Pharmaceutical composition containing cephalosporin-based antimicrobial compounds

Abstract

A pharmaceutical composition comprising a cephalosporin-based antimicrobial compound, wherein formula (I): A pharmaceutical composition comprising a compound represented by TIFF2026519674000010.tif4388, or a pharmaceutically acceptable salt thereof, and arginine. The composition exhibits excellent stability and is more clinically suitable for use.

Description

Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition containing a cephalosporin antibacterial compound and a method for producing the same.

Background Art

[0002] The development of antibacterial therapies is an ongoing challenge faced by modern society. Antibacterial agents include various antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones and other chemically synthesized drugs. Among them, β-lactam antibiotics are a very important classification. To date, there are numerous β-lactamase drugs reported in the literature research or already on the market, which have become extremely important antibacterial drugs clinically. However, the resistance problem to β-lactam drugs is becoming increasingly serious, and the number of bacteria that produce β-lactamase and acquire resistance by decomposing β-lactam drugs is increasing.

[0003] The emergence of Gram-negative bacteria with high resistance to β-lactam drugs (including cephalosporin and carbapenem) has caused serious clinical application problems. Such resistance is caused by the production of A or D-type serine β-lactamase and B-type metallo-β-lactamase that extend its substrate spectrum. It is known that metallo-β-lactamase is one of the causes of multi-drug resistance acquisition in Gram-negative bacteria. However, the development of cephalosporin compounds with more effective antibacterial activity, especially showing effectiveness against Gram-negative bacteria that produce various β-lactamases, is a difficult problem in the modern antibacterial drug research field.

[0004] According to the literature, it has been reported that cephalosporin compounds having a catechol group in the molecule have high resistance activity against Gram-negative bacteria. Its action is that the catechol group in the molecule forms a chelate with extracellular Fe 3+ and thereby the compound is in Fe in the cell membrane 3+The mechanism involves effective binding to bacterial cells via transporter systems (tonB-dependent transporter systems). This Trojan horse strategy leads to higher concentrations in the periplasmic space (the narrow space between the outer membrane and the cell wall), and binding to receptors to inhibit bacterial cell wall synthesis. Therefore, research is being conducted on compounds with catechol or similar structures in the 3- or 7-position side chain of the cephalosporin skeleton (EP0416410B1). Cefiderocol is a novel siderofoam cephalosporin (WO 2010050468, WO 2017216765, etc.), and the FDA (U.S. Food and Drug Administration) has approved the use of Shionogi's Fetroja (cefiderocol) for the treatment of complicated urinary tract infections (cUTIs), including kidney infections caused by susceptible Gram-negative bacteria, in patients 18 years of age and older.

[0005] WO 2022152146 has a structure of formula (I): [ka] As shown, we have disclosed a siderofoa cephalosporin with good antibacterial activity. However, the stability of this compound is very low, requiring the raw material to be stored at temperatures below -60°C, which poses a challenge for the manufacture of pharmaceutical products. [Overview of the project]

[0006] The object of this disclosure is to provide a pharmaceutical composition comprising a cephalosporin-based antimicrobial compound, the composition having excellent stability.

[0007] One aspect of this disclosure is formula (I): [ka] A pharmaceutical composition comprising the compound indicated by or a pharmaceutically acceptable salt thereof, and arginine was provided.

[0008] In some embodiments, the concentration of the compound represented by formula (I) or its pharmaceutically acceptable salt is 1 mg / mL to 200 mg / mL, and non-limiting examples include 1 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 40 mg / mL, 5 mg / mL. The range includes 0 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL and any range between these point values, and in some embodiments, the concentration of the compound represented by formula (I) or its pharmaceutically acceptable salt is 10 mg / mL to 180 mg / mL or 30 mg / mL to 180 mg / mL or 30 mg / mL to 150 mg / mL.

