JP2007217438A - Medical preparation for injection - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a means for suppressing the foaming which may occur in the preparation of a solution or a suspension, and particularly to provide a medicine having suppressed foaming trouble which may cause any disadvantages in the preparation of a solution or a suspension. <P>SOLUTION: The medical preparation for injection contains a pharmacologically allowable salt of a compound of formula (I) or its solvate as an active component. The preparation contains the active component and a basic substance and has a pH of ≥8.5 in the form of solution. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a means for suppressing foaming that may occur when preparing a solution or suspension. Specifically, the present invention relates to a medicine, food, or the like in which foaming during preparation of a solution or suspension, which may cause some inconvenience, is suppressed.

で示される化合物（化合物１）は、脳出血、脳梗塞、クモ膜下出血等、急性期の脳血管障害薬であり、その関連化合物とともに製造方法等が特開平７−５３４８４号（特許文献１）に記載されている。 formula:

Is a cerebrovascular disorder drug in the acute phase such as cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, etc., and its production method and the like are disclosed in JP-A-7-53484 (Patent Document 1). It is described in.

JP-A-7-53484

  The compound 1 is assumed to be administered by intravenous infusion. In this case, a freeze-dried preparation sealed in a vial or the like is once dissolved or suspended in water for injection or an infusion solution in a vial or the like, and further infusion (approximately 100 to 500 ml, Mix with pH 6-7). However, if it is mixed vigorously when dissolved / suspended in a vial etc., foaming will occur, making it difficult to transfer all active ingredients when mixing in the infusion solution, resulting in errors in the dosage, and even up to about 300 mg When the dose of this compound was increased, problems such as foaming hindered redissolution were observed. When stirring, it can be gently stirred on a desk or the like, but such use is expected to be difficult in an actual medical field, and suppression of foaming has been a problem.

  Then, based on the dissociation constant of this compound, it discovered that foaming was suppressed by adjusting pH using a basic substance, and completed this invention.

  Japanese Patent Application Laid-Open No. 9-124481 discloses a freeze-dried preparation that uses a silicon-coated vial as a preparation container to prevent the foam generated at the time of re-dissolution from adhering to the inner surface of the vial and becomes clear quickly. In the pharmaceutical field, there are few reports on antifoaming. In industrial fields other than pharmaceuticals, methods such as defoaming by adding silicone or alcohol, and mechanical foam breaking are used.

［式中、Ｒ¹は水素または代謝性エステル残基を表し、Ｒ²は水素または−Ｒ³−Ｒ⁴（ここにＲ³は、−ＳＯ₃−、−ＣＨ₂ＣＯＯ−、−ＣＯＣＯＯ−または−ＣＯＲ⁵ＣＯＯ−（ここにＲ⁵は、炭素数１〜６のアルキレンまたは炭素数２〜６のアルケニレンを表す）を表し、Ｒ⁴は水素または炭素数１〜６のアルキルを表す）である］
で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物である医薬製剤に関し；および
第２の態様として、本発明はフェノール性水酸基を有する化合物を水性溶媒により溶解または懸濁する際、該フェノール性水酸基を解離させることによりその溶解または懸濁時における泡立ちを抑制する方法； 好ましくは該化合物が以下の条件：
１）解離定数（ｐＫａ値）が８以上であり、そして
２）Ｗｉｌｈｅｌｍｙ法（溶媒は水、測定温度は２５℃）により測定される表面張力が、化合物濃度３０〜４０ｍＭの場合に６０ｍＮ／ｍ以下である、
を満たす泡立ち抑制方法であり、より好ましくは解離手段が塩基性物質を使用することであり、さらに好ましくは塩基性物質が、溶液または懸濁液状態でのｐＨを８．５以上とする泡立ち抑制方法、さらに好ましくは該化合物が上記式（Ｉ）で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物である泡立ち抑制方法、に関する。 That is, the present invention provides, as a first aspect, an active ingredient having the following conditions:
1) having a phenolic hydroxyl group,
2) The dissociation constant (pKa value) is 8 or more, and 3) 60 mN / m when the surface tension measured by the Wilhelmy method (the solvent is water and the measurement temperature is 25 ° C.) is an active ingredient concentration of 30 to 40 mM. Is
An injectable pharmaceutical preparation containing the active ingredient and a basic substance and having a pH of 8.5 or higher in a solution or suspension; preferably the active ingredient is represented by the formula (I):

