JP2009286738A - Injection agent containing carbapenem-based antibiotic - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable injection agent of 1-(2-amino-2-oxoethyl)-3-[[2-[(4S, 5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]imidazo[5,1-b]thiazol-7-yl]carbonyl]pyridinium intramolecular salt (formula (I)) useful as a medicine. <P>SOLUTION: The injection agent comprises the intramolecular salt represented by formula (I), its solvate or its salt and one or more kinds of an additive selected from an inorganic salt, a water-soluble acid amide compound, a phenol backbone-containing aromatic compound, an amino acid or its salt and a saccharide. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an injection of a carbapenem antibiotic. More specifically, 1- (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] is useful as a pharmaceutical product. ] -4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium inner salt, Soluble by blending solvate or salt thereof with at least one additive selected from inorganic salt, water-soluble acid amide compound, aromatic compound having phenol skeleton, amino acid or salt thereof, or sugar The present invention relates to an injection with improved properties and stability.

1- (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] -4-methyl-7- Oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium inner salt (hereinafter referred to as a compound of formula (I) Is a carbapenem compound having the following chemical structure, and is disclosed in WO 02/42312 (Patent Document 1) and WO 04/55027 (Patent Document 2) together with its production method.

  The compound of formula (I) is a carbapenem antibiotic, exhibits excellent antibacterial activity not only against gram-negative bacteria but also against gram-positive bacteria, and can be expected to be useful as an antibacterial agent.

In general, carbapenem antibiotics are administered intravenously by injection or infusion. As preparation forms suitable for these administration forms, solution preparations filled in vials and kits, powder-filled preparations directly filled with sterile drugs, or freeze-dried preparations are provided clinically. On the other hand, when a powder preparation or a lyophilized preparation is administered intravenously, it is necessary to dissolve the drug in a desired solvent. However, since the physicochemical properties of the drug are different for each drug, it is often impossible to completely dissolve depending on the type of solvent. Therefore, various attempts have been made to dissolve each drug using a solubilizing agent so that the drug can be quickly dissolved in a required solvent. However, even if the drug can be dissolved, addition of a solubilizing agent is known to cause a so-called combination contraindication such as deterioration in stability, coloring of the injection, or decomposition. Therefore, it is not easy to find a solubilizing agent having sufficient stability for each drug.
As a method for stably storing and dissolving a lyophilized preparation of a carbapenem antibiotic, a method (Patent Document 3) containing two or more saccharides (for example, inositol and mannitol) as an additive is known. .

WO02 / 42312 WO04 / 55027 JP-A-8-231398

  The compound of the formula (I) exhibits excellent antibacterial activity not only for gram-negative bacteria but also for gram-positive bacteria, and can be expected to be useful as an antibacterial agent. However, the solubility is not always satisfactory, and it is desired to provide a preparation, particularly an injection, which is prepared to a sufficient concentration as a pharmaceutical preparation and becomes a stable solution.

で示される1-(2-アミノ-2-オキソエチル)-3-[[2-[(4S,5R,6S)-2-カルボキシ-6-[(1R)-1-ヒドロキシエチル]-4-メチル-7-オキソ-1-アザビシクロ[3.2.0]ヘプト-2-エン-3-イル]イミダゾ[5,1-b]チアゾール-7-イル]カルボニル]ピリジニウム分子内塩、その溶媒和物、またはその塩と、無機塩、水溶性酸アミド化合物、フェノール骨格を有する芳香族化合物、アミノ酸もしくはその塩、又は、糖から選択される少なくとも１種以上の添加剤とを含有してなる注射剤。
（２）無機塩が、塩化ナトリウム、又は、塩化マグネシウムである（１）に記載の注射剤。
（３）水溶性酸アミド化合物が、アセチルトリプトファン、リドカイン、又は、ニコチン酸アミドである（１）に記載の注射剤。
（４）フェノール骨格を有する芳香族化合物が、パラオキシ安息香酸メチル、サリチル酸ナトリウム、ゲンチジン酸エタノールアミド、クレゾール、フェノール、フェノールレッド、没食子酸プロピルである（１）に記載の注射剤。
（５）アミノ酸が、アルギニン、ヒスチジン、又は、トリプトファンである（１）に記載の注射剤。
（６）糖が、精製白糖、乳糖、トレハロース、又は、マルトースである（１）に記載の注射剤。
（７）式（Ｉ）の分子内塩、その溶媒和物、またはその塩と、無機塩、水溶性酸アミド化合物、フェノール骨格を有する芳香族化合物、アミノ酸もしくはその塩、又は、糖から選択される少なくとも１種以上の添加剤を、注射用液に混合、溶解し、ｐＨ１〜２に調整した後、ｐＨ３．５〜９．５に調整することを特徴とする（１）記載注射剤の製造方法。 As a result of diligent efforts to solve the above problems, the present inventor has found an injection with improved solubility and stability. That is, 1- (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] -4 useful as a pharmaceutical product -Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium inner salt, solvate thereof Or a salt thereof, and an injection comprising at least one additive selected from an inorganic salt, a water-soluble acid amide compound, an aromatic compound having a phenol skeleton, an amino acid or a salt thereof, or a sugar Is to provide.
The present invention is as follows.
(1) The present invention provides the following formula (I):

