JP6714319B2 - Needle-like body manufacturing method - Google Patents

Description

The present invention relates to a method for manufacturing a needle-shaped body.

The transdermal absorption method, which is a method of permeating a delivery agent such as a drug through the skin and administering the delivery agent into the body, is used as a method capable of easily administering the delivery agent without causing pain to the human body. ..

In the field of transdermal administration, there has been proposed a method of perforating the skin using a needle-shaped body having a needle of the order of μm and administering a drug or the like into the skin (see Patent Document 1).

Further, as a method of manufacturing a needle-shaped body, it is proposed that an original plate is produced by using a mechanical process, a transfer plate is formed from the original plate, and a transfer process molding using the transfer plate is performed (Patent Document 2). reference).

Further, as a method of manufacturing a needle-shaped body, it has been proposed to prepare an original plate by using an etching method, form a transfer plate from the original plate, and perform transfer processing molding using the transfer plate (Patent Document 3). reference).

Further, it is desirable that the material forming the needle-shaped body is a material that does not adversely affect the human body even if the damaged needle-shaped body remains in the body. Therefore, a biocompatible material such as chitosan has been proposed as a needle-shaped body forming material (see Patent Document 4).

JP-A-48-93192 International Publication No. 2008/013282 Pamphlet International Publication No. 2008/004597 pamphlet International Publication No. 2008/020632 Pamphlet

A needle-shaped body using a biocompatible material of water-soluble polymer such as chitosan can be dissolved inside the skin after puncturing the skin. Therefore, by preparing a needle-shaped body by containing a delivery product intended for delivery into the skin in addition to the water-soluble polymer, it is possible to dissolve the water-soluble polymer when the needle-shaped body is punctured into the skin. The deliverable can be delivered intradermally.

When a needle-shaped body is made of a water-soluble polymer material, the needle-shaped body is obtained by casting the water-soluble polymer material solution on the intaglio plate of the needle and then drying it, or by freeze-drying and solidifying the material. There is a way. There is a method of heating at the desired temperature to speed up the drying, but the air remaining in the concaves of the intaglio plate expands, air bubbles are mixed into the solution filled in the intaglio plate, and the needles fill up to the tip. There is a problem that it is not done, and bubbles remain in the needle-shaped body.

As a method of avoiding the generation of bubbles during heating and drying and the inclusion of bubbles in the needle-shaped body, after supplying the material solution to the intaglio plate and placing it in a depressurized environment, the bubbles remaining in the indentations of the intaglio plate are removed and the material solution in the recess There is a method of filling. It is also possible to remove the air bubbles in the recesses by setting a pressure environment instead of a reduced pressure environment.

In order to remove the air bubbles from the recess of the intaglio under reduced pressure, it is necessary to move the air bubbles to the upper surface of the acicular body forming liquid supplied to the upper surface of the recess. However, it becomes difficult for bubbles to escape, and conversely, the inclusion of bubbles in the needle-shaped body is promoted. In addition, air bubbles generated during depressurization may remain in the needle-shaped body even after the material is solidified.

When performing needle filling into the recess in a pressurized environment, control the pressurization speed so that the needle-shaped body forming liquid supplied to the recess of the intaglio does not move from the desired supply location and the interface does not shake. While it is necessary to pressurize. Further, since a pressurizing chamber is required, there is a problem that manufacturing cost is affected.

An object of the present invention is to provide a method for manufacturing a needle-shaped body capable of filling up to the tip of a recess corresponding to a protrusion.

