JP2011083387A - Method of manufacturing needle-shaped body, needle-shaped body and needle-shaped body holding sheet - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for reproducibly and accurately manufacturing a biocompatible needle-shaped body for treatment for directly injecting medical agent to an affected area. <P>SOLUTION: A mold 21 for molding the needle-shaped body is provided with a micropore 21a which is a reversal transcription of the shape of a needle-shaped body of a master mold which is formed by transcription of the master mold in reverse formed by a plurality of etching steps and is filled with a fused biocompatible material. After solidification of the biocompatible material, the mold 21 for molding the needle-shaped body is removed. In this way, a biosoluble needle-shaped body 22b having an end part which is tapered toward its tip and a support rod portion which continues into the end part and has the same diameter over its length or has the diameter gradually reduced in the length direction is manufactured. When the master mold is etched, the support rod in any fine shape is formed by the Bosch process. The end part can be sharpened by repeating forming and removing of silicon oxide films. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing a needle-shaped body that facilitates transdermal administration of a drug, a needle-shaped body, and a needle-shaped body holding sheet. More specifically, the present invention relates to a method for producing a needle-like body of a biocompatible material, a needle-like body, and a needle-like body holding sheet.

In recent years, as a method of administering a pharmaceutical product more safely and effectively while suppressing excessive administration and side effects of the pharmaceutical product, a micron-sized needle (microneedle) is directly injected into and retained in the affected area. A method has been devised. This method is characterized in that the drug is injected and retained directly in the affected area, so that the dosage efficiency is high and the influence of side effects is small.
The needle-like body used in such a treatment method is used by perforating the skin at the tip. Therefore, the needle-like body needs to have a sharp tip for piercing the skin, and needs a sufficient length (usually 100 μm or more) to supply the drug under the skin.

  As such a needle-like body, there is a silicon needle-like body, which is used by perforating the skin after applying a drug to its tip. For example, the silicon needle described in Patent Document 1 is an anisotropic wet etching using an etching rate difference for each crystal plane orientation of a single crystal material of a silicon wafer and an isotropic etching independent of the crystal plane orientation. The tip of the microneedle is sharpened by a method combining the above.

Silicon needles have the advantage of high hardness and high perforation to the skin, but there is a problem that if the tip is damaged after the skin is perforated, it remains in the body.
On the other hand, Patent Document 2 discloses the use of a biodegradable material that does not adversely affect the human body even if a damaged needle-like body remains in the body as the material of the needle-like body.
As another method for producing a needle-like body using a biodegradable material, there is a method of using a replica mold (mold) obtained by reversing and transferring a microneedle type patch having a desired shape (reversing and transferring the unevenness). . For example, in Patent Document 3, a silicon master mold is manufactured by anisotropic etching using the crystallinity of silicon, a replica mold is manufactured by metal plating, and the replica mold is in vivo. A method for producing a fine needle by embedding / releasing a soluble material is disclosed.

JP 2002-79499 A JP 2005-154321 A International Publication 2002/64193 Pamphlet

  By the way, a needle-like body using an in-vivo-soluble material has a lower hardness than a silicon needle-like body, and therefore often has insufficient piercing properties for the skin. Therefore, it is necessary to make the tip of the needle-like body sharper in order to improve the piercing property. However, in the conventional methods disclosed in Patent Document 2 and Patent Document 3, the tip of the needle-shaped body cannot be sufficiently sharpened, and a submillimeter-order needle-shaped drug cannot be manufactured.

  Further, in the transfer forming method of Patent Document 3, since a replica mold is manufactured by metal plating, it is necessary to melt a silicon needle-like body that is a master mold, and the manufacturing process is very complicated and expensive. It is difficult to produce. Also, in this method, the tip diameter of the manufactured needle-shaped (bullet-shaped) drug is as large as about 10 microns, and further, the structure expands as it goes to the support column of these drugs. Not only does it require high needle pressure, it can damage the skin more than necessary.

  Under such circumstances, an object of the present invention is to provide a method for producing a needle-like body and a needle-like shape that have high piercing properties against the skin, can easily control the tip angle and its height, and can be integrally molded with high accuracy. Is to provide a body.

The inventors have prepared a master mold that can be used repeatedly and a replica mold that can be used repeatedly by reversing the shape of the master mold, and using this replica mold, a needle-like body and a needle-like body having in-vivo compatibility It has been found that a holding sheet can be formed efficiently.
The inventors have found that an optimum shape of the needle-shaped body of the master mold can be obtained by a plurality of different etchings, and the present invention has been completed.

