JP5380965B2 - Needle-like body and method for producing needle-like body - Google Patents

Description

  The present invention relates to a needle-shaped body and a method for manufacturing the needle-shaped body, and more particularly to a needle-shaped body having holes in an array in the pedestal portion of the needle-shaped body and a method for manufacturing the needle-shaped body.

  The percutaneous absorption method, which is a method of infiltrating a drug from the skin and administering the drug into the body, is used as a method that can be easily administered without causing pain to the human body. There are drugs that are difficult to administer by transdermal absorption. As a method of efficiently absorbing these drugs into the body, attention has been focused on a method of perforating the skin using a needle-like body having a microneedle part on the order of μm and directly administering the drug into the skin.

  The acicular body forms a perforation in the epidermis having a barrier function (more specifically, the stratum corneum formed in the outermost layer of the epidermis), and normal percutaneous absorption from the perforation is inhibited by the barrier function of the epidermis. Drugs that cannot be administered can be absorbed into the body. According to this method, it is possible to easily administer a drug subcutaneously without using a special medication device (see Patent Document 1).

  The shape of the microneedle portion of the needle-like body used at this time needs to have a sufficient thinness and tip angle for piercing the skin and a sufficient length for allowing the drug solution to penetrate subcutaneously. The diameter of the needle is several μm to several hundred μm, and the length of the needle penetrates the stratum corneum, which is the outermost layer of the skin, and does not reach the nerve layer, specifically several tens μm to several hundred μm. It is considered that the tip angle of the needle is an acute angle, specifically, 30 ° or less.

  More specifically, it is required to penetrate the stratum corneum that is the outermost skin layer. The thickness of the stratum corneum varies slightly depending on the part of the human body, but is about 20 μm. In addition, except for particularly thick parts such as palms and soles, an epidermis having a thickness of about 200 μm to 350 μm exists under the stratum corneum, and further, a dermis layer in which capillaries are stretched is present below the stratum corneum. . For this reason, in order to penetrate the stratum corneum and allow the chemical solution to penetrate, a needle of at least 20 μm or more is required.

  In addition, as a material constituting the needle-like body having the microneedle portion described above, it is desirable that the material does not adversely affect the human body even if the microneedle portion of the needle-like body that has been damaged remains in the body, As materials, biocompatible materials such as maltose, polylactic acid, and dextran are considered promising (see Patent Document 2).

2. Description of the Related Art In recent years, a drug administration method called a drug delivery system, which aims to supply a necessary minimum amount of drug to a necessary place at a necessary time without excessively administering the drug, has attracted attention. By applying the above-mentioned needle-shaped body coated with a drug to the skin, the drug is selectively introduced into the affected area without using a special machine, and the drug is gradually released at a constant rate over a certain period. It becomes possible.
Japanese Patent Application Laid-Open No. 6-192068 Japanese Patent Laid-Open No. 2005-21677 International Publication 06/0775689

In the case of administration where the drug is administered while the drug is gradually released, it is expected that the needle-like body is stuck to the skin for a long time. In this case, if the needle-like body is made of a material having a low gas permeation performance, in particular, a water vapor permeation performance, stuffiness is generated by perspiration, leading to skin irritation.

  The above-mentioned biocompatible material is not particularly inferior in water vapor transmission performance compared to other resins in the film state, so there is little risk of leading to skin irritation, but when the pedestal of the needle-shaped body is thin, When the needle-shaped body described above is applied to the skin, there is a problem that the needle tips are damaged before use by contact between the needle tips due to slight deformation of the pedestal. In that case, the problem is that the required amount of the drug cannot be administered.

  Therefore, in order to puncture the target site, the thickness of the pedestal portion of the needle-shaped body is desirably at least 100 μm or more, preferably 800 μm or more. However, as the thickness of the pedestal portion increases, A dilemma of reduced performance occurs.

In order to solve this problem, a method of making a hole in the pedestal portion of the needle-like body to promote water vapor transmission can be considered. Patent Document 3 discloses a method for manufacturing a needle-like body provided with a hole penetrating the pedestal as a drug flow path. However, in the manufacturing method disclosed in Patent Document 3, a molding method using a mold is disclosed. In this technique, it is necessary to repeat the operation of aligning the gap between the needle-like bodies and irradiating the laser beam. It takes time to produce and is not realistic.

  Therefore, in the present invention, a needle-like body in which the pedestal portion is not deformed during the operation of pasting the needle-like body and has little skin irritation even when pasted on the skin for a long time, and the needle-like body is simplified. An object of the present invention is to provide a manufacturing method.

