JP2847789B2 - Hyperthermia agent - Google Patents
Hyperthermia agentInfo
- Publication number
- JP2847789B2 JP2847789B2 JP1211504A JP21150489A JP2847789B2 JP 2847789 B2 JP2847789 B2 JP 2847789B2 JP 1211504 A JP1211504 A JP 1211504A JP 21150489 A JP21150489 A JP 21150489A JP 2847789 B2 JP2847789 B2 JP 2847789B2
- Authority
- JP
- Japan
- Prior art keywords
- dextran
- hyperthermia
- metal
- magnetic
- agent
- 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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Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は人および動物の疾患の処置のために使用しう
る温熱療法用剤に関し、特に安全で確実な癌の治療・処
置のために有効な温熱療法用剤に関する。Description: TECHNICAL FIELD The present invention relates to a hyperthermia agent which can be used for treatment of human and animal diseases, and is particularly effective for safe and reliable treatment and treatment of cancer. Related to a hyperthermia agent.
（従来の技術及び課題） 近年、人または動物の全身または局所を加温して悪性
腫瘍や前立腺肥大症などの疾患を治療・処置する試みが
行われている。(Prior art and problems) In recent years, attempts have been made to treat and treat diseases such as malignant tumors and benign prostatic hyperplasia by heating the whole or local body of humans or animals.
例えば悪性腫瘍の治療法として、直径１ミクロンを超
えない磁性酸化鉄又は水酸化第２鉄などの粒子をぶどう
糖やデキストランなどの水溶液に懸濁させて静脈内に注
射し、癌細胞に貪食させた後、電磁場にさらし、該粒子
を誘導加温して癌細胞を死滅させる方法が提案されてい
る（特開昭63−5379号公報参照）。For example, as a method for treating malignant tumors, particles such as magnetic iron oxide or ferric hydroxide not exceeding 1 micron in diameter were suspended in an aqueous solution such as glucose or dextran and injected intravenously to phagocytose cancer cells. Thereafter, a method has been proposed in which the particles are exposed to an electromagnetic field to induce heating of the particles to kill cancer cells (see JP-A-63-5379).
しかしながら、かかる磁性粒子懸濁液はコロイト安定
性が悪く、血液や組織液などいわゆる体液に出合うと短
時間で凝集し、静脈内投与では癌細胞に到達するまでに
血管や組織に沈着してしまい、癌細胞に集中せしめるこ
とが困難である。また、凝集物による循環障害が発現す
るためその用量が制限されるという難点がある。However, such magnetic particle suspensions have poor colloid stability, aggregate in a short time when they come into contact with so-called body fluids such as blood and tissue fluids, and are deposited in blood vessels and tissues by intravenous administration before they reach cancer cells, It is difficult to concentrate on cancer cells. In addition, there is a drawback in that the dose is limited due to the occurrence of circulatory disorders due to aggregates.
これらの問題をさけるために直接腫瘍組織内に磁性粒
子懸懸濁液を注射することも検討されている［第44回日
本癌学会総会抄録集、演題No.1800（昭和60年）］。し
かし、この方法によっても、磁性粒子が腫瘍組織内で容
易に凝集し、その分布が均一にならないため、腫瘍細胞
が完全に死滅せず、再発、転移等の危険があり、効果が
不確実になるばかりでなく、磁性粒子の局在は時に異常
高温部を生じ、正常組織、ことに血管の損傷をひきおこ
すという欠点がある。In order to avoid these problems, injection of a suspension of magnetic particles directly into tumor tissue is also being studied [Abstracts of the 44th Annual Meeting of the Cancer Society of Japan, Abstract No. 1800 (Showa 60)]. However, even with this method, since the magnetic particles are easily aggregated in the tumor tissue and the distribution is not uniform, the tumor cells are not completely killed, there is a risk of recurrence, metastasis, etc., and the effect is uncertain. Not only that, the localization of the magnetic particles has the disadvantage that it sometimes causes abnormally high temperature areas, causing damage to normal tissues, especially blood vessels.
また、別の問題として、かかる磁性粒子は生体内にお
ける代謝性が極めて悪く、癌治療に成功して患者が長期
生存する場合には、未知の毒性が懸念されるほか最近急
速に発達し、よく利用されるようになった核磁気共鳴断
層撮影装置、いわゆるMRIによる癌の予後判定等の大き
な障害となる等の恐れがある。Another problem is that such magnetic particles are extremely poorly metabolizable in vivo, and if cancer treatment is successful and patients survive for a long period of time, there is concern about unknown toxicity and recent rapid development, There is a fear that it may become a major obstacle to the prognosis determination of cancer by a nuclear magnetic resonance tomography apparatus that has come to be used, so-called MRI.
（発明の目的） 本発明は上記の如き欠点を克服した温熱療法用剤を開
発すべくなされたものであり、誘導加温効率が極めて高
く、生体内でのコロイド安定性に勝れ、低毒性でかつ生
体内における代謝性の良好な温熱療法用剤を提供するこ
とを目的とする。(Object of the Invention) The present invention has been made to develop an agent for hyperthermia which overcomes the above-mentioned drawbacks, has extremely high induction heating efficiency, excels in colloid stability in vivo, and has low toxicity. Another object of the present invention is to provide a thermotherapy agent which is excellent in metabolism in a living body.
（発明の開示） 本発明によれば、デキストランと金属磁性体または金
属化合物磁性体との複合体を有効成分として含有するこ
とを特徴とする温熱療法用剤が提供される。(Disclosure of the Invention) According to the present invention, there is provided an agent for hyperthermia, which comprises a complex of dextran and a magnetic metal or a magnetic metal compound as an active ingredient.
本発明の温熱療法用剤において有効成分として使用さ
れるデキストランと金属磁性体または金属化合磁性体と
の複合体は、デキストランと金属磁性体または金属化合
物磁性体とを化学的に反応させることにより製造される
ものであり、デキストラン水溶液にかかる磁性体粒子を
単に懸濁させただけの前掲特公昭63−5379号公報に記載
の組成物とは明確に区別されるものである。The complex of dextran and a metal magnetic substance or a metal compound magnetic substance used as an active ingredient in the agent for hyperthermia of the present invention is produced by chemically reacting dextran with a metal magnetic substance or a metal compound magnetic substance. This is clearly distinguished from the composition described in JP-B-63-5379, in which magnetic particles are simply suspended in an aqueous dextran solution.
