JP3783811B2

JP3783811B2 - In vivo local heating device

Info

Publication number: JP3783811B2
Application number: JP22705897A
Authority: JP
Inventors: 林猛小; 多裕之本; 海政重新; 田純吉; 林俊彦若; 頭稔矢; 山鋼太郎平
Original assignee: Dai Ichi High Frequency Co Ltd
Current assignee: Dai Ichi High Frequency Co Ltd
Priority date: 1997-08-11
Filing date: 1997-08-11
Publication date: 2006-06-07
Anticipated expiration: 2017-08-11
Also published as: JPH1157031A

Description

【０００１】
【発明の属する技術分野】
本発明は、癌の治療などのために生体の局部を集中的に加熱するのに適した生体内部加熱装置に関する。
【０００２】
【従来の技術】
癌細胞を壊死させるために患部を集中的に加熱する局部温熱療法（ハイパーサーミア法）が従来より検討されている。この方法は、癌細胞が42.5℃以上の加熱によって壊死するという知見に基づき、患部を正常細胞が侵襲されない程度の温度に加熱して癌細胞のみを選択的に壊死させることを指向したものである。
【０００３】
ここで、42.5℃という温度は、正常細胞を壊死させないまでも、このような加熱が広域に及べば生理機能に障害をもたらすので、加熱をいかに患部本位に行えるかが治療の成否を分けるポイントとなる。よって、この療法は、先ず局部加熱の行いやすい皮膚癌に適用され、次いで、生体の内奥部に適用すべく、(イ)患部を狙った電極通電式の誘電加熱，(ロ)患部を狙ってマイクロ波を適用する形式の誘電加熱，(ハ)患部に磁性針を埋込んで交番磁界により誘導加熱する方式，(ニ)患部に強磁性体の微粒子を埋込んで、これを交番磁界の印加により発熱させる方式などの諸法が試みられてきた。
【０００４】
しかし、(イ)には、電流束が体内で広がるような通電しか行えず、又、患部に配置して局部発熱させるのに好適な感受体が見当らず特定の深さ位置の局部加熱も困難であることから、結局は生体の表層部分にしか適用しがたいという限界があり、(ロ)は、適用範囲を絞りやすくなるものの、浸透深さに限界があることから、(イ)よりは深い表層部への適用に留まり、(ハ)には、埋込み可能な部位が限られるうえに、広がりを持った患部を均一に加熱するために多数の磁性針の分散配置を必要とし、治療後磁性針を取出す必要もあることから、生体への負荷が大きいという問題があり、(ニ)は、生体内奥部の加熱が可能であるものの、加熱の集中度が低く、温熱療法のための局部加熱手段としての利用に適うものではなかった。
【０００５】
【発明が解決しようとする課題】
即ち、局部温熱療法は、副作用を回避しやすいという本質的な利点を有しながら、生体内奥部にある患部を治療する手段として実用性を得るには至っていなかった。これは何よりも、生体の内奥部の小領域を集中的に加熱できる局部加熱手段を欠いているためであり、かかる局部加熱手段の提供が局部温熱療法が実用性を得るための課題となっていた。
【０００６】
【課題を解決するための手段】
上記課題を解決すべくなされた本発明の要旨は、
生体内の局部に配置されるべき、鉄系酸化物の微粒子を主成分とする感磁発熱体と、生体外部に配置して生体内部を通る磁束を形成することのできる交番磁界発生装置とを備えた、磁気ヒステリシス発熱による生体内局部の加熱が行えるようにした生体内局部加熱装置であって、前記鉄系酸化物の微粒子の比透磁率を100〜2000、平均粒径を10〜100nm、保磁力を10〜200 Oeとすると共に、前記交番磁界発生装置から、交番周波数が 50 〜 400kHz で前記保磁力の１〜 20 倍の強さの磁界を適用することにより、前記感磁発熱体に、該発熱体の配置部位周囲の生体で起こる渦電流によるジュール発熱よりも相対的に強い磁気ヒステリシス発熱を起こさせて当該発熱体を中心とした鋭い昇温分布を形成し、加熱すべき局部の集中的な加熱を行えるようにしたことを特徴とする生体内局部加熱装置。なお、ここで云う比透磁率とは、当該微粒子を焼結して調製したブロックにJISC2561に規定の試験方法を適用して求めた最大透磁率を指すものとする。導電性の低い鉄系酸化物を主成分とする上記感磁発熱体は、交番磁界中で磁気ヒステリシスにより発熱する。一方、上記感磁発熱体が配置された部位の周囲の生体は、その良導電性によって生じる渦電流によりジュール発熱する。
【０００７】
