JP4287523B2 - Antitumor agent - Google Patents

Description

で示される化合物（以下「ＴＺＴ−１０２７」という）を挙げることができる。
【００１２】
一方、Ａ成分と組み合わせて使用されるもう一方の抗腫瘍剤であるＢ成分は、いずれも公知のものであり、例えば、メルク インデックス（THE MERCK INDEX 12th EDITION）の以下のモノグラフナンバーの項に記載されている：５−フルオロウラシル（No.4219）、ドキソルビシン（No.3495）、イリノテカン（No.5104）、シスプラチン（No.2378）、サイクロホスファミド（No.2816）、エトポシド（No.3931）、パクリタキセル（No.7117）。
【００１３】
本発明のＡ成分及びＢ成分は、必要に応じて、無機酸もしくは有機酸又は無機塩基もしくは有機塩基と製薬学的に許容しうる塩を形成させて用いることができる。塩を形成させるのに用られる無機酸としては、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等が挙げられ、有機酸としては、例えば、酢酸、プロピオン酸、蓚酸、マロン酸、こはく酸、乳酸、リンゴ酸、酒石酸、クエン酸、安息香酸、メタンスルホン酸等が挙げられる。一方、塩を形成させるのに用いられる無機塩基としては、例えば、水酸化ナトリウム、水酸化アンモニウム、炭酸カリウム、炭酸水素ナトリウム、水酸化カルシウム等が挙げられ、有機塩基としては、例えば、メチルアミン、ジエチルアミン、シクロヘキシルアミン、エタノールアミン、モルホリン等を挙げることができる。
【００１４】
本発明の抗腫瘍剤は、固体形態（例えば、錠剤、硬カプセル剤、軟カプセル剤、顆粒剤、散剤、細粒剤、丸剤、トローチ錠など）、半固体形態（例えば、坐剤、軟膏など）又は液体形態（例えば、注射剤、乳剤、懸濁液、エリキシル剤、ローション、スプレーなど）のいずれかの製剤形態に調製して用いることができる。かかる製剤の製造の際に使用しうる添加物としては、例えば、でん粉、ブドウ糖、白糖、乳糖、果糖、マルトース、マンニット、ソルビット、シクロデキストリン、ケイ酸誘導体、メチルセルロース、カルボキシメチルセルロース又はその塩、アルギン酸塩、ゼラチン、ポリビニルピロリドン、炭酸カルシウム、炭酸水素ナトリウム、炭酸マグネシウム、タルク、ステアリン酸マグネシウム、アラビアゴム、ポリエチレングリコール、ｐ−ヒドロキシ安息香酸アルキルエステル、セチルアルコール、シロップ、エタノール、プロピレングリコール、ワセリン、カーボワックス、グリセリン、塩化ナトリウム、亜硫酸ナトリウム、リン酸ナトリウム、クエン酸、乳酸、水酸化ナトリウム、ポリ乳酸、ポリ乳酸−グリコール酸等が挙げられる。
【００１５】
なお、上記製剤は、有効成分であるＡ成分とＢ成分を一つの製剤中に両方とも含有する製剤として調製してもよく、また、Ａ成分とＢ成分とをそれぞれ別々の製剤として調製することもできる。
【００１６】
本発明の抗腫瘍剤は、Ａ成分とＢ成分を組み合わせて使用しさえすれば、それらを一緒に投与すること又は所定の時間間隔で別々に投与することのいずれも可能であり、医師の判断や患者の症状等に応じて、これらの投与方法を適宜選択することができる。なお、別々に投与する場合、Ａ成分とＢ成分はいずれを先に投与してもよい。
【００１７】
また、本発明の抗腫瘍剤において、Ａ成分及び／又はＢ成分を含む医薬製品の包装材料上又は包装材料内には、Ａ成分とＢ成分の組み合わせに関するこれらの使用法が記載された表示又は文書が存在していることが好ましい。
【００１８】
本発明の製剤中におけるＡ成分及びＢ成分の含有量はその剤形等に応じて変えることができるが、一般に、固体及び半固体形態の場合には０．１〜５０重量％の範囲内の濃度で、そして液体形態の場合には０．０５〜１０重量％の範囲内の濃度で抗腫瘍剤を含有することが望ましい。