[Wherein R ¹ represents hydrogen or a metabolic ester residue, R ² represents hydrogen or —R ³ —R ⁴ (wherein R ³ represents —SO ₃ —, —CH ₂ COO—, —COCOO— or —COR ⁵ COO— (wherein R ⁵ represents alkylene having 1 to 6 carbon atoms or alkenylene having 2 to 6 carbon atoms), and R ⁴ represents hydrogen or alkyl having 1 to 6 carbon atoms). ]
Or a pharmaceutically acceptable salt or solvate thereof; and as a second aspect, the present invention relates to a method of dissolving or suspending a compound having a phenolic hydroxyl group in an aqueous solvent. , A method for suppressing foaming during dissolution or suspension by dissociating the phenolic hydroxyl group; preferably, the compound has the following conditions:
1) The dissociation constant (pKa value) is 8 or more, and 2) 60 mN / m or less when the surface tension measured by the Wilhelmy method (solvent is water, measurement temperature is 25 ° C.) at a compound concentration of 30 to 40 mM. Is,
More preferably, the dissociation means is to use a basic substance, and more preferably, the basic substance has a pH of 8.5 or higher in a solution or suspension state. More preferably, the present invention relates to a method for suppressing foaming, wherein the compound is a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof.

  In a preferred aspect, the present invention relates to the pharmaceutical preparation of the first aspect, comprising 0.5 to 20 mg of a basic substance per 100 mg of active ingredient. More preferably, this invention relates to the pharmaceutical formulation of the said 1st aspect obtained by adding 5-20 mg of basic substances with respect to 100 mg of compounds shown by the formula (I), or its solvate. In another preferred embodiment, the present invention provides the foam suppression method of the second embodiment, wherein the compound is a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof. Yes, and relates to a method by adding 0.5 mg to 20 mg of basic substance to 100 mg of the compound.

  The present invention can be applied to an active ingredient having a dissociation constant (pKa value) of 8 or more. The dissociation constant of the active ingredient can be measured by techniques well known to those skilled in the art, such as potentiometric titration. In the present invention, the active ingredient preferably has a pKa value of 8 to 10, more preferably 8.5 to 9.5. When the pKa value is too high, it is necessary to increase the pH in order to dissociate the phenolic hydroxyl group, and it is necessary to readjust the pH before administration, so the practicality is low. On the other hand, if the pKa value is too low, there is no point in using the present invention because no foaming is observed during dissolution or suspension.

  In the present invention, the “surface tension measured by the Wilhelmy method” means that an active ingredient alone is dissolved or suspended in water to form an aqueous solution or suspension having an active ingredient concentration of 30 to 40 mM, under the condition of 25 ° C. by the Wilhelmy method. It means the measured surface tension. An active ingredient having a surface tension measured in this way of 60 mN / m or less, preferably 50 to 60 mN / m can be used in the present invention. When the surface tension is too high, foaming hardly occurs and no problem occurs. When the surface tension is too low, foaming is likely to occur, and this method may not be able to be suppressed to a practical level.

  The Wilhelmy method is a well-known method for measuring surface tension (physical physics (Nan Edo), K122 Determination of Surface Tension, CMC and Synergic Effects Users Manual (Kruess)), where generally clean glass or thin The end of the metal plate is suspended perpendicular to the liquid, and the force with which the thin plate is pulled down is measured.