しかして、感磁発熱体に配合する微粒子として比透磁率100以上の高透磁率のものを用いることにより、交番磁界の下での磁束の形成が感磁発熱体配置領域に集中するところとなって、感磁発熱体そのもののヒステリシス発熱の増大と、周囲の生体で起こるジュ−ル発熱の相対的な減少とがもたらされる結果、感磁発熱体配置領域を中心として鋭い昇温分布が形成されて、患部中心の集中的な加熱が行えるようになるものである。この状況を図４，図５に概念的に示す。図４において、21，21′は磁極、22は生体の一部、23は患部、24は磁束である。因に、前記従来技術の(ニ)の加熱方式の場合には図６，図７のようになる。図６において図４と同一符号は同一部材，同一部位を示す。透磁率は、電気の場合の電導度に、又、磁束は電流に相当するので、透磁率の大小によってこのような昇温分布の差が生じるものである。上記作用は比透磁率が大きいほど顕著になるが、2000近辺の比透磁率で飽和する。
【０００８】
本発明装置に用いる感磁発熱体の配合成分として鉄系酸化物を選んだのは、生体への害が少なく、又、代謝排出されやすいからである。組成としては、Fe₃O₄，γ-Fe₂O₃等の酸化鉄、あるいは、Fe₂O₃にMgO，CaO，MnO，CuO，ZnOなどの低害性の酸化物が化合したスピネル型の鉄系複合酸化物、更には、これらの鉄系酸化物の複合体、更に又、これらの鉄系酸化物にH₂Oが結合したものを例示できる。
【０００９】
上記鉄系酸化物を微粒子の形で用いるのは患部に均等に配置しやすく、又、血管などを通じた患部への輸送が可能であり、加えて、代謝排出にも有利となるからであって、これらの効果は平均粒径100nm以下で顕著となる。一方、上記微粒子が導電性の低い酸化物であることから、交番磁界の作用による発熱は前述のように磁気ヒステリシス損失によって起こる。よって、金属等の良導電体に渦電流を生じさせて発熱させる誘導加熱のように、粒径が小さ過ぎて渦電流が生じなくなるということはないが、ヒステリシス発熱の場合も、粒径が小さいほど発熱は少なくなるので、上記微粒子を配置した領域の周囲の生体で起こる渦電流発熱の大きさとの関係で前述のような鋭い昇温分布が損なわれないようにするのがよく、この観点から平均粒径を10nm以上とすることが望ましい。なお、微粒子が針状又は板状の場合には夫々の最短径（針状体の太さ又は板状体の厚さ）に対して上記寸法条件を適用するとともに、夫々の最長径（針状体の長さ又は板状体の長径）との寸法比を10程度に抑えるとよい。後述するように、本発明方法においては、必要に応じて、上記微粒子に助剤を配合した形で、あるいは、微粒子を液媒に分散させた形で用いてもよい。
【００１０】
上記感磁発熱体は、前記の通り、これに配合する微粒子の比透磁率を限定することにより生体内での集中的な発熱が可能となるものであるが、該発熱の強さを確保するために微粒子の保磁力を10〜200 Oe程度とすることが望ましい。10 Oe未満では発熱が集中的ではあっても、昇温速度が小であるため所期の温度に昇温するのに時間がかかり、一方、200 Oeを超えると昇温速度が過大となり、温度を微妙に設定しにくくなる。
【００１１】
【発明の実施の形態】
以下、本発明の実施の形態を、前記局部温熱療法への適用を例にとって説明する。まず、上記本発明装置の感磁発熱体の微粒子は、下記のように調製しておくことにより、本発明装置を局部温熱療法に利用する際の微粒子の生体内配置が有利に行える。
【００１２】
その１は、微粒子を、寒天、ゼラチン，アルギン酸塩などの生体に害を生じにくい物質を助剤としてペースト状，ゼリー状、又は、顆粒状としておくものである。これにより、部位の特定された患部に生体を切開して埋設する配置手法などにおける微粒子の取扱いが、サブミクロンの微粉体のままの形よりも容易になる。
【００１３】
その２は、微粒子に生体内部の特定の組織に対する特異的な親和性を付与しておくものである。このような微粒子は、これを分散させた輸液を静脈などの循環径路上に注射するだけで液中の微粒子が当該組織に選択的に集積される。上記親和性は、たとえば癌細胞を対象とする場合には、当該癌細胞が固有的に産出する抗原物質に対して特異的な親和性を有する抗体物質を微粒子に付着させるなどして付与することができる。又、上記処理と同時にあるいは前後して、微粒子をリン脂質によってリポソーム（分子カプセル）状に包囲し、あるいはラウリン酸などの界面活性物質により保護コロイド化を図るなどして、微粒子の輸液への分散性を向上させることができる。輸液の液媒としては、生理的食塩水など生体適合性を有する液体を適宜選定して用いることができる。又、生理的食塩水等の濃度を生体に支障のない範囲で適宜高くして液比重を高め、分散した微粒子が沈降しにくいようにすることができる。
【００１４】
