Pharmaceutical composition containing cephalosporin antibacterial compound

Abstract

The invention relates to a pharmaceutical composition containing a cephalosporin antibacterial compound, which comprises a compound as shown in a formula (I), or a pharmaceutically acceptable salt thereof, and arginine. The composition is excellent in stability and can be better applied to clinic.

Description

A pharmaceutical composition comprising a cephalosporin antibacterial compound Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition comprising a cephalosporin antibacterial compound and a preparation method thereof. Background Art

[0002] The development of antimicrobial treatment options is an ongoing challenge facing society today. Antimicrobial drugs include various antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones, and other chemically synthesized drugs. β-lactam antibiotics are a very important class. To date, numerous β-lactamase-inhibiting drugs have been reported in the literature or are now commercially available, making them extremely important clinically. However, resistance to β-lactam drugs is becoming increasingly serious, with an increasing number of bacteria acquiring resistance by producing β-lactamases that degrade these drugs.

[0003] The emergence of Gram-negative bacteria that have become highly resistant to β-lactamase drugs (including cephalosporins and carbapenems) has posed significant clinical challenges. This resistance is caused by the production of type A or D serine β-lactamases and type B metallo-β-lactamases, which extend their substrate spectrum. Metallo-β-lactamases are known to contribute to the acquisition of multidrug resistance in Gram-negative bacteria. However, the development of cephalosporin compounds with more effective antibacterial activity, particularly against Gram-negative bacteria that produce multiple β-lactamases, remains a major challenge in current antimicrobial research.

[0004] According to literature reports, cephalosporin compounds containing catechol groups in their molecules have high anti-Gram-negative bacterial activity. The role of the catechol groups in the molecules is to bind to the extracellular Fe 3+ Forming an integration complex, so that the compound passes through the Fe 3+The transport system (tonB-dependent transport system) effectively binds to the bacteria. This Trojan horse strategy allows it to reach a higher concentration in the periplasmic space (the narrow space between the outer membrane and the cell wall) and bind to receptors to inhibit the synthesis of the bacterial cell wall. Therefore, compounds with catechol or similar structures in the 3- or 7-position side chains of the cephalosporin skeleton have been studied (EP0416410B1). Cefiderocol is a new type of iron-carrier cephalosporin (WO2010050468, WO2017216765, etc.). The FDA (U.S. Food and Drug Administration) has approved Fetroja (cefiderocol) from Shionogi Pharmaceutical for the treatment of complicated urinary tract infections (cUTI) in patients 18 years of age and older, including kidney infections caused by sensitive Gram-negative bacteria.

[0005] WO2022152146 discloses a siderophore cephalosporin with a structure as shown in Formula (I), which has good antibacterial activity. However, the compound has extremely poor stability, so the raw material compound needs to be stored below -60°C, which poses a challenge to the manufacture of the formulation product.

[0006] Summary of the Invention

[0007] The object of the present disclosure is to provide a pharmaceutical composition comprising a cephalosporin antibacterial compound, wherein the composition has excellent stability.

[0008] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and arginine.

[0009] In some embodiments, the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 1 mg / mL to 200 mg / mL, non-limiting examples of which 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, 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 therebetween; in some embodiments, the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 10 mg / mL to 180 mg / mL or 30 mg / mL to 180 mg / mL or 30 mg / mL to 150 mg / mL.

[0010] The concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present disclosure, if the active substance is a pharmaceutically acceptable salt of the compound of formula (I), then the concentration of the pharmaceutically acceptable salt of the compound of formula (I) is calculated based on the concentration of the free form of the compound of formula (I).

[0011] In some embodiments, the weight-to-volume ratio of arginine is 0.01% to 30%, or 0.1% to 20%, or 1% to 15%, 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%, 1.7%, 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.

[0012] In some embodiments, the concentration of arginine is 1 mg / mL to 300 mg / mL, non-limiting examples of which 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. In some embodiments, the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from 10 mg / mL to 250 mg / mL, from 30 mg / mL to 200 mg / mL, or from 30 mg / mL to 180 mg / mL.

