JP2009061219A - Manufacturing method of fine needle - Google Patents

Manufacturing method of fine needle Download PDF

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JP2009061219A
JP2009061219A JP2007233911A JP2007233911A JP2009061219A JP 2009061219 A JP2009061219 A JP 2009061219A JP 2007233911 A JP2007233911 A JP 2007233911A JP 2007233911 A JP2007233911 A JP 2007233911A JP 2009061219 A JP2009061219 A JP 2009061219A
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mold
hole
resin
manufacturing
biodegradable resin
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Hidenori Yoshimura
英徳 吉村
Yutaka Mihara
豊 三原
Fumikazu Ohira
文和 大平
Hidetoshi Hamamoto
英利 濱本
Sakaki Ishibashi
賢樹 石橋
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MedRx Co Ltd
Kagawa University NUC
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MedRx Co Ltd
Kagawa University NUC
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    • 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

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Medical Informatics (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

<P>PROBLEM TO BE SOLVED: To manufacture massive quantities of fine needles having a stable quality without defection at the tip by using of a biodegradable resin. <P>SOLUTION: In the provided method, the transcription process is performed from a transition point of a biodegradable resin to the proximity of the melting point by using a metal mold having a penetrating hole corresponding to a desired fine needle, and the resin is demolded in adjacency to the transition point, thereby manufacturing resin-made fine needles. It results in that the tip part of the fine needle is difficult to have defection with a high reliability of the product specification. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

本発明は微小針の製造方法に関するものである。特に生体分解性の材料で構築され、アレイ（行列）状に形成された多数の微小針の製造方法に関する。   The present invention relates to a method for manufacturing a microneedle. In particular, the present invention relates to a method for manufacturing a large number of microneedles constructed of a biodegradable material and formed in an array (matrix).

薬剤を経皮的に投与する方法として、通常、皮膚表面への液剤・軟膏剤の塗布、貼付剤型の経皮投与製剤が用いられてきた。皮膚は、ヒトの場合、通常、厚さ１０〜３０μｍの層状構造を持つ角質層と、厚さ約７０μｍの表皮組織層と、厚さ約２ｍｍの真皮組織層の複数の組織から構成されている。
角質層は、皮膚の最上位にあって層状をなし、種々の薬剤が皮膚から浸透するのを防ぐ、バリヤーの働きを行っている。一般的には、皮膚のバリヤー作用の約５０〜約９０％は角質層で行われている。表皮層では角質層ほどのバリヤー作用を果たさないが、残りの約１０％以上のバリヤー作用を果たしている。一方、真皮は、真皮層と表皮層の接合部付近に豊富な毛細血管網があり、そのため、薬剤が一度真皮の深さに到達すると、その毛細血管網を伝わって、より深部の組織（毛包、筋肉等）に素早く拡散する。そして、毛細血管から血液循環を経由して薬剤が全身に拡散される。 As a method for transdermally administering a drug, generally, a liquid or ointment applied to the skin surface, or a patch-type transdermal administration preparation has been used. In the case of human beings, the skin is usually composed of a plurality of tissues including a stratum corneum having a layered structure having a thickness of 10 to 30 μm, an epidermal tissue layer having a thickness of about 70 μm, and a dermal tissue layer having a thickness of about 2 mm. .
The stratum corneum is layered on top of the skin and acts as a barrier to prevent the penetration of various drugs from the skin. In general, about 50 to about 90% of the skin barrier action occurs in the stratum corneum. The skin layer does not perform as much barrier action as the stratum corneum, but performs the remaining 10% or more barrier action. On the other hand, the dermis has an abundant capillary network near the junction between the dermis layer and the epidermis layer. Therefore, once the drug reaches the depth of the dermis, it travels through the capillary network and becomes deeper in tissues (hairs). Quickly spread to wraps, muscles, etc.) Then, the drug is diffused from the capillaries through the blood circulation throughout the body.

今日、各種の液剤・軟膏剤の塗布、貼付剤型の経皮投与製剤が開発されているが、上記角質層のバリヤー作用のため、あまり薬効成分が吸収されていない状況にある。例えば、経皮吸収効率が高いと言われているインドメタシンの経皮投与製剤においてすら、インドメタシン全量の５％程度が経皮吸収されているに過ぎないとされている。
そこで、薬剤の皮膚透過性を上げるための方法の一つとして、特許文献１に示されるように、微小針（マイクニードルまたはマイクロシリンジ）を使用し、角質層を局所的に破壊して薬剤を真皮層に強制的に投与すると言うことが試みられてきた。
この目的で使用される微小針は、真皮層に微小針が到達すればよいことから、その針の長さは３０μｍ以上であることが望ましく、その針を支持するために必要な基盤があればよいとされている。しかも、この微小針は、神経の末端が存在する真皮層に到達しないので痛くない。それ故、小児などに恐怖感を与えることなく薬剤の投与ができると言う長所が存在する。 Today, various liquid / ointment coatings and patch-type transdermal preparations have been developed. However, due to the barrier action of the stratum corneum, the medicinal components are not so much absorbed. For example, even in the formulation of indomethacin transdermally administered, which is said to have high transdermal absorption efficiency, it is said that only about 5% of the total amount of indomethacin is absorbed percutaneously.
Therefore, as one of the methods for increasing the skin permeability of the drug, as shown in Patent Document 1, a microneedle (microphone needle or microsyringe) is used to locally destroy the stratum corneum and remove the drug. Attempts have been made to force administration to the dermis layer.
Since the microneedle used for this purpose only needs to reach the dermis layer, the length of the needle is preferably 30 μm or more, and if there is a base necessary to support the needle It is said to be good. Moreover, this microneedle does not hurt because it does not reach the dermis layer where the nerve ends are present. Therefore, there is an advantage that the drug can be administered without giving fear to children.

