctures the skin has a two-step structure of the support part and the tip part, and the tip part is left in the body. Regarding the pyramid-shaped microneedle, the side edge (side edge) of the tip and the side edge (side edge) of the support part have a two-step structure in a state where the apex of the pyramid is the center of rotation. At the time of withdrawal, the base portion of the tip portion that acts as a barb is large, that is, the portion that protrudes outward from the bottom surface of the tip portion with respect to the side surface of the support portion is large. The tip can be separated and left in place. As a result, it is possible to precisely adjust the amount of drug to remain in the dermal tissue, and to administer the drug simply and in a short processing time.

According to the microneedle of the second invention, the microneedle has a two-stage structure consisting of the support portion and the tip portion of the pyramidal microneedle, and the pyramidal shape is a polypyramid not less than a triangular pyramid, and Preferably, the presence of a triangular pyramid or a square pyramid results in a larger tip base portion acting as a barb during withdrawal after intradermal puncture, i.e. outward projection of the tip bottom surface relative to the support side and lateral ridges. The portion is larger so that the base of the tip is more likely to hook into the skin, allowing for easier separation and placement of the tip from the support.

According to the microneedle of the third invention, the microneedle having a two-step structure consisting of the support portion and the tip portion of the pyramidal microneedle, the side edge (side edge) of the tip portion and the support portion The microneedle has a two-step structure in which the side edge (side edge) of the pyramid is shifted around the apex of the pyramid, and in a plan view of the microneedle from directly above, the side edge of the tip Since it has a two-step structure so that the (side side) is located in the center of the base of the support part, when pulling out after puncturing the skin, the base part of the tip part that acts as a barb is the largest in the pyramid shape, That is, the portion of the bottom surface of the distal end that protrudes outward from the side surface of the supporting portion is the largest, and as a result, the base of the distal end is easily caught on the skin, and the distal end can be easily separated from the supporting portion and left in place.

According to the microneedle of the fourth invention, the microneedle has a two-stage structure consisting of the support portion and the tip portion, and the support portion and the tip portion have similar pyramidal shapes. In addition, the structure of the mold used to manufacture the support portion and the tip portion can be simplified, and the manufacturing process can be the same, thereby reducing the cost.

According to the microneedle of the fifth invention, the microneedle has a two-stage structure consisting of the support portion and the tip portion, the tip portion has a pyramid shape, and the support portion has a truncated pyramid shape. Therefore, when the skin is punctured by applying a load to the microneedle having a two-stage structure composed of the pyramid-shaped tip and the truncated pyramid-shaped support, stress concentration at the tip of the support becomes smaller, and it becomes easier to prevent breakage of the tip portion during puncture due to application of a high load. Also, tip volume can be increased, resulting in increased drug dosage.

According to the microneedle of the sixth invention, a silicon material is used as a mold that is the base for manufacturing the support portion and the tip portion, and the pyramid shape is etched by an etching process that is excellent in fineness. As a result of the production, the tip portion having excellent sharpness can be obtained.

According to the microneedle of the seventh invention, the microneedle has a two-stage structure consisting of the support part and the tip part, and the material of the tip part is a biodegradable material, so it contains a drug component The biodegradable tip can be safely and conveniently placed in the skin.

According to the microneedle of the eighth invention, since the total height of the microneedle having a two-step structure is 0.1 mm to 2.0 mm, the tip of the microneedle is punctured into the skin having elasticity. and can be retained.

According to the microneedle of the ninth invention, since the microneedle array is formed by arranging a plurality of the microneedles, it is possible to easily change the drug dosage by changing the number of microneedles.

FIG. 4 is a diagram showing a plurality of arrays of microneedles having a two-step structure consisting of a support and a tip. FIG. 4 is a diagram showing the principle of operation of a microneedle having a two-step structure consisting of a support and a tip. FIG. 10 is a diagram showing the structure of a conventional microneedle having a two-stage structure consisting of a support portion and a tip portion. FIG. 2 is a diagram showing the structure of a microneedle having a two-stage structure consisting of a support portion and a tip portion of the present invention; FIG. 10 is a diagram showing the structure of a microneedle having a two-stage structure consisting of a support portion and a tip portion in another embodiment of the present invention; FIG. 10 is a diagram showing the structure of a microneedle having a two-stage structure consisting of a support portion and a tip portion in another embodiment of the present invention; FIG. 2 is a diagram showing a silicon needle that serves as a mold for manufacturing a support portion and a tip portion in a structure of a microneedle having a two-stage structure consisting of a support portion and a tip portion in an embodiment of the present invention. FIG. 4 is a diagram showing a method of fabricating a microneedle structure having a two-stage structure consisting of a support portion and a tip portion in an example of the present invention. FIG. 4 is a diagram showing an example of fabricating a microneedle structure having a two-stage structure consisting of a support portion and a tip portion in an embodiment of the present invention.