[0009] With regard to the concentration of the compound represented by formula (I) or its pharmaceutically acceptable salt described herein, if the active material is a pharmaceutically acceptable salt of the compound represented by formula (I), the concentration of the pharmaceutically acceptable salt of the compound represented by formula (I) is calculated based on the concentration of the free form of the compound represented by formula (I).

[0010] In some embodiments, the weight-to-volume ratio of arginine is 0.01% to 30%, or 0.1% to 20%, or 1% to 15%, and non-limiting examples include 0.02%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, and 1%. This includes 0.7%, 1.8%, 1.9%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 18.0%, 20.0%, 22.0%, 25.0%, 28.0%, 30.0%, and any range between these point values.

[0011] In some embodiments, the arginine concentration is 1 mg / mL to 300 mg / mL, and non-limiting examples include 1 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, and 110 mg / mL. The range includes L, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL and any range between these point values, and in some embodiments, the concentration of the compound represented by formula (I) or its pharmaceutically acceptable salt is 10 mg / mL to 250 mg / mL or 30 mg / mL to 200 mg / mL or 30 mg / mL to 180 mg / mL.

[0012] In some embodiments, the weight ratio of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to arginine is 1:0.1 to 1:20, for example, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, and any range between these point values.

[0013] The arginine in the pharmaceutical compositions described herein may include free arginine, arginine salts, and mixtures of free and salt forms of arginine. Unless otherwise specified, the arginine content or percentage described herein generally refers to the content or percentage of the total of all forms of arginine, calculated based on free arginine.

[0014] In some embodiments, the arginine is free arginine and / or arginine hydrochloride. In some embodiments, the weight ratio of free arginine to arginine hydrochloride may be 1:0.1 to 1:20, for example, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, and any range between these point values.

[0015] In some embodiments, the pharmaceutical composition may further contain other protective excipients, the protective excipients being selected from one or more of amino acids, sugars, high molecular weight polysaccharides, cyclodextrins, and inorganic salts, and including, but not limited to, one or more of histidine, lysine, glycine, sucrose, glucose, lactose, trehalose, maltose, inositol, hydroxyethyl starch, PEG, dextran, sulfobutyl-β-cyclodextrin, and sodium chloride.

[0016] In some embodiments, the weight-to-volume ratio of the protective excipient is 0.01% to 30%, or 0.1% to 20%, or 1% to 15%.

[0017] In some embodiments, the pharmaceutical composition further comprises sodium chloride. The concentration of the sodium chloride may be 1 mg / mL to 100 mg / mL, and non-limiting examples include 1 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL The concentrations include mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL and any range between these point values, and in some embodiments, the concentration of sodium chloride is 1 mg / mL to 80 mg / mL, 5 mg / mL to 60 mg / mL, or 5 mg / mL to 50 mg / mL.

[0018] In some embodiments, the weight ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt to sodium chloride is 1:0.01 to 1:10, for example, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.2, 1:0.3, The values ​​may be 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and any range between these point values.

[0019] In some embodiments, the pharmaceutical composition further comprises a buffer. The buffer is selected from acetate buffers, citrate buffers, histidine buffers, and succinate buffers. In some embodiments, the buffer is selected from acetate-sodium acetate, histidine-acetic acid, histidine-histidine hydrochloride, citrate-sodium citrate, succinate-histidine, and succinate-sodium succinate.

[0020] In some embodiments, the buffering agent concentration in the pharmaceutical composition is 1 mM to 50 mM, and non-limiting examples include 1 mM, 3 mM, 5 mM, 10 mM, 12 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 30 mM, 40 mM, 50 mM and any range between these point values.

[0021] In some embodiments, the pharmaceutical composition may further contain a pH adjusting agent. The pH adjusting agent includes, but is not limited to, sodium hydroxide and hydrochloric acid.

[0022] In some embodiments, the pH of the pharmaceutical composition is 5.0 to 7.0, and non-limiting examples include 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, and any range between these point values. In some embodiments, the pH is 5.0 to 6.5, or the pH is 5.3 to 6.3.

