JP5723081B2 - Medical tube or drug guidance system - Google Patents
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
本発明は、医療用チューブ又は薬剤の誘導システムに関する。 The present invention relates to a medical tube or a drug guidance system.
従来から、磁石を適用した医療用チューブを用いて、体内の医療用チューブの位置を検出する検出装置が提案されている。この検出装置は、医療用チューブに結合した磁石によって生成される静電磁場強度勾配を感知し、勾配の値および大きさを示すことが可能である。このような検出装置を使用することによって、医療用チューブの配置の迅速な検出および検証が可能となり、医療用チューブの配置をＸ線により確認する必要はない（例えば、特許文献１〜６、非特許文献１参照）。 Conventionally, a detection device that detects the position of a medical tube in the body using a medical tube to which a magnet is applied has been proposed. The detection device can sense an electrostatic field strength gradient generated by a magnet coupled to a medical tube and indicate the value and magnitude of the gradient. By using such a detection device, it is possible to quickly detect and verify the arrangement of the medical tube, and it is not necessary to confirm the arrangement of the medical tube with X-rays (for example, Patent Documents 1 to 6, Non-Patent Documents 1 to 6). Patent Document 1).
また、一般に薬剤は生体内に投与され患部に到達し、その患部局所において薬理効果を発揮することで治療効果を引き起こすが、薬剤が患部以外の組織（つまり正常組織）に到達しても治療にはならない。したがって、いかにして効率的に患部に薬剤を誘導するかが治療戦略上重要となる。このように薬剤患部に誘導する技術はドラッグ・デリバリと呼ばれ、近年研究開発が盛んに行われている。 In general, drugs are administered in vivo and reach the affected area, and cause a therapeutic effect by exerting a pharmacological effect in the affected area. Even if the drug reaches a tissue other than the affected area (that is, normal tissue), it is treated. Must not. Therefore, how to efficiently guide the drug to the affected area is important in the treatment strategy. Such a technique for guiding to a drug affected part is called drug delivery, and research and development have been actively conducted in recent years.
このドラッグ・デリバリには少なくとも二つのメリットがある。
第１のメリットは、患部組織において十分に高い薬剤濃度が得られることである。薬理効果は患部における薬剤濃度が一定以上でないと現れず、低い濃度では治療効果が望めないからである。
第２のメリットは、薬剤を患部組織のみに誘導して、不必要に正常組織に誘導させないことである。これにより副作用を抑制することができる。
This drug delivery has at least two advantages.
The first merit is that a sufficiently high drug concentration can be obtained in the affected tissue. This is because the pharmacological effect does not appear unless the drug concentration in the affected area is above a certain level, and a therapeutic effect cannot be expected at a low concentration.
The second merit is that the drug is guided only to the affected tissue and is not unnecessarily guided to the normal tissue. Thereby, a side effect can be suppressed.
このようなドラッグ・デリバリが最も効果を発揮するのが抗がん剤によるがん治療である。抗がん剤は細胞分裂の活発ながん細胞の細胞増殖を抑制するものが大半であるため、正常組織においても細胞分裂の活発な組織、例えば骨髄あるいは毛根、消化管粘膜などの細胞増殖を抑制してしまう。このため抗がん剤の投与を受けたがん患者には貧血、抜け毛、嘔吐などの副作用が発生する。これら副作用は患者にとって大きな負担となるため投薬量を制限しなければならず、抗がん剤の薬理効果を十分に得ることが出来ないという問題がある。さらに最悪の場合、副作用によって患者が死亡してしまう恐れがある。
そこで、ドラッグ・デリバリによって抗がん剤をがん細胞まで誘導し、がん細胞に集中して薬理効果を発揮させることによって、副作用を抑えつつ、効果的にがん治療を行うことができると期待されている。
Such drug delivery is most effective in cancer treatment with anticancer agents. Most anticancer drugs inhibit cell proliferation of cancer cells with active cell division, so that even normal tissues, such as bone marrow or hair roots, gastrointestinal mucosa, etc. It will be suppressed. For this reason, side effects such as anemia, hair loss, and vomiting occur in cancer patients who receive anticancer drugs. Since these side effects are a heavy burden on the patient, the dosage must be limited, and the pharmacological effect of the anticancer drug cannot be obtained sufficiently. In the worst case, side effects can cause the patient to die.
