A stable anisindione final sterilized injection and its preparation method and application

Abstract

The present application belongs to the field of pharmaceutical preparation, and particularly relates to a stable anisodamine hydrobromide final sterilized injection as well as a preparation method and application thereof. 1-100g of anisodamine hydrobromide raw material is included in 1000ml of the injection, an acidic regulator is used to adjust the pH to 2.5-5.5, water for injection is added to 1000ml, and the inner packaging material is a sulfurized intermediate borosilicate glass ampoule with a B2O3 content of 8%-12%. By changing the packaging material of the anisodamine hydrobromide injection directly contacting the medicine, the storage stability of the medicine is significantly improved, and the use safety of the product is also improved. The pH range of the present application is in a higher interval, and the quality of the injection is directly improved by combining the stability of the medicine solution.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a stable terminally sterilized scopolamine hydrobromide injection, its preparation method, and its application. Background Technology

[0002] Scopolamine hydrobromide injection is an anticholinergic drug. Currently approved formulations are packaged in borosilicate glass ampoules in 1ml:10mg (calculated as scopolamine hydrobromide) and 1ml:20mg (calculated as scopolamine hydrobromide) strengths. Clinically, it is commonly used for septic shock, treatment of organophosphorus pesticide poisoning, relief of smooth muscle spasms, and vertigo. The routes of administration include intramuscular injection, intravenous injection, or intravenous infusion.

[0003] Currently marketed anisodamine hydrobromide injection uses low-borosilicate colorless glass ampoules as the inner packaging material. According to the published standards, the API is prone to hydrolysis and impurities under the above-mentioned pH range of 4-5.5 and high temperature conditions. Therefore, a flow-through steam-assisted aseptic filtration manufacturing method is usually adopted, but the sterility level of this product cannot be guaranteed. In addition, due to the use of low-borosilicate colorless glass ampoules, the direct contact between the drug solution and the inner wall of the ampoule during the flow-through steam-assisted manufacturing process and storage can also lead to API degradation and an increase in the pH of this product, affecting the quality of the released product and further affecting the efficacy and safety of this product during storage and market use.

[0004] Therefore, there is an urgent need for a new inner packaging material to improve the quality of anisodamine hydrobromide. Summary of the Invention

[0005] To address the technical problem of urgently needing to explore a new inner packaging material to improve the quality of scopolamine hydrobromide, this invention provides a stable terminally sterilized scopolamine hydrobromide injection and its preparation method.

[0006] The technical solution adopted in this invention is as follows:

[0007] This invention provides a stable terminally sterilized injection of anisodamine hydrobromide, comprising the following components per 1000 ml of injection:

[0008] Scopolamine hydrobromide raw material: 1-100g;

[0009] Adjust the pH to 2.5–5.5 using an acidic regulator;

[0010] Add water for injection to a final volume of 1000 ml;

[0011] The inner packaging material of the injection is a sulfurized borosilicate glass ampoule with a B2O3 content of 8% to 12% and a sulfur content of 0.05% to 5%.

[0012] The injection is manufactured using a final sterilization method with F0 ≥ 12, where F0 is the standard sterilization time, which is the equivalent sterilization time given to a product at 121°C during the sterilization process.

[0013] The beneficial effects of this invention are as follows: First, because the inner packaging material uses vulcanized borosilicate glass ampoules, the sterilized samples were subjected to accelerated testing (40℃±2℃, 75%±5%RH) to assess stability. The results of three months of accelerated testing showed that the impurity content of the borosilicate glass ampoules was significantly lower than that of the low-borosilicate glass ampoules used in existing technologies, significantly improving stability and product quality. Furthermore, the stability improvement of the vulcanized borosilicate glass ampoules compared to the unvulcanized borosilicate glass ampoules was extremely significant, solving the technical problem in the background art of urgently needing to explore a new inner packaging material to improve the quality of anisodamine hydrobromide.

[0014] Secondly, since the irritant reaction is highly dependent on the pH value of the drug solution itself, within the pH range of this invention, the lower the pH value of the anisodamine hydrobromide injection, the less likely the ester in anisodamine will break down, generating impurities such as anisodamine alcohol and troponic acid. The more stable the product, the stronger the irritation to patients at a lower pH value. This invention operates within a relatively high pH range, and by considering the stability of the drug solution, a suitable pH range for this formulation has been selected, greatly improving product quality while reducing irritation.

