JP2008079919A - Needle body and method for producing needle body - Google Patents

Needle body and method for producing needle body Download PDF

Info

Publication number
JP2008079919A
JP2008079919A JP2006264636A JP2006264636A JP2008079919A JP 2008079919 A JP2008079919 A JP 2008079919A JP 2006264636 A JP2006264636 A JP 2006264636A JP 2006264636 A JP2006264636 A JP 2006264636A JP 2008079919 A JP2008079919 A JP 2008079919A
Authority
JP
Japan
Prior art keywords
needle
porous
skeleton
drug
acicular
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
JP2006264636A
Other languages
Japanese (ja)
Other versions
JP4954656B2 (en
Inventor
Daisuke Inokuchi
大輔 井ノ口
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Toppan Inc
Original Assignee
Toppan Printing Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Toppan Printing Co Ltd filed Critical Toppan Printing Co Ltd
Priority to JP2006264636A priority Critical patent/JP4954656B2/en
Publication of JP2008079919A publication Critical patent/JP2008079919A/en
Application granted granted Critical
Publication of JP4954656B2 publication Critical patent/JP4954656B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Abstract

<P>PROBLEM TO BE SOLVED: To provide a needle body which has a drug holder in at least one part and can be coated with a drug to hold so a sufficient amount of the drug in the drug holder that the needle body may supply a living body with the drug and/or may collect a blood and/or a body fluid from the living body with a largely improved efficiency, and to provide a method for producing the same. <P>SOLUTION: The minute needle body comprises a needle body skeleton for supporting the needle body and a drug holder made from a porous material at least on the surface of the needle body. The method comprises producing the needle body. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

本発明は、医療、創薬、化粧品等に用いられる微細な針状体に関する。   The present invention relates to a fine needle-like body used in medicine, drug discovery, cosmetics and the like.

薬剤を経皮的に投与する方法として、注射針による皮膚真皮層への穿刺、皮膚表面への薬剤／軟膏剤の塗布、貼付型経皮投与製剤の使用が挙げられる。   Examples of the method of transdermally administering the drug include puncture of the skin dermis layer with an injection needle, application of the drug / ointment to the skin surface, and use of a patch type transdermal preparation.

真皮層には、神経細胞が含まれるので注射針の真皮層への穿刺は疼痛を伴い、また塗布剤や貼付型経皮投与製剤では、経皮投与可能な薬剤は少ないという問題点がある。   Since the dermis layer contains nerve cells, there is a problem that puncture of the dermis layer of an injection needle is accompanied by pain, and there are few drugs that can be administered transdermally in coating agents and patch-type transdermal preparations.

経皮投与可能な薬剤が少ない理由は、角質層の不透過性による。角質層は厚さ１０〜３０μｍの層状構造をなし、種々の物質の体内への侵入、及び種々の物質の体内からの漏出を防ぐバリアとなり、そのため薬剤が角質層下へ透過することが困難となっている。   The reason why there are few drugs that can be administered transdermally is due to the impermeability of the stratum corneum. The stratum corneum has a layered structure with a thickness of 10 to 30 μm, and serves as a barrier that prevents various substances from entering the body and leakage of various substances from the body, so that it is difficult for the drug to penetrate below the stratum corneum. It has become.

経皮的に薬剤の透過性を向上させるためのデバイスの形態として、痛みを伴わない無痛針としてマイクロニードルの開発が進められている。   As a form of device for improving the permeability of a drug percutaneously, a microneedle has been developed as a painless needle without pain.

例えば、医療用マイクロニードルは体内への薬剤の供給や体内からの血液／体液の採取に用いられることを目的とする、マイクロニードルの内部に形成された貫通口を液体が通過するタイプが提案されている（特許文献１、非特許文献１）。   For example, a medical microneedle has been proposed in which a liquid passes through a through-hole formed inside the microneedle, which is intended to be used for supplying drugs into the body and collecting blood / fluid from the body. (Patent Document 1, Non-Patent Document 1).

また、アレイ状に配置した貫通口の無いマイクロニードルのニードルアレイ面に、あらかじめ薬剤を塗布し、ニードルアレイ面を皮膚に押し付けることにより、ニードル表面と皮膚の間を浸透するタイプが提案されている（特許文献２、非特許文献２）。   In addition, a type that penetrates between the needle surface and the skin by applying a drug on the needle array surface of microneedles without through-holes arranged in an array and pressing the needle array surface against the skin has been proposed. (Patent Literature 2, Non-Patent Literature 2).

更に薬剤の浸透性を向上させるためにマイクロニードル表面及び／または、マイクロニードルが形成された基板に溝を形成し、流体経路を設けたタイプが提案されている（特許文献３、特許文献４）。   Further, in order to improve the drug permeability, a type in which a groove is formed in the surface of the microneedle and / or the substrate on which the microneedle is formed to provide a fluid path has been proposed (Patent Documents 3 and 4). .

特許文献等は以下の通り。
特開２００２−３６９８１６号公報 Shyh-Chyi Kuo et al. Tamkang Journal of Science and Engineering, Vol. 7, No. 2, pp. 95-98A(2004), Novel Polymer Microneedle Arrays and PDMS Micromolding Technique 特開２００４−１１４５５２号公報 Jung-Hwan Park et al. Journal of Controlled Release 104(2005) 51-66, Biodegradable polymer microneedles : Fabrication, mechanics and transdermal drug delivery 特表２００５−５０１６１５号公報 特表２００５−５１４１７９号公報 Patent documents etc. are as follows.
JP 2002-369816 A Shyh-Chyi Kuo et al. Tamkang Journal of Science and Engineering, Vol. 7, No. 2, pp. 95-98A (2004), Novel Polymer Microneedle Arrays and PDMS Micromolding Technique JP 2004-114552 A Jung-Hwan Park et al. Journal of Controlled Release 104 (2005) 51-66, Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery JP-T-2005-501615 JP-T-2005-514179

前述した従来の技術にあっては、次の問題があった。   The prior art described above has the following problems.

