CN110934824B - Solvent system capable of effectively dissolving ornidazole or levoornidazole and application thereof - Google Patents
Solvent system capable of effectively dissolving ornidazole or levoornidazole and application thereof Download PDFInfo
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Abstract
The invention discloses a solvent system capable of effectively dissolving ornidazole or levo-ornidazole and application thereof, wherein the active component is ornidazole or levo-ornidazole, and the solvent system is an organic solvent mixed by short-chain polyethylene glycol and propylene glycol; the short-chain polyethylene glycol is preferably polyethylene glycol 300 or/and polyethylene glycol 400. The solvent system can be used for preparing ornidazole injection or levoornidazole injection. The invention has the technical advantages that the prior art can not achieve, and the prepared ornidazole injection or the levoornidazole injection has the preparation advantages of simpler prescription, safer production, more stable preparation, less solvent amount, lower content of impurities (particularly genotoxic impurities), difficult crystallization at low temperature, low incidence rate of phlebitis, no low pH infusion irritation, more suitability for patients sensitive to disulfiram reaction and the like, ensures safer clinical medication and better medication compliance of patients.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a solvent system capable of effectively dissolving ornidazole or levoornidazole and application thereof, and provides a safer ornidazole injection or levoornidazole injection and a preparation method thereof.
Background
The ornidazole and the levoornidazole are third-generation nitroimidazole broad-spectrum anti-anaerobe and antiprotozoal infection medicines after the metronidazole and the tinidazole, and have the advantages of good curative effect, good tolerance, good tissue permeability, wide in-vivo distribution, long biological half-life period and the like, so the ornidazole and the levoornidazole are the first-choice medicines for preventing and treating anaerobe infection.
At present, the ornidazole injection on the market has small-volume injection and large-volume injection, and the levoornidazole injection only has large-volume injection. However, the existing ornidazole injection and the existing levoornidazole injection have the following defects:
(1) the ornidazole small-volume injection, the large-volume injection and the levoornidazole large-volume injection which take water for injection as a solvent exist: the defect of high impurity content. The existing standards stipulate that the ornidazole injection and the levoornidazole injection have higher impurity limit, the single impurity limit of the ornidazole injection is 0.5 percent, and the total impurity limit is 1.0 percent; the limit of impurity III of the levoornidazole injection is 1.0 percent, and the limit of total impurities is 1.5 percent. ② the defect of low pH value. Impurities in the ornidazole or the water solution of the levoornidazole increase rapidly along with the increase of the pH value of the solution in the high-temperature sterilization process, and the lower pH value (the pH value is 3.0-3.5) is usually required to be maintained. And thirdly, the defect of strong vascular irritation. Because the solution of the ornidazole aqueous injection needs to control the pH value to be 3.0-3.5 and exceeds the range of the pH value which is tolerated by a human body to be 4.0-9.0, stronger vascular irritation is often generated in clinical application, and the incidence rate of infusion pain and phlebitis is increased, and statistics show that the patients suffering from pain and various phlebitis of about 59 percent.
(2) Primary ornidazole injection with great amount of propylene glycol and ethanol as solvent
There are: the risk of the propylene glycol exceeding the safe range is solved. WHO recommends that the safe use range of propylene glycol is 25mg/kg body weight per day (see document CN201710707702), which is originally researched
The specification of 3ml:0.5g and 6ml:1.0g respectively contains 1.4g and 2.8g of propylene glycol, and the daily infusion amount of the propylene glycol for 70kg of adults is 2.8g, namely 40mg/kg of body weight, calculated as 1g of ornidazole for the first clinical administration, which is far more than the recommended dosage of WHO. ② the defect of easy crystallization at low temperature. Original research
When the ornidazole is placed in a low-temperature environment below 4 ℃ for a long time, the main drug ornidazole is easy to crystallize and separate out, and hidden troubles are brought to the product quality. And the genotoxicity warning structure has high impurity content.
The prescription is easy to generate a large amount of epoxy structure genotoxicity warning structure impurities, the content can reach 0.07 percent at most, the safety is not fully evaluated, and the limit is not controlled.
(3) Primary ornidazole injection with great amount of ethanol as solvent
There are also: the disulfiram reaction of sensitive patients is easy to induce. Original research
The specifications of 3ml, 0.5g and 6ml, 1.0g respectively contain 900mg and 1800mg of ethanol, which is very easy to induce the disulfiram reaction of sensitive patients, especially infant patients, and is easy to misdiagnose and delay the best treatment time due to difficult chief complaints. Secondly, the safety risk of the production process is increased. Although the volatility of propylene glycol is low, high-concentration ethanol is still easy to volatilize from the mixed solution, and the production safety hazard is brought to the flame sealing of the glass ampoule.
