JP3323306B2 - Elcatonin aqueous solution stabilizer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a stabilizer for an aqueous solution of elcatonin.

[0002]

2. Description of the Related Art Elcatonin has a chemical name of 1-butyl-7-.
(L-2-aminobutyric acid) -26-L-aspartic acid-27-L-valine-29-L-alanine calcitonin (salmon) [1-butyric acid-7- (L-2-aminob
utyric acid) -26-L-aspartic acid -27-L
-Valine-29-L-alaninecalcitonin (salmon)]
It is a kind of calcitonin used for hypercalcemia, Paget disease of bone or osteoporosis. At present, elcatonin is used as an aqueous solution for injection. However, like other calcitonins, when a peptide drug such as elcatonin is used as an aqueous solution, heat stability (long-term storage stability), light stability, In addition, it is necessary to formulate the preparation sufficiently considering the stability against shaking during transportation and the like. Conventionally, in the preparation of an aqueous solution of elcatonin, strict selection has been made with respect to the pH of the solution, the type of buffer used, and the ionic strength, and strict selection has also been made regarding the physical properties of the glass container such as an ampule used. Was needed.

[0003]

As described above, aqueous solutions of peptidic drugs such as elcatonin are extremely delicate, and effective stabilizers thereof have been long sought.

[0004]

Means for Solving the Problems The inventors of the present invention have screened a large number of substances for an elcatonin stabilizer in the form of an aqueous solution. In some of the compounds, it was found that an extremely small amount of the compound had a stabilizing effect on elcatonin, and the present invention was reached. That is, the present invention relates to the following formulas A to D

[0005]

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[0006]

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A stabilizer for an aqueous solution of elcatonin comprising at least two of the following peptides as active ingredients: The stabilizer for the injectable aqueous solution of elcatonin of the present invention can be produced by a known method for peptide synthesis. (1) In the case of production by a liquid phase method For example, the carboxyl group of the C-terminal proline group is converted to an amide group, and the individual unprotected or preferably protected amino acids are represented by the formulas A to D in the order of amino acids. The amino acid and / or lower peptide is condensed and subjected to a cyclization reaction in any process, and the condensation reaction is performed. It is obtained by doing.

[0008] The condensation reaction and the cyclization reaction are carried out by repeating the deprotection and deprotection of the protecting group and the condensation reaction in accordance with ordinary methods for peptide synthesis. That is, various protecting groups used in the production of the present compound can be easily removed by known means such as hydrolysis, acid decomposition, reduction, aminolysis, hydrazinolysis and the like in peptide synthesis. Possible protecting groups are used. Such protecting groups are described in the literature of peptide synthetic chemistry as well as in reference books. In the present invention, for example, α-
A t-butyloxycarbonyl group, a benzyloxycarbonyl group or a p-methoxybenzyloxycarbonyl group is used for protecting the amino group, and the amino group in the side chain, that is, ε of lysine is used.
A benzyloxycarbonyl group, p-
Using a chlorobenzyloxycarbonyl group, a methyl ester group and a benzyl ester group for protecting the α-carboxyl group, and a benzyl ester group for protecting the side chain carboxyl group, that is, the carboxyl group of the side chain of aspartic acid or glutamic acid. A cyclohexyl ester group is used, a t-butyl ester group is used to protect the carboxyl group on the side chain of α-aminosuberic acid, a benzyl group is used to protect the hydroxyl groups of serine and threonine, and 2,6 is used to protect the hydroxyl group of tyrosine. It is preferable to use a dichlorobenzyl group and a mesitylene-2-sulfonyl group or a tosyl group for protecting the guanidino group of arginine.

In the synthesis of the present compounds, the condensation of individual amino acids and / or lower peptides can be carried out, for example, by combining an amino acid or a lower peptide having a protected α-amino group and an activated terminal α-carboxyl group with a free α-amino group. And an amino acid or a lower peptide having a protected terminal carboxyl group, or an activated α
-It can be carried out by reacting an amino acid or a lower peptide having an amino group and a protected terminal carboxyl group with an amino acid or a lower peptide having a free terminal carboxyl group.

In this case, the carboxyl group can be converted to an active azide, an acid anhydride, an acid imidazolide or an active ester such as a cyanomethyl ester, a p-nitrophenyl ester, an N-hydroxysuccinimide ester or the like. Can be changed. Also, carbodiimides such as N, N'-dicyclohexyl-carbodiimide (DCC), N-ethyl-N'-3
-Dimethylaminopropyl-carbodiimide, N, N '
Activated by reacting with a condensing agent such as -carbonyl-diimidazole.