【００１９】
本発明に従う抗腫瘍剤の投与量は、投与経路、症状の種類及びその軽重、医者の診断等により広範に変えることができるが、Ａ成分については、一般に許容される有効な用量は約０．１〜約１０ｍｇ／回であり、好適には約０.２〜約５ｍｇ／回とすることができる。また、Ｂ成分については、その種類によりそれぞれ投与量は異なり、一般に、５−フルオロウラシルについては約５〜約２０ｍｇ／回、ドキソルビシンについては約１０〜約３０ｍｇ／回、イリノテカンについては約５０〜約２５０ｍｇ／回、シスプラチンについては約２０〜約１２０ｍｇ／回、サイクロホスファミドについては約１００〜約１０００ｍｇ／回、エトポシドについては約８０〜約２００ｍｇ／回、パクリタキセルについては約１００〜約３５０ｍｇ／回とすることができる。
【００２０】
しかし、上記の如く患者の症状の種類及びその軽重、医師の診断に応じて上記範囲の下限よりも少ない量又は上限よりも多い量を投与することはもちろん可能である。上記投与量の薬剤は数時間乃至１ヶ月に１回投与することができる。
【００２１】
【実施例】
以下、試験例及び実施例により本発明を更に具体的に説明する。
【００２２】
試験例
７週齢のＣＤＦ１マウス（１群６匹、なお対照群は１２匹）の腹腔内に、マウス白血病Ｌ１２１０細胞を０.１ｍｌ（１０⁶ cells ／マウス）づつ移植し、移植第一日目（移植翌日）及び第五日目に薬物を静脈内に投与した。また別々に、７週齢のＣＤＦ１マウス（１群６匹）の皮下に、マウス肺癌細胞Ｍ１０９を０.１ｍｌ（２％ホモジネート／マウス）づつ移植し、移植第一日目（移植翌日）第五日目及び第九日目に薬物を静脈内に投与した。
【００２３】
抗腫瘍作用は、マウスの生死を６０日間観察した結果から下記式により延命率（ＩＬＳ,％）を求め評価した。なお、下記式中、Ｔは薬物投与群のメディアン生存日数、Ｃはコントロール群のメディアン生存日数を意味する。
【００２４】
延命率＝［（Ｔ−Ｃ）／Ｃ］Ｘ１００
マウス白血病Ｌ１２１０細胞に対する薬物投与群の延命率を下記表１に、マウス肺癌細胞Ｍ１０９に対する薬物投与群の延命率を下記表２に示す。
【００２５】
表 １（マウス白血病Ｌ１２１０細胞）
Ａ成分 Ｂ成分 延命率（％）
TZT-1027(0.75mg/kg) なし ６２
なし ５−フルオロウラシル(37.5mg/kg) ５４
TZT-1027(0.75mg/kg) ５−フルオロウラシル (37.5mg/kg) ９５
なし ドキソルビシン(7.5mg/kg) ７０
TZT-1027(0.75mg/kg) ドキソルビシン (7.5mg/kg) ９８
なし イリノテカン(25mg/kg) ７８
TZT-1027(0.75mg/kg) イリノテカン (25mg/kg) １２１
なし シスプラチン(3.75mg/kg) ５４
TZT-1027(0.75mg/kg) シスプラチン (3.75mg/kg) １１１
なし サイクロホスファミド(75mg/kg) ６６
TZT-1027(0.75mg/kg) サイクロホスファミド (75mg/kg) ９６
表 ２（マウス肺癌細胞Ｍ１０９）
Ａ成分 Ｂ成分 延命率（％）
TZT-1027(0.5mg/kg) なし ４０
なし イリノテカン(50mg/kg) ２８
TZT-1027(0.5mg/kg) イリノテカン (50mg/kg) ６０
なし エトポシド(30mg/kg) ２４
TZT-1027(0.5mg/kg) エトポシド (30mg/kg) ８２
なし パクリタキセル(40mg/kg) ６５
TZT-1027(0.5mg/kg) パクリタキセル (40mg/kg) １０６
実施例１ Ａ成分とＢ成分が別々の製剤である例
Ａ成分注射剤：

