JP2003164531A - Balloon catheter which can control release of pharmacologically active substance by temperature - Google Patents
Balloon catheter which can control release of pharmacologically active substance by temperatureInfo
- Publication number
- JP2003164531A JP2003164531A JP2001365934A JP2001365934A JP2003164531A JP 2003164531 A JP2003164531 A JP 2003164531A JP 2001365934 A JP2001365934 A JP 2001365934A JP 2001365934 A JP2001365934 A JP 2001365934A JP 2003164531 A JP2003164531 A JP 2003164531A
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- JP
- Japan
- Prior art keywords
- balloon
- balloon catheter
- copolymer
- isopropylacrylamide
- catheter according
- 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.)
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- Materials For Medical Uses (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、血管、胆管や尿管
などの管腔系器官の治療法に用いるバルーンカテーテル
に関係する。さらに詳しくは、カテーテルの先端部位近
くに位置するバルーンに薬理活性物質を担持させ、これ
を管腔系器官の疾患部位に誘導し、疾患部に特異的に薬
理活性物質を投与することを可能にするバルーンカテー
テルに関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a balloon catheter used for treating blood vessels, luminal organs such as bile ducts and ureters. More specifically, it is possible to load a pharmacologically active substance on a balloon located near the tip of the catheter, guide it to the diseased site of the luminal system organ, and administer the pharmacologically active substance specifically to the diseased site. Balloon catheter.
【０００２】[0002]
【従来の技術】従来からバルーンカテーテルを用いて薬
理活性物質を疾患部位に投与する種々の試みが行われて
きた。例えば、バルーン上に形成されたハイドロゲル層
に薬理活性物質を含浸させ、これを疾患部位に持って行
き、疾患部位に薬理活性物質を特異的に投与する試みも
行われた。しかし、通常疾患部位へバルーンを誘導する
のに数分、場合によっては数十分も要することも多く、
この時間の間にバルーン上の薬理活性物質は流れさって
しまい、有効な局所投与が行えなかった。また、微細孔
を有するバルーンを用いて、疾患部位で薬理活性物質溶
液を噴射することが行われたが、用いた薬理活性物質で
疾患部位に注入されるのは極めて僅かでであり、投与し
た薬理活性物質の大部分は例えば血流にのって全身に運
ばれ、その副作用が問題になっていた。以上が、疾患部
に効率的に薬理活性物質を投与できるバルーンカテーテ
ルの開発が望まれるゆえんである。2. Description of the Related Art Conventionally, various attempts have been made to administer a pharmacologically active substance to a disease site using a balloon catheter. For example, attempts have been made to impregnate a hydrogel layer formed on a balloon with a pharmacologically active substance, bring it to a diseased site, and specifically administer the pharmacologically active substance to the diseased site. However, it usually takes several minutes, sometimes tens of minutes, to guide the balloon to the diseased site,
During this time, the pharmacologically active substance on the balloon was washed away, and effective local administration could not be performed. Further, a balloon having fine pores was used to inject a pharmacologically active substance solution at the diseased site, but the amount of the pharmacologically active substance used was very small to be injected into the diseased site, and thus it was administered. Most of the pharmacologically active substances are carried to the whole body, for example, in the bloodstream, and their side effects have been a problem. The above is the reason why the development of a balloon catheter capable of efficiently administering a pharmacologically active substance to a diseased part is desired.
【０００３】[0003]
【発明が解決しようとする課題】バルーンカテーテルの
バルーン部位を疾患部位に誘導する数十分の間は、バル
ーンは薬理活性物質を保持し、疾患部位でバルーンを膨
らませたときにバルーンは疾患部位に押しつけられると
ともに、保持していた薬理活性物質を放出し、疾患部位
に効率よく薬理活性物質が投与できるバルーンカテーテ
ルを開発する。The balloon retains a pharmacologically active substance for several tens of minutes to guide the balloon site of the balloon catheter to the diseased site, and when the balloon is inflated at the diseased site, the balloon remains at the diseased site. We will develop a balloon catheter that can be efficiently pressed to the diseased site by releasing the retained pharmacologically active substance.