The preferred condensation method and cyclization reaction in the present invention are an azide method, an active ester method, a mixed acid anhydride method and a carbodiimide method. In each stage of the condensation, it is desirable to use a method in which racemization does not occur or a method in which racemization is minimized. Preferably, an azide method, an active ester method, a Wunsch method [Z. Naturforsc
h. , 21b, 426 (1966)] or Geige
r method (Chem. Ber., 10., 788 (197)
0)].

The cyclization reaction can be performed in the same manner as the above-mentioned condensation reaction. The condensation order and the cyclization position can be synthesized at any position as long as it is the amino acid order shown in the formula. However, the amino acid and / or lower peptide are sequentially linked from the C-terminal side, and the ω of aminosuberic acid can be synthesized. It is preferred that the bond between the carboxyl terminus and the predetermined N-terminal amino acid be the cyclization position.

A peptide having an ε-amino group, a side chain carboxyl group, a guanidino group and a hydroxyl group thus protected is obtained. These protecting groups are preferably acid-decomposed, such as trifluoromethanesulfonic acid, hydrogen fluoride anhydride and the like. In one step by the method according to the above method to obtain the desired compound. (2) In the case of production by the solid phase method In the present invention, in addition to the peptide synthesis method by the liquid phase method described above, the present compound may be synthesized by using a part or all of the peptide synthesis method by the solid phase method. it can.

For example, a C-terminal peptide fragment is synthesized by a solid phase method, a cyclic peptide fragment containing N-terminal α-aminosuberic acid is synthesized by a liquid phase method, and then the above two peptide fragments are synthesized by a solid phase method. To obtain a protected peptide resin obtained by condensation. These protecting groups and resin are eliminated in a single step by a known method, for example, a method using trifluoromethanesulfonic acid, hydrogen fluoride or the like, to obtain a target compound.

The resins used in the above solid phase method include:
Resins usually used in the solid-phase method include, for example, benzhydrylamine resin, p-methylbenzhydrylamine resin and the like. As this resin, a resin having desired properties depending on a difference in functional group equivalent or a degree of crosslinking can be obtained, and a commercially available resin can also be purchased. In the above solid phase method,
The resin is condensed one by one from the C-terminal amino acid in the order of the amino acid shown by the formula. The functional group of the amino acid is protected with a protecting group by a known method. Examples of the above protecting groups are as described above.

In the above solid phase reaction, the resin is put into a reactor, and a solvent for swelling the resin, such as dichloromethane, chloroform, dimethylformamide or benzene, is added to the resin 1.
The solvent is added at a ratio of 2 to 20 ml per g. To this, in a separate reactor, add 1 equivalent to 1 equivalent of amino group in the resin.
-6 equivalents of Boc (t-butyloxycarbonyl) amino acid is reacted with DCC, and the resulting symmetrical anhydride is separated from by-product dicyclohexylurea (DCU) and added to the reactor containing the resin. The amount of the condensing agent (DCC) used is 0.5 to 3 equivalents to 1 equivalent of the Boc-amino acid. The reaction is usually performed for 5 to 60 minutes.

A part of the Boc-amino acid-resin or Boc-peptide-resin obtained in each step may be collected, and the amount of the reacted Boc-amino acid may be determined according to a conventional method. Next, Boc, which is a protecting group for the α-amino group, may be eliminated with an acid such as trifluoroacetic acid, and a condensation reaction may be sequentially performed. The peptide synthesis by the above solid phase method uses an automatic solid phase synthesizer, but may be performed by a manual method. It is desirable that all of these operations be performed under a stream of nitrogen gas.

In this manner, a resin to which the peptide is bound is obtained. As described above, in the thus obtained protected peptide-bonded resin, the protective group and the resin are eliminated in one step by anhydrous hydrogen fluoride or the like. (3) Separation and Purification and Others The compound thus obtained can be separated and purified by a known means for purifying a peptide or protein. For example, a gel filtration method using a gel filtration agent such as Sephadex G-25, Sephadex G-50, and Sephadex LH-20, column chromatography using carboxymethylcellulose and other ion exchange resins, and a reversed-phase synthetic polymer It can be carried out by column chromatography or high performance liquid chromatography using a resin or a chemically modified silica gel carrier.

