Preparation containing ornidazole compound and preparation method and application thereof

文档序号：819008 发布日期：2021-03-30 浏览：137次中文

阅读说明：本技术 包含奥硝唑类化合物的制剂及其制备方法和用途 (Preparation containing ornidazole compound and preparation method and application thereof ) 是由杨丹陈令武丁菲张琪杨海雪汤传飞王嬿钧梁衡王旭艳陈遇峰于 2020-09-28 设计创作，主要内容包括：本发明公开一种奥硝唑制剂及其制备方法和用途。以奥硝唑类化合物计,所述包含奥硝唑类化合物的制剂的给药日剂量为0.2g至4.0g。可以为单剂量制剂或多剂量制剂,单剂量制剂中奥硝唑类化合物的含量为0.1g至2.0g,多剂量制剂中奥硝唑类化合物的总含量为0.2g至2.0g。本发明的制剂特别适于部分患者,如心肺功能不全或老年人等,能够满足临床不同人群的需求。并且,相对于q12h(每12小时一次)的给药方式,qd(一天一次)的给药方式可以增大C-(max)/MIC比值,覆盖MIC更高的细菌,以及提高临床疗效及患者依从性,不良反应趋势也有望降低。(The invention discloses an ornidazole preparation, a preparation method and application thereof. The preparation containing the ornidazole compound has the administration daily dose of 0.2g to 4.0g calculated by the ornidazole compound. Can be a single-dose preparation or a multi-dose preparation, wherein the content of the ornidazole compound in the single-dose preparation is 0.1g to 2.0g, and the total content of the ornidazole compound in the multi-dose preparation is 0.2g to 2.0 g. The preparation of the invention is particularly suitable for some patients, such as patients with heart and lung insufficiency or the elderly, and can meet the requirements of different clinical groups. Furthermore, qd (once a day) administration may be increased by C relative to q12h (once every 12 hours) max The ratio of MIC, bacteria with higher covering MIC, and the clinical effect and the patient compliance are improved, and the adverse reaction trend is expected to be reduced.)

1. A preparation containing ornidazole compounds, wherein the administration daily dose of the preparation containing ornidazole compounds is 0.2-4.0 g.

2. A single-dose preparation containing ornidazole compounds, wherein the content of the ornidazole compounds in the single-dose preparation is 0.1-2.0 g.

3. The single dose formulation of claim 2, wherein the single dose formulation is a unit dose formulation wherein the ornidazole is loaded in 1 unit pack.

4. A multi-dose formulation comprising an ornidazole compound, in which the total content of ornidazole compound in the multi-dose formulation is from 0.2g to 2.0 g.

5. A multi-dose formulation according to claim 4, wherein the multi-dose formulation comprises, e.g. consists of, 2 to 10 unit packs more than 1 unit pack. Wherein, the content of the ornidazole compounds contained in each unit package is the same, or the content of the ornidazole compounds contained in at least 2 unit packages is different.

6. The formulation according to any one of claims 1-5, wherein said ornidazole compound may be selected from ornidazole, its stereoisomers or their precursor compounds. For example, the ornidazole compound may be selected from ornidazole, levo-ornidazole or dextro-ornidazole or their precursor compounds.

Preferably, the ornidazole, l-ornidazole or d-ornidazole precursor compound may be present in the formulation in the form of its amorphous or polymorphic forms.

7. The formulation according to any one of claims 1 to 6, wherein the sodium content in the formulation according to any one of claims 1 to 6 administered to a patient daily is below 0.6 g.

Preferably, the formulation is a sterile formulation.

Preferably, the number of administrations may be once a day, twice or more a day, preferably twice, to meet the needs of the daily dose.

Preferably, the ornidazole compound is ornidazole, levo-ornidazole or a precursor compound of levo-ornidazole. Preferably containing ornidazole, disodium levoornidazole phosphate or a hydrate of either of them.

Preferably, the preparation containing the ornidazole compound can also contain pharmaceutically acceptable auxiliary materials, such as a carrier or an excipient.

8. The formulation according to any one of claims 1 to 7, wherein the formulation is an injectable (e.g. liquid injectable) or lyophilized formulation for injection.

Preferably, the concentration of the injection which is liquid injection is 3-20mg/ml calculated by the ornidazole compound.

Preferably, the liquid in the injection or the compound solution for the lyophilized preparation for injection is sodium chloride injection or glucose injection, such as 0.9% sodium chloride injection or 5% glucose injection.

Preferably, the specification of the freeze-dried preparation for injection is 0.1-0.6g based on the ornidazole compound.

Preferably, the injection or freeze-dried injection contains an ornidazole compound, preferably contains ornidazole, levo-ornidazole disodium phosphate or a hydrate of any one of the ornidazole compound and the levo-ornidazole disodium phosphate; more preferably, the injection or injection lyophilized preparation further comprises 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole in an amount of 2100mg/kg or less, preferably less than 2100 mg/kg.

Preferably, the injection or the freeze-dried preparation for injection contains an ornidazole compound, preferably contains ornidazole, levo-ornidazole disodium phosphate or any hydrate thereof, and 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole with the content of below 1000 mg/kg.

Preferably, the injection or the freeze-dried preparation for injection contains the ornidazole compound as an active ingredient in a weight percentage of 70-85% of the ornidazole or its isomer.

Preferably, the injection or the freeze-dried preparation for injection can contain citric acid, and the content of the citric acid in percentage by weight can be 10-35%.

Preferably, the pH of the injection may be 4.0 to 6.0, preferably 4.5 to 5.5.

Preferably, the pH of the solution after reconstitution of the lyophilized preparation for injection may be 4.0 to 6.0, preferably 4.5 to 5.5.

Preferably, when the pH of the solution of the injection or the freeze-dried preparation for injection after being redissolved is 4.0-6.0, the content of citric acid can be 19-45 mg/mL.

Preferably, the injection may contain water for injection, ethanol and/or propylene glycol.

Preferably, the preparation containing the ornidazole compound may optionally contain a compound shown in the following formula (IV):

preferably, the preparation containing the ornidazole compound may optionally contain 2-methyl-5-nitroimidazole.

9. A method for preparing a preparation as claimed in any one of claims 1 to 7, which comprises mixing ornidazole with pharmaceutically acceptable auxiliary materials to obtain said preparation;

preferably, the preparation method of the lyophilized preparation for injection comprises: preparing a solution from disodium levoornidazole phosphate or a hydrate thereof and water, and freeze-drying the solution to obtain the freeze-dried preparation for injection;

preferably, the pH of the solution is 4.0-6.0, preferably 4.5-5.5;

preferably, the temperature of the freeze drying is-60 ℃ to 30 ℃, preferably-50 ℃ to 25 ℃.

Preferably, the freeze-drying time is from 30 to 70h, such as from 40 to 60h, such as from 45 to 55 h.

Preferably, the freeze-drying is temperature programmed.

10. Use of a formulation according to any one of claims 1 to 7 for improving the safety and/or stability of a medicament.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a preparation containing ornidazole compounds, and a preparation method and application thereof.

Background

The ornidazole is a nitroimidazole derivative, is a drug for strongly resisting anaerobic bacteria and protozoan infection, and is a third-generation nitroimidazole derivative which is newly developed after metronidazole, and has higher curative effect, shorter treatment course, better tolerance and wider in-vivo distribution. The antimicrobial action of ornidazole is through the reduction of the nitro group in its molecule to an amino group in an anaerobic environment or through the formation of free radicals interacting with cellular components leading to the death of the microorganism. Ornidazole is 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole (CAS No.16773-42-5), and has a chemical structure shown in the following formula:

l-ornidazole (also known as "L-ornidazole", CAS No.166734-83-4) is L-isomer of ornidazole, and is mainly used for treating bacteroides fragilis, bacteroides dieselii, bacteroides ovatus, bacteroides thetaiotaomicron, bacteroides vulgatus, clostridium, eubacterium, digestive coccus and digestive streptococcus, helicobacter pylori, bacteroides melanoides, clostridium, CO₂And various infectious diseases caused by anaerobic bacteria such as the bacteria of the weaven fungi and the gingival bacteria, or used for preventing the infection before operation. L-ornidazole has the chemical structure shown in the following formula:

the research shows that compared with dextroisomer of ornidazole or its racemate, levo-ornidazole has lower neurotoxicity and thus obviously improved safety. In addition, prodrugs of l-ornidazole have been developed, including phosphate esters of l-ornidazole (also known as l-ornidazole phosphate) or salts thereof (e.g., disodium l-ornidazole phosphate). After the prodrug is administrated, the prodrug can be rapidly degraded into the levoornidazole under the action of in vivo phospholipase so as to exert the drug effect.

At present, the characteristics of the ornidazole, its stereoisomer and its prodrug, especially the medication safety, stability, therapeutic effect and patient compliance of ornidazole, l-ornidazole and its prodrug in the period of validity still receive extensive attention from drug researchers, and the direction of further research is needed.

