Pharmaceutical composition containing ornidazole compound and preparation method and application thereof

Abstract

The invention discloses a pharmaceutical composition containing an ornidazole compound as well as a preparation method and application of the pharmaceutical composition. The pharmaceutical composition comprises an ornidazole compound and 1-(2, 3-epoxypropane)-2-methyl-5-nitroimidazole, wherein the content of the 1-(2, 3-epoxypropane)-2-methyl-5-nitroimidazole is 1000 mg / kg or below. The safety and / or stability of the pharmaceutical composition in the period of validity are / is remarkably improved.

Description

[0001] This application claims priority to the following earlier application: Patent application No. 201910936095.0, filed with the China National Intellectual Property Administration on September 29, 2019, entitled "Pharmaceutical Composition Containing Ornidazole Compounds, Preparation Method Thereof and Use Thereof," the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to pharmaceutical compositions containing ornidazole compounds, their preparation methods, and uses. Background Technology

[0003] Ornidazole is a nitroimidazole derivative, a potent anti-anaerobic and antiprotozoal drug. It is a third-generation nitroimidazole derivative developed after metronidazole, offering higher efficacy, shorter treatment duration, better tolerability, and wider distribution in the body. Ornidazole's antimicrobial action is achieved through the reduction of the nitro group in its molecule to an amino group in an anaerobic environment, or through the interaction of free radicals with cellular components, leading to microbial death. Ornidazole is 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (CAS No. 16773-42-5), with the chemical structure shown below:

[0004] Ornidazole Levo-ornidazole (also known as "Levo-ornidazole", CAS No. 166734-83-4) is the levorotatory isomer of ornidazole. Clinically, it is mainly used to treat various infectious diseases caused by anaerobic bacteria such as Bacteroides fragilis, Bacteroides dichotoma, Bacteroides ovalis, Bacteroides polymorpha, Bacteroides vulgaris, Clostridium perfringens, Eubacterium, Peptococcus and Peptostreptococcus, Helicobacter pylori, Bacteroides melaninosa, Fusobacterium, CO2-phages, and Porphyromonas gingivalis, or for the preoperative prevention of such infections. Levo-ornidazole has the following chemical structure:

[0005] Levodocin Previous studies have shown that levonitrozine has lower neurotoxicity compared to the dextrorotatory isomer or its racemic form, thus significantly improving its safety profile. Furthermore, prodrugs of levonitrozine have been developed, including levonitrozine phosphate esters (also known as levonitrozine phosphate) or their salts (such as disodium levonitrozine phosphate). After administration, these prodrugs are rapidly degraded into levonitrozine by phospholipases in vivo, thereby exerting their therapeutic effect.

[0006] Currently, the safety and / or stability of ornidazole, its stereoisomers and prodrugs, especially ornidazole, levonornidazole and their prodrugs during their shelf life, remain of great interest to drug researchers and are areas that require further in-depth study. Summary of the Invention

[0007] To improve the above-mentioned technical problems, the present invention provides a pharmaceutical composition comprising an ornidazole compound and 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole in a content of less than 1000 mg / kg.

[0008] According to embodiments of the present invention, the ornidazole compound may be selected from ornidazole, its stereoisomers, or their precursor compounds. As an example, the ornidazole compound may be selected from ornidazole, levonornidazole (also known as "levonornidazole"), or dextrorotatory ornidazole (also known as "dextrorotatory ornidazole"), or their precursor compounds.

[0009] According to an embodiment of the present invention, the ornidazole has the chemical structure shown in formula (I-1):

[0010] I-1 Levo-ornidazole has the structure shown in formula (I-2):

[0011] I-2 Dextrorotatory ornidazole has the structure shown in formula (I-3):

[0012] I-3 According to embodiments of the present invention, the precursor compound of ornidazole, levonidazole, or dextroonidazole may be selected from pharmaceutically acceptable precursor compounds, such as esters or pharmaceutically acceptable salts of any of them, and their hydrates, such as amino acid esters, phosphate esters, amino acid salts of phosphate esters, and salts formed by phosphate esters with alkali metal or alkaline earth metal ions or their hydrates; for example, at least one of sodium, potassium, calcium, magnesium salts of phosphate esters or their hydrates, an exemplary example being disodium phosphate salt or its hydrate.

[0013] According to embodiments of the present invention, the precursor compound of levonornidazole may be selected from at least one of levonornidazole amino acid ester, levonornidazole phosphate, levonornidazole phosphate amino acid salt, and levonornidazole phosphate salts formed with alkali metal or alkaline earth metal ions or their hydrates; for example, at least one of the sodium, potassium, calcium, magnesium salts of levonornidazole phosphate or their hydrates, exemplarily levonornidazole phosphate disodium salt (CAS No. 909133-95-5) or its hydrate.

[0014] According to embodiments of the present invention, the precursor compound of ornidazole, levonornidazole, or dextrorotatory ornidazole may be present in the pharmaceutical composition in its amorphous or polymorphic form. Alternatively, the precursor compound of ornidazole, levonornidazole, or dextrorotatory ornidazole may also be selected from a solvate of a pharmaceutically acceptable salt of any of their esters, such as its hydrate, for example, at least one of 1, 2, 3, 4, 5, 6, or 7 hydrates of the pharmaceutically acceptable salt of the ester, examples of which may be selected from the hydrates of disodium levonornidazole phosphate, such as at least one of its 5-hydrate, 6-hydrate, or 7-hydrate.

[0015] According to an embodiment of the present invention, 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole has the structure shown in formula (II):

[0016] II.

[0017] According to embodiments of the present invention, the content of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 900 mg / kg, for example less than 800 mg / kg, less than 700 mg / kg, less than 600 mg / kg, less than 500 mg / kg, less than 400 mg / kg, less than 300 mg / kg, less than 200 mg / kg, preferably less than 100 mg / kg. Preferably, the content of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole is less than 90 mg / kg, for example less than 80 mg / kg, less than 70 mg / kg, more preferably less than 60 mg / kg, less than 50 mg / kg, less than 40 mg / kg, less than 30 mg / kg, less than 20 mg / kg, or less than 10 mg / kg.

