JPWO2005056019A1 - Malignant melanoma treatment - Google Patents
Malignant melanoma treatment Download PDFInfo
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- JPWO2005056019A1 JPWO2005056019A1 JP2005516124A JP2005516124A JPWO2005056019A1 JP WO2005056019 A1 JPWO2005056019 A1 JP WO2005056019A1 JP 2005516124 A JP2005516124 A JP 2005516124A JP 2005516124 A JP2005516124 A JP 2005516124A JP WO2005056019 A1 JPWO2005056019 A1 JP WO2005056019A1
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- Prior art keywords
- malignant melanoma
- bisphosphonate
- minodronic acid
- present
- therapeutic 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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- A—HUMAN NECESSITIES
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Abstract
本発明者等はビスホスホネートの各種薬理作用の研究を行っていたところ、意外にも代表的なビスホスホネートであるミノドロン酸が悪性黒色腫の増殖を良好に抑制し、悪性黒色腫を移植したマウスの生存率を向上させることを見出し本発明を完成した。即ち、本発明は、ビスホスホネート、特にミノドロン酸若しくはその塩を有効成分として含有する悪性黒色腫治療剤に関するものである。本発明のビスホスホネート、殊にミノドロン酸又はその塩を有効成分として含有する悪性黒色腫治療剤は、悪性黒色腫の増殖を抑制し、患者の生存率を向上させることが期待されることから、悪性黒色腫の治療に有用である。The present inventors have been studying various pharmacological actions of bisphosphonate. Surprisingly, minodronic acid, a typical bisphosphonate, successfully suppressed the growth of malignant melanoma, and survival of mice transplanted with malignant melanoma The present invention was completed by finding that the rate was improved. That is, the present invention relates to a therapeutic agent for malignant melanoma containing bisphosphonate, particularly minodronic acid or a salt thereof as an active ingredient. The therapeutic agent for malignant melanoma containing the bisphosphonate of the present invention, particularly minodronic acid or a salt thereof, as an active ingredient is expected to suppress the growth of malignant melanoma and improve the survival rate of patients. Useful for the treatment of melanoma.
Description
本発明は、医薬、殊にミノドロン酸等のビスホスホネートを有効成分として含有する悪性黒色腫治療剤に関する。 The present invention relates to a therapeutic agent for malignant melanoma containing a pharmaceutical, particularly a bisphosphonate such as minodronic acid as an active ingredient.
悪性黒色腫（メラノーマ）は色素細胞系の悪性腫瘍であり、転移を生じやすく、化学療法などでも抵抗性の悪性度の高い腫瘍として知られている。多くは表皮基底層部に存在する色素細胞（メラノサイト）の癌化によって生じ、腫瘍細胞がメラニン色素生産能を有するために、黒褐色調の皮膚病変として認められる。
悪性黒色腫の治療は、進行のステージ（病期）に応じてきめ細かな治療が提案され、原発巣の切除に加えてリンパ節郭清、化学療法等の治療方法がとられている。しかし、悪性黒色腫は抗癌剤に極めて抵抗性であるため、転移を生じた進行期の当該腫瘍に確実に奏効する治療法は現状では見出されていない。Malignant melanoma is a pigmented cell-type malignant tumor that is prone to metastasis and is known as a highly malignant tumor that is resistant to chemotherapy. Many are caused by canceration of pigment cells (melanocytes) present in the basal layer of the epidermis, and are recognized as dark brown skin lesions because the tumor cells have the ability to produce melanin pigments.
As for the treatment of malignant melanoma, detailed treatments have been proposed according to the stage of progression (stage), and in addition to excision of the primary lesion, treatment methods such as lymph node dissection, chemotherapy and the like have been taken. However, because malignant melanoma is extremely resistant to anticancer agents, no treatment has been found to be surely effective for the advanced stage tumor that has developed metastasis.
