WO1996016658A1 - Indolocarbazole derivative preparation - Google Patents
Indolocarbazole derivative preparation Download PDFInfo
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- WO1996016658A1 WO1996016658A1 PCT/JP1995/002326 JP9502326W WO9616658A1 WO 1996016658 A1 WO1996016658 A1 WO 1996016658A1 JP 9502326 W JP9502326 W JP 9502326W WO 9616658 A1 WO9616658 A1 WO 9616658A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- the present invention relates to a formulation useful as a pharmaceutical such as an anticancer drug of an indoleforce rubazole derivative or a pharmaceutically acceptable salt thereof, and a stabilizing method.
- UCN-01 has an indoloflurazole structure and is known to have oral tin kinase C inhibitory activity Antibiotics, 40, 1782 (1987), and antitumor activity [Cancer Res., 51, 4888] (1991)].
- International Publication WO 89/07105 discloses that UCN-01 derivatives have cell growth inhibitory activity.
- the present invention provides a compound of the formula (I)
- the present invention relates to a freeze-dried preparation of an indoloflurazole derivative, which is produced by freeze-drying an aqueous solution containing Further, the present invention provides a method for freeze-drying an aqueous solution containing an indoloflurazole derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof and an amino acid or a pharmaceutically acceptable salt thereof. The present invention relates to a method for stabilizing an indole-active rubazole derivative or a pharmaceutically acceptable salt thereof.
- lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, sec-butyl, terbutyl, pentyl, hexyl and the like. Represent.
- any of ⁇ -, ⁇ - and 7_ can be used.
- ⁇ -amino acids include aliphatic basic amino acids such as arginine, lysine, hydroxylysine, and orutin; aliphatic acidic amino acids such as glutamic acid and aspartic acid; glycine; alanine; And aliphatic neutral amino acids such as methine, threonine, cystine, cystine, methionine, proline and hydroquinine proline, and aromatic amino acids such as histidine, tributofan, tyrosine and phenylalanine.
- amino acids As 5-amino acids, yS-alanine, and as amino acids, 7-aminobutyric acid and the like.
- the amino acid is preferably a £ Z-amino acid, and more preferably an aliphatic basic amino acid or an aromatic amino acid.
- ⁇ -amino acid any of the D- and D-forms can be used.
- Pharmaceutically acceptable salts of compound (I) include inorganic salts such as hydrochloride, sulfate, phosphate, acetate, maleate, fumarate, tartrate, citrate, and lactate. And the like.
- the pharmacologically acceptable salts of amino acids include acid addition salts, metal salts, and ammonium salts.
- the acid addition salts include inorganic acid salts such as hydrochloride, sulfate, phosphate, and the like, and organic acid salts such as acetate, maleate, fumarate, tartrate, citrate, and lactate.
- the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, magnesium salt and calcium salt. Alkaline earth metal salts, aluminum salts, zinc salts and the like can be mentioned, and examples of the ammonium salts include salts such as ammonium and tetramethylammonium.
- the indolohydrazole derivative represented by the formula (I) can be produced by the method described in JP-A-62-220196 or WO 89/07105. Table 11 shows specific examples of these compounds.
- the preparation of the present invention is obtained by dissolving an indoloflurazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof and an amino acid or a pharmacologically acceptable salt thereof in water or a buffer solution; Can be produced by dispensing a certain amount of the above into ampoules, vials, etc., and freeze-drying.
- the concentration of the amino acid or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg / m1, preferably 1 to 200 mg / ml, more preferably 5 to 100 mg / m1.
- the aqueous solution is preferably adjusted so as to maintain the pH at 5 to 7.
- buffers such as citrate buffer, phosphate buffer, boric acid mouthwash, acetate buffer, etc.
- Acid Z trisodium citrate buffer or citrate / disodium phosphate buffer is used.
- the concentration of the buffer is between 0.001 and 0.5M, preferably between 0.005 and 0.05M.