すなわち、特許文献１や非特許文献１に記載された技術の場合、マイクロニードルの内部に貫通口を形成する必要があるため、マイクロニードルの作製工程が煩雑となってしま
う問題点や薬剤の体内への供給や体内から血液／体液の採取を行うためには、マイクロニードル内部の貫通口径が重要であり、貫通口経を大きくするとマイクロニードルの強度が低下し、貫通口経が小さくなると液体の通過が困難となってしまうため、マイクロニードルの太さと貫通口経の最適な組み合わせが制限され、良好なマイクロニードル形状を得ることが困難であった。 That is, in the case of the techniques described in Patent Document 1 and Non-Patent Document 1, since it is necessary to form a through-hole inside the microneedle, there are problems that the manufacturing process of the microneedle becomes complicated and the body of the drug. In order to supply blood or collect blood / fluid from the body, the diameter of the through-hole inside the microneedle is important. When the through-hole diameter is increased, the strength of the microneedle decreases, and when the through-hole diameter is reduced, Since the passage becomes difficult, the optimum combination of the thickness of the microneedle and the through hole diameter is limited, and it is difficult to obtain a good microneedle shape.

また特許文献２や非特許文献２に記載された技術の場合、薬剤を効率よく皮膚内に浸透させるために、表皮の厚み（５０〜１５０μｍ）を超える２００μｍ程度の長さのニードルを、アレイ状に多数配置して用いられるのが一般的であるが、従来のマイクロニードルの形状、大きさでは、ニードル１本あたりの薬剤の浸透量が足りないため、単にニードルをアレイ状に配置するだけでは、十分な量の薬剤を投与することが出来ない。また、薬剤の浸透量を高めるために、ニードルをそれ以上大きくすると、疼痛を感じてしまうため、無痛針として機能しなくなってしまう。   In the case of the techniques described in Patent Document 2 and Non-Patent Document 2, in order to efficiently infiltrate the drug into the skin, needles having a length of about 200 μm exceeding the thickness of the epidermis (50 to 150 μm) are arrayed. However, the conventional microneedle has a shape and size that is insufficient for the amount of drug permeation per needle, so simply arranging the needles in an array A sufficient amount of drug cannot be administered. Further, if the needle is further enlarged in order to increase the amount of penetration of the drug, pain will be felt, and the needle will not function as a painless needle.

また特許文献３や特許文献４に記載された技術の場合、マイクロニードルアレイ中の各マイクロニードルの表面に溝を作成する必要があるが、マイクロニードルのサイズが小さいため、正確に全てのマイクロニードルに溝を形成することが困難であった。このため、作製されたマイクロニードルアレイは、薬剤の体内への供給や体内から血液／体液の採取の効率に個体差が生じる問題があった。   Further, in the case of the techniques described in Patent Document 3 and Patent Document 4, it is necessary to create a groove on the surface of each microneedle in the microneedle array. It was difficult to form grooves. For this reason, the produced microneedle array has a problem that individual differences occur in the efficiency of supply of the drug into the body and collection of blood / fluid from the body.

本発明は、これらの問題点を解決するためになされたものであり、その目的とするところは、生体へ薬剤を供給または／及び生体から血液または／及び体液を採取する効率を大幅に向上させながら、表皮への穿刺に十分な強度を有する針状体及び、その簡便な製造方法を提供することにある。   The present invention has been made to solve these problems, and its purpose is to greatly improve the efficiency of supplying a drug to a living body and / or collecting blood or / and body fluid from a living body. However, an object is to provide a needle-like body having sufficient strength for puncturing the epidermis and a simple manufacturing method thereof.

請求項１に記載の本発明は、微細な針状体において、針状体を支持する針状体骨格部と、針状体の少なくとも表面に、多孔質材料からなる薬剤保持部とを備えたことを特徴とする針状体である。   The present invention according to claim 1 includes a fine acicular body including a acicular body skeleton portion that supports the acicular body and a drug holding portion made of a porous material on at least the surface of the acicular body. This is a needle-like body.

請求項２に記載の本発明は、請求項１に記載の針状体であって、針状体骨格部が、針状体の先端部に表出していることを特徴とする針状体である。   The present invention described in claim 2 is the needle-shaped body according to claim 1, wherein the needle-shaped body skeleton is exposed at the tip of the needle-shaped body. is there.

請求項３に記載の本発明は、請求項1または２のいずれかに記載の針状体であって、多孔質材料が多孔質シリコンであることを特徴とする針状体である。   A third aspect of the present invention is the needle-shaped body according to any one of the first or second aspects, wherein the porous material is porous silicon.

請求項４に記載の本発明は、請求項１から３のいずれかに記載の針状体であって、多孔質材料が多孔質ガラスであることを特徴とする針状体である。   The present invention described in claim 4 is the acicular body according to any one of claims 1 to 3, wherein the porous material is porous glass.

請求項５に記載の本発明は、請求項１から４のいずれかに記載の針状体であって、前記針状体が、基材上に、アレイ状の形を成して複数配置されていることを特徴とする針状体。   The present invention according to claim 5 is the acicular body according to any one of claims 1 to 4, wherein a plurality of the acicular bodies are arranged in an array on the substrate. A needle-like body characterized by

請求項６に記載の本発明は、請求項５に記載の針状体であって、基材表面に、薬剤保持層を有することを特徴とする針状体である。   The present invention according to claim 6 is the needle-like body according to claim 5, which has a drug holding layer on the surface of the substrate.

請求項７に記載の本発明は、微細な針状体の製造方法において、針状体骨格部を形成する骨格部形成工程と、前記針状体骨格部の少なくとも表面に多孔質の薬剤保持部を形成する多孔質部形成工程とを備えたことを特徴とする針状体の製造方法である。   The present invention according to claim 7 is a method for producing a fine needle-like body, wherein a skeleton part forming step for forming a needle-like body skeleton part, and a porous drug holding part on at least a surface of the needle-like body skeleton part And a porous part forming step for forming the needle-shaped body.