【０００４】[0004]
【課題を解決するための手段】本発明者は、鋭意研究を
重ねてきた結果、バルーンに、相転移して膨潤する相転
移温度が人体の体温以下、例えば３６℃以下で且つ薬理
活性物質を含有しているハイドロゲル層を有するバルー
ンカテーテル、特にバルーンに薬理活性物質を含むイソ
プロピルアクリルアミドを主成分とする共重合体のハイ
ドロゲル層を有するバルーンカテーテルを試作し、この
カテーテルが上記の目的を達成し得ることを見いだし本
発明に到達した。薬理活性物質は、化学合成された薬
剤、動植物等から抽出された天然薬剤、タンパク及び遺
伝子を含む。As a result of intensive studies, the present inventor has found that the balloon has a phase transition temperature at which it undergoes a phase transition and swells below the body temperature of the human body, for example below 36 ° C. A balloon catheter having a hydrogel layer contained therein, in particular, a balloon catheter having a hydrogel layer of a copolymer whose main component is isopropylacrylamide containing a pharmacologically active substance, was prototyped, and this catheter achieved the above-mentioned object. The inventors have found what can be done and have reached the present invention. Pharmacologically active substances include chemically synthesized drugs, natural drugs extracted from animals and plants, proteins and genes.
【０００５】本発明のバルーンカテーテルの好適例は、
温度の変化で物質透過性が劇的に変化するイソプロピル
アクリルアミドを主成分とする共重合体のハイドロゲル
層を表面に有するバルーン(A)と、カテーテルの手元か
ら体温以下の造影剤又は冷水の如き液体を注入すること
でバルーンの温度を低下させることが可能な内腔を有す
るカテーテル(B)とからなる。A preferred example of the balloon catheter of the present invention is
A balloon (A) having a hydrogel layer of a copolymer containing isopropylacrylamide as a main component whose substance permeability changes dramatically with changes in temperature, and a contrast agent or cold water below the body temperature from the catheter hand. It comprises a catheter (B) having a lumen capable of lowering the temperature of the balloon by injecting a liquid.
【０００６】[0006]
【発明の実施の形態】まず、（Ａ）について説明する。
本発明において、バルーン表面にハイドロゲル層を形成
させるのに用いるイソプロピルアクリルアミドを主成分
とする共重合体は、イソプロピルアクリルアミド、反応
性の残基である２−メタクリロイルオキシエチルイソシ
アネートまたはそのイソシアネート基をメチルエチルケ
トオキシムでブロックした化合物を第２の成分として、
物質透過性が劇的に変化する転移温度の設定を行うため
の第３の成分とをラジカル共重合することで合成され
る。BEST MODE FOR CARRYING OUT THE INVENTION First, (A) will be described.
In the present invention, the isopropylacrylamide-based copolymer used to form the hydrogel layer on the balloon surface is isopropylacrylamide, a reactive residue of 2-methacryloyloxyethylisocyanate or its isocyanate group is methylethylketo. The oxime blocked compound as the second component,
It is synthesized by radical copolymerization with a third component for setting the transition temperature at which the substance permeability changes dramatically.
【０００７】該共重合体中には第２の反応性成分が少量
でも含まれていることがバルーン上でハイドロゲル層の
形成に必要である。含まれていないと、バルーンと共重
合体との接着不良、また、ハイドロゲルが形成されな
い。It is necessary for the formation of the hydrogel layer on the balloon that the copolymer contains a small amount of the second reactive component. When it is not contained, the adhesion between the balloon and the copolymer is poor, and hydrogel is not formed.
【０００８】該共重合体の分子量は５，０００から１，
０００，０００、共重合体中のイソプロピルアクリルア
ミド残基のモル分率は１０％から９９．９９９％であ
り、望ましくは９０％から９９．９％、第２の成分であ
る反応性の残基のモル分率は０．００１％から２０％で
あり、望ましくは０．１％から１０％、転移温度の調整
に用いる第３の成分モル分率は１％から４９．９９９％
であり、望ましくは１％から２０％である。The molecular weight of the copolymer is 5,000 to 1,
, 000,000, the mole fraction of isopropylacrylamide residues in the copolymer is 10% to 99.999%, preferably 90% to 99.9%, of the reactive residues of the second component. The mole fraction is 0.001% to 20%, preferably 0.1% to 10%, and the third component mole fraction used for adjusting the transition temperature is 1% to 49.999%.
And preferably 1% to 20%.
【０００９】該共重合体中には転移温度の調整に用いる
第３の成分を組み込むが、転移温度を低く設定したい場
合はメチルメタクリレート、ブチルメタクリレートやブ
チルアクリレート等の疎水性モノマーを用い、転移温度
を高く設定したい場合はアクリルアミド等の親水性モノ
マーを用いる。A third component used for adjusting the transition temperature is incorporated in the copolymer, and when it is desired to set the transition temperature low, a hydrophobic monomer such as methyl methacrylate, butyl methacrylate or butyl acrylate is used, and the transition temperature is If you want to set a high value, use a hydrophilic monomer such as acrylamide.