In order to solve the above problems, the present invention provides a supporting substrate and a method for manufacturing a needle-shaped body having a needle-shaped protrusion on one surface of the supporting substrate,
Depressurizing the chamber to a first depressurized environment,
First needle-like body formation in which a first needle-like body forming material is dissolved or dispersed in a solvent with respect to an intaglio plate provided with a concave portion corresponding to the protrusion in a chamber depressurized to the first depressurized environment. A first supply step of supplying a liquid,
A first pressure changing step of changing the first needle-shaped body forming liquid supplied to the intaglio plate to a pressure higher than the first depressurized environment;
After the first pressure changing step, in the chamber depressurized to the first depressurized environment again,
A first drying step of drying the needle-shaped body forming liquid supplied to the intaglio plate;
Depressurizing the chamber to a second depressurized environment,
A second needle-shaped body forming material is dissolved or dispersed in a solvent with respect to the intaglio filled and dried with the first needle-shaped body forming liquid in a chamber depressurized to the second depressurized environment. A second supply step of supplying the needle-shaped body forming liquid of
A second pressure changing step of changing the second needle-shaped body forming liquid supplied to the intaglio plate to a pressure higher than the second depressurized environment;
After the second pressure changing step, in the chamber depressurized to the second depressurized environment again,
A second drying step of drying the needle-shaped body forming liquid supplied to the intaglio plate into a needle-shaped body;
And a peeling step of peeling the needle-shaped body from the intaglio plate.
The invention according to claim 2 is characterized in that the pressure change amount in the first pressure change step is within a range of 0.05 MPa or more and 0.10 MPa or less. The manufacturing method was used.
The invention according to claim 3 is the method for manufacturing a needle-shaped structure according to claim 1 or 2, wherein the pressure after the pressure change in the first pressure change step is atmospheric pressure. ..
The invention according to claim 4 is characterized in that the amount of pressure change in the second pressure changing step is in the range of 0.05 MPa or more and 0.10 MPa or less. The method for producing a needle-shaped body according to the item 1.
Further, as the invention according to claim 5, the needle-like needle according to any one of claims 1 to 4, wherein the pressure after the pressure change in the second pressure changing step is atmospheric pressure. It was a method of manufacturing the body.
In the invention according to claim 6, the pressure of the first reduced pressure environment and the pressure of the second reduced pressure environment are 0.04 MPa, and the pressure after the pressure change in the first pressure changing step and the The needle-shaped structure manufacturing method according to claim 1 , wherein the pressure after the pressure change in the second pressure changing step is 0.08 MPa .
In the invention according to claim 7 , the first needle-shaped body forming material is chitosan, chitosan succinamide, hydroxypropyl cellulose, carboxymethyl cellulose, sodium chondroitin sulfate, curdlan, trehalose, sucrose, gelatin, collagen. The method for producing a needle-shaped structure according to any one of claims 1 to 6 , characterized in that it is selected from the group consisting of citrate, pullulan, pectin, and alginate.
Further, as the invention according to claim 8 , the needle according to any one of claims 1 to 7 , wherein the first needle-shaped body forming material contains a pharmacologically active substance or a cosmetic delivery product. The method for producing a sheet was used.
In the invention according to claim 9 , the second needle-shaped body forming material is chitosan, chitosan succinamide, hydroxypropyl cellulose, carboxymethyl cellulose, sodium chondroitin sulfate, curdlan, trehalose, sucrose, gelatin, collagen. The method for producing a needle-shaped structure according to any one of claims 1 to 8 , characterized in that it is selected from the group consisting of citrus, pullulan, pectin, and alginate.
As the invention according to claim 10, wherein the second needle-like member forming material, according to any one of claims 1 to 9, characterized in that it comprises a pharmacologically active agent or cosmetic delivery thereof needles The method for producing a sheet was used.

By using the method for manufacturing a needle-shaped body of the present invention, a needle-shaped body filled up to the tip of the protrusion can be manufactured.

FIG. 1 is a perspective view of the needle-shaped body of the present invention. FIG. 2 is a schematic view of the outer shape of the needle-shaped body of the present invention. FIG. 3 is an explanatory view of the method for manufacturing the needle-shaped structure of the present invention. FIG. 4 is an explanatory view of the method for manufacturing the needle-shaped body of the present invention. FIG. 5: is explanatory drawing of the manufacturing method of the acicular body of this invention. FIG. 6 is an explanatory view of the method for manufacturing the needle-shaped body of the present invention. FIG. 7 is an explanatory view of the method for manufacturing the needle-shaped body of the present invention. FIG. 8: is explanatory drawing of the manufacturing method (modification) of the acicular body of this invention. FIG. 9 is an explanatory diagram of a method for manufacturing a needle-shaped body (modification) of the present invention.

The needle-shaped body of the present invention will be described.
FIG. 1 shows a perspective view of the needle-shaped body of the present invention. The needle-shaped body 10 of the present invention includes a needle-shaped protrusion 11 on a support substrate 12. Further, the needle-shaped body of the present invention includes at least the first layer 11A and the second layer 11B in order from the tip end side of the protrusion.

In the needle-shaped body of the present invention, the needle-shaped protrusion 11 punctures the skin. In the needle-shaped body of the present invention, the protrusion 11 may have any shape suitable for puncturing the skin. The protrusion 11 has a shape such as a cone, a pyramid, a cylinder, a prism, or a pencil shape (the body has a columnar shape and the tip has a pyramid shape). Further, any one of (1) a form in which one protrusion exists on the support substrate and (2) a form in which a plurality of protrusions are provided on the support base may be used. When a plurality of protrusions stand on the support substrate, it is preferable that the protrusions are arranged in an array. Here, the term “array” means a state in which the unit needle-shaped bodies are arranged. For example, a lattice array, a closest packing array, a concentric array, a random array, etc. are included.

In the usage form of the needle-shaped body of the present invention, an applicator for fixing the insertion position and direction of the needle-shaped body can be attached. The needle-shaped body of the present invention may have a hole in the protrusion. The hole may be a hole penetrating to the back surface of the support substrate or a non-penetrating hole. Further, holes may be provided in the supporting substrate. The hole may be a through hole reaching the back surface of the support substrate or a non-through hole.