- concentration of the indoloflurazole derivative or a pharmaceutically acceptable salt thereof to be subjected to lyophilization is 0.0101 to 100 mgZmI, preferably 0.1 to 2 Omg / m1.
- Freeze-drying is performed, for example, at 150 ° C for 3 hours (preliminary freezing), at 130 ° C for 24 hours at 0.05mbar (primary drying), and then at 25 ° C at 0.05mbar for 6 hours ( Secondary drying) It is performed by drying.
- a freeze-dried preparation containing an indole fulvazole derivative or a pharmacologically acceptable salt thereof can be obtained by closing the ampoule, vial, or the like of the container with a rubber stopper and an aluminum cap after completion of freeze-drying.
- the freeze-dried preparation of the present invention is used as an injection, sterile filtration using a membrane filter is performed before freeze-drying.
- the preparation of the present invention may be, depending on the purpose of its preparation, a pharmaceutically acceptable preservative, stabilizer, antioxidant, preservative, vehicle, binder, disintegrant, wetting agent, lubricant , Coloring agents, fragrances, flavoring agents, skins, suspending agents, emulsifiers, solubilizing agents, buffers, isotonic agents, plasticizers, surfactants, soothing agents, etc. is there.
- antioxidants such as ascorbic acid, vitamin E, and benzylhydroxytoluene; preservatives such as parabens and chlorbutanol; crystalline cellulose; hydroxypropyl starch; starch; corn starch; lactose; trehalose; Binders such as pullulan, polyvinyl alcohol, and hydroxypropyl cellulose; disintegrators such as carboxymethylcellulose and croscarmellose sodium A; lubricants such as magnesium stearate, talc, and hardened oil And soothing agents such as benzyl alcohol and lidocaine.
- preparations of the present invention include, in addition to injections, oral preparations such as tablets, pills, capsules, and granules, It can also be applied to dosage forms such as suppositories.
- the dose and frequency of administration vary depending on factors such as the patient's age, weight, and symptoms. Intermittent administration of ⁇ 2 OmgZkg once a day (single dose or daily dose) or once to three times a week or once every three weeks is appropriate.
- UCN-01 20 mg was dissolved in 20 ml of 0.02 M, pH 6.0 trisodium citrate noquenate buffer containing 800 mg of L-arginine 'hydrochloride. This solution was dispensed 1.0 ml each into a 4 ml glass vial, and lyophilized. After the freeze-drying was completed, the pressure was returned to normal pressure under a stream of nitrogen, sealed with a rubber stopper and an aluminum cap, and a lyophilized UCN-01 preparation was produced.
- UCN-01 20 mg were dissolved in 20 ml of a 0.02 M, pH 6.0 trisodium citrate / noquenate buffer solution containing 400 mg of L-lysine 'hydrochloride. This solution was dispensed into 4 ml glass vials in 1.0 ml increments, and lyophilized. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream, and the mixture was sealed with a rubber stopper and an aluminum cap to produce a freeze-dried UCN-01 preparation.
- UCN-01 and 20 mg were dissolved in 20 ml of a 0.02 M, pH 6.0 trisodium citrate buffer solution containing 400 mg of L-histidine hydrochloride. This solution was dispensed in 1.0 ml portions into 4 ml glass vials and lyophilized. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream, and the mixture was sealed with a rubber stopper and an aluminum cap to produce a freeze-dried UCN-01 preparation.
- UCN-01 20 mg was dissolved in 20 ml of 0.02 M, pH 6.0, citrate Z trisodium citrate buffer containing 200 mg of L-tributophan. This solution was dispensed into 4 ml glass vials in 1. Om 1 increments, and lyophilized. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream, and the mixture was sealed with a rubber stopper and an aluminum cap to produce a freeze-dried UCN-01 preparation.
- the freeze-dried preparations prepared in Examples 1 to 4 and Comparative Example were stored in 40 and / or 50 thermostats for 30 days.
- the remaining amount of UCN-01 was determined by using high performance liquid chromatography.