【００１０】該共重合体は、ラジカル重合によって容易
に得られるが、２−メタクリロイルオキシエチルイソシ
アネートを第２の成分として用いる場合には、イソシア
ネートが容易に水や水蒸気により容易に加水分解される
ため、用いる溶媒は十分に脱水しておく必要がある。The copolymer can be easily obtained by radical polymerization, but when 2-methacryloyloxyethyl isocyanate is used as the second component, the isocyanate is easily hydrolyzed by water or steam. The solvent used must be sufficiently dehydrated.
【００１１】次に、カテーテル(B)について説明する。
各社から市販されているバルーンカテーテルはバルーン
を広げるための内腔を有する。この内腔に液体を注入す
ることでバルーン温度を低下させることも可能である。
効率よくバルーン部の温度を低下させるには、温度の低
い液体を持続的に注入・排出する必要がある。このた
め、バルーンに通じる２つの内腔を有するバルーンカテ
ーテルが望ましい。カテーテルまたバルーンの素材とし
ては、ポリウレタン、ナイロン、ポリエステル等現行の
バルーンカテーテルの作製に用いられている素材は総て
用いることが可能であり、特に限定しない。Next, the catheter (B) will be described.
Balloon catheters commercially available from various companies have a lumen for expanding the balloon. It is also possible to lower the balloon temperature by injecting a liquid into this lumen.
In order to efficiently lower the temperature of the balloon portion, it is necessary to continuously inject and discharge the liquid of low temperature. For this reason, balloon catheters having two lumens leading to the balloon are desirable. As the material for the catheter or the balloon, any of the materials currently used in the production of balloon catheters such as polyurethane, nylon and polyester can be used, and there is no particular limitation.
【００１２】バルーン表面に形成させるイソプロピルア
クリルアミドを主成分とする共重合体層の厚さは、乾燥
状態で０．１μｍから１００μｍ、好ましくは１μｍか
ら５０μｍである。共重合体層の厚さがこの範囲である
と、薬理活性物質を担持でき、また、温度を変えること
でハイドゲルにすることができ薬理活性物質を素早く放
出できる。また、この厚さであればバルーンの広げやす
さ等の操作性に影響を与えることない。The thickness of the isopropylacrylamide-based copolymer layer formed on the surface of the balloon is 0.1 μm to 100 μm, preferably 1 μm to 50 μm in a dry state. When the thickness of the copolymer layer is within this range, a pharmacologically active substance can be supported, and a hydrogel can be formed by changing the temperature, so that the pharmacologically active substance can be rapidly released. In addition, this thickness does not affect the operability such as the ease of expanding the balloon.
【００１３】バルーン上へのイソプロピルアクリルアミ
ドを主成分とする共重合体のコーティング方法には、特
に制限はなく、例えば、（１）共重合体の溶液にバルー
ンを浸漬した後加熱乾燥する方法、（２）共重合体の溶
液を刷毛でバルーンに塗った後加熱乾燥する方法、
（３）共重合体の溶液をスプレーでバルーン上に噴霧し
た後加熱乾燥する方法、これらの方法で、共重合体層と
バルーンとの強固な接着が得られない場合、バルーン表
面の加水分解を行うことやシランカップリング剤処理す
ることで、イソシアネートと反応する水酸基やアミノ基
等の表面密度を高くするなどの処理を行う。更に、分子
鎖中に光反応性基、エポキシ基、イソシアネート基及び
酸無水物基の少なくとも1個を有し、イソプロピルアク
リルアミド又はイソプロピルアクリルアミドを主成分と
する共重合体との相溶性が良好な反応性高分子をハイド
ロゲル層に溶解させることもできる。The method for coating the copolymer containing isopropylacrylamide as a main component on the balloon is not particularly limited. For example, (1) a method in which the balloon is immersed in a solution of the copolymer and then dried by heating, 2) A method in which the solution of the copolymer is applied to the balloon with a brush and then heated and dried,
(3) A method in which a solution of the copolymer is sprayed onto the balloon and then dried by heating. When strong adhesion between the copolymer layer and the balloon cannot be obtained by these methods, hydrolysis of the balloon surface is performed. By carrying out or by treating with a silane coupling agent, treatments such as increasing the surface density of hydroxyl groups and amino groups which react with isocyanate are carried out. Furthermore, it has at least one of a photoreactive group, an epoxy group, an isocyanate group and an acid anhydride group in the molecular chain, and has good compatibility with isopropylacrylamide or a copolymer containing isopropylacrylamide as a main component. The polymer may be dissolved in the hydrogel layer.
