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WO1996016658A1 - Preparation a base d'un derive d'indolocarbazol - Google Patents

Preparation a base d'un derive d'indolocarbazol Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
freeze
acceptable salt
amino acid
pharmaceutically acceptable
drying
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.)
Ceased
Application number
PCT/JP1995/002326
Other languages
English (en)
Japanese (ja)
Inventor
Toshihito Hosokawa
Kenji Iwata
Eiji Hayakawa
Kunio Ito
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KH Neochem Co Ltd
Original Assignee
Kyowa Hakko Kogyo Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co Ltd filed Critical Kyowa Hakko Kogyo Co Ltd
Priority to AU38570/95A priority Critical patent/AU3857095A/en
Publication of WO1996016658A1 publication Critical patent/WO1996016658A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une préparation lyophilisée à base d'un dérivé d'indolocarbazol, produite par lyophilisation d'une solution aqueuse contenant un dérivé d'indolocarbazol ou un sel pharmacologiquement acceptable de celui-ci et un aminoacide ou un sel pharmacologiquement acceptable de celui-ci. La préparation selon l'invention est une préparation pharmaceutique à base d'un dérivé d'indolocarbazol ou d'un sel pharmacologiquement acceptable de celui-ci, pouvant être utilisés comme médicaments, par exemple comme agents cancérostatiques. L'invention concerne également un procédé permettant de stabiliser une telle préparation.
PCT/JP1995/002326 1994-11-29 1995-11-14 Preparation a base d'un derive d'indolocarbazol Ceased WO1996016658A1 (fr)

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 (fr) 1996-06-06

Family

ID=17817459

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/002326 Ceased WO1996016658A1 (fr) 1994-11-29 1995-11-14 Preparation a base d'un derive d'indolocarbazol

Country Status (2)

Country Link
AU (1) AU3857095A (fr)
WO (1) WO1996016658A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018012660A (ja) * 2016-07-20 2018-01-25 日本化薬株式会社 ボルテゾミブを含有する医薬組成物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58146504A (ja) * 1981-12-23 1983-09-01 シエリング・コーポレーシヨン α―インターフェロン製剤およびその製造方法
WO1989007105A1 (fr) * 1988-02-04 1989-08-10 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58146504A (ja) * 1981-12-23 1983-09-01 シエリング・コーポレーシヨン α―インターフェロン製剤およびその製造方法
WO1989007105A1 (fr) * 1988-02-04 1989-08-10 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018012660A (ja) * 2016-07-20 2018-01-25 日本化薬株式会社 ボルテゾミブを含有する医薬組成物

Also Published As

Publication number Publication date
AU3857095A (en) 1996-06-19

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