In view of the above-mentioned drawbacks, researchers have conducted research from a number of aspects to solve the corresponding technical problems.
There are techniques for reducing the content of impurities and improving the stability of large-capacity ornidazole injection or levoornidazole injection, such as CN1768742A, CN1686116A, CN1332662C, CN101732242A, CN101816650A, etc. However, the large-volume ornidazole injection or the levoornidazole injection is a water system which takes water for injection as a main solvent, and high-temperature sterilization treatment is required, so the technical problem of solubility of ornidazole or levoornidazole in water is solved by the technology, but the technical problems of high impurity content and strong vascular irritation in the defect (1) are difficult to overcome at the same time.
There are technologies, such as CN101697969A, CN102335126A, CN110538144A, CN107224429B, CN107184548B, and CN107737099B, which are developed for research on small-volume ornidazole injection or levo-ornidazole injection water systems to reduce impurity content, improve stability, and reduce toxic and side reactions. The last three of the three are used for controlling the amount of acetate, ammonium acetate and nitrate radical in the levoornidazole injection to reduce the toxic reaction incidence rate, however, the pH value is still required to be adjusted to 3.0-4.0 in the preparation process and high temperature sterilization is carried out, and the impurity control condition is not clear in the specification. CN103505411A utilizes the thickening effect and the suspending effect of long-chain polyethylene glycol 4000 to increase the physical stability of a small-volume ornidazole injection water system, but the preparation process is performed by high-temperature sterilization and pH adjustment (2.5-4.5), and meanwhile, the long-chain polyethylene glycol 4000 is often used as an excipient of a solid preparation and is used as an auxiliary material for injection, so that potential safety risk is brought to the preparation. Therefore, although these technologies solve the technical problem of solubility of ornidazole injection or levoornidazole injection in water, it is still difficult to overcome the technical problems of high impurity content and strong vascular irritation in the above-mentioned defect (1).
There is a technology for researching the drip pain and the clinical compliance problem of angiitis caused by the over low pH existing in the water system of the ornidazole injection or the levoornidazole injection. CN110538144A uses 5-10 mmol/L trisodium phosphate solution as dilute alkali solution, hopefully as product partner of ornidazole injection or levoornidazole injection, specially used for neutralizing low pH value of ornidazole injection during clinical administration, and keeping pH value within 5.0-6.0 during ornidazole injection to relieve instillation pain and cause angiitis, however, the technology is not helpful for reducing impurity content and improving stability of ornidazole injection, and simultaneously makes clinical administration of ornidazole injection more complicated.
There are technologies, such as CN103006554B, CN1040135571B, CN107496351A, CN107041868A, etc., which are developed to research organic systems of small-volume ornidazole injection or levoornidazole injection to reduce impurity content, improve stability, and reduce toxic and side reactions. The CN103006554B controls the content of impurities by controlling the proportion of ethanol to be 60-100%, and simultaneously overcomes the technical problems of high content of impurities, pH value meta-acid, over-limit use of propylene glycol and the like in the defects (1) and (2), however, the ethanol content in the specifications of 3ml:0.5g and 6ml:1.0g is 1530-2500 mg and 3060-5000 mg respectively, the risk of disulfiram reaction in the defect (3) is increased, and meanwhile, the high ethanol concentration can also increase the infusion irritation and increase the instability of low temperature. CN1040135571B utilizes glycerin and ethanol to solubilize ornidazole together, successfully overcomes the technical problems of high impurity content, pH value meta-acid, over-limit use of propylene glycol and the like in the defects (1) and (2), however, the ornidazole of the system is easy to crystallize and precipitate at low temperature (below 12 ℃), and new problems are brought to storage and clinical use of the preparation. CN107496351A utilizes absolute ethyl alcohol and polyethylene glycol-15-hydroxystearate (HS 15) to solubilize ornidazole or levoornidazole together, successfully overcomes a plurality of technical problems of high impurity content, pH value meta-acid, overuse of propylene glycol and the like in the defects (1) and (2), but the solubilization mechanism of the technology is a micelle theory, and the ornidazole and the polyethylene glycol-15-hydroxystearate can form micelles in plasma to change the in-vivo pharmaceutical behavior of the ornidazole, so that the uncertainty is brought to the curative effect and the safety of the ornidazole injection. CN107041868A adds trace acetic acid-sodium acetate water solution into propylene glycol-ethanol organic system to improve the pH value of clinical infusion and further improve infusion irritation, however, researches find that propylene glycol-ethanol system is sensitive to water, and trace water easily causes impurity increase, so that the technology is difficult to consider irritation problem and impurity increase problem.
