JPH06192084A - Inhibitor of cancer metastasis - Google Patents
Inhibitor of cancer metastasisInfo
- Publication number
- JPH06192084A JPH06192084A JP19640492A JP19640492A JPH06192084A JP H06192084 A JPH06192084 A JP H06192084A JP 19640492 A JP19640492 A JP 19640492A JP 19640492 A JP19640492 A JP 19640492A JP H06192084 A JPH06192084 A JP H06192084A
- Authority
- JP
- Japan
- Prior art keywords
- cancer metastasis
- metastasis
- flurbiprofen axetil
- flurbiprofen
- axetil
- 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.)
- Pending
Links
Abstract
Description
【０００１】[0001]
【産業上の利用分野】 本発明は、フルルビプロフェン
アキセチル（化学名を（±）−２−（２−フルオロ−
４−ビフェニリル）プロピオン酸 １−アセトキシエチ
ルエステルという）を有効成分とする癌転移抑制剤に関
する。The present invention relates to flurbiprofen axetil (chemical name: (±) -2- (2-fluoro-
4-biphenylyl) propionic acid 1-acetoxyethyl ester) as an active ingredient.
【０００２】[0002]
【従来の技術】 フルルビプロフェン アキセチルは既
に広く使用されている経口および外用の非ステロイド性
消炎鎮痛剤フルルビプロフェンのプロドラッグであり、
生体内で速やかに加水分解を受けフルルビプロフェンと
なり、薬理効果を発揮し、現在、各種癌および術後にお
ける鎮痛剤として、その有効性が認められている。BACKGROUND OF THE INVENTION Flurbiprofen Axetil is a prodrug of the widely used oral and topical non-steroidal anti-inflammatory analgesic flurbiprofen.
It is rapidly hydrolyzed in vivo to become flurbiprofen, which exerts a pharmacological effect, and its effectiveness is now recognized as an analgesic for various cancers and postoperatively.
【０００３】[0003]
【発明が解決しようとする課題】癌の治療においては、
腫瘍そのものに対する治療と共に転移の抑制も重要視さ
れている。癌の転移とは、原発腫瘍から離脱した悪性細
胞が、ときにはそこから遙かに離れた場所へと移動し、
全身に広がって形成される多発性のコロニーである。癌
が再発した場合、転移は第１の死因となる。従って、転
移を予防し、抑制することは癌の治療の重要な目標の１
つであり、転移を抑制するような治療剤の開発が望まれ
ている。DISCLOSURE OF THE INVENTION In the treatment of cancer,
Suppression of metastasis is emphasized as well as treatment of the tumor itself. Cancer metastasis means that the malignant cells that have left the primary tumor sometimes move to a place far away from them.
It is a multiple colony that spreads throughout the body. If the cancer relapses, metastasis is the primary cause of death. Therefore, preventing and suppressing metastasis is one of the important goals of cancer treatment.
Therefore, development of a therapeutic agent that suppresses metastasis is desired.
【０００４】[0004]
【課題を解決するための手段】本発明はフルルビプロフ
ェン アキセチルを有効成分とすることを特徴とする癌
転移抑制剤に関するものである。本発明の癌転移抑制剤
は通常の製剤技術により、例えば、錠剤、カプセル剤、
顆粒剤等として経口的に、注射剤、座剤、軟膏剤、貼布
剤等として非経口的に投与できる。注射剤としては大豆
油／卵黄リン脂質系を用いた水中油滴型の脂肪乳剤とす
ることができ、例えば、科研製薬株式会社製の静注用製
剤ロピオン注（登録商標）（５ｍｌ中フルルビプロフェ
ン アキセチル５０ｍｇを含有する。添加物として精製
大豆油５００ｍｇ、精製卵黄レシチン６０ｍｇ、濃グリ
セリン１１０．５ｍｇを含有する。）または同一処方を
有する製剤があげられる。The present invention relates to a cancer metastasis inhibitor, which comprises flurbiprofen axetil as an active ingredient. The cancer metastasis inhibitor of the present invention can be prepared by a conventional formulation technique, for example, tablets, capsules,
It can be administered orally as granules or the like, and parenterally as injections, suppositories, ointments, patches and the like. The injection may be an oil-in-water type fat emulsion using a soybean oil / egg yolk phospholipid system. For example, an intravenous formulation Ropion Injection (registered trademark) manufactured by Kaken Pharmaceutical Co., Ltd. (flurubi in 5 ml) It contains 50 mg of profen axetil, 500 mg of purified soybean oil, 60 mg of purified egg yolk lecithin, and 110.5 mg of concentrated glycerin as additives) or a preparation having the same formulation.