That is, the present invention relates to the following inventions.
<1> A method for producing an in vivo compatible needle having the following steps.
(1) An etching mask is formed at a predetermined position on a silicon wafer, and with the mask provided, a thinning toward the tip is performed by a Bosch process in which plasma etching and protective film formation by plasma deposition are alternately repeated. A first etching step of forming a tapered tapered tip, and a silicon needle-like body having a column having the same diameter in the longitudinal direction, or a column portion continuous with the tip, the diameter of which is reduced;
The mask is removed, the tip is etched with an etching solution and / or reactive radicals, and the formation of a silicon oxide film by thermal oxidation and the removal of the silicon oxide film with a hydrofluoric acid aqueous solution are repeatedly performed to form needles A step of manufacturing a master mold composed of a plurality of silicon needle-like bodies provided at a silicon base end including a second etching step for forming a body (2) using the master mold as a mold, A step of forming a needle-shaped body molding mold made of a flexible resin having fine holes obtained by reversing and transferring the shape of the needle-shaped body (3) In vivo compatibility with the mold for molding the needle-shaped body The step of filling the material, releasing the mold after forming the material into the shape of the micropore <2> The needle according to <1>, wherein the tip has a diameter of 3 μm or less A method of manufacturing a body.
<3> The method for producing an in vivo compatible needle-like body according to <1> or <2>, wherein in the step (1), the post part in the needle-like body is a post part having a diameter that decreases in the longitudinal direction. .
<4> The method for producing an in vivo compatible needle-like body according to any one of <1> to <3>, wherein the support in the needle-like body has one or more constrictions in the step (1). .
<5> The method for producing an in vivo compatible needle-like body according to any one of <1> to <4>, wherein in the step (2), the flexible resin is polydimethylsilane.
<6> The method for producing an in vivo compatible needle-like body according to any one of <1> to <5>, wherein in step (3), ultrasonic waves are applied.
<7> In the biocompatible acicular body according to any one of <1> to <6>, in the step (3), the material is melted under reduced pressure and filled into the needle-shaped mold. Production method.
<8> The method for producing an in vivo compatible needle-like body according to <7>, wherein in step (3), decompression and pressurization are repeated, and the in vivo compatible material is filled in the mold for needle-like body molding.
<9> The biocompatible needle according to any one of <1> to <8>, wherein in the step (3), the needle is molded by heating from the biocompatible material side to melt the needle-shaped mold. A method of manufacturing a body.
<10> A biocompatible acicular body produced by the method according to any one of <1> to <9>.
<11> The biocompatible needle according to <10>, comprising a drug component and a biosoluble polymer.
<12> A biocompatible needle-like body holding sheet in which one or more needle-like bodies according to the above <10> or <11> are held on at least one surface of a sheet-like support.

  According to the production method of the present invention, a submillimeter-order in vivo compatible needle-like body having high perforation properties for skin can be produced with high accuracy and good reproducibility. In addition, according to the production method of the present invention, a needle-like body in which the length, thickness, shape, and mixed drug can be freely selected can be obtained, so that the needle-like body can be applied to various disease treatments. Can do.

It is a schematic diagram (sectional drawing) for demonstrating the manufacturing process of the acicular body of a master mold in a process (1). It is an example (sectional drawing) of the master mold formed at the process (1). It is a schematic diagram (sectional drawing) for demonstrating the manufacturing process of the mold for acicular body formation in a process (2). It is a schematic diagram (cross-sectional view) of an acicular body manufacturing apparatus. It is a schematic diagram (sectional drawing) for demonstrating the manufacturing process of the acicular body in process (3), (a-1) and (a-2) are processes before embedding, (b) is embedding solidification. Step (c) is a peeling step. It is a perspective view of the biocompatible needlelike body (sheet shape) formed at the process (3). It is an example (cross-sectional view) of a biocompatible acicular body having a different shape. It is a photograph (one enlarged photograph) of a master mold in an example. It is an enlarged photograph of the front-end | tip part of a master mold in an Example. It is a photograph (one enlarged photograph) of the mold for needle-shaped medicine formation in an example. It is a photograph of a biocompatible acicular medicine array in an example. It is a photograph (one enlarged photograph) of a biocompatible acicular medicine in an example.

Hereinafter, the present invention will be described in detail.
The present invention relates to a method for producing an in vivo compatible needle-like body (hereinafter referred to as “the production method of the present invention”) having the following steps.
(1) An etching mask is formed at a predetermined position on a silicon wafer, and with the mask provided, a thinning toward the tip is performed by a Bosch process in which plasma etching and protective film formation by plasma deposition are alternately repeated. A first etching step of forming a tapered tapered tip, and a silicon needle-like body having a column having the same diameter in the longitudinal direction, or a column portion continuous with the tip, the diameter of which is reduced;
The mask is removed, the tip is etched with an etching solution and / or reactive radicals, and the formation of a silicon oxide film by thermal oxidation and the removal of the silicon oxide film with a hydrofluoric acid aqueous solution are repeatedly performed to form needles A second etching step for forming a body;
(2) A fine hole obtained by reversing and transferring the shape of the needle-shaped body of the master mold using the master mold as a mold A step of forming a mold for molding an in vivo compatible needle-shaped body made of a resin having flexibility (3) filling the mold for needle-shaped body molding with a biocompatible material; A step of releasing after forming into the shape of the fine hole

  Each of the steps (1) to (3) will be described in detail with reference to the drawings.