  As described above, a preferred active ingredient in the present invention is a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof.

  In the formula, a metabolic ester residue means an ester residue that is chemically or metabolically decomposed to give a pharmaceutically active compound in vivo. Simple aliphatic or aromatic esters derived from the acidic groups possessed by the original compound are preferred ester residues. More preferably, it is a C1-C6 alkyl ester of an acidic group (for example, methyl ester, ethyl ester). In some cases, double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters can also be produced.

  C1-C6 alkylene is linear or branched alkylene which has 1-6 carbon atoms, for example, a methylene, ethylene, trimethylene, tetramethylene, hexamethylene etc. can be mentioned.

  The alkenylene having 2 to 6 carbon atoms is a linear or branched alkenylene having 2 to 6 carbon atoms, preferably-(CH = CH) m- (m represents an integer of 1 to 3). .).

  The alkyl having 1 to 6 carbon atoms is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Examples include butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, s-pentyl, t-pentyl, n-hexyl, neohexyl, i-hexyl, s-hexyl, and t-hexyl.

  Further, the “pharmaceutically acceptable salt” of the compound in the active ingredient is a salt obtained by reacting with a suitable organic or inorganic acid or organic or inorganic base. Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrofluoric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, perchloric acid, hydroiodic acid, and the like. Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, mandelic acid, ascorbic acid, lactic acid, etc. . Examples of the organic base include triethylamine and pyridine. Examples of the inorganic base include alkali metals (eg, Na, K) and alkaline earth metals (eg, Ca, Mg). Solvates include solvates with organic solvents and / or water, and any number of solvent molecules may be coordinated to one molecule of the compound that is the active ingredient.

  In the present invention, the basic substance is not particularly limited as long as the solution or suspension pH of the active ingredient can be 8.5 or more, but sodium hydroxide, potassium hydroxide, calcium hydroxide and the like are particularly mentioned. It is done. As for the quantity of a basic substance, what contains 0.5-20 mg with respect to 100 mg of active ingredients is preferable. The pH of the solution or suspension of the active ingredient containing the basic substance is 8.5 or more, preferably pH 9 to 9.8.

  The amount of the basic substance “containing” in the pharmaceutical preparation of the present invention is expressed based on the amount of the basic substance added to 100 mg of the active ingredient when the pharmaceutical preparation is prepared. The change in the amount due to salt formation with a hydroxyl group shall not be considered.

  The “solution or suspension state” includes any state as long as the active ingredient is dissolved or suspended in a suitable aqueous solvent. Preferably, 10 to 500 mg, more preferably 100 to 400 mg, most preferably 250 to 350 mg of the active ingredient is dissolved or suspended using 1 to 500 ml of an aqueous solvent, preferably 1 to 50 ml, more preferably 5 to 20 ml. State. The aqueous solvent is preferably water for injection, infusion solution (physiological saline, amino acid-containing infusion solution, etc.), buffer solution (phosphate buffer solution, etc.), more preferably water for injection or infusion solution having a pH of about 5-6.

For example, when the active ingredient of the target pharmaceutical preparation is the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof (preferably compound 1),
(A) 0.5 to 5 mg of a basic substance, preferably 1 to 3 mg, more preferably 100 mg of the compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof (preferably Compound 1). Add 1.5-2.5 mg,
(B) 5 to 20 mg of a basic substance, preferably 10 to 100 mg of the compound (I) or a solvate thereof (preferably a free acid (compound 2) in which two COONa groups of the compound 1 are COOH groups). Add -20 mg, more preferably 12-18 mg,
By either of these methods, a solution or suspension having a pH of 8.5 or higher can be obtained. In addition, all the pharmaceutical preparations prepared by the above method (A) and method (B) are included in the “pharmaceutical preparation containing 0.5 to 20 mg of basic substance with respect to 100 mg of active ingredient”.

