JPH0733666A - Method of stabilizing indolocarbazole derivative - Google Patents

Abstract

PURPOSE:To further stabilize an indolocarbazole useful as an antitumor agent, having excellent long-term storage stability by lyophilizing a solution containing a specific indolocarbazole derivative and a saccharide, having a specific pH range. CONSTITUTION:A solution containing an indolocarbazole derivative (concentration is preferably 0.1-20mg/ml) of the formula (R is H or lower alkyl) and a saccharide such as lactose (concentration is preferably 1-500mg/ml), having pH5-7, is lyophilized to stabilize the indolocarbazole derivative. The dose of the lyophilized agent is preferably 0.01-20mg/kg weight daily in the case of injection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method and a method for stabilizing indolocarbazole derivatives.

[0002]

[Prior art]

[0003]

[Chemical 2]

UCN-01 has a protein kinase C inhibitory activity [Biochem. Biophys. Res. Commun., 135, 3
97 (1986)], which is known to have an antitumor effect [Ca
ncerRes., 51, 4888 (1991)]. Further, WO89 / 07 shows that the UCN-01 derivative has a cell growth inhibitory activity.
No. 105 publication.

[0005]

UCN-01 and its derivatives are easily decomposed in an aqueous solution, for example, UCN-0.
1 is most stable at around pH 6 in an aqueous solution, but it is not always sufficient considering the long-term storage stability as a drug. A long-term storable and stable formulation containing UCN-01 and its derivatives is desired.

[0006]

The present invention provides a compound of formula (I)

[0007]

[Chemical 3]

Stabilization of the indolocarbazole derivative, characterized in that a solution containing an indolocarbazole derivative represented by the formula (wherein R represents hydrogen or lower alkyl) and a saccharide and having a pH of 5 to 7 is freeze-dried. Concerning the law. Furthermore, the present invention can provide a freeze-dried preparation containing the indolocarbazole derivative stabilized by the above method.

In the definition of formula (I), lower alkyl is a straight-chain or branched C1-C6, for example methyl, ethyl, propyl, isopropyl, sec-butyl,
It means tert-butyl, pentyl, hexyl and the like. The indolocarbazole derivative represented by the formula (I) is disclosed in JP-A-62-220196 or WO89 / 071.
It can be produced by the method described in Japanese Patent Publication No. 05. The present invention will be described in detail below. The indolocarbazole derivative represented by the formula (I) and the saccharide were treated at pH 5
Dissolve in the solution prepared between 1 and 7 and freeze-dry it.

As the saccharide, lactose, sucrose, raffinose, etc., preferably lactose, are used. The sugar concentration is
0.005-1000 mg / ml, preferably 1-50
It is 0 mg / ml. The solution may be one that can maintain the pH at 5 to 7, and examples thereof include a citric acid / disodium phosphate buffer solution, a phosphate buffer solution, a borate buffer solution, an acetate buffer solution, and a citrate buffer solution. A buffer solution or the like is used.
The concentration of the buffer solution is 0.001-0.5M, preferably 0.005-0.05M. The concentration of the indolocarbazole derivative used for freeze-drying is 0.001 to 100.
It is 0 mg / ml, preferably 0.1 to 20 mg / ml. Freeze-drying is, for example, drying at -50 ° C for 3 hours (preliminary drying), at -40 ° C and 0.05 mbar for 24 hours (primary drying), and then at 25 ° C and 0.05 mbar for 6 hours (secondary drying). Done by.

If desired, a freeze-dried preparation containing an indolocarbazole derivative can be obtained by sealing 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, aseptic filtration with a membrane filter is performed before freeze-drying. The preparation of the present invention has a pharmaceutically acceptable preservative, stabilizer, and
Antioxidants, antiseptics, excipients, binders, disintegrants, wetting agents,
Include lubricants, colorants, fragrances, flavoring agents, skins, suspending agents, emulsifiers, solubilizers, buffers, isotonic agents, plasticizers, surfactants, soothing agents, etc. Is possible. For example, ascorbic acid, vitamin E, antioxidants such as benzylhydroxytoluene, parabens, preservatives such as chlorbutanol, crystalline cellulose, hydroxypropyl starch, starch, excipients such as corn starch, pullulan,
Binders such as polyvinyl alcohol and hydroxypropyl cellulose, disintegrants such as carboxymethyl cellulose and croscarmellose sodium A type, lubricants such as magnesium stearate, talc and hardened oil, or soothing agents such as benzyl alcohol and lidocaine. Can be given.