FIG. 2 shows a schematic diagram of the outer shape of the needle-shaped body of the present invention. FIG. 2A is a top view of the needle-shaped body from the side of the protrusion, and FIG. 2B is a cross-sectional view taken along the line II′ of the needle-shaped body in FIG. 2A.
In the needle-shaped body 10 of the present invention, it is preferable that the needle-shaped protruding portion 11 has a dimension and a length suitable for forming a puncture hole in the skin. Specifically, the height H of the protrusion 11 shown in FIG. 2 is preferably in the range of 10 μm or more and 1000 μm or less. The height H of the protrusion is the distance from the support substrate 12 to the tip of the protrusion 11.
The height H of the protrusion is preferably determined in consideration of the depth within the skin in which the puncture hole formed when the needle-shaped body is punctured is formed within the above range.
In particular, when the puncture hole formed when the needle-shaped body is punctured is retained “in the stratum corneum”, the height H of the protrusion of the needle-shaped body is, for example, 10 μm or more and 300 μm or less, more preferably 30 μm or more and 200 μm or less, It is desirable to be within the range.
Further, when the puncture hole formed when the needle-shaped body is punctured is limited to “a length that penetrates the stratum corneum and does not reach the nerve layer”, the height H of the protrusion of the needle-shaped body is 200 μm or more and 700 μm or more. The range is more preferably 200 μm or more and 500 μm or less, and further preferably 200 μm or more and 300 μm or less.
Furthermore, when the puncture hole formed when the needle-shaped body is punctured is "the length at which the puncture hole reaches the dermis", the height H of the protrusion of the needle-shaped body is in the range of 200 μm or more and 500 μm or less. Preferably. Further, when the puncture hole formed when the needle-shaped body is punctured is “the length at which the puncture hole reaches the epidermis”, the height H of the protruding portion of the needle-shaped body is within the range of 200 μm or more and 300 μm or less. It is preferable.

The width D of the protrusion is preferably in the range of 1 μm or more and 300 μm or less. It is preferable to determine the width D of the protrusion in consideration of how deep the puncture hole formed when the needle-shaped body is punctured within the range is to be formed in the skin.
The width D of the protrusion is the maximum length of the length of the protrusion in contact with the supporting substrate when the protrusion is projected parallel to the substrate surface. For example, when the protrusion has a conical shape, the diameter of the circle on the surface in contact with the support and the support substrate is the width D. When the protrusion is a regular quadrangular pyramid, the width D is the diagonal line of the square of the surface in contact with the protrusion and the support substrate. Further, when the protrusion is a column, the diameter of the circle on the surface in contact with the protrusion and the support substrate is the width D. When the protrusion is a regular square pole, the square diagonal of the surface in contact with the support and the support substrate has the width D.

The aspect ratio is preferably in the range of 1 or more and 10 or less. The aspect ratio A is defined by A=H/D using the length H and width D of the protrusion.
In the needle-shaped body according to the embodiment, when the protrusion has a tip angle like a cone and penetrates the stratum corneum, the tip angle θ of the protrusion is 5° or more and 30° or less, more preferably 10° or more. It is desirable to be within the range of 20° or less. The tip angle θ indicates the maximum angle (vertical angle) when the projection is projected in parallel with the surface of the supporting substrate.
In the needle-shaped body according to the embodiment, it is preferable that the support substrate is the same as the material of the protrusion. By forming the support substrate and the protrusion with the same material, the support substrate and the protrusion can be integrally formed.

Next, a method for manufacturing the needle-shaped structure of the present invention will be described.

[Step of preparing the first needle-shaped body forming liquid]
First, a first needle-shaped body forming liquid 21 in which the first needle-shaped body forming material is dissolved or dispersed in a solvent is prepared. The first needle-shaped body forming material preferably contains a water-soluble polymer or polysaccharide.

Water-soluble polymers and polysaccharides include chitosan, chitosan succinamide, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), sodium chondroitin sulfate, curdlan, trehalose, sucrose, gelatin, collagen, pullulan, pectin, alginate. , Starch, methylcellulose, hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid-based polymer, polyacrylamide (PAM), polyethylene oxide (PEO), etc. can be used, but not limited thereto. Absent. Further, these materials may be mixed.

Among them, as the first needle-shaped body forming material, from among chitosan, chitosan succinamide, hydroxypropyl cellulose, carboxymethyl cellulose, sodium chondroitin sulfate, curdlan, trehalose, sucrose, gelatin, collagen, pullulan, pectin, alginate It is preferably selected. The reason is that it is biologically safe. Note that these materials may be mixed.

The first needle-shaped body forming liquid becomes the first needle-shaped body forming liquid by dissolving or dispersing it in water or an aqueous solvent.
Further, in the needle-shaped body forming liquid, a dissolution promoting substance may be added in order to dissolve the water-soluble polymer which is the needle-shaped body forming material in water which is the solvent. For example, when chitosan is used as the first needle-shaped body forming material, it is necessary to add an acid to the needle-shaped body forming liquid. The first needle-shaped body forming liquid preferably has a fluidity such that it can flow into the intaglio plate. In addition, it is preferable that the first needle-shaped body forming liquid has been defoamed in advance. The defoaming treatment can be performed by storing the first needle-shaped body forming liquid in a reduced pressure environment.