その３は、微粒子に、上記特定組織への特異的な親和性に加えて正電荷発現性を付与するものである。このような微粒子を分散させた輸液を生体に注射すると、生体組織が通常は負に帯電していることから微粒子の正電荷により、微粒子は生体組織全体に無差別に沈着しやすくなる。即ち、静脈などの循環径路上に注射したのでは、患部に至る迄に循環径路の内壁に沈着してしまい、患部に到達しにくくなる。しかし、部位の特定された患部ないしはその近傍に局所注射した場合には、微粒子に併せて付与した特定組織への特異的な親和性による患部への選択集積能が相乗的に作用して、微粒子は患部に高濃度に配置される。因に、前記その２の処方になる輸液は患部の部位の特定にも有用である。即ち、上記輸液を静脈などに注射して感磁発熱体の微粒子を患部に選択的に集積させれば、これがＸ線，超音波などの撮影手段に対して患部の標識体となって患部の特定が容易になるものである。なお、上記標識目的の注射によって配置された微粒子は、当然ながら感磁発熱体としても機能する。よって、その２の輸液を注射し、撮影によって患部を特定し、引続いてその３の輸液を局所注射する手法を採用すれば、患部にはその２，その３の輸液中の微粒子が加算的に配置されて配置濃度が更に高まる。
【００１５】
微粒子への正電荷発現性の付与は、たとえばＮ−（α−trimethyl ammonioacetyl）−didodecyl−D−glutamateのような、生体適合性を有する陽イオン型界面活性物質あるいはアミノ酸のような両性界面活性物質（好適な等電点を有するもの）を微粒子に付着させることによって行うことができる。上記処理を、組織への親和性を付与するために抗体物質を付着させる前記その２の処理と同時に行うか、前後に行うかは、抗体の特性，コロイド化形式等を総合的に勘案して、相互に支障のないように設定するのがよい。
なお、微粒子に対する上記その２，その３の処理は、微粒子そのものを前処理する形で行ってもよく、又、微粒子を分散させた輸液に当該成分を添加する形で行ってもよい。
【００１６】
次に、本発明装置における交番磁界発生装置について、好適な形態を図１〜図３により説明する。
その１は、交番磁界発生装置Ｈを、生体10に係合させることのできる空心コイルを磁界出力部とするように構成した形態である。図１はソレノイドコイルを用いた例を示しており、１はコイル、２はコイル１に交流を通電するための電源装置、Ｓは生体内部に配置された、鉄系酸化物微粒子を配合した感磁発熱体である。この形態は、生体10を縦断する方向に磁束を形成させるのに適しており、患部を含めた広域に磁束が及ぶが、本発明装置の感磁発熱体の微粒子を患部に配置しておくことにより患部が集中加熱される。ソレノイドコイルは一体構造としても、ツーピース化してヒンジ状などにより開閉できる構造として装備しやすくしてもよい。上記図１の形態は、生体10に係合させる部材が軽量のコイルのみで済むため、設営が容易である。
【００１７】
その２は、電磁石の磁極対を磁界出力部とした形態である。図２はＣ字型の電磁石３を用いた例を示しており、４は鋼材，フェライトなどから成るコアであって、その端部５，5′が生体10の挿入される磁極対となる。６は励磁用の巻線である。この形態は生体10を横断する方向に磁束を形成させるのに適しており、重量の大きい電磁石３を生体10に係合させねばならないが、磁界の形成が患部を含む小領域で済み、且つ、磁束の集中度を高めやすいという利点がある。ここで、上記電磁石３を生体内部の特定の点又は線を中心に回動可能として磁極対の配向方位を時系列的に変化させうるようにしておくと、上記点又は線に患部を位置させることによって患部を通る磁束を複数の方位から形成できて、患部に至る迄の磁束径路上の生体の前記ジュ−ル発熱を低減できるので更に好ましい。図３は上記方式を例示したものであって、８，8′は生体10の内部の特定位置を中心に電磁石を往復回動させるための往復回転機構である。なお、上記配向方位の変化は、固定した電磁石３に対して生体10を回動させて行わせてもよい。
なお、上記空心コイル、又は、電磁石の巻線には、電源装置２から直接通電を行ってもよいが、図１に例示したように変成器（トランス）７を介して通電を行ってもよい。又、上記通電は50〜400kHzの交番周波数によって行うことが望ましい。これは、前記感磁発熱体中の微粒子が、50kHz未満では発熱が不足し、一方、400kHzを超える周波数については電源装置が高価となるからである。
【００１８】
【実施例】
図８の実験装置を用いて本発明装置による加熱態様のモデル実験を行い、本発明装置の作用効果を検証した。図８において、11は試験管，12は感磁発熱体配合ゲル，13はビーカー，14は生理的食塩水，15は誘導加熱用のコイルである。又、熱電対（図示せず）により、Ａ部，Ｂ部の温度測定が行える。
【００１９】