かかる複合体の調製に使用されるデキストランとして
は、それ自体既知のものを使用することができ、殊に、
重量平均分子量が1,000〜100,000、好ましくは4,000〜1
0,000の範囲内のものが、コロイド安定性や温度上昇効
果等の点で好適である。また、デキストランは未変性の
ものが使用可能であるが、それ自体既知の方法、例えば
アルカリ、ハロゲンまたは亜ハロゲン酸で処理すること
により還元性末端を改質したデキストラン；或いはシア
ナイドイオンで処理後加水分解することにより還元性末
端を改質したデキストランもまた使用することができ且
つその方が好ましい［改質法としては、例えば、特公昭
45−5557号公報、特公昭59−1321号、特開昭61−233001
号公報等参照］。従って、本明細書における「デキスト
ラン」なる語は、未変性のデキストランのみならず、上
記の如く改質されたデキストランをも包含する意味で使
用する。As the dextran used for the preparation of such a complex, those known per se can be used.
Weight average molecular weight of 1,000 to 100,000, preferably 4,000 to 1
Those having a molecular weight within the range of 0.000 are preferable in terms of colloid stability, temperature increasing effect and the like. Unmodified dextran can be used, but dextran whose reducing end has been modified by a method known per se, for example, treatment with alkali, halogen or halogenous acid; or after treatment with cyanide ion Dextran in which the reducing end has been modified by hydrolysis can also be used and is preferred.
No. 45-5557, Japanese Patent Publication No. 59-1321, Japanese Patent Application Laid-Open No. 61-233001
Reference]. Therefore, the term "dextran" is used herein to include not only native dextran but also dextran modified as described above.
一方、上記デキストランと反応せしめられる金属磁性
体または金属化合物磁性体としては、誘導加温により発
熱する金属または金属化合物の磁性体であり、強磁性体
及び超常磁性体が包含される。かかる磁性体は一般に微
細粒子状で使用され、その粒子径は通常平均粒子径で30
〜500Å、好ましくは50〜150Åの範囲内にあるものが適
している。On the other hand, the metal magnetic material or the metal compound magnetic material that is reacted with the dextran is a magnetic material of a metal or a metal compound that generates heat by induction heating, and includes a ferromagnetic material and a superparamagnetic material. Such a magnetic material is generally used in the form of fine particles, and the particle size is usually 30 in average particle size.
Those which are in the range of -500, preferably 50-150 are suitable.
しかして、金属磁性体としては、例えば、鉄、ニツケ
ル、コバルト、ガドリニウム等の遷移金属が挙げられ、
中でも鉄が好適である。また、金属化合物としては、例
えば、鉄、ニツケル、コバルト等の遷移金属の酸化物や
フエライト等が挙げられ、特に四三酸化鉄及びγ−酸化
鉄が好適である。Thus, examples of the metal magnetic material include iron, nickel, cobalt, and transition metals such as gadolinium.
Among them, iron is preferred. Examples of the metal compound include oxides of transition metals such as iron, nickel, and cobalt, and ferrite. Particularly, triiron tetroxide and γ-iron oxide are preferable.
以上述べたデキストランと金属磁性体または金属化合
物磁性体との反応は、例えば、特公昭59−13521号公報
に記載の方法に従い、金属磁性体または金属化合物磁性
体の水性ゾルにデキストラン又はその水溶液を添加し、
中性ないし弱酸性条件下に約90℃ないし還流温度間の温
度で約30〜約120分間加熱することにより行なうことが
できる。The reaction between dextran and the metal magnetic material or the metal compound magnetic material described above is performed, for example, by adding dextran or an aqueous solution thereof to an aqueous sol of the metal magnetic material or the metal compound magnetic material according to the method described in JP-B-59-13521. Add,
It can be carried out by heating at a temperature between about 90 ° C. and the reflux temperature for about 30 to about 120 minutes under neutral to weakly acidic conditions.
また米国特許第4,101,435号明細書に記載の方法に従
い、デキストラン、好ましくはアルカリ処理した改質デ
キストランの存在下に水性媒体中で金属化合物磁性体、
例えば磁性酸化鉄を製造し、次いで中性ないし弱酸性条
件下に約90℃ないし還流温度間の温度で約30〜約120分
間加熱することにより行なうことによっても複合体を製
造することができる。Also, according to the method described in U.S. Pat.No. 4,101,435, a metal compound magnetic material in an aqueous medium in the presence of dextran, preferably modified dextran that has been alkali-treated,
For example, a composite can be produced by producing a magnetic iron oxide and then heating it under a neutral to slightly acidic condition at a temperature between about 90 ° C. and reflux temperature for about 30 to about 120 minutes.
以上に述べた如くして調製されるデキストランと金属
磁性体又は金属化合物磁性体とを複合体は、本発明に従
い、温熱療法用剤として使用する場合、その投与に適し
た剤形に調製される。その投与の方法としては、一般
に、静脈内、腫瘍組織内、動脈内、膀胱内等への注射、
注入（点滴）が用いられるが、処置すべき疾患によって
は経口投与、直腸内投与等の方法で投与することもでき
る。The complex of dextran and metal magnetic material or metal compound magnetic material prepared as described above is prepared in a dosage form suitable for administration when used as a hyperthermia agent according to the present invention. . As a method of the administration, generally, injection into vein, tumor tissue, artery, bladder, etc.,
Injection (infusion) is used, but depending on the disease to be treated, oral administration, rectal administration and the like can be used.
しかして、注射、注入等の投与に対しては、上記複合
体を製薬学の分野で通常の方法に従い、従えば、注射用
蒸留水または生理食塩水に通常１〜60％（w/v）、好ま
しくは５〜20％（w/v）の濃度で溶解させることができ
る。Thus, for administration such as injection and infusion, the above-mentioned conjugate is prepared according to a conventional method in the field of pharmacy, and is usually 1 to 60% (w / v) in distilled water for injection or physiological saline. , Preferably at a concentration of 5 to 20% (w / v).
また、添加剤として、例えば塩化ナトリウム等の無機
塩；ブドウ糖等の単糖類；マンニトール、ソルビトール
等の糖アルコール類；クエン酸塩、酒石酸塩塔の有機酸
塩；リン酸緩衝剤、トリス緩衝剤等の生理学的に許容さ
れる種々の助剤を適宜配合してもよい。Examples of additives include inorganic salts such as sodium chloride; monosaccharides such as glucose; sugar alcohols such as mannitol and sorbitol; citrate salts, organic acid salts of tartrate towers; phosphate buffers, tris buffers, and the like. Various physiologically acceptable auxiliaries may be appropriately compounded.