請求項８に記載の本発明は、請求項７に記載の針状体の製造方法であって、基材から突出し、アレイ状に配置された針状体骨格部を形成し、多孔質部形成工程のとき、針状体骨格部の少なくとも表面に多孔質の薬剤保持部と、基材表面に多孔質の薬剤保持層と、を併せて形成することを特徴とする針状体の製造方法である。   The present invention according to claim 8 is the method for manufacturing the acicular body according to claim 7, wherein the acicular body skeleton portion protruding from the base material and arranged in an array is formed to form a porous portion. In the process, a needle-shaped body manufacturing method comprising: forming a porous drug holding portion on at least the surface of the needle-shaped body skeleton portion; and forming a porous drug holding layer on the surface of the substrate. is there.

請求項９に記載の本発明は、請求項７または８のいずれかに記載の針状体の製造方法であって、多孔質とする部位を、シリコンを用いて形成し、多孔質部形成工程に、電気化学エッチング法を用いることを特徴とする針状体の製造方法である。   The present invention according to claim 9 is the method for producing the needle-shaped body according to claim 7 or 8, wherein the porous portion is formed using silicon, and the porous portion forming step And a method for producing a needle-like body, characterized by using an electrochemical etching method.

請求項１０に記載の本発明は、請求項７または８のいずれかに記載の針状体の製造方法であって、多孔質とする部位を、ガラスを用いて形成し、多孔質部形成工程に、熱処理の後に酸処理を行うことを特徴とする針状体の製造方法である。   The present invention according to claim 10 is the method for producing the needle-shaped body according to any one of claims 7 and 8, wherein the porous portion is formed using glass, and the porous portion forming step And an acid treatment after the heat treatment.

請求項１１に記載の本発明は、請求項７から１０のいずれかに記載の針状体の製造方法であって、骨格部形成工程と、多孔質部形成工程との間に、針状体骨格部の先端部を保護する工程を行うことを特徴とする針状体の製造方法である。   The present invention according to claim 11 is the method for producing the needle-shaped body according to any one of claims 7 to 10, wherein the needle-shaped body is provided between the skeleton portion forming step and the porous portion forming step. A method for manufacturing a needle-like body, comprising performing a step of protecting a distal end portion of a skeleton portion.

本発明によると、生体に薬剤を供給または／及び生体から血液または／及び体液を採取するための針状体において、針状体の少なくとも一部に薬剤保持部が形成されることで、薬剤を針状体に塗布した際に、針状体の薬剤保持部に十分な量の薬剤を保持できるため、針状体が生体へ薬剤を供給または／及び生体から血液または／及び体液を採取する効率を大幅に向上させることが可能となる。   According to the present invention, in a needle-like body for supplying a medicine to a living body and / or collecting blood or / and body fluid from a living body, a medicine holding part is formed on at least a part of the needle-like body, Since a sufficient amount of drug can be held in the drug holding part of the needle-like body when applied to the needle-like body, the efficiency of the needle-like body supplying the drug to the living body and / or collecting blood or / and body fluid from the living body Can be greatly improved.

さらに針状体をアレイ状に配置することにより、その効果をより向上させることも可能である。また本発明の針状体は、生体へ薬剤を供給または／及び生体から血液または／及び体液を採取する効率が高いため、アレイ状に配置したときに、１つ１つの針状体を小さくしたり、要求される薬剤投与量を充足する針状体の本数を削減したりことが可能となるため、無痛針としての効果をより発揮することができる。   Furthermore, by arranging the needle-like bodies in an array, the effect can be further improved. In addition, since the needle-like body of the present invention has a high efficiency of supplying a drug to the living body and / or collecting blood or / and body fluid from the living body, each needle-like body is made smaller when arranged in an array. Or the number of needle-like bodies that satisfy the required drug dosage can be reduced, and the effect as a painless needle can be further exhibited.

以下、本発明の針状体および針状体の製造方法の一例を、図面に基づき詳細に説明する。   Hereinafter, an example of the needle-shaped body and the method for producing the needle-shaped body of the present invention will be described in detail with reference to the drawings.

図１は、本発明に係る針状体の一例を示すものであり、図１（ａ）は針状体の側面図、図１（ｂ）は針状体の断面図である。   FIG. 1 shows an example of a needle-shaped body according to the present invention. FIG. 1 (a) is a side view of the needle-shaped body, and FIG. 1 (b) is a cross-sectional view of the needle-shaped body.

また、本発明はこれに限定することなく例えば図２や図３に示す形態をとることもできる。   Moreover, this invention can also take the form shown, for example in FIG.2 and FIG.3, without being limited to this.

また図４は、本発明に係る針状体の一例を示す断面図であり、図５（ａ）〜（ｄ）は、この針状体を製造するための手順を示す工程図である。   FIG. 4 is a cross-sectional view showing an example of a needle-like body according to the present invention, and FIGS. 5A to 5D are process diagrams showing a procedure for manufacturing the needle-like body.

図１において符号Ｈは針状体を示す。針状体Ｈは、少なくとも針状体骨格部１と薬剤保持部２からなり、針状体Ｈの大きさは、高さ２０μｍ以上５００μｍ以下、好ましくは３０μｍ以上２５０μｍ以下とし、無痛針としての機能を保持するためには、皮膚における角質層の厚さ以上表皮の厚さ以下とすることが望ましい。   In FIG. 1, symbol H indicates a needle-like body. The needle-like body H is composed of at least the needle-like body skeleton 1 and the medicine holding part 2, and the size of the needle-like body H is 20 μm or more and 500 μm or less, preferably 30 μm or more and 250 μm or less, and functions as a painless needle. In order to maintain the thickness, it is desirable that the thickness of the stratum corneum in the skin is not less than the thickness of the epidermis.