【０００５】本発明における癌転移抑制剤の投与量は患
者の年齢、体重および症状、並びに剤型および投与経路
等によって異なるが、静注の場合成人に対しては一般的
に、１回につきフルルビプロフェン アキセチルとして
１〜５ｍｇ／ｋｇ、１日１〜４回の使用で、目的を達成
することができる。本発明を製剤例および試験例によ
り、更に詳細に説明するが、本発明はこれらに限定され
るものではない。The dose of the cancer metastasis inhibitor in the present invention varies depending on the age, body weight and symptom of the patient, the dosage form, the administration route, etc. The purpose can be achieved by using 1 to 5 mg / kg of biprofen axetil and 1 to 4 times a day. The present invention will be described in more detail with reference to formulation examples and test examples, but the present invention is not limited thereto.
【０００６】製剤例 精製大豆油２００ｇに精製卵黄リン脂質２４ｇ、オレイ
ン酸ナトリウム０．２５ｇ、ホスファチジン酸０．２５
ｇおよびフルルビプロフェン アキセチル２０ｇを混合
し、４０〜７５℃に加温溶解する。これに１０００ｍｌ
の蒸留水を加え、マントンーガウリン型ホモジナイザー
を用いて、１段目１００ｋｇ／ｃｍ2 、合計圧４５０ｋ
ｇ／ｃｍ2 の加圧下で１０回通過させ乳化する。次いで
この乳化液に４４．２ｇのグリセリンを加え、２０〜４
０℃の注射用蒸留水７３０ｍｌを加えホモミキサーで粗
乳化する。これを再びマントンーガウリン型ホモジナイ
ザーを用い、１段目１２０ｋｇ／ｃｍ2 合計圧５００ｋ
ｇ／ｃｍ2 の加圧下で１０回通過させ乳化する。これに
よりフルルビプロフェン アキセチルを含有の脂肪乳剤
が得られた。Formulation Example: 200 g of purified soybean oil, 24 g of purified egg yolk phospholipid, 0.25 g of sodium oleate, and 0.25 of phosphatidic acid.
g and flurbiprofen axetil 20 g are mixed and dissolved by heating at 40 to 75 ° C. 1000 ml to this
Distilled water was added, and the Manton-Gaurin type homogenizer was used, the first stage was 100 kg / cm 2 , and the total pressure was 450 k.
Emulsify by passing 10 times under a pressure of g / cm 2 . Next, 44.2 g of glycerin was added to this emulsion, and 20 to 4 was added.
Add 730 ml of distilled water for injection at 0 ° C. and roughly emulsify with a homomixer. Again using a Menton-Gaurin homogenizer, the first stage 120kg / cm 2 total pressure 500k
Emulsify by passing 10 times under a pressure of g / cm 2 . As a result, a fat emulsion containing flurbiprofen axetil was obtained.
【０００７】試験例 １ 実験的肝転移モデルにおけるフルルビプロフェン アキ
セチルの効果 実験動物としてＤＢＡ／２系マウス（♂、６週齡）を日
本エスエルシー株式会社より購入し、１週間予備飼育
後、実験を行った。フルルビプロフェン アキセチル脂
肪乳剤はロピオン注を用い、希釈にはフルルビプロフェ
ン アキセチルを含有しない脂肪乳剤を用いた。高肝転
移性Ｐ８１５（ＤＢＡ／マウス肥満細胞腫由来）株はマ
ウスの腹腔内で継代しているものを用いた。ＤＢＡ／マ
ウスの静脈内にＰ８１５の５×１０3 個／１００μｌ／
−ＰＢＳを移植し、翌日よりロピオン注を朝夕１日２回
（２ｍｇ／ｋｇ／回あるいは５ｍｇ／ｋｇ／回、一群１
０匹）１３日間連続静脈内投与した。腫瘍移植１４日目
にマウスを放血致死させ、肝臓を取り出してブアーン固
定後、肝表面転移結節数を数えた。対照群１０匹にはフ
ルルビプロフェン アキセチルを含有しない脂肪乳剤を
用いた。図１に対照群とフルルビプロフェン アキセチ
ル脂肪乳剤投与群における肝臓の転移結節数を示した。
図１に示した結果より明らかなように、フルルビプロフ
ェン アキセチル脂肪乳剤投与群において投与量に応じ
た肝転移結節数の減少が観察された。Test Example 1 Effect of flurbiprofen axetil in experimental liver metastasis model DBA / 2 strain mice (♂, 6 weeks old) were purchased from Japan SLC, Inc. as experimental animals, and after preliminarily breeding for 1 week, An experiment was conducted. Rupion injection was used as the flurbiprofen axetil fat emulsion, and a flurbiprofen axetil-free fat emulsion was used for dilution. As the highly liver metastatic P815 (DBA / mouse mastocytoma origin) strain, one that had been passaged intraperitoneally in mice was used. DBA / mouse intravenously 5 × 10 3 P815 / 100 μl /
-PBS was transplanted, and Ropion injection was performed twice a day (2 mg / kg / dose or 5 mg / kg / dose, 1 group per day) from the next day.