一方、経口投与、直腸投与に対しては、製薬学の分野
の常法に従い、適当な製薬助剤と共に、上記複合体を含
む錠剤、顆粒剤、カプセル剤、シロツプ、散剤、坐剤等
の形態に製剤化することができる。On the other hand, for oral administration and rectal administration, in the form of tablets, granules, capsules, syrups, powders, suppositories, etc. containing the above-mentioned complex together with appropriate pharmaceutical auxiliaries according to the usual methods in the field of pharmacy. Can be formulated.
本発明の温熱療法用剤を投与量は処置すべき患者の症
状の軽重、年令、疾患の部位等に依存し一概にいうこと
はできないが、少なくとも生体がもつ冷却能に打ち勝つ
だけの組織内または体液内濃度を保持できるように投与
することが必要であり、その濃度は大体0.5〜5.0％（w/
v）の範囲内である。かくして、例えば悪性腫瘍に組織
内投与する場合、悪性腫瘍容積1cm3当り金属換算で１〜
50mgの量で投与するのが適当である。しかし、この投与
量は一応の目安であり医者の診断に基いてかかる範囲よ
り少ないかまたは多い量を投与することもできる。The dose of the agent for hyperthermia of the present invention depends on the severity of the condition of the patient to be treated, age, the site of the disease, etc., and cannot be specified unconditionally, but at least within the tissue that only overcomes the cooling ability of the living body. Alternatively, it is necessary to administer so that the concentration in the body fluid can be maintained, and the concentration is approximately 0.5 to 5.0% (w /
v). Thus, for example, when administered to a malignant tumor in a tissue, the volume of the malignant tumor is 1 to 1 cm 3 in terms of metal.
Suitably, it is administered in a dose of 50 mg. However, this dose is only a rough guide, and it is possible to administer a dose smaller or larger than the above range based on the diagnosis of a doctor.
本発明の温熱療法用剤を投与された患者は、前掲特公
昭63−5379号公報に記載の如く誘導加熱装置の高周波磁
場内に置かれ、そこで温度監視下に治療、処置を受け
る。誘導加熱装置における周波数としては一般に20KHz
〜10MHz、好ましくは50〜500KHzの範囲内が適当であ
り、また、温度監視は例えば米国BAILY社製のTM54型機
に使用されている塩ビ被覆の銅−白金式センサーを用い
て行なうことができる。The patient to whom the agent for hyperthermia of the present invention has been administered is placed in a high-frequency magnetic field of an induction heating device as described in JP-B-63-5379, and undergoes treatment and treatment under temperature monitoring. Generally, the frequency in the induction heating device is 20 KHz
-10 MHz, preferably in the range of 50-500 KHz, and temperature monitoring can be performed using, for example, a PVC-coated copper-platinum sensor used in a TM54 type machine manufactured by BAILY, USA. .
本発明により提供される温熱療法用剤は、有効成分と
してデキストランと金属磁性または金属化合物磁性体と
が化学的に反応して得られる複合体を使用しているた
め、コロイド状態での安定性に優れ、生体内での特定組
織への均一分散性が良好であり従って温熱療効率に優れ
ており、しかも毒性が少なく代謝性も良好であって、悪
性腫瘍（癌）、前立腺肥大、創傷等の温熱療法に広く使
用することができる。The thermotherapeutic agent provided by the present invention uses a complex obtained by chemically reacting dextran with a magnetic metal or a magnetic metal compound as an active ingredient. It is excellent, has good uniform dispersibility in specific tissues in the living body, and is therefore excellent in thermotherapy efficiency, and has low toxicity and good metabolism, and is useful for malignant tumors (cancer), prostatic hypertrophy, wounds, etc. Can be widely used for hyperthermia.
次に、実施例、参考例及び試験例により、本発明をさ
らに具体的に説明する。Next, the present invention will be described more specifically with reference to Examples, Reference Examples and Test Examples.
参考例１（複合体の製造） アルカリ処理した改質デキストラン（重量平均分子量
4,000）169gを水552mlに溶かし、水浴で加温しながら、
撹拌下塩化第一鉄４水和物22.28g、塩化第二鉄37.02gの
混合水溶液228ml、３規定の水酸化ナトリウム40mlを加
え、次いで塩酸で中和した後１時間加熱還流し、冷却す
る。粗大粒子を遠心分離で除去し、上澄液に等量のメタ
ノールを加えて磁性酸化鉄・デキストラン複合体粗製物
を沈澱として得る。この沈澱を水に溶かし、１晩流水中
で透析し、pHを８に調整してエバポレーターで濃縮した
後0.20μｍをフイルターで濾過し、凍結乾燥して、磁性
酸化鉄・デキストラン複合体（黒色粉末35g）を得る。
このようにして得られた磁性酸化鉄・デキストラン複合
体の物性を表−Ｉに示す。Reference Example 1 (Production of composite) Modified dextran treated with alkali (weight average molecular weight
4,000) Dissolve 169 g in 552 ml of water and heat in a water bath.
Under stirring, 228 ml of a mixed aqueous solution of 22.28 g of ferrous chloride tetrahydrate and 37.02 g of ferric chloride was added, and 40 ml of 3N sodium hydroxide was added. The mixture was neutralized with hydrochloric acid, heated to reflux for 1 hour, and cooled. The coarse particles are removed by centrifugation, and an equal amount of methanol is added to the supernatant to obtain a crude magnetic iron oxide / dextran complex as a precipitate. The precipitate was dissolved in water, dialyzed in running water overnight, adjusted to pH 8, concentrated by an evaporator, filtered through a filter of 0.20 μm, lyophilized, and dried to form a magnetic iron oxide / dextran complex (black powder). 35g).
Table I shows the physical properties of the magnetic iron oxide / dextran complex thus obtained.
参考例２ デキストラン（重量平均分子量7000）250gを水1.0
に溶解し、これにヨウ素（I2）25gを加え、撹拌下に約
１時間で40％NaOH30mlを添加し、さらに２時間撹拌す
る。反応液にその３倍量のメタノールを添加し、析出物
を得る。析出物は水に再溶解し、３倍量のメタノールを
添加する再沈操作をさらに２回繰り返す。析出物の水溶
液を濾過し、pH7.5に調整した後、減圧濃縮、次いで凍
結乾燥して、改質デキストラン（白色粉末、225g）を得
る。 Reference Example 2 250 g of dextran (weight average molecular weight 7000) in water 1.0
Then, 25 g of iodine (I 2 ) was added thereto, 30 ml of 40% NaOH was added with stirring for about 1 hour, and the mixture was further stirred for 2 hours. To the reaction solution is added three times the amount of methanol to obtain a precipitate. The precipitate is redissolved in water, and the reprecipitation operation of adding three times the amount of methanol is repeated twice more. The aqueous solution of the precipitate is filtered, adjusted to pH 7.5, concentrated under reduced pressure, and then lyophilized to obtain a modified dextran (white powder, 225 g).
