JP5572310B2 - Manufacturing method of needle-shaped body - Google Patents

Description

  The present invention relates to a method for manufacturing a needle-like body, and more particularly, to a method for duplicating a needle-like body having a hole in a base portion of the needle-like body.

  The percutaneous absorption method in which a drug is administered into the body by permeating the drug from the skin is used as a method by which the drug can be easily administered without causing pain to the human body. However, depending on the type of drug, there are drugs that are difficult to administer by the transdermal absorption method. As a method of efficiently absorbing these drugs into the body, a method of perforating the skin using micron-order fine needles and administering the drug directly into the skin has attracted attention.

  The acicular body forms perforations 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 perforations is inhibited by the barrier function of the epidermis. Even drugs that cannot be administered can be absorbed into the body. According to this method, it is possible to simply administer a drug subcutaneously without using a special device for dosing (Patent Document 1).

  The shape of the fine needle-like body used at this time is required to have a sufficient fineness 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, The tip angle of the needle is preferably 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 on average. In addition, 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 exists under the epidermis. 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, the material constituting the fine needle-shaped body is preferably a material that does not adversely affect the human body even if the damaged needle-shaped body remains in the body. Examples of the material include maltose and polylactic acid. Biocompatible materials such as dextran are considered promising (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

  The needle-shaped body has a structure in which a plurality of microneedles arranged in an array on the pedestal of the needle-shaped body is stable in order to accurately puncture the target site and administer a sufficient amount of medicine into the body. Need to be. In order for the plurality of microneedles to have a stable structure, it is necessary to increase the thickness of the pedestal portion of the needle-like body and suppress deformation of the pedestal portion to a minimum. By suppressing the deformation of the pedestal portion to the minimum, it is possible to solve the problem that the microneedles come into contact with each other before use and the needle tip is damaged, making it impossible to administer the required amount.

  However, when the thickness of the pedestal portion of the needle-like body is increased, gas permeation performance, particularly water vapor permeation performance is degraded. Since the needle-like body is assumed to be stuck to the skin for a long time in order to accurately puncture the target site and administer a sufficient amount of medicine into the body, the needle-like body with reduced water vapor transmission performance is May cause stuffiness due to sweating and skin irritation.

  An object of the present invention is to ensure the structural stability of the microneedle portion of the acicular body by a pedestal portion having a sufficient thickness, and to impart sufficient water vapor permeation performance to the pedestal portion so that the needle has little skin irritation. The object of the present invention is to provide a method for manufacturing a state body.

  As a result of earnest research, the present inventor has both the structural stability of the microneedle portion and the high water vapor transmission performance of the pedestal portion by unevenly distributing holes in the pedestal portion of the needle-like body. It has been found that needles can be provided.

That is, the present invention arranges the pretreatment step of performing water treatment on the water-absorbent resin and the water-absorbent resin subjected to the water treatment on the upper surface of the replication plate having fine concave portions obtained by reversing the shape of the needle-like body. Then, after the water-absorbing resin is heated and melted, or after the heat-melting , the water-absorbing resin that has been melted after being subjected to the water-containing treatment is subjected to pressure treatment between the duplicate plate and the supporting plate facing the replica plate. To form a needle-like body having a microneedle portion and a pedestal portion, vaporize moisture in the water-absorbent resin to generate a large number of bubbles, move the bubbles to the pedestal portion, and A method for producing a needle-like body, comprising a step of forming a needle-like body in which holes are unevenly distributed in a portion.
In the present invention, the water-absorbing resin is disposed on the upper surface of the replication plate having fine concave portions in which the shape of the needle-like body is inverted, and the water-absorbing resin is heated and melted. and performing water treatment resin, the heat-melted simultaneously with or after heating melted, between the support plate facing the and to this duplication plate, pressurized water absorbent resin having undergone the water treatment in the heating and melting By pressure treatment, it is molded into a needle-like body having a microneedle part and a pedestal part, and moisture in the water absorbent resin is vaporized to generate a large number of bubbles, and the bubbles are moved to the pedestal part. And providing a needle-like body in which pores are unevenly distributed in the pedestal portion.
Furthermore, the present invention is a step of placing the water-absorbing resin on the upper surface of the replication plate provided with a fine concave portion obtained by reversing the shape of the needle-like body, and at the same time or after the heat-melting of the water-absorbing resin , The water absorbing resin is disposed between the step of contacting the water-absorbing resin with a support plate impregnated with moisture facing the replica plate and subjecting the water- absorbent resin to water treatment, and the replica plate and the support plate facing the water-repellent plate. By pressurizing the functional resin, it is molded into a needle-like body having a microneedle portion and a pedestal portion, and water in the water-absorbent resin is vaporized to generate a large number of bubbles. And moving to a pedestal portion, and providing a needle-like body in which holes are unevenly distributed in the pedestal portion.