Disclosure of Invention

In order to solve the technical problems, the invention provides a preparation containing an ornidazole compound, wherein the administration daily dose of the preparation containing the ornidazole compound is 0.2-4.0 g based on the ornidazole compound. For example, the preparation comprising ornidazole may be administered in a daily dose of 0.5g to 3.0g, for example 1.0g to 2.5g, and as a further example 1.5g to 2.0g, with examples being 0.2g, 0.3g, 0.4g, 0.5g, 0.6g, 0.7g, 0.8g, 0.9g, 1.0g, 1.1g, 1.2g, 1.3g, 1.4g, 1.5g, 1.6g, 1.7g, 1.8g, 1.9g, 2.0g, 2.1g, 2.2g, 2.3g, 2.4g, 2.5g, 3.0g of ornidazole.

The invention also provides a single-dose preparation containing the ornidazole compound, wherein the content of the ornidazole compound in the single-dose preparation is 0.1g to 2.0g, such as 0.1g, 0.125g, 0.15g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.7g, 0.8g, 0.9g, 1.0g, 1.1g, 1.2g, 1.3g, 1.4g, 1.5g, 1.6g, 1.7g, 1.8g, 1.9g, 2.0g, 2.1g, 2.2g, 2.3g, 2.4g and 2.5 g.

According to an embodiment of the invention, the single dose formulation refers to a unit dose formulation wherein the ornidazole compound is loaded in 1 unit pack.

The invention also provides an ornidazole multi-dose preparation, which is characterized in that the total content of ornidazole compounds in the multi-dose preparation is 0.2g to 2.0g, such as 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.7g, 0.8g, 0.9g, 1.0g, 1.1g, 1.2g, 1.3g, 1.4g, 1.5g, 1.6g, 1.7g, 1.8g, 1.9g, 2.0g, 2.1g, 2.2g, 2.3g, 2.4g and 2.5 g.

According to an embodiment of the invention, the multi-dose formulation comprises more than 1 unit package, e.g. consists of 2 to 10 unit packages, such as 2,3, 4, 5, 6, 7, 8, 9 or 10 unit packages. Wherein, the content of the ornidazole compounds contained in each unit package is the same, or the content of the ornidazole compounds contained in at least 2 unit packages is different.

According to an embodiment of the present invention, the ornidazole-based compound may be selected from ornidazole, its stereoisomers or their precursor compounds. As an example, the ornidazole compound may be selected from ornidazole, levoornidazole (also known as "levoornidazole") or dextroornidazole (also known as "dexornidazole") or their precursor compounds.

According to an embodiment of the present invention, the ornidazole, l-ornidazole or d-ornidazole precursor compound may be selected from its pharmaceutically acceptable precursor compound, for example from an ester of any of them or a pharmaceutically acceptable salt of the ester, and a hydrate of them, for example, at least one of an amino acid ester, a phosphoric acid ester, an amino acid salt of a phosphoric acid ester, and a salt of a phosphoric acid ester with an alkali metal or alkaline earth metal ion or a hydrate of them; for example, at least one of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, etc. of phosphoric acid ester or a hydrate thereof, and an illustrative example is disodium phosphate salt or a hydrate thereof.

According to an embodiment of the present invention, the precursor compound of l-ornidazole may be selected from at least one of l-ornidazole amino acid ester, l-ornidazole phosphate, l-ornidazole amino acid phosphate, and salts of l-ornidazole with alkali metal or alkaline earth metal ions or their hydrates; for example, at least one of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, etc. of l-ornidazole phosphate or a hydrate thereof, and exemplified by l-ornidazole phosphate disodium salt (CAS No.909133-95-5) or a hydrate thereof.

According to an embodiment of the invention, the ornidazole, the l-ornidazole or the d-ornidazole precursor compound may be present in the formulation in the form of its amorphous or polymorphic forms. Or alternatively, the ornidazole, the l-ornidazole or the d-ornidazole precursor compound may also be selected from solvates of pharmaceutically acceptable salts of esters of any of them, such as hydrates thereof, for example, at least one of 1, 2,3, 4, 5, 6 or 7 hydrates of the pharmaceutically acceptable salts of the esters, and examples thereof may be selected from hydrates of disodium salts of l-ornidazole phosphate, such as at least one of 5 hydrates, 6 hydrates, 7 hydrates thereof.

According to a preferred embodiment of the invention, the sodium content of the formulation of the invention administered to the patient daily is lower than 0.6g, preferably lower than 0.5g, more preferably lower than 0.3g, e.g. a content of 0.29g, 0.28g, 0.27g, 0.26g, 0.25g, 0.24g, 0.23g, 0.20g, 0.19g, 0.18g, 0.17g, 0.16g, 0.15g, 0.14g, 0.13g, 0.12g, 0.11g, 0.10g or lower.

According to a preferred embodiment of the invention, the formulation is a sterile formulation.

According to an embodiment of the present invention, the ornidazole named 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, CAS No.16773-42-5, has the chemical structure shown in formula (I-1) below:

l-ornidazole, also known as "L-ornidazole", CAS No.166734-83-4, has a structure shown in formula (I-2) below:

the D-ornidazole has the structure shown in the following formula (I-3):

prodrugs of l-ornidazole, including phosphate esters of l-ornidazole (also known as l-ornidazole phosphate, its CAS No.909133-75-1), have the chemical structure shown below:

or salts of l-ornidazole ester (such as disodium L-ornidazole phosphate, CAS No.909133-95-5), etc.

According to an embodiment of the present invention, the administration route of the preparation containing the ornidazole compound includes, but is not limited to, gastrointestinal administration or parenteral administration; wherein the gastrointestinal administration may be oral administration; the parenteral administration may be an injection (e.g., intravenous injection, arterial injection, intramuscular injection, subcutaneous injection, intradermal injection, etc.), vaginal administration, mucosal administration, or the like.

According to an embodiment of the invention, when the route of administration is selected from one of the above-mentioned administration by injection, the instillation rate may be 100ml/30-60min, for example selected from 100ml/30min, 100ml/35min, 100ml/40min, 100ml/45min, 100ml/50min, 100ml/55min, 100ml/60 min.

According to an embodiment of the invention, the number of administrations may be once a day, twice or more a day, preferably twice, to meet the needs of the daily dose.

According to an embodiment of the invention, the ornidazole compound is ornidazole, levo-ornidazole or a precursor compound of levo-ornidazole. Preferably containing ornidazole, disodium levoornidazole phosphate or a hydrate of either of them. Preferably, the preparation containing the ornidazole compound may not contain other active ingredients than the ornidazole compound, or may also contain other active ingredients than ornidazole, levoornidazole or a precursor compound of levoornidazole.

According to an embodiment of the present invention, the preparation containing the ornidazole compound may further comprise a pharmaceutically acceptable adjuvant, such as a carrier or an excipient. The pharmaceutically acceptable excipients are preferably chemically unreactive or inert towards the active ingredient. For example, the pharmaceutically acceptable excipient is selected from at least one of the following excipients, including but not limited to: fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, wetting agents, pH adjusting agents, solubilizers or cosolvents, osmotic pressure adjusting agents, and the like.

According to an embodiment of the present invention, the formulation comprising ornidazole compounds is a formulation for gastrointestinal administration or a formulation for parenteral administration. Wherein the gastrointestinal tract administration preparation can be tablets, dispersible tablets, capsules, sustained-release agents, granules, oral liquid, syrup and the like; the parenteral administration preparation can be an infusion preparation, an injection (such as a liquid injection), a freeze-dried preparation (such as freeze-dried powder), an effervescent tablet, a suppository, a sublingual tablet and the like, and is preferably a capsule, an injection (such as a liquid injection) or a freeze-dried preparation (such as freeze-dried powder) for injection.

According to an embodiment 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 carbonate, calcium bicarbonate, starch, carboxymethyl starch, pregelatinized starch, microcrystalline cellulose, and the like.

According to an embodiment of the present invention, the disintegrant may be selected from at least one of pregelatinized starch, microcrystalline cellulose, alginic acid, lignocellulose, sodium carboxymethyl starch, guar gum, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and the like.

According to an embodiment of the present invention, the binder may be selected from at least one of gelatin, dextrin, maltodextrine, sucrose, gum arabic, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, hypromellose, and the like.

According to an embodiment 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 glyceryl monostearate, monolaurocysteine, sodium chloride, sodium lauryl sulfate, magnesium lauryl sulfate, and the like.

According to an embodiment of the present invention, the surfactant may be selected from at least one of sodium lauryl sulfate, poloxamer, polysorbate 80, cetrimide, sodium lauryl sulfate, sodium stearate, polyoxyethylene higher fatty alcohol, sucrose ester, sorbitol fatty ester, soybean phospholipid, and the like.

According to an embodiment of the present invention, the flavoring agent is at least one of steviosin, fructose, glucose, fructose syrup, honey, aspartame, xylitol, mannitol, lactose, sorbitol, essence, maltitol, and the like.

According to an embodiment of the present invention, the wetting agent may be selected from at least one of water and ethanol, etc.

According to an embodiment of the present invention, the pH adjustor 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, and the like.

According to an embodiment of the present invention, the cosolvent may be selected from alcoholic solvents, for example, at least one selected from ethanol, glycerol, propylene glycol, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400, etc.), and the like. Preferably, the preparation containing the ornidazole compound does not contain a cosolvent.