1- (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] -4-methyl -7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium inner salt, solvate thereof, or An injection comprising the salt, and at least one additive selected from an inorganic salt, a water-soluble acid amide compound, an aromatic compound having a phenol skeleton, an amino acid or a salt thereof, or a sugar.
(2) The injection according to (1), wherein the inorganic salt is sodium chloride or magnesium chloride.
(3) The injection according to (1), wherein the water-soluble acid amide compound is acetyltryptophan, lidocaine, or nicotinic acid amide.
(4) The injection according to (1), wherein the aromatic compound having a phenol skeleton is methyl paraoxybenzoate, sodium salicylate, gentisic acid ethanolamide, cresol, phenol, phenol red, propyl gallate.
(5) The injection according to (1), wherein the amino acid is arginine, histidine, or tryptophan.
(6) The injection according to (1), wherein the sugar is purified sucrose, lactose, trehalose, or maltose.
(7) An inner salt of the formula (I), a solvate thereof, or a salt thereof, and an inorganic salt, a water-soluble acid amide compound, an aromatic compound having a phenol skeleton, an amino acid or a salt thereof, or a sugar At least one or more additives are mixed and dissolved in an injection solution, adjusted to pH 1-2, and then adjusted to pH 3.5-9.5. Method.

  The present invention relates to 1- (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] useful as a pharmaceutical product. ] -4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium inner salt, An injection with improved solubility and stability of a solvate or a salt thereof can be provided. In addition, by improving the solubility, it is possible to shorten the time when preparing injections, improve the work efficiency of medical staff, shorten the freeze-drying time of the formulation, reduce the size of the vial, etc. Cost reduction is possible. From these things, it becomes possible to provide the antibacterial agent which shows the outstanding antibacterial activity.

The compound of formula (I) may be either crystalline or amorphous. Furthermore, even if crystals of the same compound are produced, crystals having a plurality of different internal structures and physicochemical properties (crystal polymorphs) may be formed depending on the crystallization conditions. It may be any polymorph, and may be a mixture of two or more crystal polymorphs or non-crystals.
In addition, the compound of formula (I) may be a “solvate”, and the “solvate” is a hydrate that absorbs and adsorbs moisture, and also absorbs and adsorbs certain solvents. The solvate obtained by this is mentioned. Solvents for the solvate include water, methanol, ethanol and the like.
The “salt” of formula (I) is a pharmaceutically acceptable salt. Examples thereof include inorganic salts such as lithium, sodium, potassium, calcium and magnesium, or salts with organic bases such as ammonium salt, triethylamine and diisopropylethylamine. Further, salts with organic acids such as acetic acid, carbonic acid, citric acid, malic acid, oxalic acid, and methanesulfonic acid are also included. Of these, an inner salt, a sodium salt, a potassium salt, and a hydrochloride are preferable.

  In the present invention, “inorganic salt” refers to sodium chloride, magnesium chloride, potassium chloride and the like, preferably sodium chloride and magnesium chloride.