[0018] According to a preferred embodiment of the present invention, the content of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 9 mg / kg, for example less than 8 mg / kg, less than 7 mg / kg, more preferably less than 6 mg / kg, and examples of which are less than 5 mg / kg, less than 4 mg / kg, less than 3 mg / kg, less than 2 mg / kg or less than 1 mg / kg.

[0019] According to a more preferred embodiment of the present invention, the content of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 0.9 mg / kg, for example less than 0.8 mg / kg, less than 0.7 mg / kg, more preferably less than 0.6 mg / kg, and examples may be less than 0.5 mg / kg, less than 0.4 mg / kg, less than 0.3 mg / kg, less than 0.2 mg / kg or less than 0.1 mg / kg.

[0020] According to embodiments of the present invention, the content of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole in the pharmaceutical composition may be 0, meaning that the pharmaceutical composition does not contain 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole. In some embodiments of the pharmaceutical composition of the present invention, the content of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole is greater than 0, meaning that the pharmaceutical composition contains 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole.

[0021] According to embodiments of the present invention, the weight percentage content of ornidazole compounds as active ingredients in the pharmaceutical composition, calculated as levonitrile, disodium levonitrile phosphate, or any of the hydrates thereof, can be in the range of 10% to 99%, preferably 15% to 90%, for example 20% to 85%, and examples can be in the range of 72% to 83%, for example 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%.

[0022] According to embodiments of the present invention, the pharmaceutical composition may optionally include or exclude compounds represented by formula (IV):

[0023] IV.

[0024] According to embodiments of the present invention, the content of the compound represented by formula (IV) in the pharmaceutical composition may be less than 15,000 mg / kg, for example less than 14,000 mg / kg, less than 13,000 mg / kg, less than 12,000 mg / kg, less than 11,000 mg / kg, less than 10,000 mg / kg, less than 8,000 mg / kg, less than 7,000 mg / kg, less than 6,000 mg / kg, less than 5,000 mg / kg, less than 4,000 mg / kg, less than 3,000 mg / kg, or less than 2,000 mg / kg. Preferably, the content of the compound represented by formula (IV) may be less than 1,000 mg / kg, for example less than 900 mg / kg, less than 800 mg / kg, less than 700 mg / kg, less than 600 mg / kg, less than 500 mg / kg, less than 400 mg / kg, less than 300 mg / kg, less than 200 mg / kg, or less than 100 mg / kg.

[0025] According to a preferred embodiment of the present invention, the content of the compound represented by formula (IV) in the pharmaceutical composition is 90 mg / kg or less, for example, 80 mg / kg or less, 70 mg / kg or less, more preferably 60 mg / kg or less, and examples may be 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, 10 mg / kg or less, or 0. Wherein, when the content of the compound represented by formula (IV) in the pharmaceutical composition is 0, it means that the pharmaceutical composition does not contain the compound represented by formula (IV). Alternatively, the content of the compound represented by formula (IV) in the pharmaceutical composition may also be >0.

[0026] According to embodiments of the present invention, the pharmaceutical composition may optionally contain or not contain 2-methyl-5-nitroimidazole.

[0027] According to an embodiment of the present invention, the content of 2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 2000 mg / kg, for example less than 1900 mg / kg, less than 1800 mg / kg, less than 1700 mg / kg, less than 1600 mg / kg, less than 1500 mg / kg, preferably less than 1400 mg / kg, less than 1300 mg / kg, less than 1200 mg / kg, less than 1100 mg / kg, less than 1000 mg / kg, for example less than 900 mg / kg, less than 800 mg / kg, less than 700 mg / kg, less than 600 mg / kg, less than 500 mg / kg, less than 400 mg / kg, less than 300 mg / kg, less than 200 mg / kg, or less than 100 mg / kg.

[0028] According to a preferred embodiment of the present invention, the content of 2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 90 mg / kg, for example less than 80 mg / kg, less than 70 mg / kg, more preferably less than 60 mg / kg, and examples include less than 50 mg / kg, less than 40 mg / kg, less than 30 mg / kg, less than 20 mg / kg, less than 10 mg / kg, or 0. Wherein, when the content of 2-methyl-5-nitroimidazole in the pharmaceutical composition is 0, it means that the pharmaceutical composition does not contain 2-methyl-5-nitroimidazole.

[0029] According to an exemplary embodiment of the present invention, when the pharmaceutical composition contains a precursor compound of levonornidazole, it may or may not contain levonornidazole. Preferably, the content of levonornidazole is below 2000 mg / kg, for example, below 80 mg / kg, below 70 mg / kg, more preferably below 60 mg / kg, and examples may be below 50 mg / kg, below 40 mg / kg, below 30 mg / kg, below 20 mg / kg, below 10 mg / kg, or 0. Wherein, when the content of levonornidazole in the pharmaceutical composition is 0, it means that the pharmaceutical composition does not contain levonornidazole.

[0030] According to embodiments of the present invention, the pharmaceutical composition may optionally contain or exclude 1-(2,3-dihydroxypropyl)-2-methyl-5-nitroimidazole as shown in formula (III):

[0031] III According to an embodiment of the present invention, the content of 1-(2,3-dihydroxypropyl)-2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 2100 mg / kg, for example less than 2000 mg / kg, less than 1900 mg / kg, less than 1800 mg / kg, less than 1700 mg / kg, less than 1600 mg / kg, less than 1500 mg / kg, less than 1400 mg / kg, less than 1300 mg / kg, less than 1200 mg / kg, or less than 1100 mg / kg.

[0032] According to an embodiment of the present invention, the content of 1-(2,3-dihydroxypropyl)-2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 1000 mg / kg, for example less than 900 mg / kg, less than 800 mg / kg, less than 700 mg / kg, less than 600 mg / kg, less than 500 mg / kg, less than 400 mg / kg, less than 300 mg / kg, less than 200 mg / kg, or less than 100 mg / kg.

[0033] According to a preferred embodiment of the present invention, the content of the compound represented by formula (III) in the pharmaceutical composition is less than 90 mg / kg, for example less than 80 mg / kg, less than 70 mg / kg, more preferably less than 60 mg / kg, and examples may be less than 50 mg / kg, less than 40 mg / kg, less than 30 mg / kg, less than 20 mg / kg or less than 10 mg / kg.