- the formulation useful as a pharmaceutical agent such as an anticancer drug of an indole rubazole derivative or its pharmacologically acceptable salt, and a stabilization method are provided.
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Abstract
Description
明 細 書 Specification
ィンドロ力ルバゾール誘導体製剤 Indroforce rubazole derivative preparation
技 術 分 野 Technical field
本発明は、 ィンドロ力ルバゾ一ル誘導体またはその薬理的に許容される塩の 制癌剤等の医薬品として有用な製剤および安定化法に関する。 The present invention relates to a formulation useful as a pharmaceutical such as an anticancer drug of an indoleforce rubazole derivative or a pharmaceutically acceptable salt thereof, and a stabilizing method.
背 景 技 術 Background technology
式 （I) Formula (I)
UCN-01 UCN-01
UCN— 0 1は、 インドロ力ルバゾール構造を有し、 ： 口ティンキナーゼ C 阻害活性 Antibiotics, 40, 1782(1987) 、 および抗腫瘍作用を示すことが知 られている [Cancer Res., 51, 4888(1991)] 。 また、 UCN— 0 1誘導体が 細胞生育阻害活性を有することが国際公開 WO 8 9 / 0 7 1 0 5号公報に開示 されている。 UCN-01 has an indoloflurazole structure and is known to have oral tin kinase C inhibitory activity Antibiotics, 40, 1782 (1987), and antitumor activity [Cancer Res., 51, 4888] (1991)]. International Publication WO 89/07105 discloses that UCN-01 derivatives have cell growth inhibitory activity.
発 明 の 開 示 Disclosure of the invention
本発明は、 式 （I ) The present invention provides a compound of the formula (I)
式 （ I ) の定義において、 低級アルキルは、 直鎖もしくは分枝状の炭素数 1〜 6の、 例えば、 メチル、 ェチル、 プロピル、 イソプロピル、 sec-ブチル、 terい プチル、 ペンチル、 へキシル等を表す。 In the definition of formula (I), lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, sec-butyl, terbutyl, pentyl, hexyl and the like. Represent.
アミノ酸は、 α—、 β―、 7 _いずれのものも使用可能である。 α—アミノ酸 としては、 アルギニン、 リジン、 ヒドロキシリジン、 オル二チン等の脂肪族塩基 性アミノ酸、 グルタミン酸、 ァスパラギン酸等の脂肪族酸性アミノ酸、 グリシン、 ァラニン、 ノ、'リ ン、 ロイシン、 イソロイシン、 セリ ン、 スレオニン、 システィン、 シスチン、 メチォニン、 プロリ ン、 ヒ ドロキンプロリン等の脂肪族中性アミノ酸、 ヒスチジン、 トリブトファン、 チロシン、 フヱニルァラニン等の芳香族アミノ酸 等があげられる。 ；5—アミノ酸としては yS—ァラニン、 ァーアミノ酸としては 7—ァミノ酪酸等があげられる。 アミノ酸としては、 £Z—アミノ酸が好ましく、 さらに脂肪族塩基性ァミノ酸または芳香族ァミノ酸がより好ましく使用される。 α—アミノ酸としては、 し、 D L、 D体いずれも使用可能である。 As the amino acid, any of α-, β- and 7_ can be used. Examples of α-amino acids include aliphatic basic amino acids such as arginine, lysine, hydroxylysine, and orutin; aliphatic acidic amino acids such as glutamic acid and aspartic acid; glycine; alanine; And aliphatic neutral amino acids such as methine, threonine, cystine, cystine, methionine, proline and hydroquinine proline, and aromatic amino acids such as histidine, tributofan, tyrosine and phenylalanine. As 5-amino acids, yS-alanine, and as amino acids, 7-aminobutyric acid and the like. The amino acid is preferably a £ Z-amino acid, and more preferably an aliphatic basic amino acid or an aromatic amino acid. As the α-amino acid, any of the D- and D-forms can be used.
