JPH09165328A - Microsphere and composition for medicine containing the same - Google Patents
Microsphere and composition for medicine containing the sameInfo
- Publication number
- JPH09165328A JPH09165328A JP32756495A JP32756495A JPH09165328A JP H09165328 A JPH09165328 A JP H09165328A JP 32756495 A JP32756495 A JP 32756495A JP 32756495 A JP32756495 A JP 32756495A JP H09165328 A JPH09165328 A JP H09165328A
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- water
- cancer
- polymer compound
- organic polymer
- phosphate
- Prior art date
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- Manufacturing Of Micro-Capsules (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、癌の閉塞療法に有
益な、金属リン酸塩と有機高分子化合物とを含有する小
球体に関する。TECHNICAL FIELD The present invention relates to a microsphere containing a metal phosphate and an organic polymer compound, which is useful for the therapy of obstruction of cancer.
【０００２】[0002]
【従来の技術】感染症が抗生物質の登場によって克服さ
れた現在、癌は人類が直面している未解決の重大な疾患
の一つである。癌を克服すべく、種々の化学物質が開発
されてきたが、癌細胞に対する毒性と正常細胞に対する
毒性の差が少なく、癌を治療できる濃度まで投与量を挙
げることが出来なかったり、副作用のため癌は治療でき
ても延命作用にはつながらなかったりするなど、化学療
法には多くの問題が残っている。BACKGROUND OF THE INVENTION Cancer is one of the unsolved serious diseases facing humanity nowadays when infectious diseases have been overcome by the advent of antibiotics. Various chemical substances have been developed to overcome cancer, but there is little difference between the toxicity to cancer cells and the toxicity to normal cells, and it is not possible to raise the dose to a level that can treat cancer or side effects. Many problems remain with chemotherapy, such as cancer that can be treated but does not lead to life-prolonging effects.
【０００３】この化学療法を補完する目的で放射線療法
が行われているが、放射線も、抗癌剤同様、副作用の強
さに問題があった。更に、放射線療法においては、肝
臓、膵臓、脾臓等の深部癌に対しては、術中照射より他
に対処の仕様がなかった。術中照射は患者に多大な負担
をかけるため、体力の衰えた患者には適応し難く、ま
た、同時に照射できる回数が制限されるため、その効果
は限られたものになることが少なくなかった。Radiation therapy has been carried out for the purpose of complementing this chemotherapy, but radiation, like anticancer agents, also has a problem of side effects. Further, in radiation therapy, there is no other specification for coping with deep cancer such as liver, pancreas, spleen, etc. than intraoperative irradiation. Since intraoperative irradiation imposes a great burden on the patient, it is difficult to adapt to patients with weak physical strength, and the number of simultaneous irradiations is limited, so that the effect is often limited.
【０００４】このような状況下、化学療法や放射線療法
の効果を上げるため、種々の工夫がなされてきた。例え
ば、抗癌細胞モノクロナール抗体等を抗癌剤に結合さ
せ、癌配向性を高めたミサイル療法や、リピオドール等
の沃素化油脂で癌の栄養血管を封鎖すると共に抗癌剤を
担癌臓器に封じ込める抗癌剤閉塞療法などである。しか
しながら、ミサイル療法には癌に到達したときの薬物の
リリースに問題があり、一方、閉塞療法には、充分に閉
塞し得る材料が無い、例えばリピオドールのように合成
化学物質であるため閉塞材料に生体適合性がない、完全
な閉塞が行えない等という問題があった。Under these circumstances, various efforts have been made to improve the effects of chemotherapy and radiation therapy. For example, a missile therapy in which an anti-cancer cell monoclonal antibody or the like is bound to an anti-cancer agent to enhance the cancer orientation, or an anti-cancer agent occlusion therapy that blocks the nutrient blood vessels of cancer with an iodized oil such as Lipiodol and also seals the anti-cancer agent in a cancer-bearing organ. And so on. However, missile therapy suffers from drug release when it reaches cancer, while occlusion therapy lacks materials that can occlude sufficiently, for example because it is a synthetic chemical such as Lipiodol, There are problems such as lack of biocompatibility and inability to perform complete occlusion.