And the technology of preparing the ornidazole or the levoornidazole into freeze-dried powder injection to reduce the impurity content, improve the stability, reduce the toxic and side reaction and the like, such as CN103989640B, CN109771378A and the like. Although the technologies can successfully overcome the technical problems of high impurity content, pH value meta-acid, over-limit use of propylene glycol, disulfiram reaction and the like in the defects (1), (2) and (3), the technologies have the cost of reducing the sterility guarantee level and greatly increasing the biological safety risk of the ornidazole injection. In addition, CN103989640B adopts polyethylene glycol-15-hydroxystearate and beta-cyclodextrin to compound and solubilize ornidazole, and excipient mannitol is added to prepare the ornidazole into a freeze-dried preparation, wherein the mechanism of solubilizing ornidazole has the micelle theory of polyethylene glycol-15-hydroxystearate, the inclusion theory of beta-cyclodextrin and even the compound action of the two, so that the complexity of the pharmaceutical behavior in the ornidazole body can be increased, uncertainty is brought to the curative effect and safety of the injection, and the common beta-cyclodextrin is not suitable for being used as an auxiliary material for injection.
Therefore, the prior art only solves the technical problems of different aspects of the ornidazole injection or the levoornidazole injection from different angles, and cannot simultaneously solve all or most of the existing technical problems.
In summary, in view of the above drawbacks of the ornidazole injection and the levoornidazole injection, there is an urgent need to develop a solvent system capable of effectively dissolving ornidazole or levoornidazole, so as to solve the problems of impurity growth control, excessively low pH, excessive use of propylene glycol, easy crystallization at low temperature, drug-induced disulfiram reaction, production safety, and the like of the ornidazole injection or the levoornidazole injection, so as to meet clinical needs to the greatest extent and improve the medication safety and compliance of patients.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a solvent system capable of effectively dissolving ornidazole or levoornidazole and application thereof, and simultaneously solves the technical problems of impurity growth control, excessively low pH value, excessive use of propylene glycol, easy crystallization at low temperature, drug-induced disulfiram reaction, safe production and the like in the prior art, so that the clinical safe medication requirement is met to the greatest extent, and the medication compliance of patients is improved.
In order to solve the above problems in the prior art and achieve the object of the present invention, the present invention adopts the following technical solutions:
a solvent system capable of effectively dissolving ornidazole or levoornidazole is characterized in that the active ingredient is ornidazole or levoornidazole, and the solvent system is an organic solvent formed by mixing short-chain polyethylene glycol and propylene glycol.
Wherein the mixing mass fraction ratio of the short-chain polyethylene glycol to the propylene glycol in the solvent system is 30-100: 0 to 70. Preferably, the mixing mass fraction ratio is 60-90: 40 to 10.
Further, 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.
Further, the invention provides an injection, which comprises two specifications:
specification 1: the active ingredient is 0.5g of ornidazole or levo-ornidazole, and the ornidazole or levo-ornidazole is dissolved by an organic solvent and the volume is fixed to 1.0ml to 2.0 ml; preferably dissolving the organic solvent and fixing the volume to 1.5 ml;
specification 2: 1.0g of ornidazole or levo-ornidazole as an active ingredient is dissolved by an organic solvent and the volume is determined to be 2.0-4.0 ml; preferably dissolving the organic solvent and metering to 3.0 ml;
the organic solvent is short-chain polyethylene glycol and propylene glycol, and the mass fraction ratio of the organic solvent is 30-100: 0 to 70 parts by weight. Preferably, the organic solvent is a mixture of short-chain polyethylene glycol and propylene glycol in a mass fraction ratio of 60-90: 40 to 10.
Further, 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.
Further, the invention also provides a preparation method of the injection, which is prepared from the active ingredients and the organic solvent according to the mixture ratio, and the preparation method comprises the following steps:
1) dissolving: putting the organic solvent into a container, fully and uniformly mixing, then adding the active ingredients, and completely dissolving under stirring at 20-80 ℃ to obtain a solution 1;
2) removing pyrogen: removing pyrogen from the solution 1 obtained in the step 1);
3) and (3) degerming: treating the solution 2 obtained in the step 2) by a 0.20-micron microporous filter membrane to obtain a solution 3;
4) encapsulating: detecting the solution 3 obtained in the step 3) through an intermediate product, filling the qualified solution into a glass or plastic container, and sealing the container;
5) and (3) sterilization: by using F0Sterilizing the encapsulation solution obtained in the step 4) under the sterilization condition with the value of more than 8 (preferably more than 12), cooling, performing light inspection, and packaging to obtain the product; f0The value is preferably greater than 12.
