Tinidazole sodium chloride injection difficult to crystallize at low temperature as well as preparation method and application of tinidazole sodium chloride injection

Abstract

The invention discloses a tinidazole sodium chloride injection difficult to crystallize at low temperature as well as a preparation method and application of the tinidazole sodium chloride injection. Belongs to the technical field of pharmaceutical preparations. The preparation method of the tinidazole sodium chloride injection is adjusted and improved, the tinidazole at a specific nano level is prepared by performing high-pressure homogenization treatment on the tinidazole, and then the tinidazole is dissolved in a specific solvent to prepare a tinidazole solution. The preparation method comprises the following steps: preparing a tinidazole solution, pretreating the tinidazole solution with a polyvinyl alcohol modified solution, and finally mixing the tinidazole solution with a sodium chloride solution to prepare the tinidazole sodium chloride injection, so that the temperature stability of the injection is effectively improved, and the injection is not easy to crystallize at low temperature; according to the invention, the content of tinidazole in the injection is ensured not to be greatly changed, the number of particles is kept at a certain level, the quality of the product is effectively improved, and the safety is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, and more particularly to a metronidazole sodium chloride injection solution which is not prone to crystallization at low temperature, and a preparation method and application thereof. BACKGROUND

[0002] Metronidazole is an antimicrobial drug belonging to the class of nitroimidazoles, which has good antibacterial activity against most anaerobic bacteria and some protozoa. Specifically, metronidazole exerts its antibacterial effect by interfering with the DNA metabolic process of pathogens, thereby causing the death of bacteria or protozoa. It is very effective for treating intra-abdominal infections, gynecological infections-vaginal trichomoniasis, intestinal infections-giardiasis, and other infections caused by anaerobic bacteria or sensitive protozoa.

[0003] Metronidazole sodium chloride injection is a preparation form of metronidazole drugs, in which sodium chloride serves as an isotonicity adjusting agent to help maintain the osmotic pressure of the solution, match the osmotic pressure of the human body blood, reduce the irritation to the blood vessel wall, and help the distribution of the drug in the body. Preparing metronidazole into metronidazole sodium chloride injection can accelerate the exertion of drug efficacy, avoid the metabolism of the drug due to the first-pass effect, effectively improve the patient's compliance to the drug, enhance the physical and chemical stability of the drug, and ensure the quality and efficacy of the drug.

[0004] However, due to the limited solubility of metronidazole in water, especially when the temperature decreases, the solubility further decreases, and when the solution is cooled below a certain temperature, the solubility of metronidazole is not enough to maintain the amount of easily soluble drug, resulting in the precipitation of part of metronidazole in the form of crystals. Crystallization may affect the efficacy and safety of the drug, and even block the needle or infusion pipeline during use, leading to difficulty in drug administration. In order to ensure safety, once metronidazole sodium chloride injection appears crystallization, it cannot be used, which seriously affects the effective use of the drug.

[0005] Therefore, how to develop a metronidazole sodium chloride injection solution which is not prone to crystallization at low temperature, and a preparation method and application thereof, is a technical problem that needs to be solved by those skilled in the art. SUMMARY

[0006] Therefore, the present application provides a metronidazole sodium chloride injection solution which is not prone to crystallization at low temperature, and a preparation method and application thereof. Through the improvement of the preparation method, the temperature stability of the metronidazole sodium chloride injection solution is significantly improved, so that it is not prone to crystallization at low temperature.