化合物 （ I ) の薬理的に許容される塩としては、 塩酸塩、 硫酸塩、 リン酸塩等 の無機酸塩、 酢酸塩、 マレイン酸塩、 フマル酸塩、 酒石酸塩、 クェン酸塩、 乳酸 塩等の有機酸塩があげられる。 また、 アミノ酸の薬理的に許容される塩としては、 酸付加塩、 金属塩、 アンモニゥム塩等を包含する。 酸付加塩としては塩酸塩、 硫 酸塩、 リン酸塩等の無機酸塩、 酢酸塩、 マレイン酸塩、 フマル酸塩、 酒石酸塩、 クェン酸塩、 乳酸塩等の有機酸塩があげられ、 金属塩としてはリチウム塩、 ナト リウム塩、 カリウム塩等のアルカリ金属塩、 マグネシウム塩、 カルシウム塩等の アルカリ土類金属塩、 アルミニウム塩、 亜鉛塩等があげられ、 アンモニゥム塩と してはアンモニゥム、 テトラメチルアンモニゥム等の塩があげられる。 Pharmaceutically acceptable salts of compound (I) include inorganic salts such as hydrochloride, sulfate, phosphate, acetate, maleate, fumarate, tartrate, citrate, and lactate. And the like. The pharmacologically acceptable salts of amino acids include acid addition salts, metal salts, and ammonium salts. Examples of the acid addition salts include inorganic acid salts such as hydrochloride, sulfate, phosphate, and the like, and organic acid salts such as acetate, maleate, fumarate, tartrate, citrate, and lactate. Examples of the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, magnesium salt and calcium salt. Alkaline earth metal salts, aluminum salts, zinc salts and the like can be mentioned, and examples of the ammonium salts include salts such as ammonium and tetramethylammonium.
式（I)で表されるインドロ力ルバゾール誘導体は、 特開昭 62 - 220 1 96 号公報あるいは国際公開 WO 89 / 07 1 05号公報記載の方法により製造する ことができる。 それら化合物の具体例を表一 1に示す。 The indolohydrazole derivative represented by the formula (I) can be produced by the method described in JP-A-62-220196 or WO 89/07105. Table 11 shows specific examples of these compounds.
R X 分子量： MS(m/z) R X molecular weight: MS (m / z)
H 0 483(M+1)+ H 0 483 (M + 1) +
CH3 0 497(M+1)+ CH 3 0 497 (M + 1) +
し H 0 510(M)+ H 0 510 (M) +
C H s 527(M+1)+ CH s 527 (M + 1) +
i -C3H7 0 524 (M)+ n-C.H9 0 538 (M)+ i -C 3 H 7 0 524 (M) + nC.H 9 0 538 (M) +
以下に、 本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明の製剤は、 式 （ I ) で表されるインドロ力ルバゾール誘導体またはその 薬理的に許容される塩とアミノ酸またはその薬理的に許容される塩を水または緩 衡液に溶解し、 その水溶液の一定量をアンプル、 バイアル等に分注し、 凍結乾燥 することにより製造することができる。 ァミノ酸またはその薬理的に許容される塩の濃度は、 0.1〜5 0 0 mg/m 1、 好ましくは l〜2 0 0 mg/m l、 さらに好ましくは 5〜 1 0 0 mg/m 1で ある。 水溶液は、 pH 5〜7に維持できるよう調整するのが好ましく、 この目的 で、 例えばクェン酸緩衝液、 リン酸緩衝液、 ホウ酸锾銜液、 酢酸緩衝液等の緩衝 液等、 好ましくはクェン酸 Zクェン酸三ナトリウム緩衝液またはクェン酸/リン 酸ニナトリウム緩衝液等が用いられる。 緩衝液の濃度は 0.0 0 1〜0.5M、 好ま しくは 0.0 0 5〜0.0 5Mである。 凍結乾燥に供するインドロ力ルバゾール誘導 体またはその薬理的に許容される塩の濃度は、 0.0 0 1〜1 0 0mgZm I、 好ましくは 0.1〜2 Omg/m 1である。 凍結乾燥は、 例えば、 一 5 0てで 3時 間 (予備凍結） 、 一 3 0°C， 0.0 5mb a rで 2 4時間 (一次乾燥） 、 次いで 2 5 °C, 0.0 5mb a rで 6時間 （二次乾燥） 乾燥することにより行われる。 