The present invention according to claim 1 is characterized in that the pedestal portion has microneedle portions that are integrally molded in an array shape, the pedestal portion has a hole , and the hole has a tapered shape. It is a needle-like body.

  The present invention according to claim 2 is the needle-shaped body according to claim 1, wherein the pedestal of the needle-shaped body has a thickness of 100 μm or more and 1 cm or less.

  A third aspect of the present invention is the needle-shaped body according to any one of the first to second aspects, wherein the pore size is 0.1 μm or more and 100 μm or less.

The present invention according to claim 4 is the needle-like body according to any one of claims 1 to 3 , wherein the needle-like body is made of a biodegradable resin.

The present invention described in claim 5 is a method for producing the needle-shaped body according to any one of claims 1 to 4 , wherein the microneedle portion is arranged in a fine array in which the shape of the microneedle portion is inverted. The concave portion of the duplicate plate including the concave portion is filled with the resin constituting the needle-like body, and penetrates the resin layer of the flat portion of the duplicate plate where the microneedle portion is not formed from the resin surface side on the duplicate plate It is a method for manufacturing a needle-like body, characterized in that a hole is formed in a pedestal portion of the needle-like body by pressing a support plate having a convex portion capable of forming a hole to be formed.

The present invention according to claim 6 is the method for manufacturing a needle-shaped body according to claim 5 , wherein a heating mechanism is included on the duplicate plate side.

The present invention described in claim 7 is characterized in that, in the method for manufacturing a needle-like body according to claim 5 or 6 , a heating mechanism or a cooling mechanism is included in the convex portion of the support plate or in the entire support plate. It is a manufacturing method of an acicular body.

The present invention according to claim 8 is the method for producing a needle-like body according to any one of claims 5 to 7 , wherein the resin is a thermoplastic resin. is there.

The present invention according to claim 9 is the method for manufacturing a needle-shaped body according to any one of claims 5 to 8 , wherein the resin is a crystalline resin. .

  Since this invention is characterized by providing a hole in the pedestal of the needle-like body, the water vapor permeability of the needle-like body can be improved. For this reason, a needle-like body with little skin irritation is obtained even if it is applied to the skin for a long time.

  Furthermore, since the pedestal portion of the needle-like body has a thickness, it is possible to puncture the pedestal portion of the needle-like body without deformation when puncturing the needle-like body. Since the needle can be punctured without damaging the needle tip, it is possible to puncture all the needles to the target site, and it is possible to reliably administer the prescribed amount of medicine.

  Next, the hole in the pedestal pedestal has a size and shape that allows water vapor to pass through freely but liquid water does not easily pass through, preventing water from entering the needle side of the needle-shaped body. I can do it.

  In addition, since a needle-like body having pores can be easily formed and peeled without using a special apparatus, the productivity of the microstructure manufacturing process is improved.

  The present invention will be described in detail with reference to the drawings. However, the present invention is not limited to the following embodiments. FIG. 1 is a schematic plan view and a schematic cross-sectional view showing the concept of a needle-like body produced by the production method described in the present invention.

  In FIG. 1, 1 is a micro needle part of a needle-like body, and 2 is a needle-like body base part. Reference numeral 3 denotes a hole provided in the needle-like pedestal.

  The height of the microneedle part of the needle-like body 1 is preferably 20 μm or more and 1 mm or less, and the density of the microneedle part of the needle-like body 1 is 100 or more and 1000 or less, more preferably 300 or more and 800,000 per square centimeter. This or less is preferred. When the number of needles is less than 100, it is difficult to sufficiently infiltrate the drug. When the number of needles is more than 1000, the number of holes is reduced or the hole size is small. Thus, the water vapor transmission performance is lowered.

  The thickness of the pedestal 2 is preferably 100 μm or more and 1 cm or less, more preferably 800 μm or more and 5 mm or less. If the thickness is more than 5 mm, it will be difficult to hold the skin after being attached to the skin. If the thickness is less than 0.1 mm, the pedestal will be deformed when the skin is attached to the skin, and the fine needles will contact each other. Will be damaged.