Further, in the present invention, the delivery product may be contained in the first needle-shaped body forming liquid. The deliverables can include pharmacologically active substances and cosmetic deliveries. At this time, when a material having an aroma is used as a delivery product, it is possible to impart an odor during use, which is preferable for use as a beauty product.

The pharmacologically active substance may be appropriately selected depending on the application. For example, it may be a vaccine such as influenza, a drug for pain relief for cancer patients, insulin, a biologic, a gene therapy drug, an injection, an oral preparation, a skin application preparation and the like. Since the needle-shaped body of the present invention punctures the skin, it can be applied to pharmacologically active substances that require subcutaneous injection, in addition to conventional pharmacologically active substances used for transdermal administration. In particular, vaccines, which are injectables, are suitable for application to children because they do not cause pain during administration when needles are used. In addition, although it is difficult for children to take oral preparations by the conventional administration of oral preparations, the needle-shaped body is suitable for application to children because it is not necessary to take the medicine for administration.

The cosmetic delivery product is a composition used as cosmetics and beauty products. Examples thereof include moisturizers, colorants, fragrances, and physiologically active substances that exhibit cosmetic effects (wrinkle, acne, stretch marks, etc., hair loss, etc.).

[First supply step]
The needle-shaped body forming liquid 21 in which the first needle-shaped body forming material is dissolved or dispersed in the solvent and the intaglio 22 are placed in the vacuum chamber 23 (FIG. 3A). The vacuum chamber is connected to a pump and evacuated. Next, after the inside of the vacuum chamber is under a reduced pressure environment, the first needle-shaped body forming liquid is supplied to the intaglio plate (FIG. 3B). The intaglio plate has a concave portion corresponding to the protrusion. In addition, the intaglio plate may be provided with a bank (projection part) 22 ′ for controlling the wetting and spreading of the acicular body forming liquid on the intaglio plate at the peripheral portion.

The viscosity of the needle-like body forming liquid of the present invention is preferably in the range of 0.01 Pa·s or more and 100 Pa·s or less. The method for producing a needle-shaped structure according to the present invention is such that even when a needle-shaped structure forming liquid having a high viscosity in the range of 0.01 Pa·s or more and 100 Pa·s is used, the needle-shaped structure is formed to the tip of the concave portion of the intaglio plate. It is possible to fill the body forming liquid. That is, in the method for producing a needle-shaped structure of the present invention, when a needle-shaped structure forming liquid having a high viscosity within the range of 0.01 Pa·s or more and 100 Pa·s is used, an extremely high effect is exhibited. To be done.

A method of manufacturing an intaglio plate having a concave portion corresponding to the protrusion of the needle-shaped body will be described. It is possible to prepare an original plate for determining the shape of the sheet, and to produce an intaglio in which the desired shape of the needle-shaped body is inverted from the original plate. The original plate that determines the shape of the needle-shaped body can be manufactured by a known method depending on the shape of the needle-shaped body. The original plate may be formed using a fine processing technique. Examples of the fine processing technique include a lithography method, a wet etching method, a dry etching method, a sandblast method, a laser processing method, and a precision machining method. A known shape transfer method can be used to form the intaglio plate from the original plate. For example, (1) formation of Ni intaglio plate by Ni electroforming, (2) resin intaglio plate by transfer molding using a molten resin such as silicone resin, and the like.

In the method for manufacturing a needle-shaped structure of the present invention, the lower the degree of vacuum in a depressurized environment is, the more preferable in view of the filling property at the tip of the protrusion in the needle-shaped structure forming liquid supplying step. However, if the degree of vacuum in the reduced-pressure environment is too low, it takes a long time to reach the desired degree of vacuum, which may increase the manufacturing cost.

[First pressure changing step]
Next, the needle-shaped body forming liquid supplied to the intaglio plate is changed to a pressure environment higher than 0.05 MPa. In the present invention, the needle-shaped body forming liquid is supplied to the intaglio plate by supplying the needle-shaped body forming liquid to the intaglio plate in a pressure environment of 0.05 MPa or less and changing the pressure environment to a higher pressure environment than the supply step. The liquid 21 is filled in the concave tip of the intaglio plate (FIG. 4C).
In the method for manufacturing a needle-shaped body of the present invention, after the needle-shaped body forming liquid is supplied onto the intaglio plate in a pressure environment of 0.05 MPa or less, air is introduced into the vacuum chamber, and the pressure environment of the drying step is set. By changing the pressure environment to a pressure environment higher than that under the pressure environment of the supply process and equal to or lower than the atmospheric pressure (0.1 MPa), the needle-shaped body forming liquid can be filled into the concave tip of the intaglio plate. By drying and solidifying the body-forming liquid, a needle-shaped body filled up to the tip of the protrusion can be prepared.
In the present invention, the amount of pressure change in the pressure change step is preferably in the range of 0.05 MPa or more and 0.1 MPa or less. If the amount of pressure change is less than 0.05 MPa, the degree of filling up to the tip of the concave portion of the intaglio plate may decrease. The higher the pressure change amount, the more preferable. However, when the amount of pressure change exceeds 1.0 MPa, the time required to reach the vacuum becomes too long, which may increase the manufacturing cost.
Moreover, in the needle-shaped structure manufacturing method of the present invention, it is preferable in terms of manufacturing control that the pressure after the pressure change in the pressure changing step is atmospheric pressure.