Ｂ成分注射剤：

注射用水に塩化ナトリウム及び乳酸を溶かし、その溶液に主薬を溶解する。
水酸化ナトリウムでｐＨを４〜５に調整後、注射用水を加え、規定量にする。
実施例２ Ａ成分とＢ成分が１つの製剤中に同時に含まれている例
注射剤：

実施例３ （Ａ成分とＢ成分が１つの製剤中に同時に含まれている例）
徐放性注射剤：
ＴＺＴ−１０２７ ２ｍｇ、シスプラチン２０ｍｇ及び乳酸−グリコール酸共重合体（乳酸：グリコール酸＝５０：５０、分子量約５０００；商品名「ＰＬＧＡ５００５」、和光純薬工業株式会社製）６００ｍｇを塩化メチレン１ｍｌに溶解し、０．５％ポリビニルアルコール水溶液１５０ｍｌ中に小型ホモジナイザーで乳化分散後、約２時間撹拌してＯ／Ｗ型液中乾燥を行って、油相を固化させた。生成したマイクロスフェアを遠心分離で捕集し、精製水で洗浄後、水に再分散して凍結乾燥しマイクロスフェアを得た。得られたマイクロスフェアは、使用時に、Ｄ−マンニトール ５０ｍｇ／ｍｌ、カルボキシメチルセルロースナトリウム ５ｍｇ／ｍｌ及びポリソルベート８０ １ｍｇ／ｍｌを含有する懸濁液に懸濁させる。[0001]
BACKGROUND OF THE INVENTION
The present invention comprises (a) dolastatin 10 or an analog thereof (hereinafter sometimes referred to as “component A”) as an active ingredient, (b) 5-fluorouracil, doxorubicin, irinotecan, cisplatin, cyclophosphamide, etoposide and Antitumor agents for use in combination with an antitumor agent comprising one or two compounds selected from the group consisting of paclitaxel (hereinafter sometimes referred to as “B component”) as an active ingredient, these A component and B component The present invention relates to a combination of an antitumor agent and a pharmaceutical product having an indication or document on the packaging material or in the packaging material describing the use of the combination.
[0002]
[Prior art]
Dolastatin 10 is a pentapeptide extracted from the Indian sea snail by Pettit et al., And is known as a compound having a very strong cell growth inhibitory action (antitumor action) (JP-A-2-167278). No. publication). In addition, various analogs thereof have been synthesized, and they are also known to have excellent antitumor activity similar to dolastatin 10 (see, for example, International Publication WO 93/03054 pamphlet).
[0003]
On the other hand, B component 5-fluorouracil, doxorubicin, irinotecan, cisplatin, cyclophosphamide, etoposide or paclitaxel are also known as compounds exhibiting antitumor activity, and these compounds have already been marketed as antitumor agents.
[0004]
However, since compounds exhibiting antitumor activity are generally cytotoxic substances, they exhibit toxicity such as growth inhibition even for normal cells. Therefore, when using antitumor agents, they should be used in as small a dose as possible. Is desired. Therefore, in actual medical practice, try to reduce the dose of antitumor agents by combining chemotherapy and immunotherapy, radiation therapy, hyperthermia, hormone therapy, etc., or use antitumor agents with different mechanisms of action together As a whole, various attempts have been made, such as attempts to reduce the side effects of the administered antitumor agents, but there are drugs that are still sufficiently satisfactory in chemotherapy with the combination of antitumor agents. The combination has not been established.
[0005]
[Problems to be solved by the invention]
The object of the present invention is (1) selected from the group consisting of (a) dolastatin 10 or an analog thereof (component A) selected from the group consisting of (b) 5-fluorouracil, doxorubicin, irinotecan, cisplatin, cyclophosphamide, etoposide and paclitaxel. It is to provide a highly effective antitumor agent for the treatment of cancer by using in combination with two kinds of compounds (component B).
[0006]
Another object of the present invention is to provide a combination of these anti-tumor agents of component A and component B, and a medicament having a label or document that describes use of the combination on or in the packaging material. Is to provide products.
[0007]
[Means for Solving the Problems]
As a result of various studies on the antitumor effect of dolastatin 10 and its related compounds, the present inventors have surprisingly found that dolastatin 10 or its analogs include 5-fluorouracil, doxorubicin, irinotecan, cisplatin, and cyclophosphamide. It was found that the antitumor action of dolastatin 10 or an analog thereof is remarkably enhanced by using a combination of one or two compounds selected from the group consisting of etoposide and paclitaxel.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
Thus, according to the present invention, from (a) dolastatin 10 or its analog (component A) as an active ingredient, (b) from 5-fluorouracil, doxorubicin, irinotecan, cisplatin, cyclophosphamide, etoposide and paclitaxel Provided is an antitumor agent for use in combination with an antitumor agent comprising one or two compounds (component B) selected from the group consisting of as active ingredients.
[0009]
In addition, according to the present invention, a combination of an antitumor agent comprising an A component and a B component for treating a tumor by administering the A component and the B component together or separately, and a combination thereof can be used. A pharmaceutical product is provided having the described label or document on or in the packaging material.
[0010]
In the present specification, the term “dolastatin 10 analog” means a compound in which a constituent amino acid or a part of peptide of dolastatin 10 which is a pentapeptide is substituted with another amino acid or peptide, a part of the constituent amino acid or peptide. Is a compound in which other amino acids or peptides are added to the pentapeptide, a compound in which the pentapeptide is modified with a substituent, etc., and exhibits the same antitumor activity as dolastatin 10 It is used with the meaning which includes all the compounds. Specific examples of these dolastatins 10 or analogs thereof include, for example, International Publication WO95 / 09864, International Publication WO96 / 33212, in addition to the above-mentioned Japanese Patent Application Laid-Open No. 2-167278 and International Publication WO93 / 03054. Pamphlet, JP-A-6-29395, JP-A-7-70173, JP-A-8-59693, JP-A-8-81493, JP-A-8-119990, JP-A-8-188594. And those described in documents such as JP-A-9-77791, JP-A-7-506580, JP-A-8-504415, and the like. Among these, particularly preferred compounds are those represented by the following formula:
[Chemical formula 2]