[0015] Furthermore, this invention discovers that directly adding an acidic regulator to resolve the pH value avoids the technical problem of damaging the pH value by first adding an alkaline regulator, resulting in a large number of impurities, thus greatly improving the quality of scopolamine hydrobromide injection.

[0016] Finally, the injection is terminally sterilized with F0≥12, which ensures the removal of impurities and improves the quality and stability of the injection.

[0017] Based on the above technical solution, the present invention can be further improved as follows.

[0018] Furthermore, the B2O3 content of the borosilicate glass ampoule in the sulfidation process is 9-12%.

[0019] The beneficial effect of adopting the above-mentioned further solution is that the borosilicate glass ampoule with the above-mentioned content can effectively improve the stability of scopolamine hydrobromide injection.

[0020] Furthermore, the sulfur content of the borosilicate glass ampoule in the sulfurization process is 0.3% to 4%.

[0021] The beneficial effect of adopting the above-mentioned further scheme is that the sulfidated borosilicate glass ampoule has better stability and fewer impurities when used as packaging material for scopolamine hydrobromide.

[0022] Furthermore, the acidity regulator is citric acid or hydrochloric acid.

[0023] The advantage of adopting the above-mentioned further solution is that the acidity regulator produces fewer impurities.

[0024] Furthermore, the acidity regulator is 0.1 mol / L hydrochloric acid.

[0025] The advantage of adopting the above-mentioned further solution is that the above-mentioned concentration of hydrochloric acid produces fewer impurities and has a better effect.

[0026] Another aspect of the present invention provides a method for preparing the stable anisodamine hydrobromide terminally sterilized injection as described above, comprising the following steps:

[0027] S1. Take 80% of the total volume of water for injection, add scopolamine hydrobromide, stir and dissolve to obtain the initial solvent;

[0028] S2. Adjust the pH of the initial solvent obtained in step S1 to 2.5-5.5 with hydrochloric acid solution, then add water for injection to make up the total volume, and then adjust the pH to 2.5-5.5 again with hydrochloric acid solution to obtain the crude product;

[0029] S3. After vacuum filtering the crude product obtained in step S2, the filtrate is filled into borosilicate glass ampoules and then subjected to final sterilization to obtain the finished product, scopolamine hydrobromide injection.

[0030] The beneficial effects of this invention are that it discovers that directly adding an acidic regulator to adjust the pH value can avoid the technical problem of adding an alkaline regulator first, which would damage the pH value and generate a large number of impurities. Therefore, this invention adopts a process flow of first adjusting the pH value with hydrochloric acid, then replenishing the water for injection to the full volume, and finally adjusting the pH value with hydrochloric acid. This minimizes the generation of impurities and greatly improves the quality and stability of scopolamine hydrobromide injection.

[0031] Based on the above technical solution, the present invention can be further improved as follows.

[0032] Furthermore, in step S2, the concentration of the hydrochloric acid solution is 0.1 mol / L.

[0033] Furthermore, in step S3, the vacuum filtration specifically involves vacuum filtration using a φ50mm, 0.45μm polyethersulfone filter membrane.

[0034] Furthermore, in step S3, the final sterilization temperature is 121°C, and the sterilization time is 12-15 minutes.

[0035] Another aspect of the present invention provides the application of sulfidated borosilicate glass ampoules as inner packaging materials for scopolamine hydrobromide injections, wherein the sulfidated borosilicate glass ampoules contain 8% to 12% B2O3 and 0.05% to 5% sulfur. Attached Figure Description

[0036] Figure 1 Electron micrographs of the shoulder and bottom of the ampoule of Embodiment 1 of the present invention;

[0037] Figure 2 Electron micrographs of the shoulder and bottom of the ampoule of Embodiment 2 of the present invention;

[0038] Figure 3 Electron micrographs of the shoulder and bottom of the ampoule of Embodiment 3 of the present invention;

[0039] Figure 4 Electron micrographs of the shoulder and bottom of the ampoule of Embodiment 4 of the present invention;