[0007] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0008] A preparation method of a metronidazole sodium chloride injection solution which is not prone to crystallization at low temperature, comprising the following steps:

[0009] S1, preparation of sodium chloride solution: mix water for injection and sodium chloride, stir after adding activated carbon, filter to remove carbon, and prepare sodium chloride solution;

[0010] S2, preparation of nano-level tinidazole particles: disperse tinidazole in solvent to prepare a suspension, and then use high-pressure homogenization method to prepare nano-level tinidazole particles;

[0011] S3, pretreatment of nano-level tinidazole particles: mix the nano-level tinidazole particles obtained in step S2 with a polyvinyl alcohol modified solution, then stir at 0-5°C for 10-20 minutes, then adjust the temperature to 20-25°C, ultrasonic treatment for 10-25 minutes, centrifugal washing, and prepare the pretreated nano-level tinidazole solution;

[0012] S4, adjust the pH of the pretreated nano-level tinidazole solution in S3 to 4.5-5.5, then add the sodium chloride solution prepared in step S1, mix well, then add the glycerol and water mixture, stir evenly, ultrasonic treatment for 10-15 minutes, filter, sterilize, and fill to obtain tinidazole sodium chloride injection.

[0013] Preferably, the volume to mass ratio of water for injection and sodium chloride in step S1 is 50-100 ml:0.5-2.0 g.

[0014] Preferably, the high-pressure homogenization in step S2 has a pressure of 50-200 Mpa, a cycle number of 5-10 times, and a temperature of 25-35°C.

[0015] Preferably, the solvent in step S2 is prepared as follows: filter ethanol through a microporous filter with a pore size of 0.1-0.22 μm, then mix ethanol and water in a volume ratio of 2-3:50-100, and adjust the pH to 6.5-7.0.

[0016] Preferably, the polyvinyl alcohol modified solution in step S3 is prepared as follows:

[0017] (1) Dissolve polyvinyl alcohol in water for injection, then add chitosan, adjust the pH to 5.0-5.5, stir to dissolve, and obtain a mixed solution;

[0018] (2) Freeze the mixed solution obtained in step (1), then thaw, repeat freezing-thawing 3-5 times, and prepare the polyvinyl alcohol modified solution;

[0019] The mass to volume ratio of the nano-level tinidazole particles and the polyvinyl alcohol modified solution is 0.5-1.0 g:0.1-0.5 ml.

[0020] Preferably, the mass percentage of polyvinyl alcohol in the mixed solution in step (1) is 10-15%, and the mass percentage of chitosan is 0.1-0.3%; the molecular weight of the chitosan is 15000-18000 Dalton;

[0021] Preferably, the freezing temperature of the mixed solution in step (2) is -20℃ to -15℃, and the thawing temperature is room temperature.

[0022] Preferably, the proportion of tinidazole, sodium chloride and water for injection in the low-temperature non-crystallizable tinidazole sodium chloride injection product in step S4 is as follows: tinidazole 0.5-1.0g, sodium chloride 0.8-2.0g and water for injection 100-300ml.

[0023] Preferably, the amount of glycerol added in step S4 is 0.01-0.05% of the weight of tinidazole.

[0024] Another purpose of the present application is to provide a low-temperature non-crystallizable tinidazole sodium chloride injection prepared by the above method.

[0025] Another purpose of the present application is to provide the use of the above method in the preparation of a low-temperature non-crystallizable tinidazole sodium chloride injection.

[0026] Compared with the prior art, the present application has the following beneficial effects: the preparation method of the tinidazole sodium chloride injection is adjusted and improved, the specific nanoscale tinidazole is prepared by high-pressure homogenization treatment of tinidazole, then the tinidazole is dissolved in a specific solvent to prepare a tinidazole solution, the tinidazole solution is then pretreated with a polyvinyl alcohol modified solution, and finally the tinidazole solution is mixed with a sodium chloride solution to prepare the tinidazole sodium chloride injection. In the above method, the tinidazole nanoparticles have a larger surface area and higher surface energy, which helps to improve the solubility and stability of the drug, thereby reducing the possibility of crystallization under low temperature conditions. In addition, the polyvinyl alcohol (PVA) modified solution is used to pretreat the nanoscale tinidazole particles, and is combined with chitosan. PVA is a water-soluble polymer that can form a protective film on the surface of nanoparticles, preventing particle aggregation and enhancing their dispersibility in solution. In addition, chitosan, as a natural polysaccharide, has good biocompatibility and solubilizing effect, which can further stabilize the nanoparticles and inhibit the formation of crystals; adjusting the pH value to 4.5-5.5 in step S4 is very important for maintaining the solubility of tinidazole and other ingredients, which can ensure that the drug molecules are in the most stable ionic form, avoiding precipitation or crystallization caused by pH changes. Glycerol, as a polyhydric alcohol humectant, can increase the viscosity of the solution, reduce the water activity, and provide additional freeze protection, which helps to prevent the crystallization process at low temperature.