  In the present invention, the “water-soluble acid amide compound” represents acetyltryptophan, lidocaine, nicotinic acid amide, isonicotinic acid amide, N, N-dimethylacetamide, N-hydroxyethyl lactamide, etc., preferably acetyltryptophan, Examples include lidocaine and nicotinamide.

  In the present invention, the “aromatic compound having a phenol skeleton” is an aromatic compound having at least one hydroxyl group in a benzene ring. For example, methyl paraoxybenzoate, sodium salicylate, gentisic acid ethanolamide, cresol, phenol, phenol red, propyl gallate and the like can be mentioned.

  In the present invention, “amino acid or a salt thereof” represents arginine, histidine, tryptophan and the like, and preferably L-arginine, L-histidine, L-tryptophan, L-arginine hydrochloride, L-histidine hydrochloride and the like. It is done.

  In the present invention, “sugar” represents purified sucrose, lactose, trehalose, maltose and the like, and preferably, purified sucrose and maltose.

  The compounding ratio of the compound of the formula (I) with at least one additive selected from inorganic salts, water-soluble acid amide compounds, aromatic compounds having a phenol skeleton, amino acids or salts thereof, or sugars is as follows. Varies depending on the type of additive. Generally, the amount of the additive with respect to the drug is selected in the range of 0.05 to 50 times. The compound and additive are dissolved in water during production, but the higher the concentration of these additives mixed, the higher the stability and dissolution effect of the compound of formula (I).

The manufacturing method of the solution formulation and lyophilized formulation which can be used as the injection of this invention can be performed by a conventional method. As a general production method, for example, a compound of formula (I) and an inorganic salt, a water-soluble acid amide compound, an aromatic compound having a phenol skeleton, an amino acid or a salt thereof, or an additive selected from sugars are injected. Dissolve in distilled water and adjust the pH as necessary to obtain a solution. The pH value to be adjusted as an injection is from 3.5 to 9.5, preferably from 4.0 to 9.0, more preferably from 4.0 to 8.0. Selected.
Further, as another embodiment of the production method, after dissolving the compound of formula (I) and an additive having the same meaning as above in distilled water for injection, the pH is once adjusted to 2 or less with a pH adjuster, Preferably, after adjusting to 1-2, it can be adjusted to pH 3.5-9.5, preferably 4.0-9.0, more preferably 4.0-8.0.
Moreover, as a pH adjuster, it can adjust using inorganic acids, such as hydrochloric acid and a sulfuric acid, organic acids, such as acetic acid, a citric acid, and tartaric acid, sodium hydroxide, and also the additive of this invention. Moreover, you may adjust using what mixed these 2 or more types of pH adjusters.
The solution is aseptically filtered through a membrane filter, and a fixed amount of the solution is dispensed into a vial to obtain a solution preparation. Moreover, a freeze-dried preparation can be produced by freeze-drying this lysate by a conventional method. The freeze-dried preparation is usually dispensed into a fixed amount vial and sealed for clinical use. A lyophilized preparation can also be produced by dispensing a certain amount of the lysate into a vial and lyophilizing the vial. These freeze-dried preparations can be provided as preparations that can be aseptically and easily dissolved by adding an injection solution such as distilled water for injection at the time of use and stirring.

  The manufacturing method of the powder formulation which can be used as the injection of this invention can be performed by a conventional method. As a general production method, for example, a compound of formula (I) is mixed with an inorganic salt, a water-soluble acid amide compound, an aromatic compound having a phenol skeleton, an amino acid or a salt thereof, or an additive selected from sugars. Then, a certain amount can be aseptically dispensed into vials and sealed for clinical use.

  The container for dispensing the solution or the aseptically prepared mixed powder is not limited to a vial, and a kit such as an ampoule or a prefilled syringe can also be used.

  In the injection of the present invention, pharmaceutically acceptable additives usually used for injections can be further used within the range not impairing the object of the present invention. These additives include stabilizers, antioxidants, solubilizers, buffers, excipients, and / or isotonic agents.