The hole 3 preferably has a hole diameter of 0.1 μm or more and 100 μm or less on the surface side where the micro needle part of the needle-like body 1 exists. Desirably, the pore diameter is preferably 1 μm or more and 50 μm or less. When the hole diameter is larger than this, liquid water is easily transmitted, and the portion punctured by the needle-like body 1 is easily wetted. Further, if the pore diameter is smaller than this, water vapor is hardly transmitted. Furthermore, the tip tends to be damaged when it is peeled off from the support plate 13 during production, and the yield is lowered.

  Moreover, it is desirable that it is a taper shape which a diameter gradually spreads toward a needle-like body back part. By taking the taper shape, peeling from the support plate is facilitated.

  Furthermore, it is desirable that the number of convex portions of the support plate is larger than the number of convex portions of the duplicate plate. By increasing the number of holes in the needle-like body, the water vapor transmission performance is further improved, and further, the adhesion to the support plate side is improved, so that the resin peeling performance from the duplicate plate is improved.

  The material of the needle-like body can be arbitrarily selected from biodegradable thermoplastic resins.

  Hereinafter, a method for producing the needle-like body will be described. First, a mold for producing a needle-like body will be described. A plan view and a cross-sectional view of the duplicate plate 11 are shown in FIG. Reference numeral 21 denotes a surface facing the pedestal portion of the needle-like body, and reference numeral 22 denotes a fine concave portion obtained by reversing the shape of the desired needle-like body.

  The duplicate plate 11 can be produced using a mold produced by any of the already disclosed methods for producing an acicular body. For example, methods disclosed in Japanese Patent Application Laid-Open No. 2007-260889, Japanese Patent Application Laid-Open No. 2008-29386, and Japanese Patent Application Laid-Open No. 2008-29559 can be used.

  The material of the duplicate plate 11 is not particularly limited, but can be selected from copper, nickel, silicon, iron and alloys composed of any possible ratio thereof, Teflon (registered trademark) resin, silicon resin, or the like. . Moreover, the surface treating agent for improving mold release property may be apply | coated to the surface of the replication plate.

  The supply of the resin to the duplication plate may be in a molten state or a sheet-like resin. In order to keep the supplied resin at a temperature close to the melting point, it is desirable that the duplicate plate has a heating mechanism. The heating mechanism may be, for example, a hot plate provided on the back side of the duplicate plate, or may be provided with, for example, a sheet-like heater inside the duplicate plate, and further heats the duplicate plate and the entire resin. It may be something like a warm air oven.

  Next, the support plate 13 that is used to provide a hole in the pedestal 2 of the needle-like body and is positioned opposite to the duplicate plate 11 will be described. FIG. 3 shows a plan view and a sectional view of the support plate 13. Reference numeral 31 denotes a surface facing the back surface of the pedestal of the needle-like body, and reference numeral 32 denotes a fine convex part obtained by inverting the shape of a desired hole.

  The material and manufacturing method of the support plate 13 conform to those of the duplicate plate 11 and can be selected arbitrarily.

  However, it is desirable to have a heating mechanism in the convex part of the support plate 13 or in the entire support plate 13 and have a mechanism capable of heating to a temperature T of Tg <T <Tm, where Tg is the glass transition temperature of the resin and Tm is the melting point. . In particular, when the resin is a crystalline polymer, the releasability can be improved by crystallizing the portion where the resin contacts the support plate 13. Alternatively, a cooling mechanism may be provided in the convex portion of the support plate 13 or the entire support plate 13, and the convex portion of the support plate 13 may be cooled to contract the convex portion. Peeling from the support plate 13 can be promoted by the thermal expansion and contraction characteristics of the resin 12 and the support plate 13.

  It is desirable that the duplicate plate 11 and the support plate 13 have a mechanism that does not shift their positions.

  FIG. 4 is a cross-sectional view showing a concept of a method for producing a needle-like body. Reference numeral 11 denotes a replica plate including an array of fine concave portions obtained by inverting the shape of a desired needle-like body. Reference numeral 12 denotes a resin for forming a needle-like body. Reference numeral 13 denotes a supporting plate that faces the duplicate plate 11 and has a convex portion facing the flat portion of the duplicate plate 11. In FIG. 4 (a), the resin 12 is supplied onto the duplicate plate 11, and the resin is filled in the concave portion of the duplicate plate as shown in FIG. 4 (b). While holding the resin 12 in the vicinity of the melting point, as shown in FIG. 4C, the support plate 13 is melted while aligning the concave portions of the duplicate plate 11 and the convex portions of the support plate 13 so as not to coincide with each other. Place on the resin 12. After the whole is cooled and cured, the support plate 13 is pulled out vertically to peel off the resin 12 and the duplicate plate 11, and the support plate 13 is heated to a temperature equal to or higher than the glass transition point. The resin 12 is peeled off to obtain a needle-like body having holes in the pedestal.