Hereinafter, the structure of the microneedle having a two-stage structure consisting of a support portion and a tip portion of the present invention will be described in detail based on the drawings.

FIG. 1 is a diagram showing a plurality of structures of microneedles 1 having a two-stage structure consisting of a support portion 2 and a tip portion 3. FIG. A plurality of microneedles 1 having a two-step structure consisting of a support portion 2 and a tip portion 3 are formed on a substrate according to the amount of drug administered. As shown in the operating principle diagram of FIG. 2, the microneedle 1 having a two-stage structure is pierced into the skin 4 and pushed until the entire tip is inserted into the skin. It acts as a barb, and as a result, when the substrate is pulled out, the bottom surface of the tip portion is caught on the skin 4, and the tip portion 3 containing the drug component is separated from the support portion 2 and left in the skin. Since the volume of the drug that remains in the dermal tissue is determined by the volume of the distal end portion, it is possible to accurately adjust the dose of the drug, and to administer the drug simply and in a short processing time.

FIG. 3 is a diagram showing the structure of a conventional microneedle having a two-step structure consisting of a support portion 2 and a tip portion 3. As shown in FIG. In the conventional microneedle shown in FIG. 3, for example, an octagonal pyramid shape is used, and the side edge of the tip portion 3 and the side edge of the support portion 2 are two-stepped so that they coincide with the apex of the pyramid as the center of rotation. Structured microneedles are formed. Therefore, in the microneedle with such a double-decker structure, the bottom portion of the tip portion that acts as a barb during withdrawal after puncturing the skin is small, that is, the portion that protrudes outward from the bottom surface of the tip portion with respect to the side surface of the support portion. As a result, the bottom surface of the tip portion is less likely to get caught on the skin, and it is difficult to separate and indwell the tip portion 3 from the support portion 2 .

FIG. 4 is a diagram showing the structure of a microneedle having a two-step structure consisting of a support portion 2 and a tip portion 3 of the present invention. The microneedle of the present invention uses a quadrangular pyramid shape, and in the microneedle having a two-stage structure consisting of the support portion 2 and the tip portion 3, the side edge of the tip portion 3 and the side edge of the support portion 2 are the vertices of the pyramid. A microneedle having a two-step structure is formed in a state of being shifted from the center of rotation. Therefore, when the needle is pulled out after puncturing the skin, the bottom surface of the tip that acts as a barb is large, that is, the bottom surface of the tip protrudes outward from the side surface of the support is large. It is possible to easily separate the distal end portion 3 from the support portion 2 and retain it. In particular, when forming a microneedle having a two-stage structure in a state in which the side edge of the tip portion 3 and the side edge of the support portion 2 are displaced around the apex of the pyramid as the center of rotation, the microneedle is viewed from directly above. In the above, if a two-step structure is used in which the side edge of the tip portion 3 is positioned at the center of the bottom side of the support portion 2, the bottom portion of the tip portion acting as a barb is the largest, that is, the tip portion bottom surface with respect to the side surface of the support portion extends outward. has the greatest protruding part, which has the advantage that the separation of the tip 3 from the support 2 in the skin is easier. In addition, by using similar-shaped pyramids for the support part 2 and the tip part 3, the structure of the mold used as the base for manufacturing the support part 2 and the tip part 3 is simplified, and they are manufactured by the same processing process. It becomes possible to do so, and cost reduction can be achieved.

FIG. 5 is a diagram showing the structure of a microneedle having a two-stage structure consisting of a support portion 2 and a tip portion 3 in another embodiment of the present invention. In another embodiment of the present invention, triangular and hexagonal pyramid shapes form microneedles having a two-step structure. From the gist of the present invention, any polygonal pyramid may be used as long as the pyramid shape is triangular or larger. It is preferable that the number of angles of a triangular pyramid, a square pyramid, a pentagonal pyramid, or the like is small, because the effect of protruding by pressing is low.