[First drying step]
Next, the first needle-shaped body forming liquid supplied on the intaglio plate is dried and solidified to form needle-shaped bodies. It should be noted that an excess amount of the first needle-shaped body forming liquid supplied to the intaglio may be removed by a squeegee 24 or the like before drying and solidifying (FIG. 4(d)). After the intaglio is placed under the atmospheric pressure environment, the supplied needle-shaped body forming liquid 21 can be dried by placing it on the hot plate 25 (FIG. 5(e)). The heating temperature at the time of heating is preferably set to a temperature at which the acicular body forming liquid does not boil in order to avoid bubbles remaining in the acicular body. Therefore, when water is used as the solvent for the needle-shaped body forming liquid, the heating temperature is preferably in the range of 40°C or higher and 90°C or lower. The heating may be performed by any known heating means. In addition to the method of using a hot plate on which the intaglio plate to which the acicular body forming liquid is supplied is placed, the intaglio plate to which the acicular body forming liquid is supplied is heated in an oven The method of mounting in can be used. It is also possible to carry out the dry solidification at room temperature without heating.

In the method for manufacturing a needle-shaped body of the present invention, after the needle-shaped body forming liquid is supplied onto the intaglio under a pressure environment of 0.05 MPa or less, the inside of the vacuum chamber is opened to the atmospheric pressure (0.1 MPa). In terms of production cost, it is preferable to dry the intaglio needle-shaped body forming liquid under atmospheric pressure.
In addition, for example, the vacuum chamber is set to a pressure environment of 0.04 MPa, the needle-shaped body forming liquid is supplied onto the intaglio plate, and then air is introduced into the vacuum chamber to set a pressure environment of 0.08 MPa, and the pressure of 0. It is also possible to dry and solidify the needle-shaped body forming liquid on the intaglio plate under a pressure environment of 08 MPa.
Further, for example, the vacuum chamber is set to a pressure environment of 0.04 MPa, the needle-shaped body forming liquid is supplied onto the intaglio plate, and then air is introduced into the vacuum chamber to set a pressure environment of 0.08 MPa, and then the pressure is reduced again. It is also possible to dry and solidify the needle-shaped body forming liquid on the intaglio plate under the pressure environment of 0.04 MPa.

As described above, the first acicular body forming liquid is filled and dried in the intaglio plate, and the first layer 21 of the acicular body is formed in the intaglio plate.

[Step of preparing second needle-shaped body forming liquid]
Next, the second needle-shaped body forming liquid 26 in which the second needle-shaped body forming material is dissolved or dispersed in the solvent is prepared. The second needle-shaped body forming material preferably contains a water-soluble polymer or polysaccharide.

Water-soluble polymers and polysaccharides include chitosan, chitosan succinamide, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), sodium chondroitin sulfate, curdlan, trehalose, sucrose, gelatin, collagen, pullulan, pectin, alginate. , Starch, methylcellulose, hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid-based polymer, polyacrylamide (PAM), polyethylene oxide (PEO), etc. can be used, but not limited thereto. Absent. Further, these materials may be mixed.

Among them, as the second needle-shaped body forming material, from among chitosan, chitosan succinamide, hydroxypropyl cellulose, carboxymethyl cellulose, sodium chondroitin sulfate, curdlan, trehalose, sucrose, gelatin, collagen, pullulan, pectin, and alginate. It is preferably selected. The reason is that it is biologically safe. Note that these materials may be mixed.

The second needle-shaped body forming liquid 26 becomes the first needle-shaped body forming liquid by being dissolved or dispersed in water or an aqueous solvent.
Further, in the second needle-shaped body forming liquid, a dissolution promoting substance may be added in order to dissolve the water-soluble polymer which is the needle-shaped body forming material in water which is the solvent. For example, when chitosan is used as the second needle-shaped body forming material, it is necessary to add an acid to the needle-shaped body forming liquid. The second needle-shaped body forming liquid preferably has such a fluidity that it can flow into the intaglio plate. In addition, it is preferable that the second needle-shaped body forming liquid has been defoamed in advance. The defoaming treatment can be performed by storing the second needle-shaped body forming liquid in a reduced pressure environment.

Further, in the present invention, the delivery product may be contained in the second needle-shaped body forming liquid. As the delivery material, those exemplified for the first needle-shaped body forming liquid can be used.

[Second supply step]
Next, the second needle-shaped body forming liquid 26 in which the second needle-shaped body forming material is dissolved or dispersed in the solvent and the intaglio 22 are placed in the vacuum chamber (FIG. 5( f )). The vacuum chamber is connected to a pump and evacuated. Next, after the inside of the vacuum chamber is under a reduced pressure environment, the first needle-shaped body forming liquid is supplied to the intaglio plate (FIG. 6(g)). The intaglio plate has a concave portion corresponding to the protrusion. In addition, the intaglio plate may be provided with a bank (projection part) 22 ′ for controlling the wetting and spreading of the acicular body forming liquid on the intaglio plate at the peripheral portion.