参考例３ デキストラン（重量平均分子量4000）272gを水1.0
に溶解し、撹拌下濃塩酸を用いpH3.0±0.1に保持しつ
つ、次亜塩素酸ナトリウム（NaClO2）164gを約１時間で
添加する。さらにpH3.0±0.1に保持しつつ３時間撹拌
し、次いで15時間撹拌する。反応液に3.5倍量のメタノ
ールを添加し、析出物を得る。析出物は水に再溶解し、
3.5倍量のメタノールを添加する再沈操作を２回繰り返
す。析出物の水溶液を濾過し、pH7.5に調整した後、減
圧濃縮、次いで凍結乾燥して、改質デキストラン（淡黄
色の粉末、218g）を得る。Reference Example 3 272 g of dextran (weight average molecular weight 4000) was added to water 1.0
164 g of sodium hypochlorite (NaClO 2 ) in about 1 hour while maintaining the pH at 3.0 ± 0.1 with concentrated hydrochloric acid under stirring. Stir for 3 hours while maintaining the pH at 3.0 ± 0.1, and then stir for 15 hours. A 3.5-fold amount of methanol is added to the reaction solution to obtain a precipitate. The precipitate redissolves in water,
The reprecipitation operation of adding 3.5 times the amount of methanol is repeated twice. The aqueous solution of the precipitate is filtered, adjusted to pH 7.5, concentrated under reduced pressure, and then freeze-dried to obtain a modified dextran (218 g of pale yellow powder).
参考例４ アンバーライト IRA−410（ロームアンドハースト社
製イオン交換樹脂）５に水を加えて全量を７とした
スラリーに、撹拌下pHを8.0−8.7に保持しながら1M塩化
第二鉄水溶液1.0と1M塩化第一鉄水溶液500mlとの混合
液を添加する。この反応液に直ちに濃塩酸を加えてpH1.
6とし、同一pHで１時間撹拌し、次いでイオン交換樹脂
を濾別する。得られたゾルに水を加えながら限外濾過
し、磁性酸化鉄水性ゾル2.3（pH2.8、Fe含量26mg/m
l）を得る。このゾル600mlと参考例２で得られる改質デ
キストランの25w/v％水溶液300mlとを混合し、１時間還
流加熱する。冷後この反応液に濃度47％までメタノール
を添加し、析出した沈澱物を溶解し、一夜流水透析す
る。次いでpHを８に調整した後、減圧濃縮、濾過、凍結
乾燥して、磁性酸化鉄・デキストラン複合体（黒色粉
末、37g）を得る。本複合体の物性を表−２に示す。Reference Example 4 Amber Light IRA-410 (ROHM & HEARST)
Water was added to 5 to make the total amount 7
Add 1M chloride to the slurry while maintaining the pH at 8.0-8.7 with stirring.
Mixing ferric aqueous solution 1.0 with 1M ferrous chloride aqueous solution 500ml
Add the liquid. Concentrated hydrochloric acid was immediately added to the reaction mixture to adjust the pH to 1.
6 and stir at the same pH for 1 hour, then ion exchange resin
Is filtered off. Ultrafiltration while adding water to the obtained sol
And magnetic iron oxide aqueous sol 2.3 (pH 2.8, Fe content 26 mg / m
l) get 600 ml of this sol and the modified resin obtained in Reference Example 2
Mix with 300 ml of 25 w / v% aqueous solution of kisstran and return for 1 hour
Flow heating. After cooling, add methanol to the reaction mixture to a concentration of 47%.
Was added to dissolve the precipitate, and dialyzed with running water overnight.
You. Then, after adjusting the pH to 8, concentration under reduced pressure, filtration, and freezing.
Dried and dried magnetic iron oxide / dextran complex (black powder)
37g) is obtained. Table 2 shows the physical properties of the composite.
参考例５ 参考例４で製造した磁性酸化鉄水性ゾル600mlと参考
例３で得られる改質デキストランの25w/v％水溶液300ml
とを混合し、以下参考例４と同様に処理して、磁性酸化
鉄・デキストラン複合体（黒色粉末、33g）を得る。本
複合体の物性を表−３に示す。 Reference Example 5 600 ml of the magnetic iron oxide aqueous sol produced in Reference Example 4 and 300 ml of a 25 w / v% aqueous solution of the modified dextran obtained in Reference Example 3
And then treated in the same manner as in Reference Example 4 to obtain a magnetic iron oxide / dextran complex (black powder, 33 g). Table 3 shows the physical properties of the composite.
実施例１ 参考例１で得た磁性酸化鉄・デキストラン複合体粉末
2170mgに生理食塩水を加えて10mlとし、水浴中で50℃に
加温後、ポアーサイズ0.22μｍのミリポアーフイルター
を用いて濾過滅菌、滅菌ガラスアンプルに封入する。 Example 1 Magnetic iron oxide / dextran composite powder obtained in Reference Example 1
2170 mg was added with physiological saline to make 10 ml, heated to 50 ° C. in a water bath, sterilized by filtration using a Millipore filter having a pore size of 0.22 μm, and sealed in a sterilized glass ampoule.
実施例２ 参考例１で得た磁性酸化鉄・デキストラン複合体粉末
2170mgにマンニトール200mgを添加し、生理食塩水を加
えて10mLとし、ガラスアンプルに封入後121℃20分間オ
ートクレーブ滅菌する。Example 2 Magnetic iron oxide / dextran composite powder obtained in Reference example 1
200 mg of mannitol is added to 2170 mg, and physiological saline is added to make 10 mL. After sealing in a glass ampule, autoclave sterilization is performed at 121 ° C. for 20 minutes.
実施例３ 参考例１で得た磁性酸化鉄・デキストラン複合体粉末
2170mgにマンニトール200mgを加えよく混合したもの
に、用時に生理食塩水を加えて、10mlとし、ポアーサイ
ズ0.22μｍのミリポアーフイルターを用いて濾過滅菌す
る。Example 3 Magnetic iron oxide / dextran composite powder obtained in Reference example 1
To 2170 mg, mannitol 200 mg was added and mixed well, and physiological saline was added to make it 10 ml at the time of use. The mixture was sterilized by filtration using a Millipore filter having a pore size of 0.22 μm.