[0040] Figure 5 Electron micrographs of the shoulder and bottom of the ampoule in Embodiment 5 of the present invention;

[0041] Figure 6 Electron micrographs of the shoulder and bottom of the ampoule of Embodiment 6 of the present invention;

[0042] Figure 7 Electron micrographs of the shoulder and bottom of the ampoule. Detailed Implementation

[0043] The principles and features of the present invention are described below with reference to the accompanying drawings. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0044] Example 1

[0045] A stable terminally sterilized injection of anisodamine hydrobromide, comprising the following components per 1000 ml injection:

[0046] Scopolamine hydrobromide raw material: 10g;

[0047] Adjust the pH to 2.5–5.5 using 0.1 mol / L hydrochloric acid;

[0048] Add water for injection to a final volume of 1000 ml;

[0049] The inner packaging material is a Jingu low borosilicate colorless glass ampoule with a B2O3 content of less than 8%.

[0050] The specific preparation method is as follows:

[0051] S1. Take 1000ml of 80% water for injection, add 10g of anisodamine hydrobromide, stir to dissolve and obtain the initial solvent;

[0052] S2. Adjust the pH of the initial solvent obtained in step S1 to 2.5-5.5 with 0.1 mol / L hydrochloric acid solution, then replenish with water for injection to the full volume, and then adjust the pH to 2.5-5.5 again with 0.1 mol / L hydrochloric acid solution to obtain the crude product;

[0053] S3. After vacuum filtering the crude product obtained in step S2 using a φ50mm, 0.45μm polyethersulfone filter membrane, the filtrate is filled into a Jin Gu low borosilicate colorless glass ampoule and then terminally sterilized. Terminal sterilization is performed by placing it at 121℃ for 12 minutes to obtain the finished product, scopolamine hydrobromide injection.

[0054] Example 2

[0055] The difference from Example 1 is that the inner packaging material is a plain low-borosilicate colorless glass ampoule. The B2O3 content is less than 7.5%.

[0056] Example 3

[0057] The difference from Example 1 is that the inner packaging material is a borosilicate colorless glass ampoule made of gold drum material. The B2O3 content is 9.0%.

[0058] Example 4

[0059] The difference from Example 1 is that the inner packaging material is Schott borosilicate colorless glass ampoule. The B2O3 content is 10.5%.

[0060] Example 5

[0061] The difference from Example 1 is that the inner packaging material is a colorless borosilicate glass ampoule from Cangzhou Sixing Sulfated Co ...

[0062] Example 6

[0063] The difference from Example 1 is that the inner packaging material is a bimodal Grace vulcanized borosilicate colorless glass ampoule. The B2O3 content is 8.8%, and the sulfur content is 0.3%.

[0064] To illustrate the technical advantages of using borosilicate glass ampoules in this invention, the following examples 1 and 2 are provided:

[0065] Proof Example 1

[0066] The stable scopolamine hydrobromide injections obtained in Examples 1 to 6 were tested under accelerated testing conditions (40℃±2℃, 75%±5%RH) using key quality indicators such as appearance, solution clarity and color, pH, isomers, related substances, and content. Specifically, samples were tested according to the quality standard for scopolamine hydrobromide injection (CP095-2021-YX-01) SP-01-00. The test results are shown in Tables 1 to 4 below.

[0067] Table 1. Results of Sample Stability Study on Day 0

[0068]

[0069]

[0070] Summary: There were no significant differences in the properties, solution clarity and color, and content of the samples. The pH value of the borosilicate ampoules from Cangzhou Sixing Sulfurization showed no significant change compared to the unsterilized ampoules (pH: 4.4), while the pH increase of the other samples was more significant, ranging from 0.6 to 1.0. The packaging of tropinic acid, unknown monoimide (RRT = 0.77), (1',2')-dehydrated scopolamine, total impurities, and isomers using Cangzhou Sixing Sulfurization borosilicate ampoules was lower than that using other packaging materials. This indicates that the borosilicate ampoules from Cangzhou Sixing Sulfurization, as inner packaging materials, have relatively stable quality under the current process.

[0071] Table 2. Results of accelerated stability testing of samples after 1 month.