FIG. 6 is a diagram showing the structure of a microneedle having a two-stage structure consisting of a support portion 2 and a tip portion 3 in another embodiment of the present invention. In another embodiment of the present invention, the tip 3 is pyramid-shaped and the support 2 is truncated pyramid-shaped to form a microneedle with a two-stage structure. In the microneedle with this structure, the tip volume can be increased, and as a result, the drug dosage can be increased. Stress concentration is reduced, making it easier to prevent the tip portion 3 from breaking during puncture, and as a result, it is possible to use tip portion materials containing drug components with various hardnesses. The purpose of the support portion 2 is to support the tip portion 3, and any three-dimensional shape other than the truncated pyramid, such as a truncated cone, a cylinder, and a prism, may be used as long as the purpose of the support portion 2 is satisfied.

FIG. 7 is a diagram showing a silicon needle that serves as a mold for fabricating a support portion and a tip portion in a structure of a microneedle having a two-stage structure consisting of a support portion and a tip portion in an embodiment of the present invention. be. Silicon needles are produced by a photolithography process and an etching process. Specifically, an etching mask is formed on the surface of the silicon substrate by photolithography, and then the silicon needle is manufactured by etching the silicon substrate according to the shape of the etching mask. Crystal anisotropic etching, which is a three-dimensional microfabrication method that utilizes the difference in etch rate due to crystal orientation, is used for etching. An alkaline aqueous solution such as TMAH (tetramethylammonium hydroxide, KOH (potassium hydroxide), etc. is used as an etchant. A more detailed manufacturing method is shown below.

First, a single crystal silicon wafer is prepared and its surface is thermally oxidized to form an oxide film. Then, a resist is applied to, for example, the (100) surface of the silicon wafer. A photomask having a large array of mask patterns corresponding to individual microneedles is placed on the surface of a silicon wafer. The resist is patterned by irradiating the silicon wafer on which the photomask is placed with ultraviolet rays and developing it. A BHF solution is used to remove the oxide film and form an etching mask pattern on the surface of the silicon wafer.

Next, an alkaline aqueous solution is used to etch the unmasked portion of the silicon wafer surface. As the etching progresses on the (100) plane in the thickness direction of the silicon wafer, an undercut also occurs in the lower part of the oxide film which is the masking material, and as a result, microneedles are formed under the etching mask. Then, the silicon wafer on which a large number of microneedles are formed is diced into a predetermined size to obtain molds for chipped microneedles.

FIG. 8 is a diagram showing a method of fabricating a microneedle structure having a two-step structure consisting of a support portion and a tip portion in an example of the present invention.

A process of forming PDMS molds 21 and 31 as mold molds using silicon microneedles 20 and 30 functioning as molds, filling the PDMS molds 21 and 31 with a substrate material and a biodegradable material, and the process of manufacturing microneedles by aligning the tip portion 3. FIG.

In the process of forming the PDMS molds 21 and 31, which are mold molds, for the purpose of facilitating the separation of the silicon microneedles 20 and 31 from the PDMS molds 21 and 31 in the molding process, the support part and the tip part are separated. The surfaces of the silicon microneedles 20 and 30 for producing each are coated with an Au layer 40 by a sputtering method using a Cr layer as an adhesion layer. The layer thickness is, for example, 10 nm for Cr and 250 nm for Au.

Next, PDMS (polydimethylsiloxane), which is a PDMS type material, is prepared. After mixing the two-component room temperature curable PDMS main agent and the curing agent at a weight ratio of 10:1, for example, defoaming is performed for a long period of time using a vacuum pump. Then, the defoamed PDMS is filled so as to cover the surfaces of the silicon microneedles 20 and 30 for forming the support portion and the tip portion respectively, the PDMS is cured, and the cured PDMS mold is peeled off from the silicon microneedles. Thus, PDMS molds 21 and 31 for fabricating the support part and the tip part are fabricated.

In the process of molding the support part 2 using the PDMS mold 21 for the support part, the liquid material for the support part 2 is filled so as to cover the PDMS mold 21 for support part production, and the liquid support member is cured. The supporting part 2 is produced by peeling off the supporting part 2 from the PDMS mold 21 for producing the supporting part. In addition, it is preferable that the supporting member is made of a material having biocompatibility.

