WO2021135980A1 - 能有效溶解奥硝唑或左奥硝唑的溶剂体系及其应用 - Google Patents

能有效溶解奥硝唑或左奥硝唑的溶剂体系及其应用 Download PDF

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WO2021135980A1
WO2021135980A1 PCT/CN2020/137482 CN2020137482W WO2021135980A1 WO 2021135980 A1 WO2021135980 A1 WO 2021135980A1 CN 2020137482 W CN2020137482 W CN 2020137482W WO 2021135980 A1 WO2021135980 A1 WO 2021135980A1
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ornidazole
polyethylene glycol
levornidazole
injection
solution
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PCT/CN2020/137482
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French (fr)
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刘红
潘红春
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重庆典索医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • the invention relates to the technical field of pharmaceutical preparations, in particular to a solvent system that can effectively dissolve ornidazole or levornidazole and its application, and provides a safer ornidazole injection or levornidazole injection and a preparation method thereof .
  • Ornidazole and Levoornidazole are the third-generation nitroimidazole broad-spectrum anti-anaerobic and antiprotozoal drugs after metronidazole and tinidazole. They have good curative effect, good tolerability, and good tissue permeability. It has the advantages of wide distribution in the body and long biological half-life. Therefore, ornidazole and levornidazole are the drugs of choice for the prevention and treatment of anaerobic infections.
  • the existing marketed ornidazole injections include small-volume injections and large-volume injections, while levornidazole injections have only large-volume injections.
  • the existing ornidazole injection and levornidazole injection both have the following defects:
  • Ornidazole small-volume injection and large-volume injection, and levornidazole large-volume injection using water for injection as the solvent all have the following: 1The defect of high impurity content.
  • the current standard stipulates that the impurity limits of ornidazole injection and levornidazole injection are both higher.
  • the single impurity limit of ornidazole injection is 0.5%, and the total impurity limit is 1.0%; the impurity limit of levornidazole injection is 1.0%, the total impurity limit is 1.5%.
  • 2 The defect of low pH.
  • CN103505411A uses the thickening and suspending effects of long-chain polyethylene glycol 4000 to increase the physical stability of the small-volume ornidazole injection water system, but its preparation has undergone high-temperature sterilization and pH adjustment (2.5-4.5) At the same time, long-chain polyethylene glycol 4000 is often used as an excipient for solid preparations. Using it as an excipient for injection purposes will bring potential safety risks to the preparation. Therefore, although these technologies solve the technical problem of the solubility of ornidazole injection or levornidazole injection in water, it is still difficult to overcome the above-mentioned shortcomings (1) the technical problems of high impurity content and strong vascular irritation. .
  • CN110538144A uses 5-10mmol/L trisodium phosphate solution as dilute lye, hoping to be the product partner of ornidazole injection or levornidazole injection, specially used for neutralizing the low pH value of ornidazole injection during clinical administration. Maintain the pH value of ornidazole injection in the range of 5.0 to 6.0 during infusion to relieve the pain and cause vasculitis.
  • this technology does not help to reduce the impurity content and improve the stability of ornidazole injection. Make the clinical medication of ornidazole injection more complicated.
  • CN103006554B controls the impurity content by controlling the proportion of ethanol from 60% to 100%, and at the same time overcomes the above-mentioned drawbacks (1) and (2), such as high impurity content, acidic pH, and excessive use of propylene glycol.
  • CN1040135571B uses glycerin and ethanol to solubilize ornidazole together, and successfully overcomes the above-mentioned defects (1) and (2), such as high impurity content, acidic pH value, and over-limit use of propylene glycol.
  • Nitrazole is easy to crystallize at low temperature (below 12°C), which brings new problems to the storage and clinical use of the preparation.
  • CN107496351A uses absolute ethanol and polyethylene glycol-15-hydroxystearate (HS 15) to solubilize ornidazole or levornidazole, successfully overcoming the impurity content in the above-mentioned defects (1) and (2)
  • HS 15 polyethylene glycol-15-hydroxystearate
  • the solubilization mechanism of this technology is micellar theory.
  • Ornidazole may form with polyethylene glycol-15-hydroxystearate in plasma.
  • the micelles change its pharmaceutical behavior in the body, which brings uncertainty to the efficacy and safety of ornidazole injection.
  • CN107041868A adds a trace amount of acetic acid-sodium acetate aqueous solution to the propylene glycol-ethanol organic system to improve the pH value of clinical infusion, thereby improving the infusion irritation.
  • the propylene glycol-ethanol system is more sensitive to water, and trace water is extremely easy This leads to an increase in impurities. Therefore, it is difficult for this technology to balance the problem of irritation and increase in impurities.
  • CN103989640B adopts polyethylene glycol-15-hydroxystearate and ⁇ -cyclodextrin compound to solubilize ornidazole, adds excipient mannitol, and prepares it into a freeze-dried preparation, which solubilizes ornidazole
  • the mechanism exists in the micellar theory of polyethylene glycol-15-hydroxystearate, the inclusion theory of ⁇ -cyclodextrin and even the combined effect of the two, which will increase the complexity of the pharmaceutical behavior of ornidazole in vivo.
  • the efficacy and safety of its injection bring uncertainty, and in addition, ordinary ⁇ -cyclodextrin is not suitable for use as an excipient for injection purposes.
  • the purpose of the present invention is to provide a solvent system and application that can effectively dissolve ornidazole or levornidazole, and at the same time solve the problem of impurity growth control, low pH, and propylene glycol in the prior art.
  • Many technical issues such as excessive use, easy crystallization at low temperature, drug-derived disulfiram reaction, production safety, etc., in order to meet the needs of clinical safe medication to the greatest extent and increase patient medication compliance.
  • a solvent system capable of effectively dissolving ornidazole or levornidazole is characterized in that the active ingredient is ornidazole or levornidazole, and the solvent system is an organic solvent mixed with short-chain polyethylene glycol and propylene glycol.
  • the mixed mass fraction ratio of short-chain polyethylene glycol and propylene glycol in the solvent system is 30-100:0-70.
  • the mixing mass fraction ratio is 60-90:40-10.
  • the short-chain polyethylene glycol is selected from one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600. One or both of polyethylene glycol 300 and polyethylene glycol 400 are preferred.
  • the present invention provides an injection, including two specifications:
  • Active ingredient is ornidazole or levornidazole 0.5g, dissolved in an organic solvent and dilute to 1.0ml ⁇ 2.0ml; preferably dissolved in an organic solvent and dilute to 1.5ml;
  • the active ingredient is ornidazole or levornidazole 1.0g, dissolved in an organic solvent and dilute to 2.0ml ⁇ 4.0ml; preferably dissolved in an organic solvent and dilute to 3.0ml;
  • the organic solvent is a mixture of short-chain polyethylene glycol and propylene glycol in a mass fraction ratio of 30-100:0-70.