[0027] In summary, the tinidazole sodium chloride injection prepared by the above method has higher temperature stability and is not prone to crystallization at low temperature, ensuring that the content of tinidazole in the injection does not change greatly, the number of particles remains at a certain level, effectively improving the quality of the product and improving the safety. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present application will be described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor are within the scope of protection of the present application.

[0029] Embodiment 1

[0030] A preparation method of a tinidazole sodium chloride injection that is not prone to crystallization at low temperature, comprising the following steps:

[0031] S1, preparation of a sodium chloride solution: mix 50 ml of water for injection with 0.5 g of sodium chloride, stir and treat after adding activated carbon, filter out the carbon, and prepare a sodium chloride solution;

[0032] S2, Preparation of nano-level tinidazole particles: ethanol was filtered using a microporous filter membrane with a pore size of 0.1 μm, then ethanol was mixed with water in a volume ratio of 2:50, and the pH was adjusted to 6.5 to prepare a solvent;

[0033] Tinidazole was dispersed in the solvent to prepare a suspension, then high-pressure homogenization was carried out at a pressure of 50 Mpa and a temperature of 25°C, the cycle number of high-pressure homogenization was 10 times, then low-temperature centrifugal purification was carried out at 4°C, ultrafiltration concentration was carried out through an ultrafiltration membrane with a molecular weight cut-off of 50 kDa, freeze-drying was carried out, and nano-level tinidazole particles were prepared;

[0034] S3, Pretreatment of nano-level tinidazole particles:

[0035] Polyvinyl alcohol was dissolved in water for injection, then chitosan (15000 daltons) was added, the pH was adjusted to 5.0, stirring was carried out to dissolve it, a mixed solution was obtained, the mass percentage of polyvinyl alcohol in the mixed solution was 10%, and the mass percentage of chitosan was 0.1%; the mixed solution was frozen at a temperature of -20°C to -15°C, then thawed at room temperature, and the freezing-thawing operation was repeated 3-5 times to prepare a polyvinyl alcohol modified solution;

[0036] The nano-level tinidazole particles obtained in step S2 were mixed with the polyvinyl alcohol modified solution in a mass-volume ratio of 0.5g:0.1ml, then stirring treatment was carried out at 0°C for 10min, then the temperature was adjusted to 20°C, ultrasonic treatment was carried out for 10min, and centrifugal washing was carried out to prepare a pretreated nano-level tinidazole solution;

[0037] S4, The pH of the pretreated nano-level tinidazole solution in S3 was adjusted to 4.5, then the sodium chloride solution prepared in step S1 was added, stirring was carried out, then the glycerol and water mixture was added, stirring was carried out, ultrasonic treatment was carried out for 10min, filtration was carried out, sterilization was carried out, and filling was carried out to obtain a tinidazole sodium chloride injection, the proportion of tinidazole, sodium chloride and water for injection in the finished product of the injection was as follows: tinidazole 0.5g, sodium chloride 0.8g and water for injection 100ml, and the amount of glycerol added was 0.01% of the weight of tinidazole.