Fig.1 (a)-(e) is a schematic diagram (sectional drawing) for demonstrating the manufacturing process of the acicular body of a master mold in a process (1).
In this process, a silicon wafer is etched in a predetermined step to form a master mold composed of a plurality of silicon needles provided at the silicon base end. In addition, the shape of the needle-shaped body of the master mold produced in the step (1) is transferred to the biocompatible needle-shaped body that is the final product.
In the manufacturing method of the present invention, the silicon master mold formed in the step (1) is used as a mold in the step (2) and can be reused as long as it is not damaged.
Hereinafter, the first etching step and the second etching step in step (1) will be described.

(I) First Etching Step In the first etching step, an etching mask is formed at a predetermined position on the silicon wafer where the silicon needles are formed, and plasma etching (reaction is performed with the mask provided. The same as the longitudinal direction leading to the tip by a Bosch process that alternately repeats plasma deposition and protective film formation by plasma deposition. This is a step of forming a silicon needle-like body having a diameter or a column portion with a reduced diameter.
Here, the “Bosch process” is referred to as a reactive ion etching apparatus using inductively coupled plasma (hereinafter, referred to as “ICP-RIE apparatus”) as disclosed in, for example, US Pat. No. 5,501,893. ) Alternately using a plasma etching process using an etching gas such as SF ₆ and a plasma deposition process using a protective film forming gas such as C ₄ F _{8 to} deposit a fluorocarbon polymer as a protective film. By repeating this process, high-speed anisotropic etching of silicon is possible.

  In step (1), as shown in FIG. 1A, a mask 2 is provided so as to correspond to a predetermined portion of the silicon wafer 1. As will be described later, a silicon needle is formed below the mask 2.

  As the silicon wafer to be the substrate, any of single crystal silicon, polycrystalline silicon, and amorphous silicon can be used. However, the shape of the silicon needle is highly reproducible, and the tip is sharpened. Single crystal silicon that can be used is preferably used.

The mask 2 is not particularly limited as long as it is not etched in the first etching step, and an organic thin film such as a photoresist, a silicon oxide thin film, a silicon nitride thin film, various metal thin films, and a laminated film of these thin films are used.
In particular, it is preferable to form a mask pattern by a photolithography method because a high-accuracy mask can be formed by performing patterning according to the thickness and density of the needle-like body to be formed and processing silicon to be a fine needle.

The shape of the mask is not particularly limited, but since the shape of the mask affects the cross-sectional shape of the needle-like body formed in the lower part thereof, a circular shape is preferable, and the formed needle-like body has sufficient mechanical strength. A suitable diameter for having is 50 to 300 μm. The density of the mask 2 is that of a silicon needle, and is preferably 0.5 to 50 pieces / 5 mm ² .

  Next, as shown in FIG. 1B, isotropic etching is performed on the silicon wafer 1 by plasma etching (reactive radical etching) with the above-described mask 2 provided. The tip 3 is formed. Note that plasma etching (reactive radical etching) is suitable for this step because it has a feature that silicon can be etched at a high speed.

In the first etching step, the shape of the support column connected to the tip portion of the needle-shaped protrusion of the master mold is arbitrarily controlled by controlling the gas species, reaction vessel pressure, energy for gas decomposition, and substrate bias at high speed. Examples of the etching gas for the silicon wafer 1 that can be formed include SF ₆ and CF ₄ , and SF ₆ is preferably used. The flow rate of the reaction gas introduced into the apparatus is about 100 to 1000 sccm, the plasma pressure (the pressure in the chamber of the etching gas) is about 3.0 to 200 Pa, and the plasma output is about 500 to 1000 W. Moreover, although the temperature conditions of plasma processing can be set arbitrarily, it is 10-40 degreeC normally.
Under the above etching conditions, for example, isotropic etching is performed from the surface of the silicon wafer 1 over a depth of about 10 to 50 μm and a width of about 5 to 50 μm to form a certain needle shape at the tip.

Next, as shown in FIG. 1C, a protective film 3b is deposited on the side wall (inner wall) surface of the etched portion by plasma deposition using a side wall protective film forming gas. Examples of the sidewall protective film forming gas include C ₄ F _8, and the protective film 3b made of a fluorocarbon polymer is formed by depositing these sidewall protective film forming gases. The flow rate of the reaction gas introduced into the apparatus is about 50 to 500 sccm, the plasma pressure (the pressure in the chamber of the protective film forming gas) is about 3.0 to 200 Pa, and the plasma output is about 500 to 1000 W. Moreover, although the temperature conditions of plasma processing can be set arbitrarily, it is 10-40 degreeC normally.
Under the above-described protective film formation conditions, a protective film 3b having a thickness of, for example, 10 to 50 nm can be formed from the surface of the silicon wafer 1.