【００２０】
＜実験方法＞
上記実験装置を37℃恒温室内に設営し、18hr放置して均熱化させた後、通電を開始して、Ａ部及びＢ部の温度上昇を測定した。なお、ビーカー内の液の撹拌及び外界からの断熱は特に行っていないので、37℃外気放冷状態での実験となっている。
通電は、Ａ部の温度が42.5℃になるように通電をＰＩＤ制御しながら15min行なった。
【００２１】
＜実験結果＞
【００２２】
【表１】

【００２３】
表１の結果に見る通り、患部に見立てたＡ部を15min間加熱している間に、正常部に見立てたＢ部の昇温は、配合した鉄系酸化物微粒子の比透磁率が100以上であると40℃を超えなかった。
実際の生体内部では、正常部は健常な血流の下で上記実験よりはよく冷却される。即ち、微粒子の比透磁率を100以上に選定した本発明装置によれば、１回当りの加熱時間を15min程度に留めるという条件下で、正常部を40℃超に昇温させることなく患部を42.5℃以上に加熱できるという目処が、先ずは得られたことになる。即ち、上記目処を基に、加熱時間の最適化、あるいは、間欠的な繰返し加熱といった方案の検討を経て局部温熱療法の実用化が可能となるものである。
【００２４】
【発明の効果】
本発明装置は、上述のように、生体内部に配置すべき、比透磁率を高位に限定した鉄系酸化物の微粒子を主成分とする感磁発熱体と、生体を通る磁束を形成することのできる交番磁界発生装置とを有する構成により、生体内の局部を集中的に加熱できる手段を提供したものである。
本発明装置は、又、上記微粒子に患部等への選択的な集積性を付与しておくことによって、患部等に正確に適中した局部加熱を可能とした。
癌の治療手段として、患部を局部的に加熱して癌細胞を壊死させる局部温熱療法（ハイパーサーミア法）が、副作用を回避しやすいという本質的な利点を有することから、昨今益々注目されている。しかしながら、生体内の局部を集中的に加熱する手段そのものを欠いており、かかる手段の提供が切望されていた。
本発明装置の提供により、生体内局部の集中的な加熱を、しかも患部に適中させて行えるようになったことは、上記局部温熱療法の実用性を顕著に高めるものであり、医療に対する貢献は絶大である。
【図面の簡単な説明】
【図１】本発明加熱装置の一例の概念図。
【図２】本発明加熱装置の他の例の概念図。
【図３】本発明加熱装置の別例の概念図。
【図４】比透磁率100以上の微粒子を配合した感磁発熱体と交番磁界発生装置を用いた生体内奥部の加熱における磁束の形成を示す模式図。
【図５】図４の加熱における昇温分布を示す温度線図。
【図６】比透磁率100末端の微粒子を配合した感磁発熱体と交番磁界発生装置を用いた生体内奥部の加熱における磁束の形成を示す模式図。
【図７】図６の加熱における昇温分布を示す温度線図。
【図８】本発明加熱装置の加熱態様を検証するための実験装置の説明図。
【符号の説明】
Ｈ交番磁界発生装置
１コイル
２電源装置
３電磁石
４コア
５，5′ 磁極対
６巻線
10 生体
Ｓ感磁発熱体[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a living body internal heating apparatus suitable for intensively heating a local part of a living body for cancer treatment or the like.
[0002]
[Prior art]
Conventionally, local thermotherapy (hyperthermia method) that heats the affected area intensively to necrotize cancer cells has been studied. This method, which cancer cells based on the finding that necrosis by heating above 42.5 ° C., normal cells affected area was directed to be selectively necrosis only cancer cells by heating to a temperature at which not invasive It is.
[0003]
Here, the temperature of 42.5 ° C does not necrotize normal cells, but if such heating spreads over a wide area, it will damage the physiological function, so the point that determines the success or failure of the treatment depends on how the heating can be performed. It becomes. Therefore, this therapy is first applied to skin cancer that is easily subject to local heating, and then applied to the inner part of the living body. (A) Electrode conduction type dielectric heating targeting the affected part, (b) Targeting the affected part. (C) Induction heating with a magnetic needle embedded in the affected area and induction heating with an alternating magnetic field, (d) Implanting ferromagnetic particles in the affected area, Various methods such as a method of generating heat by application have been tried.
[0004]
However, in (A), it is only possible to energize so that the current flux spreads in the body, and there is no susceptor suitable for local heat generation by placing it in the affected area, and local heating at a specific depth is difficult. Therefore, after all, there is a limit that it is difficult to apply only to the surface layer part of the living body, and (b) is easier to narrow down the application range, but there is a limit to the penetration depth, so (b) In addition to the application to the deep surface layer, (c) has a limited number of implantable sites and requires a distributed arrangement of a large number of magnetic needles to uniformly heat the affected area. Since it is necessary to take out the magnetic needle, there is a problem that the load on the living body is large, and although (D) is capable of heating the inner part of the living body, the concentration of heating is low, and for thermotherapy It was not suitable for use as a local heating means.
[0005]
[Problems to be solved by the invention]
That is, local hyperthermia has an essential advantage that it is easy to avoid side effects, but has not yet achieved practicality as a means for treating an affected part in the back of a living body. This is due to the lack of local heating means that can intensively heat a small area inside the living body, and the provision of such local heating means is an issue for local thermotherapy to be practical. It was.
[0006]
[Means for Solving the Problems]
The gist of the present invention to solve the above problems is as follows.