Therefore, it is possible to effectively treat cancer while suppressing side effects by inducing anticancer drugs to cancer cells by drug delivery and concentrating on cancer cells to exert pharmacological effects. Expected.
抗がん剤以外では、例えば男性勃起不全治療薬への応用が考えられる。男性勃起不全治療薬は、ニトロ製剤との併用により重篤な全身低血圧を引き起こし死亡に至る例があり、とりわけ中高年以上の心疾患をもつ男性に問題となる。これは勃起不全治療薬が必ずしも患部に集中せず、全身の血管に作用してニトロ製剤のもつ血管拡張作用を増幅してしまうためである。そこで、ドラッグ・デリバリによって男性勃起不全治療薬を患部まで誘導し、患部に集中して薬理効果を発揮させることによって、ニトロ製剤との併用による副作用の発生を抑えることができると考えられる。 Other than anticancer agents, for example, it can be applied to male erectile dysfunction drugs. Male erectile dysfunction drugs cause serious systemic hypotension when used in combination with nitro drugs, leading to death, and are particularly problematic for men with middle-aged and older heart disease. This is because the drug for erectile dysfunction does not necessarily concentrate on the affected part, but acts on the blood vessels throughout the body to amplify the vasodilatory action of the nitro preparation. Therefore, it is considered that side effects caused by the combined use with a nitro preparation can be suppressed by inducing a drug for male erectile dysfunction to the affected area by drug delivery and concentrating on the affected area to exert a pharmacological effect.
ドラッグ・デリバリの具体的な手法としては、例えば担体（キャリア）を用いた患部組織へ誘導が検討されているが、これは患部に集中しやすい担体に薬剤を乗せて、担体に薬剤を患部まで運ばせようというものである。担体としては各種抗体やマイクロスフェア、あるいは磁性体を使用することが検討されている。なかでも有力視されているのが磁性体であり、薬剤に磁性体である担体を付着させ、磁場によって患部に集積される方法が検討されている（例えば、特許文献７参照）。この方法は誘導方法の簡便性と患部を標的にした治療が可能であることから、細胞毒性の高い抗がん剤にはとりわけ有効な手法として考えられている。 As a specific method of drug delivery, for example, guidance to a diseased tissue using a carrier (carrier) has been studied. This is because a drug is placed on a carrier that tends to concentrate on the affected area, and the drug is placed on the carrier to the affected area. It is about letting you carry it. The use of various antibodies, microspheres, or magnetic materials as the carrier has been studied. Among them, a magnetic material is considered promising, and a method of attaching a carrier, which is a magnetic material, to a drug and accumulating it in an affected area by a magnetic field has been studied (for example, see Patent Document 7). This method is considered to be a particularly effective method for anti-cancer agents having high cytotoxicity because of the simplicity of the induction method and the possibility of treatment targeting the affected area.
しかしながら、上述したように、磁性体である担体をキャリアとして用いる場合、経口投与が困難なこと、薬剤の担体分子が一般的に巨大であること、あるいは薬剤分子と担体との結合強度や親和性に技術的な問題があること、が指摘されており、実用化が困難であった。
また、磁場誘導を用いたドラッグ・デリバリ・システムは患部から磁石の距離が離れると急激に磁気力が低下するため、適用は皮下腫瘍に限られていた。
本発明は、上述した事情に鑑みてなされたものであり、従来の技術的問題を解決でき、実用化が容易なドラッグ・デリバリ・システムを実現することを目的とする。
However, as described above, when a carrier that is a magnetic substance is used as a carrier, oral administration is difficult, the carrier molecule of the drug is generally huge, or the binding strength and affinity between the drug molecule and the carrier It has been pointed out that there is a technical problem, and it was difficult to put it into practical use.
In addition, the drug delivery system using magnetic field induction has been limited to subcutaneous tumors because the magnetic force rapidly decreases as the distance of the magnet from the affected area increases.
