JP4888018B2 - Needle-like body manufacturing method and needle-like body - Google Patents

Description

  The present invention relates to a method for producing a fine needle-like body and a needle-like body.

  The percutaneous absorption method, which is a method of infiltrating a drug from the skin and administering the drug into the body, is used as a method that can be easily administered without causing pain to the human body. There are drugs that are difficult to administer by transdermal absorption. As a method for efficiently absorbing these drugs into the body, attention has been focused on a method of perforating the skin using an infinite number of micron-order needles (also referred to as microneedles) and administering the drug directly into the skin. According to this method, it is possible to easily administer a drug subcutaneously without using a special medication device (see Patent Document 1).

  The shape of the needle-like body used at this time is required to have a sufficient fineness and tip angle for piercing the skin, and a sufficient length for allowing the drug solution to penetrate subcutaneously. The diameter of the body is several μm to 100 μm, and the length of the acicular body is the length that penetrates the stratum corneum, which is the outermost layer of the skin, and does not reach the nerve layer, specifically about several tens μm to several hundred μm. It is considered desirable. In addition, the material constituting the needle-shaped body must be a material that does not adversely affect the human body even if the damaged needle-shaped body remains in the body. Biodegradable materials such as maltose, polylactic acid, and dextran are considered promising (see Patent Document 2).

  In order to produce such a fine structure at a low cost and in large quantities, a transfer molding method represented by an injection molding method, an imprinting method, a casting method, etc. is effective. However, in any method, molding is performed. Requires a mold with the desired shape reversed, and has a high aspect ratio (height or depth ratio to the diameter of the structure) like a needle-like structure, and the tip of the needle-like structure In order to form a structure that requires sharpening, the manufacturing process becomes very complicated.

  As this acicular structure manufacturing method, for example, the tip of the acicular structure is sharpened by performing anisotropic wet etching using an etching rate difference for each crystal plane orientation of a single crystal material such as a silicon wafer. Although realized, in order to obtain a high-aspect-ratio needle-like structure shape, steps such as dicing with high-precision alignment, formation of a needle-like structure side wall protective film, and various chemical treatments are required. Further, sharpening of the tip portion requires strict time control of anisotropic wet etching, and advanced processing technology is required for each process (see Patent Document 3).

  Also, a method of controlling the tip angle of the needle-like structure by performing exposure while moving the exposure mask and changing the exposure amount (see Patent Document 4), or a method of combining wet etching using a chemical solution and plasma etching Various methods have been devised such as (see Patent Document 5).

Patent documents etc. are as follows.
US Pat. No. 6,183,434 JP 2005-154321 A JP 2002-79499 A JP 2005-246595 A JP 2002-239014 A

  When the needle-like body is formed with a uniform taper angle, the needle-like body has a pyramid or conical shape. Therefore, when one of the needle length and the tip angle is determined, the other value is also determined. However, as described above, the length of the needle-shaped body should be determined from the viewpoint of the drug supply efficiency and the pain of the subject, and the tip angle of the needle-shaped body is determined by the penetration of the skin and the strength of the needle-shaped body. It must be. Therefore, it is desirable that the needle-like body has a desired tip angle and has a desired length regardless of the tip angle.

  In addition, when the needle-shaped mold is formed at once by etching, the aspect ratio of the pattern corresponding to the body of the needle-shaped body becomes very high, so ions and radicals that contribute to the etching of the substrate are caused by the tip of the needle-shaped body. It is difficult to reach the pattern corresponding to the part (hereinafter referred to as a loading effect). For this reason, it is difficult to sharpen the tip.

  Further, in the conventional method for manufacturing a needle-like body having an exposure step, alignment (hereinafter referred to as alignment) between the exposure mask and the substrate is highly necessary. In particular, when manufacturing a structure in which needle-like bodies are arranged in an array, a desired structure cannot be obtained with a slight misalignment.

  Accordingly, the present invention has been made to solve the above-described problem, and a method for manufacturing a needle-like body that can easily control the tip angle and its height and can be integrally formed in an array with high accuracy. And it aims at providing a needle-shaped object.