これまで微小針の製造方法に関して、色々な方法が報告されている。しかしその大半は、特許文献２に示されるように半導体を作製する際に用いられるＸ線照射のエッチングなどの方法を使用して、シリコン製、ガラス製、金属製の微小針を作製している。しかし、この製法では製造コストが高額となり、また破損等の問題で残留した微小針の破片が人体に障害を与えることとなる。
そこで、これを改善するために、例えば特許文献３では、ホトレジスト材料のポリメタアクリル酸メチル(ＰＭＭＡ)を用いてＸ線を照射し微小針の母型を作製し、これに金属メッキを施して母型を外し、金属の鋳雌型を作製している。この金属の鋳型に加熱ポリマー材料を押圧して、鋳型を外して目的の樹脂性微小針を作製している。
しかし、このような鋳型を使った微小針の製造方法では、鋳型から微小針を取り出す際に、摩擦応力が懸かって、微小針の先端部が欠けやすくなっている。そのため、品質のよい、先端部の欠損がない微小針を得ることは困難な状況にあった。 Various methods have been reported so far regarding methods for producing microneedles. However, most of them produce silicon, glass, and metal microneedles using a method such as etching of X-ray irradiation used when producing a semiconductor as shown in Patent Document 2. . However, in this manufacturing method, the manufacturing cost is high, and the fragments of the microneedles remaining due to problems such as breakage damage the human body.
Therefore, in order to improve this, for example, in Patent Document 3, a matrix material of a microneedle is produced by irradiating X-rays using a photoresist material polymethyl methacrylate (PMMA), and this is subjected to metal plating. The mother mold is removed, and a metal cast female mold is produced. A heated polymer material is pressed against the metal mold, and the mold is removed to produce a target resinous microneedle.
However, in such a microneedle manufacturing method using a mold, when the microneedle is taken out of the mold, frictional stress is applied and the tip of the microneedle is easily chipped. For this reason, it has been difficult to obtain a microneedle having a good quality and having no tip portion defect.

従って、現在の経皮吸収用の微小針の課題は、生体分解性の材料で形成された、ある一定の強度および耐久性を持った微小針をどのように作製するかである。更に、このような微小針は、通常使い捨てのものであるので、コスト的にも安価なものであることが必要とされている。   Therefore, the problem of the present microneedle for percutaneous absorption is how to produce a microneedle made of a biodegradable material and having a certain strength and durability. Furthermore, since such a microneedle is usually disposable, it is required to be inexpensive.

特開２００６‐１４９８１８JP 2006-149818 A 特表２００２‐５１７３００Special Table 2002-517300 特表２００３‐５０１１６３Special table 2003-501163

本発明の課題は、生体分解性材料を用いて、剣山型微小針を安価且つ量産規模で製造することを目的とする。更に詳しくは微小針の先端部分が欠けずに揃っている、規格信頼性の高い製造方法を提供することである。   An object of the present invention is to produce a Kenyama microneedle at low cost and on a mass production scale using a biodegradable material. More specifically, the present invention is to provide a manufacturing method with high standard reliability in which the tip portions of the microneedles are aligned without being chipped.

微小針の先端部分が欠ける原因は、微小針の鋳型と転写された樹脂との間に働く摩擦応力に主によるものである。鋳型と樹脂間の摩擦応力が、樹脂の破断強度を上回った時に先端部の欠損が生じることになる。この摩擦応力を減少させるためには、２つの方法がある。一つには、鋳型を適切なコーテイング剤でコートし、鋳型と樹脂の間の摩擦抵抗を減少させる方法である。また一つには、樹脂の温度を昇温させて軟化させ、摩擦抵抗を低下させる方法である。
本発明者らは、上記２つの方向性に関して鋭意検討を行った結果、微小針の鋳型には無貫通孔型ではなく貫通孔型のものが先端部の欠損率が少ないことを見出した。更に、この貫通孔にフッ素樹脂処理または金属メッキ処理をすることで、樹脂製の微小針の離型の際の鋳型側の摩擦抵抗を減少させることができた。また、離型の際の樹脂の温度を、遷移点（ガラス転移温度）を越えた近傍の温度で行うことにより、樹脂を軟化させ樹脂側の摩擦抵抗を減少させることができた。本発明者らは、これらの知見を総合してコスト的に安価で、量産可能な微小針の製造方法を完成した。 The cause of the lack of the tip of the microneedle is mainly due to the frictional stress acting between the mold of the microneedle and the transferred resin. When the frictional stress between the mold and the resin exceeds the breaking strength of the resin, the tip portion is lost. There are two ways to reduce this frictional stress. One is to coat the mold with a suitable coating agent to reduce the frictional resistance between the mold and the resin. Another method is to raise the temperature of the resin and soften it to reduce the frictional resistance.
As a result of intensive studies on the above-mentioned two directions, the present inventors have found that the microneedle mold has a through-hole type rather than a non-through-hole type and has a low defect rate at the tip. Furthermore, by applying a fluororesin treatment or a metal plating treatment to the through hole, it was possible to reduce the frictional resistance on the mold side when releasing the resin microneedle. Further, by performing the resin temperature at the time of mold release near the transition point (glass transition temperature), the resin was softened and the frictional resistance on the resin side could be reduced. The present inventors combined these findings and completed a manufacturing method of microneedles that is inexpensive and can be mass-produced.