  The injection comprising the freeze-dried preparation and powder-filled preparation of the present invention can be used after being dissolved in an injection solution such as distilled water for injection, saline solution or glucose solution at the time of use. The solution may be used by appropriately adjusting according to the concentration of the injection.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

Example 1
Add 1 mL of 1 mol / L hydrochloric acid and 4.8 mL of 1 mol / L sodium hydroxide to 1.7 g of sodium citrate, and add various kinds of additions shown in Table 1 to 3 mL of citric acid solution adjusted to 100 mL by adding distilled water for injection. The agent was added and dissolved. 1 mol / L hydrochloric acid was added to adjust the pH to 5.0 ± 1.0. 1- (2-Amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(1R), which is an active ingredient compound of formula (I) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium 30 mg of the above hydrate was added, and the mixture was stirred for 15 minutes while irradiating with ultrasonic waves. Then, the irradiation with ultrasonic waves was stopped, the mixture was stirred at room temperature for 15 to 45 minutes, and this suspension was filtered with a membrane filter. The drug concentration of the obtained filtrate was measured using a high performance liquid chromatography method. As a control, a filtrate obtained by adding only the compound of formula (I) as an active ingredient without adding an additive to a citric acid solution and carrying out the same treatment dissolution was used. The results are shown in Table 1.

Example 2
1- (2-Amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-, which is a compound of formula (I) as an active ingredient in 2 mL of distilled water for injection 6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazole-7 200 mg of a hydrate of -yl] carbonyl] pyridinium and various additives shown in Table 2 were added and mixed. It adjusted by adding 1 mol / L hydrochloric acid so that pH might become 2 or less, and the compound of Formula (I) was melt | dissolved. 1 mol / L sodium hydroxide or an additive was added to adjust the pH to 5.0 ± 1.0. This solution was filtered through a membrane filter. The drug concentration of the obtained filtrate was measured using a high performance liquid chromatography method. The results are shown in Table 2.

Example 3
Gentisic acid ethanolamide was dissolved in distilled water for injection at the ratio shown in Table 3, and the compound of formula (I) as an active ingredient, 1- (2-amino-2-oxoethyl) -3-[[2- [(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-3- [Il] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium hydrate was added in an amount corresponding to 80 mg / mL and mixed well. 2 mol / L hydrochloric acid was added to adjust the pH to 2. After confirming that the compound of formula (I), which is an active ingredient, was sufficiently dissolved, 0.2 mol / L sodium hydroxide was added to adjust the pH to 5, and the solution was filtered through a membrane filter. The prepared lysate was allowed to stand at room temperature, and the time until the insoluble matter was suspended or settled was measured. The higher the concentration of gentisic acid ethanolamide as an additive, the higher the stability of the compound of formula (I) to insoluble matter.

Example 4
1- (2-Amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6, which is a compound of formula (I) which is an active ingredient in distilled water for injection -[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazole-7- [Il] carbonyl] pyridinium hydrate was added in an amount corresponding to 100 mg / mL and mixed well. Adjust the pH to 2 by adding 4 mol / L hydrochloric acid. After confirming that the compound of the formula (I) as an active ingredient was sufficiently dissolved, L-arginine was added at a ratio shown in Table 4, and 0.2 mol / L sodium hydroxide was added to adjust the pH to 5. The lysate was filtered through a membrane filter. The prepared lysate was allowed to stand at room temperature, and the time until the insoluble matter was suspended or settled was measured. When the molar ratio of the additive L-arginine to the active ingredient was 1 or more, the stability of the compound of formula (I) with respect to the insoluble matter was increased.

Example 5
Maltose, gentisic acid ethanolamide, L-arginine and sodium chloride were prepared so as to have the ratios shown in Table 5 and dissolved in 150 mL of distilled water for injection. In this solution, the compound of the formula (I) as an active ingredient, 1- (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[( 1R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl ] 30 g (titer) of pyridinium hydrate was added and mixed well. 2 mol / L hydrochloric acid was added to adjust the pH to 2. After confirming that the compound of the formula (I) as an active ingredient was sufficiently dissolved, 0.2 mol / L sodium hydroxide was added to adjust the pH to 5. The liquid volume was adjusted to 300 mL and filtered with a membrane filter. 5 mL each was dispensed into a glass vial and lyophilized by a conventional method to prepare a lyophilized preparation. When this freeze-dried preparation is stored at 40 ° C., stored for 1 month, and stored at 60 ° C. and stored for 1 month, the residual ratio of active ingredients is determined by the amount of active ingredients before storage using high pressure liquid chromatography. It was shown by the ratio. It was confirmed that the addition of the additive improved the stability of the compound of formula (I), which is an active ingredient.