[0038] Example 2

[0039] A preparation method of a tinidazole sodium chloride injection which is not easy to crystallize at low temperature, comprising the following steps:

[0040] S1, Preparation of a sodium chloride solution: injectable water and sodium chloride were mixed in a ratio of 100ml:2.0g, activated carbon was added, stirring treatment was carried out, and carbon was removed by filtration to prepare a sodium chloride solution;

[0041] S2, Preparation of nano-scale tinidazole particles: ethanol was filtered using a microporous filter membrane with a pore size of 0.22 μm, then the ethanol was mixed with water in a volume ratio of 3:100, and the pH was adjusted to 7.0 to prepare a solvent;

[0042] Tinidazole was dispersed in the solvent to prepare a suspension, then high-pressure homogenization was performed at a pressure of 200 Mpa and a temperature of 35℃, the cycle number of high-pressure homogenization was 5 times, then low-temperature centrifugal purification was performed at 4℃, ultrafiltration concentration was performed through an ultrafiltration membrane with a molecular weight cut-off of 50 kDa, freeze-drying was performed, and nano-scale tinidazole particles were prepared;

[0043] S3, Pretreatment of nano-scale tinidazole particles:

[0044] Polyvinyl alcohol was dissolved in water for injection, then chitosan (18000 daltons) was added, the pH was adjusted to 5.5, stirring was performed to dissolve it, a mixed solution was obtained, the mass percentage of polyvinyl alcohol in the mixed solution was 15%, and the mass percentage of chitosan was 0.3%; the mixed solution was frozen at a temperature of -20℃ to -15℃, then thawed at room temperature, and the freezing-thawing operation was repeated 3-5 times to prepare a polyvinyl alcohol modified solution;

[0045] The nano-scale tinidazole particles obtained in step S2 were mixed with the polyvinyl alcohol modified solution in a mass-volume ratio of 1.0 g:0.5 ml, then stirring treatment was performed at 5℃ for 20 min, then the temperature was adjusted to 25℃, ultrasonic treatment was performed for 25 min, and centrifugal washing was performed to prepare a pretreated nano-scale tinidazole solution;

[0046] S4, The pH of the pretreated nano-scale tinidazole solution in S3 was adjusted to 5.5, then the sodium chloride solution prepared in step S1 was added, stirring was performed, then the glycerol and water mixture was added, stirring was performed, ultrasonic treatment was performed for 15 min, filtration was performed, sterilization was performed, and filling was performed to obtain a tinidazole sodium chloride injection, the proportion of tinidazole, sodium chloride, and water for injection in the finished product of the injection was as follows: tinidazole 1.0 g, sodium chloride 2.0 g, and water for injection 300 ml, and the amount of glycerol added was 0.05% of the weight of tinidazole.

[0047] Example 3

[0048] A preparation method of a tinidazole sodium chloride injection which is not easy to crystallize at low temperature, comprising the following steps:

[0049] S1, Preparation of a sodium chloride solution: water for injection and sodium chloride were mixed in a ratio of 75 ml:1.0 g, activated carbon was added, stirring treatment was performed, and carbon was removed by filtration to prepare a sodium chloride solution;

[0050] S2, Preparation of nano-scale tinidazole particles: ethanol was filtered using a microporous filter membrane with a pore size of 0.1 μm, then the ethanol was mixed with water in a volume ratio of 3:75, and the pH was adjusted to 7.0 to prepare a solvent;

[0051] Tinidazole was dispersed in the solvent to prepare a suspension, then high-pressure homogenization was performed at a pressure of 100 Mpa and a temperature of 30°C, the high-pressure homogenization was repeated 8 times, then low-temperature centrifugal purification was performed at 4°C, ultrafiltration concentration was performed using an ultrafiltration membrane with a molecular weight cut-off of 50 kDa, freeze-drying was performed to prepare nano-scale tinidazole particles;

[0052] S3, Pretreatment of nano-scale tinidazole particles:

[0053] Polyvinyl alcohol was dissolved in water for injection, then chitosan (17000 daltons) was added, the pH was adjusted to 5.0, and stirring was performed to dissolve the chitosan, thereby obtaining a mixed solution, the mass percentage of polyvinyl alcohol in the mixed solution was 12%, and the mass percentage of chitosan in the mixed solution was 0.2%; the mixed solution was frozen at a temperature of -20°C to -15°C, then thawed at room temperature, and the freezing-thawing operation was repeated 3-5 times to prepare a polyvinyl alcohol modified solution;

[0054] The nano-scale tinidazole particles obtained in step S2 were mixed with the polyvinyl alcohol modified solution in a mass-volume ratio of 1.0 g:0.5 ml, then stirring treatment was performed at 2°C for 15 min, then the temperature was adjusted to 23°C, ultrasonic treatment was performed for 20 min, and centrifugal washing was performed to prepare a pretreated nano-scale tinidazole solution;

[0055] S4, the pH of the pretreated nano-scale tinidazole solution in S3 was adjusted to 5.0, then the sodium chloride solution prepared in step S1 was added thereto, stirring was performed until the solution was uniform, then the glycerol and water mixture was added, stirring was performed until the solution was uniform, ultrasonic treatment was performed for 10 min, filtration was performed, sterilization was performed, and filling was performed to obtain tinidazole sodium chloride injection, the ratio of tinidazole, sodium chloride, and water for injection in the finished product of the injection was as follows: tinidazole 0.8 g, sodium chloride 1.5 g, and water for injection 250 ml, and the amount of glycerol added was 0.02% of the weight of tinidazole.

[0056] Comparative Example 1

[0057] The operation was basically the same as that of Example 3, except that the high-pressure homogenization conditions were different, and the high-pressure homogenization conditions of this comparative example 1 were as follows: the pressure of high-pressure homogenization was 40 Mpa, and the remaining operations were the same as those of Example 3.

[0058] Comparative Example 2

[0059] The operation was basically the same as that of Example 3, except that the high-pressure homogenization conditions were different, and the high-pressure homogenization conditions of this comparative example 2 were as follows: the temperature of high-pressure homogenization was 20°C, and the remaining operations were the same as those of Example 3.

[0060] Comparative Example 3

[0061] The operation was substantially the same as that of Example 3, except that the preparation process of the solvent in S2 was different, and the volume ratio of ethanol to water was adjusted to 5:100.

[0062] Comparative Example 4

[0063] The operation was substantially the same as that of Example 3, except that the preparation process of the solvent in S2 was different, and the pH was not adjusted after mixing ethanol with water.

[0064] Comparative Example 5

[0065] The operation was substantially the same as that of Example 3, except that the polyvinyl alcohol solution in S3 was not modified.

[0066] Comparative Example 6

[0067] The operation was substantially the same as that of Example 3, except that the nano-sized tinidazole particles in S3 were mixed with the polyvinyl alcohol modified solution without adjusting the temperature, and were directly subjected to ultrasonic treatment for 10-25 min, centrifugal washing, to prepare the pretreated nano-sized tinidazole solution.

[0068] Performance determination of tinidazole sodium chloride injection

[0069] In order to determine the performance of the tinidazole injection prepared in Examples 1-3 and Comparative Examples 1-6, the following tests were performed, and the experimental results are shown in Table 1.

[0070] 1. Appearance inspection

[0071] Evaluation content: Observe the color, clarity and presence of foreign matter of the injection.

[0072] Method: Under sufficient light, observe whether the injection is clear and transparent, colorless or light yellow, and free of visible foreign matter, using black and white background contrast.

[0073] 2. pH determination

[0074] Evaluation content: Measure the pH of the injection.

[0075] Method: Measure using a calibrated pH meter.

[0076] 3. Content determination

[0077] Evaluation content: Confirm whether the actual content of tinidazole meets the requirements of the labeled amount.