  As described above, when the pharmaceutical preparation of the present invention is prepared, in addition to the method of adding a basic substance to the target active ingredient compound, the compound having a different salt formation state ( The same pharmaceutical preparation can be prepared by various methods by adding a basic substance in an amount corresponding to the state of salt formation to a compound in a free state (including free acid, for example).

  In the case of administration by intravenous drip infusion, it can be once administered in a “solution or suspension state” in a vial or the like, and then the liquid can be transferred to an infusion bag or the like. Even if it is 8.5 or less, there is no problem because the object of the present invention has already been achieved.

  In the present invention, the pharmaceutical preparation can be in any form, as long as the pH in the solution or suspension state is 8.5 or more. Accordingly, the pharmaceutical preparations of the present invention include solutions, suspensions, and freeze-dried preparations (including infusion kit preparations such as double bag preparations).

  The present invention further contains sugars (eg glucose, maltose, lactose, sucrose, fructose, mannitol, preferably mannitol) or amino acids (preferably neutral amino acids, preferably glycine, alanine, more preferably alanine). A pharmaceutical formulation is provided. The sugar or amino acid is preferably 25% (w / w) or more of the active ingredient, more preferably 40% to 60% (w / w), and most preferably 50% (w / w). Thereby, decomposition | disassembly of an active ingredient is suppressed. There is no upper limit to the amount of sugar or amino acid added to achieve the objective of inhibiting the decomposition of the active ingredient, but if the amount of sugar or amino acid is too large, the active ingredient reacts with the sugar or amino acid to produce a new byproduct. May occur.

  The foaming suppression method of the present invention can be used not only in medicine but also in the fields of food and general chemistry, in any case where foaming is inconvenient. That is, the present invention includes 1) a phenolic hydroxyl group, 2) a dissociation constant (pKa value) of 8 or more, and 3) a surface measured by the Wilhelmy method (solvent is water, measurement temperature is 25 ° C.). In any sample containing a compound having a tension of 60 mN / m or less when the compound concentration is 30 to 40 mM, when dissolving or suspending the sample in an aqueous solvent, foaming at the time of dissolution or suspension is suppressed. Available.

  The aqueous solvent in the present invention is typically water, infusion (eg, physiological saline, amino acid-containing infusion, etc.), buffer solution, water for injection, and preferably water for injection or infusion.

  Based on this embodiment, the present invention also provides a method for suppressing foaming during storage of a solution or suspension, characterized by dissociating a phenolic hydroxyl group. A preferred dissociation means is to use a basic substance, preferably sodium hydroxide, potassium hydroxide, calcium hydroxide.

BEST MODE FOR CARRYING OUT THE INVENTION 1) Whilhelmy Method The components applicable to the present invention can be selected by the following Whilmymy method.

Preparation of measurement sample Weigh the compound to be measured and dissolve or suspend it in a certain amount of distilled water. In this way, 50 ml each of aqueous solutions of several concentrations are prepared.

Preparation of measuring device Start the surface tension meter (Kruess K12) and the measurement control / analysis PC, and open the surface tension measurement software (Kruess K122). Water is circulated from the thermostatic water bath to the measurement site of the surface tension meter to keep the temperature constant at 25 ° C. The glass vessel (diameter 65 mm, height 40 mm) into which the measurement sample is to be placed should be thoroughly washed with water and finally washed with acetone and dried.

Preparation of measurement plate The plate used for measurement is a rectangle 19mm wide and 10mm high and is usually 0.2mm thick platinum. In order to remove the residue adhered to the surface of the plate, the plate is blown with a gas burner before the measurement is started. In addition, the plate is washed with distilled water and acetone for each sample measurement and dried.

Blank measurement Place 40 ml of distilled water in a cleaned vessel and place it on a surface tension meter. Using the automatic surface detection function of the surface tension meter, immerse the tip of the plate from the water surface to a depth of 2 mm. In this state, the surface tension is measured. A graph of the surface tension time is displayed on a personal computer, but if the surface tension value is almost stable after 1 minute of measurement, the value is recorded and the measurement is stopped.