  • the organic solvent is short-chain polyethylene glycol and propylene glycol in a mixed mass fraction ratio of 60-90:40-10.
  • the short-chain polyethylene glycol is selected from one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600. One or both of polyethylene glycol 300 and polyethylene glycol 400 are preferred.
  • the present invention also provides a preparation method of injection, which is prepared from the above-mentioned active ingredients and organic solvent.
  • the preparation method includes the following steps:
  • step 2) Depyrogenation: the solution 1 obtained in step 1) is subjected to depyrogenation treatment;
  • step 3 the solution 2 obtained in step 2) is treated with a 0.20 ⁇ m microporous membrane to obtain solution 3;
  • step 3 The solution 3 obtained in step 3) is tested for intermediate products, and then filled into a glass or plastic container and sealed;
  • Sterilization Sterilize the potting solution obtained in step 4) under sterilization conditions with an F 0 value greater than 8 (preferably greater than 12), cool, light check, and package; the F 0 value is preferably greater than 12.
  • step 2) is to add medicinal charcoal to the solution 1 obtained in step 1), heat and stir at 20 to 80°C for 10 to 120 minutes, filter and decarbonize, and the obtained effluent is solution 2; alternatively, step 1)
  • the obtained solution 1 is treated with an ultrafiltration membrane device of suitable molecular weight, and the obtained effluent is solution 2; or, in the Class A clean zone, pyrogen qualified raw and auxiliary materials are used, and the prepared solution 1 is directly processed without depyrogenation treatment.
  • solution 2 is to add medicinal charcoal to the solution 1 obtained in step 1), heat and stir at 20 to 80°C for 10 to 120 minutes, filter and decarbonize, and the obtained effluent is solution 2; alternatively, step 1)
  • the obtained solution 1 is treated with an ultrafiltration membrane device of suitable molecular weight, and the obtained effluent is solution 2; or, in the Class A clean zone, pyrogen qualified raw and auxiliary materials are used, and the prepared solution 1 is directly processed without depyrogenation treatment.
  • solution 2 is to add medicinal charcoal to
  • the present invention has the following beneficial effects at the same time:
  • the present invention provides a solvent system that can effectively dissolve ornidazole or levornidazole, so that the solvent consumption of ornidazole injection or levornidazole injection is significantly reduced.
  • ornidazole or levornidazole injections with good performance of 1.5ml:0.5g and 3.0ml:1.0g can be obtained, which is 3ml compared with the marketed ornidazole injection specifications. : 0.5g, 6ml: 1.0g, 5ml: 0.25g, 5ml: 0.5g, 10ml: 0.5g, etc., which can greatly reduce the amount of solvent and increase the safety of medication.
  • the present invention provides an ornidazole injection or levornidazole injection with suitable pH.
  • the injection prepared by the invention can maintain the clinical infusion pH value of 5-7, which can greatly reduce clinical infusion irritation and phlebitis compared with the low pH value of the marketed aqueous ornidazole injection and levornidazole injection The possibility of occurrence.
  • the present invention provides an ornidazole injection or levornidazole injection that is not easy to crystallize at low temperature.
  • the optimized specifications of 1.5ml:0.5g and 3.0ml:1.0g of the present invention will not crystallize when stored in a low temperature environment of 2 ⁇ 8°C for a long time, while the propylene glycol-ethanol system of the same concentration is easy to crystallize, which can significantly increase storage and transportation stability Sex and convenience of clinical medication.
  • the present invention provides an ornidazole injection or levornidazole injection with extremely low impurity content.
  • the ornidazole or levornidazole injection prepared by the invention has few impurities, and the contents of impurity II, impurity III and total impurities are significantly lower than the original ornidazole injection It is much lower than water-based injections, and has good storage stability and compatibility stability.
  • the present invention provides an ethanol-free ornidazole injection or levornidazole injection, which can effectively avoid the occurrence of drug-induced disulfiram reactions in clinical medications, and is especially suitable for infants, young children, the elderly, and the infirm. Medication for patients with sensitive physique.
  • the present invention provides an ornidazole injection or levornidazole injection with a greatly reduced consumption of propylene glycol.
  • the injection prepared by the present invention according to the specification of 4ml:1.0g and propylene glycol accounts for 50% of the solvent, the maximum daily consumption of propylene glycol for an adult (70kg) is 29.6mg/kg body weight; according to the optimized specification of 3ml:1.0g and propylene glycol accounts for the solvent In terms of 40% and 20%, the maximum daily dosage of propylene glycol for adults (70kg) is 17.76mg/kg body weight and 8.88mg/kg body weight, far lower than The original dosage of 40mg/kg body weight is in line with the safe use range of 25mg/kg body weight per day recommended by WHO, which can eliminate the worry of ultra-safe range use.
  • the present invention provides an ornidazole injection or levornidazole injection with a high level of sterility assurance.
  • the injection prepared by the invention can be sterilized under the condition that the F 0 value is greater than 12, which can greatly reduce the risk of unqualified sterility inspection items.
  • the present invention provides an ornidazole injection or levornidazole injection that does not change the pharmaceutical behavior in the body. Utilize the invention and The rat plasma AUC 0-t of the ornidazole injection prepared by the original prescription is similar, and the drug-time curve similarity factor f2 is as high as 95%.
  • Figure 1 is the structural formula of impurity I
  • Figure 2 is the structural formula of impurity II
  • Figure 3 is the structural formula of impurity III
  • Figure 4 is a chromatogram of Example 47
  • Figure 5 is a chromatogram of Example 51
  • Figure 6 is a chromatogram of Comparative Example 25
  • Figure 7 is a chromatogram of Comparative Example 26
  • Figure 8 is a chromatogram of Comparative Example 28
  • Figure 9 is a chromatogram of Comparative Example 29.
  • Figure 10 is a chromatogram of Comparative Example 31
  • Figure 11 is a chromatogram of Comparative Example 32.
  • the present invention has gone through multiple research stages such as dissolution system establishment, impurity control test, low-temperature crystallization test, stability test, irritation test, hemolytic test, and in vivo pharmaceutical behavior evaluation. Goal and accomplish.
  • Test Example 1 Establishment of an effective dissolution system
  • One of the objectives of the present invention is to establish a solvent system that can effectively dissolve ornidazole or levornidazole, and significantly reduce the amount of solvent.
  • the inventors tested pure water system, pure organic solvent system, water and organic solvent mixed system, water and surfactant mixed system, organic solvent and surfactant mixed system, etc. The results showed that the pure water system It is difficult to effectively reduce the volume of the formulation.