To be placed station portion in a living body, and sensitive磁発heat body mainly composed of fine particles of iron oxide, and alternating magnetic field generating device disposed in a living body outside capable of forming a magnetic flux through the internal biological An in-vivo local heating apparatus capable of heating the in-vivo local area by magnetic hysteresis heating, wherein the iron oxide fine particles have a relative magnetic permeability of 100 to 2000 and an average particle diameter of 10 to 100 nm. By applying a magnetic field having an alternating frequency of 50 to 400 kHz and an intensity of 1 to 20 times the coercive force from the alternating magnetic field generator , the magnetosensitive heating element has a coercive force of 10 to 200 Oe. In addition, a magnetic hysteresis heat generation that is relatively stronger than Joule heat generation due to eddy current occurring in a living body around the heating element is formed to form a sharp temperature rise distribution centering on the heat generation element, and to be heated locally To be able to heat intensively Vivo local heating apparatus characterized. The relative permeability mentioned here refers to the maximum permeability obtained by applying a test method specified in JISC2561 to a block prepared by sintering the fine particles. The magneto-sensitive heating element mainly composed of an iron-based oxide having low conductivity generates heat due to magnetic hysteresis in an alternating magnetic field. On the other hand, the living body around the portion where the magnetosensitive heating element is disposed generates Joule heat due to the eddy current generated by the good conductivity.
[0007]
Therefore, by using fine particles blended in the magnetosensitive heating element with a high permeability of 100 or more, the formation of magnetic flux under an alternating magnetic field concentrates on the magnetosensitive heating element placement region. As a result, an increase in hysteresis heat generation of the magneto-sensitive heating element itself and a relative decrease in the Joule heat generation that occurs in the surrounding living body are brought about. Thus, the central heating of the affected area can be performed. This situation is conceptually shown in FIGS. In FIG. 4, 21 and 21 'are magnetic poles, 22 is a part of a living body, 23 is an affected part, and 24 is a magnetic flux. Incidentally, in the case of the heating method (d) of the prior art, the results are as shown in FIGS. 6, the same reference numerals as those in FIG. 4 denote the same members and the same parts. The magnetic permeability corresponds to the electric conductivity in the case of electricity, and the magnetic flux corresponds to the electric current. Therefore, the difference in the temperature rise distribution is caused by the magnitude of the magnetic permeability. The above effect becomes more pronounced as the relative permeability increases, but saturates at a relative permeability of around 2000.
[0008]
The reason why the iron-based oxide is selected as the component of the magnetosensitive heating element used in the apparatus of the present invention is that it is less harmful to the living body and is easily excreted by metabolism. The composition is a spinel type of iron oxide such as Fe ₃ O ₄ or γ-Fe ₂ O ₃ or a combination of Fe ₂ O ₃ and low-hazardous oxides such as MgO, CaO, MnO, CuO and ZnO. Examples thereof include iron-based composite oxides, composites of these iron-based oxides, and those in which H ₂ O is bonded to these iron-based oxides.
[0009]
The reason why the iron-based oxide is used in the form of fine particles is that it can be easily placed evenly in the affected area, can be transported to the affected area through blood vessels, etc., and is also advantageous for metabolic excretion. These effects become significant when the average particle size is 100 nm or less. On the other hand, since the fine particles are oxides having low conductivity, heat generation due to the action of an alternating magnetic field is caused by magnetic hysteresis loss as described above. Therefore, unlike induction heating that generates eddy current in a good conductor such as metal and generates heat, the particle size is not too small to prevent eddy current from being generated. However, in the case of hysteresis heat generation, the particle size is also small. Since the heat generation becomes less, it is better not to impair the sharp temperature rise distribution as described above in relation to the magnitude of eddy current heat generation occurring in the living body around the region where the fine particles are arranged. The average particle size is desirably 10 nm or more. When the fine particles are needle-shaped or plate-shaped, the above dimensional condition is applied to each shortest diameter (the thickness of the needle-shaped body or the thickness of the plate-shaped body), and each longest diameter (needle-shaped The dimensional ratio with respect to the length of the body or the major axis of the plate-like body may be suppressed to about 10. As will be described later, in the method of the present invention, if necessary, the fine particles may be mixed with an auxiliary agent, or the fine particles may be dispersed in a liquid medium.
[0010]