  According to the method disclosed in Example 1 of Japanese Patent Application Laid-Open No. 2008-29386, a duplicate plate in which fine concave portions were patterned on a silicon wafer was obtained. The diameter of the maximum opening of the recess was approximately 200 μm, and the depth of the recess was approximately 300 μm. The number of concave portions per square centimeter was 400. The silicon wafer was coated with a silane coupling agent to improve the releasability.

  According to the method disclosed in Example 1 of Japanese Patent Application Laid-Open No. 2007-260889, a support plate in which fine convex portions were patterned on a silicon wafer having a thickness of 1 mm was obtained. The height of the convex part was about 800 μm, the diameter of the tip was about 5 μm, and the diameter of the base part of the convex part was about 100 μm. The number of convex portions per square centimeter was 800. The silicon wafer was coated with a silane coupling agent to improve the releasability.

  High-density polyethylene (HDPE) was heated and melted at 170 ° C. and then introduced into the replica plate, and HDPE was filled in the concave portion of the replica plate. The convex part was pushed into the support plate from above the HDPE, and the convex part was brought into contact with the duplicate plate. The entire mold was quenched by nitrogen blowing, and the support plate was peeled from the duplicate plate. The HDPE was crystallized by heating it to 110 ° C. by a heating mechanism provided in the support plate, and after making it easy to peel from the support plate, the needle-like body was peeled from the support plate. The thickness of the pedestal portion of the obtained needle-like body was approximately 800 μm.

The water vapor permeability of the obtained needle-shaped high-density polyethylene was measured according to the method of JIS K 7129B. As the apparatus, Permatran-W200 manufactured by Mocon was used. The measurement conditions were 38 ° C. and 90 RH%. The water vapor permeability of the needle-like body with holes was 8000 g · μm / (m ² · day). The water vapor transmission rate of the high-density polyethylene film having almost the same film thickness as that of the needle-like pedestal was less than the detection limit.

A plan view and a cross-sectional view of a needle-shaped body manufactured by the manufacturing method described in the present invention Top view and sectional view of the duplicate Plan view and sectional view of support plate Cross-sectional view of how to create a needle

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Microneedle part of a needle-like body 2 Base part of a needle-like body 3 Hole provided in the needle-like body base part 11 Duplicated plate including an array of minute concave parts obtained by reversing the shape of the needle-like body 12 Resin 13 A supporting plate facing the duplicate plate and having a convex portion facing the flat portion of the duplicate plate 21 A surface facing the pedestal portion of the needle-like body 22 A fine concave portion obtained by reversing the shape of the desired needle-like body 31 Needle Surface facing the back of the pedestal of the pedestal 32 Fine convex part obtained by reversing the shape of the desired hole

Claims (9)

A needle-shaped body having a microneedle portion integrally molded in an array shape on a pedestal portion, provided with a hole in the pedestal portion , and the hole having a tapered shape .   The acicular body according to claim 1, wherein the thickness of the pedestal portion of the acicular body is 100 µm or more and 1 cm or less.   The needlelike object according to any one of claims 1 and 2, wherein the pore size is 0.1 µm or more and 100 µm or less. The acicular body according to any one of claims 1 to 3 , wherein the acicular body is made of a biodegradable resin. A method for producing the acicular body according to any one of claims 1 to 4 , wherein the concave portion of the duplicate plate includes concave portions arranged in a fine array in which the shape of the micro needle portion is inverted. Provided with a convex portion that fills the resin constituting the needle-like body and can form a hole penetrating the resin layer of the flat portion of the portion where the microneedle portion of the duplicate plate is not formed from the resin surface side on the duplicate plate A method of manufacturing a needle-like body, wherein a hole is formed in a pedestal portion of the needle-like body by pressing a support plate. 6. The method for manufacturing a needlelike object according to claim 5 , further comprising a heating mechanism on the duplicate plate side. The method for manufacturing a needle-shaped body according to claim 5 or 6 , wherein a heating mechanism or a cooling mechanism is included in the convex portion of the support plate or the entire support plate. The method for manufacturing a needle-shaped body according to any one of claims 5 to 7 , wherein the resin is a thermoplastic resin. The method for manufacturing a needle-shaped body according to any one of claims 5 to 8 , wherein the resin is a crystalline resin.

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