  • the volume of the solvent for dissolving 0.25g ornidazole is not less than 5ml; the remaining systems can reduce the volume of the formulation to varying degrees.
  • the solvent required for g ornidazole can be as low as 0.5ml.
  • mixed solvents have a synergistic effect on the dissolution of ornidazole, and the ratio of mixed solvents has a significant effect on the synergy.
  • the order of the synergy of some mixed solvents is: PEG200+ethanol, propylene glycol+ethanol, PEG400+ethanol, PEG400+propylene glycol, two Methylformamide+ethanol, PEG600+ethanol, glycerol+ethanol, etc. Therefore, the present invention focuses on selecting one or more mixed organic solvent systems such as short-chain polyethylene glycol, propylene glycol, ethanol, dimethylformamide, etc., to optimize the dissolution system of ornidazole and levornidazole.
  • the preferred solvent system of the present invention is PEG300-propylene glycol, PEG400-propylene glycol, PEG300-ethanol, PEG400-ethanol, and a mixed system of PEG300 and/or PEG400 and propylene glycol and/or ethanol.
  • the original propylene glycol-ethanol mixed solvent dissolves ornidazole and levornidazole in an environment of 30° C. is higher than that of the system of the present invention.
  • Test process use different proportions of PEG300-propylene glycol, PEG400-propylene glycol, PEG300-ethanol, PEG400-ethanol, PEG400-ethanol+propylene glycol, PEG300-ethanol+propylene glycol and the original propylene glycol-ethanol system 1ml, 1.5ml and 2ml to dissolve the Austrian Nitazole or Levoornidazole 0.5g, the solution was placed in a vial and sealed, and placed in a low temperature environment of 2 ⁇ 8°C for 30 days, and the crystallization of the drug was observed.
  • the amount of each component is parts by weight, the same below.
  • Test example 2 Impurity control test
  • the second objective of the present invention is to find a technical solution that can effectively control the number and content of impurities.
  • the inventors tested water systems (such as pure water systems, water and organic solvent mixed systems, water and surfactant mixed systems, etc.) and organic pure systems (such as organic solvent systems, organic solvents and surfactants).
  • water systems such as pure water systems, water and organic solvent mixed systems, water and surfactant mixed systems, etc.
  • organic pure systems such as organic solvent systems, organic solvents and surfactants.
  • the influence of the pH, acid-base substance types, preparation sequence, preparation temperature, sterilization temperature, antioxidants, residual oxygen concentration, etc. of mixed system, etc. on the impurity types and impurity content of ornidazole injection and levornidazole injection.
  • Sample preparation steps Weigh the prescribed amount of organic solvent, mix, add ornidazole or levornidazole, stir to dissolve at a certain temperature, constant volume, separate packaging, seal, sterilize at 121°C for 12 minutes, and cool to get it. Same below.
  • Impurity detection method take an appropriate amount of sample, dilute it with mobile phase to ornidazole or levornidazole concentration of about 1mg/ml, as the test solution; accurately measure 1ml of the test solution and place it in a 100ml measuring bottle. Dilute the mobile phase to the mark, shake it up, and use it as a control solution. Precisely measure 20 ⁇ l each of the test solution and the control solution, inject into the liquid chromatograph, and record the chromatogram.
  • the mobile phase is methanol-water (20:80), the detection wavelength is 318nm, and the chromatographic column is a C18 column. Calculate the content of each impurity peak according to the self-control method. Same below.
  • the chromatograms of Examples 47 and 51 and Comparative Examples 25, 26, 28, 29, 31 and 32 are shown in Figures 4-11.
  • the present invention can significantly reduce the number and content of impurities, and the impurity content is far below the 0.1% limit required by ICH, and it is difficult for the water system to control the number of impurities and reduce the impurity content.
  • the present invention is far lower than the water-based system.
  • Test example 3 pH value control test
  • the third objective of the present invention is to find a technical solution that can effectively overcome the low pH value.
  • the inventors tested the influence of the pH control of the water system and the organic pure system on the dissolution, impurity types, and impurity content of ornidazole and levornidazole. The results show that the aqueous system is difficult to increase the pH value of ornidazole injection and levornidazole injection solution, resulting in the clinical infusion pH is still low; pure organic system does not need to add acidic components to effectively control the increase in impurity content. Maintain an appropriate clinical infusion pH value of 5-7.
  • the present invention does not need to add a pH regulator, even if the infusion pH meets the human body tolerable pH value of 4-9, the present invention can maintain the human body’s well-tolerated clinical infusion pH value of 5-7 At the same time, it can effectively control the impurity level far below the limit of no more than 0.1% required by ICH, especially the PEG300/400-ethanol system.
  • the pH value of the aqueous system must be adjusted to 3.0-3.5 to control the relatively low impurity level, but it still far exceeds the 0.1% limit required by ICH.
  • the present invention achieves unexpected technical effects, which can effectively control the level of impurities and the number of impurities, especially the control of the content of potentially genotoxic impurity III, and can effectively solve the irritation and irritation caused by low pH infusion.
  • Phlebitis has a problem. This is difficult to achieve with the existing technology.
  • Test Example 4 High temperature sterilization test
  • the fourth objective of the present invention is to find a technical solution with high sterility assurance level (F0 value ⁇ 12) that can withstand over-sterilization.
  • the inventors conducted tests on the degree of resistance to high temperature sterilization of the water system and the organic pure system of ornidazole or levornidazole injection. The results show that the water-containing system has poor tolerance to high temperature sterilization, and the content and number of impurities increase significantly; while the present invention has good tolerance to high temperature sterilization.
  • the inventors surprisingly found that the ability of the present invention to withstand high temperature sterilization is significantly higher than the prior art, especially better than the water system.
  • swelling degree (the diameter of rat tail after injection-the diameter of rat tail before injection)/the diameter of rat tail before injection ⁇ 100%.
  • the inventors surprisingly found that the vascular irritation of the present invention is significantly lower than that of the propylene glycol-ethanol system.
  • mice Take SD rats into random groups (about 250g, male rats), with 3 rats in each group. Fasting for 12 hours before the experiment, inject PEG400-ethanol, PEG400-propylene glycol, propylene glycol-ethanol system ornidazole injection into the tail vein at a dose of 20mg/kg and a concentration of 5mg/ml (dilute with normal saline before use ).
  • the time of orbital blood collection after tail vein administration is 1min, 5min, 15min, 30min, 1h, 3h, 6h, 9h, 12h, 24h.
  • the blood volume is about 0.5ml and put into 50 ⁇ l centrifuge tube treated with heparin sodium. Let it stand for 30min, 8000r/min, centrifuge for 10min, take the upper plasma in a clean 0.5ml centrifuge tube, and store it in a refrigerator at -20°C for later use.