The present invention according to claim 1 is a method of manufacturing a fine needle-like body having a needle shape having a tip portion and a column portion aligned with the tip portion, the substrate having a light shielding layer and a transmission layer, Etching the transmission layer from the light shielding layer side of the substrate to form a perforation pattern corresponding to the tip of the needle-like body, and providing a resist layer made of a positive resist on the light shielding layer side of the substrate When the light is incident from the transparent layer side of the substrate, a step of performing exposure to the resist layer, have lines a development process on the resist layer, the opening of the resist pattern corresponding to the column portion of the needle-like formation And a step of filling the needle-like body material from the resist layer side, and a step of releasing the needle-like body material.

The present invention of claim 2 is a method of manufacturing the needle-like member according to claim 1, have rows arrayed patterning the light-shielding layer, etching the transparent layer from the light-shielding layer side of the substrate which is a method for manufacturing a needle-shaped body, which comprises carrying out.

  A third aspect of the present invention is a method for manufacturing the needle-shaped body according to any one of the first or second aspects, wherein the exposure is performed a plurality of times at different relative angles of the substrate and the exposure light. It is a manufacturing method of the acicular body to do. Here, a plurality of times means a method of irradiating a plurality of exposure lights and exposing at a time, a method of adjusting exposure light with a plurality of lenses or the like and performing batch irradiation from multiple directions, continuous exposure, It also includes the case of pseudo-diffused light.

  According to a fourth aspect of the present invention, a needle-shaped body produced by the method for producing a needle-shaped body according to any one of the first to third aspects is used as a mother mold, a duplicate plate is made from the mother mold, and transfer processing molding is performed. It is a manufacturing method of the acicular body characterized by performing.

  The present invention according to claim 5 is a needle-like body manufactured by the method for manufacturing a needle-like body according to any one of claims 1 to 4.

  The method for producing a needle-shaped body according to the present invention includes a step of forming a perforation pattern from a light shielding layer side of the substrate on a substrate provided with a light shielding layer and a transmission layer, and a resist layer on the light shielding layer side of the substrate. A step, light is incident from the transmission layer side of the substrate and the resist layer is exposed, a step of developing the resist layer, a step of filling the needle material from the resist layer side, And a step of releasing the needle-shaped body material.

  At this time, in the step of providing the perforation pattern on the substrate, the shape of the tip of the needle-like body to be manufactured can be controlled by controlling the shape of the perforation pattern, and in the step of forming the resist layer, By controlling the thickness of the layer, the length of the needle-like body to be produced can be controlled. That is, since the step of determining the tip shape of the needle-like body and the step of determining the length of the needle-like body can be performed separately, the tip shape and length of the needle-like body can be controlled with high accuracy. I can do it. Therefore, it becomes possible to design and manufacture the shape and dimensions of the needle-like body arbitrarily. In particular, since the step of determining the tip shape of the needle-like body can be performed independently, the shape and angle of the needle-like body tip can be designed and manufactured without considering the effect of the loading effect. It is possible to sharpen the tip.

  Further, by exposing the resist layer from the transmissive layer side, it is not necessary to perform high-level alignment, and only the resist layer corresponding to the perforated pattern portion can be selectively exposed (self-aligned exposure). For this reason, it becomes possible to manufacture a needle-like body simply without requiring strict alignment during exposure.

  In addition, the method for manufacturing a needle-shaped body of the present invention is characterized in that arraying patterning is performed on the light shielding layer.

  By performing array patterning on the light shielding layer, forming a perforated pattern, and filling the needle material, a structure in which a plurality of needle bodies are arranged in an array can be formed. At this time, by forming the needle-like body material up to the surface of the resist layer, the needle-like bodies and the sheet-like support portions arranged in an array can be easily integrally formed and manufactured.

  In addition, the method for manufacturing a needle-shaped body according to the present invention is characterized in that exposure is performed a plurality of times at different relative angles between the transparent substrate and the exposure light.