As described above, the magnetosensitive heating element is capable of intensive heat generation in the living body by limiting the relative permeability of the fine particles to be mixed therein, but ensures the strength of the heat generation. Therefore, the coercive force of the fine particles is desirably about 10 to 200 Oe. Even if heat generation is less than 10 Oe, it takes time to raise the temperature to the expected temperature because the rate of temperature rise is small.On the other hand, if it exceeds 200 Oe, the temperature rise rate becomes excessive and the temperature rises. Is difficult to set delicately.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, embodiments of the present invention will be described taking application to the local thermotherapy as an example. First, the fine particles of the magnetosensitive heating element of the above-described device of the present invention are prepared as described below, whereby the in-vivo arrangement of the particles when the device of the present invention is used for local thermotherapy can be advantageously performed.
[0012]
The first is that the fine particles are made into a paste, jelly, or granule with a substance such as agar, gelatin, alginate and the like that hardly causes harm to the living body as an auxiliary. This makes it easier to handle fine particles in an arrangement method in which a living body is incised and embedded in an affected part whose site has been specified as compared to a submicron fine powder.
[0013]
The second is to give specific affinity for a specific tissue inside the living body to the fine particles. Such fine particles are selectively accumulated in the tissue simply by injecting an infusion solution in which the fine particles are dispersed into a circulation path such as a vein. For example, in the case of targeting cancer cells, the affinity is imparted by attaching an antibody substance having specific affinity for an antigen substance produced specifically by the cancer cell to fine particles. Can do. Simultaneously with or before or after the above treatment, the microparticles are enclosed in liposomes (molecular capsules) with phospholipids, or formed into a protective colloid with a surface active substance such as lauric acid. Can be improved. As a liquid medium for infusion, a liquid having biocompatibility such as physiological saline can be appropriately selected and used. In addition, the concentration of physiological saline or the like can be appropriately increased within a range that does not affect the living body to increase the specific gravity of the liquid so that the dispersed fine particles are less likely to settle.
[0014]
The third imparts positive charge expression to the fine particles in addition to the specific affinity to the specific tissue. When such an infusion solution in which fine particles are dispersed is injected into a living body, since the living tissue is usually negatively charged, the fine particles are easily deposited indiscriminately throughout the living tissue due to the positive charge of the fine particles. That is, if the injection is made on a circulation path such as a vein, it is deposited on the inner wall of the circulation path before reaching the affected area, and it becomes difficult to reach the affected area. However, when locally injected at or near the affected area where the site is specified, the selective accumulation ability to the affected area due to specific affinity to the specific tissue given together with the microparticles acts synergistically, Is placed at a high concentration in the affected area. Incidentally, the infusion solution that is the second prescription is also useful for specifying the site of the affected area. That is, if the above-mentioned infusion solution is injected into a vein or the like and the fine particles of the magnetosensitive heating element are selectively accumulated in the affected area, this becomes a marker of the affected area with respect to imaging means such as X-rays and ultrasonic waves. It is easy to identify. Incidentally, the fine particles arranged by the above-mentioned injection for the purpose of labeling also function as a magnetosensitive heating element. Therefore, if the technique of injecting the second infusion solution, specifying the affected part by imaging, and subsequently locally injecting the third infusion solution, the particles in the second and third infusion liquids are additive to the affected part. The arrangement density is further increased.
[0015]
For imparting positive charge to microparticles, for example, N- (α-trimethyl ammonioacetyl) -didodecyl-D-glutamate, biocompatible cationic surfactants or amphoteric surfactants such as amino acids This can be carried out by attaching (having a suitable isoelectric point) to the fine particles. Whether the above treatment is performed simultaneously with or before or after the second treatment for attaching the antibody substance in order to impart affinity to the tissue, comprehensively considers the characteristics of the antibody, the colloidal form, etc. It is better to set so as not to interfere with each other.
The above-mentioned