  • Sample processing Take 100 ⁇ l of plasma sample in a 1.5ml centrifuge tube, add 10 ⁇ l of internal standard solution (40 ⁇ g/ml), vortex for 3min. Add 200 ⁇ l of methanol/isopropanol (1:1) extract, vortex for 3min, centrifuge at 12000r/min for 10min, take 20 ⁇ l of supernatant for HPLC determination, chromatographic conditions are the same as those in Examples 47-54.

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Abstract

一种能有效溶解奥硝唑或左奥硝唑的溶剂体系及其应用，活性成分为奥硝唑或左奥硝唑，所述溶剂体系为短链聚乙二醇和丙二醇混合的有机溶剂；所述短链聚乙二醇优选为聚乙二醇300或/和聚乙二醇400。所述溶剂体系可用于奥硝唑注射液或左奥硝唑注射液的制备。该奥硝唑注射液或左奥硝唑注射液同时兼具处方更简单、生产更安全、制剂更稳定、溶剂量更少、杂质(尤其基因毒性杂质)含量更低、低温不易结晶、静脉炎发生率低、无低pH输注刺激性、更适宜双硫仑反应敏感患者使用等特点的制剂优势，确保临床用药更安全，患者用药顺应性更良好。

Description

能有效溶解奥硝唑或左奥硝唑的溶剂体系及其应用 技术领域
本发明涉及药物制剂技术领域，特别涉及能有效溶解奥硝唑或左奥硝唑的溶剂体系及其应用，提供一种更安全的奥硝唑注射液或左奥硝唑注射液及其制备方法。
背景技术
奥硝唑和左奥硝唑是继甲硝唑、替硝唑之后的第三代硝基咪唑类广谱抗厌氧菌及抗原虫感染的药物，具有疗效好、耐受性好、组织渗透性好、体内分布广、生物半衰期长等优点，因此，奥硝唑和左奥硝唑是预防和治疗厌氧菌感染的首选药。
目前，现有已上市奥硝唑注射剂有小容量注射液和大容量注射液，左奥硝唑注射剂仅有大容量注射液。然而，现有奥硝唑注射剂和左奥硝唑注射剂均存在如下缺陷：
(1)以注射用水为溶媒的奥硝唑小容量注射液和大容量注射液以及左奥硝唑大容量注射液均存在：①杂质含量高的缺陷。现行标准规定奥硝唑注射剂和左奥硝唑注射剂的杂质限度均较高，奥硝唑注射液的单个杂质限度为0.5％，总杂限度为1.0％；左奥硝唑注射剂的杂质III限度为1.0％，总杂限度为1.5％。②pH值低的缺陷。在高温灭菌过程中奥硝唑或左奥硝唑水溶液的杂质随溶液pH值增加而快速增加，通常需要维持较低pH值(pH值3.0～3.5)。③血管刺激性强的缺陷。由于奥硝唑水性注射剂的溶液需要控制pH值3.0～3.5，已超出人体耐受pH值4.0～9.0的范围，因而，临床应用常会产生较强烈血管刺激性，同时还会增加输注疼痛及静脉炎的发生率，据统计显示，奥硝唑注射液引起疼痛及各种不同程度静脉炎的患者约为59％。
(2)以大量丙二醇和乙醇为溶媒的原研奥硝唑注射液
Figure PCTCN2020137482-appb-000001
存在：①丙二醇超安全范围使用的风险。WHO推荐丙二醇的安全使用范围为每日25mg/kg体重(参见文献CN201710707702)，原研
Figure PCTCN2020137482-appb-000002
的3ml:0.5g和6ml:1.0g规格中分别含丙二醇1.4g和2.8g，按临床首次给药奥硝唑1g计，70kg成人每日输注丙二醇的量为2.8g，即40mg/kg体重，远超过WHO的推荐用量。②低温易结晶的缺陷。原研
Figure PCTCN2020137482-appb-000003
长时间放置于4℃以下低温环境，主药奥硝唑易结晶析出，给产品质量带来隐患。③基因毒性警示结构杂质含量较高。
Figure PCTCN2020137482-appb-000004
处方易产生较大量的环氧结构基因毒性警示结构杂质，含量最高可达0.07％，其安全性未作充分评价，其限度也未作控制。
(3)以大量乙醇为溶媒的原研奥硝唑注射液
Figure PCTCN2020137482-appb-000005
还存在：①易诱发敏感患者的双硫仑反应。原研
Figure PCTCN2020137482-appb-000006
的3ml:0.5g和6ml:1.0g规格中分别含有900mg和1800mg乙 醇，这极易诱发敏感体质患者出现双硫仑反应，尤其是婴幼儿患者，因主诉困难，易被误诊，耽误最佳治疗时机。②增加生产过程的安全风险。尽管丙二醇的挥发性较低，但高浓度乙醇仍易于从混合液中挥发出来，给玻璃安瓿火焰封口带来生产的安全隐患。
现有技术针对上述缺陷，研究人员已从多个方面开展研究工作，以解决相应技术问题。
有针对大容量奥硝唑注射液或左奥硝唑注射液降低杂质含量、提高稳定性等的技术，如CN1768742A、CN1686116A、CN1332662C、CN101732242A、CN101816650A等。然而，大容量奥硝唑注射液或左奥硝唑注射液均为以注射用水为主要溶剂的水体系，必须经过高温灭菌处理，因此，上述技术虽然解决了奥硝唑或左奥硝唑在水中的溶解性技术问题，但难以同时克服上述缺陷(1)中的杂质含量高和血管刺激性强的技术难题。
有针对小容量奥硝唑注射液或左奥硝唑注射液水体系开展研究，以降低杂质含量、提高稳定性、降低毒副反应等的技术，如CN101697969A、CN102335126A、CN110538144A、CN107224429B、CN107184548B、CN107737099B等。其中后三者采用控制左奥硝唑注射液中乙酸根、乙酸胺和硝酸根的量来降低其毒性反应发生率，然而其制备过程中仍需调节pH值至3.0～4.0和经高温灭菌，说明书中也未明确杂质控制情况。CN103505411A利用长链聚乙二醇4000的增稠作用和助悬作用，增加了小容量奥硝唑注射液水体系的物理稳定性，但其制备经过了高温灭菌和pH调节(2.5～4.5)过程，同时长链聚乙二醇4000常作为固体制剂的赋形剂，将其作为注射用途的辅料，会给制剂带来潜在的安全风险。因此，这些技术虽然解决了奥硝唑注射液或左奥硝唑注射液在水中的溶解性技术问题，但仍难以同时克服上述缺陷(1)中的杂质含量高和血管刺激性强的技术难题。