【０００５】一方、ヒドロキシアパタイト等の水不溶性
金属リン酸塩について、その不定形粉末を抗癌剤等の担
体として癌治療に用いたり、温熱療法の熱支持体として
用いたり、癌栄養血管の閉塞剤として使用することは知
られていたが、血管内壁に傷をつけにくい小球状に加工
すること及びこのような小球体を閉塞剤として使用する
ことについては知られていなかった。On the other hand, regarding water-insoluble metal phosphates such as hydroxyapatite, its amorphous powder is used as a carrier for anti-cancer agents, etc. for cancer treatment, as a heat support for hyperthermia, and as an obstructive agent for cancer feeding blood vessels. Although it was known to be used, it was not known to process the inner wall of blood vessels into small spheres that are not easily scratched and to use such small spheres as an occluding agent.
【０００６】[0006]
【発明が解決しようとする課題】本発明は、このような
状況を踏まえてなされたものであり、有効な癌閉塞治療
が可能な血管閉塞効果の高い小球体を提供することを課
題とする。SUMMARY OF THE INVENTION The present invention has been made in view of such circumstances, and an object of the present invention is to provide a microsphere having a high vascular occlusion effect which enables effective treatment of cancer occlusion.
【０００７】[0007]
【課題を解決するための手段】本発明者らはかかる実状
に鑑みて、有効な癌治療、取り分け深部癌に対する閉塞
療法に有益な、閉塞効果が高く且つ生体適合性のある素
材を求めて鋭意研究を重ねた結果、ヒドロキシアパタイ
ト等の水不溶性金属リン酸塩と有機高分子化合物とを含
有する一定粒径の小球体が有効であることを見いだし、
発明を完成させた。In view of such circumstances, the present inventors have earnestly sought a material having a high occlusion effect and biocompatibility, which is useful for effective cancer treatment, especially occlusion therapy for deep cancer. As a result of repeated research, they found that small spheres of a certain particle size containing a water-insoluble metal phosphate such as hydroxyapatite and an organic polymer compound are effective,
Completed the invention.
【０００８】すなわち、本発明は、水不溶性金属リン酸
塩と有機高分子化合物とを含有する平均粒径０．０１〜
１０ｍｍの小球体に関する。この小球体は、好ましく
は、水可溶性リン酸塩と有機高分子化合物と水とを含む
滴下液を、リン酸とともに水不溶性塩を形成しうる金属
の水可溶性塩と水とを含む硬化液中に滴下し、水不溶性
金属リン酸塩と有機高分子化合物とを含有する小球体を
析出させることにより得られるものである。That is, according to the present invention, a water-insoluble metal phosphate and an organic polymer compound are contained in an average particle size of 0.01 to
For a 10 mm globule. This small sphere is preferably a drop solution containing a water-soluble phosphate, an organic polymer compound and water in a hardening solution containing a water-soluble salt of metal capable of forming a water-insoluble salt together with phosphoric acid and water. It is obtained by dropping into water and precipitating small spheres containing a water-insoluble metal phosphate and an organic polymer compound.
【０００９】本発明の小球体は、患部において癌の栄養
血管を良く閉塞し、癌への栄養の供給を阻害すると同時
に、この部分に投与された抗癌剤を他に漏出させること
なく止めておく作用を有するため、これを用いることに
よって効率よく癌治療を行うことができる。The microspheres of the present invention effectively block the nutrient blood vessels of the cancer in the affected area, inhibit the supply of nutrients to the cancer, and at the same time, stop the anticancer drug administered to this area without leaking it to others. Therefore, by using this, cancer treatment can be efficiently performed.
【００１０】本発明の小球体は、その構成成分の一つで
あるヒドロキシアパタイト等の金属リン酸塩が生体成分
であるため、異物認識反応を受けないことが期待でき
る。更に、その形状が従来には知られていない球状であ
ることから、注射時に血管を傷つけないことが期待でき
る。Since the metal phosphate such as hydroxyapatite which is one of the constituents of the microspheres of the present invention is a biological component, it can be expected that the microspheres will not undergo foreign body recognition reaction. Further, since the shape thereof is a spherical shape which has not been heretofore known, it can be expected that the blood vessel will not be damaged during the injection.
【００１１】以下に、本発明について詳細に述べる。The present invention will be described in detail below.