[0013] In some embodiments, the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to arginine can be 1:0.1-1:20, 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 ranges therebetween.

[0014] The arginine in the pharmaceutical composition described herein may include free arginine, salts of arginine, and mixtures of free and salt forms of arginine. The arginine content or ratio described herein, unless otherwise specified, generally refers to the total content or ratio of all forms of arginine calculated as free arginine.

[0015] In some embodiments, the arginine is free arginine and / or arginine hydrochloride. In some embodiments, the weight ratio of the free arginine to the arginine hydrochloride can be 1:0.1-1:20, 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 ranges therebetween.

[0016] In some embodiments, the pharmaceutical composition may further comprise other protective excipients, wherein the protective excipients are selected from one or more of amino acids, sugars, high molecular weight polymers, cyclodextrins, and inorganic salts, 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.

[0017] 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%.

[0018] In some embodiments, the pharmaceutical composition further comprises sodium chloride. The concentration of sodium chloride can be 1 mg / mL to 100 mg / mL, non-limiting examples of which 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, / mL, 31 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 therebetween; in some embodiments, the concentration of sodium chloride is 1 mg / mL to 80 mg / mL or 5 mg / mL to 60 mg / mL or 5 mg / mL to 50 mg / mL.

[0019] In some embodiments, the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to sodium chloride can be 1:0.01-1:10, 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, 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 in between these point values.

[0020] In some embodiments, the pharmaceutical composition may further comprise a buffer. The buffer is selected from acetate buffer, citrate buffer, histidine buffer, and succinate buffer. In some embodiments, the buffer is selected from acetic acid-sodium acetate, histidine-acetic acid, histidine-histidine hydrochloride, citric acid-sodium citrate, succinic acid-histidine, and succinic acid-sodium succinate.

[0021] In some embodiments, the buffer concentration in the pharmaceutical composition is 1 mM to 50 mM, non-limiting examples of which 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 therebetween.

[0022] In some embodiments, the pharmaceutical composition may further comprise a pH adjuster, including but not limited to sodium hydroxide, hydrochloric acid, and the like.

[0023] In some embodiments, the pH of the pharmaceutical composition is 5.0 to 7.0, non-limiting examples of which 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 therebetween. In some embodiments, the pH is 5.0 to 6.5, or the pH is 5.3 to 6.3.

[0024] In some embodiments, the pharmaceutical composition further comprises a liquid medium, such as water, physiological saline, glucose injection, etc.

[0025] In some embodiments, the pharmaceutical composition comprises:

[0026] (a) 10 mg / mL to 180 mg / mL of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and (b) 10 mg / mL to 250 mg / mL of arginine, wherein the pH of the pharmaceutical composition is 5.0 to 6.5.

[0027] In some embodiments, the pharmaceutical composition comprises:

[0028] (a) 30 mg / mL to 180 mg / mL of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and (b) 30 mg / mL to 200 mg / mL of arginine, wherein the arginine is a combination of free arginine and arginine hydrochloride, wherein the weight ratio of the free arginine to the arginine hydrochloride is 1:0.1-1:20, and the pH of the pharmaceutical composition is 5.3 to 6.3.

[0029] In some embodiments, the pharmaceutical composition comprises:

[0030] (a) 10 mg / mL to 180 mg / mL of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (b) 10 mg / mL to 250 mg / mL of arginine, and (c) 1 mg / mL to 80 mg / mL of sodium chloride, wherein the pH of the pharmaceutical composition is 5.0 to 6.5.

[0031] The present disclosure also provides a lyophilized preparation comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the lyophilized preparation is obtained by freeze-drying the pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as described above.

[0032] The present disclosure also provides a reconstituted solution containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the reconstituted solution is prepared by reconstituted the lyophilized preparation as described above.