  According to the method for producing a needle-like body of the present invention, it is possible to provide a needle-like body in which the microneedle portion has structural stability and sufficient water vapor transmission performance is imparted to the pedestal portion. In the needle-like body, since the microneedle portion has structural stability, it becomes possible to accurately puncture all the needles to the target site and reliably administer the prescribed amount of medicine. In addition, since the needle-shaped body is provided with sufficient water vapor transmission performance in the pedestal portion, there is little skin irritation and the skin can be applied for a long time.

  Hereinafter, embodiments of the present invention will be described. Note that the embodiments described below are merely examples for explaining the configuration of the present invention in detail. Accordingly, the invention should not be construed as limited based on the description set forth in the following embodiments. The scope of the present invention includes all embodiments including various modifications and improvements of the following embodiments as long as they are within the scope of the invention described in the claims.

FIG.
FIG. 1 is a schematic view showing a method for manufacturing a needle-like body.

FIG.
A pretreatment is performed in which a low molecular weight component is contained in the resin 12 for producing the needle-like body. The pretreatment may be performed at any stage before or during the melting of the resin, and the pretreatment method is not particularly limited. For example, in the pretreatment, the needle-like body may be produced by allowing the resin to stand still or melting the resin in an atmosphere filled with the low molecular weight component in a gaseous state at a high concentration. For example, specifically, when the low molecular weight component is moisture, the low molecular weight component may be left in an environment having a humidity of 50% or more. Further, as shown in FIG. 1b, when the resin 12 is filled in the replica plate 11, the resin peripheral portion may be filled with a low molecular weight component of gas.

  Furthermore, as another embodiment, after applying a low molecular weight component on the surface of the support plate 13 or impregnating the support plate 13 with the low molecular weight component, the support plate 13 is brought into contact with the surface of the resin 12. Also good. In this case, the pretreatment (FIG. 1a) for the resin 12 is performed substantially simultaneously with the heat melting treatment (FIG. 1c) and the press molding treatment (FIG. 1d), and the needle-like body 1 can be manufactured more quickly.

  The resin 12 is preferably a biocompatible resin. Specific examples include, but are not limited to, medical silicone resin, starch resin, polylactic acid (PLA), polyglycolic acid (PGA), polylactic glycolic acid copolymer, polyurethane, poly-ε- It is selected from the group consisting of caprolactone, polytrimethylene carbonate, casein plastic, and polyether polyester copolymer.

The resin 12 is preferably a water-absorbing resin . Water treatment is performed on the water- absorbent resin , and the resin containing a large amount of water is heated and melted, whereby the moisture in the resin is vaporized and a large number of bubbles 4 are generated in the resin. The water absorbent resin is not limited to this, but its water content is preferably 1% or more and 10% or less. The water absorbent resin is desirably a resin that does not adversely affect the human body. For example, a biocompatible resin such as a bioabsorbable resin is preferably used.

  The low molecular weight component desirably has a boiling point or sublimation point lower than the melting point of the resin 12. Although it depends on the molecular structure, a molecular weight of 150 or less is desirable. Further, those having a molecular structure and a functional group that are easily adsorbed inside the resin 12 are desirable. Although not specifically limited as specific examples, water, alcohols (methanol, ethanol, propanol, etc.), carboxylic acids (formic acid, acetic acid, propionic acid, etc.), carboxylic acid esters (ethyl acetate, methyl acetate, pentyl acetate, Caproic acid, etc.), aldehydes (acetaldehyde, benzaldehyde, etc.) or a solution in which these are used as a solvent and a drug is dissolved, or a solution in which these are mixed in an arbitrary ratio may be used. Further, a substance having sublimation properties such as oxalic acid, caffeine, salicylic acid, etc. may be used.