treatments

2 and 3 for the fine particles may be performed by pretreating the fine particles themselves, or may be performed by adding the components to the infusion solution in which the fine particles are dispersed.
[0016]
Next, a preferred embodiment of the alternating magnetic field generator in the apparatus of the present invention will be described with reference to FIGS.
The first is a configuration in which the alternating magnetic field generator H is configured such that an air-core coil that can be engaged with the living body 10 is a magnetic field output unit. FIG. 1 shows an example using a solenoid coil, wherein 1 is a coil, 2 is a power supply device for energizing the coil 1 with alternating current, and S is a feeling of mixing iron-based oxide fine particles disposed inside the living body. Magnetic heating element. This form is suitable for forming a magnetic flux in the longitudinal direction of the living body 10, and the magnetic flux extends over a wide area including the affected area. However, the fine particles of the magnetosensitive heating element of the device of the present invention should be arranged in the affected area. As a result, the affected area is heated intensively. The solenoid coil may be an integral structure or may be easily equipped as a two-piece structure that can be opened and closed by a hinge shape or the like. The configuration shown in FIG. 1 is easy to set up because only a lightweight coil is required to be engaged with the living body 10.
[0017]
The second is a form in which the magnetic pole pair of the electromagnet is a magnetic field output unit. FIG. 2 shows an example in which a C-shaped electromagnet 3 is used. Reference numeral 4 denotes a core made of steel, ferrite or the like, and its end portions 5 and 5 'serve as magnetic pole pairs into which the living body 10 is inserted. Reference numeral 6 denotes an exciting winding. This form is suitable for forming a magnetic flux in a direction transverse to the living body 10, and the heavy electromagnet 3 must be engaged with the living body 10, but the formation of the magnetic field suffices in a small region including the affected part, and There is an advantage that it is easy to increase the concentration of magnetic flux. Here, if the electromagnet 3 can be rotated around a specific point or line inside the living body so that the orientation direction of the magnetic pole pair can be changed in time series, the affected part is positioned at the point or line. Accordingly, it is more preferable because the magnetic flux passing through the affected area can be formed from a plurality of directions, and the above-mentioned juule heat generation of the living body on the magnetic flux path leading to the affected area can be reduced. FIG. 3 exemplifies the above-described method. Reference numerals 8 and 8 ′ denote reciprocating rotation mechanisms for reciprocatingly rotating the electromagnet around a specific position inside the living body 10. Note that the change in the orientation direction may be performed by rotating the living body 10 with respect to the fixed electromagnet 3.
The air-core coil or the electromagnet winding may be energized directly from the power supply device 2, but may be energized via a transformer 7 as illustrated in FIG. . The energization is preferably performed at an alternating frequency of 50 to 400 kHz. This is because if the fine particles in the magnetosensitive heating element are less than 50 kHz, the heat generation is insufficient, while the power supply device is expensive for frequencies exceeding 400 kHz.
[0018]
【Example】
A model experiment of the heating mode by the apparatus of the present invention was performed using the experimental apparatus of FIG. 8, and the operational effects of the apparatus of the present invention were verified. In FIG. 8, 11 is a test tube, 12 is a magnetosensitive heating element-containing gel, 13 is a beaker, 14 is physiological saline, and 15 is a coil for induction heating. Moreover, the temperature measurement of A part and B part can be performed with a thermocouple (not shown).
[0019]

[0020]
<Experiment method>
The experimental apparatus was installed in a constant temperature room at 37 ° C., allowed to stand for 18 hours and soaked, and then energization was started to measure temperature rises in the A part and the B part. In addition, since stirring of the liquid in a beaker and heat insulation from the outside were not performed, it was an experiment in a 37 ° C. outside air cooling state.
The energization was performed for 15 minutes while the energization was PID controlled so that the temperature of part A was 42.5 ° C.
[0021]
<Experimental result>
[0022]
[Table 1]