有针对奥硝唑注射剂或左奥硝唑注射剂水体系存在的因pH过低而引起的滴注疼痛和脉管炎的临床顺应性问题而开展研究的技术。CN110538144A将5～10mmol/L磷酸三钠溶液作为稀碱液，希望作为奥硝唑注射剂或左奥硝唑注射剂的产品伴侣，专门用于临床给药时中和奥硝唑注射剂的低pH值，使奥硝唑注射剂输注时维持pH值在5.0～6.0范围内，以缓解滴注疼痛和引起脉管炎，然而，该技术对奥硝唑注射剂降低杂质含量和提高稳定性并没有帮助，同时使奥硝唑注射剂的临床用药更加复杂。
有针对小容量奥硝唑注射液或左奥硝唑注射液有机体系开展研究，以降低杂质含量、提高稳定性、降低毒副反应等的技术，如CN103006554B、CN1040135571B、CN107496351A、CN107041868A等。其中，CN103006554B通过控制乙醇占比60％～100％来控制杂质含量，同时克服了上述缺陷(1)和(2)中的杂质含量高、pH值偏酸、丙二醇超限使用等的诸多技术问题，然而3ml:0.5g和6ml:1.0g规格中分别含有乙醇高达1530mg～2500mg和 3060mg～5000mg，增加了上述缺陷(3)出现双硫仑反应的风险，同时高乙醇浓度也会增加输注刺激性和增加低温的不稳定性。CN1040135571B利用甘油和乙醇共同增溶奥硝唑，成功克服了上述缺陷(1)和(2)中的杂质含量高、pH值偏酸、丙二醇超限使用等的诸多技术问题，然而该体系的奥硝唑在低温下(12℃以下)易结晶析出，给制剂的贮藏和临床使用带来了新的问题。CN107496351A利用无水乙醇和聚乙二醇-15-羟基硬脂酸酯(HS 15)共同增溶奥硝唑或左奥硝唑，成功克服了上述缺陷(1)和(2)中的杂质含量高、pH值偏酸、丙二醇超限使用等的诸多技术问题，但该技术的增溶机制为胶束理论，奥硝唑在血浆中可能与聚乙二醇-15-羟基硬脂酸酯形成胶束而改变其体内药学行为，从而给奥硝唑注射液的疗效和安全性带来不确定性。CN107041868A将微量乙酸-乙酸钠水溶液添加进丙二醇-乙醇有机体系之中，以改善临床输注的pH值，进而改善输注刺激性，然而研究发现丙二醇-乙醇体系对水较为敏感，微量水极易导致杂质增加，因此，该技术难以兼顾刺激性问题和杂质增加问题。
还有将奥硝唑或左奥硝唑制备成冻干粉针剂以降低杂质含量、提高稳定性、降低毒副反应等的技术等的技术，如CN103989640B、CN109771378A等。这些技术虽然可成功克服上述缺陷(1)、(2)和(3)中的杂质含量高、pH值偏酸、丙二醇超限使用、双硫仑反应等的诸多技术问题，然而是以降低无菌保障水平，极大增加了奥硝唑注射液的生物安全风险为代价的。此外，CN103989640B采用聚乙二醇-15-羟基硬脂酸酯和β-环糊精复合增溶奥硝唑，添加赋形剂甘露醇，将其制备成冻干制剂，其增溶奥硝唑的机制存在聚乙二醇-15-羟基硬脂酸酯的胶束理论、β-环糊精的包合理论甚至是两者的复合作用，会增加奥硝唑体内药学行为的复杂性，给其注射液的疗效和安全性带来不确定性，此外普通β-环糊精还不适合用作注射用途的辅料。
可见，现有技术均只是从不同角度解决奥硝唑注射剂或左奥硝唑注射剂不同方面的技术问题，无法同时解决存在的所有或者绝大部分技术问题。
综上所述，针对上述奥硝唑注射剂和左奥硝唑注射剂的制剂缺陷，急需开发出能有效溶解奥硝唑或左奥硝唑的溶剂体系，以同时解决奥硝唑注射剂或左奥硝唑注射剂的杂质增长控制问题、pH值过低问题、丙二醇超量使用问题、低温易结晶问题、药源性双硫仑反应问题、生产安全问题、等等，以最大程度满足临床需要，改善患者的用药安全性和顺应性。
发明内容
针对现有技术的上述不足，本发明的目的是提供一种能有效溶解奥硝唑或左奥硝唑的溶剂体系及应用，同时解决现有技术存在的杂质增长控制、pH值过低、丙二醇超量使用、 低温易结晶、药源性双硫仑反应、生产安全等诸多技术问题，以便最大程度满足临床安全用药需求，增加患者用药顺应性。
为了解决上述现有技术问题，实现本发明目的，本发明采用了如下技术方案：
一种能有效溶解奥硝唑或左奥硝唑的溶剂体系，其特征在于，活性成分为奥硝唑或左奥硝唑，所述溶剂体系为短链聚乙二醇和丙二醇混合的有机溶剂。
其中，所述溶剂体系中短链聚乙二醇和丙二醇混合质量分数比为30～100：0～70。优选混合质量分数比为60～90：40～10。
进一步，所述短链聚乙二醇选自聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600中的一种或多种。优选聚乙二醇300和聚乙二醇400的一种或二种。
进一步，本发明提供一种注射液，包括两种规格：
规格1：活性成分为奥硝唑或左奥硝唑0.5g，用有机溶剂溶解并定容至1.0ml～2.0ml；优选有机溶剂溶解并定容至1.5ml；
规格2：活性成分为奥硝唑或左奥硝唑1.0g，用有机溶剂溶解并定容至2.0ml～4.0ml；优选有机溶剂溶解并定容至3.0ml；
所述有机溶剂为短链聚乙二醇和丙二醇按质量分数比为30～100：0～70混合而成。优选有机溶剂为短链聚乙二醇和丙二醇混合质量分数比为60～90：40～10。
进一步，所述短链聚乙二醇选自聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600中的一种或多种。优选聚乙二醇300和聚乙二醇400的一种或二种。
进一步，本发明还提供一种注射液的制备方法，由上述配比的活性成分和有机溶剂配制而成，制备方法包括以下步骤：
1)溶解：将所述有机溶剂置于容器中充分混匀，然后加入活性成分，20～80℃搅拌下完全溶解，得到溶液1；
2)除热原：将步骤1)得到的溶液1经过除热原处理；
3)除菌：将步骤2)得到的溶液2经过0.20μm的微孔滤膜处理，得到溶液3；
4)灌封：将步骤3)得到的溶液3经中间品检测，合格后灌装至玻璃或塑料容器中，封口；
5)灭菌：采用F 0值大于8(优选大于12)的灭菌条件对步骤4)得到的灌封溶液进行灭菌处理，冷却，灯检，包装即得；F 0值优选大于12。