一方、ビスホスホネートは石灰化抑制物質であるピロリン酸と類似の構造を有する化合物であって、破骨細胞の機能を抑制し骨吸収抑制作用を有することから、骨粗鬆症等の代謝性骨疾患の治療に用いられている薬剤である。例えば、ミノドロン酸（１−ヒドロキシ−２−（イミダゾ［１，２−ａ］ピリジン−３−イル）エタン−１，１−ビスホスホン酸）又はその塩は、縮合複素環骨格を有するビスホスホン酸化合物であり、ページェット病、高カルシウム血症、癌の骨転移、骨粗鬆症、慢性関節リウマチ等の炎症性関節疾患に伴う骨吸収の亢進等の骨吸収を抑制すると記載されている（特許文献１参照）。また、多発性骨髄腫の治療作用並びに多発性骨髄腫の骨病変の治療作用を有することが報告されている（特許文献２参照）。
しかしながら、ビスホスホネートの悪性黒色腫に対する作用については、現在まで何等報告が無い。On the other hand, bisphosphonate is a compound with a structure similar to pyrophosphoric acid, which is a mineralization inhibitor, and suppresses the function of osteoclasts and suppresses bone resorption. Therefore, it is useful for the treatment of metabolic bone diseases such as osteoporosis. It is a drug used. For example, minodronic acid (1-hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethane-1,1-bisphosphonic acid) or a salt thereof is a bisphosphonic acid compound having a condensed heterocyclic skeleton. Yes, it is described to suppress bone resorption such as increased bone resorption associated with inflammatory joint diseases such as Paget's disease, hypercalcemia, cancer bone metastasis, osteoporosis, and rheumatoid arthritis (see Patent Document 1). . In addition, it has been reported to have a therapeutic action for multiple myeloma and a therapeutic action for bone lesions of multiple myeloma (see Patent Document 2).
However, there are no reports on the effects of bisphosphonates on malignant melanoma.
新しいタイプの、悪性黒色腫の治療剤の創製が望まれている。 Creation of a new type of therapeutic agent for malignant melanoma is desired.
本発明者等はビスホスホネートの各種薬理作用の研究を行っていたところ、意外にも代表的なビスホスホネートであるミノドロン酸が悪性黒色腫の増殖を良好に抑制し、悪性黒色腫を移植したマウスの生存率を向上させることを見出し本発明を完成した。即ち、本発明は、ビスホスホネート、特にミノドロン酸若しくはその塩を有効成分として含有する悪性黒色腫治療剤に関するものである。 The present inventors have been studying various pharmacological actions of bisphosphonate. Surprisingly, minodronic acid, a typical bisphosphonate, successfully suppressed the growth of malignant melanoma, and survival of mice transplanted with malignant melanoma The present invention was completed by finding that the rate was improved. That is, the present invention relates to a therapeutic agent for malignant melanoma containing bisphosphonate, particularly minodronic acid or a salt thereof as an active ingredient.
本発明の、「悪性黒色腫治療剤」は、後記実施例に示すとおり悪性黒色腫の増殖を抑制し、患者の生存率を向上させることが期待されることから、悪性黒色腫の治療に有用である。 The “malignant melanoma therapeutic agent” of the present invention is useful for the treatment of malignant melanoma because it is expected to suppress the growth of malignant melanoma and improve the survival rate of patients as shown in the Examples below. It is.
本発明において、「ビスホスホネート」とは、骨吸収抑制剤として公知のビスホスホン酸若しくはその製薬学的に許容される塩又はエステルであって、好ましくは、エチドロネート（ｅｔｉｄｒｏｎａｔｅ）、アレンドロネート（ａｌｅｎｄｒｏｎａｔｅ；特公平２−１３６４５号公報、特公平６−６２６５１号公報、米国特許４７０５６５１号公報）、リセドロネート（ｒｉｓｅｄｒｏｎａｔｅ；日本特許第２７０２４１９号公報、日本特許第２５６８９９９号公報、ヨーロッパ特許１８６４０５号公報）、パミドロネート（ｐａｍｉｄｒｏｎａｔｅ；特公平５−８７１７号公報、米国特許４３２７０３９号公報）、インカドロネート（ｉｎｃａｄｒｏｎａｔｅ；特公平７−６２９号公報）、クロドロネート（ｃｌｏｄｒｏｎａｔｅ）、ミノドロン酸（ｍｉｎｏｄｒｏｎｉｃ ａｃｉｄ；特公平６−９９４５７号公報）、イバンドロネート（ｉｂａｎｄｒｏｎａｔｅ；特公平８−２９１３号公報、ヨーロッパ特許２５２５０４号公報）、ゾレドロネート（ｚｏｌｅｄｒｏｎａｔｅ；日本特許第２７４４２３８号公報、ヨーロッパ特許２７５８２１号公報）、チルドロネート（ｔｉｌｕｄｒｏｎａｔｅ；特公平４−２９６７６号公報、日本特許第２７３５４６２号公報、米国特許５７３９３８１号公報）、ネリドロネート（ｎｅｒｉｄｒｏｎａｔｅ；特公昭６３−７５２６号公報、米国特許４５７８３７６号公報）等である。更に好ましくは、アレンドロネート、リセドロネート、パミドロネート、インカドロネート、ミノドロン酸、イバンドロネート及びゾレドロネート、特に好ましくは、アレンドロネート、リセドロネート、インカドロネート、ミノドロン酸及びゾレドロネートである。
ビスホスホン酸の製薬学的に許容される塩としては、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の金属を含む無機塩基、メチルアミン、エチルアミン、エタノールアミン、リジン、オルニチン等の有機塩基との塩が挙げられる。エステルとしては、好ましくはメチルエステル、エチルエステル等の低級アルキルエステルである。
これらのビスホスホネートは市販されているものを用いてもよく、上記文献記載の方法で製造してもよい。