また図４は、基板４上に針状体Ｈをアレイ状に形成したものであり、薬剤保持層５を形成することもできる。   In FIG. 4, needle-like bodies H are formed in an array on the substrate 4, and the drug holding layer 5 can also be formed.

針状体骨格部１としては、Ｎａ2Ｏ−Ｂ2Ｏ3−ＳｉＯ2系ガラス、Ｎａ2Ｏ−ＳｉＯ2系ガラス、Ｌｉ2Ｏ−ＳｉＯ2系ガラス、Ｎａ2Ｏ−Ｂ2Ｏ3系ガラス、ＰｂＯ−Ｂ2Ｏ3系ガラス、Ｎａ2Ｏ−ＣａＯ−ＳｉＯ2系ガラス、Ｎａ2Ｏ−Ｂ2Ｏ3−ＳｉＯ2系ガラス、Ｌｉ2Ｏ−Ｐ2Ｏ5−ＳｉＯ2系ガラス、Ｎａ2Ｏ−Ｂ2Ｏ3−Ｐ2Ｏ5系ガラス、等の分相性ガラスやシリコンを用いることができ、好ましくは、分相後特定の溶媒に対して、溶解度の点で大きな差があり、片方の相だけが溶出する分相性ガラスであるＮａ2Ｏ−Ｂ2Ｏ3−ＳｉＯ2系ガラス、Ｎａ2Ｏ−ＳｉＯ2系ガラスや電気化学エッチング法等により多孔質化するシリコンを用いることが望ましい。 As the acicular body skeleton 1, the Na 2 O—B 2 O 3 —SiO 2 glass, the Na 2 O—SiO 2 glass, the Li 2 O—SiO 2 glass, the Na 2 O—B 2 O 3 glass are used. Glass, PbO—B 2 O 3 glass, Na 2 O—CaO—SiO 2 glass, Na 2 O—B 2 O 3 —SiO 2 glass, Li 2 O—P 2 O 5 —SiO 2 glass, Phase separation glass such as Na 2 O—B 2 O 3 —P 2 O 5 glass or silicon can be used, and preferably, there is a large difference in solubility with respect to a specific solvent after phase separation. Using Na 2 O—B 2 O 3 —SiO 2 glass, Na 2 O—SiO 2 glass, silicon that is made porous by electrochemical etching or the like, which is a phase separation glass in which only one phase elutes Is desirable.

薬剤保持部２は、針状体骨格部１を材料に応じて多孔質化処理を行うことで形成することができる。   The drug holding part 2 can be formed by subjecting the acicular body skeleton part 1 to a porous treatment according to the material.

例えば、針状体骨格部１がシリコンからなる場合は、多孔質化処理として電気化学エッチングを行うことにより針状体骨格部１の表面を多孔質化し、表面に薬剤保持部２を有する針状体Ｈを作製することができる。   For example, when the needle-like skeleton 1 is made of silicon, the surface of the needle-like skeleton 1 is made porous by performing electrochemical etching as the porous treatment, and the needle-like skeleton 1 having the drug holding part 2 on the surface. The body H can be produced.

通常、多孔質材料からなる針状体は、強度が不足し皮膚への穿刺時に微細針構造体が倒壊してしまう問題が生じるが、本発明における針状体は、針状体骨格部１を有するために十分な強度を得ることができ、皮膚への穿刺時における針状体の倒壊問題を改善することができる。また図２や図３に示す、針状体Ｈにおいて針状体骨格部１の先端部を残存させた硬質針先端部３を有することにより、皮膚への穿刺を確実に行うことができる。   Normally, a needle-like body made of a porous material has a problem that the strength of the needle-like body is insufficient and the fine needle structure collapses when puncturing the skin. Therefore, sufficient strength can be obtained, and the problem of collapse of the needle-like body at the time of puncturing the skin can be improved. In addition, the needle-like body H shown in FIGS. 2 and 3 has the hard needle distal end portion 3 in which the distal end portion of the needle-like body skeleton portion 1 remains, so that the skin can be punctured with certainty.

また基板４は、前述した針状体骨格部１と同様な材料を使用することができ、針状体骨格部１と基板４は、同じ材料または異なった材料から形成することができ、針状体の作製方法によっては、針状体骨格部１と基板４は同じ材料とすることが望ましい。   The substrate 4 can use the same material as that of the needle-like skeleton 1 described above, and the needle-like skeleton 1 and the substrate 4 can be formed of the same material or different materials. It is desirable that the needle-like skeleton 1 and the substrate 4 are made of the same material depending on the method of manufacturing the body.

基板４上に薬剤保持層５を形成する場合は、基板４を材料に応じて多孔質化処理を行えばよい。また、針状体の作製方法によっては、針状体に形成される薬剤保持部２と基板４上に形成される薬剤保持層５を同時に形成することができる。   When the drug holding layer 5 is formed on the substrate 4, the substrate 4 may be made porous according to the material. Further, depending on the method for producing the needle-like body, the medicine holding portion 2 formed on the needle-like body and the medicine holding layer 5 formed on the substrate 4 can be formed simultaneously.

次に本発明の針状体の製造方法の一例を詳細に説明する。   Next, an example of the method for producing the needle-shaped body of the present invention will be described in detail.

まず図５（ａ）に示すように基板４上にマスク６層を形成する。マスク層６は、電子線レジスト、フォトレジスト等の感光性樹脂やＣｒ、Ｎｉ、Ｗ等の金属、シリコン酸化膜、シリコン窒化膜、ＺｒＳｉ、ＭｏＳｉ等の金属化合物を用いることができ、基板４の材料に応じて好適な材料を選ぶことが望ましい。   First, as shown in FIG. 5A, a mask 6 layer is formed on the substrate 4. The mask layer 6 can be made of a photosensitive resin such as an electron beam resist or a photoresist, a metal such as Cr, Ni, or W, a metal compound such as a silicon oxide film, a silicon nitride film, ZrSi, or MoSi. It is desirable to select a suitable material according to the material.