【００１４】バルーン上の共重合体層への薬理活性物質
の担持方法は、（１）患者の治療に用いる直前に、バル
ーン部分を４℃の薬理活性物質溶液に３０分程度漬ける
ことで、共重合体層へ薬理活性物質を含浸させ、３７℃
あるいは６０℃の温水に漬けて薬理活性物質を担持させ
る方法、（２）工場でバルーン部分を４℃の薬理活性物
質溶液に３０分程度漬けることで、共重合体層へ薬理活
性物質を含浸させ、３７℃あるいは６０℃の温水に漬け
て薬理活性物質を担持させて、さらに乾燥させた後出荷
する方法、（３）薬理活性物質がイソシアネート基と反
応しない場合は、共重合体の水溶液に薬理活性物質を混
ぜ、バルーンに上記の方法でこの溶液をコーティングす
る。The method for supporting the pharmacologically active substance on the copolymer layer on the balloon is as follows: (1) Immersing the balloon portion in a pharmacologically active substance solution at 4 ° C. for about 30 minutes immediately before using it for treatment of a patient. The polymer layer is impregnated with a pharmacologically active substance, and the temperature is 37 ° C.
Alternatively, a method of supporting the pharmacologically active substance by immersing it in warm water of 60 ° C. (2) Immersing the balloon portion in the pharmacologically active substance solution of 4 ° C. for about 30 minutes at the factory to impregnate the copolymer layer with the pharmacologically active substance , A method in which the pharmacologically active substance is carried by immersing it in warm water at 37 ° C or 60 ° C, and further dried and then shipped, (3) When the pharmacologically active substance does not react with an isocyanate group, pharmacologically, it is added to an aqueous solution of the copolymer. The active substance is mixed and the balloon is coated with this solution in the manner described above.
【００１５】実施例１
イソプロピルアクリルアミド（ＮＩＰＡＭ）とＫａｒｅ
ｎｚＭＯＩ−ＢＭ（登録商標）（昭和電工）（ＭＯＩＢ
Ｍ）との９８．４：１．６の共重合体ポリ（ＮＩＰＡＭ
−ｃｏ−ＭＯＩＢＭ）をラジカル重合にて作製した。
２．５×２．５ｃｍのガラス基板上の金薄膜上に１１−
メルカプト−１−ウンデカノールの自己組織化膜を形成
させる。この表面に２．０ｗ／ｖ％のポリ（ＮＩＰＡＭ
−ｃｏ−ＭＯＩＢＭ）のアセトン溶液を３００μｌ滴下
し、さらに１５０℃で９０分加熱することでポリＮＩＰ
ＡＭの架橋薄膜を形成させた。このポリＮＩＰＡＭの架
橋薄膜の乾燥状態での厚さは２μｍであった。[0015]Example 1
Isopropylacrylamide (NIPAM) and Kare
nzMOI-BM (registered trademark) (Showa Denko) (MOIB
98.4: 1.6 copolymer poly (NIPAM with M)
-Co-MOIBM) was prepared by radical polymerization.
11-on the gold thin film on the glass substrate of 2.5 × 2.5 cm
Formation of self-assembled film of mercapto-1-undecanol
Let 2.0 w / v% poly (NIPAM
-Co-MOIBM) acetone solution (300 μl)
And further heat at 150 ° C for 90 minutes to give poly NIP.
A crosslinked thin film of AM was formed. This poly NIPAM rack
The dry thickness of the bridge thin film was 2 μm.
【００１６】ポリＮＩＰＡＭの架橋薄膜担持ガラスプレ
ートを４℃の蛍光物質であるカルセインの１８０μｇ／
ｍｌ水溶液に浸漬し、ポリＮＩＰＡＭハイドロゲル層に
カルセイン（分子量６２２．５）を含浸させた。その後
この表面を６０℃のイオン交換水で洗浄することで、表
面に付着しているカルセインを取り除き、リリース実験
に用いた。先ず、カルセイン担持ガラスプレートを３７
℃の１００ｍｌのイオン交換水に漬け、３７℃の温水で
温めた状態で、３０分と６０分後にイオン交換水中のカ
ルセイン濃度を測定する。次ぎに、４℃の氷水で冷やし
た状態で、５分毎にイオン交換水中のカルセイン濃度を
測定する。それぞれのカルセイン濃度からポリＮＩＰＡ
Ｍ層からのカルセインリリース速度を算出した。その結
果を図１に示した。３７℃の水中では７ｎｇ／ｃｍ２・
ｍｉｎであったが、４℃の水中では１６０ｎｇ／ｃｍ２
・ｍｉｎへと上昇した。すなわち、４℃の水中では３７
℃の水中の２３倍もリリース速度が上昇した。A glass plate supporting a cross-linked thin film of polyNIPAM was coated with 180 μg of calcein which is a fluorescent substance at 4 ° C.