[0078] Method: Using high performance liquid chromatography (HPLC) to draw a standard curve according to the known concentration of the standard solution, and then determine the content of tinidazole in the sample.

[0079] 4. Osmotic pressure molar concentration

[0080] Evaluation content: Detect the osmotic pressure to ensure isotonicity with plasma and avoid causing hemolysis of red blood cells or other adverse reactions.

[0081] Method: Use freezing point depression method or vapor pressure method to determine the osmotic pressure molar concentration.

[0082] 6. Pyrogen test

[0083] Evaluation content: Evaluate whether there are pyrogen substances in the injection to prevent causing fever reactions.

[0084] Method: Observe the changes in the body temperature of rabbits to determine whether there are pyrogens.

[0085] 7. Clarity test

[0086] Evaluation content: Ensure that the injection is clear and does not contain insoluble particles.

[0087] Method: Use a microscope or a laser light scattering particle counter to detect and record the number of particles according to the method specified in the Chinese Pharmacopoeia.

[0088] 8. Stability study

[0089] Evaluation content: Investigate the physical and chemical stability of the product under different storage conditions.

[0090] Method: Conduct low-temperature stability tests and regularly sample to detect changes in key indicators.

[0091] Table 1 Performance of tinidazole sodium chloride injection in different groups

[0092] Group Appearance pH Content of tinidazole (%) Content of sodium chloride (%) Example 1 Colorless clear liquid 6.2 100.1 100.2 Example 2 Colorless clear liquid 6.3 100.2 100.4 Example 3 Colorless clear liquid 6.3 100.1 100.1 Comparative Example 1 Colorless clear liquid 6.4 86.3 103.5 Comparative Example 2 Colorless clear liquid 6.3 87.8 102.6 Comparative Example 3 Colorless clear liquid 6.4 85.4 96.4 Comparative Example 4 Colorless clear liquid 6.1 86.8 101.3 Comparative Example 5 Colorless clear liquid 5.9 72.1 95.8 Comparative Example 6 Colorless clear liquid 6.0 83.4 96.9

[0093] Result analysis, through the above determination of appearance, pH value and tinidazole and sodium chloride content in different groups, the results show that examples 1-3 and comparative examples 1-6 are all colorless and clear liquid in appearance, the pH and sodium chloride content are within the specified range, which meets the relevant standards, but there are some differences in the content of tinidazole.

[0094] On this basis, further osmotic pressure molar concentration, pyrogen detection and clarity detection were carried out for the above groups, and the experimental results are shown in Table 2.

[0095] Table 2 Osmotic pressure molar concentration, pyrogen and clarity detection of different groups

[0096]

[0097]

[0098] Result analysis: from the data content of Table 2, the osmotic pressure molar concentration of Examples 1-3 is maintained within an appropriate level, but the osmotic pressure molar concentration of Comparative Examples 1-6 is less than that of Examples 1-3, the pyrogen detection of Examples 1-3 and Comparative Examples 1-6 all meet the requirements; compared with Comparative Examples 1-6, the particle detection quantity of Examples 1-3 is less, and the safety and stability performance are better.

[0099] Further, the temperature stability of Examples 1-3 and Comparative Examples 1-6 is explored, and the physical and chemical stability of the products after 72h under different storage conditions (0℃, -5℃, -10℃) is investigated, and the experimental results are shown in Table 3.

[0100] Table 3 Temperature stability of different groups of tinidazole sodium chloride injection

[0101]

[0102]

[0103] Result analysis: by comparison, it can be known that the particle quantity and tinidazole content of different groups are determined at low temperature, and the experimental results show that at low temperature, the change range of the particle quantity and tinidazole content of Examples 1-3 is not large, while the change range of the particle quantity and tinidazole content of Comparative Examples 1-6 is very large at low temperature, which shows that the temperature stability and safety of the tinidazole sodium chloride injection prepared by the present application are higher, and the injection liquid performance is improved.