マスク層６が電子線レジストやフォトレジスト等の感光性樹脂である場合は、リソグラフィ法によりパターニングを行う。またマスク層６が金属や金属化合物である場合は、リソグラフィ法及び／またはウェットエッチング法または／及びドライエッチング法を用いてパターニングを行う。   When the mask layer 6 is a photosensitive resin such as an electron beam resist or a photoresist, patterning is performed by a lithography method. When the mask layer 6 is a metal or metal compound, patterning is performed using a lithography method and / or a wet etching method and / or a dry etching method.

次に図５（ｂ）に示すようにマスク層６が形成された基板４をドライエッチング法、ウェットエッチング法等の加工処理を行い、基板４上に針状体骨格部１を作成する。   Next, as shown in FIG. 5B, the substrate 4 on which the mask layer 6 is formed is processed by a dry etching method, a wet etching method, or the like, so that the needle-like skeleton 1 is formed on the substrate 4.

さらに図５（ｃ）に示すようにマスク層６を針状体骨格部１が形成された基板４から除去する。マスク層６が感光性樹脂なら、レジスト剥離液、硫酸水溶液等を用い、マスク層６が金属や金属化合物であれば、フッ酸水溶液、バッファードフッ酸水溶液、硫酸溶液、塩酸溶液、硝酸溶液等を用いることができる。   Further, as shown in FIG. 5C, the mask layer 6 is removed from the substrate 4 on which the needle-like body skeleton 1 is formed. If the mask layer 6 is a photosensitive resin, a resist stripping solution, a sulfuric acid aqueous solution, or the like is used. If the mask layer 6 is a metal or a metal compound, a hydrofluoric acid aqueous solution, a buffered hydrofluoric acid aqueous solution, a sulfuric acid solution, a hydrochloric acid solution, a nitric acid solution, or the like. Can be used.

最後に図５（ｄ）に示すように基板４上に形成された針状体骨格部１の表面に薬剤保持部２を形成する。また、必要に応じて基板４の表面に薬剤保持層５を形成することもできる。   Finally, as shown in FIG. 5 (d), the medicine holding part 2 is formed on the surface of the needle-like skeleton part 1 formed on the substrate 4. Moreover, the chemical | medical agent holding | maintenance layer 5 can also be formed in the surface of the board | substrate 4 as needed.

一般的に針状体骨格部１がシリコンからなる場合は、電気化学エッチング処理を行うことで針状体骨格部１の表面が多孔質化し、薬剤保持部２が形成される。   In general, when the needle-like skeleton 1 is made of silicon, the surface of the needle-like skeleton 1 is made porous by performing an electrochemical etching process, and the drug holding part 2 is formed.

また針状体骨格部１が分相性ガラスからなる場合は、まず加熱処理を行い、分相によるからみ合い構造に変え、酸処理を行うことでＳｉＯ2に富む相以外が溶出されることにより多孔質化し、薬剤保持部２が形成される。 Further, when the needle-like skeleton 1 is made of phase-separated glass, first, heat treatment is performed, the entanglement structure is changed by phase separation, and acid treatment is performed to elute other than the phase rich in SiO 2. As a result, the medicine holding part 2 is formed.

ここで加熱処理の温度は、５００℃〜１３００℃程度、好ましくは５５０℃〜６５０℃程度に設定するのが望ましい。また加熱処理の時間は、１時間〜８００時間、好ましくは、３０時間〜１００時間程度に設定するのが望ましい。   Here, the temperature of the heat treatment is desirably set to about 500 ° C. to 1300 ° C., preferably about 550 ° C. to 650 ° C. The heat treatment time is preferably set to 1 hour to 800 hours, preferably about 30 hours to 100 hours.

つまり、５００℃〜６５０℃程度の温度及び／または３０時間〜１００時間程度の加熱時間で多孔質化するために効果的な分相による絡み合い構造を得ることができる。   That is, it is possible to obtain an entangled structure by phase separation that is effective for making porous at a temperature of about 500 ° C. to 650 ° C. and / or a heating time of about 30 hours to 100 hours.

また酸処理は、硫酸溶液、塩酸溶液、硝酸溶液等を用いることができ、溶液の温度を６０℃以上、好ましくは、１００℃以上に設定することが望ましく、溶液の温度が高いほど、溶出速度が大きく、酸処理中に微細針構造体が割れる危険性を低くすることができる。   The acid treatment can use a sulfuric acid solution, a hydrochloric acid solution, a nitric acid solution, etc., and the temperature of the solution is desirably set to 60 ° C. or higher, preferably 100 ° C. or higher. The higher the temperature of the solution, the higher the elution rate. The risk of breaking the fine needle structure during the acid treatment can be reduced.

また基板４の表面に薬剤保持層５を形成する方法も前述した薬剤保持部２の形成方法を用いることができ、薬剤保持部２と薬剤保持層５を同時に形成することもできる。   Further, the method for forming the drug holding layer 5 on the surface of the substrate 4 can be the same as the method for forming the drug holding unit 2 described above, and the drug holding unit 2 and the drug holding layer 5 can be formed simultaneously.

また、図２及び図３に示される針状体Ｈ’、Ｈ”における硬質針先端部３を形成する場合は、薬剤保持部２及び／または薬剤保持層５を形成する工程の直前に、針状体骨格部１の先端に保護層を形成する必要がある。保護層は、熱硬化性樹脂や光硬化性樹脂、紫外線硬化性樹脂、電子線硬化性樹脂等を用いることができ、ディップコート法、スプレーコート法等で塗布することができる。また保護層は、微細針構造体骨格部１の先端より微細針構造体１の高さの１／５〜１／２、好ましくは１／５〜２／５程度に形成することが望ましい。   When forming the hard needle tip 3 in the needle-like bodies H ′ and H ″ shown in FIGS. 2 and 3, the needle is placed immediately before the step of forming the drug holding part 2 and / or the drug holding layer 5. It is necessary to form a protective layer at the tip of the body skeleton 1. The protective layer can be made of a thermosetting resin, a photocurable resin, an ultraviolet curable resin, an electron beam curable resin, or the like, and is dip coated. The protective layer can be applied by a method such as a spray coating method, etc. Further, the protective layer is 1/5 to 1/2, preferably 1/5 of the height of the fine needle structure 1 from the tip of the fine needle structure skeleton 1. It is desirable to form in about 2/5.