The preparation of the present invention is obtained by dissolving an indoloflurazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof and an amino acid or a pharmacologically acceptable salt thereof in water or a buffer solution; Can be produced by dispensing a certain amount of the above into ampoules, vials, etc., and freeze-drying. The concentration of the amino acid or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg / m1, preferably 1 to 200 mg / ml, more preferably 5 to 100 mg / m1. . The aqueous solution is preferably adjusted so as to maintain the pH at 5 to 7. For this purpose, for example, buffers such as citrate buffer, phosphate buffer, boric acid mouthwash, acetate buffer, etc. Acid Z trisodium citrate buffer or citrate / disodium phosphate buffer is used. The concentration of the buffer is between 0.001 and 0.5M, preferably between 0.005 and 0.05M. The concentration of the indoloflurazole derivative or a pharmaceutically acceptable salt thereof to be subjected to lyophilization is 0.0101 to 100 mgZmI, preferably 0.1 to 2 Omg / m1. Freeze-drying is performed, for example, at 150 ° C for 3 hours (preliminary freezing), at 130 ° C for 24 hours at 0.05mbar (primary drying), and then at 25 ° C at 0.05mbar for 6 hours ( Secondary drying) It is performed by drying.
ィンドロ力ルバゾール誘導体またはその薬理的に許容される塩を含有してなる 凍結乾燥製剤は、 凍結乾燥終了後、 容器のアンプル、 バイアル等をゴム栓および アルミキヤップで密封することにより得ることができる。 本発明の凍結乾燥製剤 を注射剤として使用する場合は、 凍結乾燥する前に、 メンブランフィルタ一によ る無菌濂過を行う。 A freeze-dried preparation containing an indole fulvazole derivative or a pharmacologically acceptable salt thereof can be obtained by closing the ampoule, vial, or the like of the container with a rubber stopper and an aluminum cap after completion of freeze-drying. When the freeze-dried preparation of the present invention is used as an injection, sterile filtration using a membrane filter is performed before freeze-drying.
本発明の製剤は、 その製剤化の目的に応じて、 医薬品として許容される保存剤、 安定剤、 抗酸化剤、 防腐剤、 陚形剤、 結合剤、 崩壤剤、 湿潤剤、 滑沢剤、 着色剤、 芳香剤、 矯味剤、 剤皮、 懸濁化剤、 乳化剤、 溶解補助剤、 緩衝剤、 等張化剤、 塑性剤、 界面活性剤、 無痛化剤等を含ませることが可能である。 例えば、 ァスコ ルビン酸、 ビタミ ン E、 ベンジルヒ ドロキシトルエン等の抗酸化剤、 パラベン類、 クロルブタノール等の防腐剤、 結晶セルロース、 ヒ ドロキシプロピルスターチ、 でん粉、 コーンスターチ、 乳糖、 トレハロース等の陚形剤、 プルラン、 ポリ ビニ ルアルコール、 ヒ ドロキシプロピルセルロース等の結合剤、 カルボキシメチルセ ルロース、 クロスカルメロースナトリウム A型等の崩壊剤、 ステアリ ン酸マグネ シゥム、 タルク、 硬化油等の滑沢剤、 あるいはベンジルアルコール、 リ ドカイン 等の無痛化剤等があげられる。 The preparation of the present invention may be, depending on the purpose of its preparation, a pharmaceutically acceptable preservative, stabilizer, antioxidant, preservative, vehicle, binder, disintegrant, wetting agent, lubricant , Coloring agents, fragrances, flavoring agents, skins, suspending agents, emulsifiers, solubilizing agents, buffers, isotonic agents, plasticizers, surfactants, soothing agents, etc. is there. For example, antioxidants such as ascorbic acid, vitamin E, and benzylhydroxytoluene; preservatives such as parabens and chlorbutanol; crystalline cellulose; hydroxypropyl starch; starch; corn starch; lactose; trehalose; Binders such as pullulan, polyvinyl alcohol, and hydroxypropyl cellulose; disintegrators such as carboxymethylcellulose and croscarmellose sodium A; lubricants such as magnesium stearate, talc, and hardened oil And soothing agents such as benzyl alcohol and lidocaine.