[0034] According to a more preferred embodiment of the present invention, the content of the compound represented by formula (III) in the pharmaceutical composition is less than 9 mg / kg, for example less than 8 mg / kg, less than 7 mg / kg, more preferably less than 6 mg / kg, and examples of which can be less than 5 mg / kg, less than 4 mg / kg, less than 3 mg / kg, less than 2 mg / kg, less than 1 mg / kg, or 0. Wherein, when the content of the compound represented by formula (III) in the pharmaceutical composition is 0, it means that the pharmaceutical composition does not contain the compound represented by formula (III). Alternatively, the content of the compound represented by formula (III) in the pharmaceutical composition can also be >0.

[0035] According to embodiments of the present invention, the pharmaceutical composition may further comprise pharmaceutically acceptable excipients, such as carriers or excipients. The pharmaceutically acceptable excipients are preferably non-reactive or inert to the active ingredient. For example, the pharmaceutically acceptable excipients are selected from at least one of the following, including but not limited to: fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, humectants, pH adjusters, solubilizers or cosolvents, osmotic pressure regulators, etc.

[0036] According to the technical solution of the present invention, the filler may be selected from at least one of lactose, sucrose, glucose, mannitol, sorbitol, calcium sulfate, calcium gluconate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium bicarbonate, starch, carboxymethyl starch, pregelatinized starch, and microcrystalline cellulose.

[0037] According to the technical solution of the present invention, the disintegrant may be selected from at least one of pregelatinized starch, microcrystalline cellulose, alginate, lignocellulose, sodium carboxymethyl starch, guar gum, croscarmellose, and croscarmellose sodium.

[0038] According to the technical solution of the present invention, the adhesive may be selected from at least one of gelatin, dextrin, maltodextrin, sucrose, gum arabic, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, and hydroxypropyl methylcellulose.

[0039] According to the technical solution of the present invention, the lubricant may be selected from at least one of magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl monostearate, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, sodium benzoate, adipic acid, fumaric acid, boric acid, sodium chloride, sodium oleate, glyceryl triacetate, polyoxyethylene monostearate, monolauric sucrose ester, sodium chloride, sodium lauryl sulfate, and magnesium lauryl sulfate.

[0040] According to the technical solution of the present invention, the surfactant may be selected from at least one of sodium dodecyl sulfate, poloxamer, polysorbate 80, hexadecyltrimethylamine bromide, sodium lauryl sulfate, sodium stearate sulfonate, polyoxyethylene higher fatty alcohol, sucrose ester, sorbitol fatty ester and soybean lecithin.

[0041] According to the technical solution of the present invention, the flavoring agent is at least one selected from stevia, fructose, glucose, high-fructose corn syrup, honey, aspartame, protein sugar, xylitol, mannitol, lactose, sorbitol, flavoring and maltitol.

[0042] According to the technical solution of the present invention, the pH adjuster may be selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, etc.

[0043] According to the technical solution of the present invention, the co-solvent may be selected from alcohol solvents, such as at least one selected from ethanol, glycerol, propylene glycol, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400, etc.).

[0044] According to the technical solution of the present invention, the osmotic pressure regulator may be selected from at least one of sodium chloride, glucose, fructose, phosphate, polyethylene glycol, propylene glycol, mannitol, etc.

[0045] According to the technical solution of the present invention, the pharmaceutical composition can be a formulation, such as a gastrointestinal formulation or a non-gastrointestinal formulation. The gastrointestinal formulation can be tablets, dispersible tablets, capsules, sustained-release tablets, granules, oral liquids, syrups, etc.; the non-gastrointestinal formulation can be an infusion, injection (such as a liquid injection), lyophilized formulation (such as a lyophilized powder), effervescent tablets, suppositories, sublingual tablets, etc., preferably capsules, injections (such as liquid injections), or lyophilized formulations for injection (such as lyophilized powders).

[0046] According to an exemplary embodiment of the present invention, the pharmaceutical composition is an injection or a lyophilized preparation for injection, comprising an ornidazole compound, preferably comprising ornidazole, disodium levonitrile phosphate or a hydrate of any one thereof, and 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole in a content of less than 60 mg / kg.

[0047] According to an embodiment of the present invention, in the injection solution or lyophilized formulation for injection, the weight percentage content of ornidazole compounds as active ingredients, calculated as ornidazole or its isomers, is in the range of 70% to 85%, for example 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 82%, 83%, 84%, 85%, preferably in the range of 72% to 83%.

[0048] According to embodiments of the present invention, the pharmaceutical composition, such as a lyophilized formulation for injection, may contain citric acid, wherein the weight percentage content of citric acid may be 10-35%, preferably 15-32%, for example 18-28%, 20-25%, and exemplary values ​​are 16%, 17%, 18%, 19%, 21%, 22%, 23%, 24%, 26%, 27%, and 29%.

[0049] According to an embodiment of the present invention, the pH of the injection can be 4.0-6.0, preferably 4.5-5.5, for example 4.6-5.4, 4.7-5.3, and exemplary pH values ​​are 4.8, 4.9, 5.0, 5.1, and 5.2.

[0050] According to an embodiment of the present invention, when the pH of the injection solution is 4.0-6.0, the citric acid content can be 19-45 mg / mL. For example, when pH=4.0, the citric acid content is 45 mg / mL; when pH=6.0, the citric acid content is 19 mg / mL.

[0051] According to an embodiment of the present invention, the injection solution may contain water for injection, ethanol and / or propylene glycol.

[0052] According to the technical solution of the present invention, the route of administration of the pharmaceutical composition includes, but is not limited to, gastrointestinal administration or non-gastrointestinal administration; wherein, the non-gastrointestinal administration may be injection (such as intravenous injection, arterial injection, intramuscular injection, subcutaneous injection, intradermal injection, etc.), vaginal administration or mucosal administration, etc.

[0053] According to embodiments of the present invention, the active ingredient of the pharmaceutical composition is an ornidazole compound, preferably ornidazole, levonornidazole, or a precursor compound of levonornidazole. Preferably, the pharmaceutical composition may not contain any active ingredient other than an ornidazole compound, or it may contain other active ingredients other than ornidazole, levonornidazole, or a precursor compound of levonornidazole.