前述した全ての工程もしくは、必要に応じて一部の工程を経て本発明における薬剤保持部２及び／または薬剤保持層５が形成された針状体を製造することができる。   The needle-like body in which the medicine holding part 2 and / or the medicine holding layer 5 in the present invention is formed can be manufactured through all the above-described processes or a part of the processes as necessary.

図４及び図５を参考にして本発明における実施例を説明する。まずシリコンからなる基板４にフォトレジストをスピンコート法により厚さ４０μｍで塗布し、フォトリソグラフィ法により直径５０μｍのドットパターンをＸＹ方向に１００×１００個でアレイ配列したマスク層６を形成した。   An embodiment of the present invention will be described with reference to FIGS. First, a photoresist was applied to the substrate 4 made of silicon to a thickness of 40 μm by spin coating, and a mask layer 6 was formed by arraying 100 × 100 dot patterns having a diameter of 50 μm in the XY direction by photolithography.

次に針状体骨格部１を形成する工程として、基板４をＣｌ2によるドライエッチングを実施し、高さ２５０μｍの針状体骨格部１を形成した。 Next, as a step of forming the needle-like skeleton 1, the substrate 4 was dry-etched with Cl 2 to form the needle-like skeleton 1 having a height of 250 μm.

さらにマスク層６を９６％硫酸と３０％過酸化水素水の体積比が３：１からなる硫酸過水を用いて剥離した後、最後に電気化学エッチングにより微細針構造体骨格部１及び基板４の表面を多孔質化し、薬剤保持部２及び薬剤保持層５を形成することにより本発明における針状体が完成した。   Further, the mask layer 6 is peeled off using sulfuric acid / hydrogen peroxide whose volume ratio of 96% sulfuric acid and 30% hydrogen peroxide is 3: 1, and finally, the fine needle structure skeleton 1 and the substrate 4 are formed by electrochemical etching. The needle-shaped body in the present invention was completed by making the surface of the substrate porous and forming the drug holding part 2 and the drug holding layer 5.

図１（ａ）は、本発明に係る針状体の一例の側面図であり、図１（ｂ）は断面図である。Fig.1 (a) is a side view of an example of the acicular body based on this invention, FIG.1 (b) is sectional drawing. 図２（ａ）は、本発明に係る針状体の一例の側面図であり、図２（ｂ）は、断面図である。Fig.2 (a) is a side view of an example of the acicular body based on this invention, FIG.2 (b) is sectional drawing. 図３は、本発明に係る針状体の一例の側面図または断面図である。FIG. 3 is a side view or a cross-sectional view of an example of a needle-shaped body according to the present invention. 図４は、本発明に係るアレイ状に配置された針状体の一例の断面図である。FIG. 4 is a cross-sectional view of an example of needle-like bodies arranged in an array according to the present invention. 図５（ａ）〜（ｄ）は、本発明に係るアレイ状に配置された針状体を製造するための手順を示す工程図である。5A to 5D are process diagrams showing a procedure for manufacturing the needle-like bodies arranged in an array according to the present invention.

符号の説明Explanation of symbols

１・・・針状体骨格部
２・・・薬剤保持部
３・・・硬質針先端部
４・・・基板
５・・・薬剤保持層
６・・・マスク層
Ｈ・・・針状体
Ｈ’・・・針状体
Ｈ”・・・針状体 DESCRIPTION OF SYMBOLS 1 ... Acicular body frame | skeleton part 2 ... Drug holding part 3 ... Hard needle front-end | tip part 4 ... Board | substrate 5 ... Drug holding layer 6 ... Mask layer H ... Needle-like body H '... Needle H' ... Needle

Claims (11)