即ち、本発明の要旨は以下の通りである。
（１）生体分解性樹脂の微小針の製造方法であって、
ａ）円柱状または円錐状の貫通孔を有する金属製またはフッ素樹脂製の平板を作成し、金属製平板の貫通孔にはフッ素樹脂コーテイングまたは金属メッキを行い、鋳型とする、
ｂ）生体分解性樹脂を加熱し、樹脂の遷移点から融点近傍で該鋳型に圧着させて転写加工を行う。
ｃ）樹脂の遷移点付近で、鋳型から樹脂を離型させる、
ことからなる、微小針の製造方法。
（２）生体分解性樹脂を減圧下に鋳型に圧着させることからなる、上記（１）に記載の製造方法。
（３）生体分解性樹脂がポリ乳酸である、上記（１）又は（２）に記載の製造方法。
（４）生体分解性樹脂がポリ乳酸であり、５０〜９０℃で転写加工を行い、５０℃付近の温度で離型させることを特徴とする、上記（１）〜（３）のいずれかに記載の製造方法。
（５）薬効成分が生体分解性樹脂に混合されている、上記（１）〜（４）のいずれかに記載の製造方法。
（６）円柱状または円錐状の貫通孔が以下の形状であることを特徴とする、上記（１）〜（５）のいずれかに記載の製造方法。
ａ）貫通孔の長さが３０μｍ〜２ｍｍであり、
ｂ）貫通孔の最大径が５０μｍ〜２００μｍである。
（７）フッ素樹脂コーテイングの厚さが少なくとも２０μｍ〜５０μｍである、上記（１）〜（６）のいずれかに記載の製造方法。
（８）フッ素樹脂コーテイングとして、ポリテトラフルオロエチレン（ＰＴＦＥ)の微粒子を均一に分散共析させたニッケル皮膜をコーテイングするものである、上記（１）〜（７）のいずれかに記載の製造方法。
（９）金属メッキがクロムメッキである、上記（１）〜（６）のいずれかに記載の製造方法。
（１０）金属メッキの膜厚が２０〜５０μｍである、上記（１）〜（６）のいずれかに記載の製造方法。
（１１）鋳型に圧着させて転写加工を行うことが、生体分解性樹脂が貫通孔をあふれ出ないように圧着することである、上記（１）〜（８）のいずれかに記載の製造方法。
（１０）以下の形状の円柱状または円錐状の貫通孔を有する金属製またはテフロン樹脂製の平板鋳型であって、金属製平板の貫通孔にはフッ素樹脂コーテイングまたは金属メッキが行われたもの、
ａ）平板の厚さが３０μｍ〜２ｍｍであり、
ｂ）貫通孔の最大径が５０μｍ〜２００μｍであり、
ｃ）貫通孔の本数が１０〜５００本である、
ことを特徴とする微小針作製用の鋳型。
That is, the gist of the present invention is as follows.
(1) A method for producing a biodegradable resin microneedle,
a) A flat plate made of metal or fluororesin having a cylindrical or conical through hole is prepared, and the through hole of the metal flat plate is subjected to fluororesin coating or metal plating to form a mold.
b) The biodegradable resin is heated, and the transfer process is performed by pressing the biodegradable resin to the mold near the melting point from the transition point of the resin.
c) The resin is released from the mold near the transition point of the resin.
The manufacturing method of a microneedle which consists of this.
(2) The production method according to (1) above, wherein the biodegradable resin is pressure-bonded to the mold under reduced pressure.
(3) The production method according to (1) or (2) above, wherein the biodegradable resin is polylactic acid.
(4) The biodegradable resin is polylactic acid, which is subjected to transfer processing at 50 to 90 ° C. and is released at a temperature near 50 ° C., in any one of the above (1) to (3) The manufacturing method as described.
(5) The manufacturing method in any one of said (1)-(4) with which a medicinal component is mixed with biodegradable resin.
(6) The manufacturing method according to any one of (1) to (5) above, wherein the cylindrical or conical through-hole has the following shape.
a) The length of the through hole is 30 μm to 2 mm,
b) The maximum diameter of the through hole is 50 μm to 200 μm.
(7) The manufacturing method according to any one of the above (1) to (6), wherein the thickness of the fluororesin coating is at least 20 μm to 50 μm.
(8) The manufacturing method according to any one of (1) to (7), wherein the coating is a nickel film in which fine particles of polytetrafluoroethylene (PTFE) are uniformly dispersed and co-deposited as the fluororesin coating. .
(9) The manufacturing method according to any one of (1) to (6), wherein the metal plating is chromium plating.
(10) The manufacturing method according to any one of (1) to (6), wherein the metal plating has a thickness of 20 to 50 μm.
(11) The manufacturing method according to any one of the above (1) to (8), wherein the transfer processing is performed by pressure-bonding to a mold so that the biodegradable resin does not overflow the through-hole. .
(10) A flat plate mold made of metal or Teflon resin having a cylindrical or conical through hole having the following shape, wherein the through hole of the metal flat plate is subjected to fluororesin coating or metal plating,
a) The thickness of the flat plate is 30 μm to 2 mm,
b) The maximum diameter of the through hole is 50 μm to 200 μm,
c) The number of through holes is 10 to 500.
A mold for producing a microneedle characterized by the above.

本発明の製造方法では、所望の微小針に対応する貫通孔を有する、フッ素樹脂製または金属製の平板鋳型を用いて、生体分解性樹脂に対して遷移点から融点近傍の範囲で転写加工を減圧下に行い、遷移点近傍で樹脂と鋳型を離型させ、それによって樹脂製の微小針を製造する方法である。このため、微小針の先端部分に欠損が生じ難く、製品規格的に信頼性が高いものとなっている。
In the production method of the present invention, transfer processing is performed in a range from the transition point to the melting point of the biodegradable resin using a fluororesin or metal flat plate mold having a through hole corresponding to a desired microneedle. In this method, the resin and the mold are released in the vicinity of the transition point under reduced pressure, thereby producing a resin microneedle. For this reason, it is hard to produce a defect | deletion in the front-end | tip part of a microneedle, and it is a thing with high reliability in product specification.