【００１２】（１）本発明の小球体 本発明の小球体は、水不溶性金属リン酸塩と有機高分子
化合物とを含有し、球状の形状をとることを特徴とす
る。ここで球状とは、球ないしは球に対して２０％以内
の歪みを許容した滑らかな表面を有する形状を意味す
る。大きさは、平均粒径（球の平均直径）が０．０１〜
１０ｍｍ、好ましくは０．０５〜１ｍｍである。平均粒
径がこの範囲であれば、血管内への投与が可能で且つ癌
に容易に到達することができる。(1) Small Sphere of the Present Invention The small sphere of the present invention is characterized by containing a water-insoluble metal phosphate and an organic polymer compound and having a spherical shape. Here, the sphere means a sphere or a shape having a smooth surface which allows a strain within 20% with respect to the sphere. The average particle size (average diameter of spheres) is 0.01-
It is 10 mm, preferably 0.05 to 1 mm. When the average particle size is within this range, it can be administered intravascularly and can easily reach cancer.
【００１３】水不溶性金属リン酸塩としては、好ましく
はカルシウム、ストロンチウム、ジルコニウム、バリウ
ムからなる群から選ばれる金属のリン酸塩である。その
うち、生体に豊富なカルシウムのリン酸塩が好ましい。
さらに、このような金属リン酸塩として、ヒドロキシア
パタイト又はリン酸三カルシウムが好ましい。The water-insoluble metal phosphate is preferably a metal phosphate selected from the group consisting of calcium, strontium, zirconium and barium. Among them, calcium phosphate, which is abundant in the living body, is preferable.
Furthermore, as such a metal phosphate, hydroxyapatite or tricalcium phosphate is preferable.
【００１４】有機高分子化合物としては、上記リン酸の
水不溶性塩を形成する対金属イオンによって硬化可能な
高分子化合物であればよいが、好ましくは、親水性を有
する高分子化合物が用いられる。具体的には、アルギン
酸ナトリウム、キサンタンガム、ローカストビーンガ
ム、カルボキシデキストランナトリウム、カラギーナ
ン、ペクチンからなる群から選ばれるものが挙げられ、
これらは２種以上用いてもよい。このうち、アルギン酸
ナトリウムが最も好ましい。The organic polymer compound may be any polymer compound which can be cured by a counter metal ion forming the above water-insoluble salt of phosphoric acid, but a polymer compound having hydrophilicity is preferably used. Specific examples include sodium alginate, xanthan gum, locust bean gum, carboxydextran sodium, carrageenan, and one selected from the group consisting of pectin,
You may use 2 or more types of these. Of these, sodium alginate is most preferred.
【００１５】本発明の小球体には、本発明の効果を損な
わない範囲において、他に種々の任意成分が含有されて
いてもよい。このような他の任意成分としては、炭酸カ
ルシウムや硫酸カルシウム等の種々の無機塩、シリカ等
が挙げられる。The microspheres of the present invention may contain various optional components in addition to the above, as long as the effects of the present invention are not impaired. Examples of such other optional components include various inorganic salts such as calcium carbonate and calcium sulfate, silica, and the like.
【００１６】本発明の小球体における各成分の好ましい
含有量は、リン酸が０．１〜５０重量％、金属が０．１
〜５０重量％、有機高分子化合物が０．１〜６０重量％
である。更に好ましくは、リン酸が０．５〜３０重量
％、金属が０．５〜３０重量％、有機高分子化合物が
０．５〜４０重量％である。The preferred content of each component in the microsphere of the present invention is 0.1 to 50% by weight of phosphoric acid and 0.1 of metal.
~ 50% by weight, 0.1 to 60% by weight of organic polymer compound
It is. More preferably, phosphoric acid is 0.5 to 30% by weight, metal is 0.5 to 30% by weight, and organic polymer compound is 0.5 to 40% by weight.
【００１７】本発明の小球体は親水性を有する有機高分
子化合物を含有しているので、水溶性の薬物を含浸させ
て作用させるのに優れている。従って、閉塞剤としてだ
けでなく、水溶性の抗癌剤のキャリアーとしても使うこ
とができる。Since the microspheres of the present invention contain an organic polymer compound having hydrophilicity, they are excellent in impregnating a water-soluble drug to act. Therefore, it can be used not only as an occluding agent but also as a carrier for a water-soluble anticancer agent.
【００１８】（２）本発明の小球体の製造方法 本発明の小球体は、次のような方法で製造することがで
きる。即ち、前記水可溶性リン酸塩と有機高分子化合物
と水とを含む滴下液を、リン酸とともに水不溶性塩を形
成しうる金属の水可溶性塩と水とを含む硬化液中に滴下
し、水不溶性金属リン酸塩と有機高分子化合物とを含有
する小球体を析出させることにより、目的とする小球体
が得られる。(2) Method for producing small sphere of the present invention The small sphere of the present invention can be produced by the following method. That is, a dropping solution containing the water-soluble phosphate, the organic polymer compound, and water is dropped into a hardening solution containing a water-soluble salt of metal capable of forming a water-insoluble salt together with phosphoric acid, and water. The target microspheres are obtained by precipitating the microspheres containing the insoluble metal phosphate and the organic polymer compound.