  Thereby, the diameter of a support | pillar base part can be changed, without changing the shape of a front-end | tip part. For this reason, it is possible to manufacture a needle-like body having a shape with a reinforced root portion that is subjected to great stress during piercing, and it is possible to manufacture a needle-like body that has the effect of being difficult to break during piercing It becomes.

  In addition, in the subsequent transfer processing molding process, when releasing the needle-shaped body material, a large stress applied to the root of the manufactured needle-shaped body is dispersed, so that the releasability of the transferred needle-shaped body Has the effect of improving.

  The method for producing a needle-shaped body of the present invention is characterized in that the produced needle-shaped body is used as a mother mold, a duplicate plate is made from the mother mold, and transfer processing is performed.

  Thereby, the shape of the needle-shaped body manufactured in various materials can be transferred. For this reason, for example, it becomes possible to manufacture a needle-like body using a material having a low load on a living body by transferring it to a biocompatible resin (medical silicone resin, maltose, polylactic acid, dextran, etc.). In addition, by creating a replica plate with high mechanical strength that is integrally molded, a large amount of needles can be manufactured with the same replica plate, which can reduce production costs and increase productivity. It becomes.

  Hereinafter, an example of the method for producing the needle-shaped body of the present invention will be described with reference to FIG.

  First, a substrate (101) is prepared (see FIG. 1 (a)). The substrate prepared at this time consists of two layers, a light shielding layer (102) and a light transmission layer (103). The light shielding layer is an etching mask for etching the light transmission layer, and light shielding in the subsequent lithography process. Play a role as a mask. Therefore, it is necessary that the light shielding layer itself can be processed and that sufficient light shielding properties can be obtained by subsequent lithography. The light transmissive layer is processed by wet etching or dry etching, and finally becomes the tip of the needle-like structure. Therefore, as a necessary characteristic of the light transmissive layer, there is a means for processing into a desired shape, and It is necessary to have a light transmittance that can secure a sufficient amount of light in the subsequent lithography process. As a substrate to be prepared, any substrate that satisfies these characteristics may be used. For example, blanks commonly used for photomasks include those in which Cr is formed in a quartz shape. Can be used as the light transmission layer, and Cr as the light shielding layer.

<Process for forming perforation pattern>
Next, an etching mask (104) for patterning the light shielding layer and the light transmission layer is formed on the substrate. Any etching mask may be used as long as an etching selection ratio between the light shielding layer and the light transmission layer (etching rate of the etching mask itself with respect to the etching rate to be processed) can be obtained, and the light shielding layer itself is etched when the light transmission layer is processed. In the case of functioning as a mask, the etching mask (104) can be used only for patterning the light shielding layer. Using this etching mask, a perforation pattern (105) for forming the tip of the needle-like structure is formed (see FIG. 1B).

As a processing method of the drilling pattern corresponding to the shape of the tip of the needle-shaped body,
(1) First, after performing etching using a resist pattern having a small opening diameter as an etching mask, performing multi-stage etching using a resist pattern having a larger opening diameter as an etching mask,
(2) A method in which a gradation is formed on the exposure mask, a so-called gray mask is used to form a taper on the resist pattern itself, and etching is performed.
Etc. can also be used.

  Further, as a method for forming a perforation pattern, when the perforation pattern is formed by direct processing such as a YAG laser or a femtosecond laser, the perforation pattern may be formed directly without forming the etching mask (104).

  In the present invention, since the perforation pattern that becomes the needle-like body tip portion can be processed independently, the needle-like body tip portion can be easily processed as compared with the case where the needle-like body mold is collectively formed. It becomes possible.

<Providing a resist layer on the light shielding layer side of the substrate>
Next, a resist layer (106) is formed on the substrate after the perforated pattern is formed (see FIG. 1C). This resist is a so-called positive resist whose dissolution rate in a solvent is improved by exposure to light. Since the resist film thickness becomes the height of the support portion of the needle-like structure, the final height of the needle-like structure can be controlled by controlling the resist film thickness. In this case, the resist layer may be formed by a general coating method such as a spin coating method, a spray coating method, or a slit coating method as long as it can form a desired film thickness. . The material used for the resist layer may be a so-called positive type. For example, a photosensitive dry film may be laminated on the light shielding layer instead of the resist.