(0 animals) was intravenously administered for 13 consecutive days. On the 14th day of tumor transplantation, the mice were exsanguinated to death, the livers were taken out and fixed with bourn, and the number of liver surface metastatic nodules was counted. A fat emulsion containing no flurbiprofen axetil was used as a control group of 10 animals. FIG. 1 shows the number of metastatic nodules in the liver in the control group and the flurbiprofen axetil fat emulsion administration group.
As is clear from the results shown in FIG. 1, in the flurbiprofen axetil fat emulsion administration group, a decrease in the number of liver metastasis nodules depending on the dose was observed.
【０００８】試験例 ２ 自然肺転移モデルにおけるフルルビプロフェン アキセ
チルの効果 実験動物としてＣ５７ＢＬ／６系マウス（♂、６週齡）
を日本エスエルシー株式会社より購入し、１週間予備飼
育後、実験を行った。フルルビプロフェンアキセチル脂
肪乳剤はロピオン注を、希釈にはフルルビプロフェン
アキセチルを含有しない脂肪乳剤を用いた。高肺転移性
３ＬＬ（Ｃ５７ＢＬ／６マウス肺癌由来）株はマウスの
腹腔内で継代しているものを用いた。Ｃ５７ＢＬ／６マ
ウスの左足蹠皮下に３ＬＬの５×１０5 個／５０μｌ／
−ＰＢＳを移植し、翌日よりロピオン注を朝夕１日２回
（２ｍｇ／ｋｇ／回あるいは５ｍｇ／ｋｇ／回、一群１
０匹）静脈内投与した。移植後１４日目に左膝関節部を
切断して原発巣を除去し、さらに１０日後に放血致死さ
せた。ロピオン注は屠殺前日（腫瘍移植２３日目）まで
静脈内投与し、２４日目にマウスを屠殺して肺を摘出、
ブアーン固定後その転移結節数を数えた。対照群１０匹
にはフルルビプロフェン アキセチルを含有しない脂肪
乳剤を投与した。図２に対照群とフルルビプロフェン
アキセチル脂肪乳剤投与群における肺転移結節数を示し
た。図２に示した結果より明らかなように、フルルビプ
ロフェン アキセチル脂肪乳剤投与群において投与量に
応じた肺転移結節数の減少が観察された。Test Example 2 Effect of flurbiprofen axetil in natural lung metastasis model C57BL / 6 strain mouse (♂, 6 weeks old) as an experimental animal
Was purchased from Japan SLC Co., Ltd., and after preliminary breeding for 1 week, an experiment was conducted. Flurbiprofen Axetil fat emulsion is Ropion injection, dilution is flurbiprofen
A fat emulsion containing no axetil was used. As the high lung metastatic 3LL (derived from C57BL / 6 mouse lung cancer) strain, one subcultured in the abdominal cavity of the mouse was used. Subcutaneously in the left footpad of C57BL / 6 mice, 3LL of 5 × 10 5 cells / 50 μl /
-PBS was transplanted, and Ropion injection was performed twice a day (2 mg / kg / dose or 5 mg / kg / dose, 1 group per day) from the next day.
(0 animals) administered intravenously. The left knee joint was cut 14 days after the transplantation to remove the primary lesion, and 10 days later, the animals were exsanguinated to death. Ropion injection was intravenously administered until the day before slaughter (on the 23rd day of tumor implantation), and on the 24th day, the mice were sacrificed and the lungs were excised.
The number of metastatic nodules was counted after fixing Bourne. A fat emulsion containing no flurbiprofen axetil was administered to 10 control groups. Figure 2 shows the control group and flurbiprofen
The number of lung metastases in the axetil fat emulsion administration group was shown. As is clear from the results shown in FIG. 2, in the flurbiprofen axetil fat emulsion administration group, a decrease in the number of lung metastatic nodules depending on the dose was observed.
【０００９】[0009]
【発明の効果】Ｐ８１５肥満細胞腫を用いたマウス実験
的転移モデル及び３ＬＬ肺癌を用いたマウス自然転移モ
デルにおいてフルルビプロフェン アキセチル脂肪乳剤
の静脈内投与は、その転移形成に対し抑制的に作用し
た。上記の結果より、フルルビプロフェン アキセチル
脂肪乳剤は、癌性疼痛の改善作用と共に、術中・術後の
癌転移抑制及び予防、放射線療法時の癌転移の抑制など
に効果を発揮し、癌転移抑制剤として有用である。EFFECT OF THE INVENTION In a mouse experimental metastasis model using P815 mastocytoma and a mouse spontaneous metastasis model using 3LL lung cancer, intravenous administration of flurbiprofen axetil lipid emulsion suppressively acts on its metastasis formation. did. From the above results, flurbiprofen axetil lipid emulsion exerts an effect of suppressing and preventing cancer metastasis during and after surgery, suppressing cancer metastasis during radiation therapy, as well as improving cancer pain. It is useful as an inhibitor.