According to an embodiment 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, and the like.

According to an exemplary embodiment of the present invention, the preparation containing the ornidazole compound is an injection (such as a liquid injection) or a freeze-dried preparation for injection.

Preferably, the injection is a liquid injection having a concentration of 3-20mg/ml, such as 4-18mg/ml, examples being 4mg/ml, 5mg/ml, 6mg/ml, 7mg/ml, 8mg/ml, 9mg/ml, 10mg/ml, 11mg/ml, 12mg/ml, 13mg/ml, 14mg/ml, 15mg/ml, 16mg/ml, 17mg/ml, 18mg/ml, based on the ornidazole compound.

Preferably, the specification of the freeze-dried preparation for injection is 0.1-0.6g, such as 0.12-0.5g, and further such as 0.15-0.3g, and examples thereof may be 0.125g, 0.15g, 0.16g, 0.17g, 0.18g, 0.19g, 0.20g, 0.21g, 0.22g, 0.23g, 0.24g, 0.25g, 0.3g, 0.5g based on the ornidazole compound.

According to an exemplary embodiment of the present invention, the injection or the freeze-dried injection comprises an ornidazole compound, preferably ornidazole, levo-ornidazole disodium phosphate or a hydrate of any one of the ornidazole compound and the disodium phosphate; more preferably, the injection or injection lyophilized preparation further comprises 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole in an amount of 2100mg/kg or less, preferably less than 2100mg/kg, still more preferably 1000mg/kg or less.

According to an exemplary embodiment of the present invention, the injection or lyophilized preparation for injection comprises an ornidazole compound, preferably ornidazole, disodium levoornidazole phosphate or a hydrate of any one of the ornidazole compound and 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole in an amount of less than 60 mg/kg.

According to an embodiment of the present invention, the content of the ornidazole compound as an active ingredient in the injection or lyophilized preparation for injection is in the range of 70% to 85% by weight, for example, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 82%, 83%, 84%, 85%, preferably in the range of 72% to 83% of ornidazole or its isomer.

According to an embodiment of the present invention, the injection or lyophilized preparation for injection may contain citric acid, which may be present in an amount of 10-35% by weight, preferably 15-32% by weight, such as 18-28%, 20-25%, illustratively 16%, 17%, 18%, 19%, 21%, 22%, 23%, 24%, 26%, 27%, 29%.

According to an embodiment of the invention, the pH of the injection may be 4.0-6.0, preferably 4.5-5.5, e.g. 4.6-5.4, 4.7-5.3, exemplarily 4.8, 4.9, 5.0, 5.1, 5.2.

According to an embodiment of the invention, the pH of the solution after reconstitution of the lyophilized formulation for injection may be 4.0-6.0, preferably 4.5-5.5, e.g. 4.6-5.4, 4.7-5.3, exemplary 4.8, 4.9, 5.0, 5.1, 5.2.

According to the embodiment of the invention, when the pH of the solution of the injection or the freeze-dried preparation for injection after being redissolved is 4.0-6.0, the content of citric acid can be 19-45 mg/mL. For example, at pH 4.0, the citric acid content is 45 mg/mL; when the pH value is 6.0, the content of the citric acid is 19 mg/mL.

According to an embodiment of the present invention, water for injection, ethanol and/or propylene glycol may be included in the injection. Preferably, the injection comprises water for injection.

According to an exemplary embodiment of the invention, the injection comprises either l-ornidazole disodium phosphate and citric acid.

According to exemplary embodiments of the present invention, the injection may further comprise or not comprise an ingredient selected from one of the following: ornidazole, ethanol and propylene glycol.

According to an embodiment of the invention, the preparation comprising ornidazole-like compounds comprises 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole in an amount below 2100mg/kg, preferably less than 2100 mg/kg.

According to an embodiment of the present invention, 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole has a structure as shown in the following formula (III):

according to an embodiment of the invention, the preparation containing the ornidazole compound has a percentage content of 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole below 2000mg/kg, such as below 1900mg/kg, below 1800mg/kg, below 1700mg/kg, below 1600mg/kg, below 1500mg/kg, below 1400mg/kg, below 1300mg/kg, below 1200mg/kg, below 1100 mg/kg.

According to an embodiment of the invention, the formulation comprising ornidazole compound has a percentage content of 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole below 1000mg/kg, for example below 900mg/kg, below 800mg/kg, below 700mg/kg, below 600mg/kg, below 500mg/kg, below 400mg/kg, below 300mg/kg, below 200mg/kg or below 100 mg/kg.

According to a preferred embodiment of the invention, the content of the compound represented by formula (III) in the preparation containing the ornidazole compound is below 90mg/kg, such as below 80mg/kg, below 70mg/kg, more preferably below 60mg/kg, and examples thereof may be below 50mg/kg, below 40mg/kg, below 30mg/kg, below 20mg/kg or below 10 mg/kg.

More preferably, in the preparation containing the ornidazole compound, the content of the compound represented by formula (III) is less than 9mg/kg, for example less than 8mg/kg, less than 7mg/kg, more preferably less than 6mg/kg, and examples thereof may be less than 5mg/kg, less than 4mg/kg, less than 3mg/kg, less than 2mg/kg, less than 1mg/kg or 0. Wherein, when the content of the compound shown in the formula (III) is 0, the preparation containing the ornidazole compound does not contain the compound shown in the formula (III). Alternatively, the content of the compound shown in the formula (III) in the preparation containing the ornidazole compound can be more than 0.

According to an embodiment of the present invention, the preparation containing the ornidazole compound may optionally further contain or not contain 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole, and the 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole has a structure shown in the following formula (II):

according to an embodiment of the invention, the content of the compound of formula (II) in the preparation comprising the ornidazole compound is below 900mg/kg, such as below 800mg/kg, below 700mg/kg, below 600mg/kg, below 500mg/kg, below 400mg/kg, below 300mg/kg, below 200mg/kg, below 100 mg/kg. Further, the content of the compound represented by the formula (II) is 90mg/kg or less, preferably 80mg/kg or less, for example 70mg/kg or less, 60mg/kg or less, 50mg/kg or less, 40mg/kg or less, 30mg/kg or less, 20mg/kg or less or 10mg/kg or less. More preferably, the content of the compound represented by formula (II) is 9mg/kg or less, for example 8mg/kg or less, 7mg/kg or less, more preferably 6mg/kg or less, and examples thereof may be 5mg/kg or less, 4mg/kg or less, 3mg/kg or less, 2mg/kg or less, or 1mg/kg or less.

According to a more preferred embodiment of the invention, the content of the compound of formula (II) in the preparation comprising the ornidazole compound is below 0.9mg/kg, such as below 0.8mg/kg, below 0.7mg/kg, more preferably below 0.6mg/kg, examples of which may be below 0.5mg/kg, below 0.4mg/kg, below 0.3mg/kg, below 0.2mg/kg or below 0.1 mg/kg.

According to an embodiment of the present invention, the content of 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole in the preparation containing the ornidazole compound may be 0, which means that the preparation containing the ornidazole compound does not contain 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole. In some embodiments of the ornidazole-containing formulation of the present invention, the 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole is present in an amount greater than 0, which means that the ornidazole-containing formulation contains 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole.

According to an embodiment of the present invention, the content of the ornidazole compound as an active ingredient in the preparation comprising the ornidazole compound may be in the range of 10% to 99%, preferably 15% to 90%, for example 20% to 85%, and examples thereof may be in the range of, for example, 72% to 83%, for example 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, based on l-ornidazole, l-disodium phosphate or a hydrate of any one thereof.

According to an embodiment of the present invention, the preparation containing the ornidazole compound may optionally further contain or not contain a compound represented by the following formula (IV):

according to an embodiment of the invention, in the preparation comprising the ornidazole compound, the content of the compound of formula (IV) may be 15000mg/kg or less, for example 14000mg/kg or less, 13000mg/kg or less, 12000mg/kg or less, 11000mg/kg or less, 10000mg/kg or less, 8000mg/kg or less, 7000mg/kg or less, 6000mg/kg or less, 5000mg/kg or less, 4000mg/kg or less, 3000mg/kg or less, 2000mg/kg or less. Preferably, the compound of formula (IV) may be present in an amount of 1000mg/kg or less, for example 900mg/kg or less, 800mg/kg or less, 700mg/kg or less, 600mg/kg or less, 500mg/kg or less, 400mg/kg or less, 300mg/kg or less, 200mg/kg or less or 100mg/kg or less.

According to a preferred embodiment of the invention, the content of the compound represented by formula (IV) in the preparation containing the ornidazole compound is below 90mg/kg, such as below 80mg/kg, below 70mg/kg, more preferably below 60mg/kg, and examples thereof may be below 50mg/kg, below 40mg/kg, below 30mg/kg, below 20mg/kg, below 10mg/kg or 0. Wherein, when the content of the compound shown in the formula (IV) in the preparation containing the ornidazole compound is 0, the preparation containing the ornidazole compound does not contain the compound shown in the formula (IV). Alternatively, the content of the compound shown in the formula (IV) in the preparation containing the ornidazole compound can be more than 0.