<Step of exposing the resist layer>
Next, the resist layer (106) is patterned by exposing the entire surface of the resist layer from the transmissive layer side of the substrate (107) (see FIG. 1D). The opening (108) of the resist pattern becomes a support portion of the needle-like structure. As described above, the exposure mask is a light shielding layer formed on the light transmission layer. For this reason, since patterning is self-aligned by an opening formed on the light-shielding layer, it is not necessary to perform pattern alignment required for normal overexposure, and simple and highly accurate exposure is performed. It becomes possible.

  Moreover, you may perform the exposure from which the relative angle of a board | substrate and exposure light differs multiple times.

  Here, the relative angle is an angle formed by the substrate with respect to the entrance direction of the exposure light (see FIG. 2A), and can be changed by tilting one or both of the substrate and the exposure light. I can do it. Further, the multiple exposure refers to integrated exposure of exposures having different relative angles. Therefore, in the case of multiple exposures, for example, a rotation mechanism that changes the relative angle at a constant speed is provided on the substrate side, and exposure is continuously performed while rotating the substrate. When exposure light is collectively exposed, it is included in the multiple exposures.

  Thereby, as shown in FIG. 2, by giving a certain angle to the substrate during exposure (201) (see FIG. 2A), the resist opening can be tapered (202) ( (See FIG. 2 (b)), the diameter of the base of the support can be changed without changing the shape of the tip, thereby improving the mechanical strength of the finally formed needle-like structure It is.

<Step of developing the resist layer>
Next, development processing is performed to obtain a needle-shaped structure molding die (109) (see FIG. 1E). At this time, as a developing method, a publicly known method corresponding to the selected resist layer can be used.

<Step of filling needle material>
Next, the needle-shaped material (109) is filled with a needle-shaped material (not shown).

  At this time, the material and filling method of the needle-shaped body material are not particularly limited, and a suitable method for the selected material can be appropriately selected.

  For example, when a metal or alloy such as nickel or copper is used as the acicular material, a plating method, a PVD method, a CVD method, or the like can be suitably applied as a filling method of the acicular material.

  In addition, when an inorganic compound such as silicon, quartz, or alumina is used as the needle-shaped body material, a PVD method, a CVD method, or a sintering method can be suitably used as a filling method of the needle-shaped body material.

  In addition, when an organic compound such as polyethylene, polycarbonate, and PET is used as the needle-shaped body material, an imprint method, a hot embossing method, an injection molding method, and a casting method can be suitably used as the filling method for the needle-shaped body material. .

  Here, if a biocompatible material such as medical silicone resin, maltose, polylactic acid, dextran, or the like is selected as the needle-like material, a needle-like body applicable to biological use can be manufactured.

  Further, in the step of peeling the needle-shaped body material described later from the needle-shaped structure molding die (109), in order to improve the peelability of the needle-shaped body material, the needle-shaped body material is formed before the needle-shaped body material is formed. A mold release layer for increasing the mold release effect may be formed on the surface of the structure molding die (109) (not shown).

  As the release layer, for example, a well-known fluorine-based resin can be used.

  Moreover, as a formation method of a mold release layer, thin film formation methods, such as PVD method, CVD method, a spin coat method, a dip coat method, can be used suitably.

<Step of releasing the needle-shaped body material>
Next, a step of separating the needle-shaped material and the needle-shaped structure molding die (109) is performed.

  The needle-like body 110 and the needle-like structure molding die (109) are peeled off by applying a physical peeling force to obtain the needle-like body 110 (see FIG. 1 (f)).

  When the adhesion between the needle-shaped body material and the mold for molding the needle-shaped structure (109) is strong, it is difficult to separate them by physical peeling force. Only the mold for molding the needle-like structure (109) may be selectively removed by an etching method using the difference in etching selectivity of the mold (109).