[0054] According to an exemplary embodiment of the present invention, the pharmaceutical composition comprises orthonitrofurazone disodium phosphate and citric acid, and optionally, water for injection. Preferably, the pH of the pharmaceutical composition is 4.5 to 5.5.

[0055] According to an exemplary embodiment of the present invention, the pharmaceutical composition comprises ornidazole, ethanol, propylene glycol, and water for injection, which may or may not be present.

[0056] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, comprising mixing an ornidazole compound with a pharmaceutically acceptable excipient to obtain the pharmaceutical composition.

[0057] According to an exemplary embodiment of the present invention, ornidazole, ethanol, propylene glycol and water for injection are mixed to obtain the pharmaceutical composition.

[0058] According to an exemplary embodiment of the present invention, disodium levonitrozole phosphate or its hydrate is prepared into a solution with water, and the solution is freeze-dried to obtain the pharmaceutical composition.

[0059] According to the technical solution of the present invention, the pH of the solution is 4.0-6.0, preferably 4.5-5.5, for example 4.6-5.4, 4.7-5.3, and exemplary pH values ​​are 4.8, 4.9, 5.0, 5.1, and 5.2.

[0060] According to an embodiment of the present invention, the freeze-drying temperature is -60℃ to 30℃, preferably -50℃ to 25℃.

[0061] According to an embodiment of the present invention, the freeze-drying time is 30-70 hours, for example 40-60 hours, or 45-55 hours.

[0062] According to an embodiment of the present invention, the freeze-drying is performed using programmed temperature control.

[0063] According to the technical solution of the present invention, the exemplary operation of the freeze-drying includes: placing the partially filled and stoppered semi-finished product into a freeze-drying chamber when the silicone oil temperature drops to 0°C and maintaining it for 0.5 hours; then maintaining it for 1.0 hour when the silicone oil temperature drops to -50°C; raising the temperature to -20°C and maintaining it for 3.0 hours; then lowering the temperature to -50°C and maintaining it for 3.0 hours. Turning on the vacuum pump, evacuating to 200 μbar, raising the temperature to -20°C for 1.0 hour and maintaining it for 16.0 hours; raising the temperature to -15°C for 5 minutes and maintaining it for 6.0 hours; raising the temperature to -10°C for 5 minutes and maintaining it for 1.0 hour; raising the temperature to 0°C for 10 minutes and maintaining it for 1.0 hour; raising the temperature to 10°C for 10 minutes and maintaining it for 1.0 hour; raising the temperature to 25°C for 15 minutes and maintaining it for 7.0 hours; and finally, evacuating to a maximum vacuum at 25°C and maintaining it for 13.0 hours. Perform a pressure rise test (the qualified pressure rise standard is ≤15μbar / min). After passing the test, the freeze drying is completed. Nitrogen gas is introduced into the chamber to break the vacuum (vacuum control range: 850mbar-900mbar). After full compression, the chamber is removed from the chamber.

[0064] The present invention also provides the use of the pharmaceutical composition for improving drug safety.

[0065] The present invention also provides the use of the pharmaceutical composition for improving drug stability.

[0066] The present invention also provides the use of the pharmaceutical composition in the preparation of pharmaceutical products.

[0067] Preferably, the drug is used for the prevention or treatment of diseases associated with anaerobic bacteria, such as for the prevention or treatment of infectious diseases caused by anaerobic bacteria. For example, the anaerobic bacteria may be selected from at least one of the following: Bacteroides fragilis, Bacteroides dichotoma, Bacteroides ovalis, Bacteroides polymorpha, Bacteroides vulgaris, Clostridium, Eubacterium, Peptococcus and Peptostreptococcus, Helicobacter pylori, Bacteroides melaninosa, Fusobacterium, CO2-phages, Porphyromonas gingivalis, and other anaerobic bacteria.

[0068] Preferably, the medicine is used to prevent or treat infectious diseases caused by anaerobic bacteria before and / or after surgery.

[0069] The present invention also provides a method for preventing or treating diseases associated with anaerobic bacteria, such as a method for preventing or treating infectious diseases caused by anaerobic bacteria, comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient in need.

[0070] Terminology Definitions and Explanations Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0071] The term "effective amount" or "therapeutic effective amount" refers to the amount of the compound described in this invention sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined below). Therapeutic effective amounts may vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. Specific dosages will vary depending on factors such as the particular compound selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used.

[0072] The term "patient" refers to a person who requires preventive or treatment for a disease associated with anaerobic bacteria, where the patient is a mammal, such as a rodent, cow, pig, dog, cat, or primate, and especially a human.

[0073] The term "shelf life" refers to the period during which a drug can maintain its quality as required under specified storage conditions, such as 24 months, 18 months, or 12 months.

[0074] Beneficial effects This application unexpectedly discovered that 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole, present in pharmaceutical compositions containing ornidazole compounds, is genotoxic, causing cellular DNA damage and mutagenic effects, posing a significant challenge to the safety and / or stability of such drugs during their shelf life. Such risks are controlled or even eliminated in the pharmaceutical compositions of this invention. This application found that when the weight percentage of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole is reduced to below 1000 mg / kg, preferably below 100 mg / kg, more preferably below 60 mg / kg, the safety and / or stability of such drugs can be significantly improved. Detailed Implementation

[0075] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0076] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0077] Example 1: Genotoxicity test of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole (compound of formula (II)) (a) Ames test (strain test) 1. Materials and Methods 1.1 Test Sample Name: 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole; Packaging: Ampoules; Specifications: Approximately 50mg / vial; Storage conditions: Store at 2-8ºC, protected from light and sealed.

[0078] 1.2 Solvent information Name: Sodium Chloride Injection; Manufacturer: Chenxin Pharmaceutical Co., Ltd. Properties and physicochemical characteristics: Colorless, clear liquid with a slightly salty taste; Specification: 500mL / bottle; Storage conditions: Store in a sealed container.