FIG.
Resin 12 is filled on the duplicate plate 11. The filling method of the resin 12 is not limited to this, but it is desirable to use an imprint method, a hot embossing method, an injection molding method, an extrusion molding method, and a casting method from the viewpoint of productivity.

  The duplicate plate 11 is for molding the resin 12 into the needle-like body 1 having the microneedle portion 2 and the pedestal portion 3, and is an array of fine recesses obtained by inverting the shape of the desired needle-like body. It has.

  The duplicate plate 11 is not particularly limited to this. For example, the replica plate 11 is produced by processing a ceramic substrate using a machine tool, producing a needle-like body as an original plate, and using this as a mold. . By injecting a replica plate-making material such as silicone onto the prepared mold and performing mold opening after quenching and curing, a replica plate having an uneven transfer pattern for molding a desired needle-like body is obtained. Can do.

  The duplicate plate 11 is made of a material that takes into account transferability, durability, releasability, and the like in transfer processing molding of the resin 11. The material of the duplicate plate 11 is not particularly limited, but copper, nickel, silicon, iron, aluminum, titanium, chromium, and alloys, vitreous substances, or Teflon (registered trademark) resin containing these in any ratio. , Silicone resin, and the like.

  In order to improve the peelability of the duplicate plate 11, a release layer for increasing the mold release effect may be formed on the surface of the duplicate plate 11. As the release layer, for example, a widely known fluorine-based resin can be used. Further, as a method for forming the release layer, a thin film forming method such as a PVD method, a CVD method, a spin coating method, or a dip coating method can be suitably used. By providing the release layer, it is possible to prevent structural damage to the microneedle portion 2 of the needle-like body 1 at the time of release, and to provide a more precise and complete needle-like body 1.

FIG.
The resin 12 is heated and melted. By the heat melting treatment, the low molecular weight component confined in the resin 12 by the pretreatment (including the low molecular weight component) is vaporized, and a large number of bubbles 4 are generated.

  In order to heat the resin 12 to a temperature near the melting point, it is desirable that the duplicate plate 11 is provided with a heating mechanism. Here, the “heating mechanism” means, for example, a hot plate provided on the back surface of the duplicate plate 11. As another aspect, for example, a duplicate plate 11 provided with a sheet-like heater, or a warm air oven that heats the duplicate plate 11 and the entire resin 12 may be used. As another aspect, the above-mentioned “heating mechanism” may not be provided, and a molten resin may be supplied onto the needle-like body 11 in advance.

FIG.
A pressure treatment is performed on the resin 12 by the support plate 13. Simultaneously with heat melting of the resin 12 or after heat melting, by pressing the support plate 13 against the resin 12, many bubbles 4 generated in the resin 12 are confined in the resin, and the microneedle portion of the needle-like body 1 2 can be moved to the base 3.

  The support plate 13 is disposed at a position facing the duplicate plate 11 and is used to press the resin 12 filled in the duplicate plate 11 from above. The support plate 13 is provided on the base 3 of the needle-like body 1. While controlling the thickness, it prevents a large number of bubbles 4 generated in the resin 11 from evaporating from the resin 11 and moves the bubbles 4 existing in the microneedle portion 2 of the needle-like body 1 to the pedestal portion 3. Have.

  The support plate 13 is made of a material that takes into account the thickness controllability, durability, releasability, and the like of the base forming portion of the resin 12. Although the material of the support plate 13 is not particularly limited, like the material of the duplicate plate 11, copper, nickel, silicon, iron, aluminum, titanium, chromium, and alloys and vitreous materials containing these in any ratio Or Teflon (registered trademark) resin, silicone resin, or the like.

FIG.
After pressurization by the support plate 13, the entire mold is rapidly cooled to cure the resin 12. By curing the resin 12, the bubbles 4 confined in the resin 12 are fixed as the holes 4. By separating the support plate 13 from the resin and separating the resin 12 molded on the replication plate 11 from the replication plate 11, the needle-like body 1 in which the holes 4 are unevenly distributed in the pedestal portion 3 can be obtained.

