Pharmaceutical compositions containing beta-lactamase inhibitors and their uses

Abstract

The present invention discloses a pharmaceutical composition containing a β-lactamase inhibitor and its use, specifically, pharmaceutical composition A, whose active ingredients include substance A and substance B. Substance A is compound 1 or a solvate thereof, substance B is imipenem or a solvate thereof, and the mass ratio of substance B to substance A is 1:1 to 10:1, with the mass of substance B calculated as imipenem and the mass of substance A calculated as compound 1. The pharmaceutical composition of the present invention can effectively inhibit various bacteria resistant to β-lactam antibiotics, and can significantly increase the solubility of compound 1 in aqueous solution, thereby improving its stability. [Formula 1] TIFF2026505086000024.tif26169

Description

Detailed Description of the Invention

[0001] This application claims priority from Chinese Patent Application No. 2023100766170, filed on February 2, 2023. This application cites the full text of said Chinese patent application.

[0002] Technical Field The present invention belongs to the field of pharmaceutical preparations, and in particular to pharmaceutical compositions containing β-lactamase inhibitors and uses thereof.

[0003] Background technology β-Lactam antibiotics have become the antibacterial agents of first choice in clinical practice, but the efficacy of related antibiotics is currently affected by bacterial β-lactamases that can result in resistance to penicillins, broad-spectrum cephalosporins, monolactams, and carbapenems.

[0004] β-lactamase inhibitors slow or inhibit the degradation of β-lactam antibiotics, restoring the susceptibility of bacteria resistant to β-lactam antibiotics to these antibiotics. Currently, in clinical practice, the combination of β-lactamase inhibitors with β-lactam antibiotics inactivates the hydrolytic activity of β-lactamases, thereby increasing bacterial susceptibility to β-lactam antibiotics and reducing or overcoming the problem of drug resistance. Many β-lactamase inhibitors are currently available on the market, including clavulanic acid, tazobactam, avibactam, and relebactam. However, the inhibitory effects of these β-lactamase inhibitors on β-lactamase activity are still not fully satisfactory. Therefore, there is an urgent need to develop new β-lactamase inhibitors that can be used in combination with β-lactam antibiotics to treat infections caused by bacteria resistant to β-lactam antibiotics.

[0005] The World Health Organization (WHO) has identified carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Acinetobacter spp. (CRAB) as drug-resistant bacteria that pose a serious threat. The development of a new generation of anti-resistant drugs to effectively address these issues is urgently needed. Evopoint's innovative β-lactamase inhibitor, Compound 1, specifically targets bacterial resistance and addresses the ineffectiveness of existing β-lactamase inhibitors against CRE, CRPA, and CRAB. Compound 1 effectively inhibits OXA-type β-lactamases, the primary mechanism of carbapenem resistance in Acinetobacter spp., in vitro, whereas similar commercially available or investigational products lack inhibitory activity against OXA.

[0006] International application WO2019144912A discloses a β-lactamase inhibitor or an ester, stereoisomer, or pharmaceutically acceptable salt thereof, and methods for preparing the same, as well as a pharmaceutical composition comprising the β-lactamase inhibitor or an ester, stereoisomer, or pharmaceutically acceptable salt thereof, wherein: [ka] This relates to compound 1 shown in

[0007] Compound 1 is a poorly soluble, small-molecule drug with low aqueous solubility (0.6 mg / mL). Its low stability and tendency to precipitate during storage and use make it unsuitable for use in combination with other antibacterial agents. To date, no pharmaceutical compositions containing Compound 1 have been found to effectively inhibit various bacteria resistant to β-lactam antibiotics. Furthermore, the development of an injectable formulation of Compound 1 with significantly increased solubility in aqueous solutions and improved stability is urgently needed.

[0008] Summary of the Invention The technical problem to be solved by the present invention is the gap in the field of pharmaceutical compositions containing Compound 1 that can effectively inhibit various bacteria, and to address this gap, a pharmaceutical composition containing a β-lactamase inhibitor and its use are provided. The pharmaceutical composition of the present invention can effectively inhibit various bacteria resistant to β-lactam antibiotics, and can significantly increase the solubility of Compound 1 in aqueous solution, improving its stability.

[0009] The present invention solves the above technical problems by the following technical solutions.

[0010] The present invention provides a pharmaceutical composition A, the active ingredients of which include substance A and substance B; said substance A is compound 1 or a solvate thereof; the substance B is imipenem or a solvate thereof; The mass ratio of the substance B to the substance A is 1:1 to 10:1, and the mass of the substance B is calculated as imipenem, and the mass of the substance A is calculated as compound 1.

[0011] In some embodiments, the active ingredients of said pharmaceutical composition A consist of substance A and substance B.

[0012] In some embodiments, the mass ratio of substance B to substance A is 1:1, 2:1, 3:1, 4:1, 5:1, 7:1, or 10:1.

[0013] In some embodiments, the mass ratio of the substance B to the substance A is 1:1 to 4:1. In some embodiments, the mass ratio of the substance B to the substance A is 1:1 to 2:1.

[0014] In some embodiments, the mass ratio of substance B to substance A is 2:1.

[0015] In some embodiments, the mass percentage of Compound 1 in Pharmaceutical Composition A is 2% to 15%, preferably 5% to 10%, for example, 6.44%, 6.50%, 6.97%, 7.29%, or 8.93%.

[0016] In some embodiments, the mass percentage of imipenem in Pharmaceutical Composition A is 5 to 20%, preferably 8 to 15%.

[0017] In some embodiments, in the pharmaceutical composition A, the substance B is imipenem monohydrate.

[0018] In some embodiments, in the pharmaceutical composition A, the substance B is imipenem monohydrate, and the mass percentage of the imipenem monohydrate is preferably 9% to 16%, for example, 13.81%, 13.68%, 15.45%, 13.67%, 14.80%, or 9.48%.

[0019] In some embodiments, in the pharmaceutical composition A, the substance A is compound 1.

[0020] In some embodiments, in the pharmaceutical composition A, the pharmaceutical composition A may further comprise a pharmaceutically acceptable excipient.

[0021] In some embodiments, in Pharmaceutical Composition A, the pharmaceutically acceptable excipient comprises a solubilizing agent.

[0022] In some embodiments, in said pharmaceutical composition A, said pharmaceutically acceptable excipient further comprises one or more of a bulking agent and a pH adjusting agent.

[0023] In some embodiments, in Pharmaceutical Composition A, the selected filler is selected from one or more of mannitol, lactose, sucrose, microcrystalline cellulose, glucose, fructose, povidone, and trehalose, preferably selected from mannitol and / or povidone.

[0024] In some embodiments, the mass percentage of the filler in Pharmaceutical Composition A is 0.3% to 70%, for example, 30% to 70% (preferably, 35% to 50%), for example, 0.33%, 1.29%, or 40.82%.

[0025] In some embodiments, in Pharmaceutical Composition A, the selected solubilizer is selected from one or more of sulfobutylether β-cyclodextrin sodium (SBECD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), N-methyl-D(-)-glucamine, and polysorbate 80, preferably sulfobutylether β-cyclodextrin sodium and / or 2-hydroxypropyl-β-cyclodextrin, and particularly preferably sulfobutylether β-cyclodextrin sodium.

[0026] In some embodiments, the mass percentage of the solubilizer in Pharmaceutical Composition A is 20% to 70%, for example, 20.41%, 64.38%, 62.73%, 65.03%, 64.40%, or 71.40%, preferably 50% to 70%.