  By alternately repeating the above-described plasma etching and plasma deposition, as shown in FIG. 1D, for example, a needle-like body having a predetermined shape with a height of about 100 to 600 μm of the support column 4 is formed.

  Here, one of the features of the method of the present invention is to control the plasma etching and plasma deposition conditions such as the above-mentioned gas species and their pressure, reaction vessel pressure, energy for gas decomposition, substrate bias, etc. It exists in that the shape of the support | pillar part 4 can be made into arbitrary shapes. In particular, it is preferable to change the time of plasma etching and plasma deposition. For example, in order to make the support column 4 have the same diameter in the longitudinal direction, the plasma etching and plasma deposition are performed within 1 to 3 seconds. And may be performed under the condition that these are repeated alternately.

(Ii) Second etching step The second etching step further includes the step of etching the tip with an etchant and / or reactive radicals after removing the etching mask, and then forming a silicon oxide film by thermal oxidation. And the process of repeatedly removing the silicon oxide film with a hydrofluoric acid aqueous solution.

  As shown in FIG. 1 (d), the tip of the silicon needle formed by the first etching step is not completely sharp because it is covered with an etching mask. Therefore, the tip of the silicon needle formed by the first etching step is made to have an acute angle by the second etching step.

The method for removing the etching mask is performed in a solution so that the formed silicon needle-shaped body is not damaged. A suitable example of the etching mask removing liquid is H ₂ SO ₄ / H ₂ O ₂ / H ₂ O, and the mixing volume ratio is about 3 to 9: 3: 1.

  After removing the mask, the tip of the silicon needle is isotropically etched with an etchant and / or reactive radicals.

  Examples of the etching solution include acid and alkali etching solutions, and a mixed solution of hydrofluoric acid and nitric acid can be exemplified as a suitable etching solution. The solution composition is preferably about hydrofluoric acid: nitric acid = 1: 100 to 1: 1. Although it depends on the solution composition, the temperature and time suitable for etching with an etching solution are usually 10 to 20 ° C. and 1 to 10 minutes, respectively. Moreover, it is preferable to perform the rinse with a pure water after a process.

Etching with reactive radicals can be performed under the same conditions as in the first etching step using the ICP-RIE apparatus.
As specific conditions, SF ₆ gas flow rate: 600 sccm, pressure: 100 Pa, plasma power: 600 W, etching time: 1 minute can be exemplified.

  Next, formation of a silicon oxide film by thermal oxidation and removal of the silicon oxide film by a hydrofluoric acid aqueous solution are performed on the sharpened needle-like tip by isotropic etching with the etching solution and / or reactive radical. By repeating the process, the tip portion is further sharpened.

The method for forming silicon oxide is not particularly limited, but is preferably performed by so-called wet oxidation using water vapor, and the temperature for forming silicon oxide in that case is about 900 to 1100 ° C. Silicon oxide is removed by immersing the tip of the needle-like body in a hydrofluoric acid aqueous solution, and the reaction temperature and time are preferably 10 to 20 ° C. and 5 to 20 minutes, respectively.
By repeating these steps about 1 to 10 times, it is possible to obtain a needle-like body having an acute tip whose diameter at the tip is 3 μm or less (preferably 1 μm or less). Note that the diameter of the tip can be determined from the SEM photograph of the tip.
By using a master mold having such a tip diameter, an in vivo compatible needle-like body with particularly excellent piercing properties can be obtained as a final product. When the diameter of the tip part in the master mold exceeds 3 μm, the piercing property of the needle-like body as the final product may be insufficient. The lower limit of the diameter of the tip is not particularly limited, and can be produced up to several nanometers in diameter by the Bosch process, but is usually 10 nm or more in consideration of mechanical strength and the like.

  Examples of different master molds formed in this step (1) are shown in FIGS. These master molds are obtained by changing the shape of the support column by making the plasma etching and plasma deposition conditions in the first etching process appropriate.

FIG. 2 (a) is an example in which, in the master mold, the support column 14A connected to the tip 13A has the same diameter in the longitudinal direction.
FIG. 2B shows an example in which the column portion 14B connected to the distal end portion 13B has a smaller diameter along the longitudinal direction (toward the proximal end portion 15B).
As shown in FIG. 2 (b), in order to reduce the diameter of the support portion 14B in the longitudinal direction, the plasma etching is performed for 3 seconds or longer under the above plasma etching and plasma deposition conditions. Just do it.
As will be described in detail later, the final biocompatible needle that has been transferred to such a shape is easily broken in the vicinity of the proximal end, so as a biocompatible material, biodegradability and biosolubility By using this material, it can be suitably used as a drug delivery drug. When used for such a purpose, it is preferable that the maximum diameter of the support portion 14B (joint portion between the tip portion 13B and the support portion 14B) is 50 to 300 μm. The minimum diameter of the post portion (connecting portion between the pillar portion 14B and the support portion 15B) is 90% of the maximum diameter D ₂ less (preferably, 80% or less) is preferably.