【００１９】すなわち、滴下液を硬化液中に滴下するこ
とによって、有機高分子化合物の硬化と水不溶性金属リ
ン酸塩の生成が起こり、更に有機高分子化合物の表面張
力の作用により、水不溶性金属リン酸塩と有機高分子化
合物とを含有する本発明の小球体が析出する。滴下液を
硬化液に滴下する場合は、目的とする小球体の大きさに
もよるが、滴下粒子が微細粒となるように注射器等で滴
下するのが好ましい。That is, the dropping of the dropping liquid into the hardening liquid causes the hardening of the organic polymer compound and the formation of the water-insoluble metal phosphate, and further, the surface tension of the organic polymer compound causes the water-insoluble metal. The microspheres of the present invention containing a phosphate and an organic polymer compound are deposited. When the dropping liquid is dropped into the hardening liquid, it is preferable to drop the dropping liquid with a syringe or the like so that the dropping particles become fine particles, although it depends on the size of the target small sphere.
【００２０】滴下液中における有機高分子化合物の濃度
は、好ましくは０．１〜４重量％、より好ましくは０．
２〜２重量％である。滴下液中に含まれる水可溶性リン
酸塩としては、リン酸水素二アンモニウム、リン酸アン
モニウム、リン酸トリエチルアンモニウム等の有機アミ
ン塩等が例示でき、このうち、リン酸水素二アンモニウ
ム、リン酸アンモニウムが特に好ましい。滴下液中にお
ける水可溶性リン酸塩の濃度は、好ましくは２〜１０重
量％、より好ましくは３〜８重量％である。The concentration of the organic polymer compound in the dropping solution is preferably 0.1 to 4% by weight, more preferably 0.
It is 2 to 2% by weight. Examples of the water-soluble phosphate contained in the dropping solution include diamine ammonium hydrogen phosphate, ammonium phosphate, organic amine salts such as triethylammonium phosphate, and the like. Among these, diammonium hydrogen phosphate, ammonium phosphate Is particularly preferable. The concentration of the water-soluble phosphate in the dropping solution is preferably 2 to 10% by weight, more preferably 3 to 8% by weight.
【００２１】硬化液中に含まれる、リン酸とともに水不
溶性塩を形成しうる金属の水可溶性塩としては、硝酸カ
ルシウム、酢酸カルシウム等の水可溶性カルシウム塩
や、硝酸ストロンチウム、硝酸ジルコニウム、硝酸バリ
ウム等が例示でき、このうち、硝酸カルシウムが特に好
ましい。この水可溶性塩中の金属が、滴下液の滴下によ
り供給されるリン酸とともに、本発明の小球体を構成す
る水不溶性金属リン酸塩を形成する。硬化液中における
水可溶性塩の濃度は、好ましくは４〜１５重量％、より
好ましくは５〜１０重量％である。また、硬化液は予め
ｐＨ９〜１１程度に調整するのが好ましい。Examples of the water-soluble salts of metals contained in the curing solution which are capable of forming water-insoluble salts with phosphoric acid include water-soluble calcium salts such as calcium nitrate and calcium acetate, strontium nitrate, zirconium nitrate and barium nitrate. Can be exemplified, and of these, calcium nitrate is particularly preferable. The metal in this water-soluble salt forms the water-insoluble metal phosphate that constitutes the microspheres of the present invention, together with the phosphoric acid supplied by the dropping of the dropping solution. The concentration of the water-soluble salt in the curing liquid is preferably 4 to 15% by weight, more preferably 5 to 10% by weight. Moreover, it is preferable that the pH of the curing liquid is adjusted to about 9 to 11 in advance.