【００１０】[0010]
【図１】フルルビプロフェン アキセチル脂肪乳剤の実
験的肝転移モデルにおける癌転移抑制効果を示す図であ
る。図中の●印は各マウスの肝転移結節数の分布を表
す。統計処理はｗｉｌｃｏｘｏｎ ｔｅｓｔで行い、＊
＊はＰ＜０．０１を意味する。FIG. 1 is a graph showing a cancer metastasis suppressing effect of flurbiprofen axetil fat emulsion in an experimental liver metastasis model. The symbol ● in the figure represents the distribution of the number of liver metastasis nodules in each mouse. Statistical processing is performed by the Wilcoxon test, *
* Means P <0.01.
【図２】フルルビプロフェン アキセチル脂肪乳剤の自
然肺転移モデルにおける癌転移抑制効果を示す図であ
る。図中の●印は各マウスの肺転移結節数の分布を表
す。統計処理はｗｉｌｃｏｘｏｎ ｔｅｓｔで行い、＊
はＰ＜０．０５を意味する。FIG. 2 is a graph showing a cancer metastasis suppressing effect of flurbiprofen axetil fat emulsion in a natural lung metastasis model. The symbol ● in the figure represents the distribution of the number of lung metastases in each mouse. Statistical processing is performed by the Wilcoxon test, *
Means P <0.05.
Claims (1)
成分とする癌転移抑制剤。1. A cancer metastasis inhibitor containing flurbiprofen axetil as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19640492A JPH06192084A (en) | 1992-06-30 | 1992-06-30 | Inhibitor of cancer metastasis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19640492A JPH06192084A (en) | 1992-06-30 | 1992-06-30 | Inhibitor of cancer metastasis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06192084A true JPH06192084A (en) | 1994-07-12 |
Family
ID=16357302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19640492A Pending JPH06192084A (en) | 1992-06-30 | 1992-06-30 | Inhibitor of cancer metastasis |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06192084A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784115A (en) * | 2014-01-20 | 2015-07-22 | 华东理工大学 | Flurbiprofen axetil microsphere injection and preparation method thereof |
| CN108143715A (en) * | 2016-12-02 | 2018-06-12 | 北京普德康利医药科技发展有限公司 | A kind of florfenicol residues |
| CN108619088A (en) * | 2017-03-24 | 2018-10-09 | 北京普德康利医药科技发展有限公司 | A kind of florfenicol residues |
| CN109985005A (en) * | 2017-12-29 | 2019-07-09 | 北京普德康利医药科技发展有限公司 | Flurbiprofen axetil Fat Emulsion and preparation method thereof |
| US10653667B2 (en) * | 2013-09-25 | 2020-05-19 | Nippon Chemiphar Co., Ltd | Drug for preventing, treating or preventing metastasis of giant cell tumor that occurs in bone or soft parts, chondrosarcoma, or osteosarcoma, local injection for arterial embolization, and artificial bone |
| US10660882B2 (en) | 2012-03-26 | 2020-05-26 | Nippon Chemiphar Co., Ltd. | Prophylactic or therapeutic agent for giant cell tumors occurring in bone and soft tissue or for chondrosarcoma |
-
1992
- 1992-06-30 JP JP19640492A patent/JPH06192084A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10660882B2 (en) | 2012-03-26 | 2020-05-26 | Nippon Chemiphar Co., Ltd. | Prophylactic or therapeutic agent for giant cell tumors occurring in bone and soft tissue or for chondrosarcoma |
| US10653667B2 (en) * | 2013-09-25 | 2020-05-19 | Nippon Chemiphar Co., Ltd | Drug for preventing, treating or preventing metastasis of giant cell tumor that occurs in bone or soft parts, chondrosarcoma, or osteosarcoma, local injection for arterial embolization, and artificial bone |
| CN104784115A (en) * | 2014-01-20 | 2015-07-22 | 华东理工大学 | Flurbiprofen axetil microsphere injection and preparation method thereof |
| CN108143715A (en) * | 2016-12-02 | 2018-06-12 | 北京普德康利医药科技发展有限公司 | A kind of florfenicol residues |
| CN108619088A (en) * | 2017-03-24 | 2018-10-09 | 北京普德康利医药科技发展有限公司 | A kind of florfenicol residues |
| CN109985005A (en) * | 2017-12-29 | 2019-07-09 | 北京普德康利医药科技发展有限公司 | Flurbiprofen axetil Fat Emulsion and preparation method thereof |
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