  Since the needle-shaped body 1 manufactured in the first embodiment has a large number of holes 4 in the pedestal portion 1, the needle-shaped body 1 is excellent in water vapor transmission performance, hardly sticks in the pasting area of the needle-shaped body 1, and is stuck for a long time However, skin irritation hardly occurs. In addition, since the holes 4 are unevenly distributed in the pedestal portion 3 and there are very few holes 4 in the microneedle portion 2, the holes 4 do not adversely affect the drug administration ability of the needle-like body 1. As a result, it is possible to provide an excellent needle-like body having high water vapor transmission performance without losing the drug administration ability of the existing needle-like body.

  Moreover, although the method in the first embodiment is a manufacturing method of a complicated needle-like body in which the holes 4 are unevenly distributed in the pedestal portion 3, different materials are used for the microneedle portion 2 and the pedestal portion 3. The microneedle portion 2 and the pedestal portion 3 can be integrally molded from a single resin. As a result, the molding process is simplified, which contributes to the improvement of the productivity of the needle-shaped body.

  Furthermore, since the needle-like body 1 includes many holes 4, the amount of resin to be used is reduced, which contributes to a reduction in raw material costs at a mass production site.

FIG.
FIG. 2 is a cross-sectional view of a needle-like body produced by the method according to the first embodiment.

  In FIG. 2, the needle-like body 1 includes a minute needle portion 2 and a pedestal portion 3, and a large number of minute holes 4 exist in the pedestal portion 3 at a high density.

  The needle-like body 1 produced by the method in the first embodiment has a sufficient fineness and a tip angle for piercing the skin, and a sufficient length for allowing the drug solution to penetrate subcutaneously. Specifically, although not particularly limited, it is desirable that the diameter of the microneedle portion 2 is several μm to several hundred μm, and the tip angle thereof is 30 ° or less. Subsequently, the length of the microneedle portion 2 is preferably a length that penetrates the stratum corneum that is the outermost layer of the skin. The thickness of the stratum corneum varies slightly depending on the part of the human body, but is about 20 μm on average. Under the stratum corneum is an epidermis having a thickness of about 200 μm to about 350 μm, and there is a dermis layer under which capillaries are stretched. For this reason, in order to penetrate the stratum corneum and allow the chemical solution to penetrate, the length of the needle-like body of at least about 20 μm or more is sufficient. On the other hand, for the purpose of administration in blood, the length of the needle-shaped body should be at least about 200 μm or more. In addition, the density in the needle-like body 1 of the microneedle portion 2 is preferably 100 or more and 1500 or less, more preferably 300 or more per square centimeter, in order to sufficiently penetrate the drug.

  Further, in the needle-like body 1 produced by the method in the first embodiment, the microneedle portion 2 has structural stability and is caused by contact between the microneedle portions 2 due to deformation of the pedestal portion 3. Damage to the needle tip of the microneedle portion 2 is suppressed. Although it does not specifically limit as a specific structure, The thickness of the base part 3 becomes like this. Preferably they are 100 micrometers or more and 1 cm or less, More preferably, they are 800 micrometers or more and 5 mm or less.

  Furthermore, the needle-like body 1 produced by the method according to the first embodiment has sufficient gas permeation performance, particularly sufficient water vapor permeation performance, in order to prevent stuffiness due to perspiration that leads to skin irritation. As a specific configuration, a large number of holes 4 present at high density in the pedestal portion 3 impart the above characteristics to the needle-like body 1. The pores 4 are not particularly limited, but the average diameter is preferably 0.1 μm or more and 500 μm or less, and more preferably 1 μm or more and 50 μm or less. The holes 4 having the above average diameter impart water permeability to the pedestal portion 3 and promote the evaporation of sweat at the location where the needle-like body 1 is applied. Moreover, the average diameter provides only water vapor transmission performance, prevents bacterial infection due to external air contact of the puncture portion, and can sufficiently ensure the structural strength of the needle-like body. Subsequently, the distance between the holes 4, that is, the average distance between the holes is not particularly limited, but is preferably 1 μm or more and 100 μm or less. By the average distance between the holes, extremely high water vapor transmission performance is imparted, and the structural height of the needle-like body can be sufficiently secured. Furthermore, the holes 4 are preferably closed cells. Here, “being closed cells” means that the number of closed cells existing in a predetermined region is larger than the number of open cells when the pedestal 3 is observed under a microscope. Compared to open cells, closed cells make it difficult for moisture adhering to the surface and bacteria in the outside air to enter the needle side of the needle-like body, and can effectively prevent skin diseases such as bacterial infection.