Further, the step 2) is to add medicinal carbon into the solution 1 obtained in the step 1), keep the temperature at 20-80 ℃, stir for 10-120 min, filter and remove the carbon, and obtain an effluent liquid as a solution 2; or treating the solution 1 obtained in the step 1) by using an ultrafiltration membrane device with a proper molecular weight, and obtaining an effluent as a solution 2; or, adopting pyrogen-qualified raw and auxiliary materials in the A-level clean area, and directly taking the prepared solution 1 as the solution 2 without pyrogen removal treatment.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention provides a solvent system capable of effectively dissolving ornidazole or levo-ornidazole, which can obviously reduce the dosage of the solvent of ornidazole injection or levo-ornidazole injection. By utilizing the optimized organic solvent dosage, the ornidazole or levoornidazole injection with good performance can be obtained, and compared with the ornidazole injection with the specification of 3ml, 0.5g, 6ml, 1.0g, 5ml, 0.25g, 5ml, 0.5g, 10ml and 0.5g, the solvent dosage can be greatly reduced, and the medication safety can be improved.
2. The invention provides an ornidazole injection or a levoornidazole injection with proper pH value. The injection prepared by the invention can maintain the clinical infusion pH value of 5-7, and can greatly reduce the clinical infusion irritation and the possibility of phlebitis compared with the low pH values of the water-based ornidazole injection and the levoornidazole injection which are sold in the market.
3. The invention provides an ornidazole injection or a levoornidazole injection which is not easy to crystallize and separate out at low temperature. The optimized specifications of 1.5ml:0.5g and 3.0ml:1.0g of the invention can not be crystallized and separated out after being stored for a long time in a low-temperature environment of 2-8 ℃, and a propylene glycol-ethanol system with the same concentration is easy to be crystallized and separated out, so that the storage and transportation stability and the clinical medication convenience can be obviously improved.
4. The invention provides an ornidazole injection or a levoornidazole injection with extremely low impurity content. The ornidazole or levoornidazole injection prepared by the invention has few impurities, and the contents of the impurities II, III and total impurities are obviously lower than those of the original ornidazole injection
Is further lower than the water-based injection and has good storage stability and compatibility stability.
5. The invention provides an ornidazole injection or a levoornidazole injection without ethanol, which can effectively avoid the occurrence of drug-induced disulfiram reaction of clinical medication and is particularly suitable for patients with sensitive constitutions such as infants, old people, weak people and the like.
6. The invention provides an ornidazole injection or a levoornidazole injection with greatly reduced propylene glycol consumption. According to the injection prepared by the invention, the maximum dosage of the propylene glycol for an adult (70kg) per day is 29.6mg/kg of body weight according to the specification of 4ml:1.0g and the propylene glycol accounting for 50 percent of the solvent; according to the optimized 3ml, the specification of 1.0g and the propylene glycol accounting for 40 percent and 20 percent of the solvent, the maximum dosage of the propylene glycol for an adult (70kg) per day is respectively 17.76mg/kg of body weight and 8.88mg/kg of body weight, which is far lower than that of the propylene glycol
The dosage of 40mg/kg body weight is originally researched, the safe use range of 25mg/kg body weight per day recommended by WHO is met, and the worry of using the medicine in the safe use range can be eliminated.
7. The invention provides an ornidazole injection or a levoornidazole injection with high sterility guarantee level. The injection prepared by the invention can be prepared in the step F0Sterilization with a value greater than 12 greatly reduces the risk of non-qualification of sterility test items.
8. The invention provides an ornidazole injection or a levoornidazole injection which does not change the pharmaceutical behavior in vivo. By using the invention and
rat plasma AUC of ornidazole injection prepared by original prescription0-tSimilarly, the time curve of the drug is similar to the factor f2 and is as high as 95%.
Drawings
FIG. 1 is a structural formula of impurity I;
FIG. 2 is a structural formula of impurity II;
FIG. 3 is a structural formula of impurity III;
FIG. 4 is a chromatogram of example 47;
FIG. 5 is a chromatogram of example 51;
FIG. 6 is a chromatogram of comparative example 25;
FIG. 7 is a chromatogram of comparative example 26;
FIG. 8 is a chromatogram of comparative example 28;
FIG. 9 is a chromatogram of comparative example 29;
FIG. 10 is a chromatogram of comparative example 31;
FIG. 11 is a chromatogram of comparative example 32.
Detailed Description
In order to achieve the purpose of the invention, the invention is subjected to a plurality of research stages such as dissolution system establishment, impurity control tests, low-temperature crystallization tests, stability tests, irritation tests, hemolytic tests, in vivo pharmaceutical behavior evaluation and the like, and is completed by achieving a plurality of staged targets.
The invention will now be described in further detail with reference to specific examples, but the invention is not limited thereto.