Specimen measurement After blank measurement, 40 ml of the specimen aqueous solution was placed in a washed vessel and placed on a surface tension meter. Use the automatic surface detection function of the surface tension meter to immerse the plate tip to a depth of 2 mm from the solution surface. In this state, surface tension is measured. A graph of the surface tension time is displayed on a personal computer. If the surface tension value is almost stable after 1 minute of measurement, record the value and stop the measurement. If the surface tension value is not stable and increases and decreases are observed, continue the measurement until the value stabilizes, and record the stabilized value.

2) Pharmaceutical preparation The pharmaceutical preparation of the present invention can be produced by a conventional method according to the dosage form. What is necessary is just to manufacture, for example with the following method, when manufacturing an injection.

  Tools and materials used in production are sterilized in advance by conventional methods (for example, high-pressure steam sterilization, dry heat sterilization, γ-ray sterilization, etc.) in consideration of the form of non-sterile products, heat resistance, pressure resistance, etc. .

  The active ingredient and, if necessary, sugar are weighed, placed in a dissolution vessel, an appropriate amount of solvent (for example, water for injection) is added and dissolved or suspended with stirring. The concentration of the solution or suspension may be determined in consideration of the type of solvent, the solubility of the active ingredient in the solvent, and the concentration at the time of redissolution. Further, a basic substance (for example, 0.1 to 10 mol / L aqueous solution, preferably 1 mol / L aqueous solution is used) is added to adjust the pH to 8.5 or more.

  The solution or suspension thus obtained is aseptically filtered by a conventional method. If necessary, rough filtration for the purpose of removing decomposition products, contaminants, etc. may be performed before aseptic filtration.

  If the sterile filtrate is appropriately dispensed into a vial or the like and lyophilized by a conventional method, the intended injection is obtained.

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited thereto.
Test example 1
Measurement of surface tension of compound 1 Since foaming of compound 1 was thought to be largely due to the surface activity of compound 1, the surface tension of aqueous solution of compound 1 was measured using the Wilhelmy method (suspended plate method) (physical physics chemistry (Nanjido) Determination of Surface Tension, CMC and Synergic Effects Users Manual (Kruess)).

Compound 1 was dissolved in distilled water to prepare 50 ml of aqueous solutions having various concentrations.
A surface tension meter (Kruess K12 type) and a personal computer for measurement control and analysis were started, and surface tension measurement software (Kruess K122) was opened. Water was circulated from the thermostatic water bath to the measurement site of the surface tension meter to keep the temperature constant at 25 ° C. The glass vessel (65 mm in diameter and 40 mm in height) into which the measurement sample was placed was washed thoroughly with water and finally washed with acetone and dried.
The measurement plate was a rectangle having a width of 19 mm and a height of 10 mm, and a platinum plate having a thickness of 0.2 mm was used. In order to remove the residue adhered to the surface of the plate, the plate was swollen with a gas burner before starting the measurement. In addition, the plate was washed with distilled water and acetone for each specimen measurement and dried.

  First, blank measurement was performed. Distilled water (40 ml) was placed in a washed vessel and placed on a surface tension meter. Using the automatic detection function of the surface tension meter, the tip of the plate was immersed from the water surface to a depth of 2 mm. In this state, surface tension was measured. A graph of the surface tension time was displayed on a personal computer, but the surface tension value was almost stable after 1 minute of measurement, so the value was recorded and the measurement was stopped. This measurement operation was repeated twice to obtain an average value.