実施例４ 参考例４で得た磁性酸化鉄・デキストラン複合体粉末
3053mgにクエン酸二ナトリウム127mgを加え、注射用蒸
留水に溶解して100mlとし、水浴中で50℃に加温後、ポ
ア・サイズ0.22μｍのミリポアーフイルターを用いて濾
過滅菌し、滅菌バイアル瓶に封入する。Example 4 Magnetic iron oxide / dextran composite powder obtained in Reference example 4
To 3053 mg, disodium citrate 127 mg was added, dissolved in distilled water for injection to make 100 ml, heated to 50 ° C. in a water bath, sterilized by filtration using a Millipore filter with a pore size of 0.22 μm, and sterilized vial bottle To be sealed.
実施例５ 参考例５で得た磁性酸化鉄・デキストラン複合体粉末
2620mgに生理食塩水を加えて100mlとし、実施例１と同
様の方法で製剤とする。Example 5 Magnetic iron oxide / dextran composite powder obtained in Reference example 5
Physiological saline was added to 2620 mg to make 100 ml, and the preparation was made in the same manner as in Example 1.
試験例１ 前記参考例１で製造して得た磁性酸化鉄・デキストラ
ン複合体に注射用蒸留水を加え、濃度をFeとして1.25w/
v％とした液5mlを作り、直径3cmのシャーレーに入れ、
山本ビニター製誘導加温装置TY型機を用い、周波数500K
Hz、出力4.6KWにより誘導加温実験を行い、下記の成績
を得た。なお、比較対照品として、平均粒子径約80Åの
磁性酸化鉄を濃度がFeとして1.25w/v％及び5.0w/v％と
なるように10w/v％デキストラン（重量平均分子量、70,
000）水溶液に懸濁したものを夫々5mlずつ作り、同様の
条件により誘導加温実験を行った。Test Example 1 Distilled water for injection was added to the magnetic iron oxide / dextran complex obtained in the above Reference Example 1, and the concentration was Fe of 1.25 w /
Make 5 ml of v% liquid and put it in a 3 cm diameter petri dish.
Using a Yamamoto Vinita induction heating device TY type machine, frequency 500K
An induction heating experiment was performed with an output of 4.6 KW at Hz and the following results were obtained. As a comparative product, a 10 w / v% dextran (weight average molecular weight, 70,
000) 5 ml of each suspension was prepared in an aqueous solution, and an induction heating experiment was performed under the same conditions.
また、液温の測定は米国BAILY社製TM54型温度測定機
を用いて行った。The liquid temperature was measured using a TM54 type temperature measuring device manufactured by BAILY USA.
本発明品は１分間の誘導加温により約７℃温度が上昇
した。一方、Feとして同濃度の比較対照品は同条件の誘
導加温によっても0.4℃の温度上昇に止まった。また、
比較対照品の温度上昇効率を高くする目的で調製したFe
濃度5.0w/v％のものは確かにその効率が高くなったもの
の、沈降物が生じやすいため、同条件で通電しつづけた
場合の温度上昇は不規則であった（第１図参照）。The temperature of the product of the present invention was increased by about 7 ° C. by the induction heating for 1 minute. On the other hand, the comparative product having the same concentration as Fe showed only a 0.4 ° C. temperature rise even by the induction heating under the same conditions. Also,
Fe prepared for the purpose of increasing the temperature rise efficiency of the comparative product
Although the concentration of 5.0 w / v% certainly increased its efficiency, sediment was easily generated, and the temperature rise was irregular when the current was continued under the same conditions (see FIG. 1).
試験例２ 実施例４で得た本発明の注射液5mlを直径3cmのシャー
レに入れ、試験例１と同じ装置を用い、出力1.4KWで誘
導加温試験を行つた。Test Example 2 5 ml of the injection solution of the present invention obtained in Example 4 was placed in a petri dish having a diameter of 3 cm, and an induction heating test was performed at 1.4 kW output using the same apparatus as in Test Example 1.
比較対照品は試験例１と同じものを用い、同様に試験
した。The same comparative test product was used as in Test Example 1 and the test was conducted in the same manner.
その結果、表−４に示す成績が得られた。 As a result, the results shown in Table 4 were obtained.
試験例３ 実施例５で得た本発明の注射液5mlを用い試験例２と
全く同様の方法で誘導加温試験を行つた。 Test Example 3 An induction heating test was carried out in exactly the same manner as in Test Example 2, using 5 ml of the injection solution of the present invention obtained in Example 5.
その結果、表−５に示す成績が得られた。 As a result, the results shown in Table 5 were obtained.
試験例４ 試験例２と同じ条件により本発明品の物理化学的性状
と誘導加温による、温度上昇とを関係を調べた。その結
果、表−６に示す成績を得た。 Test Example 4 The relationship between the physicochemical properties of the product of the present invention and the temperature rise due to induction heating was examined under the same conditions as in Test Example 2. As a result, the results shown in Table-6 were obtained.
温度上昇率とデキストランの、分子量とは負の酸化鉄
部分の平均粒子径、磁化率及び酸化鉄濃度とは正の相関
が認められた。 The temperature rise rate and the molecular weight of dextran were positively correlated with the average particle diameter of the negative iron oxide portion, the magnetic susceptibility and the iron oxide concentration.
試験例５ 参考例１で得た磁性酸化鉄・デキストラン複合体を注
射用蒸留水を用いて鉄濃度10w/v％の液となし、この1ml
とウサギ新鮮血清1mlとを混和し、37℃に保って凝集の
有無を肉眼により観察した。一方、比較対照品として平
均粒子径が約80Åの磁性酸化鉄粒子を10w/v％デキスト
ラン（重量平均分子量70,000）水溶液に濃度が鉄として
10w/v％となるよう懸濁し検液となし、同様に凝集の有
無を観察した。その結果、表−７に示す成績を得た。Test Example 5 The magnetic iron oxide / dextran complex obtained in Reference Example 1 was made into a solution having an iron concentration of 10 w / v% using distilled water for injection, and 1 ml of the solution was obtained.
And 1 ml of rabbit fresh serum were mixed, kept at 37 ° C., and visually observed for aggregation. On the other hand, as a comparative product, a magnetic iron oxide particle having an average particle diameter of about 80 mm was added to a 10 w / v% dextran (weight average molecular weight 70,000) aqueous solution as iron.