Test example 1: establishment of efficient dissolution System
(1) Screening of organic solvent systems
One of the objectives of the present invention is to create a solvent system that can effectively dissolve ornidazole or levoornidazole, significantly reducing the solvent usage. In order to achieve the object, the present inventors have tested a pure water system, a pure organic solvent system, a mixed system of water and an organic solvent, a mixed system of water and a surfactant, a mixed system of an organic solvent and a surfactant, etc., and as a result, it was shown that the pure water system is difficult to effectively reduce the volume of the formulation, and the volume of the solvent dissolving 0.25g of ornidazole is not less than 5 ml; the solvent volume of the preparation can be reduced to different degrees by other systems, wherein organic systems such as propylene glycol + ethanol, surfactants (such as polyethylene glycol-15-hydroxystearate, polysorbate 80 and the like), organic solvents (such as ethanol, propylene glycol, dimethylformamide and the like), short-chain polyethylene glycol (such as polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600 and the like), organic solvents (such as ethanol, propylene glycol, dimethylformamide and the like) and the like have strong capability of dissolving ornidazole and levoornidazole, and the solvent required by dissolving 0.5g of ornidazole at room temperature by a plurality of systems can be as low as 0.5 ml. Research also finds that the mixed solvent has a synergistic effect on the dissolution of ornidazole, the proportion of the mixed solvent has a remarkable influence on the synergistic effect, and the strength and the weakness of the synergistic effect of part of the mixed solvents are ranked as follows: PEG200+ ethanol, propylene glycol + ethanol, PEG400+ propylene glycol, dimethylformamide + ethanol, PEG600+ ethanol, glycerol + ethanol, and the like. Therefore, the invention focuses on selecting one or more mixed organic solvent systems of short-chain polyethylene glycol, propylene glycol, ethanol, dimethyl formamide and the like to optimize the ornidazole and levoornidazole dissolving system.
Examples 1 to 11: solubility of different organic systems in Ornidazole or Laornidazole (1) (Room temperature)
The experimental steps are as follows: mixing various solvents according to a certain proportion, adding excessive ornidazole or levoornidazole, stirring at room temperature for dissolving for 20min, filtering with 0.22 micrometer microporous membrane to remove undissolved drug, measuring absorbance of the solution by spectrophotometry (318nm), and calculating drug solubility according to standard curve. Note: the amounts of the components are the same as the following parts by weight.
Table 1: examples 1 to 11
Comparative examples 1 to 11: solubility of different organic systems in Ornidazole or Laornidazole (2) (Room temperature)
The experimental steps are as follows: the same as in examples 1 to 11.
Table 2: comparative examples 1 to 11
Examples 12 to 17 and comparative examples 12 to 16: solubility of different organic systems in Ornidazole or Laornidazole (3) (30 ℃ C.)
The experimental steps are as follows: the same procedures as in examples 1 to 11 were carried out except that the temperature was 30 ℃.
Table 3: examples 12 to 17 and comparative examples 12 to 16
Examples 18 to 26 and comparative examples 17 and 18: solubility of different organic systems in Ornidazole or Laornidazole (4) (30 ℃ C.)
The experimental steps are as follows: the same as in examples 12 to 17.
Table 4: examples 18 to 26 and comparative examples 17 and 18
According to the test results, the invention preferably has solvent systems of PEG 300-propylene glycol, PEG 400-propylene glycol, PEG 300-ethanol and PEG 400-ethanol and a mixed system of PEG300 and/or PEG400 and propylene glycol and/or ethanol, taking the safety, the use frequency, the easy processing property, the dissolving effect on ornidazole or levoornidazole and the like of each organic solvent into comprehensive consideration. Meanwhile, the capability of dissolving ornidazole and levoornidazole by the originally ground propylene glycol-ethanol mixed solvent in the environment of 30 ℃ is higher than that of the system.
(2) Low temperature stability test
The test process comprises the following steps: respectively dissolving 0.5g of ornidazole or levoornidazole by using 1ml, 1.5ml and 2ml of PEG 300-propylene glycol, PEG 400-propylene glycol, PEG 300-ethanol, PEG 400-ethanol and propylene glycol and the original ground propylene glycol-ethanol system in different proportions, placing the solution in a penicillin bottle, sealing, placing in a low-temperature environment of 2-8 ℃ for 30 days, and observing the crystallization and precipitation condition of the medicine. Note: [1] the amounts of the components are the same as the following parts by weight.
Examples 27 to 36: low temperature stability test (1)
Table 5: examples 27 to 36
Examples 37 to 46: low temperature stability test (2)
Table 6: examples 37 to 46
Comparative examples 19 to 24: low temperature stability test (3)
Table 7: comparative examples 19 to 24
According to the results, 0.5g of dissolved ornidazole or levoornidazole and the dosage of the mixed solvent of short-chain polyethylene glycol (PEG300 or PEG400) and propylene glycol and/or ethanol is not less than 1.5ml, so that good low-temperature stability of the injection can be ensured. At the same time, unexpected test results can be found, and the low-temperature stability of the original propylene glycol-ethanol solvent system under the same concentration of ornidazole is far inferior to that of the system of the invention.