−本発明の第１態様―
本発明の第一の態様は生体分解性樹脂製の微小針の製造方法に関するものである。
本発明の製造方法は、図１に示すように、フッ素樹脂製または金属製の平板に円柱状もしくは円錐状の貫通孔を有し、金属製平板の場合その貫通孔がフッ素樹脂コーティングまたは金属メッキされているものを鋳型として使用する。そして、使用する生体分解性樹脂を遷移点から融点近傍の範囲の温度になるよう加熱し、減圧下、鋳型に圧着する。図２に示すように、鋳型に樹脂が充填された後、樹脂の遷移点（ガラス転移温度）を超えた、それに近い近傍の温度で離型を行う。離型後の樹脂製微小針を常温に放冷する。以上のプロセスで、先端部に欠損の少ない微小針が得られる。例えば、ポリ乳酸の場合、遷移点から融点近傍の温度範囲は５０℃〜９０℃となっており、この温度範囲で転写工程を行い、５０℃付近で離型することが望ましい。 -First aspect of the present invention-
The first aspect of the present invention relates to a method for producing a microneedle made of a biodegradable resin.
As shown in FIG. 1, the manufacturing method of the present invention has a cylindrical or conical through-hole in a fluororesin or metal flat plate, and in the case of a metal flat plate, the through-hole has a fluororesin coating or metal plating. What is being used is used as a template. Then, the biodegradable resin to be used is heated to a temperature in the range from the transition point to the vicinity of the melting point, and pressed against the mold under reduced pressure. As shown in FIG. 2, after the mold is filled with the resin, the mold release is performed at a temperature close to and exceeding the transition point (glass transition temperature) of the resin. The resin microneedle after mold release is allowed to cool to room temperature. Through the above process, a microneedle with few defects at the tip can be obtained. For example, in the case of polylactic acid, the temperature range from the transition point to the vicinity of the melting point is 50 ° C. to 90 ° C., and it is desirable to perform the transfer process in this temperature range and release the mold at about 50 ° C.

本発明で言う「生体分解性樹脂」とは、生体内で分解して完全に溶解する高分子樹脂の中で、その分解物が生体に有害でないものを言う。例えば、ポリ乳酸、ポリカプロラクトン、ポリブチレンサクシネート、ポリ（ブチレンサクシネート／アジペート）、ポリ（ブチレンサクシネート／カーボネート）、ポリエチレンサクシネート、ポリアスパラギン酸等の化学合成高分子、例えば、コラーゲン等の天然高分子等を挙げることができる。好ましいものとしては、薬効成分を混合することを考慮すれば、遷移点が低いものが望ましく、例えばポリ乳酸、ポリカプロラクトン、ポリアスパラギン酸、ポリ（３‐ヒドロキシブタン酸）等を挙げることができる。
本発明で「フッ素樹脂」とは、ポリテトラフルオロエチレンを中心とする各種フッ素樹脂のことを言い、例えば、ポリテトラフルオロエチレン(４フッ化)、テトラフルオロエチレン・パーフルオロアルキルビニルエーテル共重合体、テトラフルオロエチレン・ヘキサフルオロプロピレン共重合体(４．６フッ化)、テトラフルオロエチレン・エチレン共重合体、ポリビニリデンフルオライド(２フッ化)、ポリクロロトリフルオロエチレン(３フッ化)、クロロトリフルオエチレン・エチレン共重合体を挙げることができる。好ましいものとして、生体分解性樹脂の遷移点から融点近傍の温度範囲で軟化せず、転写工程で変形しない物性のものが挙げられ、例えばポリテトラフルオロエチレン(４フッ化)、テトラフルオロエチレン・パーフルオロアルキルビニルエーテル共重合体、テトラフルオロエチレン・ヘキサフルオロプロピレン共重合体(４．６フッ化)、テトラフルオロエチレン・エチレン共重合体を挙げることができる。
本発明で「金属」とは、鋳型として使用できる金属であれば特に限定はされないが、例えば鋼材、銅、真鍮等を挙げることができる。より好ましくは、鋳型の耐久性や微細孔の切削性を考慮して鋼材、たとえばＳＳ４００をあげることができる。
本発明で言う「圧着」とは、樹脂の軟化状態にもよるが、貫通孔に樹脂が充填するように樹脂に圧力をかけることを言う。例えば、ポリ乳酸樹脂のシートを軟化させ、２〜５ｋｇ／ｃｍ２の範囲で鋳型に樹脂を圧着する。その際、常圧で圧着してもよいが、減圧下で圧着を行えば、貫通孔への樹脂の充填をより加速できる。例えば１０Ｐａ近傍の陰圧下で行うことができる。これにより微小針製品に空孔が生じることを回避できる。その結果、微小針の強度低下を避けることが出来る。
なお、鋳型に圧着させて樹脂に転写加工を行う際には、離型の容易さを考慮して、貫通孔から樹脂があふれ出さないようにすることが必要である。また、樹脂が貫通孔をあふれ出た場合には、あふれ出た樹脂を削除し、離型に際して障害が起きないようにする。
本発明で言う「減圧下」とは、樹脂の軟化の状況に応じて、適宜、調整できる。通常は、０.５ｍｍＨｇ〜弱陰圧の減圧下で行うことが望ましい。 The “biodegradable resin” as used in the present invention refers to a polymer resin that decomposes and dissolves completely in the living body, and the decomposition product is not harmful to the living body. For example, chemically synthesized polymers such as polylactic acid, polycaprolactone, polybutylene succinate, poly (butylene succinate / adipate), poly (butylene succinate / carbonate), polyethylene succinate, polyaspartic acid, such as collagen Examples include natural polymers. Preferred are those having a low transition point in view of mixing medicinal ingredients, such as polylactic acid, polycaprolactone, polyaspartic acid, poly (3-hydroxybutanoic acid) and the like.
In the present invention, the “fluororesin” refers to various fluororesins mainly composed of polytetrafluoroethylene, such as polytetrafluoroethylene (tetrafluoroethylene), tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer, Tetrafluoroethylene / hexafluoropropylene copolymer (4.6 fluoride), tetrafluoroethylene / ethylene copolymer, polyvinylidene fluoride (difluoride), polychlorotrifluoroethylene (trifluoride), chlorotrifluoro Mention may be made of ethylene / ethylene copolymers. Preferable examples include physical properties that do not soften in the temperature range from the transition point of the biodegradable resin to the melting point and do not deform in the transfer process. For example, polytetrafluoroethylene (tetrafluoroethylene), tetrafluoroethylene par Examples thereof include a fluoroalkyl vinyl ether copolymer, a tetrafluoroethylene / hexafluoropropylene copolymer (4.6 fluoride), and a tetrafluoroethylene / ethylene copolymer.
In the present invention, the “metal” is not particularly limited as long as it is a metal that can be used as a mold, and examples thereof include steel, copper, and brass. More preferably, a steel material such as SS400 can be used in consideration of the durability of the mold and the machinability of the fine holes.
The term “crimping” as used in the present invention refers to applying pressure to the resin so that the resin fills the through hole, although it depends on the softened state of the resin. For example, a sheet of polylactic acid resin is softened and the resin is pressure-bonded to the mold in the range of 2 to 5 kg / cm 2 . At this time, pressure bonding may be performed at normal pressure, but if pressure bonding is performed under reduced pressure, filling of the resin into the through hole can be accelerated. For example, it can be performed under a negative pressure in the vicinity of 10 Pa. Thereby, it can avoid that a void | hole produces in a microneedle product. As a result, it is possible to avoid a decrease in strength of the microneedles.
In addition, when the resin is transferred to the mold by being pressure-bonded, it is necessary to prevent the resin from overflowing from the through hole in consideration of easy release. Further, when the resin overflows the through hole, the overflowed resin is deleted so that no trouble occurs during the mold release.
In the present invention, “under reduced pressure” can be appropriately adjusted according to the softening state of the resin. Usually, it is desirable to carry out under a reduced pressure of 0.5 mmHg to weak negative pressure.