The novel compounds of the present invention can be obtained in the form of a base or a salt thereof depending on the conditions of the method. For example, a salt with a known organic acid such as acetic acid can be formed. still,
Abbreviations described herein have the following meanings. Asu: L-α-aminosuberic acid Asn: L-asparagine Asp: L-aspartic acid Ala: L-alanine Thr: L-threonine Val: L-valine His: L-histidine Arg: L-arginine Leu: L-leucine Tyr: L-tyrosine Ser: L-serine Gly: glycine Lys: L-lysine Pro: L-proline Glu: L-glutamic acid Gln: L-glutamine D-Ser: D-serine His (1-Me): L-1 -Methylhistidine Boc-: t-butyloxycarbonyl Z-: carbobenzoxy Cl-Z: p-chlorobenzyloxycarbonyl Cl2 Bzl: 2,6-dichlorobenzyl Bzl: benzyl OBzl: benzyl ester OSu: N-hydroxysuccinic acid Imidoester Tos: Tosyl TFA : Trifluoroacetic acid ether: diethyl ether DMF: N, N'-dimethylformamide MeOH: methanol DCM: dichloromethane DIEA: diisopropylethylamine HOBt: 1-hydroxybenzotriazole MBHA resin: p-methylbenzhydrylamine resin WSCD.HCl: 1- Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride At least two or more of the elcatonin stabilizers obtained by synthesis and purification in this manner are mixed in advance with the bulk elcatonin powder, and then the aqueous elcatonin solution is added. An agent is prepared, or dissolved in an aqueous solution of elcatonin, or a solution of an elcatonin stabilizer previously dissolved separately is added to an aqueous solution of elcatonin and used. The effective amount is usually 0.1 to the weight of elcatonin.
It is 5 to 15% by weight, more preferably 1 to 5% by weight.

The aqueous solution of elcatonin is not particularly limited as long as it is commonly used. Examples thereof include physiological saline and various buffers. Examples of the buffer include, for example, citric acid, acetic acid and the like and their water-soluble salts. Is exemplified. Usually, their concentration is preferably about 0.05 to 20 mM.
Is preferably 5 to 7 as a preferred example. Non-toxic strong electrolyte inorganic salts such as sodium chloride and potassium chloride may be added to this liquid as an osmotic pressure adjusting agent. The active ingredient, elcatonin, depends on the indication and usage, but is usually 1 to 40 micrograms per container, and the concentration is usually an aqueous solution in which 1 ml of these are dissolved.

The aqueous solution of elcatonin for injection containing the above-mentioned elcatonin stabilizer can be filled into a pharmaceutical glass container such as an ampoule or a vial or a plastic container to give an aqueous solution injection by a conventional method. In particular, an injection having excellent shaking stability can be obtained.

[0022]

EXAMPLES The present invention will be specifically described below with reference to production examples and examples, but the present invention is not limited to these. In the amino acid analysis in each example, 6N hydrochloric acid was added to the sample, hydrolyzed at 110 ° C. for 24 hours, and dried under reduced pressure, followed by analysis with an amino acid analyzer. Also,
The conditions of high performance liquid chromatography indicated by physical property values are as follows:
It is as follows. (High performance liquid chromatography conditions) Column: ODS column Inner diameter 4 mm, length 150 mm Eluent: Gradient A solution: 0.1% TFA water B solution: Acetonitrile Linear concentration from initial solution B concentration 15% to solution B concentration 45% Gradient elution (30 minutes) Flow rate 1 ml / min Detection wavelength 225 nm

[0023]

[Production Example 1]

[0024]

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Preparation of compound represented by formula A (hereinafter sometimes abbreviated as F01 compound) (1)

[0026]

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The title compound was prepared in Example 2 of JP-B-53-41677.
It was manufactured according to the methods (1) to (14). That is, instead of Boc-Ser (Bzl) -OSu used at a site different from
cD-Ser (Bzl) -OSu was used. (2)

[0028]

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Production of Applied Biosystems 430-A as a solid phase synthesizer
Solid phase synthesis was performed using a peptide synthesizer. M
BHA resin (Applied Biosystems, amino group 0.61m
0.8 mol (g / mol) in a reaction vessel for peptide solid phase synthesis, 8 ml of DCM (4 times, 1 minute each), 8 ml of a DCM solution containing 60% TFA (20 minutes), 4 ml of DCM (3 times, 15 seconds each), 3 ml of DMF solution containing 1 ml of DIEA (2
Each time, 1 minute each) and 8 ml of DMF (six times, 40 seconds each) in the order of stirring in a stream of nitrogen gas, followed by filtration after each treatment.