[0079] 1.3 Preparation of test sample / reference standard The test sample was prepared on the day of administration. An appropriate amount of the test sample was weighed and dissolved in an appropriate amount of sodium chloride injection to a concentration of 50 mg / mL. The solution was then filtered through a 0.2 μm filter membrane and diluted with sodium chloride injection to concentrations of 20, 8, 2, and 0.5 mg / mL, respectively.

[0080] The prepared solution should be stored at room temperature before administration.

[0081] 1.4 Experimental Methods Strains: Salmonella Typhimurium, histidine-deficient strains (TA97a, TA98, TA100, TA102, TA1535). Strains were provided by Moltox, and the bacterial culture was stored in liquid nitrogen.

[0082] SD rats were provided by Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.

[0083] Preparation of S9 mixture: This experiment used the S9 fraction from SD rat livers, with a protein concentration of 21.64 mg / mL, stored in liquid nitrogen. Before use, the S9 mixture was prepared under aseptic conditions, as shown in Table 1.

[0084] Table 1

[0085] Enrichment culture of bacterial strains: After the bacterial culture frozen in liquid nitrogen was rapidly thawed in a water bath at 37°C, 100 μl was inoculated into 20 ml of nutrient broth and incubated at 37°C in the dark with shaking (120 rpm) for 10-12 hours.

[0086] Grouped administration: Two parallel dishes were processed at each test site. Dosing information is shown in Table 2.

[0087] Table 2

[0088] Note: Group 1 is the spontaneous control group; Groups 2-6 are the test sample groups.

[0089] Take the appropriate number of glass test tubes, first dispense 2 ml of top layer culture medium into each tube (heat at 45~47℃), then add 0.1 ml of bacterial culture medium, 0.1 ml of test solution, and 0.5 ml of S9 mixture or PBS at pH 7.4 in sequence. Quickly mix on a shaker, pour the mixture onto the surface of the basal culture medium, and gently rotate to evenly spread the top layer culture medium mixture on the surface of the basal culture medium.

[0090] Place the petri dish on a horizontal table. After the culture medium solidifies, invert the petri dish and incubate at 37°C for 48-72 hours.

[0091] 1.5 Data Acquisition After incubation for approximately 48–72 hours, count the number of revertant mutant colonies in all petri dishes, and simultaneously observe the background bacterial flora under a microscope to assess whether the test sample has an inhibitory effect on the strain.

[0092] Observe the precipitation during the addition of the medicine.

[0093] 1.6 Result Determination The following criteria should be used to determine whether the test sample has antibacterial toxicity against the strain: 1) The background bacterial flora becomes thinner, which may be accompanied by a decrease in the number of reversion mutant colonies; 2) Background bacterial growth disappears, meaning bacterial growth is completely inhibited; 3) Pinpoint-sized non-reverting mutant small colonies appear (usually accompanied by the absence of background bacterial growth).

[0094] 2. Results 2.1 Sedimentation status No precipitation was observed in any of the test sample dosage groups during the sample addition process.

[0095] 2.2 Bacterial toxicity The background data for individual observations of mycelial growth are shown in Table 3 below.

[0096] Table 3: Individual data for background mycelial growth observation

[0097] Note: "√" indicates normal background bacterial growth; "-" indicates the disappearance of background bacterial growth; and "×" indicates a reduction in background bacterial growth.

[0098] The results showed that under non-metabolic activation conditions, background bacterial growth disappeared for all strains at doses of 800–5000 μg / plate, and decreased at doses of 50 and 200 μg / plate. Under metabolic activation conditions, background bacterial growth disappeared for all strains at doses of 200–5000 μg / plate, and decreased at dose of 50 μg / plate.

[0099] 2.3 Mutagenicity The results of the mutant colony count are shown in Table 4 below.

[0100] Table 4: Individual data for counting mutant colonies (colonies / plate)

[0101] The results showed that under both metabolically activated and non-metabolic activated conditions, the number of revertant mutant colonies in each strain of the spontaneous control group was within the normal reference range or slightly increased or decreased. Under non-metabolic activated conditions at doses of 50 and 200 μg / plate and under metabolic activated conditions at doses of 50 μg / plate, the number of revertant mutant colonies in each strain increased significantly, exceeding twice that of the spontaneous control group.

[0102] 3. Conclusion Under the conditions of this experiment, 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole exhibited bacterial toxicity at doses ranging from 50 to 5000 μg / plate and was mutagenic to Salmonella typhimurium, thus demonstrating genotoxicity.

[0103] (II) Micronucleus Experiment 1. Test sample and reference sample 1.1 Test Sample Name: 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole; Packaging: Ampoules; Specifications: Approximately 50mg / vial; Storage conditions: Store at 2-8ºC, protected from light and sealed.

[0104] 1.2 Reference Standard Cyclophosphamide for injection; Manufacturer: Jiangsu Hengrui Medicine Co., Ltd. Appearance and physicochemical properties: White crystalline powder; Batch number: 19061521; Specification: 0.2 g / bottle; Storage conditions: Store in a dark place and seal tightly.

[0105] 1.3 Experimental animals KM mice Grade: SPF; Selling unit: Henan Skibes Biotechnology Co., Ltd.; Quality inspection unit: Shandong Laboratory Animal Center; License number: SCXK (Yu) 2020-0005.

[0106] 2. Preparation of administration preparations The preparation process is completed under aseptic conditions. Reagent bottles and the like used are all sterilized. The preparation process is not protected from light.

[0107] Solvent (0.9% sodium chloride injection): Production unit: Anhui Shuanghe Pharmaceutical Co., Ltd.; Appearance and physicochemical properties: Colorless and clear liquid, slightly salty taste; Batch number: 20011112C Specification: 500 mL / bottle; Storage conditions: Store in a closed container.

[0108] Preparation of positive control solution (cyclophosphamide): Weigh the required amount of positive control substance (by content), add an appropriate amount of solvent and stir until clear and transparent. Finally, dilute with solvent to the required concentration. After preparation, filter with a 0.22 μm filter membrane to obtain the positive control solution.

[0109] Preparation of test substance administration preparation: Weigh the required amount of test substance (by content), add an appropriate amount of solvent and stir until clear and transparent. Finally, dilute with solvent to the required concentration. After preparation, filter with a 0.22 μm filter membrane to obtain the test substance administration preparation.