[0072]

[0073]

[0074] Summary: Compared with 0 months of accelerated processing: there were no significant differences in solution properties, clarity and color, and content among the samples. The pH of all samples decreased to some extent. The Schott borosilicate ampoule and the bimodal sulfide borosilicate ampoule, as inner packaging materials, showed the largest pH decrease (0.8). Tropical acid, unknown monoimide (RRT=0.77), and (1',2')-dehydrated scopolamine all increased. The increase in total impurities and isomers of the borosilicate ampoule, as inner packaging material, was smaller than that of other packaging materials.

[0075] Table 3. Results of accelerated stability testing of samples after 2 months.

[0076]

[0077]

[0078] Summary: Compared to 0 months after acceleration, there were no significant differences in solution properties, clarity, color, and content among the samples after 2 months. The pH of all samples decreased to some extent, with the Schott borosilicate ampoule packaging showing the largest pH decrease (1.1%). Tropical acid, unknown monoimides (RRT = 0.77), and (1',2')-dehydrated scopolamine all increased. The borosilicate ampoule packaged by Cangzhou Sixing Sulfation showed smaller increases in total impurities and isomers compared to other packaging materials.

[0079] Table 4. Results of accelerated stability testing of samples after 3 months.

[0080]

[0081] Summary: Compared to 0 months after acceleration, there were no significant differences in solution properties, clarity, color, and content among the samples after 3 months. The pH of all samples decreased to some extent (range: 0.4 → 1.1), with the Schott borosilicate ampoule packaging showing the largest pH decrease (1.1). All related substances, including tropine, unknown single impurities (RRT = 0.77), and (1',2')-dehydrated anisodamine, increased. The total impurities in the Jinggu low-borosilicate ampoule inner packaging increased by 0.86% (0.22% → 1.08%), while the total impurities in the Pingyuan low-borosilicate ampoule increased by 0.86% (0.26% → 1.14%). The total impurities in borosilicate ampoules increased by 0.79% (from 0.28% to 1.07%), Schott borosilicate ampoules increased by 0.79% (from 0.34% to 1.13%), Biphasic Grace vulcanized borosilicate ampoules increased by 0.82% (from 0.28% to 1.10%), and Cangzhou Sixing vulcanized borosilicate ampoules showed the smallest increase (0.17% to 0.57%), only 0.4%. Therefore, when borosilicate glass ampoules are used for scopolamine hydrobromide injection and the B2O3 content is 8%–12%, the stability is better than that of lower borosilicate glass ampoules. The effect is even better when the B2O3 content is 9–12%, and the impurities in the vulcanized borosilicate glass ampoules are significantly reduced by more than 50% compared to other glass ampoules, showing excellent results.

[0082] All isomer samples showed a certain increase in stability over three months compared to October, with the smallest increase observed when using borosilicate ampoules from Cangzhou Sixing Sulfation Chemical Co., Ltd. as the inner packaging material. In summary, this indicates that using borosilicate ampoules from Cangzhou Sixing Sulfation Chemical Co., Ltd. as the inner packaging material results in relatively better stability for this product.

[0083] Proof Example 2

[0084] After demonstrating the accelerated three-month process in Example 1, the ampoules of scopolamine hydrobromide injection obtained in Examples 1 to 6 were observed using electron microscopy to examine the erosion of the ampoules by the drug solution. The observation areas were the shoulder and bottom of the ampoules, and the results were as follows: Figures 1 to 6As shown in the figure, the results indicate that no tablet detachment or corrosion of the ampoule by the medication was observed in any of the ampoules. This demonstrates the safety of the invention.

[0085] To illustrate the preferred innovative effects of this invention, the following examples three and four are provided:

[0086] Example 3: Examination of the order of pH adjuster addition

[0087] Weigh out three portions of the total API (hyoscine hydrobromide) according to the registered prescription. For one portion, add 200ml of 0.1% sodium citrate-citric acid solution (pH 3.7, 0.2% citric acid) and mix well, then measure the pH. For the other portion, add 200ml of injection solution and water, mix well, measure the pH, add 0.2% citric acid, measure the pH again, incubate for 1 hour, then add 0.1% sodium citrate and adjust the pH to approximately 3.7. For the third portion, add 200ml of injection solution and water, mix well, measure the pH, add 0.1% sodium citrate, incubate for 1 hour, measure the pH again, then add 0.2% citric acid, measure the pH again, and adjust the pH to approximately 3.7. Fill 2ml colorless borosilicate glass ampoules and sterilize at 121℃ for 12 minutes. The samples were tested for properties, solution clarity and color, pH value, and related substances. The results are shown in Table 5 below:

[0088] Table 5 Results of the experiment investigating the order of pH adjuster addition

[0089]

[0090] Summary: The study investigated the order of pH adjuster addition: Direct dissolution with 0.1% sodium citrate-citric acid (pH: 3.7) and 0.2% citric acid, followed by incubation for 1 hour, then adding 0.1% sodium citrate, then dissolving again with 0.1% sodium citrate, incubating for 1 hour, and finally adding 0.2% citric acid. The results showed that the order of pH adjuster addition had no significant effect on sample properties, solution clarity and color, or pH. However, samples with sodium citrate added first showed significantly higher levels of tropine and unknown monoclonal impurities (RRT 0.78) compared to those dissolved with buffer solution or with 0.2% citric acid added first, indicating that adding alkaline adjusters first can damage them. Therefore, this invention uses acidic adjusters to avoid the damage to APIs caused by alkaline adjustments.

[0091] Example 4: Safety Experiment with Rabbits

[0092] According to the pharmacopoeia, when the pH is below 2.5, more impurities are generated in the product, which does not meet the requirements. Therefore, 18 rabbits, weighing between 2.0 and 2.2 kg, with half male and half female, were selected. The products were administered via intravenous injection through the rabbit's ear and then visually observed.

[0093] (1) Take 6 rabbits (half male and half female) and inject the hydrobromide sorbitol injection obtained in Example 1 with a pH of about 3.0. After injection, the rabbits struggled more and more, and there was obvious swelling of the ear vein.

[0094] (2) Take 6 rabbits (half male and half female) and inject the hydrobromide sorbitol injection obtained in Example 2 with a pH of about 3.7. After injection, the rabbits' struggling was reduced and the swelling reaction of the ear vein was also reduced.

[0095] (3) Take 6 rabbits (half male and half female), inject anisodamine hydrobromide injection (pH 4.8) and physiological saline. After injection, the rabbits hardly struggled and the ear vein swelling was mild.

[0096] Conclusion: Through multiple comparative experiments, after excluding human factors related to injection, it was concluded that the irritant response of this product to rabbits is largely related to the pH value of the drug solution itself. Different pH adjusters did not alleviate the irritation at low pH values, and there was no significant correlation between the type of pH adjuster used and the specific pH adjuster. Therefore, future research will focus on controlling the pH range of the drug solution within a higher range, while also considering the stability of the drug solution to screen for a suitable pH range for this formulation.

[0097] Example 5: pH Range Screening

[0098] 400 ml, 200 ml, 200 ml, 200 ml, and 400 ml of 0.1% sodium citrate solution were measured respectively. The pH was adjusted to 3.6, 3.8, 4.0, 4.2, and 4.4 with citric acid, respectively. The full amount of API in the registered formulation was added to each solution, and the mixture was stirred until dissolved. The pH was measured. The solution was then vacuum filtered through a 0.45 μm polyethersulfone membrane. The filtrate was filled into 2 ml colorless borosilicate glass ampoules and sterilized at 121℃ for 12 min. The stability of the samples was investigated (0 days, 5 days, and 10 days at 60℃). The samples were tested for appearance, clarity and color, pH value, and related substances. The results are shown in Table 6 below.

[0099] Table 6 Results of pH Range Screening and Stability Testing Experiments

[0100]

[0101]

[0102]

[0103] Summary: The pH range of scopolamine hydrobromide injection was screened, and samples were prepared using 0.1% sodium citrate-citrate buffer solutions with pH values ​​of 3.6, 3.8, 4.0, 4.2, and 4.4. Data from day 0 showed that the sample properties, solution clarity and color, and pH did not change significantly compared to before sterilization. With increasing buffer pH, the levels of related substances tropinic acid, (1',2')-dehydrated scopolamine, and total impurities gradually increased. An unknown single impurity 3 (RRT 0.78) was not detected at pH 3.6, while the levels of all other samples increased with increasing pH. Stability testing data at 60℃ for 10 days showed that, compared with day 0, the related substances tropinic acid, unknown monoclonal impurity 3 (RRT 0.78), (1',2')-dehydrated anisodamine, and total impurities of each sample increased with increasing stability testing time and pH. The increase in related substances was smallest at pH 3.6 after 10 days of high temperature (tropinic acid: 0.03% → 0.11%, unknown monoclonal impurity 3 (RRT 0.78): ND → 0.07%, (1',2')-dehydrated anisodamine). The percentages of impurities and total impurities in the sample were 0.08%→0.16% and 0.11%→0.34%, respectively. The sample with pH 4.4 showed the greatest increase in all related substances after 10 days of high temperature (tropic acid: 0.17%→0.47%, unknown single impurity 3 (RRT0.78): 0.33%→0.54%, (1',2')-dehydrated scopolamine: 0.17%→0.33%, total impurities: 0.66%→1.34%). This suggests that temperature can affect product quality, and the impact of temperature should be considered during subsequent storage.

[0104] The stability of samples sterilized with citrate buffer and 0.1 mol / L hydrochloric acid as pH adjusters at the same pH value was compared (pH: 3.6 after sterilization with citrate buffer as solvent and 0.1 mol / L hydrochloric acid solution as pH adjuster, pH: 3.6 (control group: pH: 3.3); pH: 3.8 after sterilization with citrate buffer as solvent and 0.1 mol / L hydrochloric acid solution as pH adjuster, pH: 3.8 (control group: pH: 3.5)). No significant differences were found in any of the test items between 0 days and 10 days at 60℃. For samples sterilized with citrate buffer as solvent, pH: 4.3 was compared with that of samples sterilized with 0.1 mol / L hydrochloric acid solution as pH adjuster, pH: 4.3. Central control (pH: 3.7), citrate buffer as solvent for sample 0 days and high temperature (60℃) for 10 days, total impurities were greater than 0.1 mol / L hydrochloric acid as pH adjuster. Based on the stability data of pH range investigation in previous process studies and the results of rabbit safety tests, 0.1 mol / L hydrochloric acid was used as pH adjuster. Therefore, the optimal pH control for sample preparation was 3.3-3.7 with 0.1 mol / L hydrochloric acid. The impurities in the obtained sample on day 0 all met the proposed standard (quality standard of scopolamine hydrobromide injection (CP095-2021-YX-01) SP-01-00). The second best result was pH control of 2.5-5.5 with 0.1 mol / L hydrochloric acid.

[0105] Example 6: Screening of Sterilization Conditions

[0106] Weigh the full amount of API according to the registered prescription, add 80% water for injection, stir to dissolve evenly, adjust the pH to 3.5 with 0.1 mol / L hydrochloric acid, add water for injection to 800 ml, stir to mix evenly, and measure the pH again. The solution is then vacuum filtered through a 0.45 μm polyethersulfone membrane. The filtrate is filled into 2 ml colorless borosilicate glass ampoules. After filling, the sample is divided into four equal portions: one unsterilized, one sterilized at 100℃ for 40 min by moist heat, one sterilized at 121℃ for 12 min by moist heat, and one sterilized at 121℃ for 15 min by moist heat. Sample stability was assessed (0, 5, and 10 days at high temperature (60℃) and 0, 5, and 10 days under light (5000 LUX)). The samples were tested for appearance, solution clarity and color, pH value, related substances, content, and isomers. The results are shown in Table 7 below.

[0107] Table 7 Screening and Confirmation of Sterilization Conditions

[0108]

[0109]

[0110] Summary: The sterilization conditions for scopolamine hydrobromide injection within the selected pH control range were confirmed. Sterilization tests were conducted at 100℃ for 40 min, 121℃ for 12 min, and 121℃ for 15 min, and compared with unsterilized samples. The F0 value of the unsterilized sample after 100 days of high temperature was 6; the F0 value after 100 days of high temperature at 100℃ for 40 min was 11; the F0 value after 100 days of high temperature at 121℃ for 12 min was 13.0; and the F0 value after 100 days of high temperature at 121℃ for 15 min was 15.4.