进一步，所述步骤2)为向步骤1)得到的溶液1中加入药用炭，20～80℃保温搅拌10～120min，过滤脱炭，得到的流出液为溶液2；或者，将步骤1)得到的溶液1用合适 分子量的超滤膜装置处理，得到的流出液为溶液2；或者，在A级洁净区采用热原合格的原辅料，不经过除热原处理，直接将制备的溶液1作为溶液2。
相比现有技术，本发明同时具有如下有益效果：
1、本发明提供了一种能有效溶解奥硝唑或左奥硝唑的溶剂体系，使奥硝唑注射液或左奥硝唑注射液的溶剂用量显著减少。利用本发明优化的有机溶剂用量，可获得性能良好的1.5ml:0.5g和3.0ml:1.0g规格的奥硝唑或左奥硝唑注射液，相较于已上市奥硝唑注射液规格3ml:0.5g、6ml:1.0g、5ml:0.25g、5ml:0.5g、10ml:0.5g等，可大大降低溶剂用量，增加用药安全性。
2、本发明提供了一个适宜酸碱度的奥硝唑注射液或左奥硝唑注射液。利用本发明制备的注射液可维持临床输注pH值5～7，相较于已上市水性奥硝唑注射剂和左奥硝唑注射剂的低pH值，可大幅降低临床输注刺激性和静脉炎发生的可能性。
3、本发明提供了一个低温不易结晶析出的奥硝唑注射液或左奥硝唑注射液。本发明优化的1.5ml:0.5g和3.0ml:1.0g规格，在2～8℃低温环境长时间存放不会结晶析出，而相同浓度的丙二醇-乙醇体系易于结晶析出，可显著增加贮藏运输稳定性和临床用药方便性。
4、本发明提供了一个极低杂质含量的奥硝唑注射液或左奥硝唑注射液。本发明制备的奥硝唑或左奥硝唑的注射剂的杂质个数少，杂质II、杂质III以及总杂含量均显著低于原研奥硝唑注射液
Figure PCTCN2020137482-appb-000007
更远低于水性注射剂，同时具有良好的贮藏稳定性和配伍稳定性。
5、本发明提供了一个不含乙醇的奥硝唑注射液或左奥硝唑注射液，可有效避免临床用药的药源性双硫仑反应的发生，特别适用于婴幼儿、老年、体弱等敏感体质患者用药。
6、本发明提供了一个丙二醇用量大幅降低的奥硝唑注射液或左奥硝唑注射液。利用本发明制备的注射液，按照4ml:1.0g规格以及丙二醇占溶剂50％计，成人(70kg)每天的丙二醇最大用量为29.6mg/kg体重；按照优化的3ml:1.0g规格以及丙二醇占溶剂40％和20％计，成人(70kg)每天的丙二醇最大用量分别为17.76mg/kg体重和8.88mg/kg体重，远低于
Figure PCTCN2020137482-appb-000008
原研40mg/kg体重的用量，符合WHO推荐的每日25mg/kg体重的安全使用范围，可消除超安全范围使用的担忧。
7、本发明提供了一个高无菌保障水平的奥硝唑注射液或左奥硝唑注射液。利用本发明制备的注射液，可在F 0值大于12的条件下灭菌，可大大降低无菌检查项不合格的风险。
8、本发明提供了一个不改变体内药学行为的奥硝唑注射液或左奥硝唑注射液。利用本发明和
Figure PCTCN2020137482-appb-000009
原研处方制备的奥硝唑注射液的大鼠血浆AUC 0-t相近，药时曲线相似因 子f2高达95％。
附图说明
图1为杂质I的结构式；
图2为杂质II的结构式；
图3为杂质III的结构式；
图4为实施例47色谱图；
图5为实施例51色谱图；
图6为对比例25色谱图；
图7为对比例26色谱图；
图8为对比例28色谱图；
图9为对比例29色谱图；
图10为对比例31色谱图；
图11为对比例32色谱图。
具体实施方式
为了实现本发明目的，本发明经历了溶解体系建立、杂质控制试验、低温结晶试验、稳定性试验、刺激性试验、溶血性试验、体内药学行为评价等多个研究阶段，通过实现多个阶段性目标而完成的。
下面结合本发明的实施阶段，用具体实施例对本发明作进一步的详细说明，但并不因此将本发明限制在所述的实施例范围之中。
试验例1：有效溶解体系的建立
(1)有机溶剂体系筛选
本发明的目标之一是建立一种能有效溶解奥硝唑或左奥硝唑的溶剂体系，显著减少溶剂用量。为了实现该目标，本发明人试验了纯水体系、纯有机溶剂体系、水和有机溶剂混合体系、水和表面活性剂混合体系、有机溶剂和表面活性剂混合体系等，结果显示，纯水体系难以有效降低制剂体积，溶解0.25g奥硝唑的溶剂体积不低于5ml；其余体系均能不同程度降低制剂的溶剂体积，其中丙二醇+乙醇、表面活性剂(如聚乙二醇-15-羟基硬脂酸酯、聚山梨酯80等)+有机溶剂(如乙醇、丙二醇、二甲基甲酰胺等)、短链聚乙二醇(聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600等)+有机溶剂(如乙醇、丙二醇、二甲基甲酰胺等)等有机体系具有很强溶解奥硝唑和左奥硝唑的能力，多个体系室温溶解0.5g奥硝唑所需溶剂可低至0.5ml。研究还发现，混合溶剂对奥硝唑的溶解具有 协同作用，混合溶剂比例对协同作用影响显著，部分混合溶剂的协同作用强弱排序为：PEG200+乙醇、丙二醇+乙醇、PEG400+乙醇、PEG400+丙二醇、二甲基甲酰胺+乙醇、PEG600+乙醇、甘油+乙醇等。因此，本发明重点选择短链聚乙二醇、丙二醇、乙醇、二甲基甲酰胺等的一种或多种混合有机溶剂体系，进行奥硝唑和左奥硝唑溶解体系的优化。
实施例1～11：不同有机体系对奥硝唑或左奥硝唑的溶解能力(1)(室温)
实验步骤：先按比例混合各种溶剂，再加入过量的奥硝唑或左奥硝唑，在室温下搅拌溶解20分钟，用0.22微米微孔滤膜过滤去除未溶解药物，用分光光度法(318nm)测定溶液的吸光度，根据标准曲线计算药物溶解度。注：各组分的量为重量份，下同。
表1：实施例1～11
Figure PCTCN2020137482-appb-000010
对比例1～11：不同有机体系对奥硝唑或左奥硝唑的溶解能力(2)(室温)
实验步骤：同实施例1～11。
表2：对比例1～11
Figure PCTCN2020137482-appb-000011
实施例12～17和对比例12～16：不同有机体系对奥硝唑或左奥硝唑的溶解能力(3)(30℃)
实验步骤：除温度为30℃外，其他同实施例1～11。
表3：实施例12～17和对比例12～16
Figure PCTCN2020137482-appb-000012
Figure PCTCN2020137482-appb-000013