Test example 2: test for controlling impurities
The second objective of the invention is to find a technical scheme capable of effectively controlling the number and content of impurities. In combination with the first object, the present inventors have tested the influence of the ph value, the kind of acid-base substances, the preparation order, the preparation temperature, the sterilization temperature, the antioxidant, the residual oxygen concentration, etc. of water systems (such as pure water system, mixed system of water and organic solvent, mixed system of water and surfactant, etc.) and organic pure systems (such as organic solvent system, mixed system of organic solvent and surfactant, etc.) on the impurity kind and impurity content of ornidazole injection and levoornidazole injection. The result shows that the water system is difficult to effectively reduce the content of impurities, particularly the content of the impurities II (2-methyl-5-nitro-1- (2, 3-dihydroxypropyl) imidazole, the structure of which is shown in figure 2) is high; organic systems can significantly reduce the content of impurities, particularly impurity II, whereas organic systems are prone to generate genotoxic warning structure impurity III (see figure 3). Therefore, the invention focuses on selecting organic systems for impurity control.
Examples 47 to 54 and comparative examples 25 to 32: material conditions of different systems
A sample preparation step: weighing organic solvent according to prescription amount, mixing, adding ornidazole or levoornidazole, stirring at certain temperature for dissolving, metering volume, packaging, sealing, sterilizing at 121 deg.C for 12min, and cooling. The same applies below.
The impurity detection method comprises the following steps: taking a proper amount of sample, and diluting with mobile phase until the concentration of ornidazole or levoornidazole is about 1mg/ml, and taking the sample as a test solution; precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a control solution. Precisely measuring the sample solution and the control solution by 20 μ l each, injecting into a liquid chromatograph, recording chromatogram, wherein the mobile phase is methanol-water (20:80), the detection wavelength is 318nm, and the chromatographic column is C18 column. And calculating the content of each impurity peak according to a self-comparison method. The same applies below. Chromatograms of examples 47 and 51 and comparative examples 25, 26, 28, 29, 31 and 32 are shown in FIGS. 4-11.
Table 8: examples 47 to 54 and comparative examples 25 to 32
The results show that the invention can obviously reduce the number and the content of impurities, the content of the impurities is far lower than the 0.1% limit requirement of the ICH requirement, and the number of the impurities and the content of the impurities in the water system are difficult to control. The inventors have surprisingly found that the PEG300/PEG 400-ethanol system of the invention does not produce impurity II, while the content of impurity III is below 0.02%, significantly lower than the PEG300/PEG 400-propylene glycol system and the ground propylene glycol-ethanol system. Meanwhile, the content of impurities II, III and total impurities, and the number of impurities are far lower than that of a water-based system.
Test example 3: pH control test
The invention also aims to find a technical scheme capable of effectively overcoming the low pH value. Combining the first and second objects, the inventors tested the influence of the control of the ph of the aqueous system and the organic pure system on the dissolution of ornidazole and levoornidazole, the type of impurities, the content of impurities, etc. The results show that the aqueous system is difficult to increase the pH value of the ornidazole injection and the levoornidazole injection solution, so that the clinical infusion pH value is still low; the pure organic system can effectively control the increase of the impurity content without adding an acid component, and can maintain the proper clinical infusion pH value of 5-7.
Examples 47 to 54 and comparative examples 25 to 27 and 33 to 39: effect of different system pH on related substances
Table 9: examples 47 to 54 and comparative examples 25 to 27 and 33 to 39
According to the results, the inventor surprisingly finds that the pH value of the infusion solution can be maintained to be 5-7 well tolerated by a human body, and the impurity level can be effectively controlled to be far lower than the limit of not more than 0.1% required by ICH, especially in a PEG 300/400-ethanol system, even if the infusion pH value meets the tolerance pH value of 4-9 of the human body. However, the aqueous system must be adjusted to a pH of 3.0 to 3.5 to control relatively low impurity levels, yet still far exceed the 0.1% limit required by ICH. Therefore, the invention achieves unexpected technical effects, can effectively control the impurity level and the impurity number, particularly the content of the potential genotoxic impurity III, and can effectively solve the problems of irritation and phlebitis caused by low pH value infusion. This is difficult to achieve with the prior art.