On the other hand, 2 mmol of Boc-Pro was dissolved in 5 ml of DCM, and DCC (0.5 M-D
(CM solution) 2 ml was added and reacted for 5 minutes. The reaction solution was filtered and transferred to a concentration vessel, to which 3 ml of DMF was added.
DCM was distilled off under a stream of nitrogen gas. DMF 3ml
Was added and transferred to the above-mentioned reaction vessel and reacted for 25 minutes. Then, it was washed with 8 ml of DCM (6 times, 20 seconds each) and filtered to obtain Boc-Pro-MBHA resin.

Next, the Boc-Pro-MBHA resin was washed in a reaction vessel with 8 ml of DCM (four times, 1 minute each, filtered). To this, 8 ml of a DCM solution containing 60% TFA was added, and the mixture was stirred for 20 minutes. Boc was desorbed, and the obtained resin was subjected to DCM 4m.
1 (3 times, 15 seconds each), 3 ml of DMF solution containing 1 ml of DIEA (2 times, 1 minute each), 8 ml of DMF (6 times, 40 minutes each)
Second) and filtered.

Further, 2 mmol of BocThr (Bzl) was added to DCM5
in an amino acid activation vessel.
(M-DCM solution) 2 ml was added and reacted for 5 minutes. Next, the same treatment as in the case of Boc-Pro was performed, DMF was added, and the mixture was concentrated under a nitrogen gas stream, and then transferred to a reaction vessel and reacted for 20 minutes. Then 8 ml of DCM (6 times, 20 times each
Second) and filtered to obtain Boc-Thr (Bzl) -Pro-MBHA resin.

In the following, according to the sequence of the target substance in the order from the C-terminal to the N-terminal, the corresponding protected amino acids are sequentially coupled and the last protected amino acid is bound, and then the N-terminal Boc group is deprotected. Treatment and subsequent cleaning,
2.2 g of the desired product was obtained. In the solid phase synthesis, Ar
g, Gln, 2 mmol of the corresponding protected amino acid is added to DMF-DCM (3: 1) mixed solvent 4 ml
After adding 2 ml of CC solution and 2 ml of HOBt solution (0.5 M-DMF solution) and reacting for 1 minute, the same treatment as other amino acids is performed, transferred to a reaction vessel and subjected to coupling reaction, washed with DCM, filtered, and then again. DCM in 4 ml of DMF-DCM (3: 1) mixed solvent
Solution 2ml, HOBt solution (0.5M-DMF) 2ml
Was added, and the mixture was reacted for 25 minutes, and transferred to a reaction vessel for coupling, that is, a so-called double coupling method. The amino acids used in the solid phase method and in the production examples are as follows.

[0034]

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(3) Bonding of the compound obtained in the above (1) and the compound obtained in the above (2)

[0036]

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Production of 700 mg of the compound obtained in the above (1) was mixed with 4 ml of DMF and N
Methylpyrrolidone is dissolved in a mixed solvent of 2 ml.
1.89 g of the compound obtained in the above (2) was added, and HOBt was added.
0.135 g, and cooled to -15 ° C.
0.192 g of HCl was added and stirred overnight. After completion of the reaction, the mixture was filtered by suction, and 5 ml of DMF and 5 ml of N-methylpyrrolidone 5
mixed solvent 10 ml, DMF 10 ml, DCM 10
ml, and dried under reduced pressure.
I got (4) Production of F01 compound 1.0 g of the compound obtained in the above (3) was transferred to an HF reactor (manufactured by Peptide Research Laboratories), and 2 ml of anisole was added.
, And 20 ml of anhydrous hydrogen fluoride was added thereto.
For 1 hour. After the reaction, anhydrous hydrogen fluoride was distilled off under reduced pressure, and the residue was washed with ether.
0 ml was added to extract the peptide. Extract is Dowe
x 1 × 2 column (2.6 × 15 cm).
It was eluted with 60 ml of 1M acetic acid and freeze-dried. This was purified by reversed-phase high performance liquid chromatography, and gel-filtered with 0.1 M aqueous acetic acid using Sephadex G-25 resin to obtain 4.8 mg. Physical properties Amino acid analysis values Asp 2.02 (2), Thr 3.76 (4), Ser 2.90 (3), Glu 3.13 (3), Pr
o 1.94 (2), Gly 2.96 (3), Ala 1.00 (1), Val 2.00 (2), Leu
4.75 (5), Tyr 0.77 (1), Lys 2.03 (2), His 0.93 (1), Arg
1.06 (1), Asu 1.07 (1) High performance liquid chromatography Retention time 23.3 minutes