  Next, sample measurement was performed. 40 ml of various sample aqueous solutions (compound 1 aqueous solution, pH 7 to 7.5) having various concentrations were placed in the washed vessel and placed on a surface tension meter. Using the automatic surface detection function of the surface tension meter, the tip of the plate was immersed to a depth of 2 mm from the solution surface. In this state, surface tension was measured. A graph of the surface tension time is displayed on a personal computer. If the surface tension value was almost stable after 1 minute of measurement, the value was recorded and the measurement was stopped. When the surface tension value was not stabilized and an increase or decrease was observed, measurement was continued until the value was stabilized (after about 1 to 2 minutes), and the stabilized value was recorded. This measurement operation was repeated twice to obtain an average value.

  For the measurement results, the average surface tension value (n = 2) at each concentration was plotted against the concentration (logarithm).

In addition, the surface tension was measured using aqueous solutions of various concentrations of Compound 1 adjusted to pH 9.5 with sodium hydroxide. FIG. 1 shows the relationship between the surface tension and the concentration of Compound 1 at pH 7 to 7.5 and pH 9.5.
As a result of measuring the surface tension, it was found that the decrease in surface tension was suppressed at pH 9.5 compared to pH 7 to 7.5.
The surface tension value of Compound 1 at a concentration of 37.6 mM and a temperature of 25 ° C. was 53.9 ± 0.2 mN / m.

Example 1
Add 1500 g of water for injection to 100.7 g of Compound 1 drug substance (90.0 g in terms of Compound 1 content) and 45.0 g of D-mannitol prepared according to the production method described in JP-A-7-53484, and the solution becomes light yellow and transparent. Stir until well. After dissolution, the pH was measured while adding a 1 mol / L aqueous sodium hydroxide solution little by little. When the pH of the solution reached 9.5, the addition of the aqueous sodium hydroxide solution was stopped (the actual addition amount as an aqueous solution was 55 g), and water for injection was added to bring the total weight of the solution to 1800.0 g. This preparation solution was roughly filtered with a 0.45 μm filter, and further sterile filtered with a 0.22 μm filter. 6.0 g (within ± 1%) of this sterile filtrate was dispensed per vial and lyophilized. In freeze-drying, the solution was pre-frozen at −40 ° C., then primary dried at −5 ° C. and 10 Pa for 24 hours or more, and further dried at 60 ° C. and 2 Pa for 5 hours. After completion of lyophilization, a cap was wrapped around the vial to prepare an injection preparation.

Example 2
To 2.81 g of Compound 2 (4.00 g in terms of Compound 1 content), 2.00 g of d-mannitol and 64 g of a 0.16 mol / L aqueous sodium hydroxide solution were added and dissolved. A 1 mol / L sodium hydroxide aqueous solution was added thereto to adjust the pH of the solution to 9.5 (actual addition amount as an aqueous solution: 4.79 g). Water for injection was added so that the total amount was 80.0 g, and the solution concentration was adjusted to 50.0 mg / g. The prepared solution was aseptically filtered, then dispensed at 2.00 g each, and lyophilized. The obtained freeze-dried preparation contains 100 mg of compound 1 (in terms of 2Na salt content).

Test example 2
Comparison of foaming 10 ml of water for injection was added to the preparation prepared in Example 1 or 2 and dissolved by shaking, and the appearance of the foam was inspected. Further, as a comparative preparation, 100 mg of the compound dissolved in 10 ml of water for injection (pH 7.5) was used, and the two were compared.
The results are shown in the table below.

Test example 3
Foaming of a high pH preparation without addition of mannitol To the preparation prepared according to the formulation described in Example 1 except that mannitol was not added, 10 ml of water for injection was added and dissolved by shaking, and the appearance of foaming at that time was examined. Shake caused a slight bubbling, which disappeared within 1 minute. The degree of foaming was the same as that of the preparation of Example 1 to which mannitol was added.

Test example 4
Relationship between foaming and pH Compound 1 was dissolved in water for injection (0.1% w / w), and foaming was quantitatively measured by the Ross-Miles foaming test method. The Ross-Miles foaming test method was performed according to the method defined in International Standard ISO 696-1975 except that the measurement temperature was set to 25 ° C. The relationship between the amount of foaming produced by this test and the pH is shown in FIG. It can be seen that foaming is suppressed as the pH rises.