It was suspended at 10 w / v% to prepare a test solution, and the presence or absence of aggregation was similarly observed. As a result, the results shown in Table 7 were obtained.
本発明品は血清中におけるコロイド安定性が勝れてい
た。 The product of the present invention was superior in colloid stability in serum.
試験例６ 参考例１で得た磁性酸化鉄・デキストラン複合体217m
gに注射用蒸留水を加えて1mlとし、濾過滅菌後腫瘍容積
1cm3当り0.10mlずつ腫瘍内注射し、24時間後の分布状態
を調べた。即ちコロニー計算板用3mmマス目のガラス板
を腫瘍割面に当て、黒色の注射液が存在する部分とそう
でない部分の比率を求めた。Test Example 6 217 m of magnetic iron oxide / dextran complex obtained in Reference Example 1
Add distilled water for injection to 1 g to make 1 ml.
0.10 ml was injected intratumorally per 1 cm 3, and the distribution after 24 hours was examined. That is, a 3 mm square glass plate for a colony calculation plate was applied to the tumor cleavage surface, and the ratio of the portion where the black injection solution was present to the portion where it was not was determined.
一方、比較対照品として平均粒子径が約80Åの磁性酸
化鉄を用い、濃度が鉄として10w/v％になるよう10w/v％
デキストラン（重量平均分子量70,000）水溶液に懸濁し
た液を調製した。本発明品と同様の液量、投与部位及び
観察法により試験した。因に、この懸濁液は黒褐色であ
る。On the other hand, a magnetic iron oxide having an average particle diameter of about 80 mm was used as a comparative product, and the concentration was 10 w / v% so that the iron concentration was 10 w / v%.
A solution suspended in an aqueous solution of dextran (weight average molecular weight 70,000) was prepared. The test was performed by the same liquid volume, administration site and observation method as the product of the present invention. This suspension is dark brown in color.
その結果、表−８に示す成績を得た。 As a result, the results shown in Table 8 were obtained.
本発明は腫瘍内での分布が均等であった。 The present invention had a uniform distribution within the tumor.
試験例７ BALB/c系雌性マウスにMeth−Ａ線維肉腫細胞を１×10
6個ずつ腹腔内移植し、その８日目に、参考例１で得た
磁性酸化鉄・デキストラン複合体の生理食塩水溶液をFe
として24mg/マウスの量ずつ腹腔内投与し、その２時間
後に試験例１で用いた誘導加熱装置を用い周波数500KH
z、出力4.6Kwで誘導加熱を開始し、BEALY社製、TM54型
機による直腸の測定温度が40.5乃至41.5℃になるよう装
置の電流を断続して10分間温熱治療を行い、以後生存日
数を観察した。対照群としては本発明品の腹腔内注射を
行い、誘導加熱を行わなかった群とし、次式により延命
率を算出した。なお、１群７匹のマウスを用いた。Test Example 7 Meth-A fibrosarcoma cells were cultured in BALB / c female mice at 1 × 10
Six rats were implanted intraperitoneally, and on the 8th day, a physiological saline solution of the magnetic iron oxide / dextran complex obtained in Reference Example 1 was added to Fe.
Was administered intraperitoneally in an amount of 24 mg / mouse, and two hours later, the induction heating device used in Test Example 1 was used and the frequency was 500 KH.
z, induction heating was started at an output of 4.6 Kw, and the current of the device was intermittently turned on so that the measured temperature of the rectum by BEALY Co., Ltd., TM54 machine was 40.5 to 41.5 ° C., and the heat treatment was performed for 10 minutes. Observed. As a control group, a group in which the product of the present invention was injected intraperitoneally and no induction heating was performed, and the survival rate was calculated by the following formula. In addition, 7 mice were used per group.
延命率（％）＝（HT/c−１）×100 式中、HTは温熱治療群平均生存日数であり、ｃは対照
群平均生存日数である。Survival rate (%) = (HT / c-1) × 100 In the formula, HT is the average survival days of the hyperthermia treatment group, and c is the average survival days of the control group.
また、比較対照品として、平均粒子径が約1,000Åの
四三酸化鉄を５％ぶどう糖水溶液に酸化鉄として5w/v％
となるよう懸濁した液を調製し、マウス１匹当り鉄とし
て24mgずつ腹腔内注射し、本発明品の場合と同様の試験
を行った。In addition, as a control, 5% w / v% iron oxide in 5% glucose aqueous solution containing 5% ferric oxide with an average particle size of about 1,000Å
A suspension was prepared so as to give an intraperitoneal injection of 24 mg of iron per mouse, and the same test as that of the product of the present invention was performed.
なお、これらの試験も１群７匹のマウスを用いて行っ
た。These tests were also performed using 7 mice per group.
その結果表−９に示す成績が得られた。 As a result, the results shown in Table 9 were obtained.
本試験例の担癌マウスは末期癌に相当するが、この条
件下において、本発明品の延命効果が認められた。 The tumor-bearing mouse in this test example was equivalent to terminal cancer, and under this condition, the product of the present invention exhibited a prolonged life-span effect.
一方、比較対照品には延命効果が認められなかった。 On the other hand, no life-prolonging effect was observed in the comparative product.
試験例８ BALB/c系マウスの鼠径部皮下にMeth−Ａ線維肉腫細胞
を１×106個ずつ移植して固形癌となし、この癌の長径
が１〜1.5cmになった時点を選び、参考例１で得た複合
体の水溶液を次式で求めた腫瘍容積1cm3当り鉄として12
mgの量ずつ腫瘍内注射し、その２時間後に試験例１で用
いた誘導加熱装置を用い、周波数500KHz、出力4.6Kwの
条件で誘導加熱を開始し、注射局所の皮膚温が試験例７
で用いた温度測定装置による測定値として、41〜43℃に
10分間保たれるよう誘導加温装置の電流を断続した。Test Example 8 1 × 10 6 Meth-A fibrosarcoma cells were implanted subcutaneously in the inguinal region of a BALB / c mouse to form a solid cancer, and a point in time when the major axis of the cancer became 1 to 1.5 cm was selected. The aqueous solution of the complex obtained in Reference Example 1 was used as iron per 1 cm 3 of tumor volume determined by the following equation.
Injection into the tumor was carried out in an amount of mg, and two hours later, induction heating was started under the conditions of a frequency of 500 KHz and an output of 4.6 Kw using the induction heating apparatus used in Test Example 1, and the skin temperature at the injection site was changed to Test Example 7.