According to an embodiment of the present invention, the preparation comprising the ornidazole compound may optionally further comprise or not comprise 2-methyl-5-nitroimidazole.

According to an embodiment of the invention, the preparation comprising the ornidazole compound has a 2-methyl-5-nitroimidazole content below 2000mg/kg, such as below 1900mg/kg, below 1800mg/kg, below 1700mg/kg, below 1600mg/kg, below 1500mg/kg, preferably below 1400mg/kg, below 1300mg/kg, below 1200mg/kg, below 1100mg/kg, below 1000mg/kg, such as below 900mg/kg, below 800mg/kg, below 700mg/kg, below 600mg/kg, below 500mg/kg, below 400mg/kg, below 300mg/kg, below 200mg/kg or below 100 mg/kg.

According to a preferred embodiment of the invention, the preparation containing the ornidazole compound has a 2-methyl-5-nitroimidazole content below 90mg/kg, such as below 80mg/kg, below 70mg/kg, more preferably below 60mg/kg, examples of which may be below 50mg/kg, below 40mg/kg, below 30mg/kg, below 20mg/kg, below 10mg/kg or 0. Wherein, when the content of the 2-methyl-5-nitroimidazole in the preparation containing the ornidazole compound is 0, the preparation containing the ornidazole compound does not contain the 2-methyl-5-nitroimidazole.

According to an embodiment of the present invention, the preparation comprising an ornidazole-like compound may comprise a precursor compound of l-ornidazole, preferably wherein the l-ornidazole is present in an amount of less than 2000mg/kg, such as less than 80mg/kg, less than 70mg/kg, more preferably less than 60mg/kg, examples of which may be less than 50mg/kg, less than 40mg/kg, less than 30mg/kg, less than 20mg/kg or less than 10mg/kg or 0. When the content of the l-ornidazole in the preparation containing the ornidazole compound is 0, the preparation containing the ornidazole compound does not contain the l-ornidazole.

The invention also provides a preparation method of the preparation containing the ornidazole compound, which comprises the step of mixing the ornidazole compound with pharmaceutically acceptable auxiliary materials to obtain the preparation containing the ornidazole compound.

According to an exemplary embodiment of the present invention, ornidazole, ethanol, propylene glycol and water for injection are mixed to obtain the preparation containing the ornidazole compound.

According to an exemplary embodiment of the present invention, the disodium l-ornidazole phosphate or its hydrate is prepared into a solution with water, and the solution is freeze-dried to obtain the preparation containing the ornidazole compound.

According to an embodiment of the invention, the pH of the solution is 4.0-6.0, preferably 4.5-5.5, e.g. 4.6-5.4, 4.7-5.3, exemplarily 4.8, 4.9, 5.0, 5.1, 5.2.

According to an embodiment of the invention, the temperature of the freeze-drying is between-60 ℃ and 30 ℃, preferably between-50 ℃ and 25 ℃.

According to an embodiment of the invention, the freeze-drying time is 30-70h, such as 40-60h, further such as 45-55 h.

According to an embodiment of the invention, the freeze-drying is temperature programmed.

According to an embodiment of the present invention, an exemplary operation of the freeze-drying includes: sending the semi-finished product filled with the semi-stopper into a freeze-drying box when the temperature of the silicone oil is reduced to 0 ℃, keeping for 0.5 hour, and keeping for 1.0 hour when the temperature of the silicone oil is reduced to-50 ℃; heating to-20 deg.C, and maintaining for 3.0 h; cooling to-50 deg.C, and maintaining for 3.0 h. The vacuum pump is opened, the vacuum is pumped to 200 mu bar, the temperature is raised to-20 ℃ within 1.0h, and the temperature is maintained for 16.0 h. Heating to-15 deg.C for 5min, and maintaining for 6.0 h; heating to-10 deg.C for 5min, and maintaining for 1.0 h; heating to 0 deg.C for 10min, and maintaining for 1.0 h; heating to 10 deg.C for 10min, and maintaining for 1.0 h; heating to 25 deg.C for 15min, and maintaining for 7.0 h; extreme vacuum was applied at 25 ℃ and continued for 13.0 h. Performing pressure rise test (the pressure rise qualification standard is less than or equal to 15 μ bar/min), freeze-drying after qualification, filling nitrogen into the box body to break vacuum (vacuum control range: 850mbar-900mbar), and taking out of the box after full pressure plugging.

According to an embodiment of the present invention, the preparation containing ornidazole compound is a preparation containing ornidazole compound with high safety during the expiration date.

The invention also provides application of the preparation containing the ornidazole compound in improving the safety of medicines.

The invention also provides application of the preparation containing the ornidazole compound in improving the stability of the medicament.

Preferably, the preparation containing the ornidazole compound is used for preventing or treating diseases related to anaerobes, such as preventing or treating diseases related to anaerobesInfectious diseases caused by anaerobic bacteria. For example, the anaerobic bacteria may be selected from at least one of the following, including but not limited to: bacteroides fragilis, Bacteroides dirichi, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Clostridium clostridia, Eubacterium, Pediococcus and Pediococcus, helicobacter pylori, Bacteroides melanoides, Fusobacterium, CO₂And anaerobic bacteria such as bacteriophage phagemid and gingival bacteroides.

Preferably, the preparation containing the ornidazole compound is used for preventing or treating infectious diseases caused by anaerobic bacteria before and/or after operation.

The invention also provides a method for preventing or treating diseases related to anaerobes, such as infectious diseases caused by anaerobes, which comprises the step of administering a therapeutically effective amount of the preparation containing the ornidazole compound to a patient in need thereof.

Definition and description of terms

Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to effect the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the dosage regimen to be followed, whether to administer it in combination with other compounds, the timing of administration, the tissue to be administered and the physical delivery system carried.

The term "patient" refers to a patient in need of a targeted prevention or treatment of a disease associated with anaerobes, wherein the patient is a mammal, e.g., selected from rodents, cows, pigs, dogs, cats and primates, particularly humans.

The term "expiration date" means a period of time during which the quality of a pharmaceutical product can meet regulatory requirements under defined storage conditions, for example 6 months to 36 months, such as 24 months, 18 months or 12 months.

Advantageous effects

The preparation of the invention is particularly suitable for some patients, such as patients with heart and lung insufficiency or the elderly, and can meet the requirements of different clinical groups. Furthermore, qd (once a day) administration may be increased by C relative to q12h (once every 12 hours)_maxThe ratio of MIC, bacteria with higher covering MIC, and the clinical effect and the patient compliance are improved, and the adverse reaction trend is expected to be reduced.

The inventors have surprisingly found that 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole present in formulations comprising ornidazole compounds is genotoxic, can cause damage to cellular DNA, and produces mutagenic effects. However, such dosing risks are controlled or even eliminated in the formulations of the present invention. For example, the safety and/or stability of such drugs can be significantly improved when the weight percent content of the compound is reduced to the preferred ranges described herein.

The present application surprisingly found that 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole present in formulations comprising ornidazole compounds is genotoxic, causes cellular DNA damage, and produces mutagenic effects, creating a great challenge to the safety and/or stability of such drugs during the lifetime of use. Such dosing risks are controlled or even eliminated in the present ornidazole-containing formulation. It was found that the safety and/or stability of such a drug can be significantly improved when the weight percentage content of 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole is reduced to below 1000mg/kg, preferably below 100mg/kg, more preferably below 60 mg/kg.

Drawings

FIG. 1 is a graph showing the results of the main efficacy index of example 9.

Detailed Description

Embodiments of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

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

Example 1: genotoxicity test for the Compound of formula (III)

Ames experiment (Strain experiment)

1. Materials and methods

1.1 test article

Name: 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole;

packaging: an ampoule bottle;

specification: about 50 mg/count;

storage conditions are as follows: sealing at 2-8 deg.C in dark.

1.2 vehicle information

Name: sodium chloride injection;

production unit: chenxin pharmaceutical industry, gmbh;

properties and physicochemical properties: colorless clear liquid, slightly salty taste;

specification: 500 mL/bottle;

storage conditions are as follows: and (5) sealing and storing.

1.3 preparation of test sample/reference

The test sample is prepared on the day of administration, and an appropriate amount of the test sample is weighed and dissolved by adding an appropriate amount of sodium chloride injection to make the concentration of the test sample be 50 mg/mL. The solution was filtered through a 0.2 μm filter and diluted with sodium chloride injection to a concentration of 20, 8, 2, 0.5mg/mL, respectively.

The formulated solution was stored at room temperature prior to administration.

1.4 Experimental methods

The strain is as follows: salmonella typhimurium, histidine-deficient strains (TA97a, TA98, TA100, TA102, TA 1535). The strain is provided by Moltox, and the bacterial liquid is stored in liquid nitrogen.

SD rats are offered by Zhao Zhi (Suzhou) New drug research center, Inc.

Preparing a mixed solution of S9:

SD rat liver S9 fraction with protein concentration of 21.64mg/mL was used in this experiment and stored in liquid nitrogen. Prior to use, the S9 mixture was prepared under sterile conditions, and the S9 mixture was prepared as described in Table 1.