实施例18～26和对比例17、18：不同有机体系对奥硝唑或左奥硝唑的溶解能力(4)(30℃)
实验步骤：同实施例12～17。
表4：实施例18～26和对比例17、18
Figure PCTCN2020137482-appb-000014
根据上述试验结果，综合考虑各有机溶剂的安全性、使用频率、易加工性、对奥硝唑或左奥硝唑的溶解效果等，本发明优选有溶剂体系为PEG300-丙二醇、PEG400-丙二醇、PEG300-乙醇、PEG400-乙醇，以及PEG300和/或PEG400与丙二醇和/或乙醇的混合体系。同时可见，在30℃环境中原研的丙二醇-乙醇混合溶剂溶解奥硝唑和左奥硝唑的能力高于本发明体系。
(2)低温稳定性试验
试验过程：分别用不同比例的PEG300-丙二醇、PEG400-丙二醇、PEG300-乙醇、PEG400-乙醇、PEG400-乙醇+丙二醇、PEG300-乙醇+丙二醇以及原研丙二醇-乙醇体系1ml、1.5ml和2ml，溶解奥硝唑或左奥硝唑0.5g，将溶液置于西林瓶中封口，置于2～8℃低温环境30天，观察药物结晶析出情况。注：[1]各组分的量为重量份，下同。
实施例27～36：低温稳定性试验(1)
表5：实施例27～36
Figure PCTCN2020137482-appb-000015
Figure PCTCN2020137482-appb-000016
实施例37～46：低温稳定性试验(2)
表6：实施例37～46
Figure PCTCN2020137482-appb-000017
对比例19～24：低温稳定性试验(3)
表7：对比例19～24
Figure PCTCN2020137482-appb-000018
Figure PCTCN2020137482-appb-000019
根据上述结果可知，溶解奥硝唑或左奥硝唑0.5g，短链聚乙二醇(PEG300或PEG400)与丙二醇和/或乙醇混合溶剂用量不少于1.5ml，可以确保注射液良好的低温稳定性。同时可以发现意想不到的试验结果，在相同奥硝唑浓度下原研丙二醇-乙醇溶剂体系的低温稳定性远不如本发明体系。
试验例2：杂质控制试验
本发明的目标之二是寻找一种能有效控制杂质个数和杂质含量的技术方案。结合第一目标，本发明人试验了水体系(如纯水体系、水和有机溶剂混合体系、水和表面活性剂混合体系等)和有机纯体系(如有机溶剂体系、有机溶剂和表面活性剂混合体系等)的酸碱度、酸碱物质种类、配制顺序、配制温度、灭菌温度、抗氧剂、残氧浓度等对奥硝唑注射剂和左奥硝唑注射剂杂质种类和杂质含量的影响。结果显示，水体系难以有效降低杂质含量，杂质尤其是杂质II(2-甲基-5-硝基-1-(2,3-二羟基丙基)咪唑，结构参见附图2)含量高；有机体系能显著降低的杂质含量，尤其可显著降低杂质II的含量，然而有机体系易于生成基因毒性警示结构杂质III(参见附图3)。因此，本发明重点选择有机体系进行杂质控制。
实施例47～54和对比例25～32：不同体系的有关物质情况
样品制备步骤：称取处方量的有机溶剂，混合，加入奥硝唑或左奥硝唑，在一定温度下搅拌溶解，定容，分装，封口，121℃灭菌12min，降温，即得。下同。
杂质检测方法：取样品适量，用流动相稀释至奥硝唑或左奥硝唑浓度约为1mg/ml，作为供试品溶液；精密量取供试品溶液1ml，置100ml量瓶中，用流动相稀释至刻度，摇匀，作为对照溶液。精密量取供试品溶液和对照溶液各20μl，注入液相色谱仪，记录色谱图，流动相为甲醇-水(20:80)，检测波长为318nm，色谱柱为C18柱。按自身对照法计算各杂质峰的含量。下同。实施例47和51以及对比例25、26、28、29、31和32的色谱图见附图4～11。
表8：实施例47～54和对比例25～32
Figure PCTCN2020137482-appb-000020
Figure PCTCN2020137482-appb-000021
上述结果显示，本发明可显著降低杂质的个数和含量，杂质含量均远低于ICH要求的0.1％限度要求，而水体系难以控制杂质个数和减少杂质含量。发明人地惊奇地发现，本发明PEG300/PEG400-乙醇体系不产生杂质II，同时杂质III含量低于0.02％，显著低于PEG300/PEG400-丙二醇体系和原研丙二醇-乙醇体系。同时还可见，无论杂II、杂III和总杂含量，还是杂质个数，本发明均远低于水性体系。
试验例3：pH值控制试验
本发明的目标之三是寻找一种能有效克服低pH值的技术方案。结合第一和二个目标，本发明人试验了水体系和有机纯体系的酸碱度控制对奥硝唑和左奥硝唑溶解、杂质种类、杂质含量等的影响。结果显示，含水体系难以提高奥硝唑注射剂和左奥硝唑注射剂溶液的pH值，致使临床输注pH值仍较低；纯有机体系勿需添加酸性组分即可有效控制杂质含量增长，可维持适宜的临床输注pH值5～7。
实施例47～54和对比例25～27及33～39：不同体系pH对有关物质的影响
表9：实施例47～54和对照例25～27及33～39
Figure PCTCN2020137482-appb-000022
Figure PCTCN2020137482-appb-000023
根据上述结果，发明人惊奇地发现，本发明无需添加酸碱度调节剂，即使输注pH值满足人体耐受pH值4～9，本发明可维持人体耐受良好的临床输注pH值5～7，同时可以有效控制杂质水平远低于ICH要求的不超过0.1％的限度，尤其是PEG300/400-乙醇体系。然而含水体系必须调节pH值至3.0～3.5，才能控制相对低的杂质水平，然而仍远超过ICH要求的0.1％限度。因此，本发明取得意想不到的技术效果，既可有效控制杂质水平和杂质个数，尤其是具有潜在基因毒性杂质III的含量的控制，又可有效解决低pH值输注带来的刺激性和静脉炎发生问题。这是现有技术难以达到的。
试验例4：高温灭菌试验
本发明的目标之四是寻找一种能耐受过度灭菌的高无菌保障水平(F0值≥12)的技术方案。本发明人开展了奥硝唑或左奥硝唑注射剂的水体系和有机纯体系耐受高温灭菌的程度试验。结果显示，含水体系对高温灭菌的耐受性很差，杂质含量和个数增加显著；而本发明对高温灭菌的耐受性良好。
实施例55～60和对比例40～45：不同体系灭菌条件对有关物质的影响