[0027] In some embodiments, in the pharmaceutical composition A, the mass ratio of the substance A to the solubilizing agent is 1:(2 to 13), for example, 1:2.8, 1:5, 1:7.5, 1:8, 1:9, 1:10, or 1:12.5, preferably 1:(10 to 13), and the mass of the substance A is calculated as compound 1.

[0028] In some embodiments, in Pharmaceutical Composition A, the selected pH adjuster is selected from one or more of anhydrous citric acid, sodium hydroxide, sodium bicarbonate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate, disodium tartrate, maleic acid, magnesium hydroxide, calcium hydroxide, preferably one or more of sodium bicarbonate, sodium hydroxide, and anhydrous citric acid.

[0029] In some embodiments, the mass percentage of the pH adjuster in Pharmaceutical Composition A is 0% to 2.0%, for example, 0.52%, 0.58%, 0.70%, 0.71%, or 1.83%, preferably 0.3% to 0.7%.

[0030] In some embodiments, Pharmaceutical Composition A is in the form of an injectable agent (eg, a lyophilized powder).

[0031] The present invention also provides the use of pharmaceutical composition A in the preparation of a medicament for inhibiting bacteria resistant to β-lactam antibiotics.

[0032] In some embodiments, the beta-lactam antibiotic resistant bacteria is selected from one or more of Pseudomonas aeruginosa, Acinetobacter spp., and Klebsiella pneumoniae.

[0033] The present invention also provides the use of substance A in the preparation of a medicament for inhibiting bacteria, wherein substance A is used in combination with substance B, the mass ratio of substance B to substance A being as defined above, and the bacteria being as defined above.

[0034] The present invention also provides the use of substance B in the preparation of a medicament for inhibiting bacteria, wherein substance B is used in combination with substance A, the mass ratio of substance B to substance A being as defined above, and the bacteria being as defined above.

[0035] The present invention also provides a pharmaceutical composition B, the active ingredients of which include substance A, substance B and substance C, said substance A is compound 1 or a solvate thereof; the substance B is imipenem or a solvate thereof; said substance C is cilastatin or a solvate thereof; The mass ratio of the substance C:substance B:substance A was (1-10):(1-10):1, and the mass of the substance C was calculated as cilastatin, the mass of the substance B as imipenem, and the mass of the substance A as compound 1.

[0036] In some embodiments, the active ingredients of said pharmaceutical composition B consist of substance A, substance B and substance C.

[0037] In some embodiments, the mass ratio of substance C:substance B:substance A is 1:1:1, 2:2:1, 3:3:1, 4:4:1, 5:5:1, 7:7:1, or 10:10:1.

[0038] In some embodiments, the mass ratio of substance C:substance B:substance A is (1-4):(1-4):1.

[0039] In some embodiments, the mass ratio of substance C:substance B:substance A is (1-2):(1-2):1.

[0040] In some embodiments, the mass ratio of substance C:substance B:substance A is 2:2:1.

[0041] In some embodiments, the mass percentage of Compound 1 in Pharmaceutical Composition B is 2% to 15%, preferably 5% to 10%, for example, 6.44%, 6.50%, 6.97%, 7.29%, or 8.93%.

[0042] In some embodiments, the mass percentage of imipenem in Pharmaceutical Composition B is 5 to 20%, preferably 8 to 15%.

[0043] In some embodiments, the mass percentage of cilastatin sodium in Pharmaceutical Composition B is 5 to 20%, preferably 8% to 15%, and the mass of cilastatin sodium is calculated as cilastatin.

[0044] In some embodiments, in Pharmaceutical Composition B, Substance B is imipenem monohydrate, and the mass percentage of the imipenem monohydrate is preferably 9% to 16%, for example, 13.81%, 13.68%, 15.45%, 13.67%, 14.80%, or 9.48%.

[0045] In some embodiments, in pharmaceutical composition B, substance A is compound 1.

[0046] In some embodiments, in pharmaceutical composition B, substance B is imipenem monohydrate.

[0047] In some embodiments, in pharmaceutical composition B, substance C is cilastatin sodium.

[0048] In some embodiments, in pharmaceutical composition B, substance C is present in the amorphous form of cilastatin sodium, and the mass percentage of cilastatin sodium is preferably 9% to 16%, for example, 13.81%, 13.68%, 9.48%, 13.67%, 14.80%, or 15.45%.

[0049] In some embodiments, in the pharmaceutical composition B, the pharmaceutical composition B may further comprise a pharmaceutically acceptable excipient.

[0050] In some embodiments, in Pharmaceutical Composition B, the pharmaceutically acceptable excipient comprises a solubilizer.

[0051] In some embodiments, in said pharmaceutical composition B, said pharmaceutically acceptable excipient further comprises one or more of a bulking agent and a pH adjusting agent.

[0052] In some embodiments, in Pharmaceutical Composition B, the selected filler is selected from one or more of mannitol, lactose, sucrose, microcrystalline cellulose, glucose, fructose, povidone, and trehalose, preferably selected from mannitol and / or povidone.

[0053] In some embodiments, the mass percentage of the filler in Pharmaceutical Composition B is 0.3% to 70%, for example, 30% to 70% (preferably, 35% to 50%), for example, 0.33%, 1.29%, or 40.82%.

[0054] In some embodiments, in Pharmaceutical Composition B, the selected solubilizer is selected from one or more of sulfobutylether β-cyclodextrin sodium (SBECD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), N-methyl-D(-)-glucamine, and polysorbate 80, preferably sulfobutylether β-cyclodextrin sodium and 2-hydroxypropyl-β-cyclodextrin, and particularly preferably sulfobutylether β-cyclodextrin sodium.

[0055] In some embodiments, the mass percentage of the solubilizer in Pharmaceutical Composition B is 20% to 70%, for example, 20.41%, 64.38%, 62.73%, 65.03%, 64.40%, or 71.40%, preferably 50% to 70%.

[0056] In some embodiments, in pharmaceutical composition B, the mass ratio of substance A to the solubilizing agent is 1:(2 to 13), for example, 1:2.8, 1:5, 1:7.5, 1:8, 1:9, 1:10, or 1:12.5, preferably 1:(10 to 13), and the mass of substance A is calculated as compound 1.

[0057] In some embodiments, in Pharmaceutical Composition B, the selected pH adjuster is selected from one or more of anhydrous citric acid, sodium hydroxide, sodium bicarbonate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate, disodium tartrate, maleic acid, magnesium hydroxide, calcium hydroxide, preferably one or more of sodium bicarbonate, anhydrous citric acid, and sodium hydroxide.

[0058] In some embodiments, the mass percentage of the pH adjuster in Pharmaceutical Composition B is 0% to 2.0%, for example, 0.52%, 0.58%, 0.70%, 0.71%, or 1.83%, preferably 0.3% to 0.7%.

[0059] In some embodiments, Pharmaceutical Composition B comprises Compound 1, sulfobutyl ether β-cyclodextrin sodium, mannitol, imipenem monohydrate, cilastatin sodium, and sodium bicarbonate.

[0060] In some embodiments, Pharmaceutical Composition B comprises Compound 1, sulfobutyl ether β-cyclodextrin sodium, anhydrous citric acid, sodium hydroxide, imipenem monohydrate, cilastatin sodium, and sodium bicarbonate.

[0061] In some embodiments, Pharmaceutical Composition B comprises Compound 1, sulfobutyl ether β-cyclodextrin sodium, imipenem monohydrate, cilastatin sodium, and sodium bicarbonate.

[0062] In some embodiments, Pharmaceutical Composition B comprises Compound 1, sulfobutyl ether β-cyclodextrin sodium, povidone, imipenem monohydrate, cilastatin sodium, and sodium bicarbonate.

[0063] In some embodiments, Pharmaceutical Composition B comprises 7.29% Compound 1, 20.41% sulfobutyl ether β-cyclodextrin sodium, 40.82% mannitol, 15.45% imipenem monohydrate, 15.45% cilastatin sodium, and 0.58% sodium bicarbonate, wherein the percentages are by weight.

[0064] In some embodiments, Pharmaceutical Composition B comprises 6.44% Compound 1, 64.38% sulfobutyl ether β-cyclodextrin sodium, 0.99% anhydrous citric acid, 0.32% sodium hydroxide, 13.67% imipenem monohydrate, 13.67% cilastatin sodium, and 0.52% sodium bicarbonate, wherein the percentages are by weight.

[0065] In some embodiments, Pharmaceutical Composition B comprises 6.97% Compound 1, 62.73% sulfobutyl ether β-cyclodextrin sodium, 14.80% imipenem monohydrate, 14.80% cilastatin sodium, and 0.70% sodium bicarbonate, wherein the percentages are by weight.

[0066] In some embodiments, Pharmaceutical Composition B comprises 8.93% Compound 1, 71.40% sulfobutyl ether β-cyclodextrin sodium, 9.48% imipenem monohydrate, 9.48% cilastatin sodium, and 0.71% sodium bicarbonate, wherein the percentages are by weight.

[0067] In some embodiments, Pharmaceutical Composition B comprises 6.50% Compound 1, 65.03% sulfobutyl ether β-cyclodextrin sodium, 0.33% povidone, 0.52% sodium bicarbonate, 13.81% imipenem monohydrate, and 13.81% cilastatin sodium, where the percentages are by weight.

[0068] In some embodiments, Pharmaceutical Composition B comprises 6.44% Compound 1, 64.40% sulfobutyl ether β-cyclodextrin sodium, 1.29% povidone, 0.52% sodium bicarbonate, 13.68% imipenem monohydrate, and 13.68% cilastatin sodium, where the percentages are by weight.

[0069] In some embodiments, said pharmaceutical composition B is in the form of an injectable preparation.

[0070] In some embodiments, when the pharmaceutical composition B is in the form of an injection, the content of imipenem / cilastatin / compound 1 in the pharmaceutical composition B is 250 mg / 250 mg / 125 mg or 500 mg / 500 mg / 250 mg.

[0071] The present invention also provides the use of Pharmaceutical Composition B in the preparation of a medicament for inhibiting bacteria resistant to β-lactam antibiotics.

[0072] In some embodiments, the beta-lactam antibiotic resistant bacteria is selected from one or more of Pseudomonas aeruginosa, Acinetobacter spp., and Klebsiella pneumoniae.

[0073] The present invention also provides the use of substance A in the preparation of a medicament for inhibiting bacteria, wherein said substance A is used in combination with said substance B and said substance C, wherein the mass ratio of said substance C to said substance B to said substance A is as defined above, and said bacteria is as defined above.

[0074] The present invention also provides the use of substance B in the preparation of a medicament for inhibiting bacteria, wherein substance B is used in combination with substance A and substance C, the mass ratio of substance C to substance B to substance A being as defined above, and the bacteria being as defined above.

[0075] The present invention also provides the use of substance C in the preparation of a medicament for inhibiting bacteria, wherein said substance C is used in combination with said substance A and said substance C, wherein the mass ratio of said substance C to said substance B to said substance A is as defined above, and said bacteria is as defined above.

[0076] In the present invention, the structural formula of the imipenem monohydrate is as follows: [ka]

[0077] In the present invention, the structural formula of the cilastatin sodium is as follows: [ka]

[0078] In the present invention, the structural formula of Compound 1 is as follows: [ka]

[0079] In the present invention, the term "solvate" refers to a substance formed by combining a compound with a solvent (including, but not limited to, water, methanol, ethanol, etc.). Solvates include stoichiometric solvates and non-stoichiometric solvates. Solvates include, but are not limited to, monohydrates.

[0080] The above preferred conditions can be combined in any way consistent with the common sense of a person skilled in the art to obtain preferred embodiments of the present invention.

[0081] The reagents and materials used in the present invention are commercially available.

[0082] The positive and progressive effects of the present invention are that the pharmaceutical composition of the present invention can effectively inhibit various bacteria resistant to β-lactam antibiotics, and can significantly increase the solubility of Compound 1 in aqueous solution and improve its stability.

[0083] Specific Embodiments Compound 1 used in the following examples was obtained from Bellen Chemistry Co. Ltd (China) with lot number 18090301.

[0084] The male mice used in the following examples were obtained from Charles River UK and were specific pathogen free (SPF grade).

[0085] In the following examples, culture load data were analyzed with StatsDirect software, version 3.1.14, using appropriate nonparametric statistical models (Kruskal-Wallis with Conover-Inman used for all pairwise comparisons between groups).

[0086] The method for testing the solubility of Compound 1 (or the method for testing the content of Compound 1) in Examples 6, 7, and 10 below is shown in the table below: [Table 1]

[0087] The test methods for related substances (e.g., total impurities) and moisture content in Examples 7 and 10 are shown in the following table: [Table 2] TIFF2026505086000008.tif153169

[0088] Total impurities refer to all impurities excluding compound 1, and the y fraction calculation formula is 1-(compound 1 peak area / total peak area).

[0089] Moisture measurement method: This product was taken and measured according to the moisture determination method (Chinese Pharmacopoeia 2020 Edition, Four Parts General Provisions 0832, Method 1 2).

[0090] In the examples below, the following experimental procedures were followed.

[0091] (1) Mouse immunization: To reduce neutrophil counts through immunosuppression, all mice received intraperitoneal injections of cyclophosphamide at 150 mg / kg 4 days before inoculation and 100 mg / kg 1 day before inoculation. The immunosuppressive regimen induced neutropenia, which began 24 hours after injection and continued for the duration of the study. Mice were inoculated approximately 24 hours after the second immunosuppressive dose.

[0092] (2) Bacterial culture: All bacterial strains used for inoculation were prepared from overnight broth cultures. Briefly, each strain was grown in Mueller-Hinton broth with cation-adjusted concentrations in a shaking incubator (300 RPM) at 37°C. The overnight cultures were washed twice with phosphate-buffered saline (PBS) and adjusted to optimal concentrations in PBS. The bacterial concentration was confirmed by plating samples on drug-free CLED agar medium.

[0093] (3) Under temporary general anesthesia with isoflurane inhalation, mice were inoculated by injecting 50 μL of the bacterial solution into the lateral thigh muscles on both sides. After inoculation, all mice were administered appropriate analgesics and observed until they fully recovered from anesthesia.

[0094] (4) Imipenem and Compound 1 were administered sequentially every 2 hours starting 1 hour after inoculation. First, imipenem or imipenem-cilastatin solution was injected subcutaneously, followed immediately by intravenous injection of Compound 1 solution.

[0095] For intravenous administration (IV), Compound 1 solution was prepared in Captisol solvent, a 25 mM acetate buffer (prepared with sodium acetate trihydrate) containing 10% w / v Captisol. The pH was adjusted to 5.0 with 2N acetic acid solution. The required amount of buffer was added to a weighed sample to prepare the required concentration of Compound 1 in the buffer, which was then ultrasonically heated in a water bath until a clear solution was obtained. The dose of Compound 1 was 5 mL / kg.

[0096] For subcutaneous administration (SC), imipenem solution or imipenem-cilastatin solution was prepared in sterile PBS using imipenem monohydrate or imipenem monohydrate and cilastatin sodium. PBS was added to the solid powder to obtain the desired concentration of imipenem, and the solution was sonicated in a water bath until a clear solution was obtained. The dose was 10 mL / kg.

[0097] Example 1 The mice were divided into 15 groups of 5 mice each. The test was performed according to the experimental procedure described above, and 1.83 × 10 5 The doses were administered at a concentration of colony-forming units (CFU) / g of thigh tissue according to the regimen in the table below. [Table 3]

[0098] For groups 2–15, the inoculation was terminated 9 hours after inoculation. Animals were euthanized by an overdose of sodium pentobarbital and confirmed dead by cervical dislocation. After dissection, femurs were weighed and homogenized in ice-cold sterile phosphate buffer using a Precellys bead homogenizer. The homogenates were quantitatively plated onto drug-free agar plates (CLED or PSA) and incubated at 37°C for 18–24 hours, after which colonies were counted.

[0099] For the uninoculated Group 1 (control group), the animals were euthanized by an overdose of sodium pentobarbital 1 hour after inoculation. Both thighs were dissected as described above and quantitatively cultured as the final sample.

[0100] Log 10 The change in CFU / g load and statistical significance compared to Pre-Tx are summarized in the table below. [Table 4]

[0101] Coadministration of imipenem and Compound 1 at a dose ratio of 1:1, 3:1, or 10:1 significantly reduced thigh load below plateau levels when the total imipenem dose was 100 mg / kg, 75 mg / kg, and 50 mg / kg.

[0102] Furthermore, at all dose ratios in which imipenem and Compound 1 were administered in combination, thigh load was significantly reduced compared to the group in which imipenem and Compound 1 were administered alone.

[0103] Example 2 The mice were divided into 16 groups of 5 mice each. The test was performed according to the experimental procedure described above, and 1.83 × 10 5 The doses were administered at a concentration of colony-forming units (CFU) / g of thigh tissue according to the regimen in the table below. [Table 5]

[0104] For groups 2–16, the inoculation was terminated 9 hours after inoculation. Animals were euthanized by an overdose of sodium pentobarbital and confirmed dead by cervical dislocation. After dissection, femurs were weighed and homogenized in ice-cold sterile phosphate buffer using a Precellys bead homogenizer. The homogenates were quantitatively plated onto drug-free agar plates (CLED or PSA) and incubated at 37°C for 18–24 hours, after which colonies were counted.

[0105] For the uninoculated Group 1 (control group), the animals were euthanized by an overdose of sodium pentobarbital 1 hour after inoculation. Both thighs were dissected as described above and quantitatively cultured as the final sample.

[0106] Log 10 The change in CFU / g load and statistical significance compared to Pre-Tx are summarized in the table below. [Table 6]

[0107] Coadministration of imipenem and Compound 1 at a dose ratio of 1:1, 2:1, or 4:1 significantly reduced thigh load below plateau levels at total imipenem doses of 96, 64, 48, and 32 mg / kg. No significant trends were observed in the correlation between load reduction levels and dose ratios within each total dose level.

[0108] Example 3 The mice were divided into 16 groups of 5 mice each. The test was performed according to the experimental procedure described above, and 1.8 × 10 Acinetobacter sp. AR0274 was administered. 6 The inoculum was administered at a dose of CFU / g of thigh tissue according to the regimen in the table below. [Table 7]

[0109] For groups 2–16, the inoculation was terminated 9 hours after inoculation. Animals were euthanized by an overdose of sodium pentobarbital and confirmed dead by cervical dislocation. After dissection, femurs were weighed and homogenized in ice-cold sterile phosphate buffer using a Precellys bead homogenizer. The homogenates were quantitatively plated onto drug-free agar plates (CLED or PSA) and incubated at 37°C for 18–24 hours, after which colonies were counted.

[0110] For the uninoculated Group 1 (control group), the animals were euthanized by an overdose of sodium pentobarbital 1 hour after inoculation. Both thighs were dissected as described above and quantitatively cultured as the final sample.

[0111] Log 10 The change in CFU / g load and statistical significance compared to Pre-Tx are summarized in the table below. [Table 8]

[0112] Coadministration of imipenem and Compound 1 at a 1:1, 2:1, or 4:1 dose ratio significantly reduced thigh load below plateau levels at a total imipenem dose level of 96 mg / kg. Lower total imipenem doses (64 mg / kg) also reduced thigh load below plateau levels, but this was only observed at the 1:1 and 2:1 combination dose ratios. No reduction in load was observed compared to plateau levels at total imipenem doses of 32 mg / kg or 16 mg / kg.

[0113] Furthermore, coadministration of imipenem and Compound 1 significantly reduced thigh load at all dose ratios and at total imipenem doses of 96 mg / kg and 64 mg / kg compared with vehicle, imipenem, or Compound 1 groups, but no significant reduction in thigh load was observed at lower total imipenem dose levels.

[0114] Example 4 The mice were divided into 16 groups of 5 mice each. The test was performed according to the experimental procedure described above. Klebsiella pneumoniae AR0113 was administered at 4.0 × 10 6 The dose was administered at a concentration of CFU / g of thigh tissue according to the regimen shown in the table below. [Table 9]

[0115] For groups 2–16, the inoculation was terminated 9 hours after inoculation. Animals were euthanized by an overdose of sodium pentobarbital and confirmed dead by cervical dislocation. After dissection, femurs were weighed and homogenized in ice-cold sterile phosphate buffer using a Precellys bead homogenizer. The homogenates were quantitatively plated onto drug-free agar plates (CLED or PSA) and incubated at 30°C for 12–16 hours, after which colonies were counted.

[0116] For the uninoculated Group 1 (control group), the animals were euthanized by an overdose of sodium pentobarbital 1 hour after inoculation. Both thighs were dissected as described above and quantitatively cultured as the final sample.

[0117] Log 10 The change in CFU / g load and statistical significance compared to Pre-Tx are summarized in the table below. [Table 10]

[0118] When imipenem and Compound 1 were coadministered at a dose ratio of 1:1, 2:1, or 4:1 at a total imipenem dose level of 96 mg / kg, thigh load was slightly lower but significantly reduced to below the plateau level. In the low-dose imipenem (32 mg / kg, 12 mg / kg, or 6 mg / kg) groups, thigh load did not decrease to the plateau level.

[0119] Furthermore, coadministration of imipenem and Compound 1 significantly reduced thigh load at all dose ratios at the 96 mg / kg and 64 mg / kg total imipenem dose levels compared with vehicle, imipenem, or Compound 1-treated groups, but did not reduce thigh load at lower total imipenem dose levels.

[0120] Example 5 A total of 15 strains (four strains of Pseudomonas aeruginosa, four strains of Klebsiella pneumoniae, and seven strains of Acinetobacter; see the table below for details) were selected and a dose-finding study of Compound 1 was conducted using a neutropenic mouse thigh infection model. Regarding dosage, imipenem was administered in a human-simulating dosing regimen (500 mg, 6 hours, 60 min intravenous infusion) in combination with different doses of Compound 1. [Table 11]

[0121] (1) Pseudomonas aeruginosa At time 0, the mean (±SD) bacterial load in the thighs of mice was 5.64±0.41 log 10 CFU / thigh. For the four isolates tested, sufficient bacterial growth was achieved in the neutropenic mouse thigh infection model. In untreated vehicle control mice, the mean increase in bacterial load after 24 hours was 3.33 ± 0.62 log 10 In vitro resistance to imipenem was confirmed in in vivo testing of these four strains. The mean increase in bacterial load in the imipenem-only group using a human-mimetic regimen was 2.64 ± 1.18 log 10 CFU / thigh. With a human-mimetic dosing regimen of imipenem / compound 1 500 / 250 mg (2:1), all four P. aeruginosa isolates achieved 2-log eradication rates.

[0122] (2) Acinetobacter At time 0, the mean bacterial load in the thighs of mice was 5.97 ± 0.18 log 10 CFU / thigh. For the seven isolates tested, sufficient bacterial growth was achieved in the neutropenic mouse thigh infection model. In untreated vehicle control mice, the mean increase in bacterial load after 24 hours was 2.32 ± 0.84 log 10In vitro resistance to imipenem was confirmed in in vivo testing of these seven strains. The mean increase in bacterial load in the imipenem-only group using a human-mimetic regimen was 2.16 ± 0.74 log 10 The simulated dosing regimen of imipenem / Compound 1 500 / 250 mg (2:1) achieved 1-log eradication rates for all Acinetobacter species except for ACB 160. Five of seven isolates achieved approximately 2-log eradication rates.

[0123] (3) Klebsiella pneumoniae At time 0, the mean bacterial load in the thighs of mice was 5.92 ± 0.14 log 10 CFU / thigh. Adequate bacterial growth was achieved in the neutropenic mouse thigh infection model for the four isolates tested. In untreated vehicle control mice, the mean increase in bacterial load after 4 hours was 3.15 ± 1.00. In vitro resistance to imipenem was confirmed in in vivo testing of these seven isolates. The mean increase in bacterial load in the imipenem-only group using a human-mimetic dosing regimen was 2.83 ± 0.81 log 10 The human-mimetic dosing regimen of imipenem / Compound 1 500 / 250 mg (2:1) achieved or surpassed growth plateau for all strains tested, but did not achieve a mean 1-log eradication rate.

[0124] In conclusion, the imipenem / compound 1 combination (500 / 250 mg q6h, 1 h intravenous infusion) demonstrated significant in vivo efficacy against serine carbapenemase-producing Pseudomonas aeruginosa, Acinetobacter spp., and Klebsiella pneumoniae in a neutropenic mouse thigh infection model, providing a rationale for considering this combination and dose in clinical trials for the treatment of serious infections caused by these bacteria.

[0125] The combined dose ratio test in the above examples showed that Compound 1 restored the in vivo antibacterial activity of imipenem against the tested resistant strains when the tested dose ratio of imipenem to Compound 1 was 1:1 to 10:1. When imipenem and Compound 1 were administered at sufficient doses, a combined dose ratio of 1:1 to 4:1 was suitable for Acinetobacter spp., Klebsiella pneumoniae, and Pseudomonas aeruginosa strains, and a combined dose ratio of 1:1 or 1:2 was more suitable and can be used for further nonclinical and clinical evaluations.

[0126] Example 6 Selection of the type of solubilizer The solubilizing effects of sulfobutyl ether β-cyclodextrin sodium (SBECD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) on compound 1 were investigated, using the solubilities in 50 mM pH 4.5 acetate buffer and water as controls. The results showed that SBECD and HP-β-CD solubilized compound 1, with SBECD exhibiting superior solubilizing effects. The results are shown in the table below. [Table 12]

[0127] In this field, surfactants are also used for solubilization. To further improve the solubility of Compound 1, surfactants were added based on SBECD and the solubility was examined. The results showed that the addition of surfactants did not significantly improve the solubility of Compound 1. The results are shown in the table below. [Table 13]

[0128] Example 7 Selection of the amount of solubilizer to be added The key to developing an injectable imipenem / cilastatin / Compound 1 formulation is to increase the solubility of the active ingredient, Compound 1, and improve the stability of Compound 1. We investigated the amount of SBECD added that would dissolve Compound 1 and meet the quality specifications for lyophilized powder of Compound 1 when the dissolution temperature was between 85°C and 90°C.

[0129] Formulas were designed with mass ratios of Compound 1:SBECD of 1:5, 1:7.5, 1:10, and 1:12.5, respectively, and solutions were prepared by dissolving both compounds in water at 85-90°C for 10 minutes to examine the dissolution status during each solution preparation step and the effect on the lyophilized powder of Compound 1. The results are shown in the table below. [Table 14]

[0130] When the ratio of Compound 1:SBECD was 1:5, Compound 1 was not completely dissolved during the solution preparation stage, and the reconstituted solution of the lyophilized powder after lyophilization was cloudy. When the ratio of Compound 1:SBECD was 1:7.5, Compound 1 was essentially completely dissolved during the solution preparation stage, but the reconstituted solution of the lyophilized powder after lyophilization was slightly cloudy, which was also unacceptable. When the ratio of Compound 1:SBECD was 1:10 and 1:12.5, Compound 1 was completely dissolved, and the reconstituted solution of the lyophilized powder after lyophilization was clear.

[0131] Example 8 The amounts of Compound 1 composition injection were 125 mg of Compound 1, 250 mg of imipenem, and 250 mg of cilastatin. Imipenem monohydrate and cilastatin sodium were added after converting based on their molecular formulas.

[0132] Prescription (100 vials) Compound 1 12.5g Sulfobutyl ether β-cyclodextrin sodium 35.0g Mannitol 70.0g Imipenem monohydrate 26.5g Cilastatin sodium 26.5g Sodium bicarbonate 1.0g purified water *1 Add up to 3.5L Note*1: Purified water was removed by the freeze-drying process.

[0133] Preparation process: Add an appropriate amount of water to a beaker, add 35.0 g of sulfobutyl ether beta-cyclodextrin sodium and 70.0 g of mannitol to the beaker, stir to dissolve, heat to 70 ° C in a water bath, add Compound 1 drug substance, stir to dissolve until clear, cool to room temperature, add 26.5 g of imipenem monohydrate, 26.5 g of cilastatin sodium, and 1.0 g of sodium bicarbonate, and when clear, filter through a 0.45 μm membrane filter, dispense, and freeze-dry to obtain Compound 1 composition injection.

[0134] Example 9 The amounts of Compound 1 composition injection prepared were 50 mg of Compound 1, 100 mg of imipenem, and 100 mg of cilastatin. The formulation was (for 100 vials), and imipenem monohydrate and cilastatin sodium were added after conversion based on their molecular formulas.

[0135] Compound 1 5g Sulfobutyl ether beta-cyclodextrin sodium 50g Anhydrous citric acid 0.77g 0.25g sodium hydroxide Imipenem monohydrate 10.62g Cilastatin sodium 10.62g Sodium bicarbonate 0.4g purified water *1 Add up to 1L Note*1: Purified water was removed by the freeze-drying process.

[0136] Preparation process: Add an appropriate amount of water to a beaker, add 50.0 g of sulfobutyl ether beta-cyclodextrin sodium, 0.77 g of anhydrous citric acid, and 0.25 g of sodium hydroxide to the beaker, stir to dissolve, and heat to 70°C in a water bath. Add Compound 1 drug substance and stir to dissolve until clear. After cooling to room temperature, filter through a 0.45 μm membrane filter and freeze-dry. The freeze-dried sample was pulverized, sieved, and mixed. Add 10.62 g of imipenem monohydrate, 10.62 g of cilastatin sodium, and 0.4 g of sodium bicarbonate, mix, and individually package the sample. Compound 1 composition for injection was obtained.

[0137] Example 10 The amounts of Compound 1 composition injection prepared were 250 mg of Compound 1, 500 mg of imipenem, and 500 mg of cilastatin, and imipenem monohydrate and cilastatin sodium were added after converting them based on their molecular formulas.

[0138] Prescription (100 vials) Compound 1 25.0g Sulfobutyl ether β-cyclodextrin sodium 250.0g Anhydrous citric acid 3.85g 1.25g sodium hydroxide Imipenem monohydrate 53.1g Cilastatin sodium 53.1g Sodium bicarbonate 2.0g purified water *1 Add up to 2.5L Note*1: Purified water was removed by the freeze-drying process.

[0139] Preparation process: Add an appropriate amount of water to a beaker, add 250.0 g of sulfobutyl ether beta-cyclodextrin sodium, 3.85 g of anhydrous citric acid, and 1.25 g of sodium hydroxide to the beaker, stir to dissolve, and heat to 80°C in a water bath. Add Compound 1 drug substance and stir to dissolve until clear. After cooling to room temperature, filter through a 0.45 μm membrane filter and freeze-dry. The freeze-dried sample was pulverized, sieved, and mixed. Add 53.1 g of imipenem monohydrate, 53.1 g of cilastatin sodium, and 2.0 g of sodium bicarbonate, mix, and individually package the sample. Compound 1 composition for injection was obtained. The following is the solubility data of this composition for injection at different temperatures. [Table 15]

[0140] Example 11 The amounts of Compound 1 composition injection prepared were 250 mg of Compound 1, 500 mg of imipenem, and 500 mg of cilastatin, and imipenem monohydrate and cilastatin sodium were added after converting them based on their molecular formulas.

[0141] Prescription (100 vials) Compound 1 25.0g Sulfobutyl ether β-cyclodextrin sodium 225.0g Imipenem monohydrate 53.1g Cilastatin sodium 53.1g 2.5g sodium bicarbonate purified water *1 Add up to 2.5L Note*1: Purified water was removed by the freeze-drying process.

[0142] Preparation process: Add an appropriate amount of water to a beaker, add 225.0 g of sulfobutyl ether beta-cyclodextrin sodium to the beaker, stir to dissolve, and heat to 85°C in a water bath. Add Compound 1 drug substance and stir to dissolve until clear. After cooling to room temperature, filter through a 0.45 μm membrane filter and freeze-dry. The freeze-dried sample was pulverized, sieved, and mixed. Add 53.1 g of imipenem monohydrate, 53.1 g of cilastatin sodium, and 2.5 g of sodium bicarbonate, mix, and individually package the sample. Compound 1 composition injection was obtained.

[0143] Example 12 The amounts of Compound 1 composition injection prepared were 150 mg of Compound 1, 300 mg of imipenem, and 300 mg of cilastatin sodium, and imipenem monohydrate and cilastatin sodium were added after conversion based on their molecular formulas.

[0144] Prescription (100 vials) Compound 1 15.0g Sulfobutyl ether β-cyclodextrin sodium 120.0g Imipenem monohydrate 15.93g Cilastatin sodium 15.93g Sodium bicarbonate 1.2g purified water *1 Add up to 1.5L Note*1: Purified water was removed by the freeze-drying process.

[0145] Preparation process: Add an appropriate amount of water to a beaker, add 120.0 g of sulfobutyl ether beta-cyclodextrin sodium to the beaker, stir to dissolve, and heat to 85°C in a water bath. Add Compound 1 drug substance and stir to dissolve until clear. After cooling to room temperature, filter through a 0.45 μm membrane filter and freeze-dry. The freeze-dried sample was pulverized, sieved, and mixed. Add 15.93 g of imipenem monohydrate, 15.93 g of cilastatin sodium, and 1.2 g of sodium bicarbonate, mix, and individually package the sample. Compound 1 composition injection was obtained.

[0146] Example 13 The amounts of Compound 1 composition injection prepared were 250 mg of Compound 1, 500 mg of imipenem, and 500 mg of cilastatin, and imipenem monohydrate and cilastatin sodium were added after converting them based on their molecular formulas.

[0147] Prescription (100 vials) Compound 1 25.0g Sulfobutyl ether β-cyclodextrin sodium 250.0g Povidone 1.25g Imipenem monohydrate 53.1g Cilastatin sodium 53.1g Sodium bicarbonate 2.0g purified water *1 Add up to 2.5L Note*1: Purified water was removed by the freeze-drying process.

[0148] Preparation process: Add an appropriate amount of water to a beaker, add 250.0 g of sulfobutyl ether beta-cyclodextrin sodium to the beaker, stir to dissolve, and heat to 85°C in a water bath. Add Compound 1 drug substance and stir to dissolve until clear. After cooling to room temperature, add 1.25 g of povidone, filter through a 0.45 μm membrane filter, and freeze-dry. The freeze-dried sample was crushed, sieved, and mixed. Add 53.1 g of imipenem monohydrate, 53.1 g of cilastatin sodium, and 2.0 g of sodium bicarbonate, mix, and individually package the sample. Compound 1 composition injection was obtained.

[0149] Example 14 The amounts of Compound 1 composition injection prepared were 250 mg of Compound 1, 500 mg of imipenem, and 500 mg of cilastatin, and imipenem monohydrate and cilastatin sodium were added after converting them based on their molecular formulas.

[0150] Prescription (100 vials) Compound 1 25.0g Sulfobutyl ether β-cyclodextrin sodium 250.0g Povidone 5.0g Imipenem monohydrate 53.1g Cilastatin sodium 53.1g Sodium bicarbonate 2.0g purified water *1 Add up to 2.5L Note*1: Purified water was removed by the freeze-drying process.

[0151] Preparation process: Add an appropriate amount of water to a beaker, add 250.0 g of sulfobutyl ether beta-cyclodextrin sodium to the beaker, stir to dissolve, and heat to 85°C in a water bath. Add Compound 1 drug substance and stir to dissolve until clear. After cooling to room temperature, add 5.0 g of povidone, filter through a 0.45 μm membrane filter, and freeze-dry. The freeze-dried sample was pulverized, sieved, and mixed. Add 53.1 g of imipenem monohydrate, 53.1 g of cilastatin sodium, and 2.0 g of sodium bicarbonate, mix, and individually package the sample. Compound 1 composition injection was obtained.

[0152] From the viewpoint of pharmaceutical safety, the amount of solubilizer added to injections should be kept as low as possible based on the FDA IIG database.

[0153] Since the single dose of sulfobutyl ether β-cyclodextrin sodium in the FDA IIG database, i.e., the maximum single dose, is 3200 mg and the maximum daily dose is 15 g, the ratio of imipenem / cilastatin / Compound 1 is determined to be 2:2:1, and each vial preferably contains 250 mg / 250 mg / 125 mg and 500 mg / 500 mg / 250 mg of imipenem / cilastatin / Compound 1.

Claims

1. The active ingredients include substance A and substance B, said substance A is compound 1 or a solvate thereof; the substance B is imipenem or a solvate thereof; the mass ratio of the substance B to the substance A is 1:1 to 10:1, the mass of the substance B is calculated as imipenem, and the mass of the substance A is calculated as compound 1; The structural formula of Compound 1 is: 【Chemistry 1】 Pharmaceutical composition A shown in

2. (1) The active ingredients of the pharmaceutical composition A consist of substance A and substance B; (2) In the pharmaceutical composition A, the substance B is imipenem monohydrate; and (3) The pharmaceutical composition A according to claim 1, characterized in that the mass ratio of substance B to substance A is 1:1, 2:1, 3:1, 4:1, 5:1, 7:1 or 10:

1.

3. 2. Pharmaceutical composition A according to claim 1, characterized in that the mass ratio of substance B to substance A is 1:1 to 4:1, preferably 1:1 to 2:1, particularly preferably 2:

1.

4. (1) In the pharmaceutical composition A, the substance A is compound 1; (2) In the pharmaceutical composition A, the mass percentage of the compound 1 is 2% to 15%, preferably 5% to 10%, for example, 6.44%, 6.97%, 7.29%, 6.50% or 8.93%; (3) Pharmaceutical composition A according to claim 1, characterized in that in the pharmaceutical composition A, substance B is imipenem monohydrate, and the mass percentage of the imipenem monohydrate is preferably 9% to 16%, for example, 13.81%, 13.68%, 15.45%, 13.67%, 14.80%, or 9.48%, satisfying one or more of the following conditions.

5. (1) In the pharmaceutical composition A, the mass percentage of the imipenem is 5% to 20%, preferably 8% to 15%; (2) The pharmaceutical composition A according to claim 1, characterized in that the pharmaceutical composition A satisfies one or more of the conditions that it further contains a pharmaceutically acceptable excipient.

6. 6. The pharmaceutical composition A according to claim 5, wherein the pharmaceutically acceptable excipient comprises a solubilizing agent and may further comprise one or more of a filler and a pH adjuster.

7. (1) In the pharmaceutical composition A, the selected solubilizer is selected from one or more of sulfobutyl ether β-cyclodextrin sodium, 2-hydroxypropyl-β-cyclodextrin, N-methyl-D(-)-glucamine, and polysorbate 80, preferably sulfobutyl ether β-cyclodextrin sodium and / or 2-hydroxypropyl-β-cyclodextrin, and particularly preferably sulfobutyl ether β-cyclodextrin sodium; (2) In the pharmaceutical composition A, the mass percentage of the solubilizer is 20% to 70%, for example, 20.41%, 64.38%, 62.73%, 65.03%, 64.40%, or 71.40%, preferably 50% to 70%; (3) In the pharmaceutical composition A, the mass ratio of the substance A to the solubilizer is 1:(2-13), for example, 1:2.8, 1:5, 1:7.5, 1:8, 1:9, 1:10 or 1:12.5, preferably 1:(10-13), and the mass of the substance A is calculated as compound 1; (4) When the pharmaceutically acceptable excipient further comprises a filler, in the pharmaceutical composition A, the selected filler is selected from one or more of mannitol, lactose, sucrose, crystalline cellulose, glucose, fructose, povidone, and trehalose, and preferably selected from mannitol and / or povidone; (5) When the pharmaceutically acceptable excipient further comprises a filler, the mass percentage of the filler in the pharmaceutical composition A is 0.3% to 70%, for example, 30% to 70%, preferably 35% to 50%, for example, 0.33%, 1.29%, or 40.82%; (6) When the pharmaceutically acceptable excipient further comprises a pH adjuster, in the pharmaceutical composition A, the selected pH adjuster is selected from one or more of anhydrous citric acid, sodium hydroxide, sodium bicarbonate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate, disodium tartrate, maleic acid, magnesium hydroxide, calcium hydroxide, and preferably selected from one or more of sodium bicarbonate, sodium hydroxide, and anhydrous citric acid; (7) When the pharmaceutically acceptable excipient further comprises a pH adjuster, the mass percentage of the pH adjuster in the pharmaceutical composition A is 0% to 2.0%, for example, 0.52%, 0.58%, 0.70%, 0.71%, or 1.83%, preferably 0.3% to 0.7%; and (8) The pharmaceutical composition A according to claim 6, characterized in that the pharmaceutical composition A satisfies one or more conditions of being in the form of an injection, for example, a freeze-dried powder.

8. 8. Use of pharmaceutical composition A in the preparation of a medicament for inhibiting a bacterium according to any one of claims 1 to 7, characterized in that the bacterium is a bacterium resistant to a β-lactam antibiotic, and the bacterium resistant to a β-lactam antibiotic is preferably selected from one or more of Pseudomonas aeruginosa, Acinetobacter spp. and Klebsiella pneumoniae.

9. Use of substance A in the preparation of a medicament for inhibiting bacteria, wherein substance A is used in combination with substance B, the definitions and amounts of substance B and substance A to be added are as defined in any one of claims 1 to 5, and the bacteria are as defined in claim 8.

10. Use of substance B in the preparation of a medicament for inhibiting bacteria, wherein substance B is used in combination with substance A, the definitions and amounts of substance B and substance A to be added being as defined in any one of claims 1 to 5, and the bacteria being as defined in claim 8.

11. The active ingredients include substance A, substance B, and substance C, said substance A is compound 1 or a solvate thereof; the substance B is imipenem or a solvate thereof; said substance C is cilastatin or a solvate thereof; the mass ratio of the substance C:substance B:substance A is (1-10):(1-10):1, the mass of the substance C is calculated as cilastatin, the mass of the substance B is calculated as imipenem, and the mass of the substance A is calculated as compound 1; The structural formula of Compound 1 is: 【Chemistry 2】 Pharmaceutical composition B, characterized by the following:

12. (1) The active ingredients of the pharmaceutical composition B consist of substance A, substance B, and substance C; (2) In the pharmaceutical composition B, the substance B is imipenem monohydrate; (3) In the pharmaceutical composition B, the substance C is cilastatin sodium; and (4) Pharmaceutical composition B according to claim 11, characterized in that the mass ratio of substance C:substance B:substance A satisfies one or more of the following conditions: 1:1:1, 2:2:1, 3:3:1, 4:4:1, 5:5:1, 7:7:1 or 10:10:

1.

13. 12. Pharmaceutical composition B according to claim 11, characterized in that the mass ratio of substance C:substance B:substance A is (1-4):(1-4):1, preferably (1-2):(1-2):1, particularly preferably 2:2:

1.

14. (1) In the pharmaceutical composition B, the substance A is compound 1; (2) In the pharmaceutical composition B, the mass percentage of the compound 1 is 2% to 15%, preferably 5% to 10%, for example, 6.44%, 6.50%, 6.97%, 7.29%, or 8.93%; (3) In the pharmaceutical composition B, the substance B is imipenem monohydrate, and the mass percentage of the imipenem monohydrate is preferably 9% to 16%, for example, 13.81%, 13.68%, 15.45%, 13.67%, 14.80%, or 9.48%; and (4) Pharmaceutical composition B according to claim 11, characterized in that in said pharmaceutical composition B, substance C is present in the amorphous form of cilastatin sodium, and the mass percentage of said cilastatin sodium is preferably 9% to 16%, for example, 13.81%, 13.68%, 9.48%, 13.67%, 14.80% or 15.45%.

15. (1) In the pharmaceutical composition B, the mass percentage of the imipenem is 5% to 20%, preferably 8% to 15%; (2) In the pharmaceutical composition B, the mass percentage of the cilastatin sodium is 5 to 20%, preferably 8 to 15%, and the mass of the cilastatin sodium is calculated as cilastatin; and (3) Pharmaceutical composition B according to claim 11, characterized in that said pharmaceutical composition B satisfies one or more conditions of further containing a pharmaceutically acceptable excipient.

16. 16. Pharmaceutical composition B according to claim 15, characterized in that in said pharmaceutical composition B, the pharmaceutically acceptable excipient comprises a solubilizing agent, and may further comprise one or more of a filler and a pH adjuster.

17. (1) In the pharmaceutical composition B, the selected solubilizer is selected from one or more of sulfobutyl ether β-cyclodextrin sodium, 2-hydroxypropyl-β-cyclodextrin, N-methyl-D(-)-glucamine, and polysorbate 80, preferably sulfobutyl ether β-cyclodextrin sodium and / or 2-hydroxypropyl-β-cyclodextrin, and particularly preferably sulfobutyl ether β-cyclodextrin sodium; (2) In the pharmaceutical composition B, the mass percentage of the solubilizer is 20% to 70%, for example, 20.41%, 64.38%, 62.73%, 65.03%, 64.40% or 71.40%, preferably 50% to 70%; (3) In the pharmaceutical composition B, the mass ratio of the substance A to the solubilizer is 1:(2-13), for example, 1:2.8, 1:5, 1:7.5, 1:8, 1:9, 1:10 or 1:12.5, preferably 1:(10-13), and the mass of the substance A is calculated as compound 1; (4) When the pharmaceutically acceptable excipient further comprises a filler, in the pharmaceutical composition B, the selected filler is selected from one or more of mannitol, lactose, sucrose, crystalline cellulose, glucose, fructose, povidone, and trehalose, and preferably selected from mannitol and / or povidone; (5) When the pharmaceutically acceptable excipient further comprises a filler, the mass percentage of the filler in the pharmaceutical composition B is 0.3% to 70%, for example, 30% to 70%, preferably 35% to 50%, for example, 0.33%, 1.29%, or 40.82%; (6) When the pharmaceutically acceptable excipient further comprises a pH adjuster, in the pharmaceutical composition B, the selected pH adjuster is selected from one or more of anhydrous citric acid, sodium hydroxide, sodium bicarbonate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate, disodium tartrate, maleic acid, magnesium hydroxide, calcium hydroxide, and preferably selected from one or more of sodium bicarbonate, sodium hydroxide, and anhydrous citric acid; (7) Pharmaceutical composition B according to claim 16, characterized in that when the pharmaceutically acceptable excipient further comprises a pH adjuster, the mass percentage of the pH adjuster in pharmaceutical composition B is 0% to 2.0%, for example, 0.52%, 0.58%, 0.70%, 0.71%, or 1.83%, preferably 0.3% to 0.7%.

18. (1) The pharmaceutical composition B contains Compound 1, sulfobutyl ether β-cyclodextrin sodium, mannitol, imipenem monohydrate, cilastatin sodium, and sodium bicarbonate; (2) The pharmaceutical composition B contains Compound 1, sulfobutyl ether β-cyclodextrin sodium, anhydrous citric acid, sodium hydroxide, imipenem monohydrate, cilastatin sodium, and sodium bicarbonate; (3) The pharmaceutical composition B contains Compound 1, sulfobutyl ether β-cyclodextrin sodium, imipenem monohydrate, cilastatin sodium, and sodium bicarbonate; or (4) Pharmaceutical composition B according to claim 11, characterized in that it contains Compound 1, sulfobutyl ether β-cyclodextrin sodium, povidone, imipenem monohydrate, cilastatin sodium, and sodium bicarbonate.

19. (1) The pharmaceutical composition B contains 7.29% of compound 1, 20.41% of sulfobutyl ether β-cyclodextrin sodium, 40.82% of mannitol, 15.45% of imipenem monohydrate, 15.45% of cilastatin sodium, and 0.58% of sodium bicarbonate, and the percentages are by mass; (2) The pharmaceutical composition B contains 6.44% of compound 1, 64.38% of sulfobutyl ether β-cyclodextrin sodium, 0.99% of anhydrous citric acid, 0.32% of sodium hydroxide, 13.67% of imipenem monohydrate, 13.67% of cilastatin sodium, and 0.52% of sodium bicarbonate, and the percentages are by mass; (3) The pharmaceutical composition B contains 6.97% of compound 1, 62.73% of sulfobutyl ether β-cyclodextrin sodium, 14.80% of imipenem monohydrate, 14.80% of cilastatin sodium, and 0.70% of sodium bicarbonate, and the percentages are by mass; (4) The pharmaceutical composition B contains 8.93% of compound 1, 71.40% of sulfobutyl ether β-cyclodextrin sodium, 9.48% of imipenem monohydrate, 9.48% of cilastatin sodium, and 0.71% of sodium bicarbonate, and the percentages are by mass; (5) The pharmaceutical composition B contains 6.50% of Compound 1, 65.03% of sulfobutyl ether beta-cyclodextrin sodium, 0.33% of povidone, 0.52% of sodium bicarbonate, 13.81% of imipenem monohydrate, and 13.81% of cilastatin sodium, and the percentages are by mass; or (6) Pharmaceutical composition B according to claim 11, characterized in that it contains 6.44% of compound 1, 64.40% of sulfobutyl ether β-cyclodextrin sodium, 1.29% of povidone, 0.52% of sodium bicarbonate, 13.68% of imipenem monohydrate, and 13.68% of cilastatin sodium, and the percentages are mass percentages.

20. (1) The pharmaceutical composition B is in the form of an injection; and (2) The pharmaceutical composition B according to claim 11, characterized in that when the pharmaceutical composition B is in the form of an injection, the contents of imipenem / cilastatin / compound 1 in the pharmaceutical composition B are 250 mg / 250 mg / 125 mg or 500 mg / 500 mg / 250 mg.

21. 12. Use of pharmaceutical composition B in the preparation of a medicament for inhibiting bacteria according to claim 11, characterized in that the bacteria are resistant to β-lactam antibiotics, and the bacteria resistant to β-lactam antibiotics are preferably selected from one or more of Pseudomonas aeruginosa, Acinetobacter sp. and Klebsiella pneumoniae.

22. Use of substance A in the preparation of a medicament for inhibiting bacteria, wherein the substance A is used in combination with substances B and C, the definitions and amounts of substances C, B and A to be added being as defined in any one of claims 11 to 15, and the bacteria being as defined in claim 21.

23. Use of substance B in the preparation of a medicament for inhibiting bacteria, wherein substance B is used in combination with substance A and substance C, the definitions and amounts of substance C, substance B and substance A being as defined in any one of claims 11 to 15, and the bacteria being as defined in claim 21.

24. Use of substance C in the preparation of a medicament for inhibiting bacteria, wherein the substance C is used in combination with substance A and substance B, the definitions and amounts of substance C, substance B and substance A are as defined in any one of claims 11 to 15, and the bacteria are as defined in claim 21.

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