  The acicular body was produced using the replica plate by which the fine recessed part was patterned on the silicon wafer, and the iron support plate. The size of the maximum opening of the recess was approximately 200 μm, and the depth of the recess was approximately 300 μm. The number of recesses per square centimeter was 800. In addition, a release agent was coated on the silicon wafer to improve the release property.

Starch resin bioplus HSCP (manufactured by Zhejiang Hisun Chemical) was allowed to stand in an environment of a temperature of 40 ° C. and a humidity of 90% for 3 days. Using this resin, it was heated and melted at 200 ° C. and then introduced into a replica plate, and the concave portion of the replica plate was filled with HSCP. After pressurizing 2 seconds supporting plate pressure 10 kgf / cm ² from the HSCP, it was further pressurized for 10 seconds at a pressure of 2 kgf / cm ^2. Thereafter, the support plate was left in contact with the resin, the entire mold was quenched with nitrogen blow, the support plate was removed, and the produced needle-like body was peeled from the duplicate 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-like body was measured according to the method of JIS K 7129B. As a device, 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 including pores was 8000 g · μm / (m ² · day).

  On the other hand, the water vapor transmission rate of the HSCP film (comparative example) having substantially the same film thickness as the pedestal of the needle-like body was below the detection limit.

Schematic diagram showing the method of manufacturing the needle-shaped body Sectional drawing of the acicular body produced by the method in the first embodiment

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Acicular body, 2 ... Microneedle part, 3 ... Base part, 4 ... Bubble, hole, 11 ... Duplicate plate, 12 ... Resin, 13 ... Support Edition.

Claims (4)

A pretreatment step of performing water treatment on the water absorbent resin;
The water-absorbing resin that has been subjected to the water-containing treatment is disposed on the upper surface of a replication plate having fine concave portions in which the shape of the needle-like body is inverted, and at the same time as or after the heat-melting of the water-absorbing resin , By molding the water-absorbing resin that has been melted after being subjected to the water-containing treatment between the duplicate plate and the supporting plate opposite thereto, it is molded into a needle-like body having a microneedle portion and a pedestal portion. And the process of vaporizing the water in the water-absorbent resin to generate a large number of bubbles, moving the bubbles to the pedestal portion, and forming a needle-like body in which holes are unevenly distributed in the pedestal portion;
A method for producing a needle-like body. The water-absorbing resin is placed on the upper surface of the replication plate having fine concave portions in which the shape of the needle-like body is inverted, and the water-absorbing resin is heated and melted. A process of performing;
The heating and melting simultaneously with or after heating melted, between the support plate facing the and to this duplication plate, by a water-absorbent resin having undergone the water treatment in the heating and melting to pressure treatment, the microneedles portion And forming a needle-like body having a pedestal portion, vaporizing moisture in the water-absorbent resin to generate a large number of bubbles, moving the bubbles to the pedestal portion, and providing holes in the pedestal portion. A step of making the needle-like body unevenly distributed;
A method for producing a needle-like body. Arranging the water-absorbing resin on the upper surface of the replication plate provided with fine concave portions obtained by reversing the shape of the needle-like body;
After heating and melting the same time or heating and melting of the water-absorbent resin, a support plate impregnated with the duplication plate opposed to the water in contact with the water-absorbent resin, and performing water treatment to the water-absorbent resin,
The water-absorbing resin is subjected to pressure treatment between the duplicate plate and the supporting plate opposite thereto to form a needle-like body having a microneedle portion and a pedestal portion. Vaporizing the water to generate a large number of bubbles, moving the bubbles to the pedestal portion, and forming a needle-like body in which holes are unevenly distributed in the pedestal portion;
A method for producing a needle-like body. The acicular body manufactured by the method of any one of Claims 1-3 .

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