Example 6
Maltose is dissolved in 150 mL of distilled water for injection so that the ratio shown in Table 6 is obtained, and the compound of formula (I) as an active ingredient, 1- (2-amino-2-oxoethyl) -3-[[2- [(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-3- 30 g (titer) of [Il] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium hydrate was added and mixed well. 2 mol / L hydrochloric acid was added to adjust the pH to 2. After confirming that the compound of the formula (I) as an active ingredient was sufficiently dissolved, 0.2 mol / L sodium hydroxide was added to adjust the pH to 5. Further, sodium citrate and sodium chloride were added to the solution so as to have the ratio shown in Table 6, and 0.2 mol / L sodium hydroxide was added to adjust the pH to 5. The liquid volume was adjusted to 1500 mL and filtered with a membrane filter. 25 mL each was dispensed into a glass vial and freeze-dried by a conventional method to prepare a freeze-dried preparation. When this lyophilized preparation was stored at 60 ° C. and stored for 2 weeks and 1 month, the residual ratio of the active ingredient was shown by a ratio with the amount of the active ingredient before storage using a high pressure liquid chromatography method. It was confirmed that the addition of the additive improved the stability of the compound of formula (I), which is an active ingredient.

Example 7
Maltose is dissolved in 150 mL of distilled water for injection so that the ratio shown in Table 6 is obtained, and the compound of formula (I) as an active ingredient, 1- (2-amino-2-oxoethyl) -3-[[2- [(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-3- 30 g (titer) of [Il] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium hydrate was added and mixed well. The pH was adjusted to 2 by adding 4 mol / L hydrochloric acid. After confirming that the compound of the formula (I), which is an active ingredient, was sufficiently dissolved, a pH of 5 was adjusted by adding a 3.5 mol / L L-arginine solution and 0.2 mol / L sodium hydroxide. Further, sodium chloride was added to the solution so as to have the ratio shown in Table 6, and 0.2 mol / L sodium hydroxide was added to adjust the pH to 5. The liquid volume was adjusted to 300 mL and filtered with a membrane filter. 5 mL each was dispensed into a glass vial and lyophilized by a conventional method to prepare a lyophilized preparation. When this lyophilized preparation was stored at 60 ° C. and stored for 2 weeks and 1 month, the residual ratio of the active ingredient was shown by a ratio with the amount of the active ingredient before storage using a high pressure liquid chromatography method. It was confirmed that the addition of the additive improved the stability of the compound of formula (I), which is an active ingredient.

1- (2-Amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] useful as a pharmaceutical according to the present invention ] -4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium inner salt, An injection with improved solubility and stability of a solvate or a salt thereof can be provided.

Claims (7)

Formula (I):

1- (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(1R) -1-hydroxyethyl] -4-methyl -7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium inner salt, solvate thereof, or An injection comprising the salt, and at least one additive selected from an inorganic salt, a water-soluble acid amide compound, an aromatic compound having a phenol skeleton, an amino acid or a salt thereof, or a sugar. The injection according to claim 1, wherein the inorganic salt is sodium chloride or magnesium chloride. The injection according to claim 1, wherein the water-soluble acid amide compound is acetyltryptophan, lidocaine, or nicotinic acid amide. The injection according to claim 1, wherein the aromatic compound having a phenol skeleton is methyl paraoxybenzoate, sodium salicylate, gentisic acid ethanolamide, cresol, phenol, phenol red, or propyl gallate. The injection according to claim 1, wherein the amino acid is arginine, histidine, or tryptophan. The injection according to claim 1, wherein the sugar is purified white sugar, lactose, trehalose, or maltose. At least one selected from an internal salt of formula (I), a solvate thereof, or a salt thereof, and an inorganic salt, a water-soluble acid amide compound, an aromatic compound having a phenol skeleton, an amino acid or a salt thereof, or a sugar The method for producing an injection according to claim 1, wherein the additive is mixed and dissolved in an injection solution and adjusted to pH 1-2, and then adjusted to pH 3.5-9.5.