The viscosity of the second needle-shaped body forming liquid of the present invention is preferably in the range of 0.01 Pa·s or more and 100 Pa·s or less. The method for producing a needle-shaped structure according to the present invention is such that even when a needle-shaped structure forming liquid having a high viscosity in the range of 0.01 Pa·s or more and 100 Pa·s is used, the needle-shaped structure is formed to the tip of the concave portion of the intaglio plate. It is possible to fill the body forming liquid. That is, in the method for producing a needle-shaped structure of the present invention, when a needle-shaped structure forming liquid having a high viscosity within the range of 0.01 Pa·s or more and 100 Pa·s is used, an extremely high effect is exhibited. To be done.

[Second pressure changing step]
Next, the second needle-shaped body forming liquid 26 supplied to the intaglio plate is changed to a pressure environment higher than 0.05 MPa. In the present invention, the needle-shaped body forming liquid is supplied to the intaglio plate by supplying the needle-shaped body forming liquid to the intaglio plate in a pressure environment of 0.05 MPa or less and changing the pressure environment to a higher pressure environment than the supply step. The liquid is filled in the tip of the concave portion of the intaglio plate (FIG. 6(h)).
In the method for manufacturing a needle-shaped body of the present invention, after the needle-shaped body forming liquid is supplied onto the intaglio plate in a pressure environment of 0.05 MPa or less, air is introduced into the vacuum chamber, and the pressure environment of the drying step is set. By changing the pressure environment to a pressure environment higher than that under the pressure environment of the supply process and equal to or lower than the atmospheric pressure (0.1 MPa), the needle-shaped body forming liquid can be filled into the concave tip of the intaglio plate. By drying and solidifying the body-forming liquid, a needle-shaped body filled up to the tip of the protrusion can be prepared.
In the present invention, the amount of pressure change in the pressure change step is preferably in the range of 0.05 MPa or more and 0.1 MPa or less. If the amount of pressure change is less than 0.05 MPa, the degree of filling up to the tip of the concave portion of the intaglio plate may decrease. The higher the pressure change amount, the more preferable. However, when the amount of pressure change exceeds 1.0 MPa, the time required to reach the vacuum becomes too long, which may increase the manufacturing cost.
Moreover, in the needle-shaped structure manufacturing method of the present invention, it is preferable in terms of manufacturing control that the pressure after the pressure change in the pressure changing step is atmospheric pressure.

[Second drying step]
Next, the needle-shaped body forming liquid supplied on the intaglio plate is dried and solidified to form needle-shaped bodies. The intaglio can be dried by placing it in the environment of atmospheric pressure (0.1 MPa) and then placing the supplied needle-shaped body forming liquid 26 on the hot plate 25 (FIG. 7(i)). The heating temperature at the time of heating is preferably set to a temperature at which the acicular body forming liquid does not boil in order to avoid bubbles remaining in the acicular body. Therefore, when water is used as the solvent for the needle-shaped body forming liquid, the heating temperature is preferably in the range of 40°C or higher and 90°C or lower. The heating may be performed by any known heating means. In addition to the method of using a hot plate on which the intaglio plate to which the acicular body forming liquid is supplied is placed, the intaglio plate to which the acicular body forming liquid is supplied is heated in an oven The method of mounting in can be used. It is also possible to carry out the dry solidification at room temperature without heating.

In the method for manufacturing a needle-shaped body of the present invention, after the needle-shaped body forming liquid is supplied onto the intaglio under a pressure environment of 0.05 MPa or less, the inside of the vacuum chamber is opened to the atmospheric pressure (0.1 MPa). In terms of production cost, it is preferable to dry the intaglio needle-shaped body forming liquid under atmospheric pressure.
In addition, for example, the vacuum chamber is set to a pressure environment of 0.04 MPa, the needle-shaped body forming liquid is supplied onto the intaglio plate, and then air is introduced into the vacuum chamber to set a pressure environment of 0.08 MPa, and the pressure of 0. It is also possible to dry and solidify the needle-shaped body forming liquid on the intaglio plate under a pressure environment of 08 MPa.
Further, for example, the vacuum chamber is set to a pressure environment of 0.04 MPa, the needle-shaped body forming liquid is supplied onto the intaglio plate, and then air is introduced into the vacuum chamber to set a pressure environment of 0.08 MPa, and then the pressure is reduced again. It is also possible to dry and solidify the needle-shaped body forming liquid on the intaglio plate under the pressure environment of 0.04 MPa.

[Peeling process]
Next, the needle-shaped body 21 formed on the intaglio plate 22 is peeled off (FIG. 7(j)). As a peeling means, a known physical method of peeling an intaglio plate and a needle-shaped body can be adopted. Further, it is also possible to peel it off by a scientific method such as dissolving the intaglio plate. A needle-shaped body is manufactured by the above (FIG.7(k)).