The polyNIPAM hydrogel layer was impregnated with calcein (molecular weight 622.5) by immersing it in a ml aqueous solution. After that, this surface was washed with ion-exchanged water at 60 ° C. to remove calcein adhering to the surface and used for the release experiment. First, place the glass plate with calcein on 37
The solution is immersed in 100 ml of ion-exchanged water at 0 ° C. and warmed with warm water at 37 ° C., and after 30 and 60 minutes, the calcein concentration in the ion-exchanged water is measured. Next, the calcein concentration in the ion-exchanged water is measured every 5 minutes while being cooled with ice water at 4 ° C. From each concentration of calcein, polyNIPA
The calcein release rate from the M layer was calculated. The results are shown in Fig. 1. 7 ng / cm 2 in 37 ° C water
min, but 160 ng / cm 2 in 4 ° C. water
・ Rising to min. That is, 37 in water at 4 ° C
The release rate increased to 23 times that of water at ℃.
【００１７】実施例２
ＮＩＰＡＭ と２−メタクリロイルエチルイソシアネー
ト（ＫａｒｅｎｚＭＯＩ）（昭和電工）（ＭＯＩＢＭ）
との９８．１：１．９の共重合体ポリ（ＮＩＰＡＭ−ｃ
ｏ−ＭＯＩ）をラジカル重合にて作製した。このときＫ
ａｒｅｎｚＭＯＩ中のイソシアネートの加水分解が起こ
らないように、重合時に用いる溶媒は十分脱水し、さら
に加熱を必要としないレドックス系の開始剤（過酸化ベ
ンゾイル−ジメチルアニリン）を用いた。[0017]Example 2
NIPAM and 2-methacryloylethyl isocyanate
To (Karenz MOI) (Showa Denko) (MOIBM)
98.1: 1.9 copolymer poly (NIPAM-c
o-MOI) was prepared by radical polymerization. At this time K
Hydrolysis of the isocyanate in arenzMOI occurs
The solvent used during polymerization should be thoroughly dehydrated
Redox initiators that do not require heating
Nzoyl-dimethylaniline) was used.
【００１８】２．５×２．５ｃｍの厚さ２００μｍのナ
イロン膜を1規定の水酸化ナトリウム水溶液に室温で３
時間浸漬して、膜表面の加水分解を行った。この表面に
２．５ｗ／ｖ％のポリ（ＮＩＰＡＭ−ｃｏ−ＭＯＩ）の
アセトン溶液を３００μｌ滴下し、風乾した。これを１
０回繰り返した後、５０℃で５時間加熱することでポリ
ＮＩＰＡＭの架橋薄膜を形成させた。このポリＮＩＰＡ
Ｍの架橋薄膜の乾燥状態での厚さは２５μｍであった。A 2.5 × 2.5 cm 200 μm thick nylon membrane was immersed in a 1N aqueous sodium hydroxide solution at room temperature for 3 days.
The membrane surface was hydrolyzed by immersion for a period of time. To this surface, 300 μl of a 2.5 w / v% poly (NIPAM-co-MOI) acetone solution was dropped and air-dried. This one
After repeating 0 times, a crosslinked thin film of poly NIPAM was formed by heating at 50 ° C. for 5 hours. This poly NIPA
The dry thickness of the crosslinked thin film of M was 25 μm.
【００１９】ポリＮＩＰＡＭの架橋薄膜担持ナイロン膜
を４℃の蛍光物質であるカルセインの１８０μｇ／ｍｌ
水溶液に浸漬し、ポリＮＩＰＡＭハイドロゲル層にカル
セイン（分子量６２２．５）を含浸させた。その後この
表面を６０℃のイオン交換水で洗浄することで、表面に
付着しているカルセインを取り除き、リリース実験に用
いた。先ず、カルセイン担持ナイロン膜を３７℃の１０
０ｍｌのイオン交換水に漬け、３７℃の温水で温めた状
態で、３０分と６０分後にイオン交換水中のカルセイン
濃度を測定する。次ぎに、４℃の氷水で冷やした状態
で、5分毎にイオン交換水中のカルセイン濃度を測定す
る。それぞれのカルセイン濃度よりポリＮＩＰＡＭ層か
らのカルセインリリース速度を算出した。３７℃の水中
では５ｎｇ／ｃｍ２・ｍｉｎであったが、４℃の水中で
は１５０ｎｇ／ｃｍ２・ｍｉｎへと上昇した。すなわ
ち、４℃の水中では３７℃の水中の３０倍もリリース速
度が上昇した。180 μg / ml of calcein, which is a fluorescent substance at 4 ° C., was applied to a nylon film supporting a crosslinked thin film of polyNIPAM.