In the process of molding a microneedle having a two-stage structure consisting of a support portion 2 and a tip portion 3 using a PDMS mold 31 for a tip portion, first, a tip portion forming mold formed on a PDMS mold for a tip portion is formed. Only the dents are filled with a biodegradable material containing a drug component, which is the material 32 for making the tip portion. After that, after the support portion 2 and the tip portion 3 are aligned, they are overlapped and the tip material is cured. After that, the support part 2 including the tip part 3 is peeled off from the PDMS mold 31 for the tip part to fabricate a microneedle having a two-step structure consisting of the support part 2 and the tip part 3 . In this example, collagen hyaluronic acid was used as the biodegradable material, but other biodegradable materials may be used. When the support portion 2 and the tip portion 3 are overlapped, a plate 41 having a defined thickness is sandwiched between them to control the amount of overlap between the support portion 2 and the tip portion 3 .

FIG. 9 is a diagram showing a fabrication example of a microneedle structure having a two-stage structure consisting of a support portion 2 and a tip portion 3 in an embodiment of the present invention. The shape of the tip portion 2 and the support portion 3 is a quadrangular pyramid, and the distance between the bottom surfaces of the tip portion and the support portion is 0.2 mm. In addition, when the microneedle having the two-stage structure is viewed from directly above, the square pyramid at the tip is rotated 45° with respect to the support, and the side edge of the tip 3 is positioned at the center of the base of the support 2. In other words, they are overlapped so that the outward protrusion of the bottom surface of the tip portion with respect to the side surface of the support portion is maximized.

According to the present invention, in the drug administration method by TTS using microneedles, the shape of the microneedle is a pyramid, and the pyramidal microneedle for puncturing the skin has a two-step structure of a support portion and a tip portion. Regarding the tip-separated pyramidal microneedle that leaves only the part, by making the microneedle having a two-step structure in a state where the side edge of the tip part and the side edge of the support part are shifted around the apex of the pyramid, At the time of withdrawal after puncturing the skin, the bottom surface of the tip portion acting as a barb is large, that is, the portion of the bottom surface of the tip portion that protrudes outward from the side surface of the support portion is large. It is possible to separate the tip part from the support part immediately and place it.

1: Microneedle having a two-step structure 2: Support part 3: Tip part 4: Skin 20: Silicon mold for support part production 21: PDMS mold for support part production 22: Support part production material 30: Tip part Fabrication silicon mold 31: Tip part fabrication PDMS mold 32: Tip part fabrication material 40: Metal thin film (gold thin film)
41: Board

Claims (9)

A microneedle used in a transdermal absorption system that administers drugs into the body through the skin, and has a two-stage structure consisting of a pyramidal or prismatic support and a pyramidal tip, with the bottom of the tip being the support . In a plan view in which the support portion and the tip portion overlap so as to protrude outward from the side surface, and the microneedle is viewed from directly above, the side edges of the tip portion and the side edges of the support portion are displaced . A microneedle characterized by having a two-stage structure. In the microneedle having a two-stage structure consisting of the support portion and the tip portion, in a plan view of the microneedle viewed from directly above, the side edge of the tip portion is located in the center of the bottom side of the support portion. 2. The microneedle according to claim 1, wherein the microneedle has a two-stage structure. The microneedle according to claim 1 or 2 , wherein the microneedle has a two-stage structure consisting of the support portion and the tip portion, and the support portion and the tip portion have similar pyramidal shapes. . 4. The microneedle according to claim 3, wherein the microneedle has a two-stage structure consisting of the support portion and the tip portion, and the pyramid shape is any one of a triangular pyramid, a square pyramid, and a pentagonal pyramid. . 3. The microneedle according to claim 1 or 2 , wherein the microneedle has a two-stage structure consisting of the support portion and the tip portion, wherein the tip portion has a pyramid shape and the support portion has a truncated pyramid shape. of microneedles. In the microneedle having a two-step structure consisting of the support portion and the tip portion, the mold used as the base for manufacturing the support portion and the tip portion is a silicon material, and the support portion and the tip portion 3. The microneedle according to claim 1, wherein the shape of the tip is formed by etching. 3. The microneedle according to claim 1, wherein said microneedle has a two-stage structure consisting of said support portion and said tip portion, and said tip portion is made of a biodegradable material. 1. The microneedle having a two-step structure consisting of the support portion and the tip portion, wherein the total height of the microneedle having the two -step structure is 0.1 mm to 2.0 mm. Or the microneedle according to 2 . 3. The microneedle according to claim 1, wherein the microneedle array is formed by arranging a plurality of the microneedles having a two-stage structure composed of the support portion and the tip portion.

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