Antimicrobial drug compositions, formulations, their preparation processes and uses

Abstract

This invention relates to an antibacterial pharmaceutical composition, formulation, preparation process, and use thereof, comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a buffer solution. This invention also relates to a lyophilized formulation. The pharmaceutical composition or lyophilized formulation provided by this invention can be used to treat microbial infections.

Description

Technical Field

[0001] This invention provides an antibacterial drug composition, formulation, preparation process, and uses thereof. Background Technology

[0002] Contezolid, a new generation of oxazolidinone antibacterial drugs, exerts its effects by inhibiting the formation of the functional 70S initiation complex, which is essential for bacterial proliferation. It has a broad antibacterial spectrum and strong antibacterial activity against a variety of Gram-positive bacteria, particularly showing high sensitivity against methicillin-resistant Staphylococcus aureus (MRSA), which currently poses a challenge to clinical practice. Contezolid overcomes the disadvantages of existing oxazolidinone drugs by employing a "non-coplanar" structural design with meta- and ortho-fluorine positions on the benzene ring in its molecular structure, significantly reducing the incidence of adverse reactions such as hematologic toxicity caused by oxazolidinone antibacterial drugs. Simultaneously, the dihydropyridine ring and isoxazole structure enhance binding to bacterial target sites, resulting in stronger drug activity and less likelihood of developing resistance. Contezolid is metabolized in vivo via the flavin monooxygenase pathway, and compared to drugs metabolized by the hepatic drug-metabolizing enzyme (CYP) system, it generally does not interact with most commonly used clinical drugs, making it suitable for use in special patient populations such as those with renal insufficiency and the elderly.

[0003] Chinese patent publication CN105612166A discloses a novel oxazolidinone compound, a prodrug of continazolamide, exhibiting excellent safety and antibacterial activity. Studies have found that this continazolamide prodrug is easily degraded under high temperature and humidity conditions. Even when prepared as a lyophilized formulation, its stability during preparation, transportation, and storage cannot be guaranteed; the content of the active ingredient in the formulation will significantly decrease, while the content of related substances will significantly increase. Therefore, there is a need to research and develop a technology and formulation that ensures the stable, long-term storage of this continazolamide prodrug through non-gastrointestinal administration. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides a pharmaceutical composition and a lyophilized formulation prepared from the pharmaceutical composition, which exhibits excellent stability and requires fewer types and amounts of excipients. The preparation process of the lyophilized formulation of this invention has high lyophilization efficiency, and the finished product has good appearance and stability, which can better meet the requirements for clinical use of pharmaceutical formulations. This invention also provides the pharmaceutical uses of the pharmaceutical composition and the lyophilized formulation.

[0005] In a first aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula I or a pharmaceutically acceptable salt thereof, and a buffer solution. .

[0006] In some embodiments, the mass-to-volume ratio of the compound of Formula I or its pharmaceutically acceptable salt to the buffer solution is 50–300 mg: 1 mL.

[0007] In some embodiments, the buffer solution of the present invention comprises one or more of citrate buffer, phosphate buffer, histidine buffer, and acetate buffer.

[0008] Secondly, the present invention provides a lyophilized formulation, which is prepared by lyophilizing the pharmaceutical composition described in any of the embodiments herein.

[0009] Thirdly, the present invention also provides a process for preparing a lyophilized formulation, comprising the following steps: lyophilizing a pharmaceutical composition containing a compound of formula I and / or a pharmaceutically acceptable salt thereof, thereby obtaining the product.

[0010] Fourthly, the present invention also provides the use of pharmaceutical compositions or lyophilized formulations as described in any of the embodiments herein in the preparation of medicaments for treating microbial infections in mammals.

[0011] Fifthly, the present invention also provides pharmaceutical compositions or lyophilized formulations as described in any of the embodiments herein for the treatment of mammalian microbial infections.

[0012] In a sixth aspect, the present invention also provides a method for treating microbial infections in mammals, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition or lyophilized formulation as described in any of the embodiments herein. Attached Figure Description

[0013] Figure 1 : Single-sublimation freeze-drying curve.

[0014] Figure 2 : Secondary sublimation freeze-drying curve. Detailed Implementation

[0015] The present invention will be further described below with reference to the accompanying drawings and the following embodiments. It should be understood that the accompanying drawings and the following embodiments are for illustrative purposes only and are not intended to limit the present invention.

[0016] the term To facilitate understanding of this invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. All references cited herein, including patents, patent applications, papers, textbooks, and the like, and references cited therein, are incorporated herein in their entirety to the extent that they have not already been cited. If one or more of the incorporated documents and similar materials differ from or contradict this invention, including but not limited to defined terminology, usage of terms, described techniques, and the like, this invention shall prevail.

[0017] The term "unit dose" refers to a single dose that can be administered to a subject and is easy to handle and package. For example, a unit dose can be a single tablet, pill, capsule, lozenge, suppository, drop, or a single packaged bottle (e.g., a single vial, a borosilicate glass vial for injection, an ampoule, etc.).

[0018] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “made of”.

[0019] As used herein, the term “room temperature” refers to a temperature from about 10°C to about 40°C. In some embodiments, “room temperature” refers to a temperature from about 20°C to about 30°C; in other embodiments, “room temperature” refers to 20°C, 22.5°C, 25°C, 27.5°C, and so on.

[0020] The terms "pharmaceutical composition" or "formulation" refer to a mixture containing the pharmaceutical described herein and one or more other components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition includes facilitating administration to a living organism, promoting the absorption of the active ingredient, and thereby enabling it to exert its biological activity.

[0021] As used herein, the term “about” when referring to measurable values ​​(such as quantity, duration, etc.) is intended to cover variations of ±20% or ±10% relative to a specific value, including ±5%, ±1%, and ±0.1%, as these variations are suitable for the disclosed methods.

[0022] The term "mammal" refers to all mammals, including humans, livestock, and pets.

[0023] In this invention, the amount of buffer solution refers to the total amount of buffer pairs in the buffer system that makes up the buffer solution. In some embodiments, molar concentration is used as the unit of measurement for the amount of buffer solution (or buffering agent), and its value refers to the molar concentration of buffer pairs in the buffer system of the buffer solution (or buffering agent); for example, when a citrate buffer solution composed of citric acid and sodium citrate is used as a buffer solution, a given concentration of citrate buffer solution (e.g., 20 mM) is a combined concentration of citric acid and sodium citrate (e.g., 15 mM of citric acid and 5 mM of sodium citrate; or 3.6 mM of citric acid and 16.4 mM of sodium citrate). In some implementations, molar concentration is used as the unit of measurement for the amount of buffer solution (or buffering agent), and its value refers to the molar concentration of anions in the buffer system of the buffer solution (or buffering agent); for example, when a citrate buffer composed of citric acid and sodium citrate is used as a buffer solution, a given concentration of citrate buffer (e.g., 20 mM) means that the concentration of citrate ions is 20 mM.

[0024] The term "buffer solution with a pH of about 4.5 to 5.5" refers to a reagent that, through the action of its acid / base conjugate components, enables a solution containing the reagent to resist pH changes. The buffer solution used in the pharmaceutical compositions of the present invention may have a pH in the range of about 3.5 to about 7.0, or a pH in the range of about 4.5 to about 5.5.

[0025] In this document, examples of “buffer solutions” that control the pH within this range include acetic acid, acetate (e.g., sodium acetate), succinic acid, succinate (e.g., sodium succinate), gluconic acid, histidine, histidine salt (e.g., histidine hydrochloride), methionine, citric acid, citrate, phosphate, citrate / phosphate, imidazole, combinations thereof, and other organic acid buffer solutions.

[0026] "Histidine buffer" is a buffer solution containing histidine ions. Examples of histidine buffer solutions include histidine and histidine salts, such as histidine hydrochloride, histidine acetate, histidine phosphate, and histidine sulfate, such as a histidine buffer solution containing histidine and histidine hydrochloride.

[0027] "Citrate buffer," also known as "citric acid buffer," is a buffer solution containing citrate ions. Examples of citrate buffers include sodium citrate, potassium citrate, calcium citrate, and magnesium citrate.

[0028] Acetate buffer, also known as acetate salt buffer, is a buffer solution containing acetate ions. Examples of acetate buffer solutions include acetate-sodium acetate, acetate-potassium acetate, acetate-calcium acetate, and acetate-magnesium acetate.

[0029] Phosphate buffer is a buffer solution that contains phosphate ions. Examples of phosphate buffer solutions include sodium dihydrogen phosphate-disodium hydrogen phosphate and potassium dihydrogen phosphate-disodium hydrogen phosphate.

[0030] The term “treatment” includes: (1) preventing disease, for example, preventing the development of clinical symptoms of disease in mammals that may be exposed to or pretreated with disease but have not yet experienced or shown symptoms of disease; (2) suppressing disease, for example, preventing or reducing the development of disease or its clinical symptoms; or (3) alleviating disease, for example, causing disease or its clinical symptoms to degenerate.

[0031] The terms “administration,” “giving,” and “treatment” refer to the introduction of a composition containing a therapeutic agent into a subject using any of the various methods or delivery systems known to those skilled in the art.

[0032] "Therapeutic effective dose" means that when administered to a mammal to treat a disease, the dose of a compound is sufficient to achieve that treatment. "Therapeutic effective dose" can vary depending on the compound, the severity of the disease, and the age and weight of the mammal being treated.

[0033] A "pharmaceutically acceptable salt" is a salt of a compound that possesses the desired pharmacological activity of its parent compound. Such salts include acid addition salts, formed by an inorganic acid with one or more protonable functional groups, such as primary, secondary, or tertiary amines within the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts can be formed from organic acids such as acetic acid, propionic acid, hexanoic acid, lactic acid, malonic acid, succinic acid, malic acid, tartaric acid, citric acid, lauryl sulfate, gluconic acid, and glutamic acid. Salts can be formed when one or more acidic protons present in the parent compound are replaced by a metal ion (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions, or combinations thereof) or coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc.). Pharmaceutically acceptable salts can be hydrochloride salts. Pharmaceutically acceptable salts can be sodium salts and potassium salts. In compounds having two or more ionizable groups, pharmaceutically acceptable salts may contain one or more opposing ions, such as disalts, for example, dihydrochlorides.

[0034] The term "pharmaceutically acceptable salt" includes hydrates and other solvates, as well as salts in crystalline or amorphous form. When a particular pharmaceutically acceptable salt is disclosed, it should be understood that the particular salt (e.g., a sodium salt) is an example of a salt, and other salts can be formed using techniques known to those skilled in the art. Furthermore, those skilled in the art will be able to convert pharmaceutically acceptable salts into corresponding compounds, free bases, and / or free acids using techniques generally known in the art.

[0035] The compounds disclosed in this article are generally named according to the IUPAC or CAS nomenclature system.

[0036] The following examples further illustrate the present invention in detail. It should also be understood that the following examples are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the appropriate range based on the description herein, and are not intended to be limited to the specific values ​​in the examples below.

[0037] Active ingredients In this invention, the active ingredient refers to a compound of formula I and / or its pharmaceutically acceptable salt. The chemical structure of the compound of formula I described in this invention is shown below: .

[0038] The chemical structure of the sodium salt of the compound of formula I described in this invention is shown in formula II: .

[0039] Chemical name: O-acetyl-(R)-isoxazo-3-yl((2-oxo-3-(2,3,5-trifluoro-4-(4-oxo-3,4-dihydropyridine-1(2-hydro)-yl)phenyl)oxazolidine-5-yl)methyl)aminophosphate sodium.

[0040] The sodium salt of the compound of formula I used in the embodiments of the present invention is a crystal or crystal compound of the compound of Example 1 in Chinese Patent CN111039984B (i.e., product form 3 in the patent), which is prepared according to the method shown in Example 1 of Patent CN111039984B.

[0041] Pharmaceutical Composition The present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a buffer solution.

[0042] In some embodiments, the mass-to-volume ratio of the compound of Formula I or its pharmaceutically acceptable salt to the buffer solution is 50–300 mg: 1 mL.

[0043] In some embodiments, the mass-to-volume ratio of the compound of Formula I or a pharmaceutically acceptable salt thereof to a buffer solution is 100–200 mg: 1 mL.

[0044] In some embodiments, the mass-to-volume ratio of the compound of Formula I or a pharmaceutically acceptable salt thereof to a buffer solution is 130–170 mg: 1 mL.

[0045] In some embodiments, the buffer solution of the present invention comprises one or more of citrate buffer, phosphate buffer, histidine buffer, and acetate buffer.

[0046] In some embodiments, the buffer solution of the present invention is a citrate buffer solution, wherein the citrate buffer solution is a citrate-sodium citrate buffer solution.

[0047] In some embodiments, the concentration of the buffer solution described in this invention is 5–120 mM.

[0048] In some embodiments, the concentration of the buffer solution described in this invention is 5–60 mM.

[0049] In some embodiments, the concentration of the buffer solution described in this invention is 10–50 mM.

[0050] In some embodiments, the concentration of the buffer solution described in this invention is 15–25 mM.

[0051] In some embodiments, the pH of the buffer solution described in this invention is 3.5 to 7.0.

[0052] In some embodiments, the pH of the buffer solution described in this invention is 4.5 to 5.5.

[0053] In some embodiments, the pharmaceutical composition of the present invention comprises the following raw materials: a compound of formula I or a pharmaceutically acceptable salt thereof and a 15-25 mM citrate-sodium citrate buffer solution with a pH of 4.5-5.5; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is 100-200 mg: 1 mL.

[0054] In some embodiments, the pharmaceutical composition of the present invention is prepared from any one of the raw materials shown in (1) to (7) below: (1) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 20 mM, pH 4.5 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (2) A compound of formula I or a pharmaceutically acceptable salt thereof and about 20 mM of citrate-sodium citrate buffer solution at pH 5.0 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (3) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 20 mM at pH 5.5 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (4) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 50 mM at pH 5.0 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (5) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 50 mM at pH 5.5 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (6) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 20 mM, pH 5.0 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 150 mg: 1 mL; or (7) A compound of Formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 20 mM at pH 5.5 ± 0.3; wherein the mass-to-volume ratio of the compound of Formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 150 mg: 1 mL.

[0055] In some embodiments, the citrate-sodium citrate buffer solution of the present invention is prepared by mixing a sodium citrate solution and a citric acid solution, and adjusting the pH to a target value. In some embodiments, the citrate-sodium citrate buffer solution is prepared by mixing approximately 10-50 mM citric acid solution and approximately 10-50 mM sodium citrate solution. In some embodiments, the citrate-sodium citrate buffer solution is prepared by mixing approximately 15-25 mM citric acid solution and approximately 15-25 mM sodium citrate solution. In some formulations, a citrate-sodium citrate buffer solution of approximately 20 mM with a pH of 5.0 ± 0.3 is prepared by mixing approximately 20 mM sodium citrate solution and approximately 20 mM citrate solution at a volume ratio of (1.5-2.0):1; optionally, the volume ratio is approximately 1.8:1.

[0056] In some embodiments, the pharmaceutical composition of the present invention is prepared by dissolving a compound of formula I or a pharmaceutically acceptable salt thereof in a buffer solution and filtering.

[0057] In some embodiments, the pharmaceutical composition of the present invention is prepared by dissolving the compound of formula I or a pharmaceutically acceptable salt thereof in a 15-25 mM citrate-sodium citrate buffer solution with a pH of 4.5-5.5 to prepare a solution with a concentration of 50-300 mg / mL (optionally 100-200 mg / mL, 130-170 mg / mL, 200 mg / mL or 150 mg / mL) based on the sodium salt of the compound of formula I, and then filtering to obtain the final product.

[0058] In some implementations, the filtration process involves: initial filtration through a 0.45 μm filter followed by filtration through a 0.22 μm sterilization filter.

[0059] In some embodiments, the pharmaceutical composition of the present invention is administered by injection.

[0060] In some embodiments, the pH of the pharmaceutical composition of the present invention is 5.0 ± 0.5.

[0061] In some embodiments, the pharmaceutical compositions of the present invention do not contain lyophilizing agents, matrix forming agents, and lyophilization protectants.

[0062] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a sodium and / or potassium salt of the compound of formula I, wherein the chemical structure of the sodium salt is as shown in formula II: .

[0063] In some embodiments, the unit dose of the pharmaceutical composition contains 100 to 1000 mg of the active ingredient, converted to the sodium salt of Formula I, optionally about 300 mg, about 500 mg, or about 1000 mg.

[0064] Lyophilized formulations The present invention provides a lyophilized formulation, which is prepared by lyophilizing the pharmaceutical composition described in any of the embodiments herein.

[0065] In some embodiments, the lyophilized formulation does not contain a lyophilizing agent, a skeleton forming agent, or a lyophilization protectant.

[0066] In some embodiments, the lyophilized formulation is stored at 25°C for 3 months, and the related substances detected by high performance liquid chromatography are less than 4%.

[0067] In some embodiments, the freeze-drying steps are as follows: ① Cooling: The temperature is lowered from room temperature to -25°C or below in 0.5 to 4 hours, then raised to -20 to -5°C in 0.5 to 2.5 hours and held for 1.5 to 4.5 hours; then the temperature is lowered to -30°C or below in 0.5 to 2.5 hours and held for 1 to 5 hours; ② First sublimation: Vacuum is drawn to a vacuum level below 30 Pa, the temperature is raised to -20 to -10°C in 0.5 to 2.5 hours and held for 15 to 40 hours; ③ Second sublimation: The temperature is raised to 30 to 50°C in 1 to 3 hours and held for 2 to 6 hours, while controlling the vacuum level below 20 Pa.

[0068] In some embodiments, the freeze-drying steps are as follows: ① Cooling: The temperature is lowered from room temperature to about -30°C in about 2 hours, then raised to about -10°C in about 1 hour, and held for about 2.5 hours; then the temperature is lowered to about -40°C in about 1 hour, and held for about 2 hours; ② First sublimation: Vacuum is drawn to a vacuum level below 30 Pa, the temperature is raised to about -15°C in about 1 hour, and held for about 25 hours; ③ Second sublimation: The temperature is raised to about 40°C in about 2 hours, held for about 4 hours, and the vacuum level is controlled to be below 20 Pa.

[0069] In some embodiments, the freeze-dried formulation contains 100 to 1000 mg of active ingredient per unit dose, converted to sodium salt of Formula I compound, and may be approximately 300 mg, approximately 500 mg, or approximately 1000 mg.

[0070] In some embodiments, the lyophilized formulation is administered by injection.

[0071] Preparation process of lyophilized formulations The present invention also provides a process for preparing a lyophilized formulation, comprising the following steps: lyophilizing a pharmaceutical composition containing a compound of formula I and / or a pharmaceutically acceptable salt thereof, thereby obtaining the product; .

[0072] In some embodiments, the pharmaceutical composition is as described in any of the embodiments herein.

[0073] In some embodiments, the freeze-drying steps of the present invention are as follows: ① Cooling: The temperature is lowered from room temperature to -25°C or below in 0.5 to 4 hours, then raised to -20 to -5°C in 0.5 to 2.5 hours, and held for 1.5 to 4.5 hours; then the temperature is lowered to -30°C or below in 0.5 to 2.5 hours, and held for 1 to 5 hours; ② First sublimation: Vacuum is drawn until the vacuum degree reaches below 30 Pa, the temperature is raised to -20 to -10°C in 0.5 to 2.5 hours, and held for 15 to 40 hours; ③ Second sublimation: The temperature is raised to 30 to 50°C in 1 to 3 hours, held for 2 to 6 hours, and the vacuum degree is controlled to be below 20 Pa.

[0074] In some embodiments, the freeze-drying steps of the present invention are as follows: ① Cooling: The temperature is lowered from room temperature to about -30°C in about 2 hours, then raised to about -10°C in about 1 hour, and held for about 2.5 hours; then the temperature is lowered to about -40°C in about 1 hour, and held for about 2 hours; ② First sublimation: Vacuum is drawn until the vacuum degree reaches below 30 Pa, the temperature is raised to about -15°C in about 1 hour, and held for about 25 hours; ③ Second sublimation: The temperature is raised to about 40°C in about 2 hours, held for about 4 hours, and the vacuum degree is controlled to be below 20 Pa.

[0075] Drug Use The present invention also provides the use of pharmaceutical compositions or lyophilized formulations as described in any of the embodiments herein in the preparation of medicaments for treating mammalian microbial infections.

[0076] The present invention also provides pharmaceutical compositions or lyophilized formulations as described in any of the embodiments herein for the treatment of mammalian microbial infections.

[0077] The present invention also provides a method for treating microbial infections in mammals, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition or lyophilized formulation as described in any of the embodiments herein.

[0078] In some embodiments, the microbial infection is a Gram-positive microbial infection (including Gram-positive aerobic bacteria such as multidrug-resistant Staphylococcus aureus, enterococci, streptococci, and anaerobic microorganisms such as Bacteroides and Clostridium).

[0079] In some implementations, the microbial infection is a Gram-negative microbial infection.

[0080] In some implementations, the microbial infection is Mycobacterium tuberculosis infection.

[0081] In some embodiments, the microbial infection is a complicated skin and soft tissue infection caused by Gram-positive bacteria, a diabetic foot infection, an acute bacterial skin and skin structure infection, a community-acquired pneumonia, or a hospital-acquired pneumonia.

[0082] In some implementations, the mammal is a human.

[0083] abbreviation mM: mmol / L; GMP environment: refers to a production environment that complies with Good Manufacturing Practice (GMP) for pharmaceutical manufacturing. Non-GMP environment: refers to a production environment that does not comply with Good Manufacturing Practice (GMP) for pharmaceuticals; Sodium citrate: refers to trisodium citrate, CAS number: 68-04-2.

[0084] The test method for related substances in the examples is as follows: related substances are detected by high performance liquid chromatography, and the peak area percentage of related substances is recorded.

[0085] Chromatographic conditions:

[0086] Example Example 1: Stability comparison between buffer-added and unbuffered formulations under the same pH conditions Citric acid and sodium citrate were selected as pH adjusters for the solution, and their stability in buffer solutions and aqueous solutions was compared.

[0087] Preparation of buffer solution: Take 20mM citric acid solution and 20mM sodium citrate solution, and mix them to prepare a 20mM citric acid-sodium citrate buffer solution with pH 5.3.

[0088] Preparation of the medicinal solution: Prescription 1-1: Dissolve the sodium salt of compound I in water for injection to prepare a solution with a concentration of 200 mg / mL based on the sodium salt of compound I.

[0089] Prescription 1-2: Dissolve the sodium salt of compound I in 20mM citrate-sodium citrate buffer solution at pH 5.3, adjust the pH with 20mM citrate or sodium citrate solution to make it consistent with prescription 1-1, and prepare a drug solution with a concentration of 200mg / mL based on the sodium salt of compound I.

[0090] Sample preparation: The solutions of formulations 1-1 and 1-2 were diluted with water for injection to prepare a test solution with a sodium salt concentration of 1.8 mg / mL for compound I, and stored at room temperature. The pH and related substances were measured at 0 h, 6 h, and 12 h, and the results are shown in Table 1 below.

[0091] Table 1: Test results of pH and related substances

[0092] Note: Rate of change = (test value after storage - test value at 0h) / test value at 0h × 100%.

[0093] The above results indicate that the formulation with citrate-sodium citrate buffer has better stability than the formulation without buffer. During further experimental research, the inventors of this application discovered that replacing the citrate-sodium citrate buffer with other feasible buffers did not improve the stability of the formulation.

[0094] Example 2: Comparison of stability at different pH values Preparation of buffer solutions: Take 10mM citric acid solution and 10mM sodium citrate solution, mix them together to prepare citric acid-sodium citrate buffer solutions with pH values ​​of 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 and 7.0 respectively.

[0095] Preparation of the medicinal solution: Prescription 2-1: Dissolve the sodium salt of compound I in water for injection to prepare a solution with a concentration of 200 mg / mL based on the sodium salt of compound I.

[0096] Prescriptions 2-2 to 2-10: Dissolve the sodium salt of compound I in citrate-sodium citrate buffer (10 mM, pH 3.0 to 7.0) at the above pH to prepare a solution with a concentration of 200 mg / mL based on the sodium salt of compound I.

[0097] Sample preparation: The above-prescribed solutions were diluted with water for injection to prepare test solutions with a concentration of 1.8 mg / mL (calculated as the sodium salt of compound I). The solutions were stored in a water bath at 40°C. pH and related substances were measured at 0 h and 12 h. The results are shown in Table 2 below.

[0098] Table 2: Test results for pH and related substances

[0099] Note: Change rate = (test value after 12 hours of storage - test value after 0 hours) / test value after 0 hours × 100%; * indicates that prescriptions 2-1 and 2-2 have a large amount of white flocculent precipitate, and prescription 2-3 has a small amount of white flocculent precipitate.

[0100] The above results indicate that a 10 mM citrate-sodium citrate buffer solution with a pH of 4.5–5.5 can significantly improve stability. Surprisingly, when the pH of the citrate-sodium citrate buffer solution is lower or higher than the above range, the content of related substances increases significantly (the rate of change of related substances is 378.4% at pH 3.0, 144.1% at pH 5.0, and 216.3% at pH 7.0, showing significant differences). There is no direct correlation between pH and formulation stability. This may be because the sodium salt of the active ingredient, compound I, can form a complex mixture with the citrate-sodium citrate buffer solution, with citrate playing a certain role in metal ion complexation. The system exhibits optimal stability at a pH of 4.5–5.5. The addition of related substances in this application's formulation not only reduces the content of the active pharmaceutical ingredient and affects the stability of the drug, but may also reduce its efficacy and may even harm human health or cause other side effects. Therefore, for the sake of drug safety, efficacy, and quality control, it is necessary to control it more strictly. Taking into account both pH and stability, the pH value of formulations 2-6 (pH 5.0) was initially selected as the pH of the citrate-sodium citrate buffer solution for further research.

[0101] Example 3: Effect of different ionic strength buffer solutions on stability The effects of different concentrations of citrate-sodium citrate buffer (50 mM, 20 mM, 10 mM) on stability were investigated to screen for suitable ion concentrations in the citrate-sodium citrate buffer. A control group with pH adjusted using sodium hydroxide solution was also set up to verify the necessity of using the buffer solution as a pH adjuster.

[0102] Preparation of buffer solutions: Take 10 mM citric acid solution and 10 mM sodium citrate solution, mix them together to prepare citric acid-sodium citrate buffer solutions with pH values ​​of 4.0, 4.5, 5.0, 5.5, and 6.0 respectively; take 20 mM citric acid solution and 20 mM sodium citrate solution, mix them together to prepare citric acid-sodium citrate buffer solutions with pH values ​​of 4.0, 4.5, 5.0, 5.5, and 6.0 respectively; take 50 mM citric acid solution and 50 mM sodium citrate solution, mix them together to prepare citric acid-sodium citrate buffer solutions with pH values ​​of 4.0, 4.5, 5.0, 5.5, and 6.0 respectively.

[0103] Preparation of the medicinal solution: A total of 21 formulations were prepared, each using a different buffer solution: Formulation 3-1 was a blank control without any excipients; formulations 3-2 to 3-6 used 50 mM citrate-sodium citrate buffer solutions with pH values ​​of 4.0, 4.5, 5.0, 5.5, and 6.0, respectively; formulations 3-7 to 3-11 used 20 mM citrate-sodium citrate buffer solutions with pH values ​​of 4.0, 4.5, 5.0, 5.5, and 6.0, respectively; formulations 3-12 to 3-16 used 10 mM citrate-sodium citrate buffer solutions with pH values ​​of 4.0, 4.5, 5.0, 5.5, and 6.0, respectively; and formulations 3-17 to 3-21 used sodium hydroxide solution.

[0104] Prescription 3-1: Dissolve the sodium salt of compound I in water for injection to prepare a solution with a concentration of 200 mg / mL based on the sodium salt of compound I.

[0105] Prescriptions 3-2 to 3-16: Dissolve the sodium salts of the compound of formula I in the corresponding citrate-sodium citrate buffer solution to prepare a solution with a concentration of 200 mg / mL based on the sodium salt of the compound of formula I.

[0106] Prescriptions 3-17~3-21: Dissolve the sodium salt of compound I in water for injection to prepare a solution with a concentration of 200 mg / mL based on the sodium salt of compound I. Adjust the pH to 4.0, 4.5, 5.0, 5.5 and 6.0 respectively using sodium hydroxide test solution.

[0107] Sample preparation: The drug solution was transferred to neutral borosilicate glass vials, sealed with rubber stoppers and wrapped with sealing film, and placed in a 40℃ oven. The pH and related substances were measured at 0h and 12h, and the results are shown in Table 3 below.

[0108] Table 3: Results of pH and related substance changes

[0109] Note: Rate of change = (test value after 12 hours of storage - test value after 0 hours) / test value after 0 hours × 100%.

[0110] The above results indicate that there is no direct correlation between ion concentration and formulation stability. Formulations with pH adjusted using buffer solutions showed smaller pH changes and increases in related substances compared to formulations using sodium hydroxide. Formulations with 50 mM and 20 mM citrate-sodium citrate buffer solutions were superior to those with 10 mM. Among the 50 mM and 20 mM buffer solutions, the active ingredient was most stable in the composition system when the citrate-sodium citrate buffer concentration was 20 mM and the pH was 5.0, exhibiting low ion concentration, small pH changes, and the lowest rate of change in related substances.

[0111] Example 4: Preliminary Study on Freeze-drying Process Using 20mM citrate-sodium citrate buffer (pH 5.0) as the buffer solution, with a drug volume of 2mL, and using 10mL borosilicate glass vials for injection, a lyophilization curve was designed. The pre-freezing time was initially determined to be 4h. The lyophilization cycle was determined based on the actual situation, and the duration of one drying cycle was set to be approximately 1.5 times the time when the water line disappears.

[0112] Preparation of buffer solution: Take 20mM citric acid solution and 20mM sodium citrate solution, and mix them to prepare a citric acid-sodium citrate buffer solution with a pH of 5.0.

[0113] Preparation of the drug solution: Dissolve the sodium salt of compound I in 20mM citrate-sodium citrate buffer (pH 5.0) to prepare a drug solution with a concentration of 150mg / mL based on the sodium salt of compound I.

[0114] Sample preparation: Dispense the drug solution into 10mL borosilicate glass vials, 2mL / vial. Follow the instructions... Figure 1 The curve shown is freeze-dried.

[0115] The results showed that the water line in the sample disappeared in 8 hours during the first drying process, and the product temperature reached the theoretical temperature in 7 hours. The drying duration was adjusted to 12 hours. The finished product had a good appearance, and there was no difference in appearance among the samples of each plate layer. Therefore, subsequent formulation studies will refer to this freeze-drying process.

[0116] Example 5: Screening of excipients---sucrose Freeze-dried products typically require the addition of suitable freeze-drying agents and protectants for effective freeze-drying and storage. Pre-formulation studies have shown that the sodium salt solid of Formula I compound is sensitive to humidity and temperature. Sucrose, on the other hand, has a high glass transition temperature, poor water absorption, and low crystallinity. Therefore, different proportions of sucrose were added to the formulation as freeze-drying protectants, and freeze-dried products were prepared by mixing them with 20mM citrate-sodium citrate buffer (pH 5.0). The appearance, moisture content, reconstitution time, and changes in related substances of the freeze-dried powder were investigated to determine a suitable formulation.

[0117] Preparation of buffer solution: Take 20mM citric acid solution and 20mM sodium citrate solution, and mix them to prepare a citric acid-sodium citrate buffer solution with a pH of 5.0.

[0118] Preparation of the solution: According to the prescription composition in Table 4, weigh out the corresponding amounts of sodium salt and sucrose of compound I, add the corresponding solvent to 2 mL, and stir to mix evenly.

[0119] Table 4: Prescription Composition

[0120] Sample preparation: The drug solution was dispensed into 10mL neutral borosilicate glass vials, with each vial containing 2mL, according to the instructions. Figure 1 The freeze-drying curve shown is used for freeze-drying.

[0121] Stability Comparison Study: After removal from the chamber, observe the properties and reconstitution time of different prescription samples, and test related substances. Place the remaining samples in a drug stability test chamber (40℃±2℃, RH 75%±5%), take samples at 0 days and 3 days, test related substances, and make comparisons.

[0122] (1) Appearance: Take one sample bottle of each prescription, observe and record the appearance of the sample under light. (2) Reconstitution time: Take one sample bottle of each prescription, add 2 mL of water for injection, let stand, and observe the dissolution phenomenon. (3) Related substances: Take the drug solution and detect related substances by high performance liquid chromatography.

[0123] The results are shown in Table 5.

[0124] Table 5: Test Results Table

[0125] Note: Change rate = (test value after 3 days of storage - test value after 0 hours) / test value after 0 days × 100%.

[0126] The above results indicate that there were no significant differences in appearance and moisture content among samples from different formulations, and that the sucrose-free formulation 5-1 was more soluble. Related substances analysis results show that formulation 5-1 is the optimal formulation; therefore, sucrose should not be added to the formulation.

[0127] Example 6: Screening of excipients---Mannitol Mannitol, a commonly used excipient in freeze-dried formulations, is primarily used to form a rigid, homogeneous framework to improve the appearance of the freeze-dried formulation in glass vials. To achieve a better appearance for the freeze-dried formulation, 0.8% (g / mL) mannitol was added to the formulation as a building agent. Furthermore, based on previous stability studies, the stability of samples freeze-dried in a 20mM citrate-sodium citrate buffer solution at pH 5.0 was further investigated to verify whether the stability of the freeze-dried samples was consistent with that of the solution.

[0128] Preparation of buffer solution: Take 20mM citric acid solution and 20mM sodium citrate solution, mix them together to prepare a citric acid-sodium citrate buffer solution with a pH of 5.0.

[0129] Preparation of the solution: According to the prescription composition in Table 6, weigh out the corresponding amounts of sodium salt of compound I and mannitol, add the corresponding solvent to 2 mL, and stir to mix evenly.

[0130] Table 6: Prescription Composition

[0131] Sample preparation: The drug solution was dispensed into 10mL neutral borosilicate glass vials, with each vial containing 2mL, according to the instructions. Figure 1 The freeze-drying curve shown is used for freeze-drying.

[0132] Stability Comparison Study: The samples were placed in a drug stability test chamber (40℃±2℃, RH 75%±5%), and pH and related substances were measured at 0 and 3 days. The results are shown in Table 7.

[0133] Table 7: Test Results Table

[0134] Note: Change rate = (test value after 3 days of storage - test value after 0 hours) / test value after 0 days × 100%.

[0135] The above results indicate that the appearance of the samples with added mannitol was consistent with other samples, all being white lumps with no significant differences; under 40℃ / 75%RH conditions, the increase in related substances in the samples with added mannitol was significantly higher than that in the samples without mannitol; the formulation 6-1 with 20mM citrate-sodium citrate buffer (pH 5.0) without mannitol was superior to other formulations.

[0136] The results of excipient screening showed that the sodium salt of Formula I compound, which is sensitive to humidity and temperature, exhibits superior stability in the buffer system of this application without the addition of a skeleton forming agent or a lyophilization protectant. This discovery not only reduces the number of manufacturing steps and the cost of pharmaceutical formulations, but also improves the stability of the drug, resulting in better safety and efficacy of the drug composition. This is a very unexpected finding.

[0137] Example 7: Further Study of the Freeze-drying Process To further verify the relevant key production process parameters, a laboratory-scale (500 vials) sample was prepared using 20mM citrate-sodium citrate buffer (pH 5.0) as the buffer solution for preliminary stability studies of the formulation.

[0138] Preparation of buffer solution: Take 20mM citric acid solution and 20mM sodium citrate solution, and prepare a citric acid-sodium citrate buffer solution with a pH of 5.0 by mixing them at a volume ratio of approximately 1:1.8.

[0139] Preparation of the solution: Dissolve the sodium salt of compound I in 20mM citrate-sodium citrate buffer (pH 5.0) and bring the volume to 1000mL. The concentration is 150mg / mL based on the sodium salt of compound I.

[0140] Sample preparation: Dispense the drug solution into borosilicate glass vials, 2 mL / vial. Follow the instructions... Figure 1 The curve shown is freeze-dried.

[0141] After freeze-drying, nitrogen protection was applied; the sample appeared as a white, lumpy substance with good freeze-dried appearance; preliminary stability tests were conducted on the sample at 25℃±2℃ for 1 month, 2 months, and 3 months. The results are shown in Table 8.

[0142] Table 8: Test Results Table

[0143] The results showed that the related substances level was as high as 5.5% after 3 months at 25°C, which did not meet the requirements for formulation.

[0144] Further research was conducted under a Non-GMP environment, using 20 mM citrate-sodium citrate buffer (pH 5.0) as the buffer solution, according to... Figure 1 The curve shown was used for freeze drying to prepare a scaled-up sample (1000 vials) under Non-GMP conditions for preliminary testing. The results showed that the freeze-dried sample had obvious bottom melting, which was presumably related to the increased sample quantity in this batch (the batch size increased from 500 vials to 1000 vials).

[0145] Example 8: Further Study of the Freeze-drying Process To address the problems arising during large-scale production, the freezing temperature, freezing time, drying temperature, and drying time in the freeze-drying process were studied, and the stability under GMP conditions was further investigated.

[0146] Preparation of buffer solution: Weigh the prescribed amounts of citric acid and sodium citrate, add an appropriate amount of water for injection to prepare 20 mM solutions of citric acid and sodium citrate respectively, and prepare a 20 mM citric acid-sodium citrate buffer solution with a volume ratio of approximately 1:1.8 and a pH of 5.0±0.1. Cool to 2-10°C and set aside for use.

[0147] Preparation of the drug solution: Add the above-mentioned citrate-sodium citrate buffer solution and sodium salt of Formula I compound to the mixing tank, stir until completely dissolved, and mix the drug solution evenly; perform initial filtration of the drug solution through a 0.45μm polyvinylidene fluoride capsule filter; then filter through a double-stage 0.22μm sterile filter (polyvinylidene fluoride); the concentration is approximately 150mg / mL based on the sodium salt of Formula I compound.

[0148] Filling: Fill the solution into 10mL borosilicate glass vials, 2mL / vial. (Follow the instructions...) Figure 2The freeze-drying process, as shown in the curve, is described as follows: ① Cooling: Within 2 hours, the plate temperature is lowered from room temperature to -30℃; within 1 hour, the plate temperature is raised to -10℃, held for 2.5 hours, and then lowered to -40℃, held for 2 hours; ② First sublimation: When the vacuum degree of the freeze-drying chamber reaches below 30Pa, the temperature is raised to -15℃ in about 1 hour, and held at -15℃ for 25 hours; ⑤ Second sublimation: The temperature is raised to 40℃ in about 2 hours, and held at 40℃ for 4 hours. During the second sublimation process, the vacuum degree is controlled to be below 20Pa; ⑥ After the freeze-drying process is completed, clean nitrogen is introduced into the freeze-drying chamber. With the filling chamber temperature at 18-26℃, the automatic stoppering device of the freeze dryer is activated to completely compress the rubber stoppers. The freeze dryer is then removed from the chamber and capped.

[0149] The product stability was tested under the following conditions: ① High temperature test: Temperature: 40℃; Temperature: 25℃; ② High humidity test: Humidity: 90%±5%; Humidity: 75%±5%; ③ Strong light irradiation test: Light intensity: 5000lx±500lx, 90μw / cm² 2 The results are shown in Table 9.

[0150] Table 9: Test Results Table Examination conditions shape acidity Related substances, % Moisture, % Visible foreign objects Content of active ingredient (as sodium salt of compound I), % 25℃ (10 days) off-white lumps 4.9 0.90 0.32 No foreign objects found 100.0 25℃ (January) off-white lumps 4.8 1.71 0.41 No foreign objects found 99.2 25℃ (February) off-white lumps 4.6 2.34 0.50 No foreign objects found 97.8 25℃ (March) off-white lumps 4.5 3.46 0.56 No foreign objects found 96.0 The above results indicate that the formulation and lyophilization process of the present invention, when performed as described above... Figure 2 The freeze-drying curves shown indicate that the prepared product has a good overall appearance, is easy to knock off and does not stick to the bottom, requires fewer types and amounts of excipients, and has stable quality. After 3 months at 25℃, the related substances still meet the formulation requirements. Under light (light intensity: 5000lx±500lx, 90μw / cm²), the product also performs well. 2 After being stored for 10 days under high temperature (40℃) and high humidity (90%±5% humidity, 75%±5% humidity) conditions, all indicators met the requirements of the formulation. The results of the influencing factor test also met the quality standards of the proposed formulation, indicating that the prescription is reasonable, the process is stable, and the quality is controllable, making it suitable for production. Stability during drug preparation and storage not only ensures drug quality but also leads to a relative improvement in efficacy.

[0151] Example 9 Using the same formulation and preparation process as in Example 8, the only difference being that the filling volume of the drug solution during the "filling" process was adjusted from 2 mL / bottle to 6.67 mL / bottle, a lyophilized formulation containing approximately 1000 mg of active ingredient per bottle (calculated as sodium salt of compound I) was prepared.

[0152] The above description is merely a basic illustration of the concept of this invention, and any equivalent modifications made based on the technical solutions of this invention should fall within the protection scope of this invention. Furthermore, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of those different embodiments or examples.

Claims

1. A pharmaceutical composition comprising: a compound of formula I or a pharmaceutically acceptable salt thereof and a buffer solution. ， Optionally, the mass-to-volume ratio of the compound of Formula I or its pharmaceutically acceptable salt to the buffer solution is 50–300 mg: 1 mL; Optionally, the mass-to-volume ratio of the compound of Formula I or its pharmaceutically acceptable salt to the buffer solution is 100–200 mg: 1 mL; Optionally, the mass-to-volume ratio of the compound of Formula I or its pharmaceutically acceptable salt to the buffer solution is 130–170 mg: 1 mL.

2. The pharmaceutical composition according to claim 1, characterized in that, The buffer solution comprises one or more of citrate buffer, phosphate buffer, histidine buffer, and acetate buffer; optionally, the buffer solution is citrate buffer, wherein the citrate buffer solution is citrate-sodium citrate buffer.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The concentration of the buffer solution is 5–60 mM; optionally, the concentration of the buffer solution is 10–50 mM; optionally, the concentration of the buffer solution is 15–25 mM.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The pH of the buffer solution is 4.5 to 5.

5.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition is prepared from the following raw materials: a compound of formula I or a pharmaceutically acceptable salt thereof and a 15-25 mM citrate-sodium citrate buffer solution with a pH of 4.5-5.5; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is 100-200 mg: 1 mL; optionally, the pharmaceutical composition is prepared from the raw materials shown in any one of (1) to (7) below: (1) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 20 mM, pH 4.5 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (2) A compound of formula I or a pharmaceutically acceptable salt thereof and about 20 mM of citrate-sodium citrate buffer solution at pH 5.0 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (3) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 20 mM at pH 5.5 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (4) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 50 mM at pH 5.0 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (5) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 50 mM at pH 5.5 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 200 mg: 1 mL; or (6) A compound of formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 20 mM, pH 5.0 ± 0.3; wherein the mass-to-volume ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 150 mg: 1 mL; or (7) A compound of Formula I or a pharmaceutically acceptable salt thereof and a citrate-sodium citrate buffer solution of about 20 mM at pH 5.5 ± 0.3; wherein the mass-to-volume ratio of the compound of Formula I or a pharmaceutically acceptable salt thereof to the citrate-sodium citrate buffer solution is about 150 mg: 1 mL.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition is prepared by dissolving the compound of formula I or a pharmaceutically acceptable salt thereof in a buffer solution and filtering.

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that, The compound of Formula I or a pharmaceutically acceptable salt thereof is a sodium and / or potassium salt of the compound of Formula I.

8. The pharmaceutical composition according to any one of claims 1-7, characterized in that, The unit dose of the pharmaceutical composition contains 100 to 1000 mg of the active ingredient, converted to the sodium salt of compound I, and may be approximately 300 mg, approximately 500 mg, or approximately 1000 mg.

9. A lyophilized formulation, wherein, The lyophilized formulation is prepared by lyophilizing the pharmaceutical composition according to any one of claims 1-8.

10. The lyophilized formulation according to claim 11, characterized in that, The freeze-drying process is as follows: (1) Cooling: The temperature is lowered from room temperature to -25°C or below in 0.5 to 4 hours, then raised to -20 to -5°C in 0.5 to 2.5 hours and kept at that temperature for 1.5 to 4.5 hours; then the temperature is lowered to -30°C or below in 0.5 to 2.5 hours and kept at that temperature for 1 to 5 hours; (2) First sublimation: Vacuuming is performed until the vacuum level reaches below 30 Pa, the temperature is raised to -20 to -10°C in 0.5 to 2.5 hours and kept at that temperature for 15 to 40 hours; (3) Second sublimation: The temperature is raised to 30 to 50°C in 1 to 3 hours and kept at that temperature for 2 to 3 hours. For 6 hours, the vacuum degree is controlled to be below 20 Pa; optionally, the freeze-drying steps are: (1) Cooling: the temperature is lowered from room temperature to about -30°C in about 2 hours, then raised to about -10°C in about 1 hour and kept warm for about 2.5 hours; then the temperature is lowered to about -40°C in about 1 hour and kept warm for about 2 hours; (2) First sublimation: the vacuum degree is evacuated to below 30 Pa, the temperature is raised to about -15°C in about 1 hour and kept warm for about 25 hours; (3) Second sublimation: the temperature is raised to about 40°C in about 2 hours and kept warm for about 4 hours, while controlling the vacuum degree to be below 20 Pa.

11. The lyophilized formulation according to claim 9 or 10, characterized in that, The unit dose of the lyophilized formulation contains 100 to 1000 mg of active ingredient, converted to sodium salt of compound I, and may be approximately 300 mg, approximately 500 mg, or approximately 1000 mg.

12. The lyophilized formulation according to any one of claims 9-11, characterized in that, The lyophilized formulation does not contain lyophilizing agents, skeleton forming agents, or lyophilization protectants.

13. A process for preparing a lyophilized formulation, comprising the following steps: lyophilizing a pharmaceutical composition containing a compound of formula I and / or a pharmaceutically acceptable salt thereof, thereby obtaining the product; ， Preferably, the pharmaceutical composition is the pharmaceutical composition as described in any one of claims 1-7.

14. The preparation process of the lyophilized formulation according to claim 13, characterized in that, The freeze-drying process is as follows: (1) Cooling: The temperature is lowered from room temperature to -25°C or below in 0.5 to 4 hours, then raised to -20 to -5°C in 0.5 to 2.5 hours and kept at that temperature for 1.5 to 4.5 hours; then the temperature is lowered to -30°C or below in 0.5 to 2.5 hours and kept at that temperature for 1 to 5 hours; (2) First sublimation: Vacuuming is performed until the vacuum level reaches below 30 Pa, the temperature is raised to -20 to -10°C in 0.5 to 2.5 hours and kept at that temperature for 15 to 40 hours; (3) Second sublimation: The temperature is raised to 30 to 50°C in 1 to 3 hours and kept at that temperature for 2 to 3 hours. The freeze-drying process is preferably as follows: (1) Cooling: The temperature is lowered from room temperature to about -30°C in about 2 hours, then raised to about -10°C in about 1 hour and kept warm for about 2.5 hours; then the temperature is lowered to about -40°C in about 1 hour and kept warm for about 2 hours; (2) First sublimation: Vacuum is drawn until the vacuum level reaches below 30Pa, the temperature is raised to about -15°C in about 1 hour and kept warm for about 25 hours; (3) Second sublimation: The temperature is raised to about 40°C in about 2 hours and kept warm for about 4 hours, while controlling the vacuum level to below 20Pa.

15. The pharmaceutical composition according to any one of claims 1-8 or the lyophilized formulation according to any one of claims 9-12, wherein, The pharmaceutical composition or lyophilized preparation is administered by injection.

16. Use of the pharmaceutical composition according to any one of claims 1-8 or the lyophilized formulation according to any one of claims 9-12 in the preparation of a medicament for treating microbial infections in mammals.

17. The use according to claim 16, characterized in that, The microbial infection is a Gram-positive microbial infection, a Gram-negative bacterial infection, or a Mycobacterium tuberculosis infection.

18. The use according to claim 16, characterized in that, The microbial infections include complicated skin and soft tissue infections caused by Gram-positive bacteria, diabetic foot infections, acute bacterial skin and skin structure infections, community-acquired pneumonia, and hospital-acquired pneumonia.

19. The use according to any one of claims 16-18, characterized in that, The mammal in question is a human.

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