[0023] In some embodiments, the pharmaceutical composition further comprises a liquid medium, such as water, physiological saline, glucose injection solution, etc.

[0024] In some embodiments, the pharmaceutical composition comprises (a) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof at 10 mg / mL to 180 mg / mL, and (b) arginine at 10 mg / mL to 250 mg / mL, and the pH of the pharmaceutical composition is 5.0 to 6.5.

[0025] In some embodiments, the pharmaceutical composition comprises (a) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof at 30 mg / mL to 180 mg / mL, and (b) arginine at 30 mg / mL to 200 mg / mL, wherein the arginine is a combination of free arginine and arginine hydrochloride, and the weight ratio of free arginine to arginine hydrochloride is 1:0.1 to 1:20, and the pH of the pharmaceutical composition is 5.3 to 6.3.

[0026] In some embodiments, the pharmaceutical composition comprises (a) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof at 10 mg / mL to 180 mg / mL, (b) arginine at 10 mg / mL to 250 mg / mL, and (c) sodium chloride at 1 mg / mL to 80 mg / mL, and the pH of the pharmaceutical composition is 5.0 to 6.5.

[0027] This disclosure further provides a lyophilized formulation comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the lyophilized formulation being obtained by lyophilizing a pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as described above.

[0028] The disclosure further provides a reconstituted solution comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the reconstituted solution is prepared by reconstituting the lyophilized formulation described above.

[0029] This disclosure further provides a method for producing the above-mentioned reconstituted solution, comprising the step of reconstituting the aforementioned lyophilized formulation, wherein the solution used for the reconstitution is selected from, but is not limited to, water for injection, physiological saline, or glucose solution.

[0030] The present disclosure further provides a lyophilized formulation comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the formulation can be reconstituted to form the pharmaceutical composition described above.

[0031] This disclosure further provides a method for producing a lyophilized formulation comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of lyophilizing the pharmaceutical composition described above.

[0032] This disclosure further provides a product including a container containing the pharmaceutical composition, lyophilized preparation, or reconstituted solution described above. In some embodiments, the container is an injectable drug vial made of neutral borosilicate glass.

[0033] In some embodiments, the lyophilized formulations described herein are left for one month under conditions of 25°C and 60% RH, where the purity loss of the compound represented by formula (I) or its pharmaceutically acceptable salt is less than 4.0%, and the values ​​are 4.0%, 3.9%, 3.8%, 3.7%, 3.6%, 3.5%, 3.4%, 3.3%, 3.2%, 3.1%, 3.0%, and 2.9%. The percentages may be %, 2.8%, 2.7%, 2.6%, 2.5%, 2.4%, 2.3%, 2.2%, 2.1%, 2.0%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less.

[0034] In some embodiments, the lyophilized formulations described herein are left for 3 months under conditions of 25°C and 60% RH, where the purity loss of the compound represented by formula (I) or its pharmaceutically acceptable salt is less than 5.0%, and the values ​​are 5.0%, 4.9%, 4.8%, 4.7%, 4.6%, 4.5%, 4.4%, 4.3%, 4.2%, 4.1%, 4.0%, 3.9%, 3.8%, 3.7%, 3.6%, 3.5%, and 3.4%. The percentages may be %, 3.3%, 3.2%, 3.1%, 3.0%, 2.9%, 2.8%, 2.7%, 2.6%, 2.5%, 2.4%, 2.3%, 2.2%, 2.1%, 2.0%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less.

[0035] The pharmaceutical compositions, lyophilized formulations, and reconstituted solutions described herein can be used to prevent and treat diseases caused by pathogens in mammals, including humans. These diseases include, for example, respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, myelomingitis, otitis media, enteritis, sinusitis, wound infections, and opportunistic infections.