TABLE 1

And (3) enrichment culture of the strain: after the bacterial liquid frozen and preserved by liquid nitrogen is melted in water bath at 37 ℃, 100 mu l of the bacterial liquid is inoculated into 20ml of nutrient broth and cultured for 10 to 12 hours at 37 ℃ in a dark oscillation (120 rpm).

Grouping administration: each test point processed 2 parallel dishes. The administration information is shown in table 2.

TABLE 2

Note: group 1 was a spontaneous control group; groups 2-6 are test article groups.

Taking a corresponding number of glass test tubes, subpackaging 2ml of top layer culture medium (heated at 45-47 ℃) in the test tubes, and then sequentially adding 0.1ml of bacterial culture solution, 0.1ml of test solution, 0.5ml of S9 mixture or PBS with pH 7.4. Quickly and uniformly mixing the mixture on a vibrator, pouring the mixture on the surface of the basic culture medium, and slightly rotating to uniformly spread the mixture on the surface of the basic culture medium.

Placing the plate on a horizontal desktop, inverting the plate after the culture medium is solidified, and culturing at 37 ℃ for 48-72 hours.

1.5 data acquisition

And after culturing for about 48-72 hours, counting the number of the reverted mutant colonies in all the plates, and observing the background lawn under a microscope to evaluate whether the test article has an antibacterial effect on the strains.

The precipitation was observed when the drug was added.

1.6 determination of results

Judging whether the test article has bacteriostatic toxicity to the strain according to the following criteria:

1) the background lawn becomes thinner, and the reduction of the number of revertant colonies can be accompanied;

2) the background lawn disappears, i.e. the bacterial growth is completely inhibited;

3) needle-like non-reverting mutant microcolonies (usually accompanied by background lawn deletion) appear.

2. Results

2.1 precipitation conditions

No precipitate was observed in the sample loading process for each test article dose group.

2.2 bacterial virulence

Background lawn individual data are shown in table 3 below.

Table 3: background lawn individual observation data

Note: "√" indicates that the background lawn is normal. The results show that: under the non-metabolic activation state and the metabolic activation state and under the dosage of 50-5000 mu g/dish, the background lawn of each strain is not abnormal.

2.3 mutagenicity

The results of the counter-mutant colony counts are shown in Table 4 below.

Table 4: return mutation colony count individual data (individual/dish)

The results show that: under the conditions of metabolic activation and non-metabolic activation, the number of the reversion mutation colonies of each strain of the spontaneous control group is within a normal reference range or slightly increased or decreased; under the non-metabolic activation state and the metabolic activation state and under the dosage of 50-200 mu g/dish, the number of the reversion mutation colonies of each strain is within a normal reference range or slightly increased or decreased; except that the TA1535 reversion colony number is reduced under the dosage of 5000 mug/dish, the reversion colony number of each strain is obviously increased under the dosage of 800-5000 mug/dish and is more than 2 times of that of a spontaneous control group.

3. Conclusion

Under the test condition, the 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole does not have obvious bacterial toxicity effect under the dosage of 50-5000 mug/dish, but has mutagenicity to salmonella typhimurium under the dosage of 800-5000 mug/dish, and therefore has genotoxicity.

(II) micronucleus test

1. Test and reference substances

1.1 test article

Name: 1- (2, 3-dihydroxypropyl) -2-methyl-5-nitroimidazole;

packaging: an ampoule bottle;

specification: about 50 mg/count;

storage conditions are as follows: sealing at 2-8 deg.C in dark.

1.2 reference substance

Cyclophosphamide for injection;

production unit: jiangsu Hengrui pharmaceuticals, Inc.;

condition and physicochemical properties: white; a colored crystalline powder;

batch number: 19061521, respectively;

specification: 0.2 g/bottle;

storage conditions are as follows: and (5) shading, sealing and storing.

1.3 Experimental animals

Mouse KM

Grade: SPF;

selling units: henan Spanish Biotech GmbH;

the unit of mass detection: experimental animal center in Shandong province;

license number: SCXK 2020-.

2. Preparation of drug delivery preparation

The preparation process is finished under the aseptic condition, the used reagent bottles and the like are sterilized, and the preparation process is not protected from light.

Solvent (0.9% sodium chloride injection):

production unit: anhui double crane pharmaceutical industry, Inc.;

properties and physicochemical properties: colorless clear liquid, slightly salty taste;

batch number: 20011112C

Specification: 500 mL/bottle;

storage conditions are as follows: and (5) sealing and storing.

Preparation of positive control solution (cyclophosphamide):

weighing the required amount of the positive control (calculated by content), adding a proper amount of solvent, stirring until the positive control is clear and transparent, and finally diluting the positive control to the required concentration by using the solvent. After the preparation is finished, a filter membrane with the diameter of 0.22 mu m is adopted for filtration to obtain a positive control solution.

Preparing a test article administration preparation:

weighing the required amount of the test sample (calculated by content), adding a proper amount of solvent, stirring until the test sample is clear and transparent, and finally diluting the test sample to the required concentration by using the solvent. Filtering with 0.22 μm filter membrane to obtain the test drug delivery preparation.

The doses and concentrations for each group are shown in the following table:

3. experimental system

3.1 Experimental animals

Animals used for the experiment: kunming mouse, clean grade; 24 females and 24 males were selected.

Weight and age at group: female: about 24-28 g, 8-10 weeks old; male: about 25-29 g, 8-10 weeks old.

3.2 grouping

The test has 5 groups, 10 solvent groups and test sample groups, 8 positive control groups and 48 positive control groups.

3.3 animal identification

Animals were identified on the day of reception with 3% picric acid ethanol solution, and grouped together with picric acid and house label as follows:

x is female mouse, Y is male mouse.

3.4 animal randomization group

The animals were randomly grouped according to sex and weight, and the 48 animals selected were assigned to 5 groups. The differences in body weight of the animals used for the grouping were within ± 20% of the mean body weight of the same sex category. After grouping, the average body weight of each group of animals was not statistically different at the 5.0% test level. And (5) storing and recording the rest animals after grouping, and feeding.

3.5 reagent dosage design

The experimental dose design is shown in the following table:

4. test method

4.1 administration of drugs

The administration route is as follows: the intraperitoneal injection administration route is selected.

The administration mode comprises the following steps: the administration is performed 5 times for 3 consecutive days, 1 time in the morning on the first day, and 1 time in the afternoon on the second and third days.

The administration period is as follows: and 3 days.

Dose capacity: 10 mL/kg.

Dosage: the dose was calculated from the last weight weighing.

4.2 Observation and inspection

4.2.1 death or dying

All surviving animals were observed 1 time per day.

4.2.2 body weight

An adaptation period: all animals were weighed 1 time before grouping, i.e. group weight

The administration period is as follows: the body weights were weighed in the morning before D1, D2 and D3 administration, respectively, and used to calculate the dose

4.3 test end-of-line procedure

4.3.1 unintended death animal

During the experiment, all animals did not die or moribund (see section 5.1 for a summary of die or moribund results).

4.3.2 dissection

Planned dissection date: administration end (D4)

And (3) dissecting animals: all surviving animals

The tabletting method comprises the following steps: the mice were sacrificed by cervical dislocation, femurs were taken, muscles were removed, epiphyses were cut off, marrow cavities were exposed, marrow smears were taken, fixed with methanol, and stained with gimesas.

4.3.3 microscopic examination

Planned microscopic examination date: administration end (D5)

The microscopic examination object: all animal bone marrow smears (see details 4.3.2)

The microscopic examination method comprises the following steps: the area with complete cells, uniform dispersion and proper coloring is selected under a low power microscope, 1000 micronucleoli rates of cytoplasmally clear and complete polyphilic red blood cells (PCE) are counted in each smear by observing through a high power microscope, and the result is expressed in per thousand percent (‰).

4.4 statistical analysis

SPSS16.0 statistical software is used for analysis, and the microkernel rate is equal toShow, compare with negative control, using two-sided t-test and chi²Inspection systemDesign processing, P<0.05 is statistically significant, P>0.05 is not significant, 0.01<P<0.05 is significant, P<The difference at 0.01 is very significant.

The death or moribund results were not counted and are expressed as frequency.

5 results

5.1 death or dying

The effect of the test article on the death or moribund outcome of the animals is shown in the following table. By the end of the dosing period, no death or moribund was found in all animals.

5.2 body weight

The results of the body weight examination are shown in the following table.

By the end of the dosing period, no significant abnormalities in body weight were seen in all animals.

The change of the body weight is not related to dosage, the increase and the decrease are also caused, and the change is possibly related to the difference of animal individuals and has no toxicological significance.

5.3 Micronuclear Rate of pleochromophilic erythrocytes

The statistic results of the micronucleus rate of the pleochromophilic erythrocytes are shown in the following table.

By the end of the administration period, the animals in the test article administration group showed a tendency of increasing micronucleus rate.

The micronucleus rate of the 100mg/kg dose group is remarkably different (p is less than 0.05) compared with that of the negative control group, and the micronucleus rate of other dose groups is slightly increased although no statistical difference is found, and is considered to be related to a test sample.