[0104] At the same time, in order to further determine the influence of modified polyvinyl alcohol on the experimental results, the following comparative examples are further set:

[0105] Comparative Example 7

[0106] The operation is basically the same as that of Example 3, except that in the modification process of polyvinyl alcohol in S3, the freezing temperature is -10℃.

[0107] Comparative Example 8

[0108] The operation is basically the same as that of Example 3, except that in the modification process of polyvinyl alcohol in S3, the molecular weight of chitosan is 10000 Dalton.

[0109] The physical and chemical stability of the products of Example 3 and Comparative Examples 5, 7 and 8 after 72h under different storage conditions (0℃, -5℃, -10℃) is determined, and the experimental results are shown in Table 4.

[0110] Table 4 Temperature stability of tinidazole sodium chloride injection in different groups

[0111]

[0112]

[0113] Result analysis: As can be seen from Table 4, when the freezing temperature of polyvinyl alcohol or the molecular weight of chitosan is changed, the temperature stability is worse than that of Example 3, and is equivalent to that of Comparative Example 5 without modification, which shows that the freezing temperature and the molecular weight of chitosan are crucial for the realization of the technical effect of the present application.

[0114] At the same time, the safety performance of the finished injection is also evaluated, and the experimental results show that no adverse safety problems are found.

[0115] Further, in order to verify the crystallization inhibition effect of the injection of the present application, the samples stored at low temperature (-10℃) for 72 hours are detected by differential scanning calorimetry (DSC), and the experimental results are shown in Table 5:

[0116] Table 5 DSC data of tinidazole sodium chloride injection in different groups

[0117] Group crystallization peak temperature (T c )]]> Crystallization enthalpy (ΔH C , J / g) Supercooling degree (ΔT, °C) Crystallization inhibition effect Example 3 No significant crystallization peak ≤1.0 - Significantly inhibited Comparative Example 5 10.5℃ 68.7 12.1 Almost no inhibition

[0118] Further, in order to verify the stability of the refractive liquid, the corresponding nanoparticle stability experiment is also carried out, and the changes of particle size, Zeta potential and content of different groups at 0, 3 and 6 months are measured, and the experimental results are shown in Table 6 and Table 7:

[0119] Table 6 Changes of particle size and Zeta potential of tinidazole sodium chloride injection in different groups (0 / 3 / 6 months, 25℃)

[0120]

[0121] Table 7 Content changes of tinidazole sodium chloride injection in different groups (0 / 6 months, 25℃)

[0122] Group Initial content (%) Content after 6 months (%) Example 3 100.1 99.5 Comparative Example 5 72.1 60.4

[0123] Result analysis: As can be seen from Table 6 and Table 7, the crystallization inhibition of the tinidazole sodium chloride injection prepared by the present application is: the DSC data confirms that there is no crystallization peak at low temperature for Example 3, ΔH C approaches to zero, which is significantly better than the comparative example; the stability: the changes of particle size, content, osmotic pressure and other indicators are very small within 6 months, which meets the long-term storage requirements of injection.

[0124] The various embodiments described in this specification are intended to be illustrative only and in no way limit the scope of the application. Changes and modifications can be made by those skilled in the art, which employ the principles of the application, without departing from the scope of the application. Accordingly, the application is not limited to the embodiments described herein, but instead has scope to encompass any choice whatsoever that is dependent on, or can be substituted in, the principal, new and inventive features that are described and claimed herein.

[0125] The above description of disclosed embodiments is intended to be illustrative only and not limiting of the application. Numerous modifications to these embodiments can be made by those skilled in the art without departing from the spirit or scope of the application. The scope of the application is not limited to the embodiments described herein, but rather extends to any that are dependent on, or can be substituted in, the principal, new and inventive features that are described and claimed herein.