(Hereinafter referred to as “TZT-1027”).
[0012]
On the other hand, the B component which is the other antitumor agent used in combination with the A component is a known one. For example, in the following monograph number section of the Merck Index (THE MERCK INDEX 12th EDITION) Described: 5-fluorouracil (No. 4219), doxorubicin (No. 3495), irinotecan (No. 5104), cisplatin (No. 2378), cyclophosphamide (No. 2816), etoposide (No. 3931) ), Paclitaxel (No. 7117).
[0013]
The A component and the B component of the present invention can be used by forming a pharmaceutically acceptable salt with an inorganic acid, an organic acid, an inorganic base or an organic base, if necessary. Examples of the inorganic acid used to form the salt include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of the organic acid include acetic acid, propionic acid, succinic acid, malonic acid, Examples include succinic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, and methanesulfonic acid. On the other hand, examples of the inorganic base used to form the salt include sodium hydroxide, ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, and the like. Examples of the organic base include methylamine, Examples include diethylamine, cyclohexylamine, ethanolamine, morpholine and the like.
[0014]
The antitumor agent of the present invention is in a solid form (eg, tablet, hard capsule, soft capsule, granule, powder, fine granule, pill, troche tablet, etc.), semi-solid form (eg, suppository, ointment) Etc.) or liquid form (for example, injections, emulsions, suspensions, elixirs, lotions, sprays, etc.). Examples of additives that can be used in the production of such preparations include starch, glucose, sucrose, lactose, fructose, maltose, mannitol, sorbit, cyclodextrin, silicic acid derivatives, methylcellulose, carboxymethylcellulose or salts thereof, and alginic acid. Salt, gelatin, polyvinyl pyrrolidone, calcium carbonate, sodium hydrogen carbonate, magnesium carbonate, talc, magnesium stearate, gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, cetyl alcohol, syrup, ethanol, propylene glycol, petrolatum, carbo Examples thereof include wax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid, lactic acid, sodium hydroxide, polylactic acid, and polylactic acid-glycolic acid.
[0015]
In addition, the said formulation may be prepared as a formulation which contains both A component and B component which are active ingredients in one formulation, and prepares A component and B component as separate formulations, respectively. You can also.
[0016]
As long as the antitumor agent of the present invention is used in combination with the A component and the B component, they can be administered together or separately at predetermined time intervals. These administration methods can be appropriately selected according to the patient's symptoms and the like. In addition, when administering separately, either A component and B component may administer first.
[0017]
In addition, in the antitumor agent of the present invention, on the packaging material of the pharmaceutical product containing the A component and / or the B component or in the packaging material, the indication or the use of these usages relating to the combination of the A component and the B component is described. The document is preferably present.
[0018]
The content of component A and component B in the preparation of the present invention can be changed according to the dosage form and the like, but generally in the range of 0.1 to 50% by weight in the case of solid and semi-solid forms. It is desirable to contain the antitumor agent at a concentration, and in the liquid form at a concentration in the range of 0.05 to 10% by weight.
[0019]
The dose of the antitumor agent according to the present invention can be widely varied depending on the route of administration, the type and symptom of symptoms, the doctor's diagnosis, and the like. 1 to about 10 mg / dose, preferably about 0.2 to about 5 mg / dose. In addition, the dose of component B varies depending on the type, and is generally about 5 to about 20 mg / dose for 5-fluorouracil, about 10 to about 30 mg / dose for doxorubicin, and about 50 to about 250 mg for irinotecan. About 20 to about 120 mg / dose for cisplatin, about 100 to about 1000 mg / dose for cyclophosphamide, about 80 to about 200 mg / dose for etoposide, about 100 to about 350 mg / dose for paclitaxel can do.
[0020]
However, as described above, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range depending on the type and severity of the patient's symptoms and the diagnosis of the doctor. The above dose of drug can be administered once every few hours to once a month.
[0021]
【Example】
Hereinafter, the present invention will be described more specifically with reference to test examples and examples.
[0022]
Test Example Seven weeks of CDF1 mice (6 mice per group, 12 mice in the control group) were transplanted with 0.1 ml (10 ⁶ cells / mouse) of mouse leukemia L1210 cells, and the first day of transplantation. The drug was administered intravenously (day after transplantation) and on the fifth day. Separately, 0.1 ml (2% homogenate / mouse) of mouse lung cancer cells M109 were transplanted subcutaneously into 7-week-old CDF1 mice (6 mice per group), and the fifth day of transplantation (the day after transplantation) The drug was administered intravenously on day 9 and day 9.
[0023]
The antitumor effect was evaluated by determining the survival rate (ILS,%) by the following formula from the result of observing the life and death of mice for 60 days. In the following formula, T means the median survival days of the drug administration group, and C means the median survival days of the control group.
[0024]
Life extension rate = [(TC) / C] X100
Table 1 shows the survival rate of the drug administration group for mouse leukemia L1210 cells, and Table 2 shows the survival rate of the drug administration group for mouse lung cancer cell M109.
[0025]
Table 1 (mouse leukemia L1210 cells)
A component B component Life extension rate (%)
TZT-1027 (0.75mg / kg) None 62
None 5-Fluorouracil (37.5mg / kg) 54
TZT-1027 (0.75 mg / kg) 5-Fluorouracil (37.5 mg / kg) 95
None Doxorubicin (7.5mg / kg) 70
TZT-1027 (0.75mg / kg) Doxorubicin (7.5mg / kg) 98
None Irinotecan (25mg / kg) 78
TZT-1027 (0.75mg / kg) Irinotecan (25mg / kg) 121
None Cisplatin (3.75 mg / kg) 54
TZT-1027 (0.75mg / kg) Cisplatin (3.75mg / kg) 111
None Cyclophosphamide (75 mg / kg) 66
TZT-1027 (0.75mg / kg) Cyclophosphamide (75mg / kg) 96
Table 2 (mouse lung cancer cells M109)
A component B component Life extension rate (%)
TZT-1027 (0.5mg / kg) None 40
None Irinotecan (50mg / kg) 28
TZT-1027 (0.5mg / kg) Irinotecan (50mg / kg) 60
None Etoposide (30mg / kg) 24
TZT-1027 (0.5mg / kg) Etoposide (30mg / kg) 82
None Paclitaxel (40mg / kg) 65
TZT-1027 (0.5mg / kg) Paclitaxel (40mg / kg) 106
Example 1 Example A component and B component are separate preparations A component injection:

B component injection:

Dissolve sodium chloride and lactic acid in water for injection and dissolve the active ingredient in the solution.
After adjusting the pH to 4-5 with sodium hydroxide, water for injection is added to make the specified amount.
Example 2 Example in which component A and component B are simultaneously contained in one preparation Injection:

Example 3 (Example in which component A and component B are simultaneously contained in one preparation)
Sustained release injection:
TZT-1027 2 mg, cisplatin 20 mg and lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 50: 50, molecular weight about 5000; trade name “PLGA5005”, manufactured by Wako Pure Chemical Industries, Ltd.) 600 mg dissolved in 1 ml of methylene chloride Then, after emulsifying and dispersing in 150 ml of 0.5% polyvinyl alcohol aqueous solution with a small homogenizer, the mixture was stirred for about 2 hours and dried in an O / W type liquid to solidify the oil phase. The produced microspheres were collected by centrifugation, washed with purified water, redispersed in water, and lyophilized to obtain microspheres. The obtained microspheres are suspended in a suspension containing D-mannitol 50 mg / ml, sodium carboxymethylcellulose 5 mg / ml and polysorbate 80 1 mg / ml at the time of use.

Claims (2)

Formula (I)

An antitumor agent characterized by combining a compound represented by the formula: etoposide or paclitaxel. A pharmaceutical product comprising the antitumor agent according to claim 1 and a label or document describing use of the antitumor agent on the packaging material or in the packaging material.