本発明の製剤は、 注射剤の他に、 錠剤、 丸剤、 カプセル剤、 顆粒剤等の経口剤、 坐剤等の剤型にも適用できる。 The preparations of the present invention include, in addition to injections, oral preparations such as tablets, pills, capsules, and granules, It can also be applied to dosage forms such as suppositories.
本発明の製剤を例えば抗腫瘍剤として用いる場合、 その投与量および投与回数 は、 患者の年齢、 体重、 症状等の要因により異なるが、 例えば、 注射剤として用 いる場合、 通常、 0. 0 1〜2 OmgZk gで、 1日 1回 （単回投与または連日 投与） または週に 1〜3回、 3週間に 1回等の間欠投与が適当である。 When the formulation of the present invention is used, for example, as an antitumor agent, the dose and frequency of administration vary depending on factors such as the patient's age, weight, and symptoms. Intermittent administration of ~ 2 OmgZkg once a day (single dose or daily dose) or once to three times a week or once every three weeks is appropriate.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
以下に、 本発明の実施例、 比較例および試験例を示す。 Hereinafter, examples, comparative examples, and test examples of the present invention will be described.
実施例 1 Example 1
UCN- 0 1 , 20mgを、 L—アルギニン '塩酸塩 800 m gを含有する 0.0 2 M, pH 6.0のクェン酸ノクェン酸三ナトリウム緩衝液 2 0mlに溶解し た。 この溶液を 1.0m lずつ 4m lガラスバイアルに分注した後、 凍結乾燥を行 つた。 凍結乾燥終了後、 窒素気流下常圧に戻し、 ゴム栓とアルミキャップにより 密封し、 UCN—0 1凍結乾燥製剤を製造した。 20 mg of UCN-01 was dissolved in 20 ml of 0.02 M, pH 6.0 trisodium citrate noquenate buffer containing 800 mg of L-arginine 'hydrochloride. This solution was dispensed 1.0 ml each into a 4 ml glass vial, and lyophilized. After the freeze-drying was completed, the pressure was returned to normal pressure under a stream of nitrogen, sealed with a rubber stopper and an aluminum cap, and a lyophilized UCN-01 preparation was produced.
実施例 2 Example 2
UCN- 0 1 , 2 0mgを、 L—リジン '塩酸塩 4 0 0 m gを含有する 0.02 M, p H 6.0のクェン酸ノクェン酸三ナトリウム緩衝液 2 0 m 1に溶解した。 この溶液を 1. 0 m 1ずつ 4 m 1ガラスバイアルに分注した後、 凍結乾燥を行つ た。 凍結乾燥終了後、 窒素気流下常圧に戻し、 ゴム栓とアルミキャップにより密 封し、 UCN—0 1凍結乾燥製剤を製造した。 20 mg of UCN-01 were dissolved in 20 ml of a 0.02 M, pH 6.0 trisodium citrate / noquenate buffer solution containing 400 mg of L-lysine 'hydrochloride. This solution was dispensed into 4 ml glass vials in 1.0 ml increments, and lyophilized. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream, and the mixture was sealed with a rubber stopper and an aluminum cap to produce a freeze-dried UCN-01 preparation.