8 and 9 are explanatory views of a modified example of the method for manufacturing a needle-shaped body of the present invention. The manufacturing method (modification) of the needle-shaped structure of the present invention includes the following steps after the second drying step.
[Punching process]
By the second drying step, the needle-shaped body formed on the intaglio plate is punched into a desired shape (FIGS. 8(l) and 8(m)). The punching can be performed using a punching blade such as Thomson blade 35. When punching, it is possible to punch together with the intaglio.

[Pasting process]
Next, the adhesive film 28 is attached to the back surface of the punched needle-shaped body (FIG. 9(n)). The adhesive film includes a film-shaped substrate 28B and an adhesive layer 28A. As the adhesive material, it is preferable to use an adhesive layer suitable for sticking to the skin, and one that can withstand the sterilization process can be used.

[Peeling process]
Next, the needle-shaped body formed on the intaglio plate 32 is peeled off (FIG. 9(o)). The needle-shaped body is integrally peeled off while being fixed to the adhesive material 28. A known mechanical peeling method can be adopted as the peeling means. Since the surface of the needle-shaped body on the side opposite to the surface on which the protrusion is formed is fixed to the adhesive layer of the adhesive film, it can be easily peeled off. By the above, the needle-shaped body with the adhesive material is manufactured (FIG. 9(p)). The needle-shaped body with the adhesive layer can be fixed as it is in the state where the needle-shaped body is punctured in the skin.

By using the method for manufacturing a needle-shaped body of the present invention, the needle-shaped body can be filled up to the tip without generating bubbles when filling the intaglio forming solution.

In addition, the structural example of the needle-shaped body produced by the present invention is shown.
The needle-shaped body forming material A and the needle-shaped body forming material B are different materials. Further, the delivered product X and the delivered product Y indicate different materials.
(Structure example 1)
First layer: needle-shaped body forming material A+delivery product X
Second layer: needle-shaped body forming material A
(Structure example 2)
First layer: needle-shaped body forming material A+delivery product X
Second layer: needle-shaped body forming material B
(Configuration example 3)
First layer: needle-shaped body forming material A+delivery product X
Second layer: needle-shaped body forming material A+delivery product Y
(Structure example 4)
First layer: needle-shaped body forming material A+delivery product X
Second layer: needle-shaped body forming material B+delivery product Y
(Structure example 5)
First layer: needle-shaped body forming material A
Second layer: needle-shaped body forming material A+delivery product X
(Structure example 6)
First layer: needle-shaped body forming material A
Second layer: needle-shaped body forming material B+delivery product X
(Structure example 7)
First layer: needle-shaped body forming material A+delivery product X
Second layer: needle-shaped body forming material B+delivery product X

As in the above configuration example, in the needle-shaped body of the present invention, the first layer and the second layer may be different needle-shaped body forming materials, or may be the same needle-shaped body forming material. Further, the delivery material may be contained in one of the first layer and the second layer, or may be contained in both the first layer and the second layer.

<Manufacture of needle-shaped original plate>
First, by using precision machining on a silicon substrate, 36 square needle-like original plates in which 6 square 6-row 6-row lattice-like regular quadrangles (height: 150 μm, bottom face: 60 μm×60 μm) are arranged at 1 mm intervals Formed.
<Manufacture of intaglio plate>
Next, a nickel film having a thickness of 500 μm is formed on the needle-shaped original plate formed of the silicon substrate by a plating method, and the silicon substrate is formed by heating at 90° C. and an aqueous potassium hydroxide solution having a weight percent concentration of 30%. It was removed by wet etching to form an intaglio plate made of nickel.
<Preparation of First Needle Forming Liquid>
Next, chitosan succinamide and Evans blue were dissolved in water to prepare a first acicular solution.
<First supply process>
Next, the intaglio plate was placed in a vacuum chamber and placed under a reduced pressure environment of 0.01 MPa.
Next, the first needle-shaped body forming liquid was supplied to the intaglio plate using a dispenser while maintaining the vacuum chamber under a reduced pressure environment.
<First pressure changing step>
Next, the chamber was opened to the atmosphere and returned to atmospheric pressure.
<Removal of unnecessary first acicular system liquid>
Next, the squeegee was used to remove the needle-shaped body forming liquid on the intaglio plate from the first plate.
<First drying step>
Next, the intaglio plate filled with the first acicular body forming aqueous solution was heated at 40° C. for 60 minutes using a heat source to dry and solidify the acicular body material. Here, a hot plate is used as the heat source.
<Preparation of Second Needle Forming Liquid>
Next, hydroxypropyl cellulose was dissolved in water to prepare a hydroxypropyl cellulose aqueous solution.
<Second supply process>
Next, the intaglio plate was placed in a vacuum chamber and placed under a reduced pressure environment of 0.01 MPa.
Next, the second needle-shaped body forming aqueous solution was supplied to the intaglio plate using a dispenser while maintaining the vacuum chamber under a reduced pressure environment.
<Second pressure changing step>
Next, the chamber was opened to the atmosphere and returned to atmospheric pressure.
<Second drying step>
Next, the intaglio plate filled with the acicular body forming aqueous solution was heated at 40° C. for 60 minutes using a heat source to dry and solidify the acicular body material. Here, a hot plate is used as the heat source.
<Punching process>
Next, the needle-shaped body formed on the intaglio plate was punched into a circle.
<Pasting process>
Next, a commercially available adhesive film was attached to the back surface of the needle-shaped body.
<Peeling process>
Next, the solidified needle-shaped body material was peeled from the intaglio plate to obtain a needle-shaped body.
By the above, a needle-shaped body was obtained.