さらに，上記ビスホスホネートの各種の水和物や溶媒和物、及び結晶多形の物質であってもよい。例えば、ミノドロン酸を経口投与用固形製剤として用いる場合はミノドロン酸水和物の結晶を用いるのが好ましい。In the present invention, the “bisphosphonate” is a bisphosphonic acid known as a bone resorption inhibitor, or a pharmaceutically acceptable salt or ester thereof, preferably etidronate, alendronate; JP-B-2-13645, JP-B-6-62651, U.S. Pat. No. 4,705,651), risedronate (Japanese Patent No. 2702419, Japanese Patent No. 2568999, European Patent No. 186405), pamidronate (pamidronate) No. 5-8717, U.S. Pat. No. 4327039), incadronate (No. 7-629), clodronate, mi Dronic acid (minodonic acid; Japanese Patent Publication No. 6-99457), ibandronate (Japanese Patent Publication No. 8-2913, European Patent No. 252504), zoledronicate (Japanese Patent No. 2744238, European Patent 275821) No. 4), tiludronate (Japanese Patent Publication No. 4-29676, Japanese Patent No. 2735462, US Pat. No. 5,739,381), neridronate (Japanese Patent Publication No. 63-7526, US Pat. No. 4,578,376) and the like. is there. More preferred are alendronate, risedronate, pamidronate, incadronate, minodronate, ibandronate and zoledronate, and particularly preferred are alendronate, risedronate, incadronate, minodronate and zoledronic acid.
Pharmaceutically acceptable salts of bisphosphonic acid include salts with inorganic bases including metals such as sodium, potassium, magnesium, calcium and aluminum, and salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine. Can be mentioned. The ester is preferably a lower alkyl ester such as methyl ester or ethyl ester.
These bisphosphonates may be commercially available or may be produced by the methods described in the above documents.
Furthermore, various hydrates and solvates of the above bisphosphonates, and polymorphic substances may be used. For example, when minodronic acid is used as a solid preparation for oral administration, crystals of minodronic acid hydrate are preferably used.
本発明の治療剤は、必要に応じて放射線治療や、化学療法剤等の他の既存の抗癌剤と併用することができる。本発明医薬組成物と他の抗癌剤との併用により、より優れた悪性黒色腫の抑制作用が得られる可能性も期待される。 The therapeutic agent of the present invention can be used in combination with other existing anticancer agents such as radiotherapy and chemotherapeutic agents as necessary. The combined use of the pharmaceutical composition of the present invention with other anticancer agents is also expected to give a better suppressive effect on malignant melanoma.
本発明の治療剤は，ビスホスホネートの１種又は２種以上と、製薬学的に許容される担体、具体的には、通常製剤化に用いられる薬剤用担体、賦形剤，その他添加剤を用いて、通常使用されている方法によって調製することができる。投与は錠剤，丸剤，カプセル剤，顆粒剤，散剤，液剤等による経口投与，又は，静注，筋注等の注射剤，坐剤，経皮等による非経口投与のいずれの形態であってもよい。
本発明の経口投与用の固体組成物としては，錠剤，散剤，顆粒剤等が用いられる。このような固体組成物においては，ひとつ又はそれ以上の活性物質が，少なくともひとつの不活性な希釈剤，例えば乳糖，マンニトール，ブドウ糖，ヒドロキシプロピルセルロース，微結晶セルロース，トウモロコシデンプン，ポリビニルピロリドン，メタケイ酸アルミン酸マグネシウムと混合される。組成物は，常法に従って，不活性な希釈剤以外の添加剤，例えばステアリン酸マグネシウムのような潤滑剤や繊維素グリコール酸カルシウムのような崩壊剤，安定化剤，グルタミン酸又はアスパラギン酸のような溶解補助剤を含有していてもよい。錠剤又は丸剤は必要によりショ糖，ゼラチン，ヒドロキシプロピルセルロース，ヒドロキシプロピルメチルセルロース，ヒドロキシプロピルメチルセルロースフタレートなどからなる、糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。The therapeutic agent of the present invention uses one or more of bisphosphonates and a pharmaceutically acceptable carrier, specifically, a pharmaceutical carrier, excipient, or other additive that is usually used for formulation. And can be prepared by commonly used methods. Administration is in the form of oral administration by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration by injections such as intravenous injections, intramuscular injections, suppositories, transcutaneous, etc. Also good.