[0036] The pharmaceutical compositions, lyophilized formulations, and reconstituted solutions described herein can further be used for the prevention and treatment of diseases caused by Gram-negative bacteria. The aforementioned Gram-negative bacteria are preferably intestinal Gram-negative bacteria (such as Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, and Proteus), Gram-negative bacteria that inhabit the respiratory system (such as Haemophilus and Moraxella), and glucose-non-fermenting Gram-negative bacteria (such as Pseudomonas aeruginosa, Pseudomonas other than P. aeruginosa, Stenotrophomonas, Burkholderia, and Acinetobacter).

[0037] As used herein, the terms “about” and “approximately” mean that a numerical value is within an acceptable range of a specific value measured by a person skilled in the art, and that such numerical value depends in part on how it is measured or determined (i.e., the limits of the measuring system). For example, for each practice of the art, “about” may mean a standard deviation of 1 or more than 1. Or, “about” or “substantially included” may mean a range of up to 20%. In particular with respect to biological systems or processes, the terms may mean up to one digit or up to five times the numerical value. Unless otherwise stated, whereever a specific numerical value appears in this application and claims, the meaning of “about” or “substantially included” should be assumed to be within an acceptable margin of error of that specific numerical value.

[0038] The numerical values ​​in this disclosure are instrumental measurements or values ​​calculated after instrumental measurement, and are subject to some degree of error, generally within a reasonable margin of error of ±10%. Of course, the context in which the numerical values ​​are used must be considered, for example, for the total impurity content, the numerical value may have an error change of ±10% or less after measurement, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0039] The "weight-to-volume ratio" described herein refers to the weight (in grams) of the component per 100 mL of liquid system, i.e., g / 100 mL. [Modes for carrying out the invention]

[0040] Example 1: Solubility test of the compound represented by formula (I) Different solvent systems were prepared, and the solubility of the compound shown in formula (I) was tested. The results are shown in Table 1.

[0041] [Table 1]

[0042] Example 2 Based on the formulation composition in Table 2, the compound represented by formula (I) was weighed, placed in a small beaker, suspended in sterile water for injection, and the pH was adjusted to the target level with a buffer solution or arginine while stirring. The protective excipients in the proportions shown in Table 2 were added, and after stirring and dissolution, sterile water for injection was added to adjust the concentration to the drug concentration shown in Table 2. Sterile filtration was performed to obtain the intermediate drug solution. A certain amount of the intermediate drug solution was dispensed into vials, and the final sterile powder formulation was produced by lyophilization.

[0043] [Table 2]

[0044] Example 3 The powder formulation samples prepared in Example 2 were dried, then filled with nitrogen gas and packaged. The samples were left to stand under accelerated conditions (25°C, 60% RH), and the active material and impurity content were detected. Detection method: Detection was performed using a high-performance liquid chromatography system. Chromatography column: XBridge Shield PR18, 4.6 × 150 mm, 3.5 μm. Mobile phase A: perchloric acid / water, Mobile phase B: acetonitrile / methanol / perchloric acid. Detection wavelength: 260 nm The detection results are shown in the table below.

[0045] [Table 3]

[0046] After being left for two months under accelerated conditions, the formulation containing arginine showed the smallest change in purity (<1%) and demonstrated good stability. In contrast, formulations using other protective excipients showed a significant decrease in purity.

[0047] Example 4 Based on the formulation composition in Table 4, 500 mg of the compound represented by formula (I) was weighed, placed in a small beaker, suspended in sterile water for injection, and 96 mg of arginine was added while continuously stirring. After clarification, the pH was adjusted to 5.4-5.8 with sodium hydroxide or hydrochloric acid. 609.49 mg of arginine hydrochloride was added, clarified, and then sterile water for injection was added to a final volume of 5 ml. Sterile filtration was performed to obtain the intermediate drug solution. This formulation solution was placed in a vial and freeze-dried to produce the final sterile powder formulation.