  From the above, it is possible to manufacture a fine needle-shaped body with easy control of the tip shape and length. Since the method for manufacturing the needle-like body of the present invention can separately perform the step of determining the tip shape of the needle-like body and the step of determining the length of the needle-like body, Can be accurately controlled. For this reason, it becomes possible to design and manufacture the shape and dimension of a needlelike object arbitrarily. Thereby, a needle-like body having a desired tip shape and a desired length can be easily produced.

<Needle transfer processing molding>
Hereinafter, the transfer processing molding of the needle-like body will be described with reference to FIG.

  The manufactured needle-like body (110) is used as a mother mold, a mold layer (301) is formed, and a duplicate plate (302) is formed.

  First, a template layer (301) for forming the duplicate plate (302) is formed on the surface on which the needle-like body (110) is formed (FIG. 3A).

  At this time, when the needle-shaped structure molding die (109) is formed, the material is limited by the shape processing method, but the material limitation when forming the duplicate plate (302) is greatly relaxed. There is an advantage that.

  For this reason, the material of the mold layer (301) is not particularly limited, and a material that takes into account the shape following ability to function as a duplicate plate, transfer production in transfer processing molding described later, durability, and releasability is selected. I can do it.

  For example, nickel may be used as the material of the mold layer (301). In this case, examples of the method for forming the nickel film include a plating method, a PVD method, and a CVD method.

  Next, the needle-like body (110) and the template layer (301) are separated to obtain a duplicate plate (302) (FIG. 3B).

  As a method for separating the needle-like body (110) and the mold layer (301), as in the case of separating the needle-like structure molding die (109) and the needle-like body (110) described above, Separation by peeling force or selective etching can be used.

  Next, the replica plate (302) is filled with the needle-shaped material (FIG. 3 (c)).

  The needle-shaped body material is not particularly limited, but a needle-shaped body applicable to a living body can be formed by using a medical silicone resin, maltose, polylactic acid, dextran, or the like which is a biocompatible material.

  Although there is no restriction | limiting about the filling method of needle-shaped body material, From a viewpoint of productivity, the imprint method, the hot embossing method, the injection molding method, the extrusion molding method, and the casting method can be used suitably.

  Next, the needle-shaped body material is released from the replica plate (302) to obtain a transfer-molded needle-shaped body (303) (FIG. 3 (d)).

  At this time, in order to improve the peelability of the duplicate plate (302), a release layer for increasing the mold release effect may be formed on the surface of the duplicate plate (302) before filling with the needle-shaped body material. Good (not shown).

  As the release layer, for example, a well-known fluorine-based resin can be used.

  Moreover, as a formation method of a mold release layer, thin film formation methods, such as PVD method, CVD method, a spin coat method, a dip coat method, can be used suitably.

  From the above, transfer processing molding of the needle-like body can be performed. By producing a replica plate with high mechanical strength that is integrally molded, a large amount of needle-like bodies can be manufactured with the same replica plate, which makes it possible to reduce production costs and increase productivity. .

  Details of the invention will be described below based on examples.

  First, a substrate was prepared. The substrate is quartz having a side of 150 mm and a thickness of 6.35 mm, which is used as a general photomask blank. A Cr layer having a thickness of 300 nm was formed as a light shielding layer on the quartz by a DC magnetron sputtering method. At this time, the sputtering pressure is 0.25 Pa, and the input power is 1000 W.

  Next, a positive resist OFPR-50cp manufactured by Tokyo Ohka Co., Ltd. was applied to the chromium as an etching mask so as to have a film thickness of 1 μm, and a square opening pattern having a side of 50 μm was formed by photolithography. Using this resist pattern as an etching mask, chromium was etched using a mixed solution of perchloric acid and ceric ammonium nitrate to form a square-opened chromium pattern with one side of 50 μm. After forming the chromium patterning, OFPR was removed with an organic solvent, and the dimension of the chromium pattern was measured. As a result, the dimension of the square opening pattern of chromium was 51 μm in length on one side.