Tablets, powders, granules and the like are used as the solid composition for oral administration of the present invention. In such solid compositions, one or more active substances are present in at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, corn starch, polyvinylpyrrolidone, metasilicic acid. Mixed with magnesium aluminate. The composition is prepared in accordance with conventional methods with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, stabilizers, glutamic acid or aspartic acid. It may contain a solubilizing agent. Tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance made of sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate or the like, if necessary.
経口投与用の液体組成物は，薬剤的に許容される乳濁剤，溶液剤，懸濁剤，シロップ剤，エリキシル剤等を含み，一般的に用いられる不活性な希釈剤，例えば精製水，エタノールを含む。この組成物は不活性な希釈剤以外に湿潤剤，懸濁剤のような補助剤，甘味剤，風味剤，芳香剤，防腐剤を含有していてもよい。
非経口投与用の注射用組成物としては，無菌の水性又は非水性の溶液剤，懸濁剤，乳濁剤を含有する。水性の溶液剤，懸濁剤としては，例えば注射用蒸留水及び生理食塩液が含まれる。非水溶性の溶液剤，懸濁剤としては，例えばプロピレングリコール，ポリエチレングリコール，オリーブ油のような植物油，エタノールのようなアルコール類，ポリソルベート８０等がある。このような組成物は，さらに防腐剤，湿潤剤，乳化剤，分散剤，安定化剤（例えば，ラクトース），溶解補助剤（例えば，グルタミン酸，アスパラギン酸）のような補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過，殺菌剤の配合又は照射によって無菌化される。これらはまた無菌の固体組成物を製造し，使用前に無菌水又は無菌の注射用溶媒に溶解して使用することもできる。Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water, Contains ethanol. In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.
Injectable compositions for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol,
投与量は、各ビスホスホネートの効力に応じて適宜決定される。例えば、ミノドロン酸の場合は、経口投与の場合、１日の投与量は，約０．１から２００ｍｇ、好ましくは約１から１００ｍｇ、最も好ましくは約５から５０ｍｇが適当である。これを１日１回あるいは２乃至４回に分けて投与するか、２〜１４日毎に１回あるいは１ヶ月に１回で投与してもよい。静脈投与される場合は、１回の投与量が約０．０１から１００ｍｇ、好ましくは約０．１から１０ｍｇ、更に好ましくは約０．５から５ｍｇが適当であり、これを２〜６週に１回、好ましくは３〜５週に１回、より好ましくは、４週に１回、１０〜６０分、好ましくは３０分かけて、点滴静脈内投与することができる。
投与量は、患者の体重、症状，年令，性別等を考慮して個々の場合に応じて適宜決定される。The dose is appropriately determined according to the efficacy of each bisphosphonate. For example, in the case of minodronic acid, for oral administration, the appropriate daily dosage is about 0.1 to 200 mg, preferably about 1 to 100 mg, and most preferably about 5 to 50 mg. This may be administered once a day or divided into 2 to 4 times, or once every 2 to 14 days or once a month. When administered intravenously, a single dose of about 0.01 to 100 mg, preferably about 0.1 to 10 mg, more preferably about 0.5 to 5 mg is suitable, and this should be done in 2 to 6 weeks. The intravenous infusion can be administered once, preferably once every 3 to 5 weeks, more preferably once every 4 weeks for 10 to 60 minutes, preferably 30 minutes.
The dose is appropriately determined according to individual cases in consideration of the patient's weight, symptoms, age, sex, and the like.
以下に、本発明の治療剤の効果を示す試験例を示す。なお、本発明の範囲は以下の試験例により何等限定されることはない。
ヌードマウスにおけるＧ３６１メラノーマ細胞移植腫瘍の増殖抑制試験
＜方法＞
１群５匹のヌードマウス（６週齢、♀）の腹側上部皮内にＧ３６１メラノーマ細胞１０６ｃｅｌｌｓ／マウスを移植した。ミノドロン酸水和物５μｇ／マウス（ミノドロン酸投与群）または生理食塩液（コントロール群）を連日腹腔内投与した。５日間隔で腫瘍径（短径および長径）をノギスで測定し、腫瘍体積（短径２×長径／２）を算出した。Below, the test example which shows the effect of the therapeutic agent of this invention is shown. The scope of the present invention is not limited by the following test examples.