[0038]

[Production Example 2]

[0039]

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Production of compound represented by formula B (hereinafter sometimes abbreviated as F02 compound) (1)

[0041]

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The title compound (hereinafter sometimes abbreviated to fragment (1)) was produced by the method of Examples 2 (1) to (14) of JP-B-53-41677. (2)

[0043]

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Production Example 1 After reacting and binding Boc-Pro to the MBHA resin in the same manner as in (2) and treating in the same manner, the corresponding protected amino acids are successively coupled in the order from the C-terminal to the N-terminal according to the sequence of the target compound. After ringing and coupling of the last protected amino acid, TFA treatment and subsequent washing were performed to deprotect the N-terminal Boc group, to obtain 2.5 g of the above compound. (3) Combination of the compound obtained in the above (1) and the compound obtained in the above (2) 500 mg of the compound obtained in the above (1) and 1.2 g of the compound obtained in the above (2) are used. Production Example 1. The same operation as in (3) was carried out to obtain 1.5 g of the above-mentioned target product. (4) Production of F02 compound 1.0 g of the compound obtained in the above (3) was prepared.
Treated in the same manner as in (4), purified by reversed-phase high performance liquid chromatography, and purified using Sephadex G-25 resin.
The mixture was subjected to gel filtration with 1M-acetic acid aqueous solution to obtain 13 mg of the above-mentioned target substance. Physical properties Amino acid analysis values Asp 2.88 (3), Thr 4.52 (5), Ser 2.90 (3), Glu 3.04 (3), Pr
o 1.87 (2), Gly 3.80 (4), Ala 1.00 (1), Val 2.95 (3), Leu
4.88 (5), Tyr 0.70 (1), Lys 1.99 (2), His 0.91 (1), Arg
1.96 (2), Asu 1.03 (1) High performance liquid chromatography Retention time 24.5 minutes

[0045]

[Production Example 3]

[0046]

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Production of compound represented by formula C (hereinafter sometimes abbreviated as F06 compound) (1)

[0048]

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The title compound was prepared according to the method of Examples 2 (1) to (14) of JP-B-53-41677. That is, Boc-Ser (Bzl) -OSu used at a site different from the publication
Was replaced with Boc-D-Ser (Bzl) -OSu. (2)

[0050]

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Production Example 1 In the same manner as in (2), 2.1 g of the target product was obtained. (3) Binding of the compound obtained in the above (1) and the compound obtained in the above (2) 500 mg of the compound obtained in the above (1) and 1.1 g of the compound obtained in the above (2) are used. Production Example 1. By carrying out in the same manner as in (3), 1.3 g of the above-mentioned target product was obtained. (4) Production of F06 compound 1.0 g of the compound obtained in the above (3) was prepared.
Treated in the same manner as in (4), purified by reversed-phase high performance liquid chromatography, and purified using Sephadex G-25 resin.
The solution was subjected to gel filtration with 1M-acetic acid water to obtain 5.8 mg of the above-mentioned target compound. Physical property value Amino acid analysis value Asp 2.03 (2), Thr 3.95 (4), Ser 2.90 (3), Glu 3.19 (3), Pr
o 2.25 (2), Gly 3.13 (3), Ala 1.00 (1), Val 1.93 (2), Leu
5.47 (5), Tyr 1.01 (1), Lys 2.24 (2), His 1.07 (1), Arg
1.10 (1), Asu 1.21 (1) High performance liquid chromatography Retention time 23.7 minutes

[0052]

[Production Example 4]

[0053]

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Preparation of compound represented by formula D (hereinafter sometimes abbreviated as F27 compound) (1) Preparation of fragment (1) Fragment (1) is prepared in Example 2 (1)-(2) of JP-B-53-41677. It was manufactured by the method of 14). (2)

[0055]