本発明で言う「フッ素樹脂コーテイング」とは、金属表面の潤滑処理に使われるものであれば特に限定されるものではないが、例えば、ポリテトラフルオロエチレン、テトラフルオロエチレン・ヘキサフルオロプロピレン共重合体、テトラフルオロエチレン・エチレン共重合体、テトラフルオロエチレン・パーフルオロアルキルビニルエーテル共重合体、ポリクロロトリフルオロエチレン、ポリビニリデンフルオライド等から、状況に応じて適宜一つ又は複数を選択して常法によりコーテイングすることができる。好ましくは、無電解ニッケルメッキの処理により、２０〜３５％のポリテトラフルオロエチレンを均一に分散共析コーテイングすることを挙げることができる。このコーテイングにより、金属加工表面の凹凸をマスクして円滑化すると共に、鋳型に対する樹脂の粘着性を抑制できる。従って、フッ素樹脂コーテイングの厚さは、金属加工の精度にもよるが、通常の場合、少なくとも２０〜５０μｍの厚さがあれば、より好ましくは２０〜３０μｍの厚さがあれば機械加工や微細放電加工技術による貫通孔の内部の凹凸をコーテイングして円滑化することができる。
本発明で言う「金属メッキ」とは、金属表面の潤滑処理に使われるものであれば特に限定されるものではないが、耐摩耗性のあるものが望ましい。例えばクロムメッキ等を好ましいものとして挙げることができる。金属メッキについてもフッ素樹脂コーテイングと同様に２０〜３０μｍの厚さがあれば機械加工や微細放電加工技術による貫通孔の内部の凹凸をコーテイングして円滑化することができる。
本発明で言う「離型」とは、鋳型から樹脂を分離することを言う。離型の際の樹脂温度については、好ましくは樹脂の微小針部分については遷移点を越えた、遷移点近傍の温度で分離することが望ましいが、微小針の基盤部分の温度は、樹脂の変形を防ぐために遷移点以下になっていることが望ましい。
なお、生体分解性樹脂を鋳型に圧着させ、樹脂が貫通孔をあふれ出て固化する場合には、離型が困難になる。従って、離型を容易にするために、樹脂が貫通孔をあふれ出ないようにすることが必要である。万一、あふれ出た場合には、平板上にあふれ出て固化した部分をきれいに削除し、離型に影響が出ないようにする必要がある。 The “fluororesin coating” referred to in the present invention is not particularly limited as long as it is used for lubrication of metal surfaces. For example, polytetrafluoroethylene, tetrafluoroethylene / hexafluoropropylene copolymer , Tetrafluoroethylene / ethylene copolymer, tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer, polychlorotrifluoroethylene, polyvinylidene fluoride, etc. Can be coated. Preferably, 20 to 35% polytetrafluoroethylene can be uniformly dispersed and co-deposited by electroless nickel plating. By this coating, the unevenness of the metal processed surface can be masked and smoothed, and the adhesiveness of the resin to the mold can be suppressed. Therefore, although the thickness of the fluororesin coating depends on the precision of metal processing, in general, if the thickness is at least 20 to 50 μm, more preferably 20 to 30 μm, machining or fine processing is possible. The unevenness inside the through hole can be coated and smoothed by the electric discharge machining technique.
The “metal plating” referred to in the present invention is not particularly limited as long as it is used for the lubrication treatment of the metal surface, but is preferably wear-resistant. For example, chrome plating can be cited as a preferable one. Similarly to the fluororesin coating, the metal plating can be smoothed by coating the unevenness inside the through-holes by machining or fine electrical discharge machining technology if it has a thickness of 20 to 30 μm.
“Release” in the present invention refers to separation of a resin from a mold. Regarding the resin temperature at the time of mold release, it is desirable to separate the resin microneedles at a temperature in the vicinity of the transition point that exceeds the transition point. In order to prevent this, it is desirable to be below the transition point.
Note that when the biodegradable resin is pressure-bonded to the mold and the resin overflows the through-hole and solidifies, it becomes difficult to release the mold. Therefore, in order to facilitate mold release, it is necessary to prevent the resin from overflowing the through holes. In the unlikely event that it overflows, it is necessary to cleanly remove the portion that overflowed and solidified on the flat plate so that the mold release is not affected.