2 (c) and 2 (d) are modified examples of FIG. 2 (a), and an example in which a column portion connected to the tip portion has one or more constrictions.
By using such a master mold, it is possible to obtain a needle-like body made of a biocompatible material having a constricted shape as described later. The needle-like body can be easily broken from the constriction, and there is an advantage that the needle-like body made of the broken biocompatible material can be effectively stopped at the affected part.
In the case of FIG. 2C, specific conditions for forming such a master mold are as follows. First, plasma etching and plasma deposition are performed within 1 to 3 seconds as in FIG. 2A. Repeat alternately. When the etching proceeds to a predetermined position, the constricted portion is produced by performing the plasma etching for a long time of 20 to 50 seconds. Thereafter, it can be produced by returning to the original etching conditions. In the case of FIG. 2 (d), plasma etching and plasma deposition are alternately repeated as in FIG. 2 (a). At that time, by increasing the plasma etching time to 5 to 20 seconds, the needle with severe irregularities is formed. Can be made.

Next, process (2) is demonstrated.
In the step (2), the master mold formed in the step (1) is used as a mold, and a needle-shaped body made of a flexible resin is provided with fine holes obtained by reversing and transferring the shape of the needle-shaped body of the master mold. This is a step of forming a mold for use. In the step (2), by using the high-precision master mold obtained in the step (1), high accuracy of the needle-shaped body molding mold formed by reversing and transferring the master mold is realized. .

  The resin having flexibility is not particularly limited as long as it has good releasability from the master mold and has appropriate mechanical strength. Specifically, a silicon resin can be cited, and in particular, polydimethylsilane (PDMS) or a silicon resin mainly composed of PDMS has a groove structure on the side surface as shown in FIGS. 2 (c) and 2 (d). A certain master mold is preferable because it can be removed.

  As a method of forming a resin having flexibility, a method of releasing a master mold after pouring a thermosetting resin into a master mold and heating it to an appropriate temperature, or a molten resin as shown in FIG. And a method of embedding the master mold in a molten resin and then cooling to release the master mold.

Step (3) is a step of embedding a biocompatible material into the needle-shaped body molding mold prepared in step (2), and molding the material into the shape of the fine holes, and then releasing the mold.
In this step, the needle-like body molding mold can be reversely transferred, that is, a needle-like body to which the master mold is transferred can be formed.

The biocompatible needle-like body refers to a needle made of a material that is compatible with the living body, and includes a concept including a case where a target drug component is added to the biocompatible material. In the present invention, the “in-vivo compatible material” may be any material that can coexist with the living body while performing its original function without giving adverse effects or strong stimulation to the living body for a long period of time, and has in-vivo solubility. It includes not only materials but also materials that do not have in vivo solubility.
Examples of a method for imparting a drug component to a biocompatible material include (1) a method of kneading a biocompatible material and a drug component to form a needle, and (2) a drug on a needle of the biocompatible material. Examples include a method of coating the components. In addition, after puncturing the skin with a needle-like body made of a biocompatible material that does not dissolve in the living body, the needle-like body or the needle-like body holding sheet is removed, and a drug component is separately administered (for example, containing a drug) According to the method of applying a patch, it is not always necessary to add a drug component to the needle of the biocompatible material.

  The drug component may be any drug that has an imparting property to in-vivo compatible materials, and the skin is made of a drug having a molecular weight of 500 or more, a water-soluble drug, or a transdermal absorbent that is difficult to permeate the skin with a transdermal absorbent. Examples include drugs that exhibit irritation. These may be used alone or in combination of two or more. Of these, the needles of the present invention include vaccines, anticancer agents, antibody drugs and the like currently administered as injections from the viewpoint that administration by patients themselves is possible even if they are not medical personnel. It can be suitably used as a pharmaceutical ingredient.

  Specific examples of biocompatible materials include polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, polycaprolactone, polycarbonate, nylon, polyvinyl alcohol, silicone, polyester, polyurethane, polyethylene, polyethylene terephthalate, polystyrene, and polypropylene. , Synthetic polymers such as polytetrafluoroethylene, polymethyl methacrylate, poly 2-hydroxyethyl methacrylate, various proteins such as collagen, gelatin, albumin, cellulose, amylose, dextran, chitin, chitosan, hyaluronic acid Mention may be made of natural polymers such as sugars. Among these, polylactic acid having high mechanical strength and high solubility in vivo is particularly preferable. These may be used alone or in combination of two or more.