As the value measured by the temperature measuring device used in
The current of the induction heating device was interrupted so as to be maintained for 10 minutes.
また、試験例６で用いたものと動じ比較対照品を用
い、鉄換算として、本発明品と同量を腫瘍内注射し、前
述の条件下に誘導加熱した。In addition, the same amount as that of the product of the present invention was injected intratumorally in terms of iron, using a comparative control product similar to that used in Test Example 6, and induction-heated under the conditions described above.
以後、これら担癌マウス及び同様の処理を行い、誘導
加熱のみを実施しなかった担癌マウスの生存日数を観察
し、試験例７と同様の式により延命率を算出した。Thereafter, these tumor-bearing mice and the same treatment were performed, and the survival days of the tumor-bearing mice that were not subjected to induction heating alone were observed. The survival rate was calculated by the same formula as in Test Example 7.
式中、d1は腫瘍の長径（cm）であり、 d2は腫瘍の短径（cm）である。 Where d 1 is the major axis of the tumor (cm) and d 2 is the minor axis of the tumor (cm).
試験の結果、表−10に示す成績を得た。 As a result of the test, the results shown in Table 10 were obtained.
試験例９ 呑竜系ラツトの腹腔内に腹水肝癌AH60C細胞を１×106
個ずつ腹腔内移植し、その６日後に参考例１で得た複合
体の2.6w/v％水溶液（Fe換算1.2w/v％）又は5.2w/v％水
溶液を調製し、それらを担癌ラツト１匹当り夫々5mlず
つ腹腔内注射し、その約２時間後に、試験例７と同様の
方法により誘導加温を行った。また5.2w/v％水溶液5ml
を注射した群の半数である７匹には翌々日に同条件の誘
導加温治療を実施した。 Test Example 9 1 × 10 6 ascites hepatoma AH60C cells were injected into the abdominal cavity of a dragon-type rat.
Six days after intraperitoneal transplantation, a 2.6 w / v% aqueous solution (1.2 w / v% in terms of Fe) or a 5.2 w / v% aqueous solution of the complex obtained in Reference Example 1 was prepared, and these were cancer-bearing. Each rat was intraperitoneally injected at 5 ml per rat, and about 2 hours later, induction heating was performed in the same manner as in Test Example 7. In addition, 5ml of 5.2w / v% aqueous solution
7 days, which is half of the group injected with, received induction heating treatment under the same conditions the next day.
以後、生存日数を観察し、試験例７と同様に延命率を
求めた。Thereafter, the number of surviving days was observed, and the survival rate was determined in the same manner as in Test Example 7.
その結果、表−11に示す成績が得られた。 As a result, the results shown in Table 11 were obtained.
試験例10 呑竜系ラツトの腹腔内に腹水肝癌AH60C細胞を５×106
個ずつ移植し、その６日後に実施例４で得た本発明の注
射液を担癌ラツト１匹当りそれぞれ5mlずつ腹腔内注射
し、試験例７と同様の方法により抗腫瘍効果を試験し
た。 Test Example 10 5 × 10 6 ascites hepatoma AH60C cells in the abdominal cavity of a drunken rat
Six days after transplantation, the injection solution of the present invention obtained in Example 4 was injected intraperitoneally 5 ml per tumor-bearing rat six days later, and the antitumor effect was tested in the same manner as in Test Example 7.
その結果、表−12に示す成績が得られた。 As a result, the results shown in Table-12 were obtained.
試験例11 実施例５で得た本発明の注射液を用い、試験例10と同
じ方法により抗腫瘍効果を試験した。 Test Example 11 Using the injection solution of the present invention obtained in Example 5, the antitumor effect was tested in the same manner as in Test Example 10.
その結果、表−13に示す成績が得られた。 As a result, the results shown in Table 13 were obtained.
試験例12 試験例９と同じ系統のラツトを足蹠皮下に腹水肝癌AH
60C細胞を１×106個ずつ移植して固形癌となし、それら
が増殖して、足蹠の厚みが1cmを越え、足全体に癌が認
められる時点で、移植足の容積を水置換法により測定
し、その容積1cm3当り、実施例１で得た本発明の注射液
を鉄として12mgずつ腫瘍内に注射し、その約２時間後
に、試験例８と同様の誘導加温治療を実施した。その12
日後に再び足容積を測定した。 Test Example 12 Rats of the same strain as in Test Example 9 were subcutaneously injected into the footpad ascites hepatoma AH.
Transplantation of 1 × 10 6 60C cells into solid tumors to produce solid tumors, when they proliferate, the thickness of the footpad exceeds 1 cm, and when cancer is observed in the whole foot, the volume of the transplanted foot is replaced by the water replacement method. The injection solution of the present invention obtained in Example 1 was injected into the tumor in an amount of 12 mg per 1 cm 3 of the volume as iron, and about 2 hours later, the same induction heating treatment as in Test Example 8 was performed. did. Part 12
Days later, paw volume was measured again.
その結果、表−14に示す成績が得られた。 As a result, the results shown in Table 14 were obtained.
試験例13 正常BALB/cマウス１群７匹の腹腔内に参考例１で得た
複合体の生理食塩水溶解液（鉄濃度0.3w/v％）と試験例
６で用いた比較対照品の10w/v％デキストラン（重量平
均分子量70,000）水溶液希釈液（鉄濃度0.3w/v％）とを
夫々5mlずつ注射し、試験例７と同じ装置を用い周波数5
00KHz、出力4.6Kwの条件により連続10分間誘導加温し、
副作用の有無を該マウスの２週間後までの生死により判
定した。 Test Example 13 A saline solution (iron concentration 0.3 w / v%) of the complex obtained in Reference Example 1 was intraperitoneally administered to a group of 7 normal BALB / c mice intraperitoneally and the comparative control product used in Test Example 6 5 ml each of a 10 w / v% dextran (weight average molecular weight 70,000) aqueous solution diluent (iron concentration 0.3 w / v%) was injected, and the same device as used in Test Example 7 was used.
Induction heating for 10 minutes continuously under the conditions of 00KHz and output 4.6Kw,
The presence or absence of side effects was determined by the survival of the mice up to 2 weeks later.
その結果、表−15に示す成績が得られた。 As a result, the results shown in Table 15 were obtained.