本発明で言う「薬効成分」とは、非経口投与されるものであれば特に限定されるものではないが、生体分解性樹脂の遷移点の温度で安定な薬効成分が好ましい。例えば、皮下注射や静脈注射に用いられる薬効成分の中で、熱安定性の良いものを使用することができる。例えば、リスペリドン、オランザピン、クロザピン等の抗精神病薬、例えばインドメタシン、エトドラグ、ジクロフェナク等の非ステロイド性消炎鎮痛剤、リドカイン、ジブカイン等の局所麻酔剤などを挙げることができる。
なお、薬効成分は生体分解性樹脂と共に練り合わせ加温し、樹脂の遷移点以上の温度で融解することが望ましい。これにより薬効成分を含有する樹脂製微小針を作製することができる。 The “medicinal component” referred to in the present invention is not particularly limited as long as it is administered parenterally, but a medicinal component that is stable at the temperature of the transition point of the biodegradable resin is preferable. For example, among the medicinal ingredients used for subcutaneous injection and intravenous injection, those having good heat stability can be used. For example, antipsychotics such as risperidone, olanzapine and clozapine, non-steroidal anti-inflammatory analgesics such as indomethacin, etodolag and diclofenac, and local anesthetics such as lidocaine and dibucaine can be mentioned.
It is desirable that the medicinal component is kneaded and heated together with the biodegradable resin and melted at a temperature equal to or higher than the transition point of the resin. Thereby, a resin microneedle containing a medicinal component can be produced.

−本発明の第２態様―
本発明の第２態様としては、微小針を製造するための鋳型に関するものである。
本発明で言う「平板鋳型」とは、微小針の高さに応じた厚みを持つテフロン製平板や金属製平板に、機械加工や微細放電加工技術により複数の貫通孔が空けられているものを言う。
貫通孔の形状は、開口部の径が最大部分で５０〜２００μｍ程度で、形状は大きな円柱状もしくは円錐状の穴である。図２に示されるように、貫通孔にフッ素樹脂コーティングを行い、マイクロニードルの寸法の孔径を形成させる。好ましい開口部の最大径は８０〜１２０μｍである。
なお、フッ素樹脂製または金属製の金型の厚みは、３０μｍ〜２ｍｍであり、より好ましくは、３０μｍ〜１ｍｍである。 -Second aspect of the present invention-
As a 2nd aspect of this invention, it is related with the casting_mold | template for manufacturing a microneedle.
The term “flat plate mold” as used in the present invention refers to a Teflon flat plate or metal flat plate having a thickness corresponding to the height of a microneedle, in which a plurality of through holes are formed by machining or micro electric discharge machining technology. To tell.
The shape of the through hole is a large columnar or conical hole with the diameter of the opening being about 50 to 200 μm at the maximum portion. As shown in FIG. 2, a fluororesin coating is applied to the through hole to form a hole diameter of the size of the microneedle. The maximum diameter of a preferable opening is 80 to 120 μm.
The thickness of the fluororesin or metal mold is 30 μm to 2 mm, and more preferably 30 μm to 1 mm.

本発明の鋳型は貫通孔を有することを特徴としており、無貫通孔を有する鋳型よりも優れた機能を有している。例えば、図２に示されるように、樹脂の圧着を行う場合、無貫通孔の鋳型であれば生体分解性樹脂によって孔がふさがり空気が抜けず充分に樹脂が流入しないことが起きる。また、離型を行う場合には、無貫通孔の鋳型であれば図２のように空気溜りが陰圧になり樹脂の離型が難しくなり、針が折れたりすることが生じる。しかし、貫通孔を有する本発明の鋳型では上記の障害は解消されている。
更に、減圧下で圧着を行うことにより、鋳型への樹脂の流入充填は加速される。しかし、無貫通孔の鋳型であれば、返って離型の際に大きな陰圧の負荷が掛かるので、微小針の先端部分が破損して鋳型に残留することになる。本発明の貫通孔の鋳型であれば、減圧下で行うことにより、製品の微小針に空気が混入せず、微小針の強度を維持し、更には微小針の先端部分の欠失の少ない品質の安定した製品を製造することができるようになっている。 The mold of the present invention is characterized by having through holes, and has a function superior to that of a mold having no through holes. For example, as shown in FIG. 2, when a resin is pressure-bonded, if the mold is a non-through hole, the hole may be blocked by the biodegradable resin and the air will not escape and the resin will not flow sufficiently. Further, when mold release is performed, if the mold has no through holes, the air pocket becomes a negative pressure as shown in FIG. 2, making it difficult to release the resin, and the needle may be broken. However, the above-described obstacles are eliminated in the mold of the present invention having a through hole.
Furthermore, the inflow filling of the resin into the mold is accelerated by performing the pressure bonding under reduced pressure. However, in the case of a mold with no through-hole, a large negative pressure load is applied when releasing the mold, so that the tip portion of the microneedle is damaged and remains in the mold. With the through-hole mold of the present invention, by performing under reduced pressure, air is not mixed into the microneedles of the product, the strength of the microneedles is maintained, and furthermore, the quality of the tip portion of the microneedles is small. It is now possible to manufacture stable products.