[Confirmation experiment]
Observation with a microscope confirmed that the tip of the needle-shaped body had a sharp tip and the first needle-shaped body forming liquid was filled up to the tip of the concave portion of the intaglio plate.
Furthermore, it was confirmed that the color of Evans blue was concentrated on the upper part of the needle-shaped body.
Further, no bubbles were observed at the interface between the blue portion and the transparent portion at the tip of the needle-shaped body.

The needle-shaped body of the present invention can be used in various fields that require fine needle-shaped bodies. For example, application can be expected as a needle-shaped body used for MEMS devices, optical members, sample jigs, drug discovery, medical applications, cosmetics, beauty applications, and the like.

10... Needle-like body 11... Protrusion 11A... First layer 12... Support substrate 21... First needle-like body forming liquid (first layer)
22... Intaglio 22'... Bank 23... Vacuum chamber 23a... Pump 24... Squeegee 25... Hot plate 26... Second needle-shaped body forming liquid (second layer)
27... Thomson blade 28... Adhesive film 28A... Adhesive layer 28B... Substrate

Claims (10)

A method of manufacturing a needle-shaped body comprising a support substrate and a needle-shaped protrusion on one surface of the support substrate,
Depressurizing the chamber to a first depressurized environment,
First needle-like body formation in which a first needle-like body forming material is dissolved or dispersed in a solvent with respect to an intaglio plate provided with a concave portion corresponding to the protrusion in a chamber depressurized to the first depressurized environment. A first supply step of supplying a liquid,
A first pressure changing step of changing the first needle-shaped body forming liquid supplied to the intaglio plate to a pressure higher than the first depressurized environment;
After the first pressure changing step, in the chamber depressurized to the first depressurized environment again,
A first drying step of drying the needle-shaped body forming liquid supplied to the intaglio plate;
Depressurizing the chamber to a second depressurized environment,
A second needle-shaped body forming material is dissolved or dispersed in a solvent with respect to the intaglio filled and dried with the first needle-shaped body forming liquid in a chamber depressurized to the second depressurized environment. A second supply step of supplying the needle-shaped body forming liquid of
A second pressure changing step of changing the second needle-shaped body forming liquid supplied to the intaglio plate to a pressure higher than the second depressurized environment;
After the second pressure changing step, in the chamber depressurized to the second depressurized environment again,
A second drying step of drying the needle-shaped body forming liquid supplied to the intaglio plate into a needle-shaped body;
A peeling step of peeling the needle-shaped body from the intaglio plate, the method for manufacturing a needle-shaped body. The method for manufacturing a needle-shaped structure according to claim 1, wherein the amount of pressure change in the first pressure change step is in the range of 0.05 MPa or more and 0.10 MPa or less. The method for producing a needle-shaped structure according to claim 1, wherein the pressure after the pressure change in the first pressure change step is atmospheric pressure. The method for manufacturing a needle-shaped structure according to any one of claims 1 to 3, wherein the amount of pressure change in the second pressure change step is in the range of 0.05 MPa or more and 0.10 MPa or less. The method for manufacturing a needle-shaped structure according to any one of claims 1 to 4, wherein the pressure after the pressure change in the second pressure change step is atmospheric pressure. The pressure of the first reduced pressure environment and the pressure of the second reduced pressure environment are 0.04 MPa, The pressure after the pressure change in the first pressure change step and the pressure after the pressure change in the second pressure change step
The needle-shaped structure according to claim 1, wherein the pressure after the pressure change is 0.08 MPa.
Manufacturing method. The first acicular material is selected from chitosan, chitosan succinamide, hydroxypropyl cellulose, carboxymethyl cellulose, sodium chondroitin sulfate, curdlan, trehalose, sucrose, gelatin, collagen, pullulan, pectin, alginate. The method for manufacturing a needle-shaped structure according to any one of claims 1 to 6 , characterized in that. The method for producing a needle-shaped structure according to any one of claims 1 to 7 , wherein the first needle-shaped structure forming material contains a pharmacologically active substance or a cosmetic delivery product. The second acicular material is selected from chitosan, chitosan succinamide, hydroxypropyl cellulose, carboxymethyl cellulose, sodium chondroitin sulfate, curdlan, trehalose, sucrose, gelatin, collagen, pullulan, pectin, alginate. The method for manufacturing a needle-shaped structure according to any one of claims 1 to 8 , characterized in that. The method for producing a needle-shaped structure according to any one of claims 1 to 9 , wherein the second needle-shaped structure forming material contains a pharmacologically active substance or a cosmetic delivery product.

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