Test example 4: high temperature sterilization test
The fourth objective of the invention is to find a technical scheme of high sterility assurance level (F0 value is more than or equal to 12) which can resist over-sterilization. The inventor carries out the test of the high temperature sterilization resistance degree of the water system and the organic pure system of the ornidazole or the levo-ornidazole injection. The results show that the aqueous system has poor tolerance to high-temperature sterilization, and the content and the number of impurities are obviously increased; the invention has good tolerance to high-temperature sterilization.
Examples 55 to 60 and comparative examples 40 to 45: effect of different system sterilization conditions on related substances table 10: examples 55 to 60 and comparative examples 40 to 45
Based on the above results, the inventors have surprisingly found that the ability of the present invention to withstand high temperature sterilization is significantly higher than the prior art, especially over aqueous systems.
Test example 5: tail vein irritation test
The experimental steps are as follows: respectively and slowly injecting 3 ornidazole injections of PEG 400-ethanol (3:2), PEG 400-propylene glycol (3:2) and propylene glycol-ethanol (original research) systems and normal saline into 3 rat tail veins of male and female mice respectively, wherein the administration amount is 78mg/kg, the diameter of the rat tail is measured by a vernier caliper at a position 1cm above the proximal end of a puncture point, and the measurement time is 5, 10, 15, 30, 45, 1, 2, 4, 8, 12, 24 and 48 hours before administration and after administration.
And (3) calculating the swelling degree: swelling degree (diameter of rat tail after injection-diameter of rat tail before injection)/diameter of rat tail before injection x 100%.
Examples 61 to 64 and comparative examples 46 to 49: different systems of mouse tail vein irritation test
Based on the above results, the inventors have surprisingly found that the vascular irritation of the present invention is significantly less than that of propylene glycol-ethanol systems.
Test example 6: pharmacokinetic testing in rats
The experimental steps are as follows: SD rats were randomly grouped (approximately 250g, male mice) with 3 rats each. Fasting is carried out for 12h before experiment, ornidazole injection of PEG 400-ethanol, PEG 400-propylene glycol and propylene glycol-ethanol system is injected into tail vein, administration dose is 20mg/kg, and administration concentration is 5mg/ml (diluted by normal saline before use). The blood sampling time of the orbit after tail vein administration is 1min, 5min, 15min, 30min, 1h, 3h, 6h, 9h, 12h and 24h, the blood sampling amount is about 0.5ml, the blood is filled into a 50 mul centrifuge tube treated by heparin sodium, the centrifuge is kept still for 30min at 8000r/min and is centrifuged for 10min, and the upper plasma is taken out and stored in a clean 0.5ml centrifuge tube at the temperature of 20 ℃ below zero for standby.
Sample treatment: plasma samples (100. mu.l) were taken in 1.5ml centrifuge tubes, 10. mu.l of internal standard solution (40. mu.g/ml) was added and vortexed for 3 min. Adding 200. mu.l of methanol/isopropanol (1:1) extract, vortexing for 3min, centrifuging at 12000r/min for 10min, and collecting 20. mu.l of supernatant for HPLC assay under the same chromatographic conditions as in examples 47-54.
Based on the above results, the inventors surprisingly found that the plasma ACU of the present invention is very close to the plasma ACU of the original research system, and the similarity of the curve at the time of medicine exceeds 90%, indicating that the present invention does not change the ornidazole or the in vivo pharmaceutical behavior of ornidazole.
The above description is only exemplary of the present invention and should not be taken as limiting, and any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. A solvent system capable of effectively dissolving ornidazole or levoornidazole is characterized in that the active ingredient is ornidazole or levoornidazole, and the solvent system is an organic solvent mixed by short-chain polyethylene glycol and propylene glycol;
the mixing mass fraction ratio of the short-chain polyethylene glycol to the propylene glycol in the solvent system is 60-90: 40-10;
the short-chain polyethylene glycol is one or two of polyethylene glycol 300 and polyethylene glycol 400.
2. An injection, comprising two specifications:
specification 1: the active ingredient is 0.5g of ornidazole or levo-ornidazole, and the ornidazole or levo-ornidazole is dissolved by an organic solvent and the volume is fixed to 1.0ml to 2.0 ml;
specification 2: 1.0g of ornidazole or levo-ornidazole as an active ingredient is dissolved by an organic solvent and the volume is determined to be 2.0-4.0 ml;
the organic solvent is short-chain polyethylene glycol and propylene glycol which are 60-90 mass percent: 40-10 by mixing; the short-chain polyethylene glycol is one or two of polyethylene glycol 300 and polyethylene glycol 400;
the preparation method of the injection comprises the following steps:
1) dissolving: putting the organic solvent into a container, fully and uniformly mixing, then adding the active ingredients, and completely dissolving under stirring at 20-80 ℃ to obtain a solution 1;
2) removing pyrogen: removing pyrogen from the solution 1 obtained in the step 1);
3) and (3) degerming: treating the solution 2 obtained in the step 2) by a 0.20-micron microporous filter membrane to obtain a solution 3;
4) encapsulating: detecting the solution 3 obtained in the step 3) through an intermediate product, filling the qualified solution into a glass or plastic container, and sealing the container;
5) and (3) sterilization: by using F0Sterilizing the encapsulation solution obtained in the step 4) under the sterilization condition with the value larger than 8, cooling, inspecting by lamp, and packaging.