The preparation of the present invention can be applied not only to injections but also to oral dosage forms such as tablets, pills, capsules and granules, and suppositories. When the preparation of the present invention is used as, for example, an antitumor agent, the dose and frequency of administration vary depending on factors such as the age, body weight, and symptoms of the patient, but when used as an injection, for example, it is usually 0.01 to 20 mg. 1 / kg
Once daily (single dose or daily administration) or 1 to 3 per week
Intermittent administration, such as once every three weeks, is suitable.

The following are examples of the present invention, comparative examples and test examples.

[0014]

【Example】

Example 1 UCN-01, 20 mg and lactose 200 mg were added to 0.0
It was dissolved in 20 ml of 2M pH 6.0 citric acid / disodium phosphate buffer. 4m each of this solution 0.5ml
After dispensing into 1 glass vial, freeze-drying was performed. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream and sealed with a rubber stopper and an aluminum cap to produce a UCN-01 freeze-dried preparation.

Example 2 UCN-01 (20 mg) and lactose 400 mg (0.0 mg)
It was dissolved in 20 ml of 2M pH 6.0 citric acid / disodium phosphate buffer. 4m each of this solution 0.5ml
After dispensing into 1 glass vial, freeze-drying was performed. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream and sealed with a rubber stopper and an aluminum cap to produce a UCN-01 freeze-dried preparation.

Example 3 UCN-01 (20 mg) and lactose (1000 mg) were added to 0.
It was dissolved in 20 ml of a citric acid / disodium phosphate buffer of 02M, pH 6.0. 0.5 ml of this solution 4
After dispensing into a ml glass vial, lyophilization was performed.
After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream and sealed with a rubber stopper and an aluminum cap to produce a UCN-01 freeze-dried preparation.

Comparative Example 20 mg of UCN-01 was dissolved in 20 ml of 0.02 M citric acid / disodium phosphate buffer having a pH of 6.0. After 0.5 ml of this solution was dispensed into 4 ml glass vials, freeze-drying was performed. After the freeze-drying was completed, the pressure was returned to normal pressure under a nitrogen stream and sealed with a rubber stopper and an aluminum cap to produce a UCN-01 freeze-dried preparation.

Test Example Three freeze-dried preparations prepared in Examples 1 to 3 and Comparative Example were prepared.
It was stored in a constant temperature bath of 0 to 40 ° C. for 30 days. UCN-01
The residual amount was analyzed by high performance liquid chromatography. High-performance liquid chromatography analysis condition column: Capsule pack PAK C18 AG120
S-5 4.6 × 250 mm Mobile phase: 0.05 M, p containing 0.3% triethylamine
H7 phosphate buffer / acetonitrile / tetrahydrofuran (65 parts by volume / 20 parts by volume / 15 parts by volume) Flow rate: 1.0 ml / min Detection wavelength: 285 nm The results are shown in Table 1.

[0019]

[Table 1]

[0020]

INDUSTRIAL APPLICABILITY The present invention provides a method for stabilizing an indolocarbazole derivative, and a freeze-dried preparation containing the indolocarbazole derivative stabilized by the method.

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Claims (2)

[Claims] 1. Formula (I): P containing an indolocarbazole derivative represented by the formula (wherein R represents hydrogen or lower alkyl) and a saccharide.
A method for stabilizing an indolocarbazole derivative, which comprises freeze-drying a solution of H5 to H7. 2. A freeze-dried preparation containing an indolocarbazole derivative stabilized by the method according to claim 1.