Next, based on FIG.4 and FIG.5, the manufacturing process of the biocompatible acicular body which concerns on embodiment of this invention is demonstrated.
As shown in FIG. 4, in the needle-like body manufacturing apparatus 20 according to the embodiment of the present invention, the container 20a supplies nitrogen, air, or the like from the gas supply port 20b, and a gas discharge port 20c by an exhaust pump (not shown). By evacuating, the internal pressure can be adjusted, and the internal temperature can be adjusted by the heating heater 20d provided in the upper part of the container. And in the lower part of the container 20a, it arrange | positions at the cooling stand 20g provided with the refrigerant | coolant supply pipe | tube 20e and the refrigerant | coolant discharge pipe 20f, and the ultrasonic applicator 20h is provided under the cooling pedestal 20g. The needle-shaped body molding mold 22 is disposed on the cooling table 20g, and the temperature can be controlled by the heater 20d and the cooling table 20g.

  FIG. 5 is a schematic diagram for explaining a manufacturing process of the needle-shaped body. First, as a pre-implantation process, after the liquid biocompatible material 24a is melted to an appropriate temperature, the fine holes of the mold 21 for forming the needle-like body are discharged from a nozzle 23 such as a hot melt gun or a dispenser. 5a (FIG. 5 (a-1)), or the solid in-vivo compatible material 24b is finely arranged to raise the temperature of the mold 21 for forming the needle-like body (FIG. 5 (a-2)). Then, the in-vivo compatible material is filled in the fine hole 21a of the needle-shaped mold 21. Next, the needle-like body molding mold 21 is cooled as an embedding and solidifying step to obtain a solidified biocompatible needle-like body 22a (FIG. 5B). Finally, by removing the needle-shaped body molding mold 21 as a peeling step, an in-vivo compatible needle-shaped body 22b in which the shape of the needle-shaped body molding mold 21 is reversely transferred can be obtained (FIG. 5C). ). In addition, by irradiating the ultrasonic wave with the ultrasonic applicator 20h, the melted biocompatible material can be suitably filled in the needle-shaped mold 21.

  In addition, the groove | channel of the mold for needle-shaped object shaping | molding which reversely transferred the shape of the needle-shaped object in a master mold as mentioned above is about 50-300 micrometers in diameter, Furthermore, an entrance is narrow and an aspect ratio is large. Therefore, depending on the type of biocompatible material, even if you try to put it in the groove, the internal bubbles may not be removed, and bubbles may remain inside the final needle or the shape of the needle May be incomplete.

Therefore, it is preferable to melt the biocompatible material under reduced pressure (see FIGS. 4 and 5) and fill the micropores of the needle-shaped body molding mold, It is preferable to fill the material into the mold for forming a needle-like body. By performing such an operation, the molten biocompatible material can be suitably filled into the micropores of the needle-shaped body molding mold. The decompression / pressurization conditions are not particularly limited as long as the melted biocompatible material can be suitably filled into the micropores of the needle-shaped body molding mold, but the preferred decompression conditions are about 1 Pa. The condition is about 10 ⁶ Pa.
As described above, combining with ultrasonic irradiation further improves the filling property of the biocompatible material into the needle-shaped mold.

  In addition, when the biocompatible material is melted, the needle-like body is separated by heating from the material side with a heater, an infrared lamp, etc., and cooling the back surface of the mold for molding the needle-like body (see FIGS. 4 and 5). Not only can the molding time be shortened, but it is possible to repeatedly use the mold for forming the needle-like body.

  Hereinafter, the formed biocompatible needle will be described. The needle-shaped body of the present invention can be manufactured with good reproducibility, particularly by employing the above-described method for manufacturing the needle-shaped body of the present invention.

The biocompatible acicular body produced by the production method of the present invention is generally in the form of a sheet in which a plurality of acicular bodies are connected as shown in FIG.
This sheet-like needle-like body may be used as it is as a needle-like body holding sheet depending on the application, or each needle-like body may be folded and used as a single needle-like body.
Moreover, after making it a single acicular body, it can also be affixed on a suitable sheet | seat and can also be used as a acicular body holding sheet.

  FIGS. 7A to 7D are cross-sectional views of one needle-like body, each of which has a different shape of the support column. These needle-shaped bodies can be formed using a mold for needle-shaped molding obtained by reversing and transferring the master mold illustrated in FIGS.