微細な針状体において、
針状体を支持する針状体骨格部と、
針状体の少なくとも表面に、多孔質材料からなる薬剤保持部と
を備えたことを特徴とする針状体。 In fine needles,
A needle-like body skeleton that supports the needle-like body;
A needle-like body comprising a needle holder made of a porous material on at least the surface of the needle-like body. 請求項１に記載の針状体であって、
針状体骨格部が、針状体の先端部に表出していること
を特徴とする針状体。 The acicular body according to claim 1,
A needle-like body, wherein the needle-like body skeleton is exposed at the tip of the needle-like body. 請求項1または２のいずれかに記載の針状体であって、
多孔質材料が多孔質シリコンであること
を特徴とする針状体。 The acicular body according to claim 1 or 2,
An acicular body characterized in that the porous material is porous silicon. 請求項１から３のいずれかに記載の針状体であって、
多孔質材料が多孔質ガラスであること
を特徴とする針状体。 The acicular body according to any one of claims 1 to 3,
An acicular body characterized in that the porous material is porous glass. 請求項１から４のいずれかに記載の針状体であって、
前記針状体が、基材上に、アレイ状の形を成して複数配置されていること
を特徴とする針状体。 The needle-shaped body according to any one of claims 1 to 4,
A plurality of needle-like bodies arranged in an array shape on a substrate. 請求項５に記載の針状体であって、
基材表面に、薬剤保持層を有すること
を特徴とする針状体。 The acicular body according to claim 5,
A needle-like body comprising a drug retaining layer on a substrate surface. 微細な針状体の製造方法において、
針状体骨格部を形成する骨格部形成工程と、
前記針状体骨格部の少なくとも表面に多孔質の薬剤保持部を形成する多孔質部形成工程とを備えたことを特徴とする針状体の製造方法。 In the method for producing fine needles,
A skeleton part forming step for forming a needle-like body skeleton part;
A method for producing a needle-like body, comprising: a porous part forming step of forming a porous drug holding part on at least the surface of the needle-like body skeleton part. 請求項７に記載の針状体の製造方法であって、
基材から突出し、アレイ状に配置された針状体骨格部を形成し、
多孔質部形成工程のとき、針状体骨格部の少なくとも表面に多孔質の薬剤保持部と、基材表面に多孔質の薬剤保持層と、を併せて形成すること
を特徴とする針状体の製造方法。 It is a manufacturing method of the acicular body according to claim 7,
Projecting from the base material, forming an acicular skeleton that is arranged in an array,
In the porous part forming step, the needle-like body is characterized by forming a porous drug holding part on at least the surface of the needle-like skeleton part and a porous drug holding layer on the substrate surface. Manufacturing method. 請求項７または８のいずれかに記載の針状体の製造方法であって、
多孔質とする部位を、シリコンを用いて形成し、
多孔質部形成工程に、電気化学エッチング法を用いること
を特徴とする針状体の製造方法。 It is a manufacturing method of the acicular body according to any one of claims 7 and 8,
A porous part is formed using silicon,
A method for producing a needle-like body, wherein an electrochemical etching method is used in the porous portion forming step. 請求項７または８のいずれかに記載の針状体の製造方法であって、
多孔質とする部位を、ガラスを用いて形成し、
多孔質部形成工程に、熱処理の後に酸処理を行うこと
を特徴とする針状体の製造方法。 It is a manufacturing method of the acicular body according to any one of claims 7 and 8,
A porous part is formed using glass,
A method for producing a needle-like body, wherein an acid treatment is performed after the heat treatment in the porous portion forming step. 請求項７から１０のいずれかに記載の針状体の製造方法であって、
骨格部形成工程と、多孔質部形成工程との間に、
針状体骨格部の先端部を保護する工程を行うこと
を特徴とする針状体の製造方法。 It is a manufacturing method of the needlelike object according to any one of claims 7 to 10,
Between the skeleton part forming step and the porous part forming step,
A method of manufacturing a needle-like body, comprising performing a step of protecting the tip of the needle-like body skeleton.
JP2006264636A 2006-09-28 2006-09-28 Acicular body and method for producing acicular body Active JP4954656B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2006264636A JP4954656B2 (en) 2006-09-28 2006-09-28 Acicular body and method for producing acicular body

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2006264636A JP4954656B2 (en) 2006-09-28 2006-09-28 Acicular body and method for producing acicular body

Publications (2)

Publication Number Publication Date
JP2008079919A true JP2008079919A (en) 2008-04-10
JP4954656B2 JP4954656B2 (en) 2012-06-20

Family

ID=39351361

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2006264636A Active JP4954656B2 (en) 2006-09-28 2006-09-28 Acicular body and method for producing acicular body

Country Status (1)

Country Link
JP (1) JP4954656B2 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010069252A (en) * 2008-09-22 2010-04-02 Fujifilm Corp Method for manufacturing transdermal absorption sheet
WO2010126174A1 (en) 2009-05-01 2010-11-04 Nanbu Plastics Co., Ltd. Transdermal administration device
KR101458486B1 (en) * 2014-02-26 2014-11-07 재단법인대구경북과학기술원 Porous acupuncture-needle and Manufacturing method thereof
KR101544867B1 (en) * 2013-07-04 2015-08-17 주식회사 엘지생활건강 Nano-porous microneedle having two layers and its manufacturing method
JP2015531644A (en) * 2012-09-13 2015-11-05 アミール，アブラハム Delivery device and method for skin augmentation
KR101615749B1 (en) * 2016-03-17 2016-04-27 재단법인대구경북과학기술원 Manufacturing method of porous acupuncture-needle
KR101615750B1 (en) * 2014-10-27 2016-04-27 재단법인대구경북과학기술원 Porous acupuncture-needle and Manufacturing method thereof
KR101621945B1 (en) 2015-07-02 2016-05-17 주식회사 엘지생활건강 Nano-porous microneedle having two layers and its manufacturing method
KR101746024B1 (en) * 2016-07-14 2017-06-12 경북대학교 산학협력단 Micro needle which coated porous coating layer and manufacturing method of this and micro needle patch using the micro needle
WO2018199610A1 (en) * 2017-04-26 2018-11-01 재단법인대구경북과학기술원 Porous acupuncture needle plated with noble metal nanoparticles and manufacturing method therefor
WO2019176126A1 (en) * 2018-03-16 2019-09-19 国立大学法人東京大学 Inspection chip and inspection device

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004504120A (en) * 2000-07-21 2004-02-12 グラクソスミスクライン　バイオロジカルズ　ソシエテ　アノニム vaccine
JP2005514179A (en) * 2002-01-15 2005-05-19 スリーエム イノベイティブ プロパティズ カンパニー Microneedle device and manufacturing method
WO2006080508A1 (en) * 2005-01-31 2006-08-03 Bioserentach Co., Ltd. Transdermal absorption preparation, sheet holding transdermal absorption preparation and transdermal absorption preparation holder

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004504120A (en) * 2000-07-21 2004-02-12 グラクソスミスクライン　バイオロジカルズ　ソシエテ　アノニム vaccine
JP2005514179A (en) * 2002-01-15 2005-05-19 スリーエム イノベイティブ プロパティズ カンパニー Microneedle device and manufacturing method
WO2006080508A1 (en) * 2005-01-31 2006-08-03 Bioserentach Co., Ltd. Transdermal absorption preparation, sheet holding transdermal absorption preparation and transdermal absorption preparation holder