以下に実施例を挙げて本発明をより具体的に説明するが、本発明は、下記実施例によって限定されるものではなく、前・後記の趣旨に適合しうる範囲で適宜変更して実施することも可能であり、それらはいずれも本発明の技術的範囲に包含される。   The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to the following examples, and may be appropriately modified and implemented within a range that can meet the purpose described above and below. All of which are within the scope of the present invention.

（実施例１）金属製およびフッ素樹脂製鋳型の製造
ポリ乳酸を押し付けることによって剣山状に成形する図３のＡ部（ＳＳ４００鋼材）は，厚み１ｍｍのところに直径２００μｍの貫通穴が４００μｍ間隔で縦横１５行×１５列，計２２５個機械加工にてあけられている。ドリルを使用し，送り速度を遅くすることで図４に示すように貫通孔の内表面の粗さをできるだけ小さくし滑らかにしている．ポリテトラフルオロエチレン型の場合も厚み１ｍｍのポリテトラフルオロエチレンに貫通孔列を機械加工で同様にあける。 (Example 1) Manufacture of metal and fluororesin molds Part A of Fig. 3 (SS400 steel material) molded into a sword shape by pressing polylactic acid has 200 mm diameter through holes at 400 mm intervals at a thickness of 1 mm. Vertical and horizontal 15 rows x 15 columns, a total of 225 holes are machined. By using a drill and slowing the feed rate, the inner surface roughness of the through-hole is made as small and smooth as possible as shown in Fig. 4. In the case of the polytetrafluoroethylene type, a through-hole array is similarly formed by machining in polytetrafluoroethylene having a thickness of 1 mm.

（実施例２）金属鋳型の貫通孔へのフッ素樹脂コーテイング
実施例１で得られた金属鋳型の表面スケールを除去した後、ポリテトラフルオロエチレン微粒子を含む無電解ニッケル液に浸漬し、均一な分散共析コーテイングを行う。水洗後乾燥し、熱処理（３００℃×１ｈｒ）を行って、被膜中に２０〜３５％のポリテトラフルオロエチレンを含有するニッケルメッキを行った。被覆された貫通孔を図５に示す。
図５に示されるように、貫通孔の内表面がポリテトラフルオロエチレンコーティングによって微細な凹凸が消され，一層平滑化されていることが分かる。
なお、この時の機械加工による貫通孔の凹凸は約２０〜３０μｍ以下の範囲であった。 (Example 2) Coating of fluororesin into through hole of metal mold After removing the surface scale of the metal mold obtained in Example 1, it was immersed in an electroless nickel solution containing polytetrafluoroethylene fine particles, and uniformly dispersed Perform eutectoid coating. After washing with water and drying, heat treatment (300 ° C. × 1 hr) was performed, and nickel plating containing 20 to 35% polytetrafluoroethylene in the coating was performed. The coated through hole is shown in FIG.
As shown in FIG. 5, it can be seen that the inner surface of the through hole is smoothed by the fine irregularities removed by the polytetrafluoroethylene coating.
In addition, the unevenness | corrugation of the through-hole by the machining at this time was the range of about 20-30 micrometers or less.

（実施例３）ポリ乳酸を用いた微小針の製造
実施例２で得られたフッ素樹脂コーティングされた金属鋳型に融点近傍まで加熱したポリ乳酸シートを常圧下、圧着して貫通穴にポリ乳酸を流入充填させる。次に遷移点近傍の温度まで冷却してポリ乳酸と鋳型を離型させ、剣山形状の微小針を製造した。
得られたポリ乳酸の剣山形状の微小針は、図６に示されるように直径約７０μｍ、高さ６００μｍの針が並んでいる。

(Example 3) Manufacture of microneedles using polylactic acid A polylactic acid sheet heated to the vicinity of the melting point was pressed on the fluororesin-coated metal mold obtained in Example 2 under normal pressure, and the polylactic acid was applied to the through hole. Fill with inflow. Next, it was cooled to a temperature in the vicinity of the transition point to release the polylactic acid and the mold, thereby producing a sword-shaped microneedle.
As shown in FIG. 6, the obtained polylactic acid sword mountain-shaped microneedles have needles with a diameter of about 70 μm and a height of 600 μm.

本発明の微小針の製造方法により、製品規格的に信頼性が高い剣山形微小針の大量生産が可能になった。また、生体分解性樹脂としてポリ乳酸を使用すれば、この樹脂の遷移点から融点近傍の温度範囲が５０℃〜９０℃であるため、この温度範囲内で熱安定性の良い薬剤であれば、生体分解性樹脂の中に加えることにより、薬剤の経皮吸収性の良い新たな製剤を作製することができる。
The manufacturing method of microneedles of the present invention has enabled mass production of Kenyama microneedles with high product standard reliability. Also, if polylactic acid is used as a biodegradable resin, the temperature range from the transition point of this resin to the vicinity of the melting point is 50 ° C. to 90 ° C., so if it is a drug with good thermal stability within this temperature range, By adding it to the biodegradable resin, a new preparation having a good transdermal absorbability of the drug can be prepared.