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Production Example 1 Production Example 1 as in (2). When the sequence produced in (2) is combined with the changed predetermined His, Boc-Hi
Solid phase synthesis was performed using Boc-His (1-Me) instead of s (Tos) to obtain 2.1 g. (3) Binding of the compound obtained in the above (1) and the compound obtained in the above (2) 500 mg of the compound obtained in the above (1) and 1.1 g of the compound obtained in the above (2) are used. Production Example 1. By carrying out in the same manner as in (3), 1.3 g of the above-mentioned target product was obtained. (4) Production of F27 compound 1.0 g of the compound obtained in the above (3) was prepared.
Treated in the same manner as in (4), purified by reversed-phase high performance liquid chromatography, and purified using Sephadex G-25 resin.
The mixture was subjected to gel filtration with 1M aqueous acetic acid to obtain 5.5 mg of the above-mentioned target substance. Physical property value Amino acid analysis value Asp 1.97 (2), Thr 3.66 (4), Ser 2.50 (3), Glu 3.00 (3), Pr
o 1.95 (2), Gly 2.91 (3), Ala 1.00 (1), Val 1.96 (2) Leu
4.69 (5), Tyr 0.74 (1), Lys 1.92 (2), Arg 0.96 (1), Asu
1.19 (1), His (1-Me) 0.83 (1) High performance liquid chromatography Retention time 25.5 minutes

[0057]

Example 1 In order to examine the stabilizing effect of the four kinds of elcatonin stabilizers obtained by synthesizing and purifying in Production Examples 1 to 4, each was added to an aqueous solution of elcatonin for injection.
Elcatonin was tested for shaking stability. 1) Preparation of an aqueous solution of elcatonin for injection: distilled water 1000
4.63 sodium citrate.3H ₂ O per ml
g, 0.37 g of anhydrous citric acid and 7.0 g of sodium chloride were added and dissolved to prepare an aqueous solution having a pH of 6.0. Elcatonin was dissolved in this aqueous solution to a concentration of about 10 μg / ml to prepare an aqueous solution of elcatonin for injection. 2) Preparation of injection: 4.63 g of sodium citrate.3H ₂ O, 0.37 g of anhydrous citric acid, and 7.0 g of sodium chloride were added and dissolved in 1,000 ml of distilled water to prepare an aqueous solution having a pH of 6.0. did. In this aqueous solution, the four kinds of elcatonin stabilizers produced in Production Examples 1 to 4 were each dissolved to a concentration of about 10 μg / ml or about 1.0 μg / ml to prepare an aqueous solution of the elcatonin stabilizer. . 2.5 ml of each of this aqueous solution of elcatonin stabilizer and 100 ml of aqueous solution of elcatonin for injection
Was mixed to prepare a test solution of an aqueous solution for injection of elcatonin in which the total amount of the stabilizer was 5% or 0.5% based on the amount of elcatonin. Next, 1 ml of each test solution was filled into a normal untreated glass ampoule to prepare about 50 ampules each.

As a control, an injection containing only the aqueous solution for injection of elcatonin without the stabilizer of the present invention was similarly prepared.
0 were prepared. 3) Stability test: The ampoule of the test solution was placed in a thermostat shaker, and the content of elcatonin was measured over time by liquid chromatography to examine the shaking stability. - shaking conditions [amplitude: 10 cm, shaking rate: 180 times / min, temperature: 25 ° C], liquid chromatography measurement conditions [column: ODS column (4.6 × 150 mm), mobile phase: CH ₃ CN @ -
0.1% TFA (1: 2), flow rate: 1 ml / min, detection: UV220 nm] Table 1 shows the residual ratio of the injection in each ampule for 4 weeks with shaking.

[0059]

[Table 1]

As is clear from Table 1, the ampoule of the elcatonin aqueous solution for injection containing the elcatonin stabilizer of the present invention had better shaking stability than the control ampoule containing no stabilizer. .

[0061]

Industrial Applicability The peptide of the present invention can improve the stability of elcatonin in an aqueous solution for injection, particularly the shaking stability, in a very small amount, and is useful as a stabilizer for an elcatonin aqueous solution injection. .

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-58-148827 (JP, A) JP-A-3-90033 (JP, A) JP-A-5-178894 (JP, A) (58) Field (Int.Cl. ⁷ , DB name) A61K 38/00-38/58 A61K 47/42 A61K 9/08 C07K 14/585 CA (STN) MEDLINE (STN) BIOSIS (STN) REGISTRY (STN) JICST file ( JOIS)

Claims (1)

(57) [Claims] 1. The following A to D: Embedded image A shaking stabilizer for an aqueous solution of elcatonin comprising at least two or more of the peptides represented by the following formula: