A kind of levornidazole sodium chloride injection in medium borosilicate glass bottle and preparation method thereof

Abstract

The present invention proposes a kind of levonidazole sodium chloride injection in a medium borosilicate glass bottle and a preparation method thereof, and relates to the field of medicine. It includes: S1, weighing the required amount of levonidazole, sodium chloride and water for injection, and setting aside; S2, taking a portion of the water for injection, adding hydrochloric acid solution, and adjusting the pH value of the agent to 3.0; S3, adding the levonidazole and sodium chloride of step S1 to the water for injection of step S2, and stirring until the levonidazole and sodium chloride are completely dissolved; S4, adjusting the pH value of the solution of step S3 to 3.5 with hydrochloric acid solution; S5, adding water for injection to the full amount, then filling it into a medium borosilicate glass injection bottle, adding a stopper and rolling the cap; S6, then steam sterilizing the injection bottle of step S5, the heating time is 10-15min, and the cooling time is 5-10min. It controls the heating and cooling time, and after high temperature sterilization, the impurities produced are very few, and the product qualification rate is high.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a levornidazole sodium chloride injection packaged in a medium-borosilicate glass bottle and a preparation method thereof. Background Art

[0002] Levoornidazole is used to treat infections caused by anaerobic bacteria. Levoornidazole sodium chloride injection is indicated for the treatment of various infectious diseases caused by sensitive anaerobic bacteria such as Bacteroides fragilis, Bacteroides dissimilaris, Bacteroides ovale, Bacteroides thetaiotaomicron, Bacteroides vulgaris, Clostridium, Eubacterium, Peptococcus and Peptostreptococcus, Helicobacter pylori, Bacteroides melaninus, Fusobacterium, C02-phagocytosis, Bacteroides gingivalis, etc. In clinical practice, intravenous injection of levonidazole sodium chloride injection before and after surgery can prevent and treat anaerobic infections, and it is widely used in clinical practice.

[0003] When preparing a large volume of levonidazole sodium chloride injection, terminal sterilization is required, that is, the filled injection bottle is sterilized. However, levonidazole sodium chloride injection is prone to produce impurities such as nitrates and nitrites at high temperatures, and the presence of impurities seriously affects the efficacy of levonidazole sodium chloride injection and brings certain side effects. In addition, as the levonidazole sodium chloride injection is exposed to high temperatures for a longer time, the more impurities it produces, and in extreme cases, the impurities exceed the standard, and the product quality is unqualified. During the production process of levonidazole sodium chloride injection, the bottle containing levonidazole sodium chloride injection needs to be sterilized at high temperature, which is inevitably exposed to a high temperature environment. In order to reduce the generation of impurities, it is extremely important to control the parameters such as the heating and cooling rate, time, and temperature during the sterilization process. At present, the terminal sterilization of levonidazole sodium chloride injection bottles still has the problem of long exposure time in a high temperature environment, resulting in more impurities in levonidazole sodium chloride injection. Summary of the invention

[0004] The object of the present invention is to provide a levornidazole sodium chloride injection packaged in a medium-borosilicate glass bottle, which produces very few impurities and has a high product qualification rate after high-temperature sterilization.

[0005] Another object of the present invention is to provide a method for preparing levornidazole sodium chloride injection in a medium-borosilicate glass bottle, which controls the heating and cooling time of steam sterilization to quickly increase and decrease the temperature in a short time to reduce the exposure time of the injection to a high temperature environment and reduce the impurity rate.

[0006] The present invention solves the technical problem by adopting the following technical solutions.

[0007] On the one hand, an embodiment of the present invention provides a method for preparing levornidazole sodium chloride injection in a medium borosilicate glass bottle, comprising the following steps:

[0008] S1, weigh the required amount of levornidazole, sodium chloride and water for injection and set aside;

[0009] S2, take a portion of the water for injection, add hydrochloric acid solution, and adjust the pH to 3.0;

[0010] S3, adding the levornidazole and sodium chloride in step S1 to the water for injection in step S2, and stirring until the levornidazole and sodium chloride are completely dissolved;

[0011] S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution;

[0012] S5, add water for injection to the full amount, then fill into medium borosilicate glass injection bottles, add stoppers and caps;

[0013] S6, then steam sterilize the injection bottle in step S5, with a heating time of 10-15 minutes and a cooling time of 5-10 minutes.

[0014] In the preparation method of the levornidazole sodium chloride injection of the present invention, by controlling the heating and cooling time, the temperature is quickly raised and lowered while meeting the sterilization time, thereby reducing the exposure time of the injection in a high-temperature environment, reducing the generation of impurities, and further controlling the impurity rate, thereby improving the quality of the injection.

[0015] The medium borosilicate glass bottle used in the present invention, wherein the borosilicate glass has a high boron content, has excellent acid resistance, water resistance, alkali resistance, heat resistance and cold resistance, and is not easy to break or crack during rapid cooling. And the medium borosilicate glass bottle has high transparency, and it is easy to observe the transparency and color of the injection in the bottle, which is convenient for judging whether the injection after sterilization is qualified in terms of color and clarity. In addition, the chemical stability of the medium borosilicate glass bottle is good, and it can withstand the test of various chemical environments, and is particularly suitable for preparations with acidic and alkaline pH values, while the left ornidazole sodium chloride injection is acidic. The left ornidazole sodium chloride injection is stored in the medium borosilicate glass bottle. During storage, the impurities in the medium borosilicate glass bottle are not easy to dissolve, which can ensure the safety of the injection, and can also be stored for a long time.

[0016] In combination with the use of medium borosilicate glass bottles as containers in the present invention, they can withstand rapid cooling, can simultaneously meet the temperature reduction requirements of rapid cooling, and can also ensure the yield rate during the sterilization process, reduce the bottle explosion rate, and save production costs.

[0017] In some embodiments of the present invention, in step S6, the steam sterilization is: placing the injection bottle in a steam sterilizer, heating it from room temperature to 121°C within 10-15 minutes, keeping it warm for 8-12 minutes, and then cooling it by spraying cold water, cooling it to 50°C within 5-10 minutes.

[0018] In some embodiments of the present invention, in step S2, the amount of water for injection is 80-90% of the total volume of step S5.

[0019] In some embodiments of the present invention, in step S2, the amount of water for injection is 90% of the total volume of step S5.

[0020] In some embodiments of the present invention, in step S1, there are 100 parts by volume of water for injection, 0.5 parts by weight of levornidazole, and 0.83 parts by weight of sodium chloride.

[0021] In some embodiments of the present invention, in step S6, the heat preservation time is 8 minutes. The heat preservation time is the time for the injection bottle to be sterilized in steam. The sterilization time of 8 minutes can make the product reach the sterility level.

[0022] On the other hand, an embodiment of the present invention provides a levornidazole sodium chloride injection packaged in a medium-borosilicate glass bottle, which is prepared by the above method.

[0023] Compared with the prior art, the embodiments of the present invention have at least the following advantages or beneficial effects:

[0024] In the present invention, medium-borosilicate glass bottles are used as containers to hold large-volume injection solutions. Medium-borosilicate glass bottles have a low expansion coefficient and are highly resistant to extreme cold and heat. During steam sterilization, when the temperature is quickly reduced by spraying cold water, the medium-borosilicate glass bottles are not prone to bursting, thereby reducing operational risks, saving costs, and being more environmentally friendly.

[0025] Secondly, in the present invention, during steam sterilization, the heating time is 10-15 minutes, and the cooling time is 5-10 minutes. The heating and cooling in a short time can effectively control the time of the injection liquid being exposed to high temperature, reduce the generation of impurities in the preparation, and thus improve the injection liquid yield and quality. The total impurities in the injection liquid prepared by the method of the present invention can be controlled to be less than 0.4%. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0027] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other. The present invention will be described in detail below with reference to specific embodiments.

[0028] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0029] Example 1

[0030] The levornidazole sodium chloride injection was prepared according to the following steps.

[0031] S1, weigh 0.5 g of levornidazole, 0.83 g of sodium chloride and 100 ml of water for injection, and set aside;

[0032] S2, take 90% of the total amount of water for injection, add hydrochloric acid solution, and adjust the pH to 3.0;

[0033] S3, adding 0.5 g of levonidazole and 0.83 g of sodium chloride in step S1 to the water for injection in step S2, and stirring until the levonidazole and sodium chloride are completely dissolved;

[0034] S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution;

[0035] S5, add water for injection to the full amount, then fill into a 100 ml medium borosilicate glass injection bottle, add a stopper and cap;

[0036] S6, then place the injection bottle of step S5 in a steam sterilizer for steam sterilization, heating it from room temperature to 121°C for 12 minutes, sterilizing it in steam at this temperature for 8 minutes, then spraying it with cold water to cool it down to 50°C for 6 minutes, and obtaining an injection solution.

[0037] Example 2

[0038] The levornidazole sodium chloride injection was prepared according to the following steps.

[0039] S1, weigh 0.5 g of levornidazole, 0.83 g of sodium chloride and 100 ml of water for injection, and set aside;

[0040] S2, take 90% of the total amount of water for injection, add hydrochloric acid solution, and adjust the pH to 3.0;

[0041] S3, adding 0.5 g of levonidazole and 0.83 g of sodium chloride in step S1 to the water for injection in step S2, and stirring until the levonidazole and sodium chloride are completely dissolved;

[0042] S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution;

[0043] S5, add water for injection to the full amount, then fill into a 100 ml medium borosilicate glass injection bottle, add a stopper and cap;

[0044] S6, then place the injection bottle of step S5 in a steam sterilizer for steam sterilization, heating it from room temperature to 121°C for 15 minutes, sterilizing it in steam at this temperature for 8 minutes, then spraying it with cold water to cool it down to 50°C for 9 minutes, and obtaining an injection solution.

[0045] Example 3

[0046] The levornidazole sodium chloride injection was prepared according to the following steps.

[0047] S1, weigh 0.5 g of levornidazole, 0.83 g of sodium chloride and 100 ml of water for injection, and set aside;

[0048] S2, take 80% of the total amount of water for injection, add hydrochloric acid solution, and adjust the pH to 3.0;

[0049] S3, adding 0.5 g of levonidazole and 0.83 g of sodium chloride in step S1 to the water for injection in step S2, and stirring until the levonidazole and sodium chloride are completely dissolved;

[0050] S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution;

[0051] S5, add water for injection to the full amount, then fill into a 100 ml medium borosilicate glass injection bottle, add a stopper and cap;

[0052] S6, then place the injection bottle of step S5 in a steam sterilizer for steam sterilization, heating it from room temperature to 121°C for 10 minutes, and sterilizing it in steam at this temperature for 8 minutes, then spraying it with cold water to cool it down to 50°C for 10 minutes, and obtaining an injection solution.

[0053] Example 4

[0054] The levornidazole sodium chloride injection was prepared according to the following steps.

[0055] S1, weigh 0.5 g of levornidazole, 0.83 g of sodium chloride and 100 ml of water for injection, and set aside;

[0056] S2, take 90% of the total amount of water for injection, add hydrochloric acid solution, and adjust the pH to 3.0;

[0057] S3, adding 0.5 g of levonidazole and 0.83 g of sodium chloride in step S1 to the water for injection in step S2, and stirring until the levonidazole and sodium chloride are completely dissolved;

[0058] S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution;

[0059] S5, add water for injection to the full amount, then fill into a 100 ml medium borosilicate glass injection bottle, add a stopper and cap;

[0060] S6, then place the injection bottle of step S5 in a steam sterilizer for steam sterilization, heating it from room temperature to 121°C for 15 minutes, and sterilizing it in steam at this temperature for 10 minutes, then spraying it with cold water to cool it down to 50°C for 5 minutes, and obtaining an injection solution.

[0061] Example 5

[0062] The levornidazole sodium chloride injection was prepared according to the following steps.

[0063] S1, weigh 0.5 g of levornidazole, 0.83 g of sodium chloride and 100 ml of water for injection, and set aside;

[0064] S2, take 90% of the total amount of water for injection, the water temperature is 50°C, add hydrochloric acid solution, and adjust the pH to 3.0;

[0065] S3, adding 0.5 g of levonidazole and 0.83 g of sodium chloride in step S1 to the water for injection in step S2, and stirring until the levonidazole and sodium chloride are completely dissolved;

[0066] S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution;

[0067] S5, add water for injection to the full amount, then fill into a 100 ml medium borosilicate glass injection bottle, add a stopper and cap;

[0068] S6, then place the injection bottle of step S5 in a steam sterilizer for steam sterilization, heating it from room temperature to 121°C for 10 minutes, and sterilizing it in steam at this temperature for 12 minutes, then spraying it with cold water to cool it down to 50°C for 10 minutes, and obtaining an injection solution.

[0069] Comparative Example 1

[0070] The levornidazole sodium chloride injection was prepared according to the following steps.

[0071] S1, weigh 0.5 g of levornidazole, 0.83 g of sodium chloride and 100 ml of water for injection, and set aside;

[0072] S2, take 90% of the total amount of water for injection, add hydrochloric acid solution, and adjust the pH to 3.0;

[0073] S3, adding 0.5 g of levonidazole and 0.83 g of sodium chloride in step S1 to the water for injection in step S2, and stirring until the levonidazole and sodium chloride are completely dissolved;

[0074] S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution;

[0075] S5, add water for injection to the full amount, then fill into a 100 ml medium borosilicate glass injection bottle, add a stopper and cap;

[0076] S6, then place the injection bottle of step S5 in a steam sterilizer for steam sterilization, heating it from room temperature to 121°C for 15 minutes, and sterilizing it in steam at this temperature for 8 minutes, then spraying it with cold water to cool it down to 70°C for 28 minutes, and obtaining an injection solution.

[0077] Comparative Example 2

[0078] The levornidazole sodium chloride injection was prepared according to the following steps.

[0079] S1, weigh 0.5 g of levornidazole, 0.83 g of sodium chloride and 100 ml of water for injection, and set aside;

[0080] S2, take 90% of the total amount of water for injection, add hydrochloric acid solution, and adjust the pH to 3.0;

[0081] S3, adding 0.5 g of levonidazole and 0.83 g of sodium chloride in step S1 to the water for injection in step S2, and stirring until the levonidazole and sodium chloride are completely dissolved;

[0082] S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution;

[0083] S5, add water for injection to the full amount, then fill into a 100 ml medium borosilicate glass injection bottle, add a stopper and cap;

[0084] S6, then placing the injection bottle of step S5 in a steam sterilizer for steam sterilization, heating it from room temperature to 121°C for 25 minutes, and sterilizing it in steam at this temperature for 8 minutes, then cooling it with cold water spray, cooling it to 70°C for more than 70 minutes, and obtaining an injection solution.

[0085] Experimental example

[0086] The injections of Examples 1-4 and Comparative Examples 1-2 were used as samples, and the content of impurities in the samples was detected according to the method for related substances of levonidazole sodium chloride injection included in the text of the second variety of the Chinese Pharmacopoeia 2020 edition. The results are shown in Table 1.

[0087] Table 1 Impurity content of Examples 1-4 and Comparative Examples 1-2

[0088]

[0089] It can be seen from Table 1 above that by controlling the heating and cooling time and the heat preservation time during sterilization, the time the preparation is exposed to high temperature is controlled. The shorter the exposure time at high temperature, the fewer impurities in the preparation. On the contrary, as the exposure time increases, the impurities in the preparation also increase accordingly. As in Examples 1 and 2, under the same heat preservation and sterilization time, the heating time and cooling time of Example 2 are longer than those of Example 1, that is, the exposure time of Example 2 at high temperature is long, and its impurity content is higher than that of Example 1. The preparations of Comparative Examples 1 and 2 are significantly longer in exposure time at high temperature than those of Examples 1-4, and their total impurity rate is high, even exceeding the control standard of the impurity rate of the preparation. In addition, the injection bottles of Examples 1-4 and Comparative Examples 1-2 did not explode during the steam sterilization process. It can be seen that the medium borosilicate glass injection bottles used in the present invention have good temperature difference resistance and do not explode during rapid cooling.

[0090] The embodiments described above are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A method for preparing levornidazole sodium chloride injection in a medium borosilicate glass bottle, characterized in that: The following steps are involved: S1, according to 100 parts by volume of water for injection, 0.5 parts by weight of levornidazole, and 0.83 parts by weight of sodium chloride, weigh the required amount of levornidazole, sodium chloride and water for injection, spare; S2, take a portion of the water for injection, add hydrochloric acid solution, and adjust the pH to 3.0; S3, adding the levornidazole and sodium chloride in step S1 to the water for injection in step S2, Stir until levornidazole and sodium chloride are completely dissolved; S4, adjusting the pH value of the solution in step S3 to 3.5 with a hydrochloric acid solution; S5, add water for injection to the full amount, then fill into medium borosilicate glass injection bottles, add stoppers and caps; S6, then steam sterilize the injection bottle in step S5, and the steam sterilization process is as follows: The injection bottle is placed in a steam sterilizer, heated from room temperature to 121°C within 10-15 minutes, kept warm for 8-12 minutes, and then cooled by spraying with cold water, and cooled to 50°C within 5-10 minutes.

2. The method for preparing the levornidazole sodium chloride injection in a medium borosilicate glass bottle according to claim 1, characterized in that: In step S2, the amount of water for injection is 80-90% of the total volume of step S5.

3. The method for preparing the levornidazole sodium chloride injection in a medium borosilicate glass bottle according to claim 2, characterized in that: In step S2, the amount of water for injection is 90% of the total volume of step S5.

4. The method for preparing the levornidazole sodium chloride injection in a medium borosilicate glass bottle according to claim 1, characterized in that: In step S6, the insulation time is 8 minutes.

5. A levornidazole sodium chloride injection in a medium borosilicate glass bottle, characterized in that: The method is prepared by any one of claims 1 to 4.

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