[0111] Results of sample testing on day 0: Compared with unsterilized samples, there were no significant differences in sample properties, solution clarity and color, pH, content, and isomers under various sterilization conditions. Related substances all showed an increase. Comparing samples under various sterilization conditions, related substances showed a gradual increase with increasing sterilization condition F0. Stability study for 10 days:

[0112] The pH, content, related substances, and isomers of the samples after 10 days of light exposure showed no significant changes compared to day 0. However, the total impurities and isomers of the samples after 10 days of high temperature exposure increased compared to day 0. The increase in the samples after terminal sterilization was slightly greater than that after non-terminal sterilization. Furthermore, there were no significant differences in the results of each test item between the two terminal sterilization methods, indicating that this product can withstand terminal sterilization.

[0113] The pH, content, related substances, and isomers of the samples exposed to light for 100 days showed no significant changes compared to day 0. However, the total impurities and isomers of the samples exposed to high temperature for 10 days increased significantly compared to day 0. Under the conditions of unsterilized samples, the total impurities increased by 0.48% after 100℃ for 40 min; the total impurities increased by 0.26% after 100℃ for 100 min; the total impurities increased by 0.17% after 121℃ for 12 min; and the total impurities increased by 0.14% after 121℃ for 15 min. Therefore, 121℃ moist heat sterilization for 12 min was selected as the optimal final sterilization condition for this product.

[0114] In the description of this specification, the terms "one embodiment," "some embodiments," "specific embodiment," etc., refer to a specific feature, structure, material, or characteristic described in connection with that embodiment or example, which is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0115] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A stable terminally sterilized injection of anisodamine hydrobromide, characterized in that, Each 1000ml of injection contains the following ingredients: Scopolamine hydrobromide raw material: 1-100g; Adjust the pH to 3.3–3.7 using an acidic regulator; Add water for injection to a final volume of 1000 ml; The inner packaging material of the injection is a sulfurized borosilicate glass ampoule with a B2O3 content of 8% to 12% and a sulfur content of 0.3% to 4%. The injection is manufactured using a final sterilization method with F0 ≥ 12, where F0 is the standard sterilization time, which is the equivalent sterilization time given to a product at 121°C during the sterilization process.

2. The stable anisodamine hydrobromide terminally sterilized injection according to claim 1, characterized in that, The B2O3 content of the borosilicate glass ampoule in the sulfidation process is 9-12%.

3. The stable anisodamine hydrobromide terminally sterilized injection according to claim 1, characterized in that, The acidity regulator is citric acid or hydrochloric acid.

4. The stable anisodamine hydrobromide terminally sterilized injection according to claim 3, characterized in that, The acidity regulator is 0.1 mol / L hydrochloric acid.

5. A method for preparing a stable anisodamine hydrobromide terminally sterilized injection as described in any one of claims 1 to 4, characterized in that, Includes the following steps: S1. Take 80% of the total volume of water for injection, add scopolamine hydrobromide, stir and dissolve to obtain the initial solvent; S2. Adjust the pH of the initial solvent obtained in step S1 to 2.5-5.5 with hydrochloric acid solution, then replenish it to the full volume with water for injection, and then adjust the pH to 3.3-3.7 with hydrochloric acid solution to obtain the crude product; S3. After vacuum filtering the crude product obtained in step S2, the filtrate is filled into borosilicate glass ampoules and then subjected to final sterilization to obtain the finished product, scopolamine hydrobromide injection.

6. The method for preparing the stable scopolamine hydrobromide injection according to claim 5, characterized in that, In step S2, the concentration of the hydrochloric acid solution is 0.1 mol / L.

7. The method for preparing the stable scopolamine hydrobromide injection according to claim 5, characterized in that, In step S3, the vacuum filtration specifically refers to vacuum filtration using a Φ50mm, 0.45μm polyethersulfone filter membrane.

8. The method for preparing the stable scopolamine hydrobromide injection according to claim 5, characterized in that, In step S3, the final sterilization temperature is 121°C and the sterilization time is 12-15 minutes.

9. The application of sulfided borosilicate glass ampoules as inner packaging materials for scopolamine hydrobromide injections, characterized in that... The borosilicate glass ampoule containing the vulcanized material contains 8%–12% B2O3 and 0.3%–4% sulfur.

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