【００２２】硬化液中に析出した小球体は、ろ過等によ
って回収される。このようにして得られた小球体を、更
に必要に応じて分級することにより、望む粒径分布を有
する小球体を得ることができる。尚、前述した本発明の
小球体に含有され得る炭酸カルシウム等の他の任意成分
は、例えば、滴下液又は硬化液中に予め含有させておく
等の方法により、小球体に含有させることができる。The small spheres deposited in the hardening liquid are recovered by filtration or the like. By further classifying the thus obtained small spheres, it is possible to obtain small spheres having a desired particle size distribution. Incidentally, other optional components such as calcium carbonate which may be contained in the above-mentioned microspheres of the present invention can be contained in the microspheres by a method such as being contained in a dropping liquid or a curing liquid in advance. .
【００２３】（３）本発明の血管閉塞剤及び医薬用組成
物 本発明の小球体は、生体適合性のある素材からなり、且
つ血管内壁に傷をつけにくい小球状に加工されているた
め、癌栄養血管の閉塞剤などの血管閉塞剤の有効成分と
して用いることができる。(3) Vascular occlusion agent and pharmaceutical composition of the present invention Since the microspheres of the present invention are made of a biocompatible material, and are processed into a microsphere that does not easily damage the inner wall of the blood vessel, It can be used as an active ingredient of a vaso-occlusive agent such as a cancer-vegetative blood vessel occluding agent.
【００２４】本発明の組成物は、かかる小球体を含有す
ることを特徴とするものであって、医薬としての用途に
好適である。具体的な用途としては、癌、取り分け深部
癌の癌閉塞療法における閉塞剤として用いることができ
る。深部癌としては、膵癌、肝癌、胆嚢癌、脾臓癌が挙
げられる。The composition of the present invention is characterized by containing such microspheres, and is suitable for use as a medicine. As a specific use, it can be used as an occluding agent in cancer obstruction therapy for cancer, especially deep cancer. Deep cancer includes pancreatic cancer, liver cancer, gallbladder cancer, and spleen cancer.
【００２５】本発明の医薬用組成物には、上記小球体以
外に、通常の医薬用組成物で用いられる製剤化のための
任意成分を含有することができる。任意成分としては、
賦形剤、増量剤、結合剤、被覆剤、糖衣剤、安定剤、崩
壊剤、着色剤、滑沢剤、ｐＨ調製剤、可溶化剤、分散
剤、増粘剤、等張剤等が例示できる。The pharmaceutical composition of the present invention may contain, in addition to the above-mentioned small spheres, optional components used for the formulation used in ordinary pharmaceutical compositions. As an optional component,
Excipients, fillers, binders, coating agents, sugar coating agents, stabilizers, disintegrating agents, coloring agents, lubricants, pH adjusting agents, solubilizing agents, dispersing agents, thickening agents, isotonic agents, etc. it can.
【００２６】投与経路としては、経口投与、経直腸投与
等も考えられるが、注射による投与が最も好ましく、従
って本発明の医薬用組成物は、剤型が注射剤であるのが
好ましい。注射による投与としては、皮下投与、腹腔内
投与、動脈投与、静脈投与等が例示できる。このうち、
患部付近の動脈への動脈注射又は患部への直接投与が最
も好ましい。これはファイバースコープ等を用いて投与
することも可能である。Although oral administration, rectal administration and the like can be considered as administration routes, administration by injection is most preferable, and therefore the pharmaceutical composition of the present invention preferably has an injectable form. Examples of administration by injection include subcutaneous administration, intraperitoneal administration, arterial administration, and intravenous administration. this house,
Most preferred is arterial injection into the artery near the affected area or direct administration to the affected area. It can also be administered using a fiberscope or the like.
【００２７】本発明の医薬用組成物の好適な投与量は、
症状、性別、年齢、体型により異なるが、大凡、成人一
人一日当たり、１０ｍｇ〜１００００ｍｇを一回乃至数
回に分けて投与するのが好ましい。又、本発明の医薬用
組成物は生体物質ないしはその近似体であるので安全性
に優れている。本発明の医薬用組成物を投与することに
より、容易に癌の栄養血管を閉塞し得るとともに、同時
に投与した抗癌剤を長く貯留させることができる。A suitable dose of the pharmaceutical composition of the present invention is
Although it varies depending on the symptom, sex, age, and body type, it is preferable to administer 10 mg to 10000 mg per day for an adult in one to several divided doses. In addition, the pharmaceutical composition of the present invention is a biological substance or an analogue thereof, and therefore is excellent in safety. By administering the pharmaceutical composition of the present invention, the feeding blood vessels of cancer can be easily blocked, and the simultaneously administered anticancer agent can be stored for a long time.