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010069252A (en) * 2008-09-22 2010-04-02 Fujifilm Corp Method for manufacturing transdermal absorption sheet
WO2010126174A1 (en) 2009-05-01 2010-11-04 Nanbu Plastics Co., Ltd. Transdermal administration device
US8690838B2 (en) 2009-05-01 2014-04-08 Nanbu Plastics Co., Ltd. Transdermal administration device
JP2015531644A (en) * 2012-09-13 2015-11-05 アミール，アブラハム Delivery device and method for skin augmentation
US10420921B2 (en) 2012-09-13 2019-09-24 Avraham Amir Delivery devices and methods for skin augmentation
KR101544867B1 (en) * 2013-07-04 2015-08-17 주식회사 엘지생활건강 Nano-porous microneedle having two layers and its manufacturing method
US10245211B2 (en) 2014-02-26 2019-04-02 Daegu Gyeongbuk Institute Of Science And Technology Porous acupuncture needle and method for manufacturing same
KR101458486B1 (en) * 2014-02-26 2014-11-07 재단법인대구경북과학기술원 Porous acupuncture-needle and Manufacturing method thereof
WO2015129967A1 (en) * 2014-02-26 2015-09-03 재단법인대구경북과학기술원 Porous acupuncture needle and method for manufacturing same
CN106061455A (en) * 2014-02-26 2016-10-26 大邱庆北科学技术院 Porous acupuncture needle and method for manufacturing same
KR101615750B1 (en) * 2014-10-27 2016-04-27 재단법인대구경북과학기술원 Porous acupuncture-needle and Manufacturing method thereof
WO2016068405A1 (en) * 2014-10-27 2016-05-06 재단법인대구경북과학기술원 Porous hand acupuncture needle and manufacturing method therefor
KR101621945B1 (en) 2015-07-02 2016-05-17 주식회사 엘지생활건강 Nano-porous microneedle having two layers and its manufacturing method
KR101615749B1 (en) * 2016-03-17 2016-04-27 재단법인대구경북과학기술원 Manufacturing method of porous acupuncture-needle
KR101746024B1 (en) * 2016-07-14 2017-06-12 경북대학교 산학협력단 Micro needle which coated porous coating layer and manufacturing method of this and micro needle patch using the micro needle
WO2018199610A1 (en) * 2017-04-26 2018-11-01 재단법인대구경북과학기술원 Porous acupuncture needle plated with noble metal nanoparticles and manufacturing method therefor
WO2019176126A1 (en) * 2018-03-16 2019-09-19 国立大学法人東京大学 Inspection chip and inspection device
CN111836582A (en) * 2018-03-16 2020-10-27 国立大学法人东京大学 Detection chip and detection device
JPWO2019176126A1 (en) * 2018-03-16 2021-03-11 国立大学法人 東京大学 Inspection chip and inspection equipment
JP7129720B2 (en) 2018-03-16 2022-09-02 国立大学法人 東京大学 Inspection chip and inspection device

Also Published As

Publication number Publication date
JP4954656B2 (en) 2012-06-20

Similar Documents

Publication Publication Date Title
JP4954656B2 (en) Acicular body and method for producing acicular body
US9283365B2 (en) Patch production
KR100793615B1 (en) A biodegradable solid type microneedle and methods for preparing it
JP5020080B2 (en) Manufacturing method of medical equipment
JP2009540984A (en) Method for producing porous microneedles and use thereof
WO2006101459A1 (en) Microneedles
JP4908893B2 (en) Medicinal product carrying device, method for producing the same, and method for producing a mold for producing a medicinal product carrying device
JP2008194288A (en) Needle-like body and method for producing needle-like body
KR101261466B1 (en) The method for manufacturing hallow micro needle structures
JP5053645B2 (en) Medicinal product carrying device and method for producing the same
JP2006296924A (en) Acupuncture and moxibustion needle
KR101983970B1 (en) The multi-step stuctured microneedle patch and the producing method for the same
US20120004614A1 (en) Production Process for a Microneedle Arrangement and Corresponding Microneedle Arrangement and Use
JP2009240410A (en) Stylet array and method for manufacturing the array
JP4888011B2 (en) Needle-like body and manufacturing method thereof
JP4978245B2 (en) Needle-shaped body, needle-shaped body manufacturing method, and drug transport device
CN108751120B (en) Preparation method of silicon-based microneedle array patch
JP2005334594A (en) Medication patch with carbon nanotube protrusion
JP5216312B2 (en) Manufacturing method of medical equipment
KR102144831B1 (en) Micro needle array making process
JP2010142474A (en) Needle-shaped body and method for manufacturing the needle-shaped body
JP2011078654A (en) Microneedle array and method of manufacturing microneedle array
WO2011015650A2 (en) Method of producing microneedles
JP2009195378A (en) Manufacturing method of hollow needle-like object and hollow needle-like object
JP2009078074A (en) Method for manufacturing microneedle

Legal Events

Date Code Title Description
A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20090825

A711 Notification of change in applicant

Free format text: JAPANESE INTERMEDIATE CODE: A711

Effective date: 20100625

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20100818

RD03 Notification of appointment of power of attorney

Free format text: JAPANESE INTERMEDIATE CODE: A7423

Effective date: 20110527

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A821

Effective date: 20110527

A977 Report on retrieval

Free format text: JAPANESE INTERMEDIATE CODE: A971007

Effective date: 20110728

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20110802

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20111003

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20120306

A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20120314

R150 Certificate of patent or registration of utility model

Ref document number: 4954656

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

Free format text: JAPANESE INTERMEDIATE CODE: R150

FPAY Renewal fee payment (event date is renewal date of database)

Free format text: PAYMENT UNTIL: 20150323

Year of fee payment: 3

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

S533 Written request for registration of change of name

Free format text: JAPANESE INTERMEDIATE CODE: R313533

R350 Written notification of registration of transfer

Free format text: JAPANESE INTERMEDIATE CODE: R350

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250