貫通孔のフッ素樹脂コーテイングの概略図Schematic of fluororesin coating of through hole 貫通孔と無貫通孔との効果の対比概略図Schematic comparison of the effects of through holes and non-through holes 機械加工して貫通孔が開いた金属金型Metal mold with through holes opened by machining 貫通孔フッ素樹脂コーテイング前の内表面Inner surface before through hole fluoropolymer coating 貫通孔フッ素樹脂コーテイング後の内表面Inner surface after through-hole fluoropolymer coating ポリ乳酸の剣山形状の微小針Polylactic acid sword mountain shaped micro needle

Claims (12)

生体分解性樹脂の微小針の製造方法であって、
ａ）円柱状または円錐状の貫通孔を有する金属製またはフッ素樹脂製の平板を作成し、金属製平板の貫通孔にはフッ素樹脂コーテイングまたは金属メッキを行い、鋳型とする、
ｂ）生体分解性樹脂を加熱し、樹脂の遷移点から融点近傍で該鋳型に圧着させて転写加工を行う。
ｃ）樹脂の遷移点付近で、鋳型から樹脂を離型させる、
ことからなる、微小針の製造方法。 A method for producing a biodegradable resin microneedle,
a) A flat plate made of metal or fluororesin having a cylindrical or conical through hole is prepared, and the through hole of the metal flat plate is subjected to fluororesin coating or metal plating to form a mold.
b) The biodegradable resin is heated, and the transfer process is performed by pressing the biodegradable resin to the mold near the melting point from the transition point of the resin.
c) The resin is released from the mold near the transition point of the resin.
The manufacturing method of a microneedle which consists of this. 生体分解性樹脂を減圧下に鋳型に圧着させることからなる、請求項１に記載の製造方法。   The manufacturing method according to claim 1, wherein the biodegradable resin is pressure-bonded to the mold under reduced pressure. 生体分解性樹脂がポリ乳酸である、請求項１又は２に記載の製造方法。   The production method according to claim 1 or 2, wherein the biodegradable resin is polylactic acid. 生体分解性樹脂がポリ乳酸であり、５０〜９０℃で転写加工を行い、５０℃付近の温度で離型させることを特徴とする、請求項１〜３のいずれかに記載の製造方法。   The production method according to any one of claims 1 to 3, wherein the biodegradable resin is polylactic acid, transfer processing is performed at 50 to 90 ° C, and release is performed at a temperature around 50 ° C. 薬効成分が生体分解性樹脂に混合されている、請求項１〜４のいずれかに記載の製造方法。   The manufacturing method in any one of Claims 1-4 with which the medicinal component is mixed with biodegradable resin. 円柱状または円錐状の貫通孔が以下の形状であることを特徴とする、請求項１〜５のいずれかに記載の製造方法。
ａ）貫通孔の長さが３０μｍ〜２ｍｍであり、
ｂ）貫通孔の最大径が５０μｍ〜２００μｍである。 6. The manufacturing method according to claim 1, wherein the cylindrical or conical through hole has the following shape.
a) The length of the through hole is 30 μm to 2 mm,
b) The maximum diameter of the through hole is 50 μm to 200 μm. フッ素樹脂コーテイングの厚さが少なくとも２０μｍ〜５０μｍである、請求項１〜６のいずれかに記載の製造方法。   The manufacturing method in any one of Claims 1-6 whose thickness of a fluororesin coating is at least 20 micrometers-50 micrometers. フッ素樹脂コーテイングとして、ポリテトラフルオロエチレン（ＰＴＦＥ)の微粒子を均一に分散共析させたニッケル皮膜でコーテイングするものである、請求項１〜７のいずれかに記載の製造方法。   The manufacturing method according to any one of claims 1 to 7, wherein the fluororesin coating is performed by coating with a nickel film in which fine particles of polytetrafluoroethylene (PTFE) are uniformly dispersed and co-deposited. 金属メッキがクロムメッキである、請求項１〜６のいずれかに記載の製造方法。   The manufacturing method in any one of Claims 1-6 whose metal plating is chromium plating. 金属メッキの膜厚が２０〜５０μｍである、請求項１〜６のいずれかに記載の製造方法。   The manufacturing method in any one of Claims 1-6 whose film thickness of metal plating is 20-50 micrometers. 鋳型に圧着させて転写加工を行うことが、生体分解性樹脂が貫通孔をあふれ出ないように圧着することである、請求項１〜９のいずれかに記載の製造方法。   The manufacturing method according to any one of claims 1 to 9, wherein the transfer processing is performed by pressure-bonding to a mold so that the biodegradable resin does not overflow the through-hole. 以下の形状の円柱状または円錐状の貫通孔を有する金属製またはフッ素樹脂製の平板鋳型であって、金属製平板の貫通孔にはフッ素樹脂コーテイングまたは金属メッキが行われたもの、
ａ）平板の厚さが３０μｍ〜２ｍｍであり、
ｂ）貫通孔の最大径が５０μｍ〜２００μｍであり、
ｃ）貫通孔の本数が１０〜５００本である、
ことを特徴とする微小針作製用の鋳型。 A flat plate mold made of metal or fluororesin having a cylindrical or conical through hole having the following shape, wherein the through hole of the metal flat plate is subjected to fluororesin coating or metal plating,
a) The thickness of the flat plate is 30 μm to 2 mm,
b) The maximum diameter of the through hole is 50 μm to 200 μm,
c) The number of through holes is 10 to 500.
A mold for producing a microneedle characterized by the above.
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