【００２８】また、本発明の医薬用組成物には、癌の治
療で用いられる各種の薬剤を含有させることができる。
このような薬剤としては、リピオドールのような放射線
造影剤ないしは血管閉塞剤、シスプラチン、ＳＭＡＮＣ
Ｓ、アドリアマイシン、アクチノマイシン、ネオカルチ
ノスタチン、フルオロウラシルとその誘導体等の抗癌
剤、エトポシド等のアポトーシス誘導剤、ステロイドホ
ルモン類、シクロフォスファミド等の免疫抑制剤、モル
ヒネ等の痛み止めの為の麻薬等が例示できる。In addition, the pharmaceutical composition of the present invention may contain various drugs used in the treatment of cancer.
Such agents include radiocontrast agents such as Lipiodol or vaso-occlusive agents, cisplatin, SMANC.
Anticancer agents such as S, adriamycin, actinomycin, neocarzinostatin, fluorouracil and its derivatives, apoptosis inducers such as etoposide, immunosuppressants such as steroid hormones and cyclophosphamide, and narcotics for pain relief such as morphine Etc. can be illustrated.
【００２９】[0029]
【発明の実施の形態】以下に例を挙げて発明の実施の形
態について説明するが、本発明がこれらの例のみに限定
を受けないことは言うまでもない。BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below with reference to examples, but it goes without saying that the present invention is not limited to these examples.
【００３０】＜例１：小球体の製造例＞アルギン酸ナト
リウムを２重量％含む０．１Ｍリン酸水素二アンモニウ
ム水溶液を調製し、これを滴下液とした。一方、硬化液
としてトリエチルアミンを加えてｐＨを９に調整した硝
酸カルシウムの０．５Ｍ水溶液を用意し、これに前記滴
下液を注射器（注射針：３３Ｇ）を用いて滴下して、小
球体を析出させた。これをろ過して回収し、目的とする
小球体を得た（小球体１）。この小球体の形状は、直径
の平均が４００μｍの球状であることが電子顕微鏡写真
より明らかになった。<Example 1: Production Example of Microspheres> A 0.1 M diammonium hydrogen phosphate aqueous solution containing 2% by weight of sodium alginate was prepared and used as a dropping solution. On the other hand, a 0.5 M aqueous solution of calcium nitrate whose pH was adjusted to 9 by adding triethylamine as a hardening liquid was prepared, and the above dropping liquid was dropped into this using a syringe (injection needle: 33G) to deposit microspheres. Let This was filtered and collected, and the target small sphere was obtained (small sphere 1). The electron micrograph revealed that the shape of the small sphere was a sphere having an average diameter of 400 μm.
【００３１】＜例２：製剤例＞例１で得られた小球体１
を用いて、表１に示す処方に従って注射剤を調製した。
即ち、表１の処方成分を混合分散し、アンプルに詰めて
密封した後、滅菌して注射剤とした。<Example 2: Formulation example> Microsphere 1 obtained in Example 1
Was used to prepare an injection according to the formulation shown in Table 1.
That is, the formulation components shown in Table 1 were mixed and dispersed, filled in an ampoule, sealed, and then sterilized to obtain an injection.
【００３２】[0032]
【表１】 表１ ────────────────── 処方成分 処方割合 ────────────────── 注射用蒸留水 ９８．１重量％ 塩化ナトリウム ０．９重量％ 小球体１ １ 重量％ ──────────────────[Table 1] Table 1 ────────────────── Prescription ingredients Prescription ratio ─────────────────── Distilled water for injection 98.1% by weight Sodium chloride 0.9% by weight Small spheres 11% by weight ───────────────────
【００３３】＜例３：製剤例＞例１で得られた小球体１
を用いて、表２に示す処方に従って注射剤を作成した。
即ち、表２の処方成分を混合分散し、アンプルに詰めて
密封した後、滅菌して注射剤とした。<Example 3: Formulation example> Microsphere 1 obtained in Example 1
Was used to prepare an injection according to the formulation shown in Table 2.
That is, the formulation components shown in Table 2 were mixed and dispersed, filled in an ampoule, sealed, and then sterilized to obtain an injection.
【００３４】[0034]
【表２】 表２ ──────────────────── 処方成分 処方割合 ──────────────────── 注射用蒸留水 ９７．１重量％ 塩化ナトリウム ０．９重量％ 小球体１ １ 重量％ ネオカルチノスタチン １ 重量％ ────────────────────[Table 2] Table 2 ──────────────────── Prescription component Prescription ratio ───────────────────── Distilled water for injection 97.1% by weight Sodium chloride 0.9% by weight Small spheres 11% by weight Neocarzinostatin 1% by weight ────────────────────
【００３５】[0035]
【実施例】以下に本発明の実施例を説明する。Embodiments of the present invention will be described below.