The needle-shaped body 30 (FIG. 7A) is an example in which the support column portion 34 connected to the distal end portion 33 has the same diameter in the longitudinal direction. The diameter D ₁ of the column 34 is about 50 to 300 μm. The length L ₁ of the distal portion 33 is about 50 to 200 [mu] m, the length L ₂ of the struts 34, the diameter D ₁ of the length L ₁ and struts 34 of the distal portion 33 is about 200~800μm is The most distal end 33a of the distal end portion 33 is arbitrarily determined within a range having a projecting hole property.
When the diameter of the tip portion is 3 μm or less, the length L ₁ of the tip portion 33 is preferably 50 to 200 μm, and the diameter D ₁ of the column portion 34 is preferably 50 to 300 μm.
L _{2 of the} column part 34 is arbitrary depending on its application, and the length in the longitudinal direction is usually 200 to 1000 μm.

The needle-like body 40 (FIG. 7B) is an example in which the diameter of the support portion 44 decreases in the longitudinal direction, and the maximum diameter D ₂ (the tip portion 43 and the support portion is perpendicular to the longitudinal direction of the support portion 44. The diameter of the seam of 44 is about 50 to 300 μm, and the minimum diameter D ₃ (the seam between the support 44 and the base end 45) is determined in a range smaller than the maximum diameter D ₂ , and preferably about 30 to 70 μm. It is. In the column part 44 having such a shape, it can be easily broken from the joint between the column part 44 and the base end part 45, and the needle-like body can be stopped at the affected part after perforation. Moreover, it can use suitably as a drug delivery type | mold medicine by using as a biocompatible acicular body as a biodegradable material. Note that the length L ₁ of the tip and the length L ₂ of the column are the same as those of the needle-like body 30.

The needle-like body 50 (FIG. 7C) is a modification of the needle-like body 30 and is an example in which the column portion 54 connected to the tip portion has one constriction 54a. The needle-like body can be easily broken from the constriction, and the same effect as the needle-like body 40 can be expected.
The needle-like body 60 (FIG. 7D) is another modification of the needle-like body 30, and the column portion 64 connected to the tip portion has a plurality of constrictions 64a. The presence of the protrusions 64b formed by the plurality of constrictions 64a has an advantage that the tip of the biocompatible needle-like body can be broken after perforation to effectively stop the drug at the affected part.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

Step (1): Production of Master Mold An etching apparatus (model number: 800iPB) manufactured by Samco Corporation was used.
As a first etching step, steam oxidation at 1050 ° C. was performed on a single crystal Si substrate having a thickness of about 700 μm to form a silicon oxide film having a thickness of about 300 nm on the surface of the Si substrate. Next, in order to pattern the formed silicon oxide film, a pattern having a diameter of 100 μm is produced using a photoresist having a thickness of about 3 μm (manufactured by Rohm and Haas, model number: S800) to a density of 36/5 mm ^2. did. After creating the photoresist pattern, the silicon oxide film was removed with a 5% HF aqueous solution to complete an etching mask. The etching mask was a two-layer film of photoresist (3 μm) / silicon oxide film (300 nm). Subsequently, needles were produced using the Bosch process.

The conditions of the Bosch process are as follows.
(Plasma etching conditions)
Etching gas: SF ₆
Gas flow rate: 300sccm
Plasma pressure (etching gas chamber pressure): 100 Pa
Plasma output: 500W
Temperature: Room temperature (Plasma deposition condition)
Side wall protective film forming gas: C ₄ F ₈
Gas flow rate: 200sccm
Plasma pressure (pressure inside protective film forming chamber): 100 Pa
Plasma output: 500W
Temperature: Room temperature The tip portion was prepared by fixing the plasma deposition time to 2 seconds and changing the plasma etching time to 30, 20, 15, 10, 5, 3, 2 seconds. The longitudinal portion was repeatedly performed until the plasma etching time and the plasma position time were fixed at 2 seconds and reached a predetermined length.

Next, as a second etching step, the etching mask was removed with a 5% HF aqueous solution and then sharpened by thermal oxidation and removal of the silicon oxide film. Thermal oxidation was performed using steam gas at 1000 ° C. for 1 hour. The removal of the silicon oxide film was performed by immersing in a 5% HF aqueous solution for 10 minutes. This process was repeated 10 times to sharpen.
FIG. 8 shows a photograph of the master mold produced (one enlarged photograph), and FIG. 9 shows an enlarged photograph of the tip of the master mold. The diameter of the tip was 1 μm or less (average value).

Step (2): Production of mold for needle-like body molding PDMS (manufactured by Shin-Etsu Chemical Co., Ltd., main agent: KE-1310ST, curing agent: CAT1310S) was poured at room temperature with the needle of the master mold facing up. Then, it was made to dry in air | atmosphere for 12 hours, the master mold was peeled, and the mold for needle-shaped object shaping | molding was produced.
FIG. 9 shows a cross-sectional photograph (one enlarged photograph) of the produced mold for needle-like body molding.