表10：实施例55～60和对比例40～45
Figure PCTCN2020137482-appb-000024
Figure PCTCN2020137482-appb-000025
根据上述结果，发明人惊奇地发现，本发明耐受高温灭菌的能力显著高于现有技术，尤其优于水体系。
试验例5：尾静脉刺激性试验
实验步骤：取PEG400-乙醇(3:2)、PEG400-丙二醇(3:2)和丙二醇-乙醇(原研)体系的奥硝唑注射液以及生理盐水，分别缓慢注射雌雄小鼠尾静脉各3只，给药量为78mg/kg，于穿刺点近心端上方1cm处用游标卡尺测量鼠尾直径，测量时间为给药前、给药后5、10、15、30、45、1、2、4、8、12、24和48h。
肿胀程度计算：肿胀度＝(注射后鼠尾直径－注射前鼠尾直径)/注射前鼠尾直径×100％。
实施例61～64和对比例46～49：不同体系的小鼠尾静脉刺激性试验
Figure PCTCN2020137482-appb-000026
根据上述结果，发明人惊奇地发现，本发明的血管刺激性明显小于丙二醇-乙醇体系。
试验例6：大鼠体内药物代谢动力学试验
实验步骤：取SD大鼠随机分组(约250g，雄鼠)，每组各3只。实验前禁食12h，尾静脉注射PEG400-乙醇、PEG400-丙二醇、丙二醇-乙醇体系的奥硝唑注射液，给药剂量20mg/kg，给药浓度为5mg/ml(临用前用生理盐水稀释)。尾静脉给药后的眼眶取血时间为1min、5min、15min、30min、1h、3h、6h、9h、12h、24h，取血量约0.5ml，装入经肝素钠处理过50μl离心管中，静置30min，8000r/min，离心10min，取上层血浆于洁净的0.5ml离心管中，置-20℃冰箱保存备用。
样品处理：取血浆样品100μl于1.5ml离心管中，加入10μl内标液(40μg/ml)，涡旋3min。加入200μl甲醇/异丙醇(1:1)提取液，涡旋3min，12000r/min离心10min，取上清液20μl进行HPLC测定，色谱条件同实施例47～54。
药代学参数 PEG400-乙醇体系 PEG400-丙二醇体系 丙二醇-乙醇体系
AUC 0-t(μg/ml*h) 35.036 33.036 29.864
AUC 0-∞(μg/ml*h) 38.335 34.335 31.810
t 1/2(h) 1.847 1.652 1.528
Cl(L/h/kg) 0.472 0.514 0.629
V(L/kg) 1.259 1.281 1.386
MRT 0-t(h) 2.552 2.211 1.982
根据上述结果，发明人惊奇地发现，本发明的血浆ACU与原研体系血浆ACU非常接近，药时曲线相似度超过90％，表明本发明未改变奥硝唑或奥硝唑的体内药学行为。
以上所述仅为本发明的较佳实施例而已，并不以本发明为限制，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种能有效溶解奥硝唑或左奥硝唑的溶剂体系，其特征在于，活性成分为奥硝唑或左奥硝唑，所述溶剂体系为短链聚乙二醇和丙二醇混合的有机溶剂。
  2. 根据权利要求1所述能有效溶解奥硝唑或左奥硝唑的溶剂体系，其特征在于，所述溶剂体系中短链聚乙二醇和丙二醇混合质量分数比为30～100：0～70。
  3. 根据权利要求1所述能有效溶解奥硝唑或左奥硝唑的溶剂体系，其特征在于，所述溶剂体系中短链聚乙二醇和丙二醇混合质量分数比为60～90：40～10。
  4. 根据权利要求1所述能有效溶解奥硝唑或左奥硝唑的溶剂体系，其特征在于，所述短链聚乙二醇选自聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600中的一种或多种。
  5. 一种注射液，其特征在于，包括两种规格：
    规格1：活性成分为奥硝唑或左奥硝唑0.5g，用有机溶剂溶解并定容至1.0ml～2.0ml；
    规格2：活性成分为奥硝唑或左奥硝唑1.0g，用有机溶剂溶解并定容至2.0ml～4.0ml。
    所述有机溶剂为短链聚乙二醇和丙二醇按质量分数比为30～100：0～70混合而成。
  6. 根据权利要求5所述注射液，其特征在于，
    规格1：活性成分为奥硝唑或左奥硝唑0.5g，用有机溶剂溶解并定容至1.5ml；
    规格2：活性成分为奥硝唑或左奥硝唑1.0g，用有机溶剂溶解并定容至3.0ml；
    其中，所述有机溶剂为短链聚乙二醇和丙二醇混合质量分数比为60～90：40～10。
  7. 根据权利要求5所述注射液，其特征在于，所述短链聚乙二醇选自聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600中的一种或多种。
  8. 根据权利要求5所述注射液，其特征在于，所述短链聚乙二醇优选聚乙二醇300和聚乙二醇400的一种或二种。
  9. 一种注射液的制备方法，其特征在于，由权利要求5、6或7所述活性成分和有机溶剂配制而成，制备方法包括以下步骤：
    1)溶解：将所述有机溶剂置于容器中充分混匀，然后加入活性成分，20～80℃搅拌下完全溶解，得到溶液1；
    2)除热原：将步骤1)得到的溶液1经过除热原处理；
    3)除菌：将步骤2)得到的溶液2经过0.20μm的微孔滤膜处理，得到溶液3；
    4)灌封：将步骤3)得到的溶液3经中间品检测，合格后灌装至玻璃或塑料容器中，封口；
    5)灭菌：采用F 0值大于8(优选大于12)的灭菌条件对步骤4)得到的灌封溶液进 行灭菌处理，冷却，灯检，包装即得；F 0值优选大于12。
  10. 根据权利要求9所述注射液的制备方法，其特征在于，所述步骤2)的方法为：向步骤1)得到的溶液1中加入药用炭，20～80℃保温搅拌10～120min，过滤脱炭，得到的流出液为溶液2；或者，将步骤1)得到的溶液1用合适分子量的超滤膜装置处理，得到的流出液为溶液2；或者，在A级洁净区采用热原合格的原辅料，不经过除热原处理，直接将制备的溶液1作为溶液2。
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