The polyNIPAM hydrogel layer was immersed in an aqueous solution to impregnate calcein (molecular weight 622.5). After that, this surface was washed with ion-exchanged water at 60 ° C. to remove calcein adhering to the surface and used for the release experiment. First, the calcein-supported nylon membrane was placed at 37 ° C at 10 ° C.
After being immersed in 0 ml of ion-exchanged water and warmed with warm water of 37 ° C., the calcein concentration in the ion-exchanged water is measured after 30 minutes and 60 minutes. Next, the calcein concentration in the ion-exchanged water is measured every 5 minutes while cooling with ice water at 4 ° C. The calcein release rate from the poly NIPAM layer was calculated from the respective calcein concentrations. It was 5 ng / cm 2 · min in 37 ° C water, but increased to 150 ng / cm 2 · min in 4 ° C water. That is, the release rate in water at 4 ° C increased 30 times that in water at 37 ° C.
【００２０】実施例３
実施例２で作製したポリ（ＮＩＰＡＭ−ｃｏ−ＭＯＩ）
を用いた。川澄化学工業株式会社から商品名「エンデバ
ー」として販売されているバルーンカテーテルのバルー
ン部分に１％トリレンジイソシアネートのメチルエチル
ケトン溶液を刷毛塗りした後、室温で軽く乾燥させる。
この表面に３．０ｗ／ｖ％のポリ（ＮＩＰＡＭ−ｃｏ−
ＭＯＩ）のジオキサン溶液を刷毛塗りした後、さらに５
０℃で５時間加熱することでバルーン上にポリＮＩＰＡ
Ｍの架橋薄膜を形成させた。このポリＮＩＰＡＭの架橋
薄膜の乾燥状態での厚さは約３０μｍであった。[0020]Example 3
Poly (NIPAM-co-MOI) prepared in Example 2
Was used. Product name "Endeva" from Kawasumi Chemical Co., Ltd.
Balloon catheters sold as
1% tolylene diisocyanate methyl ethyl
After brushing with the ketone solution, lightly dry at room temperature.
3.0 w / v% poly (NIPAM-co-
After brushing the MOI) dioxane solution,
PolyNIPA on balloon by heating at 0 ℃ for 5 hours
A cross-linked thin film of M was formed. Crosslinking of this poly NIPAM
The dry thickness of the thin film was about 30 μm.
【００２１】ポリＮＩＰＡＭの架橋薄膜担持バルーン部
分を４℃の蛍光物質であるカルセインの１８０μｇ／ｍ
ｌ水溶液に浸漬し、ポリＮＩＰＡＭハイドロゲル層にカ
ルセイン（分子量６２２．５）を含浸させた。その後こ
の表面を６０℃のイオン交換水で洗浄することで、表面
に付着しているカルセインを取り除き、リリース実験に
用いた。先ず、カルセイン担持バルーン部分を３７℃の
１００ｍｌのイオン交換水に漬け、３７℃の温水で温め
た状態で、３０分と６０分後にイオン交換水中のカルセ
イン濃度を測定する。次ぎ、４℃の氷水で冷やした状態
で、５分毎にイオン交換水中のカルセイン濃度を測定す
る。それぞれのカルセイン濃度からポリＮＩＰＡＭ層か
らのカルセインリリース速度を算出した。３７℃の水中
では８ｎｇ／ｃｍ２・ｍｉｎであったが、４℃の水中で
は２００ｎｇ／ｃｍ２・ｍｉｎへと上昇した。すなわ
ち、４℃の水中では３７℃の水中の約２５倍もリリース
速度が上昇した。The crosslinked thin film-supporting balloon portion of poly-NIPAM was filled with 180 μg / m 2 of calcein which is a fluorescent substance at 4 ° C.