Step (3): Production of needle-shaped body Using the needle-shaped body manufacturing apparatus having the configuration shown in FIG. 4, a biocompatible material was embedded in the mold for needle-shaped body molding under the following conditions.
Biocompatible material: Polylactic acid (Wako Pure Chemical Industries, Ltd. L-PLA-0020)

Degree of vacuum: 10Pa
Temperature: 240 ° C
Time: 60min
Thereafter, natural cooling was performed to solidify the biocompatible material, and then release was performed.
FIG. 11 shows a photograph of the biocompatible needle-shaped drug array produced, and FIG. 12 shows a photograph of the needle-shaped drug (one enlarged photograph).

Drug administration Drug: Ifenprodil tartrate The skin at the administration site is punctured with a needle-like body. After the puncture, the needle is removed from the skin.
A solution obtained by dissolving ifenprodil tartrate in a 20% aqueous solution of ethanol to make 5% is soaked in absorbent cotton and affixed to the skin to which needles are applied.

  According to the manufacturing method of the present invention, it is possible to manufacture a needle-like body for performing treatment by directly implanting a drug into an affected area with high reproducibility and high accuracy. Therefore, the technology of the present invention can be used for a medication that is difficult to administer so far and that has few side effects.

DESCRIPTION OF SYMBOLS 1 Silicon wafer 2 Etching mask 3 Front-end | tip part 3a The most advanced 3b protective film 4 Support | pillar part 5 Base end part 10A, 10B, 10C, 10D Master mold 11A, 11B, 11C, 11D Needle-like body 12A, 12B, 12C, 12D cutting edge 13A, 13B, 13C, 13D tip 14A, 14B, 14C, 14D column 15A, 15B, 15C, 15D base end 16C, 16D constriction 17D protrusion 20 needle body manufacturing apparatus 20a container 20b gas Supply port 20c Gas discharge port 20d Heater 20e Refrigerant supply tube 20f Refrigerant discharge tube 20g Cooling stand 20h Ultrasonic applicator 21 Needle-shaped molding mold 21a Micro hole 22 In vivo compatible needle 22a Solidified biocompatible needle 22b (Biocompatible) Needle-like body 23 Nozzle 24a Liquid living body Internal compatible material 24b Solid biocompatible material 30, 40, 50, 60 (Biocompatible) Needle-shaped body 33, 43, 53, 63 Tip 33a, 43a, 53a, 63a The most advanced tip 34 , 44, 54, 64 Prop section 35, 45, 55, 65 Base end 54a, 64a Constriction 64b Projection

Claims (12)

A method for producing an in vivo compatible needle-like body, comprising the following steps.
(1) An etching mask is formed at a predetermined position on a silicon wafer, and with the mask provided, a thinning toward the tip is performed by a Bosch process in which plasma etching and protective film formation by plasma deposition are alternately repeated. A first etching step of forming a tapered tapered tip, and a silicon needle-like body having a column having the same diameter in the longitudinal direction, or a column portion continuous with the tip, the diameter of which is reduced;
The mask is removed, the tip is etched with an etching solution and / or reactive radicals, and the formation of a silicon oxide film by thermal oxidation and the removal of the silicon oxide film with a hydrofluoric acid aqueous solution are repeatedly performed to form needles A second etching step for forming a body;
(2) A fine hole obtained by reversing and transferring the shape of the needle-shaped body of the master mold using the master mold as a mold (3) forming a needle-shaped body molding mold made of a flexible resin, and filling the needle-shaped body molding mold with a biocompatible material; Process of releasing after forming into shape   The method for manufacturing a needle-shaped body according to claim 1, wherein the tip has a diameter of 3 µm or less.   The method for manufacturing a needle-shaped body according to claim 1 or 2, wherein in the step (1), the strut portion in the needle-shaped body is a strut portion whose diameter decreases in the longitudinal direction.   The method of manufacturing a needle-like body according to any one of claims 1 to 3, wherein in the step (1), the support portion in the needle-like body has one or more constrictions.   The method for producing a needle-like body according to any one of claims 1 to 4, wherein in the step (2), the flexible resin is polydimethylsilane.   6. The method for producing a needle-like body according to any one of 1 to 5, wherein in the step (3), an ultrasonic wave is irradiated when filling the biocompatible material.   The method for producing a needlelike object according to any one of claims 1 to 6, wherein in the step (3), the material is melted under reduced pressure and filled into the mold for needlelike object molding.   The method for manufacturing a needle-shaped body according to claim 7, wherein in the step (3), pressure reduction and pressurization are repeated to fill the mold for needle-shaped body molding.   In the step (3), the needle-shaped body is manufactured by heating from the side of the needle-shaped body to melt and filling the material into a mold for forming the needle-shaped body. Method.   An in vivo compatible needle-like body produced by the method according to any one of claims 1 to 8.   The in vivo soluble needle according to claim 10, comprising a drug component and an in vivo soluble material.   A needle-shaped object holding sheet comprising one or more needle-shaped objects according to claim 10 or 11 held on at least one surface of a sheet-shaped support.