[0023]
As can be seen from the results in Table 1, while heating the part A, which is assumed to be the affected part, for 15 minutes, the temperature rise of the part B, which is assumed to be the normal part, is such that the relative permeability of the blended iron-based oxide fine particles is 100 or more. The temperature did not exceed 40 ° C.
In an actual living body, the normal part is cooled better than the above experiment under a healthy blood flow. That is, according to the device of the present invention in which the relative permeability of the fine particles is selected to be 100 or more, the affected part can be treated without raising the normal part to over 40 ° C. under the condition that the heating time per one time is kept at about 15 minutes. First of all, the prospect of heating to 42.5 ° C. or higher is obtained. That is, based on the above-mentioned target, it is possible to put local thermotherapy into practical use through examination of methods such as optimization of heating time or intermittent repeated heating.
[0024]
【The invention's effect】
As described above, the apparatus of the present invention forms a magnetic flux that passes through a living body and a magnetosensitive heating element mainly composed of fine particles of an iron-based oxide whose relative permeability is limited to a high level, which should be disposed inside the living body. By means of a configuration having an alternating magnetic field generating device capable of performing the above, means for intensively heating a local part in a living body is provided.
The device of the present invention also enables local heating that is accurately applied to the affected area by providing the fine particles with selective accumulation on the affected area.
As a means for treating cancer, local hyperthermia (hyperthermia method) that locally heats an affected area to necrotize cancer cells has an essential advantage of easily avoiding side effects, and thus has attracted increasing attention recently. However, there is a lack of means for intensively heating local parts in the living body, and provision of such means has been desired.
The provision of the device of the present invention makes it possible to perform intensive heating of the local area in the living body while making it suitable for the affected area, which significantly enhances the practicality of the local thermotherapy, and contributes to medical care. It is huge.
[Brief description of the drawings]
FIG. 1 is a conceptual diagram of an example of a heating apparatus according to the present invention.
FIG. 2 is a conceptual diagram of another example of the heating device of the present invention.
FIG. 3 is a conceptual diagram of another example of the heating device of the present invention.
FIG. 4 is a schematic diagram showing the formation of magnetic flux in heating the inner part of a living body using a magneto-sensitive heating element containing fine particles having a relative permeability of 100 or more and an alternating magnetic field generator.
5 is a temperature diagram showing a temperature rise distribution in the heating of FIG. 4. FIG.
FIG. 6 is a schematic diagram showing the formation of magnetic flux in heating the inner part of a living body using a magneto-sensitive heating element mixed with fine particles having a relative permeability of 100 terminals and an alternating magnetic field generator.
7 is a temperature diagram showing a temperature rise distribution in the heating shown in FIG. 6;
FIG. 8 is an explanatory diagram of an experimental apparatus for verifying the heating mode of the heating apparatus of the present invention.
[Explanation of symbols]
H Alternating magnetic field generator 1 Coil 2 Power supply 3 Electromagnet 4 Core 5, 5 'Magnetic pole pair 6 Winding
10 Living body S Magnetosensitive heating element

Claims

To be placed station portion in a living body, and sensitive磁発heat body mainly composed of fine particles of iron oxide, and alternating magnetic field generating device disposed in a living body outside capable of forming a magnetic flux through the internal biological An in-vivo local heating apparatus capable of heating the in-vivo local area by magnetic hysteresis heat generation, wherein the iron oxide fine particles have a relative magnetic permeability of 100 to 2000 and an average particle diameter of 10 to 100 nm. By applying a magnetic field having an alternating frequency of 50 to 400 kHz and an intensity of 1 to 20 times the coercive force from the alternating magnetic field generator , the magnetosensitive heating element has a coercive force of 10 to 200 Oe. A magnetic hysteresis heat generation that is relatively stronger than Joule heat generation due to eddy currents occurring in the living body around the heating element arrangement site to form a sharp temperature rise distribution centering on the heating element, and to be heated locally To be able to heat intensively Vivo local heating apparatus characterized.

The fine particles, biological low damage resistance aid paste using, jelly, or in vivo station unit heating apparatus according to claim 1 which has been gathered into granules.

The fine particles in vivo station unit heating apparatus according to claim 1 or 2 specific affinity was imparted to the tissue to be heated of a living body.

Vivo station unit heating apparatus according to claim 1 or 2 specific affinity and positive charges expressing imparted to the tissue to be heated of a living body to the fine particles.

The alternating magnetic field generator comprises a magnetic field output unit including a coil that can be placed surrounding the living body, in vivo station unit according to claim 1 and a power supply for energizing the alternating current to said coil Heating device.

The alternating magnetic field generator is any of claims 1 to 4 having an electromagnet having a magnetic field output unit comprising a pole pair can be placed across the living body, and a power supply device for energizing the alternating current winding of the electromagnet vivo station unit heating apparatus of crab according.

The in-vivo according to claim 6 , wherein the electromagnet is rotatable relative to a specific point or line inside the living body so that the direction of the magnetic flux passing through the inside of the living body can be changed in time series. station unit heating apparatus.