Conclusion 6

Under the test condition, the Kunming mouse is subjected to intraperitoneal injection for 3 days continuously and is given with impurity III with the concentration of 2.88, 48 and 100mg/kg, no animal death or dying is seen in the test period, no obvious abnormality related to the test sample is seen in the body weight, and the increase of the micronucleus rate of the pleochromophilus red cells is seen under the dosage of more than or equal to 100mg/kg, and the micronucleus rate is considered to be related to the test sample. The level of no observed adverse effect in this test (NOOBSERVED ADDVERSE EFFECT level, NOAEL) was 48 mg/kg.

According to the ICH M7 (international human drug registration technical co-ordination) guidelines, genotoxic impurity limits were calculated as follows:

the impurity limit is the acceptable daily intake of the impurity (i.e., PDE value)/maximum daily dosage of the drug.

PDE (NOEL) × body weight/(F1 × F2 × F3 × F4 × F5)

Wherein, the NOEL of the mouse is 48 mg/kg/day; f1-12, the human dose was extrapolated from the mouse dose; f2 ═ 10, see FDA ICH-Q3C guidelines; f3 is 10, and the experimental period does not exceed 10 days; f4 ═ 1, no serious toxic reaction was considered to be found; f5 ═ 1; regulating body weight to 50 kg; the calculation results are as follows:

PDE＝48mg/kg(NOEL)×50/(12×10×10×1×1)＝2mg；

the impurity limit is 2mg/2g (the maximum daily dose of the compound is 2g determined by clinical tests and the like) 1000ppm is 1000 mg/kg.

Example 2: genotoxicity test of 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole (Compound of formula (II))

Ames experiment (Strain experiment)

1. Materials and methods

1.1 test article

Name: 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole;

packaging: an ampoule bottle;

specification: about 50 mg/count;

storage conditions are as follows: sealing at 2-8 deg.C in dark.

1.2 vehicle information

Name: sodium chloride injection;

production unit: chenxin pharmaceutical industry, gmbh;

properties and physicochemical properties: colorless clear liquid, slightly salty taste;

specification: 500 mL/bottle;

storage conditions are as follows: and (5) sealing and storing.

1.3 preparation of test sample/reference

The formulated solution was stored at room temperature prior to administration.

1.4 Experimental methods

SD rats are offered by Zhao Zhi (Suzhou) New drug research center, Inc.

Preparing a mixed solution of S9:

TABLE 5

Grouping administration: each test point processed 2 parallel dishes. The administration information is shown in table 6.

TABLE 6

Note: group 1 was a spontaneous control group; groups 2-6 are test article groups.

Placing the plate on a horizontal desktop, inverting the plate after the culture medium is solidified, and culturing at 37 ℃ for 48-72 hours.

1.5 data acquisition

The precipitation was observed when the drug was added.

1.6 determination of results

Judging whether the test article has bacteriostatic toxicity to the strain according to the following criteria:

1) the background lawn becomes thinner, and the reduction of the number of revertant colonies can be accompanied;

2) the background lawn disappears, i.e. the bacterial growth is completely inhibited;

3) needle-like non-reverting mutant microcolonies (usually accompanied by background lawn deletion) appear.

2. Results

2.1 precipitation conditions

No precipitate was observed in the sample loading process for each test article dose group.

2.2 bacterial virulence

Background lawn individual data are shown in table 7 below.

Table 7: background lawn individual observation data

Note: "√" indicates that the background lawn is normal; "-" indicates disappearance of background lawn, and X indicates decrease of background lawn.

The results show that: under the condition of non-metabolic activation, under the dosage of 800-5000 mu g/dish, background lawn of each strain disappears, and under the dosage of 50-200 mu g/dish, background lawn of each strain decreases. Under the condition of metabolic activation, under the dosage of 200-5000 mug/dish, background lawn of each strain disappears, and under the dosage of 50 mug/dish, background lawn of each strain is reduced.

2.3 mutagenicity

The results of the counter-mutant colony counts are shown in Table 8 below.

Table 8: return mutation colony count individual data (individual/dish)

The results show that: under the conditions of metabolic activation and non-metabolic activation, the number of the reversion mutation colonies of each strain of the spontaneous control group is within a normal reference range or slightly increased or decreased; under the dosage of 50 and 200 mug/dish in the non-metabolic activation state and the dosage of 50 mug/dish in the metabolic activation state, the number of the reversion mutation colonies of each strain is obviously increased and is 2 times higher than that of a spontaneous control group.

3. Conclusion

Under the test condition, the 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole has a bacterial toxicity effect under the dosage of 50-5000 mu g/dish, has mutagenicity on salmonella typhimurium, and has genotoxicity.

(II) micronucleus test

1. Test and reference substances

1.1 test article

Name: 1- (2, 3-epoxypropane) -2-methyl-5-nitroimidazole;

packaging: an ampoule bottle;

specification: about 50 mg/count;

storage conditions are as follows: sealing at 2-8 deg.C in dark.

1.2 reference substance

Cyclophosphamide for injection;

production unit: jiangsu Hengrui pharmaceuticals, Inc.;

condition and physicochemical properties: white; a colored crystalline powder;

batch number: 19061521, respectively;

specification: 0.2 g/bottle;

storage conditions are as follows: and (5) shading, sealing and storing.

1.3 Experimental animals

Mouse KM

Grade: SPF;

selling units: henan Spanish Biotech GmbH;

the unit of mass detection: experimental animal center in Shandong province;

license number: SCXK 2020-.

2. Preparation of drug delivery preparation

The preparation process is finished under the aseptic condition, the used reagent bottles and the like are sterilized, and the preparation process is not protected from light.

Solvent (0.9% sodium chloride injection):

production unit: anhui double crane pharmaceutical industry, Inc.;

properties and physicochemical properties: colorless clear liquid, slightly salty taste;

batch number: 20011112C

Specification: 500 mL/bottle;

storage conditions are as follows: and (5) sealing and storing.

Preparation of positive control solution (cyclophosphamide):

Preparing a test article administration preparation:

The doses and concentrations for each group are shown in the following table:

3. experimental system

3.1 Experimental animals

Animals used for the experiment: kunming mouse, clean grade; 24 females and 24 males were selected.

Weight and age at group: female: about 24-28 g, 8-10 weeks old; male: about 25-29 g, 8-10 weeks old.

3.2 grouping

The test has 5 groups, 10 solvent groups and test sample groups, 8 positive control groups and 48 positive control groups.

3.3 animal identification

Animals were identified on the day of reception with 3% picric acid ethanol solution, and grouped together with picric acid and house label as follows:

x is female mouse, Y is male mouse.

3.4 animal randomization group

3.5 reagent dosage design

The experimental dose design is shown in the following table:

4. test method

4.1 administration of drugs

The administration route is as follows: the intraperitoneal injection administration route is selected.

The administration period is as follows: and 3 days.

Dose capacity: 10 mL/kg.

Dosage: the dose was calculated from the last weight weighing.

4.2 Observation and inspection

4.2.1 death or dying

All surviving animals were observed 1 time per day.

4.2.2 body weight

An adaptation period: all animals were weighed 1 time before grouping, i.e. group weight

The administration period is as follows: the body weights were weighed in the morning before D1, D2, and D3 administration, respectively, and used to calculate the dose amounts.

4.3 test end-of-line procedure

4.3.1 unintended death animal

During the experiment, all animals did not die or moribund (see section 5.1 for a summary of die or moribund results).

4.3.2 dissection

Planned dissection date: administration end (D4)

And (3) dissecting animals: all surviving animals

4.3.3 microscopic examination

Planned microscopic examination date: administration end (D5)

The microscopic examination object: all animal bone marrow smears (see details 4.3.2)

4.4 statistical analysis

SPSS16.0 statistical software is used for analysis, and the microkernel rate is equal toShow, compare with negative control, using two-sided t-test and chi²The test is statistically processed, P<0.05 is statistically significant, P>0.05 is not significant, 0.01<P<0.05 is significant, P<The difference at 0.01 is very significant.

The death or moribund results were not counted and are expressed as frequency.

5 results

5.1 death or dying

The effect of the test article on the death or moribund outcome of the animals is shown in the following table. By the end of the dosing period, no death or moribund was found in all animals.

5.2 body weight

The results of the body weight examination are shown in the following table.

During the experiment, the animals in the test article administration group showed a weight loss tendency.

The weight of the animals in the 100mg/kg dose group D3 showed a decrease trend and showed dose correlation, and the other animals showed a smaller weight increase and showed dose correlation, although no statistical difference in weight change, and were considered to be related to the test sample.

5.3 Micronuclear Rate of pleochromophilic erythrocytes

The statistic results of the micronucleus rate of the pleochromophilic erythrocytes are shown in the following table.

During the experiment, the animals of the test article administration group showed a rising trend of micronucleus rate.

The micronucleus rates of the 48mg/kg dose group and the 100mg/kg dose group are very different from those of the negative control group (p is less than 0.01), and although no statistical difference is found in other dose groups, the micronucleus rates are also seen to be slightly increased, so that dose correlation is shown, and the micronucleus rates are considered to be related to the test sample.