実施例 3 Example 3
UCN- 0 1 , 2 0mgを、 L—ヒスチジン ·塩酸塩 4 00 mgを含有する 0.0 2 M, p H 6.0のクェン酸 クェン酸三ナ卜リウム緩衝液 2 0m lに溶解 した。 この溶液を 1.0 m 1ずつ 4 m 1ガラスバイアルに分注した後、 凍結乾燥を 行った。 凍結乾燥終了後、 窒素気流下常圧に戻し、 ゴム栓とアルミキャップに より密封し、 UCN— 0 1凍結乾燥製剤を製造した。 UCN-01 and 20 mg were dissolved in 20 ml of a 0.02 M, pH 6.0 trisodium citrate buffer solution containing 400 mg of L-histidine hydrochloride. This solution was dispensed in 1.0 ml portions into 4 ml glass vials and lyophilized. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream, and the mixture was sealed with a rubber stopper and an aluminum cap to produce a freeze-dried UCN-01 preparation.
実施例 4 Example 4
UCN- 0 1 , 20mgを、 L—トリブトファン 2 0 0 m gを含有する 0.0 2 M, p H 6.0のクェン酸 Zクェン酸三ナトリウム緩衝液 2 0 m 1に溶解した。 この溶液を 1. Om 1ずつ 4 m 1ガラスバイアルに分注した後、 凍結乾燥を行った。 凍結乾燥終了後、 窒素気流下常圧に戻し、 ゴム栓とアルミキャップにより密封し、 UCN- 0 1凍結乾燥製剤を製造した。 20 mg of UCN-01 was dissolved in 20 ml of 0.02 M, pH 6.0, citrate Z trisodium citrate buffer containing 200 mg of L-tributophan. This solution was dispensed into 4 ml glass vials in 1. Om 1 increments, and lyophilized. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream, and the mixture was sealed with a rubber stopper and an aluminum cap to produce a freeze-dried UCN-01 preparation.
比較例 Comparative example
UCN— 0 1, 2 0mgを、 0.0 2M， p H 6.0のクェン酸 Zクェン酸三ナト リウム緩衝液 2 Om lに溶解した。 この溶液を 1.0 m lずつ 4 m lガラスバイァ ルに分注した後、 凍結乾燥を行った。 凍桔乾燥終了後、 窒素気流下常圧に戻し、 ゴム栓とアルミキャップにより密封し、 UCN— 0 1凍結乾燥製剤を製造した。 試験例 UCN—0.10 mg was dissolved in 2 Oml of 0.02 M, pH 6.0, citrate Z sodium citrate buffer. This solution was dispensed in 1.0 ml portions into 4 ml glass vials and freeze-dried. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream, and the mixture was sealed with a rubber stopper and an aluminum cap to produce a freeze-dried UCN-01 preparation. Test example
実施例 1〜 4および比較例で調製した凍結乾燥製剤を 4 0 および または 5 0 の恒温槽に 3 0日間保存した。 UCN— 0 1の残存量を高速液体クロマト グラフィーを用いて求めた。 The freeze-dried preparations prepared in Examples 1 to 4 and Comparative Example were stored in 40 and / or 50 thermostats for 30 days. The remaining amount of UCN-01 was determined by using high performance liquid chromatography.
高速液体クロマトグラフィー分析条件 High-performance liquid chromatography analysis conditions
カラム： カプセルパック PAK C 1 8 UG 1 2 0 S— 5 4.6 x 2 5 0 mm 移動相： 2 OmMトリス（ヒ ドロキシメチル）ァミノメタン一塩酸緩銜液 （pH 9.0) ノアセトニトリル/テトラヒ ドロフラン （6 0 ： 2 2 ： 1 8、 v/v/v) 流速： 0.8 m 1 Z分 Column: Capsule pack PAK C 18 UG 12 20 S— 5 4.6 x 250 mm Mobile phase: 2 OmM tris (hydroxymethyl) aminoaminohydrochloride monohydrochloride (pH 9.0) Noacetonitrile / tetrahydrofuran (60: 22:18, v / v / v) Velocity: 0.8 m 1 Z min
検出波長： 2 8 5 nm Detection wavelength: 285 nm
結果を表— 2に示す。 表一 2より、 UCN— 0 1は、 アミノ酸またはその塩を 含む凍結乾燥製剤とすることにより、 保存安定性が大幅に向上することが明らか となった。 The results are shown in Table-2. From Table 1, it was revealed that storage stability of UCN-101 was significantly improved by using a lyophilized preparation containing an amino acid or a salt thereof.