【００３６】[0036]
【実施例１】 ＜貯留性試験＞ラットを用いて投与した本発明の小球体
の貯留性を調べた。即ち、ウィスター系雄性ラット１群
５匹をペントバルビタールで麻酔した後、上腹部を正中
に切開した。次いで、本発明の閉塞剤である前記小球体
１を32Ｐでラベルしたものを腹腔内に２１ｍｇ（２８ｄ
ｐｍ／体重（ｍｇ））埋め込んで閉腹した。これを一定
時間ごとに屠殺して各臓器を取り出しホモジネートし、
溶解剤を加えて溶解させ、各臓器の放射線強度を液体シ
ンチレーションカウンターで測定した。Example 1 <Reservability test> The retentivity of the microspheres of the present invention administered using rats was examined. That is, 5 male Wistar rats per group were anesthetized with pentobarbital, and the upper abdomen was incised in the midline. Then, the microsphere 1 which is the occluding agent of the present invention labeled with 32 P was intraperitoneally administered at 21 mg (28 d
pm / body weight (mg) was embedded and the abdomen was closed. This is slaughtered at regular intervals and each organ is taken out and homogenized,
A lysing agent was added and dissolved, and the radiation intensity of each organ was measured by a liquid scintillation counter.
【００３７】これを臓器重量で除し、単位重量当たりの
放射線強度を測定した。結果を表３に示す。これより、
本発明の閉塞剤である小球体は、投与箇所である腹腔に
良く貯留し、他に放射性物質が移行していないことがわ
かる。従って、本発明の小球体により栄養血管を効率よ
く閉塞し得ることがわかる。This was divided by the organ weight, and the radiation intensity per unit weight was measured. Table 3 shows the results. Than this,
It can be seen that the microspheres, which are the occluding agent of the present invention, are well retained in the abdominal cavity, which is the administration site, and that no other radioactive substances have migrated. Therefore, it can be seen that the microspheres of the present invention can efficiently block the feeding blood vessels.
【００３８】[0038]
【表３】 [Table 3]
【００３９】[0039]
【発明の効果】本発明の小球体は、生体適合性のある素
材からなり、且つ血管内壁に傷をつけにくい小球状に加
工されているため、患部において癌の栄養血管を良く閉
塞し、癌への栄養の供給を阻害すると同時に、この部分
に投与された抗癌剤を他に漏出させることなく止めてお
く作用を有するものであり、血管閉塞剤として有効に利
用することができる。EFFECTS OF THE INVENTION Since the microspheres of the present invention are made of a biocompatible material and are processed into small spheres that are less likely to damage the inner wall of blood vessels, they can occlude the feeding blood vessels of cancer well in the affected area. It has the effect of inhibiting the supply of nutrients to the area and at the same time stopping the anti-cancer agent administered to this part without leaking it to other parts, and can be effectively used as a vaso-occlusive agent.
【００４０】また、親水性を有する有機高分子化合物を
用いることにより、水溶性の薬物を含浸させて作用させ
るのに優れた小球体とすることができるため、閉塞剤と
してだけでなく、水溶性の抗癌剤のキャリアーとして使
うこともできる。Further, by using an organic polymer compound having hydrophilicity, it is possible to form small spheres which are excellent in impregnating a water-soluble drug to act, and therefore, not only as a blocking agent but also as a water-soluble drug. It can also be used as a carrier for anti-cancer drugs.
【００４１】よって、かかる小球体を含有する本発明の
医薬用組成物は、有効な癌治療、取り分け深部癌に対す
る閉塞療法に有益であり、膵癌や肝癌等の癌の効率よい
治療への貢献が期待できる。Therefore, the pharmaceutical composition of the present invention containing such microspheres is useful for effective cancer treatment, especially for obstruction therapy for deep cancer, and contributes to efficient treatment of cancer such as pancreatic cancer and liver cancer. Can be expected.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 // Ｃ０１Ｂ 25/32 Ｂ０１Ｊ 13/02 Ｇ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification number Office reference number FI technical display location // C01B 25/32 B01J 13/02 G
Claims (10)
物とを含有する平均粒径０．０１〜１０ｍｍの小球体。1. A small sphere having an average particle size of 0.01 to 10 mm, which contains a water-insoluble metal phosphate and an organic polymer compound.