Conclusion 6

Under the test condition, the Kunming mouse is subjected to intraperitoneal injection for 3 consecutive days to give test compound with the concentration of 2.88, 48 and 100mg/kg, no animal death or dying is seen in the test period, the weight of animals in a test administration group is reduced under the dosage of more than or equal to 100mg/kg, and the rate of the chromophilous erythrocyte micronucleus is increased under the dosage of more than or equal to 48mg/kg, so that the test compound is considered to be related to the test. The level of no observed adverse effect in this test (NOOBSERVED ADDVERSE EFFECT level, NOAEL) was 2.88 mg/kg.

According to the ICH M7 (international human drug registration technical co-ordination) guidelines, genotoxic impurity limits were calculated as follows:

the impurity limit is the acceptable daily intake of the impurity (i.e., PDE value)/maximum daily dosage of the drug.

PDE (NOEL) × body weight/(F1 × F2 × F3 × F4 × F5)

Wherein, the NOEL of the mouse is 2.88 mg/kg/day; f1-12, the human dose was extrapolated from the mouse dose; f2 ═ 10, see FDA ICH-Q3C guidelines; f3 is 10, and the experimental period does not exceed 10 days; f4 ═ 1, no serious toxic reaction was considered to be found; f5 ═ 1; regulating body weight to 50 kg; the calculation results are as follows:

PDE＝2.88mg/kg(NOEL)×50/(12×10×10×1×1)＝0.12mg；

the impurity limit is 0.12mg/2g (the maximum daily dose of the compound in a human body is determined to be 2g according to clinical tests and the like), 60ppm is 60 mg/kg.

Example 3: genotoxicity test of the Compound of formula (IV)

The method of example 1 was used except that the test article was replaced with the compound of formula (IV), and the results showed that the compound exhibited no genotoxicity at the doses of 50, 200, 800, 2000, 5000. mu.g/dish.

EXAMPLE 4 lyophilized preparation for injection

The formulation of the lyophilized formulation for injection is as follows:

6000g of disodium L-ornidazole phosphate

2700g of citric acid 1140-

Adding water for injection to 60L

30000 pieces of the extract were prepared.

The preparation method of the prescription comprises the following steps:

adding a part of citric acid into injection water with the temperature below 20 ℃ and the total volume of the prescription of 80%, stirring until the citric acid is completely dissolved, adding the levo-ornidazole disodium phosphate according to the prescription amount, stirring until the levo-ornidazole disodium phosphate is completely dissolved, and adjusting the pH value of a preparation solution to 4.0-6.0. And then adding cooled injection water into the residual citric acid to prepare a solution with the concentration of 20g/100mL to adjust the pH of the prepared solution to 4.5-5.5. Adding water for injection (below 20 deg.C) according to the density of the medicinal liquid (1.063g/ml) to the total amount of the prescription. Stirring for about 15min, and filtering the prepared medicinal liquid with filters (0.2 μm/0.22 μm; nylon 66) of A05NF2PH4 and KA3NFP 1.

Sending the filtered liquid medicine into a freeze-drying box when the temperature of the silicone oil is reduced to 0 ℃, keeping for 0.5 hour, and keeping for 1.0 hour when the temperature of the silicone oil is reduced to-50 ℃; heating to-20 deg.C, and maintaining for 3.0 h; cooling to-50 deg.C, and maintaining for 3.0 h. The vacuum pump is opened, the vacuum is pumped to 200 mu bar, the temperature is raised to-20 ℃ within 1.0h, and the temperature is maintained for 16.0 h. Heating to-15 deg.C for 5min, and maintaining for 6.0 h; heating to-10 deg.C for 5min, and maintaining for 1.0 h; heating to 0 deg.C for 10min, and maintaining for 1.0 h; heating to 10 deg.C for 10min, and maintaining for 1.0 h; heating to 25 deg.C for 15min, and maintaining for 7.0 h; extreme vacuum was applied at 25 ℃ and continued for 13.0 h. Performing a pressure rise test (the pressure rise qualification standard is less than or equal to 15 μ bar/min), after the freeze-drying is finished, filling nitrogen into the box body to break vacuum (the vacuum control range is 850mbar-900mbar), and obtaining the freeze-dried preparation.

The above preparation method is repeated, and 3 batches of finished products are obtained by co-production and are marked as S1, S2 and S3, and the immediate test results are shown in Table 9.

TABLE 9 inspection results of the finished products

The accelerated stability of the S1, S2 and S3 products was tested (test conditions: temperature 25 ℃. + -. 2 ℃ C., humidity 60% RH. + -. 5% RH), and the test results are shown in tables 10-12.

TABLE 10S1 test results for accelerated stability of finished products

TABLE 11S2 test results for accelerated stability of finished product

TABLE 12S3 test results for accelerated stability of finished products

The long-term stability of the finished products S1, S2 and S3 was examined (long-term stability test condition: 5 ℃. + -. 3 ℃) and the examination results are shown in tables 13-15.

TABLE 13S1 Long term stability test results for finished products

TABLE 14S2 test results for Long-term stability of finished product

TABLE 15S3 Long term stability test results for finished products

The experimental result shows that the freeze-dried preparation has good medication safety and stability.

The detection method of each substance was as follows:

the instrument comprises the following steps: liquid chromatography tandem mass spectrometer, model 1290LC-6470LC/TQ, Agilent technologies, Inc.

(1) Chromatographic conditions

A chromatographic column: svea Core Shell C18 (100 mm. times.4.6 mm. times.2.6 μm)

Mobile phase: a (10mmol ammonium formate aqueous solution) B (methanol)

Flow rate: 0.6mL/min

Sample introduction volume: 5 μ L

Gradient program:

time (min)	Mobile phase a (% by volume)	Mobile phase B (% by volume)
			0.00	90	10
0.20	90	10
			1.00	80	20
2.50	80	20
			4.00	70	30
5.50	70	30
			6.00	10	90
8.00	10	90
			8.01	90	10
10.00	90	10

(2) Conditions of Mass Spectrometry

Type of ion source: AJS ESI ion source

Collision gas (N)₂) Flow rate: 8L/min

Sheath gas (N)₂) Flow rate: 11L/min

Temperature of sheath gas: 350 deg.C

Spraying voltage: 3500V

Nozzle voltage: 500V

EMV gain: 200V

The collection mode is as follows: multiple reactive ion monitoring (MRM).

(3) Preparation of blank solution

Blank solution: i.e. pure water.

(4) Control solution: precisely weighing 10mg of 2-methyl-5-nitroimidazole, the compound of formula (II) and the compound of formula (III) as reference substances, respectively placing the reference substances in a10 mL volumetric flask, and fixing the volume to the scale with blank solution to obtain reference substance stock solution. From these, 0.1mL of the stock solutions of the control samples were precisely measured in 10mL volumetric flasks, and the blank solution was added to the volume to the scale as an intermediate solution of the control sample (i.e., 10. mu.g/mL). From the medium, 5mL of the solution was precisely measured in a 50mL volumetric flask, and the volume was adjusted to the scale with a blank solution as a control working solution (i.e., 1. mu.g/mL). Precisely measuring 0.6mL from the medium into a10 mL volumetric flask, and fixing the volume to the scale with the blank solution to obtain a reference substance solution of 60 ng/mL.

(5) System applicability solution: precisely weighing 10mg (calculated by levo ornidazole phosphate disodium) of a test sample in a10 mL volumetric flask, and fixing the volume of a blank solution to a scale. Taking 1mL of the solution into a10 mL volumetric flask, adding a compound (60mg/kg) of the formula (II), a compound (60mg/kg) of the formula (III) and a reference substance of 2-methyl-5-nitroimidazole (60mg/kg) with the limit concentration (taking 0.6mL of the reference substance working solution under the item (4) into the volumetric flask), and diluting the blank solution to a constant volume (namely 60 ng/mL).

(6) Preparing a test solution: precisely weighing 10mg (calculated by L-ornidazole phosphate disodium) of a sample in a10 mL volumetric flask, and fixing the volume to a scale by using a blank solution to obtain the product.

(7) Preparing a mixed test solution: precisely weighing 10mg of a test sample (calculated by levo ornidazole phosphate disodium) into a10 mL volumetric flask, adding a compound (60mg/kg) with a limit concentration (0.6 mL of a reference working solution under the item of 3.4) in the formula (II), a compound (60mg/kg) in the formula (III) and a reference substance of 2-methyl-5-nitroimidazole (60mg/kg), and fixing the volume of a blank solution to a scale (namely 60 ng/mL).

(8) Limitation: the residual quantity of the compound of formula (II), the compound of formula (III) and the 2-methyl-5-nitroimidazole reference substance in the product is not more than 60 mg/kg.

In the above experimental results, the detection limit concentration of each substance is 0.1ng/mL, and the content Relative Standard Deviation (RSD) meets the acceptable standard.

EXAMPLE 5 lyophilized preparation for injection

The formulation of the lyophilized formulation for injection is as follows:

6000g of disodium L-ornidazole phosphate

1660g or 1740g of citric acid

Adding water for injection to 60L

30000 pieces of the extract were prepared.