The present invention has been made in view of the above-described circumstances, and an object of the present invention is to realize a drug delivery system that can solve the conventional technical problems and can be easily put into practical use.
本発明は、（１）先端部又は少なくとも一部に、強磁性部を備えた、医療用チューブ；
（２）前記強磁性部は、電磁石又は永久磁石からなる、前記（１）に記載の医療用チューブ；
（３）前記強磁性部は、医療用チューブの内部に植え込まれてなる、前記（１）又は（２）に記載の医療用チューブ；
（４）前記強磁性部は、医療用チューブに巻きつけられてなる、前記（１）又は（２）に記載の医療用チューブ；
（５）下記式（１）で示される磁性抗がん剤からなる薬剤を、当該薬剤の磁性を利用して所定の患部に誘導する誘導システムであって、前記（１）〜（４）のいずれかに記載の医療用チューブを患者の体内に導入する手段と、前記薬剤を目的とする組織又は患部に誘導する手段と、を備える、薬剤の誘導システム；
(2) The medical tube according to (1), wherein the ferromagnetic portion is made of an electromagnet or a permanent magnet;
(3) The medical tube according to (1) or (2), wherein the ferromagnetic portion is implanted inside a medical tube;
(4) The medical tube according to (1) or (2), wherein the ferromagnetic part is wound around a medical tube;
(5) A guidance system for guiding a drug composed of a magnetic anticancer drug represented by the following formula (1) to a predetermined affected area using the magnetism of the drug, wherein (1) to (4) A drug guiding system comprising: a means for introducing the medical tube according to any one of the above into a patient's body; and a means for guiding the drug to a target tissue or affected area;
本発明によれば、薬剤そのものが有する磁性を利用して、強磁性部を備えた医療用チューブを用いて薬剤を体深部の患部まで磁場誘導することができるため、従来における、経口投与が困難なこと、薬剤の担体分子が一般的に巨大であること、あるいは薬剤分子と担体との結合強度や親和性に技術的な問題があること、といった問題を解決することができる。
また、本発明によれば、体深部まで薬剤誘導が可能な磁場誘導ドラッグ・デリバリ・システムを実現することができる。
According to the present invention, since the drug can be magnetically induced to the affected part in the deep part of the body using a medical tube having a ferromagnetic part using the magnetism of the drug itself, conventional oral administration is difficult. In addition, it is possible to solve problems such as that drug carrier molecules are generally huge, or that there are technical problems in the binding strength and affinity between the drug molecules and the carrier.
In addition, according to the present invention, it is possible to realize a magnetic field induction drug delivery system capable of guiding a drug to the deep part of the body.
次に、本発明の実施の形態について説明する。以下の実施形態は、本発明を説明するための例示であり、本発明をこの実施形態にのみ限定する趣旨ではない。本発明は、その要旨を逸脱しない限り、さまざまな形態で実施することができる。 Next, an embodiment of the present invention will be described. The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.
（医療用チューブ）
本発明の医療用チューブは、先端部又は少なくとも一部に、強磁性部を備える。
図１に、医療用チューブの一例を示すように、医療用チューブ１０の先端には、強磁性部１１が装着されている。
医療チューブ１０を患者の体内（血管内）に導入した後、Ｘ線、ＭＲＩ、ＣＴ又は磁気センサにより位置決めする。これにより、医療用チューブ１０を用いて患部１３の近傍へ強磁性部１１を移動させて、薬剤１２を磁場で誘導する。
(Medical tube)
The medical tube of the present invention includes a ferromagnetic portion at the tip or at least a part thereof.
As shown in FIG. 1 as an example of a medical tube, a
After introducing the
前記強磁性部１１は、電磁石又は永久磁石からなることが好ましい。
前記強磁性部１１を、医療用チューブ１０の先端に設ける場合、強磁性部１１は、ネオジウム系永久磁石、又は電磁石が好ましい。
The
When the
医療用チューブとしては、カテーテル、ガイドワイヤ、ステント、シャント、が挙げら得る。 Examples of the medical tube include a catheter, a guide wire, a stent, and a shunt.