水とを含む滴下液を、リン酸とともに水不溶性塩を形成
しうる金属の水可溶性塩と水とを含む硬化液中に滴下
し、水不溶性金属リン酸塩と有機高分子化合物とを含有
する小球体を析出させることにより得られる、請求項１
記載の小球体。2. A dropping solution containing a water-soluble phosphate, an organic polymer compound and water is dropped into a hardening solution containing a water-soluble salt of a metal capable of forming a water-insoluble salt together with phosphoric acid and water. , Obtained by depositing small spheres containing a water-insoluble metal phosphate and an organic polymer compound.
The described sphere.
タイト又はリン酸三カルシウムである、請求項１又は２
記載の小球体。3. The water-insoluble metal phosphate is hydroxyapatite or tricalcium phosphate.
The described sphere.
ム、キサンタンガム、ローカストビーンガム、カルボキ
シデキストランナトリウム、カラギーナン、ペクチンか
らなる群から選ばれる１種以上である請求項１〜３のい
ずれかに記載の小球体。4. The microsphere according to claim 1, wherein the organic polymer compound is one or more selected from the group consisting of sodium alginate, xanthan gum, locust bean gum, sodium carboxydextran, carrageenan and pectin. .
を有効成分とする血管閉塞剤。5. A vaso-occlusive agent comprising the microsphere according to any one of claims 1 to 4 as an active ingredient.
薬用組成物。6. A pharmaceutical composition containing the vasoocclusive agent according to claim 5.
とする請求項６に記載の組成物。7. The composition according to claim 6, which is used for cancer obstruction therapy for deep cancer.
癌である請求項７記載の組成物。8. The composition according to claim 7, wherein the deep cancer is pancreatic cancer, liver cancer, gallbladder cancer, or spleen cancer.
れかに記載の組成物。9. The composition according to claim 6, wherein the dosage form is an injection.
と水とを含む滴下液を、リン酸とともに水不溶性塩を形
成しうる金属の水可溶性塩と水とを含む硬化液中に滴下
し、水不溶性金属リン酸塩と有機高分子化合物とを含有
する小球体を析出させる析出工程を含む、請求項１記載
の小球体の製造方法。10. A dropping solution containing a water-soluble phosphate, an organic polymer compound and water is dropped into a hardening solution containing a water-soluble salt of a metal capable of forming a water-insoluble salt together with phosphoric acid and water. The method for producing microspheres according to claim 1, comprising a precipitation step of precipitating microspheres containing a water-insoluble metal phosphate and an organic polymer compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32756495A JPH09165328A (en) | 1995-12-15 | 1995-12-15 | Microsphere and composition for medicine containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32756495A JPH09165328A (en) | 1995-12-15 | 1995-12-15 | Microsphere and composition for medicine containing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH09165328A true JPH09165328A (en) | 1997-06-24 |
Family
ID=18200481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP32756495A Pending JPH09165328A (en) | 1995-12-15 | 1995-12-15 | Microsphere and composition for medicine containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH09165328A (en) |
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| JP2005537070A (en) * | 2002-08-30 | 2005-12-08 | ボストン サイエンティフィック リミテッド | Embolization |
| WO2005118685A1 (en) * | 2004-06-03 | 2005-12-15 | Regen Biotech, Inc. | High molecular substance beads having water-insoluble inorganic compounds encapsulated therein, their preparation method and use |
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1995
- 1995-12-15 JP JP32756495A patent/JPH09165328A/en active Pending
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| EP1870089A1 (en) * | 2005-04-15 | 2007-12-26 | Beijing Shengyiyao Science & Technology Development Co., Ltd | A gynecological pharmaceutics-containing microspherical vascular suppository of sodium alginate and its preparation method |
| EP1870089A4 (en) * | 2005-04-15 | 2012-10-03 | Beijing Shengyiyao Science & Technology Dev Co Ltd | A gynecological pharmaceutics-containing microspherical vascular suppository of sodium alginate and its preparation method |
| JP2008535870A (en) * | 2005-04-15 | 2008-09-04 | ベイジン シェンギュイヤオ サイエンス アンド テクノロジー ディブロプメント コー．，エルティーディ | Sodium alginate microsphere vascular embolic agent containing gynecological drug and its preparation |
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