また剖検の結果比較対照品は腸間膜の一部及び肝と胃
の膜に著しい凝集沈着が認められた。これは誘導加温中
に直腸温には反映されない部位で異常高温を生じたこと
を意味する。 At necropsy, remarkably coagulated deposits were observed on a part of the mesentery and liver and stomach membranes. This means that an abnormally high temperature occurred at a site not reflected in the rectal temperature during the induction heating.
一方、本発明品は均等に分布し、そのような副作用は
なかった。On the other hand, the products of the present invention were evenly distributed and did not have such side effects.
試験例14 dd系マウス１群５匹を用いて参考例１で得た複合体の
生理食塩水溶液を静脈投与におけるLD50を測定した。ま
た、試験例６で用いた比較対照品のLD50も同様に測定し
た。Test Example 14 Using a group of five dd mice, the LD 50 of the complex obtained in Reference Example 1 in intravenous administration of the physiological saline solution was measured. The LD 50 of the comparative product used in Test Example 6 was measured in the same manner.
なお、LD50の算出法はLitchfield ＆ Wilcoxon法によ
った。The LD 50 was calculated by the Litchfield & Wilcoxon method.
その結果、表−16に示す成績が得られた。 As a result, the results shown in Table 16 were obtained.
本発明は極めて低毒性であった。 The present invention has extremely low toxicity.
試験例15 Wistar系ラットに試験例14で用いた本発明品及び比較
対照品をFeとして5mg/kgの量ずつiv投与し、経日的に肝
を摘出して、ホモジネートとなし、NMR測定装置を用い
てT2緩和時間を測定し、生体内代謝性を検討した。Test Example 15 Wistar rats were iv-administered with the product of the present invention and the control product used in Test Example 14 in an amount of 5 mg / kg as Fe, and the liver was excised daily to obtain a homogenate. It measured the T 2 relaxation time was used to study the in vivo metabolic.
肝臓における半減期は表−17のとおりであった。 The half-life in the liver was as shown in Table-17.
第１図は試験例１における誘導加温試験結果を示すグラ
フである。FIG. 1 is a graph showing the results of an induction heating test in Test Example 1.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ａ６１Ｎ 2/08 Ａ６１Ｎ 1/42 Ｄ ──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. 6 Identification code FI A61N 2/08 A61N 1/42 D
Claims (9)
物磁性体との複合体を有効成分として含有することを特
徴とする温熱療法用剤。1. An agent for hyperthermia, comprising a complex of dextran and a magnetic metal or a magnetic metal compound as an active ingredient.
くは4,000乃至10,000の範囲内の重量平均分子量を有す
る特許請求の範囲第１項記載の温熱療法用剤。2. The agent for hyperthermia according to claim 1, wherein the dextran has a weight average molecular weight in the range of 1,000 to 100,000, preferably 4,000 to 10,000.
亜ハロゲン酸で処理することにより還元性末端を改質し
たデキストラン、或いはシアナイドイオンで処理後加水
分解することにより還元性末端を改質したデキストラン
である、特許請求の範囲第１項または第２項記載の温熱
療法用剤。3. A dextran having a reducing terminal modified by treating the dextran with an alkali, a halogen or a halogenous acid, or a dextran having a modified reducing terminal modified by a treatment with a cyanide ion followed by hydrolysis. The agent for hyperthermia according to claim 1 or 2.
乃至500Å、好ましくは50Å乃至150Åの範囲内の平均粒
子径を有する特許請求の範囲第１〜３項のいずれか１項
に記載の温熱療法用剤。4. The method according to claim 1, wherein the metal magnetic material or the metal chemical magnetic material has a thickness of 30 °.
The agent for hyperthermia according to any one of claims 1 to 3, which has an average particle size in the range of from 500 to 500, preferably from 50 to 150.
性体または超常磁性体である特許請求の範囲第１〜４項
のいずれか１項に記載の温熱療法用剤。5. The hyperthermia agent according to claim 1, wherein the metal magnetic substance or the metal compound magnetic substance is a ferromagnetic substance or a superparamagnetic substance.
コバルトまたは金属ガドリニウムである特許請求の範囲
第１〜５項のいずれか１項に記載の温熱療法用剤。6. The agent for hyperthermia according to claim 1, wherein the metal magnetic substance is metal iron, metal nickel, metal cobalt, or metal gadolinium.
バルトの酸化物である特許請求の範囲第１〜５項のいず
れか１項に記載の温熱療法用剤。7. The hyperthermia agent according to claim 1, wherein the magnetic metal compound is an oxide of iron, nickel or cobalt.
酸化鉄である特許請求の範囲第７項記載の温熱療法用
剤。8. The magnetic compound according to claim 1, wherein the magnetic material is iron trioxide or γ-iron.
8. The hyperthermia agent according to claim 7, which is iron oxide.
に使用する特許請求の範囲第１〜８項のいずれか１項に
記載の温熱療法用剤。9. The agent for hyperthermia according to any one of claims 1 to 8, which is used for hyperthermia of malignant tumors in humans and animals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1211504A JP2847789B2 (en) | 1988-08-19 | 1989-08-18 | Hyperthermia agent |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20481488 | 1988-08-19 | ||
| JP63-204814 | 1988-08-19 | ||
| JP1211504A JP2847789B2 (en) | 1988-08-19 | 1989-08-18 | Hyperthermia agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02174720A JPH02174720A (en) | 1990-07-06 |
| JP2847789B2 true JP2847789B2 (en) | 1999-01-20 |
Family
ID=26514683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1211504A Expired - Fee Related JP2847789B2 (en) | 1988-08-19 | 1989-08-18 | Hyperthermia agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2847789B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9056128B2 (en) * | 2003-01-31 | 2015-06-16 | Otsuka Pharmaceutical Factory, Inc. | Adjuvant used in dielectric heating-assisted cancer treatment, and cancer treatment method |
| EP1810688A1 (en) * | 2004-11-10 | 2007-07-25 | Konica Minolta Medical & Graphic, Inc. | Pharmaceutical preparation containing coated magnetic particles and method for production thereof, and diagnosis therapy system |
| EP1952919B1 (en) | 2007-02-02 | 2013-04-24 | FUJIFILM Corporation | Magnetic nanoparticles and aqueous colloid composition containing the same |
| JP2009234923A (en) * | 2008-03-25 | 2009-10-15 | Toda Kogyo Corp | Magnetically susceptible heating element for thermotherapy and therapeutic formulation |
-
1989
- 1989-08-18 JP JP1211504A patent/JP2847789B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02174720A (en) | 1990-07-06 |
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