[0110] The doses and concentrations of each group are shown in the following table:

[0111] 3. Experimental system 3.1 Experimental animals Animals used in the test: Kunming mice, clean grade; 24 females and 24 males are selected.

[0112] Body weight and age during grouping: Females: about 24 - 28 g, 8 - 10 weeks old; Males: about 25 - 29 g, 8 - 10 weeks old.

[0113] 3.2 Grouping This experiment consisted of 5 groups: 10 mice in each solvent group and test sample group, and 8 mice in each positive control group, for a total of 48 mice.

[0114] 3.3 Animal Identification Animals were identified using a 3% picric acid ethanol solution on the day of arrival. After grouping, they were identified using both picric acid and cage tags. The cage tag identification is shown in the table below:

[0115] X represents a female mouse, and Y represents a male mouse.

[0116] 3.4 Randomization of Animals Animals were randomly assigned to 5 groups based on sex and weight. The weight difference between groups was within ±20% of the average weight of the same sex. After grouping, there was no statistically significant difference in the average weight of each group at the 5.0% significance level. The remaining animals were then recorded and fed.

[0117] 3.5 Reagent Dosage Design The dosage design for this experiment is shown in the table below:

[0118] 4. Test Methods 4.1 Administration Route of administration: Intraperitoneal injection is the preferred route of administration.

[0119] Administration method: Administer 5 times over 3 consecutive days, with 1 dose on the morning of the first day, and 1 dose each in the morning and afternoon of the second and third days.

[0120] Dosage period: 3 days.

[0121] Dosage volume: 10 mL / kg.

[0122] Dosage: Calculate the dosage based on the most recent body weight measurement.

[0123] 4.2 Observation and Inspection 4.2.1 Death or near death All surviving animals were observed once a day.

[0124] 4.2.2 Weight Adaptation period: All animals were weighed once before being grouped, i.e., group weight. Dosing schedule: Weigh yourself in the morning before administration on days 1, 2, and 3, and use the weight for calculating the dosage. 4.3 Test Termination Procedure 4.3.1 Unplanned animal deaths During the experiment, no animals were observed to die or be near death (the summary results of deaths or near death are shown in Section 5.1).

[0125] 4.3.2 Anatomical Specimen Preparation Scheduled date of dissection: End of dosing period (D4) Animals for dissection: All surviving animals Specimen preparation method: The mice were sacrificed by cervical dislocation. The femurs were taken, the muscles were removed, the epiphyses were cut off, the bone marrow cavity was exposed, and bone marrow smears were taken, fixed with methanol and stained with Gimesa.

[0126] 4.3.3 Microscopic Examination Scheduled date of microscopic examination: End of dosing period (D5) Objects for microscopic examination: Bone marrow smears of all animals (see 4.3.2 for details) Microscopic examination method: Under a low-power microscope, areas with intact, evenly dispersed, and properly stained cells were selected, and observed under a high-power microscope. The micronucleus rate of 1000 polychromatic erythrocytes (PCE) with clear and intact cytoplasm was counted for each smear, and the results were expressed as per mille (‰).

[0127] 4.4 Statistical Analysis Analysis was performed using SPSS 16.0 statistical software. The micronucleus rates were expressed as mean ± s, compared with the negative control group, and two-sided t-test and χ 2 test were used for statistical analysis. P < 0.05 was considered statistically significant, P > 0.05 was considered not significant, 0.01 < P < 0.05 was considered significantly different, and P < 0.01 was considered extremely significantly different.

[0128] The results of death or near death were not statistically analyzed and were expressed in the form of frequency.

[0129] 5 Results 5.1 Death or Near Death The effects of the test article on the death or near death of animals are shown in the following table. By the end of the dosing period, no death or near death was found in all animals.

[0130]

[0131] 5.2 Body Weight The results of body weight examination are shown in the following table.

[0132]

[0133] During the experiment, the body weight of the animals in the test article dosing groups showed a downward trend.

[0134] In the 100 mg / kg dose group, the body weight showed a downward trend at D3, and it was dose-related. Although there were no statistically significant differences in the body weight changes of other animals, a small increase in body weight was also observed, and it was dose-related, which could be considered related to the test article.

[0135] 5.3 Micronucleus rate of polychromatic erythrocytes The statistical results of the micronucleus rate of polychromatic erythrocytes are shown in the table below.

[0136]

[0137] During the experiment, the animals in the test sample administration group showed an increasing trend in micronucleus rate.

[0138] The micronucleus rate in the 48 mg / kg and 100 mg / kg dose groups was significantly different from that in the negative control group (p<0.01). Although no statistical difference was observed in other dose groups, a slight increase in the micronucleus rate was also observed, showing a dose-related relationship, which can be considered to be related to the test sample.

[0139] 6 Conclusions Under the experimental conditions, Kunming mice were administered the test compound via intraperitoneal injection for three consecutive days at concentrations of 2.88, 48, and 100 mg / kg. No animal deaths or near-death experiences were observed during the experiment. Animals in the test compound administration groups showed weight loss at doses ≥100 mg / kg and an increase in the micronucleus rate of polychromatic erythrocytes at doses ≥48 mg / kg, which was considered related to the test compound. The no-observed adverse effect level (NOAEL) in this experiment was 2.88 mg / kg.

[0140] According to ICHM7 (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines, the limits for genotoxic impurities are calculated as follows: Impurity limit = acceptable daily intake of impurity (i.e., PDE value) / maximum daily dose of drug.

[0141] PDE = NOEL × Adjusted weight / (F1 × F2 × F3 × F4 × F5) The NOEL in mice was 2.88 mg / kg / day; F1=12, estimating the human dose from the mouse dose; F2=10, referring to the FDA ICH-Q3C guidelines; F3=10, the experimental period did not exceed 10 days; F4=1, considering no serious toxic reactions were found; F5=1; the body weight was adjusted to 50 kg; the calculation results are as follows: PDE=2.88mg / kg (NOEL)×50 / (12×10×10×1×1)=0.12mg; Impurity limit = 0.12 mg / 2g (based on clinical trials, the maximum daily dose of this type of compound for humans is 2g) = 60 ppm = 60 mg / kg.