[0033] The present disclosure also provides a method for preparing the aforementioned reconstituted solution, which comprises the step of reconstituted the aforementioned lyophilized preparation, wherein the solution used for reconstitution is selected from but not limited to water for injection, physiological saline or glucose solution.

[0034] The present disclosure also provides a lyophilized preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the preparation can form the pharmaceutical composition described above after reconstitution.

[0035] The present disclosure also provides a method for preparing a lyophilized preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which comprises the step of freeze-drying the pharmaceutical composition as described above.

[0036] The present disclosure also provides a product, comprising a container, wherein the container is filled with the pharmaceutical composition, lyophilized preparation or reconstituted solution as described above. In some embodiments, the container is a neutral borosilicate glass tube injection bottle.

[0037] In some embodiments, the lyophilized formulation of the present disclosure is placed under conditions of 25° C. and 60% RH for 1 month, and the purity of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof decreases by less than 4.0%, and may be 4.0%, 3.9%, 3.8%, 3.7%, 3.6%, 3.5%, 3.4%, 3.3%, 3.2%, 3.1%, 3.0%, 2.9%, 2.8 ...9%, 3.8%, 3.9%, 3.8%, 3.9%, 3.8%, 3.9%, 3.8%, 3.9%, 3.8%, 3.9%, 3.8%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3.9%, 3 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.

[0038] In some embodiments, the lyophilized formulation of the present disclosure is placed under conditions of 25° C. and 60% RH for 3 months, and the purity of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof decreases by less than 5.0%, and can be 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%, 3.4%, 3.3%, 4.4%, 4.6 ... 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.

[0039] The pharmaceutical compositions, lyophilized formulations, and reconstituted solutions disclosed herein can be used to prevent and treat diseases caused by pathogenic bacteria in mammals, including humans. Examples of such uses include airway infections, urinary tract infections, respiratory infections, septicemia, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, myelomeningomyelitis, otitis media, enteritis, empyema, traumatic infections, and opportunistic infections.

[0040] The pharmaceutical composition, lyophilized preparation, and reconstituted solution disclosed herein can also be used to prevent and treat diseases caused by Gram-negative bacteria. The Gram-negative bacteria are preferably Gram-negative bacteria of intestinal bacteria (Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.), Gram-negative bacteria living in the respiratory system (Haemophilus, Moraxella, etc.) and glucose non-fermenting Gram-negative bacteria (Pseudomonas aeruginosa, Pseudomonas other than P. aeruginosa, Stenotrophomonas, Burkholderia, Acinetobacter, etc.).

[0041] As used herein, the terms "about" and "approximately" refer to values ​​that are within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, in each practice in the art, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%. In addition, particularly for biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. Unless otherwise indicated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[0042] The numerical values ​​in this disclosure are instrumental measurements or calculated values ​​after instrumental measurement, and are subject to a certain degree of error. Generally speaking, a value within a reasonable error range of plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used must be considered. For example, the total impurity content, which is a value with an error variation of no more than plus or minus 10% after measurement, can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0043] The “weight to volume ratio” described in the present disclosure refers to the weight (in g) of the component contained in every 100 mL of liquid system, that is, g / 100 mL. DETAILED DESCRIPTION

[0044] Example 1: Solubility test of the compound represented by formula (I)

[0045] Different solvent systems were prepared to test the solubility of the compound represented by formula (I). The results are shown in Table 1.

[0046] Table 1 Solubility test

[0047] Example 2

[0048] According to the formulation in Table 2, the compound represented by Formula (I) was weighed, added to a small beaker, and suspended in water for injection. During stirring, the target pH was adjusted using a buffer solution or arginine. The protective excipients listed in Table 2 were added proportionally. After stirring and dissolving, water for injection was added to adjust the concentration to the drug concentration shown in Table 2. Sterile filtration was performed to obtain an intermediate drug solution. A certain amount of the intermediate drug solution was dispensed into vials and freeze-dried to obtain the final sterile powder preparation.