Example 3
Effect of suppressing degradation product formation by adding mannitol After the preparation prepared in Example 1 was stored at 50 ° C. for 2 months, the amount of degradation product produced by hydrolysis was compared using liquid chromatography. Typical decomposition products are as follows.

表２から、D-マンニトールの添加によって分解生成物である化合物Aの生成が抑制されることが示された。またこのことから化合物１の含量低下が抑制されることが分かる。 Table 2 shows the relationship between the content of Compound 1 and the amount of degradation product and the amount of D-mannitol added in the preparation before storage and after storage at 50 ° C. for 2 months. High performance liquid chromatography (HPLC) was used for the measurement. The HPLC measurement conditions are shown below.
Equipment: Waters 600E, 484,712 wisp, 741, FD20A
Column: J'sphere ODS-L80, S-4μm, 80A 150 × 4.6 mmφ
Mobile phase: water / acetonitrile / acetic acid = 100/100/1
Flow rate: 1.0 ml / min
Injection volume: 20 μL (when measuring impurities): 10 μL (when compound 1 is determined)
Detection wavelength: 275 nm
Detection sensitivity (AUFS): 0.64 (when measuring impurities)
: 0.20 (when compound 1 is determined)
Sample dilution solvent: water / acetonitrile / acetic acid-= 100/100/1
Sample concentration
1mg / ml (for impurity measurement)
60.0μg / ml (for compound 1 measurement)

From Table 2, it was shown that the addition of D-mannitol suppresses the formation of compound A, which is a decomposition product. Moreover, it turns out that the content fall of the compound 1 is suppressed from this.

  The foaming suppression method of the present invention can be used when preparing food or pharmaceutical solutions or suspensions, and is useful for smooth food production, processing, accurate pharmaceutical administration, and the like.

It is a graph which shows the relationship between the compound 1 density | concentration in pH 7-7.5 and pH9.5, and surface tension. It is a graph which shows the amount of the foaming produced | generated by the Ross-Miles foaming test method, and the relationship of pH.

Claims (11)

The active ingredient is formula (I):

A pharmaceutical preparation for injection, which is a pharmaceutically acceptable salt of the compound represented by the formula (1) or a solvate thereof, contains the active ingredient and a basic substance, and has a pH of 8.5 or more in a solution state.   The pharmaceutical preparation according to claim 1, which is freeze-dried.   The pharmaceutical preparation according to claim 1, which is prepared by dissolving the pharmaceutical preparation according to claim 2 in water for injection or infusion.   The pharmaceutical preparation according to claim 3, wherein the dissolution is carried out with water for injection or 5 to 20 ml of infusion.   The pharmaceutical preparation according to any one of claims 1 to 4, wherein the basic substance is sodium hydroxide.   Pharmaceutical formulation in any one of Claims 1-5 whose pH in a solution state is 9-9.8.   The pharmaceutical formulation in any one of Claims 1-6 containing 0.5-20 mg of basic substances with respect to 100 mg of active ingredients.   The pharmaceutical formulation in any one of Claims 1-7 obtained by adding 5-20 mg of basic substances with respect to 100 mg of active ingredients.   The pharmaceutical preparation according to any one of claims 1 to 8, wherein foaming during dissolution is suppressed.   When a pharmaceutically acceptable salt of a compound represented by the formula (I) according to claim 1 or a solvate thereof is dissolved in an aqueous solvent, a pH of 8 in a solution state is obtained by coexisting a basic substance. A method of adjusting to 5 or more and suppressing foaming during dissolution.   The method according to claim 10, wherein 0.5 to 20 mg of a basic substance coexists with 100 mg of a pharmaceutically acceptable salt of a compound represented by the formula (I) according to claim 1 or a solvate thereof. A method of suppressing foaming.

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