[0142] Example 2: Genotoxicity test of compound (IV) The method of Example 1 was used, except that 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole of formula (II) was replaced with the compound of formula (IV). The results showed that the compound did not exhibit genotoxicity at doses of 50, 200, 800, 2000 and 5000 μg / plate.

[0143] Example 3: Lyophilized Formulation for Injection The formulation for the lyophilized preparation for injection is as follows: 6000g of disodium levonornidazole phosphate Citric acid 1140-2700g Add water for injection to 60L Prepared to produce 30,000 units.

[0144] The preparation method of this prescription includes the following steps: Add a portion of citric acid to 80% of the total volume of the prescription in water for injection at 20°C or below, and stir until completely dissolved. Then add the prescribed amount of disodium levonitroazole phosphate and stir until completely dissolved. The pH of the prepared solution should be 4.0–6.0. ​​Next, take the remaining citric acid and dissolve it in cooled water for injection to prepare a solution with a concentration of 20 g / 100 mL to adjust the pH of the prepared solution to 4.5–5.5. Based on the drug density (1.063 g / mL), add water for injection (at 20°C or below) to the total prescription volume. Continue stirring for approximately 15 minutes. Filter the prepared solution through filters of type A05NF2PH4 and KA3NFP1 (0.2 μm / 0.22 μm; membrane material: nylon 66).

[0145] The filtered drug solution was placed in a freeze-drying chamber when the silicone oil temperature dropped to 0℃ and maintained for 0.5 hours. Then, when the silicone oil temperature dropped to -50℃, it was maintained for 1.0 hour; the temperature was then raised to -20℃ and maintained for 3.0 hours; finally, it was lowered to -50℃ and maintained for 3.0 hours. The vacuum pump was turned on, and a vacuum of 200 μbar was drawn. The temperature was then raised to -20℃ in 1.0 hour and maintained for 16.0 hours. The temperature was then raised to -15℃ in 5 minutes and maintained for 6.0 hours; then raised to -10℃ in 5 minutes and maintained for 1.0 hour; then raised to 0℃ in 10 minutes and maintained for 1.0 hour; then raised to 10℃ in 10 minutes and maintained for 1.0 hour; finally, the temperature was raised to 25℃ in 15 minutes and maintained for 7.0 hours; and finally, an ultimate vacuum was drawn at 25℃ and maintained for 13.0 hours. A pressure rise test was conducted (the qualified pressure rise standard is ≤15μbar / min). After passing the test, the freeze-drying was completed. Nitrogen gas was then introduced into the chamber to break the vacuum (vacuum control range: 850mbar~900mbar) to obtain the freeze-dried formulation.

[0146] The above preparation method was repeated to produce a total of 3 batches of finished products, denoted as S1, S2 and S3. The immediate inspection results are shown in Table 5.

[0147] Table 5 Finished Product Inspection Results

[0148] The accelerated stability of the finished products S1, S2 and S3 was tested (test conditions: temperature 25℃±2℃, humidity 60% RH±5% RH), and the test results are shown in Table 6-8.

[0149] Table 6. Accelerated stability test results of S1 finished product

[0150] Table 7. Accelerated stability test results of S2 finished product

[0151] Table 8. Accelerated stability test results of S3 finished product

[0152] The long-term stability of finished products S1, S2, and S3 was tested (long-term stability test conditions: 5℃±3℃), and the test results are shown in Table 9-11.

[0153] Table 9. Results of Long-Term Stability Test for S1 Finished Product

[0154] Table 10 Results of Long-Term Stability Test of S2 Finished Product

[0155] Table 11 Results of Long-Term Stability Test of S3 Finished Product

[0156] Experimental results show that the lyophilized formulation has good drug safety and stability.

[0157] The detection methods for each substance are as follows: Instrument: Liquid Chromatography-Tandem Mass Spectrometry System, Model 1290LC-6470LC / TQ, Agilent Technologies Inc.

[0158] (1) Chromatographic conditions Column: Svea Core Shell C18 (100mm × 4.6mm × 2.6μm) Mobile phase: A: (10 mmol ammonium formate aqueous solution) B: (methanol) Flow rate: 0.6 mL / min Injection volume: 5 μL Gradient procedure:

[0159] (2) Mass spectrometry conditions Ion source type: AJS ESI ion source Collision gas (N2) flow rate: 8 L / min Sheath gas (N2) flow rate: 11 L / min Sheath gas temperature: 350℃ Spray voltage: 3500V Nozzle voltage: 500V EMV gain: 200V Acquisition method: Multiple reaction monitoring (MRM).

[0160] (3) Preparation of blank solution Blank solution: that is, pure water.

[0161] (4) Reference solutions: Accurately weigh 10 mg of 2-methyl-5-nitroimidazole, compound (II), and compound (III) into 10 mL volumetric flasks, and dilute to the mark with blank solution to obtain reference stock solutions. Accurately measure 0.1 mL of each reference stock solution into 10 mL volumetric flasks, and dilute to the mark with blank solution to obtain intermediate reference solutions (i.e., 10 μg / mL). Accurately measure 5 mL of each into 50 mL volumetric flasks, and dilute to the mark with blank solution to obtain working reference solutions (i.e., 1 μg / mL). Accurately measure 0.6 mL of each into 10 mL volumetric flasks, and dilute to the mark with blank solution to obtain a 60 ng / mL reference solution.

[0162] (5) System suitability solution: Accurately weigh 10 mg of the test sample (calculated as disodium levonitrophosphate) into a 10 mL volumetric flask, and dilute the blank solution to the mark. Take 1 mL of this solution into a 10 mL volumetric flask, add the limit point concentration (take 0.6 mL of the "reference working solution" under item (4) into the above volumetric flask) of compound (II) (60 mg / kg), compound (III) (60 mg / kg), and 2-methyl-5-nitroimidazole (60 mg / kg) reference standard, and dilute the blank solution to the mark (i.e., 60 ng / mL).

[0163] (6) Preparation of test solution: Accurately weigh 10 mg of test sample (calculated as disodium levonitrile phosphate) into a 10 mL volumetric flask, and dilute to the mark with blank solution.