前記強磁性部は、医療用チューブの内部に植え込まれて構成されてもよく、あるいは、医療用チューブに巻きつけられて構成されてもよい。
具体的には、医療用チューブの全体又は一部の被膜をラバー磁石で構成することが好ましい。
The ferromagnetic part may be configured by being implanted inside a medical tube, or may be configured by being wound around a medical tube.
Specifically, it is preferable that the whole or a part of the coating of the medical tube is composed of a rubber magnet.
（薬剤の誘導システム）
本発明の薬剤の誘導システムは、下記式（１）で示される磁性抗がん剤からなる薬剤を、当該薬剤の磁性を利用して所定の患部に誘導する誘導システムであって、前記医療用チューブを患者の体内に導入する手段と、前記薬剤を目的とする組織又は患部に誘導する手段と、を備える。
The drug guidance system of the present invention is a guidance system for guiding a drug composed of a magnetic anticancer drug represented by the following formula (1) to a predetermined affected area using the magnetism of the drug. Means for introducing the tube into the body of the patient, and means for guiding the drug to the target tissue or affected area.
上記式（１）で示される薬剤は、抗がん作用をもち、室温で強磁性体的性質をもつ鉄サレン錯体である。
本発明の薬剤の誘導システムによれば、体内に投与された前記薬剤を、その磁性を利用して所定の患部に誘導することができる。また、体内に投与された薬剤の磁気を検出することで、本発明薬剤の体内動態を検知することができる。
また、先端を電磁石にした医療チューブを用いることで直接患部へ磁性薬剤を運ぶことが可能である。すなわち、電磁石についた磁性薬剤を医療用チューブを介して患部に運び、患部に着いたら電磁石の電源を切ることで、目的の患部に磁性薬剤を放出することができる。
The drug represented by the above formula (1) is an iron-salen complex having an anticancer effect and having ferromagnetic properties at room temperature.
According to the drug guidance system of the present invention, the drug administered into the body can be guided to a predetermined affected area using its magnetism. Moreover, the pharmacokinetics of the drug of the present invention can be detected by detecting the magnetism of the drug administered into the body.
In addition, it is possible to carry the magnetic drug directly to the affected area by using a medical tube whose tip is an electromagnet. That is, the magnetic drug attached to the electromagnet can be delivered to the affected area through the medical tube, and when the magnetic drug is reached, the power supply to the electromagnet is turned off to release the magnetic drug to the target affected area.
以下、本発明を実施例によりさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
（実施例１）
鉄サレン錯体の合成を、次のように行った。
The iron-salen complex was synthesized as follows.
4-nitrophenol (25g, 0.18mol)、hexamethylene tetramine (25g, 0.18mol)、 polyphosphoric acid (200ml)の混合物を１時間１００℃で攪拌した。その後、その混合物を500mlの酢酸エチルと１Lの水の中に入れ、完全に溶解するまで攪拌した。さらにその溶液に400mlの酢酸エチルを追加で加えたところその溶液は２つの相に分離し、水の相を取り除き、残りの化合物を塩性溶剤で２回洗浄し、無水MgSO4で乾燥させた結果、compound 2が１７ｇ（収率57%）合成できた。 A mixture of 4-nitrophenol (25 g, 0.18 mol), hexamethylene tetramine (25 g, 0.18 mol), and polyphosphoric acid (200 ml) was stirred at 100 ° C. for 1 hour. The mixture was then taken up in 500 ml ethyl acetate and 1 L water and stirred until completely dissolved. An additional 400 ml of ethyl acetate was added to the solution and the solution separated into two phases, the water phase was removed, the remaining compound was washed twice with a salt solvent and dried over anhydrous MgSO 4 . As a result, 17 g (yield 57%) of compound 2 was synthesized.
compound 2 (17g, 0.10mol), acetic anhydride (200ml), H2SO4 (少々)を室温で１時間攪拌させた。得られた溶液は、氷水（２L）の中に0.5時間混ぜ、加水分解を行った。得られた溶液をフィルターにかけ、大気中で乾燥させたところ白い粉末状のものが得られた。酢酸エチルを含む溶液を使ってその粉末を再結晶化させたところ、２４ｇのCompound 3（収率76%）の白い結晶を得ることができた。 Compound 2 (17 g, 0.10 mol), acetic anhydride (200 ml) and H 2 SO 4 (a little) were stirred at room temperature for 1 hour. The resulting solution was hydrolyzed by mixing in ice water (2 L) for 0.5 hour. The obtained solution was filtered and dried in the air to obtain a white powder. When the powder was recrystallized using a solution containing ethyl acetate, 24 g of Compound 3 (yield 76%) of white crystals could be obtained.
compound 3 (24g, 77mmol)とメタノール(500ml)に10%のパラジウムを担持したカーボン(2.4g)の混合物を一晩 1.5気圧の水素還元雰囲気で還元した。終了後、フィルターでろ過したところ茶色油状のcompound 4 (21g)が合成できた。 A mixture of compound 3 (24 g, 77 mmol) and carbon (2.4 g) with 10% palladium on methanol (500 ml) was reduced overnight in a 1.5 atmosphere hydrogen reduction atmosphere. After completion, the mixture was filtered with a filter to synthesize brown oily compound 4 (21 g).
無水ジクロメタン(DCM) (200ml)にcompound 4 (21g, 75mmol), di(tert-butyl) dicarbonate (18g, 82mmol)を窒素雰囲気で一晩攪拌した。得られた溶液を真空中で蒸発させた後、メタノール(100ml)で溶解させた。その後、水酸化ナトリウム(15g, 374mmol)と水(50ml)を加え、5時間還流させた。その後冷却し、フィルターでろ過し、水で洗浄後、真空中て乾燥させたところ茶色化合物がえられた。
得られた化合物は、シリカジェルを使ったフラッシュクロマトグラフィーを２回行うことで、10gのcompound 6（収率58%）が得られた。
Compound 4 (21 g, 75 mmol) and di (tert-butyl) dicarbonate (18 g, 82 mmol) were stirred in anhydrous dichloromethane (DCM) (200 ml) overnight in a nitrogen atmosphere. The resulting solution was evaporated in vacuo and then dissolved with methanol (100 ml). Thereafter, sodium hydroxide (15 g, 374 mmol) and water (50 ml) were added and refluxed for 5 hours. Thereafter, the mixture was cooled, filtered through a filter, washed with water, and then dried in vacuo to obtain a brown compound.
The obtained compound was subjected to flash chromatography using silica gel twice to obtain 10 g of compound 6 (yield 58%).
無水エタノール400mlの中にcompound 6 (10g, 42mmol)を入れ、加熱しながら還流させ、無水エタノール20mlにエチレンジアミン(1.3g, 21mmol)を0.5時間攪拌しながら数滴加えた。そして、その混合溶液を氷の容器に入れて冷却し15分間かき混ぜた。その後、200mlのエタノールで洗浄しフィルターをかけ、真空で乾燥させたところcompound 7が8.5g （収率82%）で合成できた。 Compound 6 (10 g, 42 mmol) was placed in 400 ml of absolute ethanol, refluxed with heating, and ethylenediamine (1.3 g, 21 mmol) was added to 20 ml of absolute ethanol with stirring for several hours with a few drops. The mixed solution was cooled in an ice container and stirred for 15 minutes. Thereafter, it was washed with 200 ml of ethanol, filtered, and dried under vacuum. Compound 7 was synthesized in 8.5 g (yield 82%).
無水メタノール(50ml)の中にcompound 7 (8.2g, 16mmol)、triethylamine (22ml, 160mmol)を入れ、10mlメタノールの中にFeCl3(2.7g, 16mmol)を加えた溶液を窒素雰囲気下で混合した。室温窒素雰囲気で１時間混合したところ茶色の化合物が得られた。その後、真空中で乾燥させた。得られた化合物はジクロロメタン400mlで希釈し、塩性溶液で２回洗浄し、Na2SO4で乾燥させ、真空中で乾燥させたところ鉄サレン錯体（complex A）が得られた。
得られた化合物はジエチルエーテルとパラフィンの溶液中で再結晶させ高速液化クロマトグラフィーで測定したところ純度95%以上のcomplex A(鉄サレン錯体)5.7g（収率62%）を得た。
Compound 7 (8.2 g, 16 mmol) and triethylamine (22 ml, 160 mmol) were put in anhydrous methanol (50 ml), and a solution of FeCl 3 (2.7 g, 16 mmol) in 10 ml methanol was mixed under a nitrogen atmosphere. . When mixed for 1 hour in a nitrogen atmosphere at room temperature, a brown compound was obtained. Then, it was dried in vacuum. The obtained compound was diluted with 400 ml of dichloromethane, washed twice with a salt solution, dried with Na 2 SO 4 , and dried in vacuo to obtain an iron salen complex (complex A).
The obtained compound was recrystallized in a solution of diethyl ether and paraffin and measured by high performance liquefaction chromatography to obtain 5.7 g of complex A (iron-salen complex) having a purity of 95% or more (yield 62%).
Claims (5)
チューブの先端部又は少なくとも一部に電磁石からなる強磁性部が巻きつけられている医療用チューブを患者の体の血管内に導入して、当該医療チューブを患部の近傍に位置決めする導入手段と、
前記電磁石に電源を適用して、前記患者に投与され、前記血管内の前記薬剤を前記電磁石の磁場で前記患部に誘導した後、前記電磁石の磁場を切って前記薬剤を前記磁場から前記患部に対して放出する誘導手段と、
を備える、薬剤の誘導システム。
An introduction means for introducing a medical tube in which a ferromagnetic portion made of an electromagnet is wound around the distal end portion or at least a part of the tube into a blood vessel of a patient's body, and positioning the medical tube in the vicinity of the affected portion;
A power source is applied to the electromagnet and administered to the patient. After the drug in the blood vessel is guided to the affected area by the magnetic field of the electromagnet, the magnetic field of the electromagnet is turned off and the drug is transferred from the magnetic field to the affected area. Inducing means for releasing against,
A drug guidance system comprising:
先端部又は少なくとも一部に電磁石からなる強磁性部を備え、血管内に導入される医療用チューブと、
前記血管内に導入された医療用チューブの前記強磁性部を、Ｘ線、ＭＲＩ、ＣＴ又は磁気センサにより位置決めする位置決め手段と、
前記強磁性部の電源制御手段と、
を備え、
前記位置決め手段が、前記患部の近傍の位置に前記強磁性部を位置決めし、
前記電源制御手段が、前記体内に投与され前記血管内での前記磁性薬剤をその磁性により前記強磁性部に保持させ、
次いで、前記電源制御手段が、前記患部で前記強磁性部の電源を制御して前記強磁性部の磁場を切ることにより前記磁性薬剤を前記強磁性部から前記患部に対して放出し、
さらに、当該磁性薬剤の磁気を検出して当該磁性薬剤の体内動態を得るように構成された薬剤の誘導システム。 A drug induction system that uses the magnetic properties of a magnetic drug to guide the magnetic drug to an affected area in the body,
A medical tube provided with a ferromagnetic portion made of an electromagnet at the tip or at least a part thereof, and introduced into a blood vessel;
Positioning means for positioning the ferromagnetic part of the medical tube introduced into the blood vessel by X-ray, MRI, CT or a magnetic sensor;
Power control means for the ferromagnetic part ;
With
The positioning means positions the ferromagnetic part at a position near the affected part ;
The power source control means is administered into the body and the magnetic agent in the blood vessel is held in the ferromagnetic part by its magnetism;
Then, the power supply control means, said magnetic drug release to the affected area from the ferromagnetic portion by controlling the power of the ferromagnetic portion in the affected area off a magnetic field of the ferromagnetic part,
Furthermore, the chemical | medical agent induction | guidance | derivation system comprised so that the magnetism of the said magnetic chemical | medical agent might be detected and the pharmacokinetics of the said magnetic chemical | medical agent might be obtained.
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