表— 2 : UCN— 0 1の保存安定性 Table 2: Storage stability of UCN-01
UCN- 0 1の残存率 （％) Residual rate of UCN-01 (%)
例番号 アミノ酸※ 4 0°C 5 0°C Example number Amino acid * 40 ° C 50 ° C
実施例 1 Arg- HC1 1 0 0. 1 1 0 0. 0 Example 1 Arg-HC1 1 0 0 .1 1 0 0 .0
実施例 2 Lys · HCl 9 8. 9 9 6. 3 Example 2 LysHCl 9 8.99.6.3
実施例 3 His · HCl 1 0 0. 4 9 9. 7 Example 3 HisHCl 100.0.4 99.7
実施例 4 Trp 9 9. 8 9 7. 7 Example 4 Trp 9 9.8 9.7
比較例 なし 9 0， 3 Comparative example None 9 0, 3
· Arg · HCl L一アルギニン ·塩酸塩 · Arg · HCl L-arginine · Hydrochloride
Lys · HCl L一リ ジン ·塩酸塩 Lys · HCl L monolysine · hydrochloride
His · HCl L—ヒスチジン ·塩酸塩 His · HCl L-histidine · hydrochloride
Trp L—トリブトファン Trp L—Tributane
産業上の利用可能性 Industrial applicability
本発明により、 ィンドロ力ルバゾール誘導体またはその薬理的に許容される塩 の制癌剤等の医薬品として有用な製剤および安定化法が提供される。 ADVANTAGE OF THE INVENTION According to this invention, the formulation useful as a pharmaceutical agent, such as an anticancer drug of an indole rubazole derivative or its pharmacologically acceptable salt, and a stabilization method are provided.
Claims
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU38570/95A AU3857095A (en) | 1994-11-29 | 1995-11-14 | Indolocarbazole derivative preparation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29519794 | 1994-11-29 | ||
| JP6/295197 | 1994-11-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996016658A1 true WO1996016658A1 (en) | 1996-06-06 |
Family
ID=17817459
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1995/002326 Ceased WO1996016658A1 (en) | 1994-11-29 | 1995-11-14 | Indolocarbazole derivative preparation |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU3857095A (en) |
| WO (1) | WO1996016658A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018012660A (en) * | 2016-07-20 | 2018-01-25 | 日本化薬株式会社 | Pharmaceutical composition containing bortezomib |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58146504A (en) * | 1981-12-23 | 1983-09-01 | シエリング・コーポレーシヨン | Interferon medicine and manufacture |
| WO1989007105A1 (en) * | 1988-02-04 | 1989-08-10 | Kyowa Hakko Kogyo Co., Ltd. | Staurosporin derivatives |
-
1995
- 1995-11-14 WO PCT/JP1995/002326 patent/WO1996016658A1/en not_active Ceased
- 1995-11-14 AU AU38570/95A patent/AU3857095A/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58146504A (en) * | 1981-12-23 | 1983-09-01 | シエリング・コーポレーシヨン | Interferon medicine and manufacture |
| WO1989007105A1 (en) * | 1988-02-04 | 1989-08-10 | Kyowa Hakko Kogyo Co., Ltd. | Staurosporin derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018012660A (en) * | 2016-07-20 | 2018-01-25 | 日本化薬株式会社 | Pharmaceutical composition containing bortezomib |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3857095A (en) | 1996-06-19 |
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