[0048] [Table 4]

[0049] The stability of the formulation under accelerated conditions (25°C, 60%RH) is as follows:

[0050] [Table 5]

Claims

1. Equation (I): 【Chemistry 1】 A pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable salt thereof, and arginine.

2. The pharmaceutical composition according to claim 1, wherein the concentration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 1 mg / mL to 200 mg / mL, preferably 10 mg / mL to 180 mg / mL, more preferably 30 mg / mL to 180 mg / mL, and most preferably 30 mg / mL to 150 mg / mL.

3. The pharmaceutical composition according to claim 1 or 2, wherein the weight-to-volume ratio of the arginine is 0.01% to 30%, preferably 0.1% to 20%, and more preferably 1% to 15%.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the concentration of arginine is 1 mg / mL to 300 mg / mL, preferably 10 mg / mL to 250 mg / mL, more preferably 30 mg / mL to 200 mg / mL, and most preferably 30 mg / mL to 180 mg / mL.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the weight ratio of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to arginine is 1:0.1 to 1:

20.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition further comprises another protective excipient, wherein the protective excipient is preferably selected from one or more of amino acids, sugars, high molecular weight polysaccharides, cyclodextrins, and inorganic salts, and more preferably one or more of histidine, lysine, glycine, sucrose, glucose, lactose, trehalose, maltose, inositol, hydroxyethyl starch, PEG, dextran, sulfobutyl-β-cyclodextrin, and sodium chloride.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition further comprises a buffer, the buffer is preferably selected from an acetate buffer, a citrate buffer, a histidine buffer, and a succinate buffer.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises a pH adjusting agent, preferably the pH adjusting agent being hydrochloric acid and / or sodium hydroxide.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pH of the pharmaceutical composition is 5.0 to 7.0, preferably 5.0 to 6.5, and more preferably 5.3 to 6.

3.

10. The aforementioned pharmaceutical composition (a) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a concentration of 10 mg / mL to 180 mg / mL, and (b) arginine in a concentration of 10 mg / mL to 250 mg / mL, wherein the pH of the pharmaceutical composition is 5.0 to 6.

5. Preferably, the pharmaceutical composition is (a) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in an amount of 30 mg / mL to 180 mg / mL, and (b) arginine in an amount of 30 mg / mL to 200 mg / mL, wherein the arginine is a combination of free arginine and arginine hydrochloride, the weight ratio of free arginine to arginine hydrochloride is 1:0.1 to 1:20, and the pH of the pharmaceutical composition is 5.3 to 6.3, or The aforementioned pharmaceutical composition A pharmaceutical composition according to any one of claims 1 to 9, comprising (a) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in an amount of 10 mg / mL to 180 mg / mL, (b) arginine in an amount of 10 mg / mL to 250 mg / mL, and (c) sodium chloride in an amount of 1 mg / mL to 80 mg / mL, wherein the pH of the pharmaceutical composition is 5.0 to 6.

5.

11. A lyophilized preparation that can form the pharmaceutical composition described in any one of claims 1 to 10 after reconstitution.

12. A lyophilized preparation obtained by lyophilizing a pharmaceutical composition according to any one of claims 1 to 10.

13. A reconstituted solution produced by reconstituting the lyophilized formulation according to claim 11 or 12.

14. Uses of the pharmaceutical composition according to any one of claims 1 to 10, the lyophilized preparation according to claim 11 or 12, or the reconstituted solution according to claim 13, in the manufacture of a drug for treating diseases caused by pathogens in mammals, wherein the diseases are preferably respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, myelomingitis, otitis media, enteritis, sinusitis, wound infections, and opportunistic infections.

15. Uses of the pharmaceutical composition according to any one of claims 1 to 10, the lyophilized preparation according to claim 11 or 12, or the reconstituted solution according to claim 13, in the manufacture of a drug for treating a disease caused by Gram-negative bacteria.

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