The preparation method of the prescription comprises the following steps:

1440g of citric acid is added into injection water with the temperature below 20 ℃ and the total volume of the prescription of 80 percent, the stirring speed is 500-1000 rpm, the stirring is carried out for at least 10min, after the citric acid is completely dissolved, the prescription amount of the disodium levoornidazole phosphate is added, and the stirring is carried out for at least 10min until the disodium levoornidazole phosphate is completely dissolved. Adding appropriate amount of the rest citric acid into cooled injectable water to obtain solution with concentration of 20g/100mL, and adjusting pH of the solution to 5.1 (total amount of citric acid 1660g) or 5.0 (total amount of citric acid 1740 g). Adding injectable water (below 20 deg.C) to 60L, stirring for about 15min, and pre-filtering with filter membrane of NRG29325 (PALL, 0.2 μm pore diameter, nylon 66).

EXAMPLE 6 lyophilized preparation for injection

Prescription of lyophilized preparation for single injection:

l-ornidazole disodium phosphate 200mg

Citric acid 38-90mg

Adding water for injection to 2mL

The pH value is 4.5-5.5.

Referring to the lyophilization preparation process and detection method in example 4, 12 batches of lyophilized formulations were prepared.

(1) The content of each substance in the lyophilized preparation was measured in real time, and the measurement results are shown in table 16.

TABLE 16 results of sample examination

In the above experimental results, the detection limit concentration of each substance is 0.1ng/mL, and the content Relative Standard Deviation (RSD) meets the acceptable standard.

The other indexes of the 12 batches of freeze-dried preparations all meet the requirements of finished products shown in the table 9.

Example 7 genotoxicity test

The samples of examples 4-6 were tested according to the genotoxicity test method of example 1-2, and the results showed that: examples 4-6 samples of lyophilized formulations were not genotoxic.

EXAMPLE 8 Ornidazole injection

The prescription of the ornidazole injection is as follows:

ornidazole 500mg

0.9g of ethanol

Propylene glycol 1mL

Water for injection was added to 3 mL.

The preparation process of the ornidazole injection comprises the following steps: mixing the ornidazole, the ethanol, the propylene glycol and the water for injection according to the above dosage to prepare the ornidazole injection. According to the substance detection method in example 4, the ornidazole injection of this example contains less than 60mg/kg of the compound of formula (III) and less than 2100mg/kg of the compound of formula (III).

The samples of example 8 were tested according to the genotoxicity test method of example 1-2, and the results showed that: the injection of example 8 has no genotoxicity.

Example 9 clinical drug efficacy test

The purpose of the test is as follows: the safety and effectiveness of the product in treating pelvic anaerobic bacteria infection under two dosing schemes of qd (once-a-day dosing) and q12h (twice-a-day dosing, namely once-a-12 h dosing) are evaluated by taking the levoornidazole sodium chloride injection as a control.

Grouping medical records:

the study adopts a random double-blind design, 146 female patients aged 18 to 65 years are randomly enrolled, the subjects are not used with effective anti-anaerobe medicaments for 72 hours before enrollment, and the patients who need to be treated by injection and are infected by the gynecological pelvic cavity comprising anaerobes: women in the sexual activity stage and patients with STI (sexually transmitted infection) have no other causes if the following conditions are met: 1) uterine tenderness or adnexal tenderness or cervical tenderness; 2) at the same time, at least one additional condition is met: the body temperature (axillary temperature) is more than or equal to 37.8 ℃; cervical or vaginal purulent secretions; the vaginal secretion is detected to have leukocytosis (the white blood cell count under each high power microscope is more than or equal to 15); the conventional white blood cell count of the blood is more than or equal to 10 multiplied by 109/L; the C-reactive protein is elevated.

The tests were divided into three groups, test 1 (qd), test 2 (q12 h) and control. 50 cases in the test 1 group, 47 cases in the test 2 group and 49 cases in the control group; 10 cases of shedding in the test process, the shedding rate is 6.85%. 144 cases of FAS panel were included, 49 cases in trial 1 group, 46 cases in trial 2 group, and 49 cases in control group; the PPS sets 131 are included, wherein 44 cases of a test 1 group, 42 cases of a test 2 group and 45 cases of a control group; 144 cases of the SS group were included, 49 cases in the test 1 group, 46 cases in the test 2 group, and 49 cases in the control group. The general data condition, the past medical history and the accompanying diseases of the subject, physical examination and vital sign analysis, gynecological examination, total scores of symptom signs and baseline anaerobe positive rate, laboratory examination of the subject and comparison difference between three groups of treatment compliance have no statistical significance (P is more than 0.05).

The administration scheme is as follows:

test drugs, dosages and methods of administration: lyophilized powder for injection of disodium levoornidazole phosphate was prepared according to example 5, with a specification of 0.2 g/ampoule (calculated as disodium levoornidazole phosphate), intravenously instilled, test 1 group: 8 pieces each time, and every 24 h; test 2 groups: 4 pieces each time, and every 12 h.

Control drugs, doses and methods of administration: injection of sodium chloride and levo-ornidazole100 ml: 0.5g of ornidazole: 0.83g of sodium chloride, and 100ml of the solution is added by intravenous drip once every 12 h.

In the infusion treatment process, levofloxacin hydrochloride and sodium chloride injection is used as basic treatment medicine, and the using amount is 0.5g per time and once a day according to the medicine specification. All the subjects in the group are changed into oral medication after receiving intravenous infusion therapy for 7 days, and the dosage of the levofloxacin hydrochloride capsule is 0.1g (1 granule) per time, and the levofloxacin hydrochloride capsule is taken once every morning and evening; the ornidazole capsule is administered in an amount of 500mg (2 capsules) each time, once a day, in the morning and at night, for 7 days continuously, and for a total treatment period of 14 days. During the treatment period, follow-up visits are carried out on the 3 rd day of treatment, the 7 th day of treatment, the 14 +/-2 th day of treatment and the 7 +/-2 th day after the treatment is finished, and the combined medication, vital signs, effectiveness and safety items of the subjects are checked and recorded in detail.

Basic drugs, dosages and methods of administration: levofloxacin hydrochloride sodium chloride injection100 ml: levofloxacin hydrochloride (as C)₁₈H₂₀FN₃O₄Calculated) 0.5g and 0.9g of sodium chloride, and the mixture is intravenously dripped with 100ml of the mixture once a day.

Levofloxacin hydrochloride capsuleWith C₁₈H₂₀FN₃O₄It is administered orally at a dose of 0.1g (1 granule) per adult, and 2 times daily (taken in the morning and evening).

Ornidazole capsule0.25g, orally administered, 500mg (2 capsules) per adult, 2 times daily (taken once in the morning and evening).

And (3) test results:

the results of the treatment are shown in figure 1. As can be seen from fig. 1, the main efficacy indexes are: the curative ratio of the PPS is 90.91 percent in the test 1 group, 85.71 percent and 80 percent in the test 2 group and the control group, 5.2 percent of the curative ratio of the test 1 group is improved than that of the test 2 group, and 10.91 percent of the curative ratio of the PPS is improved than that of the control group. The FAS set cure rate in the test 1 group is 83.67%, the cure rate in the test 2 group and the control group is 82.61% and 77.55%, the cure rate in the test 1 group is improved by 1.06% compared with the test 2 group, and the cure rate in the control group is improved by 6.12%. Therefore, there was a tendency for the qd group and q12h group to have improved efficacy.

The incidence rate of adverse reactions of the control group is 38.78%; the incidence rate of the test 1 group is 18.37%; the incidence in trial 2 group was 21.74%. That is, the incidence of adverse reactions was reduced by 20.41% in the test 1 group and by 3.37% in the control group relative to the test 2 group.

The test result shows that: the preparation of the invention is safe and well tolerated by intravenous drip in a q12h or qd mode for 7 consecutive days without serious adverse reactions. The safety tolerance of qd group is better than q12h group, C_maxSignificantly higher than the q12h group, while the accumulation factor is significantly smaller than the q12h group. The results show that qd administration mode can improve the peak concentration of the drug without increasing the incidence rate of adverse reactions under the condition of the same daily dosage of administration, thereby leading C_maxThe MIC ratio is increased, and for the nitroimidazole antibacterial drug levoornidazole with concentration dependence, the qd administration mode is favorable for reaching the PK/Pharmacodynamics (PD) target value to improve the bactericidal activity, possibly increasing the clinical curative effect of anti-infection treatment, reducing the occurrence of bacterial drug resistance and improving the patient compliance. The injection levoornidazole disodium phosphate is used as the sodium salt of levorotatory isomer phosphate derivative of ornidazole of a third-generation nitroimidazole antibacterial, has good anti-anaerobic bacteria and anti-protozoan (such as trichomonas) infection effects, and has obviously lower adverse reaction than ornidazole. The product is expected to replace ornidazole in clinic, so as to increase the clinical curative effect of anti-infection treatment, reduce the occurrence of bacterial drug resistance and improve the compliance of patients.

The above description has been made of exemplary embodiments of the present invention. However, the scope of the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement and the like made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

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Preparation containing ornidazole compound and preparation method and application thereof

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