[0164] (7) Preparation of the test solution with added impurities: Accurately weigh 10 mg of the test sample (calculated as disodium levonitrophosphate) into a 10 mL volumetric flask, add the limit point concentration (take 0.6 mL of the "reference working solution" under "3.4" into the above volumetric flask) of compound (II) (60 mg / kg), compound (III) (60 mg / kg), and 2-methyl-5-nitroimidazole (60 mg / kg) reference standard, and dilute the blank solution to the mark (i.e. 60 ng / mL) to obtain the solution.

[0165] (8) Limits: The residues of compound (II), compound (III) and 2-methyl-5-nitroimidazole reference standard in this product shall not exceed 60 mg / kg.

[0166] In the experimental results in the table above, the detection limit concentration for each substance was 0.1 ng / mL, and the relative standard deviation (RSD) of the content met the acceptable standard.

[0167] Example 4: Lyophilized Formulation for Injection Formulation of a single-vial lyophilized injection preparation: Levodocinoxazole phosphate disodium 200mg Citric acid 38-90mg Add water for injection to 2 mL The pH value is 4.5~5.5.

[0168] Following the freeze-drying preparation process and testing method in Example 3, 12 batches of freeze-dried formulations were prepared.

[0169] (1) The content of each substance in the freeze-dried preparation was tested immediately, and the test results are shown in Table 12.

[0170] Table 12 Sample Test Results

[0171] In the experimental results in the table above, the detection limit concentration for each substance was 0.1 ng / mL, and the relative standard deviation (RSD) of the content met the acceptable standard.

[0172] All other indicators of the above 12 batches of lyophilized preparations meet the finished product requirements shown in Table 5.

[0173] Example 5 Genotoxicity Test The samples from Examples 3-4 were tested according to the genotoxicity test method in Example 1. The results showed that the lyophilized formulations from Examples 3-4 did not have genotoxicity.

[0174] Example 6 Ornidazole Injection The prescription for ornidazole injection is as follows: Ornidazole 500mg 0.9g of ethanol 1 mL of propylene glycol Add water for injection to a final volume of 3 mL.

[0175] Preparation process of ornidazole injection: Ornidazole, ethanol, propylene glycol and water for injection in the above-mentioned amounts are mixed to prepare ornidazole injection. According to the substance detection method in Example 3, the content of compound (II) in ornidazole injection is less than 60 mg / kg.

[0176] The sample from Example 6 was tested according to the genotoxicity test method in Example 1. The results showed that the injection solution of Example 6 did not have genotoxicity.

[0177] The exemplary embodiments of the present invention have been described above. However, the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an ornidazole compound and 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole in a concentration of less than 1000 mg / kg; The ornidazole compounds may be selected from ornidazole, its stereoisomers or their precursors, preferably from ornidazole, levonornidazole or dextroornidazole or their precursors; The precursor compounds of ornidazole, levonornidazole, or dextroornidazole may be selected from pharmaceutically acceptable precursor compounds, such as esters of ornidazole or levonornidazole, or pharmaceutically acceptable salts of said esters, or hydrates thereof, such as disodium levonornidazole phosphate or its hydrate.

2. The pharmaceutical composition according to claim 1, characterized in that, Based on the hydrate of ornidazole, levonornidazole, disodium levonornidazole phosphate, or any one thereof, the weight percentage content of the ornidazole compound as the active ingredient in the pharmaceutical composition may be in the range of 10% to 99%, preferably 15% to 90%, for example 20% to 85%.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole described herein has the structure shown in formula (II): II The content of 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole is preferably below 100 mg / kg, more preferably below 60 mg / kg.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The pharmaceutical composition may also optionally contain or exclude a compound represented by formula (IV): IV; Preferably, the content of the compound represented by formula (IV) in the pharmaceutical composition is less than 15,000 mg / kg; Preferably, the pharmaceutical composition may also optionally contain or exclude 2-methyl-5-nitroimidazole; Preferably, the weight percentage content of 2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 2000 mg / kg; Preferably, the pharmaceutical composition also optionally comprises or excludes 1-(2,3-dihydroxypropyl)-2-methyl-5-nitroimidazole of formula (III): III Preferably, the content of 1-(2,3-dihydroxypropyl)-2-methyl-5-nitroimidazole in the pharmaceutical composition is less than 2100 mg / kg.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition also contains pharmaceutically acceptable excipients; Preferably, the pharmaceutically acceptable excipients are selected from at least one of the following: fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, humectants, pH adjusters, solubilizers or cosolvents, and osmotic pressure regulators.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition is a formulation, preferably a gastrointestinal or non-gastrointestinal formulation. Preferably, the pharmaceutical composition is an injection or a lyophilized preparation for injection, comprising an ornidazole compound, preferably comprising ornidazole, levonornidazole, disodium levonornidazole phosphate or a hydrate of any one thereof, and 1-(2,3-epoxypropane)-2-methyl-5-nitroimidazole in a content of less than 60 mg / kg; Preferably, the pharmaceutical composition contains citric acid, and the citric acid content is 10-35% by weight. Preferably, the pH of the injection is 4.0-6.0; Preferably, the injection solution may contain water for injection, ethanol and / or propylene glycol.

7. A method for preparing the pharmaceutical composition according to any one of claims 1-6, characterized in that, The preparation method includes mixing an ornidazole compound with a pharmaceutically acceptable excipient to obtain the pharmaceutical composition. Preferably, the disodium levonitrozole phosphate or its hydrate is dissolved in water to form a solution, and the solution is freeze-dried to obtain the pharmaceutical composition; Preferably, the pH of the solution is 4.0-6.0, more preferably 4.5-5.5; Preferably, the freeze-drying temperature is -60℃ to 30℃, more preferably -50℃ to 25℃; Preferably, the freeze-drying time is 30-70 hours, for example 40-60 hours, or 45-55 hours; Preferably, the freeze-drying is performed using programmed temperature control.

8. The pharmaceutical composition according to any one of claims 1-6 is used to improve drug safety.

9. The pharmaceutical composition according to any one of claims 1-6 is used to improve drug stability.

10. The pharmaceutical composition according to any one of claims 1-6 is used to prepare a pharmaceutical product.

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