Then, the polyNIPAM hydrogel layer was impregnated with calcein (molecular weight: 622.5). After that, this surface was washed with ion-exchanged water at 60 ° C. to remove calcein adhering to the surface and used for the release experiment. First, the calcein-carrying balloon portion is immersed in 100 ml of ion-exchanged water at 37 ° C., and while heated with warm water at 37 ° C., the calcein concentration in the ion-exchanged water is measured after 30 minutes and 60 minutes. Next, the calcein concentration in the ion-exchanged water is measured every 5 minutes in a state of being cooled with ice water at 4 ° C. The calcein release rate from the poly NIPAM layer was calculated from the respective calcein concentrations. It was 8 ng / cm 2 · min in 37 ° C water, but increased to 200 ng / cm 2 · min in 4 ° C water. That is, the release rate in water at 4 ° C increased about 25 times that in water at 37 ° C.
【００２２】実施例４
エタノール１００ｍｌ及び水２５ｍｌにイソプロピルア
クリルアミド７ｇと分子鎖中にベンゾフェノン基を有す
るポリビニルピロリドン共重合体０．６ｇ及び光反応性
スルフォン酸ナトリウム０．１８ｇとを溶解してコーテ
ィング溶液を調整した。このコーティング溶液をＰＴＣ
Ａバルーンカテーテルのバルーン部に塗布、一晩室温で
乾燥した後、バルーン部２６０ｎｍの紫外線を５ｍＷａ
／ｃｍ２照射してコーティング層を固定化した。実施例
３と同じ方法でカルセインリリース速度を測定したとこ
ろ、４℃の水中では３７℃の約１６倍のリリース速度を
示した。[0022]Example 4
Isopropyl acetate in 100 ml of ethanol and 25 ml of water.
It has a benzophenone group in the molecular chain with 7 g of crylamide.
Polyvinylpyrrolidone copolymer 0.6 g and photoreactivity
Dissolve 0.18g of sodium sulfonate and coat
The ing solution was prepared. Apply this coating solution to PTC
A Apply to the balloon part of the balloon catheter, overnight at room temperature
After drying, the balloon part is irradiated with 260 nm ultraviolet light at 5 mWa.
/ CmTwoThe coating layer was fixed by irradiation. Example
The calcein release rate was measured in the same way as in 3.
Approximately 16 times faster than 37 ° C release rate in 4 ° C water
Indicated.
【００２３】[0023]
【発明の効果】本発明のバルーンカテーテルによれば、
バルーンカテーテルのバルーン部位を疾患部位に誘導す
る数十分の間は、バルーンは薬理活性物質を保持し、疾
患部位でバルーンを膨らませたときにバルーンは疾患部
位に押しつけられるとともに、保持していた薬理活性物
質を放出し、疾患部位に効率よく薬理活性物質が投与で
きる。According to the balloon catheter of the present invention,
The balloon retains the pharmacologically active substance for several tens of minutes to guide the balloon site of the balloon catheter to the disease site, and when the balloon is inflated at the disease site, the balloon is pressed against the disease site and the pharmacology retained The active substance is released, and the pharmacologically active substance can be efficiently administered to the disease site.
【図１】実施例１におけるカルセインリリース速度を示
す線図。FIG. 1 is a diagram showing a calcein release rate in Example 1.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｍ 25/00 ４１０Ｚ (72)発明者 平田 伊佐雄 兵庫県神戸市須磨区中落合３丁目１番440 −806 Ｆターム(参考） 4C081 AC08 AC10 BB06 CA08 CA10 CC01 CE02 DA03 DC03 4C167 AA06 BB02 BB27 CC08 CC26 EE08 GG02 GG16 ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 7 Identification code FI theme code (reference) A61M 25/00 410Z (72) Inventor Isao Hirata 3-chome Nakaochiai 1-chome, 440-806, Suma-ku, Kobe-shi, Hyogo F-term (reference) 4C081 AC08 AC10 BB06 CA08 CA10 CC01 CE02 DA03 DC03 4C167 AA06 BB02 BB27 CC08 CC26 EE08 GG02 GG16
Claims (11)
温度が人体の体温よりも低く且つ薬理活性物質を含有し
ているハイドロゲル層を有するバルーンカテーテル。1. A balloon catheter having a hydrogel layer, which has a phase transition temperature at which a phase transition and swelling is lower than the body temperature of a human body and which contains a pharmacologically active substance, in a balloon.
１記載のバルーンカテーテル。2. The balloon catheter according to claim 1, wherein the phase transition temperature is 36 ° C. or lower.
ルアミドを主成分とする共重合体から成る、請求項１又
は２記載のバルーンカテーテル。3. The balloon catheter according to claim 1, wherein the hydrogel layer is made of a copolymer containing isopropylacrylamide as a main component.