Growth inhibition test of G361 melanoma cell transplanted tumor in nude mice <Method>
＜結果及び考察＞
ヌードマウスに移植したＧ３６１メラノーマ細胞の増殖は速く、４０日後に腫瘍体積は５００−６００ｍｍ３に達した。一方、ミノドロン酸投与群では、Ｇ３６１ラノーマ細胞の腫瘍増殖は４０日間にわたりほぼ完全に抑制された（図１参照）。Ｋａｐｌａｎ−Ｍｅｉｅｒ解析からミノドロン酸投与群ではコントロール群に比較してマウスの生存率は有意に高かった（図２参照）。<Results and discussion>
The growth of G361 melanoma cells transplanted into nude mice was fast and the tumor volume reached 500-600 mm 3 after 40 days. On the other hand, in the minodronic acid administration group, tumor growth of G361 lanoma cells was almost completely suppressed over 40 days (see FIG. 1). From the Kaplan-Meier analysis, the survival rate of mice was significantly higher in the minodronic acid administration group than in the control group (see FIG. 2).
本発明の「悪性黒色腫治療剤」は、悪性黒色腫の増殖を抑制し、患者の生存率を向上させることが期待されることから、悪性黒色腫の治療に適用できる。 The “malignant melanoma therapeutic agent” of the present invention can be applied to the treatment of malignant melanoma because it is expected to suppress the growth of malignant melanoma and improve the survival rate of patients.
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|---|
| JPN6010065285, Ｃ．Ｒｉｅｂｅｌｉｎｇ, "Ｔｈｅ ｂｉｓｐｈｏｓｐｈｏｎａｔｅ ｐａｍｉｄｒｏｎａｔｅ ｉｎｄｕｃｅｓ ａｐｏｐｔｏｓｉｓ ｉｎ ｈｕｍａｎ ｍｅｌａｎｏｍａ ｃｅｌｌｓ ｉｎ ｖｉｔｒｏ", Ｂｒｉｔｉｓｈ Ｊｏｕｒｎａｌ ｏｆ Ｃａｎｃｅｒ, 2002, Ｖｏｌ．８７， Ｎｏ．３, ｐ３６６−３７１ * |
| JPN6010065286, Ｊ．−Ｍ．ｄｅｓ Ｇｒｏｔｔｅｓ, "Ｈｙｐｅｒｃａｌｃａｅｍｉａ ｏｆ ｍｅｌａｎｏｍａ：ｉｎｃｉｄｅｎｃｅ， ｐａｔｈｏｇｅｎｅｓｉｓ ａｎｄ ｔｈｅｒａｐｙ ｗｉｔｈ ｂｉｓｐｈｏｓｐｈｏｎａｔｅｓ", Ｍｅｌａｎｏｍａ Ｒｅｓｅａｒｃｈ, 2001, Ｖｏｌ．１１, ｐ４７７−４８２ * |
| JPN6010065287, ＯＬＬＩ ＴＥＲＯＮＥＮ, "ＭＭＰ Ｉｎｈｉｂｉｔｉｏｎ ａｎｄ Ｄｏｗｎｒｅｇｕｌａｔｉｏｎ ｂｙ Ｂｉｓｐｈｏｓｐｈｏｎａｔｅｓ", Ａｎｎａｌｓ ｏｆ ｔｈｅ ｎｅｗ ｙｏｒｋ ａｃａｄｅｍｙ ｏｆ ｓｃｉｅｎｃｅｓ, 19990630, Ｖｏｌ．８７８, ｐ４５３−４６５ * |
| JPN6010065288, Ｓｏｒｂｅｒａ．Ｌ．Ａ．, "Ｍｉｎｏｄｒｏｎｉｃ ａｃｉｄ：ｔｒｅａｔｍｅｎｔ ｏｆ ｏｓｔｅｏｐｏｒｏｓｉｓ， ｔｒｅａｔｍｅｎｔ ｏｆ ｂｏｎｅ ｍｅｔａｓｔａｓｉｓ， ｔｒｅａｔｍｅｎｔ ｏｆ ｍｕｌｔｉｐｌｅ ｍｙｅｌｏ", Ｄｒｕｇｓ Ｆｕｔｕｒｅ, 2002, Ｖｏｌ．２７，Ｎｏ．１０, ｐ９３５−９４１ * |
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| Publication number | Publication date |
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| JP4692283B2 (en) | 2011-06-01 |
| WO2005056019A1 (en) | 2005-06-23 |
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