Claims

1. A method for preparing a tinidazole sodium chloride injection solution which is not easily crystallized at low temperatures, characterized by, It comprises the following steps: S1, preparation of sodium chloride solution: mixing water for injection and sodium chloride, stirring after adding activated carbon, filtering out carbon, and obtaining sodium chloride solution; S2, preparation of nano-level tinidazole particles: dispersing tinidazole in solvent to prepare a suspension, and then using high-pressure homogenization method to prepare nano-level tinidazole particles; S3, pretreatment of nano-level tinidazole particles: mixing the nano-level tinidazole particles obtained in step S2 with polyvinyl alcohol modified solution, then stirring at 0-5℃ for 10-20min, adjusting the temperature to 20-25℃, ultrasonic treatment for 10-25min, centrifugal washing, and obtaining pretreated nano-level tinidazole solution; S4, adjusting the pH of the pretreated nano-level tinidazole solution in S3 to 4.5-5.5, then adding the sodium chloride solution prepared in step S1, mixing, adding glycerol and water mixture, stirring, ultrasonic treatment for 10-15min, filtering, sterilizing, and filling to obtain tinidazole sodium chloride injection.

2. The process for the preparation of a low temperature non-crystallizable tinidazole sodium chloride injection as claimed in claim 1, wherein, The volume to mass ratio of water for injection and sodium chloride in step S1 is 50-100ml:0.5-2.0g.

3. The process for the preparation of a low temperature non-crystallizable metronidazole sodium chloride injection as claimed in claim 1, wherein, The pressure of high-pressure homogenization in step S2 is 50-200Mpa; the cycle number is 5-10 times; and the temperature is 25-35℃.

4. The process for the preparation of a low temperature non-crystallizable metronidazole sodium chloride injection as claimed in claim 1, wherein, The specific preparation process of the solvent in step S2 is as follows: filtering ethanol with microporous filter membrane with pore size of 0.1-0.22μm, then mixing ethanol and water according to the volume ratio of 2-3:50-100, and adjusting the pH to 6.5-7.

0.

5. The process for the preparation of a low temperature non-crystallizable metronidazole sodium chloride injection as claimed in claim 1, wherein, The polyvinyl alcohol modified solution in step S3 is prepared by the following method: (1) dissolving polyvinyl alcohol in water for injection, then adding chitosan, adjusting the pH to 5.0-5.5, stirring to dissolve, and obtaining a mixed solution; (2) freezing the mixed solution obtained in step (1), then thawing, repeating freezing-thawing for 3-5 times, and obtaining polyvinyl alcohol modified solution; The mass to volume ratio of nano-level tinidazole particles and polyvinyl alcohol modified solution is 0.5-1.0g:0.1-0.5ml.

6. The process for the preparation of a low temperature non-crystallizable sodium chloride injection of tinidazole as claimed in claim 5, wherein, The mass percentage of polyvinyl alcohol in the mixed solution in step (1) is 10-15%, and the mass percentage of chitosan is 0.1-0.3%; the molecular weight of chitosan is 15000-18000 Dalton; The freezing temperature of the mixed solution in step (2) is-20℃ to-15℃, and the thawing temperature is room temperature.

7. A process for the preparation of a low temperature non-crystallizable metronidazole sodium chloride injection as claimed in claim 1, wherein, The proportion of tinidazole, sodium chloride and water for injection in the low-temperature crystallization-resistant tinidazole sodium chloride injection product in step S4 is as follows: tinidazole 0.5-1.0g, sodium chloride 0.8-2.0g and water for injection 100-300ml.

8. A process for the preparation of a low temperature non-crystallizable metronidazole sodium chloride injection as claimed in claim 1, wherein, The amount of glycerol added in step S4 is 0.01-0.05% of the weight of tinidazole.

9. The low-temperature crystallization-resistant tinidazole sodium chloride injection prepared by the method of any one of claims 1-8.

10. The use of the method of any one of claims 1-8 in the preparation of low-temperature crystallization-resistant tinidazole sodium chloride injection.

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