後バルーン内にカテーテルを通じて液体を注入ことで、
バルーン壁を疾患部へ押しつけ、さらに、バルーン壁か
ら薬理活性を持つ物質を疾患部位へ放出させることがで
きる、請求項１から３までのいずれかに記載のバルーン
カテーテル。4. A balloon part is guided to a diseased part, and then a liquid is injected into the balloon through a catheter,
The balloon catheter according to any one of claims 1 to 3, which is capable of pressing a balloon wall against a diseased part and further releasing a substance having a pharmacological activity from the balloon wall to the diseased part.
温度を低下させることが可能なダブルの内腔を有する、
請求項４記載のバルーンカテーテル。5. A double lumen capable of lowering the temperature of the balloon by injecting and discharging liquid.
The balloon catheter according to claim 4.
する共重合体は、２−メタクリロイルオキシエチルイソ
シアネート（別名２−イソシアナトエチルメタクリレー
ト）を共重合体成分の一つとして含む、請求項１から５
までのいずれかに記載のバルーンカテーテル。6. The isopropylacrylamide-based copolymer comprises 2-methacryloyloxyethyl isocyanate (also known as 2-isocyanatoethyl methacrylate) as one of the copolymer components.
The balloon catheter according to any one of 1 to 3 above.
する共重合体は、２−メタクリロイルオキシエチル イ
ソシアネート（別名２−イソシアナトエチルメタクリレ
ート）のイソシアネート基をメチルエチルケトオキシム
でブロックした化合物を共重合体成分の一つとして含
む、請求項１から５までのいずれかに記載のバルーンカ
テーテル。7. A copolymer having isopropylacrylamide as a main component is a compound obtained by blocking the isocyanate group of 2-methacryloyloxyethyl isocyanate (also called 2-isocyanatoethyl methacrylate) with methylethylketoxime as one of the copolymer components. The balloon catheter according to any one of claims 1 to 5, which is included as.
する共重合体は、ビニル単量体共重合体成分も含む、請
求項６から７までのいずれかに記載のバルーンカテーテ
ル。8. The balloon catheter according to claim 6, wherein the copolymer containing isopropylacrylamide as a main component also contains a vinyl monomer copolymer component.
ルアミド又はイソプロピルアクリルアミドを主成分とす
る共重合体と分子鎖中に光反応性基、エポキシ基、イソ
シアネート基及び酸無水物基の少なくとも1個を有し、
イソプロピルアクリルアミド又はイソプロピルアクリル
アミドを主成分とする共重合体との相溶性が良好な反応
性高分子で構成される、請求項１から８までのいずれか
に記載のバルーンカテーテル。9. The hydrogel layer has at least one of a photoreactive group, an epoxy group, an isocyanate group and an acid anhydride group in the molecular chain with isopropylacrylamide or a copolymer containing isopropylacrylamide as a main component. ,
The balloon catheter according to any one of claims 1 to 8, which is composed of a reactive polymer having good compatibility with isopropylacrylamide or a copolymer having isopropylacrylamide as a main component.
る、請求項９記載のバルーンカテーテル。10. The balloon catheter according to claim 9, wherein the photoreactive group is a benzophenone group.
して架橋した、請求項９又は１０記載のバルーンカテー
テル。11. The balloon catheter according to claim 9, wherein the hydrogel layer is cross-linked by light irradiation or heat treatment.
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|---|---|---|---|
| JP2001365934A JP4398124B2 (en) | 2001-11-30 | 2001-11-30 | Balloon catheter that can control the release of pharmacologically active substances by temperature |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001365934A JP4398124B2 (en) | 2001-11-30 | 2001-11-30 | Balloon catheter that can control the release of pharmacologically active substances by temperature |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2003164531A true JP2003164531A (en) | 2003-06-10 |
| JP4398124B2 JP4398124B2 (en) | 2010-01-13 |
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|---|---|---|---|
| JP2001365934A Expired - Fee Related JP4398124B2 (en) | 2001-11-30 | 2001-11-30 | Balloon catheter that can control the release of pharmacologically active substances by temperature |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007181691A (en) * | 2005-12-30 | 2007-07-19 | Cordis Corp | Biologically active block copolymer |
| JP2007229249A (en) * | 2006-03-01 | 2007-09-13 | Olympus Corp | Method of supplying cell sheet |
| JP2021137460A (en) * | 2020-03-09 | 2021-09-16 | テルモ株式会社 | catheter |
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| JP2021137460A (en) * | 2020-03-09 | 2021-09-16 | テルモ株式会社 | catheter |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4398124B2 (en) | 2010-01-13 |
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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| LAPS | Cancellation because of no payment of annual fees |