  Using the opening pattern formed on the Cr layer as an etching mask, covalent bonding plasma etching using a mixed gas of fluorocarbon gas and oxygen was performed to form a perforated pattern on quartz. When the cross-sectional shape of the quartz perforation pattern produced by the same process was measured, a perforation pattern having a depth of 150 μm was formed. In addition, the angle of the deepest part of the drilling pattern that becomes the final needle-like structure tip was about 21 °.

Next, a positive resist LA-900 manufactured by Tokyo Ohka Co., Ltd. was formed as a resist layer on this substrate by spin coating. At this time, the film thickness of LA-900 was 100 μm. This resist layer is exposed from the back side using the Cr opening pattern of the substrate as an exposure mask and developed using organic alkali to complete a resist pattern with an opening size of 51 μm and a height of 100 μm that will become the support column of the acicular structure I let you.

  Based on the substrate on which the resist pattern was formed, a first replicated plate was produced in which the irregularities were inverted by the Ni electroforming method. In this case, the Ni layer formed by DC magnetron sputtering was used as the seed layer, and the thickness of the seed layer was 30 nm, and the electroplating was performed in a commonly used nickel sulfamate bath. Furthermore, after surface oxidizing the surface of the produced 1st replication plate by oxygen plasma treatment, the 2nd replication plate which carried out electrolytic Ni plating again and reversed the unevenness | corrugation was produced.

  When this second duplicated plate was used for transfer molding by the imprint method using maltose, dextran, and polylactic acid as materials, needles having a diameter of about 50 μm, a height of about 250 μm, and a tip angle of about 21 ° were used. It was confirmed that a shaped structure, a so-called needle-like structure was formed.

  The method for producing a needle-shaped body according to the present invention is suitable for integrally molding fine needle-shaped bodies and sheet-like support portions arranged in an array, and not only medical treatment but also MEMS devices, drug discovery, and cosmetics. It can be expected to be used in various fields.

It is sectional process drawing which shows the manufacturing method in this invention. It is sectional process drawing which shows the manufacturing method which performs the exposure from which the relative angle of the board | substrate and exposure light in this invention differs. It is a figure which shows the manufacturing method using the transfer process shaping | molding in this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 101,201 ... Substrate 102 ... Light shielding layer 103 ... Transmission layer 104 ... Etching mask for patterning light transmission layer 105 ... Perforation pattern 106 ... Resist layer 107 ... Needle shape Exposure of resist layer for forming structure pillar portion 108... Resist pattern opening 109, 209... Needle structure molding die 110, 303... Needle body 301. ..Copying version

Claims (5)

In the manufacturing method of a fine needle-like body provided with a strut portion in which the needle shape is aligned with the tip portion ,
Etching the light- transmitting layer from the light-shielding layer side of the substrate to the substrate provided with the light-shielding layer and the light-transmitting layer, and forming a perforation pattern corresponding to the tip of the needle-shaped body ;
Providing a resist layer made of a positive resist on the light shielding layer side of the substrate;
Entering light from the transmission layer side of the substrate and exposing the resist layer;
A step of forming the resist had lines the development processing layer, the openings of the resist pattern corresponding to the column portion of the needle body,
Filling the acicular material from the resist layer side;
And a step of releasing the needle-shaped body material. It is a manufacturing method of the acicular body according to claim 1,
There rows arrayed patterning the light-shielding layer, the manufacturing method of the needle body, characterized in that etching is performed with respect to the transmission layer from the light-shielding layer side of the substrate. It is a manufacturing method of the acicular body according to any one of claims 1 and 2,
A method of manufacturing a needle-like body, wherein exposure is performed a plurality of times at different relative angles between the substrate and exposure light. The needle-shaped body produced by the method for producing a needle-shaped body according to any one of claims 1 to 3 is used as a matrix.
Make a duplicate version from the matrix,
A method for producing a needle-like body, comprising performing transfer processing molding.   The acicular body manufactured by the manufacturing method of the acicular body in any one of Claim 1 to 4.