3. The injection according to claim 2,
specification 1: the active ingredient is 0.5g of ornidazole or levo-ornidazole, and the solution is dissolved by an organic solvent and the volume is determined to 1.5 ml;
specification 2: the active ingredient is ornidazole or levoornidazole 1.0g, dissolved by organic solvent and fixed volume to 3.0 ml.
4. The injection according to claim 2, wherein the method of step 2) is: adding medicinal carbon into the solution 1 obtained in the step 1), keeping the temperature at 20-80 ℃, stirring for 10-120 min, and filtering to remove carbon to obtain an effluent liquid as a solution 2; or treating the solution 1 obtained in the step 1) by using an ultrafiltration membrane device with a proper molecular weight, and obtaining an effluent as a solution 2; or, adopting pyrogen-qualified raw and auxiliary materials in the A-level clean area, and directly taking the prepared solution 1 as the solution 2 without pyrogen removal treatment.
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| CN201911398273.5A CN110934824B (en) | 2019-12-30 | 2019-12-30 | Solvent system capable of effectively dissolving ornidazole or levoornidazole and application thereof |
| PCT/CN2020/137482 WO2021135980A1 (en) | 2019-12-30 | 2020-12-18 | Solvent system capable of effectively dissolving ornidazole or levornidazole, and application thereof |
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| CN112569229A (en) * | 2019-09-29 | 2021-03-30 | 扬子江药业集团南京海陵药业有限公司 | Preparation containing ornidazole compound and preparation method and application thereof |
| CN110934824B (en) * | 2019-12-30 | 2022-02-15 | 重庆典索医药科技有限公司 | Solvent system capable of effectively dissolving ornidazole or levoornidazole and application thereof |
| CN111888328B (en) * | 2020-08-21 | 2022-12-30 | 山东致泰医药技术有限公司 | Ornidazole injection with rapid and stable performance and preparation method thereof |
| CN112107539A (en) * | 2020-10-30 | 2020-12-22 | 康普药业股份有限公司 | Ornidazole injection and preparation method thereof |
| CN113968820A (en) * | 2021-11-30 | 2022-01-25 | 湖北省宏源药业科技股份有限公司 | 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound and preparation method thereof |
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| WO2002094179A2 (en) * | 2001-05-23 | 2002-11-28 | J.B. Chemicals & Pharmaceuticals Ltd. | Novel topical microbicidal compositions |
| CN1332662C (en) * | 2005-04-29 | 2007-08-22 | 南京圣和药业有限公司 | Levo ornidazole vein administration agent and its preparation method |
| CN101278934B (en) * | 2008-05-29 | 2010-12-29 | 姚俊华 | Oral soft capsule compound preparations for curing cold |
| CN102188369A (en) * | 2011-04-27 | 2011-09-21 | 中国人民解放军第二军医大学 | Easily sublimating medicament injection solution and intravenous injection thereof |
| CN102552127B (en) * | 2012-01-31 | 2013-12-11 | 石家庄开发区博欣医药科技开发有限公司 | Ornidazole injection |
| CN103505411A (en) * | 2012-06-27 | 2014-01-15 | 威海威太医药技术开发有限公司 | Ornidazole injection |
| CN104510702B (en) * | 2013-10-05 | 2017-09-12 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing Ornidazole and its preparation |
| CN103989640B (en) * | 2014-05-08 | 2015-04-08 | 武汉长联来福制药股份有限公司 | Ornidazole intravenous administration preparation and preparation method |
| CN104188903B (en) * | 2014-09-01 | 2016-09-21 | 北京蓝丹医药科技有限公司 | Ornidazole injection and preparation method thereof |
| CN106176585A (en) * | 2016-07-11 | 2016-12-07 | 山西普德药业有限公司 | A kind of preparation method of ornidazole injection |
| CN106309359A (en) * | 2016-08-31 | 2017-01-11 | 北京京科泰来科技有限公司 | Omidazole injection |
| IN201711023120A (en) * | 2017-06-30 | 2019-01-04 | ||
| CN110934824B (en) * | 2019-12-30 | 2022-02-15 | 重庆典索医药科技有限公司 | Solvent system capable of effectively dissolving ornidazole or levoornidazole and application thereof |
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