[0049] Table 2 Composition

[0050] Example 3

[0051] The powdered preparation sample prepared in Example 2 was dried and then nitrogen-filled and packaged. The sample was placed under accelerated conditions (25°C, 60% RH) and the active ingredient and impurity content of the sample were determined. Detection method: Detection was performed using a high-performance liquid chromatography system. 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.

[0052] The test results are shown in the table below.

[0053] Table 3 Stability test

[0054] After 2 months of storage under accelerated conditions, the purity of the formulation containing arginine changed minimally (<1%), indicating good stability, while the purity of the formulations using other protective excipients decreased significantly.

[0055] Example 4

[0056] According to the formulation in Table 4, 500 mg of the compound represented by formula (I) was weighed, added to a small beaker, and suspended in water for injection. While stirring continuously, 96 mg of arginine was added, and after dissolving, the pH was adjusted to 5.4-5.8 using sodium hydroxide or hydrochloric acid. 609.49 mg of arginine hydrochloride was added, and after dissolving, the volume was made up to 5 ml with water for injection. Sterile filtration was performed to obtain an intermediate drug solution. The preparation solution was filled into a vial and freeze-dried to obtain the final sterile powder preparation.

[0057] Table 4 (Specification: 500 mg) Note: [1] The total amount of arginine and arginine hydrochloride is calculated as arginine, accounting for 12% of the prescription. [2] Water for injection is removed during the freeze-drying process.

[0058] The stability of the formulations under accelerated conditions (25°C, 60% RH) is as follows.

[0059] Table 5 Stability test

Claims

1. A pharmaceutical composition comprising a compound represented by formula (I) 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 arginine is 0.01% to 30%, preferably 0.1% to 20%, more preferably 1% to 15%.

4. A 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, 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 1:0.1-1:

20.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition further comprises other protective excipients, wherein the protective excipients are preferably selected from one or more of amino acids, sugars, high molecular weight polymer sugars, cyclodextrins, and inorganic salts, 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, wherein the buffer is preferably selected from acetate buffer, citrate buffer, histidine buffer and succinate buffer.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises a pH adjuster, preferably the pH adjuster is 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, more preferably 5.3 to 6.

3.

10. The pharmaceutical composition according to any one of claims 1 to 9, comprising: (a) 10 mg / mL to 180 mg / mL of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (b) 10 mg / mL to 250 mg / mL of arginine, wherein the pH of the pharmaceutical composition is 5.0 to 6.5, Preferably, the pharmaceutical composition comprises: (a) 30 mg / mL to 180 mg / mL of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (b) 30 mg / mL to 200 mg / mL of arginine, wherein the arginine is a combination of free arginine and arginine hydrochloride, wherein the weight ratio of the free arginine to the arginine hydrochloride is 1:0.1-1:20, and the pH of the pharmaceutical composition is 5.3 to 6.3; or The pharmaceutical composition comprises: (a) 10 mg / mL to 180 mg / mL of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (b) 10 mg / mL to 250 mg / mL of arginine, and (c) 1 mg / mL to 80 mg / mL of sodium chloride, wherein the pH of the pharmaceutical composition is 5.0 to 6.

5.

11. A lyophilized preparation, wherein the lyophilized preparation can form the pharmaceutical composition according to any one of claims 1 to 10 after being reconstituted. 12 . A lyophilized preparation, wherein the lyophilized preparation is obtained by freeze-drying the pharmaceutical composition according to claim 1 .

13. A reconstituted solution, wherein the reconstituted solution is prepared by reconstituted the lyophilized preparation according to claim 11 or 12.

14. Use 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 preparation of a drug for treating a disease caused by pathogenic bacteria in a mammal, wherein the drug is preferably used for treating respiratory tract infections, urinary tract infections, respiratory infections, septicemia, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, myelomeningomyelitis, otitis media, enteritis, empyema, traumatic infections, and opportunistic infections.

15. Use 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 preparation of a drug for treating a disease caused by Gram-negative bacteria.

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